radiation therapy for oropharyngeal squamous cell ... · 40 conflict of interest disclosure...

NOT TO BE COPIED, DISSEMINATED OR REFERENCED

Radiation Therapy for Oropharyngeal Squamous Cell Carcinoma: An ASTRO Evidence 1

Based Clinical Practice Guideline 2

3 David J. Sher, MD, MPH1, David J. Adelstein MD, FACP2, Gopal Bajaj, MD3, David M. Brizel, 4

MD4 , Ezra E. Cohen, MD5, Aditya Halthore, MD6, Louis B. Harrison, MD7, Charles Lu, MD8, 5

Benjamin J. Moeller, MD9, Harry Quon, MD, PhD10, James W. Rocco, MD, PhD11, Erich M. 6

Sturgis, MD, MPH12, Roy B. Tishler, MD, PhD13, Andy Trotti, MD14, John Waldron, MD15, 7

Avraham Eisbruch, MD16 8

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1. Department of Radiation Oncology, UT Southwestern, Dallas , Texas 10

2. Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer 11

Institute, Cleveland, Ohio 12

3. Department of Radiation Oncology, Inova Dwight and Martha Schar Cancer Institute, 13

Falls Church, VA 14

4. Department of Radiation Oncology, Duke University Medical Center, Durham, North 15

Carolina 16

5. Department of Radiation Oncology, University of California, San Diego, California 17

6. Department of Radiation Medicine, Northwell Health, Lake Success, New York. 18

7. Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida 19

8. Department of Radiation Oncology, UT MD Anderson Cancer Center, Houston, 20

Texas 21

9. Department of Radiation Oncology, North Shore-LIJ Health System, Bellerose, New 22

York 23

10. Department of Radiation Oncology, John Hopkins, Baltimore, Maryland 24

11. Department of Otolaryngology-Head and Neck Surgery, The Ohio State University 25

Wexner Medical Center, Columbus, Ohio 26

12. Department of Head and Neck Surgery and Department of Epidemiology, The 27

University of Texas MD Anderson Cancer Center, Houston, Texas 28

13. Department of Radiation Oncology, Brigham and Women's Physician Organization, 29

Boston, Massachusetts 30

14. Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida 31

15. Department of Radiation Oncology, Princess Margaret Cancer Center, Ontario, 32

Canada 33

16. Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 34

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Conflict of Interest Disclosure Statement 40

The guideline panelists were required to complete disclosure statements before initiating 41

work on this project. These statements are maintained at the American Society for Radiation 42

Oncology (ASTRO) Headquarters in Fairfax, VA, and pertinent disclosures are published within 43

this report. The ASTRO Conflict of Interest Disclosure Statement seeks to provide a broad 44

disclosure of outside interests. The guideline panel chairs (AE and DS), in concert with the 45

ASTRO COI review committee, ASTRO legal counsel, and ASTRO guidelines subcommittee 46

chair and vice-chair, reviewed these disclosures and approved the participation of all task force 47

members for all key questions. 48

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Acknowledgements 51

The authors thank the following individuals who served as expert reviewers of the 52

manuscript: Steven Frank, MD, Nancy Lee, MD, and Cristina Rodriguez, MD, none of whom 53

have any relevant conflicts of interest. Gratitude is extended to Warren Caldwell, for serving as a 54

patient advocate for this guideline. The authors also thank ASTRO staff members Margaret 55

Amankwa-Sakyi, Sokny Lim and Caroline Patton for the systematic literature review assistance 56

and administrative support. 57

The Oropharyngeal Squamous Cell Carcinoma Guideline panel, created by the guidelines 58

subcommittee of the Clinical Affairs and Quality Committee of ASTRO, prepared this 59

document. ASTRO guidelines present scientific, health, and safety information and may to some 60

extent reflect scientific or medical opinion. They are made available to ASTRO members and to 61

the public for educational and informational purposes only. Commercial use of any content in 62

this guideline without the prior written consent of ASTRO is strictly prohibited. 63


Adherence to this guideline will not ensure successful treatment in every situation. 64

Furthermore, this guideline should not be deemed inclusive of all proper methods of care or 65

exclusive of other methods of care reasonably directed to obtaining the same results. The 66

physician must make the ultimate judgment regarding the propriety of any specific therapy in 67

light of all the circumstances presented by the individual patient. ASTRO assumes no liability 68

for the information, conclusions, and findings contained in its guidelines. In addition, this 69

guideline cannot be assumed to apply to the use of these interventions performed in the context 70

of clinical trials, given that clinical studies are designed to evaluate or validate innovative 71

approaches in a disease for which improved treatments are needed or are being explored. 72

The guideline panel recommends that providers discuss with patients’ shortly after 73

diagnosis what to expect regarding symptoms, treatment-related toxicities, outcomes including 74

risk of recurrence, and effects of the disease and the treatments on quality of life. 75

This guideline was prepared on the basis of information available at the time the panel 76

was conducting its research and discussions on this topic. There may be new developments that 77

are not reflected in this guideline and that may, over time, be a basis for ASTRO to consider 78

revisiting and updating the guideline. 79

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Abstract 81

Purpose: To present evidence-based guidelines for the treatment of oropharyngeal squamous 82

cell carcinoma (OPSCC) with definitive or adjuvant radiotherapy (RT). 83

Methods and Materials: The American Society for Radiation Oncology (ASTRO) convened 84

the OPSCC Guideline Panel to perform a systematic literature review investigating the following 85

key questions: (1) When is it appropriate to add systemic therapy to definitive RT in the 86

treatment of OPSCC? (2) When is it appropriate to deliver post-operative RT with and without 87

systemic therapy following primary surgery of OPSCC? (3) When is it appropriate to use 88

induction chemotherapy in the treatment of OPSCC? (4) What are the appropriate dose, 89

fractionation, and volume regimens with and without systemic therapy in the treatment of 90

OPSCC? The GRADE methodology was followed in the construction and assessment of the 91

recommendation statements, and a predefined consensus-building process was implemented to 92

arrive at the final statements. 93

Results: Patients with stage IV and stage T3 N0-1 OPSCC treated with definitive radiotherapy 94

should receive concurrent high-dose intermittent cisplatin (HDIC). Patients receiving adjuvant 95

radiotherapy following surgical resection for positive surgical margins or extracapsular extension 96

should be treated with concurrent HDIC, and individuals with these risk factors who are 97

intolerant of cisplatin should not routinely receive adjuvant concurrent systemic therapy. 98

Induction chemotherapy (IC) should not be routinely delivered to patients with OPSCC. For 99

patients with stage IV and stage T3 N0-1 OPSCC ineligible for concurrent chemoradiotherapy, 100

altered fractionation RT should be used. Patients with tonsillar fossa-only, T1-2 N0-1 OPSCC 101

should receive ipsilateral radiotherapy. Recommendation statements do not vary by human 102

papillomavirus (HPV) status. 103


104

Conclusion: The successful management of OPSCC requires the coordination and collaboration 105

of radiation, medical and surgical oncologists. When high-level data are absent for clinical 106

decision-making, treatment recommendations should incorporate patient values and preferences 107

to arrive at the optimal therapeutic approach. 108

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Introduction 127

The oropharynx is an anatomic site within the head and neck that includes the tonsils, 128

base of tongue, soft palate, and the upper lateral and posterior pharyngeal walls. It is lined by 129

squamous epithelium, and thus squamous cell carcinoma composes the vast majority of 130

malignancies that arise from the oropharynx. The epidemiology and prognosis of oropharyngeal 131

squamous cell carcinoma (OPSCC) has changed dramatically over the past 30 years, such that its 132

treatment and expected outcomes are nearly unrecognizable from a generation ago. 133

Indeed, human papillomavirus (HPV) associated cancers of the oropharynx are now 134

widely recognized as a distinct clinical disease with regard to risk factor profiles, clinical and 135

molecular characteristics, treatment response and prognosis.1 Human papillomavirus HPV-136

associated cancers arise from the lingual and palatine tonsils within the oropharynx, are poorly 137

differentiated and present with early T stage and advanced N stage. When compared to patients 138

with HPV-negative disease, patients with HPV-positive tumors are more frequently male, young, 139

and possess a favorable performance status. 3 The incidence of HPV-positive OPSCC has 140

increased by over 200% between 1988 and 2004, whereas the incidence of HPV-negative 141

OPSCC declined by half over that same era.2 Individuals with HPV-driven oropharynx cancers 142

have an estimated 50% reduction in risk of death when compared to patients with HPV-negative 143

tumors.3 The recognition of this powerful prognostic and predictive influence of HPV has 144

generated a wide array of treatment paradigms for OPSCC, which further highlights the 145

importance of evidence-based medicine to guide clinical practice. 146

The purpose of this clinical practice guideline is to systematically review the evidence for 147

effective treatment of OPSCC with definitive or adjuvant radiotherapy. Recommendation 148

statements are independent of HPV status, given the current absence of high-level, high-quality 149


data confirming treatment decisions should differ by cancer etiology. The panel used a 150

formalized literature review process, complemented by expert opinion where appropriate, to 151

make recommendations on the use of concurrent systemic therapy in the primary and post-152

operative settings, adjuvant radiotherapy following curative surgery, neoadjuvant chemotherapy 153

prior to radiotherapy, and dose, fractionation and neck volume decisions faced in the 154

management of this disease. 155

156

Methods and Materials 157

Process 158

The Guidelines Subcommittee of the Clinical Affairs and Quality Council identified 159

OPSCC as a disease that provides many challenges to the radiation oncologist, as well as to the 160

medical and surgical oncology multidisciplinary team. Given its rapidly increasing prevalence 161

and the various treatment options with differing short- and long-term toxicity profiles, OPSCC 162

was considered a high-priority topic in need of an evidence-based practice guideline. In 163

accordance with established ASTRO policy, the Guidelines Subcommittee recruited a guideline 164

panel of recognized experts in oropharyngeal cancer, including radiation oncologists, medical 165

oncologists, otolaryngologists, and a patient advocate. Panel members were drawn from 166

academic settings, private practice, and residency. Four specific key questions (KQs) were 167

proposed, which addressed: (KQ1) the addition of concurrent systemic therapy to radiotherapy, 168

(KQ2) the delivery of post-operative radiotherapy with and without systemic therapy following 169

primary surgery, (KQ3) the use of induction chemotherapy, and (KQ4) the optimal dose-170

fractionation regimens with and without systemic therapy, as well as nodal volumes for primary 171


tonsillar cancer. In September 2014, the ASTRO Board of Directors approved the proposal and 172

panel membership. 173

Through a series of communications by conference calls and emails between December 174

2014 and February 2016, the guideline panel, with ASTRO staff support, completed the 175

systematic review, created literature tables, and formulated the recommendation statements and 176

narratives for the guideline. The members of the task force were divided into four writing groups 177

by KQs, according to their areas of expertise. The initial draft of the manuscript was reviewed by 178

three expert reviewers (see Acknowledgements) and ASTRO legal counsel. A revised draft was 179

placed on the ASTRO Web site in MONTH 2016 for a four/six-week period of public comment. 180

Following integration of the feedback, the document was submitted for approval to the ASTRO 181

Board of Directors in MONTH 2016. The ASTRO Guidelines Subcommittee intends to monitor 182

this guideline and initiate an update when appropriate, according to existing ASTRO policies. 183

184

Literature Review 185

186 A systematic review of the literature was performed in early 2015 to form the basis of the 187

guideline. An analytic framework incorporating the population, interventions, comparators, and 188

outcomes (PICO) was first used to develop and refine search strategies for each KQ. The 189

searches were conducted in MEDLINE PubMed and designed to identify studies published in 190

English between January 1990 and December 2014 that evaluated adults with OPSCC who were 191

treated with primary radiotherapy, adjuvant radiotherapy, or radiotherapy with concurrent 192

systemic therapy. Both MeSH terms and text words were utilized and terms common to all 193

searches included: oropharyngeal neoplasms, carcinoma squamous cell, and radiotherapy. 194

Additional terms specific to each KQ were also incorporated. The outcomes of interest were 195


overall and progression-free survival, recurrence rates, toxicity, and quality of life. The initial 196

literature review was conducted in December 2014. The electronic searches were supplemented 197

by hand searches. 198

A total of 2615 abstracts were retrieved. The articles were then reviewed by ASTRO 199

staff, the co-chairs of the guideline, and the writing groups for each KQ. During the first round of 200

screening, 2452 articles were eliminated based on the inclusion and exclusion criteria. The 201

inclusion criteria were: patients ≥18 years or older, all stages of oropharyngeal cancer, and 202

publication date 1990 to 2014. Included treatments were: primary radiotherapy, primary 203

chemoradiation, primary surgery with adjuvant radiotherapy with or without systemic therapy, or 204

IC followed by radiation therapy or chemoradiotherapy. The exclusion criteria were: pre-clinical 205

or non-human studies, case reports/series, non-English language, available in abstract only, 206

pediatric patients, distant metastasis, non-squamous cell carcinoma, and otherwise not clinically 207

relevant to the key clinical questions. The panelists on KQ 1, 3 and 4 generally only considered 208

articles in which the percentage of OPSCC patients was greater than 50%; the panelists on KQ 2 209

did not have an absolute threshold because OPSCC patients typically comprise a minority of 210

individuals in post-operative studies. Ultimately, 119 full-text articles were chosen for inclusion 211

and abstracted into detailed literature tables to provide supporting evidence for the clinical 212

guideline recommendations. 213

Because expression of the p16 protein is typically used as a surrogate for HPV infection, 214

4 the two words – p16-positive and HPV-positive – are sometimes used interchangeably (and 215

incorrectly). However, throughout this guideline, the mention of p16 will be reserved for clinical 216

studies in which its status was assessed and reported. 217

218


Grading of Evidence, Recommendations, and Consensus Methodology 219

Guideline recommendation statements were generated from this literature review, with 220

high-quality evidence forming the basis of the statements whenever possible, in accordance with 221

Institute of Medicine (IOM) standards; 5 expert opinion supplemented the evidence base if high-222

level data were not available. The GRADE (Grading of Recommendations, Assessment, 223

Development and Evaluations) methodology was followed in the construction and assessment of 224

the recommendation statements. GRADE is an explicit, systematic approach to defining the 225

recommendation strength and quality of evidence.6,7 226

Recommendation strengths were dichotomized as “strong” or “conditional.” 227

Strong recommendations were made when the panel was very confident that the benefits of the 228

intervention clearly outweighed the harms; conditional recommendations were made when the 229

ratio between risks and benefits was more balanced. Per the GRADE formalism, a “strong” 230

recommendation implies that the panelists believe “all or almost all informed people would make 231

the recommended choice for or against an intervention.” 7 A “conditional” recommendation 232

implies that “most informed people would choose the recommended course of action, but a 233

substantial number would not. When a recommendation is weak, clinicians and other health care 234

providers need to devote more time to the process of shared decision making by which they 235

ensure that the informed choice reflects individual values and preferences.”5 The importance of 236

patient preferences and shared decision-making was highlighted in each conditional 237

recommendation statement. 238

The GRADE methodology defines “quality of evidence” as a rating that indicates “the 239

extent of our confidence that the estimates of an effect are adequate to support a particular 240

decision or recommendation.”6 The quality of evidence underlying each recommendation 241


statement was categorized as either high, moderate, low. 6 Although GRADE does provide for a 242

“very low” quality, the panel did not consider this rating for consistency with prior ASTRO 243

guidelines. Descriptions of each quality level are below: 244

High: We are very confident that the true effect lies close to that of the estimate of 245

the effect. 246

Moderate: We are moderately confident in the effect estimate: The true effect is 247

likely to be close to the estimate of the effect, but there is a possibility that it is 248

substantially different 249

Low: Our confidence in the effect estimate is limited: The true effect may be 250

substantially different from the estimate of the effect 251

The degree of consensus among the panelists on each recommendation statement was 252

evaluated through a modified Delphi approach. A survey was sent by ASTRO staff to the panel 253

members, who rated their agreement with each recommendation on a five-point Likert scale, 254

ranging from strongly disagree to strongly agree (higher score corresponds with stronger 255

agreement). A pre-specified threshold of ≥ 75% of raters was determined to indicate when 256

consensus was achieved.8 If a recommendation statement did not meet this threshold, it was 257

modified and re-surveyed, or excluded from the guideline. The final set of recommendation 258

statements were achieved after 2 surveys. The guideline statements, along with the 259

corresponding ratings of recommendation strength, quality of evidence, and level of consensus, 260

are listed in Table 1. 261

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Results 265

266

Key Question 1. When is it appropriate to add systemic therapy to definitive radiotherapy 267

in the treatment of oropharyngeal squamous cell carcinoma (OPSCC)? 268 269

1. In the scenario of stage IVA-B disease? 270

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272 Statement 1A. Concurrent high-dose intermittent cisplatin should be delivered to patients with 273

stage IVA-B oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 274

o Recommendation strength: Strong 275

o Quality of evidence: High 276

277 Statement 1B. Concurrent cetuximab or carboplatin-fluorouracil should be delivered to patients 278

with stage IVA-B oropharyngeal squamous cell carcinoma receiving definitive radiotherapy who 279 are not medically fit for high-dose cisplatin. 280



283 Statement 1C. Concurrent weekly cisplatin may be delivered to patients with stage IVA-B 284

oropharyngeal squamous cell carcinoma receiving definitive radiotherapy who are not medically 285 fit for high-dose cisplatin, after a careful discussion of patient preferences and the limited 286 prospective data supporting this regimen. 287

o Recommendation strength: Conditional 288

o Quality of evidence: Low 289

290

Statement 1D. Concurrent cetuximab should not be delivered in combination with chemotherapy 291 to patients with stage IVA-B oropharyngeal squamous cell carcinoma receiving definitive 292 radiotherapy. 293



296 Statement 1E. Intra-arterial chemotherapy should not be delivered to patients with stage IVA-B 297

oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 298 o Recommendation strength: Strong 299


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Narrative 303 304

The role of concurrent cytotoxic chemotherapy combined with radiotherapy 305

Several phase III trials have randomized patients with locally advanced, non-metastatic 306

head and neck squamous cell carcinoma to treatment with conventionally- or altered-fractionated 307


radiotherapy alone versus treatment with concurrent chemoradiotherapy (Table 2). All of the 308

studies in this systematic review were predominantly composed of patients with oropharynx 309

cancer, and the clear majority of patients presented with stage IV disease. In the six studies that 310

directly compared standard fractionation radiotherapy to combined concurrent 311

chemoradiotherapy, dose and fractionation schemes were relatively uniform, with total delivered 312

doses approaching 66-70.2 Gy in 1.8-2 Gy fractions.9-15 The chemotherapy regimens were 313

variable, including bolus cisplatin9, weekly cisplatin, 25 carboplatin-fluorouracil, 15,16 daily 314

carboplatin,11 and bleomycin-mitomycin. 14 315

The five trials comparing altered fractionation radiotherapy (3 accelerated, 2 316

hyperfractionated) with and without concurrent chemotherapy also employed a variety of 317

systemic therapy regimens, including carboplatin-fluorouracil,17 daily cisplatin,18 cisplatin-318

fluorouracil,19 high-intensity cisplatin-fluorouracil (bolus cisplatin every 2 weeks),20 and 319

fluorouracil-mitomycin.21,22 However, as opposed to the conventionally fractionated trials, in 320

which the radiotherapy was standardized between the two arms, two of these studies20,21 used 321

different radiotherapy schemes for the radiotherapy-alone arm. The ARO 95-06 trial12 treated 322

patients to a total dose of 77.6 Gy without chemotherapy and 70.6 Gy with chemotherapy, and 323

the GORTEC trial23 delivered 64 Gy in 5 weeks with chemotherapy and the same dose in 3 324

weeks without chemotherapy. 325

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Impact on overall survival 327

In all but two of the 6 studies of conventionally fractionated radiation therapy, 328

chemoradiotherapy significantly improved overall survival.10,11,14,24,25 Most of these studies 329

reported the statistically significant improvement in OS at 3 years, with the absolute benefit of 330


chemoradiotherapy ranging between 14% and 24%.10,11,24 The few studies with longer follow-up 331

showed a persistent but smaller survival advantage to concurrent chemotherapy. For example, 332

the 5-year OS difference in GORTEC 94-0126 was 6% (22% vs. 16%, p=0.05), whereas in the 333

AIRO study11 using daily carboplatin, the 5-year survival difference was less than 3%. In 334

contrast, neither the Mumbai trial25 (weekly cisplatin) nor the ORO 93-0127 (carboplatin-335

fluorouracil) showed an OS advantage with concurrent chemotherapy, although disease-free 336

survival was significantly improved with chemotherapy in both studies; it is notable that both of 337

these trials included a third arm of altered fractionation alone, and so the total numbers of 338

patients in each arm were less than 70, likely underpowering the studies for an OS endpoint. 339

Among the 5 studies of chemoradiotherapy with altered fractionation, three of them 340

showed an absolute OS advantage with the addition of concurrent chemotherapy, ranging from 341

5%20 (5-year ARO 95-06, fluorouracil and mitomycin) to 9.8%28 (5-year, Semrau et al, 342

carboplatin and fluorouracil) to 24%19 (3-year, Wendt et al, cisplatin and fluorouracil). Among 343

the other two trials, concurrent daily cisplatin improved cancer-specific survival in SAKK 344

10/9418 by an absolute 12% at 10 years, and concurrent carboplatin-fluorouracil with very 345

accelerated radiotherapy in Bourhis et al.23 reduced the risk of any cancer progression by nearly 346

25%, but toxic deaths precluded a survival benefit. 347

The data from the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-348

NC Meta-analysis) 29 corroborated the conclusions drawn from these individual phase III 349

randomized trials. In the most recent update from this group, Blanchard et al.29 analyzed over 350

5800 patients with oropharynx cancer and showed that the concomitant addition of 351

chemotherapy to radiotherapy resulted in an 8.1% absolute benefit in OS at 5 years30, translating 352

into a relative 22% reduction in overall mortality. By contrast, adjuvant or neoadjuvant 353


chemotherapy administration was not associated with a survival benefit. There was no significant 354

heterogeneity in chemotherapy treatment effect by fractionation regimen, although only the use 355

of platinum-fluorouracil (HR 0.83, 95% CI 0.75-0.91) or platinum monotherapy (HR 0.70, 95% 356

CI 0.59-0.84) was significantly associated with survival. Additional univariable analyses 357

suggested that the survival benefit with concurrent chemotherapy was largely restricted to 358

younger patients (HR for 61 years or older, 0.97, 95% CI 0.87-1.08) and patients with stage IV 359

disease (HR for stage III disease, 1.01, 95% CI 0.88-1.14). However, multivariable analysis 360

showed that only favorable performance status and type of chemotherapy (i.e. platinum-based 361

chemotherapy with or without 5-FU) were significantly associated with overall survival. 362

363

Impact on locoregional control 364

The three trials of conventionally fractionated radiotherapy that reported locoregional 365

control (LRC) outcomes showed a statistically significant improvement in patients receiving 366

concurrent chemotherapy. Denis et al. and Ruo Redda et al.11,16 demonstrated an absolute 3-year 367

LRC benefit with concurrent chemotherapy of 24% and 8.7%, respectively 11,16, although 368

notably, the LRC difference in Ruo Redda et al.11 was only statistically significant among stage 369

IV patients. Ghosh-Laskar25 found that weekly cisplatin improved LRC by an absolute 17% at 5 370

years. The four studies of concurrent chemotherapy with altered fractionation that presented 371

distinct LRC probabilities consistently found that concomitant treatment significantly reduced 372

locoregional failure, with the absolute benefits of 8% (10-year, SAKK 10/94), 18,28 12% (5-year, 373

Semrau et al), 28 19% (3-year, Wendt et al), 19and 13%22 (3-year, 28 Budach et al). 374

In the recent MACH-NC meta-analysis 31 that did not distinguish by tumor site, Pignon 375

and colleagues showed that concurrent chemoradiotherapy significantly improved LRC, with an 376


absolute improvement of 9.3% and 13.5% among all studies and those with platinum-377

fluorouracil, respectively. These absolute improvements translated into hazard reductions of 0.74 378

and 0.66 for all studies and those with platinum-fluorouracil, respectively (p<0.0001). 379

380

Impact on distant metastases 381

One of the challenges in interpreting the impact of chemotherapy on distant metastasis is 382

the inability of trials to distinguish between metastasis arising from a first locoregional failure 383

versus metastasis as the first site of failure. That said, none of the randomized studies of 384

concurrent chemotherapy in conventionally fractionated radiotherapy found an improvement in 385

distant control with systemic therapy, and of the five trials of altered fractionation, only the 386

Swiss Group for Clinical Cancer Research (SAKK) trial18 of daily cisplatin showed an 387

improvement in distant metastasis-free survival. In this study, concurrent chemotherapy 388

improved 10-year distant metastasis free survival by 15% at 10 years, but only 9 total patients in 389

the entire study developed an isolated metastasis without prior locoregional failure; thus, one 390

may assume that this presumptive improvement in distant control was a function of reduced 391

locoregional recurrence. 392

In contrast, the MACH-NC meta-analysis31, which benefitted from the increased power 393

of thousands of patients, showed a small but statistically significant improvement in distant 394

control with concurrent treatment; the absolute improvement was 2.5% for all patients, with a 395

relative improvement of 0.88 (95% CI 0.77-1.0, p=0.04). As stated above, this reduction in 396

distant metastasis with concurrent systemic treatment may reflect less propagation from fewer 397

locoregional recurrences. 398

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Complications 400

While most of these phase III randomized studies show that adding chemotherapy to 401

radiotherapy improves survival, the combination clearly increased the risk of severe, acute 402

toxicities. For example, Adelstein et al.24 reported that patients receiving standard fractionation 403

RT with or without concurrent cisplatin had an overall grade 3 to 5 incidence of 85% and 51%, 404

respectively, of which leukopenia, anemia, and renal toxicities were the most significant. In this 405

Intergroup trial, 9 approximately 15% of patients treated with bolus cisplatin did not complete 406

treatment, and delivering three cycles of bolus cisplatin has been consistently challenging. For 407

example, in RTOG 0129, 32 which compared accelerated versus conventional radiotherapy with 408

concurrent bolus cisplatin in both arms, only 69% of patients in the conventional fractionation 409

arm received all 3 cycles, and approximately 24% of patients received only two courses of bolus 410

cisplatin. 411

In a review of the original GORTEC studies, Bourhis et al. showed that 71% of patients 412

receiving radiation with carboplatin and 5-FU developed acute grade 3 or 4 mucositis, compared 413

to only 39% of those receiving RT alone.33 Even weekly cisplatin in the Mumbai trial increased 414

the risk of grade 3 or 4 mucositis (35% vs. 21%, p value not reported), and daily carboplatin also 415

increased the risk of grade 2 toxicities (type not recorded). The combination of mitomycin-C and 416

bleomycin increased the risk of grade 3 or 4 mucositis by almost one-third. 417

The studies of concurrent chemotherapy with altered fractionation also found increases in 418

acute toxicity. The Starr et al. study showed statistically significant worse acute toxicities in the 419

arm receiving carboplatin and 5-FU—grade 3 and 4 mucositis was 68% versus 52% and grade 3 420

and 4 vomiting was 8.2% versus 1.6%.17 Similarly, the use of concurrent cisplatin-fluorouracil 421

with split-course hyperfractionation more than doubled the risk of acute grade 3-4 mucositis 422


(38% vs. 16%). In the GORTEC accelerated radiotherapy trial, 20 the very accelerated RT-alone 423

arm led to more acute mucosal toxicity, but a high early death rate from non-cancer cause 424

(almost 20% at 1 year) revealed the potentially life-threatening complications of intensive 425

chemotherapy with extreme acceleration. On the other hand, the higher radiation dose in ARO 426

95-06 21 actually showed more mucosal and skin toxicity in the radiotherapy alone cohort, and 427

the SAKK study18 using daily cisplatin found fewer than 10% of chemotherapy patients 428

developed a grade 3-4 hematologic toxicity, with no difference in acute radiotherapy effects. 429

Despite these acute toxicities, these trials consistently showed no significant increase in 430

high-grade late morbidity with concurrent therapy. A careful toxicity analysis of patients treated 431

on GORTEC 94-0126 showed that only grade 3-4 dental toxicity was significantly worse with 432

chemotherapy (44% vs. 12%). The ORO 93-0127 study showed numerically more tissue, skin and 433

mucosal side effects with chemotherapy, but these were not statistically tested and reported to be 434

typically transient. Neither daily carboplatin, weekly cisplatin nor mitomycin-bleomycin 435

increased the risk of late toxicity. Moreover, none of the five trials involving altered fractionation 436

with chemotherapy showed a significant increase in serious late toxicities. 437

438

Comparisons between chemotherapy regimens 439

While the studies mentioned above consistently showed LRC and typically OS benefits 440

from concurrent chemotherapy, it is important to note that the choice of systemic agents varied 441

considerably among each trial—bolus cisplatin, carboplatin/5-fluorouracil, cisplatin/5-442

fluorouracil, low-dose carboplatin alone, and bleomycin/mitomycin C, were each selected and 443

administered at varying schedules and frequencies. Unfortunately, there are far fewer studies 444

comparing different chemotherapy regimens and schedules to each other. 445


RTOG 970334 randomized over 241 patients to conventionally fractionated radiotherapy 446

plus either concurrent cisplatin-fluorouracil in the last 2 weeks of radiation therapy, daily 447

hydroxyurea-fluorouracil, or weekly cisplatin-paclitaxel; patients receiving daily chemotherapy 448

were treated every other week. Interestingly, all of the arms compared favorably to historical 449

controls, although the arms were not directly compared to each other. However, none of these 450

alternative regimens have been prospectively tested against more standard agents such as bolus 451

cisplatin. 452

The RTOG did not publish an additional randomized trial on competing chemotherapy 453

agents in head and neck cancer until RTOG 0522, which compared bolus cisplatin with bolus 454

cisplatin plus cetuximab, concurrent with accelerated radiotherapy.35 Nearly 900 patients were 455

enrolled in this trial, which confirmed that the addition of cetuximab did not improve outcomes. 456

Locoregional control, disease-free survival, and OS were not significantly different between the 457

two arms, and acute grade 3 and 4 toxicities were uniformly higher in the cetuximab arm, with a 458

low but statistically significant increase in toxic death. Thus, cetuximab should not be combined 459

with cytotoxic chemotherapy unless on a clinical trial. 460

Erlotinib is an oral biologic agent that targets EGFR by tyrosine kinase inhibition. It has 461

been used successfully in treating certain types of non-small cell lung cancer and, like 462

cetuximab, has demonstrated synergism when combined with chemotherapy or radiation in the 463

pre-clinical setting. Martins et al.36 performed a phase II randomized trial of cisplatin and 464

radiotherapy with or without concurrent erlotinib for stage III and IV locally advanced head and 465

neck cancers, most of which were oropharynx cancer. In results that echoed RTOG 0522,35 no 466

improvement was seen in complete response rates, LRC, progression-free survival, or OS at a 467


median follow up of 26 months, showing that an alternative method of EGFR inhibition is also 468

ineffective in combination with concurrent cisplatin. 469

The RTOG also obliquely asked a chemotherapy question in RTOG 01294,37, whose 470

primary hypothesis involved accelerated fractionation. This study randomized 743 patients to 471

either 3 cycles of bolus cisplatin with conventionally fractionated radiation therapy (RT) or 2 472

cycles of bolus cisplatin with accelerated RT.4,37 The trial showed no difference in any endpoint 473

between the arms, including distant metastasis, again confirming that the primary role of 474

chemotherapy is radiosensitization. In a subset analysis, the authors showed that patients 475

receiving only 1 cycle of cisplatin experienced markedly inferior survival. However, among 476

patients treated with conventionally fractionated RT, there was no statistically significant 477

survival decrement among the 24% of individuals who only received 2 cycles (HR 1.15, 95% CI 478

0.81-1.62). Although this finding casts some doubt on the benefit of the third cycle in the context 479

of standard fractionation, it is notable that (a) the upper end of the confidence interval was 1.62, 480

(b) the survival curve for patients receiving 2 cycles appears to separate from the curve for the 481

cohort receiving 3 cycles, and (c) this analysis was only based on 86 patients. 482

Finally, there is only one phase III trial comparing different modes of cisplatin 483

administration. Historically, there has been interest in delivering cisplatin intra-arterially, to 484

maximize the cisplatin dose to the tumor while infusing sodium thiosulphate systemically to 485

minimize cisplatin toxicity.38 The RTOG performed a multi-institutional phase II trial39 based on 486

this approach that produced results sufficiently promising for further study, and in fact, a 487

randomized controlled trial of this technique has been published. In this Dutch study by Rasch et 488

al.,40 239 patients with stage IV head and neck SCC received once-daily radiotherapy to 70 Gy 489

and were randomized to intravenous (three cycles of bolus infusion) versus intra-arterial (4 490


courses) cisplatin. 40 At 3 years, there was no difference in OS (51% vs. 47%), distant metastasis-491

free survival (69% vs. 66%), and LRC (65% vs 63%). High-grade (i.e. > grade 2) renal toxicity 492

was more common in patients receiving intravenous cisplatin (9% vs. 1%), although only one 493

patient experienced permanent nephrotoxicity, and this patient was not dialysis-dependent. On 494

the other hand, neurological toxicity (> grade 2) was significantly more common in the intra-495

arterial cohort (8 patients vs. 1) Given the technical and logistical challenges of administration 496

and the absence of any oncologic benefit but an increase in neurological toxicity, intra-arterial 497

chemotherapy should not be administered unless on a clinical protocol. 498

499

Summary of cytotoxic chemotherapy 500

The data are consistent that concurrent chemotherapy in combination with radiation 501

therapy improves LRC for patients with locally advanced oropharyngeal squamous cell 502

carcinoma, treated with either conventional or altered fractionation. In most of these studies, the 503

reduction in locoregional progression translated into a significant and meaningful OS benefit. 504

Although chemotherapy significantly increased acute toxicities, late effects were comparable to 505

treatment with radiotherapy alone, such that the survival benefits of concurrent therapy clearly 506

outweigh the non-trivial but short-term risks. Since the vast majority of the patients in these trials 507

presented with stage IV disease, concurrent systemic therapy should be delivered in this 508

population of patients. 509

510

The role of cetuximab combined with radiotherapy 511

Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor 512

(EGFR), which is a growth factor receptor overexpressed in head and neck cancer and associated 513


with poor prognosis. Pre-clinical data suggested synergy between cetuximab and radiotherapy, 514

and a preliminary phase I trial produced encouraging tolerability and response rates. These 515

promising outcomes generated a phase III randomized trial comparing radiotherapy alone (using 516

standard or altered fractionation) with radiotherapy plus cetuximab. The results of this trial were 517

first published in 2006 with a median follow-up of 54 months, revealing a clinically and 518

statistically significant improvement in OS with the addition of the antibody (hazard ratio 0.74, 519

95% CI 0.57-0.97), with an absolute 3 year survival difference of 10% (p=0.05). Similar to 520

cytotoxic chemotherapy, the benefit from combined modality therapy was in LRC, with a 521

relative 32% reduction in locoregional failure and absolute difference of 13% at 3 years 522

(p=0.01). There was no difference in distant metastases. There was no significant difference in 523

any acute adverse event except acneiform rash and infusion-related events, which were 524

substantially more common with cetuximab (17% vs. 1% for grade 3 or greater rash, p<0.001; 525

3% vs 0% for grade 3 or greater infusion reaction, p=0.01). The risk of mucositis (any grade) 526

was the same between the arms. 527

The results were updated in 2010 with a median follow-up of 60 months and additional 528

survival data on 40% of the surviving patients. The OS advantage was maintained (HR 0.73, 529

95% CI 0.56-0.95) was an absolute 5-year survival difference of 9%. Patterns-of-failure 530

information was not reported. Patients who developed a prominent rash experienced markedly 531

superior survival in comparison to those who did not (HR 0.49, median survivals 68.8 months vs. 532

25.6 months, p=0.002). A series of subset analyses suggested that the following cohorts 533

experienced significant benefit from cetuximab: oropharynx site, American Joint Committee on 534

Cancer (AJCC) T1-3, USA site, altered fractionation treatment, node-positivity, superior 535

performance status, male gender, and younger age (< 65 years). Of the 110 patients 65 years or 536


older, there was a non-significant trend favoring radiation therapy alone. It is critical to note, 537

though, that even though patients were stratified by Karnofsky Performance Status (KPS) (90-538

100 vs lower), nodal status (N0 versus N+), tumor stage (T1-3 vs. T4), and radiation 539

fractionation regimen, the numbers in the subgroups were quite small, and so these results should 540

be considered hypothesis-generating. 541

A phase II randomized prospective trial sought to improve upon the results of Bonner et 542

al. by comparing concurrent cetuximab-radiotherapy with the same regimen plus 12 weeks of 543

adjuvant cetuximab.41 The authors of this study hypothesized that continued epidermal growth 544

factor receptor (EGFR) blockade by maintenance cetuximab would serve to eradicate any 545

residual disease after concurrent treatment. Although there was a trend for improved response 546

rates at 12 weeks, with adjuvant cetuximab, there was no significant improvement in LRC or OS 547

between the two arms. Therefore cetuximab should be delivered per the Bonner protocol when it 548

is used in combination with radiotherapy. 549

550

Summary of systemic therapy for stage IVA-B disease 551

There are no randomized trials that have defined an optimal chemotherapy regimen, but 552

individual studies have most commonly incorporated cisplatin and/or fluorouracil. Although 553

high-dose intermittent (i.e. bolus) cisplatin can be challenging to deliver, it has the longest track 554

record in large multi-institutional trials in the United States, with a well-known and largely 555

predictable side effect profile. Carboplatin-fluorouracil has also been shown to improve OS in 556

comparison to radiotherapy alone and is thus a viable alternative to bolus cisplatin. However, 557

there is far less practitioner experience with delivering this regimen concurrently with head and 558

neck radiotherapy, which is significantly more resource-intensive than cisplatin monotherapy. In 559


addition, there are few reported toxicity data on carboplatin-fluorouracil in the intensity – 560

modulated radiation therapy (IMRT) era, and whether the low-dose bath seen with IMRT would 561

be particularly accentuated by a well-known mucositic agent (fluorouracil) is unknown. Thus, for 562

patients expected to tolerate high-dose intermittent cisplatin administration, the panel strongly 563

recommends its use for patients with stage IVA-B OPSCC. 564

A non-trivial percentage of patients with OPSCC may not tolerate bolus cisplatin 565

administration for a variety of reasons, including hearing loss or compromised renal function. In 566

this circumstance, the panel strongly recommends the use of concurrent carboplatin-fluorouracil 567

or cetuximab with definitive radiotherapy. As detailed above, the former regimen has a 568

consistent history of improving OS in combination with radiotherapy, and concurrent cetuximab 569

was shown in a phase III trial to improve OS in comparison to radiotherapy alone.35 There are 570

several retrospective studies comparing outcomes with cetuximab-radiotherapy with 571

chemoradiotherapy, but these publications are conflicting and too laden with confounding and 572

selection bias for consideration in this guideline. Therefore the panel did not prioritize one drug 573

over another for patients who do not receive high-dose cisplatin. The results from RTOG 1016 574

should provide important guidance in selecting the optimal concurrent systemic therapy for 575

patients with p16-positive oropharyngeal cancer. 576

Although weekly cisplatin may be an acceptable alternative to high-dose administration, 577

the evidence suggesting a survival benefit with its use is significantly weaker and based on 578

extrapolation rather than high-level evidence. So while the panel concluded that weekly cisplatin 579

may be given if the patient is not a candidate for bolus delivery, the lack of data guiding its use 580

must be made very clear to the patient, especially in the face of high-level data supporting OS 581

gains with competing regimens. 582


The panel recognized that there is a population of patients with stage IVA-B (and stage 583

III) OPSCC who will not be candidates for concurrent systemic therapy. KQ4 discusses the 584

benefits and risks of altered fractionation radiotherapy to provide additional recommendations on 585

optimal treatment of this cohort. 586

587

588

2. In the scenario of stage III disease? 589 590

Statement 1F. Concurrent systemic therapy should be delivered to patients with T3 N0-1 591 oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 592


o Quality of evidence: Moderate 594

595 Statement 1G. Concurrent systemic therapy may be delivered to patients with T1-T2 N1 596

oropharyngeal squamous cell carcinoma receiving definitive radiotherapy who are considered at 597 particularly significant risk for locoregional recurrence, after a careful discussion of patient 598 preferences and the limited evidence supporting its use. 599



602 3. In the scenario of stage I-II disease? 603 604

Statement 1H. Concurrent systemic therapy should not be delivered to patients with stage I-II 605 oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 606



609

Narrative 610

611 The addition of concurrent systemic therapy to primary radiotherapy for patients with 612

stage III oropharyngeal squamous cell carcinoma may be appropriate in certain patient 613

subgroups. Randomized controlled trials have generally included both stage III and IV patients, 614

with the stage III subgroup representing a minority (4 – 32%) of the total study population in the 615

studies reviewed. These trials are underpowered to address the magnitude of benefit of 616


concurrent systemic therapy in the stage III subgroup. In addition, stage III patients are 617

heterogeneous, and include those with T3 N0-1 and T1-2 N1 tumors. 618

Since concurrent systemic therapy improves outcomes primarily through 619

radiosensitization, the key issue is the expected LRC probability with radiotherapy alone in this 620

population. Retrospective studies have shown that local tumor control is strongly related to 621

tumor volume and tumor stage. For example, Lok et al.42 reported the effect of tumor volumes on 622

outcomes of 340 OPSCC patients managed with radiation and concurrent chemotherapy at 623

Memorial Sloan Kettering between 1998-2009. Volumes of the primary site gross tumor (GTVp) 624

were calculated from the original IMRT plans. When dichotomized at the median volume (32.79 625

cm3) GTVp was demonstrated to be an independent predictor of 2 year OS on multivariate 626

analysis (94.3% vs 82.7%, p=0.0003). Similarly, two year probabilities of local failure (LF) at 627

the primary site were 1.3 % vs 10.4% (HR=6.01, p=0.004) based on a GTVp cut-off of 32.79 628

cm. 3 The authors observed that GTVp was a more reliable predictor of OS and LF than T 629

category (dichotomized as T1-2 vs T3-4). 630

Garden et al. 43 have reported a retrospective analysis of 1046 OPSCC treated at MD 631

Anderson between 2000 and 2007. Locoregional control at 5 years for 640 patients presenting 632

with T1-2 disease was 91% for those given concurrent chemotherapy and 95% for those treated 633

with radiation alone. In contrast, patients with T3-4 disease treated with concurrent 634

chemoradiotherapy achieved a LRC probability of only 77%, which dropped to 63% with 635

radiotherapy alone. A comparable retrospective analysis from the University of Florida described 636

the LRC outcomes in 130 OPSCC patients treated with definitive radiotherapy, 89% and 61% of 637

whom received AccF and/or concurrent chemotherapy, respectively. When evaluating their local 638

control outcomes, the authors found that T1 and T2 lesions experienced 5-year control 639


probabilities of 93% and 91%, respectively, whereas T3 and T4 tumors recurred locally 82% and 640

67% of the time, respectively. These data are persuasive that patients with larger volume disease 641

need additional local therapy beyond conventional radiotherapy alone. In fact, the MACH-NC 642

meta-analysis31 showed a significant OS improvement with chemotherapy for patients with stage 643

III head and neck cancer, although the results were not broken down by T stage. Since 644

concurrent chemotherapy is consistently associated with LRC and OS benefits in the 645

aforementioned randomized trials, the panel strongly recommends that patients with T3 N0-1 646

OPSCC receive concurrent systemic therapy with primary radiotherapy. 647

The degree to which low-bulk disease, namely non-T3 stage III (T1-T2, N1) OPSCC, 648

benefit from treatment intensification with concurrent systemic therapy is uncertain, and it 649

remains controversial whether the added toxicity of concurrent systemic therapy is warranted in 650

this population. Consider that the volume of a T2 tumor may range from 8 cm3 to 64 cm3, and 651

thus the baseline risk of local recurrence may vary significantly in this tumor category. Other 652

tumor features may also impact the perceived locoregional failure risk for a patient with T1-2 N1 653

disease, such as its human papillomavirus (HPV) status and the patient’s smoking history. For 654

most patients with the T1-2 N1 OPSCC, the panel believes that radiotherapy alone should be 655

sufficient to obtain LRC. However, certain patients with T1-2 N1 OPSCC who are considered at 656

particularly significant risk for locoregional recurrence may receive concurrent systemic therapy 657

with primary radiotherapy, since the absolute benefit of combined modality therapy may warrant 658

its toxicities in this population. The potential benefit of concurrent systemic therapy is even less 659

compelling in smaller tumors, unless there are other features suggesting radioresistance. Patient 660

preferences must be engaged on the toxicity of concurrent therapy versus modestly improved 661

tumor control, and the limited data guiding this recommendation should be made explicit. 662


The use of concurrent systemic therapy has not been rigorously examined in patients with 663

stage I and II OPSCC, a population with favorable LRC outcomes with radiotherapy alone. For 664

example, in the MACH-NC meta-analysis, 31 just over 500 patients with stage I-II disease were 665

included in the study (versus over 6,000 for stage IV cancer), and the hazard ratio for 666

chemotherapy was approximately one. Therefore these patients should not be treated with 667

concurrent systemic therapy. 668

669

Key Question 2: When is it appropriate to deliver post-operative radiotherapy with and 670

without systemic therapy following primary surgery of oropharyngeal squamous cell 671

carcinoma (OPSCC)? 672

1. In the scenario of positive margins and/or extracapsular nodal extension (ECE)? 673

674 Statement 2A. Concurrent high-dose intermittent cisplatin should be delivered with post-675

operative radiotherapy to patients with positive surgical margins and/or extracapsular nodal 676

extension; this high-risk population includes patients independent of HPV status or the extent of 677

extranodal tumor. 678



681

Statement 2B. Concurrent weekly cisplatin may be delivered with post-operative radiotherapy to 682

patients who are considered inappropriate for standard high-dose intermittent cisplatin after a 683

careful discussion of patient preferences and the limited evidence supporting this treatment 684

schedule. 685



688 Statement 2C. For the high-risk post-operative patient unable to receive cisplatin-based 689

concurrent chemoradiotherapy, radiotherapy alone should be routinely delivered without 690

concurrent systemic therapy; given the limited evidence supporting alternative regimens, 691

treatment with non-cisplatin systemic therapy should be accompanied by a careful discussion of 692

the risks and unknown benefits of the combination. 693




696 Statement 2D. Patients treated with post-operative radiotherapy should not receive concurrent 697

weekly carboplatin. 698



701 Statement 2E. Patients treated with post-operative radiotherapy should not receive cetuximab, 702

either alone or in combination with chemotherapy, although such regimens are currently under 703

investigation. 704



707 Statement 2F. Patients treated with post-operative radiotherapy should not routinely receive 708

concurrent weekly docetaxel given the limited evidence supporting its use, although such 709

regimens are currently under investigation. 710



713 Statement 2G. Patients treated with post-operative radiotherapy should not receive concurrent 714

mitomycin-C, alone or with bleomycin, given the limited evidence and experience supporting 715

its use. 716



719 Statement 2H. Post-operative chemotherapy should not be delivered alone or sequentially with 720

post-operative radiotherapy. 721



724

Narrative 725

726 Is there a patient population that will benefit from the addition of chemotherapy to post-727

operative radiotherapy? What drug and treatment schedule should be used? 728

The results of two landmark trials of adjuvant chemoradiotherapy, EORTC 2293144 and 729

RTOG 950145, were published simultaneously in 2004 (Table 3). Both studies compared post-730


operative radiotherapy (PORT) with post-operative chemoradiotherapy, using concurrent high-731

dose intermittent cisplatin (100 mg/m2 every three weeks for three doses) in patients deemed at 732

high risk for disease recurrence. High-risk disease was defined as positive surgical margins, or 733

extracapsular nodal involvement in both trials, but the RTOG study45 also included involvement 734

of two or more regional nodes, and the EORTC study44 included perineural disease, vascular 735

embolism, or level 4 or 5 nodal involvement in oral cavity or oropharynx primary cancers. It 736

should be noted that in the RTOG trial, a positive surgical margin was defined as microscopic 737

tumor at the tumor specimen edge. In the EORTC trial44 however, tumor within 5 mm of the 738

specimen edge was considered a positive margin. Initial results from both studies demonstrated 739

an improvement in LRC and disease/progression-free survival with chemoradiotherapy. Overall 740

survival was statistically better in the EORTC study44 but only trended towards improvement in 741

the first RTOG report. Long-term follow-up from the RTOG trial has been reported46, however, 742

and it no longer demonstrated any statistical benefit from the chemotherapy in the primary 743

comparisons. 744

It is of note that distant metastases were not reduced by the chemotherapy in either trial, 745

and all three cisplatin doses could be given to only 49% and 61% of the EORTC44 and RTOG45 746

patients respectively. Acute toxicity, specifically mucositis, myelosuppression, nausea and 747

vomiting, was increased in the chemoradiotherapy patients. However, no statistically significant 748

increase in total late grade 3-5 toxicity could be identified after chemoradiotherapy in either 749

study. This acute toxicity burden must temper any enthusiasm to use concurrent chemotherapy 750

in an unselected population of patients receiving PORT. 751

The difference in survival outcomes, and the long-term results from the RTOG study 752

merit further discussion. Bernier and colleagues47 performed a pooled analysis of the 750 753


patients from both trials, and confirmed an improvement in all endpoints, including OS, in the 754

patients treated with chemotherapy. They suggested, however, that not all of the “high-risk” 755

eligibility criteria conferred sufficient risk to merit the addition of concurrent chemotherapy. In 756

their retrospective, unplanned subgroup analysis from these two trials, the addition of concurrent 757

cisplatin proved beneficial only in those high-risk patients with either positive surgical margins 758

or extracapsular nodal involvement. While benefit in patients with the other risk features 759

remained a possibility, it could not be statistically demonstrated. Similar conclusions were drawn 760

from the long-term RTOG 9501 follow-up report.46 Again using retrospective, unplanned 761

subgroup analysis, an improved loco-regional control and disease-free survival (with a strong 762

trend towards an improved OS) was identified in the chemoradiotherapy-treated patients with 763

positive surgical margins or extracapsular nodal extension. These observations have led to the 764

current strong recommendations for the addition of concurrent high-dose intermittent cisplatin to 765

adjuvant radiotherapy in these two high-risk post-operative populations. Patients with other risk 766

features, whose surgical procedure and/or pathologic findings imply a particularly significant 767

risk of locoregional recurrence may still benefit from concurrent cisplatin, although the evidence 768

is limited and inconclusive. 769

The improved prognosis and increasing incidence of HPV-positive oropharynx cancer, 770

however, could not be assessed in these trials and may have impacted the observed results.48 In 771

the EORTC study 30% of the patients had an oropharynx cancer compared to 42% in the RTOG 772

report (48% on the chemoradiotherapy arm and 37% of the radiotherapy alone arm). It is 773

unknown if these good prognosis HPV-positive patients require or benefit from more intensive 774

adjuvant therapy, even in the presence of conventional “high-risk” features. 775


The implications of extracapsular nodal extension in oropharynx cancer, and in 776

particular, the HPV-positive patient have also been questioned. Retrospective reports from 777

several groups have suggested that extracapsular nodal disease has limited prognostic importance 778

in these patients, especially when it is only microscopically present in an HPV-positive patient.49-779

52 Prospective studies that replicate these provocative retrospective results are needed before 780

PORT alone can be recommended for HPV-positive head and neck cancer with ECE. In addition, 781

to enhance its prognostic power, ECE reporting has recently been refined with the introduction 782

of a five point scale (0-4), and further multi-institutional study is required for this modification to 783

be used in clinical practice.53 784

Reasonable concern clearly exists about the applicability of RTOG 950145 and EORTC44 785

22931 to the growing population of patients with HPV-positive oropharynx cancer48 and the 786

prognostic implications of early extracapsular nodal involvement. To date, however, these two 787

trials provide the best available evidence and continue to drive the current adjuvant 788

recommendations. Well-designed HPV-specific trials are currently underway to better address 789

these many unresolved questions. Similar concerns have also led to greater sophistication and 790

nuance in the studies designed for the definitive management of oropharynx cancer. Such 791

concerns do not render current treatment standards invalid; they only lend urgency to further 792

investigation. 793

794

Can radiotherapy and a weekly concurrent cisplatin administration schedule be used instead of 795

giving 100 mg/m2 given every three weeks? 796


The high-dose, every three week cisplatin administration schedule (100 mg/m2 q3weeks 797

for 3 doses) has proven difficult to administer. It is associated with gastrointestinal, renal, 798

mucosal and neurologic toxicity, and most large multi-institutional studies (including RTOG 799

9501 and EORTC 22931) have reported that only 50-70% of patients can receive all three drug 800

doses. In recent years there has been considerable interest in the lower dose weekly drug 801

administration schedules (30-40 mg/m2/week) based on the unproven assumption being made 802

that such regimens will produce less toxicity, and, as such will allow equivalent or greater drug 803

administration with equal treatment efficacy. No prospective, randomized comparisons have yet 804

been completed comparing these two drug treatment schedules, however, and their equivalence 805

is unknown. 806

In the post-operative setting Bachaud et al. 54,55 reported the results of a very small phase 807

III trial comparing PORT alone with radiotherapy and weekly cisplatin; 50 mg/week 808

(approximately 25-30 mg/m2) for 7-9 doses in 83 patients (14% oropharynx cancer). Both 809

disease-free and OS, as well as OS without locoregional treatment failure, were significantly 810

improved in the chemotherapy treated patients. Distant metastases were not impacted by the 811

chemotherapy, although toxicity was significantly worse. 812

Geiger et al.56 conducted a retrospective analysis of 104 post-operative patients treated 813

with radiotherapy and either concurrent high-dose intermittent (100 mg/m2 q3weeks for 3 doses), 814

or low dose weekly (25-30 mg/m2/week for 6 doses) cisplatin. Sixty-one percent of the patients 815

had an oropharynx cancer, and 86% of these oropharynx cancers were HPV/p16 positive. Total 816

drug administration was significantly greater in the high-dose intermittent group, but no 817

difference was observed in either relapse-free or OS between patients treated with the two 818


different cisplatin schedules. There was also no outcome difference identified when the analysis 819

was limited to the HPV-positive oropharynx cancer patients. 820

Because of the increasing community acceptance of weekly cisplatin regimens despite 821

this lack of demonstrated equivalence, the NRG adopted weekly dosing as the control arm in 822

RTOG 1216, its current phase II/III trial exploring the substitution of docetaxel and cetuximab 823

for cisplatin in the postoperative adjuvant treatment of patients with high risk disease. Despite 824

the inclusion of weekly cisplatin as the control arm in this study, the panel does not feel the 825

evidence supporting its use is currently sufficient to strongly recommend its delivery in lieu of 826

high-dose intermittent cisplatin when the latter would be tolerated, as the high-dose regimen was 827

evaluated in two large prospective phase III randomized trials with positive results. 828

829

Are there alternative systemic treatment regimens that can be used concurrently with 830

radiotherapy, particularly in the medically compromised patient? 831

Cisplatin remains the only systemic agent with level 1 evidence supporting its use 832

concurrently with radiotherapy in high-risk post-operative patients. Several other systemic agents 833

have been tested in small phase II and phase III trials with limited success (Table 4). All studies 834

report greater toxicity when chemotherapy is added to radiotherapy without a proven survival 835

benefit. 836

Radiotherapy and concurrent single agent mitomycin C (15 mg/m2 for 1-2 doses) has 837

been compared to a radiation therapy control arm in three separate randomized trials at Yale 838

University.57-61 Pooled results from the 205 post-operatively treated patients (23% oropharynx 839

cancer) have been reported. Conventional high-risk features were not required for entry on these 840


trials although 27% had positive surgical margins and 34% had more than one positive node. 841

Locoregional control proved statistically superior in those patients treated with mitomycin C; 842

however, no difference was observed in the rate of distant metastases or in overall survival. 843

Post-operative radiotherapy with mitomycin C (15 mg/m2) was also studied by Smid, 844

Zakotnik et al.,62,63 who combined it with bleomycin (5 mg twice weekly) and compared it to 845

radiotherapy alone in 114 patients (30% oropharynx cancer); 59% of whom had either positive 846

surgical margins or extracapsular nodal extension. Both LRC and disease-free survival were 847

significantly improved in the chemotherapy treated patients, although OS only trended better 848

(55% vs. 37%, p=0.09). Distant metastases were not improved by the use of chemotherapy. 849

This work, from both groups, provided modestly encouraging evidence of a potential role 850

for mitomycin C in this setting, although patient sample sizes were small. Mitomycin C has not 851

been further pursued in part due to the stronger data that emerged about concurrent cisplatin, and 852

in part due to general concerns about the toxicity of this agent. Because of both the lack of an OS 853

benefit and absence of modern experience of combining this agent with radiotherapy, the panel 854

strongly recommends not combining mitomycin C with post-operative radiotherapy. 855

Concurrent carboplatin has also been studied. Racadot et al.64 report the results of a 856

randomized comparison between PORT alone, and PORT with concurrent carboplatin (50 mg/m2 857

twice weekly) in 144 patients (49% oropharynx cancer) with node positive disease. No outcome 858

differences were observed. Similarly, Argiris et al.65 studied a post-operative patient population 859

(32% oropharynx cancer) defined by positive margins, multiple node positivity, angiolymphatic 860

or perineural invasion (PNI), or extracapsular nodal involvement, randomizing between 861

radiotherapy and radiotherapy with concomitant carboplatin 100 mg/m2 weekly. Only 72 patients 862


were evaluated on the trial and no statistically meaningful outcome difference was observed, 863

perhaps reflecting the insufficient sample size. Further studies of post-operative carboplatin and 864

radiotherapy have not been reported, and since both randomized trials were negative, the panel 865

strongly recommends against using concurrent carboplatin in the post-operative setting. 866

A large multi-institutional phase III study from the United Kingdom randomly compared 867

PORT with radiotherapy and chemotherapy (either methotrexate alone, or methotrexate, 868

vincristine, bleomycin and fluorouracil) in 253 post-operative patients (23% oropharynx cancer). 869

Patients were described as “generally at high risk due to margin status or advanced stage of 870

disease.” No outcome benefit was observed in the chemotherapy treated patients using this non-871

platinum containing regimen.66 872

Cetuximab and the other EGFR inhibitors have been considered promising agents in the 873

management of head and neck squamous cell cancer. When combined with radiotherapy in the 874

definitive treatment of locoregionally advanced disease, a survival benefit (but no impact on 875

distant metastases) has been demonstrated in comparison to radiation therapy alone. This result 876

has suggested the possibility that radiotherapy and cetuximab may also be a valuable post-877

operative adjuvant regimen to explore. The NRG is currently comparing this combination to 878

radiation therapy alone in “intermediate risk” patients after surgical resection in RTOG 0920.67 879

However, since there are no prospective or even retrospective studies suggesting efficacy in this 880

scenario, the panel strongly recommends against using cetuximab with PORT if not on clinical 881

trial. 882

The taxanes (paclitaxel and docetaxel) have been investigated by the RTOG in a series of 883

post-operative trials.68 RTOG 0024 explored immediate post-operative paclitaxel followed by 884


concurrent chemoradiotherapy with weekly paclitaxel and cisplatin in 70 high-risk post-operative 885

patients (34% oropharynx cancer) in a single arm phase II trial.68 Toxicity appeared acceptable 886

and results comparable to historical controls using high-dose cisplatin. This study was followed 887

by RTOG 0234, a phase II randomized trial comparing post-operative cetuximab and 888

radiotherapy with either concurrent weekly cisplatin or weekly docetaxel, in 203 high risk 889

patients (36% oropharynx cancer).69 The radiotherapy, cetuximab and docetaxel arm appeared 890

more promising and this combination is now being formally tested in a phase II/III trial70 in 891

comparison to radiotherapy and cisplatin. Pending the results of this study, though, the use of 892

docetaxel with PORT – a combination never prospectively evaluated – should not be routinely 893

implemented with post-operative radiotherapy. 894

It should again be noted that the benefit from cisplatin reflects an improvement in loco-895

regional control, not a reduction in distant metastases. There is no phase III evidence 896

demonstrating an improvement in distant metastatic recurrence from any systemic agent in this 897

setting. In patients with a contraindication to cisplatin, radiation therapy alone provides a LRC 898

benefit, and is the recommended treatment choice, even when the risk of disease recurrence is 899

high. 900

901

Is there a role for post-operative adjuvant chemotherapy alone, or for the sequential 902

administration or chemotherapy and radiotherapy, rather than concurrent treatment? 903

The MACH-NC Meta-analysis 31,71 reported on 12 trials of more than 2500 patients, 904

comparing adjuvant chemotherapy after locoregional treatment to locoregional treatment alone. 905


No impact could be identified on either disease recurrence or death from the use of the adjuvant 906

chemotherapy. Adjuvant chemotherapy is not considered a standard approach in this disease. 907

Laramore et al.72 reported the results of Intergroup study 0034, a phase III randomized 908

trial conducted in 448 patients (25% oropharynx cancer) comparing PORT alone, with sequential 909

chemotherapy (fluorouracil and cisplatin for 3 cycles) followed by radiotherapy. No difference in 910

LRC, disease-free survival or OS could be identified between the two treatment arms, although a 911

statistically significant increase in distant metastases was seen in the patients not given 912

chemotherapy. Sequential treatment with post-operative chemotherapy and radiotherapy is not 913

recommended in this disease. 914

915

2. In the scenario of intermediate-risk pathologic factors such as lymphovascular invasion 916

(LVI), perineural invasion (PNI), T3-4 disease, or positive lymph nodes? 917

918 Statement 2I. Patients with intermediate-risk factors should not routinely receive concurrent 919

systemic therapy with post-operative radiotherapy. 920



923 Statement 2J. Patients with intermediate-risk factors whose surgical procedure and/or 924

pathologic findings imply a particularly significant risk of locoregional recurrence may receive 925

concurrent cisplatin-based chemotherapy after a careful discussion of patient preferences and the 926

limited evidence supporting its use in this scenario; alternative systemic treatment regimens 927

should only be used in the context of a clinical trial. 928



931 Statement 2K. Post-operative radiotherapy should be delivered to patients with pathologic T3 or 932

T4 disease. 933




936 Statement 2L. Post-operative radiotherapy should be delivered to patients with pathologic N2 or 937

N3 disease. 938



941 Statement 2M. Post-operative radiotherapy may be delivered to patients with pathologic N1 942

disease after a careful discussion of patient preferences and the limited evidence of outcomes 943

following surgery alone in this scenario. 944



947 Statement 2N. Post-operative radiotherapy may be delivered to patients with LVI and/or PNI as 948

the only risk factor(s) after a careful discussion of patient preferences and the limited evidence of 949

outcomes following surgery alone in this scenario. 950



953

Narrative 954

955 The risk of locoregional recurrence following definitive surgical resection and neck 956

dissection is influenced by several factors. The clinical and pathologic features most clearly 957

associated with subsequent locoregional progression are positive margins and extracapsular 958

nodal extension, the implications of which were discussed above. On the other hand, due to the 959

paucity of prospective randomized trials of adjuvant radiotherapy alone versus observation 960

following surgery, the vast majority of data implicating other risk factors with locoregional 961

recurrence are retrospective. Thus, there is almost no high-level evidence to guide adjuvant 962

treatment recommendations in the negative margin, non-ECE setting, despite several other risk 963

factors serving as eligibility criteria for active prospective randomized trials evaluating the role 964

of adjuvant radiation therapy with or without chemotherapy. Nevertheless, this population 965

comprises a significant percentage of patients for whom PORT must be considered, and so the 966


panel used higher-quality retrospective data and expert opinion to derive treatment 967

recommendations (Table 5). 968

Pathologic nodal stage is a commonly used pathologic risk factor in the adjuvant 969

decision-making process. Resection of bulkier nodes may leave behind occult microscopic 970

disease, and with more pathologically involved nodes, there is theoretically a higher likelihood 971

of additional microscopic nodal deposits in dissected or undissected tissue. Indeed, the evidence 972

supports a significant risk of regional progression in patients with N2 or N3 disease. In one of the 973

few prospective trials of adjuvant radiotherapy dose escalation, Peters et al. showed that among 974

all patients, those with more than 1 positive node (i.e. N2b) experienced a higher risk of 975

locoregional recurrence (30% vs 16%, p=0.08), despite radiotherapy delivery to all patients. 976

Langendijk et al.73 performed a large retrospective analysis to define subgroups of patients with 977

locally advanced head and neck cancer (20% oropharyngeal cancer) at higher risk for 978

locoregional recurrence following surgery and post-operative radiotherapy. On multivariable 979

analysis, patients with pN2b-N2c and pN3 disease had significantly higher risks of locoregional 980

recurrence in comparison to pN0-N2a status (RR 1.7 and 3.5, respectively), and patients with an 981

N3 neck were placed in the “very high risk” category (5 year LRC of 58%) regardless of ECE or 982

the primary tumor characteristics. Similarly, Ambrosch et al.74 reported a large series of 503 983

patients treated with neck dissection with or without adjuvant radiotherapy. The 48 patients with 984

N2 disease treated without adjuvant radiotherapy experienced a 3-year neck recurrence risk of 985

24%, in comparison to 7% of the 188 N2-positive treated with post-operative radiotherapy. 986

Notably, among all patients with regional recurrence, successful salvage was feasible in only 987

24% of patients, and 67% of patients died specifically from the neck progression. In a smaller 988

surgical series from Mayo Clinic, 2 out of 11 (17%) pathologic N2b oropharynx cancer patients 989


observed after neck dissection developed a regional recurrence, as did 1 of 2 pathologic N3 990

patients. 991

The risk of regional recurrence in patients with a pathologically N1 neck is more 992

controversial. In a paper restricted to individuals with pN1 disease without extracapsular 993

extension (29% oropharynx), Jackel et al.75 reported the risks of locoregional recurrence with 994

and without adjuvant radiotherapy. Patients observed after primary surgery (n=72) experienced a 995

crude risk of any regional recurrence of 21%, with 10% of observed patients developing an 996

isolated nodal failure; the estimated 3-year risk of isolated neck recurrence in this population was 997

11.2% (vs. 2.9% in patients who were irradiated, p=0.09); three of the 7 patients with isolated 998

regional recurrence died from cancer. Somewhat conflicting data on the N1 neck were presented 999

in the Ambrosch study,74 in which the 3-year neck recurrence risk for the 48 pN1 patients treated 1000

with surgery alone was 6.3%. This number was only slightly higher than the neck recurrence risk 1001

in pN0 patients observed after surgery (5.5% out of 213 patients). However, only 28% of these 1002

patients had oropharyngeal cancer, and the majority was either oral cavity or larynx, which have 1003

different patterns of nodal spread. In particular, oropharyngeal cancer is significantly more likely 1004

to metastasize to the retropharyngeal nodes, which are treated with radiotherapy but not accessed 1005

with conventional neck dissection; the absolute risk of retropharyngeal lymph node involvement 1006

in OPSCC has been reported between 20-30%.76,77 Smaller, modern series in oropharynx cancer 1007

also suggest high control rates following neck dissection alone for N1 disease. None of the 10 1008

patients observed with pN1 disease in the Mayo clinic series developed a regional recurrence, 1009

and none of the 10 patients with pN1 disease in the Penn prospective study of transoral robotic 1010

surgery (TORS) 78 alone developed a neck progression. One significant consideration in 1011

evaluating all of these data is the reality that the quality of the neck dissections was not formally 1012


standardized, both in terms of surgical technique (e.g. levels dissected and number of nodes 1013

harvested) and pathologic evaluation processes. Thus one must recognize this limitation in 1014

applying these results to a given neck dissection. 1015

Two related surveillance, Epidemiology, and End Results Program (SEER) studies 1016

investigated the survival benefit of adjuvant RT following surgery for non-nasopharynx head and 1017

neck carcinoma with positive lymph nodes, and both showed a significant OS advantage for all 1018

nodal stages. For instance, Kao et al.79 showed that the absolute survival gains for patients with 1019

N1, N2a, N2b, and N2c-3 were 8.2%, 16.6%, 23.9%, and 12.2%, respectively (all p<0.0001). 1020

Patients with oropharyngeal cancer experienced an absolute survival improvement of 8.2% with 1021

adjuvant radiotherapy (p=0.0003). Although these survival improvements are impressive, any 1022

SEER study is limited by the nature of its retrospective, population-based data collection. For 1023

example, performance status, chemotherapy administration, ECE status, and pre-treatment 1024

imaging were all unknown. Nevertheless, these data do support a benefit of adjuvant 1025

radiotherapy for all node-positive disease. 1026

Taken together, this evidence is persuasive that individuals with pathologic N2 and N3 1027

disease experience an unacceptably high regional recurrence risk without radiotherapy, and 1028

therefore the panel strongly recommends that these patients receive adjuvant RT. Patients with 1029

pathologic N1 oropharynx cancer are clearly at lower risk for nodal progression following neck 1030

dissection, but there is substantial uncertainty on the true probability of regional recurrence in 1031

this population. Moreover, while it is intuitive and accepted that patients not receiving 1032

radiotherapy will have improved quality-of-life in comparison to those who do, the poor salvage 1033

ability (and potential mortality) of a neck recurrence must be considered in this decision. Since 1034

the panel favors a potential progression and/or survival benefit over modest, albeit meaningful, 1035


quality-of-life improvements, it conditionally recommends adjuvant radiotherapy in this 1036

population. That said, it is critical to discuss the uncertainty in the recurrence risk with the 1037

patient, and the physician should engage patient preferences and values on the balance between 1038

the risks of radiotherapy versus the potential for unsalvageable regional progression. 1039

Pathologic T stage has also been frequently investigated in retrospective studies as a 1040

predictor of locoregional recurrence. Leemans et al80 reported on 244 head and neck cancer 1041

patients (13% oropharynx) treated with primary surgery with or without adjuvant radiotherapy. 1042

Clinical T stage was the most significant predictor of local recurrence, with a crude recurrence 1043

risk of 5.3% for T1-2 versus 16.2% for T3-4 disease (p=0.015), and the actuarial absolute 1044

difference at 5 years was almost 20%. In a retrospective analysis of 420 oropharyngeal and 1045

hypopharyngeal patients from the Centre Henri Becquerel treated with surgery and PORT 1046

radiotherapy, advancing T stage was strongly associated locoregional relapse (relative risk 1.85, 1047

p<0.0001) on multivariable analysis, with T stage treated as a continuous variable; absolute risks 1048

were not stated. In the Langendijk73 analysis in which all patients received adjuvant 1049

radiotherapy, T stage did not correlate with LRC on univariable analysis. However, after 1050

identifying patients with positive or close margins (5 mm or less, which is typically seen in 1051

larger tumors of the oropharynx), patients with T3-4 disease experienced significantly worse 1052

LRC than those with T1-2 disease (absolute difference 10%). The majority of these failures were 1053

in the T3 population (5-year LRC of 51%). 1054

A retrospective analysis of p16-positive patients by Haughey et al.81 nicely showed a 1055

significant increase in the risk of any recurrence as a function of pathology T stage: 1.5%, 5.5%, 1056

11.5%, and 28.6% for T1, T2, T3 and T4 respectively. Indeed, on multivariable analysis of 1057

disease-free survival, both clinical T stage (T3-4 vs T1-2) and pathologic T stage (T3-4 vs T1-2) 1058


increased the hazard by over 3-fold. However, there were only 2 local recurrences in the entire 1059

series (both in T3 patients, 1 of whom did not receive adjuvant radiotherapy), so T stage was not 1060

a predictor of local-only recurrence. In the Ambrosch et al.74 study that primarily focused on 1061

regional recurrences after neck dissection, pT3/pT4 disease was significantly associated with 1062

worsened OS on multivariable analysis (risk ratio 1.6, p=0.0009), but local failure patterns were 1063

not mentioned. 1064

Both of these latter studies highlight a major challenge in analyzing the literature to 1065

derive adjuvant treatment recommendations in patients with T3-4 disease: almost all of these 1066

individuals received post-operative radiotherapy. While the retrospective data are convincing 1067

that these patients have a worse overall prognosis, it is hard to calculate an absolute local 1068

recurrence risk with and without radiotherapy. Nevertheless, the panel concluded that the 1069

existing literature support an increased risk of local recurrence with pathologic T3 or T4 disease 1070

even with radiotherapy, and moreover, there are insufficient LRC data to support the oncologic 1071

safety of observation following resection of T3-4 oropharyngeal cancer. Therefore the panel does 1072

strongly recommend adjuvant RT in this population. 1073

It is particularly difficult to estimate the risk of locoregional recurrence in patients for 1074

whom PNI or LVI is the only adverse pathologic factor. These characteristics are often found in 1075

patients with other known risk factors for recurrence and this confounding can be difficult to 1076

resolve.81 Secondly, retrospective studies don’t always comment on these factors because they 1077

are not always properly recorded in the pathology report. Finally, historically radiation 1078

oncologists have always treated patients with LVI or PNI, and there is very little information on 1079

outcomes without adjuvant radiotherapy. For example, the large retrospective analysis from 1080

Langendijk et al.73 found that patients with PNI had a significantly higher risk of locoregional 1081


recurrence (31% vs 22% at 5 years, p<0.026), as did patients with angioinvasive (33% vs 21%, 1082

p=0.011) or lymphangioinvasive growth (38% vs. 23%, p=0.046). However, none of these 1083

factors were significant on multivariable analysis. Haughey et al. found on univariable analysis 1084

that angioinvasion was borderline associated with disease-free survival (p=0.062) and powerfully 1085

associated with disease-specific survival (HR 13.16, p=0.002). These relationships became non-1086

significant on multivariable analysis. Moreover, only 26 patients had this pathologic factor, and 1087

of these 26, five recurred but 4 were distant metastases. There was no association between PNI 1088

and outcome in this large analysis. 1089

There are data supporting these characteristics as independent risk factors for 1090

locoregional recurrence. In a retrospective analysis of 80 consecutive head and neck patients 1091

(28% oropharynx) treated with primary surgery at the University of Utrecht, LVI was 1092

significantly associated with local failure on both univariable analysis (50% failure with vs. 16% 1093

without, p=0.001) and multivariable analysis (p=0.005). Perineural invasion was qualitatively 1094

associated with local failure (27% with and 15% without), but it was non-significant on both 1095

univariable and multivariable analysis.82 In the retrospective study from the Centre Henri 1096

Becquerel,83 individuals with tumor emboli in the vessels or nerves experienced an 1097

approximately 10% increased risk of locoregional recurrence. However, in a multivariable 1098

analysis of local relapse incorporating T and N stage, margin status, age, tumor emboli was 1099

marginally non-significant (relative risk 1.48, p=0.061). In another bi-institutional retrospective 1100

analysis of oral cavity and oropharyngeal cancer (33% oropharynx), McMahon et al.84 showed 1101

that PNI was a significant predictor of local recurrence in both institutions, and vascular and LVI 1102

was a significant predictor of local recurrence in only one of them. However, on multivariable 1103

analysis incorporating all patients, only PNI (over all other variables) was significantly 1104


associated with local recurrence. Neither PNI nor LVI were independently associated with 1105

disease-specific survival on multivariable analysis. Fagan et al.85 retrospectively evaluated the 1106

prognostic influence of PNI in 142 patients (66 with oral cavity or oropharynx) treated with 1107

primary surgery with or without adjuvant radiotherapy. Over half of the patients had PNI, and it 1108

was significantly associated with local recurrence (23% vs. 9%, p=0.02) and disease-specific 1109

mortality. Finally, Lanzer and colleagues analyzed locoregional and distant recurrence patterns 1110

in 291 head and neck cancer patients, 32% of whom had oropharynx cancer. Among all patients, 1111

the presence of PNI was associated with a higher risk of ipsilateral and contralateral lymph node 1112

recurrence, but there were no independent associations between PNI and disease-free or overall 1113

survival.86 1114

Two retrospective analyses restricted to oral cavity cancer highlight the uncertainty in the 1115

adjuvant management of this population. In a large series of 460 patients with node-negative oral 1116

cavity cancer87, Liao et al. showed that the presence of PNI was not associated with local control 1117

or OS and the addition of radiotherapy to patients with PNI did not improve any outcome; only 1118

44 patients with PNI were observed. On the other hand, Chinn et al.88 reported on a cohort of 88 1119

node-negative oral cavity patients from the University of Michigan, finding that PNI was 1120

associated with worse LRC (35% vs. 12%, p=0.037) and a shorter disease-free interval on 1121

multivariable analysis; in addition, the addition of radiotherapy significantly improved both 1122

endpoints.88 However, only six patients with PNI were observed, limiting the interpretation of 1123

this comparison. 1124

In summary, these entirely retrospective data are mixed on the relationship between 1125

locoregional failure and LVI and PNI, but there is certainly the suggestion that they reflect more 1126

aggressive locoregional disease. Given the morbidity and mortality risk of local recurrence, 1127


adjuvant radiotherapy may be used for patients with either pathologic factor as the only adverse 1128

characteristic. Both the lack of high-quality evidence and the conflicting retrospective data 1129

guiding this recommendation need to be described to patients, and their preferences and values 1130

on toxicity versus the risk of recurrence need to be explored. 1131

3. In the scenario of no pathologic risk factors? 1132

1133

Statement 2O. Post-operative radiotherapy may be delivered to patients without conventional 1134

adverse pathologic risk factors only if the clinical and surgical findings imply a particularly 1135

significant risk of locoregional recurrence, after a careful discussion of patient preferences and 1136

the potential harms and benefits of radiotherapy. 1137



1140

Narrative 1141

1142 There are limited prospective data that report outcomes following primary surgery alone 1143

for oropharyngeal cancer. In a multi-institutional prospective trial evaluating a post-surgical 1144

adjuvant therapy paradigm, Ang et al.89 demonstrated that when the surgical bed was at a low 1145

risk for relapse, defined by the absence of any adverse pathologic features (i.e. T1-2, N0, 1146

negative margin, no PNI, non-oral cavity site), observation was associated with a local-regional 1147

relapse of approximately 10% at 5-years, despite significantly older staging and surgical 1148

techniques. Investigators from University of Pennsylvania characterized the oncologic results of 1149

30 patients treated with TORS alone on a prospective trial.78 Positive margins were defined as 1150

tumor within 2 mm of the margin, and the surgeons paid exquisite detail to the margin 1151

evaluation. All patients in this cohort had final negative margins, although one patient required 1152

an additional resection for carcinoma in situ at the inked margin. Three patients had ECE, and 15 1153

patients were node-positive (10 N1, 5 N2a or N2b). With a minimum follow-up of 18 months, 1154

one patient (3% of total) with initial T2N0 stage developed a local recurrence, successfully 1155


salvaged with chemoradiotherapy. Three patients (10% of total) experienced a regional 1156

recurrence, two of whom had N2b nodal stage at original presentation and refused the 1157

recommendation to receive adjuvant radiotherapy. One patient with T2N0 cancer recurred in the 1158

ipsilateral high-neck. All patients were alive without evidence of disease at the time of the 1159

publication. 1160

Psychogios et al.90 published a retrospective series of 228 patients with T2 N0-3 1161

oropharyngeal cancer treated with primary surgery with or without adjuvant radiation treatment. 1162

Out of the 69 patients with negative margins and no pathologically involved lymph nodes, there 1163

was no difference in disease-specific survival between the 20 observed patients versus the 49 1164

treated with radiation therapy (81.5% vs. 80.0%, p=0.361). 1165

A joint publication from Mayo-Jacksonville and Mayo-Arizona retrospectively analyzed 1166

outcomes following transoral laser microsurgery alone in 69 patients, all of whom had negative 1167

margins. 91 Twenty-five of these patients had an indication for RT (i.e. ECE, N2 status, LVI) but 1168

declined, and 44 individuals did not have an indication for RT. After a mean follow-up of 44 1169

months, only 3 patients recurred at the primary site (two T1, one T2 cancer, for a 5-year local 1170

control estimate of 95%). Forty-four patients were recommended to undergo observation, and 4 1171

of these patients recurred in the neck, leading to 5-year LRC estimates of only 90%, 73%, and 1172

70% for stage I, II and III, respectively. However, two of those 4 patients did not have a neck 1173

dissection and were observed. The 5-year disease-specific and OS probability for stage I and II 1174

disease was 88% and 79%, respectively. Of the 25 patients with an indication for adjuvant 1175

radiotherapy, 4 developed a regional failure, with a 5-year estimate of LRC of 74%. 1176


One of the challenges in interpreting pathologic data following transoral excision of 1177

oropharyngeal cancer is the lack of meaningful data on the appropriate surgical margin, which is 1178

not standardized. The most comprehensive study of margin status in head and neck cancer was 1179

based on 827 oral cavity cancer patients (343 stage I-II) and suggested that local control rates 1180

were significantly improved with a margin width of 7 mm or more, although even wider margin 1181

distances also seemed to predict for local failure.87 Of course, none of these patients had 1182

oropharyngeal cancer, and it is unclear whether these results can be translated to a separate 1183

disease site with different anatomy and even biology. For example, Wong and colleagues found 1184

no difference in local recurrence between close (1-5 mm) and negative (> 5 mm) margins treated 1185

with surgery alone, although only 32 of 192 patients had oropharyngeal cancer.92 There is a 1186

general consensus among head and neck surgeons that invasive cancer within 5 mm or less is an 1187

adverse prognostic feature requiring adjuvant therapy, 92 but whether this rule of thumb holds 1188

with modern surgical techniques in the oropharynx is unknown. Thus, while patients with 1189

pathological stage I-II disease with wide margins, a pathologically negative neck and no other 1190

adverse pathologic factors can typically be observed, patients whose surgical procedure or 1191

margin width are more concerning for local recurrence may be considered for adjuvant therapy. 1192

Careful discussion and collaboration between the members of the multidisciplinary team is 1193

necessary to optimize locoregional therapy, and patient preferences on the relative risks and 1194

benefits of radiotherapy versus observation must be understood. 1195

The active phase II study Eastern Cooperative Oncology Group (ECOG) 331193 will 1196

significantly improve our ability to estimate LRC rates following surgery alone for patients with 1197

p16-positive oropharynx cancer. Patients with T1-2, N0-N1 (without extracapsular extension) 1198


and clear (> 3 mm) margins, will be observed after transoral surgery, and the final results of this 1199

study will further refine these recommendations. 1200

1201


Key Question 3: When is it appropriate to use induction chemotherapy in the treatment of 1202

oropharyngeal squamous cell carcinoma (OPSCC)? 1203

1204 Statement 3A. Induction chemotherapy should not be routinely delivered to patients with 1205

OPSCC. 1206 o Recommendation strength: Strong 1207 o Quality of evidence: High 1208

1209

Narrative 1210

1211 The curative treatment for the majority of patients with locally advanced OPSCC requires 1212

a multidisciplinary effort, often involving various combinations of radiotherapy, chemotherapy, 1213

and surgery. Despite decades of clinical research (Table 6), however, the optimal integration of 1214

chemotherapy with radiotherapy in this setting has been controversial, and study interpretation 1215

has been complicated by changing local therapy paradigms and epidemiologic shifts. It has been 1216

recognized since the mid-1980s that patients demonstrated high response rates to neoadjuvant or 1217

IC, and the clinical utility of IC was established in landmark trials of advanced larynx (VA 1218

Larynx) and pyriform sinus (EORTC) cancers, which revealed that radical surgery was avoidable 1219

without any decrement in survival. However, whether IC improves outcomes in OPSCC requires 1220

a different calculus, since OSrather than organ preservation is the key issue and outcome of 1221

concern. 1222

One of the earliest studies of IC using modern regimens was an Italian multi-center 1223

randomized trial,94,95 which compared 4 cycles of cisplatin-fluorouracil (PF) followed by 1224

locoregional therapy with locoregional therapy alone. Operable patients were treated with 1225

resection and adjuvant RT, and inoperable patients received definitive RT alone (65-70 Gy). 1226

Slightly over half of all patients on both arms of the study had OPSCC. When the operable and 1227

inoperable patients were pooled, there was essentially no impact of IC on OS, or local control 1228

(LC), but a significant improvement in distant relapse-free survival (DRFS) was seen. A subset 1229


analysis of the inoperable group demonstrated significantly improved LC, DRFS and OS; in 1230

terms of toxicity, over a third of IC patients had at least one dose reduction, and grade 2 or 1231

greater toxicities were common, including hematologic, stomatitis, vomiting, renal and cardiac 1232

changes. 1233

The French cooperative group GETTEC96 performed the only available randomized 1234

study of IC strictly in patients with OPSCC, demonstrating a significant improvement in OS 1235

(median OS 5.1 vs. 3.3 years) with PF-based IC followed by local therapy (either surgery and 1236

PORT alone or definitive radiotherapy alone to 70 Gy) compared to an identical non-IC arm. 1237

These survival gains were seen despite the trial closing early due to concerns of the 1238

appropriateness of a chemotherapy-alone arm. The toxicity reported here focused exclusively on 1239

the induction component of the treatment and consisted of hematologic (26%), digestive (22%) 1240

and mucosal (13%) side effects. 1241

The updated meta-analysis of chemotherapy in head and neck cancer 31 provided 1242

additional information on the benefits of IC. This study found that in comparison to radiotherapy 1243

alone, concurrent chemoradiotherapy improved LRC (HR 0.74, p<0.0001), distant metastasis 1244

(HR 0.88, p=0.04), and overall survival (HR 0.81, 95% CI 0.78-0.86). In contrast, the analysis of 1245

31 trials that compared IC plus local therapy with local therapy alone found that IC did not 1246

improve overall survival(OS) or LRC, but it did significantly and meaningfully improve the risk 1247

of distant failure (HR 0.73, p=0.0001). However, IC did improve OS in the subset of trials using 1248

PF (HR 0.90, 95% CI 0.82-0.99), supporting the hypothesis that a reduction in distant metastases 1249

with modern chemotherapy regimens may translate into an OS benefit, despite the high 1250

competing risk of locoregional failure in this population. 1251


It is critical to note that radiotherapy alone – not concurrent chemoradiotherapy – was the 1252

standard non-surgical locoregional therapy in both of these randomized trials, as well as the non-1253

surgical arms included in the meta-analysis. Since concurrent chemoradiotherapy is now 1254

understood to improve LRC and OS, the inadequate local therapy arm in these trials of IC may 1255

entirely explain the survival gain with neoadjuvant chemotherapy. This limitation in trial design 1256

was only recently rectified in published randomized trials, as will be described below. 1257

The insight that PF-based therapies were associated with a survival benefit produced 1258

substantial interest in improving the efficacy of IC, eventually leading to 3-drug regimens, of 1259

which TPF (taxane, cisplatin, and 5-FU) was the most frequently tested. This triplet was 1260

shown to be highly active in early trials and set the stage for two landmark randomized trials 1261

comparing TPF with PF. The TAX 324 study examined what has become the North American 1262

model for IC, termed “sequential therapy,” involving IC followed by concurrent 1263

chemoradiotherapy.97 1264

Patients were eligible if they had squamous cell carcinoma of the oropharynx, oral 1265

cavity, larynx or hypopharynx; slightly more than 50% of the patients in each arm had OPSCC. 1266

Patients received 3 cycles of IC followed by daily radiation therapy (2 Gy per fraction to 70-74 1267

Gy total) with weekly carboplatin. The addition of docetaxel significantly improved OS (3-year 1268

OS 62% vs. 48%), which was apparently mediated through an improvement in locoregional 1269

failure (38% vs. 30%), rather than distant metastasis. Hematologic toxicity was substantial, as 1270

grade 3-4 neutropenia (83% vs. 56%) and grade 3-4 thrombocytopenia (11% vs. 4%) were also 1271

each significantly increased in the docetaxel arm. Importantly, more than 20% of patients in both 1272

arms never completed chemoradiotherapy per protocol. 1273


The TAX 323 study98 had different entry criteria, only allowing unresectable patients, 1274

and a slightly altered treatment schema consisting of 4 cycles of IC, followed by radiation 1275

therapy alone (standard or accelerated fractionation). Oropharyngeal cancer represented 1276

slightly less than 50% of the total. Similar results were obtained as in TAX 324, 97,99 though 1277

the magnitude of clinical benefit was smaller (median OS 18.8 vs. 14.5 months). 1278

Approximately 10% of patients in the TPF arm did not receive radiotherapy, and an additional 1279

5% did not complete the full course. In a follow up quality of life (QoL) study, van Herpen et 1280

al.100 demonstrated trends for improved QoL with TPF both during treatment and through 6 1281

months of follow-up, although the magnitude of improvement was not deemed “clinically 1282

meaningful.” 1283

After these data established that TPF was superior to the previously accepted standard 1284

regimen, PF, the next logical question was whether IC adds substantially to concurrent 1285

chemoradiotherapy, which had been the established standard-of-care for locally advanced 1286

disease. Two small phase II studies first investigated this hypothesis. Pacagnella and colleagues94 1287

compared TPF IC followed by concurrent chemoradiotherapy (70 Gy with 2 cycles of concurrent 1288

PF) to concurrent chemoradiotherapy alone in 101 patients. Just over 50% of the patients in this 1289

study had OPSCC. The primary endpoint (rate of radiologic complete response at 6-8 weeks 1290

post-radiation) was significantly increased for the IC arm (21% vs. 50%). One limitation of this 1291

study was the non-standard concurrent regimen in this trial, consisting of two cycles of 1292

chemotherapy spaced 5 weeks apart, with conventionally fractionated RT. Another randomized 1293

phase II study, from India,101 assigned 105 eligible oropharyngeal cancer patients to either 1294

concurrent chemoradiotherapy (weekly cisplatin with 66-70 Gy) or 2-3 cycles of TPF IC 1295


followed by the same chemoradiotherapy. There were no significant differences in clinical 1296

outcomes or toxicities between the two arms. 1297

Three recent phase III studies directly compared optimal induction and optimal 1298

concurrent treatment. The Dana-Farber Cancer Institute-based multi-institutional group 1299

(PARADIGM)102 looked at a comparison between TPF IC followed by chemoradiotherapy 1300

(weekly carboplatin or docetaxel with 70-72 Gy) versus a concurrent regimen consisting of 1301

concomitant boost radiation therapy and 2 cycles of concurrent bolus cisplatin. The University of 1302

Chicago-based DeCIDE study103 used a slightly different model: the chemoradiotherapy 1303

consisted of Taxotere, 5-FU and hydroxyurea with BID radiotherapy (1.5 Gy per fraction), every 1304

other week, versus two 21-day cycles of IC followed by the same CRT regimen. The primary 1305

end point for both trials was OS. Just over half of patients in these studies had OPSCC. Both 1306

studies closed prematurely without meeting their accrual targets, and both ultimately were 1307

underpowered, due in part to the underestimation of OS in the standard arm. Neither 1308

demonstrated significant improvements in clinical outcomes between the IC and traditional 1309

chemoradiotherapy arms, although patients treated with IC clearly experienced higher toxicity. 1310

In PARADIGM,102 more induction patients developed febrile neutropenia, and there were more 1311

serious adverse events (52 versus 22) with IC. Similarly, there were substantially more serious 1312

adverse events in the induction arm of DeCIDE 103 (47% vs. 28%), and 5 patients died due to 1313

treatment-related toxicity in the induction arm, versus none in the CRT cohort. 1314

The Spanish Head and Neck Cancer Cooperative Group104 performed a 3-armed phase 3 1315

study comparing the two induction combinations (TPF vs. PF) and concurrent 1316

chemoradiotherapy. Patients were treated with either 3 cycles of IC, followed by a concurrent 1317

regimen consisting of 70 Gy with 3 cycles of bolus cisplatin, or the same concurrent regimen 1318


alone. Inclusion criteria specified unresectable, locally advanced head and neck cancer, and 55% 1319

of the patients had OPSCC. No significant improvement in any clinical outcome was found 1320

between any of the 3 arms of the study when analyzed on an intention-to-treat basis. However, a 1321

remarkable fraction of patients treated with IC – approximately 30% – never received 1322

radiotherapy, and an additional number could not complete the planned chemoradiotherapy. 1323

Moreover, of those induction patients who proceeded to CRT, there was significantly more grade 1324

3-4 stomatitis and dysphagia in patients previously treated with IC. An unplanned “per protocol” 1325

subset analysis was able to demonstrate improved progression-free survival (HR 0.7) for the 1326

induction arms versus the concurrent arm, without an associated improvement in OS, potentially 1327

reflecting the selection bias for induction patients tolerant of and responsive to chemotherapy. 1328

These three randomized trials found no progression-free or OS benefit with IC, yet all 1329

three studies confirmed higher rates of serious adverse events. Thus, induction chemotherapy 1330

should not be routinely implemented in patients with stage IV OPSCC. 1331

1332

Considerations in the discussion of induction chemotherapy 1333

The panel considered the potential indications for IC at length, and as expected, there was 1334

robust discussion. Several key limitations of the available studies on the question of IC for 1335

OPSCC were noted. First, the vast majority of the referenced studies enrolled locally advanced 1336

head and neck cancer patients with diverse primary subsites, including the oral cavity and 1337

pharyngolaryngeal axis. Oropharyngeal cancer representation on most of these studies ranged 1338

from only 40-60%. Clearly, prognosis varies widely across the diseases encountered in the non-1339

OPSCC subsites, and the resulting mixed outcomes in the pooled analyses may obscure 1340

conclusions that could be drawn specifically from the data on OPSCC patients. 1341


Second, the epidemiology of OPSCC has shifted during the evolution of the IC literature, 1342

with the emergence of HPV-related disease, and none of the reported IC trials had the 1343

opportunity to factor these shifts into their statistical plans. Recent studies have shown better-1344

than-anticipated disease control rates, likely reflecting the increased predominance of HPV-1345

related OPSCC (representing over 80% of OPSCC patients on the DeCIDE study, for example). 1346

With such sizeable changes in expected-to-observed outcomes, the initial power calculations for 1347

both PARADIGM and DeCIDE 102,103 were incapable of accurately predicting the number of 1348

patients required to address the primary hypothesis, and the resulting statistical power suffered 1349

from the small number of events. 1350

Furthermore, there is significant uncertainty in the optimal patient population that would 1351

potentially benefit from IC. As seen in several individual trials and confirmed in the meta-1352

analysis, IC reduces the risk of distant metastasis. Thus patients with more modest risks of 1353

distant disease are unlikely to see OS gains with systemically-active chemotherapy; the toxicity 1354

of IC and the risk of compromising successful local therapy will outweigh the improved 1355

treatment of micrometastatic disease. Only 10% and 23% of patients in PARADIGM102 1356

presented with N3 or T4 disease, respectively, and thus one could argue that the baseline risk of 1357

metastatic disease was too low to expect to see a survival advantage with IC, irrespective of the 1358

prevalence of HPV-positive disease. 1359

Subset analyses of DeCIDE103 provide some insight into the potential benefit of IC in 1360

these advanced cases. Among the 96 patients with N2c or N3 nodal disease, there was a non-1361

significant trend (p=0.19) for improved survival with IC. Moreover, the cumulative incidence of 1362

distant metastasis in patients with LRC was significantly worse with CRT alone (absolute 1363

difference approximately 10%, p=0.043), supporting the hypothesis that improved systemic 1364


control may translate to an OS benefit in patients at sufficiently high risk for distant metastasis, 1365

such as in those with advanced nodal presentations. 1366

Indeed, although historically the risk of locoregional failure has been substantially greater 1367

than that of metastasis, certain populations of patients do appear to be at particularly high risk for 1368

distant spread. For example, in a retrospective analysis of over 300 patients treated at the 1369

University of Chicago105 (slightly under half with OPSCC), patients with N2c or N3 disease 1370

experienced a greater than 2-fold risk of distant failure in comparison to lower volume nodal 1371

stage; nearly 40% of these patients treated with CRT-alone developed distant metastases. More 1372

recent data restricted to oropharyngeal cancer suggest similar patterns of failure. Investigators 1373

from Princess Margaret Cancer Centre performed a retrospective analysis of patients with 1374

oropharyngeal cancer treated with RT alone or CRT and described subgroups of both HPV-1375

negative and HPV-positive disease that were at significantly higher risk for distant spread106. 1376

Individuals with HPV-negative, T3-4 or N3 cancer, experienced a distant metastasis risk of 28%, 1377

and those with HPV-positive, T4 or N3 cancer experienced a metastasis risk of 22%, which may 1378

be sufficiently high to see a survival gain with IC. On the other hand, the locoregional failure 1379

risks in the high-risk HPV-positive and negative cohorts were 18% and 38%, respectively, so 1380

that the competing risks of locoregional failure may mitigate any theoretical survival gain from 1381

micrometastasis eradication. Regardless of the therapeutic paradigm, though, it is important to 1382

recognize that there are sub-populations of even HPV-positive patients whose survival outcome 1383

need significant improvement. In fact, in a separate analysis, these investigators found that 1384

younger HPV-positive patients with T4 or N3 disease achieved a 5-year survival of only 57% 1385

with CRT, implying that substantial improvements in their treatment paradigm are critically 1386

needed.107 1387


Unfortunately, it is unlikely that the comparative benefit of IC in a higher-risk cohort will 1388

ever be answered or even revisited through future clinical trials. Induction chemotherapy is 1389

currently incorporated into clinical trials in order to select responsive HPV-positive patients for 1390

subsequent de-escalation,108 which is a research question to be answered in the coming years. 1391

One may conclude from the MACH meta-analysis109 that IC using modern agents appears to 1392

modestly improve survival over RT alone or surgery through its effect on distant metastasis, 1393

which supplies the proof of principle that treating micrometastatic disease may improve oOS. 1394

Nevertheless, the high-level data do not support this conclusion when the standard comparator is 1395

chemoradiotherapy. Three phase III randomized trials comparing IC and chemoradiation therapy 1396

(CRT) with CRT alone were all clearly negative; IC was associated with more toxicity without a 1397

proven survival benefit. While each study has recognized limitations, in light of this high-level 1398

evidence, the panel chose not to specify a high-risk cohort of patients for whom IC may be 1399

considered. 1400


Key Question 4: What are the appropriate dose, fractionation, and volume regimens with 1401

and without systemic therapy in the treatment of oropharyngeal squamous cell carcinoma 1402

(OPSCC)? 1403

1404

In the scenario of definitive non-surgical therapy? 1405

1406 Statement 4A. A dose of 70 Gy over 7 weeks should be delivered to gross primary and nodal 1407

disease in patients with stage III-IV oropharyngeal squamous cell carcinoma selected to receive 1408

standard, once-daily definitive radiotherapy. 1409



1412 Statement 4B. The biologically equivalent dose of approximately 50 Gy in 2 Gy fractions or 1413

slightly higher should be delivered electively to clinically- and radiographically-negative regions 1414

at-risk for microscopic spread of tumor. 1415



1418

Statement 4C. Altered fractionation should be used in patients with stage IVA-B oropharyngeal 1419

squamous cell carcinoma treated with definitive radiotherapy who are not receiving concurrent 1420

systemic therapy. 1421



1424

Statement 4D. Either accelerated radiotherapy or hyperfractionated radiotherapy may be used in 1425

patients with oropharyngeal squamous cell carcinoma treated with altered fractionation definitive 1426

radiotherapy after a careful discussion of patient preferences and the limited evidence supporting 1427

one regimen over the other. 1428



1431

Statement 4E. Either standard, once-daily radiotherapy or accelerated fractionation may be used 1432

when treating oropharyngeal squamous cell carcinoma with concurrent systemic therapy after a 1433

careful discussion of patient preferences and the risks and benefits of both approaches. 1434



1437

Statement 4F. Altered fractionation should be used in patients with T3 N0-1 oropharyngeal 1438

squamous cell carcinoma treated with definitive radiotherapy who do not receive concurrent 1439

systemic therapy. 1440




1443

Statement 4G: Altered fractionation may be used in patients with T1-2 N1 or T2 N0 1444

oropharyngeal squamous cell carcinoma treated with definitive radiotherapy alone who are 1445

considered at particularly significant risk of locoregional recurrence, after a careful discussion of 1446

patient preferences and the limited evidence supporting its use in this scenario. 1447



1450

Narrative 1451

1452 A relatively large body of literature has reported outcomes for OPSCC patients in the 1453

setting of randomized clinical trials. Important caveats in interpreting this literature, much of 1454

which directly tested dose and fractionation, must include the recognition that most of these 1455

studies included patients with advanced squamous carcinomas arising in sites other than the 1456

oropharynx, including oral cavity, larynx and hypopharynx. Although these studies described 1457

the relative proportions of these primary sites, their conclusions were often based on a pooled 1458

analysis. Human papillomavirus-associated OPSCC has been increasing in prevalence and 1459

proven to have a much more favorable prognosis than non-HPV related OPSCC.2 The proportion 1460

of OPSCC patients with HPV-related cancers in most landmark studies of fractionation remains 1461

unknown and is likely to be significantly lower than in contemporary patient populations, raising 1462

the question of the generalizability of older studies to modern cohorts. The panel recognizes 1463

there is important ongoing work examining the different outcomes between and within HPV 1464

positive and negative OPSCC in order to define prognostic subgroups. 89,107,110 This research has 1465

led to the development and implementation of prospective clinical trials examining treatment de-1466

intensification strategies for favorable prognostic subgroups.93 In the future, these studies may 1467

result in significant changes in the recommended radiotherapy doses for the management of 1468

favorable-risk disease. To date, the results of radiotherapy de-intensification approaches are not 1469


yet available and there are no prospective randomized data suggesting that HPV-positive patients 1470

gain any less benefit from altered fractionation regimens. Thus any recommendation made for 1471

oropharyngeal cancer patients within these guidelines apply equally to HPV-positive and 1472

negative individuals. 1473

Primary radiation therapy has long been a standard-of-care for the management of 1474

OPSCC, and acceptable doses to gross disease and elective regions is the first consideration in 1475

the discussion of dose and fractionation regimens. There have been no randomized trials 1476

comparing total radiotherapy dose delivered once-daily for OPSCC, and a variety of dose-1477

fractionation regimens have evolved over the years. In the United Kingdom, the treatment 1478

approach classically delivered 50-55 Gy in 15-20 fractions over 3-4 weeks, while in Europe and 1479

most of North America, more extended fractionation schemes were employed, delivering 66-72 1480

Gy in 32-40 fractions over 6.5 to 8 weeks.111 Though retrospective in nature, comparisons 1481

between these regimens suggested that shorter courses delivering less total dose with larger 1482

fraction sizes resulted in lower rates of control for advanced disease with increased late 1483

effects.111 This observation, combined with the enhanced toxicity in combining concurrent 1484

chemotherapy with fraction sizes greater than 2 Gy, resulted in the emergence of a total dose of 1485

68-70 Gy delivered in 33-35 fractions over 6.5 to 7 weeks as the most common once-daily 1486

fractionation regimen. 1487

The delivery of 70 Gy to gross disease has been selected as the standard treatment 1488

approach for many practice-defining randomized trials of both fractionation and concurrent 1489

chemotherapy, including RTOG 9003, 112 EORTC 22851,113 the US Intergroup study,9 and 1490

RTOG 0129.37 Thus, when choosing a conventionally fractionated, once-daily radiotherapy 1491


regimen for patients with stage III-IV OPSCC, the panel considers 70 Gy over 7 weeks to be the 1492

reference standard. 1493

1494

Standard Prophylactic Dose to Elective Volumes at Risk of Microscopic Disease 1495

The radiotherapeutic management of all stages of OPSCC requires treatment to be 1496

delivered electively beyond areas of apparent gross disease. Elective volumes include margins 1497

around gross disease as well as nodal levels at risk of harboring microscopic nodal metastasis. 1498

The location and extent of these elective volumes will be dictated by specific characteristics of 1499

the primary tumor (size and anatomic extent) and grossly involved nodes. The anatomic 1500

delineation of node levels at risk should be consistent with published guidelines.114 The dose and 1501

volume of elective irradiation is often the driver of dose to critical organs-at-risk, including 1502

salivary glands and dysphagia-associated structures such as the larynx and pharyngeal 1503

constrictors, emphasizing the importance of considering the dose necessary to sterilize 1504

microscopic disease. 1505

Although the evidence is nearly entirely retrospective, prophylactic radiotherapy at 2 Gy 1506

per day to a total dose of 50 Gy has been widely regarded as the standard dose for the elective 1507

treatment of areas at risk for subclinical or microscopic involvement. This dose was first 1508

suggested by Fletcher based on observations of control rates in head and neck and breast cancer 1509

patients.115 Withers et al.111 expanded these observations to a wider range of patients, concluding 1510

a dose of 50 Gy in 2 Gy fractions was necessary to achieve a 90% reduction in the incidence of 1511

recurrence within the electively irradiated tissues. Although this dose has been utilized in many 1512

clinical trials, many do not specifically report rates of nodal failure, or distinguish between in-1513

field versus elective failure. Nevertheless, some insights may be gleaned from these trials. 1514


For example, the DAHANCA 6/7 trials116 limited dose to a maximum 50 Gy in 2 Gy 1515

fractions to elective neck regions and observed isolated neck failure (elective and therapeutic 1516

regions) in only 69/1476 (4.7%) patients. Goshal et al.117 delivered 44-45 Gy to the elective neck 1517

regions and reported isolated regional failures in 37/285 (12.9%) patients. The ARTSCAN 1518

randomized trial7 comparing conventionally-fractionated radiotherapy with treatment over 4.5 1519

weeks118 treated the elective nodal regions to 46 Gy and reported isolated nodal failure in 34/733 1520

(4.6%) patients. These three randomized studies have cumulatively reported isolated nodal 1521

failures in 140/2494 (5.6%) of patients receiving the equivalent of 50 Gy in 2 Gy fractions or less 1522

to elective nodal regions. These recurrences would have included failures occurring in pre-1523

existing nodes, and therefore the failure rates in the elective volumes could be assumed to be less 1524

than this. 1525

Retrospective analyses that have specifically identified electively irradiated neck failures 1526

include Lambrecht et al.119, observing only 2 recurrences out of 368 (<1%) in elective neck 1527

regions receiving 44-50 Gy. More recently, investigators from MD Anderson reported a risk of 1528

elective regional failure with primary control of only 4/776 (< 1%), and many of these controlled 1529

patients were treated with a low anterior neck field to 50 Gy.120 With the emergence of routine 1530

IMRT planning and simultaneous integrated boost/“dose-painting” approaches, radiotherapy 1531

plans are now often delivered in a single phase, rather than the conventional, serial cone-down 1532

approach using 2 Gy per fraction. Thus, a plan delivering 70 Gy in 35 fractions to sites of gross 1533

disease must simultaneously deliver 56 Gy in 35 fractions of 1.6 Gy to areas of subclinical or 1534

microscopic involvement to achieve the radiobiologic equivalent of 50 Gy in 25 fractions. Using 1535

this approach, Duprez et al.121 have a reported regional relapse risk in 3/286 (1%) patients within 1536

the elective neck volumes receiving 56 Gy. 1537


The panel therefore believes there is sufficient evidence to strongly recommend the 1538

ongoing use of a radiobiologic equivalent of 50 Gy delivered in 2 Gy fractions to electively treat 1539

areas at risk of subclinical or microscopic involvement. The high rates of neck control observed 1540

with this approach raise the possibility of elective dose reduction, which would be expected to 1541

reduce dose to the salivary tissue and pharyngeal constrictors. In fact, if one considers that 1542

concurrent chemotherapy increases the biologically effective dose of any given dose of 1543

irradiation,122 treatment with concurrent chemoradiotherapy may afford the opportunity for dose 1544

reduction. At this time, however, there is insufficient data to recommend elective doses reduction 1545

below the equivalent of 50 Gy in 2 Gy fractions, although this is an area of active research.123 1546

1547

Altered fractionation radiotherapy without concurrent chemotherapy 1548

Poor historical outcomes for patients with stage III-IV OPSCC treated with 1549

conventionally-fractionated radiotherapy alone10 led to efforts to improve oncologic results by 1550

intensifying treatment. This intensification utilized two distinct approaches. One approach was 1551

the addition of cytotoxic systemic therapy delivered concurrently with radiotherapy, and the 1552

other was to alter the radiotherapy fractionation schemes from standard, once-daily 1553

administration. 1554

The concept of altered fractionation (AF) refers to fractionation regimens that differ from 1555

standard, once-daily treatment. Altered fractionation-regimens are based on radiobiologic 1556

principles that suggest giving a higher total dose and/or giving it over a shorter total treatment 1557

time (to counter tumor repopulation) will result in improved tumor control. Similar principles 1558

suggest delivering this dose with reduced fraction sizes (< 2 Gy) should result in reduced late 1559

tissue effects permitting delivery of a higher total dose. Altered fractionation regimens may be 1560


classified as either accelerated, delivering a similar or reduced total dose over a shorter total 1561

time, or hyperfractionated, delivering an increased total dose over a similar time with multiple 1562

small daily fractions. Many AF regimes represent a hybrid of these approaches. 1563

Altered fractionation regimens for the treatment of head and neck squamous carcinomas, 1564

including OPSCC, have been compared to standard radiotherapy in a number of randomized 1565

phase III clinical studies (Table 7). The majority of these studies have demonstrated that AF 1566

regimens improve LRC by 8-20% compared to once-daily radiotherapy alone, but the increased 1567

control in the primary site and neck generally did not translate into an OS advantage. In addition, 1568

this disease control improvement frequently came at the cost of increased but manageable acute 1569

toxicity, with a variable impact on the risk for late toxicities. 1570

Accelerated regimens with or without a total dose reduction have been the AF approach 1571

most often compared with standard radiotherapy. In the landmark RTOG 9003 trial124 reported 1572

results on 1073 patient randomized to one of three AF arms compared to standard radiotherapy 1573

(70 Gy in 2 Gy fractions over 7 weeks). Two of these arms represented accelerated treatment 1574

delivered over 6 weeks. One arm delivered twice-daily (BID) treatment throughout but had a 1575

two-week break, to achieve a total dose of 67.2 Gy, while the other arm employed a scheme 1576

without a break, delivering once daily 1.8 Gy for six weeks with a second 1.5 Gy fraction as a 1577

concomitant boost to the primary on the last 12 treatment days for a total dose of 72 Gy. The 1578

concomitant boost arm demonstrated an absolute improvement of 9.5% and 7.6% in two year 1579

LRC and disease free survival (DFS) (p=0.05 and 0.054 respectively) which came at a cost of an 1580

absolute increase of 24% in grade 3 or higher acute toxicity (multiple endpoints). The split 1581

course arm demonstrated no significant improvement in LRC or DFS and neither arm improved 1582

OS. The recent final analysis of RTOG 9003112 demonstrated that the initially improved LRC 1583


with accelerated radiotherapy lost its statistical significance with longer follow-up, and overall 1584

survival (OS) was still unaffected by this regimen. Although the continuous acceleration arm did 1585

improve disease-free survival (HR 0.82, p=0.05), there were non-significant trends for worse late 1586

toxicity in this arm. Notably, patients who were disease-free at 1-year were significantly more 1587

likely to be feeding tube dependent with continuous accelerated radiotherapy (1-year probability 1588

13.4% vs. 4.6%, p=0.02). 1589

The DAHANCA group125 randomized 1485 patients with squamous cell carcinoma of the 1590

head and neck (larynx, pharynx and oral cavity) to receive standard radiotherapy (66-68 Gy in 1591

2Gy fractions) delivered 5 days per week versus the same dose delivered in an accelerated 1592

fashion with 6 fractions per week. They observed a statistically significant 10% benefit in 5 year 1593

LRC (70% vs 60%) and a 13% benefit in DFS (73% vs 66%) for the accelerated regimen. No 1594

benefit in OS was observed. Patients treated with the accelerated regimen experienced a 20% 1595

higher risk of acute confluent mucositis, and the duration of this acute mucositis was longer, but 1596

there was no significant difference in longer-term mucosal toxicities. A similar LRC benefit 1597

(absolute 12%) was observed with this regimen when the study was later replicated in 908 1598

patients with more advanced disease, 126 with a parallel increase in acute but not late mucosal 1599

toxicity. In an interesting subgroup analysis of the original DAHANCA study,127 the LRC 1600

benefit of radiotherapy acceleration was maintained in p16 positive (mostly oropharynx) patients 1601

and was perhaps even greater than that observed in p16 negative (mostly non-oropharynx) 1602

patients.127 1603

The EORTC 22851 trial113 randomized 500 patients to receive 72 Gy delivered in twice-1604

daily fractionation over 5 weeks versus standard fractionation (70 Gy in 2 Gy fractions over 7 1605

weeks). Although this study demonstrated a 13% improvement in LRC at 5 years the actuarial 1606


rates of grade 3-4 late toxicity in the accelerated arm was 37% at 3 years versus 15% for the 1607

control arm. This finding, coupled with increased rates of acute toxicity and the lack of an 1608

overall or cancer-specific survival benefit, led the authors to conclude that a less toxic scheme 1609

should be used and emphasizes that there is a limit to the degree of safe acceleration. 1610

It should be noted not all studies have demonstrated significant benefits to accelerated 1611

radiotherapy. The TROG group128 reported outcomes for 343 patients (67% OPSCC) randomized 1612

to accelerated radiotherapy (59.4 Gy in 1.8 Gy bid over 24 days) versus standard 70 Gy in 2 Gy 1613

fractions over 7 weeks). In this modest sized study they observed a nonsignificant trend towards 1614

improved disease free and disease specific survival at 5 years (41% and 46% vs 35% and 40% 1615

respectively, p=0.323 and 0.398) for the accelerated arm. The multicenter Swedish ARTSCAN 1616

study7 randomized 750 patients (48% OPSCC) to standard radiotherapy (68 Gy in 2 Gy fractions 1617

over 7 weeks) versus accelerated radiotherapy (1.1 Gy + 2 Gy/day over 4.5 weeks to 68 Gy). No 1618

significant difference was observed in OS or loco-regional control between the two arms. 1619

The use of pure hyperfractionation has been demonstrated to improve outcomes. The 1620

EORTC 22791 study 129 reported the results of 325 patients with T2-T3, N0-N1 OPSCC 1621

randomized to receive 70 Gy in 35 daily fractions over 7 weeks or hyperfractionated treatment 1622

delivering 1.15 Gy BID to a total dose of 80.5 Gy over 7 weeks. A significant improvement was 1623

seen in 5 year rates of local control at the primary site (59% vs 40% p=0.02) in the 1624

hyperfractionation arm, although improvement in OS was only borderline significant (p=0.08). 1625

There was a significant increase in acute mucositis with hyperfractionation (18% absolute 1626

increase in grade 3 mucositis), but there was no difference in any late effect between the two 1627

arms. 1628


One arm of RTOG 9003112 utilized a hyperfractionated approach, delivering 68 BID 1629

fractions of 1.2 Gy to a total dose of 81.6 Gy. The final analysis observed not only an improved 1630

and sustained rate of LRC (relative reduction in locoregional failure of 21%) but also an OS 1631

advantage when patients were censored at 5 years (HR 0.81, p=0.05). This benefit was lost with 1632

longer follow-up, which may relate to second primary cancers or death from other causes 1633

obscuring a disease control benefit from hyperfractionation. Treatment with hyperfractionation 1634

was associated with significantly more acute toxicity: 54% of patients in this cohort experienced 1635

at least one grade 3 toxicity, versus 35% of patients treated once-daily. However, there was no 1636

significant increase in late toxicities with hyperfractionation, although disease-free patients were 1637

more likely to be gastrostomy-dependent in comparison to disease-free individuals treated with 1638

standard fractionation (17.3% vs. 4.6%, p<0.01). 1639

These results were largely echoed by a large meta-analysis (MARCH) based on 1640

individual patient data, which examined outcomes for 6,515 patients enrolled in 15 randomized 1641

trials comparing standard to AF radiation therapy (accelerated or hyperfractionated) for 1642

advanced head and neck cancers.130,131 Oropharyngeal cancer comprised approximately 44% of 1643

all patients. This meta-analysis reported absolute reductions in the 5-year risk of locoregional 1644

recurrence of 9.4% and 7.3% in patients treated with hyperfractionation or accelerated 1645

fractionation (without dose-reduction) regimens, respectively. Most of this benefit was due to 1646

reduced recurrence at the primary site. The absolute probability of OS at 5 years was 1647

significantly improved by 3.4% with altered fractionation. There was no significant difference in 1648

this benefit for tumors arising in the oropharynx compared to hypopharynx larynx or oral cavity, 1649

but the survival advantage with AF was lost in patients older than 71 years. The survival benefit 1650

was significantly greater with hyperfractionation (8.2% vs. 2% at 5 years for patients receiving 1651


hyperfractionation and accelerated radiotherapy without a dose-reduction, respectively). 1652

Although one may conclude that hyperfractionation may be the superior approach, the trials of 1653

acceleration and hyperfractionation evaluated fundamentally different patient populations; 1654

accelerated radiotherapy was more often employed in larynx cancer and patients with earlier-1655

stage disease, such that improved LRC was less likely to translate into an OS benefit. 1656

Although individual trials were unable to confirm an OS advantage with altered 1657

fractionation, the majority of studies have demonstrated consistent and meaningful 1658

improvements in LRC and trends towards reductions in overall mortality. The influential 1659

MARCH meta-analysis provided further evidence for the superiority of AF in patients with 1660

locally advanced head and neck cancer. Given the adverse clinical consequences of locoregional 1661

failure and the potential for a survival gain with its use the panel strongly recommends AF 1662

radiation therapy should be used for patients with stage IVA-B OPSCC managed with primary 1663

radiation therapy without concurrent systemic therapy. In comparison to treatment with 1664

concurrent chemotherapy, in which late toxicities were comparable to patients treated with 1665

radiotherapy alone, there were somewhat consistent signals that AF modestly worsened late 1666

toxicities. One particularly important late toxicity is swallowing dysfunction, which in the worst 1667

case can lead to the long-term requirement for enteral feeding. However, modern radiotherapy 1668

techniques may minimize these risks, as a large multi-institution pooled analysis of 2,315 1669

OPSCC patients managed with IMRT concluded that there was no difference in one year rates of 1670

gastrostomy tube dependence between patients managed with standard versus accelerated 1671

radiotherapy.132 Nevertheless, in patients treated with altered fractionation, particular attention 1672

must be paid to the dysphagia organs-at-risk and early and persistent swallowing rehabilitation. 1673


It is unclear whether hyperfractionation or acceleration is a better treatment paradigm. 1674

The only study comparing the two concepts was RTOG 9003, 112 which slightly favored 1675

hyperfractionation, but this study was not designed to compare the experimental arms; the 1676

MARCH meta-analysis also suggested an improvement with hyperfractionation, but as detailed 1677

above, there are significant flaws with this indirect comparison. Nevertheless, hyperfractionation 1678

regimens delivered without concurrent chemotherapy are not in wide-spread use for the 1679

management of OPSCC. This pattern is in part due to the increased resources required to deliver 1680

these treatments, coupled with the emergence of concurrent chemotherapy approaches that 1681

mitigated the benefit of altered fractionation. Accelerated radiotherapy, particularly using the 1682

DAHANCA approach, 125 is significantly more convenient than BID treatments over 7 weeks, 1683

and provides a more practical platform for both clinical trials and routine practice. That said, at 1684

the present time, the panel concludes the available evidence supports the use of either form of 1685

AF for the management of stage IVA-B OPSCC in patients not receiving systemic therapy, and 1686

the relative strengths and weaknesses of the strategies should be carefully discussed with 1687

patients. 1688

1689

Altered fractionation radiotherapy for patients with stage III oropharyngeal cancer 1690

Deriving recommendations for patients with stage III OPSCC is more challenging; stage 1691

III disease may present with a wide range of primary tumor volumes (T1-T3, N1). The majority 1692

of patients in randomized studies of AF presented with stage IV disease, and thus the advantages 1693

of this approach are less clear with lower-bulk disease. Although most of the studies included 1694

patients with stage III disease, the proportion of patients with this stage was typically less than 1695

30%, and the outcomes were rarely stratified by T and N or AJCC stage. One exception is 1696


EORTC 22791, 129 which randomized patients with T1-3 N0-1 oropharyngeal cancer to 1697

hyperfractionation or conventional daily radiotherapy. Although the study showed an overall 1698

benefit in LRC, this gain was strictly in patients with T3 tumors. Similarly, in EORTC 22851, 113 1699

which randomized stage III and IV patients (all disease sites) to accelerated or conventional 1700

radiotherapy, the LRC advantage with acceleration was only seen in N2-3 or T4 patients. Both 1701

studies emphasize the concept that relative benefit of AF is greatest with larger volume disease. 1702

As detailed in the narrative of KQ1, single institution retrospective reports have also 1703

described significant differences in local control as a function of T-stage or tumor volume. The 1704

preponderance of data strongly suggest that patients with larger volume disease need additional 1705

local therapy beyond conventional radiotherapy alone. Since concurrent systemic therapy is most 1706

consistently associated with superior LRC and OS, patients with T3 N0-1 disease who are 1707

candidates for concomitant systemic therapy should receive it, as detailed in KQ1. For 1708

individuals who would not tolerate such treatment, the panel strongly recommends AF alone. 1709

The data guiding radiotherapy fractionation recommendations for stage II and III (T1-2 1710

N1) are far less compelling, and there is significant volume heterogeneity even in this cohort. For 1711

individuals with T2 N0 and T1-2 N1 stage III disease considered at particularly significant risk 1712

for primary and/or nodal recurrence, AF may be employed, but the clinician must weigh the 1713

patient’s estimated risk of locoregional failure with conventional treatment against the 1714

recognized toxicities of altered fractionation. The relative lack of data guiding this 1715

recommendation should be carefully discussed with patients. 1716

The use of modestly accelerated radiotherapy alone was shown to result in excellent 1717

outcomes in RTOG 0022, 133 which treated 67 patients with T1-2 N0-1 OPSCC with 66 Gy in 30 1718

fractions. Most (75%) of these patients had T2 disease. There were 7 locoregional failures, all in 1719


current or former smokers (7/36, accounting for crude 19% risk of failure in this cohort), 1720

although 2 of these recurrences were in patients with major dosimetric violations. Only six 1721

patients had new or continuing grade 3 or 4 toxicity after 15 months. In total, these prospective 1722

data suggest that this accelerated regimen is a reasonable approach for selected patients. 1723

1724

Altered fractionation radiotherapy with concurrent chemotherapy 1725

The therapeutic alternative to AF for locally advanced head and neck cancer is concurrent 1726

chemoradiotherapy, the benefits of which were discussed in a prior narrative (KQ1). A large 1727

meta-analysis has reported improved survival and LRC with the addition of concurrent 1728

chemotherapy to radiotherapy,31 a benefit maintained using either standard or altered 1729

fractionation. The emergence of data demonstrating improved outcomes with either AF approach 1730

or the addition of chemotherapy to standard, once-daily radiotherapy naturally led to studies 1731

examining the addition of chemotherapy to AF radiation therapy. Initially the addition of 1732

chemotherapy to AF radiotherapy was compared to AF radiotherapy alone. Several randomized 1733

studies have demonstrated improved LRC and survival with such a strategy.17,134-136 For 1734

example, Brizel et al.134 achieved this with similar levels of toxicity, but this required a reduced 1735

radiotherapy dose and treatment break. Bensadoun et al. maintained the same dose of 1736

radiotherapy in both arms (75.6-80.4 Gy) while delivering full dose cisplatin (100 mg/m2) and 5-1737

fuorouracil infusion. Although the reported toxicity data was similar between the two arms they 1738

described a 13.6% risk of “early death” in the combined treatment arm, emphasizing the 1739

potential risk in this treatment strategy. 1740

The next logical question was whether accelerated chemoradiotherapy was superior to 1741

conventionally-fractionated chemoradiotherapy, a hypothesis that was examined in two large 1742


phase III studies. RTOG 012932 randomized 743 patients to standard fractionation (70 Gy in 35 1743

fractions over 7 weeks) delivered with 3 cycles of concurrent cisplatin or accelerated 1744

fractionation (70 Gy in 35 fractions over 6 weeks) delivered with 2 cycles of concurrent 1745

cisplatin.37 The mature results of this study (median follow-up 7.9 years) indicated no difference 1746

in progression free survival or OS with similar acute and late toxicities. Groupe d'Oncologie 1747

Radiothérapie Tête et Cou (GORTEC) 99-0223 was a three arm study randomizing 840 patients 1748

to either standard chemoradiotherapy (70 Gy in 7 weeks plus 3 cycles carboplatin-fluorouracil) 1749

versus accelerated chemoradiotherapy (70 Gy in 6 weeks plus 2 cycles carboplatin-fluorouracil) 1750

versus very accelerated radiotherapy alone (64.8 Gy in 1.8 Gy bid over 3.5 weeks).23 No 1751

difference was observed between the chemoradiotherapy and accelerated chemoradiotherapy 1752

arms in 3 year rates of locoregional failure, distant metastasis, progression-free survival, OS or 1753

acute or late toxicity, with both chemotherapy arms superior to the very accelerated radiotherapy 1754

approach in all aspects. 1755

The addition of chemotherapy to aggressive AF approaches must be considered with 1756

caution given the potential for increased acute and late effects associated with this approach. For 1757

this reason, both RTOG 012932 and GORTEC 99-02137 delivered less chemotherapy in the AF 1758

arm than the standard fractionation arm. This strategy seems to have been successful in 1759

maintaining equivalent toxicities between the arms without compromising tumor control. In 1760

RTOG 0129, there were no statistically significant differences in acute or late toxicities, although 1761

there was a trend for increased long-term gastrostomy dependence in the accelerated arm (13.2% 1762

vs. 5.9% at 5 years, p=0.08). On the other hand, more patients received the correct numbers of 1763

cisplatin cycles in the accelerated arm (88% vs. 69%), owing to the challenge of managing the 1764

toxicities with bolus cisplatin. Similarly, in GORTEC 9902, 137 92% of patients in the 1765


accelerated chemoradiotherapy arm received the correct number of cycles, in comparison to only 1766

71% of individuals in the conventional arm. 1767

Since two large phase III trials have shown no significant difference in oncologic 1768

outcomes or toxicities between conventional and accelerated fractionation (AccF) with three and 1769

two cycles of bolus cisplatin or carboplatin/fluorouracil, respectively, the panel concludes either 1770

fractionation approach may be considered for patients with stage IVA-B oropharyngeal cancer 1771

treated with these chemotherapy regimens. The relative risks and benefits of more chemotherapy 1772

versus more intensive radiation treatment should be carefully discussed with the patient, and the 1773

decision should be made on a patient-specific basis, in concert with their preferences and values. 1774

1775

In the scenario of adjuvant post-operative radiotherapy? 1776

1777 Statement 4H. Adjuvant post-operative radiotherapy should be delivered to regions of 1778

microscopically-positive primary site surgical margins and extracapsular nodal extension at 2 1779 Gy/fraction once daily to a total dose between 60 and 66 Gy. 1780

o Recommendation strength: Strong 1781 o Quality of evidence: Moderate 1782

1783 Statement 4I. Adjuvant post-operative radiotherapy delivered without concurrent systemic 1784

therapy should treat regions of microscopically-positive primary site surgical margins and 1785 extracapsular nodal extension at 2 Gy/fraction once daily to a total dose of 66 Gy, although there 1786 are limited data guiding this recommendation. 1787

o Recommendation strength: Conditional 1788 o Quality of evidence: Weak 1789

1790 Statement 4J. Adjuvant post-operative radiotherapy should be delivered to the tumor bed and 1791

involved, dissected lymph node regions at 2 Gy/fraction once daily to a total dose of 60 Gy in the 1792 absence of primary site positive margins and extracapsular nodal extension. 1793


1796

1797

Narrative 1798

1799 A dearth of prospective randomized data exist addressing dose-fractionation issues in the 1800

post-operative, high-risk setting. Peters et al.138 randomized patients receiving PORT alone (18% 1801


oropharynx) to one of four dose levels depending on the type and number of adverse pathologic 1802

risk factors. Patients deemed lower-risk were first randomized to 52.2-54 Gy versus 63 Gy, but 1803

an interim analysis showed this lower dose was inadequate, and the study was completed 1804

comparing 57.6 Gy in 32 fractions with 63 Gy in 35 fractions in this lower-risk population. The 1805

higher-risk patients were randomized to 63 Gy in 35 fractions versus 68.4 Gy in 38 fractions. 1806

Because the risk stratification was a function of both the type and number of adverse 1807

characteristics, patients with ECE and positive margins (less than 5 mm) were included in all 1808

dose levels. The authors found no difference in 2 year recurrence rates for all higher-risk 1809

patients. However, in a post hoc subset analysis, patients with ECE experienced superior 2-year 1810

LRC with 63 Gy and 68.4 Gy versus 57.6 Gy, but no difference between the higher dose levels 1811

(74% and 72% versus 52%, respectively, p=0.03). Consistent with this finding, in a retrospective 1812

analysis of 102 oral cavity/oropharynx patients treated with differing doses of PORT, Zelefsky et 1813

al.139 showed that non-oral tongue patients with positive or close margins receiving a minimum 1814

of 60 Gy had significantly improved LRC versus lower doses (92% vs. 44% at 7 years, 1815

p=0.0007). 1816

Ang et al.4 performed a randomized assessment of AccF vs conventional fractionation 1817

(CF) in high-risk post-operative patients (63 Gy/5 weeks vs 63 Gy/7weeks). There were trends 1818

towards improved LRC (p=0.11) and OS (p=0.08) with acceleration, the latter result partially 1819

owing to a 33 % incidence of distant failure. Accelerated fractionation increased grade 3 mucosal 1820

toxicity (62% vs 36%). Sanguineti et al.140 also compared AccF vs CF (64 Gy/5 weeks vs 60 1821

Gy/6 weeks). There were no differences with respect to local-regional control, distant failure, nor 1822

overall survival. Grade 3 mucosal toxicity was significantly increased, however (53% vs 27%). 1823

Suwinski et al.141 also compared post-operative AccF against CF. Approximately 40% of the 1824


patients had oral cavity/oropharynx primaries, and AccF resulted in significantly better local-1825

regional control (74% vs 53%) in this subset. There was no difference in OS with accelerated 1826

treatment. Again the cost was a significantly higher incidence of grade 3 mucosal toxicity with 1827

AF (60% vs 33%). 1828

Caution should be exercised in attempting to apply these data to the clinical setting. The 1829

vast majority of patients with high-risk pathologic features now receive concurrent 1830

chemoradiotherapy rather than RT alone. Additionally, a minority of the patients treated on the 1831

aforementioned trials had OPC primary tumors (17-40%). These trials enrolled most of their 1832

subjects during the 1980s and 1990s, and OPC itself has evolved since then from a smoking 1833

related disease to one that is predominantly caused by HPV infection. Most investigational 1834

efforts for the latter are focused on therapeutic de-escalation given its more favorable prognosis. 1835

Changes in RT delivery techniques must also be kept in mind when interpreting these 1836

data. Most of the patients were treated with Co-60 or 4 MV photons using 2-D parallel opposed 1837

fields prescribed at mid-plane. It is likely that the prescribed daily dose of 1.8 Gy was 10-15% 1838

higher (2.0-2.1 Gy) in the neck as a consequence of dose inhomogeneity. In this respect, past is 1839

prologue for patients treated with contemporary IMRT dose painting techniques that commonly 1840

deliver daily doses of 2.2 Gy to high risk regions. Lukens et al. have shown a significantly 1841

increased risk of soft tissue necrosis when daily fractions of this size are used for PORT in 1842

OPSCC.142 1843

In summary, the small volume of randomized data suggests improved LRC with 1844

treatment doses beyond 57.6 Gy for patients with positive margins and/or ECE. The three 1845

randomized trials of accelerated radiotherapy provided mixed results on LRC, but they were 1846

consistent in showing no OS benefit and markedly increased mucosal toxicity with intensified 1847


treatment. Therefore the panel strongly recommends that patients receiving adjuvant PORT for 1848

positive margins and/or ECE are treated using daily fraction sizes of 2 Gy to a total dose between 1849

60 and 66 Gy. This dose (60 Gy) is comparable to the 63 Gy in 7 weeks from Peters et al. while 1850

reducing the total package time (i.e. time from surgery to the end of radiotherapy). 1851

There are insufficient data to properly answer whether dose-escalation beyond 60 Gy 1852

provides additional clinical benefit in patients with high-risk pathology. As detailed above, the 1853

Peters trial138 showed no further benefit to 68.4 Gy in this population. That said, the landmark 1854

RTOG 950145,46 and EORTC 2293144 trials used post-operative doses of 60-66 Gy (RTOG) and 1855

66 Gy (EORTC) to regions of highest risk. Without concurrent cisplatin, patients in the RTOG 1856

trial with positive margins and/or ECE had a 10-year locoregional recurrence risk of 33%, and 1857

individuals in the EORTC study treated with radiotherapy alone had a 5-year locoregional 1858

recurrence risk of 31%. Given these poor LRC outcomes with radiotherapy alone, the expert 1859

panel is more concerned with the complications of locoregional failure than mucositis. The panel 1860

conditionally recommends that patients with positive margins and/or ECE receiving PORT alone 1861

receive a total dose to these regions of 66 Gy in 2 Gy fractions, although the lack of high-quality 1862

data guiding this statement must be acknowledged. 1863

The evidence guiding dose and fractionation regimens in the setting of negative margins 1864

and no ECE is similarly scant. The Peters study initially randomized low risk patients to 52.2-54 1865

Gy vs 63 Gy at 1.8 Gy per fraction. Because of a higher incidence of local failure in the low dose 1866

cohort (p=0.02), the total dose subsequently was increased to 57.6 Gy. No advantages were 1867

observed with 63 Gy vs 57.6 Gy, but grade 3-4 toxicity was higher (7.7% vs 3.3%) with the 1868

higher dose. Low risk was defined as having not more than one of the following factors: oral 1869

cavity primary, mucosal margins close or positive, nerve invasion, ≥2 positive lymph nodes, 1870


largest node > 3 cm, treatment delay greater than 6 weeks, and performance status > or = 2. 1871

Ang’s trial4 used the same clinical and pathologic criteria with low risk defined as having none 1872

of them and intermediate risk as having only one exclusive of ECE. Low-risk patients were 1873

observed; all intermediate risk patients (n=31) received 57.6 Gy and had the same local-regional 1874

control as the low risk patients. 1875

The panel considers that the dose of 57.6 Gy in 1.8 Gy fractions is approximately 1876

equivalent to 56 Gy in 2 Gy fractions. The daily dose is higher and total treatment time is shorter 1877

with 2 Gy fractions, arguing in favor of 56 Gy as the reference dose. However, because there are 1878

few data showing successful long-term control outcomes with 56 Gy, and as stated above, the 1879

true dose to involved stations using opposed lateral fields was presumably higher than the 1880

nominal dose, the panel chose a more conservative level and strongly recommends delivering 60 1881

Gy to the tumor bed and involved lymph node stations in the absence of positive surgical margin 1882

(PSM) and ECE. 1883

Currently, the most significant issue concerns the distinction between low risk and high-1884

risk disease. It is important to recognize that most patients with high risk disease now receive 1885

adjuvant chemoradiotherapy (vide supra). Features including perineural invasion (PNI) and 1886

multiple positive lymph nodes in addition to PSM and ECE conferred eligibility into the RTOG 1887

and EORTC trials that developed this standard. The majority of the patients on these trials did 1888

not have oropharyngeal cancer, however, and secondary analyses have shown that chemotherapy 1889

did not clearly augment the effectiveness of RT for lower-risk pathologic features such as PNI 1890

and multiple nodes. Consequently, one could rationally infer in a contemporary setting that there 1891

is no benefit to be gained from dose escalation or acceleration without PSM or ECE. 1892


Consensus still exists that primary site PSM is a high risk feature. For surgically treated 1893

HPV(+) disease, however, some recent large retrospective studies suggest that minimal nodal 1894

ECE no longer constitutes high risk disease49,50 and that these patients do just as well with 1895

adjuvant RT only (60 Gy) instead of adjuvant chemoradiotherapy. The older studies of post-1896

operative irradiation followed the traditional paradigm of dose intensification to improve 1897

outcome. Since HPV (+) driven disease has a much more favorable prognosis than its HPV(-) 1898

counterpart, current developmental strategies are focused on therapeutic deintensification. ECOG 1899

331193 is a randomized phase 2 study enrolling p16-positive oropharyngeal cancer patients who 1900

have undergone transoral resection. Patients with “intermediate-risk” pathologic factors (defined 1901

as PNI, LVI, 2-4 LN’s, <1 mm ECE, and/or margins <3 mm) will be randomized to receive 2 Gy 1902

daily either on an investigational arm of 50 Gy or a control arm of 60 Gy. The outcomes of this 1903

trial will help to redefine the standard-of-care for patients receiving adjuvant PORT in this 1904

population, but pending the mature results of this study, post-operative treatment dose and 1905

fractionation should not vary by p16 status. 1906

1907

1908

In the scenario of early T-stage tonsillar carcinoma? 1909 1910

Statement 4K. Unilateral radiotherapy should be delivered to patients with well-lateralized 1911 (confined to tonsillar fossa), T1-T2 tonsillar cancer and N0-N1 nodal category. 1912


1915 Statement 4L. Unilateral radiotherapy may be delivered to patients with lateralized (< 1 cm of 1916

soft palate extension but without base of tongue involvement) T1-T2 N0-N2a tonsillar cancer 1917 without clinical or radiographic evidence of extra-capsular extension, after careful discussion of 1918 patient preferences and the relative benefits of unilateral treatment versus the potential for 1919 contralateral nodal recurrence and subsequent salvage treatment. 1920

o Recommendation strength: Conditional 1921 o Quality of evidence: Low 1922

1923


1924

Narrative 1925

1926 The hypothetical advantages of ipsilateral-only radiotherapy for tonsillar cancer include 1927

improved short- and long-term functional outcomes and quality-of-life. In addition, the smaller 1928

treatment volumes may potentially lower the small but non-zero long-term risk of radiation-1929

associated malignancies, particularly in the younger population of patients with HPV-associated 1930

disease. The key concern of restricting radiotherapy to the ipsilateral side is the risk of 1931

contralateral nodal recurrence. 1932

As suggested from both historical surgical literature on patterns of cervical metastases as 1933

well as more recent surgical series of tonsillar cancer patients undergoing bilateral neck 1934

dissections, contralateral nodal spread typically occurs either directly through soft palate or base 1935

of tongue involvement or via aberrant/retrograde flow from bulky unilateral nodal disease. In a 1936

review of 352 patients with oropharyngeal cancer (197 with tonsillar cancer) treated with 1937

surgical resection including bilateral neck dissection, investigators from Ludwig Maximilians 1938

University in Munich143 demonstrated that contralateral nodal metastasis was dramatically lower 1939

for tonsillar cancers (14.7%) as compared to cancers of the base of tongue, soft palate, or 1940

pharyngeal wall (28.8%, 25.9%, and 50.0%, respectively). Among tonsillar cancers risk for 1941

contralateral metastasis increased with higher T-category (6.3% for T1, 17.5% for T2, and 17.3% 1942

for T3-4), though local extension of tonsillar cancers to involve the base of tongue, soft palate or 1943

pharyngeal wall was not described. Additionally, risk for contralateral nodal metastases among 1944

all patients was strongly associated with N2b ipsilateral nodal category (P < 0.001). Investigators 1945

from Hallym University in Seoul144 have described a series of 76 patients with tonsillar cancer 1946

treated with surgery (including 14 having elective contralateral neck dissection for contralateral 1947

N0 status). Contralateral metastases were significantly associated with T3 category, base of 1948


tongue involvement, soft palate involvement, and ipsilateral neck multilevel involvement, though 1949

only ipsilateral multilevel involvement was significant after multivariate adjustment. In another 1950

publication from this group on a subset of 53 patients,145 these contralateral nodal metastases 1951

were also associated with posterior pharyngeal wall involvement and extracapsular spread in the 1952

ipsilateral nodal metastases. Investigators from Yonsei University in Seoul146 reported on the 1953

pathologic findings in 43 patients with tonsillar cancer treated with surgery including elective 1954

contralateral neck dissection (contralateral N0 status). The authors did not comment on soft 1955

palate or base of tongue invasion, but there was a correlation of contralateral occult metastatic 1956

rate with T-category (0% for T1, 4.5% for T2, and 33.3% for T3-4) and N-category (0 for N0, 1957

18.2% for N1-2a, and 27.3% for N2b). Consequently, these well-documented patterns of cervical 1958

metastases from tonsillar cancer treated with surgery provide support that the concept of 1959

unilateral radiotherapy for patients with early-stage, lateralized tonsillar cancer. 1960

The evidence in the literature supporting the above consensus statement regarding 1961

ipsilateral-only radiotherapy is chiefly comprised of retrospective data with inherit selection and 1962

publication biases, variable follow-up time, limited evidence using modern radiotherapy 1963

techniques, and a lack of data on whether these findings apply specifically to oropharyngeal 1964

cancer resulting from HPV. In developing these guideline statements, we have identified 10 1965

studies which met our initial criteria for review (Table 8 and 9). 1966

One study was described as an “investigational trial” of ipsilateral-only radiotherapy, 147 1967

and this small study included 22 oropharyngeal cancers (13 of the tonsil) patients of whom only 1968

15 were treated with definitive radiotherapy (7) or chemoradiotherapy (8). Primary endpoints of 1969

this study were prospectively recorded patient recurrence in the contralateral neck and reported 1970

xerostomia score. There were 2 (9%) patients with oropharyngeal cancer (both of the tonsil) who 1971


recurred in the contralateral neck; both were T3 N2b. No patient developed grade 2-3 1972

xerostomia. The other prospective study of ipsilateral-only radiotherapy148 included only 20 1973

patients with tonsillar cancers (none of which involved the base of tongue or soft palate) of 1974

whom only 6 received definitive chemoradiotherapy (using IMRT approximately half the time). 1975

No patient developed a contralateral nodal recurrence. Only one patient developed a grade 2 1976

xerostomia and there were no grade 3 or late toxicities; however, 11 patients did require a 1977

treatment break. 1978

Of the remaining 8 studies, all were retrospective with 3 being generally small. 149-151 In a 1979

study of 32 patients with oropharyngeal cancer (12 with soft palate primaries and 20 with tonsil 1980

primaries, 7 with soft palate extension and 5 with base of tongue extension) treated with 1981

ipsilateral-only radiotherapy (38% received concurrent carboplatin), Kagei et al.149 found no 1982

patient developing a contralateral nodal recurrence. Only 3 patients developed grade 2 1983

xerostomia, and with exception of one case of grade 3 osteoradionecrosis, there were no grade 3 1984

or late toxicities. In a study of 20 patients with tonsillar cancer, of whom 70% received post-1985

operative ipsilateral-only radiotherapy, Koo et al150 found no patient developed a contralateral 1986

nodal recurrence. Only one patient developed grade 2 xerostomia, and there were no grade 3 or 1987

late toxicities. In a study of 58 patients with tonsillar cancer treated with unilateral radiotherapy, 1988

Liu et al.151found no patient developed a contralateral nodal recurrence. Of note, this is the only 1989

study with p16 data: of 15 patients tested, 60% were p16 positive. Only 4 patients treated 1990

unilaterally developed late toxicities, a significantly smaller percentage than the rate of late 1991

toxicity (22%) of among patients with tonsillar cancer treated with bilateral radiotherapy. 1992

While the remaining 5 studies are also retrospective, each included more than 100 1993

patients with oropharyngeal cancer and all but one with exclusively tonsillar cancer patients as 1994


well as all but one having the vast majority of patients (>90%) treated with definitive radiation 1995

therapy. Jackson et al.152 reviewed 178 patients with tonsil cancer treated with ipsilateral-only 1996

definitive radiotherapy, although the local extent of disease was not stated beyond T category. 1997

The details of contralateral nodal recurrence were detailed only for the 155 with N0-N1 disease 1998

and among these there were 4 (2.6%) contralateral recurrences (initial stage: one T2N0, one 1999

T3N0, and 2 T1-3N1). Three out of 82 patients (3.6%) of patients with stage III disease 2000

developed a contralateral recurrence, though it is possible that many patients in this older series 2001

(1975-1993) were under staged due to substandard (by today’s standards) imaging. Reported late 2002

toxicities included 2 with grade 2 soft tissue necrosis, 4 with grade 3 osteonecrosis, and 2 with 2003

grade 4 osteonecrosis. 2004

In the largest study to date, O’Sullivan et al.153 reported on 228 patients with tonsillar 2005

cancer treated with definitive ipsilateral-only radiotherapy. Eight patients (3.5%) developed 2006

contralateral nodal recurrence; however, 5 were detected synchronously with a primary site 2007

recurrence and 3 also had ipsilateral nodal recurrence. There were only 3 patients (1.3%) with 2008

exclusive contralateral nodal recurrence, and of these 3, 2 had T3 primaries (all 3 with significant 2009

[>1cm] palate involvement and 2 with significant base of tongue involvement). Of the 30 2010

patients with T3 primaries, 3 developed a contralateral recurrence. Notably, none of the 36 2011

patients with lateral palate involvement (< 1 cm) developed a contralateral recurrence, although 2 2012

out of 39 (5%) patients with lateral base of tongue invasion did, one of which was the only site of 2013

recurrence. While all contralateral nodal recurrences occurred among the 41 N1 patients and 2014

none among the 36 patients with N2 disease (28 N2a, 8 N2b), this is an older series of patients 2015

(1970-1991) in which cross-sectional imaging was “not employed for stage allocation.” 2016

Consequently, it is likely that some proportion of the N1 patients would have been classified as 2017


N2b had contemporary imaging tools been available. The reported 5-year rate of grade 3-4 2018

toxicity was 3.4% (chiefly osteonecrosis), although the radiotherapy was 2D-based, without CT-2019

planning. 2020

A recent series by Lynch et al.154 reported the outcomes of 136 patients with tonsillar 2021

cancer treated with primary surgical resection and post-operative ipsilateral-only radiotherapy 2022

with or without chemotherapy. None of these patients had base of tongue involvement, and only 2023

7 patients had lateral (< 1cm) soft palate extension. Eight patients (6%) recurred in the 2024

contralateral neck with 6 (4% of total) of those recurrences being the solitary site of progression. 2025

All 6 of these patients presented with the initial nodal category N2b, with 5 having extra-capsular 2026

extension and 5 being current smokers with >10 pack-years smoking history. Two of the 7 2027

patients with lateral soft palate involvement developed a contralateral recurrence. Late toxicity 2028

included grade 3 osteonecrosis in 9 (7%) and grade 3 fibrosis in 3 (2.2%), and only 8 patients 2029

(6%) required a feeding tube. 2030

The final 2 papers were large series with a majority of patients treated with definitive 2031

intensity modulated radiation therapy (IMRT) and very small proportion receiving 2032

chemotherapy. Chronowski et al.155 found a contralateral recurrence rate of 2% in a series of 102 2033

patients with tonsillar cancer treated with ipsilateral-only radiotherapy, though one of these was 2034

likely a second primary of the contralateral base of tongue. Only patients with primaries 2035

confined to the tonsillar fossa or with less than 1 cm of soft palate extension (base of tongue 2036

involvement was an exclusion) were considered for ipsilateral radiotherapy. A total of 43 N2 (21 2037

N2a, 22 N2b) patients were included in this analysis, and none of them developed a contralateral 2038

recurrence. Long term toxicity rates were not reported, though 9% of patients required feeding 2039

tubes during radiotherapy. In the study by Al-Mamgani et al,156 185 patients (47 with soft palate 2040


primaries and 32 with N2b nodal metastases) were treated with ipsilateral-only radiotherapy, 2041

there were only 2 contralateral recurrences (1.1% of the entire cohort), and one of these was 2042

initially T1N2b (the other T2N0; both confined to the tonsillar fossa). Late grade 3 toxicity was 2043

only 2.2%, while late grade 2 toxicity was 13%. 2044

The oncologic safety of ipsilateral-only radiation therapy for HPV-associated tonsillar 2045

cancer is suggested by high control rates and low contralateral metastases rates in these relatively 2046

modern series, in which a substantial proportion of patients presumably had disease attributable 2047

to HPV. However, the propensity of small HPV-associated oropharyngeal cancers to metastasize 2048

to lymph nodes raises some concern of whether this population has a higher risk of occult 2049

contralateral lymph nodes and subsequent contralateral nodal recurrence. In a small retrospective 2050

study restricted to T1-T2 tonsillar cancers reported by Shoushtari et al.,157 25% of 28 patients 2051

with p16 positive T1-T2 tonsillar cancer presented with clinically-evident, contralateral nodal 2052

metastases, as compared to none of the 13 patients with p16 negative T1-T2 tonsillar cancer. 2053

The key issue, though, is not the incidence of contralateral clinically-evident lymph node 2054

metastases but rather the baseline risk of occult contralateral lymph node metastases and the risk 2055

of subsequent contralateral recurrence. However, to date there are no data available to inform 2056

whether HPV-associated tonsillar cancers have a higher baseline risk of occult contralateral 2057

lymph node metastases and risk of subsequent contralateral recurrence. Also, whether these risks 2058

are modified by past smoking history is unknown. Consequently, the recommendations regarding 2059

the use of ipsilateral-only radiation therapy are made independent of HPV status and smoking 2060

history. 2061

A substantial experience supports the use of ipsilateral only radiation therapy for tonsillar 2062

cancer confined to the tonsillar fossa with limited nodal metastases as effective therapy with high 2063


survival rates, expected in-field control, and very rare contralateral recurrence. In addition, the 2064

majority (9 of 10) of N0-N1 patients with contralateral recurrence were observed in series dating 2065

back to the 1970s, with many such patients likely with under-staged N-category due to lack of 2066

modern cross-sectional imaging. Ipsilateral treatment should also reduce the risk of late 2067

toxicities, including xerostomia, dysphagia, and second primary malignancies. The panel 2068

therefore strongly recommends ipsilateral treatment in this cohort. Care in the use of ipsilateral-2069

only radiation therapy must be taken in cases of T1/T2 category OPSCC with soft palate 2070

involvement and/or N2a categories (Table 10). There is limited clinical experience that can 2071

confirm low contralateral recurrence rates in these scenarios, although the existent data reviewed 2072

above are sufficiently encouraging that ipsilateral radiotherapy may be used in this population, 2073

provided patient preferences are fully engaged on the expected quality-of-life benefits versus the 2074

uncertain risk of contralateral recurrence. 2075

On the other hand, the vast majority of reported contralateral recurrences occurred in 2076

patients with classical contraindications to unilateral treatment (e.g. significant involvement of 2077

soft palate, base of tongue and/or T3 primary size) or tumor characteristics that suggest aberrant 2078

lymphatic flow (i.e. ECE, advanced N2b cases) (Table 9). Thus the panel does not consider 2079

ipsilateral radiotherapy reasonable in the presence of these factors. The panel did discuss whether 2080

patients with small-volume N2b disease or those with minimal base of tongue invasion should be 2081

eligible for ipsilateral radiotherapy. Because of the paucity of data suggesting a low contralateral 2082

recurrence risk in these individuals, they are not included in the conditional recommendation for 2083

the use of ipsilateral radiotherapy. 2084

Future research will hopefully provide additional guidance on this important treatment 2085

planning decision. For example, we eagerly await outcomes and contralateral recurrence risk to 2086


be reported on series of HPV-associated T1-T2 tonsillar cancers. At present, neither the more 2087

favorable prognosis not the propensity for lymph node metastases of HPV-associated tonsillar 2088

cancer can inform the decision to spare the contralateral neck from radiation therapy. Similarly, 2089

prospective studies of patients with N2b nodal category are needed to better understand the 2090

contralateral recurrence risk with ipsilateral radiotherapy and further motivate treatment 2091

decisions in this relatively common clinical presentation. 2092

2093

2094

2095

2096

2097

2098


Epilogue: Reflections from the patient advocate 2099

2100 ASTRO clinical practice guidelines include a patient advocate to ensure the patient 2101

perspective is considered during the guideline process and maximize the patient-centeredness of 2102

the product. We asked the patient advocate (Warren Caldwell) for this guideline to provide his 2103

“recommendations” on how medical professionals can improve the care for individuals 2104

diagnosed with oropharyngeal squamous cell carcinoma. His thoughts are below: 2105

2106

1. The sound of a silent cell phone of one awaiting biopsy results is deafening. It will be a 2107

kindness of unimaginable proportion to inform patients in an expeditious manner of the 2108

results of biopsies and scans. When it is clinically possible, avoid scheduling these tests 2109

when results will be extended over a weekend. 2110

2111

2. There is no bad way to inform a patient of good news and no good way to inform them of 2112

such existentially bad news. Make these calls when you have time to patiently respond to 2113

a hundred questions as this is not one of life’s multi-tasking moments for your patient. 2114

They will be riveted to your every word. 2115

2116

3. When the call has ended, the patient’s brain will race: I am self-employed. Will I be able 2117

to work? Should I sell my nice car and get a clunker? Why didn’t I buy life insurance? 2118

Will I see my son earn his Eagle Scout? Will I be at his wedding? Will I play with 2119

grandkids? 2120

2121


4. How much knowledge is too much for a new patient? A new patient may self-triage with 2122

their need to know, but discuss their desire to hear details early in the conversation. 2123

2124

5. An important blade on the Swiss Army Knife of a patient’s resources to fight the fight is 2125

empowerment. The sudden discovery that so many things are out of one’s control places 2126

a premium on the things that are under one’s control. A shift away from the traditional 2127

paternalistic form of physician/patient relationship towards a teammate approach fosters a 2128

sense of self-control in a world that is madly spinning out of control. 2129

2130

6. The emerging science behind treatment options of OPSCC suggest that there are some 2131

gray areas in utilizing the tools of surgery, radiotherapy and systemic treatment. The 2132

engagement of patient preferences in determining treatment options is a preferred means 2133

of practicing medicine. Explain, Engage and Ask. Formulate a plan together. 2134

2135

7. Establish an understanding of a patient’s aversion to risk versus embrace of reward. Do 2136

they have a predisposition to be more aggressive with a possible loss of quality of life or 2137

less aggressive with the cancer more likely to recur? 2138

2139

8. If a patient elects to go less aggressively, this position should be afforded the same 2140

respect as any other. If they choose to reject some aspect of the recommended treatment, 2141

afford them the dignity and feeling of control of self-directed treatment. 2142

2143


9. Engage the family during the new patient discussion and enlist them as part of the team. 2144

One could successfully beat it without family but it would be immeasurably more 2145

difficult. 2146

2147

10. Are we getting better and better at fighting the actual disease process but not providing a 2148

great deal of formal attention to the psychosocial aspects of the ordeal? Everyone has 2149

their own unique journey and no amount of counseling or therapy will standardize it (nor 2150

should it) but the lack of the same leaves patients to their own devices and some are 2151

better equipped than others. 2152

2153

11. There will be quite a lot of data management that most will not be used to handling. 2154

Encourage them to buy a Spandex type file in which to keep all appointment calendars, 2155

labs, reports, documents, insurance, and written prescriptions in one place. Use pill 2156

containers to help manage medications. Consider giving them these things as part of a 2157

new patient package. 2158

2159

12. The prospect of the loss of one’s teeth is terrifying to comprehend. Impossibly so. It is 2160

disquieting to be a fortunate ex-patient counseling a less fortunate ex-patient who is sad 2161

that “I used to be attractive, now I look like a different person.” Encourage patients to use 2162

their dental trays in the shower. It gives them a regular routine to use them and they are 2163

able to spit excess fluoride saliva down the drain. 2164

2165


13. The radiation mask is a special hurdle. The loss of control by being imprisoned by 2166

something one millionth of an inch from one’s face is near complete. If a patient exhibits 2167

complete anxiety, medicate them. But if a patient must drive themselves to appointments 2168

and cannot be medicated, encourage them to leave home early for the appointment to 2169

avoid traffic stress. Listen to comforting music on the way to the hospital. Breathe slowly 2170

and deeply. Close one’s eyes during treatment. Offer them the opportunity to listen to 2171

music of their choice during the treatment. 2172

2173

14. The loss of taste is much more of a loss than it would seem on the surface. It is shocking 2174

how important the sensation of taste is in driving a person’s appetite. Indeed, when one 2175

cannot taste, the act of eating is actually a tiresome ordeal in itself. 2176

2177

15. Have patients keep Magic Mouthwash (a lidocaine mixture) right next to their chair and 2178

bedside, not in the kitchen. Keep it super-convenient and they will use it more regularly. 2179

Recommend that patients keep moisturizer in their vehicles so that they may slather it on 2180

their necks immediately after the treatment. Make the supportive care as convenient as 2181

possible for themselves. 2182

2183

16. Post-surgical and radiation mucositis can make it very difficult to sleep in a normal 2184

position. Encourage patients to purchase and utilize a reclining chair to sleep in and when 2185

they transition back to a bed, have them elevate with multiple pillows. When awake and 2186

in the chair, set up a TV tray and line up all the accoutrements of healing. Water, spit cup, 2187

prescriptions, books, TV remote. 2188


2189

17. Encourage the patient to take mastery over their mind. Have them hang a white dry erase 2190

board or the like at their home or office. Sequentially number the amount of treatments 2191

(30, 29, 28….1, DONE). Make it a ceremony to “X” out each number as it progresses. 2192

Look forward to it. Engage family and allow them to “X” out some of the days. Write 2193

slogans of encouragement on this board. 2194

2195

18. Once the miraculous “tah-dah” moment of finishing treatment is reached, the “New 2196

Normal” begins. As the treatment “gift” keeps on giving in the weeks and months 2197

following radiation, a patient may feel the need for additional sleep. Encourage naps as 2198

necessary. This “lack of productivity” can result in financial strain due to reduced income 2199

but it is a matter of aligning things in their necessary hierarchy of importance. 2200

2201

19. The effect of radiotherapy on the skin can cause the neck to look twenty years older than 2202

the rest of the patient. Don’t discount the importance of trying to reduce the long-term 2203

visible side effects of treatment. 2204

2205

20. The hiring process for staff should place a special premium on the human quality of 2206

kindness. The smallest act of kindness will be something the patient will remember for 2207

life. Begin with the valet in the parking lot. They are the first face a patient will encounter 2208

and the last to see and have an opportunity to place their positive imprint on the entire 2209

visit. The same care should be extended with check-in staff, nurses and of course, 2210


physician assistants and physicians. By doing so, you will be treating patients as a human 2211

being instead of a disease, which is crucial to maintain dignity throughout the process. 2212

2213

21. If the patient has children, forcefully encourage (and remind) them to vaccinate their kids 2214

against HPV. Motivate them to be strong advocates for HPV vaccination for their 2215

extended family and friends. 2216

2217

2218

22. If you have read this far, I thank you from the depths of my heart. It is because of 2219

you and people like you that I backpacked 110 miles at Philmont Scout Ranch with 2220

my son last year. Remember why you do what you do! 2221

2222

2223


TABLES 2224

2225 Table 1. Recommendation statements, including recommendation strength, quality of evidence, and percent consensus. 2226

2227

Guideline statement Strength of

recommendation

Quality of

evidence

Percent (%) agreement

with guideline

statement

KQ1. When is it appropriate to add systemic therapy to definitive radiotherapy in the treatment of oropharyngeal

squamous cell carcinoma (OPSCC)?

In the scenario of stage IV A-B disease:

A. Concurrent high-dose intermittent cisplatin should be

delivered to patients with stage IVA-B oropharyngeal

squamous cell carcinoma receiving definitive radiotherapy. Strong High 100%

B. Concurrent cetuximab or carboplatin-fluorouracil should

be delivered to patients with stage IVA-B

oropharyngeal squamous cell carcinoma receiving definitive

radiotherapy who are not medically fit for high-dose

cisplatin.

Strong High 88%

C. Concurrent weekly cisplatin may be delivered to patients

with stage IVA-B oropharyngeal squamous cell carcinoma

receiving definitive radiotherapy who are not medically fit

for high-dose cisplatin, after a careful discussion of patient

preferences and the limited prospective data supporting this

regimen.

Conditional Low 94%

D. Concurrent cetuximab should not be delivered in

combination with chemotherapy to patients with stage IVA-

B oropharyngeal squamous cell carcinoma receiving

definitive radiotherapy.

Strong High 100%


E. Intra-arterial chemotherapy should not be delivered to

patients with stage IVA-B oropharyngeal squamous cell

carcinoma receiving definitive radiotherapy. Strong High 100%

In the scenario of stage III disease:

F. Concurrent systemic therapy should be delivered to

patients with T3 N0-1 oropharyngeal squamous cell

carcinoma receiving definitive radiotherapy. Strong Moderate 100%

G. Concurrent systemic therapy may be delivered to patients

with T1-T2 N1 oropharyngeal squamous cell carcinoma

receiving definitive radiotherapy who are considered at

particularly significant risk for locoregional recurrence, after

a careful discussion of patient preferences and the limited

evidence supporting its use.

Conditional Low 88%

In the scenario of stage I-II disease:

H. Concurrent systemic therapy should not be delivered to

patients with stage I-II oropharyngeal squamous cell

carcinoma receiving definitive radiotherapy. Strong Low 100%

KQ2. When is it appropriate to deliver post-operative radiotherapy with and without systemic therapy following primary

surgery of oropharyngeal squamous cell carcinoma (OPSCC)?

In the scenario of positive margins and/or extrascapsular nodal extension (ECE)?

A. Concurrent high-dose intermittent cisplatin should be

delivered with post-operative radiotherapy to patients with

positive surgical margins and/or extracapsular nodal

extension; this high-risk population includes patients

independent of HPV status or the extent of extranodal tumor.

Strong Moderate 100%


B. Concurrent weekly cisplatin may be delivered with post-

operative radiotherapy to patients who are considered

inappropriate for standard high-dose intermittent cisplatin

after a careful discussion of patient preferences and the

limited evidence supporting this treatment schedule.

Conditional Low 94%

C. For the high-risk post-operative patient unable to receive

cisplatin-based concurrent chemoradiotherapy, radiotherapy

alone should be routinely delivered without concurrent

systemic therapy; given the limited evidence supporting

alternative regimens, treatment with non-cisplatin systemic

therapy should be accompanied by a careful discussion of the

risks and unknown benefits of the combination.

Strong Moderate 94%

D. Patients treated with post-operative radiotherapy should

not receive concurrent weekly carboplatin. Strong Moderate 88%

E. Patients treated with post-operative radiotherapy should

not receive cetuximab, either alone or in combination with

chemotherapy, although such regimens are currently under

investigation.

Strong Low 94%

F. Patients treated with post-operative radiotherapy should

not routinely receive concurrent weekly docetaxel given the

limited evidence supporting its use, although such regimens

are currently under investigation.

Strong Low 88%

G. Patients treated with post-operative radiotherapy should

not receive concurrent mitomycin-C, alone or with

bleomycin, given the limited evidence and experience

supporting its use.


H. Post-operative chemotherapy should not be delivered

alone or sequentially with post-operative radiotherapy. Strong High 94%

In the scenario of intermediate-risk pathologic factors such as lymphovascular invasion (LVI), perineural invasion (PNI), T3-

4 disease, or positive lymph nodes:


I. Patients with intermediate-risk factors should not routinely

receive concurrent systemic therapy with post-operative

radiotherapy. Strong Moderate 88%

J. Patients with intermediate-risk factors whose surgical

procedure and/or pathologic findings imply a particularly

significant risk of locoregional recurrence may receive

concurrent cisplatin-based chemotherapy after a careful

discussion of patient preferences and the limited evidence

supporting its use in this scenario; alternative systemic

treatment regimens should only be used in the context of a

clinical trial

Conditional Low 88%

K. Post-operative radiotherapy should be delivered to

patients with pathologic T3 or T4 disease. Strong Low 94%

L. Post-operative radiotherapy should be delivered to patients

with pathologic N2 or N3 disease. Strong Low 100%

M. Post-operative radiotherapy may be delivered to patients

with pathologic N1 disease after a careful discussion of

patient preferences and the limited evidence of outcomes

following surgery alone in this scenario.

Conditional Low 88%

N. Post-operative radiotherapy may be delivered to patients

with LVI and/or PNI as the only risk factor(s), after a careful

discussion of patient preferences and the limited evidence of

outcomes following surgery alone in this scenario.

Conditional Low 100%

In the scenario of no pathologic risk factors:

O. Post-operative radiotherapy may be delivered to patients

without conventional adverse pathologic risk factors only if

the clinical and surgical findings imply a particularly

significant risk of locoregional recurrence, after a careful

discussion of patient preferences and the potential harms and

benefits of radiotherapy.

Conditional Low 88%


KQ3. When is it appropriate to use induction chemotherapy in the treatment of oropharyngeal squamous cell carcinoma

(OPSCC)?

A. Induction chemotherapy should not be routinely delivered

to patients with OPSCC. Strong High 100%

KQ4. What are the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the

treatment of oropharyngeal squamous cell carcinoma (OPSCC)?

In the scenario of definitive non-surgical therapy:

A. A dose of 70 Gy over 7 weeks should be delivered to

gross primary and nodal disease in patients with stage III-IV

oropharyngeal squamous cell carcinoma selected to receive

standard, once-daily definitive radiotherapy.


B. The biologically equivalent dose of approximately 50 Gy

in 2 Gy fractions or slightly higher should be delivered

electively to clinically- and radiographically-negative regions

at-risk for microscopic spread of tumor.

Strong Low 100%

C. Altered fractionation should be used in patients with stage

IVA-B oropharyngeal squamous cell carcinoma treated with

definitive radiotherapy who are not receiving concurrent

systemic therapy.

Strong High 94%

D. Either accelerated radiotherapy or hyperfractionated

radiotherapy may be used in patients with oropharyngeal

squamous cell carcinoma treated with altered fractionation

definitive radiotherapy after a careful discussion of patient

preferences and the limited evidence supporting one regimen

over the other.

Conditional High 100%


E. Either standard, once-daily radiotherapy or accelerated

fractionation may be used when treating oropharyngeal

squamous cell carcinoma with concurrent systemic therapy,

after a careful discussion of patient preferences and the risks

and benefits of both approaches.

Conditional High 88%

F. Altered fractionation should be used in patients with T3

N0-1 oropharyngeal squamous cell carcinoma treated with

definitive radiotherapy who do not receive concurrent

systemic therapy.

Strong Moderate 94%

G. Altered fractionation may be used in patients with T1-2

N1 or T2 N0 oropharyngeal squamous cell carcinoma treated

with definitive radiotherapy alone who are considered at

particularly significant risk of locoregional recurrence, after a

careful discussion of patient preferences and the limited

evidence supporting its use in this scenario.

Conditional Low 100%

In the scenario of adjuvant postoperative radiotherapy:

H. Adjuvant post-operative radiotherapy should be delivered

to regions of microscopically-positive primary site surgical

margins and extracapsular nodal extension at 2 Gy/fraction

once daily to a total dose between 60 and 66 Gy


I. Adjuvant post-operative radiotherapy delivered without

concurrent systemic therapy should treat regions of

microscopically-positive primary site surgical margins and

extracapsular nodal extension at 2 Gy/fraction once daily to a

total dose of 66 Gy, although there are limited data guiding

this recommendation.

Conditional Weak 100%

J. Adjuvant post-operative radiotherapy should be delivered

to the tumor bed and involved, dissected lymph node regions

at 2 Gy/fraction once daily to a total dose of 60 Gy in the

absence of primary site positive margins and extracapsular

nodal extension.



In the scenario of early T-stage tonsillar carcinoma:

K. Unilateral radiotherapy should be delivered to patients

with well-lateralized (confined to tonsillar fossa), T1-T2

tonsillar cancer and N0-N1 nodal category. Strong Moderate 88%

L. Unilateral radiotherapy may be delivered to patients with

lateralized (< 1cm of soft palate extension but without base

of tongue involvement) T1-T2 N0-N2a tonsillar cancer

without clinical or radiographic evidence of extra-capsular

extension, after careful discussion of patient preferences and

the relative benefits of unilateral treatment versus the

potential for contralateral nodal recurrence and subsequent

salvage treatment.

Low Conditional 100%

2228


Table 2: Summary of phase III randomized trials comparing definitive radiotherapy with definitive radiotherapy plus 2229

concurrent systemic therapy (Key Question 1) 2230 2231

Author and

year

Number

of

patients

%

oropharynx

% stage

III Radiotherapy regimen

Chemotherapy

regimen/

schedule

LRC benefit OS benefit

Adelstein,

20039

295 total

(271

analyzed)

59% 4% 70 Gy in 35 fx over 7 weeks

Bolus cisplatin q3

weeks vs. cisplatin

+ 5-FU with split-

course

--

YES

3-year: 23% (RT) vs.

37% (RT + bolus) vs.

p=0.014

Ruo Redda,

201011

164 (157

analyzed) 56% 23%

70 Gy in 35 daily fx over 7

weeks

Carboplatin q2

weeks NO

YES

5-year: 6.9% (RT) vs.

9% (CRT), p=0.02

Zakotnik,

199814 64 64% 6%

66-70 Gy in 33 to 35 daily

fx over 7 weeks

Mitomycin C after

10 Gy and on last

day of RT +

bleomycin twice

weekly

--

NO

Except 10% vs. 38%

for oropharyngeal,

p=0.019

Denis,

200416 226 100% 32%


weeks

Carboplatin and 5-

FU q3 weeks

YES

5-year: 24.7% (RT)

vs. 47.6% (CRT),

p=0.002

YES

5-year: 15.8% (RT)

vs. 22.4% (CRT),

p=0.05

Semrau,

200617 240 74% 4%

50.4 Gy in 28 daily fx over

38 days + 19.5 Gy boost in

13 daily fx (total 69.9 Gy)

Continuous

infusion 5-FU and

carboplatin for 5d,

weeks 1 and 6

YES

5-year survival with

LRC: 12.6% (RT)

vs. 22.7% (CRT),

p=0.01

YES

5-year: 15.8% (RT)

vs. 25.6% (CRT),

p=0.016


Author and

year

Number

of

patients

%

oropharynx

% stage


Chemotherapy

regimen/

schedule


Ghadjar,

201218

224 100%

29% (plus

5% stage

II)

74.4 Gy in 62 fx BID

Daily cisplatin 20

mg/m2 for 5d,

weeks 1 and 5

YES

10-year: 40% (CRT)

vs. 32% (RT)

p=0.049

NO

Wendt,

199819

298 (270

analyzed) 42%

Not

reported;

5% T1-2,

35% N0-1

70.2 Gy in 39 fx BID over

51 days in 3 cycles of 23.4

Gy with 11 days in between

Cisplatin, 5-FU,

and leucovorin q3

weeks

YES

3-year: 17% (RT)

vs. 36% (CRT),

p<0.004

YES


48% (CRT),

p<0.0003

Bourhis,

201120 109 62% 0%

64 Gy in 32 fx BID (very

accelerated RT alone) vs.

62-64 Gy in 31-32 fx BID

with RT every other wk

(CRT)

Cisplatin and 5-FU

q2 weeks

YES

5-year freedom from

locoregional or

distant failure:

49.1% (CRT) vs.

25% (RT), p=0.005

NO

Budach,

200522

384 60% 6%

16 Gy in 8 daily fx + 61.6

Gy in 44 fx BID (total 77.6

Gy) (RT) vs. 30 Gy in 15

daily fx + 40.6 Gy in 29 fx

BID (total 70.6 Gy)(CRT)

Continuous

infusion

fluorouracil on

days 1-5 + bolus

mitomycin on days

5 and 36

YES

5-year: 37.4% (RT)

vs. 49.9% (CRT),

p=0.001

YES

5-year: 23.7% (RT)

vs. 28.6% (CRT),

p=0.023

Bourhis,

201223 840 66% N/R


weeks (CRT) vs. 40 Gy in

20 daily fx over 4 weeks

plus 30 Gy in 20 fx BID

over 2 weeks (AccRT) vs.

64.8 Gy in 36 fx BID over

3.5 weeks (VeryAccRT)

Carboplatin (3

cycles of 4 days

for CRT, 2 cycles

of 5 days for

AccRT) +

YES

3-year: 58.3%

(CRT) vs. 54.6%

(AccRT) vs. 50.1%

(VeryAccRT),

YES

3-year: 42.6% (CRT)

vs. 36.5%

(VeryAccRT),

p=0.040


Author and

year

Number

of

patients

%

oropharynx

% stage


Chemotherapy

regimen/

schedule


fluorouracil (q3

wks for CRT, q4

wks for AccRT)

p=0.033 (AccRT vs.

VeryAccRT),

p=0.045 (CRT vs.

VeryAccRT)

Ghosh-

Laskar,

201425

186 89%

46%

(stage II

and III)

66-70 Gy in 5 fx per week

(CRT) vs. 66-70 Gy in 6 fx

per week (AccRT)

Weekly cisplatin

30 mg/m2

YES

5-year: 32%

(ConvRT) vs. 49%

(CRT) vs. 27%

(AccRT), p=0.049

NO

Fallai, 200627

Olmi,

2003158 192 100% 27% (all

T3 N0-1)

66-70 Gy in 33-35 daily fx

(RT arm 1, CRT) vs. 64-

67.2 Gy in 40-42 fx BID,

with 2 week break (RT arm

2)

Carboplatin and 5-

FU q4 weeks

YES

5-year: 21% (RT 1)

vs. 18% (RT 2) vs.

48% (CRT), p=0.02

NO

Ang, 201435 891 70% 14%

72 Gy in 42 fx (3d-CRT) or

70 Gy in 35 fx (IMRT) over

6 weeks

Bolus cisplatin q3

weeks vs. bolus

cisplatin +

cetuximab

NO NO

Nguyen-Tan,

201437

Ang, 20104

743 (721

analyzed) 60% 22%

70 Gy in 35 fx over 7 weeks

(ConvRT) vs. 72 Gy in 42

fx over 6 weeks (AccRT)

Bolus cisplatin q3

weeks (3 cycles for

ConvRT, 2 cycles

for AccRT)

NO NO

Rasch,

201040 239 63% 5%

46 Gy in 23 daily fx + 24

Gy boost in 12 daily fx

(total 70 Gy)

Weekly intra-

arterial cisplatin

vs. intravenous

cisplatin q3 weeks

NO NO

Bonner,

2006159,160 424 60% 25%


weeks or 72-76.8 Gy in 60-

64 fx BID over 10 weeks or

Weekly cetuximab

(+ loading dose YES

YES


Author and

year

Number

of

patients

%

oropharynx

% stage


Chemotherapy

regimen/

schedule


32.4 Gy in 18 daily fx +

39.6 Gy boost in 24 fx BID

one week before

RT)

3-year: 34% (RT)

vs. 47% (CRT),

p<0.01


55% (CRT), p=0.05

5-year: 36.4% (RT)

vs. 45.6% (CRT),

p=0.018

Abbreviations: CRT = Chemoradiotherapy; -- = Not Reported, NS= Not significant; ConvRT: Conventional radiotherapy; AccRT: 2232

Accelerated radiotherapy; Fx: Fractions; BID: Twice daily; LRC = locoregional control; OS = overall survival. 2233

2234

2235


Table 3. Summary of phase III randomized trials comparing postoperative radiotherapy with postoperative radiotherapy plus 2236

concurrent high-dose intermittent cisplatin (Key Question 2). 2237

Trial number

Number

of

patients

Median

follow-up

%

oropharynx LRC Benefit DM Benefit DFS/PFS Benefit OS Benefit

Bernier,

200444

(EORTC

22931)

334 5 years 30%

YES

5-year cumulative

incidence of

recurrence: 18%

CRT vs. 31% RT

(p=0.007)

NO

YES

5-year: 47%

(CRT) vs. 36%

(RT) (p=0.04)

YES

5-year: 53%

(CRT) vs. 40%

(RT) (p=0.02)

Cooper, 200445

(NRG 9501) 416 3.8 years 42%

YES

At median follow-

up 45.9 months,

cumulative

incidence of

recurrence: 19%

CRT vs. 30%

CRT (p=0.01)

NO

YES

Hazard ratio 0.78

(p=0.04) favoring

CRT

NO

Cooper, 201246

(NRG 9501) 410 9.4 years 42% NO NO NO NO

Abbreviations: EORTC = European Organisation for Research and Treatment of Cancer; NRG =; LRC = locoregional control; DM = 2238

distant metastasis; DFS = disease-free survival; OS = overall survival; CRT = chemoradiotherapy; RT = radiotherapy 2239

2240

2241

2242


Table 4. Summary of phase III randomized trials comparing postoperative radiotherapy with postoperative radiotherapy plus 2243

concurrent systemic therapy not using high-dose intermittent cisplatin (Key Question 2) 2244

Author

and year

Number

of

patients

Patient risk

factors

%

oropharyn

x

Chemotherap

y

schedule

RT dose/

schedule LRC Benefit DM Benefit DFS Benefit OS Benefit

Bachaud,

199654

Bachaud,

199155

83

ECE: 100%

PSM: 35%

≥3 positive

nodes or

bulky mass:

33%

15%

Cisplatin

weekly 50 mg

x 7-9

54 Gy in 32 fx

over 6.5

weeks

Close/positive

margins: boost

to 65-70 Gy in

1.8-2.0 Gy fxs

Metastatic

nodes: boost

to 65-74 Gy in

3 Gy fxs

YES

5-yr survival

without LRR

55% (RT) vs.

70% (CRT),

p=0.05

NO

YES

5-year: 23%

(RT) vs. 45%

(CRT), p<0.02

YES

2-year: 13%

(RT) vs. 36%

(CRT), p<0.01

Rewari,

200657 205

PSM

27%

≥2 positive

nodes: 34%

23%

Mitomycin C

15 mg/m2 x 1-

2

At least 54 Gy

in 27-30 fxs

over 5.5-6

weeks, median

60 Gy

YES

5-year (crude):

69.9% (RT)

vs. 85.3%

(CRT),

p=0.008

NO -- NO

Zakotnik,

200763

Smid,

200362

114

ECE: 53%

PSM: 12%

LVI: 18%

PNI: 4%

30%

Mitomycin C

15 mg/m2

Bleomycin

5 mg twice

weekly

56–70 Gy in

28-35 fxs over

5.5-7 weeks

YES

5-year: 65%

(RT) vs. 88%

(CRT),

p=0.026

NO

YES

5-year: 33%

(RT) vs. 53%

(CRT),

p=0.035

NO


Author

and year

Number

of

patients

Patient risk

factors

%

oropharyn

x

Chemotherap

y

schedule

RT dose/

schedule LRC Benefit DM Benefit DFS Benefit OS Benefit

Racadot,

200864 144

ECE: 31%

PSM:

22%

≥2 positive

nodes: 36%

49%

Carboplatin 50

mg/m2 twice

weekly x 6-8

weeks

54 Gy in 30 fx

over 6 weeks

for negative

margins

72 Gy in 40 fx

over 8 weeks

for positive

margins

NO -- -- NO

Argiris,

200865 72

ECE: 75%

PSM: 29%

PNI: 10%

32%

Carboplatin

100 mg/m2

weekly x 6

weeks

At least 59.4

Gy in 33 fxs

over 6.5 weeks

(boost

allowed)

NO NO NO NO

Tobias,

201066

253

(pts who

received

surgery)

PSM: 53% 23%

Methotrexate

or vincristine,

bleomycin,

fluorouracil +

methotrexate

on days 1 + 14

of RT

Varied by

center -- -- NO NO

Abbreviations: RT: Radiation Therapy; CRT: Chemoradiotherapy; Pts: Patients; Fx: Fractions; Yrs = Years; -- = Not reported; DM = 2245

Distant metastases; OS = overall survival; LRC = locoregional control; LRF = locoregional failure; w/o = Without; NS = Not 2246

significant; Min = Minimum; DFS = disease-free survival; ECE = extracapsular extension; PSM = positive surgical margins; PNI = 2247

perineural invasion; LVI = lymphovascular invasion; 2248

2249

2250


Table 5. Summary of key studies investigating intermediate-risk pathologic factors for recurrence following primary surgical 2251

resection with and without adjuvant radiotherapy (Key Question 2) 2252 2253

Author and

year

Number of

patients

%

oropharynx

N stage:

N0/N1/N2/

N3

T stage:

T1/T2/T3/T

4

Prevalence

of LVI

and/or PNI

LRF Impact DFS Impact OS Impact

Langendijk,

200573

801

20%

N0: 29%

N1: 15%

N2a: 3%

N2b: 37%

N2c: 13%

N3: 3%

T1: 12%

T2: 24%

T3: 32%

T4: 32%

LVI: 4%

PNI: 16%

YES (LVI, PNI)

5-year:

33% (LVI present)

vs. 21% (LVI

absent), p=0.011

31% (PNI present)

vs. 22% (PNI

absent), p=0.026

YES

5-year: 65% (class

I) vs. 47% (class

II) vs. 32% (class

III), p<0.0001*

YES

5-year: 67% (class

I) vs. 50% (class II)

vs. 36% (class III),

p<0.0001*

Ambrosch,

200174 503 28%

N0: 50%

N1: 18%

N2a: 2%

N2b: 26%

N2c: 5%

T1: 14%

T2: 38%

T3: 30%

T4: 18%

(oropharynx

only)

--

P values not reported

3-year: 8.5%

(surgery) vs. 4.7%

(surgery + RT)

Failure in neck

without RT:

pN0: 5.5% vs. 0%

pN1: 6.3% vs. 3%

pN2: 24% vs. 7%

--

YES

pT category: risk

ratio 1.6, pT3/4 vs.

pT1/2 (p=0.0009)

pN category: risk

ratio 1.9 and 2.8 for

pN1 and pN2,

respectively vs.

pN0 (p=0.0001)

Jackel,

200875 118 29% N1: 100%

T1: 24%

T2: 38%

T3: 27%

--

NO (+/- RT)

Any regional failure

without RT: 9% vs.

-- NO (+/- RT)


Author and

year

Number of

patients

%

oropharynx

N stage:

N0/N1/N2/

N3

T stage:

T1/T2/T3/T

4

Prevalence

of LVI

and/or PNI


T4: 12%

(oropharynx

only)

21% (10% isolated,

no p value)

3-year risk of

isolated regional

recurrence: 11.2%

(no RT) vs. 2.9% RT

(p=0.09)

Leemans,

199480 244 13% N/R

Tx: 2%

T1: 7%

T2: 27%

T3: 43%

T4: 21%

--

YES (T stage)

94.7% (T1-2) vs.

83.8% (T3-T4),

p=0.015

(primary site failure)

-- --

Haughey,

201281 171 100%

N0: 9%

N1: 14%

N2a: 18%

N2b: 42%

N2c: 10%

N3: 7%

T1: 41%

T2: 34%

T3: 16%

T4: 9%

LVI: 15%

PNI: 12%

--

NO (T-stage) --

Ravasz,

199382 80 28% N/R

T1-T2: 15%

T3-T4: 85%

LVI: 41%

PNI: 13%

YES (LVI)

50% (LVI present)

vs. 16% (LVI

absent), p=0.005

(local only failure))

(PNI not significant)

-- --


Author and

year

Number of

patients

%

oropharynx

N stage:

N0/N1/N2/

N3

T stage:

T1/T2/T3/T

4

Prevalence

of LVI

and/or PNI


Bastit,

200183 420

45%

N0: 32%

N1: 29%

N2: 34%

N3: 5%

T1: 5%

T2: 30%

T3: 55%

T4: 11%

Either LVI or

PNI: 18%

YES (LVI)

Tumor emboli RR

1.48, p=0.061

-- --

McMahon,

200384

237

Sydney, 95

Lanarkshir

e

42%

Sydney,

23%

Lanarkshire

Sydney

N0: 43%

N1: 15%

N2a: 3%

N2b: 29%

N2c: 7%

N3: 3%

Lanarkshire

N0: 69%

N1: 10%

N2a: 2%

N2b: 13%

N2c: 4%

N3: 1%

Sydney

T1: 18%

T2: 41%

T3: 30%

T4: 11%

Lanarkshire

T1: 17%

T2: 63%

T3: 17%

T4: 4%

--

YES (PNI)

(on multivariable

analysis)

--

NO (PNI, LVI)

Fagan,199885 142

47% (oral

cavity and

oropharynx)

N/R

T1: 8%

T2: 42%

T3: 26%

T4: 24%

PNI: 52%

YES (PNI)

23% (PNI present)

vs. 9% (PNI absent),

p=0.02

(local only; oral

cavity + oropharynx)

--

--


Author and

year

Number of

patients

%

oropharynx

N stage:

N0/N1/N2/

N3

T stage:

T1/T2/T3/T

4

Prevalence

of LVI

and/or PNI


Lanzer,

201386 291 32%

N0: 37%

N1: 13%

N2a: 10%

N2b: 31%

N2c: 5%

N3: 4%

T1-2: 52%

T3-4: 30%

Tx: 8%

LVI: 7%

PNI: 8%

YES (PNI)

Ipsilateral regional

recurrence:

26% (PNI present)

vs. 6% (PNI absent),

p=0.001

19% (LVI present)

vs. 7% (LVI absent),

p=0.048

Contralateral

regional recurrence:

9% (PNI present) vs.

1% (PNI absent),

p=0.002

LVI: negative

NO (PNI, LVI)

NO (PNI, LVI)

Peters,

1993138 240 18%

Nx: 8%

N0: 38%

N1: 18%

N2: 22%

N3: 15%

Tx: 11%

T1: 2%

T2: 18%

T3: 50%

T4: 22%

PNI: 24% NO (PNI) -- --

Abbreviations: LVI: Lymphovascular invasion; PNI: Perineural invasion; --: Not reported; LRF = locoregional failure; DFS = 2254

disease-free survival; OS = overall survival 2255

* Class I (intermediate risk): free surgical margins and no extranodal spread; class II (high risk): T1, T2, and T4 tumors with close or 2256

positive surgical margins or one lymph node metastasis with extranodal spread; class III (very high risk):T3 tumors with close or 2257

positive surgical margins or multiple lymph node metastases with extranodal spread or N3 neck. 2258

2259


Table 6. Summary of phase III randomized trials comparing radiotherapy (or chemoradiotherapy) with induction 2260

chemotherapy followed by the same (Key Question 3) 2261

Author

and year

Number of

patients

%

oropharynx

Induction

regimen

Concurrent

regimen

Radiotherapy

regimen

LRC

Benefit DM Benefit OS Benefit

Induction chemotherapy followed by local therapy (surgery or radiotherapy alone)

Zorat 2004,

Pacagnella

199494

237

59.3%

(group A),

54.6%

(group B)

Cisplatin-5FU x

4 cycles None

Resection and

adjuvant RT

(45-50 Gy) for

operable pts

and definitive

RT for

inoperable

(65-70 Gy)

(group B)

YES

84% (group

A) vs 72%

(group B),

p=0.05

YES

3 years: 24% DM

(IC) vs. 42% DM

(RT only),

(p=0.04)

YES

5/10 years:

21%/16% vs.

8%/6%, p=0.04 for

inoperable patients

Domenge,

200096

318 (161pts -

no IC grp) 100%

Cisplatin-5FU x

3 cycles None

70 Gy/35 fx

over 7 weeks,

plus 5 Gy

boost to

residual tumor;

or resection

NO NO

YES

Median 5.1 yr in

IC vs. 3.3 yr RT/

surgery alone

(p=0.03)

Lewin,199

7161 461 55%

Cisplatin-5FU x

3 cycles None

64-70 Gy in 2

Gy daily fx -- NO NO

Sequential (Induction chemotherapy followed by chemotherapy)

Hitt,201416

2

439 pts: 155

(TPF-CRT),

156 ( PF-

CRT ) and

128 (CRT

alone)

43%

Cisplatin-5FU

vs. Cisplatin-

5FU-Docetaxel x

3 cycles

Bolus

cisplatin q3

weeks

70 Gy/35 daily

fx NO NO NO

Haddad,

2013102

145 55%

Cisplatin-5FU-

Docetaxel x 3

cycles

Bolus

cisplatin q3

weeks (no

CRT: 72 Gy in

6 weeks NO NO NO


Author

and year

Number of

patients

%

oropharynx

Induction

regimen

Concurrent

regimen

Radiotherapy

regimen

LRC

Benefit DM Benefit OS Benefit

IC); weekly

carboplatin

(AUC 1.5)

after TPF for

good

responders,

weekly

docetaxel (20

mg/m2) for

poor

responders

(accelerate

boost)

Post-IC: 72 Gy

in 6 weeks for

poor

responders; 70

Gy in 7 weeks

for good

responders

Cohen,

2014103 285 58%

Cisplatin-5FU-

Docetaxel x 2

cycles

Docetaxel,

hydroxyurea,

5-FU

74-75 Gy in 4

courses of BID

RT, 1 week

apart

NO

NO

Except

~10% (IC) vs.

20% (CRT) DM

without prior LRR

(p=0.043)

NO

Abbreviations: CRT = Chemoradiotherapy; RT = Radiotherapy; -- = Not Reported; IC = induction chemotherapy; NS= Not 2262

significant; Fx: Fractions; BID: Twice daily; DM = distant metastasis; Gy = Gray; LRR = locoregional recurrence. FU = fluorouracil; 2263

TPF = docetaxel, cisplatin, fluoruracil; AUC = area under curve. 2264

2265

2266

2267

2268


Table 7: Summary of phase III randomized trials comparing radiotherapy with altered fractionation radiotherapy. (Key 2269

Question 4) 2270 2271

Author

and year

Number

of

patients

%

oropharynx

% stage

III

Altered

fractionation RT

regimen

Reference

RT regimen

Chemotherapy

regimen/

schedule

LRC Benefit OS Benefit

Bourhis,

201223

840 66% --

40 Gy in 20 daily

fx over 4 weeks

plus 30 Gy in 20

fx BID over 2

weeks (AFX),

64.8 Gy in 36 fx

BID over 3.5

weeks (VeryAFX)

70 Gy 35

fractions over

7 weeks

Carboplatin (3

cycles of 4 days

for CRT, 2

cycles of 5 days

for AFX) +

fluorouracil (q3

wks for CRT,

q4 wks for

AFX)

YES (to CRT)

3-year: 58.3% (CRT)

vs. 54.6% (AFX) vs.

50.1% (VeryAFX),

p=0.033 (AFX vs.

VeryAFX), p=0.045

(CRT vs. VeryAFX)

YES (to CRT)

3-year: 42.6%

(CRT)

vs. 36.5%

(VeryAFX),

p=0.040

Nguyen-

Tan,

201437

743 (721

analyzed)

60% 21%

AFX with boost

plus cisplatin (72

Gy in 42 fxs over

6 weeks)

70 Gy in 35

fractions over

7 weeks plus

cisplatin

Bolus cisplatin

q3 weeks (3

cycles for SFX,

2 cycles for

AFX)

NO NO

Beitler,

2014112 1076 60%

Not

reported

HFX (81.6 Gy

BID);

AFX-continuous

(72 Gy in 6

weeks); AFX-split

(67.2 Gy with 2-

wk rest after 38.4

Gy)

70 Gy/35 fx,

once-daily None

NO

Except HFX vs. SFX

HR 0.79, p=0.05 (if

censoring after 5

years)

NO

Except HFX vs.

SFX HR 0.81,

p=0.05 (if

censoring after 5

years)

Horiot,

1997113 500 100% --

Hyperfractionated

and AFX (72 Gy

in 45 fx over 5

weeks)

70 Gy in 35 fx None

YES

5 years: 46% SFX arm

vs. 59% AFX arm;

p=0.02

NO


Author

and year

Number

of

patients

%

oropharynx

% stage

III

Altered

fractionation RT

regimen

Reference

RT regimen

Chemotherapy

regimen/

schedule

LRC Benefit OS Benefit

Zackrisson,

2011118 750 49% 28%

AFX (68 Gy in 23

fxs of 2 Gy and 20

daily boost fxs of

1.1 Gy,over 4.5

weeks)

68 Gy/34 fx,

once-daily None NO NO

Overgaard1

25 1476

29%

(pharynx) 21%

AFX, 66-68

Gy/33-34 fx, 6 fx

per week

66-68 Gy in

33-34 fx, 5 fx

per week

None

YES

5-year: 70% (AFX) vs

60% (SFX)

group

p = 0.0005

NO

Overgaard1

26 900

53%

(pharynx) 37%

AFX, 66-70

Gy/33-35 fx, 6 fx

per week

66-68 Gy in

33-34 fx, 5 fx

per week

None

YES

5 years: 42% (AFX)

vs 30% (SFX)

group

p = 0.004

NO

Poulsen,

2001128 343 67%

Favorable-

12 %

Unfavorab

le- 19%

AFX (59.4 Gy in

33 fxs over 24

days)

70 Gy in 35

fxs over 49

days

None NO NO

Horiot,

1992129 325 100% 56%

80.5 Gy in 70 BID

fractions in 7

weeks

70 Gy 35

fractions over

7 weeks

None

YES

5-year: 59% (HFX) vs.

40% (SFX) (p=0.02)

NO

Abbreviations: OS: Overall survival; DFS: Disease free survival; AFX: Accelerated radiotherapy; Not reported; SFX: Standard 2272

fractionation; fx: Fractions; CRT: Conventional chemoradiotherapy; BID = twice per day. 2273

2274

2275


Table 8. Studies exploring the role of ipsilateral-only radiation therapy in patients with oropharyngeal cancer squamous cell 2276

carcinoma, including years, primary site distribution, treatment, and TNM staging (Key Question 4) 2277

Author and

year Years of

Treatment

Number of

patients

(#OP)

% OP

Cancers

in the

Tonsil

%

Definitiv

e XRT

% IMRT %

Chemo

% T-

Category

% N-Category

% Stage

O’Sullivan

et al110 1970-1991 228 (228) 100 100 0 0

Tx: 0

T1: 32

T2: 52

T3: 13

T4: 3

Nx: 0

N0:58

N1:25

N2a:12

N2b:4

N3:1

I: 19

II: 33

III: 28

IV: 20

Corvo et al147 2001-2002 30 (22) 59 68 0 53 -- -- --

Rusthoven et

al148 2003-2007 20 (20) 100 30 45 95

Tx: 0

T1: 55

T2: 35

T3: 10

T4: 0

Nx: 0

N0: 0

N1: 20

N2a: 15

N2b: 65

N3: 0

I: 0

II: 0

III: 20

IV: 80

Kagei et al149 1989-1996 32 (32) 63 100 0 0

Tx: 0

T1: 21

T2: 38

T3: 37

T4: 6

Nx: 0

N0:69

N1:16

N2a:13

N2b:13

N3:3

--

Koo et al150 2003-2011 20 (20) 100 30 30 30

Tx: 0

T1: 35

T2: 60

T3: 5

T4: 0

Nx: 0

N0: 10

N1: 40

N2a: 10

N2b: 40

N3: 0

I: 5

II: 45

III: 50

IV: 0

Liu et al*151 1990-2002 58 (58) 100 100 0 -37 Tx: 2 Nx: 0 I: 10


T1: 15

T2: 52

T3: 29

T4: 2

N0: 43

N1: 24

N2a: 18

N2b: 7

N3: 9

II: 17

III: 40

IV: 33

Jackson et al152 1975-1993 178 (178) 100 100 0 0

Tx: 0

T1: 21

T2: 45

T3: 29

T4: 5

Nx: 0

N0:57

N1:30

N2a: 4

N2b: 4

N3: 9

I: 13

II: 24

III: 46

IV: 17

Lynch et al**154 1995-2011 136 (136) 100 43 0 -63

Tx: 0

T1: 42

T2: 54

T3: 4

T4: 0

Nx: 0

N0: 20

N1: 15

N2a: 23

N2b: 40

N3: 2

--

Chronowski et

al155 1970-2007 102 (102) 100 92 67 5

Tx: 17

T1: 51

T2: 33

T3: 0

T4: 0

Nx: 2

N0: 32

N1: 22

N2a: 21

N2b: 22

N3: 0

--

Al-Mamgani et

al156 2000-2011 185 (185) 70 100 100 6

Tx: 0

T1: 27

T2: 66

T3: 7

T4: 0

Nx: 0

N0: 50

N1: 23

N2a: 10

N2b: 17

N3: 0

--

*Smoking status available for 53 patients with 38% current smokers and 17% never smokers; P16 available for 15 patients with 60% 2278

P16 positive 2279

**Smoking status available for 113 patients with 54% having >10 pack/years and 37% never smokers 2280


Table 9. Studies exploring the role of ipsilateral-only radiation therapy in patients with oropharyngeal cancer with details of 2281

survival and contralateral nodal metastases (Key Question 4) 2282 2283

Author and year % Grade

3+

Late

Toxicity

5yr %

Overall

Survival

5yr %

Disease

Specific

Survival

5yr %

Local

Recurrence

5yr %

Regional

Recurrenc

e

Crude

Contralater

al Nodal

Recurrence

Risk (%)

Isolated

(no other

site of

recurrence)

Contralater

al

Recurrence

Risk (%)

TNM of Those

with Isolated

Contralateral

Recurrence

O’Sullivan et al110 3.4 N/R 76 (3yr) 23 (3yr) 19 (3yr) 3.5 3 T2N1 (SP-BOT

ext.)

Corvo et al147 N/R N/R N/R N/R N/R 6.7 6.7 T3N2b

Rusthoven et al148 0 80 (2yr) 80 (2yr

DFS) 21 (2yr) 0 0 0 N/A

Kagei et al149 3.1 64 (3yr) 79 (3yr) 26 19 0 0 N.A.

Koo et al150 0 95 95 (PFS) 5 0 0 0 N/A

Liu et al*151 7 N/R 83 (crude

DFS) 9 4 0 0 N/A


Jackson et al152 3.4 56 69 25 14 2.6 N/R

T2N0

T3N0

T1-3N1

T1-3N1

Lynch et al**154 9 89 86 2 (crude) 7 (crude) 5.9 4.4

T2N2b

T2N2b (ECE)

T2N2b (ECE)

T2N2b (ECE)

T2N2b (ECE)

T2N2b (ECE)

Chronowski et al155 N/R 95 96 (DFS) 0 2 2 1 T2N0 (spm)

Al-Mamgani et al156 2.2 70 84 (DFS) 9 4 1.1 1.1 T1N2b

T2N0

Abbreviations: YR: year; N/R: Not Reported; DFS: Disease-free survival; PFS: Progression-free survival; N/A: Not applicable; SP-2284

BOT ext.: Soft palate and/or base of tongue extension; spm: most likely a second primary malignancy of contralateral base of tongue 2285

with nodal metastasis; ECE: Extra-capsular nodal extension 2286

2287

2288

2289

2290

2291

2292

2293

2294


Table 10. Consensus statement for use of ipsilateral-only radiation therapy in patients with oropharyngeal squamous cell 2295

carcinoma (Key Question 4). 2296 2297

Strongly

recommended

(if all of the

following)

Conditionally

recommended

(based on extension or N

category)

Primary Site Tonsil Tonsil

Soft Palate involvement None <1cm

T Category T1 or T2 T1 or T2

N Category N0 or N1 N2a

Extra-Capsular Nodal Extension None None

Human Papillomavirus Status Unknown impact Unknown impact

2298


References: 2299

1. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human 2300 papillomavirus and a subset of head and neck cancers. Journal of the National Cancer Institute. 2301 May 3 2000;92(9):709-720. 2302

2. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal 2303 cancer incidence in the United States. Journal of clinical oncology : official journal of the 2304 American Society of Clinical Oncology. Nov 10 2011;29(32):4294-4301. 2305

3. Gillison ML, D'Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus 2306 type 16-positive and human papillomavirus type 16-negative head and neck cancers. Journal of 2307 the National Cancer Institute. Mar 19 2008;100(6):407-420. 2308

4. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 2309 oropharyngeal cancer. N Engl J Med. Jul 1 2010;363(1):24-35. 2310

5. Graham R, Mancher M, Wolman DM, Greenfield S, Steinberg E., eds. Clinical Practice Guidelines 2311 We Can Trust. Washington, DC: The National Academies Press;2011. 2312

6. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of 2313 evidence. Journal of clinical epidemiology. Apr 2011;64(4):401-406. 2314

7. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to 2315 recommendations: the significance and presentation of recommendations. Journal of clinical 2316 epidemiology. Jul 2013;66(7):719-725. 2317

8. Loblaw DA, Prestrud AA, Somerfield MR, et al. American Society of Clinical Oncology Clinical 2318 Practice Guidelines: formal systematic review-based consensus methodology. J Clin Oncol. 2319 2012;30(25):3136-3140. 2320

9. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation 2321 therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable 2322 squamous cell head and neck cancer. J Clin Oncol. Jan 1 2003;21(1):92-98. 2323

10. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant 2324 chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Journal of the 2325 National Cancer Institute. Dec 15 1999;91(24):2081-2086. 2326

11. Ruo Redda MG, Ragona R, Ricardi U, et al. Radiotherapy alone or with concomitant daily low-2327 dose carboplatin in locally advanced, unresectable head and neck cancer: definitive results of a 2328 phase III study with a follow-up period of up to ten years. Tumori. Mar-Apr 2010;96(2):246-253. 2329

12. Zakotnik B, Smid L, Budihna M, et al. Concomitant radiotherapy with mitomycin C and 2330 bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. 2331 International journal of radiation oncology, biology, physics. Jul 15 1998;41(5):1121-1127. 2332

13. Ghosh-Laskar S, Kalyani N, Gupta T, et al. Conventional radiotherapy versus concurrent 2333 chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of 2334 head and neck: Results of a prospective randomized trial. Head & neck. Sep 15 2014. 2335

14. Zakotnik B, Smid L, Budihna M, et al. Concomitant radiotherapy with mitomycin C and 2336 bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. 2337 Int J Radiat Oncol Biol Phys. Jul 15 1998;41(5):1121-1127. 2338

15. Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: 2339 conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant 2340 radiotherapy and chemotherapy--a multicenter randomized trial. International journal of 2341 radiation oncology, biology, physics. Jan 1 2003;55(1):78-92. 2342

16. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and 2343 Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant 2344


radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol. Jan 1 2004;22(1):69-2345 76. 2346

17. Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits 2347 the additional benefit of simultaneous chemotherapy--results of a multicentric randomized 2348 German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. Aug 1 2349 2001;50(5):1161-1171. 2350

18. Ghadjar P, Simcock M, Studer G, et al. Concomitant cisplatin and hyperfractionated radiotherapy 2351 in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial 2352 (SAKK 10/94). Int J Radiat Oncol Biol Phys. Feb 1 2012;82(2):524-531. 2353

19. Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus 2354 radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin 2355 Oncol. Apr 1998;16(4):1318-1324. 2356

20. Bourhis J, Lapeyre M, Tortochaux J, et al. Accelerated radiotherapy and concomitant high dose 2357 chemotherapy in non resectable stage IV locally advanced HNSCC: results of a GORTEC 2358 randomized trial. Radiother Oncol. Jul 2011;100(1):56-61. 2359

21. Budach V, Stromberger C, Poettgen C, et al. Hyperfractionated accelerated radiation therapy 2360 (HART) of 70.6 Gy with concurrent 5-FU/Mitomycin C is superior to HART of 77.6 Gy alone in 2361 locally advanced head and neck cancer: long-term results of the ARO 95-06 randomized phase III 2362 trial. International journal of radiation oncology, biology, physics. Apr 1 2015;91(5):916-924. 2363

22. Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated chemoradiation with 2364 concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated 2365 accelerated radiation therapy alone in locally advanced head and neck cancer: final results of 2366 the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 2367 Prospective Randomized Trial. J Clin Oncol. Feb 20 2005;23(6):1125-1135. 2368

23. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of 2369 radiotherapy with or without concomitant chemotherapy in locally advanced head and neck 2370 carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. The Lancet. Oncology. Feb 2371 2012;13(2):145-153. 2372

24. Adelstein DJ. Oropharyngeal cancer: the role of chemotherapy. Current treatment options in 2373 oncology. Feb 2003;4(1):3-13. 2374

25. Ghosh-Laskar S, Kalyani N, Gupta T, et al. Conventional radiotherapy versus concurrent 2375 chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of 2376 head and neck: Results of a prospective randomized trial. Head Neck. Sep 15 2014. 2377

26. Denis F, Garaud P, Bardet E, et al. Late toxicity results of the GORTEC 94-01 randomized trial 2378 comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx 2379 carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. 2380 International journal of radiation oncology, biology, physics. Jan 1 2003;55(1):93-98. 2381

27. Fallai C, Bolner A, Signor M, et al. Long-term results of conventional radiotherapy versus 2382 accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and 2383 chemotherapy in locoregionally advanced carcinoma of the oropharynx. Tumori. 2006;92(1):41-2384 54. 2385

28. Semrau R, Mueller RP, Stuetzer H, et al. Efficacy of intensified hyperfractionated and accelerated 2386 radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results 2387 of a randomized multicentric trial in advanced head-and-neck cancer. International journal of 2388 radiation oncology, biology, physics. Apr 1 2006;64(5):1308-1316. 2389


29. Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck 2390

cancer (MACH-NC): a comprehensive analysis by tumour site. Radiotherapy and oncology : 2391 journal of the European Society for Therapeutic Radiology and Oncology. Jul 2011;100(1):33-40. 2392

30. Blanchard P, Hill C, Guihenneuc-Jouyaux C, Baey C, Bourhis J, Pignon JP. Mixed treatment 2393 comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and 2394 neck cancer. Journal of clinical epidemiology. Sep 2011;64(9):985-992. 2395

31. Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck 2396 cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and 2397 oncology : journal of the European Society for Therapeutic Radiology and Oncology. Jul 2398 2009;92(1):4-14. 2399

32. Xiao C, Hanlon A, Zhang Q, et al. Risk factors for clinician-reported symptom clusters in patients 2400 with advanced head and neck cancer in a phase 3 randomized clinical trial: RTOG 0129. Cancer. 2401 Mar 15 2014;120(6):848-854. 2402

33. Bourhis J, Calais G, Lapeyre M, et al. Concomitant radiochemotherapy or accelerated 2403 radiotherapy: analysis of two randomized trials of the French Head and Neck Cancer Group 2404 (GORTEC). Seminars in oncology. Dec 2004;31(6):822-826. 2405

34. Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-2406 03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced 2407 squamous cell carcinomas of the head and neck. Journal of clinical oncology : official journal of 2408 the American Society of Clinical Oncology. Jul 15 2004;22(14):2856-2864. 2409

35. Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated 2410 radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: 2411 RTOG 0522. J Clin Oncol. Sep 20 2014;32(27):2940-2950. 2412

36. Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without 2413 erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized 2414 phase II trial. Journal of clinical oncology : official journal of the American Society of Clinical 2415 Oncology. Apr 10 2013;31(11):1415-1421. 2416

37. Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized Phase III Trial to Test Accelerated Versus 2417 Standard Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas 2418 in the Radiation Therapy Oncology Group 0129 Trial: Long-Term Report of Efficacy and Toxicity. J 2419 Clin Oncol. Dec 1 2014;32(34):3858-3867. 2420

38. Alkureishi LW, de Bree R, Ross GL. RADPLAT: an alternative to surgery? The oncologist. May 2421 2006;11(5):469-480. 2422

39. Kumar P RK, Harris J, McCulloch T, Cmelak A, Sofferman R, Levine P, Fu K. Mature results of 2423 Radiation Therapy Oncology Group (RTOG) Trial 9615 using intra-arterial cisplatin (IA-P) and 2424 concurrent radiation therapy (RT) for stage IV-T4 head/neck (H/N) squamous cell carcinoma 2425 (SCCa). Journal of Clinical Oncology. 2005;Vol 23, No 16S (June 1 Supplement), 2005: 5579. 2426

40. Rasch CR, Hauptmann M, Schornagel J, et al. Intra-arterial versus intravenous chemoradiation 2427 for advanced head and neck cancer: Results of a randomized phase 3 trial. Cancer. May 1 2428 2010;116(9):2159-2165. 2429

41. Mesia R, Rueda A, Vera R, et al. Adjuvant therapy with cetuximab for locally advanced squamous 2430 cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial. Annals 2431 of oncology : official journal of the European Society for Medical Oncology / ESMO. Feb 2432 2013;24(2):448-453. 2433

42. Lok BH, Setton J, Caria N, et al. Intensity-modulated radiation therapy in oropharyngeal 2434 carcinoma: effect of tumor volume on clinical outcomes. International journal of radiation 2435 oncology, biology, physics. Apr 1 2012;82(5):1851-1857. 2436


43. Garden AS, Asper JA, Morrison WH, et al. Is concurrent chemoradiation the treatment of choice 2437

for all patients with Stage III or IV head and neck carcinoma? Cancer. Mar 15 2004;100(6):1171-2438 1178. 2439

44. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant 2440 chemotherapy for locally advanced head and neck cancer. The New England journal of medicine. 2441 May 6 2004;350(19):1945-1952. 2442

45. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and 2443 chemotherapy for high-risk squamous-cell carcinoma of the head and neck. The New England 2444 journal of medicine. May 6 2004;350(19):1937-1944. 2445

46. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III 2446 trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell 2447 carcinoma of the head and neck. International journal of radiation oncology, biology, physics. 2448 Dec 1 2012;84(5):1198-1205. 2449

47. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck 2450 cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials 2451 of the EORTC (#22931) and RTOG (# 9501). Head & neck. Oct 2005;27(10):843-850. 2452

48. Sinha P, Piccirillo JF, Kallogjeri D, Spitznagel EL, Haughey BH. The role of postoperative 2453 chemoradiation for oropharynx carcinoma: A critical appraisal of the published literature and 2454 National Comprehensive Cancer Network guidelines. Cancer. Jun 1 2015;121(11):1747-1754. 2455

49. Sinha P, Lewis JS, Jr., Piccirillo JF, Kallogjeri D, Haughey BH. Extracapsular spread and adjuvant 2456 therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer. Jul 15 2457 2012;118(14):3519-3530. 2458

50. Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: 2459 impact of site and human papillomavirus status. Cancer. Sep 15 2013;119(18):3302-3308. 2460

51. Klozar J, Koslabova E, Kratochvil V, Salakova M, Tachezy R. Nodal status is not a prognostic factor 2461 in patients with HPV-positive oral/oropharyngeal tumors. Journal of surgical oncology. May 2462 2013;107(6):625-633. 2463

52. Iyer NG, Dogan S, Palmer F, et al. Detailed Analysis of Clinicopathologic Factors Demonstrate 2464 Distinct Difference in Outcome and Prognostic Factors Between Surgically Treated HPV-Positive 2465 and Negative Oropharyngeal Cancer. Annals of surgical oncology. Mar 24 2015. 2466

53. Lewis JS, Jr., Carpenter DH, Thorstad WL, Zhang Q, Haughey BH. Extracapsular extension is a 2467 poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell 2468 carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of 2469 Pathology, Inc. Nov 2011;24(11):1413-1420. 2470

54. Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined 2471 postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck 2472 carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys. Dec 1 1996;36(5):999-2473 1004. 2474

55. Bachaud JM, David JM, Boussin G, Daly N. Combined postoperative radiotherapy and weekly 2475 cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: 2476 preliminary report of a randomized trial. International journal of radiation oncology, biology, 2477 physics. Feb 1991;20(2):243-246. 2478

56. Geiger JL, Lazim AF, Walsh FJ, et al. Adjuvant chemoradiation therapy with high-dose versus 2479 weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck 2480 squamous cell carcinoma. Oral oncology. Apr 2014;50(4):311-318. 2481


57. Rewari AN, Haffty BG, Wilson LD, et al. Postoperative concurrent chemoradiotherapy with 2482

mitomycin in advanced squamous cell carcinoma of the head and neck: results from three 2483 prospective randomized trials. Cancer journal (Sudbury, Mass.). Mar-Apr 2006;12(2):123-129. 2484

58. Weissberg JB, Son YH, Papac RJ, et al. Randomized clinical trial of mitomycin C as an adjunct to 2485 radiotherapy in head and neck cancer. International journal of radiation oncology, biology, 2486 physics. Jul 1989;17(1):3-9. 2487

59. Haffty BG, Son YH, Sasaki CT, et al. Mitomycin C as an adjunct to postoperative radiation therapy 2488 in squamous cell carcinoma of the head and neck: results from two randomized clinical trials. 2489 International journal of radiation oncology, biology, physics. Sep 30 1993;27(2):241-250. 2490

60. Haffty BG, Son YH, Wilson LD, et al. Bioreductive alkylating agent porfiromycin in combination 2491 with radiation therapy for the management of squamous cell carcinoma of the head and neck. 2492 Radiation oncology investigations. 1997;5(5):235-245. 2493

61. Haffty BG, Wilson LD, Son YH, et al. Concurrent chemo-radiotherapy with mitomycin C 2494 compared with porfiromycin in squamous cell cancer of the head and neck: final results of a 2495 randomized clinical trial. International journal of radiation oncology, biology, physics. Jan 1 2496 2005;61(1):119-128. 2497

62. Smid L, Budihna M, Zakotnik B, et al. Postoperative concomitant irradiation and chemotherapy 2498 with mitomycin C and bleomycin for advanced head-and-neck carcinoma. International journal 2499 of radiation oncology, biology, physics. Jul 15 2003;56(4):1055-1062. 2500

63. Zakotnik B, Budihna M, Smid L, et al. Patterns of failure in patients with locally advanced head 2501 and neck cancer treated postoperatively with irradiation or concomitant irradiation with 2502 Mitomycin C and Bleomycin. International journal of radiation oncology, biology, physics. Mar 1 2503 2007;67(3):685-690. 2504

64. Racadot S, Mercier M, Dussart S, et al. Randomized clinical trial of post-operative radiotherapy 2505 versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node 2506 involvement. Radiotherapy and oncology : journal of the European Society for Therapeutic 2507 Radiology and Oncology. May 2008;87(2):164-172. 2508

65. Argiris A, Karamouzis MV, Johnson JT, et al. Long-term results of a phase III randomized trial of 2509 postoperative radiotherapy with or without carboplatin in patients with high-risk head and neck 2510 cancer. The Laryngoscope. Mar 2008;118(3):444-449. 2511

66. Tobias JS, Monson K, Gupta N, et al. Chemoradiotherapy for locally advanced head and neck 2512 cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial. The Lancet. Oncology. Jan 2513 2010;11(1):66-74. 2514

67. Machtay Mitchell M. A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- 2515 Cetuximab for Locally-Advanced Resected Head and Neck Cancer. 2516

68. Rosenthal DI, Harris J, Forastiere AA, et al. Early postoperative paclitaxel followed by concurrent 2517 paclitaxel and cisplatin with radiation therapy for patients with resected high-risk head and neck 2518 squamous cell carcinoma: report of the phase II trial RTOG 0024. Journal of clinical oncology : 2519 official journal of the American Society of Clinical Oncology. Oct 1 2009;27(28):4727-4732. 2520

69. Harari PM, Harris J, Kies MS, et al. Postoperative chemoradiotherapy and cetuximab for high-risk 2521 squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. 2522 Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 10 2523 2014;32(23):2486-2495. 2524

70. Harari PM, Paul M, Rosenthal David I. Randomized Phase II/III Trial of Surgery and Postoperative 2525 Radiation Delivered with Concurrent Cisplatin versus Docetaxel versus Docetaxel and Cetuximab 2526 for High-Risk Squamous Cell Cancer of the Head and Neck. 3/5/2015. 2527


71. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for 2528

head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. 2529 MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. 2530 Lancet. Mar 18 2000;355(9208):949-955. 2531

72. Laramore GE, Scott CB, al-Sarraf M, et al. Adjuvant chemotherapy for resectable squamous cell 2532 carcinomas of the head and neck: report on Intergroup Study 0034. International journal of 2533 radiation oncology, biology, physics. 1992;23(4):705-713. 2534

73. Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. Risk-group 2535 definition by recursive partitioning analysis of patients with squamous cell head and neck 2536 carcinoma treated with surgery and postoperative radiotherapy. Cancer. Oct 1 2537 2005;104(7):1408-1417. 2538

74. Ambrosch P, Kron M, Pradier O, Steiner W. Efficacy of selective neck dissection: a review of 503 2539 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper 2540 aerodigestive tract. Otolaryngology--head and neck surgery : official journal of American 2541 Academy of Otolaryngology-Head and Neck Surgery. Feb 2001;124(2):180-187. 2542

75. Jackel MC, Ambrosch P, Christiansen H, Martin A, Steiner W. Value of postoperative 2543 radiotherapy in patients with pathologic N1 neck disease. Head & neck. Jul 2008;30(7):875-882. 2544

76. Shimizu K, Inoue H, Saitoh M, et al. Distribution and impact of lymph node metastases in 2545 oropharyngeal cancer. Acta oto-laryngologica. Aug 2006;126(8):872-877. 2546

77. McLaughlin MP, Mendenhall WM, Mancuso AA, et al. Retropharyngeal adenopathy as a 2547 predictor of outcome in squamous cell carcinoma of the head and neck. Head & neck. May-Jun 2548 1995;17(3):190-198. 2549

78. Weinstein GS, Quon H, Newman HJ, et al. Transoral robotic surgery alone for oropharyngeal 2550 cancer: an analysis of local control. Archives of otolaryngology--head & neck surgery. Jul 2551 2012;138(7):628-634. 2552

79. Kao J, Lavaf A, Teng MS, Huang D, Genden EM. Adjuvant radiotherapy and survival for patients 2553 with node-positive head and neck cancer: an analysis by primary site and nodal stage. 2554 International journal of radiation oncology, biology, physics. Jun 1 2008;71(2):362-370. 2555

80. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Recurrence at the primary site in head 2556 and neck cancer and the significance of neck lymph node metastases as a prognostic factor. 2557 Cancer. Jan 1 1994;73(1):187-190. 2558

81. Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p16+ 2559 oropharyngeal cancer. The Laryngoscope. Sep 2012;122 Suppl 2:S13-33. 2560

82. Ravasz LA, Hordijk GJ, Slootweg PJ, Smit F, Tweel IV. Uni- and multivariate analysis of eight 2561 indications for post-operative radiotherapy and their significance for local-regional cure in 2562 advanced head and neck cancer. The Journal of laryngology and otology. May 1993;107(5):437-2563 440. 2564

83. Bastit L, Blot E, Debourdeau P, Menard J, Bastit P, Le Fur R. Influence of the delay of adjuvant 2565 postoperative radiation therapy on relapse and survival in oropharyngeal and hypopharyngeal 2566 cancers. International journal of radiation oncology, biology, physics. Jan 1 2001;49(1):139-146. 2567

84. McMahon J, O'Brien CJ, Pathak I, et al. Influence of condition of surgical margins on local 2568 recurrence and disease-specific survival in oral and oropharyngeal cancer. The British journal of 2569 oral & maxillofacial surgery. Aug 2003;41(4):224-231. 2570

85. Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT. Perineural invasion in squamous 2571 cell carcinoma of the head and neck. Archives of otolaryngology--head & neck surgery. Jun 2572 1998;124(6):637-640. 2573


86. Lanzer M, Gander T, Kruse A, Luebbers HT, Reinisch S. Influence of histopathologic factors on 2574

pattern of metastasis in squamous cell carcinoma of the head and neck. The Laryngoscope. May 2575 2014;124(5):E160-166. 2576

87. Liao CT, Chang JT, Wang HM, et al. Does adjuvant radiation therapy improve outcomes in pT1-2577 3N0 oral cavity cancer with tumor-free margins and perineural invasion? International journal of 2578 radiation oncology, biology, physics. Jun 1 2008;71(2):371-376. 2579

88. Chinn SB, Spector ME, Bellile EL, et al. Impact of perineural invasion in the pathologically N0 2580 neck in oral cavity squamous cell carcinoma. Otolaryngology--head and neck surgery : official 2581 journal of American Academy of Otolaryngology-Head and Neck Surgery. Dec 2013;149(6):893-2582 899. 2583

89. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of 2584 surgery plus radiotherapy in advanced head-and-neck cancer. International journal of radiation 2585 oncology, biology, physics. Nov 1 2001;51(3):571-578. 2586

90. Psychogios G, Mantsopoulos K, Kuenzel J, et al. Primary surgical treatment of T2 oropharyngeal 2587 carcinoma. Journal of surgical oncology. Jun 1 2012;105(7):719-723. 2588

91. Grant DG, Hinni ML, Salassa JR, Perry WC, Hayden RE, Casler JD. Oropharyngeal cancer: a case 2589 for single modality treatment with transoral laser microsurgery. Archives of otolaryngology--2590 head & neck surgery. Dec 2009;135(12):1225-1230. 2591

92. Alicandri-Ciufelli M, Bonali M, Piccinini A, et al. Surgical margins in head and neck squamous cell 2592 carcinoma: what is 'close'? European archives of oto-rhino-laryngology : official journal of the 2593 European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German 2594 Society for Oto-Rhino-Laryngology - Head and Neck Surgery. Sep 2013;270(10):2603-2609. 2595

93. Group ECO. Transoral Surgery Followed By Low-Dose or Standard-Dose Radiation Therapy With 2596 or Without Chemotherapy in Treating Patients With HPV Positive Stage III-IVA Oropharyngeal 2597 Cancer. 2598

94. Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or 2599 IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. 2600 Journal of the National Cancer Institute. 1994;86(4):265-272. 2601

95. Zorat PL, Paccagnella A, Cavaniglia G, et al. Randomized phase III trial of neoadjuvant 2602 chemotherapy in head and neck cancer: 10-year follow-up. Journal of the National Cancer 2603 Institute. 2004;96(22):1714-1717. 2604

96. Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in 2605 oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tete et du Cou (GETTEC). 2606 Br J Cancer. 2000;83(12):1594-1598. 2607

97. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in 2608 head and neck cancer. N Engl J Med. 2007;357(17):1705-1715. 2609

98. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in 2610 unresectable head and neck cancer. The New England journal of medicine. Oct 25 2611 2007;357(17):1695-1704. 2612

99. Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil 2613 alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head 2614 and neck: long-term results of the TAX 324 randomised phase 3 trial. The Lancet. Oncology. 2615 2011;12(2):153-159. 2616

100. van Herpen CM, Mauer ME, Mesia R, et al. Short-term health-related quality of life and 2617 symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) 2618 for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 2619 24971/TAX 323). British journal of cancer. Oct 12 2010;103(8):1173-1181. 2620


101. Gupta D, Shukla P, Bisht SS, et al. A prospective comparision of sequential chemoradiation vs 2621

concurrent chemoradiation in locally advanced oropharyngeal carcinomas. Cancer Biol Ther. 2622 2009;8(3):213-217. 2623

102. Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent 2624 chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy 2625 alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. The 2626 Lancet. Oncology. Mar 2013;14(3):257-264. 2627

103. Cohen EE, Karrison TG, Kocherginsky M, et al. Phase III randomized trial of induction 2628 chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2629 2014;32(25):2735-2743. 2630

104. Hitt R, Grau JJ, Lopez-Pousa A, et al. A randomized phase III trial comparing induction 2631 chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment 2632 of unresectable head and neck cancer. Ann Oncol. 2014;25(1):216-225. 2633

105. Brockstein B, Haraf DJ, Rademaker AW, et al. Patterns of failure, prognostic factors and survival 2634 in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: 2635 a 9-year, 337-patient, multi-institutional experience. Annals of oncology : official journal of the 2636 European Society for Medical Oncology / ESMO. Aug 2004;15(8):1179-1186. 2637

106. O'Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human 2638 papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. 2639 Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Feb 10 2640 2013;31(5):543-550. 2641

107. Huang SH, Xu W, Waldron J, et al. Refining American Joint Committee on Cancer/Union for 2642 International Cancer Control TNM stage and prognostic groups for human papillomavirus-2643 related oropharyngeal carcinomas. Journal of clinical oncology : official journal of the American 2644 Society of Clinical Oncology. Mar 10 2015;33(8):836-845. 2645

108. Cmelak A, et al. Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable 2646 oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to 2647 induction chemotherapy (IC). . Journal of Clinical Oncology. 2014;Vol 32, No 18_suppl 2648

109. Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck 2649 cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2650 2009;92(1):4-14. 2651

110. O'Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral radiotherapy in 2652 carcinoma of the tonsillar region. International journal of radiation oncology, biology, physics. 2653 Oct 1 2001;51(2):332-343. 2654

111. Withers HR, Peters LJ, Taylor JM, et al. Local control of carcinoma of the tonsil by radiation 2655 therapy: an analysis of patterns of fractionation in nine institutions. International journal of 2656 radiation oncology, biology, physics. Oct 15 1995;33(3):549-562. 2657

112. Beitler JJ, Zhang Q, Fu KK, et al. Final results of local-regional control and late toxicity of RTOG 2658 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck 2659 cancer. Int J Radiat Oncol Biol Phys. 2014;89(1):13-20. 2660

113. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to 2661 conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced 2662 head and neck cancers: results of the EORTC 22851 randomized trial. Radiotherapy and 2663 oncology : journal of the European Society for Therapeutic Radiology and Oncology. Aug 2664 1997;44(2):111-121. 2665

114. Gregoire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck 2666 tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus 2667


guidelines. Radiotherapy and oncology : journal of the European Society for Therapeutic 2668 Radiology and Oncology. Jan 2014;110(1):172-181. 2669

115. Fletcher GH. Elective irradiation of subclinical disease in cancers of the head and neck. Cancer. 2670 Jun 1972;29(6):1450-1454. 2671

116. Overgaard J, Alsner J, Eriksen J, Horsman MR, Grau C. Importance of overall treatment time for 2672 the response to radiotherapy in patients with squamous cell carcinoma of the head and neck. 2673 Rays. Jul-Sep 2000;25(3):313-319. 2674

117. Ghoshal S, Goda JS, Mallick I, Kehwar TS, Sharma SC. Concomitant boost radiotherapy compared 2675 with conventional radiotherapy in squamous cell carcinoma of the head and neck--a phase III 2676 trial from a single institution in India. Clinical oncology (Royal College of Radiologists (Great 2677 Britain)). Apr 2008;20(3):212-220. 2678

118. Zackrisson B, Nilsson P, Kjellen E, et al. Two-year results from a Swedish study on conventional 2679 versus accelerated radiotherapy in head and neck squamous cell carcinoma--the ARTSCAN 2680 study. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology 2681 and Oncology. Jul 2011;100(1):41-48. 2682

119. Lambrecht M, Dirix P, Van den Bogaert W, Nuyts S. Incidence of isolated regional recurrence 2683 after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma. 2684 Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and 2685 Oncology. Dec 2009;93(3):498-502. 2686

120. Garden AS, Dong L, Morrison WH, et al. Patterns of disease recurrence following treatment of 2687 oropharyngeal cancer with intensity modulated radiation therapy. International journal of 2688 radiation oncology, biology, physics. Mar 15 2013;85(4):941-947. 2689

121. Duprez F, Bonte K, De Neve W, Boterberg T, De Gersem W, Madani I. Regional relapse after 2690 intensity-modulated radiotherapy for head-and-neck cancer. International journal of radiation 2691 oncology, biology, physics. Feb 1 2011;79(2):450-458. 2692

122. Kasibhatla M, Kirkpatrick JP, Brizel DM. How much radiation is the chemotherapy worth in 2693 advanced head and neck cancer? International journal of radiation oncology, biology, physics. 2694 Aug 1 2007;68(5):1491-1495. 2695

123. Nuyts S, Lambrecht M, Duprez F, et al. Reduction of the dose to the elective neck in head and 2696 neck squamous cell carcinoma, a randomized clinical trial using intensity modulated 2697 radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity. Radiotherapy and 2698 oncology : journal of the European Society for Therapeutic Radiology and Oncology. Nov 2699 2013;109(2):323-329. 2700

124. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized 2701 study to compare hyperfractionation and two variants of accelerated fractionation to standard 2702 fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 2703 9003. International journal of radiation oncology, biology, physics. Aug 1 2000;48(1):7-16. 2704

125. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of 2705 conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 2706 randomised controlled trial. Lancet. Sep 20 2003;362(9388):933-940. 2707

126. Overgaard J, Mohanti BK, Begum N, et al. Five versus six fractions of radiotherapy per week for 2708 squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre 2709 trial. The Lancet. Oncology. Jun 2010;11(6):553-560. 2710

127. Lassen P, Eriksen JG, Krogdahl A, et al. The influence of HPV-associated p16-expression on 2711 accelerated fractionated radiotherapy in head and neck cancer: evaluation of the randomised 2712 DAHANCA 6&7 trial. Radiother Oncol. 2011;100(1):49-55. 2713


128. Poulsen MG, Denham JW, Peters LJ, et al. A randomised trial of accelerated and conventional 2714

radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman 2715 Radiation Oncology Group Study. Radiotherapy and oncology : journal of the European Society 2716 for Therapeutic Radiology and Oncology. Aug 2001;60(2):113-122. 2717

129. Horiot JC, Le Fur R, N'Guyen T, et al. Hyperfractionation versus conventional fractionation in 2718 oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of 2719 radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic 2720 Radiology and Oncology. Dec 1992;25(4):231-241. 2721

130. Bourhis J, Lapeyre M, Tortochaux J, et al. Phase III randomized trial of very accelerated radiation 2722 therapy compared with conventional radiation therapy in squamous cell head and neck cancer: 2723 a GORTEC trial. Journal of clinical oncology : official journal of the American Society of Clinical 2724 Oncology. Jun 20 2006;24(18):2873-2878. 2725

131. Baujat B, Bourhis J, Blanchard P, et al. Hyperfractionated or accelerated radiotherapy for head 2726 and neck cancer. The Cochrane database of systematic reviews. 2010(12):Cd002026. 2727

132. Setton J, Lee NY, Riaz N, et al. A multi-institution pooled analysis of gastrostomy tube 2728 dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated 2729 radiotherapy. Cancer. Jan 15 2015;121(2):294-301. 2730

133. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated 2731 intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). 2732 International journal of radiation oncology, biology, physics. Apr 2010;76(5):1333-1338. 2733

134. Brizel DM. Radiotherapy and concurrent chemotherapy for the treatment of locally advanced 2734 head and neck squamous cell carcinoma. Seminars in radiation oncology. Oct 1998;8(4):237-246. 2735

135. Bensadoun RJ, Benezery K, Dassonville O, et al. French multicenter phase III randomized study 2736 testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) 2737 in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC). Int J Radiat Oncol 2738 Biol Phys. 2006;64(4):983-994. 2739

136. Huguenin P, Beer KT, Allal A, et al. Concomitant cisplatin significantly improves locoregional 2740 control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin 2741 Oncol. Dec 1 2004;22(23):4665-4673. 2742

137. Heijstek MW, Kamphuis S, Armbrust W, et al. Effects of the live attenuated measles-mumps-2743 rubella booster vaccination on disease activity in patients with juvenile idiopathic arthritis: a 2744 randomized trial. Jama. Jun 19 2013;309(23):2449-2456. 2745

138. Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy 2746 of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol 2747 Phys. 1993;26(1):3-11. 2748

139. Zelefsky MJ, Harrison LB, Fass DE, Armstrong JG, Shah JP, Strong EW. Postoperative radiation 2749 therapy for squamous cell carcinomas of the oral cavity and oropharynx: impact of therapy on 2750 patients with positive surgical margins. International journal of radiation oncology, biology, 2751 physics. Jan 1993;25(1):17-21. 2752

140. Sanguineti G, Richetti A, Bignardi M, et al. Accelerated versus conventional fractionated 2753 postoperative radiotherapy for advanced head and neck cancer: results of a multicenter Phase 2754 III study. International journal of radiation oncology, biology, physics. Mar 1 2005;61(3):762-771. 2755

141. Suwinski R, Bankowska-Wozniak M, Majewski W, et al. Randomized clinical trial on 7-days-a-2756 week postoperative radiotherapy for high-risk squamous cell head and neck cancer. 2757 Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and 2758 Oncology. May 2008;87(2):155-163. 2759


142. Lukens JN, Lin A, Gamerman V, et al. Late consequential surgical bed soft tissue necrosis in 2760

advanced oropharyngeal squamous cell carcinomas treated with transoral robotic surgery and 2761 postoperative radiation therapy. International journal of radiation oncology, biology, physics. 2762 Aug 1 2014;89(5):981-988. 2763

143. Olzowy B, Tsalemchuk Y, Schotten KJ, Reichel O, Harreus U. Frequency of bilateral cervical 2764 metastases in oropharyngeal squamous cell carcinoma: a retrospective analysis of 352 cases 2765 after bilateral neck dissection. Head & neck. Feb 2011;33(2):239-243. 2766

144. Chung EJ, Oh JI, Choi KY, et al. Pattern of cervical lymph node metastasis in tonsil cancer: 2767 predictive factor analysis of contralateral and retropharyngeal lymph node metastasis. Oral 2768 oncology. Aug 2011;47(8):758-762. 2769

145. Lee DJ, Kwon MJ, Nam ES, et al. Histopathologic predictors of lymph node metastasis and 2770 prognosis in tonsillar squamous cell carcinoma. Korean journal of pathology. Jun 2771 2013;47(3):203-210. 2772

146. Lim YC, Lee SY, Lim JY, et al. Management of contralateral N0 neck in tonsillar squamous cell 2773 carcinoma. The Laryngoscope. Sep 2005;115(9):1672-1675. 2774

147. Corvo R, Foppiano F, Bacigalupo A, Berretta L, Benasso M, Vitale V. Contralateral parotid-sparing 2775 radiotherapy in patients with unilateral squamous cell carcinoma of the head and neck: 2776 technical methodology and preliminary results. Tumori. Jan-Feb 2004;90(1):66-72. 2777

148. Rusthoven KE, Raben D, Schneider C, Witt R, Sammons S, Raben A. Freedom from local and 2778 regional failure of contralateral neck with ipsilateral neck radiotherapy for node-positive tonsil 2779 cancer: results of a prospective management approach. International journal of radiation 2780 oncology, biology, physics. Aug 1 2009;74(5):1365-1370. 2781

149. Kagei K, Shirato H, Nishioka T, et al. Ipsilateral irradiation for carcinomas of tonsillar region and 2782 soft palate based on computed tomographic simulation. Radiotherapy and oncology : journal of 2783 the European Society for Therapeutic Radiology and Oncology. Feb 2000;54(2):117-121. 2784

150. Koo TR, Wu HG. Long-term results of ipsilateral radiotherapy for tonsil cancer. Radiation 2785 oncology journal. Jun 2013;31(2):66-71. 2786

151. Liu C, Dutu G, Peters LJ, Rischin D, Corry J. Tonsillar cancer: the Peter MacCallum experience 2787 with unilateral and bilateral irradiation. Head & neck. Mar 2014;36(3):317-322. 2788

152. Jackson SM, Hay JH, Flores AD, et al. Cancer of the tonsil: the results of ipsilateral radiation 2789 treatment. Radiotherapy and oncology : journal of the European Society for Therapeutic 2790 Radiology and Oncology. May 1999;51(2):123-128. 2791

153. O'Sullivan B, Huang SH, Perez-Ordonez B, et al. Outcomes of HPV-related oropharyngeal cancer 2792 patients treated by radiotherapy alone using altered fractionation. Radiotherapy and oncology : 2793 journal of the European Society for Therapeutic Radiology and Oncology. Apr 2012;103(1):49-56. 2794

154. Lynch J, Lal P, Schick U, et al. Multiple cervical lymph node involvement and extra-capsular 2795 extension predict for contralateral nodal recurrence after ipsilateral radiotherapy for squamous 2796 cell carcinoma of the tonsil. Oral oncology. Sep 2014;50(9):901-906. 2797

155. Chronowski GM, Garden AS, Morrison WH, et al. Unilateral radiotherapy for the treatment of 2798 tonsil cancer. International journal of radiation oncology, biology, physics. May 1 2799 2012;83(1):204-209. 2800

156. Al-Mamgani A, van Rooij P, Fransen D, Levendag P. Unilateral neck irradiation for well-2801 lateralized oropharyngeal cancer. Radiotherapy and oncology : journal of the European Society 2802 for Therapeutic Radiology and Oncology. Jan 2013;106(1):69-73. 2803

157. Shoushtari AN, Meeneghan M, Treharne GC, et al. Clinical nodal staging of T1-2 tonsillar 2804 squamous cell carcinoma stratified by p16 status and implications for ipsilateral neck irradiation. 2805 Cancer journal (Sudbury, Mass.). May-Jun 2010;16(3):284-287. 2806


158. Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: 2807

conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant 2808 radiotherapy and chemotherapy--a multicenter randomized trial. Int J Radiat Oncol Biol Phys. 2809 Jan 1 2003;55(1):78-92. 2810

159. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma 2811 of the head and neck. N Engl J Med. Feb 9 2006;354(6):567-578. 2812

160. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced 2813 head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation 2814 between cetuximab-induced rash and survival. The Lancet. Oncology. Jan 2010;11(1):21-28. 2815

161. Lewin F, Damber L, Jonsson H, et al. Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil 2816 in advanced squamous cell carcinoma of the head and neck: a randomized phase III study. 2817 Radiother Oncol. 1997;43(1):23-28. 2818

162. Hitt R, Grau JJ, Lopez-Pousa A, et al. A randomized phase III trial comparing induction 2819 chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment 2820 of unresectable head and neck cancer. Annals of oncology : official journal of the European 2821 Society for Medical Oncology / ESMO. Jan 2014;25(1):216-225. 2822 2823

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