2016 therapeutic advances in localized pancreatic cancer

Copyright 2016 American Medical Association. All rights reserved.

Therapeutic Advances in Localized Pancreatic CancerSusan Tsai, MD, MHS; Douglas B. Evans, MD

P ancreatic cancer (PC) is a rising public health threat and is an-ticipated to account for more than 48 000 cancer-relateddeaths by 2030, a death rate that will be surpassed only by

lung cancer.1 In contrast to the improvements seen in the oncologictreatments of many solid-organ cancers, the survival of patients withPC has remained largely unchanged over the past 3 decades.2 Signifi-cant advances in surgical technique have resulted in decreased peri-operative morbidity and mortality after pancreatic resection, but thishas not improved the median overall survival of patients with localizedoperable PC.3 In fact, one of the proposed reasons for the lack of im-provement in survival among operated on patients has been the in-creased use of surgery in patients previously considered high risk orinoperable.3 Thus, gains in preoperative staging, including improvedradiographic detection of metastatic disease, must be weighed againstthe use of surgery in high-risk patients with more advanced local tu-mors and medical comorbidities. Regardless of the reason, a mediansurvival of 24 months for patients treated with a surgery-first approachwith or without adjuvant therapy is unacceptable.3 Based on the ob-servation that most patients who undergo successful surgery will de-velop systemic recurrence, a growing number of clinicians and scien-

tists now support the hypothesis that most patients with PC havesystemic disease at the time of diagnosis, even in the absence of radio-graphic evidence of distant metastases.4-6 One of the most revolution-ary changes in the management of PC has been a greater appreciationfor the early metastatic potential of PC; tumor biology has importantimplications for treatment sequencing.7-9 Treatment strategies haveevolved to prioritize early systemic therapy for patients with localizedPC. In this review, we highlight the rationale for neoadjuvant treatmentsequencing, identify new diagnostic biomarkers in development, andexamine alternative therapeutic modalities, which are increasinglyincorporated into the treatment of patients with PC.

Treatment Sequencing for PatientsWith Localized Pancreatic Cancer

As with most other solid tumors, treatments for patients with PC arestage specific. Current staging is defined by objective radiologic clas-sification of the extent of disease largely through the use of com-

IMPORTANCE It is estimated that pancreatic cancer (PC) will become the second leadingcause of cancer-related death in the United States by 2030.

OBSERVATIONS Clinical and preclinical data support the understanding that PC metastasesoccur early in the pathogenesis of this disease, even before the primary tumor can be detected.This has important implications for the clinical management of patients with localized PC, assurgery alone is unlikely to be curative for most patients. The delivery of postoperative adjuvanttherapy is problematic in this disease because of the magnitude of the operation needed toremove the primary tumor, which can affect patient recovery and delay (sometimes indefinitely)the delivery of systemic therapy. For these reasons, the use of chemotherapy and/orchemoradiation prior to surgery (neoadjuvant therapy) is increasingly recognized as thepreferred strategy for treatment sequencing. Neoadjuvant therapy is recommended for patientswith borderline resectable PC and, at some centers, neoadjuvant therapy has been extended topatients with resectable PC as well. Importantly, therapeutic advances in multidrug systemictherapy and radiation therapy have already been adopted in the neoadjuvant setting wheretreatment toxicity will not be compounded by surgical recovery. In addition, the use of local-regional therapies in highly selected patients with locally advanced PC, following a prolongedperiod of induction systemic therapy, will be an area of intense scrutiny. Future improvements indiagnostic biomarkers may allow for real-time sequencing of multimodality therapy for individualpatients based on a more accurate and timely assessment of treatment response.

CONCLUSIONS AND RELEVANCE Neoadjuvant treatment sequencing allows patients to receivemultimodality therapy in a manner that prioritizes early exposure to systemic therapy tomaximize the treatment of micrometastatic disease in an immune-competent host prior tosurgical intervention. Patients who complete all intended neoadjuvant therapy, includingsurgery, experience an overall survival benefit that is unmatched by a surgery-first approach.

JAMA Surg. doi:10.1001/jamasurg.2016.1113Published online June 8, 2016.

Author Affiliations: The PancreaticCancer Program, The MedicalCollege of Wisconsin, Milwaukee;Department of Surgery, The MedicalCollege of Wisconsin, Milwaukee.

Corresponding Author: Susan Tsai,MD, MHS, Department of Surgery,The Medical College of Wisconsin,9200 W Wisconsin Ave, Milwaukee,WI 53226 ([email protected]).

Clinical Review & Education

Review

jamasurgery.com (Reprinted) JAMA Surgery Published online June 8, 2016 E1


Downloaded From: http://archsurg.jamanetwork.com/ by a University College London User on 06/10/2016

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamasurg.2016.1113&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamasurg.2016.1113

mailto:[email protected]

http://www.jamasurgery.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamasurg.2016.1113


puted tomographic imaging (Table 1).11 Contrast-enhanced multi-planar computed tomography provides highly accurate assessmentsof tumor-vessel associations, which can be used to reproducibly de-fine the clinical stage of PC. Classification of resectable, borderlineresectable (BLR), and locally advanced PC has been defined by con-sensus guidelines and are essential to the development of stage-specific treatment plans.12,13 Although computed tomography andother cross-sectional imaging studies are extremely accurate at de-fining the extent of the primary tumor, the detection of metastaticdisease continues to be challenging. At least 10% to 20% of pa-tients with PC will have radiographically occult metastases at the timeof laparoscopy or laparotomy14,15; this number may be higher in somecenters throughout the world.16-18 Furthermore, within 6 monthsof successful surgery, up to 60% of patients with PC experience dis-ease relapse, as reported in the CONKO-001 (Charité Onkologie 001)Study, a landmark randomized trial that compared adjuvant gem-citabine with observation in patients with resected PC.19 In addi-tion, more than 76% of patients who undergo surgical resection ofthe primary tumor will develop distant metastatic disease as the firstevidence of disease recurrence.5,6

Owing to the high probability of disease relapse, consensusguidelines recommend systemic therapy for all patients with local-

ized PC.12 The current challenge for patients with localized PC is thetreatment of clinically/radiographically occult metastases, which arepresent in most patients who are eligible for surgical resection. Thereare 2 logical approaches to address the presence of micrometa-static disease: deliver systemic therapy in either the postoperative(adjuvant) or preoperative (neoadjuvant) period. Multiple random-ized clinical trials have assessed the benefit of adjuvant chemo-therapy or chemoradiation and have consistently demonstrated anoverall improvement in median survival with adjuvant therapy (me-dian overall survival, approximately 24 months) as compared withsurgery alone.19-22 However, it is important to recognize 2 critical limi-tations of this approach. First, adjuvant trials had an inherent selec-tion bias because they excluded patients who experienced signifi-cant surgical morbidity or mortality, rendering them ineligible for trialeligibility at 8 to 12 weeks after surgery. Overall 90-day mortality af-ter pancreatectomy has been reported to be as high as 7.4% and pro-cedure-related complications can occur in more than 30% ofpatients.23,24 Therefore, the survival durations reported in adju-vant trials following pancreatectomy are superior to what can beachieved in general practice as such trials included only a subset ofall patients who underwent surgery with curative intent. Second,completion of adjuvant therapy can be challenging even when suc-cessfully initiated in the postoperative setting. In the CONKO-001trial, 90% of patients (168/186) received a single dose of therapy,87% (138/161) received 1 cycle of therapy, and only 62% of patients(111/179) were able to complete all 6 cycles of gemcitabine.25 Out-side the context of a clinical trial, analysis of the Surveillance, Epi-demiology, and End Results Program database suggests that ap-proximately 50% of eligible patients received adjuvant therapyfollowing major pancreatic resection for cancer.26 Given the lim-ited feasibility of delivering adjuvant therapy and the increased tox-icity of more effective contemporary systemic therapies, alterna-tive treatment sequencing strategies have evolved.

Rationale for Neoadjuvant Treatment SequencingIn contrast to an adjuvant approach, chemotherapy and chemora-diation may be more reliably delivered to patients being consid-ered for curative surgery in the neoadjuvant setting. In 2 neoadju-vant trials, chemoradiation was completed by 84 of 85 patients

Key PointsQuestion What is the benefit of neoadjuvant therapy for localizedpancreatic cancer?

Findings In this review, neoadjuvant treatment sequencing wasfound to be associated with improved surgical selection byidentifying patients with aggressive disease biology who are athigh risk for early disease progression and, therefore, not likely tobenefit from surgical resection. The median overall survival ofpatients who complete neoadjuvant therapy and surgery isapproximately 36 months compared with 24 months for patientstreated with a surgery-first approach.

Meaning Patients with pancreatic cancer may benefit fromneoadjuvant therapy to identify patients with pancreatic cancerwho will most benefit from surgical resection and avoid surgicalmorbidity in those patients in whom surgery provides nooncologic benefit.

Table 1. Definitions of Clinical Stage: Comparison of MCWvs NCCN Staging Criteriaa

Stage MCW NCCN Version 2.2015Resectable

SMA,celiac

No abutment No abutment

Hepaticartery

No abutment No abutment

SMV-PV ≤50% narrowing ofSMV, PV, or SMV-PV

No tumor contact or ≤180° contactwithout vein contour irregularity

Borderline Resectable

SMA ≤180° (abutment) ≤180° (abutment)

Celiac ≤180° (abutment) ≤180° (abutment); >180° withoutinvolvement of the aorta and amenableto celiac resection (HA-GDA notinvolved)b

Hepaticartery

Abutment or shortsegment encasementc

Contact without extension to celiac orHA bifurcationc

SMV-PV >50% narrowing ofSMV, PV, SMV/PV, orshort-segmentocclusionc

Contact >180° or contour irregularityor thrombosis and reconstructionpossible (suitable proximal and distaltargets)c

Other CT scan findingssuspicious but notdiagnostic ofmetastatic disease

Tumor contact with the inferior venacava

Locally Advanced

SMA,celiac

>180°(encasement) >180° (encasement); Tumor contactwith first jejunal SMA branchd

SMV-PV Occlusion withoutoption forreconstruction

Unreconstructable SMV/PV; Contactwith most proximal draining jejunalbranch to SMVd

Abbreviations: CT, computed tomography; GDA, gastroduodenal artery;HA, Hepatic artery; MCW, Medical College of Wisconsin; NCCN, NationalComprehensive Cancer Network; PV, portal vein; SMA, superior mesentericartery; SMV, superior mesenteric vein.a Adapted with permission from Wolters Kluwer Health Inc.10

b Also considered locally advanced, refer to NCCN guidelines.c Amenable to reconstruction.d Unresectable.

Clinical Review & Education Review Therapeutic Advances in Localized Pancreatic Cancer

E2 JAMA Surgery Published online June 8, 2016 (Reprinted) jamasurgery.com





(99%) and chemotherapy followed by chemoradiation was com-pleted by 79 of 90 patients (88%).27,28 In addition, neoadjuvanttherapy affords a 2- to 30-month window in which patients with un-favorable tumor biology who are at risk for developing metastaticdisease progression can be identified prior to surgery. Among the10% to 30% of patients who develop disease progression, neoad-juvant treatment sequencing prevents an operative intervention(that would have no oncologic benefit) without any delay in expo-sure to additional/alternative systemic therapy, which is an impor-tant consideration in this era of improved multiagent chemo-therapy. Initial concerns regarding the safety and feasibility ofneoadjuvant therapy have been largely unfounded. Foremost wasthe concern that patients with potentially operable PC may de-velop local disease progression, which would prevent potentially cu-rative surgical resection; the “window of opportunity” for surgerycould be lost. Such concerns regarding local disease progression havenot been realized,27-29 For example, among 176 patients who wereenrolled in 2 clinical trials, less than 1% of eligible patients were foundto have isolated local disease progression at the time of restagingafter neoadjuvant therapy (before planned surgery).27,28 In a con-temporary experience from our institution, only 4 of 246 patients(1.6%) were found to have local disease progression after neoadju-vant therapy; all 4 patients were assessed as having BLR disease atthe time of diagnosis.29 In addition, concerns over the toxicity of neo-adjuvant therapy and the effect of treatment-related adverse ef-fects on operative morbidity and mortality were not observed.27,28,30

The incidence of pancreatic fistula, the most frequent serious com-plication associated with pancreatectomy, is reduced after neoad-juvant therapy as the treated pancreas becomes more firm in re-sponse to chemoradiation.31-33 An analysis of the National SurgicalQuality Improvement Program database demonstrated no differ-ences in 30-day mortality and morbidity rates among patientstreated with neoadjuvant therapy as compared with patients whoreceived surgery first.34 Furthermore, the addition of radiation mayhave important implications as several series have reported de-creased rates of positive margins (R1 or R2) and node-positive dis-ease following neoadjuvant therapy.31-33 Most importantly, amongpatients who are able to complete all intended neoadjuvant therapyand surgery, median overall survival is improved by almost 12 months(34-45 months vs 22-26 months) as compared with a surgery-firstapproach.3,27,28,35

Attempts at the prospective comparison of neoadjuvanttherapy with a surgery-first approach have been unsuccessful.16,17

It is not surprising that such clinical trials have failed to meetaccrual targets, as patients and referring physicians are, in general,unwilling to participate in clinical trials (phase II or III) that involverandomization to 2 noticeably different treatment arms. Tradition-ally, randomized clinical trials usually share a common backbone oftherapy (often considered the most effective therapy) on which anovel therapy is added to 1 arm. The difference between arms isviewed (by the patient) as small and often the unique drug ornovel therapy in the experimental arm can only be accessedthrough the trial mechanism. For patients with localized, operablePC, the difference between immediate surgery and neoadjuvanttherapy is viewed as too great; patients assume that their physi-cian must know which is better and, therefore, decline to partici-pate. However, there are multiple advantages to using neoadju-vant treatment sequencing in clinical trial design, including

identification of patients with micrometastatic disease (avoidanceof stage misclassification) and the ability to observe radiographic,biochemical, and histologic responses to therapy (not possible inthe adjuvant setting). For these reasons, neoadjuvant therapy isan attractive backbone for future studies of multimodality therapyin localized PC. Neoadjuvant treatment sequencing also allows forthe expansion of window-of-opportunity trials to patients withoperable PC (who have an intact immune system in the absence ofsurgery-induced immune suppression) and gets around the prob-lem of delivering complicated multiagent systemic therapy (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin [FOLFIRINOX]and gemcitabine doublets/triplets) to patients challenged by post-surgical recovery.

Treatment Sequencing for Localized Pancreatic CancerMultiple investigators have reported results after treating patientswith neoadjuvant therapy (Table 2). Overall, comparison of single-institutional series is complicated by variability in the staging defi-nitions, chemotherapeutic agents, and radiation therapy plans.41

With an intention-to-treat analysis (including all patients in whomneoadjuvant therapy is initiated), median overall survivals range from23 to 33 months.38,42 No specific preoperative regimen has been uni-versally recommended and may vary by institution and ongoing clini-cal trials. At our institution, clinical trial enrollment is strongly en-couraged. When this is not possible, neoadjuvant treatment ofresectable PC incorporates systemic gemcitabine and externalbeam radiation therapy (Figure, A). This regimen is a slight modifi-cation of the neoadjuvant treatment schema reported by Evans andcolleagues,27 which resulted in a median survival of almost 3 yearsin those patients who completed all therapy to include surgery.Available clinical trials in this country are evaluating the use ofFOLFIRINOX and gemcitabine/nab-paclitaxel given prior to sur-gery (clinicaltrials.gov Identifier: NCT02243007).43 At our institu-tion, clinical trial development for patients with resectable PC hasemphasized molecular profiling of the fine-needle aspiration speci-men as a guide to the choice of systemic therapy given prior to op-eration (clinicaltrials.gov Identifier: NCT01726582).44 Emerging clini-cal trials will likely favor systemic therapy followed by chemoradiationin an effort to deliver all intended nonsurgical therapy prior to op-eration; the delivery of adjuvant therapy to patients who have alsoreceived neoadjuvant treatment (especially with contemporarytherapies) is quite difficult even by an experienced physician teamat a high-volume cancer center.

Patients with BLR PC are fundamentally different from thosewith resectable disease owing to a higher risk for harboring radio-graphically occult distant metastatic disease1,2; the highest risk fora positive margin of resection due to tumor-artery abutment3; andthe need for a more complex operation usually involving vascularresection and reconstruction. For these reasons, at some institu-tions, neoadjuvant therapy for patients with BLR PC includes bothsystemic therapy and chemoradiation. Chemoradiation has beenthought to be particularly important to facilitate a margin-negativeresection for those patients with arterial abutment. At our institu-tion, 2 months of neoadjuvant chemotherapy is given followed bychemoradiation prior to considering surgery (Figure, B). This gen-eral treatment schema has been the foundation of treatment se-quencing for those patients with BLR PC who are treated either inor out of a clinical trial.

Therapeutic Advances in Localized Pancreatic Cancer Review Clinical Review & Education




http://clinicaltrials.gov/show/NCT02243007




Importance of Assessing Treatment ResponseThe assessment of treatment response is critically important and inpatients with localized PC, defining treatment response to therapycan be particularly challenging. At the Medical College of Wiscon-sin, treatment response is assessed using 3 critically important cri-teria: performance status; cross-sectional imaging ; and serum bio-markers such as carbohydrate antigen (CA) 19-9.10 Althoughcontemporary chemotherapy regimens, such as FOLFIRINOX and

gemcitabine/nab-paclitaxel, have been associated with 30% to 40%response rates among patients with more advanced disease, themany patients with localized PC are likely to have minimal to mod-est radiographic changes in tumor size even in the setting of clinicalbenefit and a normalization of CA19-9.14,36,45,46 This is likely owingto the dense stromal component of PC, which remains radiographi-cally unchanged even when histologic response is significant.47 More-over, even in those tumors that demonstrate a decrease in overall

Figure. Sequencing of Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer Outside of the Context of a Clinical Trial(Trial Usually Preferred)

Resectable pancreatic cancerA

Dual-phaseCT staging;

CA19-9

Diagnosiswith EUS/FNA

RestagingCT; CA19-9

RestagingCT;CA19-9

Adjuvant therapyfor 4 moSurgeryWeekly gemcitabine and external-beam radiation

therapy 50.4 Gy in 28 fractions, M-F

Dual-phaseCT staging;

CA19-9

Diagnosiswith EUS/FNA

RestagingCT; CA19-9

RestagingCT; CA19-9

RestagingCT;CA19-9

Adjuvanttherapyfor 4 mo

SurgeryInduction

chemotherapyfor 2 mo

Gemcitabine-basedchemoradiation

50.4 Gy in28 fractions, M-F

Borderline resectable pancreatic cancerB

Future clinical trials will likely incorporate all intended systemic therapy andchemoradiation prior to surgery, for reasons that span both host/tumor biologyand practical considerations. The delivery of postoperative adjuvant therapy isdifficult and, in some patients of advanced age, made more difficult withinduction therapy prior to surgery. With improved techniques for the rapidassessment of treatment response, we may enter an exciting time in the

management of localized pancreatic cancer that allows for the application oftumor/patient-specific systemic therapy (with or without chemoradiation)followed by the selective application of surgery to responding patients.CA indicates carbohydrate antigen; CT, computed tomography;EUS, endoscopic ultrasonography; FNA, fine-needle aspiration; M-F, Mondaythrough Friday.

Table 2. Selected Large Series of Neoadjuvant Therapy for Localized PC

Source DesignNo. ofPatients Neoadjuvant Therapy

Completed AllNeoadjuvant Therapyand Surgery, No. (%)

R0 Resection,No. (%)

Median OS of PatientsCompleting AllIntended Therapy, mo

R PC

Evans et al,27

2008Phase II 86 Gemcitabine, 400 mg/m2, with

30-Gy radiation73 (84) 68 (94) 34

Varadhacharyet al,28 2008

Phase II 90 Gemcitabine, 750 mg/m2; cisplatin,30 mg/m2; and 30-Gy radiation

62 (69) 62 (100) 31

Christianset al,35 2016

Single-institutionretrospective

69 Most received gemcitabine,400 mg/m2, and 5040-Gy radiation

60 (87) 58 (97) 45

BLR PC

Katz et al,36

2012Single-institutionretrospective

122 Gemcitabine-based chemotherapyand 5040-Gy radiation

85 (66) 80 (95) 33

Motoi et al,37

2013Phase II 35 Gemcitabine, 1000 mg/m2; S-1,

40 mg/m230 (85) 31 (86) 20

Rose et al,38

2014Single-institutionretrospective

64 Gemcitabine, 1000 mg/m2 anddocetaxel, 80 mg/m2 ± 5040-Gyradiation

31 (48) 27 (87) Not met at medianfollow-up of 21.6 mo

Varadhacharyet al, 39 2015

Phase II 22 FOLFIRINOX and 50.4-Gy radiation 15 (68) 13 (93) NA

R and BLR

Takahashiet al,40 2013

Phase II 268 Gemcitabine, 1000 mg/m2, and50-Gy radiation

207 (77) R: 162 (99);BLR: 42 (98)

5-y survival; R: 57%;BLR: 34%

Abbreviations: BLR, borderline resectable; FOLFIRINOX, fluorouracil, leucovorin, irinotecan and oxaliplatin; NA, not available; OS, overall survival; PC, pancreaticcancer; R, resectable.







size/largest diameter, the relationship of the tumor to adjacent bloodvessels generally does not change. A change in clinical stage, reflect-ing a change in local tumor-vessel anatomy, in response to neoad-juvant therapy rarely occurs.36 Therefore, the use of restagingimaging should primarily be performed to (1) identify local or dis-tant disease progression, which would alter clinical management,and (2) facilitate operative planning. Importantly, careful attentionto radiographic findings allows for a detailed preoperative plan, es-pecially when vascular reconstruction is anticipated. Vascular re-sections at the time of pancreatectomy should occur as plannedevents rather than an emergent response to vascular injury. Unex-pected vascular injuries can compromise the completeness of theresection, resulting in a positive margin.48,49

Improvement in performance status and a decline in CA19-9 lev-els are used as surrogate markers of response under the assump-tion that extrapancreatic micrometastatic disease has likely re-sponded to therapy if the condition of the patient improves and thelevel of CA19-9 declines. Although most patients experience a de-cline in CA19-9 levels in response to neoadjuvant therapy, 14% of pa-tients (27/194) had an increase in CA19-9 levels, and among thesepatients, metastatic disease was detected in 56% (15/27).50 There-fore, clinicians should have a low threshold for expanding the diag-nostic workup (magnetic resonance imaging of liver or positron emis-sion tomography) prior to surgery in patients who have a risingCA19-9 level after neoadjuvant therapy. In fact, as additional bio-markers beyond CA19-9 become available, dynamic changes in bio-marker response to neoadjuvant therapy may be able to more ac-curately predict the anticipated benefit from surgery. This will beespecially important in those patients of advanced age or definedmedical comorbidities in whom surgery may be of increased risk.

Advances in TherapeuticsFollowing the success of FOLFIRINOX and gemcitabine/nab-paclitaxel in the management of metastatic PC, there has been re-newed enthusiasm for drug development in PC. A unique advan-tage of neoadjuvant as compared with adjuvant clinical trials is theability to assess treatment efficacy in the resected specimen (patho-logic response) following induction therapy.47 Neoadjuvant trials mayprovide an opportunity to assess both pathologic response and dy-namic monitoring of biomarker response to treatment, which mayin turn facilitate smaller adaptive clinical trial designs. Herein, we high-light a few novel developments within each aspect of multimodal-ity therapy for patients with localized PC.

Systemic TherapyFollowing the experience of FOLFIRINOX and gemcitabine/nab-paclitaxel in the metastatic setting, a growing number of programshave explored the use of these regimens for the management of pa-tients with localized disease, especially those with BLR PC.45,46 Earlyexperience with neoadjuvant FOLFIRINOX demonstrated that thistherapy can be administered safely and can be associated with a sig-nificant pathologic response.30 The initial report of neoadjuvantFOLFIRINOX and chemoradiation included 18 patients with BLR PC,of which 12 (67%) completed all neoadjuvant therapy and surgery.30

Of note, only 2 (17%) of the 12 patients were found to have node-positive disease, and all 12 patients had negative (R0) margins. Simi-

larly, in another series of 47 patients with BLR and locally advancedPC, neoadjuvant FOLFIRINOX with or without radiation therapy wasassociated with an 85% (40/47) resection rate and only 14 of 40patients (35%) had node-positive disease.51 The Alliance A021101Trial investigated the use of 4 cycles of preoperative FOLFIRINOXfollowed by 50.4 Gy of radiation therapy with concurrent ca-pecitabine in patients with BLR PC.52 Reported at the 2015 Ameri-can Society of Clinical Oncology meeting, 15 of the 22 patients (68%)completed all neoadjuvant therapy and surgery, and 2 of 22 pa-tients (9%) had a pathologic complete response. A follow-upstudy using a randomized phase II design is being developed tospecifically examine the benefit of chemoradiation. In addition,neoadjuvant therapy with gemcitabine/nab-paclitaxel is also beingstudied in a prospective randomized clinical phase II study compar-ing perioperative gemcitabine/nab-paclitaxel vs adjuvant gem-citabine/nab-paclitaxel in patients with resectable PC (NEONAX Trial;clinicaltrials.gov Identifier: NCT02047513).53

Radiation TherapyAs the survival durations of patients with localized PC increase, localdisease control may become a more significant clinical concern. Localrecurrence rates after surgery have been reported to range from 20%to 60% and the incorporation of chemoradiation to augment local con-trol seems logical.54,55 Conventional chemoradiation regimens thatinvolve 3-dimensional conformal radiation have been enhanced bytechniques that improve radiation dose escalation such as intensity-modulated radiation therapy or stereotactic body radiation (SBRT). Inparticular, interest inSBRThasdevelopedbecauseoftheshorter lengthof treatment (5 days vs 28 days). Initial reports of single-fraction SBRT(25 Gy) in locally advanced PC was met with little enthusiasm owingto the increased rates of late gastrointestinal toxicities.56 Other stud-ies that used fractionated SBRT reported similar rates of local controlwith comparable toxicity with intensity-modulated radiation therapyin patients with locally advanced PC.57,58 The extrapolation of SBRT tothe neoadjuvant setting has been reported by 2 centers.57,59 In a ret-rospective report of 73 patients with BLR PC, 3 cycles of gemcitabine/taxotere/xeloda chemotherapy was followed by 5 fractions of SBRT toinclude25Gytothegrosstumorvolumeand35Gytotheareaoftumor-vesselabutment.57 Followingneoadjuvanttherapy,31ofthe73patients(42%) underwent resection. R0 resections were achieved in 30 of 31patients (97%) but only 20 of 31 tumors (65%) were node negative;a number lower than other reports with neoadjuvant therapy. Four pa-tients who did not undergo surgery experienced late-grade 3 toxicities;3hadgastrointestinalbleedingthatrequiredembolizationand1patienthad failure to thrive and required feeding tube placement. Of the 31 pa-tients who underwent resection, 7 (23%) had complications includingwound infection (n = 2), wound dehiscence (n = 1), and anastomoticleak (n = 4). Another group has reported on pathologic response fol-lowing SBRT for both locally advanced and BLR PC.59 Gemcitabine-based chemotherapy or FOLFIRINOX was delivered to 11 patients fol-lowed by SBRT to a dose of 24 Gy in 1 fraction or 36 Gy in 3 fractions.An R0 resection was achieved in 10 of the 11 patients and 3 patients hadcomplete pathologic responses. There was 1 perioperative mortalityrelated to postoperative bleeding and pancreatic fistula. In addition,2 patients developed delayed pseudoaneurysms, which were attrib-uted to the SBRT and occurred at 4.5 to 6.6 months following surgery.Both required embolization and 1 patient died secondary to complica-tions related to the embolization. Proponents of SBRT extol the expe-








ditiousdeliveryofhigh-doseradiation,whichminimizestheoveralltimetaking therapy and may facilitate a longer period of systemic chemo-therapy. As the experience with SBRT matures, it will be important tocharacterize the incidence of late toxicities, surgical complications, andthe ability to achieve local control before it can be accepted as equiva-lent to standard-fractionation intensity-modulated radiation therapy.

Surgery in the Setting of Locally AdvancedPancreatic CancerGiven the improved response rates seen with current systemic thera-pies, patients who were previously thought to have nonsurgical dis-ease are being reconsidered for surgery. Such patients have often re-ceived a lengthy course (�4 months) of systemic therapy, oftenfollowed by chemoradiation, and are then found to have a good per-formance status with a low or normalized serum level of CA19-9.60

Following such extended therapy, patients without disease progres-sion have 3 options; a treatment break (rarely preferred by the asymp-tomatic patient with a normalized CA19-9 level), maintenance che-motherapy, or surgery. Surgery is often considered because there arefew other attractive options, complete histologic responses are rarewith systemic therapy and chemoradiation, and surgical resection ofthe primary tumor is thought to offer the only option for possible cure

or long-term survival. However, it is important to remember that suchresponding patients will likely realize a significant survival benefit evenwithout surgery, as they have been preselected based on responseto induction therapy. Therefore, it is critically important that surgerybe applied only to carefully selected patients using objective criteriaand not because other therapies have been exhausted and the medi-cal team is unsure of what to do next.

ConclusionsThe limited and clinically insignificant gains in survival for patientswith localized PC over the past 3 decades have been due, in largepart, to the application of a local therapy (surgery) to a systemic dis-ease. In contrast to a surgery-first strategy, neoadjuvant treatmentsequencing will ensure the receipt of systemic therapy by all pa-tients and improve the discrimination between patients who will andwill not benefit from surgery. With growing acceptance, neoadju-vant therapy will be the backbone for most future studies of multi-modality therapy in localized PC, which will increasingly incorpo-rate novel investigational drug therapies and evolving techniquesand fractionation schemes for the delivery of radiation therapy.

ARTICLE INFORMATION

Accepted for Publication: March 11, 2016.

Published Online: June 8, 2016.doi:10.1001/jamasurg.2016.1113.

Author Contributions: Drs Tsai and Evans had fullaccess to all of the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis.Study concept and design: Both authors.Drafting of the manuscript: Both authors.Statistical analysis: Evans.Administrative, technical, or material support: Tsai.

Conflict of Interest Disclosures: None reported.

Funding/Support: We acknowledge the supportof the We Care Fund for Medical Innovation andResearch, the Ronald Burklund Eich PancreaticResearch Fund, and the Lockton Fund forPancreatic Cancer Research from the Departmentof Surgery at the Medical College of Wisconsin. DrTsai acknowledges support from the institutionalresearch grant 86-004-26 from the AmericanCancer Society.

Role of the Funder/Sponsor: The funders hadno role in the design and conduct of the study;collection, management, analysis, andinterpretation of the data; preparation, review, orapproval of the manuscript; and decision to submitthe manuscript for publication.

Additional Contributions: We thank Wendy Behrsfor assistance with manuscript preparation. She didnot receive compensation. The Pancreatic CancerProgram at the Medical College of Wisconsin isgrateful for the courageous patients and familieswho have formed the basis of our experience andreinforce the importance of multimodality care.

REFERENCES

1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB,Fleshman JM, Matrisian LM. Projecting cancerincidence and deaths to 2030: the unexpected

burden of thyroid, liver, and pancreas cancers in theUnited States. Cancer Res. 2014;74(11):2913-2921.

2. National Cancer Institute. SEER stat fact sheets:pancreas cancer. http://seer.cancer.gov/statfacts/html/pancreas.html. Published October 30, 2013.Accessed May 12, 2016.

3. Winter JM, Brennan MF, Tang LH, et al. Survivalafter resection of pancreatic adenocarcinoma:results from a single institution over three decades.Ann Surg Oncol. 2012;19(1):169-175.

4. Sohal DP, Walsh RM, Ramanathan RK, KhoranaAA. Pancreatic adenocarcinoma: treating a systemicdisease with systemic therapy. J Natl Cancer Inst.2014;106(3):dju011.

5. Iacobuzio-Donahue CA, Fu B, Yachida S, et al.DPC4 gene status of the primary carcinomacorrelates with patterns of failure in patients withpancreatic cancer. J Clin Oncol. 2009;27(11):1806-1813.

6. Gnerlich JL, Luka SR, Deshpande AD, et al.Microscopic margins and patterns of treatmentfailure in resected pancreatic adenocarcinoma.Arch Surg. 2012;147(8):753-760.

7. Rhim AD, Mirek ET, Aiello NM, et al. EMT anddissemination precede pancreatic tumor formation.Cell. 2012;148(1-2):349-361.

8. Tuveson DA, Neoptolemos JP. Understandingmetastasis in pancreatic cancer: a call for newclinical approaches. Cell. 2012;148(1-2):21-23.

9. Heestand GM, Murphy JD, Lowy AM. Approachto patients with pancreatic cancer withoutdetectable metastases. J Clin Oncol. 2015;33(16):1770-1778.

10. Evans DB, George B, Tsai S. Non-metastaticpancreatic cancer: resectable, borderlineresectable, and locally advanced-definitions ofincreasing importance for the optimal delivery ofmultimodality therapy. Ann Surg Oncol. 2015;22(11):3409-3413.

11. Appel BL, Tolat P, Evans DB, Tsai S. Currentstaging systems for pancreatic cancer. Cancer J.2012;18(6):539-549.

12. Tempero MA, Malafa MP, Behrman SW, et al.Pancreatic adenocarcinoma, version 2.2014:featured updates to the NCCN guidelines. J NatlCompr Canc Netw. 2014;12(8):1083-1093.

13. Evans DB, Farnell MB, Lillemoe KD, Vollmer C Jr,Strasberg SM, Schulick RD. Surgical treatment ofresectable and borderline resectable pancreascancer: expert consensus statement. Ann Surg Oncol.2009;16(7):1736-1744.

14. Tran Cao HS, Balachandran A, Wang H, et al.Radiographic tumor-vein interface as a predictor ofintraoperative, pathologic, and oncologic outcomesin resectable and borderline resectable pancreaticcancer. J Gastrointest Surg. 2014;18(2):269-278.

15. Raman SP, Horton KM, Fishman EK.Multimodality imaging of pancreaticcancer-computed tomography, magnetic resonanceimaging, and positron emission tomography. CancerJ. 2012;18(6):511-522.

16. Casadei R, Di Marco M, Ricci C, et al.Neoadjuvant chemoradiotherapy and surgery vssurgery alone in resectable pancreatic cancer:a single-center prospective, randomized, controlledtrial which failed to achieve accrual targets.J Gastrointest Surg. 2015;19(10):1802-1812.

17. Golcher H, Brunner TB, Witzigmann H, et al.Neoadjuvant chemoradiation therapy withgemcitabine/cisplatin and surgery versusimmediate surgery in resectable pancreatic cancer:results of the first prospective randomized phase IItrial. Strahlenther Onkol. 2015;191(1):7-16.

18. Glant JA, Waters JA, House MG, et al. Does theinterval from imaging to operation affect the rate ofunanticipated metastasis encountered duringoperation for pancreatic adenocarcinoma? Surgery.2011;150(4):607-616.

19. Oettle H, Post S, Neuhaus P, et al. Adjuvantchemotherapy with gemcitabine vs observation in





http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamasurg.2016.1113&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamasurg.2016.1113

http://www.ncbi.nlm.nih.gov/pubmed/24840647

http://seer.cancer.gov/statfacts/html/pancreas.html

http://seer.cancer.gov/statfacts/html/pancreas.html




























patients undergoing curative-intent resection ofpancreatic cancer: a randomized controlled trial.JAMA. 2007;297(3):267-277.

20. Kalser MH, Ellenberg SS. Pancreatic cancer:adjuvant combined radiation and chemotherapyfollowing curative resection. Arch Surg. 1985;120(8):899-903.

21. Neoptolemos JP, Stocken DD, Friess H, et al;European Study Group for Pancreatic Cancer.A randomized trial of chemoradiotherapy andchemotherapy after resection of pancreatic cancer.N Engl J Med. 2004;350(12):1200-1210.

22. Klinkenbijl JH, Jeekel J, Sahmoud T, et al.Adjuvant radiotherapy and 5-fluorouracil aftercurative resection of cancer of the pancreas andperiampullary region: phase III trial of the EORTCgastrointestinal tract cancer cooperative group.Ann Surg. 1999;230(6):776-782.

23. Swanson RS, Pezzi CM, Mallin K, Loomis AM,Winchester DP. The 90-day mortality afterpancreatectomy for cancer is double the 30-daymortality: more than 20,000 resections from thenational cancer data base. Ann Surg Oncol. 2014;21(13):4059-4067.

24. Winter JM, Cameron JL, Campbell KA, et al.1423 Pancreaticoduodenectomies for pancreaticcancer: a single-institution experience.J Gastrointest Surg. 2006;10(9):1199-1210; discussion1210-1211.

25. Oettle H, Neuhaus P, Hochhaus A, et al.Adjuvant chemotherapy with gemcitabine andlong-term outcomes among patients with resectedpancreatic cancer: the CONKO-001 randomizedtrial. JAMA. 2013;310(14):1473-1481.

26. Mayo SC, Gilson MM, Herman JM, et al.Management of patients with pancreaticadenocarcinoma: national trends in patientselection, operative management, and use ofadjuvant therapy. J Am Coll Surg. 2012;214(1):33-45.

27. Evans DB, Varadhachary GR, Crane CH, et al.Preoperative gemcitabine-based chemoradiationfor patients with resectable adenocarcinoma of thepancreatic head. J Clin Oncol. 2008;26(21):3496-3502.

28. Varadhachary GR, Wolff RA, Crane CH, et al.Preoperative gemcitabine and cisplatin followed bygemcitabine-based chemoradiation for resectableadenocarcinoma of the pancreatic head. J Clin Oncol.2008;26(21):3487-3495.

29. Miura JT, Krepline AN, George B, et al. Use ofneoadjuvant therapy in patients 75 years of age andolder with pancreatic cancer. Surgery. 2015;158(6):1545-1555.

30. Christians KK, Tsai S, Mahmoud A, et al.Neoadjuvant FOLFIRINOX for borderline resectablepancreas cancer: a new treatment paradigm?Oncologist. 2014;19(3):266-274.

31. Takahashi H, Ogawa H, Ohigashi H, et al.Preoperative chemoradiation reduces the risk ofpancreatic fistula after distal pancreatectomy forpancreatic adenocarcinoma. Surgery. 2011;150(3):547-556.

32. Raut CP, Evans DB, Crane CH, Pisters PW,Wolff RA. Neoadjuvant therapy for resectablepancreatic cancer. Surg Oncol Clin N Am.2004;13(4):639-661, ix.

33. Willett CG, Lewandrowski K, Warshaw AL,Efird J, Compton CC. Resection margins incarcinoma of the head of the pancreas: implicationsfor radiation therapy. Ann Surg. 1993;217(2):144-148.

34. Cooper AB, Parmar AD, Riall TS, et al. Doesthe use of neoadjuvant therapy for pancreaticadenocarcinoma increase postoperative morbidityand mortality rates? J Gastrointest Surg. 2015;19(1):80-86.

35. Christians KK, Heimler JW, George B, et al.Survival of patients with resectable pancreaticcancer who received neoadjuvant therapy. Surgery.2016;159(3):893-900.

36. Katz MH, Fleming JB, Bhosale P, et al.Response of borderline resectable pancreaticcancer to neoadjuvant therapy is not reflected byradiographic indicators. Cancer. 2012;118(23):5749-5756.

37. Motoi F, Ishida K, Fujishima F, et al.Neoadjuvant chemotherapy with gemcitabine andS-1 for resectable and borderline pancreatic ductaladenocarcinoma: results from a prospectivemulti-institutional phase 2 trial. Ann Surg Oncol.2013;20(12):3794-3801.

38. Rose JB, Rocha FG, Alseidi A, et al. Extendedneoadjuvant chemotherapy for borderlineresectable pancreatic cancer demonstratespromising postoperative outcomes and survival.Ann Surg Oncol. 2014;21(5):1530-1537.

39. Varadhachary GR, Fleming JB, Crane CH, et al.Phase II study of preoperation mFOLFIRINOX andchemoradiation for high-risk resectable andborderline resectable pancreatic adenocarcinoma.J Clin Oncol. 2015; 33(suppl 3; abstract 362).

40. Takahashi H, Ohigashi H, Gotoh K, et al.Preoperative gemcitabine-based chemoradiationtherapy for resectable and borderline resectablepancreatic cancer. Ann Surg. 2013;258(6):1040-1050.

41. Assifi MM, Lu X, Eibl G, Reber HA, Li G, HinesOJ. Neoadjuvant therapy in pancreaticadenocarcinoma: a meta-analysis of phase II trials.Surgery. 2011;150(3):466-473.

42. Chun YS, Milestone BN, Watson JC, et al.Defining venous involvement in borderlineresectable pancreatic cancer. Ann Surg Oncol. 2010;17(11):2832-2838.

43. ClinicalTrials.gov. Phase II NeoadjuvantChemotherapy (Gemcitabine and Nab-Paclitaxel vsmFOLFIRINOX) and Stereotactic Body RadiationTherapy for Borderline Resectable PancreaticCancer. [Cited 12/04/15]. https://clinicaltrials.gov/ct2/results?term=NCT02241551&Search=Search.Accessed May 12, 2016.

44. ClinicalTrials.gov. Pancreas Cancer: MolecularProfiling as a Guide to Therapy Before and AfterSurgery. [Cited 12/04/15]. https://clinicaltrials.gov/ct2/results?term=NCT01726582&Search=Search.Accessed May 12, 2016.

45. Von Hoff DD, Goldstein D, Renschler MF.Albumin-bound paclitaxel plus gemcitabine inpancreatic cancer. N Engl J Med. 2014;370(5):479-480.

46. Conroy T, Desseigne F, Ychou M, et al; GroupeTumeurs Digestives of Unicancer; PRODIGEIntergroup. FOLFIRINOX versus gemcitabine formetastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.

47. Verbeke C, Löhr M, Karlsson JS, Del Chiaro M.Pathology reporting of pancreatic cancer followingneoadjuvant therapy: challenges and uncertainties.Cancer Treat Rev. 2015;41(1):17-26.

48. Ravikumar R, Sabin C, Abu Hilal M, et al;UK Vascular Resection in Pancreatic Cancer StudyGroup. Portal vein resection in borderlineresectable pancreatic cancer: a United Kingdommulticenter study. J Am Coll Surg. 2014;218(3):401-411.

49. Smoot RL, Christein JD, Farnell MB. Durabilityof portal venous reconstruction following resectionduring pancreaticoduodenectomy. J GastrointestSurg. 2006;10(10):1371-5.

50. Aldakkak M, Christians KK, Krepline AN, et al.Pre-treatment carbohydrate antigen 19-9 does notpredict the response to neoadjuvant therapy inpatients with localized pancreatic cancer. HPB(Oxford). 2015;17(10):942-952.

51. Ferrone CR, Marchegiani G, Hong TS, et al.Radiological and surgical implications ofneoadjuvant treatment with FOLFIRINOX for locallyadvanced and borderline resectable pancreaticcancer. Ann Surg. 2015;261(1):12-17.

52. Katz MH, Marsh R, Herman JM, et al. Borderlineresectable pancreatic cancer: need forstandardization and methods for optimal clinicaltrial design. Ann Surg Oncol. 2013;20(8):2787-2795.

53. ClinicalTrials.gov. Neoadjuvant Plus Adjuvant orOnly Adjuvant Nab-Paclitaxel Plus Gemcitabine forResectable Pancreatic Cancer. [Cited 12/04/15].https://clinicaltrials.gov/ct2/results?term=NCT02047513&Search=Search. Accessed May 12,2016.

54. Smeenk HG, van Eijck CH, Hop WC, et al.Long-term survival and metastatic pattern ofpancreatic and periampullary cancer after adjuvantchemoradiation or observation: long-term results ofEORTC trial 40891. Ann Surg. 2007;246(5):734-740.

55. Khawaja MR, Kleyman S, Yu Z, et al. Adjuvantgemcitabine and gemcitabine-basedchemoradiotherapy versus gemcitabine alone afterpancreatic cancer resection: the Indiana Universityexperience [published online August 13, 2014].Am J Clin Oncol.

56. Koong AC, Le QT, Ho A, et al. Phase I study ofstereotactic radiosurgery in patients with locallyadvanced pancreatic cancer. Int J Radiat Oncol BiolPhys. 2004;58(4):1017-1021.

57. Chuong MD, Springett GM, Freilich JM, et al.Stereotactic body radiation therapy for locallyadvanced and borderline resectable pancreaticcancer is effective and well tolerated. Int J RadiatOncol Biol Phys. 2013;86(3):516-522.

58. Mahadevan A, Jain S, Goldstein M, et al.Stereotactic body radiotherapy and gemcitabine forlocally advanced pancreatic cancer. Int J RadiatOncol Biol Phys. 2010;78(3):735-742.

59. Rajagopalan MS, Heron DE, Wegner RE, et al.Pathologic response with neoadjuvantchemotherapy and stereotactic body radiotherapyfor borderline resectable and locally-advancedpancreatic cancer. Radiat Oncol. 2013;8:254.

60. Christians KK, Pilgrim CH, Tsai S, et al. Arterialresection at the time of pancreatectomy for cancer.Surgery. 2014;155(5):919-926.









































https://clinicaltrials.gov/ct2/results?term=NCT02241551&Search=Search
































2016 therapeutic advances in localized pancreatic cancer

Documents