Induction Chemotherapy followed by concurrent CT-RT versus CT-

RT in advanced Oral Cancers

Dr Santam Chakraborty, Assistant Professor,Tata Memorial Hospital, Mumbai

HN

Rationale for Neoadjuvant Chemotherapy

● Induction / Neoadjuvant chemotherapy :○ Early initiation of systemic therapy - potentially better control of micrometastatic disease○ Locoregional tumor downstaging○ In vivo assessment of tumor chemosensitivity. ○ Potential to select disease with “bad biology”

● Development and use of Platinum and 5 Fluorouracil combination chemotherapy in 1970’s - showed impressive response rates.

Between Oct 1, 1979 and Aug 1, 1982, 93 patients with advanced squamous carcinoma of the head and neck were given neoadjuvant treatment with cisplatin, bleomycin sulfate, and methotrexate before standard local treatment. Ninety-three patients were evaluable for response. The response rates were as follows: complete response, 24%; partial response, 64%; and no response, 12%. Differences in primary tumor site, performance status at presentation, histologic grade, and tumor size did not correlate with response to this chemotherapy. For patients achieving notable tumor reduction to 2 cm or less, standard local treatment with either surgery plus radiotherapy or high-dose radiotherapy alone was effective in controlling local disease. For patients with larger tumor masses following neoadjuvant chemotherapy, surgical resectability appeared to improve local control rates. In our series, patients not receiving maximal standard local treatment often had relapse of local disease despite favorable responses to chemotherapy

Ervin et al Arch Otolaryngol 1984;110:241-245

Results with CT RT (MACH-NC)

Pignon J-P, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009 Jul;92(1):4–14.

Results with CT RT (MACH-NC)

Neoadjuvant Concomitant

Oral cavity +3.8% [−1.1; 8.7] +6.9% [2.8; 11.0]

Oropharynx −0.6% [−4.9; 3.7] +8.4% [5.1; 11.7]

Larynx −1.4% [−9.6; 6.8] +5.4% [0.7; 10.1]

Hypopharynx +3.3% [−2.4; 9.0] +3.2% [−1.7; 8.1]

Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011 Jul;100(1):33–40.

Neoadjuvant Therapy Trials (MACH-NC)

● A total 31 trials evaluating NACT in HNC were evaluated as a part of this meta-analysis.

○ 5269 patients were treated

○ Platinum based chemotherapy

used in 25 of the studies (3851

patients ~ 73% of the patient)

○ Most studies utilizing platinum

utilized CDDP + 5 FU

○ Most used radiotherapy /

surgery as the locoregional

treatment.

Neoadjuvant Therapy Trials (MACH-NC)

4.3%2.5%

Toxicity associated with CT-RT

● Increasing awareness of the toxicity associated with CT-RT in the 90’s.● In addition to the substantial increase in acute toxicities reported from all

studies, RTOG demonstrated a significant burden of late toxicities:○ Subset analysis of 3 RTOG trials ○ 43% of the patients had late toxicity○ Correlated with:

■ Laryngopharyngeal primaries■ Old Age■ Advanced T stage ■ Neck dissection after CT-RT

Why NACT with CT-RT in LAHNSCC ?

Improved distant control Lets see if patients with improved LRC after CT RT benefit from the distant mets reducing ability of NACT

Potentially equivalent efficacy in hypopharyngeal cancers

May be a good way to improve laryngeal preservation in these tumors

Impressive responses Can we reduce the normal tissue exposure to high dose radiation with potentially reduced toxicities.

Addition of Taxanes to PF

TAX 323 TAX 324

Dose of CDDP / 5FU 75 mg/m2 / 750 mg/m2 100 mg/m2 / 1000 mg/m2

Patients 350 250

Primary End Point PFS (HR 0.67) OS (HR 0.65)

Control Group Outcome Median PFS = 10 months Median OS = 28 months

Inclusion Unresectable Unresectable / Low surgical curability

Local RT Only RT (Conventional or Accelerated / Hyperfractionated)

CT RT with 70 - 74 Gy and weekly Carboplatin

Neck Dissection Considered for all patients Selected

Hypopharyngeal cancers 29.3% 14%

T4 73% 42%

N2-3 71.8% 64%

Outcomes of TPF vs PF

OS: 7.4%

LRR: 7.4%

PFS: 7.1%

DMFS: 6.4%

Other Outcomes from meta-analysis

● No difference in non-cancer mortality between PF and TPF● Except for 1 trial (Hitt et al), no differences in the early (90 day) mortality were

observed● Compliance with RT as well as concurrent chemotherapy was significantly

better in the TPF arm !!○ One possible explanation is higher risk of progression with PF○ Another explanation is reduced toxicity in TPF as compared to PF (? reduced CDDP dose)

● 71% of the patients receiving TPF and 68% of the patients receiving PF further underwent CT-RT.

The role of induction chemotherapy was debatable in the early 1990s, but during the last 15 years, randomized clinical trials have provided level 1 evidence that cisplatin and 5-FU induction therapy is equivalent to chemoradiotherapy,In addition, several studies have shown that induction therapy is significantly more effective in terms of survival and organ preservation than surgery with or without radiotherapy in locally advanced SCCHN (Br J Cancer 83:1594-1598, 2000; ASCO 2006 abstract 5517; J Natl Cancer Inst 88:890-898, 1996; J Natl Cancer Inst 86:265-272, 1994; J Clin Oncol 12:385-395, 1994; J Natl Cancer Inst 96:1714-1717, 2004).

What is the Clinical Role of Induction Therapy in Locally Advanced Squamous Cell Cancer of the Head and Neck? CancerNetwork August 11, 2010

Examining the quoted evidence

GETTEC (2000)

PF vs Local Therapy

318 Local therapy : Sx + RT in responders , RT alone in non responders

Improved OS in the NACT arm (5.1 years vs 3.3 years)

Intergroup 91-11()

Induction PF vs CT RT vs RT alone

515 Local therapy : RT / CT in responders, Sx + RT in non responders

Significantly improved LC and Laryngeal preservation with CT RT

EORTC (2006) Induction PF + RT vs Surgery

202 Local therapy: Sx + RT in control arm, Sx in partial responders, RT in complete responders

Laryngeal preservation in 1/3rd without compromising survival

Paccagnella (1993/2004)

Induction PF vs Local Therapy

237 Local therapy: SX+RT in operable and RT alone in inoperable

Reduced DM in patients receiving induction chemotherapy. Better outcomes in patients with inoperable cancers

Taylor (1994) Induction PF vs CT RT

215 Local therapy : RT both arms Poorer local control and cancer related mortality in the Induction arm

Meta Analysis of CT RT vs ICT + CTRT

Budach et al conducted a meta-analysis of trials which directly compared Induction chemotherapy followed by chemoradiation to chemoradiation alone.

● Identified 6 RCTs - 1 chinese RCT excluded due to inadequate information● 1022 patients with OS data● 862 patients with PFS data● Meta-analysis of effect size on OS / PFS with cox regression using random

effect model

Budach W, Bölke E, Kammers K, Gerber PA, Orth K, Gripp S, et al. Induction chemotherapy followed by concurrent radio-chemotherapy versus concurrent radio-chemotherapy alone as treatment of locally advanced squamous cell carcinoma of the head and neck (HNSCC): A meta-analysis of randomized trials. Radiother Oncol. 2016/2;118(2):238–43.

Studies included

Accrued Planned PS 1 Oropharynx T4 N3

Cohen (2014) (DeCIDE)

285 400 14% 58% 20% 11%

Takacsi-Nagy (2015) (Hungary)

66 99 - 60% 73% 11%

Hitt (2014) (Spain) 439 439 70% 42% 75% 10%

Haddad (2013) (PARADIGM)

145 330 33% 55% 24% 9%

Ghi (2014) (Italy) 258 258 20% 57% 42% 7%

Studies included

Induction RT RT Dose Concurrent Chemo

Cohen (2014) (DeCIDE)

TPF x 2 HFRT 75 Gy / 50 # / 25 days (BID)

Docetaxel / 5FU / Hydroxyurea

Takacsi-Nagy (2015) (Hungary)

TPF x 2 CRT 70 Gy / 35# / 49 days (OD)

CDDP 3 weekly

Hitt (2014) (Spain) TPF x 3 CRT 70 Gy / 35# / 49 days (OD)

CDDP 3 weekly

Haddad (2013) (PARADIGM)

TPF x 3 CRT/ Accelerated Boost

70 Gy / 35# / 49 days (OD) or 70 gy / 35# /42 days (OD

Docetaxel / Carboplatin weekly

Ghi (2014) (Italy) TPF x 3 CRT 70 Gy / 35# / 49 days (OD)

CDDP/5FU or Cetuximab

The postmortem ...

● The only study which actually reported an improvement with TPF was the study by Ghi et al (Italian trial). - however mainly due to patients receiving cetuximab

● Inadequate accrual (DeCIDE & PARADIGM)● The Hungarian study was stopped prematurely due to 3 deaths in the TPF arm● Compliance to concurrent chemotherapy after induction remained an issue:

○ DeCIDE : 10%○ Hitt et al : 27%○ PARADIGM : 18%

Additional findings from Kim’s Meta-analysis

● There were some additional findings in the meta-analysis by Kim et al

○ Improved OS and PFS in patients with

non-oropharyngeal cancers

○ Relative gain of 34% in the response rate

with TPF + CT RT

○ A trend towards a reduced risk of distant

metastases without an effect on LRR○ 25% failed to complete CT RT.

Combining ICT with Biotherapy

Given the potential reduced toxicity with Cetuximab the TREMPLIN results are relevant:

● 116 patients randomized into 3 weekly CDDP versus weekly Cetuximab after induction TPF x 2

● Laryngeal / Hypopharyngeal cancers with specific goal to ascertain laryngeal preservation

● Difficult to deliver CRT / BRT after ICT with more than half of the patients requiring protocol modifications during delivery of CDDP based CT-RT.

● No increase in laryngeal preservation rate in either of the arms.

Combining ICT with Biotherapy

The results of the GORTEC 2007-02 have also been presented in ASCO 2016:

● Compared ICT f/b Cetux + RT versus CT-RT (Carboplatin + 5FU)● Restricted to node positive patients (N2b/c - N3)● 370 patients● No difference in OS / LRRFS / DMFS● Substantial increase in toxicity in the ICT arm

Overall the study results affirm that standard CT-RT remain the standard of care in these patients also.

Nail in the coffin ?

Results from Asia in the community

● Chen et al reported outcomes of a National Cohort study from Taiwan. ● Two databases : National Cancer Registry & National Health Insurance (99%

coverage)● Combined datasets released through Collaboration Center of Health

Information Application ● 10,721 patients with 4.9 years FU:

○ Concurrent CT-RT : 7968○ Docetaxel based ICT : 503○ Platinum based ICT : 2322

Results from Asia in the community

●

Summary of Evidence

● Addition of ICT prior to CRT fails to improve outcomes as compared to CTRT○ Poorer compliance to CRT○ Chemoselection of more resistant clones○ Accelerated repopulation at the time of radiotherapy○ Aggravation of toxicity due to residual effects of NACT

● ICT prior to CTRT provides little advantage in terms of laryngeal preservation● ICT prior Cetux-RT is not better tolerated than CT-RT (TREMPLIN)● ICT prior to CDDP (3 weekly) is not better than ICT prior to CDDP (weekly)

(CONDOR)● Combining Cetux-RT with ICT is not superior to CTRT alone even in the high

risk unresectable N2b/c - N3 population. (GORTEC 2007-02)

What are the unknowns

● Suggestion of a benefit of induction CT RT in patients with non-oropharyngeal malignancies

● Differential benefit in HPV positive patients vs HPV negative patients

ICT in HPV negative

● Lorch et al presented the experience of 279 patients in whom 23% had HPV negative disease (Dana Farber)

● 42% received ICT and 58% CT - RT● 3 year OS in patients treated with ICT was 85% vs 75% in patients treated with

CT-RT

Conclusions

● Within the limitations of the current evidence addition of induction chemotherapy prior to concurrent chemoradiation does not seem to improve outcomes.

● Some suggestion of benefit in selected population likely to be offset with the difficulty in treating these patients with significant comorbidities and exposure to alcohol and tobacco

● Should only be practised under strict institutional protocols with rigorous patient selection, supportive care and patient education.

Thank You