Laryngeal and hypopharyngeal cancers

Laryngeal and hypopharyngeal cancers Induction Chemotherapy in combined modality approaches Atenas 16.09.2017 Ana Ferreira Castro, MD Medical Oncology Centro Hospitalar do Porto Instituto de Ciências Biomédicas de Abel Salazar Chair of Portuguese Head and Neck Study Group

Principles of Systemic Therapy for LA HNSCC Primary systemic therapy concurrent RT Patients appropriate for Systemic Therapy High Dose Cisplatin (preferred) (Category 1) Cetuximab (Category 1) oropharynx, hypopharynx, larynx) Carboplatin/ Infusional 5FU (Category 1) Weekly Cisplatin 40 mg/m2 (Category 2B) Carboplatin/Paclitaxel (Category 2B) Other (Category 2A): 5FU/hydroxyurea; Cisplatin/paclitaxel; Carboplatin/5FU Induction/sequential chemotherapy Docetaxel/cisplatin/5FU (Category 1) Paclitaxel/cisplatin/infusional 5FU Following induction, agent to be used: Cetuximab or weekly Carboplatin Cisplatin-based induction chemotherapy followed High-dose cisplatin CRT is not recommended due to toxicity concerns. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Head and Neck Cancer, V.2.2017. Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

Rationale for Induction Chemotherapy in Locally Advanced HNSCC HNSCC is highly responsive to chemotherapy In locally advanced HNSCC, high response rates (about 80%), including many complete responses, are observed 1 Chemotherapy predicts complete response to subsequent radiotherapy 2 that allows for patient selection for laryngeal-sparring approaches Induction chemotherapy may improve local disease control and eradicate micrometastatic disease 1. Argiris A et al. Oncology (Williston Park). 2005;19(6):759-770. 2. Ensley JF, et al. Cancer. 1984;54(5):811-814.

Which Patient Population Could Benefit From Induction Chemotherapy? Organ preservation? Unresectable patients? Larynx preservation? Reduction of distant metastases? Risk of increased toxicity Potential benefits Potential risks

Induction Chemotherapy for HNSCC: Taxane/Cisplatin/5-FU vs Cisplatin/5-FU Study Population Regimen RT Outcome P value GORTEC 1 Larynx and hypopharynx, organ preservation T: 75 mg/m 2 P: 75 mg/m 2 F: 750 mg/m 2 CI x 5 days 3 cycles Standard RT Better organ preservation for TPF.03 Hitt et al. 2 Resectable and unresectable Taxol: 175 mg/m 2 P: 100 mg/m 2 F: 500 mg/m 2 CI x 5 days 3 cycles RT/cisplatin Improved survival in patients with unresectable HNC for TPF.05 T: 75 mg/m 2 Vermorken et al. EORTC 3 Unresectable P: 75 mg/m 2 F: 750 mg/m 2 CI x 5 days 4 cycles Standard RT Improved survival for TPF.02 Posner et al. TAX324 4 Unresectable, resectable with poor outcome T: 75 mg/m 2 ; P: 100 mg/m 2 ; F: 1000 mg/m 2 CI x 4 days 3 cycles RT/carboplatin Improved survival for TPF.0006 1. Janoray G, et al. J Clin Oncol. 2015;33(suppl): Abstract 6002. 2. Hitt R et al. J Clin Oncol. 2005;23(34):8636-8645. 3. Vermorken JB et al. N Engl J Med. 2007;357(17):1695-1704. 4. Posner MR et al. N Engl J Med. 2007;357(17):1705-1715.

ICT is an emerging treatment paradigm with the potential to improve OS: Organ preservation Study Treatment 1º endpoint VALCSG 1 TREMPLIN 2 PF RT vs surgery + RT TPF (CRT vs cetuximab + RT) 2-year OS TTCC 2007-02 3 TPF cetuximab + RT 3-year LEDFS RTOG 91-11 4 (PF RT) vs CRT vs RT Potential for organ preservation with ICT? Ongoing trials are evaluating cetuximab-containing sequential regimens as a potential approach to increase efficacy and decrease toxicity 5 8 LP LFS LEDFS, laryngo-esophageal dysfunction free survival; LFS, laryngectomy-free survival; LP, larynx preservation; PF, platinum-based CT + 5-FU 1. Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685 1690; 2. Lefebvre J-L, et al. J Clin Oncol 2013;31:853 859; 3. Mesia R, et al. ASCO 2015 (Abstract No. 6037); 4. Forastiere AA, et al. J Clin Oncol 2013;31:845 852; 5. clinicaltrials.gov/ct2/show/nct00508664; 6. clinicaltrials.gov/ct2/show/nct00716391; 7. clinicaltrials.gov/ct2/show/nct01233843; 8. clinicaltrials.gov/ct2/show/nct00999700

Phase III Randomized Trials of Induction Chemotherapy Followed by CRT vs CRT Alone Study Regimens HR for OS P value TTCC (Spain) 1 N = 439 TPF x 3 CRT (cisplatin) PF x 3 CRT (cisplatin) CRT (cisplatin) for TPF 1.1 (0.82-1.48).49 for PF 0.97 (0.72-1.32).87 Paradigm (USA) 2 N = 145 (/300) TPF x 3 CRT (carbo or docetaxel) CRT (cisplatin) 1.09 (0.59-2.03).77 DeCIDE (USA) 3 N=285 (/400) H&N07 (Italy) 4,5 N = 421 TPF x 2 CRT (THFX) CRT (THFX) TPF CRT (cisplatin + 5FU) or BRT (cetuximab) CRT (cisplatin+ 5FU) or BRT (cetuximab) 0.91 (0.59-1.41).68 0.73 (0.55-0.97).029 1. Hitt R, et al. Ann Oncol. 2014;25(1):216-225. 2. Haddad R, et al. Lancet Oncol. 2013;14(3):257-264. 3. Cohen EE, et al. J Clin Oncol. 2014;32(25):2735 2743. 4. Ghi MG, et al. Bonner JA, et al. Presented at: 5 th ICHNO International Conference; February 12-14, 2015: Nice, France. Abstract: OC-006. 5. Ghi MG, et al. J Clin Oncol. 2014;32(suppl): Abstract 6004.

ICT is an emerging treatment paradigm with the potential to improve OS: Unresectable SCCHN H&N07 study 1 Unresectable LA SCCHN: CRT or cetuximab + RT vs TPF CRT or cetuximab + RT All SCCHN TPF induction (n=181) No induction (n=191) Adjusted HR (95% CI) p value Median OS, months 54.7 31.7 0.73 (0.55 0.97) 0.029 Median PFS, months 30.5 18.5 0.72 (0.55 0.93) 0.013 Complete response, n (%) 77 (42.5) 53 (28) 0.0028 Prior studies in unresectable LA SCCHN 2 4 Study Treatment 1º endpoint DeCIDE 2 * (TPF CRT) vs CRT 3-year OS PARADIGM 3 * (TPF CRT) vs CRT 3-year OS TTCC 4 (TPF CRT) vs (PF CRT) vs CRT PFS, TTTF Benefit with ICT? *Small sample size with limited statistical power; Spanish Head And Neck Cancer Cooperative Group; No statistically significant difference in outcome OS, overall survival; PFS, progression-free survival; TPF, docetaxel, carboplatin, and 5-FU; TTTF, time to treatment failure 1. Ghi MG, et al. ICHNO 2015 (Abstract No. OC-006); 2. Cohen EE, et al. J Clin Oncol 2014;32:2735 2743; 3. Haddad RI, et al. Lancet Oncol 2013;14:257 264; 4. Hitt R, et al. Ann Oncol 2014;25:216 225

Induction CT Study 1 Treatment Endpoint Outcome p-value TAX 323 (PF vs TPF) RT PFS TPF > PF 0.007 TAX 324 (PF vs TPF) CRT OS TPF > PF 0.004 Pointreau 2009 (PF vs TPF) CRT 3-year larynx preservation rate TPF > PF 0.03 DeCIDE (TPF CRT) vs CRT 3-year OS ICT = CT + RT 0.70 PARADIGM (TPF CRT) vs CRT 3-year OS ICT = CT + RT 0.77 H&N07 2 TPF CRT vs TPF cetuximab + RT vs CRT vs cetuximab + RT 3-year OS ICT > no ICT 0.03 TREMPLIN TPF (CRT vs cetuximab + RT) Larynx preservation rate, OS CT + RT = cetuximab + RT NS More acute and late toxicity with CRT Adiction of Taxanes to ICT improved outcomes vs PF 1 Next generation regimens, including Cetuximab, are under evaluation, as a better combination with less toxicity and with more efficacy 2,3 ICT, induction CT; NS, not significant; PF, platinum based CT + 5-FU; PFS, progression-free survival 1. Argiris A. Crit Rev Oncol Hematol 2013;88:57 74 2. Lefebvre J-L, et al. J Clin Oncol 2013;31:853 859 3. Ghi MG, et al. Presented at ASCO 2014 (Abstract No. 6004)

Cumulative cisplatin exposure is becoming increasingly relevant for management decisions Cisplatin accumulation in the tissues 1 can reach a level above which toxicity becomes unacceptable and further exposure becomes unwise 2,3 ICT might result in cisplatin build-up that places a patient into the gray zone for further cisplatin therapy 1,2,4 Phase 3 DeCIDE study in patients with LA SCCHN: 3 Grade 3 toxicity Reduction in white blood cell count (% patients) Reduction in absolute neutrophil count (% patients) ICT* + CRT (n=124) CRT alone (n=133) p value 26 11 0.021 14 4 0.039 *ICT consisted of TPF or PF 1. Arany I, Safirstein RL. Semin Nephrol 2003;23:460 464; 2. Gamelin E et al. Cancer Chemother Pharmacol 1995;37:97 102; 3. Cohen EE, et al. J Clin Oncol 2014;32:2735 2743; 4. Bourhis J et al. Eur J Cancer 2010;46:1979 1989

Meta-analysisof ICT

Meta-analysisof ICT

Meta-analysisof ICT

TREMPLIN ICT Chemotherapy Fase II en pcts candidatos a laringectomía total Main Objective: Larynx preservation at 3 months of treatment Secundary Objectives: Larynx preservation and OS at 18 months of treatment Lefebvre J et al. J Clin Oncol 2009;27(Suppl. 15):Abstract 6010; J Clin Oncol. 2013 Jan 22. [Epub ahead of print]

TREMPLIN - results Endpoint* Cetuximab + RT (n = 56) CRT (n = 60) Larynx preservation at 3 months (LP) 93% 95% Larynx function preservation 18 months (LFP) 82% 87% Overall Survival (OS) 18 months 89% 92% OS 36 months 73% 75% OS (ITT pts with respnse to ICT) *Todas las comparaciones son estadísticamente no-significativas (p>0.05)

TREMPLIN toxicity J Clin Oncol. 2013 Jan 22. [Epubaheadof print]

TREMPLIN treatment compliance More patients complied with planed treatment with Cetuximab+RT vs CT+RT Patients who finished RT after ICT (%) 43 71 Lefebvre J et al. J Clin Oncol 2009;27(Suppl. 15):Abstract 6010; J Clin Oncol. 2013 Jan 22. [Epub ahead of print]

TREMPLIN salvage surgery J Clin Oncol. 2013 Jan 22. [Epub ahead of print]

The choice of treatment for an individual with LA SCCHN depends on a variety of factors LA SCCHN 1 YES Resectable? NO Is surgery the best treatment option? NO RT-based treatment YES Organ preservation? Surgery Follow-up Follow-up Adjuvant therapy (RT/CRT) ICT CRT or cetuximab + RT YES Sequential therapy? NO CRT or cetuximab + RT or RT alone Characteristics may vary between patients from Europe, the US, and the rest of the world 2,3 CRT, chemoradiotherapy; ICT, induction chemotherapy; LA, locally advanced; RT, radiotherapy 1. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers V1.2015; 2. Ang KK, et al. N Engl J Med 2010;363:24 35; 3. Granata R, et al. Ann Oncol 2012;23:1832 1837

Status of Induction Chemotherapy Induction chemotherapy is a treatment option in LA HNSCC Induction chemotherapy does not improve survival Induction chemotherapy is an evidence-based option for laryngeal preservation Selected patients may benefit TPF is a standard regimen but associated with considerable toxicities; mortality risk of about 5% Novel regimens with targeted agents should be explored in the induction setting

CONCLUSIONS Multidisciplinary approach is crucial for head and neck patients CRT and CET+RT has the same efficacy and Cetuximab+RT less systemic toxicity and can be used after ICT Compliance after ICT with Cetuximab+RT is higher and the late toxicity is lower Patients selection should be made according clinical data

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