INDUCTION CHEMOTHERAPY LAHNC INDUCTION CHEMOTHERAPY THE NEW STANDARD TREATMENT Ricardo Hitt Hospital 12 de Octubre SEOM 2009

BASIS OF ICT CELLULAR BASIS BIOLOGICAL CONCEPT PARAMETER OF SURVIVAL PATIENTS SELECTION

OROPHARYNX TUMOR

PHARYNX TUMOR

PHARYNX TUMOR

LOCAL-CONTROL AND TUMORAL VOLUME

Prognostic impact of tumor volumetry in patients with locally advanced head and neck cancer treated by radiotherapy alone or radiochemotherapy (Plataniotis et al Int J Radiation Oncol 2004) Tumor volume is one of the main reported factors determining the outcome of treatment HNC CT digitized: tumor volume cubic centimeters Total gross tumor volume < 22.8cc were more likely to achieve a complete response and had a median survival of 45 months Total gross volume > 22.8 cc median survival of 12 months.(p=0.01)

UNRESECTABLE SCCHN Phase III Trial Unresectable SCCHN (JCO 2003, Adelstein) A: Radiotherapy (OS= 23%) 295 patients B: CRT, Cisplatin 100 mg/m2( OS= 37%) 3 years C: Split course CF (OS= 27%)

R91-11 Schema RANDOMIZE STRATIFY CDDP/5-FU Location: Glottis Supraglottic RANDOMIZE CR,PR x 1 Cycle RT STRATIFY Arm 1: CDDP/5-FU x 2 cycles T Stage: T2 T3, Fixed cord T3, No cord fixation T4, with base of tongue 1 cm NR Surgery RT Arm 2: Radiation Therapy + CDDP N Stage N0, N1 N2, N3 Arm 3: Radiation Therapy

Overall Survival FORASTIERE NEJM Dead / Total RT + Induction 89 / 173 RT + Concomitant 106 / 171 RT Alone 96 / 171 FORASTIERE NEJM

CHEMORADIOTHERAPY CRT IS BETTER THAN RT IS THERE SOME CHANGE IN THE NATURAL HISTORY OF LAHNC? YES: CRT IS BETTER THAN RT

Results : Overall survival 105 comparisons and 17 858 pts Chemotherapy timing Risk reduction Absolute benefit at 5 years * p-value Adjuvant Neoadjuvant Concomitant -6 % 4 % 19 % NS < 0.0001 - 2 % 2 % 8 % The results of this update confirmed those of the first MA, with a somewhat deleterious effect of the adjuvant setting, the almost nil effect in terms of OS for the NACT but it was before the taxane era, and a small but significant impact of concomitant, platinum-based chemoradiation. Total 12 % < 0.0001 5 % * 5-year survival rate in control group : 30%

ASCO 1982: The Platinum Revolution 35 previously untreated pts: 3 cycles cisplatin-5FU (CF) Response > 50% Complete response 94% 63% Decker D et al. ASCO Annual Meeting. Saint Louis 1982, Abstract C-757 Decker DA et al. Cancer 1983;51:1353-5 60 tumors treated with platinum-based chemotherapy 42 responses > 50% 18 responses < 50% 25 years ago medical oncologists treated the first head and neck cancer patients with cisplatin therapy. In those years the different researchers reported a high response rate to this therapy without rigurous evaluation about the response. after RT after RT Ensley J et al. ASCO Annual Meeting. Saint Louis 1982, Abstract C-767 Ensley JF et al. Cancer 1984;54:811-4 97% 6%

Rationale for induction CT Induction CT: high RR ( 70%-80%); RC (5% - 30%) 1- 4 cycles prior to RT Subsequent RT or surgery not compromised Not clear if local control increased Response to induction CT predicts response to RT Part of a larynx preservation strategy What was the rationale for the use of induction chemotherapy? High response rate as front line, in patients with response the following treatment was not altered, response to induction chemotherapy predicted response to radiotherapy and was a part of laryx preservation strategy.

Improved Complete Response Rate and Survival in Advanced Head and Neck Cancer After Three-Course Induction Therapy With 120-Hour 5-FU Infusion and Cisplatin MICHAEL ROONEY, MD,.t JULIE KISH, MD,JOHN JACOBS, MD.( JEANNIE KINZIE, MD,ARTHUR WEAVER, MD., JOHN CRISSMAN. MD. AND MUHYl AL-SARRAF. MD This is a classical report from Al-Sarraf. In this paper it was demonstrated Cancer 55: 1 1 23- I 1 28. 1985.

That patients with complete response to induction chemotherapy had benefits in survival. For this reason complete response to induction therapy may predict benefits in overall survival.

SCCHNC HOW CAN WE IMPROVE THESE RESULTS? Change the schedule of ICT Change the approach of treatment Now how can we improve these results? Probably by changing the schedule and changing the approach of the treatment

Phase III Study Comparing Cisplatin (P) & 5-Fluoruracil (F) Versus P, F and Paclitaxel (T) as induction therapy in Locally Advanced Head & Neck Cancer (LAHNC) Hitt et al (JCO 2005)

Time to Treatment Failure PF (n= 193): 133 (69%) events PFT (n= 189): 108 (57%) events Log-rank, p= 0.0062 Tarone-Ware, p= 0.0031 PF (median)= 11.6 (8.66 - 14.54) PFT (median)= 19.87 (13.78 - 25.95)

HNSCC: Taxotere in Locally-Advanced Disease Overall Survival TAX 324 30% reduction in risk of death TAX 323 29% reduction in risk of death 50 10 20 30 40 60 70 80 90 100 TPF Survival Probability (%) PF TPF Here we have both studies where we observe that PF schedule was improved with the addition of Taxotere, in terms of overall survival PF 6 12 18 24 30 36 42 48 54 60 66 72 6 12 18 24 30 36 42 48 54 60 66 72 Survival Time (months) Survival Time (months) Posner et al. ASCO 2006. Remenaer et al., ASCO 2006

CHANGE APPROACH INDUCTION CHEMOTHERAPY CHEMORADIOTERAPY CR/PR OBJECTIVE: FINAL CR BENEFIT SURVIVAL?

On behalf of the Spanish Head and Neck Cancer Cooperative Group, Spain Final results of a randomized Phase III trial comparing induction chemotherapy (ICT) with cisplatin/5-FU (PF) or docetaxel/cisplatin/5-FU (TPF) followed by chemoradiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC) Ricardo Hitt, MD, PhD JJ Grau, A Lopez Pousa, A Berrocal, C Garcia-Giron, A Irigoyen, J Sastre, J Martinez-Trufero, H Cortés-Funes, J Cruz-Hernandez On behalf of the Spanish Head and Neck Cancer Cooperative Group, Spain

Study design R CRT Neck dissection PF 3 cycles q3w CRT Surgery N=439 sample size refres to IIT population. Check demographics etc to see if all are PP TPF 3 cycles q3w CRT

Safety: Adverse events Grade 3/4 AEs, % patients CRT (N=119) PF plus CRT (N=156) TPF plus CRT (N=153) Total ICT (TPF + PF) (N=309) Neutropenia 20 38 34 36 Febrile neutropenia 1 3 18 10 Thrombocytopenia 4 Asthenia 9 14 11 Mucositis 31 46 42 44

Secondary endpoint: LCR (evaluable) % patients CRT (N=119) Combined ICT + CRT (N=234)

Primary endpoint: TTF (evaluable) CRT; median 5.0 months HR = 0.57; 95% CI, 0.45–0.74; p<0.0001 ICT + CRT; median 12.5 months ICT + CRT CRT E N Number of patients at risk 157 234 120 78 48 26 10 96 119 36 17 11 4 (months)

Secondary endpoint: TTP (evaluable) CRT; median 13.1 months HR = 0.79; 95% CI, 0.60–1.03; p=0.056 ICT + CRT; median 18.5 months ICT + CRT CRT E N Number of patients at risk 141 234 149 95 57 29 10 82 119 65 42 26 17 5 (months)

CHEMORADIOTHERAPY HNC STANDARD TREATMENT OLD STANDARD GOLD STANDARD CRT TPF/CRT

PROBLEMS WITH ICT/CRT PATIENTS SELECTION CENTER EXPERIENCE INTENSIVE SUPPORTIVE CARE

Head and Neck Cancer Pretreatment considerations Comorbid chronic diseases Pulmonary Cardiovascular Digestive Malnutrition Resulting from poor dietary habits or symptoms Severe in over 25% of patients Oral health Periodontal disease, infections, and caries common Dental rehabilitation indicated prior to radiotherapy AS YOU CAN SEE, HEAD AND NECK CANCER PATIENTS HAVE A LOT OF PROBLEMS APART FROM THEIR CANCER SITUATION .FOR EXAMPLE THEY MAY HAVE PULMONARY PROBLEMS ETC, BUT, THE BIGGEST PROBLEM IS USUALLY MALNUTRICION.WE SHOULD REMEMBER THAT THESE COMORBILITY SITUATIONS ARE STRONGLY RELATED TO THE TOXICITY THAT DIFFERENT TREATMENTS GENERATE. Schantz SP, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;797-860.

SURVIVAL PARAMETER OVERALL SURVIVAL TIME TO PROGRESSION TIME TO TREATMENT FAILURE: time from response, toxicity, death

LAHNC STANDARD TREATMENT OLD STANDARD GOLD STANDARD CRT TPF/CRT