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Laryngeal Preservation Using Radiation Therapy 1903: Schepegrell was the first to perform radiation therapy for the treatment of laryngeal cancer Conventional external beam radiation produced disappointing results for advanced stage cancers (Local control: 65% for T3 glottic, 60% for T4 glottic and 50% for T4 supraglottic) Hyperfractionated regimen (bid XRT): improved local control by approximately 20% Accelerated dose regimen or accelerated regimen with concomitant boost All regimen resulted in improved local control but no survival benefit and increased toxicity Chemotherapy and Organ Preservation 1982: At ASCO, WSU present the first report of induction chemotherapy in 34 patients Chemosensitive tumors were also radiosensitive This led to the hypothesis that chemotherapy could be used to select tumors for effective treatment without laryngectomy This small pilot study led to the design of the VA Laryngeal Cooperative Study #268 2
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Larynx Preservation Larynx Preservation Long Term Quality of Life RANDOMIZED PATIENTS Larynx preserved Laryngectomy PATIENTS ALIVE With larynx Without larynx 166 103 (62%) 63 79 52 (66%) 27 Measure SF-36* Mental health HNQOL* Pain Speech Mod./severe depression Pre-treatment Post-treatment Surg + XRT (n=25) 63.0 64.3 66.5 Chemo + XRT (n=21) 76.0 81.3 66.0 10% 11% 28% 15% * All domains better for chemo + XRT, except speech P value <.05 <.05 N.S. Key Findings Important in Design of Future Studies Surgery is important component, salvage is challenging Neck management may differ from primary, (persistent occult disease 30-40% of N2,3) Systemic treatment of micrometastases must be considered No improvement in survival compared to surgery 4
EORTC Trial Stage II-IV cancers of the pyriform sinus or aryepiglottic fold induction chemo plus definitive radiation therapy in CRs vs. conventional treatment Results in 194 patients with 51 months median follow-up: equivalent survival EORTC Trial fewer failures at distant sites in the induction chemotherapy arm than in the immediate surgery arm (25% versus 36% respectively, p = 0.041). 5
R91-11 Phase III Trial to Preserve the Larynx Arm 1: Cisplatin/5-FU x 2 NR CR, PR cisplatin/5-fu x 1 surgery RT RT Arm 2: Radiation therapy with cisplatin Arm 3: Radiation therapy Patients entered Ineligible Eligibility pending Data pending Patient Enrollment Arm 1 Arm 2 Arm 3 Total 180 182 185 547 5 5 9 19 3 1 4 8 1 7 2 10 Analyzable 171 169 170 510 Median follow-up of surviving patients: 36 months Surgical Management Patients presenting with N2 or N3 neck disease (single node > 3 cm or multiple nodes) had a planned neck dissection 8 weeks after completing treatment Laryngectomy and neck dissection were performed for progression (induction arm) or persistent or recurrent local/regional disease (CT/XRT, RT arms). 6
Intergroup Trial R91-11 100 Overall Survival 76.5% Adequate patient numbers Homogeneous population Important Question: What is the real benefit of adding chemotherapy to radiation with respect to survival, larynx preservation and morbidity? % A L I V E 75 50 25 0 76.0% 75.7% 59.9% Induction CT Concurrent CT (p=0.70 vs. Induction) RT alone (p=0.59 vs. Induction) 0 1 2 3 4 5 YEARS FROM RANDOMIZATION 54.0% 53.4% % P R E S E R V E D 100 75 50 25 0 Larynx Preservation Induction 88.0% 73.6% 59.3% Concurrent (p=0.0047 vs. Induction) RT alone (p=0.22 vs. Induction) 0 1 2 3 4 5 YEARS FROM RANDOMIZATION 84.5% 70.8% 63.5% % A L I V E (N E D) Disease-Free Survival 100 75 50 25 0 63.4% 54.5% 42.9% Induction CT Concurrent CT (p=0.56 vs. Induction) RT alone (p=0.0075 vs. Induction) 0 1 2 3 4 5 YEARS FROM RANDOMIZATION 44.2% 42.3% 30.4% 7
100 75 Distant Metastases 93.1% 91.8% 84.6% 86.6% 85.9% 75.8% Important Points in Interpreting These Data % F A I L E D 50 25 Induction CT Concurrent CT (p=0.97 vs. Induction) Timing of salvage laryngectomy is potentially confusing endpoint (early salvage may be better) The success of salvage surgery must be known RT alone (p=0.044 vs. Induction) 0 0 1 2 3 4 5 YEARS FROM RANDOMIZATION RT 91-11 Survival by Salvage Laryngectomy VA CSP268 Survival by Salvage Laryngectomy Weber, et al, Arch Oto-HNS, 2003 8
COMPLICATIONS ASSOC. WITH CONCURRENT CHEMO/XRT Stricture Radiation necrosis Chronic laryngeal edema Trach dependence Swallowing disorders Michigan Chemoselection Approach Search for tumor characteristics, clinical and biologic, that predict success VA laryngeal study taught us that patients who had a CR after single dose were the most successful 9
Organ Preservation by Cycle of Chemotherapy CR BY CYCLE (N) % CR ORGAN PRES. 2 cycles (49) 30% 86% 3 cycles (20) 12% 70% Patient Population Patient Population Stage III 46 (47%) T 2 = 9 N 0 = 53 (55%) Stage IV 51 (53%) T 3 = 56 N 1 = 17 TOTAL 97 T 4 = 32 N 2 = 24 N 3 = 3 10
Patient Population Primary Tumor Response After One Cycle CR = 15 (16%) Supraglottic Glottic 75 22 (77%) (23%) PR = 58 (61%) NR = 22 (23%) *2 patients were N/E, response did not differ by T class, Stage or site Overall Survival Fig 1. Overall survival 25 deaths: 13 HNSCC, 12 Other Cause of HNSCC Deaths: Local/regional 4 Distant Metastases 9 Median Follow up=41.9 months Urba, S. et al. J Clin Oncol; 24:593-598 2006 11
UMCC 9520 Overall Survival by T Class Fig 2. Disease-free survival 1.00 % Overall Survival 0.75 0.50 0.25 T2+T3 (n=65) Urba, S. et al. J Clin Oncol; 24:593-598 2006 Laryngeal Preservation Rate = 71% Fig 3. Survival of patients with larynx and free of disease Laryngectomy = 28/97 (29%) Timing of laryngectomy Planned after NR = 22* Late salvage = 6 (13-36 months) *3 non-responders did not undergo laryngectomy because of myocardial infarct, metastatic or unresectable disease. Urba, S. et al. J Clin Oncol; 24:593-598 2006 12
Survival 3 Year COMPARISON OF PATIENT POPULATIONS UMCC 9520 VA-CSP 268 Overall Survival = 85% (95% CI= 71-91%) Disease Free Survival = 78% (69-89%) Laryngectomy-free Survival = 61% (48-70%) Larynx preservation rate = 71% Median f/u = 29 months N Glottis Supraglottis T 2 T 3 T 4 N 0,1 N 2, 3 97 23% 77% 9% 56% 33% 72% 28% 332 37% 63% 9% 65% 26% 72% 28% Comparison of Survival:VA Larynx Trial vs UMCC9520 COMPARISON OF PATIENT POPULATIONS Intergroup R91-11 UMCC 9520 N Glottis Supraglottis T 2 T 3 T 4 N 0,1 N 2, 3 Male Female 497 32% 68% 9% 81% 10% 69% 31% 77% 23% 97 23% 77% 9% 58% 32% 72% 29% 79% 21% 13
Survival Comparisons Three Trials 3 YEAR SURVIVAL UMCC-9520 CT/XRT RT 91-11 VA-CSP 268 Overall 80% 70% 53% Comparison with Historic Controls U of M V.A. Int 9111* 5-Year Survival Overall 71% 43% 55% Disease-Free 78% 55% - Laryngectomy- Free 61% 58% 34% *ctx/xrt arm Fig 4. Survival of patients with organ preservation versus laryngectomy Take Home Points A single cycle of induction chemotherapy was highly successful in selecting patients for organ preservation with chemo/radiation. Urba, S. et al. J Clin Oncol; 24:593-598 2006 14
Take Home Points Take Home Points Overall 3-year survival rates appear improved with this approach to larynx preservation compared to historical controls. Surgery remains a critical component of treatment and early salvage appears to be more effective than late salvage Randomized comparison to standard treatment regimens is necessary to confirm the survival advantage of this approach French HN Onc Trial TPF vs PF Calais, 2008 Calais, 2008 15
Calais, 2008 Calais, 2008 R A N D O M I Z E Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF vs PF Followed by Chemoradiotherapy T P F P F cbdca auc 1.5 Weekly EUA Daily Radiotherapy Surgery TPF: Docetaxel 75 D1 + Cisplatin 100 D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 Posner NEJM, 2007 Characteristics of Hypopharynx and Larynx Cases Treated On TAX 324 TPF PF P Number 90 76 Hypopharynx 43 (48%) 34 (45%) Larynx 47 (52%) 42 (55%) Median Age (Range) 56 (39-82) 59 (37-80) P=.21 T Stage T1/2 T3 T4 Nodal Stage N0/1 N2 N3 Clinical Stage III IV Posner, Ann Oncol 2009 15 (17%) 35 (39%) 40 (44%) 43 (47%) 35 (39%) 12 (13%) 22 (24%) 68 (76%) 17 (22%) 33 (43%) 26 (34%) 33 (46%) 31 (40%) 12 (15%) 22 (29%) 54 (71%) P=.37 P=.81 P=.60 16
Larynx and Hypopharynx Survival and Progression Free Survival Laryngeal Cancer in the United States: Changes in Demographics, Patterns of Care, and Survival TPF PF P Number 90 76 Overall Survival Median, mo (range) 2 Year 3 Year Hazard ratio PFS ( Equivalent to LFS) Median, mo (range) 2 Year 3 Year Hazard ratio 59 (31-NR) 24 (13-42) 64% (54-74%) 50% (38-61%) 57% (46-68%) 40% (29-52%) 0.62 (0.41-0.94).024 21 (12-59) 48% (37-58%) 43% (32-54%) 11 (8-14) 33% (22-43%) 29% (19-40%) 0.66 (0.45-0.97).032 Posner, Ann Oncol 2009 The Laryngoscope Volume 116, Issue S111, pages 1-13, 2 JAN 2009 DOI: 10.1097/01.mlg.0000236095.97947.26 http://onlinelibrary.wiley.com/doi/10.1097/01.mlg.0000236095.97947.26/full#fig7 Laryngeal Cancer in the United States: Changes in Demographics, Patterns of Care, and Survival Case 67 year old man Mild stridor Hoarse for 8 months Cord immobile Imaging The Laryngoscope Volume 116, Issue S111, pages 1-13, 2 JAN 2009 DOI: 10.1097/01.mlg.0000236095.97947.26 http://onlinelibrary.wiley.com/doi/10.1097/01.mlg.0000236095.97947.26/full#fig1 17
Chemoselection as a strategy for organ preservation in patients with T4 laryngeal squamous cell carcinoma with cartilage invasion The Laryngoscope Volume 119, Issue 8, pages 1510-1517, 5 JUN 2009 DOI: 10.1002/lary.20294 http://onlinelibrary.wiley.com/doi/10.1002/lary.20294/full#fig3 Chemoselection as a strategy for organ preservation in patients with T4 laryngeal squamous cell carcinoma with cartilage invasion Univ of Chicago T4 Study Similar survival to RTOG 91-11 25% persistent tracheostomy 15% permanent G tube 30% normal, 60% hoarseness and 10% aphonic The Laryngoscope Volume 119, Issue 8, pages 1510-1517, 5 JUN 2009 DOI: 10.1002/lary.20294 http://onlinelibrary.wiley.com/doi/10.1002/lary.20294/full#fig2 18
Summary of Treatment Approaches Consider surgery for small T stage, advance neck stage Organ preservation strategies are ideal for T3 Surgery is the treatment of choice for T4 cancers 19
Looking to the Future Organ Preservation Exciting time for new paradigms Potent chemo - high CR rates Beginning to understand the biology Tailored Treatment Matrix Factors Surgery Radiation Chemo Biologics Proliferation Low High Nl to low + Questions? Immunogenic High CD8? High CD4? Tumor Volume High Low Vascular Low Host Immune Intact Poor Partial? p53 Express. p53- p53- p53+ + p53 Mutation wtp53 wtp53 mutp53 + Apoptosis Inc Bclx Low Bclx Low Bclx + EGFR Inc EGFR Low EGFR +/- + Growth Pattern Low High High? VEGF Low High High + HPV + +/- -? p53 Ab + - -? 20