Larynx Preservation: the Nonsurgical Approach by Jan B. Vermorken

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Larynx Preservation: the Nonsurgical Approach by Jan B. Vermorken

  1. 1. The International Federation of Head and Neck Oncologic SocietiesCurrent Concepts in Head and Neck Surgery and Oncology 2012 Larynx Preservation: the Nonsurgical Approach Jan B. Vermorken
  2. 2. Outline •  Considerations in decision making •  Milestones in larynx preservation •  Role of radiotherapy •  The importance of timing chemotherapy •  First generation larynx preservation trials •  Second generation larynx preservation trials •  The design of future trials2012 •  Conclusions
  3. 3. New Findings in Recent Years •  HPV is a risk factor for cancer of the oropharynx •  Therapeutic agents against molecular targets (EGFR) •  Expanded role of chemotherapy (IC, CCRT) •  Improved irradiation techniques (IMRT) •  New imaging techniques (PET)2012 •  Survivorship issues Haddad RI, Shin DM N Engl J Med 2008; 359: 1143-54
  4. 4. Biologist HN Surgeon Pathologist Radiation Oncologist Anesthesiologist Medical Internist Oncologist GP Patient Dietician Speech Therapist Radiologist Social worker Psychologist Guidelines Clinical trials2012
  5. 5. Considerations in Decision Making •  Define risk group (TNM, UICC, AJCC) •  Pretreatment considerations1 –  Comorbid chronic disease (pulmonary, CV, digest.) –  Malnutrition (severe in > 25% of patients) –  Oral health (periodontal disease, infections, caries) •  Morbidity of treatment (radiotherapy, chemotherapy, targeted therapy, surgery)1 •  What do patients want? (cure, long living, no pain)22012 1Schantz SP et al. Cancer: Principles & Practice of Oncology, 6th ed. 2001; 797-860 2List, Head and Neck, 2004
  6. 6. ESMO Clinical Practice Guidelines 2010 Locoregionally Advanced Disease Level of Grade of evidence recommendationSurgery → RT or CCRT I AConcomitant CT and I ART*Cetuximab plus RT II BICT → RT for organ II ApreservationCCRT for organ II Apreservation 2012 *in case of mutilating surgery and in nonresectable disease Gregoire V et al, Ann Oncol 2010: 21 (suppl 5): VI84-VI86
  7. 7. Milestones in Larynx Preservation Courtesy of Prof. J-L Lefebvre Randomized trials on larynx preservation 1st. TL 1st. RT VA EORTC RTOG GORTEC EORTC Tremplin 1st. PLs 1873 1878 1903 1970s 1994 1996 2003 2005 2007 2009 partial radiotherapy laser ASCO biotherapy TORSsurgery 2012 CTscan 1982 MRI chemotherapy
  8. 8. Radical (Mutilating?) Surgery in LC and HPC Total laryngectomy (± partial pharyngectomy), Centre Oscar Lambret (1974 - 1983): 5-yr results site: # control survival > clavicles larynx * 254 88 % 48 % hypopharynx ** 244 84 % 35 % NB: postop RT * 40 %. ** 100%2012
  9. 9. Alternative to Mutilating Surgery •  Non-Mutilating Surgery -  endoscopic laser CO² surgery -  extended partial surgery • Non-Surgical Treatment -  definitive radiation therapy -  chemotherapy-based protocols2012
  10. 10. Altered vs Standard Fractionation Meta-Analysis Regimens Absolute benefit Risk p at 5 years reductionLocal-regional ControlHyperfractionation 9.4 % 24 % <0.0001AFX (≅ Total Dose) 7.3 % 21 % <0.0001 (â Total Dose) 2.3 % 10 % NSSurvivalAll group 3.4 % 8% 0.0032012 Bourhis (Pignon), Lancet 368:843, 2006
  11. 11. Meta-Analysis : Trials on Altered Fractionation Survival by Site No. Deaths / No. EnteredCategory Alt. fractionated RT Control O-E Variance Hazard Ratio Interaction test SiteOral cavity 282/370 278/346 -15.7 134.9 p = 0.20Oropharynx 1150/1673 1127/1576 -53.9 561.2Larynx 586/1231 553/1142 -19.9 276.8Hypopharynx 235/297 227/282 -12.3 110.7Others 52/69 45/72 8.9 19.6 0.0 0.5 1.0 1.5 2.0 Alt. fractionated RT better | Control better 2012 Bourhis J et al. Lancet 2006
  12. 12. Alternative to Mutilating Surgery •  non mutilating surgery -  endoscopic laser CO² surgery -  extended partial surgery •  non surgical treatment -  definitive radiation therapy -  chemotherapy-based protocols2012
  13. 13. Rationale for 1st Generation LP Trials •  High response rates with induction chemotherapy –  Response > 90%, complete resp.> 60% (Decker et al, Cancer 1983) •  Chemotherapy may predict radiosensitivity –  42/60 CR/PR → after RT, CRR 97%2012 –  18/60 NC/PD → after RT, CRR 6% (Ensley et al, Cancer 1984)
  14. 14. Neoadjuvant Chemotherapy in Resectable SCCHN 1st generationStudy Tumor Size Treatment No. of Survival LPGroup and stage arms pts (at 2 or 5 yrs)VA Larynx TL + RND + RT 332 60% (2) T1-T4, N2-3 CT → RT* 68% (2) 64%EORTC Hypopharynx TL + RND + RT 202 35% (5) T2-T4, N0-2b CT → RT* 30% (5) 57%2012 * non-responders → S + RT
  15. 15. 10090 Duration of Survival8070 Hazard Ratio: 0.88 (95% CI: 0.65 - 1.19)60 P-value for non-inferiority of LP: P=0.0015504030 Larynx preservation20 Surgery10 0 (years) 0 2 4 6 8 10 12 14 16O N Number of patients at risk : Treatment81 94 49 36 26 14 9 5 3 Surgery83 100 62 47 27 17 8 4 1 LP 2012
  16. 16. Randomized Trials of ICT in LA-HNC RevisitedTrial Arms OutcomeCA 139-322 (2005) PF vs PPF CCR (TTP, OS*)Resectable/nonresectable CRT (CDDP) Improved with PPFEORTC 24971/TAX 323 PF vs TPF PFS (RR, OS)°Nonresectable (2007) RT Improved with TPFTAX 324 (2007) PF vs TPF OS (PFS, RR)°Resectable/nonresectable CRT (Cb) Improved with TPFGORTEC 2000-01 PF vs TPF LP (OS, DFS)+ 2012Resectable (2009) T(P)L vs RT Improved with TPF *significant only in unresectable disease (JCO); °(Vermorken, Posner) NEJM; + (Pointreau) JNCI
  17. 17. GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and Larynx Cancer 2012 At 3 years: LP 70.3% with TPF, 57.5% with PF (p=0.03) Pointreau Y, et al. J Natl Cancer Inst 2009; 101: 498-506
  18. 18. Radiation + Chemotherapy vs Radiotherapy Alone Meta-analysis Absolute benefit Risk pRegimens at 5 years reductionAdjuvant 1% 2 % NSNeoadjuvant 2% 5 % NS- NACT with PF 5% 12 % 0.01Concurrent 8% 19 % < 0.00012012 Pignon et al, Lancet 335:949, 2000 (Pooled data from trials performed between 1965 and 1993) Monnerat et al, Ann Oncol 2002; 13: 995-1006
  19. 19. Neoadjuvant Chemotherapy in Resectable SCCHN 2nd generation LP trialsStudy Tumor size Treatment No. of 5-yearGroup and stage arms pts survival Glottic & supragl. PF → RT 173 59.2%RTOG N0-1, N2, N3 CRT (CDDP) 172 54.6%91-11A T2, T3+, T3-, T4 RT 173 53.5%EORTC Larynx & Hypophar PF x 2-4 → RT 224 48.5%24954B T2-T4, N0-N2 PF alt. RT 286 51.9% 2012 +with fixed cord involvement; -without cord fixation Aforastiere A et al, ASCO 2006; Blefebvre JL et al, JNCI 2009
  20. 20. Larynx preservation rates according to treatment group2012 Forastiere et al, 2003
  21. 21. RTOG 91-11:Phase III Trial of Larynx Preservation: ASCO- 5-Year Update #5517 PF CRT XRT LFS 44.6% 46.6% 33.9% p < .011 LRC 54.9%* 68.8%* 51% p < .0018 DM 14.3% 13.2% 22.3% DFS 38.6%* 39% 27.3%* p < .0016 Survival 59.2% 54.6% 53.5% 1.  PF was Equivalent to CRT for LFS 2.  CRT had Better LRC Than PF 3.  DFS Was Identical But Overall Survival Favored PF2012 4.  Did Patients Fare Better With PF Because They Had Subtle Improvements in Function
  22. 22. RTOG 91-11Phase III Trial of Larynx Preservation Laryngectomy-Free Overall Survival Survival2012 LFS=laryngectomy-free survival Forastiere. ASCO. 2006
  23. 23. RTOG 91-11: Cause of Death Induction Concomitant RT Alone n=89 n=106 n=96 # (%) # (%) # (%)Larynx cancer 41 (46) 37 (35) 56 (58)Second primary 11 (12) 17 (16) 12 (13)Complication of 8 (9) 10 (9) 5 (5)protocol treatmentComplication of other 2 (2) 2 (2) 0 (0)treatmentUnrelated to cancer 18 (20) 36 (34) 18 (19)or treatment 2012Unknown 9 (10) 4 (4) 5 (5)
  24. 24. CCRT: Late Toxicity Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14) 50 43% Patients (%) 40 30 27% 20 13% 12% 10% 10 0 Any severe Feeding-tube Pharyngeal Laryngeal Death late toxicity dependence dysfunction dysfunction >2 yrs post-RT2012 Machtay M, et al. J Clin Oncol 2008; 26: 3582–3589
  25. 25. EORTC 24954 Eligible pts. (previously untreated larynx /hypopharynx) amenable to TL R<50% TL + PORT 2 cycles PF* RP TL + PORT R SEQ 2 cycles PF* RT 70 Gy A R ≥ 50% N RC Follow-up D O M ALT 1cycle RT RT 1cycle RT 1cycle 1cycle PF** 20 Gy 20 Gy PF** 20 Gy PF** PF** RP RC* P 100mg/m2 d1- 5FU 1000mg/m2 d1-5** P 20 mg/m2 d1-5 – 5FU 200mg/m2 d1-5 TL + PORT Follow-up 2012 Lefebvre JL et al. J Natl Cancer Inst. 2009
  26. 26. EORTC 24954: Global Results at 5 Yrs Sequential Alternating (N=224) (N=226) % % p- Events without Events without value event event Survival with 160 30.5 154 36.2 0.15 functional larynxLarynx preservation 107 53.2 94 59.8 0.10 Progression-free 140 41.0 139 41.8 0.75 survival Overall survival 125 48.5 122 51.9 0.45 Acute toxicity: SEQ > ALT 2012 Late toxicity: SEQ = ALT Lefebvre JL et al. J Natl Cancer Inst. 2009
  27. 27. Conclusion: How Aggressive Should We be For Larynx Preservation? SCRT: ICT followed by CCRT substancial toxicity best protocol still unknown place of biotherapies CCRT: RT + Px3 substancial toxicity around 80 % larynx preservation no impact on survival Triplet ICT: TPF followed by RT still good tolerance/ compliance to Tx around 70 % larynx preservation no impact on survival Doublet ICT: PF followed by RT good tolerance/compliance to Tx around 60 % larynx preservation no impact on survival 2012 Courtesy of J-L Lefebvre
  28. 28. How to Design Future Trials? Primary endpoint: •  laryngo-esophageal dysfunction-free survival •  events are -  death -  local failure -  laryngectomy -  trach for ≥ 2years -  feeding tube ≥ 2 years Secondary endpoints: •  overall survival •  progression-free survival •  locoregional control •  time to tracheotomy2012 •  time to laryngectomy Lefebvre JL and Ang KK. Int J Radiat Oncol Biol Phys 2009
  29. 29. Sequential ICT and CCRT: the Dilemma Efficacy vs ToxicityThe “best”: The “best”: TPFx3 RT + Px3 ICT CCRT ??? ??? Options: Reducing ICT to maintain CCRT?2012 Reducing CCRT to maintain ICT? Alternative option for CCRT after ICT?
  30. 30. How to Balance Efficacy vs Toxicity? •  Reducing intensity of ICT: –  Only 1 cycle PF, then decide to TL or CCRT (cisplatin) (Worden et al, 2009) •  Reducing intensity of CCRT –  Carboplatin during RT (AUC 1.5/wk) following 3xTPF (Posner et al, 2007) •  Alternative enhancement of RT2012 –  Cetuximab during RT following 3xTPF (Lefebvre et al, 2011)
  31. 31. What is the Optimal ST Design?The Randomized Phase II Study: TREMPLINPreviously untreated SCC larynx/hypopharynx suitable for TLPrimary endpoint: larynx preservation 3 months after treatmentSecondary endpoints: larynx function preservation and survival 18 months after treatment RT 70 Gy TPF Cisplatin 100 mg/m² on days 1, 22 and 43 3 cycles, 1 cycle q3weeks T = 75 mg/m² on day 1 ≥ PR P = 75 mg/m² on day 1 R 5-FU = 750 mg/m² on day 1 to 5 RT 70 Gy Cetuximab 400 mg/m² 1 wk prior to RT <PR then 250 mg/m² weekly on wks 1 to 7 Total laryngectomy + postop RT 2012 Response evaluation by endoscopy and CT scan Lefebvre et al for GORTEC and GETTEC groups (abstract #6010) 5-fluorouracil, T=docetaxel TL=total laryngectomy, PR=partial response, RT=radiation therapy, CT=computed tomography
  32. 32. Compliance to TreatmentRadiotherapy Cisplatin arm (n=60) Cetuximab arm (n=56)Not done 2 0Mean dose 69 (24**-74) 69.5 (56-76)No of cycles: 7 - 40 (71%) 6 - 4 5 - 4 4 - 1 3 26 (43%) 2012 1 refusal and 1 rapid evolution, **another rapid evoluation, 1 ***3 infusion-related reactions 2 Lefebvre et al, ASCO 2011 24
  33. 33. Acute Toxicity CDDP arm (n=58*) CET arm (n=56) p-valueGrade 3 mucositis 25 (43%) 24 (43%) NSGrade 4 mucositis 2 1Grade 3 infield skin tox. 14 (24%) 29 (52%) < 0.001Grade 4 infield skin tox. 1 3Other tox. Justifying dosemodification- Renal 9 (15.5%) 0- hematologic 8 (14.0) 0- poor general condition 7 (12.0%) 1 (1.7%)- infusion –related react. 0 3 (5.0%)- Protocol modifications** 33 (57%) 19 (29%) 0.02 2012 * 2 patients did not start; ** due to acute toxicity. Lefebvre et al, ASCO 2011
  34. 34. Assesment of Failures (Intent to Treat) Last evaluation with a median At 18 months after end follow-up of 36 months of treatment cisplatin cetuximab p value cisplatin cetuximab p value arm arm arm armTotal of local (+/- regional) 5 (8.3 %) 8 (14.3 %) Log-rank: 7 (11.7 %) 12 (21.4 %) Log-rank:failures 0.30 0.14 Feasible salvage 0/4* 7/8 0.01 1/6* 9/12 0.04 Total laryngectomy (1 refused) Successful salvage 0/1 7/8 total laryngectomyUltimate local failure rate 6 (10 %)* 5 (8.9 %) NSRegional failure alone 5 (8.3 %) 5 (8.9 %) NS 5 (8.3 %) 5 (8.9 %) NSDistant metastases 2 (3.3 %) 2 (3.6 %) NSSecond primary tumor 3 (5 %) 3 (5.3 %) NS 2012 * Data missing for 1 patient lost to follow-up at 5 months Lefebvre et al, ASCO 2011
  35. 35. Overall Survival (Intent to Treat)2012
  36. 36. Conclusions •  Upfront surgery remains the best option in some cases (cases for partial surgery, transglottic and T4) • Salvage surgery plays a major role in organ preserving treatments • Organ preserving strategies do not jeopardize survival and disease control but, to date, no non- operative treatment has provided a better survival that upfront surgery •  Distant metastases remain a concern2012 • Non-operative treatments must be evaluated in the light of disease control AND of survival AND of quality of the function

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