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Trials in esophageal cancer.pptx

  3. 3. PROF S.SUBBIAH et al.
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  6. 6. PROF S.SUBBIAH et al. NATURAL HISTORY AND PATTERNS OF FAILURE • Lack of serosa & rich submucosal lymphatics network- lead to high occult nodal metastases- account for high local recurrence rates. • CERVICAL DEFINITIVE CHEMORADIATION is the standard care • UPPER THORACIC SCC MORE COMMON.HENCE LRR • MIDDLE THORACIC MORE COMMON(RT > Chemo) • LOWER THORACIC ADC MORE COMMON.HENCE • OG JUNCTION DISTANT METASTASES MORE COMMON(Chemo>RT)
  7. 7. PROF S.SUBBIAH et al. • Cervical & upper thoracic esophagus(<5 cm from cricopharyngeus): DEFINITIVE CHEMORADIATION- 50.4 Gy RT with cisplatin& 5-FU(Addition of paclitaxel- RT DOSE to 45Gy) • Middle & distal thoracic esophagus: Preoperative chemoradiation-41.4 Gy RT with paclitaxel & carboplatin. • GEJ Adenocarcinoma: Preoperative chemotherapy with FLOT – 5 FU,Leucovorin,Oxaliplatin,Docetaxel.
  8. 8. PROF S.SUBBIAH et al.
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  15. 15. PROF S.SUBBIAH et al. Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC • Chemotherapy followed by surgery versussurgery alone in patients with resectable oesophageal squamous cell carcinoma: Longterm results of a randomized controlled trial • Jurjen J Boonstra, Tjebbe C Kok, Bas PL WijnhovenMark van Heijl Mark I van Berge Henegouwen Fiebo JW ten Kate, Peter D Siersema Winand NM DinjensJan JB van Lanschot Hugo W Tilanus and Ate van der Gaast
  16. 16. PROF S.SUBBIAH et al. BOONSTRA ET AL 2011 CS GRP • Cisplatin 80 mg/m2 D1+ Etoposide 100 mg/m2 D1-2 X 2-4 cycles • Improved operability • SX-71% -R0 RESECTION • 25%-R1 RESECTION • 4%-R2 RESECTION • Median survival: 16 months S GRP • SX-57% -R0 resection • 29%-R1 RESECTION • 14%-R2 RESECTION • Median survival: 12 months
  17. 17. PROF S.SUBBIAH et al. Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma(JCOG9907) • A Randomized Trial Comparing Postoperative Adjuvant Chemotherapy with Cisplatin and 5-Fluorouracil Versus Preoperative Chemotherapy for Localized Advanced Squamous Cell Carcinoma of the Thoracic Esophagus (JCOG9907) • Nobutoshi Ando, MD, , Hoichi Kato, Hiroyasu Igaki, Masayuki Shinoda, , Soji Ozawa, MD,FACS4 Hideaki Shimizu, , Tsutomu Nakamura, MD, Hiroshi Yabusaki, , Norio Aoyama, Akira Kurita, MDKenichiro Ikeda, , Tatsuo Kanda, , Toshimasa Tsujinaka, , Kenichi Nakamura, and Haruhiko Fukuda
  18. 18. PROF S.SUBBIAH et al. ANDO ET AL 2011 PREOP CHEMO • 2 Cycles of cisplatin 80 mg/m2 + 5 FU 800 mg/m2, 3 weeks apart F/B SX • R0 RESECTION:96% • 5 yr PFS :44% • 5 YR OS : 55% SURGERY • Upfront Surgery F/B Postop chemotherapy – 2 cycles of PF(If pN1) • RO RESECTION:91% • 5 YR PFS 39% • 5 YR OS: 43%
  19. 19. PROF S.SUBBIAH et al. Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus-INT 0113 TRIAL. • Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. • D P Kelsen 1, R Ginsberg, T F Pajak, D G Sheahan, L Gunderson, J Mortimer, N Estes, D G Haller, J Ajani, W Kocha, B D Minsky, J A Roth
  20. 20. PROF S.SUBBIAH et al. KELSEN ET AL 1998 • The U.S. Intergroup Trial 113 (INT-0113) randomized 467 -immediate surgery OR to 3 cycles of PF followed by surgery and then, for those patients whose resection was curative (R0), 2 cycles of PF as adjuvant . • No differences in - curative resection rate (59% versus 62%), treatment mortality (6% versus 7%), median OS (16.1 versus 14.9 months), or 3-year survival (26% versus 23%) • The pattern of failure was also similar for the two treatment groups (local recurrence 31% versus 32% and distant recurrence of 50% versus 41%).
  21. 21. PROF S.SUBBIAH et al. Two cycles of preoperative cisplatin and fluorouracil improve survival without additional serious adverse events in the treatment of patients with resectable oesophageal cancer.(MRC TRIAL) • Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial • Medical research council esophageal cancer working group.
  22. 22. PROF S.SUBBIAH et al. MRC ESOPHAGEAL CANCER WORKING GROUP-2002 • 802 patients,31% -SCC & 69% ADENO • Patients – 2 cycles of cisplatin and continuous infusion 5-FU followed by surgery or immediate surgery. • Rate of curative resection similar.
  23. 23. PROF S.SUBBIAH et al. MRC • Cisplatin 160 mg/m2 3weeks • 5 FU 8000 mg/m2 • No postoperative chemotherapy • Shorter time to surgery(2 months) • Reduced dosages, effective compliance, shorter time to surgery lead to translation to better OS. INT 0113 • Cisplatin 300 mg/m2 8 weeks • 5 FU 15,000 mg/m2 • 2 cycles of cisplatin and 5 FU • Longer time to surgery(3 months) • High doses of the chemotherapy lead to high toxic effects; reduced compliance & nullified the benefits of surgery.
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  25. 25. PROF S.SUBBIAH et al. Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care(OEO2 TRIAL) • Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer • William H Allum 1, Sally P Stenning, John Bancewicz, Peter I Clark, Ruth E Langley
  26. 26. PROF S.SUBBIAH et al. OEO2 TRIAL 2008 SURGERY ALONE(434) • R0 RESECTION:40% • R1:17% • R2:12.9% 5 yr survival:17.1% PREOP CHEMO(437) • Cisplatin 80 mg/m2 D1 • 5 FU 1000 mg/m2 D1-D3 X 2 CYCLES 3 weeks apart • R0-42.4 % • R1-18% • R2-8.6% 5 yr survival: 23 %
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  28. 28. PROF S.SUBBIAH et al. In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression- free and overall survival(MAGIC TRIAL) • Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer • David Cunningham, M.D., William H. Allum, M.D., Sally P. Stenning, M.Sc., Jeremy N. Thompson, M.Chir., • Cornelis J.H. Van de Velde, M.D., Ph.D., Marianne Nicolson, M.D., J. Howard Scarffe, M.D., Fiona J. Lofts, Ph.D., • Stephen J. Falk, M.D., Timothy J. Iveson, M.D., David B. Smith, M.D., Ruth E. Langley, M.D., Ph.D., • Monica Verma, M.Sc., Simon Weeden, M.Sc., and Yu Jo Chua, M.B., B.S., for the MAGIC Trial Participants
  29. 29. PROF S.SUBBIAH et al. CUNNINGHAM ET AL 2006 • 503 patients - 3 cycles of preoperative and 3 cycles of postoperative epirubicin/cisplatin/5- FU(ECF) or surgery alone. • 26% -GEJ and lower esophagus. • Preoperative chemotherapy - with a 6-month improvement in PFS, a 4-month improvement in median survival, and a 13% improvement in 5-year OS (23% to 36%)
  30. 30. PROF S.SUBBIAH et al. In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS • Perioperative Chemotherapy Compared With Surgery Alone for Resectable Gastroesophageal Adenocarcinoma: An FNCLCC and FFCD Multicenter Phase III Trial • Marc Ychou, Vale´rie Boige, Jean-Pierre Pignon, Thierry Conroy, Olivier Bouche´, Gilles Lebreton, • Muriel Ducourtieux, Laurent Bedenne, Jean-Michel Fabre, Bernard Saint- Aubert, Jean Gene`ve, Philippe Lasser, and Philippe Rougier.
  31. 31. PROF S.SUBBIAH et al. FNCLCC / FFCD Multicenter Phase III Trial 2011 • Perioperative Chemotherapy Compared With Surgery Alone for Resectable Gastroesophageal Adenocarcinoma. • 224 patients -- perioperative chemotherapy and surgery or surgery alone . • Chemotherapy consisted of 2-3 preoperative cycles of IV cisplatin (100 mg/m2 ) on day 1, and a continuous IV infusion of fluorouracil (800 mg/m2 /d) for 5 consecutive days (days 1 to 5) every 28 days and 3-4 postoperative cycles of the same regimen.
  32. 32. PROF S.SUBBIAH et al. • RESULTS: Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%) and a better disease- free survival (5-year rate: 34% v 19%. ) • Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%). • Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia). • Postoperative morbidity was similar in the two groups.
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  34. 34. PROF S.SUBBIAH et al. Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus. • A COMPARISON OF MULTIMODAL THERAPY AND SURGERY FOR ESOPHAGEAL ADENOCARCINOMA • THOMAS N. WALSH, M.D., NOIRIN NOONAN, M.B., DONAL HOLLYWOOD, PH.D., ALAN KELLY, PH.D., C.STAT., NAPOLEON KEELING, M.D., AND THOMAS P.J. HENNESSY, M.D
  35. 35. PROF S.SUBBIAH et al. WALSH ET AL 1996 • SURGERY ALONE ARM • Median survival : 11 months • PREOP CRT ARM • 5 FU 15mg/kg D1-D5 + • Cisplatin 75 mg/m2 D7 X 2 cycles • F/B 40 GY RT • Median survival: 32 months
  36. 36. PROF S.SUBBIAH et al. Combined therapy increases the survival of patients who have squamous or adenocarcinoma of the Esophagus T1-3 N0-1 M0 compared with RT alone(RTOG 85-01 TRIAL) • Chemoradiotherapy of locally advanced esophageal cancer • Long term followup of a randomised trial RTOG 85-01
  37. 37. PROF S.SUBBIAH et al. RTOG 85-01 1999 • Randomisation: Combined modality group – 50 Gy RT with cisplatin 75 mg/sq.m and 5 FU 1gm/sq.m VS RT alone 64 Gy in 32#. • RESULTS: Combined therapy survival > RT alone. • OS at 5 yr -26 % in CT vs 0 % RT alone. • This trial did not address the potential role of surgery .
  38. 38. PROF S.SUBBIAH et al. Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15-- >20%). • Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group) • S J Arnott 1, W Duncan, M Gignoux, D J Girling, H S Hansen, B Launois, K Nygaard, M K Parmar, A Roussel, G Spiliopoulos, L A Stewart, J F Tierney, W Mei, Z Rugang
  39. 39. PROF S.SUBBIAH et al. META ANALYSIS 1998
  40. 40. PROF S.SUBBIAH et al. Randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference • Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. • S G Urba 1, M B Orringer, A Turrisi, M Iannettoni, A Forastiere, M Strawderman
  41. 41. PROF S.SUBBIAH et al. URBA ET AL 2001 SURGERY ALONE • Upfront Trans- hiatal esophagectomy. Median survival: 17.6 months 3 yr survival: 16 months PREOP CRT • Cisplatin 20 mg/m2( D1-D5 & D17-D21) • 5 FU 300 mg/m2/d (D1- D21) • Vinblastine 1mg/m2/d(D1- D4 & D17-D21) • RT-45 Gy (1.5 Gy #) Median survival :16.9 months 3 yr survival : 30 months
  42. 42. PROF S.SUBBIAH et al. The promising 5-year survival results and low rate of late cancer-related deaths suggest that these regimens of intensive neoadjuvant therapy may improve the overall cure rate. The pathologic stage after neoadjuvant therapy is an important predictor of survival and may be useful in selecting patients for novel adjuvant therapies. Isolated local failure is uncommon, indicating that efforts to improve the therapeutic outcome should focus on optimizing systemic therapy rather than intensifying the RT. Additional randomized data are needed to assess the benefits of this therapeutic approach fully. • Mature survival results with preoperative cisplatin, protracted infusion 5-fluorouracil, and 44-Gy radiotherapy for esophageal cancer • Lawrence Kleinberg 1, Jonathan P S Knisely, Richard Heitmiller, Marriana Zahurak, Ronald Salem, Barbara Burtness, Elizabeth I Heath, Arlene A Forastiere
  43. 43. PROF S.SUBBIAH et al. KLEINBERG ET AL 2003 TRIAL A(50) • 44 Gy RT+ Cisplatin 26 mg/m2 D1-5 & D26-30 + 5-FU 300 mg/m2/d D1-30 Surgery done No adjuvant treatment TRIAL B(42) 44 Gy RT+ Cisplatin 20 mg/m2 D1-5 & D26-30 +5 FU 225 mg/m2/dD1-30 Surgery done Adjuvant chemotherapy- paclitaxel 135 mg/m2 D1 & cisplatin 75 mg/m2 D2 X 3 cycles. The observed 2- and 5-year survival rate and median survival was 57%, 40%, and 35 months, respectively.
  44. 44. PROF S.SUBBIAH et al. Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates(CROSS PROTOCOL) • Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer P. van Hagen, M.C.C.M. Hulshof, J.J.B. van Lanschot, E.W. Steyerberg, M.I. van Berge Henegouwen, B.P.L. Wijnhoven, D.J. Richel, G.A.P. Nieuwenhuijzen, G.A.P. Hospers, J.J. Bonenkamp, M.A. Cuesta, R.J.B. Blaisse, et al., for the CROSS Group*
  45. 45. PROF S.SUBBIAH et al. CROSS PROTOCOL 2015 • Randomisation - weekly administration of 5 cycles of NACRT (IV carboplatin [AUC 2] & IV paclitaxel [50 mg/m²] for 23 days) with concurrent RT (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, OR Surgery alone. • 368 patients; 188 in surgery alone & 180 in CRT f/b Surgery. 84 –SCC; 184- Adenocarcinoma.
  46. 46. PROF S.SUBBIAH et al. • RESULTS: median follow-up of 84·1 months , median OS- 48·6 months in the NACRT + surgery group ; 24 months in the surgery alone group . • Median overall survival for patients with SCC was 81·6 months in the NACRT + surgery group and 21·1 months in the surgery alone group ; • For patients with adenocarcinomas, it was 43·2 months in the NACRT + surgery group and 27·1 months in the surgery alone group.
  47. 47. PROF S.SUBBIAH et al. • Long-term follow-up confirms the overall survival benefits for NACRT when added to surgery. • This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes.
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  49. 49. PROF S.SUBBIAH et al. Data suggest that, in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation-FFCD 9102 TRIAL • Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102 • Laurent Bedenne 1, Pierre Michel, Olivier Bouché, Chantal Milan, Christophe Mariette, Thierry Conroy, Denis Pezet, Bernard Roullet, Jean-François Seitz, Jean-Philippe Herr, Bernard Paillot, Patrick Arveux, Franck Bonnetain, Christine Binquet
  50. 50. PROF S.SUBBIAH et al. FFCD 9102 2007 • 2 cycles of PF +45 Gy RT • ARM A ARM B (complete response) • SURGERY 3 cycles of PF+20 Gy RT 2 yr survival:34% 2 yr survival:40% Median survival:17.7 m median survival:19.3 m
  51. 51. PROF S.SUBBIAH et al. Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group • Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus • Michael Stahl , Martin Stuschke, Nils Lehmann, Hans-Joachim Meyer, Martin K Walz, Siegfried Seeber, Bodo Klump, Wilfried Budach, Reinhard Teichmann, Marcus Schmitt, Gerd Schmitt, Claus Franke, Hansjochen Wilke
  52. 52. PROF S.SUBBIAH et al. STAHL ET AL 2005 3 cycles of FLEP • ARM A ARM B • PE + 40 Gy RT PE +65 Gy RT • SURGERY NO SURGERY • 2 yr PFS: 64.3% 2 yr PFS:40.7% • Mortality: 12.8% Mortality: 3.5%
  53. 53. PROF S.SUBBIAH et al.