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Induction Therapy for Locally Advanced Esophageal Cancer

2009 년 제 25 차 대한흉부외과학회 춘계학술대회. Induction Therapy for Locally Advanced Esophageal Cancer. May 28, 2009 Yong Hee Kim , MD, PhD Dept. of Thoracic & Cardiovascular Surgery ASAN Medical Center, University of Ulsan College of Medicine. Overall Survival after Esophagectomy.

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Induction Therapy for Locally Advanced Esophageal Cancer

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  1. 2009년 제 25 차 대한흉부외과학회 춘계학술대회 Induction Therapy for Locally Advanced Esophageal Cancer May 28, 2009 Yong Hee Kim,MD, PhD Dept. of Thoracic & Cardiovascular Surgery ASAN Medical Center, University of Ulsan College of Medicine

  2. Overall Survival after Esophagectomy Locally advanced esophageal cancer by surgery alone : 5-YSR : < 20 ~ 30% Survival (%) Years Rice, Dis Eso 2009;22

  3. Treatment of Esophageal Cancer • Surgery Alone • Radiation Alone • Chemotherapy Alone • Nonsurgical: Definitive Chemoradiation • Preoperative Radiation • Postoperative Radiation • Preoperative Chemotherapy • Preoperative Cheomoradiotherapy • Postoperative Chemotherapy • Palliation

  4. Rationale of Multimodality Therapy • Poor survival with surgery alone • Distant dissemination of disease occurs early • Downsize tumors - improve resection rate, and local control - improve control of micrometastatic disease

  5. Preoperative ChemoRadiation Therapy (CRT) in Locally Advanced Esophageal Cancer • RTOG* trial 8501 (1992) - RT 6,400 cGy vs 5,000 cGy + FU / Cisplatin - 5-YSR : 32% vs 12% • GI Intergroup 0113 (1997) - Preop / postop CTx with FU / Cisplatin vs Surgery - no survival benefit • Medical Research Council Study (2002) - induction CTx - median survival benefit : 3.5 months *, Radiation Therapy Oncology Group

  6. Survival Benefit, Yes ? :CALBG 9781 p = 0.002 Tepper, J Clin Oncol 2008;26

  7. Survival Benefit, No ? : USA Intergroup 113 p = NS Kelsen, J Clin Oncol 2007;25 (Update RTOG trial 8911)

  8. Methodological Concerns in CRT • Optimal radiation dose • Adequate radiation field • Chemotherapeutic agents • Administration schedule • Control side effect

  9. Patients Selection for CRT ASAN Medical Center • Indications for CRT - pathologically confirmed esophageal cancer - surgically resectable clinical stage of II/III by CT - age : 18 ~ 75, ECOG performance 0 ~ 2 - adequate bone marrow function, LFT, renal function • Exclusion Criteria for CRT - stage I by EUS - invasion to recurrent laryngeal n., trachea, aorta - evidence of esophageal fistula, malignant pleural effusion - metastatic LN at celiac or paraaortic LN - inadequate cardiac/pulmonary function

  10. Protocol of CRT in Esophageal Ca.

  11. Prospective Clinical Trials in Asan Medical Center 1993 - 1997 1999 - 2002 2003 - 2005

  12. Phase II study in AMC Treatment Scheme of Induction Chemotherapy (Capecitibine, CDDP) followed by Concurrent Chemoradiation Diagnostic work up (GFS,CT, EUS, PET) Stage II,III resectable esophageal SCC CAP 1000mg/m2 bid (D1-14) CDDP 60mg/m2 (D1) 3 wks later CAP 800mg/m2 bid 5 days/wk) CDDP 30mg/m2 (D1, 8,15, 22) RT 46Gy, 2Gy/Fx, 23 Fx 4-6 wks later Surgery

  13. Randomized phase II study of preoperative concurrent chemoradiotherapy with or without induction chemotherapy with S-1/oxaliplatin in patients with resectable esophageal cancer 2008 - 2010

  14. Review of Phase II trials of CRT

  15. Review of Randomized Phase III studies

  16. Phase III trials of Impact of CRT MRCOCWP, Medical Research Council Oesophageal Cancer Working Party

  17. Prognostic Factors forCRT + S Good performance status Major response to chemoradiation Presence of micrometastases Number of pathologic metastases Early metabolic response with FDG PET - Siewert, Ann Surg 2007;246 - Port, Ann Thorac Surg 2007;84 => > 50% reduction in maxSUV median survival 35.5 vs 17.9 mo

  18. Predictor of Prognosis for CRT + S • Favorable prognosis - female with clinical response to CRT - esophagectomy - good performance - initial stage II • Poor prognosis - poor performance status - severe dysphagia - poor clinical response to CRT

  19. Effect of Esophagectomy on Survival All patients (n=180, p < 0.001) cCR or PR (p = 0.001) AMC, I J Radiat Oncol 2008;71

  20. Overall Survival by Type of Resection USA Intergroup 113 (Update RTOG trial 8911) Kelsen, J Clin Oncol 2007;25

  21. Spread of Esophageal Cancer Intraesophageal spread - "skip" or "satellite" lesion ; submucosal spread Direct extension to adjacent structure Lymphatic spread - extensive submucosal longitudinal lymphatics

  22. Lymphatics of Esophageal Wall “skip or satellite nodule formation”

  23. Extent of Esophageal Resection Microscopic spread by length of margin - resection margin : 3 cm 64% - resection margin : 6 cm 22% - resection margin : 9 cm 11% - resection margin : 10.5 cm 3% Miller (Br J Surg 1962:49) : > 10 cm DiMusto (Ann Thorac Surg 2007;83): > 5 ~ 6 cm

  24. Survival based on No. of Positive LNs Kesler, Ann Thorac Surg 2005;79

  25. Survival based on Response to CRT Kesler, Ann Thorac Surg 2005;79

  26. Response to CRT 3-YSR 70.4% 3-YSR 41.8% Rizk, J Clin Oncol 2007;25

  27. Survival by Response to CRT in AMC p = 0.006 pCR Non-pCR Median FU = 77.4 mo

  28. Survival Curves by Response to CRT USA Intergroup 113 (Update RTOG trial 8911) Kelsen, J Clin Oncol 2007;25

  29. Definition of Response :CALBG 9781 • Complete response - no gross or microscopic tumor in surgical specimen using light microscope • Partial response - shrinkage in tumor size c/w the original GFS - macroscopic or microscopic residual tumor • Progession - increase in ≥ 25% of perpendicular diameters • Stable Tepper, J Clin Oncol 2008;26

  30. Tumor-Regression Grade to CRT TRG 5 TRG 4 TRG 3 TRG 2 TRG 1 Fareed, Gut 2009;58

  31. Response Evaluation after CRT The diagnostic accuracy is inadequate for objective response evaluation after induction CRT Schneider, Ann Surg 2008;248

  32. MUNICON trial Metabolic response evalUation for Individualisation of neoadjuvant Chemotherapy in oesOphageal and oesophagogastric adeNocarcinoma • Metabolic response by FDG-PET : - decrease of 35% or more in tumor SUV at induction CRT 2weeks - continue induction CRT followed by surgery - longer survival in response group • Predictive role of response - major histological response : 58% - metabolic response may correlate with tumor response Lordick, Lancet Oncol 2007;87

  33. Heterogenicity in Response to CRT • Age, sex, ethnicity, drug-drug interaction, genetic variation in pharmacokinetics, pharmacodynamic, drug action pathways • Genetic variation in AKT1, AKT2, FRAP1 - FRAP1SNPs; increase risk of death - AKT2, FRAP1; poor response to treatment - AKT1:rs3803304; better response to treatment

  34. Pathways Involved in Repair of CRT Injury AP, apurinic / apyrimidinic; ERCC, excision repair cross-complementing group; FEN-1, flap structure specific endonuclease 1; PCNA, proliferating cell nuclear antigen; RPA, replication protein A; RFC, replication factor C; XPA and XPC, xeroderma pigmentosum complementation groups A and C; XRCC1, x ray cross-complementation group 1 Fareed, Gut 2009;58

  35. OS according to Tx (CRT-S versus S) for patients with ERCC1-negative and ERCC1-positive tumors Median OS in ERCC1 ( - ) = 51.2 mo p = ns Median OS in ERCC1 ( + ) = 43.2 mo AMC, Clin Cancer Research 2008;14

  36. Surgical Considerations of CRT - I Poorer nutritional status Depressed respiratory activity Depressed mental condition Diminished immunologic reserves Lower WBC or Hb level

  37. Surgical Considerations of CRT-II • Increase postoperative morbidity • Increase operative mortality - 2~5% vs > 10% - Jones (1997), Hennequin (2001), Nakadi (2002) • Fail to receive surgery d/t progression • Late complication - Murthy (J Clin Oncol 2009;4) - pleural effusion : 2 times - pericardial effusion : 5 times

  38. Comparison of Postoperative Result Nabeya, Dis Eso 2005;18

  39. Review of Recent Meta-analysis *ns, not significant

  40. Summaries • If surgery is performed in patients with locally advanced esophageal cancer, there may be small survival advantage if combined with induction chemoradiation therapy. • Preoperative chemo/chemoradiotherapy is probably useful for subgroup of patients, but not clear for whom. • Further efforts should be made in optimization of multimodality therapy in locally advanced esophageal cancer.

  41. Future Improvements • Incorporation of targeted agents that add minimally to existing toxicity • Use of molecular predictors of response to individualize selection of the chemotherapeutic regimen • Early identification of responders such that therapy might be altered dynamically • How to restage patients after completion of their treatment - accurate restaging provides prognostic information - accurate restaging can help direct subsequent treatment decisions

  42. Thanks for Your Attention !

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