1. GI POSTER SESSION ESOPHAGEAL CANCER Joel Tepper, MD Dept of Radiation Oncology UNC School of Medicine

2. A Scandinavian randomized trial of Chemoradiotherapy versus Surgery alone in patients with resectable esophageal cancer Hanna Carstens, Maria Albertsson, Signe Friesland, Gunnar Adell, Gunnar Wagenius, Gunilla Frykholm, Ivan Farago, Helge E. Myrvold, Dag Stockeld 2007 ASCO Annual Meeting

3. Methods Accrual between 2000 and 2004 91 patients with esophageal cancer Resectable squamous cell carcinoma or adenocarcinoma Primary located above the cardia No metastases Endoscopy (+/- EUS) + CT staging

4. Chemotherapy One cycle induction, 2 cycles with RT Cisplatin 100 mg/m2, day 1 5-fluorouracil 750 mg/m2/24 hours, infusion day 1-5, Three weeks cycles

5. Local Therapy 64 Gy, 5 days/wk, 200 cGy/fx 5 cm proximal and distal margin to 44 Gy Supraclav nodes treated for tumors above the carina, celiac nodes for tumors below the carina 2 cm margins to 64 Gy Surgery- Ivor-Lewis esophagectomy

6. Results Survival defined from randomisation Intent to treat analysis 50% adenoca 80% male 55% Stage III Treatments generally well tolerated Surgery performed in 39 pts –32/39 (76%) had radical resection 10 pts with micro or macro residual disease –Median hospital stay- 18 days

7. Survival 1 year2 year4 yearMedian (mos) RT + chemo 56%37%29%12.8 Surgery alone 55%25%23%15.8

8. Esophageal cancer Reasonable treatment arms Only 91 pts accrued –Low power to detect a survival difference between the two approaches No suggestion of a survival difference Supports other data suggesting that primary radiation therapy with concurrent chemo is equivalent to surgery in survival No obvious morbidity differences No local control data provided –May be of great importance for QOL analysis Quality of life data could be of importance

9. Combination of endoscopic mucosal resection and chemoradiotherapy as a nonsurgical treatments for patients with clinical stage I esophageal squamous cell carcinoma. K. Minashi, A. Ohtsu, K. Mera, M. Muto, T. Yano, M. Tahara, T. Doi, M. Nishimura, K. Nihei

10. Tumors: depth < focal SM invasion & width < 2/3 circumference Pathology: M & vessel infiltration (-) Primary CRT Prophylactic CRTObservation only Treatment algorithm of EMR/CRT for clinical Stage I ESCC Primary EMR Salvage EMR Local residual, recurrent or metachronous lesion Pathology: SM or M with vessel infiltration (+) Incomplete resectionComplete resection Tumors: depth > focal SM invasion or width > 2/3 circumference

11. A saline solution of dilute epinephrine (0.02 mg/ml) was injected into the SM layer. The lesion was held up by forceps and resected using a high- frequency electrified snare wire. When en bloc resection was not possible, the lesions were removed piecemeal. Procedure of EMR

12. Eligibility Squamous cell ca Clinical Stage I Age < 75 PS < 2 Only focal submucosal invasion < 2/3 circumference RT (40 Gy with 1 week break)/5-FU (400 mg/m2/d x 10)/platinum (40 mg/m2/d x 2) for submucosal invasion at EMR Other pts received 60 Gy (with 2 week break)/5-FU (800 mg/m2 x5, twice)/platinum (80 mg/m2/d x 2) without EMR

13. Therapy Received 86 pts 41 primary EMR –11 received planned RT + chemo 1 required salvage surgery –1 esophagectomy 45 primary RT/chemo –11 required salvage EMR –2 required salvage surgery –1 chemotherapy for local recurrence

14. 4 - Year Survival Median 5 year followup All patients 75% Primary EMR 78% Primary RT + chemo73%

15. Discussion Group of patients not commonly seen in the US Can these pts be easily identified? Good survival results, but very early subset of patients Radiation dose scheme unconventional Unclear whether better outcomes could result from more aggressive therapy

16. Impact of radiation regimen on local relapse-free survival and palliative procedures for patients with resectable locally advanced esophageal cancer treated with chemoradiation Results based on a phase III trial from the Fédération Francophone de Cancérologie Digestive (FFCD 9102). Impact of radiation regimen on local relapse-free survival and palliative procedures for patients with resectable locally advanced esophageal cancer treated with chemoradiation Results based on a phase III trial from the Fédération Francophone de Cancérologie Digestive (FFCD 9102). G CREHANGE, F BONNETAIN, P MAINGON, L BEDENNE et al. on behalf of the

17. Background and Purpose FFCD 9102 trial demonstrated that exclusive chemoradiation (ECRT) is an alternative to surgery (S) for responding patients. FFCD 9102 trial demonstrated that exclusive chemoradiation (ECRT) is an alternative to surgery (S) for responding patients. To compare 2 schemes of RT allowed by the protocol- short or long course RT To compare 2 schemes of RT allowed by the protocol- short or long course RT To explore their impact on palliative procedures, Local Relapse-Free Survival and Overall Survival To explore their impact on palliative procedures, Local Relapse-Free Survival and Overall Survival Analysis : all eligible patients Analysis : all eligible patients Subgroup analysis : operated and non-operated patients Subgroup analysis : operated and non-operated patients (1) Bedenne L et al: Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 25:1160-1168, 2007

18. Eligibility Criteria SCC or adenocarcinoma SCC or adenocarcinoma Upper, middle or inferior 1/3 (except cervical) Upper, middle or inferior 1/3 (except cervical) T3 N0-1 according to CT or EUS staging T3 N0-1 according to CT or EUS staging M0 M0 Judged resectable Judged resectable WHO  2 WHO  2

19. Population 1993 – 2000 = 57 Centers 1993 – 2000 = 57 Centers

20. FFCD 9102 RT Design - Split-course : R D1 D22 A : Surgery D1 D22 A : Surgery CT CT D43 D64 D92 D43 D64 D92 RT B : RT B : - Conventional: R D1 D22 A : Surgery CT CT B : D43 D64 D92 B : D43 D64 D92RT 15Gy/5*3Gy/1w 46Gy/5*2Gy/4.5w 20Gy/5*2Gy/2w 15Gy/5*3Gy/1w

21. FFCD 9102 CT Design  Chemotherapy : - 5 FU- CI :800 mg/m 2 /d x 5 - CDDP :75 mg/m 2 D2 or 15 mg/m 2 /d x 5 Radiation Therapy Radiation Therapy –Short course- 3 Gy x 5, weeks 1 and 4, (total 30 Gy), »plus 3 Gy x 5 if no surgery (total 45 Gy) –Long course- 2 Gy x 23- (total 46 Gy), »plus 2 Gy x 10 if no surgery (total 66 Gy)

22. Patients’ baseline characteristics All patients n (%) SRT 285 (64) PRT161(36)p Mean tumor length - cm 6.86.50.86 Mean diameter - cm 3.23.20.65 N+ - n (%) SCC - no. (%) 122 (43) 158 (92) 70 (44) 72 (82) 0.970.01

23. Results – Local Relapse Free Survival log-rank p=0.002 n=446 77% 57% HR = 0.52 ; [CI95 0.34 – 0.79]

24. Results – Overall Survival log-rank p =0.25

25. PP according to the radiation scheme all eligible patients (n= 446) P-RTSC-RTp Mean length of hospital stay 48.0 d 60.5 d 0.0003 Mean number of dilatation sessions 0.60.70.4 Mean number of stents 0.20.30.03 Mean number of any PP 1.01.50.001 Mean dysphagia grade 3.03.10.2

26. DISCUSSION Little data on RT technique in esophageal cancer Major interest in more accelerated radiation schemes in a variety of tumors –Minimal comparative data –Risk of increased acute and late toxicity –Biological basis to be concerned about late effects with high doses per fraction –Potential advantage to decreasing overall time of treatment to prevent repopulation

27. DISCUSSION Study not randomized regarding radiation treatment schedule, so results could be biased Although adenocarcinomas were allowed on trial this was a study of squamous cell carcinomas –Toxicity end-points are unlikely to be effected by the histology of the primary Substantial patient numbers

28. DISCUSSION Local control was inferior with short course therapy Acute toxicity was the same Late toxicity was worse with short course –Stent rate –Number of palliative procedures –Length of hospital stay (total) An increased radiation dose in short course arm could have resulted in equivalent local control, but probably with substantially more acute and late toxicity

29. DISCUSSION Even as a non-randomized retrospective analysis this trial provides valuable information on likely role of short course radiation therapy Standard radiation fractionation should be used except in the clinical trial setting.

30. DEFINITIVE CHEMORADIOTHERAPY (CRT) WITH FOLFOX 4 OR 5FU-CISPLATIN AS FIRST-LINE TREATMENT OF PATIENTS (PTS) WITH INOPERABLE ESOPHAGEAL CANCER (IEC) : FINAL RESULTS OF A RANDOMIZED PHASE II STUDY T. Conroy (1), Y. Yataghene (2), PL. Etienne (3), P. Michel (4), H. Senellart (5), JL. Raoul (6), L. Mineur (7), M. Rives (8), X. Mirabel (9), A. Adenis (9). (1) Centre Alexis Vautrin, Nancy ; (2) sanofi-aventis france, Paris ; (3) Clinique Armoricaine, St- Brieuc ; (4) University Hospital, Rouen; (5) Centre Rene Gauducheau, Nantes ; (6) Centre Eugene Marquis Rennes ; (7) Clinique Sainte Catherine, Avignon ; (8) Centre Claudius Regaud, Toulouse; (9) Centre Oscar Lambret, Lille; France.

31. Background (1) In inoperable esophageal cancer, concurrent chemoradiotherapy using 5FU-Cisplatin is the standard of care 5FU-Cisplatin regimen: –20% of patients experienced major toxicities –40 % of patients could not complete full sequence of treatment Oxaliplatin has shown encouraging activity in tumors that respond to cisplatin or carboplatin Oxaliplatin/5-fluorouracil/leucovorin is active in gastric adenocarcinoma Phase I data demonstrate safety of RT/FU/oxaliplatin

32. Objectives Primary Objectives : -feasibility (completion of full planned treatment) 1 of FOLFOX 4 regimen or 5-FU/Cisplatin regimen with concomitant radiotherapy as first-line treatment of inoperable advanced esophageal cancer. -To assess endoscopic complete response 2 rate in both arms.

33. Methods Initial randomized Phase II At the end of the first part of the trial (randomised phase II)- 88 patients (44 in each arm), decision to continue the study will be based on -Good accrual rates (88 patients < 18 months) -Completion of full treatment in over 60% in the experimental arm (Folfox) -Endoscopic complete response rate of Folfox arm equal or superior to the endoscopic response rate of 5FU/Cisplatin arm.

34. Methods Main inclusion criteria adenocarcinoma, squamous cell or adenosquamous carcinoma of the esophagus Patients unfit for surgery or locally advanced esophageal carcinoma (disease status : any T, N0 or N1, M0 or M1a) No prior treatment for esophageal cancer

35. Treatment Chemotherapy in Folfox arm : six bi-weekly cycles of FOLFOX 4, the first 3 cycles starting on D1, D15 and D29 concomitant with 5 weeks’ radiotherapy; On day 1, Oxaliplatin 85mg/m², on D1 and D2: leucovorin 200mg/m², 5-FU bolus 400mg/m²/d + 600mg/m²/d continuous IV infusion (1) Giovannini M et al.; J Clin. Oncol. 2004; 22 (14S) : 324 s; Abstract 4044 Arm Folfox 4-RT (50Gy) (1) CRT d29-30 RT d31-33 d36-40 RT Cycle 3 d22-26 RTCRT d15-16 RT d17-19 Cycle 2 CRT d1-2 RT d3-5 d8-12 RT Cycle 1 CT d71-72 Cycle 6 CT d57-58 Cycle 5 CT d43-44 Cycle 4 Tumor assessment W 1W 3W 5 W 7W 9W 11 W 15

36. Treatment Chemotherapy in 5FU-Cisplatin arm : two cycles of 5-FU/Cisplatin on week 1 and 5 of radiotherapy and two cycles of chemotherapy with 5-FU / Cisplatin on weeks 8 and 11; On D1, Cisplatin 75 mg/m² and from day 1 to 4, 5-FU 1000 mg/m²/day (2) Herskovic A et al, N Engl J Med 1992;326:1593-8 Arm 5FU-Cisplatin-RT (50Gy) (2) d34-49 RTCRT d29-32 RT d33 Cycle 2 d22-26 RT d15-19 CRT d1-4 RT d5 d8-12 RT Cycle 1 CT d71-74 Cycle 4 CT d50-53 Cycle 3 W 1 Tumor assessment W 8 W 11 W 15 W 5

37. RESULTS 80% of pts with squamous cell ca 55% Stage III- almost all the others Stage II App 90% pts completed planned RT/chemo App 75% pts completed planned chemo Toxicities very similar between arms (except neurotoxicity in FOLFOX arm) Endoscopic CR- 45% vs 30% favoring FOLFOX

38. Efficacy results FOLFOX regimen n = 53 No. of patients (%) 5FU-Cisplatin regimen n = 44 No. of patients (%) Median [Confidence Interval 95%] Event-Free Survival (EFS) 14.3 mth [8.6-16.1]7.8 mth [5.3-12.1] Time to Progression (TTP)15.2 mth [9.9-18.9] 9.4 mth [7.2- ongoing ] Overall Survival (OS)22.7 mth [7.1 - ongoing ] 14.9 mth [9.6-19.0 ]

39. Results – Overall Survival Folfox arm5-FU / Cisplatin arm Folfox arm 22.7 mth [7.1-ongoing] 5-FU / Cisplatin arm 14.9 mth [9.6-19.0]

40. DISCUSSION Definitive radiochemotherapy with FOLFOX 4 is feasible in inoperable esophageal cancer. Survival data are promising, but Phase II data are often encouraging Investigators appropriately plan to continue this approach as a phase III trial The hope that this regimen would decrease toxicity compared to FU/platinum was not realized

41. E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/RT or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged adenocarcinoma of the esophagus L. Kleinberg, M. E. Powell, A. Forastiere, S. Keller, P. Anne, A. B. Benson

42. Trial Parameters Adenocarcinoma T 2-3 N 0 M 0, T 1-3 N 1 M 0, T 1-3 N 0 M 1a Surgically resectable ECOG PS 0-1 Trial objectives –Path CR rate –Toxicity –Survival 47 pts per arm 45% path CR rate worthy of further study

43. Paclitaxel/Cisplatin Neoadjuvant –Paclitaxel 50 mg/m2 (1 hr) d1, 8, 15, 22, 29 –Cisplatin 30 mg/m2 d1, 8, 15, 22, 29 RT- 45 Gy Surgery- 1 field nodal dissection Adjuvant –3 cycles –Paclitaxel 175 mg/m2 and Cisplatin 75 mg/m2 on day 1

44. Chemotherapy: CPT-11/Cisplatin Neoadjuvant –CPT-11 65 mg/m2 day 1, 8, 22, 29 –Cisplatin 30 mg/m2 day 1, 8, 22, 29 RT- 45 Gy Surgery- 1 field nodal dissection Adjuvant –3 cycles –CPT-11 65 mg/m2 and Cisplatin 30 mg/m2 on day 1 and 8

45. Outcome Surgery % of all patients R0 Resection % of all patients pCR of % of all patients pCR of all going to surgery CPT11 Cisplatin (N=46) 89%83%15%16% Paclitaxel/ Cisplatin (N=44) 82%70%16%19%

46. DISCUSSION Regimens had complete response rates less than 20% Pretreatment EUS staging did not influence response to therapy Toxicity of both regimens similar and not superior to 5FU/platinum regimens 50% of patients received all planned chemotherapy Follow-up for survival outcome continues

47. DISCUSSION FU/cisplatin has still not been displaced as the standard chemotherapy with RT in esophageal cancer –Phase II study with FOLFOX is encouraging and is being pursued Radiation therapy with concurrent chemotherapy is an option instead of surgery –Need to remember the risk of increased local failure even if survival is no different

48. DISCUSSION Radiation delivery system does matter –Standard fractionation (180-200 cGy/fx) should be used except in a clinical trial It may be possible to use much less aggressive therapy in patients with very early disease –These patients are rarely seen in the US –Specialized techniques and lack of expertise may make the use of EMR difficult