Gastroesophageal Junction Adenocarcinoma: What is the best adjuvant regimen? Michael G. Haddock M.D. Mayo Clinic Rochester, MN Locally Advanced GE Junction ACA CT S CT or CT S CT/RT
Proposition Chemoradiation is preferred over chemotherapy alone as adjuvant therapy for locally advanced ACA of the GE junction
I wish to make a plea for phasing out radiotherapy wherever possible. it is the most unphysiologic i and destructive thing we can do to patients. if two methods are equally effective against a malignancy and one of them is radiation, I submit your only logical choice is the other method. Dr. James Nelson Brooklyn, New York Assumptions Stage: T3-4, N0-1, M0 Performance status 0-1 Good candidate for surgery medically High quality therapy is available Goal is cure Can t cure patient unless locoregional disease is eliminated
What is the risk of local relapse after surgical resection? Patterns of Failure University of Minnesota Reoperative Series 107 patients with gastric cancer 68 patients 2nd look laparotomy 39 patients symptomatic 2nd look Pattern Only Component LRF 22% 67% PS 3% 41% DM 5% 22% Gunderson, IJROBP 8:1-11, 1982
Patterns of Failure Gastric Cancer Pattern of failure Clinical Reoperation Autopsy LRF 38% 67% 80-93% PS 23% 41% 30-50% DM 52% 22% 49% Adapted from Smalley, Int. J Radiation Oncology Biol Phys 52:283-292, 292, 2002
Esophageal Cancer Neoadjuvant Chemo: INT 0113, RTOG 8911 443 pts 207 SQC 236 ACA R Preop* CDDP 5-FU x3 Med S 2yrS LF 16.1 mo 38% 27% Surgery 16.8 mo 40% 29%* *1.5% neutropenic sepsis deaths *29% LF in R0, 41% in R1 Kelsen, NEJM339:1979, 1998 Gastric Cancer Patterns of Relapse Memoral Sloan Kettering 1985 2000 1172 R0 gastric resections Relapse data in 367 of 496 relapse pts Component of locoregional failure in 54% D Angelica Ann Surg 2004; 240:808
Can residual disease after surgery be eradicated by non-surgical therapies? Esophageal Cancer: RT + Chemo RTOG 8501 Schema 64 Gy / 32 fractions 123 pts 108 SQC 15 ACA R 50 Gy in 25 fractions 5FU, 1 gm/m 2 /day x 4 d weeks 1,5,8,11 CDDP, 75 mg/m 2 IV bolus weeks 1,5,8,11 Herskovic, NEJM 326:1593-1598, 1992.
RTOG 8501 Survival by Treatment Arm 100 Alive (%) 80 60 40 P<0.0001 RT + chemotherapy 20 RT only Al-Sarraf M et al: JCO 15:283, 1997 0 0 1 2 3 4 5 Years from randomization Can chemotherapy alone eradicate residual locoregional disease?
Adjuvant Chemotherapy for Esophageal and Gastric Cancer Negative Studies #pts Chemotherapy INT 0113 440 5-FU/CDDP EORTC 40954 144 5-FU/CDDP Positive Studies OE02 802 5-FU/CDDP MAGIC 503 ECF Gastric Cancer - Adjuvant Chemo MAGIC Trial (MRC ST02) 503 pts ACA stomach EG junction lower esophagus R ECF S ECF x3 x3 Curative 5 yr OS resection 36% 69% Surgery alone 23% 66% Cunningham, N Engl J Med 355:11-20, 2006 OS HR 0.75, P = 0.009
MAGIC Trial Survival Esophageal Cancer: Neoadjuvant Chemo MRC-OE02 802 pts, resectable SQC (247) Med S 2yrS ACA (533) 5-FU Surgery 17 mo 43% CDDP R P = 0.004 Surgery 13.5 mo 34% Preoperative radiotherapy allowed (9%), same on both arms MRC Lancet 359:1727-33, 2002
MRC-OE02 MRC Lancet 359:1727-33, 2002 Gastric Cancer: Neoadjuvant CT EORTC 40954 Deaths Events 144 Locally advanced 53% proximal CT = 5FU/CDDP R CT S 32 40 S 35 44 Schuhmacher, JCO 28:5210, 2010
Esophageal Cancer Neoadjuvant Chemo: INT 0113, RTOG 8911 467 pts R Preop* CDDP 5-FU x3 Surgery Med S 1yrS 2yrS 16.1 mo 62% 38% 16.8 mo 62% 40% *1.5% neutropenic sepsis deaths Additional 2 cycles of chemotherapy postop Kelsen, NEJM339:1979, 1998
Is Trimodality Therapy an Effective Strategy?
Esophageal Cancer: Preop RT + CT CALGB C-9781 500 pts/ 5 yrs surgery alone SQC or ACA T1-3 NxM0 R Resectable Not more than 2 cm into cardia 5-FU + CDDP + 50.4 Gy followed by surgery Closed Early (56 pts) due to poor accrual Tepper, JCO 2008;26:1086-1092 CALGB 9781 100 P<0.008 80 Overall survival (%) 60 40 20 Trimodality (30) Surgery (26) 0 0 1 2 3 4 Years from study entry Adapted from Krasna et al: ASCO GI Symposium, 2006 Original: www.asco.org
CALGB 9781 Trimodality arm: 30 patients, 23 ACA, 7 SQC Median survival 4.5 yrs 5-yr survival 39% 5-yr progression free survival 28% Local relapse 13% Tepper, JCO 2008;26:1086-1092 CROSS Phase III trial Preop CT/RT vs S alone Med S 3-yr S Surgery 26 mos 48% 363 pts T2-3N0-1 86 SQC 273 ACA R 41.4 Gy CBDCA S paclitaxel 49 mos 59% A.V. Gaast, ASCO 2010
Gastric Cancer Adjuvant Therapy Intergroup 0116 T3-4 and/or N+ Complete resection 85% node + 603 pts Observation R Macdonald, NEJM 345:725, 2001 5-FU CF x1 45 Gy 5-FU 5-FU CF CF x 2 Intergroup Gastric Adjuvant Study Survival 100 80 Survival (%) 60 40 Chemo-RT 3 yr S 50% 20 0 NEJM 345:725, 2001 P=0.005 Surgery only 3 yr S 41% 0 24 48 72 96 120 Months after registration
100 80 Overall Survival by Treatment Arm Proximal Location Median N Events (mo) 5-FU + leucovorin 79 59 26 + RT Observation 71 61 23 % 60 40 20 0 0 24 48 72 96 120 144 Months after registration Gastric Surgical Intergroup Trial Relapse Patterns 50 Observation Radiochemotherapy 40 46% % 30 20 10 0 19% Courtesy of S. Smalley 7% 27% 12% 13% Local Regional Distant
Chemotherapy or Chemoradiotherapy? Gastric Cancer Adjuvant Therapy MAGIC and 0116 S alone CMT 5 yr survival 0116 26% 44% MAGIC 23% 36% Local relapse 0116 19% 7% MAGIC* 21% 14% *24% of patients who died had LR prior to death
Australian Meta-Analysis Chemotherapy and RT vs Surgery Alone Study Nygaard Apinop LePrise Bosset Urba Walsh Burmeister Lee All (published) Walsh Tepper All 0.2 0.5 1 2 5 Favors Favors chemoradiotherapy surgery alone Val Gebski et al: Lancet Oncol 8:226, 2007 CP1320703-1 Australian Meta-Analysis Hazard ratio for all cause mortality for preoperative chemort was 0.81 (P = 0.002) Hazard ratio for all cause mortality for preoperative p chemotherapy was 0.90 (P = 0.05) Val Gebski, et al. Lancet Oncol 8:226-34, 2007
Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Arm A T3-4 GE junction ACA PLF I PLF II PLF III (3 weeks) Surgery Week 1 67 13 14 17 20-21 PLF I PLF II 15 x 2 Gy in 3 weeks Surgery Arm B PE (1 week) PLF: Cisplatin 50mg/m2, 1h, d 1, 15, 29. Leukovorin/5-FU 500 mg/m2 d 1, 8, 15, 22, 29, 36 PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5 Stahl, JCO 27:851, 2009 Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Overall Survival Strata 5FU/CDDP S (2% pcr) Survival 100 75 50 CT CDDP/etop/ 30 Gy/15 S (16% pcr) Arm B (60) 25 0 0 1 2 3 4 5 6 Stahl, JCO 27:851, 2009 P=0.07 Arm A (59) Years
Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Freedom from Local Tumor Progression Survival distribution function 100 75 50 25 0 P=0.06 Stahl, JCO 27:851, 2009 Strata Randomized Arm A Censored randomized Arm A Randomized Arm B Censored randomized Arm B Arm B Arm A 0 1 2 3 4 5 6 Years Gastric Adjuvant Therapy CRITICS trial DCCG,GOF Ib-IVaIVa Gastric GEJ 788 pts R ECC x 3 D1+surgery ECC x 3 ECC x 3 D1+ surgery CT/RT ECC: Epirubicin 50mg/m2, CDDP 60 mg/m2, capecitabine 1000 mg/m2 bid CT/RT: 45 Gy in 25 fractions + capecitabine 575 mg/m2 bid
Gastric Adjuvant Therapy ARTIST trial 한국 CP x 6 Ib-IVaIVa D2 R Gastric 458 pts 2004-8 CP x 2 CT/RT CP x 2 CP: Capecitabine 1000 mg/m2 bid, CDDP 60 mg/m2 CT/RT: 45 Gy in 25 fractions + capecitabine 825 mg/m2 bid Locally Advanced Esophageal Cancer CT S CT or CT S CT/RT or CT/RT S CT
GE Junction Cancer: Post-op op RT