Management of Squamous Cell Cancer of the Esophagus: Surgery Should Follow Chemo + RT David H. Ilson, MD, PhD Gastrointestinal Oncology Service Memorial Sloan Kettering Cancer Center
Disclosure Consulting AMGEN Bayer Lilly/Imclone Pieris Roche/Genentech Astra Zeneca Bristol Myers Squibb Merck Pfizer Astellas
Esophageal Squamous Cancer: Neoadjuvant Therapy Survival with surgery alone: < 20-40% Preop Chemo or Chemo + RT + / - Surgery Common Western practice Survival improvements over surgery alone Older trials: 6%-12% CROSS for Squamous Cancer: OS 81.6 mos CRT + S vs 21.1 mos S Why Operate after Chemo + RT? Improve OS High rate of local persistence/recurrence with Chemo RT alone Reduce catastrophic local failure
Esophageal Squamous Cancer: Failure of Preop Chemo in the West Preop CF failed U.S. INT 113: 450 pts: No impact on OS, R0 59-62% No benefit for Squamous Cancer MRC 0E0-2: 800 pts: 5 year 6% OS increase Only due to increase in R0 54% 60% Squamous 9% OS increase Kelsen NEJM 1998, Alllum J Clin Oncol 2009
Esophageal Squamous Cancer: Preop Chemo Japanese Trials CF + Surgery Problematic JCOG9210: Post op Chemo DFS, but no OS benefit, only in N+ JCOG9907: Preop Chemo > Post op Chemo In contrast to JCOG9210, No DFS benefit, no benefit for N1 disease OS benefit only in N0 All pts 12% 5 yr OS benefit Only 65% of post op pts received chemo compared to 100% preop arm Ando JCO 2003, Ando Ann Surg Onc 2012
Herskovic NEJM 1992
Local Recurrence with ChemoRT: 45%
Chemoradiotherapy + / - Surgery: Phase III, Squamous 5-FU, Cisplatin, VP16 Cis/VP16 + RT Surgery or additional CRT Author Pt No. Histol. Therapy Med. Surv. O.S. Local Control Stahl 86 Squam Chemo RT + S 16.4 mos 31% 3 yr (NS) 64% 86 Squam Chemo RT 14.9 mos 24% 3 yr 41% Treatment Mortality 12.8% CRT + S, 3.5% S Stahl JCO 23: 2310; 2005
Chemo RT + / - Surgery: Squamous Cancer Overall Survival Freedom From Local Recurrence Stahl JCO 23: 2310; 2005
Chemo RT or Chemo RT Surgery only in Responding Patients: FFCD 9102 455 pts, 259 responders randomized: Non responders excluded. Author Pt No. Histol. Therapy Med. Surv. O.S. Local Control Bedenne 259 Squam Chemo RT + S 17.7 mos 34% 2 yr 66% Squam Chemo RT 19.3 mos 40% 2 yr 57% Treatment Mortality S 9.3% CRT 0.8% Bedenne et al JCO 25: 1160; 2007
OS in Responding Patients: CRT + / Surgery
Outcome of non randomized, non responder patients: Bedenne Trial 112 of 192 non randomized / nonresponder pts (58%) went to surgery, R0 71% (40% all pts) Median OS 17.3 mo in resected pts 18 non responder patients had TRG 1-2 (23% resected, 16% all pts) Median OS not reached vs 12.7 mos partial/progression path response Median OS of 17.3 mo non randomized pts = 18.9 mo OS randomized pts undergoing surgery patients Surgery plays a role in non responder pts Bedenne EJC 2015
Esophageal Cancer: Predictive Accuracy of post ChemoRT Endoscopy 137 pts: Chemo RT surgery EGD and biopsy Surgery 104 pts (76%) negative biopsy post therapy Poor Predictor: Only 35% had pathologic CR at surgery A negative biopsy better predictor for squamous cell carcinoma (p <0.001) Sarkaria JCO 24: Abs 4024, 182, 2006
PET Scan and Path CR: Esophageal Cancer 493 pts, AC and Squamous, treated with preop chemo RT PET scan prior to therapy, after chemort PET response not associated with pcr or nodal disease Squamous cancer patients: SUV response correlated with pcr SUV reduction < 50% pcr 29%, 50-75% pcr 44% SUV reduction > 75%: pcr 85% Rizk J Clin Oncol 27: Abstr 4552; 2009
Paclitaxel 50mg/m 2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29 Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE) Van Hagen et al NEJM 366: 2074; 2012
CROSS Trial: Resection rate and resection margins Resection rate of all randomized patients Surgery alone CRT + surgery 186/188 (99%) 168/178 (95%) Resection margins Surgery alone CRT + surgery R0 111/161 (69%) 148/161 (92%) p<0.002 ITT R0 111/188 (59%) 148/178 (83%) R0 = no tumor within 1 mm of the resection margins 16 CROSS study
OS and Outcomes Improved with Chemo RT + Surgery 5-year survival 47% versus 34% Squamous HR 0.48 (p = 0.008) OS 81.6 mo vs 21.1 mo PFS 74.7 mo vs 11.6 mo Local progression all patients 22% CRT + S vs 38% S pcr : 49% SCC Low operative mortality: 2-3% Shapiro J, Lancet Oncol 16: 1090; 2015
Esophageal Squamous Cancer: Chemo RT + Surgery is Favored Highest overall survival achieved with CRT + S Significant reductions in local recurrence All patients should be considered for surgery Surgery in non responders achieves long term survival Patients with good response to CRT Individualize the role of surgery vs observation Medically fit patients for surgery Better means to ID residual disease