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

Nonoperative Chemoradiotherapy

U.S. RTOG Trial 85-01

mskcc dhi 1999

Esophageal Ca

Locally Advanced,

Squamous Adeno

6400 cGy

Alone

5000 cGy + 5FU /

Cis x 2

+ 5-FU / Cis x 2

Herskovic NEJM 1992

Local Recurrence

with ChemoRT: 45%

Chemoradiotherapy + / - Surgery: Phase III, Squamous

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%

5-FU, Cisplatin, VP16 Cis/VP16 + RT Surgery or

additional CRT

Stahl JCO 23: 2310; 2005

Treatment Mortality 12.8% CRT + S, 3.5% S

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

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%

455 pts, 259 responders randomized: Non responders excluded.

Bedenne et al JCO 25: 1160; 2007

Treatment Mortality S 9.3% CRT 0.8%

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

Van Hagen et al NEJM 366: 2074; 2012

Paclitaxel 50mg/m2 + 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)

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

CROSS study16

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