AATS/STS General Thoracic Surgery Symposium Surgery for Squamous Cell Cancer of the Esophagus: Only for Salvage or as Part of Combined Modality Therapy? Stephen G. Swisher, MD AATS/STS General Thoracic Surgery Symposium Seattle, WA April 26, 2015 14:15- 14:30 Surgery for Squamous Cell Cancer of the Esophagus: Only for Salvage or as Part of Combined Modality Therapy?
*Stephen G. Swisher, MD Anderson Cancer Center Stephen - Preferably, the presentation should start with a clinical case to then gradually work your way back to the take-home message which should be the last slide with 3/4 bullet pointed statements and the answer to the main question expressed in the title of your presentation. SPF I plan to discuss today currrent approaches in the management of squamous and adenocarcinoma of the esophagus

Esophageal Resections Histology - MDACC As you all know there has been a dramatic shift in North America and Europe in the histology of esophageal cancer from scca to adenocarcinoma. Consistent with these reports, our institution has seen a dramatic increase in the proportion of adenocarcinoma from 40% to 90% with a reduction in squamous cell carcinoma from 60% to 10%. MDACC Thoracic Surgery Database

Esophageal Cancer Case #1 52 yo female who developed dysphagia and found to have middle SCCA esophagus. EGD-EUS-T3N1, 25-33 cm. CT-PET- no distant metastases. Bronchoscopy- No tracheal mucosa involvement The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

Esophageal Cancer Treatments Type of Esoph after Chemoradiation Definitive Chemoradiation     Salvage Esophagectomy RTOG 8501 FFCD 9102 Preoperative Chemoradiation  Planned Esophagectomy CROSS - Trimodality Chemoradiation  or    Selective Esophagectomy RTOG 0246 Locoregional failure which was 60% in RTOG 94-05 would be carefully evaluated with serial endoscopy and biopsy and CT scans. Indication for salvage surgery would be bx positive disease, failure to epithelialize and non-dilatable strictures. Additionally CT evidence of increasing mass without systemic metastases would be criteria for salvage therapy according to the investigator. This would be up to the individual investigators but would include surgical salvage if appropriate.

Definitive Chemoradiation Well what about the strategy of preoperative chemoradiation for GEJ adenocarcinoma.

44% Locoregional Failure 7% Site of Recurrence Not Known Definitive Chemoradiation SCCA– RTOG 85-01 – CRT vs RT alone 44% Locoregional Failure 7% Site of Recurrence Not Known Definitive CRT Did this improved locoregional control did not result in improved long-term survival with overlapping curves. Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality. Herskovic et al., NEJM, 2001

44% Locoregional Failure 7% Site of Recurrence Not Known Definitive Chemoradiation RTOG 85-01 – Long-Term Results 44% Locoregional Failure 7% Site of Recurrence Not Known Definitive CRT 129 pt randomized; 73 pts non-randomized arms Cooper et al., JAMA, 1999

Preop CRT  Surg Well what about the strategy of preoperative chemoradiation for GEJ adenocarcinoma.

Preoperative Chemoradiation CROSS Trial Did this improved locoregional control did not result in improved long-term survival with overlapping curves. Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality. van Hagen et al., NEJM, 2012

Preoperative Chemoradiation CROSS Trial Path CR: 18/37 pts SCCA 47%; 28/121 pts (23%); p<0.008 van Hagen et al., NEJM, 2012

Preoperative Chemoradiation CROSS Trial Path CR Adeno SCCA p CROSS 28/121 (23%) 18/37 (47%) P<0.008 Path CR: 18/37 pts SCCA 47%; 28/121 pts (23%); p<0.008 van Hagen et al., NEJM, 2012

Preoperative Chemoradiation CROSS Trial Path CR Adeno SCCA p CROSS 28/121 (23%) 18/37 (47%) P<0.008 MDACC 55/193 (29%) 13/42 (31%) NS Path CR: 18/37 pts SCCA 47%; 28/121 pts (23%); p<0.008 van Hagen et al., NEJM, 2012 Rohatgi et al., Cancer 2005

Definitive CRT vs Preop CRT Surg Because of this increased toxicity, it was elected to eliminate the induction chemotherapy and compare a higher dose of radiation therapy with the standard 50.4 gy utilized in RTOG 85-01.

dCRT vs CRTPlanned Eso Squam Responders– FFCD 9102 Surgery N=129 Multi-center Eso: SCCA T3-4,N0-3,M0 N=455 Responders N=259 20Gy 5FU/CDDP x 3 N=130 Another randomized study which was recently reported was FFCD 9102. The French multi-center trial which treated 455 predominantly squamous cell carcinoma with Concurrent 46gy 5fu and cis. 259 responders were then randomized to surgery or additional radiation and chemotherapy. 46Gy 5-FU/CDDP x 2 Bedenne et al., JCO, 2007

1.63 HR Locoregional Relapse dCRT vs CRTPlanned Eso Squam Responders– FFCD 9102 1.63 HR Locoregional Relapse CRT Alone (p=0.03) Did this improved locoregional control did not result in improved long-term survival with overlapping curves. Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality. Palliative intervention for dysphagia .0002 No. of patients 31 60 % 24.0 46.2 Dilatation No. of patients 24 18 % 18.6 13.8 Stent No. of patients 7 42 % 5.4 32.3 Dysphagia grade 3‡ at last follow-up before death§ .04 No. of patients/No. of dead patients 38/60 36/79 % 63.3 45.6 2-year recurrence probability, % .23 Rate 56.7 59.6 SE 5.4 4.8 Locoregional probability, % .0014 Rate 33.6 43.0 SE 5.3 4.9 Metastatic probability, % .24 Rate 39.1 29.0 SE 5.3 4.7 Bedenne et al., JCO, 2007

Def CRT vs Preop CRTSurg Squam – German Trial R A N D O M I Z E Chem/RT (Cis, Etop + 50 gy HF or 60 gy HDR) Chemo FLEP N=86 Surgery T1-4a N0-3 M0 SCCA Multi-Center Chemo/RT (Cis, Etop + 64.8 gy) Chemo FLEP N=86 Stahl and his colleagues randomized predominantly squamous cell carcinoma patients to FLEP chemotherapy followed by concurrent chemoradiation (with hyperfractionated 50 gy and cis and 5-FU) followed by surgery or Or concurrent chemoradiation alone with (cisplatinum and etoposide and 64.8 gy) Stahl et al., JCO,2005

Chemo/RT +/- Surgery: Phase III Esophageal Cancer: German Trial Overall Survival p = ns 172 patients randomized per arm (86 pts per arm). SCCA – FLEP then EP + 65 Gy CRT or FLEP then 45 Gy + EP CRT and Surgery. Rx related mortality 12.8% in surgery arm vs 3.5% CRT arm. Locoregional control at 2 years significantly better with surgery. No statistical difference in overall survival at 2 years but Trial underpowered, time point to look for difference is prior to split so this trial may actually be positive at different timepoint with less treatment related mortality. Stahl et al., JCO, 2005

Definitive CRT and Salvage Esophagectomy Investigators were still frustrated, however, by the high locoregional failure rates of 40 to 60% and strategies to improve this were evaluated. Investigators decided to try adding additional induction chemotherapy prior to the concurrent chemoradiation and to increase the dose of radiation therapy to 64.8 gy.

The resultant single arm trial (INT 0122) evaluated this strategy with 45 patients who were treated with 3 months of cisplatinum and 5-FU followed by concurrent chemoradiation with cisplatinum, 5FU and radiation to 64.8 gy. Swisher et al., JTCVS, 123:175-83, 2002

1.63 HR Locoregional Relapse Salvage Esophagectomy Literature Review 1.63 HR Locoregional Relapse CRT Alone (p=0.03) Kyushu University, Japan Did this improved locoregional control did not result in improved long-term survival with overlapping curves. Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality. Palliative intervention for dysphagia .0002 No. of patients 31 60 % 24.0 46.2 Dilatation No. of patients 24 18 % 18.6 13.8 Stent No. of patients 7 42 % 5.4 32.3 Dysphagia grade 3‡ at last follow-up before death§ .04 No. of patients/No. of dead patients 38/60 36/79 % 63.3 45.6 2-year recurrence probability, % .23 Rate 56.7 59.6 SE 5.4 4.8 Locoregional probability, % .0014 Rate 33.6 43.0 SE 5.3 4.9 Metastatic probability, % .24 Rate 39.1 29.0 SE 5.3 4.7 Thorpe et al., Br J Surg, 2007

Salvage Esophagectomy in Modern Era Investigators were still frustrated, however, by the high locoregional failure rates of 40 to 60% and strategies to improve this were evaluated. Investigators decided to try adding additional induction chemotherapy prior to the concurrent chemoradiation and to increase the dose of radiation therapy to 64.8 gy.

Salvage Esophagectomy 2 Stage Procedure Two-Stage Operation for High-Risk Patients with Thoracic Esophageal Cancer: An Old Operation Revisited Masaru Morita, MD, PhD, FACS, Tomonori Nakanoko, MD, Nobuhide Kubo, MD, Yoshihiko Fujinaka, MD, Keisuke Ikeda, MD, Akinori Egashira, MD, PhD, Hiroshi Saeki, MD, PhD, Hideaki Uchiyama, MD, PhD, FACS, Takefumi Ohga, MD, PhD, Yoshihiro Kakeji, MD, PhD, FACS, Ken Shirabe, MD, PhD, FACS, Tetsuo Ikeda, MD, PhD, Shunichi Tsujitani, MD, PhD, FACS, and Yoshihiko Maehara, MD, PhD, FACS Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ABSTRACT Purpose. An esophagectomy followed by reconstruction for esophageal cancer is a highly aggressive operation. The purpose of this study was to justify a two-stage operation for high-risk patients with esophageal cancer. Methods. The clinical results of 27 patients who underwent two-stage operation were compared with 118 patients who underwent a simultaneous resection and reconstruction (control subjects). The reasons for the selection of the two-stage operation were underlying general disease in 13 patients (liver dysfunction, n = 6; pulmonary disease, n = 3; poor performance status, n = 2; diabetes and renal failure, n = 1 each) and high-risk operation in 14 other patients (colon interposition, n = 7; salvage operation after definitive chemoradiotherapy, n = 4; and intraoperative events, n = 3). The patients initially underwent an esophagectomy and a cervical esophagostomy. Reconstruction was usually performed 2–3 weeks later. Results. The patients in the two-stage group were older than the control patients (mean 67.8 vs. 61.6 years old). The morbidity rate of the two-stage operation was 29.6%, which was not statistically different than control patients (32.2%). Postoperative complications in the two-stage operation were anastomotic leakage in 5 patients, and pneumonia and wound infection in 1 patient each. No patient experienced in-hospital death. The survival rates were not statistically different between the two groups. Conclusion. A two-stage operation is a safe operation that prevents the occurrence of critical postoperative First Stage Second Stage 27 High Risk Pts (7 Salvage) No Increased Morbidity vs 118 Low Risk Pts Morita et al, Ann Surg Onc, 2011

Salvage Esophagectomy Free Jejunal Interposition Long-segment, supercharged, pedicled jejunal flap for total esophageal reconstruction Anthony J. Ascioti, MD, a Wayne L. Hofstetter, MD, Michael J. Miller, MD, b David C. Rice, MD, Stephen G. Swisher, MD, Ara A. Vaporciyan, MD, Jack A. Roth, MD, J. B. Putnam, MD, d W. Roy Smythe, MD, e Barry W. Feig, MD, c Paul F. Mansfield, MD, Peter W. T. Pisters, MD, Marla T. Torres, BS, and Garrett L. Walsh, MDa Objective: Many patients with cancer have limited esophageal reconstruction options when the stomach is unavailable as a replacement conduit or when longsegment discontinuity exists. Jejunum has been used as an alternative conduit, both as a pedicled or free flap interposition; however, reports of this are usually limited to short-segment repairs. Microvascular augmentation of a pedicled jejunal flap allows creation of a longer conduit, making it possible to replace the entire esophagus with jejunum. Few reports describe this technique in patients with cancer. We report our initial experience with “supercharged” pedicled jejunum as an alternative conduit for total esophageal reconstruction. Methods: Review of a prospectively collected departmental database was performed to identify those patients who underwent total esophageal reconstruction with supercharged pedicled jejunum. Data regarding their perioperative course and postoperative function were gathered from the prospectively collected clinical data, review of hospital records, and patient interviews. Results: Total esophageal reconstruction with supercharged pedicled jejunum was attempted in 26 patients (age range, 37-74 years) between March 2000 and April 2004. Twenty-four of 26 patients were ultimately discharged with an intact supercharged pedicled jejunum flap, for an overall success rate of 92.3%. One patient experienced intraoperative flap loss caused by technical difficulties harvesting the flap and never had the flap interposed. One other flap loss occurred in the early postoperative period in a patient who had multisystem organ failure after a prolonged reconstruction. Cervical anastomotic leaks occurred in 19.2% (5/26) of the patients. Two midconduit leaks occurred that were suspicious for iatrogenic perforation from nasogastric tube placement; one required reoperation. One additional early reoperation was performed for cecal ischemia. There were no mortalities. Functional results were available in 95.4% (21/22) of the patients receiving supercharged pedicled jejunum who survived at least 6 months after reconstruction. At the time of follow-up, 95% (20/21) of the patients were tolerating regular diet, and 76.2% (16/21) did not require any supplemental alimentation. Ninety-five percent (20/21) of the patients were free from reflux symptoms, and 80.9% (17/21) had no dumping symptoms. Only 1 patient required dilation of a midconduit stricture. One patient required late reoperation for conduit redundancy. Conclusions: Supercharged pedicled jejunum is a suitable alternative conduit for total esophageal replacement in patients with cancer with otherwise limited reconstructive options. Functional outcomes are excellent, despite the severity of disease and technical challenges in this patient population. by D. RIce Jejunal Free Graft Ascioti et al, Ann Thor Surg, 2005

Salvage Esophagectomy Omental Transposition And a somewhat worrisome, but statistically in-significant trend in the peri-operative mortality. To note, none of the 3 deaths in the salvage group were attributed to leak (arlene, let’s look up afib rate in both groups) Courtesy of David Rice MD

Salvage Esophagectomy Omental Transposition And a somewhat worrisome, but statistically in-significant trend in the peri-operative mortality. To note, none of the 3 deaths in the salvage group were attributed to leak (arlene, let’s look up afib rate in both groups) Courtesy of David Rice MD

MDACC: Omental Transpostion Salvage Esophageal Anastomotic Leak Objective: An uncontained thoracic anastomotic leak may cause severe morbidity or mortality. Thoracic transposition of an omental flap along with the gastric conduit may decrease leak incidence, severity, or need for reoperations after esophagectomy. Methods: We identified 607 patients who underwent esophagectomy with thoracic anastomosis between January 2001 and August 2011. All patients were studied for leak postoperatively. Four leak grades were defined, ranging from radiographic leak to conduit loss. Univariate and multivariate analyses were performed to identify variables associated with anastomotic leak. Results: Omental reinforcement was used in 215 of 607 patients (35%). Anastomotic leak occurred in 51 of 607 patients (8.4%). Patients with omentumhad a significantly lower (odds ratio [OR], 0.4; P¼.014) anastomotic leak rate (4.7%) compared with patients without omentum (10.5%). Salvage resections were performed in 69 patients and 23 (32%) received omentum; the leak rate with omentum was 4.6% compared with 15% without (OR, 0.27; P ¼ .24). Patients undergoing planned esophagectomy with omentum had a significantly lower leak rate than patients without omentum (4.7%vs 9.8%) (OR, 0.43; P ¼ .04). Reoperations to rescue an anastomotic leak (Grade 3) was less common with omentum (OR, 0.26; P¼ .024). Multivariate analysis identified omental reinforcement (OR, 0.45; P ¼ .034) and surgeon (OR, 3.4; P ¼ .001) as variables predictive of an anastomotic leak. Conclusions: Omental reinforcement of thoracic esophagogastric anastomoses decreases overall leak rate and need for reoperation. We recommend pedicled omental transposition to reinforce all thoracic anastomoses. Endoscopic evaluation of significant anastomotic leaks is still warranted. (J Thorac Cardiovasc Surg 2012;144:1146-51) There was a significantly lower overall leak rate in the group with omental reinforcement of the thoracic anastomosis compared to patients without omentum. Sepesi et al., JTCVS,144:1146-51; 2012

Salvage Esophagectomy Op Mortality – Modern Era Planned n=521 p value LOS (days) 12 (4-153) 11 (0-88) NS 30d Mortality 2 (3.1%) 15 (2.9%) 90d Mortality 3 (4.6%) 27 (5.2%) Marks et al., AATS, 2012

CRT and Selective Esophagectomy Investigators were still frustrated, however, by the high locoregional failure rates of 40 to 60% and strategies to improve this were evaluated. Investigators decided to try adding additional induction chemotherapy prior to the concurrent chemoradiation and to increase the dose of radiation therapy to 64.8 gy.

63% 3YR; 37% 5 YR SURVIVAL Enrollment requirements included resectable esophageal cancer patients who were without metastases and whose clinical stage by EUS was greater than T1N0 Eligible patients were then treated initially with 2 cycles of 5-FU, cisplatinum and paclitaxel (5-FU (650 mg/m2/d), Cisplatin (15 mg/m2/d), Paclitaxel (200 mg/m2/d) followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fx) and Daily 5-FU (300 mg/m2/d), and Cisplatin (15 mg/m2/d) Patients were then restaged 4 to 6 weeks after chemoradiation and if there was no evidence of residual cancer they were followed with serial endoscopies, CTs, PETs. If residual or recurrent locoregional cancer was identified without evidence of metastatic disease patients were evaluated for salvage esophagectomy

21/41 pts esoph preservation 51% SCCA-CROSS-25 %;CALGB 9781-23%; RTO 0246-275; SCOPE1 71%-cetux; rtog 8501-75%

Esophageal Cancer Case #1 Treated with Definitive Chemoradiation: Oxaliplatin and 5-fluoruracil and RT to 54.4 Gy. EGD – ulcer, NED – refused surgery. The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

Esophageal Cancer Case #1 16 months later dysphagia CT-PET –Increase FDG (SUV 17) circum middle eso; EGD revealed necrotic SCCA in middle eso Bronch: Necrotic ulcer R BI with fragments of Squamous Cell Carinoma The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

Esophageal Cancer Case #2 EUS: 16-19 cm, recurrent squamous cell carcinoma CT-PET: proximal eso FDG avid lesion (SUV-8.9), no distant metastases Bronchoscopy: fistulous communication 8 cm proximal to carina The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

SCCA Esophageal Cancer MDACC Combined Modality Approach ChemoRT (50.4 Gy) Low Risk Surgery and Mid/Dist Location Planned Esophagectomy Loco- Regionally SCCA Eso Cancer ChemoRT (50.4 Gy) Purpose: The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites. Methods and Materials: The study was designed to detect an improvement in 1-year survival from 60% to 77.5% (a = 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg2/day), cisplatin (15 mg/mg2/day), and paclitaxel (200 mg/mg2/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg2/day) with cisplatin (15 mg/mg2/ day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease. Results: Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was $T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%. Conclusions: In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival High Risk Surgery Or Cerv Location Selective Esophagectomy

Summary SCCA Eso Cancer-Combined Modality Approach Upper Eso Location – laryngopharygectomy Definitive Chemoradation Salvage Esophagectomy for Recurrent Local Disease Middle/Lower Eso Location – Good Risk Preop CRT  Planned Esophagectomy Middle/Lower Eso Location – Poor Risk CRT  Clin CR  Selective Esophagect for Recurrent Local Disease CRT  Clin non-CR  Consider Selective Esophagect In summary then: Chemoradiation alone with concurrent chemoradiation in SCCA appears to lead to improved survival and local control compared to radiation therapy. The optimal regimen appears to be concurrent chemoradiation with RT to 50.4 gy. The randomized trials in SCCA demostrate that surgery add improved locoregional control but no statistical improvement in survival perhaps because of high treatment related mortalit, targeting responders and looking at low numbers. In adenocarcinoma the role of chemoradiation alone is still under evaluation and selective surgery will be reported in RTOG 0246 this fall at ASTRO Alternative strategies to improve chemoradiation alone is to add novel therapeutics to improve the subset of patients who undergo pathologic response following chemoradiation.