NEWS AND VIEWS

Esophageal Nightmare: Cancer Recurrence After Definitive Chemoradiation. Is Salvage Esophagectomy Possible? Thomas W. Rice, MD*,†

INTRODUCTION Recurrent esophageal cancer is common after a disease-free period, as is persistent cancer following definitive therapy for locally advanced esophageal cancer. Treatment failure following definitive chemoradiotherapy in RTOG-8501 was 46% at a minimum of 5 years of follow-up.1 Remembering that a patient must survive to experience recurrence (competing risk of death), 20% of patients had recurrence after clinical complete response and 26% had persistent cancer. Treatment of recurrent or persistent esophageal cancer after primary therapy is typically palliative and most commonly nonsurgical. To determine if salvage esophagectomy following definitive nonsurgical therapy is beneficial, the literature must be carefully assessed. LITERATURE REVIEW The literature on salvage esophagectomy after definitive chemoradiotherapy comprises exclusively retrospective, single-institution observational studies, and case reports. The evidence-based grading of this literature is 2C.2 Recommendations are weak and based on low- or very low-quality evidence. The authors cannot ensure that alternative therapies are equal or inferior, because they are not reported. Thus, this literature reports treatment of highly selected patients representing a fraction of those failing definitive chemoradiotherapy, which certainly is not the fate of most patients with recurrent or persistent cancer following definitive chemoradiotherapy. In 2007, Gardner-Thorpe et al.3 reviewed 9 singleinstitution series of salvage esophagectomy following * Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio † Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.

Address reprint requests to Thomas W. Rice, MD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Ave, Desk J4-1, Cleveland, OH 44195. E-mail: [email protected]

1043-0679/$-see front matter ª 2013 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.semtcvs.2013.05.003

definitive chemoradiotherapy. A total of 105 patients, predominately with squamous cell carcinoma, were included in this simple evaluation. Salvage esophagectomy was an uncommon operation, with centers performing 1-3 procedures per year, representing 1.7%-4.2% of their esophagectomy volume. Morbidity was significant, and 3 centers reported it was higher than that following neoadjuvant chemoradiotherapy. Anastomotic leak was reported in 18% of patients and conduit complications (necrosis and fistula) in 5%. Complications accounted for 42% of the 11% in-hospital mortality. Median survival ranged from 7-32 months, with nearly all deaths after discharge due to cancer. R0 resection was associated with improved survival in 4 series. In 3 series, no patient with R1 or R2 resection survived more than 13 months. There was some evidence that patients with recurrent cancer after chemoradiotherapy did better than those with persistent cancer. Nishimura et al.4 reported results of salvage esophagectomy in 46 patients treated 1-7 months after definitive chemoradiotherapy. This group comprised 16% of patients with persistent or recurrent cancer after chemoradiotherapy. Operative mortality was 15%. Complications were frequent, with anastomotic leak, in 22% of patients, being the most common. Median survival was 22 months, and 3year survival was 17%. There were no predictors of survival; however, the 3 long-term survivors were ypN0 at salvage esophagectomy. Piessen et al.5 reported salvage esophagectomy in 98 of 472 patients (20%) treated with definitive chemoradiotherapy. Sixty-two percent had R0 resection, which was associated with improved median survival: 19 months vs 9 months in R1 and R2 patients (P o 0.001). In-hospital mortality was 3.1% and morbidity 33%. There were no R1 or R2 survivors after 26 months. Predictors of R0 resection were cancer length ≤5 cm on barium esophagram (P ¼ 0.05) and contact between the primary cancer and aorta ≤901 on computed tomography (CT) scan (P ¼ 0.04). 83

RECURRENCE AFTER DEFINITIVE CHEMORADIATION D’Journo et al.6 reported their 10-year salvage esophagectomy experience in 24 patients (9% of esophagectomies). Eighty-eight percent had R0 resection. Thirty- and 90-day mortality was high, 21% and 25%, respectively, and 45% developed a complication. Radiation dose more than 55 Gy was associated with increased mortality, morbidity, length of stay, and blood transfusions. Five-year disease-free survival was 21%. R0 resection was associated with best 5-year survival (36% vs 0% for R1 and R2), but this small experience did not reach statistical significance (P ¼ 0.7). Four studies have compared salvage esophagectomy with esophagectomy alone or esophagectomy as a component of neoadjuvant chemoradiotherapy.7-10 Smithers et al.7 reported the results of salvage esophagectomy in 14 patients (4% of patients treated with definitive chemoradiotherapy) and compared them with 53 patients treated with neoadjuvant chemoradiotherapy. No statistical assessments of the comparisons were made. Median time from chemoradiotherapy to esophagectomy was 28 weeks in salvage patients vs 4 weeks in neoadjuvant patients. Salvage esophagectomy patients had more respiratory complications and longer intensive care unit and hospital stays. Anastomotic leaks, transfusion requirements, and operative mortality were greater in salvage patients. Survival at 3 years was 24% for salvage patients and 53% for neoadjuvant patients. Survival after salvage esophagectomy was better for patients with recurrent cancer (25 months) than for those with persistent cancer (13 months). Chao et al.8 reported on 84 patients treated definitively with chemoradiotherapy. Forty-seven had persistent or recurrent cancer, of whom 27 had salvage esophagectomy. Compared with patients receiving definitive chemoradiotherapy alone, salvage esophagectomy patients had significantly better survival: 25% at 5 years vs 0% for those undergoing chemoradiotherapy alone (P ¼ 0.003). Compared with patients receiving neoadjuvant therapy, salvage esophagectomy patients were significantly older (P ¼ 0.04) and had more cervical and upper third thoracic cancers (P ¼ 0.05), fewer R0 resections (P ¼ 0.001), more pulmonary complications (P ¼ 0.006), more anastomotic leaks (P ¼ 0.002), and higher operative mortality. However, survival was similar. In salvage esophagectomy patients, multivariable analysis identified low preoperative albumin level (P ¼ 0.07) and anastomotic leak (P ¼ 0.02) as predictors of hospital mortality, and R1 and R2 resections (P ¼ 0.04) as predictors of disease-specific mortality. Morita et al.9 reported on 27 salvage esophagectomy patients and compared them both with patients who received neoadjuvant therapy and with

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patients who received esophagectomy alone. Complications were associated with the use of chemoradiotherapy and were most common in salvage patients (25% esophagectomy alone, 40% neoadjuvant therapy, and 59% salvage esophagectomy, P o 0.001). Salvage patients were 4 times more likely to experience a pulmonary complication than those receiving esophagectomy alone. Preoperative therapy and retrosternal or subcutaneous routes of reconstruction were associated with increased risk of anastomotic leak. Operative mortality was increased in salvage patients, but was not statistically significant (2.4% vs 2.0% vs 7.4%, respectively). Compared with patients who had salvage esophagectomy for recurrent cancer, patients who had salvage esophagectomy for persistent cancer were less likely to have a R0 resection (P ¼ 0.07) and had worse 5-year survival (15% vs 70%, respectively, P ¼ 0.008). Tachimori et al.10 treated 59 patients with salvage esophagectomy who had failed definitive chemoradiotherapy (radiation dose 460 Gy) and compared them with 553 patients who had esophagectomy alone. Salvage esophagectomy patients had significantly more respiratory complications (32% vs 20%, respectively, P ¼ 0.05), anastomotic leaks (31% vs 25%, P ¼ 0.003), wound infections (27% vs 15%, P ¼ 0.02), and hospital mortality (8% vs 2%, P ¼ 0.01) than patients who had esophagectomy alone. Tracheobronchial and gastric conduit necroses were highly lethal complications of salvage esophagectomy. Three-year survival after salvage esophagectomy was 38% compared with 58% following esophagectomy alone. However, T4 cancer and R1 and R2 resections were confounded in the analysis, leading the authors to conclude that only R0 resection was associated with improved survival in salvage esophagectomy patients. GENERAL PRINCIPLE—R0 RESECTION Although the quality of evidence is extremely poor, the overwhelming message from the literature is that R0 resection is a prerequisite if salvage esophagectomy is to offer a survival benefit. Preoperative identification of an R0 patient is problematic. The published salvage esophagectomy experience represents only a fraction of 1% of patients with failed nonsurgical therapy for esophageal cancer; thus, these patients are extremely selected. Even in these patients, R0 resection was not assured. It is evident that only the rare patient with failed therapy is presently considered for or would benefit from salvage surgery. Although not absolute, an R0 resection may be more likely in the

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RECURRENCE AFTER DEFINITIVE CHEMORADIATION setting of recurrence after definitive chemoradiotherapy and less likely with persistent cancer after definitive chemoradiotherapy. In these patients, a longer disease-free interval is favorable. Salvage esophagectomy of smaller cancers and cancers without clinical evidence of invasion of adjacent structures (T4) is more likely to produce R0 resection. A surrogate for R0 resection may be a ypN0 or rpN0 cancer. PATIENT SELECTION—RECURRENCE: CANCER RE-STAGING Patients with M1, T4, and most Nþ (N1 relative contraindication and N2 or N3 absolute contraindication) recurrent esophageal cancers are not candidates for salvage esophagectomy. First, M1 cancers must be excluded. CT/positron emission tomography scanning is the essential restaging imaging modality. Any distant hypermetabolic focus must be sampled to confirm its nature. Magnetic resonance imaging of the brain is indicated for the evaluation of clinical signs or symptoms. However, its performance as a last step in restaging (all other restaging excludes non-brain M1, T4, and Nþ) of all potential candidates for salvage esophagectomy can be argued because of a 13% prevalence of brain metastases following definitive chemoradiotherapy for esophageal cancer.11 Additional imaging would be dictated by the findings of these principal restaging tools. Esophagogastroduodenoscopy with biopsy and endoscopic ultrasound (EUS) is the next step in restaging. However, repeat esophagoscopy and rebiopsy may not identify residual mucosal cancer after aggressive therapy. Residual cancer at biopsy after chemoradiotherapy had sensitivity and negative predictive value of 23% and specificity and positive predictive value of 92% for cancer in esophagectomy specimens.12 Biopsy-positive patients were more likely to have residual positive regional lymph nodes compared with biopsy-negative patients. EUS is inaccurate in determining T classification after chemoradiotherapy, with reported accuracies of 27%-47%. The most common error is overstaging, because EUS is unable to distinguish cancer from inflammation and fibrosis produced by chemoradiotherapy. EUS accuracy for N classification after chemoradiotherapy is poor and ranged from 49%71%. The primary reasons for this inaccuracy are alterations in the ultrasound appearance of lymph nodes after chemoradiotherapy such that established EUS criteria do not apply and residual foci of cancer within the nodes that are too small for detection by any modality other than pathologic analysis. EUS-directed fine-needle aspiration is necessary for restaging. Any hypermetabolic focus detected by

PET and any EUS abnormality must be sampled to differentiate recurrent or persistent cancer from reactive and inflammatory changes. This includes all suspicious mural findings, regional lymph nodes, and periesophageal M1 sites. Use of ancillary staging modalities would be dictated by the classification to be defined (T4, Nþ, M1), tissue to be sampled, site of recurrence, and prior therapy. These procedures include laryngoscopy, bronchoscopy, mediastinoscopy, thoracoscopy, laparoscopy, surface ultrasonography, and simple incisional or excisional biopsy. At a minimum, aspiration and cytologic review is necessary, but biopsy and histopathologic review is preferred. PROCEDURE-SPECIFIC COMPLICATIONS Compared with esophagectomy in other clinical settings, complications are much increased in patients undergoing salvage esophagectomy, and perhaps are the highest seen. Complications are typically those following esophagectomy and are most frequently pulmonary and anastomotic. Conduit and airway necroses following salvage esophagectomy are frequently lethal. Prior high-dose radiation therapy and patient debility (reflected by low serum albumen) have been reported to be predictive of postoperative morbidity and mortality. Complications are associated with postoperative mortality following salvage esophagectomy. RESULTS The infrequent, supremely selected patient who is a candidate for salvage esophagectomy following definitive therapy can at best expect a median survival of 12-36 months, a 5-year survival of 25%-35%, and a disease-free survival of 10%-20% if R0 resection is possible. Death is frequently due to persistent or recurrent cancer. In patients undergoing R1 or R2 resections, it is rare to survive 2 years following salvage esophagectomy. ALTERNATIVE TO SALVAGE ESOPHAGECTOMY For early-stage esophageal cancers, it has been reported that the major determinant of which treatment is prescribed is who—which subspecialty— sees the patient first.13 This no doubt is the case for many patients with esophageal cancer. To avoid the “nightmare” of salvage esophagectomy, consideration of surgery for esophageal cancer should occur before treatment is delivered. This mandates a multidisciplinary treatment panel with surgical input. If esophagectomy is indicated in the patient’s future, it would be to his or her benefit to prescribe it as part of the initial, definitive therapy. The need for salvage

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RECURRENCE AFTER DEFINITIVE CHEMORADIATION esophagectomy, a failure of treatment planning, can be avoided. SUMMARY Salvage esophagectomy is a rare treatment option in patients failing definitive treatment of esophageal cancer. The ideal patient has recurrent cancer with a long disease-free interval. R0 resection is necessary if long-term survival is to be realized. Patients with small recurrent cancers without M1, T4, or Nþ

1. Cooper JS, Guo MD, Herskovic A, et al: Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. J Am Med Assoc 281:1623–1627, 1999 2. Guyatt G, Gutterman D, Baumann MH, et al: Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American College of Chest Physicians Task Force. Chest 129:174–181, 2006 3. Gardner-Thorpe J, Hardwick RH, Dwerryhouse SJ: Salvage esophagectomy after local failure of definitive chemoradiotherapy. Br J Surg 94: 1059–1066, 2007 4. Nishimura M, Daiko H, Yoshida J, et al: Salvage esophagectomy following definitive chemoradiotherapy. Gen Thorac Cardiovasc Surg 55: 461–465, 2007

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disease are most likely to benefit from salvage esophagectomy. Complications are frequent and are typically pulmonary or anastomotic. Mortality is significant, with 25%-35% survival at most following R0 resection. Most deaths are secondary to cancer or salvage esophagectomy. R1 and R2 resections are to be avoided. Better multimodality treatment planning would eliminate the “nightmare” of salvage esophagectomy.

5. Piessen G, Briez N, Triboulet J-P, et al: Patients with locally advanced esophageal carcinoma nonresponder to radiochemotherapy: Who will benefit from surgery? Ann Surg Oncol 14: 2036–2044, 2007 6. D’Journo X-B, Michelet P, Doddoli C, et al: Indications and outcome of salvage esophagectomy for oesophageal cancer. Eur J Cardiothorac Surg 33:1117–1123, 2008 7. Smithers BM, Cullinan M, Thomas JM, et al: Outcomes of salvage esophagectomy post definitive chemoradiotherapy compared with resection following preoperative neoadjuvant chemoradiotherapy. Dis Esophagus 20:471–477, 2007 8. Chao YK, Chan SC, Chang HK, et al: Salvage surgery after failed chemoradiotherapy in squamous cell carcinoma of the esophagus. Eur J Surg Oncol 35:289–294, 2009 9. Morita M, Kumashiro R, Hisamatsu Y, et al: Clinical significance of salvage esophagectomy

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for remnant or recurrent cancer following definitive chemoradiotherapy. J Gastroenterol 46:1284–1291, 2011 Tachimori Y, Kanamori N, Uemura N, et al: Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg 137: 49–54, 2009 Smith RS, Miller RC: Incidence of brain metastasis in patients with esophageal carcinoma. World J Gastroenterol 17:2407–2410, 2011 Yang Q, Cleary KR, Yao JC, et al: Significance of post-chemoradiation biopsy in predicting residual esophageal carcinoma in the surgical specimen. Dis Esophagus 17:38–43, 2004 Yachimski P, Nishioka NS, Richards E, et al: Treatment of Barrett’s esophagus with highgrade dysplasia or cancer: Predictors of surgical versus endoscopic therapy. Clin Gastroenterol Hepatol 6:1206–1211, 2008

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