Aggressive Multimodality Therapy for Stage III Esophageal Cancer: A Phase I/II Study

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1 Aggressive Multimodality Therapy for Stage III Esophageal Cancer: A Phase I/II Study E. Pendleton Alexander, MD, Timothy Lipman, MD, John Harmon, MD, and Robert Wadleigh, MD Divisions of Cardiothoracic Surgery, Gastroenterology, General Surgery, and Medical Oncology, Washington, DC VAMC and George Washington University Medical Center, Washington, DC Background. Stage III advanced locoregional esophageal carcinoma is frequently unresectable and inconsistently represented in therapeutic trials of esophageal cancer. Methods. From 1992 to 1998, 34 of 131 total esophageal cancer patients were designated stage III (16 T3N1, 9 T4N0, 9 T4N1) and medically fit to enter a combined modality protocol with continuous infusion 5-fluorouracil (CI5-FU, 300 to 600 mg/m 2 /day), high-dose external beam irradiation (60 Gy), and interval esophagectomy. Staging before and after induction therapy included computed tomography, endoscopy, and endoscopic ultrasound. Results. Significant toxicity from induction therapy included death (5/34; 14.7%), pneumonitis (5/34; 14.7%), mucositis (13/34; 38%), and hand-foot syndrome (3/34; 8.8%). In addition to the five deaths, 11 patients did not proceed to operation because of development of esophagorespiratory fistula in 3, distant disease in 2, persistence of T4 stage in 2, progression of comorbidities in 2, and patient refusal in 2. There was a discrepancy between clinical complete response (ccr) at restaging 56% (19/34) and pathologic CR (pcr) noted at the time of operation (8/34; 23.5%). Complete resections were possible in 16 of 18 patients explored. Complications in 4 patients included: death (1), airway injury (1), chylothorax requiring reoperation (1), anastomotic leak (1), recurrent nerve injury with vocal cord paresis (2), and ascaris infection (1). Actuarial survival analysis using the Kaplan-Meier method and log-rank testing showed a 36-month survival of 20% for the group as a whole and 27% for patients restaged ccr (ccr vs PR, p ). Treatment failure is predominantly distant, with good local control in resected patients. N0 node status was strongly associated with survival (N0 vs N1 p ). There is a trend towards improved survival in the resected group (resected 22% vs nonresected 10% at 3 years, p 0.17). Conclusions. Response rates and survival are commensurate with multiple completed phase II and III trials. These are attained at a higher treatment-related mortality. T4 patients can be successfully resected in selected patients. Even in advanced disease, nodal status is a significant predictor of survival. (Ann Thorac Surg 2000;69:363 8) 2000 by The Society of Thoracic Surgeons Multiple phase II and several randomized trials have been completed demonstrating that neoadjuvant chemoradiotherapy for esophageal carcinoma can provide complete response rates (CR) of 20% to 40%, median survival of 16 to 24 months, and a therapy related mortality rate of 5% to 12%. These trials have entered patients from multiple stages, and have inconsistently included the various TNM subsets of stage III: T3N1, T4N0, and T4N1 [1 6]. T3N1 has been generally considered to be incurable by operation alone, and T4 lesions are generally considered to be inoperable [7, 8]. Advances in staging hold promise for the development of stage-specific therapy [9, 10]. With these considerations, we initiated a trial of aggressive therapy for advanced locoregional stage III esophageal carcinoma, with a regimen including higher Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12 14, Address reprint requests to Dr Alexander, Division of Cardiothoracic Surgery, George Washington University Medical Center, 50 Irving St, NW, Washington, DC 20422; epalexander@med.va.gov. than usual radiation dosages (60 Gy) and continuous infusion 5-fluorouracil (300 to 600 mg/m 2 /day) at radiosensitizing doses. The aim of this trial was to establish whether response rates, treatment-related mortality, and survival commensurate with previously reported experiences could be obtained in advanced locoregional disease, and whether resection could be offered to patients previously considered unresectable. This trial was designed to evaluate the premise that more intensive induction therapy may be more appropriate for lesions generally considered incurable or inoperative by employing a higher than usual target radiation dose along with a continuous infusion of the chemotherapeutic agent with the highest documented response rate for esophageal cancer [11, 12]. Patients and Methods Patient Population and Eligibility Out of a total of 131 patients seen from May 1992 to May 1998 at the Washington DC VAMC, 34 patients with 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (99)

2 364 ALEXANDER ET AL Ann Thorac Surg STAGE III ESOPHAGEAL CANCER 2000;69:363 8 untreated advanced locoregional nonmetastatic esophageal carcinoma were designated stage III and medically fit to enter a multimodal protocol. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic function defined as a white blood cell count of more than /L, platelet count more than /L, creatinine level less than 2.0 mg/dl, and bilirubin level of 2.0 mg/dl or less. Pulmonary function testing, dobutamine thallium, and echocardiography were required to establish operative cardiopulmonary risk. Exclusion criteria included a tumor located within the first 4 cm of the esophagus and celiac node disease. All patients entered had bulky mid-thoracic lesions. The study was approved by the Human Studies Committee, and written informed consent was obtained from all participants. Evaluation and Staging Initial evaluation included a detailed history and physical examination, chest radiography, and computerized tomography (CT) of the lower neck, chest, and upper abdomen. Barium swallow, esophagoscopy with biopsy, and bronchoscopy were performed in all patients. Esophageal ultrasound (EUS) was performed in the last 29 consecutive patients. Intravascular ultrasound was used to confirm aortic invasion in 2 patients. The last 13 consecutive patients underwent staging thoracoscopy and laparoscopy. Care was taken to avoid systematic upstaging. Bronchoscopic evidence of invasion or infiltration was required rather than abutment or juxtaposition to define a primary tumor as T4 airway. Concurrence was generally required between EUS and CT. Bone and head CT scans were obtained as warranted by clinical suspicion of metastatic disease. Tumor stage was defined according to the classification of the American Joint Committee on Cancer (AJCC) [13]. Patient Characteristics Of the 34 patients enrolled, all were male (18 black and 16 white). Mean age was 63 years at diagnosis (range 45 to 78 years). All patients presented with dysphagia and weight loss (mean 12.6 kg, range 4 to 31 kg). All patients had a history of tobacco abuse, and 32 of 34 had history of ethanol abuse. Comorbidities, especially chronic lung disease and vascular disease, were common. Prior aerodigestive tract malignancies had occurred in 5 of 34 patients. In this atavistic population of esophageal carcinoma, histology was predominantly squamous, with only 3 of 34 having adenocarcinoma. Staging before initiaion of therapy was: 16 T3N1, 9 T4N0, and 9 T4N1. The designator T4 was given for airway invasion in 16 and aortic invasion in 2. After initial evaluation, 28 of 34 patients received a percutaneous endoscopic gastrostomy for nutritional support, and all patients received long-term central venous access. Chemoradiotherapy The target of radiotherapy was the macroscopic tumor and involved lymph nodes, if any, surrounded by at least 4-cm proximal and distal margins and a 2-cm radial margin. The target area was extended to the inferior cervical area in the case of tumors above the carina. The anatomical mediastinum and the celiac area were not routinely treated. Treatment portals consisted of anteroposterior, posteroanterior, and opposed lateral fields. The spinal cord was shielded after 40 Gy. The specified dose was delivered at the intersection of the central axis of the beams, according to international guidelines [14]. A total dose of 60 Gy in 1.8-Gy daily fractions, 5 days a week, was received by each patient completing therapy. Chemotherapy consisted of continuous infusion 5-fluorouracil (CI5FU) and ran concurrently for the duration of radiotherapy. CI5FU was selected because of its effectiveness as a radiation sensitizer and high documented response rate in esophageal cancer [11, 12]. Target dosage was changed over the course of the protocol in response to perceived efficacy and toxicity. Target dosage varied as follows: 6 patients, 300 mg/m 2 /day; 13 patients, 400 mg/m 2 /day; 8 patients, 500 mg/m 2 /day; and 7 patients, 600 mg/m 2 /day. Transient dosage adjustments including discontinuation were made in individual patients in response to toxicity. Toxicity was defined according to the Cancer and Leukemia Group B expanded common toxicity criteria. Restaging After induction therapy, all tumors were restaged with esophagoscopy and CT scan. Esophageal ultrasound was performed in 21 of 34 patients, and bronchoscopy selectively. Absence of tumor on restaging was designated a clinical complete response (ccr). Exploration was planned if a patient s overall condition was adequate and there was no evidence of unresectability at restaging. Surgery Resection was planned for 1 month after the conclusion of neoadjuvant therapy, but was commonly delayed to allow the patient to recover from induction treatment. Sixteen of the 18 patients explored underwent complete resection. Nine patients had transhiatal esophagectomies and 7 had a right thoracotomy. Operative approach was planned on the basis of preoperative staging with thoracotomy planned for most lesions initially staged T4. A trans-hiatal approach was used in selected T4 patients designated ccr after induction therapy. All resected patients had a cervical esophagastrostomy, pyloroplasty, and a feeding jejunostomy. The pathologic stage of the tumor was determined according to the classification of the AJCC. The absence of viable tumor in the resected specimen was designated a pathologic complete response (pcr). Follow-up Follow-up evaluation was performed at least every 3 months with repeat CT scanning, barium swallow, bronchoscopy, and endoscopy when appropriate. Treatment failure was defined by any morphologic evidence of tumor, and the pattern of failure, local, distant or both, was recorded regardless of whether the patient pro-

3 Ann Thorac Surg ALEXANDER ET AL 2000;69:363 8 STAGE III ESOPHAGEAL CANCER 365 ceeded to resection or not [15, 16]. All in-hospital deaths were included in the survival analysis, and all deaths were presumed to be secondary to esophageal cancer. Statistical Analysis Survival was measured from the date of diagnosis to the date of death or October 1, Actuarial survival was calculated using the Kaplan-Meier method and comparisons made using the log-rank test. Fisher s exact test was used to determine whether a relationship existed between two nominal variables. Analysis of variance (ANOVA) was used to test for a relationship among multiple variables. Results Chemoradiotherapy Toxicity Induction therapy was rigorous and toxic. Five of 34 patients (14.7%) died during induction therapy: 4 from pneumonitis and 1 from cytomegalovirus sepsis. Pneumonitis occurred in a total of 5 patients and occurred predominantly at CI5FU doses greater than 400 mg/m 2 / day. Analysis of age, tumor stage, and 5FU dose by ANOVA did not, however, identify any statistically significant association between these variables and the development of pneumonitis. Pneumonitis was not seen in patients receiving 300/m 2 /day. Anorexia and fatigue occurred in virtually all patients. Other complications requiring modifications in CI5FU dosing in individual patients included grade 2 mucositis in 9 of 34 (38%), and grade 3 mucositis in 5 of 34 (14.7%). There was grade 2 neutropenia and grade 3 neutropenia each in 8 of 34 patients (24%). Hand-foot syndrome occurred in 3 of 34 patients (9%). Chemoradiotherapy Response At restaging, there was no demonstrable tumor in 19 of 34 patients, for a clinical complete response (ccr) rate of 56%. A partial response (PR) was noted in 10 other patients, for a PR of 29.4%, but only 3 of these patients had actual downstaging. For the entire patient group, downstaging occurred in 22 of 34 (64.7%). Restaging bronchoscopy in the 16 T4 airway patients demonstrated no identifiable tumor in 11 patients. Relief of dysphagia occurred in many but not all patients with downstaging. For the group as a whole, 14 of 34 (41%) had relief of dysphagia after induction therapy. Responses to chemoradiotherapy were occasionally dramatic given the extent of the primary tumor (Fig 1). Fig 1. CT scans showing response to 60 Gy external beam irradiation and continuous-infusion 5-fluorouracil (400 mg/m 2 /day). (A) Initial staging, T4N0; (B) before surgical resection after completion of chemoradiotherapy, T0N0. Surgery Eighteen of 29 survivors of induction therapy underwent surgical exploration. Eleven patients did not proceed to operation because of development of distant disease in 2, development of tracheoesophegeal fistula in 3, persistence of T4 stage in 2, progression of comorbidities in 2, and patient refusal in 2. Two explored patients could not be resected because of T4 status identified intraoperatively. Complete resections were performed in 16 patients. Initial staging of these patients was T3N1 in 6, T4N0 in 6, and T4N1 in 4. Out of a total of 18 patients initially staged T4, including 14 with airway involvement, 10 resections were possible after induction therapy. Pathologic staging demonstrated no residual tumor in 8 patients, for a pcr of 8 of 34 (23.5%). This was substantially less than the ccr at restaging for all patients (56%), and the ccr at restaging before operation in patients resected (13/34; 38%). Progression of staging from protocol entry through treatment is summarized in Figure 2. Death resulted from resection in 1 patient, for an operative mortality rate of 6% (1/16). Combined with the deaths from induction therapy, this made the overall treatment mortality rate 17.6% (6/34). Other complications included airway injury (1), chylothorax requiring reoperation (1), anastomotic leak (1), recurrent nerve injury with vocal cord paresis (2), and ascaris infection (1). Survival At a median follow-up of 41 months, the actuarial survival for all patients entering the protocol at 12, 24, and 36 months was 58%, 28%, and 20%, respectively (Fig 3). Of all patients staged ccr, the 12-, 24-, and 36-month

4 366 ALEXANDER ET AL Ann Thorac Surg STAGE III ESOPHAGEAL CANCER 2000;69:363 8 Fig 2. Progression of staging in 34 patients with stage III esophageal carcinoma, including initial staging, restaging after neoadjuvant therapy, and staging at the time of exploration and/or resection. Thickness of lines corresponds to number of patients. actuarial survival was 69%, 48%, and 27%, respectively (Fig 4), and was significantly different from the group staged PR. There was a trend towards improved survival in the resected group versus the unresected group, but this failed to reach significance ( p 0.17) (Fig 5). Nodal status was a powerful predictor of survival, with a 57% survival at 36 months for N0 patients and 0% survival at 36 months for N1 patients. In spite of having large invasive bulky tumors, patients with an initial staging of T4N0 had a 12-, 24-, and 36-month actuarial survival of 89%, 77%, and 57%, respectively (Fig 6). Pattern of Failure For the group as a whole, locoregional control was good. Persistent or recurrent local disease was the first indicator of macroscopic treatment failure in 4 of 34 patients (12%). Distant treatment failure, occurring either as metastatic disease, or persistence or recurrence outside the radiation port, occurred in 12 of 34 (35%). Local and distant treatment failure were identified simultaneously in 3 of 34 patients (9%), making the total local failure rate 7 of 34 (20%) and the total distant failure rate 15 of 34 (44%). Treatment failure in resected patients was predominantly distant in 7 of 16 (41%), with simultaneous local and distant failure in 1 patient and local failure in 1 patient. Consequently, excellent locoregional control was obtained in 14 of 16 (87.5%) resected patients. Comment Aggressive therapy for this group of patients with advanced locoregional stage III esophageal cancer resulted in a ccr of 56% and a pcr of 23.5%, at the expense of a treatment related mortality rate of 17.6%. These response rates are similar but the mortality is higher in comparison with multiple completed trials [1 6]. Pneumonitis was the most significant contributing factor to this high mortality rate. Pneumonitis was not seen in patients treated at the lower level of CI5FU dosing (300 mg/m 2 /day). Fig 3. Actuarial survival for the group as a whole. Fig 4. Actuarial survival for patients restaged ccr and PR after chemoradiotherapy and including all subsequent treatment. The difference between the ccr group and the PR group was highly significant.

5 Ann Thorac Surg ALEXANDER ET AL 2000;69:363 8 STAGE III ESOPHAGEAL CANCER 367 Fig 5. Actuarial survival for resected and unresected patients. The difference approaches statistical significance. Whether a higher treatment mortality will continue to accompany aggressive multimodality treatment of advanced lesions will need to be established with further study. Selected T4 lesions can be successfully resected after aggressive induction therapy. Even in large, bulky, invasive lesions, nodal status remains a powerful determinant of survival, making accurate staging vital in planning therapy. One other published report supports an aggressive approach in patients with tracheobronchial involvement, with 9 of 23 patients successfully undergoing surgery after induction chemoradiotherapy [17]. Could the favorable results reported here in T4N0 patients have resulted from incorrectly staging lesions that were actually T3N0? Staging was performed with care to avoid upstaging. Multiple staging modalities were used but interpreted conservatively. Tracheoesophageal fistulae (TEF) developed in 3 patients all actually initially staged T3N1. Does aggressive therapy of airway involvement promote the development of TEF? In this series of patients, airway involvement was successfully treated in three times as many patients as those developing TEF. An aggressive approach appears warranted in T4NO patients, and operation should be considered in patients Fig 6. Actuarial survival for N0 and N1 patients within stage III. The difference between these groups was highly significant. with a dramatic response to induction therapy. This issue also awaits further study. The role of surgery in the multimodal therapy of esophageal cancer has been questioned. The wide discrepancy between clinical and pathologic staging seen in this study, and widely reported elsewhere [1, 2], commonly results from the inability to image or biopsy residual viable tumor in an esophagus with regenerated squamous epithelium and a small intramural deposit of tumor. Resection after ccr removes these foci when present, at least limiting the potential for locoregional recurrence. Locoregional control is excellent with resection in this series, and this is symptomatically very important to patients. The trend towards improved survival with resection in this series may become significant with longer follow-up, as resection may contribute to the development of the late plateau in actuarial survival curves. Does the absence of a broader chemotherapeutic regimen, including agents such as cisplatinum or taxol, hasten distant treatment failure? The distant treatment failure rate noted in this series is commensurate with those reported elsewhere [1 6, 15, 16]. The theoretic attractiveness of induction chemotherapy in killing micrometastatic disease has not been supported by a recently completed intergroup trial, which showed no advantage to neoadjuvant chemotherapy [18]. Until newer agents with novel actions are available, the principal value of chemotherapy may come from its radiosensitizing properties. In conclusion, response rates demonstrated in multiple completed trials are possible in advanced locoregional disease at a higher level of treatment mortality. T4 lesions can be downstaged and resected with long-term survival. Even in large, bulky, invasive lesions, nodal status is a critical determinant of survival. References 1. Ajani JA. Current status of new drugs and multidisciplinary approaches in patients with carcinoma of the esophagus. Chest 1998;113: Ilson DH, Bains M, Ginsberg RJ, Kelsen DP. Neoadjuvant therapy of esophageal cancer. Surg Oncol Clin North Am 1997;6: Nygaard K, Hagen S, Hansen HS, et al. Preoperative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of preoperative radiotherapy and chemotherapy. The second Scandinavian Trial in esophageal cancer. World J Surg 1992;16: Walsh TN, Noonal N, Hollywood D, Kelly A, Keeling N, Hennessy TPJ. A comparison of multimodality therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335: Urba S, Orringer M, Turrisi A, et al. A randomized trial comparing transhiatal esophagecomy (THE) to preoperative concurrent chemoradiation (CT/XRT) followed by esophagectomy in locoregional esophageal carcinoma [Abstract]. Proc Am Soc Clin Oncol 1995;14:A Al-Sarraf M, Martz K, Herskovic A, et al. Superiority of chemoradiotherapy vs radiotherapy in patients with esophageal cancer: final report of an intergroup randomized and confirmed study [Abstract]. Proc Am Soc Clin Oncol 1996; 15:206.

6 368 ALEXANDER ET AL Ann Thorac Surg STAGE III ESOPHAGEAL CANCER 2000;69: Murray GF, Wilcox BR, Stared PIK. The assessment of operability of esophageal carcinoma. Ann Thorac Surg 1977; 23: Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma. I. A critical review of surgery. Br J Surg 1980;67: Krasna MJ, Reed C, Jaklitsch MT, et al. Thoracoscopic staging for esophageal cancer: a prospective, multiinstitutional trial. Ann Thorac Surg 1995;60: LoCicero J. Laparoscopy/thoracoscopy for staging. II. Pretherapy nodal evaluation in carcinoma of the esophagus. Semin Surg Oncol 1993;9: Wittes RE, Adrianza ME, Parsons R, et al. Compilation of phase II results with single antineoplastic agents. Cancer Treat Rep 1985;4: Ajani JA. Contribution of chemotherapy in the treatment of carcinoma of the esophagus: results and commentary. Semin Oncol 1994;21: Beahrs OH, Heusen DE, Hutter RV, Myers MH, eds. Manual for staging cancer, 3rd ed. Philadelphia: Lippincott; 1988: Dose specification for reporting external beam therapy with photons and electrons. ICRU Report 29. Washington, DC: International Commission on Radiation Unit and Measurements, Aisner J, Forastiere A, Aroney R. Patterns of recurrence for cancer of the lung and esophagus. Cancer Treat Symp 1983;2: Sugimachi K, Inokuchi K, Kuwano H, Kai H, Okamura T, Okudaira Y. Patterns of recurrence after curative resection for carcinoma of the thoracic part of the esophagus. Surg Gynecol Obstet 1983;157: Sileni VC, Tomio L, Koussis H, et al. Concomitant radiotherapy and chemotherapy followed by surgery in esophageal carcinoma with bronchotracheal involvement [abstract]. Proc Am Soc Clin Oncol 1996;15: Kelsen DP, Ginsberg R, Qian C, et al. Chemotherapy followed by operation versus operation alone in the treatment of patients with localized esophageal cancer: a preliminary report of intergroup study 113 (RT0G 89-11) [Abstract]. Proc Am Soc Clin Oncol 1997;16:A276. DISCUSSION DR CHARLES L. WILLEKES (Muskegon, MI): That was an excellent paper. I enjoyed it very much. One question: did you notice any difference in the histological subtypes, squamous versus adenocarcinoma? And second of all, those patients who underwent complete resection, in regard to the number of nodes or the distance of the nodes from the primary tumor, were there any differences in outcome? DR ALEXANDER: There were only three adenocarcinomas in this series, and the adenocarcinomas that were stage T4 were T4 because of aortic invasion. We have seen one adenocarcinoma with airway invasion. In terms of numbers of lymph nodes and distant lymph nodes, an exclusion criterion for this protocol was celiac lymph node disease. In terms of numbers of lymph nodes, we did not use lymph node mapping, which I think everyone should, so our data are incomplete on that. I would tell you that my impression is that patients meeting the new N2 staging criterion for esophageal cancer do much worse, and, in general, lymphatic metastases appears to be a very powerful predictor of survival, as we showed, even in patients with huge primary tumors. I think it would be worse in patients with more extensive lymph adenopathy.