J Clin Oncol 22: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 22 NUMBER 22 NOVEMBER JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Adjuvant Chemotherapy for Resected Adenocarcinoma of the Esophagus, Gastro-Esophageal Junction, and Cardia: Phase II Trial (E8296) of the Eastern Cooperative Oncology Group Mary Armanios, Ronghui Xu, Arlene A. Forastiere, Daniel G. Haller, John W. Kugler, and Al B. Benson III From the Johns Hopkins University, Baltimore, MD; Dana-Farber Cancer Institute, Boston, MA; University of Pennsylvania, Philadelphia, PA; Illinois Oncology Research Association, Peoria; and Northwestern University, Chicago, IL Submitted June 4, 2004; accepted August 30, This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA16116, CA15488, CA13650, CA17145, and from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Study presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, Authors disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Mary Armanios, MD, Johns Hopkins University, 1650 Orleans St, CRB 186, Baltimore, MD 21205; marmani1@jhmi.edu by American Society of Clinical Oncology X/04/ /$20.00 DOI: /JCO A B S T R A C T Purpose To evaluate the effect of postoperative paclitaxel and cisplatin on 2-year survival in patients with completely resected adenocarcinoma of the distal esophagus, gastro-esophageal (GE) junction, and cardia. Patients and Methods We conducted a multicenter phase II trial. Patients had pathologically staged T2 nodepositive to T3-4, any node status adenocarcinoma of the distal esophagus, GE junction, or gastric cardia with negative margins (R0). Treatment consisted of four cycles of paclitaxel 175 mg/m 2 intravenously (IV) over 3 hours followed by cisplatin 75 mg/m 2 IV every 21 days. A positive outcome was considered to be an improvement in 2-year survival rate by 20% compared to historic controls. Results Fifty-nine patients were recruited from 20 centers. Of 55 eligible patients, 49 (89%) had lymph node involvement. Forty-six patients (84%) completed all four cycles. Of the total 59 patients, 31 (56%) developed grade 3 or 4 toxicity with leukopenia/neutropenia, nausea/ vomiting, and metabolic toxicities were most common. The median follow-up for surviving patients was 4 years. At 2 years, 33 patients were alive and 22 were dead, with a survival rate of 60% (95% CI, 46% to 73%; one-sided P.0008 compared with the historic controls). Conclusion Our data suggest that adjuvant paclitaxel and cisplatin may improve survival in R0 resected patients with locally advanced adenocarcinoma of the distal esophagus, GE junction, and cardia. These results warrant further testing in randomized trials. J Clin Oncol 22: by American Society of Clinical Oncology INTRODUCTION Adenocarcinoma of the esophagus accounts for 60% of all esophageal cancers in the United States. For complex reasons that remain unclear, its incidence continues to rise. Surgical resection remains a standard of care, and two-thirds of patients with locoregional disease can undergo potentially curative resection. 1 However, despite aggressive surgical treatment, only one-third of patients undergoing curative resection are alive beyond 2 years, with the majority developing distant metastases most commonly in the lungs, liver, and bone. 2,3 Adenocarcinoma of the distal esophagus, gastro-esophageal (GE) junction, and cardia is generally regarded as a unique clinical entity. This grouping is based on epidemiologic data showing a predominance of disease in males, an association with Barrett s esophagus in the majority of 4495

2 Armanios et al patients, and a similar pattern of spread to lower esophageal nodes. 4 Clinically, adenocarcinoma of the cardia shares a common distant pattern of recurrence with esophageal and GE junction cancers. This distinguishes it from other gastric cancers in which local failure patterns predominate. Although some have advocated the use of a separate staging system for these esophagocardia cancers, they continue to be staged based on traditional anatomic boundaries, although treatment planning may differ. Postoperative chemotherapy has not been studied in the randomized setting as a sole adjunctive modality to surgery in adenocarcinoma of the esophagus. The INT0116 trial evaluated chemoradiotherapy in patients with completely resected adenocarcinoma of the stomach and found a 7-month improvement in median survival in the treatment arm compared with the surgery-alone arm. 5 Twenty percent of the treated patients had disease in the cardia or GE junction, but the study was not statistically powered to measure a survival difference in this subset. In squamous cell carcinoma, the Japanese Clinical Oncology Group randomly assigned 242 patients with R0 resection to postoperative fluorouracil and cisplatin compared to observation and found no overall survival benefit at 5 years. 6 A subset analysis showed a significant survival improvement with adjuvant chemotherapy in patients with pathologically affected lymph nodes compared with patients who had no affected nodes. However, in squamous cell carcinoma, as in the Japanese cohort, the dominant pattern of first recurrence is local and patients often have comorbidities affecting their tolerance to adjuvant treatment. Although the survival, stage-for-stage, appears to be comparable in both histologies, 3,7,8 the pattern of failure is well established to be different. Cisplatin-based chemotherapy has long been the backbone of treatment in esophageal cancers 9 and paclitaxel is active as a single agent. 10,11 The combination of paclitaxel and cisplatin was tested in patients with advanced esophageal carcinomas with an objective response of 49%. 12,13 We thus designed a phase II, multicenter study to evaluate the impact on survival of postoperative chemotherapy in patients with curatively resected esophageal adenocarcinoma. Radiation therapy was not included because of the predominantly distant pattern of recurrence. PATIENTS AND METHODS Eligibility Criteria Eligibility criteria included: age 18 years; ability to give informed consent; histologic proof of adenocarcinoma of the esophagus, GE junction, or cardia status post total resection (transhiatal or transthoracic), and pathologic stage from T2 nodepositive M0 to T3-4 any node status, M0 disease, with negative proximal and distal margins (R0 resection); and Eastern Cooperative Oncology Group performance status 0 or 1. Patients were enrolled 4 to 12 weeks from the date of surgery and had to be without clinical evidence of locoregional or distant recurrence as assessed by computed tomography (CT) scan of the chest, abdomen and pelvis and with stable or increasing weight at the time of protocol entry. Treatment was started within 3 days of enrollment. Adequate organ function was required within 2 weeks of registration and was defined as: absolute neutrophil count (ANC) 1,500/mm 3, platelets 120,000/ mm 3, serum creatinine or creatinine clearance (CrCl) within normal institutional limits, AST and bilirubin the institutional upper limit of normal. Initial dose modification was not needed for bilirubin between1.5 to 2.0 mg/dl. No prior chemotherapy or concurrent radiation therapy was allowed. Patients were required to be without clinically significant hearing loss or symptomatic peripheral neuropathy as judged by initial history and physical examination. Institutional review and approval were required. Treatment The regimen consisted of paclitaxel 175 mg/m 2 intravenously (IV) as a 3-hour infusion on day 1, followed by cisplatin 75 mg/m 2 IV on day 1 repeated every 3 weeks for a total of four cycles. Appropriate premedications, antiemetics, and hydration were recommended. Dose Modification All toxicities were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria. To receive treatment, patients had to have an ANC 1,500/mm 3 and platelets 100,000/mm 3 on day 1 of therapy. Dose modification based on nadir toxicity of previous cycle was allowed with grade 4 neutropenia lasting 5 days, or febrile/neutropenia requiring hospitalization, or grade 4 thrombocytopenia requiring a reduction of both doses by 20%. For renal dysfunction, no modification of the paclitaxel dose was made. Creatinine clearance was required when the creatinine was above normal for institutions. For a CrCl 50 ml/min, no dose modification was made; 40 to 49, a 50% dose reduction was made; and CrCl 40, no cisplatin was given. Patients who developed grade 3 or 4 sensory or motor neuropathy defined as mild to moderate parastehesias, hearing loss, or objective weakness interfering with function had treatment terminated. Treatment was terminated early if objective disease recurrence was seen, if unacceptable toxicity developed, or if the patient wished to stop. Patient Evaluation The designations of distal esophagus, GE junction, and cardia primary site were determined by the local pathologist based on the main bulk of the tumor as per the American Joint Committee on Cancer Staging Manual criteria. 14 Pathologic staging systems for both esophageal and gastric cancer were used when the epicenter of disease bridged the GE junction. Cardia cancers were defined as being within 2 cm from the GE junction. Pathology reports were centrally reviewed by the study chair to confirm eligibility and disease site designation. Patients were followed every 3 months starting 3 weeks after the final cycle of treatment for 2 years, then every 6 months from 2 to 5 years, and yearly thereafter. CT scans were obtained every 6 months up to 4 years. Study Design The primary end point was 2-year survival. Secondary end points were disease-free survival time and feasibility (compliance 4496 JOURNAL OF CLINICAL ONCOLOGY

3 Adjuvant Therapy for Esophageal Adenocarcinoma and toxicity) of administering four courses of paclitaxel and cisplatin after esophagogastrectomy. Statistical Methods The study was designed to have 90% power to detect a 20% improvement in the 2-year survival rate from 38% to 58% (onesided P-value of.05). The preset 2-year survival was based on data from 135 patients in the surgery control arm of the United States intergroup trial INT0113 who underwent R0 resection. 7 The accrual goal was 55 patients, assuming that 50 would be eligible. No early stopping was planned in the design. Overall survival was defined as the time from study entry to death. Disease-free survival was the time from study entry to disease recurrence (defined as the date of biopsy-proven recurrence or clear evidence of progression by CT) or death of any cause. Overall survival and disease-free survival curves were generated by the Kaplan-Meier method. RESULTS Between June 1998 and March 2000, 59 patients were enrolled in 20 centers. Of these, 55 were eligible; four were ineligible (two with positive margins, one distal gastric cancer, and one metastatic disease). This analysis was performed in April Patient characteristics are shown in Table 1. The majority of patients were male with T3N1, GE Table 1. Patient Characteristics No. of Patients % Total patients 59 Eligible Age, years Median 62 Range Sex Female 3 5 Male ECOG performance status Primary sites Distal esophagus 9 16 T2N1 4 T3N1 5 GE junction T2N1 1 T3N0 4 T3N1 27 T3N2 1 T4N1 1 Cardia T2N1 3 T3N0 2 T3N1 4 T3N2 3 Abbreviations: ECOG, Eastern Cooperative Oncology Group; GE, gastro-esophageal. junction cancers. Forty-nine (89%) of 55 patients had positive lymph nodes. Two patients with primary disease in the cardia had pathologically affected celiac lymph nodes. Both of these patients died from metastatic disease within 3 years of the surgery date. Forty-six patients (84%) completed all four cycles of therapy, and the mean number of cycles administered was 3.7. Table 2 provides the grade 3/4 toxicities. Of the total 59 patients (including four ineligible patients), 32 (54%) developed grade 3 or 4 toxicity with leukopenia or neutropenia (16 of 59 patients), and nausea/vomiting (seven of 59 patients), with metabolic (five of 59 patients) and sensory/ motor neuropathy (five of 59 patients) as the most common toxicities. One patient died suddenly on day 18 of cycle 1 of an unclear cause. At 2 years, 33 of 55 eligible patients were alive with a survival rate of 60% (95% CI, 46% to 73%). This rejects the projected 2-year survival rate of 38% with surgery alone under the null hypothesis with a one-sided P-value of At the time of analysis, the median follow-up is 4 years (range, 2.9 to 4.9 years) for the 17 surviving patients. Figure 1 shows the Kaplan-Meier curves of the overall survival and of the diseasefree survival for all eligible patients. The median survival is 2.6 years with a median disease-free survival of 1.6 years. One-year and 3-year survivals are 80% and 42%, respectively. Sites of first failure in 38 patients are shown in Table 3. As expected, distant metastasis was predominant. Table 2. Adverse Events (N 59) No. of Patients Adverse Event Grade 3 Grade 4 Leukopenia/neutropenia 9/0 4/3 Neurologic 5 0 Metabolic 5 1 Nausea 5 Arthralgia/myalgia 2/1 Anorexia 2 Hypotension 2 1 Anemia 1 Infection 1 Febrile neutropenia 1 Vomiting 1 1 Diarrhea 1 1 Phlebitis 1 Weight loss 1 Fatigue 1 Dehydration 1 Pain 1 Worst degree NOTE. Adverse events graded according to the National Cancer Institute Common Toxicity Criteria. One patient died on day 18 of cycle 1 of unclear cause

4 Armanios et al Table 3. Site of First Recurrence (n 55) Site No. of Patients % Distant Locoregional (anastomosis, duodenal) 2 5 Both local and distant 3 8 Unknown 4 11 Total 38 Fig 1. Kaplan-Meier curves of (A) overall and (B) disease-free survival of eligible patients. The dashes represent pointwise 95% CIs. Survival at 1, 2, and 3 years was 80%, 60%, and 44%, respectively. At 2 years, this was statistically significant with a P-value of DISCUSSION We conducted a multi-institutional phase II study to assess the effect of adjuvant cisplatin and paclitaxel on the survival of patients with R0 resected, locally advanced adenocarcinoma of the distal esophagus, GE junction, and cardia. We found a statistically significant benefit compared with historic controls who underwent a similar R0 resection as their only therapy in INT0113. To our knowledge, this is the first multicenter trial of its kind and the first to show benefit compared with historic controls. In general, the therapy was tolerable with manageable toxicities and the majority of patients were able to complete it fully. A few important differences are worth noting. In INT0113, the surgery arm patients were enrolled preoperatively and their survival was measured from the time of study entry. The INT0113 intention-to-treat survival analysis included 6% of patients who died from surgery-related complications. In contrast, E8296 patients were enrolled 4 to 12 weeks after surgery and had to fit eligibility criteria of adequate performance and nutritional status. These latter criteria may, therefore, knowingly introduce a selection bias and are an attempt to offer systemic therapy to high-risk patients who recover well after surgery. A larger European trial of perioperative chemotherapy also included a surgery control arm that may be considered comparable to our group of patients. The Medical Research Council trial randomly assigned 802 patients with squamous cell and adenocarcinoma of the esophagus to immediate surgery compared with two cycles of cisplatin and fluorouracil followed by surgery. A statistically significant improvement in survival was found in the treatment arm. This benefit also held in the subset analysis of 533 patients with adenocarcinoma where the 2-year survival in the surgery only arm (n 268) was 30%. These statistics are from patients who were also enrolled preoperatively and were eligible regardless of postoperative disease status (ie, residual micro- or macroscopic residual disease). Taken together, such differences make accurate historic control comparisons difficult and can only be resolved in a headto-head randomized trial. For the moment, our results suggest a possible survival improvement compared with surgery alone and further studies of postoperative chemotherapy seem feasible and warranted in this population. Finally, since the launching of this trial, there have been changes in practice which may contribute to better defining the role of adjuvant therapy today. Several trials have demonstrated the superiority of positron emission tomography over CT in detecting subclinical distant metastases JOURNAL OF CLINICAL ONCOLOGY

5 Adjuvant Therapy for Esophageal Adenocarcinoma Primary surgery in this setting is generally noncurative with most patients relapsing within 1 year With appropriate staging of patients who have localized disease at presentation, it may prove easier to measure benefits from adjuvant treatment. In addition, there has been a trend to treat patients with locoregional disease with upfront chemoradiotherapy followed by surgical resection. Although controversy remains as to the impact of this approach on survival, 2,18-21 it continues to be used because of its tolerability as well as based on improvements in locoregional control. 22 Furthermore, in patients who are downstaged to pathologic complete responses, 25% to 30% of all comers, or those with minimal residual disease (eg, T1), long-term survival can be achieved. 23,24 For patients with more residual disease, the outcome remains poor, with, as in our patients, distant failure predominating. This pattern of failure underscores the need for better systemic therapy to address and change the natural history of this disease. We have shown in this phase II multicenter trial a statistically significant improvement in survival in patients with R0 resected, predominantly node-positive adenocarcinoma of the distal esophagus, GE junction, and cardia compared with historic controls. Approaches using adjuvant systemic therapy warrant further study in randomized trials. Authors Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Schrump DS, Forastiere AA, Minsky BD: Cancer of the Esophagus, in DeVita V (ed): Cancer: Principles and Practice of Oncology. Philadelphia, Lippincott Williams & Wilkins, 2001, pp Urba SG, Orringer MB, Turrisi A, et al: Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. 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