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© 1999 American Society for Clinical Oncology Phase II Trial of Weekly Irinotecan Plus Cisplatin in Advanced Esophageal CancerFrom the Gastrointestinal Oncology Service, Departments of Medicine, Biostatistics, and Psychiatry, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to David H. Ilson, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email ilsond{at}mskcc.org
PURPOSE: To evaluate the response, toxicity, survival, and quality of life in patients with unresectable or metastatic esophageal cancer treated with weekly irinotecan and cisplatin. PATIENTS AND METHODS: Thirty-five patients with metastatic or unresectable esophageal adenocarcinoma (23 patients) or squamous cell carcinoma (12 patients) were treated. No prior chemotherapy was allowed. The majority of patients had metastatic and bidimensionally measurable disease (34 patients each [97%]). Patients were treated with cisplatin 30 mg/m2 and irinotecan 65 mg/m2, repeated weekly for 4 weeks, followed by a 2-week rest period. Treatment was recycled every 6 weeks. Degree of dysphagia relief was monitored, and quality of life was measured prospectively using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 and Functional Assessment of Cancer Therapy–General instruments. RESULTS: Thirty-five patients were assessable for response and toxicity. Major objective responses were observed in 20 patients (57%; 95% confidence interval, 41% to 73%), including two complete responses (6%). Similar response rates were observed for adenocarcinoma (12 of 23 patients; 52%) and squamous carcinoma (eight of 12 patients; 66%). The median duration of response was 4.2 months (range, 1 to 8.8+ months). Median actuarial survival was 14.6 months (range, 1 to 15.2+ months). In 20 patients with dysphagia assessable at baseline, 18 (90%) noted either improvement or resolution of dysphagia on chemotherapy. Global quality of life improved in responding patients, primarily because of improvements in pain, emotional state, and relationships with family and friends. Toxicity was relatively mild and included only three patients (9%) with grade 4 neutropenia and four (11%) with grade 3 diarrhea. There were no treatment-related deaths. CONCLUSION: The combination of weekly cisplatin plus irinotecan had significant activity in metastatic esophageal carcinoma and resulted in significant relief of dysphagia. The regimen was well tolerated, with acceptable myelosuppression and rare treatment-related diarrhea. Further evaluation of the combination of weekly irinotecan and cisplatin, including the addition of other agents to this regimen, is indicated.
IN 1998, 12,500 NEW cases of esophageal cancer were diagnosed in the United States,1 and more than 90% of patients died of their disease, accounting for 2% of American cancer deaths. Adenocarcinoma of the esophagus or gastroesophageal junction, a previously rare disease, is rapidly increasing in incidence in the United States and western countries and now accounts for more than half of newly diagnosed cases.2 Half of patients diagnosed with esophageal cancer present with overt metastatic disease, and chemotherapy is the mainstay of palliation in this setting. In patients who present initially with locoregional disease, the majority will eventually develop metastatic disease as well, with or without local recurrence of disease. Metastatic esophageal carcinoma is an incurable disease with a median survival duration of 4 to 8 months. Combination chemotherapy, most often cisplatin-based, results in partial responses in 25% to 50% of patients with metastatic disease and rare complete responses, including a 35% response rate reported for the commonly used combination of cisplatin and fluorouracil.3 Although few studies of chemotherapy have been reported in metastatic adenocarcinoma of the esophagus, recent chemotherapy trials indicate an overlap in response rates for adenocarcinoma and squamous carcinoma.4 Responses to chemotherapy are generally short-lived, and toxicity of cisplatin-based chemotherapy, particularly in the palliation of metastatic disease, is often substantial and underscores the need to identify new agents in the treatment of esophageal carcinoma. The camptothecins, plant alkaloids derived from the Camptotheca acuminata tree, are a novel class of antineoplastic agents that act primarily by inhibition of the topoisomerase I enzyme.5,6 Irinotecan (Camptosar 7; Pharmacia & Upjohn, Kalamazoo, MI), a semisynthetic, water-soluble camptothecin, has a broad spectrum of antitumor activity, including activity in colorectal and non—small-cell lung cancer. In clinical trials, single-agent irinotecan has significant activity in advanced gastric cancer, with a reported response rate of 33%.7 Preclinical studies indicate potential synergy between irinotecan with cisplatin, and two recent trials of monthly cisplatin and bimonthly irinotecan in metastatic gastric cancer reported response rates of 42% to 48%, suggesting significant potential clinical antitumor synergy.8,9 A phase I study at Memorial Sloan-Kettering Cancer Center examined the combination of irinotecan and cisplatin given on a weekly schedule.10 Patients received cisplatin at a fixed dose of 30 mg/m2 followed by escalating doses of irinotecan given once per week for 4 weeks followed by a 2-week rest period. Neutropenia was dose-limiting, and other toxicities were minimal. The recommended phase II dose of irinotecan was 65 mg/m2. Encouraging antitumor activity included a partial response in a patient with a gastroesophageal junction tumor metastatic to the liver. Based on the experience in our phase I trial, we undertook this phase II trial of weekly cisplatin and irinotecan in advanced esophageal cancer. The purpose of the trial was to assess the response, toxicity, and survival of patients treated with weekly cisplatin and irinotecan. Because few chemotherapy trials in esophageal cancer have evaluated symptomatic relief or quality of life on therapy, we also prospectively evaluated potential relief of dysphagia and quality of life on study.
The study reported herein was a single-institution phase II trial that accrued patients at the Memorial Sloan-Kettering Cancer Center in New York, NY. The study was approved by the institutional review board, and patients were required to provide signed informed consent.
Patients were eligible if they had histologic proof of unresectable or metastatic squamous cell carcinoma or adenocarcinoma of the esophagus. Patients with tumors of the gastroesophageal junction were eligible if at least 50% of the tumor involved the esophagus. Patients with gastric cancers were not eligible. Patients were Patients were required to have bidimensionally measurable or assessable disease. Bidimensionally measurable disease was defined as tumor masses that could be evaluated by radiograph, computed tomography, or physical examination in which two perpendicular dimensions could be obtained and monitored serially. Response criteria reported by Miller et al were used.11 A complete response required disappearance of all evidence of tumor for at least 4 weeks, and for patients with the primary tumor in place or with locally recurrent disease, endoscopic confirmation of a complete response with normal endoscopic biopsy specimens or brushings was required. A partial response was defined as a more than 50% reduction in the sum of the products of the longest perpendicular diameters of indicator lesions for a period of at least 4 weeks. A minor response was defined as a more than 25% but less than 50% reduction in measurable tumor area for at least a 4-week period. Assessable disease was defined as radiographically distinct unidimensional tumor that could be evaluated serially by radiographic studies (ie, the primary tumor evaluated by double-contrast barium esophagram or computed tomography). Response in assessable disease was defined as a more than 50% improvement in unidimensional disease as determined by at least two observers. All scans were reviewed for response by the reference radiologist (M.G.). Duration of response was defined as time from documentation of the response to documentation of disease progression. Pretreatment evaluation included a complete history and physical examination and documentation of performance status. Laboratory evaluation included a complete blood count, urinalysis, a chemistry panel with liver function tests, partial thromboplastin time, and prothrombin time. All patients had a pretreatment 12-lead electrocardiogram. Radiographic evaluation included a chest radiograph, a double-contrast barium esophagram in selected patients with the primary tumor in place, and computed tomography of the chest and abdomen. Before each treatment cycle, a complete blood count, chemistry panel, and liver function tests were repeated. A weekly complete blood count and a serum creatinine measurement were obtained during the 4-week treatment period and during the 2-week rest period. Repeat radiographic studies were performed after the first and second treatment cycles and subsequently after every two treatment cycles. Quality of life was assessed using the Functional Assessment of Cancer Therapy–General (FACT-G)12 and European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C-3013 instruments, and dysphagia was quantitated using a published dysphagia scale.14 Assessment of quality of life and dysphagia were made before study entry, after the first and second cycle, and then every other cycle. The FACT-G quality-of-life measure consists of 27 items grouped into five subscales: physical well-being, social/family well-being (ie, relationship with family and friends), relationship with doctor, emotional well-being, and functional well-being. The EORTC QLQ-C30 is a quality-of-life measure for cancer patients with any cancer diagnosis and consists of 30 items that assess general physical symptoms, physical functioning, fatigue/malaise, social and emotional functioning, and overall quality of life. All subscale scores were transformed to a scale of 0 to 100, with higher scores on functional scales representing a better level of functioning and higher scores on symptom scales represented worse symptoms.
Treatment was delivered in the outpatient setting. Antiemetic premedication included dexamethasone 20 mg intravenously and granisetron 2 mg orally. Patients were hydrated with 5% dextrose in normal saline to a total volume of
All toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were examined weekly by the physician during treatment weeks for the first two cycles, and on subsequent cycles were examined on alternate weeks by the physician for toxicity assessment. Dose attenuation for irinotecan by 10 mg/m2 was made for grade 3/4 diarrhea or mucositis or for grade 4 fatigue lasting for more than 3 days. On the day of treatment, the WBC count had to be
Statistical Analysis
Patient Characteristics Patient characteristics are listed in Table 1. Thirty-eight patients were accrued from July 1997 through September 1998, and 35 patients were assessable for both response and toxicity. Twenty-five patients with adenocarcinoma were accrued, but two patients were found to be subsequently ineligible: in one patient, a repeat biopsy during therapy suggested the tumor was neuroendocrine in origin, and in the second patient, repeat endoscopy showed that the tumor was a gastric cancer. Thirteen patients with squamous carcinoma were accrued as of this report, and accrual to this histology is ongoing; one patient was found to be subsequently ineligible because a repeat biopsy during therapy indicated that the tumor was neuroendocrine in origin. Of the patients with adenocarcinoma, five had lesions of the distal esophagus (22%) and 18 had lesions of the gastroesophageal junction (78%). Thirty-four patients (97%) had metastatic disease, and the majority (32 patients; 91%) had either the primary tumor in place or locally recurrent disease in addition to distant metastatic disease. Nearly half of the patients had hepatic metastases (17 patients; 49%). Only one patient had locally recurrent disease only. Four patients (11%) had undergone a prior esophagectomy with curative intent. No patients received prior chemotherapy or radiotherapy. The performance status of patients was good, with a median Karnofsky performance status of 80%. The majority of patients (34 of 35; 97%) had bidimensionally measurable disease.
Response and Survival
After an excellent response to protocol therapy, definitive local therapy using combined chemoradiotherapy was attempted in five patients with prior objective responses who had M1 disease in celiac, mediastinal, or supraclavicular lymph nodes. Three of these patients had achieved a prior partial response and two a prior complete response. All five patients received radiotherapy with concurrent fluorouracil plus either cisplatin or mitomycin, and three of five patients (including the two prior complete responses) remained free of disease after completing chemoradiotherapy at a follow-up duration of 3 to 10 months. Patient survival was determined by Kaplan-Meier analysis. The median actuarial survival was 14.6 months (range, 1 to 15+ months). The median actuarial survival for adenocarcinoma was 14.6 months, and the median survival for squamous carcinoma has not yet been reached.
Dysphagia and Quality of Life There was a significant improvement in patients' overall quality of life as measured by both the FACT-G and EORTC QLQ-C30. Improvements in overall quality of life observed in the FACT-G by both cycle 1 (P < .05) and cycle 2 (P = .004) were largely found in patients who responded to treatment (complete and partial responders), with significantly greater quality-of-life scores by cycle 1 (P < .01) and cycle 2 (P = .007) from baseline levels. These findings were primarily a result of the improvement in responders' FACT-G emotional well-being scores from baseline to cycle 1 (P = .002) and cycle 2 (P = .01), as well as social/family well-being scores from baseline to cycle 2 (P < .05). A similar trend in quality of life was observed for nonresponders (minor response, stable disease, and progressive disease). This was a surprising observation, although a significant number of patients (seven of 15) in the nonresponder category had a minor response, and only one patient had disease progression as the best response (Table 2). The improvement in emotional state found in the FACT-G was mirrored by the results from the EORTC, with responders having significantly higher emotional functioning scores by cycle 4 from baseline levels (P < .05). Importantly, there was also a significant reduction in responders' pain throughout the course of treatment, with EORTC pain scores reduced from baseline levels by cycle 1 (P < .05), cycle 2 (P < .05), and cycle 4 (P < .05). Responders' EORTC role (ie, work-related) functioning scores also significantly improved by cycle 4 from baseline levels (P < .05).
Toxicity
Six patients (17%) required hospitalization for toxicity, most commonly for neutropenic fever, but also for cerebrovascular accident (one patient) and supraventricular tachycardia (one patient) that may or may not have been treatment-related. One patient was hospitalized for severe hyperglycemia from corticosteroids given as antiemetic prophylaxis.
A total of 118 cycles were delivered in 35 patients, with a median of four cycles per patient (range, one to seven cycles). Dose attenuation was required only in seven patients (20%) and in only nine cycles (8%). Irinotecan was attenuated in four patients, cisplatin in one patient, and both irinotecan and cisplatin in two patients, with dose reduction made for hematologic toxicity, increase in serum creatinine level, or severe and intractable nausea. Twenty-three patients (66%) had either delay of treatment by 1 to 2 weeks or shortening of a treatment cycle to 3 weeks, and 42 treatment cycles (36%) were affected. The majority of affected cycles (29 of 42; 69%) were a treatment delay only, with shortening of the treatment cycle to 3 weeks being less common (13 cycles; 31%). Despite treatment delays, 453 (96%) of 472 planned treatments were delivered. The most common cause of treatment delay or cycle shortening was hematologic toxicity (35 cycles), but hospitalization for neutropenic fever was rare, and most delays were for 1 week to allow recovery to a WBC count of
We observed substantial activity for the combination of weekly irinotecan and cisplatin in esophageal cancer. The observed response rate of 52% in adenocarcinoma, the preliminary observation of a 66% response rate in squamous cancer, and the encouraging median actuarial survival duration of 14.6 months compare favorably to other reported combination chemotherapy trials. Accrual of patients with squamous cancer continues to define better the response rate, as of this writing. A trial of irinotecan in esophageal cancer, which is ongoing at the Dana-Farber Cancer Institute, is currently evaluating the single-agent activity in advanced disease. Remarkable in the current trial was the relative absence of grade 3/4 toxicity other than myelosuppression, which was moderate. Although treatment delays of 1 week were common to allow recovery of blood counts, the majority of planned therapy was delivered, and hospitalization for neutropenic fever was rare. An alternative schedule of therapy, using 2 sequential weeks of therapy with 1 week of rest, rather than 4 weeks of therapy with 2 weeks of rest, is one strategy to overcome the delay of therapy in patients (which usually occurred during week 3 or 4 of the cycle). Severe diarrhea, a complication of higher-dose single-agent irinotecan, was uncommon in this trial. Asthenia and nausea, common complications of cisplatin-based chemotherapy, were also not observed using a regimen of low-dose cisplatin given weekly despite the cumulative dose per cycle of cisplatin of 120 mg/m2. Few previous trials of chemotherapy in esophageal cancer have prospectively evaluated relief of dysphagia or quality of life achieved with chemotherapy. One trial of etoposide and cisplatin in metastatic or unresectable esophageal cancer reported dysphagia relief in 89% of patients, indicating that chemotherapy may lead to significant dysphagia palliation.17 The present trial substantiates the ability of chemotherapy to relieve dysphagia, with the majority (90%) of patients with dysphagia at baseline experiencing improvement or resolution of swallowing difficulties. The substantial response rate observed on this trial was the most likely cause for the improvement in patients' quality of life, particularly in terms of reduced pain and emotional distress, with consequent improvements in relationships with family and friends. Significant reductions in responders' pain, improvements in work-related functioning, and relationships with family and friends from baseline levels were achieved even at cycle 4 for patients remaining on treatment. Similar trends in quality of life were observed for responders and nonresponders (a category in which nearly half of the patients had a minor response). It is not possible to draw any conclusions concerning these findings given the small patient numbers and the phase II design of the trial. The findings from the exploratory use of quality-of-life instruments in the current trial indicate that subsequent trials should include a quality-of-life component to establish more definitively the quality-of-life benefit resulting from this regimen. No definitive conclusions can be drawn concerning the effect of irinotecan/cisplatin on patients' quality of life until a phase III trial is conducted. The combination of irinotecan and cisplatin has substantial activity in esophageal carcinoma, and given the tolerance of therapy and the palliation of dysphagia, a comparison of this regimen to conventional fluorouracil plus cisplatin or to newer paclitaxel-containing regimens is indicated. Given the tolerance of weekly irinotecan and cisplatin, it is likely that the addition of other chemotherapy agents to this regimen will be feasible. Given that irinotecan may also be an effective radiosensitizing agent, as demonstrated in preclinical studies,18 the evaluation of irinotecan/cisplatin in combination with concurrent radiotherapy in locally advanced disease is also warranted.
Supported in part by a grant from Pharmacia & Upjohn, Kalamazoo, MI.
Presented at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 15-19, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 years of age and were required to have a Karnofsky performance status 
1.5 mg/dL, AST 
2 test; P = .4). The duration of response ranged from 1 to 8.8+ months (median, 4.2 months), and the median duration of response was comparable for adenocarcinoma and squamous carcinoma (medians, 4.9 and 3.8 months, respectively). Responses were observed at all sites of disease and included partial and complete responses in the primary tumor, liver, lung, and lymph node metastases. Partial responses were observed after a median of one cycle (range, one to two cycles), and the two complete responses were observed after three cycles. Complete responses were observed in one patient with adenocarcinoma with hilar, mediastinal, and celiac lymph node disease and one patient with squamous carcinoma with bulky celiac lymph nodes. Complete responses were determined by computed tomography and repeat endoscopy with normal biopsy specimens. Positron emission tomography in both patients also showed no evidence of residual active disease. 
