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© 2003 American Society for Clinical Oncology Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer
From the Gastrointestinal Oncology Service, Department of Medicine, and Departments of Surgery, Radiation Oncology, and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to David H. Ilson, MD, PhD, 1275 York Ave, New York, NY 10021; email: ilsond{at}mskcc.org.
Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.
ESOPHAGEAL CARCINOMA is an aggressive cancer with a poor prognosis. In 2002, 13,100 Americans were diagnosed with esophageal cancer, and more than 90% of these patients will die of their disease.1 Despite treatment with surgery, definitive chemoradiotherapy, or the combined use of preoperative chemoradiotherapy followed by surgery, less than 20% to 35% 5-year survival rates are generally achieved.2–5 The mucosal and gastrointestinal toxicity of fluorouracil (FU) and cisplatin combined with concurrent radiotherapy and the dysphagia caused by the primary tumor have led many investigators to require the placement of enteral feeding tubes in patients before chemoradiotherapy to ensure nutritional support. The limited effectiveness and the toxicity of currently used combined-modality therapy mandate the evaluation of new chemotherapy agents in esophageal cancer. Irinotecan, an inhibitor of topoisomerase-1, has emerged as a significant new cytotoxic agent with a broad spectrum of antitumor activity. Recent American trials of irinotecan as a single agent indicate modest activity in gastroesophageal cancer,6,7 and trials combining weekly irinotecan with cisplatin report response rates exceeding 50%.8,9 Preclinical studies have indicated that the camptothecins have a radiation sensitization enhancement comparable with other standard drugs used in combined-modality therapy.10,11 A significant increase in the proportion of cells in the G2 or M phase, the most radiosensitive phase of the cell cycle, occurs after treatment with SN-38 (the active metabolite of irinotecan).12 Treatment with irinotecan before radiation therapy may increase the number of DNA-protein crosslinks and convert single-strand DNA breaks to lethal double-strand breaks.13,14 Phase I and II studies of weekly irinotecan and radiation therapy in non–small-cell lung cancer in Japan indicate dose-limiting toxicity (DLT), including esophagitis, pneumonitis, and diarrhea.15,16 In the current phase I trial, our goal was to determine the maximum-tolerated dose (MTD) and DLT of weekly irinotecan combined with weekly cisplatin and concurrent radiation therapy. Given our observation of dysphagia relief with irinotecan and cisplatin,8 we delivered induction chemotherapy with irinotecan and cisplatin before adding concurrent radiotherapy.
Patient Eligibility All patients had histologically confirmed squamous cell carcinoma, adenocarcinoma, or poorly differentiated non–small-cell carcinoma of the esophagus, which was locally advanced, included clinical stages II to III disease (T1 N1 M0, T2–4 N0–1 M0), and was staged by computed tomography (CT) scan and endoscopic ultrasound (EUS). Patients with T1N0 disease were excluded. For tumors of the gastroesophageal junction, at least 50% of the tumor had to involve the distal esophagus. Participants were required to be at least 18 years of age and to provide written informed consent before treatment. Patients were required to have a Karnofsky performance status of 70% or greater (Eastern Cooperative Oncology Group performance status  2) and adequate hematologic, renal, and hepatic function as defined by an absolute neutrophil count  1.5 x 109/L, platelets 100 x 109/L, hemoglobin 9.0 gm/dL, serum creatinine 1.5 mg/dL, and total serum bilirubin 1.5 mg/dL. No prior chemotherapy or radiotherapy was permitted. Metastatic disease to supraclavicular or celiac lymph nodes or metastatic disease with biopsy-proven tumor invasion of the tracheobronchial tree or with tracheoesophageal fistula was not permitted. Severe comorbid conditions, including cardiac disease graded as New York Heart Association class 3 or 4, or myocardial infarction within the last 6 months also resulted in patient exclusion. Patients with a history of prior malignancy, other than basal cell carcinoma of the skin or in situ cervical carcinoma, diagnosed or treated within 3 years of entrance onto the study were ineligible. Patients with known Gilbert’s syndrome or with a history of seizure disorder who were receiving antiepileptic medication were also ineligible.
Pretreatment Evaluation and Evaluation on Study
Treatment Plan and Definition of DLT
Combined chemoradiotherapy was begun during week 8. Radiation therapy was administered in 1.8-Gy daily fractions to a total dose of 50.4 Gy, as described in the subsection Radiation Therapy. During radiotherapy, chemotherapy was administered weekly each Monday of weeks 8, 9, 11, and 12. Cisplatin was administered at a dose of 30 mg/m2, followed by irinotecan given at escalating doses (40, 50, 65, and 80 mg/m2). Dose reduction of irinotecan was not permitted during combined chemoradiotherapy. A dose reduction in cisplatin to 15 mg/m2 was permitted if the serum creatinine increased above 1.6 mg/dL but remained 2.0 mg/dL. DLT during combined chemoradiotherapy was defined as the need for a delay of therapy greater than 2 weeks because of hematologic or nonhematologic toxicity. Hospitalization for toxicity during chemoradiotherapy was not defined as dose-limiting unless such toxicity led to a 2-week delay in chemoradiotherapy. If therapy was delayed because of toxicity, both chemotherapy and radiotherapy were delayed until the resolution of toxicity to grade 1 or less. With the observation of pulmonary emboli on the posttreatment CT scans in three of the first 15 patients (see "Results," under Toxicity: Chemoradiotherapy), low-dose Warfarin prophylaxis (1 mg) was instituted during combined chemoradiotherapy beginning 3 days before the initiation of combined chemoradiation. Warfarin was continued until 4 weeks after completion of combined chemoradiotherapy. A weekly prothrombin time was obtained in patients receiving Warfarin prophylaxis. Granulocyte colony-stimulating factor was not used during combined chemoradiotherapy.
Statistical Design
Radiation Therapy
The superior and inferior borders of the radiation field were 5 cm beyond the primary tumor. The lateral, anterior, and posterior borders of the field were
Criteria for Toxicity and Response
Patients
Toxicity: Induction Chemotherapy All patients were assessable for both toxicity and response. Toxicities observed during induction chemotherapy are listed in Table 2  . Only one patient (5%) experienced grade 3 diarrhea, and other toxicity was mainly grade 1 to 2 (primarily grade 1 diarrhea, nausea, and fatigue). Hematologic toxicity was primarily neutropenia, with six patients (32%) experiencing grade 3 neutropenia. In the first 12 patients, induction chemotherapy was delivered weekly for 4 consecutive weeks, with 2 weeks of rest. Three (25%) of these 12 patients were hospitalized for neutropenic fever during induction therapy, and one patient also experienced grade 3 diarrhea during the hospital stay. The induction therapies of all three patients were shortened to 3 treatment weeks. Two additional patients had shortening of induction therapy to 3 treatment weeks because of neutropenia in one patient and hospitalization for feeding tube placement in a second patient with severe, persistent dysphagia; both of these patients also had therapy delays because of grade 2 diarrhea. Two (17%) of 12 patients required a dose reduction in irinotecan to complete induction chemotherapy. Because the toxicity during induction therapy was observed after a third consecutive week of treatment, the protocol was amended to a 2-week-on, 1-week-off treatment schedule, shifting the rest breaks to week 3 and week 6. Of the seven patients subsequently treated on this modified schedule, none were hospitalized for therapy-related toxicity, and all completed four induction treatments. Two patients experienced grade 3 neutropenia, which led to a 1-week delay in induction therapy, but both patients received all four induction treatments. The day 1, day 8 schedule of induction chemotherapy (2 weeks on, 1 week off) seemed to improve the delivery of induction therapy, although hematologic nadirs were comparable for the two treatment schedules (Table 3).
Toxicity: Chemoradiotherapy The toxicities of combined chemoradiotherapy are listed in Table 4 . Therapy was well tolerated at all dose levels of irinotecan. No grade 3 or grade 4 diarrhea, esophagitis, or stomatitis was observed. Gastrointestinal toxicity was manageable. Ten patients experienced grade 1 to 2 diarrhea, and seven patients experienced grade 1 (six patients) or 2 (one patient) esophagitis. No patients experienced grade 3 or 4 nausea or vomiting. One patient (5%), who was treated at the 50-mg/m2 irinotecan dose level, experienced grade 3 pulmonary toxicity that may have been related to acute radiation pneumonitis. The pneumonitis was reversible, and the patient was ultimately referred for surgical resection after treatment with prednisone. With observation of pulmonary toxicity at the 50-mg/m2 dose level, a total of seven patients were recruited to the 65-mg/m2 dose level, and six patients were recruited to the subsequent 80-mg/m2 dose level. No additional patients developed pulmonary toxicity. With the exception of the patient with pneumonitis, no patient was hospitalized during the administration of chemoradiation for therapy-related toxicity. Hematologic toxicity was also minimal. Nadir values by irinotecan dose level are listed in Table 5. Only four patients (21%) experienced grade 3 neutropenia, and one patient (5%) experienced grade 3 thrombocytopenia.
An unexpected toxicity, which occurred in three (20%) of the first 15 patients treated, was the development of asymptomatic pulmonary emboli on the scheduled posttreatment CT scan of the chest and abdomen obtained 4 to 6 weeks after completion of chemoradiotherapy. All three patients required brief hospitalization for anticoagulation. In only one patient, a coincident deep venous thrombosis was documented. This patient had significant underlying chronic obstructive pulmonary disease and, at eventual surgery, underwent a palliative resection. Disseminated disease developed within 4 months of surgery. A second patient with a pulmonary embolism, the patient with radiation pneumonitis, was on prednisone at the time of the event. This patient ultimately developed metastatic disease 5 months after surgery. The third patient with a pulmonary embolus had a pathologic complete response at surgery, which is ongoing at 19 months. Underlying medical conditions in this patient included adult-onset diabetes and gout. Because of the observation of pulmonary emboli after combined chemoradiotherapy, we adopted the use low-dose warfarin prophylaxis during radiotherapy. Patients were treated with 1 mg of warfarin daily, commencing 3 days before the start of combined chemoradiotherapy and continuing for 4 weeks after completion of radiotherapy. No further thromboembolic events were observed in the four additional patients treated on protocol. DLT, defined as a treatment delay of greater than 2 weeks for toxicity, was observed when irinotecan was escalated to 80 mg/m2. Two of six patients treated at this dose level had a greater than 2-week delay in radiotherapy because of neutropenia, with one patient delayed because of both neutropenia and thrombocytopenia. A third patient had a treatment delay of less than 2 weeks, and this delay did not result in a DLT. Therefore, the recommended phase II dose of irinotecan to combine with weekly cisplatin and radiotherapy was established as 65 mg/m2. Delays in radiotherapy were uncommon until the irinotecan dose level of 80 mg/m2 was evaluated. Only two (15%) of 13 patients treated at the 40-, 50-, or 65-mg/m2 dose levels experienced any delay in radiotherapy during chemotherapy (non–dose-limiting), whereas three (50%) of six patients treated at the 80-mg/m2 dose level experienced a delay in radiotherapy because of hematologic toxicity.
Dysphagia Relief and Response to Therapy
Response to induction chemotherapy was evaluated with barium esophagram before initiation of combined chemoradiotherapy. Complete resolution of the esophageal mass was seen in one patient, and partial radiologic responses were seen in four patients, for an overall major response rate of 26%. The remaining patients had either minor responses (six patients, 32%) or stable disease (eight patients, 42%). No patient had radiographic progression of disease during induction therapy, and all patients were referred to proceed with combined chemoradiotherapy. All 19 patients were assessable for response. Two patients (11%) developed evidence of metastatic disease in abdominal lymph nodes outside of the radiotherapy field, despite evidence of a partial response in the primary tumor noted at endoscopy in one patient. Two patients achieved a clinical complete response (negative posttreatment endoscopy with negative biopsy) and were followed by observation without surgery; one of these responses remains durable at 34+ months after therapy was initiated. Fifteen patients underwent surgical resection. Four (27%) of 15 patients achieved a pathologic complete response (95% confidence interval, 8% to 55%). Fourteen patients had complete resections with negative margins (93% of resected patients), and eleven (73%) had evidence of downstaging at surgery. Clinical or pathologic complete responses were achieved in a total of six (32%) of 19 patients (95% confidence interval, 13% to 55%). Pathologic and clinical complete responses were seen at all the dose levels of irinotecan that were delivered, including two pathologic complete responses in three patients treated at the 40-mg/m2 dose level, two clinical complete responses at the 50- and 65-mg/m2 dose levels, and two pathologic complete responses in six patients treated at the 80-mg/m2 dose level. The median survival of all 19 patients was 25 months (range, 8.6 to 35.2 months). Eight patients (42%) remain alive and free of disease at a median follow-up of 21 months. Four of six patients who achieved clinical or pathologic complete response remain free of disease at a median follow-up of 26.7 months, and four of 10 patients who underwent resection of viable cancer at surgery remain free of disease at a median follow-up of 19.2 months. One patient (5%) died of protracted postsurgical complications 4 months after surgery, and one clinical complete responder died of probable locally recurrent disease, with fatal hematemesis, 2 years after initiation of therapy. Of six patients with documented recurrent disease, three patients experienced recurrence of distant disease only (including one patient with a pathologic complete response who developed brain metastases), and three patients developed their first site of recurrence locoregionally (anastomotic recurrence, n = 1; mediastinal nodal recurrence, n = 2). Surgical complications in the 15 resected patients included anastomotic leak (four patients, 27%), wound infection (three patients, 20%), and postoperative death (one patient, 7%) as a result of protracted postoperative complications (including diaphragmatic wound dehiscence).
The landmark Radiation Therapy Oncology Group Trial 85–01 established combined chemoradiotherapy with FU and cisplatin as the standard of care in the nonoperative management of locally advanced esophageal cancer. However, a survival rate of only 27% at 5 years was achieved on this trial.4 The subsequent use of FU, cisplatin, and radiation as preoperative therapy followed by surgery has been extensively studied in phase II and phase III trials in esophageal cancer. At best, pathologic complete responses are achieved in 20% to 40% of patients, with a 5-year survival rate of 35% or less. Randomized trials comparing the use of preoperative chemoradiotherapy with FU and cisplatin have not clearly indicated a benefit for preoperative treatment compared with surgery alone.2,5 The toxicity of such therapy is substantial, including gastrointestinal and mucosal toxicity. Better-tolerated and potentially more-effective agents need to be evaluated in combination with radiotherapy in esophageal cancer. Furthermore, intensification of the radiation dose from 50.4 Gy to 64.8 Gy in patients receiving FU, cisplatin, and radiation has not improved survival.18 Recent trials in advanced, metastatic esophageal cancer have evaluated newer agents, including paclitaxel and irinotecan, given in combination with cisplatin without FU. Reported response rates for these non–FU-containing regimens are in excess of 40% to 50%.19–21,8 In a previous trial, we reported a 57% response rate for weekly irinotecan and cisplatin in advanced esophageal cancer.8 A high degree of palliation of dysphagia was achieved. The results from this trial prompted us to evaluate, in a phase I trial, the addition of concurrent radiotherapy to weekly irinotecan and cisplatin. The current trial demonstrates that a combination of weekly irinotecan, cisplatin, and concurrent radiotherapy is feasible and well tolerated. Full doses of irinotecan (65 mg/m2) and cisplatin (30 mg/m2) can be combined with concurrent radiotherapy. By using a weekly schedule of a non–FU-containing chemotherapy regimen, hematologic toxicity was tolerable, and gastrointestinal toxicity was relatively minimal. No grade 3 or 4 esophagitis was observed, and only one (5%) of 19 patients required hospitalization for toxicity during combined chemoradiotherapy. The delivery of only four chemotherapy treatments during the 5.5 weeks of radiotherapy resulted in a relative ease of treatment administration. Central venous access was not required because chemotherapy was administered by bolus infusion. The overall complete response rate of 32% and pathologic complete response rate of 27% may be comparable with results obtained with conventional FU, cisplatin, and radiotherapy or with newer chemoradiotherapy regimens that incorporate taxanes with concurrent radiotherapy.22–26 Although some trials using FU, cisplatin, and radiotherapy have reported pathologic complete response rates as high as 51%,27 response rates across phase II and III trials vary significantly, and a direct comparison to the results obtained in the current trial would require a phase III trial. The potential lessening of gastrointestinal toxicity seen in the current trial has also been reported in trials using the weekly administration of taxane-based chemotherapy during radiotherapy.22,23 Induction chemotherapy before combined chemoradiotherapy led to significant relief of dysphagia in the majority of patients. The relief of dysphagia with induction chemotherapy and the relative absence of esophagitis, stomatitis, and diarrhea during combined chemoradiotherapy resulted in the rare need for enteral feeding tube placement (one patient, 5%). The delivery of induction chemotherapy, however, was compromised by our initial choice of 4 sequential weeks of induction chemotherapy. With a change to a 2-week-on, 1-week-off schedule, we were able to deliver all 4 planned weeks of induction chemotherapy. The improved tolerance of this regimen, versus 4 sequential weeks of therapy, was also born out by the relative absence of toxicity using this schedule during concurrent radiotherapy. Trials attempting to intensify the delivery of chemotherapy to combined-modality therapy have generally added additional cycles of adjuvant chemotherapy after the completion of chemoradiotherapy4 or after surgery.3,28 The approach of induction chemotherapy has the advantage of delivering chemotherapy when patients may be best able to tolerate systemic therapy, before the delivery of radiation and before surgery. Other recently reported pilot trials have delivered induction chemotherapy before the start of combined chemoradiotherapy.29,30 The observation in this trial of thromboembolic complications was unexpected. Previous reports of the use of weekly irinotecan and cisplatin in advanced disease have not indicated an increased incidence of thromboembolic complications.8,9 There have been recent reports of a potential increase in fatal thromboembolic complications using irinotecan combination chemotherapy in the treatment of colorectal cancer.31 The original report of irinotecan in combination with bolus FU in advanced colorectal cancer, however, did not indicate an increased incidence of thromboembolic complications.32 The observation of thromboembolic events on the current trial may be fortuitous, or it may be related to the underlying malignancy or to medical comorbidities in the patients affected. The enhanced sensitivity of spiral CT scan imaging may also have increased the potential to detect subclinical pulmonary emboli. The patients who developed thromboemboli during the course of the trial were not experiencing severe dehydration or diarrhea, which might have potentially increased the risk of developing embolic events. The observation of thromboembolic events prompted us to incorporate low-dose warfarin prophylaxis in subsequent patients treated during combined chemoradiotherapy, and no embolic events were noted in patients receiving warfarin prophylaxis. Further evaluation of weekly cisplatin, irinotecan, and radiotherapy is planned as a formal phase II preoperative trial at MSKCC. At the cooperative group level, the Eastern Cooperative Oncology Group is now comparing weekly irinotecan and cisplatin with weekly paclitaxel and cisplatin plus radiotherapy as preoperative treatment in locally advanced esophageal cancer. The regimen of weekly irinotecan, cisplatin and radiotherapy may provide a feasible platform for the addition of other agents. Trials combining chemotherapy with molecularly targeted agents, including selective cyclo-oxygenase 2 inhibitors, monoclonal antibodies against the epidermal growth factor receptor, or agents that inhibit the tyrosine kinase associated with the epidermal growth factor receptor, are planned. A future comparison of irinotecan, cisplatin, and radiation to conventional FU-containing chemoradiotherapy should also be considered.
Supported in part by a grant from Pfizer, New York, NY.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
