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© 2002 American Society for Clinical Oncology Prospective Randomized Trial Comparing Mitomycin, Cisplatin, and Protracted Venous-Infusion Fluorouracil (PVI 5-FU) With Epirubicin, Cisplatin, and PVI 5-FU in Advanced Esophagogastric CancerByFrom the Department of Medicine and Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, Surrey; Aberdeen Royal Infirmary, Aberdeen; Christie Hospital, Manchester; Cookridge Hospital, Leeds; Guy’s Hospital, and St George’s Hospital, London; Wythenshaw Hospital, Manchester; Salisbury District Hospital, Salisbury; and Royal Bournemouth and Poole Hospitals, Dorset, United Kingdom. Address reprint to requests to D. Cunningham, MD, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, United Kingdom, SM2 5PT; email: david.cunningham{at}icr.ac.uk
PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m2 every 3 weeks, cisplatin 60 mg/m2 every 3 weeks and PVI 5-FU 200 mg/m2/d) or MCF (mitomycin 7 mg/m2 every 6 weeks, cisplatin 60 mg/m2 every 3 weeks, and PVI 5-FU 300 mg/m2/d) and analyzed for survival, response, toxicity, and quality of life (QOL). RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P = .692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P = .315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.
GLOBALLY, OESOPHAGOGASTRIC cancer is the second most common cancer after lung cancer and one of the most frequent causes of cancer death.1 In most countries, the incidence of gastric cancer has declined because of a decrease in tumors of the gastric body and antrum, whereas the incidence of adenocarcinomas of the esophagogastric junction and cardia have been increasing. The majority of patients have locally inoperable or metastatic disease at presentation, with only 20% to 30% of patients being suitable for curative surgery. Consequently, the prognosis for patients is poor, with a 5-year survival of 10% to 15% from diagnosis. In advanced disease, chemotherapy has resulted in survival and quality of life (QOL) benefits compared with supportive care alone in four randomized studies.2-5 The epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) regimen was developed in the Gastrointestinal unit of the Royal Marsden Hospital.6 The choice of drugs in the regimen was based on their single-agent activity in upper gastrointestinal cancer7-10 and on the synergy between 5-FU and cisplatin.11 An anthracycline was included because of anticipated enhanced cytotoxicity in combination with the other two drugs, and epirubicin was chosen instead of doxorubicin because of its lower toxicity.12 Evidence for this enhanced cytotoxicity was provided by a randomized trial in advanced gastric cancer demonstrating a survival benefit from the addition of epirubicin to a combination of bolus 5-FU and cisplatin.13 Encouraging results were observed with the ECF regimen in phase II studies, with response rates ranging from 55% to 67%.14-18 A prospective multicenter randomized trial comparing ECF to 5-FU, doxorubicin, and methotrexate (FAMTX) in advanced esophagogastric cancer demonstrated superior response rates, failure-free and overall survival, and better QOL with ECF compared with FAMTX.19 However, epirubicin is known to cause alopecia, mucositis, and myelosuppression. In addition, because both epirubicin and 5-FU can cause stomatitis, the dose of PVI 5-FU used in ECF was restricted to 200 mg/m2/d compared with 300 mg/m2/d as a single agent or in combination with cisplatin. In vitro, the combination of 5-FU and mitomycin produce synergistic inhibition of growth of lymphoma and sarcoma cell lines.20 In human colon cancer cell lines, the combination has additive effects when mitomycin is given before a 5-day continuous infusion of 5-FU.21 In advanced colorectal cancer, we reported significantly better response rates and progression-free survival with the combination of PVI 5-FU and bolus mitomycin compared with single-agent PVI 5-FU.22 Mitomycin is only mildly myelosuppressive and is not associated with stomatitis. Consequently, we modified the ECF regimen by substituting epirubicin with mitomycin, continuing with the same dose of cisplatin, and increasing the dose of PVI 5-FU (MCF). We report the results of a multicenter randomized study comparing MCF with ECF chemotherapy in advanced esophagogastric cancer using survival, failure-free survival, response, QOL, and toxicity as the study’s end points.
Patient Eligibility Patients were required to have histologically confirmed inoperable adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma of the esophagus, esophagogastric junction (OGJ), or stomach. Tumors of the lower esophagus were classified as esophageal when more than 50% extended into the esophagus, whereas tumors with more than 50% of their extent in the stomach were classified as OGJ carcinomas. The primary tumor was classified as inoperable on the basis of either the findings at laparotomy or computed tomography (CT) scan and endoscopic results. Patients were required to have adequate bone marrow (platelets > 100 x 109/L, WBC count > 3 x 109/L), renal (glomerular filtration rate  60 mL/min and serum creatinine within the normal range), and hepatic (bilirubin < 30 mol/L) function, Eastern Cooperative Oncology Group performance status of 0 to 2, life expectancy of at least 3 months, and no concurrent uncontrolled medical illness. If there was suspicion of left ventricular dysfunction, then a multigated cardiac scan was performed. If the left ventricular ejection fraction was less than 50%, then patients were excluded from the trial. Pregnant or lactating women were excluded, and patients were advised to take adequate precautions to prevent pregnancy. Participants gave written informed consent before entering the study, which was approved by Scientific and Research Ethics Committees of the participating institutions.
Chemotherapy
ECF Regimen
MCF Regimen
Evaluation of Toxicity and Dose Adjustments
Evaluation of Response
QOL
Statistical Methods A stratified (by center) randomization list was generated independently by the Clinical Trials Office, Institute of Cancer Research, using random permuted blocks. Randomization was allocated by telephone. Data analysis was performed after the completion of randomization.
Categorical data such as tumor response rates and toxicity analysis of grade 3 to 4 versus 0 to 2 were compared using the
The hazard ratio (HR) from the Cox model was then used to assess superiority of MCF over ECF in the study. In this relative risk model, the HR for the standard arm (ECF) is taken to be 1 and the range of equivalence of the HR can be expressed as the range QOL raw scores were linearly transformed into functional and symptom scales using the EORTC’s standard method. The change from baseline was compared for the two treatment arms using the nonparametric Mann-Whitney test.
Five hundred eighty patients (290 in each arm) were randomized from 13 oncology centers in the United Kingdom between July 1995 and August 1998. Six patients (three ECF and three MCF) were ineligible because of inadequate renal function (n = 3), abnormal ECG (n = 1), and nonesophagogastric primary cancer (n = 2; one breast and one uterus). Therefore, 574 patients (289 ECF and 285 MCF) were eligible for analysis on an intent-to-treat basis (Fig 1). The two groups were well matched for pretreatment characteristics (Table 1) except for locally advanced disease, which was present in 46% in the ECF arm compared with 37% in the MCF arm (P = .03). This imbalance was corrected in the multivariate analysis.
Response Treatment data were available for 560 patients on September 11, 2000. Ten patients were nonassessable for response by CT scan and/or endoscopy. Consequently, 550 patients (278 ECF and 272 MCF) were included in the response analysis (Table 2).
Objective responses were observed in 118 patients (30 complete responses [CR] and 88 partial responses [PR]) treated with ECF for a response rate of 42.4% (95% CI, 37% to 48%), and 120 patients (22 CR and 98 PR) treated with MCF demonstrated objective responses for a response rate of 44.1% (95% CI, 38% to 50%) (Table 2). There was no statistically significant difference in response rates (P = .692). The corresponding rates of progressive disease were 21% with ECF and 17% with MCF. A further 11 patients (seven ECF and four MCF) died before an initial response assessment. Two hundred thirty-three patients with locally advanced disease (131 ECF and 102 MCF, P = .03) participated in the study. Three patients (two ECF and one MCF) were nonassessable for response with 230 assessable (129 ECF and 101 MCF). The response rate for locally advanced disease was 49.6% (95% CI, 41% to 58%) (23 CR and 41 PR) with ECF and 55.4% (95% CI, 46% to 65%) (13 CR and 43 PR) with MCF (P = .379). Fifteen patients with locally advanced disease treated with ECF went on to surgery (10 complete resections, one palliative esophagectomy, and four laparotomy only because of inoperable disease). After MCF, 15 patients were considered for curative surgery (14 complete resections, one laparotomy alone). Two resection specimens demonstrated a pathologic complete response (one ECF and one MCF), but all other specimens demonstrated residual carcinoma. Response according to the site of the primary tumor is listed in Table 3. There were no significant differences in response rate according to site of primary cancer between the two treatment arms. The response rate was significantly higher among patients with cancer of the OGJ (48.0%) compared with patients with gastric cancer (37.0%; P = .041). However, there was no significant difference in response rate between cancers of the esophagus (43.4%) and OGJ (P = .416), nor between esophageal and gastric cancer (P = .18). Furthermore, there was no significant difference for response rate by disease site between the two treatment arms (Table 4). Symptom response rates were high with no significant differences between the two treatment arms (Table 5).
Toxicity The median number of cycles was six (range, one to eight cycles) with ECF and five (range, one to 10 cycles) with MCF chemotherapy. Treatment delays occurred in 50% of patients treated with ECF compared with 58% of patients treated with MCF (P = .048). Total 5-FU dose was significantly higher with MCF (32,760 mg) than with ECF (23,016 mg) (P < .00001). The dose-intensity of 5-FU was also greater with MCF (195.7 mg/m2/d) compared with ECF (137.7 mg/m2/d). Cisplatin and epirubicin were reduced in 30% and 26% of patients, respectively, treated with ECF. For patients treated with MCF cisplatin was reduced in 37% and mitomycin in 28% of patients. The treatment was well tolerated, and toxicity is listed in Table 6. There was significantly more CTC grades 3/4 neutropenia with ECF (P = .03) whereas thrombocytopenia (P < .00001) and plantar-palmar erythema (P = .002) were more frequent with MCF. ECF resulted in more CTC grade 2 alopecia (P < .0001). Eight patients treated with MCF developed red cell fragmentation compared with none treated with ECF. One patient treated with MCF developed hemolytic uremic syndrome. There were two toxic deaths (one ECF and one MCF), one caused by neutropenic sepsis, the other caused by neutropenia and an associated chest infection.
The incidence of complications from central venous catheters was similar in the two treatment arms. The most frequent complications were exit site infection (16%), pain (11%), and thrombosis (7%). Other complications included blocked lines (5%), lines falling out (3.3%), pneumothorax (1.9%), and septicaemia (1.4%). Prospectively collected data for complications of central venous lines requiring removal were available for Royal Marsden Hospital (22 of 185 patients; 11.9%); complications were thrombosis (n = 6), infection (n = 11), pain (n = 4), and end of line broken (n = 1).
Survival
Median failure-free survival was 7 months with both ECF and MCF (P = .572) (Fig 3). The multivariate analysis of failure-free survival produced similar results to the survival analysis, with MCF having a HR of 1.073 (95% CI, 0.891 to 1.292; P = .457) compared with ECF after accounting for advanced disease (HR = 1.319; 95% CI, 1.088 to 1.598), low albumen (HR = 0.969; 95% CI, 0.955 to 0.984), low sodium (HR = 0.969; 95% CI, 0.953 to 0.984), and high bilirubin (HR = 1.015; 95% CI, 1.002 to 1.028). Again performance status did not significantly influence the final model (P = .092).
For patients with locally advanced disease, median survival was 11.8 months with ECF and 12.6 months with MCF (P = .406). One-year and 2-year survivals were 47.7% (95% CI, 38% to 56%) and 16.3% (95% CI, 10% to 24.3%) with ECF and 50.4% (95% CI, 40% to 60%) and 21.2% (95% CI, 13% to 31%) with MCF patients, respectively. Forty-nine patients have survived for 2 or more years (range, 24.4 to 49.7 months) from randomization (21 [7.3%] ECF and 28 [9.8%] MCF; P = .632). Eleven patients in the ECF arm and 13 in the MCF arm had locally advanced disease. Potentially curative surgery was performed in 10 of these patients after chemotherapy (three ECF and seven MCF patients). Twenty-eight patients remain alive (26.9 to 49.7 months from randomization), of whom 22 are also progression-free (10 ECF and 12 MCF).
QOL
The results of this, the largest reported, multicenter, randomized, trial in advanced esophagogastric cancer confirmed the median survival for patients treated with ECF observed in the randomized comparison with FAMTX.19,33 In addition, this trial confirmed the response rates achieved with ECF; interestingly higher response rates were observed among tumors of the OGJ compared with gastric carcinomas. Many regimens have demonstrated high response rates in phase II studies, but subsequently, no survival benefit is observed in randomized studies. The combination of 5-FU, doxorubicin, and mitomycin (FAM) was initially associated with a response rate in excess of 40%.34 In comparison, FAMTX resulted in response rates of 30% to 60% in phase II studies.35,36 A randomized comparison of FAM with FAMTX conducted by the EORTC demonstrated an improvement from 29 weeks to 42 weeks with FAMTX.37 The combination of etoposide, doxorubicin, and cisplatin (EAP) was associated with a response rate of 64% in an early phase II trial.38 However, a subsequent randomized comparison with FAMTX revealed greater toxicity with EAP without any survival advantage.39 In the randomized comparison of FAMTX with ECF, response rates of 21% were obtained with FAMTX.19 In addition, survival with FAMTX was shorter than previously reported at 6.1 months.33 The EORTC have recently reported a randomized study in which 399 patients with advanced gastric cancer were randomized to either FAMTX or etoposide, folinic acid, and 5-FU (ELF) or 5-FU and cisplatin (FUP).40 Response rates of 12%, 9%, and 20% were reported for FAMTX, ELF, and FUP, with median survival times of 6.7 months, 7.2 months, and 7.2 months, respectively. In the randomized comparison of ECF with FAMTX, the median survival was 8.7 months for patients treated with ECF. In the current study median survival with ECF is similar (9.4 months). Furthermore, response rates with ECF were similar in the two studies, 45% and 42% respectively. Consequently, this second randomized trial has confirmed the efficacy of ECF for the treatment of advanced esophagogastric cancer. This study was initiated as it was anticipated that a further incremental improvement in survival may be achieved with MCF consequent on the increased dose of 5-FU compared with ECF. The trial design did not include stratification for patients with locally advanced or metastatic disease. During the analysis to account for the imbalance in patients with locally advanced disease, multivariate analysis was performed. Despite a significantly higher total dose delivered and increased dose-intensity of 5-FU with MCF both Kaplan-Meier and multivariate analyses demonstrate nonsuperiority of MCF. Symptom response rates were high and similar with ECF and MCF. Both regimens were well tolerated, with acceptable rates of CTC grade 3/4 nonhematologic toxicity. MCF resulted in more plantar-palmar erythema because of the higher dose of 5-FU. The presence of the anthracycline in ECF resulted in significantly more grade 2 alopecia. ECF and MCF result in lethargy relatively frequently with CTC grade 3/4 lethargy observed in 18% and 15% of patients, respectively. Both regimens result in considerable rates of hematologic toxicity. MCF resulted in more leucopenia (all grades) and thrombocytopenia (all grades and grades 3/4) as a result of the presence of mitomycin. In addition, there was significantly more anemia with MCF using the P for trend test. In contrast, ECF resulted in significantly more CTC grade 3/4 neutropenia but without any increase in the incidence of fever or infection. Only two thirds of the study population completed a QOL questionnaire before treatment. In addition, there were high rates of attrition after 3 and 6 months on treatment. Consequently, caution is required in interpreting the findings of the small samples available for QOL studies. Nonetheless, studies indicate that global QOL scores were maintained during chemotherapy with ECF and were better than those for MCF after both 3 and 6 months treatment. The maintenance of global QOL during treatment with ECF is consistent with the observations of Webb.19 In addition, the current study suggests physical, emotional, and cognitive functioning were superior during treatment with ECF compared with MCF. In contrast, fatigue was more common amongst patients treated with MCF. It is hypothesized that the inferior QOL with MCF was because of the increased incidence of leucopenia, anemia, and plantar-palmar erythema. This study is the first to demonstrate a significantly higher response rate among patients with OGJ cancer than patients with gastric cancer. The reasons for this are not clear, but it is consistent with the concept that OGJ carcinoma has a different etiology and natural history from gastric cancer. Furthermore, the observation is of significance given the rising incidence of cancer of the OGJ and declining incidence in cancers of the body of the stomach. This study confirms that the ECF regimen should be regarded as a reference treatment in advanced esophagogastric cancer. It can be offered to all patients with good performance status (Eastern Cooperative Oncology Group 0 to 2) based on the evidence of survival data from two large randomized studies. The regimen forms the standard arm of our current randomized trial.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, with Fishers exact test used where appropriate. The 
-R to 
)% confidence interval (95% CI) for the study have would have to be greater than 
