290 A Phase II Study of 5-Fluorouracil, Leucovorin, and Interferon-␣ in the Treatment of Patients with Metastatic or Recurrent Gastric Carcinoma An Eastern Cooperative Oncology Group Study (E5292) Gary R. Hudes, M.D.1 Stuart Lipsitz, Sc.D.2 Jean Grem, M.D.3 Mary Morrisey, Sc.D.2 Louis Weiner, M.D.1 John W. Kugler, M.D.4 Al Benson III, M.D.5 1 Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 2 Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts. 3 Medicine Branch, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland. 4 Illinois Oncology Research Association, Peoria, Illinois. 5 Division of Hematology/Oncology, Northwestern University Medical Center, Chicago, Illinois. Presented in part at the 31st Annual Meeting of the American Society of Clinical Oncology, Los Angeles California, May 20 –23, 1995. This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA18281, CA23318, CA21076, CA17145, CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Address for reprints: Gary R. Hudes, M.D., Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Received February 12, 1998; revision received June 2, 1998; accepted June 26, 1998. © 1999 American Cancer Society BACKGROUND. Chemotherapy has a limited impact on adenocarcinoma of the stomach. Although biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) and interferon-␣ (IFN-␣) has improved the outcomes of patients with metastatic colorectal carcinoma compared with 5-FU alone, this approach has not been extensively evaluated in the treatment of advanced gastric carcinoma. METHODS. Twenty-seven patients with bidimensionally measurable, metastatic gastric carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 received the combination of IFN-␣ (5 million U/m2 administered subcutaneously daily on Days 1–7), LV (500 mg/m2 administered intravenously over 30 minutes immediately after IFN-␣ on Days 2– 6), and 5-FU (370 mg/m2 given as an intravenous bolus 60 minutes after LV on Days 2– 6), with treatment repeated every 4 weeks. Oral cryotherapy was administered routinely before each dose of 5-FU to reduce the incidence of severe stomatitis. RESULTS. The median age of the patients was 58 years (range, 20 –76), and 22 patients had residual, unresectable primary lesions. The median number of cycles received was 3 (range, 1–11). Of 24 patients who received at least 2 cycles of treatment, 15 (62.5%) did not require dose reduction for toxicity during the initial 2 cycles. The predominant toxicities were gastrointestinal: diarrhea and stomatitis of Grade 3– 4 occurred in 28.6% and 35.7% of patients, respectively. Other severe (Grade 3– 4) toxicities were granulocytopenia (which occurred in 21.4% of patients) and fatigue (in 10.7%). Fever and flu-like symptoms were common but usually mild. Of 24 patients who were evaluable for response, 3 had partial responses (PR) of 16, 23, and 33 weeks’ duration, respectively, for a response rate of 12.5% (95% confidence interval ⫽ 2.7–32.4%). Two additional patients had reductions in tumor size sufficient for PR, but scans to document the minimum required response duration of 4 weeks were not obtained before progressive disease occurred. The median progression-free and overall survivals were 2.5 and 7.8 months, respectively. CONCLUSIONS. Although this regimen can be administered safely with appropriate supportive care to patients with good performance status, it has limited therapeutic activity in patients with advanced gastric carcinoma. Cancer 1999;85:290 – 4. © 1999 American Cancer Society. KEYWORDS: gastric carcinoma, 5-fluorouracil, interferon, chemotherapy. A lthough declining in incidence, adenocarcinoma of the stomach remains a significant cause of cancer death in the U. S. and the second leading cause of cancer death worldwide. Approximately 50% of patients with this malignancy present with tumors that are locally 5-FU, LV, and IFN-␣ in Gastric Carcinoma/Hudes et al. advanced or metastatic, considered beyond the hope of curative surgical resection. The impact of systemic chemotherapy in adenocarcinoma of the stomach has been minimal, with median survival unaffected by currently available agents and combinations.1 There is a great need to identify more active agents and combinations for the treatment of patients with metastatic disease, and for those patients with resectable tumors who could benefit from effective adjuvant therapy to decrease the risk of tumor recurrence. When administered as a single agent, 5-fluorouracil (5-FU) has generated objective regressions in approximately 20% of patients with advanced gastric carcinoma.2 The biochemical modulation of 5-FU by leucovorin (LV) and interferon-␣ (IFN-␣) has been associated with improved response rates in patients with metastatic colorectal carcinoma.3,4 The activity of the 5-FU and LV and 5-FU and IFN-␣ regimens prompted investigation of a three-drug regimen of 5-FU, LV, and IFN-␣ as described by Grem et al.5 The combination of 5-FU, LV, and IFN-␣ produced a 54% partial response rate in a Phase II trial involving 44 patients with colorectal carcinoma.6 Biochemical modulation of 5-FU has been evaluated less extensively in gastric carcinoma. Based on the promising results reported in colorectal carcinoma, a Phase II trial of 5-FU, LV, and IFN-␣ in patients with adenocarcinoma of the stomach was initiated by the Eastern Cooperative Oncology Group (ECOG). The objectives of this trial were: 1) to determine the response rate, time to progression, and survival in patients with advanced gastric carcinoma treated with recombinant IFN-␣-2b given on Days 1–7 in combination with bolus 5-FU/LV given on Days 2– 6; 2) to evaluate all toxicities of the combination of 5-FU, LV, and IFN␣-2b in this patient population; and 3) to determine the dose intensity of 5-FU given with LV and IFN-␣-2b on this schedule in a homogenous patient population with no prior chemotherapy for metastatic or recurrent disease. PATIENTS AND METHODS Between November 1992 and September 1993, 28 patients from 17 ECOG institutions were enrolled on this Phase II trial. Eligibility for the trial required histologically proven advanced or metastatic adenocarcinoma of stomach (excluding patients with tumors of the distal esophagus or gastroesophageal junction) considered beyond the hope of cure by surgical resection; at least 1 metastatic site measurable in 2 dimensions; no prior chemotherapy for metastatic disease and at least 1 year between the completion of adjuvant chemotherapy and protocol entry; an ECOG performance status of 0 or 1; adequate caloric intake and estimated 291 life expectancy of at least 3 months; a leukocyte count ⱖ 4000/L or granulocyte count ⱖ 2000/L, platelets ⱖ 100,000/L, serum creatinine ⱕ 2.0 mg/dL, total bilirubin ⱕ 2.0 mg/dL, and aspartate aminotransferase (AST) ⱕ 4 times the upper limit of normal. Written informed consent was obtained from each patient according to institutional and federal guidelines. Patients had the following evaluations before treatment: history and physical examination, weight, ECOG performance status, complete blood count, serum creatinine, alkaline phosphatase, AST, total bilirubin, chest radiograph, and computed tomography (CT) scans or other imaging studies as needed for disease measurement. Premenopausal females were required to have a negative serum pregnancy test. Patients and caregivers were instructed on subcutaneous injection technique prior to beginning treatment. Weight, performance status, and complete blood counts were repeated weekly during protocol therapy. Creatinine and other chemistries were repeated prior to each subsequent course (every 4 weeks), and CT scans and other studies for assessment of response were obtained every 2 courses. Treatment was comprised of recombinant IFN␣-2b (Intron-A; Schering, Kenilworth, NJ) administered subcutaneously at a dosage of 5 ⫻ 106 U/m2 daily on Days 1–7 of each 4-week cycle. Patients or family members were instructed on the administration technique to permit home administration of the IFN-␣ on Days 1 and 7. On Days 2– 6, patients received calcium LV at a dosage of 500 mg/m2 by intravenous infusion over 30 minutes immediately after IFN-␣. 5-FU was given at a dosage of 370 mg/m2 by bolus injection 60 minutes after completion of each LV infusion on Days 2– 6. The treatment was repeated every 28 days provided toxicity had resolved. In view of the potential for severe gastrointestinal toxicity from the treatment, the following supportive care measures were required: 1) patients were educated regarding the need for prompt notification of the treating physician if mouth pain and/or diarrhea occurred; 2) prophylaxis against stomatitis included oral cryotherapy7 with each dose of 5-FU, sodium bicarbonate mouth rinses, and oral antimicrobial rinses with chlorhexidine; 3) for Grade 1–2 diarrhea, early intervention was comprised of antidiarrheal medication, instructing patients to increase fluid intake, and treatment of stomatitis, if present, to permit continued oral intake. Toxicity was graded according to the common toxicity criteria (Cancer Therapy Evaluation Program [CTEP]) and response was assessed by ECOG solid tumor response criteria.8 Treatment was modified for toxicity according to the following. Subsequent 292 CANCER January 15, 1999 / Volume 85 / Number 2 courses of treatment were delayed up to 3 weeks for Day 1 absolute granulocyte count (AGC) ⬍ 1500/L or platelet count ⬍ 80,000/L. For nadir blood counts, the dose of 5-FU was reduced by 25% for AGC ⬍ 500/L or platelet count ⬍ 25,000/L. For any grade of diarrhea or the appearance of ⱖ Grade 2 stomatitis (oral ulceration) during the 5 days of therapy administration, treatment was discontinued for that cycle. In addition, the dose of 5-FU was reduced by 25% for diarrhea or mucositis of Grade 3 or 4 occurring at any time. A 25% reduction of IFN-␣ was permitted for intolerable constitutional symptoms such as fatigue, malaise, arthralgia, myalgia, or anorexia. Study Design and Statistical Considerations The primary endpoint was tumor response. A twostage design was utilized so that the trial could be stopped early if the treatment did not produce a response rate consistent with known combinations of 5-FU. The response rate of interest was 40%. If there were ⱕ 4 responses (complete or partial responses) among the initial 20 evaluable patients, then the treatment would be considered not sufficiently promising. If ⱖ 5 responses were observed among the initial 20 eligible patients, an additional 22 patients could be accrued. The probability that the trial would be stopped early (i.e., ⱕ 4 responses in the first 20 eligible patients) was approximately 0.051 if the true response rate was at least 40%. If the trial continued to 40 patients and at least 13 responses were observed, then the treatment would be considered promising and the 90% confidence interval (95% CI) for the true response rate would be 20 – 47%. RESULTS The study was opened in November of 1992 and was closed in August 1993, having met and exceeded the first stage accrual of patients. The study was terminated due to an insufficient number of responses in the first stage. Patient characteristics are summarized in Table 1. A total of 28 patients were registered, 24 of whom were eligible and evaluable for toxicity and response. Four patients were not evaluable for the following reasons: 2 patients had primary gastroesophageal junction tumors and were ineligible, 1 patient lacked measurable disease, and 1 patient withdrew from the protocol after only 1 day of treatment. All 28 patients were evaluable for toxicity. A total of 102 cycles of therapy were administered, with a median of 3 cycles per patient (range, 1–11). Fifteen patients (62.5%) received TABLE 1 Patient Characteristics No. (%) Total registered Total eligible Evaluable for response Evaluable for toxicity ECOG performance status 0 1 Male/female Median age (yrs) (range) Prior therapy Gastrectomy Radiotherapy Chemotherapy Sites of measurable disease Lymph nodes Liver Lung Other soft tissue Median no. of cycles (range) 28 25 24 28 9 15 17/7 58 (20–76) 6 0 0 13 10 2 6 3 (1–11) ECOG: Eastern Cooperative Oncology Group. the full planned dose intensity of all drugs during the initial 2 cycles. Of the 24 patients evaluable for response, 3 had partial responses lasting 16, 23, and 33 weeks, respectively, for a response rate of 12.5% (95% CI, 2.7–32.4%). The sites of response were the liver in two patients and the lymph nodes in one patient. Two additional patients had ⱖ 50% decrease in tumor size after 2 cycles of treatment, but could not be considered partial responders by the protocol criteria because repeat CT scans were not performed to document a response duration of at least 4 weeks. One of these patients had a 50% reduction in retroperitoneal lymph nodes and experienced Grade 2 nausea, emesis, diarrhea, and stomatitis. This patient refused further treatment and presented 1 year later for terminal care. The second patient had an 80% reduction in liver metastases and retroperitoneal adenopathy, but developed progressive disease in the liver 2 months later. A CT scan to confirm a response duration of at least 4 weeks was not obtained. The remaining 19 patients had disease progression at a median of 2.5 months from protocol entry. The median survival of all registered patients was 7.7 months. Toxicity is summarized in Table 2. The principal toxicities were granulocytopenia, stomatitis, and diarrhea. Grade 3 or 4 granulocytopenia occurred in 7 patients (25%). Documented sepsis or other infection occurred in four patients. Thrombocytopenia and anemia were mild. Despite oral cryotherapy in all but 5-FU, LV, and IFN-␣ in Gastric Carcinoma/Hudes et al. TABLE 2 Toxicity (Worst Grade) (N ⴝ 28) Granulocytopenia Thrombocytopenia Anemia Fever Nausea Emesis Diarrhea Stomatitis Weight loss Fatigue Flu-like reaction Alopecia 0 1 2 3 4 Grade 3/4 15 18 8 10 9 10 6 9 11 18 14 18 2 8 11 12 8 10 6 4 7 2 8 8 4 1 7 4 9 7 8 4 9 5 6 2 3 1 1 2 2 1 5 8 1 3 — — 4 — 1 — — — 3 3 — — — — (25) (3.6) (7.1) (7.1) (7.1) (3.6) (28.6) (39.3) (3.6) (10.7) — — 5 of the patients, 10 patients (35.7%) experienced Grade 3 or 4 stomatitis during treatment, most commonly during Cycles 1 or 2. There was no correlation between oral cryotherapy and the severity of stomatitis. Grade 3 or 4 diarrhea occurred in eight patients. Grade 2 or 3 fatigue occurred in five and three patients, respectively. Flu-like symptoms resulting from administration of IFN-␣ were common but usually mild. There was one episode of Grade 4 dermatologic toxicity comprised of scrotal erythema and sloughing. Toxicity prompted reduction of the 5-FU dose for the first or second treatment cycle in seven patients. The dose of IFN-␣ was reduced by 25% for 2 patients. Only 2 patients required a delay in treatment for the first 2 cycles, both for 1 week, to allow recovery from toxicity. schedule described in this Phase II trial does not merit further study in patients with gastric carcinoma. These results differ from those of Jäger et al., who observed 10 complete responses and 20 partial responses for a total of 30 objective responses in 72 patients (42%; 95% CI, 28 –57%) utilizing 5-FU, 500 mg/m2, bolus together with LV, 500 mg/m2, over 2 hours and IFN-␣ 6 ⫻ 106 U subcutaneously, with all agents given once a week.14 These authors reported that the median time to progression and survival were 6 and 9 months, respectively. It is interesting to note that the myelotoxicity and gastrointestinal toxicity reported by Jäger et al. appeared to be less than those observed in the current study. The reason for the different levels of activity in the current study and that of Jäger et al. is not clear. Although the schedules differed significantly, the dose intensities of 5-FU and IFN-␣ per 4-week cycle were similar in the 2 studies. With appropriate supportive care, the combination of 5-FU and LV daily for 5 days and IFN-␣ daily for 7 days can be administered safely to patients with advanced gastric carcinoma and a good ECOG performance status. However, this combination has limited activity and cannot be recommended as conventional therapy for this tumor. The results of this trial do not suggest that the combination is likely to offer more benefit than the combination of 5-FU and LV. REFERENCES 1. 2. DISCUSSION Effective treatment for metastatic gastric carcinoma has been elusive. Combination therapies that employ two or more of the known active agents have failed to extend the median survival of patients with this tumor. In contrast to colorectal carcinoma, there has been little evidence that biochemical modulation of 5-FU by LV or IFN-␣ improves on the estimated 20% response rate and 5– 6-month median survival of single agent 5-FU in patients with advanced/metastatic gastric carcinoma. 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