A phase II study of weekly methotrexate, cisplatin, and 24-hour infusion of high-dose 5-fluorouracil and leucovorin (MP-HDFL) in patients with metastatic and recurrent esophageal cancer-improving toxicity profile by infusional schedule and double biochemical modulation of 5-fluorouracil.
BACKGROUND
Patients with advanced esophageal cancer are frequently not indicated for intensive chemotherapy due to aero-digestive tract complications. In order to improve the therapeutic index of systemic chemotherapy for these patients, we designed a weekly MP-HDFL protocol, which took advantage of the low toxicity of the infusional dosing schedule for cisplatin and 5-fluorouracil (5-FU), and double biochemical modulation of 5-FU by methotrexate and leucovorin.


METHODS
Between April 1997 and April 2001, a total of 26 patients (M:F = 22:4) with a median age of 59.5 (range: 43-81) years were enrolled into this phase II clinical trial prospectively. There were 12 patients with de novo metastatic disease, 13 with recurrent disease (including 7 relapsed from previous concurrent chemoradiotherapy incorporating cisplatin and 5-FU), and one with locally advanced disease. The weekly MP-HDFL protocol was composed of methotrexate 40 mg/m2, i.v., on days 1, 8, 15; cisplatin 35 mg/m2, 24-hour IVF, on days 2, 9, 16; and 5-FU 2,600 mg/m2 and leucovorin 300 mg/m2, 24-hour IVF, on days 2, 9, 16; repeated every 28 days.


RESULTS
A total of 97 courses were given with an average of 3.7 courses per patient (range: 1-19). All of the patients were assessable for evaluation of toxicity. Grades 3/4 leukopenia and thrombocytopenia were noted in 13 (14%) and 17 (18%) of the treatment courses, respectively. There were 3 episodes of febrile neutropenia in 2 patients, and lethal sepsis in one patient. The Grades 3/4 non-hematological toxicities were infrequent. Among 25 patients with recurrent or metastatic disease, 7 had partial response and 12 had stable disease. The response rate for the intent- to treat group was 28% (95% C.I.:12%-49%). The median survival was 5 months (range: 1-28 months).


CONCLUSIONS
Weekly MP-HDFL combination chemotherapy is associated with mild and acceptable toxicity, and has modest palliative activity in a portion of advanced esophageal cancer patients. However, a more active and better tolerated anticancer drug combination is needed to improve the outcome of these patients.
Hsu
Chih-Hung
CH
Department of Oncology, National Taiwan University Hospital, Cancer Research Center, National Taiwan University College of Medicine, Taiwan.
Cheng
Ann-Lii
AL
Hsu
Chiun
C
Yang
Chih-Hsin
CH
Lu
Yen-Shen
YS
Lin
Chia-Chi
CC
Bu
Ching-Fang
CF
Yeh
Kun-Huei
KH
D000230:Adenocarcinoma / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011446:Prospective Studies
D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate