Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741.
BACKGROUND
Intergroup Trial N9741 evaluated 5-fluorouracil (5-FU)/leucovorin (LV) administered in conjunction with either irinotecan or oxaliplatin in the first-line treatment of advanced colorectal carcinoma (CRC). The current report describes two treatment arms that were withdrawn from the protocol due to unexpected treatment-related toxicities and a high mortality rate. The complications observed in these arms highlight the importance of aggressive and immediate supportive care in the management of digestive toxicity.


METHODS
In Trial N9741, patients were randomly assigned to receive one of the following six regimens: 1) irinotecan plus bolus 5-FU/LV (Arm A); 2) sequential irinotecan plus bolus 5-FU/LV (Arm B); 3) bolus 5-FU/LV only (Mayo Clinic regimen; Arm D); 4) oxaliplatin plus bolus 5-FU/LV (Arm E); 5) oxaliplatin plus infusional 5-FU/LV (Arm F); or 6) oxaliplatin plus irinotecan (Arm G). In the current study, the authors investigated treatment-related toxicity in patients who received either of the two combination regimens containing daily bolus 5-FU (i.e., patients in Arm B or Arm E).


RESULTS
Sixty-one and 47 patients were enrolled in Arm B and Arm E, respectively. Diarrhea and neutropenia were the most common toxicities in both groups. Five patients in Arm B (8.2%) and 4 patients in Arm E (8.5%) died within 60 days of study entry. All fatal toxicities occurred within 15 days of treatment administration, and all deaths were associated with the simultaneous occurrence of multiple symptoms, which were dominated by Grade > or = 3 diarrhea.


CONCLUSIONS
Combination regimens containing daily bolus 5-FU/LV and oxaliplatin or irinotecan can be associated with severe gastrointestinal toxicity and high mortality rates. Therefore, the authors recommend the use of more tolerable infusional 5-FU-based regimens in the treatment of metastatic CRC.
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Thierry
T
Delaunoit
Richard M
RM
Goldberg
Daniel J
DJ
Sargent
Roscoe F
RF
Morton
Charles S
CS
Fuchs
Brian P
BP
Findlay
Sachdev P
SP
Thomas
Muhammad
M
Salim
Paul L
PL
Schaefer
Philip J
PJ
Stella
Erin
E
Green
James A
JA
Mailliard
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D016032:Randomized Controlled Trials as Topic
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin