Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial

Abstract

Background. Cancer is most common in older age groups, but little information is available with regard to the impact of age on chemotherapy toxicity. This study was undertaken to determine if age is an independent risk factor for 5‐fluorouracil (5‐FU) toxicity. Methods. Toxicity data from a prospective, randomized, multiinstitution trial of 5‐FU‐based treatment for advanced colorectal cancer were analyzed. Toxicity for each organ system was graded. Individual organ toxicity proportions were compared using chi‐square analysis. A logistic regression was performed using age (younger than 70 years vs. 70 years or older), sex, treatment arm, performance status, and length of therapy as model parameters to predict severe toxicity. Toxicity in 331 patients was analyzed. Results. Advanced age was significantly associated with the occurrence of any severe toxicity (58 vs. 36%, P < 0.001), leukopenia (24 vs. 10%, P < 0.005), diarrhea (24 vs. 14%, P = 0.01), vomiting (15 vs. 5%, P = 0.01), severe toxicity in more than 2 organ systems (10 vs. 3%, P = 0.02), and treatment mortality (9 vs. 2%, P = 0.01). By univariate analysis, age (P < 0.001) and sex (P < 0.0001) were independent predictors of severe toxicity. Twenty‐two of 27 women age 70 years or older had severe toxicity. Conclusions. Age 70 years or older and sex are risk factors for severe toxicity from 5‐FU‐based chemotherapy. Advanced age does not contraindicate the use of this type of chemotherapy, but close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are required. Dosing decisions in older patients are difficult and must integrate assessments of organ function, comorbidities, overall physical status, and goals of treatment, in an effort to ensure the best possible outcome for these patients.

Side effects during chemotherapy predict tumour response in advanced colorectal cancer

“…The current analysis also shows no difference between sexes in objective response rate or survival. The same is true for various otherwise rather divergent data about age and toxicity (Stein et al, 1995;Cascinu et al, 1996;Chiara et al, 1998;Popescu et al, 1999). Response and survival were not affected in these studies as they were in the current study, regardless of a difference in tolerance of 5-FU-based therapy between younger and older patients.…”

“…Apart from another small patient series with rectal cancer undergoing preoperative radiochemotherapy (Dahl et al, 1994), to our knowledge, no other conclusive data are available about treatment tolerance as a potential prognostic marker for response despite the fact that in 480% of all patients receiving chemotherapy some kind of side effects (of course largely depending on which chemotherapy regimen is administered) will occur. Apart from use of inappropriate drug dosages in patients with impaired renal or hepatic function, presence of well-defined anticancer drug-specific risk factors such as DPD deficiency in case of FU-based chemotherapy (Diasio et al, 1988(Diasio et al, , 1998Johnson et al, 1999;Milano et al, 1999), and to some extend gender (Stein et al, 1995;Sloan et al, 2002) and age 465 (Stein et al, 1995;Cascinu et al, 1996;Chiara et al, 1998;Popescu et al, 1999), the reason/mechanism is still unclear which predisposes patients to experience chemotherapy-related side effects.…”

Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly

“…Previous retrospective studies evaluating 5-FU þ leucovorin regimens in an elderly population reported severe toxicity in 20% of patients treated with the LV5FU2 regimen (Mabro et al, 1999) and in 58% of patients One patient was treated with an association of raltitrexed and oxaliplatin, two patients with an association of capecitabine and oxaliplatin and one patient with an association of raltitrexed and irinotecan. Oxaliplatin or irinotecan chemotherapy in the elderly T Aparicio et al treated with the 5-FU bolus regimen (Stein et al, 1995). We report severe neutropenia in 14 and 23% of patients treated with oxaliplatin and irinotecan, respectively.…”

“…Nevertheless, patients over 75 years have been usually excluded from randomised clinical trials evaluating chemotherapy for advanced colorectal cancer (Trimble et al, 1994;Kohne et al, 2001). Few data are available on chemotherapy in elderly patients, but it has been suggested that 5-fluorouracil (5-FU)-based chemotherapy efficacy was comparable to that in younger patients (Stein et al, 1995;Chiara et al, 1998;Mabro et al, 1999;Popescu et al, 1999;Magne et al, 2002). Tolerance was comparable except in one study evaluating chemotherapy with bolus 5-FU (Stein et al, 1995).…”

“…Few data are available on chemotherapy in elderly patients, but it has been suggested that 5-fluorouracil (5-FU)-based chemotherapy efficacy was comparable to that in younger patients (Stein et al, 1995;Chiara et al, 1998;Mabro et al, 1999;Popescu et al, 1999;Magne et al, 2002). Tolerance was comparable except in one study evaluating chemotherapy with bolus 5-FU (Stein et al, 1995). A survival benefit was demonstrated in one unpublished randomised study comparing 5-FU-based chemotherapy to best supportive care in elderly patients (Beretta et al, 1997).…”