Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer.

BACKGROUND: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied. PATIENTS AND METHODS: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle. RESULTS: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients. CONCLUSIONS: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.

Treatment of the cancer anorexia-cachexia syndrome: a critical reappraisal.

Cancer anorexia-cachexia syndrome (CACS) is a combination of anorexia, tissue wasting, weight loss and poor performance status. Some CACS symptoms are due to a macrophage production of TNF and IL-1, while the metabolic effects are mainly explained by the release of IL-6 from tumor cells. Clinical treatment of CACS involves progestational agents (medroxyprogesterone acetate, MPA, megestrol acetate, MA) for long term treatment. The use of prokinetic agents (like metoclopramide) is recommended, especially if patients need concomitant opioid treatment for pain; if otherwise indicated, corticosteroids are useful for short periods. The administration of artificial nutrition should be individualized following the clinical condition of the patient and possibly taking into account the wishes of the patient. The practical evaluation criteria of the drugs employed for CACS are based on weight increase and appetite stimulation. Hence, a new approach to the mechanism of action of MPA, MA and of other agents is urgently needed.

Application of quantitative analysis to biologic profile evaluation in breast cancer.

BACKGROUND: The biologic profile of 907 infiltrating breast carcinomas was determined considering estrogen receptor (ER) and progesterone receptor (PR), proliferation index (PI) and c-erbB-2/Neu expression. The relationship with pathologic parameters (lymph node status, size, histotype) were studied by a multivariate analysis. The clinical prognostic power of biologic profile also was evaluated for 265 patients. METHODS: In 907 infiltrating breast carcinomas, the quantitation of ER, PR, an PI was obtained with an image analysis system (CAS 200, Becton Dickinson Cell Analysis Systems, San Jose, CA); Neu was evaluated semiquantitatively. A clinical study of 265 patients was performed (median follow-up, 42.5 months). RESULTS: Seventy-seven percent of tumors were ER-positive, 70% were PR-positive, 58% had a high PI, and 35% were Neu-positive. The overall analysis indicated a direct correlation between ER and PR (Spearmans' rho [rs] = 0.47, P < 0.001) and an inverse correlation between PI and ER (rs = -0.39, P < 0.001), PI and PR (rs = -0.32, P < 0.001), Neu and ER (rs = -0.20, P < 0.001), and Neu and PR (rs = -0.21, P < 0.001). Cluster analysis, performed based on the biologic profile (ER, PR, PI, c-erbB-2/Neu expression), identified two final groups of tumors with different pathologic features. This study showed a longer relapse free interval for patients with ER- and PR- positive tumors (P = 0.016 and P = 0.007) and low PI and Neu-negative tumors (P < 0.001 and P = 0.047). CONCLUSIONS: These results stress the importance of the biologic profile for defining tumor behavior and patient management, leading to integration of, and eventually the substitution for, the actual staging system.