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Results for “Maximum Tolerated Dose”

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PubMed1992

Comparison of the dependence of the TD50 on maximum tolerated dose for mutagens and nonmutagens.

The relationship between the minimum TD50 (i.e., the TD50 measured at the most sensitive site) and the maximum dose administered (maxD) in rodent carcinogenicity bioassays was investigated separately for mice and rats. The relationship between log(1/TD50) and log(1/maxD) was analyzed as a function of (1) mutagenicity and (2) the statistical significance cutoff for selecting the minimum TD50 values. For rat bioassays, the variance of log(1/TD50) is larger and the correlation of log(1/TD50) with log(1/maxD) is weaker for mutagens than for nonmutagens, suggesting that the relationship between minimum TD50 and MTD is, in general, stronger for nonmutagens than for mutagens. The difference in correlation does not depend on the TD50 statistical significance cutoff, but the difference in variance is not significant for the most stringently selected dataset. For mouse bioassays, no significant mutagen/nonmutagen differences in log(1/TD50) variance are found. A significantly weaker correlation of log(1/TD50) with log(1/maxD) for mutagens in comparison to nonmutagens occurs only for the dataset with minimum TD50 chosen at the least stringent level, suggesting that this difference may be due to chance variation. We also looked for changes in correlation and regression parameters as a function of mutagenic potency in Salmonella; the variance of log(1/TD50) and its correlation with log(1/maxD) are not found to vary in a consistent manner. Taken as a whole, our results indicate that (1) mutagenicity is a determinant of the TD50/maxD relationship in rats and (2) any effect that mutagenicity may exert on the TD50/maxD relationship in mice is unimportant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Phase I study with dose escalation of gemcitabine and cisplatin in combination with ifosfamide (GIP) in patients with non-small-cell lung carcinoma.

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.

Adult↗
PubMed1995

Etoposide (VP-16) and cisplatin at maximum tolerated dose in non-small cell lung carcinoma: a Cancer and Leukemia Group B study.

A multi-institutional cooperative group trial was undertaken by the Cancer and Leukemia Group B (CALGB) to evaluate the efficacy of the combination of cisplatin and intravenous etoposide for the treatment of metastatic or recurrent non-small cell lung cancer (NSCLC). The doses used were those previously determined to be the maximally tolerated dose of this drug combination. Forty patients were entered into the trial, 37 of whom were eligible for evaluation. Cisplatin (35 mg/M2/day for 3 days) and etoposide (200 mg/M2/day for 3 days) were administered every 28 days for a planned 6 cycles of therapy. Sixteen of 37 evaluable patients (43%) responded to therapy. Myelosuppression was the dominant toxicity, with 89% of the patients experiencing grade 4 neutropenia, and nearly half grade 3 or 4 thrombocytopenia. Median survival was 8.5 months, with 30% of the patients alive at 1 year and 10% alive at 2 years. Malaise, fatigue, and peripheral neuropathy were the other major toxicities. The combination of etoposide at the dose of 200 mg/M2/day for 3 days and cisplatin at 35 mg/M2/day for 3 days is a highly potent combination against metastatic non-small cell carcinoma.

Adult↗
PubMed2004

Results of a phase I study to determine the maximum tolerated dose of capecitabine when given concurrently with radical radiotherapy in the treatment of squamous cell carcinoma of the head and neck.

Capecitabine is preferentially converted to 5-fluorouracil within tumours, exploiting the higher levels of thymidine phosphorylase (TP) found in areas of poor perfusion and hypoxia. In addition radiation leads to up regulation of TP expression. To exploit these advantages of capecitabine as a synchronous chemoradiotherapy agent patients with advanced squamous cell carcinoma of the head and neck were recruited into a phase I non-randomised dose finding study. Capecitabine was given twice daily, 7 days a week at a dose starting at 350 mg/m(2) bid. Radiotherapy using a beam directed technique was prescribed to 55 Gy in 20 fractions over 4 weeks. A total of 24 patients were treated. Dose-limiting toxicity (grade IV mucositis) was reached at a capecitabine dose of 550 mg/m(2) bid. Radiotherapy was completed without delay in all cases. There was no systemic drug related toxicity. Capecitabine offers the prospect of an orally administered drug for use synchronously with radiotherapy, which in doses up to 500 mg/m(2) bid is well tolerated.

Administration, Oral↗
PubMed1996

Correlation between sensitivity in vitro of patient chronic lymphocytic leukemia cells and clinical systemic exposure at the maximum tolerated dose for cell cycle phase-specific (type 2) anticancer drugs.

Previously in Anti-cancer Drugs we have reported a high correlation between clinical plasma concentration-time products (C x T) and the concentration of cytotoxic drugs giving 50% cell survival (IC50) in primary cultures of human lymphatic cells. In the present study we investigated the relationship separately for cell cycle-specific (type 1) and cell cycle non-specific (type 2) drugs in chronic lymphatic leukemia cells. A high correlation (R = 0.92) was observed between C x T and IC50 for cell cycle non-specific drugs, while for cell cycle-specific, or C x T-dependent, drugs, the relationship was much weaker (R = 0.58). Since the opposite pattern has been observed for the relationship between clinical C x T and LD10 in mice, these results further imply that drug sensitivity assays may be a useful complement to animal data in the selection of starting dose and dose escalation procedure in phase I clinical trials of new cytotoxic drugs.

Animals↗
PubMed1988

Reevaluation of the maximum tolerated dose of continuous venous infusion of 5-fluorouracil with pharmacokinetics.

5-Fluorouracil (5-FU) was administered as a continuous ambulatory venous infusion to 25 patients in a Phase I trial. The principal dose limiting toxic effect observed was mucositis. Skin rash and diarrhea occurred less frequently. Hematological toxicity was modest, and no hepatic toxicity was seen. One partial remission of 138 days duration was seen in a patient with metastatic breast carcinoma who was previously refractory to a 5-FU combination regimen. Patient tolerance of 5-FU delivered in this manner appeared highly variable. On the basis of this trial, we recommend that future studies evaluating the efficacy of long-term venous infusion of 5-FU should utilize a dosage of 450 mg/m2/day.

Diarrhea↗
PubMed1997

Serum LDH and ALP isozyme activities in mice bearing solid Ehrlich carcinoma and/or treated with the maximum tolerated dose (MTD) of aloin.

Determination of total LDH and ALP activities and their isozyme patterns in the sera of normal and tumour-bearing animals treated with aloin, a natural anthraquinone with potential antitumour activity, was carried out at 3, 6 and 9 weeks of treatment. Treatment of normal mice with the MTD of aloin (50 mg/Kg b.w.) showed non-significant changes in serum total LDH and ALP activities along with their isozymes throughout the experimental periods. In untreated tumour-bearing animals, serum LDH activity and its isozymes: LDH1-LDH5 showed highly significant increases (192, 32.4, 25.2, 24.7, 29.2 and 30.6%, respectively) after 3 weeks. Highly significant inhibition was recorded in serum total ALP activity and its intestinal and bone isozymes (64, 100 and 56%, respectively), while liver ALP isozyme was increased by 82.3%. Treatment of tumour-bearing mice with the MTD of aloin manifested a significant gradual improvement in both enzyme activities and their isozymes, which were normalized at the end of the experiment (9 weeks), with the exception of intestinal ALP isozyme. All results were reported in comparison to the normal control group.

Alkaline Phosphatase↗
PubMed1990

Statistical requirements of phase I studies.

Methodological aspects of planning and evaluating phase I studies in oncology--the link between preclinical research and approval of clinical efficacy--include the human starting dose, maximum tolerable dose and dose escalation schemes. Statistical requirements of phase I studies are presented here, emphasizing the urgency of their application in current practice. For the maximum tolerable dose a distinction will be made between an individual- and a population-based approach, which is crucial for a correct definition and statistical parameter estimation. Weaknesses of the dose escalation scheme according to the modified Fibonacci scheme are shown and contrasted with the recently proposed pharmacokinetically guided dose escalation. Comprehensive phase I/II information processing is recommended for validating current practice.

Antineoplastic Agents↗