Integration of chemotherapy into combined modality treatment of solid tumors

Summary.-The responses of 6 human colorectal tumour xenografts to 7 cytotoxic agents have been established. Tumour responses have been quantified by growth inhibition, and the time taken for 3H-thymidine fractional incorporation (TFI) to recover to the control value after treatment. The chemosensitivity of each tumour line to a spectrum of agents was individual, and no pattern of response which would allow prediction of individual agent efficacy was apparent. Cyclophosphamide, methyl-CCNU and 5-fluorouracil produced marked growth inhibition in individual tumour lines, whereas actinomycin-D, cis-dichlorodiammine platinum, doxorubicin and pentamethylmelamine showed little activity. Data presented agree with clinical evaluation for single-agent therapy. The uptake and incorporation of radiolabelled 5-fluorouracil into 4 tumour lines is reported. No marked differences between 3 FUinsensitive lines and 1 sensitive line have been observed.

Section: Distribution and Incorporation Of 3h-5fusupporting

confidence: 88%

mentioning

confidence: 99%

Evaluation of single-agent therapy in human colorectal tumour xenografts

Houghton¹,

Houghton²

1978

“…The alkylating agent mitomycin C and the anti-metabolite methotrexate both have single agent activity in breast cancer with low subjective toxicity (De Lena et al, 1982;van Oosterom et al, 1982;Carter, 1976). However, when used in combination with melphalan (Perez et al, 1984) cumulative myelosuppression became a problem.…”

mentioning

confidence: 99%

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer

Powles

Jones²,

Judson³

et al. 1991

Summary This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m 2 (day 1), mitozantrone 7 -8 mg m-2 (day I and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The Table 1. A total of 217 patients were entered into the study and after exclusions because of protocol violation (prior chemotherapy) there remained 106 patients who received 3M and 105 patients who received VAC. The median age was 55 (range 36-77) years for 3M and 58 (range 30-76) years for VAC. The median disease-free interval (primary diagnosis to first relapse) was similar for 3M (16 months) and VAC (15 months) and the median time from relapse to start of chemotherapy was also similar (8 months) for both regimens. Most patients (66% for both 3M and VAC) had received prior endocrine therapy consistent with our policy of using endocrine treatment for first relapse.

“…Methotrexate is effective as a single agent in metastatic breast cancer (Carter, 1976), and many patients currently receive methotrexate in first line combination therapy. Therefore, treatment with piritrexim, which could potentially also circumvent methotrexate resistance, could be of value in patients previously treated for breast carcinoma.…”

Section: Piritreximmentioning

confidence: 99%

A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer

Vries

Gietema²,

Workman³

et al. 1993

Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma.