Oleg S. Selawry

Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide

Abstract Suggestions are made for the conduct of chemotherapy trials in patients with cancer. Application of the principles involved are illustrated in a comparative study of triethylene thiophosphoramide and nitrogen mustard in cancer of the lung and breast, melanoma, and Hodgkins disease. Neither drug was appreciably effective in cancer of the lung which had previously been irradiated or in melanoma. In cancer of the lung not previously irradiated and in cancer of the breast, 30 to 50 per cent reduction in tumor size occurred in 10 to 26 per cent of the patients. In Hodgkins disease certain factors limit the completeness of the comparison, but it is possible to draw the tentative conclusion that thio-TEPA was less active than HN2 (in the doses used) in inducing remissions. The advantages and disadvantages of this type of trial are discussed and several suggestions are made for improved experimental design.

The role of vincristine in the treatment of childhood acute leukemia

In a study of 117 patients under the age of 20 with acute leukemia, vincristine (VCR), at 2 mg. per square meter body surface per week, produced complete remissions in 55 per cent and partial remissions in 15 per cent. The drug also induced second remissions. Patients entering complete remission with VCR were randomly allocated to maintenance therapy with VCR or placebo. The median duration of remission was short: 9 weeks for VCR compared with 6 weeks for placebo. The probability of serious neurological toxicity computed according to the time of exposure to VCR, based on the supposition that VCR was not used for maintenance therapy, indicated that the minimal theoretical risk of toxicity for the highest complete remission rate occurred at 4 weeks (38 per cent remissions with 5 per cent toxicity). At 6 weeks, the corresponding probabilities were 54 and 16 per cent.

Clinical studies of dichloromethotrexate (NSC 29630)

Dichloromethotrexate (DCM) is much superior to methotrexate (MTX) in inhibiting L1210 leukemia and C3H lymphosarcoma in mice. This greater effectiveness obtains for parenterally administered DCM and is much less apparent when DCM is given by mouth. The toxicity of DCM in animals is qualitatively similar to that produced by MTX. DCM is fifty to one hundred fold less toxic than MTX in rats and mice but only tenfold less toxic in dogs. It is concluded from clinical studies reported in this paper that: (1) The tolerated dose of DCM is fivefold that of MTX and the toxic manifestations are similar. (2) The tolerated doses of oral and iniramuscular DCM are equivalent. (3) Equitoxic, and presumably optimal, doses of oral DCM, oral MTX, and intramuscular DCM produce comparable antitumor effects in adults with lymphosarcoma and Hodgkins disease. There is complete tumor regression in 10 to 20 per cent and partial regression in another 20 to 30 per cent of patients. These tumor regressions are, in general, short‐lasting. (4) The dose response relationship is steep. A twofold difference in dose of DCM or MTX results in a significant difference in toxicity and antitumor effect. (5) There are at least four other more effective modalities of treatment for lymphoma which should be employed before conventional folic acid antagonist therapy is considered.

Methotrexate compared with placebo in lung cancer

Two hundred thirty‐nine patients with microscopically proven, inoperable bronchogenic carcinoma were allocated at random to receive twice weekly I.M. injections of either methotrexate at “high dose” of 0.6 mg/kg/dose or methotrexate at “low dose” of 0.2 mg/kg or visually indistinguishable placebo in the same volume of 0.1 ml/kg for four months. Twelve patients were invalidated for procedural reasons. Objective response (50% tumor regression) was dose‐related with 21% of 48 patients with measurable disease on high dose, 11% of 37 patients on low dose, and 6% of 32 patients on placebo. Corresponding response rates for epidermoid carcinoma were 35% of 23 patients, 9% of 11 patients, and 0 of 13 patients. Responders in the two treatment groups had a three to four fold increase of median survival (p < .05). Non‐responders on high and low dose methotrexate lived as long as patients on placebo. Leukopenic patients in all three treatment groups lived substantially longer than patients without leukopenia < 4,500/mm3, irrespective of presence or absence of objective response. All three regimens were well tolerated. None of the patients had life‐threatening toxicity. It is concluded that methotrexate at “high dose” is a potentially useful drug for temporary palliation of epidermoid carcinoma of the lung. Cancer 40:4–8, 1977.

The Use of Liquid Cholesteric Crystals for Thermographic Measurement of Skin Temperature in Man

Abstract The skin over subcutaneous lesions of primary or metastatic carcinomas and sarcomas is frequently warmer than the apparently normal surrounding skin.1–3 Thus thermotopographic measurement of skin temperature over tumor lesions can be useful for measurement of size, vascular physiology and response to treatment.

The superiority of CCNU in the treatment of advanced hodgkin's disease: Cancer and leukemia group b study

In a randomized study, the effect of single agent therapy with CCNU was compared with that of BCNU in previously treated patients with advanced Hodgkins disease. The dosage of CCNU was 100 mg/m2 p.o. q. 6 weeks and of BCNU, 200 mg/m2, q. 6 weeks with dose modification adjusted to individual tolerance.

A comparative study of optimal medical care with and without azaserine in multiple myeloma.

A comparative clinical study of optimal medical care plus azaserine versus optimal medical care plus a placebo was accomplished in 20 patients with multiple myeloma. Azaserine was originally studied in myeloma because of reported effects on a plasma cell neoplasm in mice. The controlled study was undertaken because suggestive activity in myeloma had previously been seen. The 9 azaserine‐treated patients sustained more toxicity than the 11 placebo‐treated patients. No important difference in tumor behavior was detectable between the azaserine and placebo‐treated groups as determined by physical examination or the several hematologic, biochemical, and roentgenologic measurements made.

A Randomized Clinical Trial in Bronchogenic Small-Cell Carcinoma Evaluating Alternating Maintenance Therapy of Vincristine, Adriamycin, Procarbazine, and Etoposide (VAPE) with Cyclophosphamide, CCNU, and Methotrexate (CCM) versus CCM Maintenance Alone in Complete Responders Following VAPE Induction and Late Intensification

Initially, 109 evaluable patients with locally advanced or metastatic small cell lung cancer (SCLC) were treated with vincristine, Adriamycin, procarbazine, and etoposide (VAPE). Partial (PR) or nonresponders (NR) were crossed to CCM (cyclophosphamide, CCNU, and mcthotrexate) and then to HMiVe (hexamethylmelaminc, mitomycin C, vin-blastine) sequentially at maximum response. Complete responders (CR) were intensified by 50% with VAPE primarily and randomized to VAPE, alternating with CCM or CCM alone during maintenance. CR patients with limited disease received local thoracic irradiation and prophylactic cranial irradiation (PCI), whereas those with extensive disease received PCI alone. There were 45 patients (41%) who achieved a CR to chemotherapy, and 27 patients were eligible for randomization. Of 12 CR patients randomized to alternating therapy (VAPE/CCM), the median survival was 25.9 months compared to 12.9 months for 15 CR patients randomized to continuous CCM (P = .049). In addition, 35 patients achieved a PR (32%) and 29 were NR (27%). Overall median survivals were significantly different for the CR patients (13.0 months) as compared to PR (7.6 months) and NR patients (6.4 months). Late intensification did not appear to add substantially to survival while contributing to toxicity. In summary, VAPE is a new outpatient regimen for SCLC, which is highly effective as an induction regimen with moderate hematologic toxicity and predominantly gastrointestinal nonhematologic toxicity.