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PubMed1982

Chemotherapy and combined modality therapy for Hodgkin's disease: a progress report on Cancer and Leukemia Group B studies.

Between 1974 and 1977, the Cancer and Leukemia Group B (CALGB) initiated four studies which address current major questions in the therapy for Hodgkin's disease. The efficacy of chemotherapy alone as compared with combined modality therapy in patients with poor-prognostic stages I and II is evaluated in CALGB 7751. Currently, both therapies produce very high complete remission rates in asymptomatic patients; the remission rate is better with combined modality therapy in symptomatic patients. Single and combined modality therapies are compared for stage III patients in CALGB 7451. Complete remission rates have been similar, but relapse-free survival is superior for patients treated with local nodal radiotherapy followed by chemotherapy (P = 0.04). In particular, stage IIIA patients with nodular sclerosis seem to benefit from the inclusion of radiotherapy in their initial treatment. In CALGB 7551, the efficacy of chemotherapy alone versus chemotherapy plus radiotherapy to areas of bulky disease is under study in patients with stages IIIB and IV. Currently, a relapse rate of less than 10% has been seen among sites irradiated, and survival is best for patients treated with radiotherapy bracketed by chemotherapy. Finally, the role of two alternating non-cross-resistant combination chemotherapy programs is being studied in CALGB 7552. Relapse-free and overall survival is better with the doxorubicin-containing regimen than with either the alternating or alternate chemotherapy program. At present, the median followup for each of these studies is less than 5 years. Further observation is required to answer the critical questions relating to prolonged disease-free survival and cure.

Adult↗
PubMed1982

Chemotherapy strategies to improve the control of Hodgkin's disease: the Richard and Hinda Rosenthal Foundation Award Lecture.

The paper reviews new chemotherapy strategies for intermediate and advanced stages of Hodgkin's disease as well as the implications of recent biological concepts and mathematical models which appear useful in the interpretation and design of new treatments. The development and the application of the Adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) combination was based on critical reevaluation of benefits and limits of the mechlorethamine-vincristine-procarbazine-prednisone (MOPP) combination. The attempts to develop non-cross-resistant regimens, such as ABVD, arose intuitively at first from the desire to improve salvage treatment in MOPP-refractory patients; more recently, a theoretical framework for this approach has been proposed by Goldie and Coldman (Cancer Treat. Rep., 63: 1727-1733, 1979). The 5-year results achieved with different forms of salvage chemotherapy and with the cyclic delivery of non-cross-resistant combinations (MOPP and ABVD) can be explained largely by the assumption that drug-resistant mutants represent a major limiting factor in the cure of Hodgkin's disease, as well as of other neoplasms, by chemotherapy. The initial results from a prospective randomized trial indicate that the administration as front-line therapy of non-cross-resistant regimens is a logical and powerful strategic approach and therefore that it may constitute an important avenue of clinical research. Recent observations also emphasized the problem of the quality of life, since the administration of multidrug combinations not including alkylating agents and/or procarbazine appears to be associated with a decreased incidence of carcinogenesis and sterility. The departure from the standard practice of utilizing a single multidrug regimen for chemotherapy of Hodgkin's disease should be supported by sound research and controlled studies built on drug combinations of known efficacy and toxicity.

Antineoplastic Agents↗
PubMed1983

[Small-cell anaplastic bronchopulmonary cancers. Prognostic and therapeutic review apropos 49 cases].

This retrospective study of 49 patients with small-cell broncho-pulmonary carcinoma showed the principal prognostic factor to be the response to chemotherapy: an initial treatment association of cyclophosphamide (800 mg/m2), adriamycin (60 mg/m2), methotrexate (40 mg/m2) and CCNU (60 mg/m2) every four weeks was used in 40 patients, out of 46 patients who underwent chemotherapy. All cases were followed up for a minimum of 6 months except 2 who were lost to follow-up; there are 9 survivors, all of whom initially had an apparent complete remission: the extension of the disease seemed to be of less prognostic significance than the response to treatment. The response rate to this protocol was 84 p. cent with 52 p. cent apparent complete remissions. The mean global survival rate was 9 months (mean survival rate of treated patients: 11.46 months). Some patients with disseminated carcinoma initially had very prolonged survival. The association of a final session of thoracic radiotherapy seemed to be useful (the 4 patients who underwent radiotherapy after 8 to 12 sessions of chemotherapy are still alive after an average of 18 months follow-up with no signs of recurrence).

Adult↗
PubMed1982

Repair of DNA alkylation induced in L1210 leukemia and murine bone marrow by three chloroethylnitrosoureas.

The removal of DNA adducts is an essential step of DNA repair following exposure to chloroethylnitrosoureas. Adduct removal was evaluated in both L1210 and murine bone marrow DNA for lesions induced by three chloroethylnitrosoureas. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, a marrow-toxic agent with high carbamoylating activity, was not removed in either system for at least 6 to 12 hr. These results were compared with those obtained with two glucose-linked chloroethylnitrosoureas, chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea. Both of these agents have low marrow toxicity at therapeutic doses. Chlorozotocin, which has very low chemical carbamoylating activity, was found to permit approximately 40% removal of drug-derived DNA adducts in both systems within the first 6 hr and approximately 50% by 18 hr. The second glucose-linked analog, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, has relatively high carbamoylating activity and was found to inhibit early removal of DNA adducts as effectively as does 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. It would thus appear that the selective marrow-sparing property of the sugar-linked chloroethylnitrosoureas is not dependent upon carbamoylation-mediated differences in the rate and extent of DNA adduct removal. In view of the comparable therapeutic activity of the three drugs for L1210 leukemia, therapeutic efficacy does not appear to be impaired by the increased rate of adduct removal observed with chlorozotocin in this system.

Alkylation↗
PubMed1983

Increased mutagenicity of chloroethylnitrosoureas in the presence of a rat liver S9 microsome mixture.

The mechanism for an enhanced effect of Aroclor 1254-induced Sprague-Dawley rat liver 9,000 x g supernatant (S9) microsome preparation on the mutagenicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-N-nitrosourea (CCNU), and 2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose (chlorozotocin) for Salmonella typhimurium strain TA1535 was studied. Although all three compounds were direct-acting mutagens, rat liver S9 increased the mutagenic response to BCNU, CCNU, and chlorozotocin. The enhanced mutagenic effect was independent of NADPH. Heat-denatured S9 enhanced the mutagenicity of BCNU and CCNU, but not that of chlorozotocin. Mutagenic enhancement, however, was less than that observed with untreated S9. The substitution of extractable S9 lipid and bovine serum albumin for S9 in the reaction mixture resulted in an enhanced mutagenicity of CCNU with little or no effect on BCNU or chlorozotocin mutagenicity. These results suggest that the enhanced mutagenicity of CCNU, and possibly that of BCNU, in the presence of S9 was due in part to nonspecific factors that are present in the S9 preparation.

Animals↗
PubMed1983

[Multiple myeloma with high tumoral mass. Treatment combining melphalan, cyclophosphamide, vincristine, CCNU and prednisone. 35 cases].

The results of a combination chemotherapy trial (melphalan, CCNU, vincristine, cyclophosphamide) involving 28 patients with stage III (n = 21) or stage II (n = 7) multiple myeloma suggest a high response rate, with a mean 71% malignant cell destruction in 78.5% of the patients. A longer survival in responsive stage III patients as compared with patients treated with alkylating agents seems likely, but this can only be established by a randomized trial. Despite haematological side-effects, this combination therapy may be used in high risk patients, especially those resistant to a single alkylating agent and in whom the frequency, intensity and duration of responses appears to be the same as in previously untreated patients. In contrast, only one of the 7 patients treated for relapse after previous response to a single alkylating agent responded to the combination chemotherapy.

Adult↗
PubMed1982

[Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas].

This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.

Carmustine↗
PubMed1984

Chemotherapy of hormonally unresponsive prostatic carcinoma.

The national Prostatic Cancer Project has evaluated single and combination chemotherapeutic agents for the treatment of patients with advanced prostatic cancer that has been unresponsive to hormonal therapy. Although regression rates have been modest, a number of drugs have shown some efficacy and are now undergoing testing in combination. Current trials of the LH-RH agonists and the antiandrogen flutamide are in progress. These trials have demonstrated a role for chemotherapy in the treatment of the patient who has failed hormonal therapy.

Antineoplastic Agents↗
PubMedDate not supplied

Chemotherapy of human tumor xenografts in genetically athymic mice.

A series of studies were undertaken to evaluate the chemotherapeutic response to various antineoplastic drugs of human breast (MX-1) or colon (CX-2) tumor xenografts growing in genetically athymic (nude) mice. Fragments (2mm3) of either tumor type were implanted subcutaneously into the subaxillary region of NIH Swiss nude mice, and single drug therapy was started when tumors became palpable and were growing progressively. 5-Fluorouracil (5-FU) administered on a Q7DX3 schedule starting on Day 21 post tumor implantation elicited significant retardation in the growth rate of CX-2 tumor. A single treatment with methyl-CCNU induced temporary tumor regression. Against MX-1 tumor, both cyclophosphamide and melphalan induced tumor regressions with no recurrence. 5-FU slowed but did not arrest growth of MX-1 tumor. These tumor systems grown in nude mice appear to be suitable models for in vivo screening of anticancer agents that would prove clinically active.

Animals↗