Use of 5-fluorouracil, bleomycetin and platidiam in combined treatment of localized cancer of the larynx]

Preliminary results of chemoradiotherapy in 30 patients with the larynx cancer T3T4N0M0 are presented. Two treatment schemes were applied. According to scheme I, the treatment was started with chemotherapy with 5-fluorouracil in doses of 1000 mg on days 1, 2 and 3, bleomycetin in doses of 15 mg on days 1, 2 and 3 and platidiam in doses of 120 mg/m2 on day 4 followed by radiotherapy to the total dose of 66 to 70 Gy. Scheme II included two analogous courses of the chemotherapy, one prior to the radiotherapy and the other after irradiation in a dose of 38 to 40 Gy, after a two-week interval the radiotherapy was continued to doses of 66 to 70 Gy. 15 patients were treated in accordance with each scheme. Complete resorption of the tumor was observed in 66.6 and 83.3 per cent of the patients treated according to schemes I and II, respectively. The results showed that the use of 5-fluorouracil, bleomycetin and platidiam in combination with radiotherapy was promising in treatment of patients with local cancer of the larynx.     

Use of bleomycetin in malignant testicular tumors and the problem of studying bleomycin analogs

The efficacy of the chemotherapy of 16 patients with metastases of malignant tumors of the testicle was studied. The chemotherapy included vinblastine, platidiam and bleomycetin. The latter was used in a dose of 10 mg daily intramuscularly or as long-term intravenous infusions. As a result of the treatment complete and partial regression of the tumors was observed in 5 (31 per cent) and 4 (25 per cent) patients, respectively. Leukopenia was the main side effect. By present the total doses of bleomycetin had amounted to 250 mg for 4 patients and to 300-350 mg for 7 patients. No signs of pulmonary toxicity were observed with the use of these doses. The problem of clinical studies of bleomycin analogs is discussed.     

Adriamycin in the combined chemotherapy of small-cell lung cancer

The results of combined chemotherapy and chemoradiotherapy of 158 patients with small cell lung cancer are presented. Adriamycin was used as one of the components of the induction chemotherapy of 98 out of the 158 patients. Chemoradiotherapy (nitrosomethylurea, methotrexate, CCNU, adriamycin, vincristine, DTIC, radiotherapy) was performed according to 4 schemes and combined chemotherapy (cyclophosphamide, adriamycin, methotrexate, or CCNU, cyclophosphamide, methotrexate plus adriamycin, vincristine, natulan) was performed according to 2 schemes. The total efficacy (complete and partial regression) of the 6 schemes averaged to 80 per cent. The number of patients with complete regression amounted to 29 per cent. Long-term survival for more than 2 years was observed in 17 per cent of the patients. No signs of metastases or relapses for 5 years were recorded in 6 per cent of patients. Adriamycin is one of the most active antitumor drugs in combined chemotherapy and chemoradiotherapy of small cell lung cancer.     

The results of the use of bleomycin and its analogs in the VAB-6 protocol in treating testicular tumors

Efficacy and toxicity of VAB-6 combinations with bleomycin, bleomycetin or peplomycin were studied in treatment of 77 patients with metastases of germ-cell tumors: testicle tumors in 71 patients and extragonadal tumors in 6 patients. After the chemotherapy complete regression was observed in 37 patients (48.7 per cent). In 44 patients (57.1 per cent) residual metastases after the chemotherapy were resected. The frequency of complete regression after using the VAB-6 combinations with bleomycin, bleomycetin and peplomycin amounted to 58.8, 61.5 and 47.1 per cent respectively. The treatment results depended on the disease extent. When the disease extent was minimal complete regression was observed in 87.5 per cent of the patients. The respective figures for the disease moderate and significant extents were 66.7 and 37.8 per cent. During the average observation period of 22.1 months (7-40 months) 39 patients survived and had no signs of the disease. The combinations markedly differed in their toxicity.     

Results of the clinical study of the antineoplastic antibiotic bleomycetin

Bleomycetin was applied to the treatment of 68 patients with common forms of malignant tumors. The objective therapeutic effect was observed in 21 patients (31 per cent). The frequency of the favourable therapeutic effects was the most significant in the group of patients with generalized forms of lymphogranulomatosis: objective remissions for 1 to 4 months and stabilization of the tumor process were attained in 12 (41 per cent) and 8 out of 29 patients, respectively, in 9 patients (31 per cent) treated with bleomycetin progression of the underlying disease was recorded. A less pronounced therapeutic effect (33 per cent of the remissions) was recorded in the patients with nonlymphogranulomatous lymphomas. The use of bleomycetin in 48 out of 68 patients was complicated by certain adverse reactions. Intravenous infusions of bleomycetin in a dose of 10-15 mg twice a week (the total dose up to 125 mg) may be recommended as the initial therapeutic regimen in the oncological practice. The trials have showed that bleomycetin made in the USSR has a sufficiently pronounced activity against lymphogranulomatosis and nonlymphogranulomatous lymphomas. In this respect it is not inferior to the bleomycin analog made in Japan.     

Clinical evaluation of a bleomycin-group antitumor antibiotic bleomycetin

The efficacy of bleomycetin or bleomycin A5 was studied in 128 patients with different malignant neoplasms. The antibiotic was used as a systemic or intracavitary chemotherapeutic agent. Bleomycetin was effective in 75-80, 81.8, 58.3, 70 and 50 per cent of the cases with disseminated derminogenic tumor of the testicle, squamous cell carcinoma of the head and neck, cancer of the penis, carcinoma of the skin and lymphogranulomatosis, respectively. When used intracavitarily the drug was effective in 41.2 per cent of the patients with cancer of the ovaries and lungs, teratoblastoma of the ovaries, cancer of the mammary gland and sarcoma of the soft tissues. Hyperthermia and focal hyperkeratosis as the adverse reactions were observed in 40.6 and 5.4 per cent of the patients, respectively. No toxicity with respect to the lungs was registered.     

Belomycetin in the combined chemotherapy of testicular tumors

The results of the treatment of 21 patients with testicle tumors of various histological structure, stages III and IV, are presented. The combination of bleomycetin (bleomycin A5), an antitumor antibiotic made in the USSR, with vinblastine and platinum derivatives was used. The antitumor effect was observed in 63 per cent of patients, including 21 per cent of patients with complete regression of tumors. The periods of complete and partial remission were 3--13 and 1--9 months, respectively. The combination is sufficiently effective and may be recommended for the treatment of patients with disseminated malignant tumors of the testicle.     

Elaboration of the combination of antitumor preparations bleomycetin + 5-fluorouracil + cisplatin

Clinical trials on efficacy and toxicity of combined use of bleomycetin, 5-fluorouracil and cisplatin in patients with disseminated tumor processes were conducted. Two regimens were applied. Regimen I included intravenous administration of cisplatin in a dose of 100-150 mg/m2 on day 1, intramuscular administration of bleomycetin in a dose of 10 mg on days 2-4 and intravenous jet injection of 5-fluorouracil in a dose of 400 mg/m2 on days 2-4. Regimen II consisted of intramuscular administration of bleomycetin in a dose of 10 mg on days 1-3, intravenous jet injection of 5-fluorouracil in a dose of 400 mg/m2 on the same days and intravenous administration of cisplatin in a dose of 100-150 mg/m2 on day 4. The intervals between the courses amounted to 4 weeks. Complete regression of cervical carcinoma relapsing was observed in 1 patient. In 5 patients i.e. 1 with small-cell lung cancer, 3 with squamous cell lung cancer and 1 with metastases of low-differentiated cancer from an undetected focus to supraclavicular lymph nodes the effect was partial. Long-term stabilization of the disease at the background of the treatment for 6-7 months was stated in 3 patients. On the whole the objective response was in 6 out of 22 patients or in 27 per cent. 7 of them were treated with cisplatin in a dose of 150 mg/m2. The regimens of the combined use of 5-fluorouracil, bleomycetin and cisplatin were low toxic. The therapeutic effect showed that the combination was of practical value.     

The effect of chemotherapy on the in vivo frequency of glycophorin A 'null' variant erythrocytes

A human in vivo somatic cell assay based on the enumeration of variant erythrocytes lacking expression of an allelic form of the cell-surface sialoglycoprotein, glycophorin A, was applied to the study of blood samples from patients obtained prior to, during, and following chemotherapy for malignant disease in order to determine the effect of mutagenic chemical agents on the frequency of variant cells. In 22 patients assayed prior to therapy, the mean variant cell frequency was 11.9 per million, which was not significantly different from that observed in healthy controls. In an initial cross-sectional survey, blood samples were obtained at various times during and after therapy from 30 patients diagnosed with a variety of malignancies who were treated with one or more known mutagenic agents including adriamycin, bleomycin, cis-platinum, cyclophosphamide, dacarbazine, etoposide, lomustine, mechlorethamine, melphalan, mitomycin C, and procarbazine. Significant elevations in the mean frequency of variant cells over pre-therapy and normal levels were observed in samples obtained during and after therapy. In a time-series study, 14 breast cancer patients treated with CAF (cyclophosphamide, adriamycin, 5-fluorouracil), CMF (cyclophosphamide, methotrexate, 5-fluorouracil), or VMF (vinblastine, methotrexate, 5-fluorouracil) adjuvant chemotherapy were sampled repeatedly during and after therapy. For the CAF and CMF patients an increase in the frequency of variant cells was observed with a lag in the appearance of induced variants after initiation of therapy; variant frequencies gradually increased during therapy reaching a maximum at or shortly after the end of therapy, then declined to near pre-therapy levels within 6 months. The maximum level of induced variants ranged from 2- to 7-fold over pre-therapy or normal levels depending on the combination of agents used. The breast cancer patients treated with both adriamycin and cyclophosphamide showed consistent elevations in the frequency of variant cells; patients treated only with cyclophosphamide showed lower and more variable elevations. The data demonstrate that mutagenic chemotherapy agents induce elevated levels of glycophorin A variant erythrocytes consistent with the hypothesis that variant cells result from somatic mutation. The elevations in variant cells were transient, suggesting that these agents primarily affect the rapidly cycling committed erythroid cell population.     

Trial of the use of bleomycin in combination with other chemopreparations for treating the metastases of squamous cell cancer in various sites

The data on the treatment of 19 patients with squamous cell carcinoma of different sites are presented. A combination of chemotherapeutics, including methotrexate, adriamycin and bleomycin was used. The combination was effective and low toxic. It may be recommended for the treatment of the above form of carcinoma.     

The effect of chemotherapy on the in vivo frequency of glycophorin A ‘null’ variant erythrocytes

A human in vivo somatic cell assay based on the enumeration of variant erythrocytes lacking expression of an allelic form of the cell-surface sialoglycoprotein, glycophorin A, was applied to the study of blood samples from patients obtained prior to, during, and following chemotherapy for malignant disease in order to determine the effect of mutagenic chemical agents on the frequency of variant cells. In 22 patients assayed prior to therapy, the mean variant cell frequency was 11.9 per million, which was not significantly different from that observed in healthy controls. In an initial cross-sectional survey, blood samples were obtained at various times during and after therapy from 30 patients diagnosed with a variety of malignancies who were treated with one or more known mutagenic agents including adriamycin, bleomycin, cis-platinum, cyclophosphamide, dacarbazine, etoposide, lomustine, mechlorethamine, melphalan, mitomycin C, and procarbazine. Significant elevations in the mean frequency of variant cells over pre-therapy and normal levels were observed in samples obtained during and after therapy. In a time-series study, 14 breast cancer patients treated with CAF (cyclophosphamide, adriamycin, 5-fluorouracil), CMF (cyclophosphamide, methotrexate, 5-fluorouracil), or VMF (vinblastine, methotrexate, 5-fluorouracil) adjuvant chemotherapy were sampled repeatedly during and after therapy. For the CAF and CMF patients an increase in the frequency of variant cells was observed with a lag in the appearance of induced variants after initiation of therapy; variant frequencies gradually increased during therapy reaching a maximum at or shortly after the end of therapy, then declined to near pre-therapy levels within 6 months. The maximum level of induced variants ranged from 2- to 7-fold over pre-therapy or normal levels depending on the combination of agents used. The breast cancer patients treated with both adriamycin     

Investigations into sister chromatid exchange in patients under cytostatic therapy

Summary In vivo sister chromatid exchange (SCE) determinations were carried out in patients with Psoriasis vulgaris under methotrexate therapy and patients with histologically verified bronchial carcinoma under cyclophosphamide, methotrexate or a combined chemotherapy. A pronounced increase in SCE rate was only found after cyclophosphamide treatment.Abbreviation Cyclo cyclophosphamide - MTX methotrexate - FU fluorouracil - Pred prednisolone - VB vinblastine - VC vincristine - BM bleomycin     

Regional immunotherapy has a detrimental effect on the response to combined irradiation and chemotherapy in locally advanced non-small cell bronchogenic carcinoma

Summary Twenty-one patients with stage III M₀ non-oat cell bronchogenic carcinoma confined to the thorax were randomized to receive either intrapleural BCG (10⁷ cfu, Tice strain) or intrapleural saline 3 weeks prior to beginning combined irradiation and chemotherapy. Radiation to the primary tumor and regional nodes was given at a dose of 3,000 rad in ten sessions and was followed in 7–14 days by CAMP chemotherapy (cyclophosphamide, adriamycin, methotrexate, and procarbazine) for a planned duration of 6 months. Isoniazid, 300 mg/day, was given to all patients for 3 months starting 1 week after intrapleural therapy. There were no significant differences in pretreatment prognostic factors or in response to radiation therapy. The patients receiving intrapleural BCG in addition to radiation and chemotherapy had a median survival of 18 weeks, significantly shorter than that for the patients receiving intrapleural saline (54 weeks, P=0.017).Presented in part at the 16th Annual Meeting of the American Society of Clinical Oncology, San Diego, California, May 27, 1980     

Comparative evaluation of the results of mono- and polychemotherapy of disseminated forms of breast cancer using the CMFVP program and anthracycline antibiotics (carminomycin and adriamycin)

A total of 203 out patients with disseminated cancer of the mammary glands subjected to chemotherapy were followed up. Of these, 44 patients were treated according to the CMFVP program, 66 were subjected to monochemotherapy with carminomycin, 42 were treated with combinations of carminomycin and dibromdulcytol, 14 patients received monochemotherapy with adriamycin and 37 polychemotherapy according to the scheme of fluorouracil + adriamycin + cyclophosphamide. In addition to the early-demonstrated efficacy of adriamycin and the Cooper scheme, the comparative estimation of the treatment programs showed that carminomycin, a new antitumor antibiotic made in the USSR, had an obvious activity when used alone or in combination with dibromdulcytol, an alkylating agent, in the treatment of primary extended forms, relapses and metastases of mammary tumors. The data indicate that wide use of carminomycin which is comparatively low toxic is advisable in the treatment of disseminated cancer of the mammary gland.     

Adjuvant chemotherapy for breast cancer: side effects and quality of life.

In a trial of postoperative adjuvant chemotherapy women with primary breast cancer and spread to one or more axillary nodes were randomised to receive a six-month course of either the single agent chlorambucil or the five-drug combination of chlorambucil, methotrexate, fluorouracil, vincristine, and adriamycin. On completing the treatment 47 patients were asked to fill in questionnaires at home on the side effects of treatment and its influence on the quality of their life. Side effects including nausea, vomiting, malaise, and alopecia had been severe enough to interfere with their lifestyle in 9 (42%) of the patients who had received the single agent and 19 (79%) of those who had received multiple-drug treatment. Various other side effects were reported by a few patients. Seven (29%) of the patients who had received the multiple-drug schedule voluntarily added that the treatment had been "unbearable" or "could never be gone though again." The proportion of patients who had experienced severe side effects while receiving the treatment was considerable; hence such adjuvant chemotherapy is justifiable only if it will substantially improve a patient''s prognosis.     

Purulent complications in the surgical treatment of patients with mouth cancer and their prevention]

Local purulent complications after surgical operations for mouth cancer were recorded in 49 (61.3 per cent) out of 80 cases and were mainly due to associations of 2 or more pathogens. The analysis of the factors influencing the development of the complications showed that there was no reliable increase in the number of the complications in the patients subjected at the first stage to the treatment with various antitumor agents: 17 (53.1 per cent) events in the group of the patients subjected to radiotherapy in a total focal dose of 40 Gy, 8 (72.7 per cent) events in the group of the patients subjected to radiotherapy in a dose of more than 60 Gy, 13 (59.1 per cent) events in the group of the patients treated with antitumor drugs and 8 (66.7 per cent) events in the group of the patients operated at the first stage of the treatment. The incidence of osteomyelitis was significantly higher in the group of the patients subjected to radiotherapy before the operation: 13 (30.2 per cent) events vs. 2 (5.4 per cent) in the group of the patients not subjected to radiotherapy. With increasing of the radiation dose, the incidence of osteomyelitis as well increased: 8 (25.0 per cent) osteomyelitis events in the group of the patients subjected to radiotherapy in a dose of 40 Gy and 5 (45.5 per cent) events in the group of the patients subjected to radiotherapy in a dose of more than 60 Gy. The method of osteosynthesis of the lower maxilla with titanium miniplates was also of great importance. The use of various schemes for antibiotic prophylaxis of wound infection in such patients was equally efficient.     

Cefepime in the treatment of infection in neutropenic patients]

Cefepime, a fourth-generation cephalosporin, was used in the treatment of 11 febrile episodes in 8 patients with profound neutropenia. The patients were neutropenic because of high-dose chemotherapy with stem-cell rescue or second-line salvage chemotherapy for malignant lymphomas (5 patients) or solid tumors (3 patients). The median duration of grade-IV neutropenia (according to the WHO classification) was 11 days (7 to 14). Cefepime was used as the monotherapy in a dose of 2 g thrice daily. Disappearance of the infection signs was recorded in 8 episodes (73 per cent). In 3 episodes (23 per cent) cefepime was replaced by another drug. The tolerability of cefepime was good and no adverse events were observed with the exception of 1 event of an allergic reaction.     

Carminomycin in drug combination in breast cancer and soft tissue sarcomas]

Thirteen patients with neglected mammary cancer were treated with karminomycin in combination with hexamethylmelamine. Twelve out of the 13 patients were previously subjected many times to cytostatic and hormonal therapy. A significant therapeutic effect was registered in 5 out the 13 patients (38 per cent), the total rate of the objective effect being 54 per cent. The remission period with a significant effect was 6 to 9 months. Fifteen patients with sarcoma metastases in the soft tissue were treated with karminomycin in combnation with methotrexate and cyclophosphane. A significant therapeutic effect was observed in 45 per cent of the cases with synovial sarcoma, hemangyopericitoma and leuomyosarcoma, the remission period being 4 to 12 months. The side effects of the above combinations were determined.     

Toxicity, pharmacokinetics and pharmacodynamics of the Soviet bleomycin, bleomycetin, in a single administration to laboratory animals]

Toxicity of bleomycetin (bleomycin A2) administered intravenously, intraperitoneally, subcutaneously or intramusculary in a single dose to animals was almost identical. On its oral administration bleomycetin was 10--14 times less toxic than on its parenteral use. Rats were somewhat less sensitive to bleomycetin than mice. Bleomycetin had no significant effect on the level of the arterial pressure, respiration, ECG characteristics and elements of the vegetative nervous system in narcotized cats. After a single intravenous or subcutaneous administration to rabbits bleomycetin was detectable in the blood for 4--5 hours. The highest bleomycetin levels were registered in the skin, kidneys and lungs. Bleomycetin was mainly excreted with the urine.     

Efficacy of a combination of dioxidine with beta-lactam antibiotics in the prevention and treatment of purulent-inflammatory complications

Schemes for prevention and treatment of purulent inflammatory complications were developed on the basis of in vitro studies on antimicrobial activity of dioxidine and 7 beta-lactam antibiotics such as mezlocillin, carbenicillin, ampicillin, cefotaxime, cefoxitin, cefuroxime and cephalothin under conditions of aero- and anaerobiosis with an account of the isolated microflora, its sensitivity to antibacterial agents and conditions required for vital activity of obligate anaerobes in humans, i.e. decreased partial oxygen pressure, low oxidation-reduction potentials and high tissue concentrations of carbon dioxide. The use of dioxidine in combination with the antimicrobial drugs enabled one to decrease the number of cases with purulent inflammatory complications after large intestine esophagoplasty to 30.4 per cent against 67.5 per cent in the control group of the patients untreated preventively with the antibacterial drugs. The number of cases with similar complications after gastrectomy amounted to 16.1 per cent against 62 per cent in the control. The use of dioxidine+ in combination with ampicillin and cefotaxime in treatment of purulent necrotic affections of the foot in patients with diabetes mellitus enabled one to increase the number of satisfactory outcomes by 32 per cent, to decrease the number of high amputations by 21.9 per cent and to lower the number of deaths more than 2-fold as compared to the results in the control group of the patients subjected to chemotherapy based on sensitivity of the aerobic microflora alone.