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Adriamycin, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU, NSC 409962) and cyclophosphamide therapy of drug-resistant metastatic breast carcinoma.

Thirty-two evaluable patients with metastatic carcinoma of the breast received chemotherapy consisting of BCNU plus cyclophosphamide followed in 18 hours by Adriamycin. Treatments were repeated every 4 weeks. Complete or partial responses were observed in 14 patients (43.7%) and in 12 of 27 drug-resistant patients (44.4%). An additional 26% of patients had objective improvement, for an overall objective response rate of 70.4% in drug-resistant patients. Skin, lymph node, and soft tissue metastases more frequently responded to therapy, while hepatic, peritoneal, and osseous metastases responded with an intermediate frequency. Pulmonary, pleural, and central nervous system metastases did not respond to therapy. The median duration of complete and partial responses was 6.8 months, and the median survival of these patients was 9.6 months. Overall, the median survival of all patients in this study was 6.5 months. The dose-limiting toxicity was myelosuppression, particularly granulocytopenia. Congestive heart failure and stomatitis were rare. This combination of drugs is a reasonably well-tolerated regimen for treating advanced breast carcinoma in an ambulatory setting, and produces a high rate of objective antitumor response of moderate duration.

Adenocarcinoma↗

Acute leukemia complicating treatment of glioblastoma multiforme.

A five-year-old girl developed acute myelomonocytic leukemia after fifteen months of intensive chemotherapy and irradiation for glioblastoma multiforme. The leukemia became manifest while the patient was in a remarkable remission brought about by treatment with high-dose methotrexate with citrovorum rescue. This is the first reported association of these disorders in the same patient. It is possible that the leukemia was induced by the treatment, since both radiation and the chemotherapeutic drugs used have been shown to be leukemogenic in some circumstances. The patient developed leukemia in a setting of relatively normal peripheral blood counts, having had very little myelosuppression from her treatment.

Antineoplastic Agents↗

Vincristine, prednisone and L-asparaginase in the induction of remission in children with acute lymphoblastic leukemia following relapse.

Two hundred and twenty-seven children with recurrent acute lymphoblastic leukemia were treated with various combinations of vincristine, prednisone, cyclophosphamide and L-asparaginase in an approach to the induction of remission. The combination of L-asparaginase 1,000 mu/kg iv q.d. x 10, vincristine 2.0 mg/m2iv q.w. x 4 and prednisone 40 mg/m2 p.o.q.d. x 28 days was found to be highly effective. The incidence of remission was 73%. No significant improvement was achieved when cyclophosphamide was added to this regimen. Various combinations of cytosine arabinoside, cyclophosphamide, vincristine, prednisone, BCNU or CCNU failed to maintain remission duration for more than two or three months. Neither BCNU nor CCNU prevented the development of CNS leukemia.

Adolescent↗

Prolonged complete remission following high dose chemotherapy of Burkitt's lymphoma in relapse.

Fourteen patients with American Burkitt's lymphoma resistant to conventional chemotherapy were treated with high-dose combination chemotherapy and intensive supportive care. Four patients died shortly after chemotherapy, 3 of an acute carditis. All ten remaining patients demonstrated tumor regression and 3 remain in prolonged complete unmaintained remission 29+, 19+, and 9+ months after treatment. These findings demonstrate that high-dose chemotherapy will benefit some patients with Burkitt's lymphoma unresponsive to conventional chemotherapy, but the medullary and extramedullary toxicity of this treatment strategy remains a formidable obstacle.

Adolescent↗

Treatment of histiocytic and mixed lymphomas: a comparison of two, three and four drug chemotherapy.

The Eastern Cooperative Oncology Group has studied 187 patients with generalized progressive malignant lymphoma classified as having the histologic sub-types histiocytic or mixed. Histology review by the Pathology Panel for Lymphoma Clinical Trials demonstrated a 31% disparity with contributing institution's pathologists in regard to cell type, but good agreement with interpretation of nodular or diffuse nodal pattern. Patients were assigned at random to treatment with cyclophosphamide 1 g/m2 on day 1 and prednisone 100 mg/m2 daily for five days (CP); CP plus vincristine 1 mg/m2 on day 1 (CVP); or CVP plus BCNU 60 mg/m2 on day 1 (BCVP). Chemotherapy was given for nine, twenty-one day cycles. The observed complete remission rates were CP-21%, CVP 34%, BCVP 34%. Both CVP and BCVP had significantly more complete remissions than CP, but survival following CVP (118 weeks) was significantly longer than that following either BCVP (76 weeks) or CP (74 weeks). Histologic sub-type, lymph node pattern, response to chemotherapy, performance status and stage of disease were also found to influence survival.

Adult↗

Adriamycin, 1,3-bis (2-chloroethyl) 1 nitrosourea (BCNU, NSC No. 409962), cyclophosphamide plus prednisone (ABC-P) in melphalanresistant multiple myeloma.

Fourteen patients with multiple myeloma resistant to melphalan plus prednisone were treated with BCNU 50 mg/m2 plus cyclophosphamide 200 mg/m2 on day 1, adriamycin 20 mg/m2 on day 2 and prednisone 60 mg orally, daily for days 1 through 5. Therapy was repeated every four weeks. Depending upon criteria used, objective antitumor responses were achieved in five to nine of the 14 patients. Mean survival was 9.5 months and actuarial median survival was 7.0 months. Six patients are alive, four to 35 months after initiation of therapy. This preliminary report indicates that this combination may be a useful treatment program in the management of patients with advanced multiple myeloma. A review of studies employing adriamycin plus BCNU suggests that these regimens currently offer the most effective treatment of melphalan-resistant patients.

Aged↗

Combination chemotherapy against B16 melanoma: bleomycin/vinblastine, bleomycin/cis-diamminedichloroplatinum, 5-fluorouracil/BCNU and 5-fluorouracil/methyl-CCNU.

Four antitumor drug combinations which are currently in clinical use were evaluated experimentally using the murine B16 melanoma model. Bleomycin plus vinblastine produced an increase in life span over either of the two agents alone against both intraperitoneal and subcutaneous B16. This combination also resulted in a large number of long-term survivors. Bleomycin plus cis-platinum produced slight enhancement against subcutaneous B16, but showed no advantage against intraperitoneal B16. The combination of 5-fluorouracil plus methyl-CCNU significantly increased survival time against the intraperitoneal tumor, and produced long-term survivors as well. The combination of 5-fluorouracil plus BCNU was not more effective than BCNU or 5-fluorouracil alone. These data were compared with the degree of success reported from the clinics against a variety of solid human neoplasms.

Animals↗

Diffuse well-differentiated lymphocytic lymphoma (DLWD): response and survival.

34 patients with the diagnosis of diffuse well-differentiated lymphocytic lymphoma (DLWD), confirmed by a Pathology Panel, who were entered on a previously reported Eastern Cooperative Oncology Group study (EST 1472), were analyzed for response and survival. The response rates were as follows: CR 32%, PR 39%, NC or PD 29%. Survival analysis according to chemotherapy response revealed an estimated two-year survivorship of CR 89%, PR 65%, NC 69%, and PD 44%. Comparison with NLPD entered on the same study showed a two-year survival of 83% for NLPD and 67% for DLWD, indicating significantly poorer survival for DLWD as compared to NLPD (p less than .05). Median survival for DLWD from diagnosis was 39.0 + months. The presence of lymphocytosis over 4000/mm3 had little effect on response rates or survival. We conclude that DLWD is a less favorable lymphoma type than NLPD and should be treated with aggressive chemotherapy since achievement of CR seems to effect survival favorably.

Aged↗

A comparative study of a BCNU containing 4-drug program versus MOPP versus 3-drug combinations in advanced Hodgkin's disease: a cooperative study by the Cancer and Leukemia Group B.

A prospective randomized trial by CALGB examined the relative value of four chemotherapy regimens in 537 patients with stage III B and IV Hodgkin's disease. A new combination BOPP, derived by substitution of BCNU for nitrogen mustard in the MOPP regimen, was compared to MOPP and to two 3-drug regimens, derived by removing the procarbazine in BOPP (BOP) or removing the alkylating agent (OPP). The 4-drug programs gave significantly higher frequency of complete remissions (BOPP 67%, MOPP 63%) than the 3-drug regimens (BOP 40%, OPP 42%), and significantly longer duration of remission and survival. BOPP had a therapeutic activity equal to MOPP, and was accompanied by less toxicity. After 6 cycles of induction chemotherapy, responding patients, both CR and PR, were continued on maintenance chemotherapy for 3 years. No significant difference in relapse rate was demonstrated following maintenance treatment with either vinblastine, chlorambucil, or chlorambucil plus monthly vincristine + prednisone doses. Nor could a reinforcement phase late in the maintenance program be shown to influence the relapse rate. The median survival for all patients entered on the 4-drug programs was 5 years, while the median has not yet been reached at 6 years for those patients, who obtained CR.

Adult↗

Combination chemotherapy in recurrent medulloblastoma.

Five children with recurrent medulloblastomas were treated with Vincristine, BCNU, Methotrexate and Dexamethasone. All five patients responded to therapy. Two of the patients are alive and well 30 and 48 months later; one died of disease 19 months after first recurrence; one developed a further recurrence at 18 months but responded to additional chemotherapy and is alive; and the fifth patient developed a second recurrence after 28 months but has responded to repeat chemotherapy and radiotherapy and is now asymptomatic. These results support the concept that medulloblastomas are sensitive to chemotherapy and suggest that chemotherapy should be considered in cases of recurrent medulloblastomas. In addition, the importance of trials now in progress which employ both adjuvant chemotherapy and radiotherapy in newly diagnosed medulloblastomas is apparent.

Adolescent↗

Multiple pulmonary lesions in a patient treated with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) for glioblastoma multiforme.

A patient with a glioblastoma multiforme who was treated with BCNU, developed rapidly progressive pulmonary disease. The pulmonary changes were studied pathologically and included atypical alveolar cell hyperplasia, hyaline membranes, and interstitial fibrosis. These lesions contributed to the patient's demise and may be related to the administration of BCNU.

Brain Neoplasms↗

Pulmonary toxicity of bischloronitrosourea: report of a case with transient response to corticosteroid therapy.

A case of interstitial pulmonary fibrosis secondary to bischloronitrosourea (BCNU) in a 49-year-old man with carcinoma of the pancreas is reported. The diagnosis was suggested by deteriorating oxygenation, restrictive changes on pulmonary function studies, and increased interstitial markings radiographically in the lower lung fields. Transbronchial biopsy excluded infectious etiologies and confirmed a bland nonspecific interstitial pulmonary fibrosis of recent origin. The patient responded dramatically to high dose corticosteroids, but relapsed when the corticosteroids were decreased. We believe there is now convincing evidence that prolonged use of BCNU can cause potentially fatal interstitial pulmonary fibrosis. Patients should be followed with serial chest radiographs and pulmonary function studies. If diagnosed early, this process may respond to high dose corticosteroid therapy.

Carmustine↗

Adriamycin, BCNU plus cyclophosphamide (ABC) in advanced carcinoma of the head and neck.

Forty-four patients with advanced carcinoma of the head and neck were treated with cyclophosphamide, 400 mg/m2 plus BCNU, 100 mg/m2 day 1 followed by adriamycin 40 mg/m2 day 2, with therapy repeated every 4 weeks. Of 31 evaluable patients, there were 1 complete response, and 10 partial responses (35%). Four of 8 patients without prior chemotherapy had complete or partial responses, as did 7 of 23 patients who had received prior chemotherapy. The mean survival for patients with partial responses was 8.8 months, and for patients with stable disease was 7.8 months. The mean time to progression for patients with partial responses was 5.4 months, and for patients with stable disease was 3.2 months. Granulocytopenia was the dose limiting toxicity, and patients with increasing degrees of myelosuppression appeared to have higher quality responses and longer survival. The ABC treatment program is useful in the palliative management of patients with advanced carcinoma of the head and neck.

Antineoplastic Agents↗

Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma: a preliminary report.

Nine patients with intracerebral metastasis from lung carcinoma were treated with intracarotid and intravertebral artery infusion of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Four of these patients considered definite responders showed unequivocal clinical improvement and definite decreases in the size of tumors evaluated by neurologic examination, computerized tomographic (CT) scan and radionuclide brain scan (RBS). One patient's clinical condition stabilized with doubtful improvement of diagnostic tests (probable responder). The remaining four patients had further unfavorable progression of the clinical and scan findings and were clearly nonresponders. Complications were transient and included: local pain in the eye, orbit, and occipital-nuchal area during infusion in 7 patients, focal seizure in 3 patients, mild confusion with disorientation in 2 patients, and nausea in 2 patients. Our findings suggest that intra-arterial BCNU therapy may be effective and may be used as an adjuvant to surgery and/or radiotherapy for the treatment of metastatic brain tumor from lung carcinoma.

Adult↗

Adriamycin, BCNU, ftorafur chemotherapy of pancreatic and biliary tract cancer.

Twenty-six evaluable patients with disseminated or locally unresectable pancreatic or biliary tract carcinoma received Ftorafur (4 g/m2 iv day 1 and 22 and 2 g/m2 iv day 4 and 26), Adriamycin (60 mg/m1 IV day 1 and 45 mg/m2 iv day 22) and BCNU (150 MG/M2 IV DAY 1) combination chemotherapy (FAB) repeated at 6--8 week intervals. Two (29%) complete and one (14%) partial remissions were observed in 7 patients with biliary carcinoma while 5 of 19 (26%) patients with pancreatic carcinoma achieved partial remissions. Median survival for responding patients was approximately 11 months (range 7--16+) with median survivals of about 6 months (p less than 0.05 and about 3 months (p less than 0.05) for patients with stable and progressive disease. Major drug toxicity was myelosuppression with median lowest granulocyte counts of 1,000/microliters and platelet counts of 88,000/microliters. Approximately 25% of patients required antibiotic therapy for fever of unknown origin or documented infections. Other tolerable drug toxicities included nausea, vomiting and mucositis. The FAB regimen appears quite promising in biliary tract cancer and has efficacy in pancreatic carcinoma that warrants further clinical trials. Because of myelotoxicity observed with this regimen we now recommend a BCNU starting dose of 100 mg/m2 instead of 150 mg/m2.

Adult↗

Phase II study of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU, NSC No. 409962) with amphotericin B in bronchogenic carcinoma.

Eighteen patients with unresectable bronchogenic carcinoma were treated with amphotericin B (7.5 mg/m2 on day 1, 15 mg/m2 on day 2, and 30 mg/m2 on days 3 and 4) plus BCNU (250 mg/m2 on day 4 following amphotericin B) with courses of therapy repeated every 8 weeks. All patients had metastatic disease, and 5 had received prior chemotherapy. Antitumor responses were observed in 8 patients. Six patients had partial responses (greater than 50% decrease in tumor area): 1 of 3 with small cell undifferentiated carcinoma, 1 of 4 patients with large cell undifferentiated carcinoma, 2 of 7 patients with adenocarcinoma, and 2 of 4 patients with epidermoid carcinoma. Two patients had objective improvement (25--50% decrease in tumor area): 1 with small cell undifferentiated carcinoma and 1 with epidermoid carcinoma. The median duration of remission was 3 months. The median duration of survival was 7 months for patients achieving partial response, and only 2 months for other patients. Myelosuppression was the dose limiting toxicity. One patient died with hepatocellular dysfunction, possibly related to BCNU. Transient hypotension was observed in 2 patients. We conclude that amphotericin B plus BCNU produced an encouragingly high response rate in patients with bronchogenic carcinoma, and that a randomized phase III trial is warranted to determine whether amphotericin B enhances the antitumor effects of nitrosoureas or other known antitumor agents.

Adenocarcinoma↗