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PubMed1987

Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma.

Twenty-three patients with metastatic melanoma were treated with combination therapy consisting of dacarbazine (220 mg/m2) and cisplatin (25 mg/m2) iv daily for 3 days every 3 weeks, carmustine (150 mg/m2) iv every 6 weeks, and tamoxifen (10 mg) orally twice daily. In 20 evaluable patients, there were no complete responses and ten partial responses. The median remission duration has not yet been reached but exceeds 7 months. Treatment was relatively well tolerated. However, six patients developed deep venous thrombosis, and four of these six suffered pulmonary emboli. Our data support a previous study and suggest that this combination warrants comparison with the active single components in a randomized prospective trial.

Adult↗
PubMed1987

Simultaneous radiotherapy and chemotherapy in the treatment of brain metastases of malignant solid tumours.

Between January 1982 and June 1985, 105 patients with brain metastases of malignant solid tumours were treated in the Robert Janker Clinic. In order to optimize the overall response rates, concomitant radiotherapy and cytostatic chemotherapy was used. In most cases the primary tumour was located in the breast or the lung. Radiotherapy was performed with a Cobalt 60 equipment. The whole brain was irradiated in daily fractions of 15 Gy up to total dose of 45 Gy. Using a slit-course technique this dose was distributed to the three cycles of chemotherapy and given simultaneously, i.e. 15 Gy/ by course. The chemotherapeutic regimen consisted of ifosfamide daily for five days at 2g/m2 and the nitrosurea derivative carmustin (BCNU) at 30 mg/m2 on days 1, 3 and 5. After a free interval of four to five weeks the concomitant radiotherapy and chemotherapy was repeated twice. The tolerance of the treatment was generally good; no severe haematological or gastrointestinal complications occurred. There was a complete and permanent alopecia in all patients caused by the radiation. All patients received a cranial computerized axial tomographic scan prior to and after the treatment. According to the criteria of the International Union Against Cancer, there was a complete remission in 26 of the 105 patients and a partial remission in 49; 19 patients showed a stable disease. Only 12 of the 105 treated patients had a progression of their metastases. Only patients with partial or complete remissions after the treatment belong to the "long-term" survivors.

Adolescent↗
PubMed1985

Lymphomatoid papulosis associated with plaque-stage and granulomatous mycosis fungoides.

A 47-year-old black man had typical papulonodular lesions of lymphomatoid papulosis (LyP) with concurrent plaque-stage mycosis fungoides (MF). Both diagnoses were confirmed histologically. This supports the concept that LyP is part of the spectrum of cutaneous T-cell lymphoproliferative disorders. The patient also had a large nodule and a deeply infiltrated plaque, each of which exhibited a deep granulomatous reaction. These were interpreted as representing granulomatous MF. Clinically, there was an evolution from a predominance of LyP lesions to a predominance of MF plaques. Topical carmustine therapy resulted in a substantial decrease in the number and size of both LyP and MF lesions. Both lesion types involuted with hypopigmentation.

Administration, Topical↗
PubMed1985

Enhanced acute lung damage in mice following administration of 1,3-bis(2-chloroethyl)-1-nitrosourea.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), also known as carmustine, is a lipid soluble anticancer drug which produces pulmonary fibrosis in up to 30% of the patients who receive this drug. The major risk factor for this disorder is preexisting lung damage. Animal models of this interaction have not been reported previously. A diffuse alveolar lesion was produced in male BALB/c mice by the administration of butylated hydroxytoluene (BHT). Total lung hydroxyproline levels, an index of fibrosis, were not increased in mice 21 days after single doses of BHT or BCNU. Total lung DNA synthesis, an index of pulmonary damage, was slightly increased after 15 and 18 days in rats and mice treated with BCNU (15 and 35 mg/kg, respectively). This suggested that a single dose of BCNU had only a minimal toxic effect on lung tissue. Combined treatments in mice given BHT (350 or 400 mg/kg), followed on Day 1 by BCNU (35 mg/kg), resulted in the deposition of significantly more hydroxyproline than with either agent alone. This enhancement was not seen following lower doses of BHT and was diminished when the dose of BCNU was decreased. Delaying the administration of BCNU (35 mg/kg) until Day 3 or 5 eliminated increases in hydroxyproline content, but not histological evidence of enhanced lung damage. Additional histological analyses confirmed the presence of an increased fibrotic reaction, especially when high doses of BCNU were administered 1 day after BHT (400 mg/kg). Most of the lungs were totally consolidated with numerous hyperactive fibroblasts and a large number of giant type II cells with atypical nuclei. These effects may be related to the ability of BCNU to inhibit pulmonary glutathione reductase activity and the increased DNA synthesis normally seen after BHT. These data show that BCNU treatment can enhance BHT-induced lung damage resulting in a fibrotic lesion similar to that seen in some human patients. This effect is dependent on the extent of the initial lung lesion as well as the time when BCNU is administered and may represent an animal model of the primary risk factor for the development of pulmonary fibrosis in human patients receiving this drug.

Animals↗
PubMed1979

Improved survival of increased-risk myeloma patients on combined triple-alkylating-agent therapy: a study of the CALGB.

Two hundred fifty-two previously untreated evaluable patients with multiple myeloma were entered into a study testing a regimen of three intravenous alkylating agents, melphalan, cyclophosphamide, and carmustine (BCNU), given in combination (BCMP) against a regimen employing oral melphalan (MP). Both regimens included a tapering course of prednisone. Objective responses based on the Myeloma Task Force criteria were significantly more frequent in the group receiving BCMP. Survival for the entire group of BCMP-treated patients was not significantly better than that for MP-treated patients (p = 0.62). However, when the survival of the poor-risk (high tumor cell load) group of patients treated with BCMP was compared with the survival of the poor-risk (high tumor cell load) group of patients treated with MP, an improvement in survival attributable to BCMP therapy was seen (p = 0.049 and 0.02, respectively). In the good-risk (low and intermediate tumor cell load) group, BCMP treatment resulted in a trend toward poorer survival, but this did not achieve statistical significance (p = 0.080 and 0.23, respectively). These results indicate that optimal therapy in myeloma may be dependent on the extent of disease at the time of first treatment. Additional studies to explore the effects of treatment intensity and duration are needed in order to design improved myeloma treatment based on the patient's extent of disease.

Alkylating Agents↗
PubMed1977

Paraneoplastic syndrome in childhood.

The case of five-year old boy is reported who at the age of 18 months had successfully been operated upon for neuroblastoma and who had subsequently signs of cerebellar encephalopathy. The paraneoplastic conditions of childhood are discussed in connection with the reported case. Opsoclonus was not observed in the patient, and symptoms showed rapid improvement on methotrexate, carmustine and CCNU treatment. Six months later the child was free of neurological disturbances and only displayed a slight mental retardation (IQ: 88). Cytological alterations observed in the CSF during the cerebellar encephalopathy are described in detail. At present, 41 months after the operation the child is well and free of symptoms.

Brain Diseases↗
PubMed1984

Responses of RIF tumors to heat and drugs: dependence on tumor size.

The effects of hyperthermia and drugs on RIF tumors of three sizes were studied in C3H mice. The animals were treated with bleomycin, carmustine, or a combination of both drugs and with or without concomitant localized hyperthermia. The hyperthermia dose was 44 degrees C for 30 minutes for each treatment. Each animal was given two treatments, 7 days apart. The tumors were classified according to approximate size: 0.1, 0.3, or 0.7 cm3. Among the animals bearing the smaller tumors, no cures were observed. Growth delay measurements indicated that heat and drugs had approximately additive effects. Several cures were seen among the animals bearing medium- and large-sized tumors. Our results indicate that medium and large tumors may respond better to the combination treatment than small tumors.

Animals↗
PubMed1984

Therapy for multiple myeloma with alternating non-cross-resistant chemotherapy combinations: heterogeneity of tumor responsiveness.

Thirty-five previously untreated patients with multiple myeloma were treated with a 60-week course of alternating, potentially non-cross-resistant chemotherapy combinations (melphalan and prednisone; vincristine, cyclophosphamide, doxorubicin, and prednisone; and carmustine, melphalan, and prednisone), alternating every 15 weeks in an attempt to prevent the development of drug resistance. The overall objective response rate (greater than 50% decrease in M protein) was 60% and six patients (17%) had a complete disappearance of the M protein. After 60 weeks, chemotherapy was discontinued in 17 responding or stable patients until relapse occurred from 4 to 39 months later (median, 12 months). Patients relapsing late (greater than 12 months after discontinuation of therapy) responded more frequently than those relapsing earlier to the reinstitution of the same chemotherapy program. The overall response rate and the actuarial median survival of 26 months in the 35 patients do not differ from the results reported recently with nonalternating combinations given until clinical tumor progression. The failure of this study to prolong survival by using alternating regimens may be due to (a) the likely possibility that the initial two regimens are not actually non-cross-resistant in most myeloma patients, and (b) the long interval between the alternating regimens, particularly in the face of the low response rate to the initial regimen of melphalan and prednisone.

Adult↗
PubMedDate not supplied

Superselective injection of BCNU through a latex calibrated-leak balloon.

Carmustine (BCNU) has been used extensively to treat glioblastomas by injection through a catheter placed in the cervical internal carotid artery. The technique causes severe pain to the eye and has resulted in ipsilateral blindness. The use of a latex calibrated-leak balloon positioned above the ophthalmic artery in the internal carotid artery or in one of its branches appears to circumvent the ocular complications mentioned. At an infusion rate at 125 ml/hr the balloon does not inflate and does not occlude the artery. This new technique has been used to treat 10 patients without complications.

Brain Neoplasms↗
PubMed1984

Potentiation of cytotoxicity of anticancer agents by several different polyene antibiotics.

The ability of several different polyenes to potentiate the cytotoxicity of carmustine, lomustine (LOM), and doxorubicin (DX) against AKR mouse leukemia was quantitated. All polyenes could potentiate the cytotoxicity of the anticancer agents; however, the methyl ester derivatives of the heptaenes amphotericin B and candicidin and the triene trienine were most effective with potentiations in the order of ten thousandfold for DX and LOM. A steep dose-response relationship for the polyenes was also noted. Neither the toxicity of the polyenes nor their level of potentiation could be correlated with structure or class.

Animals↗
PubMed1984

Arterial drug infusion with extracorporeal removal. I. Theoretic basis with particular reference to the brain.

The pharmacokinetic advantage of intra-arterial drug administration can be improved if blood from the infused region is perfused through a suitable extracorporeal device. The extent of improvement depends on the blood flow to the device, the fraction of the vascular drainage that can be obtained, and the drug extraction by the device. A relatively simple equation is derived to assess the pharmacokinetic advantage and to define the governing parameters. Application of the theory to the treatment of brain tumors includes a discussion of the selection of an experimental animal and interpretation of results. It is suggested that tumor exposure to carmustine comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.

Animals↗
PubMed1982

Treatment of advanced Hodgkin's disease: 10-year experience in the Eastern Cooperative Oncology group.

Between 1972 and 1981, the Eastern Cooperative Oncology Group completed two major studies of advanced Hodgkin's disease. The first trial EST 2472, demonstrated that the five-drug combination of carmustine (BCNU), cyclophosphamide, vinblastine, procarbazine, and prednisone (BCVPP) is an effective alternative to mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) chemotherapy. Although the complete remission (CR) rate for BCVPP (77%) was similar to that for MOPP (73%) in this randomized trial, the choice of induction chemotherapy significantly influenced CR duration. Patients achieving CR with BCVPP had a significantly greater disease-free survival than those who achieved CR with MOPP (65% vs 50%, respectively, at 5 years, P = 0.02). Overall survival is not different at this time between patients who received BCVPP and those who received MOPP. BCVPP produced significantly less gastrointestinal toxicity and neurotoxicity than MOPP. There was no influence on CR duration or survival with maintenance chemotherapy or BCG immunotherapy when compared to no further treatment. In the second trial, EST 1476, there was only a 58% CR rate with six cycles of low-dose bleomycin-MOPP induction chemotherapy. Complete responders and continuing partial responders were then randomized to receive either non-cross-resistant chemotherapy with doxorubicin, bleomycin, vinblastine, and DTIC (dacarbazine) (ABVD) or low-dose radiotherapy to all sites of pretreatment involvement except bone marrow. Fifty percent of the partial responses were converted to CR with either ABVD or radiotherapy consolidation. The overall CR rate at the end of consolidation was 68%. At the present time, there is no significant difference in disease-free or overall survival between ABVD and radiotherapy.

Adult↗
PubMed1982

Chemotherapy for advanced Hodgkin's disease: conclusions from the Southeastern Cancer Study Group.

The Southeastern Cancer Study Group has explored a variety of approaches to the management of advanced Hodgkin's disease. These have largely involved the use of nitrosoureas, especially BCNU (carmustine), alone or in combination with other agents. Initial phase II trials of BCNU as a single agent in patients refractory to mechlorethamine demonstrated considerable antitumor activity. Exploratory experiments with BCNU in combination with alkylating agents, vinca alkaloids, and corticosteroids resulted in the development of the combination BVCPP (BCNU, vinblastine, cyclophosphamide, procarbazine, and prednisone). BVCPP, given only once monthly, produces at least a 65% complete response rate with minimal to moderate toxicity, making it an effective alternative to other regimens such as MOPP. Alternating BVCPP with a non-cross-resistant combination (doxorubicin, DTIc [dacarbazine], and bleomycin) offered no advantage in response rate or survival. Continued research with new agents and/or combined modality approaches is necessary in view of continued primary and secondary treatment failure with all regimens used for the management of advanced Hodgkin's disease.

Antineoplastic Agents↗
PubMed1982

Vincristine, BCNU, doxorubicin, and prednisone (VBAP) combination in the treatment of relapsing or resistant multiple myeloma: a Southwest Oncology Group study.

A total of 151 patients with myeloma who had relapsed with or were resistant to melphalan and/or cyclophosphamide (Cytoxan) with prednisone received vincristine, carmustine (BCNU), doxorubicin (Adriamycin), and prednisone (VBAP) at 21-day intervals; 39 patients (25%) responded. Of the 123 patients with relapsing myeloma, 37 (30%) responded. Only two (7%) of the 28 patients with resistant myeloma responded. The regimen was well-tolerated in patients who had not had prior extensive irradiation. Thrombocytopenia was the most frequent form of toxicity. Survival was significantly longer in those patients responding to VBAP (median, 78 weeks) than in those not responding (median, 33 weeks) (P = 0.002). VBAP is a safe, effective regimen for patients with myeloma who relapse with alkylating agents.

Antineoplastic Agents↗
PubMed1982

Development and characterization of a cyclophosphamide-resistant mouse plasmacytoma cell line.

Murine LPC-1 plasmacytoma is sensitive to treatment with cyclophosphamide (CY), and animals bearing this tumor in advanced stages can be cured with doses as small as 60 mg/kg. With repeated transfer of LPC-1 cells followed by subcurative CY therapy, we have developed from this CY-sensitive parent line (CY-S) a stable CY-resistant subline (CY-R) that is unaffected by doses as large as 250 mg/kg. Stability of this induced CY resistance in the absence of CY treatment has been demonstrated for greater than 14 transfer generations. The CY-R subline has been compared to the CY-S parent line and shown to be similar with respect to morphology, growth kinetics, survival time, synthesis of IgG 2a kappa M component, and DNA content and distribution. The CY-S parent line responds in vivo to CY analogs (ifosfamide and trofosfamide), as judged by decreased tumor mass and increased survival; the CY-R subline is resistant to the CY analogs. The response to carmustine (BCNU) was tested, and resistance to CY did not predict for response to this alkylating agent since the effect on both CY-S and CY-R lines was equal. The significance of the development of this CY-resistant subline and the implications for future research into the mechanisms of such resistance are discussed.

Animals↗
PubMed1994

High-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy: analysis by age.

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Autologous stem cell transplantation for refractory and relapsed Hodgkin's disease: factors predictive of prolonged survival.

We analyzed patient, disease, and treatment related factors associated with long-term disease-free survival (DFS) in 62 patients with refractory or recurrent Hodgkin's disease treated with high-dose cyclophosphamide (6000 mg/m2), carmustine (BCNU; 300 mg/m2), and etoposide (900 mg/m2) (CBV) followed by autologous stem cell transplantation. There were no deaths resulting from toxicity of the preparative regimen, and all patients survived the peritransplant period. At 28 days post-transplant, the complete response (CR) rate was 76%. Patients who achieved a CR had a 50% estimated 3-year DFS (95% CI, 35-64%). Twenty-three (37%) patients remain in continuous clinical remission 1.3 to 7.7 years (median 3.8 years) after transplantation. In a univariate analysis, factors significantly associated with improved DFS included absence of B symptoms (fever, night sweats and unexplained weight loss) at transplant, response to pre-transplant salvage chemotherapy, less tumor bulk at time of transplant, and fewer prior treatment regimens. Stepwise multivariate analysis showed that the absence of B symptoms at time of transplant was independently and significantly associated with improved DFS after transplantation. CBV with autologous stem cell support can produce durable remissions with acceptable toxicity in a substantial proportion of patients who are asymptomatic at time of transplant. Earlier application of transplantation or development of additional effective antineoplastic modalities will be required to improve the results of transplantation for patients with advanced Hodgkin's disease.

Adolescent↗
PubMed1995

High-dose chemotherapy with BEAC regimen and autologous bone marrow transplantation for intermediate grade and immunoblastic lymphoma: durable complete remissions, but a high rate of regimen-related toxicity.

Forty-eight adult patients with recurrent or refractory intermediate grade or immunoblastic lymphoma received high-dose carmustine (BCNU), etoposide, Ara C and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (BMT). Median follow-up is 906 days (range 613-2067 days). The complete remission rate was 42% and 22% had a partial response. Actuarial failure-free survival is 30% +/- 6.6%. Twenty one patients relapsed or progressed. Only one relapse occurred > 1 year after autologous BMT. Adverse prognostic factors for failure-free survival include high LDH at the time of autologous BMT, chemotherapy-refractory disease and multiple prior relapses. Patients with chemotherapy responsive first salvage (those achieving first CR only with salvage chemotherapy and those with first relapse, responding to salvage chemotherapy) had a failure-free survival of 52% +/- 10% vs 12% +/- 6% for those with more advanced disease. Of 13 patients who had no adverse factors, only two relapsed. Treatment-related mortality occurred in 23%, including infection (n = 4), cardiac toxicity (n = 4), pulmonary toxicity (n = 2) and hemorrhage (n = 1). Pulmonary toxicity was more common among patients who had received prior radiation-therapy to the chest. BEAC chemotherapy with autologous BMT is an effective but relatively toxic regimen for patients with relapsed or refractory lymphomas. The combination of chemotherapy-responsive disease after failure of one chemotherapy regimen and normal LDH identifies patients with a favorable prognosis. Alternative cytotoxic regimens require evaluation, with the goal of reducing treatment related mortality. More effective cytoreductive therapy is required for patient with poor prognostic features.

Adolescent↗