High-dose BCNU Research Articles

High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma.

Fourteen patients with small cell carcinoma of the lung in relapse or with disease refractory to chemotherapy were treated with carmustine (BCNU) at doses of 600 to 1000 mg/m2 intravenously followed by autologous bone marrow transplantation. All patients previously were treated with cyclophosphamide, doxorubicin, vincristine, and etoposide. Seven of the 14 patients responded to the high-dose BCNU (50% response with 95% confidence limits ranging from 23% to 77%). Three patients had a complete response, and four had a partial response. Regrowth of tumor occurred within 60 days of treatment in the responding patients. Death occurred in six patients before the recovery of the platelet count to 50,000 cells/microliters. Although the response rate was high, the toxicity was excessive. In the dosage range of 600 to 1000 mg/m2 in heavily pretreated patients, BCNU is not recommended, but additional investigation may be warranted in patients with central nervous system metastases who previously were treated with radiation therapy.

High-dose carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support: excessive hepatic toxicity

Intensive doses of carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support were given to four patients with advanced melanoma. Three developed clinically diagnosed, severe veno-occlusive liver disease, which was fatal in two cases. The dose of carboplatin (450 mg/m2) was comparable with that used in ambulatory regimens. At the doses and schedule employed, this three-drug combination produced excessive hepatic toxicity. Caution is suggested when giving carboplatin in combination with intensive doses of other chemotherapeutic agents with known hepatotoxic potential.

Chemotherapy for malignant melanoma: combinations and high doses produce more responses without survival benefit

In a consecutive series of studies, 164 patients with symptomatic and/or visceral metastatic malignant melanoma were treated with single agent vindesine, high dose melphalan with autologous bone marrow transplantation (AMBT), high dose BCNU with ABMT or the BOLD (bleomycin, vincristine, CCNU and DTIC) combination. The high dose treatments and the combination chemotherapy resulted in significantly higher response rates but no prolongation of survival. Factors associated with longer survival included the absence of visceral metastases, the absence of bulky disease and good performance status. For all treatments, life table estimates of survival at 1 and 2 years were only 10% and 4% respectively.

Pathology of high-dose intraarterial BCNU

Current radiotherapy and chemotherapy for high-grade and/or recurrent astrocytomas result in only moderate increases in survival time. In an attempt to improve this, high-dose intraarterial 1,3-bis-(2-chloroethyl)-l-nitrosurea (BCNU) was utilized on 41 patients with these neoplasms over a 4-year period at our institution. Eight of the 41 patients came to biopsy or autopsy at times sufficiently following intraarterial BCNU infusion and with adequate tissue samples to evaluate the histological changes induced by the drug. Two of the eight patients received no additional radiotherapy or chemotherapy. The other five received conventional whole brain irradiation, and one additionally received 50 mg of intravenous 2-deoxy-5-fluorouridine (FUdR). The eight patients showed mild to severe amounts of bland coagulative necrosis, vascular hyalinization, perithelial fibroblastic proliferation, and endothelial atypia. One of these patients had a recognized severe clinical leukoencephalopathy, and the pathological changes were maximal in this individual. Six patients had radiological evidence of increased necrosis and clinical deterioration prebiopsy or preautopsy, but, within this group, there were no distinguishing clinical features. Microscopic changes were severe in two of these patients. A final patient died of unrelated septic shock 5 days after a single infusion of intraarterial BCNU, and the microscopic changes were least extensive in her. This study suggests that high-dose intraarterial BCNU can cause a leukoencephalopathy, sometimes severe, either alone or in synergistic fashion with cranial irradiation. Occurrence of such leukoen-cephalopathy is not always predictable based on BCNU dosage and cannot always be reliably distinguished from tumor regrowth or tumor necrosis by radiological and clinical evaluation. Hence, caution most be exercised in continuation of high-dose intraarterial BCNU protocols.

High-dose chemotherapy with autologous bone marrow support in advanced malignant melanoma.

Eight patients with advanced malignant melanoma were treated with high-dose melphalan (80-90 mg/m2) and BCNU (600-800 mg/m2). In all patients autologous bone marrow preservation was performed prior to therapy. Bone marrow was stored for 48 h in a refrigerator at 10 degrees C and reinfused 48 h post-therapy. Three patients had a complete response (CR), 1 a partial response and 4 patients no response. Two patients with CR died 4 and 5 months after therapy. One had an interstitial pneumonitis and 1 patient died from unknown cause. The third patient had a relapse 12 months after therapy. Major side effects were severe nausea/vomiting and a mild mucositis. Two patients suffered from BCNU-related encephalopathy. All patients had a full hematologic reconstitution after 6 weeks. High-dose chemotherapy with autologous bone marrow support achieves a high response rate. Long-term disease-free survival, however, was not seen with this approach.

High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma.

In a series of 22 patients, high dose BCNU (800-1,000mg m-2) with autologous bone marrow transplantation was given as the first post-surgical treatment for grade IV astrocytoma and followed by full dose radiotherapy. When compared to historical experience and matched to control patients in national studies, there appeared to be a small prolongation of survival but no increase in the proportion of long survivors. Acute myelosuppression was mild but toxicity to lung and liver was substantial and limited further dose escalation. Late bone marrow failure was seen in 4 patients. Pharmacokinetic studies were performed and suggested that the late marrow failure was due to persistence of BCNU at the time of marrow return. Despite the suggestion of a prolongation of survival this approach is not routinely recommended and a randomised trial is probably not justified.

Prolongation of survival for high-grade malignant gliomas with adjuvant high-dose BCNU and autologous bone marrow transplantation.

Employment of postoperative brain irradiation in the initial management of high-grade malignant glial tumors has now become standard. The addition of conventional chemotherapy to irradiation has not significantly improved median survival beyond 1 year. We treated 25 consecutive patients (13 pilot patients and 12 protocol patients) with histologically confirmed unresectable grade 3 or 4 malignant gliomas with high-dose BCNU (carmustine) followed by autologous bone marrow transplantation and whole brain irradiation. Within 3 weeks of initial surgery, each patient had autologous bone marrow stored (median 2 X 10(8) nucleated cells/kg), and then received BCNU 1,050 mg/m2 intravenously (IV). Peripheral granulocytes recovered (greater than 500/microL) at a median of 19 days (range, 10 to 37 days), and platelets recovered (greater than 20,000/microL) at a median of 18 days (range, 13 to 40 days), following bone marrow infusion. Patients received 60 Gy whole brain irradiation when granulocytes were greater than 1,500/microL. Toxicity was well tolerated. Nausea occurred in 19 patients (76%); however, only eight patients (32%) experienced vomiting (mild in three, moderate in five). Eleven patients (44%) did not require empiric antibiotics, six of whom never developed an absolute granulocyte count less than 500/microL. Three patients with a poor performance status died early (one seizure with vomiting and asphyxiation; one, klebsiella urinary tract infection (UTI) with bacteremia; one, candidal pneumonia), and one additional patient who was performing well died of pulmonary hemorrhage. The 13 pilot patients have now been followed for a median of 23 months, with a significant survival advantage compared with the 52 consecutive historical control patients who received similar surgery and radiotherapy without high-dose BCNU (P = .037). The overall study group of 25 patients also has a significant survival advantage when compared with the same historical control group, with a projected median survival of 26 months (P = .007). This new approach using early postoperative intensive therapy consisting of high-dose BCNU, autologous bone marrow transplantation, and whole brain irradiation appears to significantly improve survival.

High-dose chemotherapy without autologous bone marrow transplantation in melanoma.

High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse.

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.

Treatment of the blastic transformation of chronic granulocytic leukemia using high dose BCNU chemotherapy and cryopreserved autologous peripheral blood stem cells.

Seven nonsplenectomized patients with blastic CGL have received high dose BCNU chemotherapy followed by cryopreserved peripheral blood stem cells (PBSC). The PBSC obtained at diagnosis were stored in the vapor phase of liquid nitrogen in 10% dimethyl sulfoxide for 11-46 months prior to use. Patients received 2.9 X 10(8) (1.9-7.8) thawed washed mononuclear cells/kg over 30 minutes with minimal morbidity. One patient was not rendered pancytopenic and died with blastic leukemia at 4 months. One patient, previously treated with daily busulfan, died of progressive hepatic failure 2 months after high dose BCNU. Restoration of the chronic phase of CGL was observed in the remaining five patients. Peripheral blood counts returned to normal ranges after a median of 19 days. Median survival for all patients is 11 months. Cytogenetic studies revealed elimination of acquired aneuploid cell lines in four of seven patients with persistence of Ph1. We conclude that: 1) frozen PBSC retain their viability for up to 4 years after cryopreservation and 2) the use of autologous PBSC following ablative chemotherapy may be associated with both symptomatic and karyotypic improvement in patients with blastic CGL.

Autologous bone marrow transplantation following high-dose chemotherapy with cyclophosphamide, BCNU and VP-16 in small cell carcinoma of the lung and a review of current literature

Four patients with limited disease small cell carcinoma of the lung were treated with high-dose cyclophosphamide (120 mg/kg over days 1 and 2), BCNU (400 mg/m 2 over days 1 and 2) and VP-16 (200 mg days 1–5) used as intensification treatment after conventional chemotherapy. To ameliorate hematopoietic toxicity, autologous bone marrow cells collected and cryopreserved prior to treatment were reinfused on day 8. In three patients clinical response was evaluable. Two achieved a complete remission: one died without evidence of tumor after 3 months; the other had a regional relapse after 6 months. One patient who had progression of disease on conventional chemotherapy was refractory to high-dose treatment. Three patients developed diffuse interstitial pneumonitis 3 weeks after treatment and two died of respiratory failure. High-dose intensification chemotherapy with autologous marrow reinfusion may complement the effects of standard combination chemotherapy in small cell carcinoma of the lung. The current status of this approach is reviewed.

High dose BCNU with autologous bone marrow rescue in the treatment of recurrent malignant gliomas.

Eleven patients with malignant gliomas recurring after surgery and radiation therapy, were treated with high dose BCNU 1 050-1 200 mg/M2 with autologous bone marrow rescue. Four patients also received concomitant 5-fluorouracil 1 000 mg/M2/24 hr daily for three days. Eight of ten evaluable patients demonstrated improvement on CAT scan as well as a decrease in steroid requirement. All patients surviving longer than two weeks after BCNU administration experienced full hematologic recovery. No delayed myelosuppression was seen after a single course of high dose therapy. Two patients died as a result of therapy, one following a second induction of BCNU for a total cumulative BCNU dose of 2 400 mg/M2 and one of infection while cytopenic. Additional toxicity includes one steroid-responsive interstitial pneumonitis, one centrilobular necrosis of the liver which spontaneously resolved and one episode of deep vein thrombosis. With limitation on the maximum BCNU dose and distribution of the total dose over three days, high dose BCNU can be administered with acceptable toxicity. This approach may offer a higher response rate than that expected for standard dose BCNU.

Hemorrhagic encephalitis produced by selective non-occlusive intracarotid BCNU injection in dogs.

A selective non-occlusive technique was developed for administration of BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) into the internal carotid artery of the dog, and the neuropathological effects in the brain were studied. One out of three dogs showed ipsilateral hemorrhagic necrotizing encephalitis at doses of 102 mg/sq m, and all of three dogs showed similar but more severe pathology at doses of 215 to 232 mg/sq m. This study and previous studies in the dog and monkey suggest definite thresholds above which cerebral toxicity occurs when BCNU is administered via the intracarotid route. Greater dilution of drug in the larger territory of supply of the human internal carotid artery allows somewhat higher doses in man. The pathology of the lesion induced by BCNU suggests a primary vascular injury as a pathogenic mechanism, consonant with similar findings following high-dose systemic BCNU administration in man. Investigators conducting ongoing and future trials of intracarotid BCNU in the human for the treatment of intracranial neoplasms should be especially vigilant for a similar toxic effect.

Nursing management of the patient receiving high-dose BCNU with autologous bone marrow harvest.

Nursing management of the patient receiving high-dose BCNU with autologous bone marrow harvest.

High dose BCNU followed by autologous bone marrow infusion in glioblastoma multiforme.

Four patients with glioblastoma multiforme were treated with high dose BCNU, 800 mg/m2, and autologous marrow transplantation. Two patients were treated in their first and 2 in their second remission. All patients are alive between 1 and 12 months from transplantation.

Encephalomyelopathy following high-dose BCNU therapy

Encephalomyelopathy following high-dose BCNU therapy

Bone marrow harvesting and high-dose BCNU therapy

Bone marrow harvesting and high-dose BCNU therapy

High-dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme.

Eleven patients with recurrent malignant glioma were treated with single high doses of BCNU ranging from 600 to 1400 mg/sq m. To prevent the characteristic late myelosuppression observed after conventional doses of BCNU, autologous bone marrow harvested just before drug treatment was infused 24 to 36 hours after therapy. Higher doses of BCNU causes earlier and more profound myelosuppression; one patient died on pancytopenia, breakdown of the gut epithelium, and Clostridium septicemia 10 days after receiving 1400 mg/sq m of BCNU. All patients experienced transient emesis; four developed transient elevation of hepatic enzymes, two reversible interstitial pulmonary infiltrates, and two who received 1400 mg/sq m BCNU suffered irreversible cortical damage. Eight patients receiving 600 to 1200 mg/sq m demonstrated reconstitution of polymorphonuclear leukocytes an platelets within at least 30 days after treatment. With a follow-up time of up to 19 months, four patients improved, three stabilized, and three deteriorated and died. The median survival time was 7 months. Computerized tomography performed on patients receiving constant corticosteroids showed diminished contrast enhancement and mass effect in eight patients. High-dose BCNU at doses up to 1200 mg/sq m with marrow rescue is a feasible approach to the treatment of patients with glioblastoma.