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PubMed2006

Clinical experience: practical management of five patients with cutaneous T-cell lymphoma (CTCL)-related symptoms.

There are now a wide variety of therapeutic options for managing patients with cutaneous T-cell lymphoma-related symptoms. These include skin-directed therapies such as psoralen with UVA irradiation (PUVA), topical chemotherapies such as mechlorethamine (nitrogen mustard) and carmustine (BCNU), electron beam radiation, and systemic therapies such as chemotherapy, photopheresis, and interferons. Although treatment algorithms exist for patients with early stage disease, often treatments are individualized, based on patient specific factors, cost, and accessibility of referral centers for specialized therapies. This article provides details of five real-life case studies to illustrate how cutaneous T-cell lymphoma management can be tailored to the needs of each individual patient.

Aged↗

PubMed2000

Phase II study of second-line therapy with DTIC, BCNU, cisplatin and tamoxifen (Dartmouth regimen) chemotherapy in patients with malignant melanoma previously treated with dacarbazine.

This study assessed response rates to combination dacarbazine (DTIC), BCNU (carmustine), cisplatin and tamoxifen (DBPT) chemotherapy in patients with progressive metastatic melanoma previously treated with DTIC, as an evaluation of DBPT as a second-line regimen, and as an indirect comparison of DBPT with DTIC. Thirty-five consecutive patients received DBPT. The patients were divided into two groups. Group 1 comprised 17 patients with progressive disease (PD) on DTIC + tamoxifen therapy who were switched directly to DBPT. Group 2 comprised 18 patients not immediately switched to DBPT and included patients who had either a partial response (PR; one patient) or developed stable disease (SD; four patients) with DTIC, or received adjuvant DTIC (nine patients). All except four patients had received tamoxifen at the time of initial DTIC treatment. Median times since stopping DTIC were 22 days (range 20-41) and 285 days (range 50-1,240) in Groups 1 and 2 respectively. In Group 1, one patient developed SD for 5 months and the remainder had PD. In Group 2, there were two PRs, four patients with SD (4, 5, 6, and 6 months), and 11 with PD. These results indicate that the DBPT regimen is not of value in melanoma primarily refractory to DTIC. There were responses in patients not directly switched from DTIC to DBPT, suggesting combination therapy may be of value in a small subgroup of melanoma patients.

Adult↗

PubMed1976

[Treatment of metastasising melanoma with a combination of cytostatic agents (author's transl)].

In a prospective phase-II study of 16 patients with melanoma in stage III, the influence of a combination of cytostatic drugs on tumour growth was studied. All patients had extensive metastases in soft tissues, intestines and, some of them, in bone. The treatment consisted of brief infusions of 2 mg vincristine, 200 mg carmustine and 600 mg dacarbazine per m2 body surface for six days, repeated at seven week intervals up to six times. Two of the 16 patients had complete and two had partial remission, while two remained in status quo for four and five months, respectively. In the remaining ten patients the combined therapy had no influence on the progression of the disease: the more extensive the tumour spread and the worse the general condition of the patient, the less successful was the treatment.

Adult↗

PubMed1986

[Adjuvant chemotherapy in addition to radical surgical treatment of regional lymph node metastases in malignant melanoma].

Thirty-three patients with malignant melanoma and regional lymph node metastases who underwent lymph node dissection were additionally given polychemotherapy with carmustine, hydroxycarbamide and dacarbazine immediately before surgery and up to five times postoperatively. Twenty-nine patients were only treated surgically. These two groups were comparable as regards prognostic criteria, in particular tumour size, ulceration and the number of lymph nodes affected, although the individual follow-up periods varied considerably. The group given chemotherapy showed better results than the control group undergoing surgery alone. The log rank test yielded a significant difference (P less than 0.05) with respect to the probability of relapse-free survival but not as regards probability of survival time. Patients with ulcerated primary melanomas and with a large number of affected lymph nodes had a less favourable prognosis. The major side effects of chemotherapy were transient nausea and bone marrow depression.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1986

[Results with the use of the M-2 protocol in plasmacytoma].

99 patients with multiple myeloma were treated over a period of 6 1/2 years; 62 of these were initially treated with vincristine, carmustine, cyclophosphamide, melphalan and prednisone: M 2-Protocol. Response to this therapy was assessed after three therapy cycles had been completed, which had been given at intervals of 5-6 weeks. In patients responding to the therapy, treatment was continued until a maximum regression of the paraproteins was achieved. By the end of May 1985, the data of 52 patients could be evaluated, in 31 (60%) of whom remission was observed. Median survival time of all patients was 27 months. In 18 patients with "complete" remission the median has not yet been reached after 40 months. In 13 patients with partial remission, the median survival time was 36 months. In patients with complete remission, the median remission period was 26.5 months, in patients with partial remission 13.9 months.

Adult↗

PubMed1980

Prediction of BCNU pulmonary toxicity in patients with malignant gliomas: an assessment of risk factors.

Symptomatic pulmonary disease occurred in 20 per cent of 93 patients with anaplastic gliomas being treated with carmustine (BCNU). An analysis of the variables has revealed a relation between the occurrence of pulmonary toxicity on the one hand, and the total cumulative dose of BCNU, the number of cycles over which the BCNU was administered, the history of lung disease, the patient's age, and the platelet-count nadir after the first course of BCNU on the other. An equation has been generated that allows prediction of pulmonary toxicity during the course of therapy with BCNU with 80 per cent accuracy. Pretreatment analysis of individual cases should allow safe use of BCNU and prevention of most of the serious pulmonary complications caused by this drug.

Adult↗

PubMed2000

Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents.

BACKGROUND: The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents. METHODS: We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome. RESULTS: The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status. CONCLUSIONS: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.

Analysis of Variance↗

PubMed2003

MRP1-transfected cells do not show increased resistance against oxidative stress.

Sensitivity of V79 Chinese hamster cells and V79 cells transfected with human MRP1 gene to several agents inducing oxidative stress was compared. Cells overexpressing MRP1 did not show increased resistance to tert-butyl hydroperoxide, diamide, paraquat, menadione, dichromate and carmustine as estimated by cell survival and DNA damage assessed by comet assay. These findings suggest that overexpression of MRP1 does not confer increased resistance to oxidative stress.

Animals↗

PubMed1992

A prospective randomized study of two alternating, non cross-resistant chemotherapies for advanced Hodgkin's disease.

Fifty-four newly diagnosed patients with advanced Hodgkin's disease were randomized between two alternating non cross-resistant chemotherapies: MOPP-ABVD (MOPP: Mustine, Vincristine, Procarbazine, Prednisone-ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine) and MOPP-ABVD-CEM (CEM: Carmustine, Etoposide, methyl-GAG). There were no significant differences between the two therapies as far as complete remission, survival, relapse free survival and toxicity were concerned. This study does not support the use of MOPP-ABVD-CEM for improving the long-term outcome of patients with advanced Hodgkin's disease.

Adult↗

PubMed2000

Phase II trial of subcutaneous interleukin-2, subcutaneous interferon-alpha, intravenous combination chemotherapy, and oral tamoxifen in the treatment of metastatic melanoma: final results of cancer biotherapy research group 94-11.

BACKGROUND: The treatment of metastatic melanoma remains unsatisfactory despite encouraging results with biotherapy and combination chemotherapy. Combining these two modalities may improve outcomes for such patients. METHODS: Eligible patients had metastatic melanoma, were in good medical condition, and had not been treated previously for metastatic disease. A 42-day treatment cycle consisted of: tamoxifen 10 mg p.o. b.i.d. days 1-42, carmustine 150 mg/m2 i.v. on day three, dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 i.v. q.d. days 3-5, and 24-26, interferon-alpha 2b 6.0 MU/m2 s.c. days 8-12 and 29-33, and interleukin-2 11 MU/m2 s.c. days 8, 10, 12 and 29, 31, 33. In the absence of tumor progression, patients could receive up to six cycles of alternating treatment. Toxicity and tumor response was assessed following each treatment cycle; survival was determined from the first date of treatment. RESULTS: The 28 melanoma patients included 21 men and 7 women, with a median age of 55 years with a range of 26-77. Fifty-four percent were asymptomatic when treatment was initiated. Eighty percent had soft tissue metastases, 32% lung, 28% liver, and 8% bone. There were nine patients with significant tumor responses (three complete, six partial) for a response rate of 32% (18-57% 95% CI) based on intent-to-treat analysis, and 38% (18-57%, 95% CI) for the 24 patients who were evaluable for response. The months of duration of survival for responders were 38.9+, 27.2+, 22.8+, 16.3, 13.2, 9.4, 7.5, 6.5+, and 5.8. At a median follow-up of 31 months, the median duration of event-free survival was 4.6 months; median survival was 9.4 months. The survival rate one year from initiating treatment was 42%; 2-year survival was 14%. The most frequent toxicities were 96% nausea/vomiting, 80% fatigue, 73% thrombocytopenia, 60% neutropenia, and 44% fever. Two patients experienced early death that may have been treatment related; one died of cardiovascular complications and the other of a central nervous system event. CONCLUSION: This outpatient regimen was associated with significant toxicity including a 7% rate of possible treatment-related death. Tumor regression rates and survival were similar to results reported for chemotherapy alone, or inpatient IL-2-based therapy, but did not suggest an improvement in outcome.

Administration, Oral↗

PubMed2005

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of carmustine (BCNU) in combination with temozolomide as first-line chemotherapy before and after radiotherapy (RT) in patients with inoperable, newly diagnosed glioblastoma multiforme (GBM). PATIENTS AND METHODS: Forty patients were treated with BCNU (150 mg/m2) on day 1 and temozolomide (110 mg/m2/day) on days 1 through 5 of each 42-day cycle for up to four cycles prior to conventional RT (2 Gy fractions to a total of 60 Gy). After RT, BCNU + temozolomide was administered for four additional cycles or until progression. The primary end point was response rate; secondary end points included progression-free survival (PFS); overall survival (OS) and safety. RESULTS: Sixty per cent of patients completed four cycles of neo-adjuvant BCNU + temozolomide. Objective response rate (intention-to-treat) was 42.5% (95% confidence interval 27% to 58%), including two (5%) complete and 15 (37.5%) partial responses. In the eligible population (n=37) the objective response rate was 46%. Nine (24%) patients had stable disease and 14 (35%) had progressive disease. Median PFS and OS were 7.4 and 12.7 months, respectively. Age was the only significant prognostic factor and tumor location (lobar versus multifocal versus corpus callosum) showed a trend. Grade 3-4 toxicities included thrombocytopenia (n=11) and neutropenia (n=7) for both pre- and post-RT chemotherapy. Four patients required platelet transfusions. No patient discontinued treatment because of toxicity. CONCLUSIONS: The combination of BCNU plus temozolomide as neo-adjuvant therapy in inoperable GBM exhibited promising activity with a good safety profile and warrants further evaluation.

Adult↗

PubMed2005

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study.

BACKGROUND: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. RESULTS: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. CONCLUSIONS: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

Adolescent↗

PubMed1998

O6-alkylguanine DNA lesions trigger apoptosis.

It is unclear whether alkylating agents induce apoptosis because they damage DNA, or because they damage other cellular targets. Isogenic Chinese hamster ovary (CHO) cell lines varying in the repair of O6-alkylguanine (O6AlkG) were examined for their propensity to undergo alkylation-induced apoptosis. Robust O6AlkG repair virtually eliminated the apoptogenic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU, carmustine), as did the expression of BCL-2. O6AlkG repair had no effect on apoptosis induced by tumor necrosis factor alpha or by gamma-irradiation. We conclude that alkylating agents induce apoptosis by virtue of their ability to modify DNA bases and, more specifically, that O6AlkG lesions can trigger such programmed cell death.

Animals↗

PubMed1987

Transfectant CHO cells expressing O6-alkylguanine-DNA-alkyltransferase display increased resistance to DNA damage other than O6-guanine alkylation.

BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea, Carmustine] is a nitrosourea that crosslinks DNA and is useful in cancer chemotherapy. Tumor cells resistant to BCNU produce high levels of O6-alkylguanine-DNA-alkyltransferase (AT), a protein that removes the O6-guanine adduct formed by BCNU prior to crosslinking. By the transfection of a human cosmid library into the Chinese hamster ovary cell line AA8, several transgenic cell lines which express the AT gene have been constructed. These 'BR' cells were isolated on the basis of their resistance to G-418 and BCNU. Like human mer+ strains, BR cells (relative to the parental AA8 cells) are approximately 500 times more resistant to the cytotoxic effects of 80 microM BCNU. Treatment with exogenous O6-methylguanine (O6MG), which depletes cellular AT, abolishes their BCNU resistance. Also consistent with the mer+ phenotype, BR cells are resistant to the mutagenic and killing activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Treatment with exogenous O6MG, while reversing the resistance to MNNG mutation, does not reverse the resistance to MNNG killing. Unexpectedly, BR cells also exhibit resistance to killing by dimethylsulfate (DMS). The BR cells are not, however, detectably resistant to UV light. These results suggest that AT activity in mammalian cells is closely linked to the activity of other DNA repair pathways.

Alkylation↗

PubMed1984

Antibody-dependent killing of tumor cells by polymorphonuclear leukocytes. Involvement of oxidative and nonoxidative mechanisms.

Antibody-dependent cellular cytotoxicity (ADCC) against Raji cells was used as a model system to investigate the polymorphonuclear leukocyte (PMN) mechanisms involved in tumor cell lysis. PMN killed target cells by nonoxidative means, as indicated by the following observations: PMN from patients with chronic granulomatous disease (CGD), defective in their metabolic burst, lysed Raji cells normally; impairment of the oxidative metabolism of normal PMN by phenylbutazone did not affect ADCC. Rosenthal's inhibitor of phospholipase A2 completely prevented the lysis, suggesting the involvement of this enzyme in the target cell damage. The inhibition of the Raji cell glutathione redox cycle by carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] increased cell susceptibility to PMN-mediated ADCC. This increment of lysis was related to oxidative killing systems. In fact, CGD PMN had an ADCC against BCNU-treated Raji cells lower than that mediated by normal PMN, but comparable to that observed with untreated targets, and phenylbutazone reduced the lysis of BCNU-treated Raji cells by normal PMN to the level observed with the use of untreated targets. The remaining ADCC against BCNU-treated Raji cells mediated by CGD PMN and by normal PMN in the presence of phenylbutazone was suppressed by Rosenthal's inhibitor. Thus PMN killed sensitized BCNU-treated Raji cells by use of both oxidative and nonoxidative means. The results indicate that the interaction of sensitized Raji cells with PMN triggers simultaneously oxidative and non-oxidative potentially lytic systems and the mediator(s) of Raji cell lysis actually operating may depend on the metabolic state of the target cells themselves. Therefore, the lysis of sensitized tumor cells might not reflect the simple effect of PMN tumoricidal systems; rather it should be regarded as a result of an inability of the target cells to escape the various PMN cytolytic mechanisms.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1990

High-dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with refractory malignancies.

Forty patients with refractory solid tumors or non-Hodgkin's lymphoma were treated with high-dose cyclophosphamide, thiotepa, and carmustine (BCNU), followed by autologous stem cell rescue, in a phase I dose escalation study. The dose-limiting toxic effect was delayed drug-induced pulmonary disease, seen in three patients who received 660-750 mg of BCNU/m2 in combination with cyclophosphamide and thiotepa. The early death rate due to toxic effects was 20%; all deaths were attributed to sepsis or respiratory failure. The overall response rate was 63%. The median time to disease progression was 14 weeks. Although this regimen provided effective cytoreduction, its use in heavily pretreated patients with bulky disease is of limited value.

Adult↗

PubMed1992

Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme.

BACKGROUND: Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme, drug resistance occurs frequently, resulting in tumor progression and death. Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT). Depletion of this protein with alkylguanines or methylating agents, however, restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas (e.g., carmustine [BCNU]). PURPOSE: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine. METHODS: Xenografts were grown subcutaneously in athymic BALB/c mice. BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2, 75 mg/m2, or 38 mg/m2--i.e., 1.0, 0.75, or 0.38, respectively, of the dose lethal to 10% of treated animals (LD10). Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine (240 mg/m2) or with streptozocin (600 mg/m2) daily for 4 days. Response was assessed by tumor growth delay and tumor regression. AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment, at the time tumors were excised. RESULTS: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection. After 6 hours, levels changed to 7%, 61%, and 116% of control values in D341 Med and 0%, 79%, and 21% of control values in D-456 MG, respectively. Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10. Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft. In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine. Following therapy with BCNU plus O6-benzylguanine at 0.38 LD10, tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts. CONCLUSION: We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU, which would allow subsequent design of phase I clinical trials.

Animals↗

PubMed1992

Enhancement of alkylating agent activity by SR-4233 in the FSaIIC murine fibrosarcoma.

BACKGROUND: The most commonly used antineoplastic drugs are more cytotoxic toward normally oxygenated tumor cells than toward hypoxic tumor cells. PURPOSE AND METHODS: To examine the ability of SR-4233, a new cytotoxic agent, to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents, we tested the cytotoxic effect of SR-4233 alone and in combination with varying doses of cisplatin (CDDP), cyclophosphamide (CPM), carmustine (BCNU), or melphalan (L-PAM) on tumor cells and bone marrow cells isolated from C3H/FeJ mice bearing the FSaIIC fibrosarcoma. RESULTS: When SR-4233 alone was given, tumor cell killing was limited. When SR-4233 was administered just before single-dose treatment with CDDP, CPM, BCNU, or L-PAM, however, marked dose enhancement leading to increased cytotoxic effects on tumor cells and on bone marrow cells was observed. Similar experiments with tumor cell subpopulations, selected by Hoechst 33342 dye diffusion, confirmed that while cytotoxicity to both bright (oxygenated) and dim (hypoxic) cells was increased by combining each alkylating agent with SR-4233, the enhancement of the effect was relatively greater in the subpopulation of dim cells. The delay in the growth of tumors in animals treated with the combination of SR-4233 and CDDP, CPM, or L-PAM was 1.6-fold to 5.3-fold greater than that in animals treated with each alkylating agent alone. CONCLUSION: Our results suggest that SR-4233 may have the potential to improve the clinical efficacy of commonly used antitumor alkylating agents.

Alkylating Agents↗