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PubMed1984

A randomized trial of melphalan and prednisone versus melphalan, prednisone, cyclophosphamide, MeCCNU, and vincristine in untreated multiple myeloma.

In a randomized study with 234 previously untreated patients with multiple myeloma, 129 were treated with melphalan (8 mg/m2 perorally for four days) and prednisone (40 mg/m2 perorally for seven days, both every four weeks) and 105 with melphalan and prednisone at the same doses plus cyclophosphamide (600 mg/m2 intravenously every four weeks), MeCCNU (100 mg/m2 PO every eight weeks), and vincristine (MPCCV, 0.6 mg/m2 IV every four weeks). A total of 49 (38%) of the 129 patients treated with melphalan and prednisone (MP) and 48 (46%) of the 105 patients treated with MPCCV showed good response (GR) (P not significant); the overall response rates were 58% and 70%, respectively. Thirty-seven percent of the MP group and 39% of the MPCCV group remain alive at 48 months from first treatment (P not significant). The estimated 48-month survival from first treatment, according to different prognostic factors at diagnosis, in both groups was as follows: stage 1,56%; stage II, 46%, and stage III, 23% (I and II v III P less than .001). Survival at 48 months according to response was GR, 68%; partial response (PR), 33%; and null, 16% (GR v null, P less than .0005; GR v PR, P less than .0005). Survival according to renal function was 43% for a creatinine level less than 2 mg/100 mL and 27% for a creatine level greater than or equal to 2 mg/100 mL (P less than .0005). No significant difference has been found between the two treatment schedules in terms of response rate and survival time, in any stage of disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

Aged↗
PubMed1986

Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma. A phase III study of the Piedmont Oncology Association.

One-hundred thirty eligible patients with advanced colorectal carcinoma who had received no prior chemotherapy were randomized to either methyl-CCNU, 70 mg/m2 orally every 6 weeks on day 1, mitomycin C, 10 mg/m2 intravenously every 6 weeks on day 1, and 5-fluorouracil (5-FU), 400 mg/m2 intravenously weekly--(MMF)--or 5-FU, 600 mg/m2 intravenously weekly (5-FU). One hundred twenty-six patients are evaluable for response. Of 62 patients treated with MMF, one (2%) achieved complete remission, and three (5%) attained partial remission. Of 64 patients treated with 5-FU, two (3%) achieved complete remission, and eight (13%) attained partial remission. The median survival for patients receiving MMF was 9.5 months compared with 10.3 months for patients receiving 5-FU. The survival distributions for the two regimens were not significantly different, either unadjusted or adjusted for pretreatment characteristics. Performance status and lactic dehydrogenase (LDH) were both significantly associated with survival. Patients with liver metastases only and normal liver function tests had a median survival of 19.8 months and a 40% response rate. This randomized phase III trial did not show any therapeutic advantage for MMF compared to 5-FU therapy alone in advanced colorectal cancer. In addition, hematologic toxicity was significantly greater with the combination (MMF) regimen.

Adolescent↗
PubMed1987

The effect on survival of initial chemotherapy in advanced breast cancer: polychemotherapy versus single drug.

Since current clinical trials assessing new agents occur in patients with advanced breast cancer having failed one and sometimes many polychemotherapy programs, these new agents may not be given a fair trial. In an effort to assess the possibility of using an alternative study design, we analyzed older clinical trials that used a controlled study design, randomizing between a single new drug and an established polychemotherapy program with a cross-over design upon failure. We were interested in noting that the pooled data did display a slight survival advantage (median 3.7 months) for the group receiving polychemotherapy as initial therapy. The survival distributions were clearly not significant using the log rank test, but did approach significance using the Smirnov. It is apparent that, while some slight advantage does occur for that group of patients receiving initial polychemotherapy, the magnitude of this effect is not great and is short in duration. Serious consideration should be given to the assessment of new agents as first-line therapy, particularly should they have a unique mode of action or lessened morbidities or toxicities.

Antineoplastic Agents↗
PubMed1987

An EORTC Gastrointestinal Group phase III evaluation of combinations of methyl-CCNU, 5-fluorouracil, and adriamycin in advanced gastric cancer.

In a prospective phase III multicenter trial, 189 patients with advanced measurable and nonmeasurable gastric cancer were randomized to receive 5-fluorouracil (5-FU) combined with Adriamycin (FA) or FA plus methyl-CCNU (MeFA). The response rate in patients with measurable disease was 10% (three of 29), and 18% (five of 28), respectively. No difference in the duration of survival was detected (P = .14; log rank test). Median survivals were 21 and 32 weeks, respectively. Toxicity was moderate, but there have been two toxic deaths among the patients who received FA. Because of the low response rate and the short survival, neither regimen can be recommended for the treatment of advanced gastric cancer.

Adenocarcinoma↗
PubMed1988

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.

Adenocarcinoma↗
PubMed1994

The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.

PURPOSE: We assessed the prognostic importance of the level of thymidylate synthase (TS) expression in patients with primary rectal cancer and whether, for Dukes' B and C cancer patients, the benefit of chemotherapy was associated with TS expression. PATIENTS AND METHODS: The level of TS expression in the primary rectal cancers of 294 of 801 patients enrolled on protocol R-01 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was immunohistochemically assessed with the monoclonal antibody TS 106. RESULTS: Forty-nine percent of patients whose tumors had low TS levels (n = 91) were disease free at 5 years compared with 27% of patients with high levels of TS (n = 203; P < .01). Moreover, 60% of patients with low TS levels were alive after 5 years compared with 40% of patients with high TS levels (P < .01). The level of TS protein was significantly associated with Dukes' stage (P < .01); patients with a more advanced Dukes' stage had a significantly higher level of TS. The level of TS expression remained prognostic for both disease-free survival (P < .01) and survival (P < .05) independent of Dukes' stage and other pathologic characteristics evaluated. Thirty-eight percent and 54% of patients with high TS levels (n = 71) were disease free and alive, respectively, after 5 years when treated with chemotherapy, compared with 17% and 31%, respectively, of similar patients when treated with surgery alone (n = 64) (P < .01). No difference was noted in disease-free survival (P = .46) or survival (P = .43) in patients with low TS levels. CONCLUSION: The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer. Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels. Prospective studies measuring TS levels will be needed to understand further the role of TS as a prognosticator of survival and chemotherapeutic benefit.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Intraarterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and systemic chemotherapy for malignant gliomas: a follow-up study.

Twenty-five adults who harbored malignant gliomas received 72 courses of intraarterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (100 mg/m2) and 67 courses of systemic vincristine (1.0 mg/m2) and procarbazine (100 mg/m2) as induction therapy (BVP) followed by 106 courses of systemic 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU) (130 mg/m2), vincristine, and procarbazine as maintenance therapy (MVP). With a 6-week interval between each treatment, the median and range for the number of courses of BVP were 3 and 1 to 4 and those for MVP were 3 and 0 to 14, respectively. Fifteen patients (60%) responded to both BVP and MVP, and 10 (40%) did not. The overall median survival time was 12.7 months (range, 1.8 to 48.5+ months). Two of 3 patients who had recurrent gliomas responded and survived for 37+ to 45+ months. Seven of 10 who had nonirradiated glioblastomas responded and survived for 9 to 22 months. Four who had nonirradiated anaplastic astrocytomas all responded and survived for 38+ to 48.5+ months. Two who also received radiotherapy (1 glioblastoma and 1 primitive neuroectodermal tumor) benefited and survived for 16.9 and 28.5+ months. All who did not respond favorably died within 8 months. During the infusion of BCNU, complications included transient orbital and head pain, periorbital and scleral erythema in all patients, and a focal seizure in 1 (4%). During the 6-month induction periods, leukopenia and thrombocytopenia occurred in 1 (4%), deep vein thrombosis occurred in 9 (36%), pulmonary emboli occurred in 8 (32%), upper respiratory infections occurred in 6 (24%), pneumonia occurred in 9 (36%), and herpes zoster occurred in 1 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1976

Concepts for treatment of micrometastases developed in murine systems.

Small tumor cell foci, whether left in situ during primary surgical excision or escaping lethal radiation damage, as well as distant metastases, are the primary reason for treatment failure in man and are the proper targets for the chemotherapist and immunotherapist. Since cure probably requires reduction of the total body burden of tumor cells to very small numbers (possibly to less than one cell), and since first-order kinetics of tumor cell kill by drugs appears to be a natural law in cancer chemotherapy, drug treatment should be started as soon as possible after likely noncurative primary treatment with surgery or radiation. Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable tumor cells undergoing active cell replication) is inversely related to population size. Tumor cells in micrometastases should, therefore, be more sensitive to anticancer drugs active against anabolizing cells than are tumor cells in the larger, grossly apparent primary tumor from which they were derived. This indicates the probability that micrometastases will be effectively responsive to more drugs than is the primary and clinically apparent tumor from which they came. Studies with at least four metastatic and uniformly fatal murine solid tumors (lung, breast, colon, and melanoma) have demonstrated significantly improved cure rates with drug treatment following surgical removal of the grossly apparent primary tumor than can be obtained with either surgery or drug treatment when used alone. Further, both disease staging and drug dosage have been shown to influence cure rates of combined-modality treatment. With several mouse tumors, a significantly smaller number of viable tumor cells can establish lethal tumors in the presence of radiation-inactivated tumor cells than in their absence. This suggests that small numbers of residual viable tumor cells in radiation-treated tumor sites may be a greater threat to clinical cure than smaller tumor cell populations remaining in situ after surgery.

Adenocarcinoma↗
PubMed1988

Cytostatic drug therapy in disseminated colorectal cancer.

5-FU is the best available single drug in advanced colorectal disease. After systemic administration approximately 15% of the patients achieve a short-lived objective remission. Survival is not prolonged by therapy. Several chemotherapy combinations have in preliminary phase II studies given higher response rates (30-50%), but when evaluated in controlled studies, no advantage over single-drug 5-FU has been verified. At present, two combinations, MOF-S and sequential MTX/5-FU/Leucovorin seem promising, but more experience is needed before general acceptance. In cases of liver dissemination, regional hepatic infusion therapy causes objective tumour regression more often than systemic therapy. However, median survival is most likely the same for both treatment modalities, and since hepatic artery infusion is the most expensive therapeutic modality, routine use of hepatic artery infusion is discouraged. Outside clinical trials, systemic or regional chemotherapy is hardly indicated in advanced colorectal disease apart from certain selected symptomatic patients.

Antineoplastic Agents↗
PubMed1979

Effect of macrophage activation by immunoadjuvants on serum levels of lysosomal hydrolases in mice.

The effect of pyran copolymer, injected into mice bearing the M109 Madison lung carcinoma, on serum concentrations of lysozyme, beta-glucuronidase, and N-acetyl-beta, D-glucosaminidase was studied and compared with that of other immunoadjuvants. Increases in lysozyme levels ranging from 50 to 100% were observed after injection of pyran, BCG and Bru-Pel; increases in the levels of the other enzymes were less consistent. Other immunoadjuvants were less effective in raising serum concentrations of lysosomal enzymes. The findings were correlated with the results of previous studies on macrophage activation and antineoplastic action produced by these immunoadjuvants and suggest that serum levels of lysozyme can serve as indices of these effects.

Acetylglucosaminidase↗
PubMed1979

The effect of early treatment with methyl-CCNU on the lymphoid organs and the humoral immune response in chickens.

Presented are data upon the effect of a single or muliple administration of methyl-CCNU (a nitrosourea derivative an alkylating agent, and anticancer drug) to newly-hatched chicks. Lethal and sublethal doses of methyl-CCNU caused temporary damage to the lymphoid organs, of which the bursa was apparently the most sensitive. The decreased weight and the morphological changes observed in the bursa of treated chicks were accompanied by a parallel decrease in serum gamma-globulins level. The humoral immune response of animals treated with me-CCNU to sheep red blood cells and to killed Brucella abortus organisms was impaired in about 30% of the treated animals examined 8-10 weeks following 2 injections of 3 mg me-CCNU (given at the day of hatching and the next day). The thymus recovered rather rapidly from treatment. The time schedule of mortality and the early and late toxic manifestations of the drug as observed in chickens, in this study, are similar to previous reports obtained in mammals. Prolonged effects, however, were noted to some extent on body and spleen weight, and most dramatically, on testicular weight, morphology, and function.

Animals↗
PubMed1990

Modulation of mammalian O6-alkylguanine-DNA alkyltransferase in vivo by O6-benzylguanine and its effect on the sensitivity of a human glioma tumor to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea.

Experiments were carried out in mice and hamsters to determine whether the activity of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, in tissues and tumors was reduced by treatment with O6-benzylguanine in vivo. Following intraperitoneal injection of O6-benzylguanine, there was a rapid and complete loss of alkyltransferase activity in both livers and kidneys of mice and hamsters. The activity in mouse tissues was slowly restored, reaching pretreatment activities at 16 hr and 72 hr after injection of O6-benzylguanine at 10 mg/kg or 126 mg/kg, respectively. The activity in hamster liver was restored at a significantly lower rate, reaching less than 20% pretreatment activity 72 hr after treatment with 100 mg/kg of O6-benzylguanine. The efficient reduction of alkyltransferase activity by O6-benzylguanine was in sharp contrast to the inability of O6-methylguanine to bring about similar reductions. Activities dropped to about 55% of pretreatment activities in several mouse organs 4 hr after treatment with 126 mg/kg of O6-methylguanine compared to a more than 90% reduction in activity in animals after treatment with O6-benzylguanine. The sensitivity of SF767 cells to meCCNU after treatment with O6-benzylguanine was increased substantially. Furthermore, treatment of nude mice carrying SF767 tumor with 60 mg/kg of O6-benzylguanine prior to either 7.5 or 15 mg/kg of meCCNU led to significant inhibition of tumor growth. These studies indicate that O6-benzylguanine is a suitable compound for use in experiments to examine the role of the alkyltransferase protein in vivo in counteracting the effects of alkylating agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

5-Fluorouracil (5-FU), methyl-CCNU, and vincristine in the treatment of advanced colorectal cancer: phase II study utilizing weekly 5-FU.

We report a phase II trial of 5-fluorouracil (5-FU), methyl-CCNU, and vincristine (FMV) combination chemotherapy in advanced colorectal carcinoma. Ten of 25 patients (40%) achieved an objective tumor regression after treatment with FMV chemotherapy. The main toxicities of FMV were hematologic and gastrointestinal. 5-FU was administered in a weekly rather than a loading-dose schedule which allowed for sensitive adjustment of drug dosages according to hematologic toxicity; only 16% of the patients (four of 25) had a wbc count less than 2000 cells/mm3. FMV is significantly more active than 5-FU alone in the treatment of advanced colorectal cancer; however this regimen does not significantly improve survival in responding patients.

Adult↗
PubMed1998

[MMC conditioning regimen (Melphalan, MeCCNU and cyclophosphamide) followed by allogeneic peripheral blood stem cells transplantation for chronic myeloid leukemia].

This paper reports 3 cases of allogeneic peripheral blood stem cell transplantation (Allo-PBSCT) for the patients with chronic myeloid leukemia (CML). The patients received MMC preparative regimen with high dose chemotherapy (Melphalan 170 mg/m2, p.o. on Day-5, MeCCNU 400 mg/m2, p.o. on Day-4, and Cyclophosphomide 60 mg/kg/day, i.v. on Days-3 and -2). The HLA-identical sibling donors received filgrastim (rhG-CSF) for mobilization at a dose of 300 micrograms/day for 6 days. Leukaphereses were done at the 6th day of mobilization. A median of 8000 ml (2 times total blood volume) of blood was processed the collecting: 2.5-4.5 x 10(8)/kg MNC, 12.8-20.0 x 10(6)/kg CD34+ cells (including 4.8-7.5 x 10(6)/kg CD34+CD33-, 8.0-13.0 x 10(6)/kg CD34+CD33+), and 3.5-4.3 x 10(5)/kg CFU-GM. Cyclosporin A and methotrexate were used for GVHD prophylaxis. Hematopoitic function recovered as for 14-20 days to > 0.5 x 10(9)/L of neutrophil count, and for 16-34 days to > 20 x 10(9)/L of platelet count. At day + 100, chromosome analysis of bone marrow cells showed that complete chimera without ph1 positive chromosome in Cases 1 and 3, and a partial chimera with 73% donor karyotype in Case 2. All patients now are in disease free survival. No episode of acute graft versus host disease (GVHD) developed. It was concluded that HLA matched sibling allogeneic PBSCT result in rapid hematopoitic reconstitution and the MMC conditioning regimen is effective both in leukemic cells eradication and in immunosuppression for stem cells engraftment, and the drug related toxicity could be tolerated by patients.

Adult↗