Modified BuCy is an alternative conditioning regimen for lymphoma patients undergoing autologous stem cell transplantation.

The aim of this study is to determine whether the modified BuCy (semustine, cytarabine, busulfan, and cyclophosphamide, mBuCy) conditioning regimen can be safely used as an alternative to the SEAM (semustine, etoposide, cytarabine, and melphalan) regimen by comparing the efficacy and toxicity of the mBuCy and SEAM regimens. We matched 34 pairs of patients with regard to disease status at the time of autologous stem cell transplantation (auto-SCT). We found no significant difference in the time of platelet engraftment between the two groups. Furthermore, neutrophil engraftment was somewhat faster in the mBuCy group than in the SEAM group (median: 9 days vs 10 days, p = 0.015). With regard to toxicity, the incidence of nausea/vomiting, hepatic impairment, renal impairment, pulmonary infection, and treatment-related mortality (TRM) was similar between the two groups. In addition, compared to patients conditioned with SEAM, patients conditioned with mBuCy were less likely to develop mucositis and diarrhea (p = 0.027; p = 0.050). The 2-year progression-free survival (PFS) rates in the mBuCy and SEAM groups were 79% and 70% (p = 0.378), respectively, and the 2-year overall survival (OS) rates were 81% and 78.0%, respectively (p = 0.789). These analyses showed that the mBuCy conditioning regimen was well tolerated and can be used as an alternative to the SEAM regimen for lymphoma.

[Multicenter randomized controlled study of temozolomide versus semustine in the treatment of recurrent malignant glioma].

OBJECTIVE: To evaluate the efficacy and safety of temozolomide (TMZ) versus semustine (Me-CCNU) in the treatment of recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). METHODS: A total of 151 patients with recurrent GBM or AA were enrolled into this randomized, multicentre and open-label study. And 144 patients (intent-to-treat (ITT) population) were assigned randomly into 2 groups. TMZ was given orally at 200 or 150 mg×m(-2)d(-1) (prior chemotherapy) for 5 days, repeated every 28 days. Me-CCNU was given orally at 150 mg×m(-2)×d(-1) once, repeated every 28 days. The treatment periods were within 2 - 6 months and the follow-up period was 6 months. Gadopentetate dimeglumine-magnetic resonance imaging (GD-MRI) or contrast-enhanced computed tomography was performed at 2, 3 and 6 months after treatment to evaluate the image-based progression. Progression-free survival (PFS), overall survival rates at the end of follow-up period and adverse events rates were evaluated. RESULTS: PFS at 6 months was 78.87% in TMZ group and 55.88% in Me-CCNU group (P < 0.05). Overall survival rates at the end of follow-up period were 96.89% in TMZ group and 97.30% in Me-CCNU group (P > 0.05). The objective response rate of TMZ and Me-CCNU groups were complete response (CR) (19.44% vs 6.38%), partial response (PR) (26.39% vs 14.89%), stable disease (SD) (26.39% vs 34.03%) and progressive disease (PD) (27.78% vs 44.68%, P < 0.01). Adverse events rates of TMZ and Me-CCNU were 29.11% and 45.15% respectively (P < 0.05). CONCLUSION: The efficacy of TMZ for patients with recurrent GBM or AA is better than that of Me-CCNU. And TMZ has an acceptable safety profile and its adverse events are mostly mild.

Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01.

Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986. Their average time on study was 64.1 months. The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients). The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = .006) and in survival (P = .05). Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions. Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy. When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs. 47%; P less than .001; relative odds, 2.00) and in survival (37% vs. 60%; P = .001; relative odds, 1.93), was restricted to males. When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients. When the group receiving post-operative radiation (4,600-4,700 rad in 26-27 fractions; 5,100-5,300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = .06). No significant benefit in overall disease-free survival (P = .4) or survival (P = .7) from the use of radiation has been demonstrated. The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant. In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer. The observed advantage was restricted to males. Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival.

Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01.

Data are presented from 1,166 patients with Dukes B and C carcinoma of the colon who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-01 between November 1977 and February 1983. Patients were randomized to one of three therapeutic categories: 1) no further treatment following curative resection (394 patients); 2) postoperative chemotherapy consisting of 5-fluorouracil, semustine, and vincristine (379 patients); or 3) postoperative BCG (393 patients). The average time on study was 77.3 months. A comparison between patients receiving postoperative adjuvant chemotherapy and those treated with surgery alone indicated that there was an overall improvement in disease-free survival (P = .02) and survival (P = .05) in favor of the chemotherapy-treated group. At 5 years of follow-up, patients treated with surgery alone were at 1.29 times the risk of developing a treatment failure and at 1.31 times the likelihood of dying as were similar patients treated with combination adjuvant chemotherapy. Comparison of the BCG-treated group with the group treated with surgery alone indicated that there was no statistically significant difference in disease-free survival (P = .09). There was, however, a survival advantage in favor of the BCG-treated group (P = .03). At 5 years of follow-up, patients randomized to the surgery-alone arm were at 1.28 times the risk of dying as were similar patients treated with BCG. Further investigation disclosed that this survival advantage in favor of BCG was a result of a diminution in deaths that were non-cancer related. When analyses were conducted on which events not related to cancer recurrence were eliminated, the survival difference between the BCG and control groups became nonsignificant (P = .40); the cumulative odds at 5 years decreased from 1.28 to 1.10. The findings from this study are the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.

5-Fluorouracil, 1,3-bis(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea: effect on the human granulopoietic system.

The reaction pattern of the normal (nonleukemic) human granulopoietic system to single-agent treatment with 5-fluorouracil (FUra) and to a combination of FUra with two nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), was studied serially by morphologic and in vitro culture methods. The granulopoietic toxicity of FUra was acute and rapidly (by day 21) reversible. In contrast, the toxicity of the combination regimens was long lasting. Evidence exists that an early toxicity (that of FUra) and a delayed toxicity (that of the nitrosourea) were overlapping. Toxicity of BCNU and MeCCNU was most pronounced at the level of in vitro colony-forming units of the granulopoietic system (G-CFUc). G-CFUc compartments of bone marrow and peripheral blood continued to be reduced in size at the time of recovery of the peripheral blood granulocyte count from nitrosourea-induced toxicity. This finding may be responsible for the cumulative toxicity to the human hematopoietic system that frequently has been observed after repeated administration of nitrosourea compounds.

Chemotherapy of an experimental glioma with nitrosoureas.

Chemotherapy experiments were performed with 2 nitro-sourea drugs in an experimental mouse brain tumor model. Cell suspensions of a transplantable mouse ependymoblastoma were injected i.c. by means of a stereotactic frame. The drugs used were 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea and were given by either i.p. or by direct intraneoplastic (i.n.) injection on the fifth day after tumor cell implantation. Injections i.n. of drugs were made with the stereotactic frame. Both drugs were highly effective in increasing the median day of death and in yielding large numbers of long-term survivors. Effectiveness was evident after i.p. or i.n. injection. However, with certain dosage schedules such as every 2 hr for 5 injections daily on 2 consecutive days, i.n. injection was more effective and less toxic than i.p. injection. The reason why repeated i.n. injections produced less toxicity than repeated i.p. injections is not definitely known but may be due to local metabolism of the drugs in the tumors and surrounding brain to a less toxic form. This is the first laboratory report of direct i.n. injection of the nitrosoureas, and the authors consider these results encouraging.

Nephrotoxicity of semustine (methyl-CCNU) in patients with malignant melanoma receiving adjuvant chemotherapy.

The nephrotoxicity of semustine (methyl-CCNU) has been studied in 45 adult patients with surgically resected Stage I or II malignant melanoma who received this drug as adjuvant chemotherapy. Abnormalities of renal function (including three cases of renal failure) were noted in seven of 45 patients (16 percent); all these patients received more than 1,400 mg/m2. This represents an incidence of 26 percent in patients receiving more than 1,400 mg/m2 of semustine. Two distinct patterns emerged. Abnormal serum creatinine levels developed in two patients while receiving semustine and later progressed to renal failure. Five patients had normal serum creatinine levels throughout their treatment courses but had abnormal creatinine values one month to two years following the completion of drug therapy. Renal failure developed in one of these patients, but the remaining four have had stable renal function for one to two years of additional follow-up. No clinical signs of renal insufficiency were detected in any patients receiving less than 1,400 mg/m2 of semustine. No changes unequivocally attributable to semustine were seen in eight patients at autopsy despite the fact that three had received greater than 1,900 mg/m2 of nitrosourea. This incidence of nephrotoxicity appears to be significantly lower than that previously reported in children. Guidelines for future therapy with semustine are described.

The effect of combination chemotherapy on the reticuloendothelial system in man.

The effect of adjuvant combination chemotherapy (vincristine, CCNU/MeCCNU, 5-fluorouracil) on the phagocytic and catabolic properties of the reticuloendothelial system (RES) was studied in 4 patients before and during the anticancer treatment. The results indicate a transient impairment of both these functions, more prolonged with regard to phagocytosis. No significant changes were noted in the mobile macrophage system. This suggests that chemotherapy induces a depression especially of the stationary macrophage populations in the liver, spleen and bone-marrow.

Clinical trial of adjuvant chemotherapy after surgical resection of colorectal cancer metastatic to the liver.

Adjuvant chemotherapy consisting of 5-fluorouracil and semustine was given to 26 patients who had undergone resection (with curative intent) of hepatic metastatic lesions from a primary colorectal carcinoma. Our objective was to obtain preliminary observations regarding the effectiveness of this regimen for improving the long-term survival associated with hepatic resection alone in these patients (the overall 5-year survival after hepatic resection is 25% at our institution). At the time of analysis, the malignant disease had progressed in 19 of our patients, and 17 patients had died. For all patients who receive adjuvant chemotherapy, the median duration of survival is 34 months, and the estimated 5-year survival is 15%. Statistical analysis indicated no significant advantage in survival for the study patients in comparison with 26 control patients who were treated with hepatic resection only and were closely matched for prognostic factors. Because 5-fluorouracil plus semustine conferred no apparent beneficial effects as an adjuvant treatment in this exploratory study, we do not recommend a definitive randomized trial of this regimen.

Biphenotypic leukemia with unusual chromosomal translocation in a patient treated for melanoma.

A patient in complete remission from malignant melanoma but with refractory anemia after nitrosourea treatment developed acute biphenotypic leukemia. This disease, progression was accompanied by expansion of a cytogenetically abnormal clone. At first cytogenetic analysis, 1 year post discontinuation of chemotherapy, only 25% of the metaphases examined were hypodiploid with monosomy 7. Six months later, all of the metaphases seen were 45,XY,-7. Six months before overt acute leukemia was diagnosed, an additional chromosome abnormality emerged, t(2;3)(q31;q27). Although the translocation was present in all metaphases examined, the patient progressed into an acute leukemia with two components: one TdT-positive, Ia-positive, and the other TdT-negative, Ia-positive, monocytoid antigen-positive. This mixed leukemia was identified by double fluorescence staining for intranuclear TdT and surface labeling with a monocyte-specific monoclonal antibody.

Activity of 5-fluorouracil, mitomycin C, and methyl CCNU in inoperable adenocarcinoma of pancreas.

Twenty-two patients with inoperable adenocarcinoma of the pancreas were treated with 5-fluorouracil (5-FU), mitomycin C (Mito-C), and 1(-2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU). Fifteen were evaluable by completing 2 months of therapy. Two patients achieved a complete remission with the above combination. A partial remission seen in four other patients, which produced a response rate of 40% of evaluable, and 27% of entered, patients. Three had stable disease. The average time to progression in this study was 8 months. This combination was well tolerated and no deaths were secondary to drug therapy. Mucositis, leukopenia, thrombocytopenia, and hyperpigmentation were the significant toxicities seen in this study. These observations are worthy of further investigation.

Sequential phase II studies of chemotherapy for colorectal cancer with 5-fluorouracil and vindesine with or without methyl-1,3 cis(2 chloroethyl)-1-nitrosourea.

Vindesine, a newer vinca alkaloid, has been demonstrated to have activity against colorectal cancer during phase I studies. This report describes the results of two phase II trials in which vindesine was administered with 5-fluorouracil (5-FU) or in combination with 5-FU and methyl-1,3 cis(2 chloroethyl)-1-nitrosourea (MeCCNU). One of 16 patients (6%) given 5-FU-vindesine, and 4 of 31 (13%) patients in the 5-FU-vindesine-MeCCNU group achieved partial response (PR). Stable disease was observed in 50% of the 5-FU vindesine and 48% of the 5-FU-vindesine-MeCCNU group. In each treatment group, survival of respondents and those with stable disease was statistically superior (p less than 0.02) to that of those with progressive disease; there was no difference however, in overall survival between the two treatment groups and no enhancement of survival compared to published reports of results with 5-FU alone. No chemotherapy-related deaths occurred and both treatment regimens were well tolerated. Myelosuppression, which occurred with equal (50%) frequency in both regimens, was the major dose-limiting toxicity. MeCCNU increased the incidence of gastrointestinal toxicity. Vindesine neurotoxicity occurred in approximately 4% of the evaluable courses in each group. Combination therapy with 5-FU vindesine with or without MeCCNU in the dosages administered did not significantly increase the activity of 5-FU. Further evaluation of vindesine will require dosage modification.

The efficacy of 5-fluorouracil, mitomycin C, and methyl CCNU in advanced colorectal cancer.

Sixty-six patients with advanced colorectal cancer were treated with 5-fluorouracil, Mitomycin C, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. Fifty-seven patients were evaluable by completing 2 months of therapy. Nine patients (16.0%) achieved a complete remission (CR) with the above combination. A partial remission (PR) was seen in 9 patients. The response rate (CR + PR) was 32%. The average duration of response was 8.5 months. Mucositis, leukopenia, and thrombocytopenia were the significant toxicities experienced in this study.

[Nitrosourea-induced lung diseases]. / La pneumopathie des nitrosourées.

Nitrosoureas belong to the group of alkylating agents, and are increasingly used in the treatment of brain malignancies, due to their excellent penetration through the hemo-meningeal barrier. Since 1976, pulmonary toxicity from nitrosoureas has emerged as a significant problem, especially with BCNU, and 72 cases are available in the literature for review. While it is difficult to ascertain the exact prevalence of nitrosourea lung (estimate range between 1 and 20%), it is now clear that a direct relationship exists between cumulated exposure to the nitrosourea, and the likelihood of developing pulmonary toxicity. The clinical picture is that of a diffuse, severe fibrosis with hypoxemia. Histopathology, available in 55 reports, showed diffuse bland fibrosis. The outcome is poor with 67% of the patients dead by the time of publication. While we feel that corticosteroids should be tried for any possible beneficial effect, they seem to be of limited help.

[Treatment of advanced digestive cancer with fluorouracil and methyl-CCNU]. / Tratamiento del cáncer digestivo avanzado con fluoracilo y metil - CCNU.

We relate the experience obtained by treatment of 20 advanced digestive cancer patients, with the association of 5 fluorouracil and methyl-C.C.N.U. Objective response was found in 4 patients (20%). Toxicity consisted of leucopenia in 3 patients, allergic phenomena in 2 and diarrhea in 1 patient. Mean survival is increased in 3 months in responders, when compared with non-responders, although this difference has not statistical value.

A randomized phase II study of CEOP with or without semustine as induction chemotherapy in patients with stage IE/IIE extranodal NK/T-cell lymphoma, nasal type in the upper aerodigestive tract.

PURPOSE: In this randomized phase II study, we evaluated the efficacy of semustine added to CEOP regimen as induction chemotherapy in patients with stage I(E)/II(E) extranodal NK/T-cell lymphoma, nasal type in the upper aerodigestive tract. PATIENTS AND METHODS: Seventy-five eligible patients were randomized to receive either CEOP or CEOP plus semustine followed by involved-field radiotherapy. RESULTS: The overall response rate of induction chemotherapy was 57.9% in CEOP arm compared with 62.2% in CEOP plus semustine arm (P=0.71). With a median follow-up of 30.1 months, 2-year overall survival was 73.3% and 62.2%, respectively (P=0.37). Toxicities in both arms were comparable and manageable. Through univariate and multivariate analysis, PS of 2, Stage II(E) and elevated LDH level were identified to be adverse prognostic factors. A new prognostic index categorized three groups of patients (low risk, no adverse factors; intermediate risk, one factor; and high risk, 2 or 3 factors) with highly significant difference of prognosis. Two-year overall survival was 87.5%, 60.6% and 30%, respectively (P=0.0002). CONCLUSIONS: The addition of semustine to CEOP regimen was not associated with improved efficacy. More effective treatment needs to be explored in patients with intermediate or high risk.