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.

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.

[The kidney in children under chemotherapy]. / Le rein de l'enfant face à la chimiothérapie.

Nowadays more and more children survive after an intensive anti-tumoral therapy. The price to pay consists of numerous and relatively frequent long-term sequelae (secondary tumors, neuropsychological deficits, endocrine or cardiac damage). After chemotherapy, we sometimes observe renal side-effects, either tubular (metabolic acidosis, hypokalemia, hypomagnesemia, proteinuria, Fanconi syndrome, rickets) or glomerular (acute or chronic decreased GFR). These renal toxic side-effects are encountered especially after cisplatinum and ifosfamide, less frequently after carboplatin and cyclophosphamide. The pediatrician has to be aware of these toxic nephrologic side-effects, to look out for them and monitor carefully the renal function of all paediatric patients receiving these potentially nephrotoxic chemotherapies.

[Developments up to now and current status of adjuvant chemo- and radiotherapy in colonic and rectal carcinoma]. / Bisherige Entwicklungen und aktueller Stand der adjuvanten Chemo- und Radiotherapie beim Kolon- und Rektumkarzinom.

A review is given of the historical and current concepts of adjuvant chemo- and radiotherapy of colorectal cancer. Early studies analyzing the use of single drug regimens were followed by a second study generation investigating adjuvant chemotherapeutic combinations. 5-FU proved to be the most efficient single drug investigated and 5-FU/MeCCNU/vincristin the most efficient chemotherapeutic combination, but no significant improvement in 5-year survival rates was achieved. Clear progress was noted with the introduction of levamisol (LEV) for modulation of 5-FU. A 33% improval in the 5-year survival rate in patients with stage III colon carcinoma was documented. It was therefore recommended (NIH consensus conference 1990) that all patients with stage III colon carcinoma be treated with this regimen unless admitted to other trials of adjuvant therapy. Preoperative radiotherapy with a dosage of 35-45 Gy can lead to downstaging of rectal cancer. Nevertheless, significant improvement in patient survival has not been proved convincingly using either isolated pre- or postoperative adjuvant radiotherapy. However, combined radiochemotherapy has been shown to improve both patient survival and local tumor control compared to surgical resection alone. It is therefore recommended that all stage II and III rectal cancer patients be treated with adjuvant combined radiochemotherapy. 5-FU/MeCCNU is currently expected to be the most efficient chemotherapy in combination with radiotherapy. Early data point out that MeCCNU could possibly be omitted. Intraoperative radiotherapy (IORT) allows further dosage escalation in order to improve local tumor control without affecting radiosensitive structures. Available data are still sparse and mostly based on the treatment of advanced carcinoma. A general validation of IORT is not yet possible, but current data are promising.

[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.

Adjuvant therapy for patients with colon and rectum cancer.

The National Institutes of Health Consensus Development Conference on Adjuvant Therapy for Patients With Colon and Rectum Cancer brought together surgeons, medical oncologists, radiation oncologists, gastroenterologists, other health care providers, and the public to address the issues regarding adjuvant therapy for colon and rectum cancer. Following 1 1/2 days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared a consensus statement. Among their findings, the panel recommended that patients with Stage III colon cancer should receive adjuvant therapy with 5-fluorouracil (5-FU) and levamisole. Specific adjuvant therapy is not recommended for Stage II colon cancer patients outside of clinical trials. For rectal cancer, the panel recommended that adjuvant therapy combining chemotherapy and radiation therapy improves local control and survival for Stage II and III patients. The most effective combination at present appears to be 5-FU, methyl-CCNU, and high-dose pelvic irradiation. However, the use of methyl-CCNU outside of clinical trials is discouraged because of documented toxicities. The panel concluded that patients with Stage I colon and rectal cancers are at low risk of recurrence and do not warrant adjuvant therapy. The panel also recommended that the American Joint Committee on Cancer system for classifying stages of colon and rectal cancer, known as the TNM system, become the standard measurement used in clinical trials and in clinical practice.

Pulmonary fibrosis associated with low-dose adjuvant methyl-CCNU.

Pulmonary fibrosis is a serious side effect of nitrosourea therapy, occurring most frequently in patients treated with BCNU. Pulmonary fibrosis developed in a 63 year-old male patient while being treated with adjuvant methyl-CCNU for rectal carcinoma. This toxicity is rare with methyl-CCNU, having only been reported once previously. The case of methyl-CCNU-induced pulmonary fibrosis reported here occurred at a much lower total dose than the first reported case (604 mg/m2 vs. 2,733 mg/m2). Details of the case history, including radiographic and pathologic findings, are presented.

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.

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.

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.

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.

Chemical cholecystitis after intrahepatic chemotherapy. The case for prophylactic cholecystectomy during pump placement.

Recent repopularization of intrahepatic infusion chemotherapy has been made possible by the development of the implantable Infusaid pump. Surgical placement of a catheter into the gastroduodenal artery with division of collaterals to the stomach, duodenum, and pancreas has reduced the incidence of gastroduodenal ulceration and pancreatitis. The risk of chemical cholecystitis similarly demands prevention. Anatomically, the cystic artery is a branch of the right hepatic artery in over 95 percent of patients. As a result, even a normal gallbladder is subjected to high-dose chemotherapy with the risk of development of drug-induced cholecystitis. In our first six patients undergoing pump implantation who had normal appearing gallbladders at the time of surgery, two developed symptomatic cholecystitis, necessitating cholecystectomy after receiving intrahepatic chemotherapy. As a result, we recommend elective cholecystectomy at the time of arterial catheterization for intrahepatic chemotherapy.

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.

Prolongation of the disease-free interval in surgically treated rectal carcinoma.

To assess the effects of postoperative radiation therapy and chemotherapy on tumor recurrence and patient survival, 227 patients (data on 202 of whom were analyzed) who had undergone "curative" surgical resection for rectal adenocarcinoma were prospectively and randomly assigned to one of four treatments: no adjuvant therapy (concurrent controls, 58 patients), postoperative radiotherapy with 4000 or 4800 rad (50 patients), postoperative chemotherapy (fluorouracil and semustine [methyl-CCNU], 48 patients), or a combination of radiation therapy and chemotherapy (46 patients). Five years after the entry of the last patient and with a median follow-up of all survivors for 80 months, the recurrence rate was highest among the control patients (55 per cent) and lowest among the patients receiving a combination of adjuvant radiation and chemotherapy (33 per cent). Time to tumor recurrence differed significantly among the four treatment groups (P less than 0.04); it was significantly prolonged by combined radiation and chemotherapy as compared with resection alone (P less than 0.009). Overall survival did not differ significantly among the treatment groups. The superiority of the combined-modality regimen appeared to be attributable to the effects of radiation therapy and chemotherapy in controlling local and distant recurrences, respectively. We conclude that this study provides evidence supporting the use of postoperative radiation therapy in conjunction with chemotherapy in patients who have had "curative" resection of rectal cancer with involvement of perirectal fat or regional nodes or both (Stages B2 and C).