Carl G. Kardinal

Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2 months of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide (AC) with 6 months of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with breast cancer nonresponsive to tamoxifen (TAM, T). A second aim was to determine whether AC followed in 6 months by intravenous (IV) CMF was more effective than AC without reinduction therapy. Through 3 years of follow-up, findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups. Since the outcome from AC and CMF was almost identical, the issue arises concerning which regimen is more appropriate for the treatment of breast cancer patients. AC seems preferable since, following total mastectomy, AC was completed on day 63 versus day 154 for conventional CMF; patients visited health professionals three times as often for conventional CMF as for AC; women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF; and nausea-control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC. The difference in the amount of alopecia between the two treatment groups was less than anticipated. While alopecia was almost universally observed following AC therapy, 71% of the CMF patients also had hair loss and, in 41%, the loss was greater than 50%. This study and NSABP B-16, which evaluates the worth of AC therapy in TAM-responsive patients, indicate the merit of 2 months of AC therapy for all positive-node breast cancer patients.

Further Evaluation of Intensified and Increased Total Dose of Cyclophosphamide for the Treatment of Primary Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-25

PURPOSEnIn 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results.nnnPATIENTS AND METHODSnPatients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival.nnnRESULTSnNo significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups.nnnCONCLUSIONnBecause intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

Nicotine Patch Therapy Based on Smoking Rate Followed by Bupropion for Prevention of Relapse to Smoking

PURPOSEnTo determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy.nnnPARTICIPANTS AND METHODSnFourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment.nnnRESULTSnOf 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P =.73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P =.12).nnnCONCLUSIONnTailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.

Safety and Toxicity Analysis of Oxaliplatin Combined With Fluorouracil or as a Single Agent in Patients With Previously Treated Advanced Colorectal Cancer

PURPOSEnTwo consecutive compassionate use studies of oxaliplatin were conducted in the United States and Canada in more than 5000 patients with locally advanced or metastatic colorectal carcinoma who had experienced treatment failure after at least one prior chemotherapy regimen.nnnPATIENTS AND METHODSnThe main focus was safety. Patients were assigned to treatment with either single-agent oxaliplatin or oxaliplatin in combination with fluorouracil (FU) and with or without leucovorin (LV) in various regimens. Response data collection was not a trial objective, but time to treatment failure (TTF) was recorded in the first cohort (1370 patients).nnnRESULTSnAll treatment regimens were well tolerated, with an overall incidence of grade 3 or 4 hematologic toxicity of 23.2%, grade 3 or 4 treatment-related gastrointestinal toxicity of 26.4% (including diarrhea, vomiting, and mucositis), and grade 3 neurosensory toxicity 3.9%. Similar results were reported in the second cohort (3806 patients), in which the eligibility criteria were much less restrictive. In the first cohort (in which 83% received prior irinotecan), median TTF was 14 weeks, and was similar for the five regimens combining oxaliplatin and FU with or without LV, but significantly shorter for the single-agent oxaliplatin arm. The overall dose-intensity of oxaliplatin was maintained at 85.5% (range, 80.6% to 94.3%) of that prescribed by protocol (average 36.7 mg/m2/wk).nnnCONCLUSIONnThese data in a heavily pretreated patient population confirm that oxaliplatin is safe when used as a single agent or with a variety of FU-based regimens as salvage therapy in patients with advanced colorectal cancer.

Gemcitabine/Epirubicin/Paclitaxel as Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group

BACKGROUNDnThis phase II protocol of neoadjuvant chemotherapy with gemcitabine/epirubicin/paclitaxel (GET) was designed to determine the pathologic complete response (pCR) rate in the breast, clinical response rate, disease-free survival, and overall survival at 2 years as well as toxicity in patients with locally advanced breast cancer. This trial also evaluated the feasibility of tissue collection for gene-expression profiling.nnnPATIENTS AND METHODSnSeventy-six women with stage IIB, IIIA, and IIIB breast cancer were entered into this trial. Patients received a maximum of 6 cycles of neoadjuvant GET chemotherapy every 21 days (gemcitabine 1000 mg/m2 intravenously [i.v.] on days 1 and 4, epirubicin 90 mg/m2 i.v. bolus on day 1, and paclitaxel 175 mg/m2 i.v. on day 1). After chemotherapy, patients underwent surgery and were assessed for pathologic response.nnnRESULTSnThe pCR rate among the 74 patients evaluable for efficacy was 23% (95% CI, 14%-34.2%). Adverse events among the 76 patients evaluable for toxicity included anemia requiring transfusion (14.5%), infection with grade 3/4 neutropenia (10.5%), febrile neutropenia (7.9%), and platelet transfusion (6.6%). Infectious complications occurred in 24 patients (31.6%), of whom 18.4% were in the setting of neutropenia. High-quality RNA and successful probe synthesis were obtained from all pretreatment core biopsy specimens that contained tumor cells (n=66; 88%).nnnCONCLUSIONnNeoadjuvant GET chemotherapy is an active regimen but with substantial toxicity. Tissue collection for gene-expression profiling is feasible in a multi-institutional setting.