David B. Duggan

Improved Outcomes From Adding Sequential Paclitaxel but Not From Escalating Doxorubicin Dose in an Adjuvant Chemotherapy Regimen for Patients With Node-Positive Primary Breast Cancer

PURPOSE This study was designed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a standard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival. PATIENTS AND METHODS After surgical treatment, 3,121 women with operable breast cancer and involved lymph nodes were randomly assigned to receive a combination of cyclophosphamide (C), 600 mg/m(2), with one of three doses of doxorubicin (A), 60, 75, or 90 mg/m(2), for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2). Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. RESULTS There was no evidence of a doxorubicin dose effect. At 5 years, disease-free survival was 69%, 66%, and 67% for patients randomly assigned to 60, 75, and 90 mg/m(2), respectively. The hazard reductions from adding paclitaxel to CA were 17% for recurrence (adjusted Wald chi(2) P =.0023; unadjusted Wilcoxon P =.0011) and 18% for death (adjusted P =.0064; unadjusted P =.0098). At 5 years, the disease-free survival (+/- SE) was 65% (+/- 1) and 70% (+/- 1), and overall survival was 77% (+/- 1) and 80% (+/- 1) after CA alone or CA plus paclitaxel, respectively. The effects of adding paclitaxel were not significantly different in subsets defined by the protocol, but in an unplanned subset analysis, the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 (95% confidence interval, 0.59 to 0.86) for those with estrogen receptor-negative tumors and only 0.91 (95% confidence interval, 0.78 to 1.07) for patients with estrogen receptor-positive tumors, almost all of whom received adjuvant tamoxifen. The additional toxicity from adding four cycles of paclitaxel was generally modest. CONCLUSION The addition of four cycles of paclitaxel after the completion of a standard course of CA improves the disease-free and overall survival of patients with early breast cancer.

Randomized Comparison of ABVD and MOPP/ABV Hybrid for the Treatment of Advanced Hodgkin’s Disease: Report of an Intergroup Trial

PURPOSE In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkins disease. We compared these regimens as initial chemotherapy for Hodgkins disease. PATIENTS AND METHODS Adult patients (N = 856) with advanced Hodgkins disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. RESULTS The rates of complete remission (76% v 80%, P =.16), failure-free survival at 5 years (63% v 66%, P =.42), and overall survival at 5 years (82% v 81%, P =.82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P =.060 and.001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P =.057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P =.13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P =.011). CONCLUSION ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkins disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkins disease.

Failure of Higher-Dose Paclitaxel to Improve Outcome in Patients With Metastatic Breast Cancer: Cancer and Leukemia Group B Trial 9342

PURPOSE Cancer and Leukemia Group B Protocol 9342 was initiated to determine the optimal dose of paclitaxel administered as a 3-hour infusion every 3 weeks to women with metastatic breast cancer. PATIENTS AND METHODS Four hundred seventy-four women with metastatic breast cancer who had received one or no prior chemotherapy regimens were randomly assigned to one of three paclitaxel dosing regimens-175 mg/m(2), 210 mg/m(2), or 250 mg/m(2)-each administered as a 3-hour infusion every 3 weeks. Women completed self-administered quality of life and symptom assessment questionnaires at baseline and after three cycles of treatment. RESULTS No evidence of a significant dose-response relationship was demonstrated over the dose range assessed. Response rates were 23%, 26%, and 21% for the three regimens, respectively. A marginally significant association (P =.04) was seen between dose and time to progression; however, in a multivariate analysis, the difference was even less apparent. No statistically significant difference was seen in survival. Neurotoxicity and hematologic toxicity were more severe on the higher dose arms. There was no significant difference in quality of life on the three arms. CONCLUSION Higher doses of paclitaxel administered as a 3-hour infusion to women with metastatic breast cancer did not improve response rate, survival, or quality of life. There was a slight improvement in time to progression with higher dose therapy, which was offset by greater toxicity. When a 3-hour infusion of paclitaxel is administered every 3 weeks, 175 mg/m(2) should be considered the optimal dose.

A randomized clinical trial comparing melphalan/prednisone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study.

PURPOSE This clinical trial was designed to compare the effectiveness of the standard melphalan and prednisone regimen to that of melphalan, prednisone, and interferon in patients with untreated multiple myeloma. PATIENTS AND METHODS Between October 1985 and March 1988, 278 patients were accrued to a multi-institutional, randomized clinical trial. Responding patients were treated for 2 years before termination of therapy. RESULTS After a median follow-up of 23 months, the overall remission rate for the melphalan/prednisone treatment group was 44% compared with 33% for the group receiving melphalan/prednisone/interferon alfa-2b. The durations of response and survival were identical for the two treatment groups. Median survival was 3.17 years on melphalan/prednisone treatment and 3.0 years on melphalan/prednisone/interferon alfa-2b treatment. Both hematologic and nonhematologic toxicities were greater in the melphalan/prednisone/interferon alfa-2b treatment group, but were usually of a mild or moderate degree and did not interfere with the completion of therapy. The frequency of deaths in the two treatment groups attributable to the treatment itself was similar. CONCLUSION This study shows no advantage to the concomitant delivery of interferon alfa-2b with standard melphalan and prednisone as initial treatment for patients with multiple myeloma.

Etoposide, vinblastine, and doxorubicin: an active regimen for the treatment of Hodgkin's disease in relapse following MOPP. Cancer and Leukemia Group B.

PURPOSE To evaluate the activity and toxicity of combined etoposide, vinblastine, and doxorubicin (EVA) in advanced Hodgkins disease (HD) in relapse from or refractory to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). PATIENTS AND METHODS Eligible patients were more than 15 years of age and had received only one prior course of MOPP and were in relapse with measurable disease. The EVA regimen (etoposide 100 mg/m2 intravenously [IV] on days 1, 2, and 3; vinblastine 6 mg/m2 IV on day 1; and doxorubicin 50 mg/m2 IV on day 1) was administered every 28 days for a minimum of four and a maximum of six cycles. Patients were restaged at 3 and 6 months. RESULTS Forty-five eligible patients were treated, with an overall response rate of 73%. There were 40% complete responses (CRs) and 33% partial responses (PRs). The median follow-up time in 42 months. The median time to treatment failure (TTF) is 10 months, with 31% continuing progression-free. Eighteen patients achieved a second CR, with only seven recurrences in that group. Failure-free survival and overall survival were significantly better in patients whose first MOPP-induced remission was longer than 12 months and who were free of B symptoms at relapse. Toxicity was primarily myelosuppression, which resulted in two toxic deaths. Pulmonary toxicity was not observed. CONCLUSION EVA is an effective second-line regimen for the treatment of HD in relapse following MOPP chemotherapy.

A case of fatal Pemphigus Vulgaris in association with beta interferon and interleukin-2 therapy

Beta interferon (β‐IFN) and interleukin‐2 (IL‐2) have been utilized in experimental cancer therapy because of their effects on the immune system. We report here a patient treated with IL‐2 and β‐IFN who rapidly developed an immune‐mediated, bullous exfoliative dermatitis and who ultimately died. Various etiologic mechanisms are proposed.

Every Error a Treasure: Improving Medication Use with a Nonpunitive Reporting System

BACKGROUND The fear of reprisal, combined with the additional time required for reporting, are significant disincentives to reporting of medical events. Such considerations provided an incentive for the Upstate Medical University Hospital (Syracuse, New York) to develop monitoring systems to decrease the potential for drug harm. IMPLEMENTING A NONPUNITIVE REPORTING SYSTEM: Previously, a convenient, point-based score card system for punishment and remediation led to underreporting and hindered the identification of safety improvement opportunities in medication use processes. Nursing buy-in was accomplished through careful initial negotiations that emphasized that patients were best served by learning from errors in the medication use process. The revised medication event reporting policy, as established in October 2000 for all staff, severed the link between reporting errors and performance evaluations. RESULTS Data collected 18 months before the policy change was compared with data collected after the policy change was enacted in October 2000. The number of reports received each month increased from an average of 19 to 102 (p < .001). DISCUSSION Substantive quality improvements in medication have been achieved by using a systematic approach to the analysis of the markedly increased number of reported medication events following the introduction of a nonpunitive reporting system.

Lack of Attenuation in the Antitumor Effect of Tamoxifen by Chronic CYP Isoform Inhibition

Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor‐positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long‐term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4‐hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty‐eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4‐hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression.

A phase II trial of didemnin B in myeloma. A Cancer and Leukemia Group B (CALGB) study.

Didemnin B is a member of a class of compounds, derived from a marine source, undergoing phase II study. Twenty-two patients with relapsed myeloma were treated with didemnin B at an initial dose of 4.9 mg/m2, given once every 28 days. All were evaluable for toxicity, and 15 were evaluable for myeloma response. No tumor regressions occurred in the 15 patients evaluable for response. Vomiting was the major toxicity, occurring in 73% of patients despite vigorous pre- and post-treatment medication with at least three intravenous antiemetics. Two instances of grade 4 hypersensitivity reaction occurred. We conclude that didemnin B has no activity at this dose and schedule in myeloma that has relapsed after one or two prior therapeutic regimens.

A phase II study of recombinant interleukin-2 with or without recombinant interferon-β in non-Hodgkin's lymphoma. A study of the cancer and leukemia group B

Interleukin-2 (IL-2) and interferon-beta (IFN-beta) have demonstrated activity against lymphoid malignancies, presumably mediated by the augmentation of lymphokine-activated killer (LAK) cell and natural killer (NK) cell activity. There is in vitro and in vivo evidence to suggest that the combination of IL-2 and IFN-beta is synergistic. The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II trial of IL-2 with or without IFN-beta in 49 patients with relapsed or refractory non-Hodgkins lymphoma (NHL). Overall toxicity was severe, with 17 patients experiencing life-threatening toxicity. Three patients had treatment-related deaths. Responses were noted in seven patients (17%). There were no meaningful differences between treatment arms in toxicity profile, response rate, or modulation of in vivo NK and LAK activity. We conclude that IL-2 with or without IFN-beta is not effective therapy for NHL in the doses and schedule used in this study.