M. Robert Cooper

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.

Chemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD

BACKGROUND AND METHODS MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkins disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkins disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen. RESULTS Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose. CONCLUSIONS In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkins disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

Interrupted versus Continuous Chemotherapy in Patients with Metastatic Breast Cancer

BACKGROUND Chemotherapy for metastatic breast cancer is palliative, and the optimal duration of therapy is unknown. We designed a trial to determine whether continuous treatment is superior to stopping treatment after a brief induction period and resuming treatment when the disease progresses. METHODS We treated 250 women with metastatic breast cancer with six courses of cyclophosphamide, doxorubicin, and fluorouracil given every three weeks. At the completion of this induction period, women whose disease either regressed or remained stable were randomly assigned to receive either continued treatment with cyclophosphamide, methotrexate, and fluorouracil (maintenance therapy) or no further treatment (observation) followed by treatment with cyclophosphamide, methotrexate, and fluorouracil when disease progression became evident (reinduction). RESULTS The combined rate of complete and partial responses after initial therapy was 30 percent (71 of 233 patients who could be evaluated; 95 percent confidence interval, 25 percent to 37 percent). In another 42 percent (98 patients), the disease remained stable. A total of 145 patients were randomized. Seventy-one were randomly assigned to the maintenance-therapy group, and 74 to the observation group. The median time to progression was 9.4 months for patients in the maintenance-therapy group and 3.2 months for patients in the observation group (P less than 0.001). After reinduction therapy, the median time to progression was 3.5 months. The median length of survival from the time of initial therapy was 14.8 months for all 250 patients; it was 21.1 months for the 71 patients in the maintenance-therapy group and 19.6 months for the 74 patients in the observation group (P = 0.67). Maintenance therapy was the most important determinant of the time before progression (P less than 0.001), but it was not associated with prolonged survival. The changes in performance status were similar in the patients in both groups, but nausea, vomiting, and mucositis were significantly more frequent in the maintenance-therapy group. CONCLUSIONS In patients with breast cancer who received induction chemotherapy for 18 weeks, subsequent continuous chemotherapy was associated with a significant prolongation of the time before progression as compared with those receiving no further therapy; overall survival, however, was not significantly different in the two groups.

Complete Deficiency of Leukocyte Glucose-6-Phosphate Dehydrogenase with Defective Bactericidal Activity

A 52 yr old Caucasian female (F. E.) had hemolytic anemia, a leukemoid reaction, and fatal sepsis due to Escherichia coli. Her leukocytes ingested bacteria normally but did not kill catalase positive Staphylococcus aureus, Escherichia coli, and Serratia marcescens. An H(2)O(2)-producing bacterium, Streptococcus faecalis, was killed normally. Granule myeloperoxidase, acid and alkaline phosphatase, and beta glucuronidase activities were normal, and these enzymes shifted normally to the phagocyte vacuole (light and electron microscopy). Intravacuolar reduction of nitroblue tetrazolium did not occur. Moreover, only minimal quantities of H(2)O(2) were generated, and the hexose monophosphate shunt (HMPS) was not stimulated during phagocytosis. These observations suggested the diagnosis of chronic granulomatous disease. However, in contrast to control and chronic granulomatous disease leukocytes, glucose-6-phosphate dehydrogenase activity was completely absent in F. E. leukocytes whereas NADH oxidase and NADPH oxidase activities were both normal. Unlike chronic granulomatous disease, methylene blue did not stimulate the hexose monophosphate shunt in F. E. cells. Thus, F. E. and chronic granulomatous disease leukocytes appear to share certain metabolic and bactericidal defects, but the metabolic basis of the abnormality differs. Chronic granulomatous disease cells lack oxidase activity which produces H(2)O(2); F. E. cells had normal levels of oxidase activity but failed to produce NADPH due to complete glucose-6-phosphate dehydrogenase deficiency. These data indicate that a complete absence of leukocyte glucose-6-phosphate dehydrogenase with defective hexose monophosphate shunt activity is associated with low H(2)O(2) production and inadequate bactericidal activity, and further suggest an important role for NADPH in the production of H(2)O(2) in human granulocytes.

Hodgkin disease survivors at increased risk for problems in psychosocial adaptation

Background. The long‐term psychosocial adaptations of 273 survivors of advanced Hodgkin disease were assessed to determine the nature and extent of problems experienced and to identify those at high risk for maladaptation.

A modified procedure for the determination of loukocyte alkaline phosphatase

Abstract Although the determination of serum alkaline phosphatase in a glycine buffer is a standard procedure, this buffer is totally unsuitable for assaying the leukocyte enzyme. The leukocyte enzyme is almost totally inhibited by preincubation in 0.1 m glycine for 5 minutes; hence the reaction is not linear with time when run in this buffer. A satisfactory assay for the leukocyte enzyme employing 2-amino-2-methyl-1-propanol buffer is outlined.

Written informed consent in patients with breast cancer

One hundred breast cancer patients, 35 adjuvant and 65 advanced, were interviewed 0–24 months after the start of chemotherapy to assess their knowledge and perceptions of the purposes, risks and benefits of treatment. Prior to therapy, all had been given verbal explanations and had signed informed consent forms explicitly detailing drugs, objectives and possible adverse effects of therapy. Seventeen percent of adjuvant and 29% of advanced patients were unable to name any of their drugs. While most patients recognized distressing side effects such as nausea and hair loss, less than 50% were aware of the potentially lethal complications of infection and bleeding. While the purpose of adjuvant therapy was cure, only 29% of the adjuvant patients were aware of this. In contrast, 35% of the advanced patients incorrectly stated that they were told their therapy was potentially curative. Explanations given by a nurse in addition to a physician were better understood than those given by a physician alone. We conclude that, in spite of intensive efforts at improving informed consent procedures, current results are unsatisfactory.

Carboplatin in malignant mesothelioma: A phase II study of the cancer and leukemia Group B

SummaryCarboplatin (400 mg/m2) was given at 28-day intervals to 41 patients with malignant mesothelioma. In all, 40 patients were eligible and evaluable for response. Partial responses were seen in 2 cases (5%); regression of evaluable disease, in 1 patient (2%); and stable disease, in 19 subjects (48%). A median of two doses of carboplatin per patient resulted in mild toxicity. Leukopenia (≤2,000 cells/μl) and thrombocytopenia (<100,000 cells/μl) were seen in only 6% and 20% of the patients, respectively. Median survival from study entry was estimated at 7.1 months, with a 1-year survival of 25%±7%. Carboplatin given at a dose of 400 mg/m2 at 28-day intervals shows minor activity against malignant mesothelioma.

Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial.

Adriamycin is of noteworthy efficacy in the treatment of metastatic breast cancer. Its role in combination regimens is under investigation. One hundred seventy‐five women with advanced breast cancer were entered into a prospectively randomized trial comparing two five‐drug regimens. Regimen CMFVP consisted of cyclophosphamide (C), methotrexate (M), 5‐fluorouracil (F), vincristine (V), and prednisone (P). Regimen CAFVP was identical but substituted Adriamycin (A) for methotrexate. Twenty‐seven patients were disqualified; 148 were evaluable. With CMFVP the complete response rate (CR) was 11%, and the partial response rate (PR) was 46%; with CAFVP, CR was 13% and PR was 45%. Duration of response tended to be slightly longer for patients on the Adriamycin arm. The median survival for CR and PR patients with CMFVP was 20.2 months, which was shorter (p =.07) than the 33 month median survival with CAFVP. Although statistical significance was not reached at the 5% level, the increased survival of responders on the Adriamycin regimen supports the data of other studies which suggest that first line combination chemotherapy in advanced breast cancer should include Adriamycin. Cancer 42:2141–2148, 1978.

Comparison of psychosocial adaptation and sexual function of survivors of advanced Hodgkin disease treated by MOPP, ABVD, or MOPP alternating with ABVD.

Background. Survivors of advanced Hodgkin disease, who were assigned randomly to treatment by mechlorethamine, vincristine, procarbazine, and prednisone (MOPP); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or MOPP alternating with ABVD in a clinical trial of the Cancer and Leukemia Group B (protocol 8251), were compared in terms of their psychosocial adaptation and psychosexual function an average of 2.2 years after completion of treatment (range, 1‐5 years). The study was undertaken to determine if there were differences among treatments in these functional areas as a consequence of differential long‐term gonadal damage in the three regimens.