Brenda W. Cooper

A phase I and pharmacodynamic study of sequential topotecan and etoposide in patients with relapsed or refractory acute myelogenous and lymphoblastic leukemia

We designed a pharmacokinetic and pharmacodynamic phase I study of sequential topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of etoposide for patients with refractory acute leukemia based upon synergistic anti-tumor activity of topoisomerase I and II inhibitors in vitro. Eight of the 29 patients achieved bone marrow aplasia and two patients achieved clinical remission. Common grade 3-4 toxicities included hepatic and gastrointestinal dysfunction, and correlated with increased steady-state plasma topotecan concentration. The predicted up-regulation of topoisomerase II activity by topoisomerase I inhibition was not observed at this dose and schedule and may provide insight into the modest anti-leukemia activity of the regimen.

A Phase II Study of Radiotherapy and Concurrent Paclitaxel Chemotherapy in Breast-Conserving Treatment for Node-Positive Breast Cancer

PURPOSE Administering adjuvant chemotherapy before breast radiotherapy decreases the risk of systemic recurrence, but delays in radiotherapy could yield higher local failure. We assessed the feasibility and efficacy of placing radiotherapy earlier in the breast-conserving treatment course for lymph node-positive breast cancer. METHODS AND MATERIALS Between June 2000 and December 2004, 44 women with node-positive Stage II and III breast cancer were entered into this trial. Breast-conserving surgery and 4 cycles of doxorubicin (60 mg/m(2))/cyclophosphamide (600 mg/m(2)) were followed by 4 cycles of paclitaxel (175 mg/m(2)) delivered every 3 weeks. Radiotherapy was concurrent with the first 2 cycles of paclitaxel. The breast received 39.6 Gy in 22 fractions with a tumor bed boost of 14 Gy in 7 fractions. Regional lymphatics were included when indicated. Functional lung volume was assessed by use of the diffusing capacity for carbon monoxide as a proxy. Breast cosmesis was evaluated with the Harvard criteria. RESULTS The 5-year actuarial rate of disease-free survival is 88%, and overall survival is 93%. There have been no local failures. Median follow-up is 75 months. No cases of radiation pneumonitis developed. There was no significant change in the diffusing capacity for carbon monoxide either immediately after radiotherapy (p = 0.51) or with extended follow-up (p = 0.63). Volume of irradiated breast tissue correlated with acute cosmesis, and acute Grade 3 skin toxicity developed in 2 patients. Late cosmesis was not adversely affected. CONCLUSIONS Concurrent paclitaxel chemotherapy and radiotherapy after breast-conserving surgery shortened total treatment time, provided excellent local control, and was well tolerated.

Renal dysfunction during high-dose cisplatin therapy and autologous hematopoietic stem cell transplantation: Effect of aminoglycoside therapy

PURPOSE Renal dysfunction is a common cause of morbidity after cancer therapy and bone marrow transplantation. In this study, we evaluated the effects of aminoglycosides and other nephrotoxic antibiotics on the occurrence of renal dysfunction in patients who received high-dose cisplatin-containing chemotherapy regimens. PATIENTS AND METHODS The subjects of this analysis were 102 consecutive patients, studied from September 1985 to February 1991, who received high-dose cisplatin, administered as 40 mg/m2 for 5 consecutive days in 3% saline with saline hydration and mannitol diuresis, followed by autologous stem cell transplantation. Renal dysfunction was defined as an increase in serum creatinine greater than or equal to 44.2 mumol/L above baseline. RESULTS Characteristics of the 43 patients who were given aminoglycosides were similar to those in patients who did not receive aminoglycosides with respect to initial renal function, age, cancer type, and previous exposure to cisplatin. Patients who experienced serious treatment-related toxicities such as hemorrhage or septicemia were more likely to have received aminoglycoside antibiotics (p = 0.005). A multivariate analysis showed that increased duration of neutropenia, advanced patient age, and amphotericin B use were predictors of renal failure. Aminoglycoside therapy did not significantly increase the risk of renal dysfunction. CONCLUSIONS Our data suggest that with appropriate supportive care measures, aminoglycosides can safely be administered to febrile, neutropenic patients who recently have received high-dose cisplatin therapy.

Cefoperazone/sulbactam versus cefoperazone plus mezlocillin: empiric therapy for febrile, neutropenic bone marrow transplant patients

We conducted a prospective, randomized trial in 132 patients undergoing bone marrow transplantation comparing cefoperazone in combination with sulbactam (S), N = 66, vs. cefoperazone plus mezlocillin (CM), N = 66, as empiric antibiotic therapy for fever and neutropenia. Overall duration of neutropenia was 3-55 (median, 13) days. Forty-one patients had positive initial cultures (S = 22 and CM = 19). Twelve of these 41 patients responded to initial study antibacterial agent treatment (S = 6 and CM = 6). Twenty-nine of 41 patients were withdrawn from study because of clinical deterioration, continued fever, or persistently positive cultures (S = 16 and CM = 13). Of the 90 patients who had culture-negative fever (S = 44 and CM = 46), 44 subjects responded with or without the addition of amphotericin B (S = 21 and CM = 23). Thirty-seven of 90 patients were withdrawn from study due to continued fever or clinical deterioration (S = 17 and CM = 20). Nine patients were withdrawn as a result of rash or diarrhea (S = 6 and CM = 3). We conclude that in patients undergoing bone marrow transplantation, there was no difference in efficacy between cefoperazone/sulbactam and the combination of cefoperazone plus mezlocillin in the empiric treatment of the febrile neutropenic patient. Since the majority of initial infections were due to gram positive bacteria, consideration should be given to broadening initial empiric antibacterial agent therapy with drugs that possess potent activity against these organisms.

Phase II study of fludarabine, carboplatin, and topotecan with thalidomide (FCTT) for patients with relapsed/refractory or secondary acute myelogenous leukemia, chronic myeloid leukemia and advanced myelodysplastic syndromes

6630 Background: Limited treatment options are available for patients with AML that has relapsed or develops as a result of prior chemotherapy or hematologic disorders. Methods: We designed a phase II study of fludarabine (15mg/m2 x 5 days) given concurrently with carboplatin (AUC 12 by CIVI over 5 days) followed by topotecan (0.85 mg/m2 daily by CIVI over 72 hours) based on promising results of a phase I study. Thalidomide was given at a dose of 100mg daily for 1 week then 200 mg daily for potential anti-angiogenic activity as well as single agent response in myelodysplasia. 35 pts were enrolled with median age 60 years (range 40 to 78). 14 pts had AML secondary to cytotoxic chemotherapy or prior hematologic conditions and had not received prior therapy for acute leukemia (Group 1). 21 pts had relapsed or refractory AML (Group 2). Two patients had failed prior autologous stem cell transplantation. Results: Seven of 14 (50%) pts in Group 1 and 8 of 21 (38%) pts in Group 2 achieved bone marrow aplasia. Fou...