Faculty Bibliography

Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming 'cleavable complex,' a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 'free' topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy

PURPOSE: To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS: Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS: The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION: DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

Single agent activity of vinorelbine in previously untreated breast cancer and its predictable toxicity make it ideal for combination with cisplatin, a drug we found to be very active in combination with paclitaxel (J Clin Oncol; 14:1993, 1996), but with a high rate of neurotoxicity limiting duration of therapy. Eligibility included: histologically proven locally advanced or metastatic measurable breast cancer, ECOG performance status (PS) of 2 or less, adequate organ function. Cisplatin was given at a dose of 75 mg/m2 on day 1, with vinorelbine 30 mg/m2 days 1 and 8 of a 21 day cycle; day 8 vinorelbine dose was modified for neutropenia and thrombocytopenia. 24 patients (pts) entered the study, of whom 23 were eligible and 1 too early for response evaluation. 20 pts were treated as first line therapy for advanced disease (10 locally advanced and 10 metastatic). 3 pts were treated as second-line therapy for metastatic disease. Median age was 49 (range 32-67), median ECOG PS = 0. Nine pts had prior adjuvant chemotherapy and 8 pts had prior RT. A total of 91 cycles of chemotherapy were given with a median of 3 per pt. Hematological toxicity included leukopenia gr 3 = 4 pts, gr 4 = 2; neutropenia gr 3 = 4, gr 4 = 7 pts; no gr 3 or 4 thrombocytopenia. Non-heme toxicity included: N/V gr 2 = 6 pts, gr 3 = 1; neuropathy gr 1 = 10; gr 2 = 2; renal gr 2 = 1 pt. Responses seen included 2 CRs and 6 PRs (of 9 evaluable) locally advanced, 1 CR and 5 PRs (of 10) in metastatic disease, and 1 CR + 1 PR (of 3) second line therapy. Overall response rate was 73% (4 CR + 12 PR + 4 SD = 18% CR and 55% PR) of 22 evaluable pts. These data suggest that combined vinorelbine/cisplatin therapy is highly active in locally advanced and metastatic breast cancer without the high incidence of dose-limiting neurotoxicity seen in our prior paclitaxel/cisplatin trial. Accrual is continuing to improve the 95% confidence interval. (C) American Society of Clinical Oncology 1997

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients

OBJECTIVE: Our purpose was to evaluate the safety and biologic effects of PIXY321 after chemotherapy in patients with ovarian carcinoma. STUDY DESIGN: A multicenter, nonrandomized, phase I/II study of subcutaneously administered PIXY321 after the second cycle of chemotherapy in cohorts of three or more patients at 50, 125, 250, 500, 750, or 100 micrograms/m2 per day. RESULTS: Cyclophosphamide (600 mg/m2) and carboplatin (400 mg/m2) were administered every 28 days to 34 patients. At doses > or = 500 mg/m2 per day, the median nadir platelet and median nadir absolute neutrophil counts in cycle 2 (with PIXY321) compared with cycle 1 (control) were both higher in 13 of 26 (50%) patients. Twenty-one patients were withdrawn from the study. A total of 17 of 21 (81%) were removed for myelosuppression (n = 15) or PIXY321 toxicity (n = 2). A total of 28 of 34 (82%) patients had injection site reactions. Thirty-seven nonhematologic grade 3 events occurred. CONCLUSIONS: At these doses and schedules PIXY321 can be safely administered. Aggressive dosing of cyclophosphamide and carboplatin could not be maintained for six cycles in the majority (62%) of patients

Topotecan, a topoisomerase-1 inhibitor, may have greater therapeutic index when given by prolonged infusion. In an earlier phase I trial of escalating low-dose infusion (MTD = 0.53 mg/m2/d x 21d) for previously treated pts (JCO; 12:553 1994), 3/6 heavily treated ovarian cancer pts responded. We administered 60 cycles of TPT to 16 pts in a phase II study starting at 0.4 mg/m2/d x 21 days. All pts had one prior platinum-containing chemotherapy regimen with progression or recurrence (early less than 6 mo vs later). All pts had PS 0-1, normal heme parameters and Creat less than 1.6. Measurable disease (greater than 2 cm on CT scan) was required. Four pts were able to be escalated to 0.5 mg/m2/d for 11 cycles and 6 were reduced to 0.3 in 15 cycles. Responses are presented in a table. Four pts had stable disease (3 still on rx), and 6 PD. Overall response rate is at least 37% (95% CI =12-62%). Hematologic toxicity included leukopenia and neutropenia gr 3 = 4 pts (7%) and gr 4 = 1 pt (2%) but no grade 3 or 4 thrombopenia. Eight pts required blood transfusions. Non-heme toxicity included grade 1 nausea = 7 pts and gr 2 =3 pts; grade 1 fatigue =5 and gr 1 alopecia = 4 pts. Two catheter related thromboses occurred; 2 had sepsis. Weekly PBMC topo-1 levels were obtained for pharmacodynamic studies (abstract submitted). This response rate is among the highest reported for second-line therapy of ovarian cancer and is seen in both platinum resistant and refractory disease. Data on these and additional pts currently being accrued will be presented. (C) American Society of Clinical Oncology 1997

Chemotherapy drugs have been reported to cause cardiac side effects including cardiomyopathy, ischemia, arrhythmias, and myocardial necrosis. Most important in terms of daily practice is anthracycline-induced cardiomyopathy. The bisdioxopiperazine compound, dexrazoxane (ICRF-187, ADR-529), has been shown to prevent this cumulative side effect of the anthracyclines. Recent randomized trials performed in breast cancer and in pediatric sarcoma patients have demonstrated the efficacy of this approach, which permits the administration of anthracyclines to greater cumulative doses and thus leads to a substantial reduction in the incidence of decreased left-ventricular ejection fraction or congestive heart failure. Response rates were not significantly different with the use of dexrazoxane in these trials. The risk ratio for a cardiac event was decreased by two to threefold in randomized breast studies involving more than 700 women. Paclitaxel also has been reported to cause arrhythmias and possibly ischemia. In a large data base, National Cancer Institute investigators found a 0.29% incidence of grade 4 or 5 cardiac toxicities, including heart block, ventricular tachycardia, and ischemic events. Other important chemotherapy-related cardiac toxicities discussed include fluorouracil-induced angina and arrhythmias, interleukin-4 induced-cardiomyopathy, and cardiotoxicity associated with autologous bone marrow transplantation procedures

The purpose of this study was to estimate the response rate, response duration, and survival of patients with advanced ovarian cancer treated with a 132-hr continuous infusion of high-dose calcium leucovorin in combination with five consecutive daily bolus doses of 5-fluorouracil (5-FU) and to correlate changes in CA-125 levels with clinical and radiologic assessment of disease progression. Forty-six heavily pretreated patients [median number of previous chemotherapy regimens, 2.5 (range 1-7)] with advanced ovarian cancer received 132-hr continuous infusions of calcium leucovorin (500 mg/m2/day) for 5 1/2 days, with daily bolus doses of 5-FU (370 mg/m2/day) for 5 days beginning 24 hr after initiation of the calcium leucovorin. Twenty-three patients had clinically measurable disease and 23 had evaluable disease; CA-125 levels were performed prior to each treatment course and after the final course of therapy. One of 42 patients had a partial response to combination chemotherapy (duration, 8.9 months); 16/42 had stable disease [median duration, 4.9 months (range, 2.4-9.0 months)]. Toxicity of combination therapy included mild myelosuppression and stomatitis, similar to previously reported toxicity profiles for the 5-FU and calcium leucovorin combinations. Sensitivity of CA-125 levels as a single indicator of disease progression was 55%. The combination of infusional high-dose calcium leucovorin and 5-FU has little activity in refractory ovarian cancer. CA-125 levels incorrectly predict clinical disease activity in about one-third of cases and should not be the sole criterion for determination of clinical response when evaluating chemotherapeutic efficacy in heavily pretreated patients.

The hematopoietic growth factor, recombinant human interleukin-3 (rhu IL-3), stimulates production of both leukocytes and platelets, and thus potentially has greater utility than growth factors that solely stimulate leukocytes production when employed with dose-intensive chemotherapeutic regimens. To determine the optimal schedule for administration of rhu IL-3 in combination with cyclophosphamide and carboplatin, an aggressive regimen for the treatment of advanced ovarian cancer, a phase I trial was initiated by the New York Gynecologic Oncology Group. Following surgical debulking, all patients received cyclophosphamide and carboplatin for 6 cycles. rhu IL-3 was administered at 50, 250, or 500 microgram subcutaneously for 5 days either immediately prior to or after administration of chemotherapy. Cohorts of six patients were treated at each dose level (three pre- and three postchemotherapy). Eighteen patients received 91 cycles of treatment. The major toxicities attributable to rhu IL-3 included fevers, chills, malaise, nausea, and headache, but were not dose-limiting at the doses of rhu IL-3 employed. The major finding of this study was that rhu IL-3 administered after chemotherapy offered greater platelet protection than rhu IL-3 administered prior to chemotherapy as assessed by median platelet nadir and duration of platelet counts < 50,000/mm3. A second major finding was a dose-response relationship for rhu IL-3: the two higher doses employed, 250 and 500 micrograms, offered more effective platelet protection than the lower dose employed, 50 micrograms. rhu IL-3 had no significant effects on leukocyte nadirs or duration of nadirs at any schedule or dose employed. rhu IL-3 may reduced the thrombocytopenia associated with aggressive treatment with cyclophosphamide and carboplatin, although this remains to be confirmed in a randomized, placebo-controlled trial. The effects of rhu IL-3 are dose- and schedule-dependent