Faculty Bibliography

PURPOSE: Most ovarian cancers recur after first-line treatment. We studied the pharmacology, tolerability, and therapeutic potential of intraperitoneal (IP) topotecan, alone and with IP cisplatin. METHODS: Patients received IP topotecan 1.5 mg (flat dose) daily on days 1-5 (level 0) via IP catheter. Subsequent cohorts received IP cisplatin 50 mg/m(2) on day 1 added to topotecan 1.5 mg on days 1-3 (level I), topotecan 1.25 mg on days 1-3 (level II), or topotecan 1.25 mg on days 1-5 (level III). Plasma and IP concentrations of total and lactone (E-ring closed) topotecan were measured on days 1 and 2 in cycles 1 and 2. RESULTS: Sixteen patients (15 tubo-ovarian, 1 gastric cancers) were entered at levels 0 (3), I (4), II (4), or III (5). Dose-limiting neutropenias occurred in seven patients at dose levels I and III; grade 3 thrombocytopenia occurred in two at level III. Other toxicities included grade 1 hives in two, serum creatinine elevations in two, and Staphylococcus epidermidis and chemical peritonitis (one each). A median progression-free survival of 13 months was recorded among ovarian cancer patients who had minimal (6) or no residuum (3) after platinum-based induction; 5 are alive at 4 years. Topotecan's AUC IP/AUC plasma ratios ranged from 13 to 119. CONCLUSION: Topotecan IP for 3-5 days is tolerable; occasionally, myelosuppression is dose-limiting. Topotecan 1.25 mg (days 1-3) with IP cisplatin 50 mg/m(2) (day 1) is a regimen suitable for consolidation in phase 3 trials.

PURPOSE: Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial. PATIENTS AND METHODS: Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control. RESULTS: Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients. CONCLUSION: Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.

In 1996, intraperitoneal (IP) administration of cisplatin plus intravenous (i.v.) cyclophosphamide proved superior to both drugs given intravenously at the same doses--which, at the time, was the standard treatment in the United States. The IP 'option' was not adopted, however, because the standard treatment had shifted to i.v. cisplatin plus paclitaxel.Two additional phase III trials by the Gynecologic Oncology Group (GOG) comparing IP versus i.v. cisplatin, but including other variables, have shown similar superior effects of the IP route on outcome, but with toxicities-particularly local tolerance and neuropathy--increased. An ongoing trial by the GOG is again looking into an IP versus i.v. comparison, and introducing in one of the IP arms the substitution of IP carboplatin for IP cisplatin. All three arms of this trial contain bevacizumab (Avastin). Two other trials comparing i.v. versus IP administration of platinums or platinums and paclitaxel have just been launched, led by Japanese and Canadian investigators, respectively. While awaiting additional data on the ongoing debate over IP versus i.v. therapy, it is important that we consider issues concerning why the IP route may be relevant, how can one increase the safety of this route, and who should be treated and with what drugs, particularly when faced with a patient outside the clinical trials setting. The underlying hypothesis for use of IP therapy is based on the existence of a dose-effect relationship for platinum drugs in ovarian cancer. We review the known data on this relationship, and explore why interest in platinum drugs has become the central focus of ovarian cancer treatment.