Dava J. Garcia

Safety aspects of pegylated liposomal doxorubicin in patients with cancer

SummaryEncapsulation in polyethylene glycol-coated (pegylated; Stealth®) liposomes alters the pharmacokinetic characteristics, and hence the safety and tolerability profile, of doxorubicin.Pegylated liposomal doxorubicin administered as a single agent is generally well tolerated. Grade III/IV leucopenia, stomatitis and palmar-plantar erythrodysaesthesia affected 16, 6 and 18% of solid tumour patients, respectively. Other adverse effects included nausea and vomiting and alopecia. Acute hypersensitivity infusion reactions have been reported in up to 9% of patients in some studies. Recently published data from a phase II trial in patients with refractory ovarian cancer showed no alopecia or cardiotoxicity and little nausea and vomiting after pegylated liposomal doxorubicin. Unlike free doxorubicin, pegylated liposomal doxorubicin is not a vesicant.Preliminary data, not yet confirmed in comparative studies, suggest that the pegylated liposomal formulation may be less cardiotoxic than free doxorubicin. Mucositis, however, appears to be increased. Studies to determine optimal dosing schedules and safety of pegylated liposomal doxorubicin in combination with other agents are ongoing.

In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers

Abstract Purpose: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. Methods: The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensitivity of 36 fresh tumor samples obtained during initial exploratory laparotomy from patients with newly diagnosed stage III – IV epithelial ovarian cancer who had received no prior chemotherapy or radiation therapy. Tumor samples were exposed to the platinum analogs for 1 h at concentrations of 10 and 100 μg/ml of nedaplatin and cisplatin and 100 and 1000 μg/ml of carboplatin. The resulting survival data were used to estimate the IC50 (drug concentration associated with 50% inhibition of tumor colony forming units, TCFUs) of each of the platinum analogs for each of the tumor samples, as well as the estimated survival following exposure to clinically achievable drug levels (i.e. the ultrafiltrable platinum area under the plasma disappearance curve, AUC, achieved in cancer patients following administration of standard or phase II doses). Results: At the lowest concentration tested (i.e. 10 μg/ml nedaplatin and cisplatin and 100 μg/ml carboplatin) the percentages of tumor samples which were sensitive (as defined by 50% or less survival of TCFUs as compared with controls) were 42, 50, and 40% for nedaplatin, cisplatin and carboplatin, respectively. The median IC50 values were 28.5, 12 and 121 μg/ml for nedaplatin, cisplatin and carboplatin, respectively. The estimated percentage of tumors sensitive to clinically achievable dose levels was 42% for nedaplatin and 36% for cisplatin and carboplatin. Nedaplatin and carboplatin proved relatively crossresistant with cisplatin in vitro; of the 18 tumor samples which were resistant to cisplatin, only 5 (28%) were sensitive to nedaplatin and 3 of 17 (18%) were sensitive to carboplatin. Conclusion: Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity, and large in vivo bioavailability establish nedaplatin as a promising platinum analog for further clinical development as a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.

Amifostine pretreatment for protection against topotecan-induced hematologic toxicity: results of a multicenter phase III trial in patients with advanced gynecologic malignancies☆

OBJECTIVE To determine if amifostine could reduce the hematologic toxicity associated with topotecan. METHODS Thirty patients with recurrent/refractory gynecologic malignancies were randomized to receive topotecan (TOPO) (1.5 mg/m(2)/day days 1-5) with or without amifostine (AMI/TOPO) (500 mg/m(2)/day days 1-5) every 3 weeks for six cycles. The primary study endpoints were the incidence of grade 3 and 4 neutropenia. RESULTS Fifteen patients were randomized to each arm for a total of 49 TOPO and 53 AMI/TOPO cycles. Patient characteristics and pretreatment ANC were similar between groups. Topotecan 1.5 mg/m(2)/day days 1-5 was initially administered to seven patients. Five developed neutropenic fevers, one an uncomplicated grade 4 neutropenia, and the other an uncomplicated grade 3 neutropenia. There were two treatment-related deaths due to sepsis (one in each treatment arm). The starting dose was thereafter reduced to 1.25 mg/m(2)/day days 1-5 every 21 days. No treatment related deaths occurred after this dose reduction. The incidence of combined grade 3/4 neutropenia was reduced from 67% (33/49 cycles) to 38% (20/53 cycles) with the addition of amifostine (P = 0.003; OR 0.29; 95% CI 0.12-0.71). CONCLUSIONS Topotecan at 1.5 mg/m(2)/day days 1-5 in heavily pretreated patients resulted in excessive toxicity not manageable with amifostine. At the reduced topotecan dose (1.25 mg/m(2) x 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.

Southwest Oncology Group Experience with Intraperitoneal Chemotherapy of Ovarian Cancer

Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the United States, and over 14,000 women will die of this disease in 1999 (1). During the past two decades, median survival has improved dramatically with the advent of platinum-and paclitaxel-based chemotherapy. In the early 1970s, the median survival of a woman with stage III disease was approx 12 mo (2). With currently available therapies, median survival has been extended to longer than 45 mo for patients with stage III disease and optimal surgical resections during the initial exploratory laparotomy (3,4). Unfortunately, despite significant gains in therapeutic efficacy and high response rates to primary chemotherapy regimens, the majority of women with advanced OC develop drug-resistant tumors, and eventually succumb to their disease.