Faculty Bibliography

The current standard of care in ovarian cancer is complete surgical cytoreduction followed by adjuvant (postoperative) platinum-based chemotherapy. Taxanes are frequently combined with platinum compounds in the adjuvant chemotherapy setting and, whether they are given in combination or sequentially, they produce greater progression-free and overall survival than historical combination regimens. Because the treatment of ovarian cancer relies on chemotherapy, this article reviews the evidence for a correlation between chemotherapy delivered at full dose on schedule (FDOS) and patient outcomes. Meta-analyses have suggested that the dose intensities of cisplatin and carboplatin correlate with survival. However, the findings in these hypothesis-generating analyses have not been confirmed in prospective trials. In addition, increasing the dose of cisplatin above a certain threshold is not recommended in ovarian cancer because of the greater toxicity with higher doses of platinum compounds. The delivered dose intensities of taxanes used as single agents have not been shown to correlate with patient outcomes, but adding a taxane to platinum compounds appears both to attenuate the toxicity of the platinum compounds and to facilitate the delivery of FDOS chemotherapy. In the literature on ovarian cancer there is no clear consensus on the benefit of maintaining FDOS chemotherapy. Clinical studies, especially a proposed trial of a dose-dense carboplatin and paclitaxel combination, may provide stronger evidence for the effect of FDOS chemotherapy in ovarian cancer

Platinum/taxane regimens induce high response rates and prolong survival in women with ovarian cancer. After recurrence, however, response to second-line chemotherapy is limited. Pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), is the only liposomal anthracycline indicated for second-line treatment of platinum- and paclitaxel-refractory ovarian cancer. Response rates ranged from 14% to 20% in nonrandomized trials of this patient population. In a large phase 3 randomized trial, single-agent PLD and topotecan had similar efficacy overall in response rates, but PLD-treated patients had significantly improved overall survival compared with topotecan with a pronounced advantage in platinum-sensitive patients. Another randomized trial reported that PLD and paclitaxel were comparable with regards to response rate, progression-free survival, and overall survival, regardless of the degree of platinum sensitivity. Additional nonrandomized trials of PLD in combination with other active agents resulted in response rates ranging from 20% to 76%. PLD is generally well tolerated and its side-effect profile compares favorably with other commonly used chemotherapeutic agents in this clinical setting. Proper dosing and monitoring may further enhance tolerability while preserving the efficacy of this versatile agent for ovarian cancer

Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients

Three decades since the introduction of cisplatin into clinical cancer treatment, this drug and its second generation analogues, carboplatin and oxaliplatin, form an integral part of recent evolving achievements in the treatment of solid tumors. For example, landmark studies have established a role for cisplatin after resection in lung cancer, and improved survival from platinum-based chemoradiation in cancer of the uterine cervix and combination chemotherapy in mesothelioma, small cell lung, ovarian, and endometrial cancers. Colon cancer survival has improved with the addition of oxaliplatin to its treatment. Here we summarize how insights into the mechanism of action of platinum compounds and studies of their structure-activity relationships may identify platinums with unusual selectivity towards tumors such as melanoma, renal cell, and breast cancer and other cancers not usually treated with existing platinums. Both new drug development and mechanistic studies with established drugs should lead to the next generation of clinical studies with platinum compounds, and their integration with emerging 'targeted therapies'

PURPOSE. To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA. EXPERIMENTAL DESIGN. To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients. RESULTS. Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean+/-SD end-of-infusion CSA level (HPLC assay) was 1253+/-400 microg/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC. CONCLUSIONS. Steady-state levels of >1 microg/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics

OBJECTIVE: To evaluate the combination of cisplatin and irinotecan as first-line treatment of patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. METHODS: Patients with no prior treatment for metastatic disease, presence of measurable tumors, performance status of 0 or 1, and adequate bone marrow, renal, and hepatic functions were potentially eligible for this trial. Cisplatin and irinotecan were given weekly at starting doses of 25 and 65 mg/m(2), respectively, for three consecutive weeks. Cycles were to be repeated every 28 days with dose adjustments as required. Patient accrual was based on a two-stage design with at least seven responses out of 28 patients in the first stage required to proceed to a second stage of accrual seeking a response rate of 40% or better. RESULTS: Of 34 patients entered onto the study, 31 were eligible and 27 were evaluable for response. Ten had received prior chemoradiation containing cisplatin. Among the five (two complete and three partial) observed responses, two were in the subset of patients who had received prior chemoradiation. This level of activity was deemed insufficient to warrant a second stage of accrual. Predominant toxicities were myelosuppression and gastrointestinal symptoms, although six patients experienced none of these adverse effects. CONCLUSION: At these doses, weekly cisplatin and irinotecan failed to demonstrate sufficient activity to undertake a phase III study. Although not apparent in this study, prior chemoradiation may affect response to platinum-based combinations and its impact should be considered in the design of future trials