Faculty Bibliography

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'

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

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers

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 compounds have long played a role in the treatment of gynecologic cancers. Single-agent cisplatin and carboplatin have shown activity in endometrial cancer, and more recent studies have begun to investigate a variety of new platinum-based combinations. In cervical cancer, chemotherapy is used primarily to treat advanced or recurrent disease. Agents with proven single-agent activity in this setting include cisplatin, ifosfamide, and doxorubicin, and a number of cisplatin-based combination therapies are under clinical investigation. A variety of cisplatin-based combinations have also been used in ovarian cancer chemotherapy, with more recent studies investigating the substitution of carboplatin or oxaliplatin for cisplatin and the addition of paclitaxel. This review will examine recent clinical data on the use of platinum-based chemotherapies for the treatment of these gynecologic cancers

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