Paclitaxel in Cisplatin or Carboplatin-Pretreated Ovarian Cancer

There has been a steady improvement in the survival of patients with advanced ovarian cancer. This has been the result of a more skilled surgical approach to these patients and the development of more effective chemotherapy with a better integration of both modalities in first-line treatment. The current optimal chemotherapeutic approach consists of a platinum compound together with paclitaxel. This recommendation is based upon level I evidence of two large randomized trials which established that the combination of paclitaxel-cisplatin was superior to cyclophosphamide-cisplatin. The long-term follow-up of one of these studies continues to show a significant difference in survival at 5 years. Neurotoxicity has been problematic with these regimens, in particular when paclitaxel was given with the higher dosed shorter infusion schedule, as was done in the European-Canadian Intergroup study. Several approaches to reduce this toxicity have been studied. Among these are the use of different paclitaxel infusion schedules, and the application of less neurotoxic platinum compounds. Weekly paclitaxel has a different toxicity profile than the higher dosed three-weekly schedules, with less neutropenia, alopecia, arthralgia and neurotoxicity. Four platinum compounds are currently marketed: cisplatin, carboplatin, oxaliplatin, and nedaplatin. Of these only cisplatin, carboplatin, and nedaplatin have been approved for the treatment of patients with ovarian cancer (nedaplatin only in Japan). The equivalence of carboplatin and cisplatin has been suggested from trials without a taxoid. Three randomized studies of paclitaxel-carboplatin vs. paclitaxel-cisplatin concluded that paclitaxel-carboplatin is the preferred regimen in terms of (less) toxicity and, where studied, in terms of quality of life. So far, no difference in response rates or progression-free survival has been shown. More mature data on overall survival are awaited. Oxaliplatin (a diaminocyclohexane platinum compound) is of interest because it is only partially cross-resistant with cis- or carboplatin and devoid of severe bone marrow suppression, nephrotoxicity, or ototoxicity. Its dose-limiting toxicity is an unusual form of sensory neuropathy, which is cumulative and, contrary to cisplatin's neurotoxicity, generally reversible. Combinations with other active standard agents, as well as platinum compounds and/or taxoids, are feasible and have shown interesting activity. Similar to carboplatin and oxaliplatin, nedaplatin (cis-diammineglycolatoplatinum) can be given without hydration; its dose-limiting toxicity is myelosuppression, in particular thrombocytopenia. Although activity has been shown, no data from randomized comparative trials are available to allow a judgement on its potential advantages.

Section: Integration Of Paclitaxel In the Treatment Of Epithelial Ovamentioning

confidence: 99%

The integration of paclitaxel and new platinum compounds in the treatment of advanced ovarian cancer

Vermorken¹

2001

“…Several trials have evaluated the efficacy of paclitaxel for second‐line therapy of patients previously treated with platinum. Dosages of 135–200 mg/m 2 every 3 weeks, or 60–100 mg/m 2 every week, yielded response rates of 13–38% and a median survival of 9.6–13.2 months ( 24–29 ) . Doses >175 mg/m 2 every 3 weeks seemed to offer no therapeutic benefit, while at the same time increasing the drug's toxicity ( 30 ) .…”

Section: Gemcitabine In Combination With Taxanesmentioning

confidence: 99%

Review of gemcitabine-based combinations for platinum-resistant ovarian cancer

Sehouli

2005

Gemcitabine, an analog of deoxycytidine, is an anticancer nucleoside with proven activity in different solid malignancies. The efficacy of gemcitabine as a single agent or as part of a combination treatment has been evaluated in several trials, and antitumor activity has been observed in patients with sensitivity and resistance to both platinum and paclitaxel. In this context, preclinical studies have shown that gemcitabine-based combinations increase the cytotoxic action of the treatment and can potentially overcome drug resistance. The toxicity profile of gemcitabine, and its proven action in relapsed ovarian cancer, allows for the development of a hypothesis stating that a specific choice of drugs with different mechanisms and non-cross-resistance can increase the chance of response and prolong its duration and that of other outcome measures. This article provides an update of new clinical approaches with gemcitabine in combination with other nonplatinum drugs for the management of patients with platinum-resistant ovarian cancer.

“…In 1996, the results of a randomized Gynecologic Oncology Group (GOG) study (protocol #111) showed a significant outcome advantage in suboptimally debulked patients when paclitaxel plus cisplatin were combined (TP; paclitaxel as a 24-h infusion at a dose of (8) 135/24h 1000 a 22 Eisenhauer (9) 135, 175/24h, 3 h 407 b 17 TB Huinink (10) 175/3h 114 b 13 Pectasides (11) 175/3h 41 17 Tropé (12) 175/3h 112 28 Bolis (13) 175/3h 41 b 17 Tay (14) 200/3h 26 38 a (15) . Long-term follow-up data were reported in 1999 at the 7th Meeting of the International Gynecologic Cancer Society in Rome (16) .…”

Section: Integration Of Paclitaxel In the Treatment Of Epithelial Ovamentioning

confidence: 99%

The integration of paclitaxel and new platinum compounds in the treatment of advanced ovarian cancer

Vermorken

2001

There has been a steady improvement in the survival of patients with advanced ovarian cancer. This has been the result of a more skilled surgical approach to these patients and the development of more effective chemotherapy with a better integration of both modalities in first-line treatment. The current optimal chemotherapeutic approach consists of a platinum compound together with paclitaxel. This recommendation is based upon level I evidence of two large randomized trials which established that the combination of paclitaxel-cisplatin was superior to cyclophosphamide-cisplatin. The long-term follow-up of one of these studies continues to show a significant difference in survival at 5 years.Neurotoxicity has been problematic with these regimens, in particular when paclitaxel was given with the higher dosed shorter infusion schedule, as was done in the European-Canadian Intergroup study. Several approaches to reduce this toxicity have been studied. Among these are the use of different paclitaxel infusion schedules, and the application of less neurotoxic platinum compounds. Weekly paclitaxel has a different toxicity profile than the higher dosed three-weekly schedules, with less neutropenia, alopecia, arthralgia and neurotoxicity.Four platinum compounds are currently marketed: cisplatin, carboplatin, oxaliplatin, and nedaplatin. Of these only cisplatin, carboplatin, and nedaplatin have been approved for the treatment of patients with ovarian cancer (nedaplatin only in Japan). The equivalence of carboplatin and cisplatin has been suggested from trials without a taxoid. Three randomized studies of paclitaxel-carboplatin vs. paclitaxel-cisplatin concluded that paclitaxel-carboplatin is the preferred regimen in terms of (less) toxicity and, where studied, in terms of quality of life. So far, no difference in response rates or progression-free survival has been shown. More mature data on overall survival are awaited. Oxaliplatin (a diaminocyclohexane platinum compound) is of interest because it is only partially cross-resistant with cis- or carboplatin and devoid of severe bone marrow suppression, nephrotoxicity, or ototoxicity. Its dose-limiting toxicity is an unusual form of sensory neuropathy, which is cumulative and, contrary to cisplatin's neurotoxicity, generally reversible. Combinations with other active standard agents, as well as platinum compounds and/or taxoids, are feasible and have shown interesting activity. Similar to carboplatin and oxaliplatin, nedaplatin (cis-diammineglycolatoplatinum) can be given without hydration; its dose-limiting toxicity is myelosuppression, in particular thrombocytopenia. Although activity has been shown, no data from randomized comparative trials are available to allow a judgement on its potential advantages.