First-line Therapy For Ovarian Cancer Research Articles

Docetaxel in ovarian cancer: Phase III perspectives and future development

In the mid 1990s, the incorporation of paclitaxel into platinum-based therapy for ovarian cancer marked a significant advance in treatment. Future progress will probably involve reductions in toxicity, which may be achieved by combining the less neurotoxic agent docetaxel with carboplatin. In an international phase III study, 1,077 chemotherapy-naive patients with stage Ic-IV ovarian cancer were randomized to receive carboplatin targeted to an AUC of 5 plus either docetaxel 75 mg/m(2) or paclitaxel 75 mg/m(2) for six cycles. Patients treated with paclitaxel plus carboplatin experienced significantly greater neurotoxicity than those treated with docetaxel plus carboplatin. Docetaxel/carboplatin and paclitaxel/carboplatin produced similar rates of objective response (66% and 62%, respectively), and initial data on progression-free survival indicate that the two treatments appear very similar in efficacy. Thus, docetaxel may prove to be a valid alternative to paclitaxel as part of first-line therapy in ovarian cancer. Nevertheless, there remains considerable scope for improvements in treatment. There is the possibility of using existing drugs more effectively, perhaps by the use of sequential rather than concurrent regimens. This would allow the most active drugs to be used at full dose, increase tolerability, and avoid the possibility of negative drug interaction. The integration of molecularly targeted agents, such as those directed at epidermal growth factor receptors, into existing regimens is highly promising but will need to be explored in randomized trials of first-line therapy. Because the prime obstacle to successful treatment is the acquisition of drug resistance, understanding the underlying mechanisms is an important future priority. One candidate is mismatch repair deficiency; the interest here is that experimental resistance reversal is achievable with hypomethylating agents, raising the possibility of future clinical trials if the clinical relevance of this mechanism can be confirmed.

Docetaxel in ovarian cancer: phase III perspectives and future development.

In the mid 1990s, the incorporation of paclitaxel into platinum-based therapy for ovarian cancer marked a significant advance in treatment. Future progress will probably involve reductions in toxicity, which may be achieved by combining the less neurotoxic agent docetaxel with carboplatin. In an international phase III study, 1,077 chemotherapy-naive patients with stage Ic-IV ovarian cancer were randomized to receive carboplatin targeted to an AUC of 5 plus either docetaxel 75 mg/m(2) or paclitaxel 75 mg/m(2) for six cycles. Patients treated with paclitaxel plus carboplatin experienced significantly greater neurotoxicity than those treated with docetaxel plus carboplatin. Docetaxel/carboplatin and paclitaxel/carboplatin produced similar rates of objective response (66% and 62%, respectively), and initial data on progression-free survival indicate that the two treatments appear very similar in efficacy. Thus, docetaxel may prove to be a valid alternative to paclitaxel as part of first-line therapy in ovarian cancer. Nevertheless, there remains considerable scope for improvements in treatment. There is the possibility of using existing drugs more effectively, perhaps by the use of sequential rather than concurrent regimens. This would allow the most active drugs to be used at full dose, increase tolerability, and avoid the possibility of negative drug interaction. The integration of molecularly targeted agents, such as those directed at epidermal growth factor receptors, into existing regimens is highly promising but will need to be explored in randomized trials of first-line therapy. Because the prime obstacle to successful treatment is the acquisition of drug resistance, understanding the underlying mechanisms is an important future priority. One candidate is mismatch repair deficiency; the interest here is that experimental resistance reversal is achievable with hypomethylating agents, raising the possibility of future clinical trials if the clinical relevance of this mechanism can be confirmed.

Phase I Study of Alternating Doublets of Topotecan/Carboplatin and Paclitaxel/Carboplatin in Patients with Newly Diagnosed, Advanced Ovarian Cancer

Objective. The aim of this study was to evaluate topotecan with carboplatin in an alternating doublet with carboplatin and paclitaxel in first-line ovarian cancer.Methods. Patients with newly diagnosed stage III/IV ovarian cancer were studied. The maximum tolerated dose (MTD) of topotecan (cycles 1, 3, 5, 7) in an alternating doublet regimen was determined through standard dose escalation in cohorts of three; doses of carboplatin (area under the curve [AUC] 4 to 5) and paclitaxel (175 mg/m2, cycles 2, 4, 6, 8) were fixed. Dose-limiting toxicity (DLT) was defined only for cycle 1 as febrile neutropenia, prolonged grade 4 granulocytopenia, grade 4 thrombocytopenia, ≥grade 3 nonhematologic toxicity, or failure to recover in ≤7 days. The use of granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was also studied.Results. Thirty-seven patients received 142 cycles of topotecan/carboplatin. Hematologic DLTs included grade 4 neutropenia (59 events, 42% of cycles) and thrombocytopenia (32 events, 23% of cycles). Granulocytopenia was generally short-lived, and only 2 cases of febrile neutropenia occurred. The MTD was 1.0 mg/m2/day topotecan and carboplatin AUC 4, alternating with 175 mg/m2 paclitaxel and carboplatin AUC 4. Although G-CSF effectively managed myelosuppression, thrombocytopenia developed in later cycles, limiting further topotecan dose escalation. The median progression-free survival was 20.5 months, and elevated pretreatment CA-125 levels normalized in 29 of 34 (85%) patients.Conclusion. The establishment of a reasonably well-tolerated alternating doublet regimen, coupled with evidence of antitumor activity, provides the basis for further investigation of topotecan in first-line therapy of ovarian cancer. Topotecan (1.0 mg/m2 daily for 3 days) was chosen for further evaluation in a phase II study.

Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models.

SCH58500 (ACN53) is a replication-deficient, type 5 adenovirus (Ad) expressing human wild-type p53 tumor suppressor. It is currently undergoing clinical trials as a cancer therapeutic. Many SCH58500 clinical trials incorporate an arm comparing traditional chemotherapy against chemotherapy combined with SCH58500. Paclitaxel was chosen for combination therapy in the preclinical study reported here due to its extensive use as a first-line therapy in ovarian cancer, its synergy with SCH58500 in preclinical cancer models, and its activation of p53-independent apoptosis, which might result in a "lowered threshold" for tumor cell death. SCID mice bearing human tumor xenografts were dosed with intratumoral vehicle, control Ad vector, or SCH58500, with or without paclitaxel. Real-time quantitative reverse transcriptase polymerase chain reaction assays were developed and validated to quantitate expression of p53, the p53 downstream effector gene p21, and the apoptosis-related genes, bax, bcl-2, and survivin. Protein expression was confirmed using immunohistochemical assays for p53 and p21. Only tumors injected with SCH58500 had detectable levels of exogenous p53 DNA and mRNA. After SCH58500 treatment, 3-11-fold elevations of p21 expression were observed in tumor xenografts containing nonfunctional p53 (MDA-MB-468, MDA-MB-231, MIAPaCa2, DU-145, and SK-OV-3), but no change in p21 mRNA in wild-type p53 PA-1 tumors. Immunohistochemical assays confirmed induction of p21 protein in MDAMB-468 and SK-OV-3 cells, but not in PA-1 cells. Ad vector alone or paclitaxel alone had no effect on p21 mRNA levels in most tumors. However, paclitaxel suppressed p21 expression induced by SCH58500 4-fold in DU-145 and SK-OV-3 tumors. Paclitaxel also affected expression of the housekeeping gene gapdh. There was no consistent pattern to the changes in bax, bcl-2, or survivin after SCH58500 treatment with or without paclitaxel between tumor types, although there were consistent responses within individual tumor lines. The mRNA ratios for bax/bcl-2 and bax/survivin were also not informative across tumor types. Of the genes examined, only p21 gave a predictable response 24 hours after p53 gene therapy and therefore, p21 expression may be useful for confirming SCH58500 activity in human tumor biopsies.

Comparing Cost-Effectiveness Analyses for the Clinical Oncology Setting: The Example of the Gynecologic Oncology Group 111 Trial

For the practicing oncologist, balancing quality of care with cost containment has become an unavoidable challenge. The development of new technologies, increased patient awareness, growth of managed care, and aging of our population represent conflicting interests in this endeavor. Medical literature has recently been inundated with economic analyses in an effort to approach some of these difficult questions, but often times it is difficult to see how this research applies to any particular oncologist's practice. This article identifies many of the key issues raised in the critical evaluation of cost-effectiveness analyses as they relate to the practicing oncologist. We offer suggestions on the interpretation of these studies to the clinical setting, using the recently published Journal of Clinical Oncology articles on cost-effectiveness analyses of paclitaxel-cisplatin as first-line therapy for ovarian cancer as examples.

Tolerance of twenty-four hour paclitaxel and carboplatin as first-line therapy in ovarian, peritoneal and fallopian tube carcinoma.

Rose PG, Fusco N, Fluellen L, Rodriguiz M. Tolerance of twenty-four hour paclitaxel and carboplatin as first-line therapy in ovarian, peritoneal and fallopian tube carcinoma. A combination of a platinum and taxane are accepted as standard first-line therapy for ovarian cancer. However, both 24-h paclitaxel and cisplatin and 3-h paclitaxel and carboplatin have significant neurotoxicity. The present study was undertaken to determine the toxicity of 24-h paclitaxel and carboplatin as first-line therapy. Ovarian, peritoneal, and fallopian tubal carcinoma patients treated with 24-h paclitaxel and carboplatin as first-line therapy were retrospectively reviewed. Paclitaxel was administered at a dose of 135 mg/m2 as a 24-h infusion followed by carboplatin at an AUC of 5 every 21 days. Toxicity was graded according to NCI Common Toxicity Scale. Fourteen patients with ovarian, peritoneal or tubal carcinoma were studied. Twelve were treated primarily with paclitaxel and carboplatin and two were originally treated with paclitaxel and cisplatin for two cycles but switched to paclitaxel and carboplatin for severe cisplatin-associated toxicities. A total of 86 courses were administered (median 6, range 1-9). Hematologic toxicity was the principal toxicity with neutropenic fever occurring in 8 patients (57%). The duration of neutropenia was brief and no septic deaths occurred. Following paclitaxel dose reduction to 110 mg/m2 neutropenic sepsis did not recur except in one patient with recurrent C. difficile colitis. The two patients who switched from paclitaxel/cisplatin to paclitaxel/carboplatin reported better tolerance of the chemotherapy regimen. Among the 13 patients with ovarian and peritoneal carcinoma 100% achieved a clinical complete response. Although associated with a high incidence of neutropenia, this regimen had rare severe or chronic toxicities in particular neurotoxicity and a high response rate.