Weight change during chemotherapy as a potential prognostic factor for stage III epithelial ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: Platinum/Paclitaxel-based chemotherapy is a current treatment for advanced epithelial ovarian cancer. We sought to explore the association between weight change during treatment and survival, as well as the association between pre-chemotherapy body mass index (BMI) and survival. METHODS: A retrospective data review was conducted of 792 advanced ovarian cancer patients who participated in a phase III randomized trial of cisplatin/paclitaxel versus carboplatin/paclitaxel. Pre-chemotherapy BMI was calculated following surgery. Weight change was defined as the ratio of body weight at completion of protocol therapy to pre-chemotherapy body weight. Progression-free survival (PFS) and overall survival (OS), classified by BMI or relative weight change, were estimated by Kaplan-Meier, and associations were assessed using a Cox model controlled for known prognostic variables (age, race, performance status, histology, tumor grade, tumor residual and treatment group). RESULTS: There was no association between pre-chemotherapy BMI and survival. There was a significant relationship between median OS and weight change as follows: >5% decrease=48.0 months; 0-5% decrease=49.3 months; 0-5% increase=61.1 months; and >5% increase=68.2 months. Adjusted for covariates, the relative risk of death increased by 7% for each 5% decrease in body weight (HR=0.93, 95% CI=0.88-0.99; p=0.013). CONCLUSIONS: Change of body weight during primary chemotherapy was a strong prognostic factor for overall survival. Loss of body weight during primary therapy is an indicator for poor OS; weight gain is an indicator for improved survival. This study supports the development of strategies to minimize weight loss that can be assessed in a prospective, randomized study to improve patient outcomes.

Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Challenges for chemotherapy in ovarian cancer.

BACKGROUND: Ovarian cancer is treated with surgery followed by combination chemotherapy with paclitaxel plus carboplatin. In an effort to improve outcomes, clinical trials are evaluating the following strategies: maintenance therapy; intraperitoneal drug administration; new combinations; novel cytotoxics; combination chemotherapy for recurrent disease; and molecular-targeted therapies. PATIENTS AND METHODS: Clinical trials evaluating the above strategies are being performed in ovarian cancer in patients with: (1) previously untreated advanced ovarian cancer; (2) platinum-sensitive recurrent disease; and (3) platinum-resistant recurrent disease. RESULTS: Combination chemotherapy regimens are superior to single-agent therapy in recurrent ovarian cancer. Molecular-targeted therapy has produced objective responses in previously treated patients. Maintenance therapy of any type has not been shown to prolong survival. Intraperitoneal therapy has resulted in improved survival with considerable toxicity in patients with small-volume stage III disease. CONCLUSIONS: Numerous novel clinical strategies are being evaluated in ovarian cancers that have the potential to improve outcomes compared to standard therapy.

Treatment goals in ovarian cancer.

Ovarian cancer remains the number one gynecological killer in the Western world. Most ovarian cancer patients present with advanced-stage disease and are treated with cytoreductive surgery followed by combination chemotherapy. While the majority of patients respond to treatment, most will relapse such that the 5-year survival rates for advanced disease are approximately 20-25%. Overall survival and progression-free survival (PFS) are the primary endpoints in clinical trials in patients with advanced ovarian cancer. In patients with early-stage ovarian cancer, PFS may be the preferred trial endpoint, whereas in patients with recurrent ovarian cancer, the primary goal of therapy remains palliation and control of symptoms. Recent studies in recurrent disease have demonstrated that chemotherapy can improve the endpoints of PFS and overall survival, and so they are being used as the primary endpoints for comparing new regimens in phase III trials in relapsed patients. However, it would be easier to compare new treatment modalities if a uniformly accepted instrument was available that could evaluate quality of life and symptom control.

Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5.

Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well tolerated standard regimen, providing a basis for the reference arm in GOG0182-ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second-look surgical outcomes, followed by an update on the current status of GOG0182-ICON5.

Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel versus cisplatin and paclitaxel (GOG158) and an update on GOG0182-ICON5.

Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well-tolerated standard regimen, providing a basis for the reference arm in GOG0182-ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second-look surgical outcomes, followed by an update on the current status of GOG0182-ICON5.

The current role of gemcitabine in ovarian cancer.

Despite advances in treatment, ovarian cancer remains the number one gynecologic killer in the Western world. Cytoreductive surgery followed by combination chemotherapy results in an approximately 75% complete remission rate in patients with advanced ovarian cancer. Unfortunately, most patients who do achieve a clinical complete remission ultimately have disease recurrence, at which point a cure remains elusive. Two major strategies are currently being tested in clinical trials in an effort to improve survival. The first is to develop more effective combination chemotherapy regimens that not only increase the overall response rate, but also lead to an increased duration of response. The second is to develop effective maintenance therapies that prevent or delay relapses in those patients who do achieve a complete remission following standard chemotherapy. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) has undergone investigation in a series of phase I and II clinical trials that have demonstrated its safety and efficacy. It is currently being tested in novel, new combinations for use in previously untreated patients as part of the strategy to develop more effective induction chemotherapy for patients with advanced ovarian cancer. Semin Oncol 28 (suppl 7):18-24.

Phase I trial of multiple cycles of high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell support as front-line therapy.

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m(2)), and topotecan (10-15 mg/m(2)), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m(2) when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m(2). The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m(2), and topotecan 10 mg/m(2). Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.

Paclitaxel (Taxol)/carboplatin combination chemotherapy in the treatment of advanced ovarian cancer.

The activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in advanced ovarian cancer, both as a single agent and in combination chemotherapy, has been demonstrated in numerous phase I/II trials. Paclitaxel/platinum combinations have produced encouraging results in phase III trials and are now considered standard therapy for advanced disease. Carboplatin, an effective but more tolerable analog of cisplatin, has been substituted for cisplatin to reduce the toxicity of the paclitaxel/cisplatin regimen. A recent phase III equivalency trial of the Gynecologic Oncology Group (GOG 158) was conducted to rigorously compare paclitaxel/carboplatin with paclitaxel/cisplatin in the treatment of optimal stage III ovarian cancer. In a preliminary analysis of this trial, paclitaxel/carboplatin was better tolerated with no apparent difference in efficacy from paclitaxel/cisplatin. The improved toxicity profile and equivalent activity of paclitaxel/carboplatin also are suggested by preliminary results from other phase III trials. The results indicate that paclitaxel/carboplatin has a higher therapeutic index and is preferred over paclitaxel/cisplatin for advanced ovarian cancer.

The role of gemcitabine in the treatment of ovarian cancer.

Epithelial ovarian cancer remains the number one gynecologic killer in the Western world. The standard therapeutic approach for patients with advanced-stage epithelial ovarian cancer has been cytoreductive surgery followed by combination chemotherapy. Despite improvements in outcome associated with carboplatin/ paclitaxel-based chemotherapy, most patients with advanced ovarian cancer are not cured by this combination. Gemcitabine has been shown to be an active agent in the treatment of patients with recurrent ovarian cancer. The response rate of approximately 19% noted with single-agent gemcitabine is associated with acceptable toxicity. In addition, gemcitabine can be combined with other active agents, including carboplatin and paclitaxel. Clinical trials will be performed to evaluate whether a three-drug combination including gemcitabine will be superior to treatment with the standard approach of carboplatin plus paclitaxel.

Paclitaxel by 1-h infusion in combination with carboplatin in advanced non-small cell lung carcinoma (NSCLC).

In our previous study, FCCC 93-024, paclitaxel by 24-h infusion combined with carboplatin yielded a response rate of 62% and median survival of 54 weeks in advanced non-small cell lung cancer (NSCLC). Myelosuppression proved dose-limiting, requiring the routine use of granulocyte-colony stimulating factor (G-CSF). Based on the reported activity of 1-h paclitaxel infusion in NSCLC and minimal myelosuppression at doses of 135 and 200 mg/m2 every 3 weeks and the suggestion of a dose-response relationship, we launched an intrapatient dose escalation trial of combination carboplatin and 1-h paclitaxel. Chemotherapy-naïve patients with advanced NSCLC received paclitaxel 175 mg/m2 1-h and carboplatin dosed to a fixed targeted area under the concentration-time curve (AUC) of 7.5 at three weekly intervals for six cycles. In the absence of grade 4 myelosuppression, paclitaxel was escalated by 35 mg/m2/cycle on an intrapatient basis to a maximum dose of 280 mg/m2 by cycle 4. G-CSF was not routinely used. 57 patients (pts) were accrued from November 1994 through to April 1996. 44 pts (77%) had Eastern Cooperative Oncology Group (ECOG) performance status 1. Median age was 64 (range: 34-80) years. Cumulative peripheral sensory neuropathy proved dose-limiting and prohibitive in the first 20 evaluable patients (cohort A): grade > or = 1 in 15 patients (75%), grade 3 in 6 (30%), generally occurring at paclitaxel doses > or = 215 mg/m2 and obligating 3 patients to have treatment halted in the absence of disease progression. The protocol, therefore, was revised and the initial paclitaxel dose reduced to 135 mg/m2 with intrapatient dose escalation of 40 mg/m2/cycle to a maximum dose of 215 mg/m2, recapitulating the original dosing schema used in FCCC 93-024. 35 patients were enrolled in this second cohort (B); 33 proved evaluable. Whilst 17 (52%) experienced peripheral sensory neuropathy, grade 3 neurotoxicity developed in only 3 (9%). Myelosuppression also was less pronounced, with 42% exhibiting grade 4 granulocytopenia and 30% grade > or = 3 thrombocytopenia in cohort B compared with 70% and 50%, respectively in cohort A. Of the first 22 patients accrued to cohort A, 12 (55%) had major objective responses. Median survival was 48.5 weeks, 1-year survival rate 45% and 2-year survival rate 18%. Of 33 evaluable patients in cohort B, 9 (27%) had major objective responses. Median survival was 46 weeks, 1-year survival rate 47% and 2-year survival rate 12%. Combination paclitaxel by 1-h infusion and carboplatin at a fixed targeted AUC of 7.5 is active in advanced NSCLC. Neurotoxicity, not myelosuppression, proved dose-limiting at paclitaxel doses exceeding 215 mg/m2. Lower doses may be associated with lower response rates, but do not appear to compromise survival.

HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, and ovarian cancer.

HER-2/neu is overexpressed in most epithelial malignancies. Lung cancer, prostate cancer, and ovarian cancer are common epithelial tumors in which clinical trials are currently in progress to explore the potential therapeutic role for monoclonal antibodies to HER-2/neu (trastuzumab [Herceptin; Genentech, Inc, South San Francisco, CA]). In preclinical studies with tumor cell lines, trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents. Clinical trials investigating combination chemotherapy with trastuzumab and a variety of chemotherapeutic agents are already in progress in lung cancer.

Optimum chemotherapy for ovarian cancer.

A series of prospective randomized trials recently have defined the new standard of care for chemotherapy patients with ovarian cancer. The current preferred regimen consists of carboplatin (dosed to an area-under-the-curve [AUC] of 5.0-7.5) plus paclitaxel (175 mg/m2-3 h infusion). This is an outpatient regimen that does not require growth factor support and six cycles are administered on a 21-day schedule. There is no evidence that any type of additional therapy impacts upon survival, including additional cycles of the same chemotherapy or switching to an alternative intravenous chemotherapy, high-dose chemotherapy with hematologic support, intraperitoneal chemotherapy, or whole abdominal radiation. The majority of patients will achieve a clinical complete remission with the regimen although the relapse rate remains high. Current trials are exploring new schedules of drug delivery as well as new combinations which include new agents such as gemcitabine and topotecan.

Phase I trial of multiple cycles of high-dose chemotherapy supported by autologous peripheral-blood stem cells.

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin and paclitaxel with hematopoietic peripheral-blood stem cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with cyclophosphamide, etoposide, and granulocyte-macrophage colony-stimulating factor (GM-CSF). After one cycle of conventional-dose carboplatin and cyclophosphamide with GM-CSF, patients received multiple cycles of high-dose carboplatin (area under the concentration-time curve [AUC], 12 to 20) and paclitaxel (250 mg/m(2)) with PBSC and GM-CSF repeated every 28 days. RESULTS: Twenty-four of 28 patients were assessable for toxicity and clinical outcome. Dose-limiting toxicities were dehydration, diarrhea, and electrolyte imbalances. The maximum-tolerated dose of carboplatin was AUC 16 (equivalent to a median of 1,189 mg/m(2)). The relationship of target AUC to measured AUC was linear (r(2) =. 29; P =.0011). The overall response rate was 96%, with a complete clinical response rate of 67%. The median time to progression from the first PBSC reinfusion was 49.5 weeks (range, 8 to 156+ weeks). CONCLUSION: Multiple cycles of high-dose carboplatin (AUC 16) and paclitaxel (250 mg/m(2)) can be safely administered with GM-CSF and PBSC support. Although this regimen is safe, feasible, and active, the use of multiple cycles of high-dose chemotherapy as front-line treatment remains experimental and should only be used in the context of a clinical trial.

The Gynecologic Oncology Group experience in ovarian cancer.

Trials performed in the past 15 years by the Gynecologic Oncology Group identified as optimal a platinum/taxane combination as the backbone to treat chemonaive ovarian cancer. Comparison to a triplet adding a third drug to the backbone is least likely to significantly improve outcome, however, of the drugs currently available for addition; doxil, etoposide, gemcitabine, and topotecan; none appears to be any better or worse than was paclitaxel a decade ago. An approach more likely to improve outcome would be to incorporate as many of these "new" drugs as possible using sequential doublets. Some doublets have a better biochemical rationale such as cisplatin and gemcitabine (inhibition of DNA repair) or topotecan and either doxil or etoposide (upregulation of topoisomerase II levels by topotecan followed by a topoisomerase II inhibitor.

Intraperitoneal treatment and dose-intense therapy in ovarian cancer.

BACKGROUND: There has been a longstanding controversy regarding the role of high-dose chemotherapy in patients with advanced ovarian cancer. Based on retrospective studies, it has been suggested that there will be improved results when doses of platinum compounds in particular are increased. High-dose therapy can be administered using an intraperitoneal route of drug delivery or with haematologic support in the form of autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transfusions (PBSCT). METHODS: Experienced clinical investigators reviewed published data available on high-dose chemotherapy and intraperitoneal drug delivery. In addition, ongoing clinical trials of ABMT or PBSCT were also reviewed. RESULTS: Prospective randomised trials have failed to demonstrate that doubling the dose of platinum compounds increases survival in patients with advanced ovarian cancer. Intraperitoneal chemotherapy with cisplatin or paclitaxel remains an area of investigation and prospective randomised trials in previously untreated patients as well as part of consolidation therapy in patients achieving a complete remission are in progress. Phase II trials of high-dose chemotherapy with ABMT or PBSCT in previously treated patients with advanced ovarian cancer have produced higher response rates than achieved with conventional doses although there has been no proven impact upon survival. Prospective randomised trials in previously untreated patients are in progress. Until the completion of these trials, high-dose chemotherapy with ABMT or PBSCT and intraperitoneal chemotherapy should be considered investigational.