William P. McGuire

Prognostic Factors for Stage III Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSEnConflicting results on prognostic factors for advanced epithelial ovarian cancer (EOC) have been reported because of small sample size and heterogeneity of study population. The purpose of this study was to identify factors predictive of poor prognosis in a similarly treated population of women with advanced EOC.nnnPATIENTS AND METHODSnA retrospective review of demographic, pathologic, treatment, and outcome data from 1,895 patients with International Federation of Gynecology and Obstetrics stage III EOC who had undergone primary surgery followed by six cycles of intravenous platinum/paclitaxel was conducted. A proportional hazards model was used to assess the association of prognostic factors with progression-free survival (PFS) and overall survival (OS).nnnRESULTSnIncreasing age was associated with increased risks for disease progression (HR = 1.06; 95% CI, 1.02 to 1.11 for an increase every 10 years) and death (HR = 1.12; 95% CI, 1.06 to 1.18). Mucinous or clear-cell histology was associated with a worse PFS and OS compared with serous carcinomas. Patients with performance status (PS) 1 or 2 were at an increased risk for recurrence compared with PS 0 (HR = 1.12; 95% CI, 1.01 to 1.24). Compared with patients with microscopic residual disease, patients with 0.1 to 1.0 cm and > 1.0 cm residual disease had an increased risk of recurrence (HR = 1.96; 95% CI, 1.70 to 2.26; and HR = 2.36; 95% CI, 2.04 to 2.73, respectively) and death (HR = 2.11; 95% CI, 1.78 to 2.49; P < .001; and HR = 2.47; 95% CI, 2.09 to 2.92, respectively).nnnCONCLUSIONnAge, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials.

Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125.

PURPOSEnTo produce definitions based on serial CA 125 levels to measure response of ovarian carcinoma in patients receiving first-line chemotherapy.nnnPATIENTS AND METHODSnDefinitions were derived from analysis of 277 patients in North Thames Ovary Trial 3. Patient data were then incorporated into a computer program and tested against 254 patients in North Thames Ovary Trial 4 and 458 patients in Gynecologic Oncology Group (GOG) protocol 97. For optimum detection of response, three response definitions have been combined into a computer program. The precise definitions use mathematic logic and take account of factors such as intervening samples. Response to a specific treatment has occurred if after two samples there has been a 50% decrease, confirmed by a fourth sample (50% response), or a serial decrease over three samples of greater than 75% (75% response). The final sample has to be at least 28 days after the previous sample.nnnRESULTSnSix hundred twenty of 989 patients were considered assessable for response according to CA 125 level. Only two patients (0.3%) had a CA 125 response at the time of clinical progression. The CA 125 response rate was 62% and 54% in the North Thames trials. In the GOG trial, it was 66% in all 317 patients assessable for CA 125 and 67% in 221 patients whose CA 125 level was not measurable according to GOG criteria, compared with a GOG-defined response rate of 62%. The sensitivity for detecting GOG-defined response was at least 68%.nnnCONCLUSIONnDefinitions based on a 50% or 75% decrease of CA 125 levels have been shown reliably to define partial response of ovarian cancer in patients receiving first-line chemotherapy. These definitions should be used in addition to or instead of standard response criteria.

Tumor Residual After Surgical Cytoreduction in Prediction of Clinical Outcome in Stage IV Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSEnTo identify factors predictive of poor prognosis in a similarly treated population of women with stage IV epithelial ovarian cancer (EOC).nnnPATIENTS AND METHODSnA retrospective review of 360 patients with International Federation of Gynecology and Obstetrics stage IV EOC who underwent primary surgery followed by six cycles of intravenous platinum/paclitaxel was performed. A proportional hazards model was used to assess the association of potential prognostic factors with progression-free survival (PFS) and overall survival (OS).nnnRESULTSnThe median PFS and OS for this group of stage IV ovarian cancer patients was 12 and 29 months, respectively. Multivariate regression analysis revealed that histology, malignant pleural effusion, intraparenchymal liver metastasis, and residual tumor size were significant prognostic variables. Whereas patients with microscopic residual disease had the best outcome, patients with 0.1 to 1.0 cm residual disease and patients with 1.1 to 5.0 cm residual disease had similar PFS and OS. Patients with a residual size more than 5 cm had a diminished PFS and OS when compared with all other groups. Median OS for microscopic, 0.1 to 5.0 cm, and more than 5.0 cm residual disease was 64, 30, and 19 months, respectively.nnnCONCLUSIONnPatients with more than 5 cm residual disease have the shortest PFS and OS, whereas patients with 0.1 to 1.0 and 1.1 to 5.0 cm have similar outcome. These findings suggest that ultraradical cytoreductive procedures might be targeted for selected patients in whom microscopic residual disease is achievable. Patients with less than 5.0 cm of disease initially and significant disease and/or comorbidities precluding microscopic cytoreduction may be considered for alternative therapeutic options other than primary cytoreduction.

Topotecan Has Substantial Antitumor Activity as First-Line Salvage Therapy in Platinum-Sensitive Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study

PURPOSEnTopotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients.nnnPATIENTS AND METHODSnPatients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m(2) intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days.nnnRESULTSnForty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients.nnnCONCLUSIONnTopotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.

Comparison of Standard and CA-125 Response Criteria in Patients With Epithelial Ovarian Cancer Treated With Platinum or Paclitaxel

PURPOSEnTo assess CA-125 as a measure of response in patients treated with paclitaxel.nnnPATIENTS AND METHODSnOne hundred forty-four patients treated with paclitaxel derived from four different trials and 625 patients treated with platinum from two trials were analyzed using precisely defined 50% and 75% reductions in CA-125. The standard and CA-125 response rates to paclitaxel and platinum were compared. In addition, we analyzed individual patient groups in which there was a difference in response according to the two response criteria.nnnRESULTSnPatients with stable disease as determined by standard criteria who were treated with platinum and responded according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P<.001). Standard and CA-125 response rates for patients treated with platinum (58.93% v 61.31%, respectively) and paclitaxel (30.65% v 31.67%, respectively) were very similar, as were rates of false-positive prediction of response by CA-125 (platinum 2.2% and paclitaxel 2.9%). Responders to paclitaxel had a significantly improved progression-free survival compared with non-responders by both standard criteria (median progression-free survival, 6.8 v 2.5 months; P<.001) and CA-125 criteria (median progression-free survival, 6.8 v 3.4 months; P<.001).nnnCONCLUSIONnForassessing activity of therapy for ovarian cancer, these data show that precise 50% or 75% CA-125 response criteria are as sensitive as standard response criteria. We propose that they may be used as a measure of response in lieu of or in addition to standard response criteria in clinical trials involving epithelial ovarian cancer. Sensitivity is maintained whether patients are treated with platinum or paclitaxel.

Phase II Study of Paclitaxel and Valspodar (PSC 833) in Refractory Ovarian Carcinoma: A Gynecologic Oncology Group Study

PURPOSEnA phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein-mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer.nnnPATIENTS AND METHODSnPatients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2) intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein.nnnRESULTSnOf 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were > or = 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients.nnnCONCLUSIONnValspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.

Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group.

PURPOSEnThe purpose of this study was to determine whether amifostine (WR-2721) prevents or ameliorates clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy.nnnMATERIALS AND METHODSnThe chemotherapy program consisted of intravenous paclitaxel 175 mg/m2 over 3 hours followed by amifostine 740 mg/m2 and cisplatin 75 mg/m2 administered over 90 minutes beginning 15 minutes after amifostine administration. At baseline, before each treatment cycle, and for 3 months after completing chemotherapy, patients were evaluated for evidence of neurotoxicity and other treatment-related adverse effects using three methods: standard clinical evaluation (National Cancer Institute common toxicity criteria [CTC] grading), a neurotoxicity questionnaire to assess symptoms and limitations imposed by peripheral neuropathy, and vibration perception threshold (VPT) testing.nnnRESULTSnFour of 27 assessable patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. This number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed.nnnCONCLUSIONnAmifostines level of activity in this trial was insufficient to warrant further study in a phase III trial. Based on the receiver operating characteristic analysis, it would appear that VPT measurements are less sensitive to the development of peripheral neuropathy than the neurotoxicity questionnaire. The questionnaire, referred to as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, may be used instead of VPT measurements in future studies of chemotherapy-induced peripheral neuropathy.

Current approaches and challenges in managing and monitoring treatment response in ovarian cancer.

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Treatment of recurrent ovarian cancer remains a challenge despite advances in surgical and chemotherapeutic options. A goal of many providers is to detect recurrences as early as possible and initiate treatment though there is controversy as to whether this impacts outcome. Elevations in CA125 and radiological findings may precede symptoms of recurrence by several months. While detection of recurrences by physical exam alone is unusual, a thorough exam in conjunction with reported symptoms and elevated CA125 is sufficient to detect 80-90% of recurrences. A spiral CT scan may be used to confirm recurrence in the setting of asymptomatic CA125 elevation and a PET/CT can yield additional insight if the CT is inconclusive. Initiating chemotherapy prior to the development of symptoms, even in the setting of elevated CA125, does not impact overall survival primarily because the efficacy of available treatments in the recurrent setting is poor. More information about tumor biology and ways to predict which patients will benefit from available treatment options is required. Consequently, the approach to post-treatment surveillance should be individualized taking into account the clinical benefit of the second-line therapy, versus the costs and morbidity of the surveillance method.

Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group Study

PURPOSEnTo compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC).nnnMETHODSnBiochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400 mg or tamoxifen 20mg orally twice daily for up to 1 year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post-treatment serum.nnnRESULTSnOf the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR = 1.31, 95% confidence interval [CI] = 0.93-1.85), an increased risk of death (HR = 1.76, 95% CI = 1.16-2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS.nnnCONCLUSIONnThalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort.

CA-125 Change After Chemotherapy in Prediction of Treatment Outcome Among Advanced Mucinous and Clear Cell Epithelial Ovarian Cancers : A Gynecologic Oncology Group Study

There are limited data regarding unique clinical or laboratory features associated with advanced clear cell (CC) and mucinous (MU) epithelial ovarian cancers (EOC), particularly the relationship between CA‐125 antigen levels and prognosis.