Gynecologic Oncology Group Performance Status Research Articles

Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240)

On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. National Cancer Institute.

Hepatic resection during cytoreductive surgery for primary or recurrent epithelial ovarian cancer.

Surgical cytoreduction remains a cornerstone in the management of patients with advanced and recurrent epithelial ovarian cancer. Parenchymal liver metastases determine stage VI disease and are commonly considered a major limit in the achievement of an optimal cytoreduction. The purpose of this manuscript was to discuss the rationale of liver resection and the morbidity related to this procedure in advanced and recurrent ovarian cancer. A search of the National Library of Medicine's MEDLINE/PubMed database until March 2015 was performed using the keywords: "ovarian cancer," "hepatic," "liver," and "metastases." In patients with liver metastases, hepatic resection is associated with a similar prognosis as stage IIIC patients. The length of the disease-free interval between primary diagnosis and occurrence of liver metastases, as well as residual disease after resection, is the most important prognostic factors. In addition, the number of liver lesions, resection margins, and the gynecologic oncology group performance status seem to play also an important role in determining outcome. In properly selected patients, liver resections at the time of cytoreduction increase rates of optimal cytoreduction and improve survival in advanced-stage and recurrent ovarian cancer patients.

Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: A Gynecologic Oncology Group study

ObjectiveThis two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC). MethodsEligible patients had persistent or recurrent EMC after receiving 1–2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status≤2. Treatment consisted of bevacizumab 10mg/kg every other week and temsirolimus 25mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria. ResultsFifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal–vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9months, respectively. ConclusionCombination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.

Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study

Purpose The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix. Patients and methods Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤ 2. Treatment consisted of cetuximab 400 mg/m 2 initial dose followed by 250 mg/m 2 weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design. Results Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n = 25, 71.4%) or 2 (n = 10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n = 5), GI (n = 4), anemia (n = 2), constitutional (n = 3), infection (n = 2), vascular (n = 2), pain (n = 2), and pulmonary, neurological, vomiting and metabolic (n = 1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology. Conclusion Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.

A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: A Gynecologic Oncology Group Study

Background Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel. Methods Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy ( n = 5) or recurrence within 6 months of treatment completion ( n = 42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m 2 days 1, 8, and 15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%). Results Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34–78) years, serous histology: 72%, and high-grade: 81%. Efficacy: one complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95% CI: 2.2–6.7); overall survival was 17.4 months (95% CI: 13.2–20.8). Seventeen patients (36%) had PFS >6 months. Toxicity: there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1. Conclusions Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.

Does the progression‐free interval after primary chemotherapy predict survival after salvage chemotherapy in advanced and recurrent endometrial cancer?

This study evaluated whether progression-free interval (PFI) following primary chemotherapy (PCT) was predictive of overall survival (OS) after second-line chemotherapy in advanced/recurrent endometrial cancer (EC). This is a pooled analysis of patients who recurred after PCT and were treated with second-line chemotherapy on Gynecologic Oncology Group trials. PFI-1 measured from initiation of PCT to recurrence or treatment-free interval (TFI) measured from completion of PCT to initiation of second-line chemotherapy was evaluated in relation to clinical outcomes. A total of 586 patients treated on 5 phase 3 PCT protocols were included. Baseline factors in primary setting associated with clinical outcome after PCT were also predictive of OS after second-line chemotherapy, including race, Gynecologic Oncology Group performance status, grade, and prior radiation therapy (P<.01). PFI-1 was the most significant factor predictive of survival after second-line chemotherapy, with a 30% reduction in the risk of death for PFI-1>6 months compared with ≤6 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.59-0.84 [P<.0001]) and median OS after second-line chemotherapy of 10 versus 5 months. A total of 275 patients treated on 9 phase 2 second-line chemotherapy protocols were also evaluated, and TFI>3 months was associated with a 25% reduction in the risk of death (HR, 0.75; 95% CI, 0.57-0.97 [P=.030]) and median OS after second-line chemotherapy of 10 versus 7 months compared with TFI≤3 months. The tumor response to second-line chemotherapy was 9.6% versus 5.8%; the difference was not statistically significant. Time to recurrence after PCT is predictive of survival after recurrence in advanced/recurrent EC. However, there is no evidence that this variable can be used in selecting salvage chemotherapy.

A phase II evaluation of nab-paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: A Gynecologic Oncology Group (GOG) study.

5010 Background: Nab-paclitaxel (Abraxane, ABX) is a novel cremophor-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel, and is currently approved for recurrent breast cancer. This is the first report of weekly abraxane in patients with recurrent ovarian, fallopian tube or peritoneal cancer (OC). Methods: Eligible patients had OC, that was persistent (n = 5) or progressed within 6 months of completion (n = 42) of primary platinum and taxane-based chemotherapy. All patients were required to have measurable disease, no prior therapy for recurrent disease and GOG performance status of ≤ 2. Treatment was ABX 100 mg/m2 days 1,8,15 on a 28-day schedule. The primary endpoint was RECIST response rate (RR), evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%). Results: 51 patients were enrolled, of which 47 are evaluable; median time from frontline therapy completion to registration was just 21 days. Patient demographics include median age: 59 (34-78) years, primary site ovary: 87%, serous histology: 72%, and high-grade: 81%. All patients had measurable disease, one prior chemotherapy regimen and prior surgery. Efficacy: partial response was confirmed in 11 patients (23%); 17 patients (36%) had stable disease. The median progression-free survival (PFS) was 4.5 months (95%CI: 2.1-6.7); overall survival was 17.4 months (95%CI: 12.5, not estimable). 17 patients (36%) had PFS > 6 months. Toxicity: there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2: 5; and grade 3: 1. Conclusions: ABX appears to have substantial single-agent activity and to be tolerable in this cohort of highly refractory ovarian cancer patients previously treated with paclitaxel, and further investigation is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience Abraxis BioScience

Prognostic relevance of c-MYC gene amplification and polysomy for chromosome 8 in suboptimally-resected, advanced stage epithelial ovarian cancers: A Gynecologic Oncology Group study

Objective The Gynecologic Oncology Group (GOG) examined the prognostic relevance of c-MYC amplification and polysomy 8 in epithelial ovarian cancer (EOC). Methods Women with suboptimally-resected, advanced stage EOC who participated in GOG-111, a multicenter randomized phase III trial of cyclophosphamide + cisplatin vs. paclitaxel + cisplatin, and who provided a tumor block through GOG-9404 were eligible. Fluorescence in situ hybridization (FISH) with probes for c-MYC and the centromere of chromosome 8 (CEP8) was used to examine c-MYC amplification (≥ 2 copies c-MYC/CEP8) and polysomy 8 (≥ 4 CEP8 copies). Results c-MYC amplification, defined as ≥ 2 copies c-MYC/CEP8, was observed in 29% (28/97) of EOCs and levels were ranged from 2.0–3.3 copies of c-MYC/CEP8. c-MYC amplification was not associated with patient age, race, GOG performance status, stage, cell type, grade, measurable disease status following surgery, tumor response or disease status following platinum-based combination chemotherapy. Women with vs. without c-MYC amplification did not have an increased risk of disease progression (hazard ratio [HR] = 1.03; 95% confidence interval [CI] = 0.65–1.64; p = 0.884) or death (HR = 1.08; 95% CI = 0.68–1.72; p = 0.745). c-MYC amplification was not an independent prognostic factor for progression-free survival (HR = 1.03, 95% CI = 0.57–1.85; p = 0.922) or overall survival (HR = 1.01, 95% CI = 0.56–1.80; p = 0.982). Similar insignificant results were obtained for c-MYC amplification categorized as ≥ 1.5 copies c-MYC/CEP8. Polysomy 8 was observed in 22 patients without c-MYC amplification and 3 with c-MYC amplification, and was associated with age and measurable disease status, but not other clinical covariates or outcomes. Conclusions c-MYC amplification and polysomy 8 have limited predictive or prognostic value in suboptimally-resected, advanced stage EOC treated with platinum-based combination chemotherapy.

A phase II evaluation of bevacizumab in the treatment of recurrent or persistent endometrial cancer: A Gynecologic Oncology Group (GOG) Study

5531 Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. This is the first report of the activity of bevacizumab in patients with recurrent or persistent endometrial cancer (EMC). Methods: Eligible patients had persistent or recurrent EMC after receiving 1–2 prior cytotoxic regimens, measurable disease, and GOG performance status &lt; 2. Treatment consisted of BV 15 mg/kg IV q 3 weeks until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at 6 months, objective response rate, and toxicity by NCI CTCAE v3.0. The clinical trial was carried out in a flexible 2-stage group sequential design intended to detect either cytostatic or cytotoxic activity. Sample sizes were targeted to limit the probability of designating ineffective regimens as being active 10% with at least 90% statistical power. Clinically significant improvements were 20% increases in the proportion responding or surviving progression-free at 6 months over historical controls. Results: From March 2006 to January 2008, 56 patients were enrolled. Two were excluded due to a second primary and one due to inadequate pathology; thus, the sample included 53 patients. Median age was 62 (range 44–84) years, and prior treatment consisted of 1 or 2 regimens in 33 and 20 patients, respectively. Twenty-eight patients (52.8%) had prior radiation. Early results showed 8/53 (15.1%) response rate, with 1 complete response and 7 partial responses; and 19/53 (35.8%) of patients progression free at 6 months with 2 patients pending at the time of data analysis. Median PFS was 4.2 months. Median Overall survival (OS) was 10.5 months. The following grade 3 or 4 toxicities were observed: anemia (1 grade 3), cardiovascular (4 grade 3), constitutional (2 grade 3), hemorrhage (1 grade 3), hepatic (1 grade 3), musculoskeletal (2 grade 3), metabolic (1 grade 3, 1 grade 4), neurologic (1 grade 3), pain (4 grade 3), and vascular (1 grade 3, 1 grade 4). Conclusions: BV appears to have single agent activity in women with recurrent or persistent EMC and warrants further investigation. No significant financial relationships to disclose.

A phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: A Gynecologic Oncology Group (GOG) study

5515 Background: Both platinum and taxane compounds have demonstrated activity in uterine carcinosarcoma (malignant mixed Mullerian tumor). Ifosfamide plus paclitaxel is the regimen supported by randomized phase III trials through the GOG. However, the toxicity, multi-day schedule, and limited activity of this regimen indicate that development of other regimens is still needed. The primary aims of this prospective study were to estimate the antitumor activity and toxicity of paclitaxel plus carboplatin in patients with uterine carcinosarcomas. Methods: Eligible patients had advanced stage (III or IV), persistent, or recurrent measurable disease with histologic confirmation of the primary tumor, no prior chemotherapy, and a GOG Performance Status of 2 or better. At entry hematologic and all other labs were within pre-defined limits. Patients received the combination of paclitaxel 175 mg/m2 IV over 3 hours plus carboplatin (AUC 6) IV over 30 minutes every 3 weeks until disease progression or adverse effects prohibit further therapy. The primary endpoint of confirmed response was assessed by RECIST criteria. CTCAE v3 was used to grade adverse events. This study used an optimal but flexible two-stage design with early stopping guidelines intended to limit patient accrual to inactive treatments. Forty to 47 eligible patients were targeted for accrual. Central pathology review (CPR) is still pending for 5 patients. Results: Fifty-five patients were entered on study with 9 being excluded from analysis; 7 with unconfirmed diagnosis at CPR and 2 were never treated. Treatment was generally tolerated with expected hematologic toxicity and minimal non-hematologic grade 4 toxicity (1 cardiovascular and 2 pain) with 59% of patients completing 6 or more cycles of chemotherapy. The proportion of patients with confirmed complete and partial responses were 11% and 41%, respectively (52%; 95% CI 37%-67%). Additionally 4% experienced an unconfirmed response and 26% had stable disease. Conclusions: Paclitaxel plus carboplatin demonstrates anti-tumor activity against uterine carcinosarcoma with acceptable toxicity and warrants further evaluation in phase III randomized trials. No significant financial relationships to disclose.

Associations between ERBB2 amplification and progression-free survival and overall survival in advanced stage, suboptimally-resected epithelial ovarian cancers: A Gynecologic Oncology Group study

Objective(s) The Gynecologic Oncology Group (GOG) examined the association between ERBB2 amplification and clinical covariates, tumor response, disease status post-chemotherapy, progression-free survival (PFS), and overall survival (OS) in epithelial ovarian cancer (EOC). Methods Women with suboptimally-resected, advanced stage EOC who participated in GOG-111, a multi-center randomized phase III trial of cyclophosphamide + cisplatin versus paclitaxel + cisplatin, and provided a tumor block through the companion protocol GOG-9404 were eligible. ERBB2 amplification was examined using fluorescence in situ hybridization (FISH) with probes for ERBB2 and the centromere of chromosome 17 (CEP17). Results ERBB2 amplification, defined as > 2 copies of ERBB2/CEP17, was a rare event in EOC with 7% (9/133) of women exhibiting between 2.2 and 33.7 copies of ERBB2/CEP17, and was not associated with patient age, race, GOG performance status, stage, cell type, grade, measurable disease status, volume of ascites, tumor response or disease status post-chemotherapy. Women with > 2 verses ≤ 2 copies of ERBB2/CEP17 did not have a reduced risk of disease progression (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.27–1.16; p = 0.120) or death (HR = 0.57; 95% CI = 0.26–1.23; p = 0.152), and ERBB2 amplification was not an independent prognostic factor for PFS or OS. ERBB2 amplification, defined as > 4 copies of ERBB2/nuclei, was observed in 9% (12/133) of women with levels ranging from 4.2 to 49.2 copies of ERBB2/nuclei, and was associated with older age and volume of ascites, but not with the other clinical covariates or outcome. Conclusion(s) ERBB2 amplification is a rare event and has no predictive or prognostic value in suboptimally-resected, advanced stage EOC treated with platinum-based combination chemotherapy.

Associations between p53 overexpression and multiple measures of clinical outcome in high-risk, early stage or suboptimally-resected, advanced stage epithelial ovarian cancers: A Gynecologic Oncology Group study

Objective The Gynecologic Oncology Group (GOG) performed a detailed analysis of p53 overexpression in previously-untreated women with invasive early or advanced stage epithelial ovarian cancer (EOC). Methods Women were eligible for the study if they provided a tumor block for translational research and participated in either GOG-157, a randomized phase III trial of three versus (vs.) six cycles of paclitaxel + carboplatin in high-risk, early stage EOC, or GOG-111, a randomized phase III trial of cyclophosphamide + cisplatin vs. paclitaxel + cisplatin in suboptimally-resected, advanced stage EOC. The N-terminal DO-7 p53 antibody was used to examine the expression of the major normal and mutant p53-isoforms. p53 overexpression was defined as ≥ 10% tumor cells exhibiting nuclear staining. Results p53 was overexpressed in 51% (73/143) and 66% (90/136) of cases in the GOG-157 and GOG-111 cohorts, respectively. In the GOG-157 cohort, p53 overexpression was not associated with any clinical characteristics or overall survival (OS) but was associated with worse progression-free survival (PFS) (logrank test: p = 0.013; unadjusted Cox modeling: p = 0.015). In the GOG-111 cohort, p53 overexpression was associated with GOG performance status ( p = 0.018) and grade ( p = 0.003), but not with age, stage, cell type or with tumor response and disease status after primary chemotherapy, PFS or OS. Adjusted Cox regression modeling demonstrated that p53 overexpression was not an independent prognostic factor for PFS or OS in either cohort. Conclusions p53 overexpression assessed by DO-7 immunostaining is common in early and advanced stage EOC, but has limited prognostic value in women treated with surgical staging and platinum-based combination chemotherapy.

Phase II evaluation of capecitabine in refractory nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study

We conducted a multi-institutional study to assess the activity and toxicity of capecitabine in patients with persistent or recurrent nonsquamous cancer of the cervix. Eligible patients were required to possess adequate renal, hepatic and bone marrow function and a Gynecologic Oncology Group performance status of 0-2. Histologic confirmation of the original primary cancer was mandated. Patients must have received one prior systemic chemotherapeutic regimen for cervical cancer that did not include the chemotherapy that may have been administered in conjunction with prior radiation therapy. The initial dose schedule was 2500 mg/m2 orally daily in two divided doses for 14 consecutive days, followed by a 7-day rest, such that each cycle was 21 days. Responses were assessed using response evaluation criteria in solid tumors. Twenty-one patients were entered into the trial. One patient was declared ineligible for wrong cell type; thus, 20 were evaluable for toxicity. A median of 2.5 cycles was administered (range 1-11). There was one septic death. Grade 4 neutropenia, renal, neurologic, and pulmonary toxicity was seen in 5%, 5%, 5%, and 10% patients, respectively. There were no responses. Nine patients (45%) each had stable disease and nine showed progression. The remaining two cases (10%) did not have subsequent disease assessment and response could not be assessed. Oral capecitabine at the dose and schedule tested has insignificant activity in nonsquamous cervical cancer patients previously treated with chemotherapy.

Phase II Trial of Bevacizumab in Persistent or Recurrent Epithelial Ovarian Cancer or Primary Peritoneal Cancer: A Gynecologic Oncology Group Study

Vascular endothelial growth factor (VEGF) seems to be a promoter of tumor progression for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). We conducted a phase II trial to assess the efficacy and tolerability of single-agent bevacizumab, an anti-VEGF monoclonal antibody. Eligible patients had persistent or recurrent EOC/PPC after one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of at least 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. The study consisted of 62 eligible and assessable patients, median age 57 years, 41 (66.1%) having received two prior regimens and 36 (58.1%) [CORRECTED] considered platinum resistant. Grade 3 adverse events at least possibly related to bevacizumab were hematologic (1), GI (3), hypertension (6), thromboembolism (1), allergy (2), hepatic (1), pain (3), coagulation (1), constitutional (1), and dyspnea (1). Grade 4 adverse events included pulmonary embolus (1), vomiting and constipation (1), and proteinuria (1). Thirteen patients (21.0%) experienced clinical responses (two complete, 11 partial; median response duration, 10 months), and 25 (40.3%) survived progression free for at least 6 months. Median PFS and overall survival were 4.7 and 17 months, respectively. There was no significant association of prior platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance status with the hazard of progression or death. Bevacizumab seems to be well tolerated and active in the second- and third-line treatment of patients with EOC/PPC and merits phase III investigation.

Phase II trial of liposomal doxorubicin at 40 mg/m 2 every 4 weeks in endometrial carcinoma: A Gynecologic Oncology Group Study

Objective. In patients with disseminated endometrial carcinoma, liposomal doxorubicin has possible advantages over doxorubicin which has proven single agent activity but well known cardiac toxicity. Before replacing doxorubicin in clinical trials, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of liposomal doxorubicin (Ortho Biotech Products L. P., Raritan, NJ) in first-line therapy of patients with disseminated endometrial carcinoma. Methods. Patients with initial histologic confirmation of endometrial carcinoma presenting with disseminated or recurrent cancer who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0–2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Liposomal doxorubicin 40 mg/m 2 was given by intravenous injection on an every 4-week cycle until toxicity or progression. Patients who remained free from tumor progression or intolerable toxicity received at least one to a maximum of 20 cycles of liposomal doxorubicin. Results. Fifty-six patients were registered, of whom three were determined ineligible (prior malignancy = 2, inadequate pathology material = 1). One patient never received therapy, leaving 52 evaluable patients. Two patients (3.8%) achieved a complete response, four (7.7%) exhibited a partial response, and 31 (59.7%) had stable disease. The most common adverse events were constitutional (32/52), anemia (28/52), pain (27/52), dermatologic (25/52), and cardiovascular (12/52). Conclusions. In this trial, liposomal doxorubicin had a response rate of 11.5% in first-line treatment of disseminated endometrial carcinoma when given at 40 mg/m 2 every 4 weeks. In view of the associated skin toxicity at this dose, liposomal doxorubicin does not appear to be a suitable replacement for the more active doxorubicin for therapy of endometrial carcinoma.

Phase II trial of liposomal doxorubicinin disseminated endometrial carcinoma: A Gynecologic Oncology Group study

5019 Background: In spite of the proven high activity of doxorubicin as a single agent in chemotherapy of endometrial carcinoma, the Gynecologic Oncology Group (GOG) prudently decided to conduct a phase II clinical trial of liposomal doxorubicin, (from Ortho Biotech Products L.P., Raritan, NJ), in patients with disseminated endometrial carcinoma before replacing doxorubicin with liposomal doxorubicin. Methods: Eligible patients with initial histologic confirmation of endometrial carcinoma presenting with disseminated cancer had not previously received cytotoxic drugs. Also, eligible patients had measurable disease, GOG performance status 0–2, and adequate bone marrow, renal and hepatic function according to standard criteria. Liposomal doxorubicin 40 mg/m2 was given by intravenous injection on an every four week cycle. Patients who remained free from tumor progression or intolerable toxicity received at least one to a maximum of 20 cycles of liposomal doxorubicin. Response by measurable disease change and survival were the endpoints of the trial compared to historical controls especially that of doxorubicin alone. Results: Fifty-six patients were registered, of whom three were determined ineligible (prior malignancy=2, inadequate pathology material=1). One patient never received therapy, leaving 52 evaluable patients. Two patients (3.8%) achieved a complete response, four (7.7%) exhibited a partial response, and 31 (59.7%) had stable disease. The most common adverse effects were constitutional (32/52), anemia (28/52), pain (27/52), dermatologic (25/52) and cardiovascular (12/52). Conclusions: In this trial, liposomal doxorubicin had a response rate of 11.5% in first line treatment of disseminated endometrial carcinoma with tolerable toxicity when given at 40 mg/m2 every four weeks. It is unlikely that liposomal doxorubicin with the associated skin toxicity at this dose would be suitable as a replacement for the much more active doxorubicin for therapy of endometrial carcinoma. No significant financial relationships to disclose.

Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study

5009 Background: Development of targeted therapeutics is considered critical to improve outcomes for patients with EOC/PPC. Vascular Endothelial Growth Factor (VEGF) appears to be a promoter of tumor progression via induction of angiogenesis. Bevacizumab is a recombinant humanized anti-human VEGF monoclonal antibody recently FDA-approved to treat metastatic colorectal cancer. Methods: Eligible patients had persistent or recurrent EOC/PPC after receiving 1–2 prior cytotoxic regimens, measurable disease, and GOG performance status ≤ 2. Treatment consisted of bevacizumab 15 mg/kg IV Q 3 weeks until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at 6 months, objective response rate, and toxicity by NCI criteria. The single-stage design limits the probability of declaring the agent active to 10% when inactive according to both tumor response and PFS at 6 months but is capable of detecting activity on either scale with 90% power. Results: From 4/02 to 8/04, 64 patients were enrolled. Two were excluded for wrong primary and borderline histology; thus, the sample included 62 patients. Median age was 57 (range 18–79) years, and prior treatment consisted of 1 or 2 regimens in 23 and 39 patients, respectively. The median disease free interval from completion of primary cytotoxic chemotherapy to first recurrence was 6.5 months. Early results showed some patients had confirmed objective responses and PFS in some was at least 6 months. The following grade 3 or 4 toxicities were observed: allergy (1 grade 3), cardiovascular (4 grade 3; 1 grade 4), gastrointestinal (3 grade 3), hepatic (1 grade 3), pain (2 grade 3), and pulmonary (1 grade 4). As of 11/15/04, 36 patients were off study, including 29 for disease progression and 1 for toxicity in 33 cases reported. Conclusions: Preliminary evidence exists for objective responses to bevacizumab, presumably a cytostatic agent. Efficacy and toxicity data for this study is expected to reach maturity and be analyzed in March, 2005, and comprehensive results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech BioOncology

Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group Study

Objective. The Gynecologic Oncology Group (GOG) has studied a number of drugs to determine their activity in patients with previously treated squamous and nonsquamous cancer arising in the uterine cervix. A Phase II study with intravenous vinorelbine was initiated for this purpose in patients with Stage IVB, recurrent, or persistent nonsquamous carcinomas who had received one prior chemotherapy or were not eligible for other studies. Methods. Eligible patients had to have measurable disease, GOG performance status of 0–2 and adequate bone marrow, liver, and renal function. The treatment consisted of vinorelbine 30 mg/m 2 on days 1 and 8, repeated every 21 days. Tumor measurements and toxicities were recorded every treatment cycle. Results. Thirty patients were enrolled with 28 patients deemed eligible and evaluable. Only two confirmed partial responses (7.1%) were noted. Neutropenia was the most common toxicity with 9 of 28 (32%) experiencing either grade 3 or 4 changes. Anemia was severe in seven. Neuropathy was more than mild in three patients. Severe events, such as fatigue, hypertension, or pulmonary changes attributed to drug administration, occurred only in one or two instances. Conclusion. With the dose schedule and assessment criteria employed, vinorelbine had only minimal activity in nonsquamous cancer of the cervix.

Psychometric Evaluation of Two Scales Assessing Functional Status and Peripheral Neuropathy Associated With Chemotherapy for Ovarian Cancer: A Gynecologic Oncology Group Study

To evaluate the psychometric properties of two adapted scales, one for functional status and one for peripheral neuropathy secondary to neurotoxic chemotherapy. Repeated measures methodologic design conducted within a Gynecologic Oncology Group (GOG) phase III clinical trial that randomly assigned patients with advanced epithelial ovarian cancer to cisplatin and cyclophosphamide or cisplatin and paclitaxel. 8 GOG institutions participating in the GOG clinical trial. 88 evaluable outpatients enrolled in the GOG clinical trial. Sample size at time 1 (T1) was 88 patients and at time 2 (T2) was 67 patients. All scales were administered at T1 (prior to initiation of chemotherapy) and T2 (after six cycles of chemotherapy but prior to second-look laparotomy). Internal consistency reliability, criterion validity, and construct validity were evaluated, and clinical application was explored. Self-reported peripheral neuropathy and functional status (comprised of physical function and role function subscales), the GOG performance status scale, and the GOG toxicity criteria. Reliability coefficients at T1 were physical function = 0.83, role function = 0.96, and peripheral neuropathy = 0.91; at T2, they were physical function = 0.83, role function = 0.92, and peripheral neuropathy = 0.89. At T1, physical function and role function correlated positively with performance status. Peripheral neuropathy correlated positively with GOG toxicity criteria used at T2. Principal component factor analysis suggested that the functional status scale had a two-factor structure with factors representing general and specific mobility and that the peripheral neuropathy scale also had a two-factor structure with factors representing foot and hand neuropathy. The physical function, role function, and peripheral neuropathy scales have internal consistency, reliability, criterion validity, and construct validity. However, revision of the scales should address modification of specific questions and consider increasing the Likert scale from a four-point to a five- or seven-point scale to enhance clinical sensitivity and application. With minor modifications, these scales should be useful in assessing physical function, role function, and peripheral neuropathy in patients who receive agents that may cause peripheral neuropathy.

A Phase III Trial of Ifosfamide with or without Cisplatin in Carcinosarcoma of the Uterus: A Gynecologic Oncology Group Study

Objective. The aims of this study were to substantiate the previously reported activity of ifosfamide in patients with advanced, persistent, or recurrent carcinosarcoma (mixed mesodermal sarcoma) of the uterus, and to determine whether the addition of cisplatin results in an improved response or survival. Secondarily, we sought to determine the toxicity of ifosfamide–cisplatin in this patient population.Methods. Patients were randomized to receive ifosfamide (1.5 g/m2/day) times 5 days every 3 weeks for eight courses with mesna uroprotection, with or without cisplatin (20 mg/m2/day) times 5 days. No patient had received previous chemotherapy.Results. Of 224 patients entered on this study, 30 were ineligible for a variety of reasons, leaving 194 evaluable patients. Early in the study, the dose of the combination regimen was reduced by 20% (1 day) because of toxicity. The investigational arms were balanced for age, grade, and Gynecologic Oncology Group performance status. Percentages of adverse effects reported in 191 patients receiving chemotherapy included (ifosfamide/cisplatin–ifosfamide) grade 3 or 4 granulocytopenia (36/60), grade 3 or 4 anemia (8/17), grade 3 or 4 central nervous system toxicity (19/14), and grade 3 or 4 peripheral neuropathy (1/12). Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide–cisplatin therapy was (0.36 versus 0.54) overall, 0.47 versus 0.61 for pelvic, 0.21 versus 0.54 for lung, and 0.33 versus 0.40 for “other” metastatic sites of measurable disease. The relative odds ratio of response adjusted for measurable sites of disease was 1.82 (P = 0.03, one-tailed test; 95% lower confidence limit, 1.06). Progression-free survival (PFS) and survival data suggest that the combination offers a slight prolongation of PFS (relative risk, 0.73; 95% upper confidence limit, 0.94; P = 0.02, one-tailed test), but no significant survival benefit (relative risk, 0.80, 95% upper confidence limit, 1.03; P = 0.071, one-tailed test).Conclusion. The addition of cisplatin to ifosfamide appears to offer a small improvement in progression-free survival over ifosfamide alone in the management of advanced carcinosarcoma of the uterus; the added toxicity may not justify the use of this combination.