Bevacizumab plus fosbretabulin in recurrent ovarian cancer: Overall survival and exploratory analyses of a randomized phase II NRG oncology/gynecologic oncology group study.

OBJECTIVE: To explore the relationship between tumor size and response to combined anti-vascular targeted therapy using the anti-angiogenesis inhibitor, bevacizumab, and the tubulin-binding vascular disrupting agent, fosbretabulin. METHODS: An exploratory, post-hoc analysis of the randomized phase II trial, Gynecologic Oncology Group-0186I, was performed. One hundred and seven patients with recurrent ovarian carcinoma, treated with up to 3 prior regimens, were randomized to bevacizumab 15 mg/kg body weight with or without intravenous fosbretabulin 60 mg/m2 body surface area every 21 days until progression or unacceptable toxicity. The primary analysis favored the combination (HR 0.69; 95% CI, 0.47-1.00; p = .049) [Monk BJ, et al. J Clin Oncol 2016;34:2279-86]. The Cox proportional hazards model was used to estimate the treatment effect in various subpopulations. RESULTS: With extended follow-up, the median PFS for bevacizumab plus fosbretabulin was 7.6  months as compared to 4.8  months with bevacizumab alone (HR 0.74; 90% CI, 0.54-1.02). Overall survival was similar in the experimental and control arms (25.2 vs 24.4 mos, respectively, HR 0.85; 90% CI, 0.59-1.22; p = .461). Eighty-one patients had measurable disease and median tumor size was 5.7  cm. In the ≤5.7  cm subgroup, the HR for progression or death was 0.77 (90% CI 0.45-1.31). Patients with tumors >5.7  cm (n = 40) had a HR for progression or death of 0.55; 90% CI, 0.32-0.96; p = .075). CONCLUSIONS: Although no significant survival benefit was observed, the trend showing a reduced HR for progression or death with increasing tumor size when fosbretabulin is added to bevacizumab compared to bevacizumab alone warrants further study.

Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy Plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study.

PURPOSE: To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma. METHODS: Eligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22. RESULTS: A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm. CONCLUSION: Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.

Correlation between Surgeon's assessment and radiographic evaluation of residual disease in women with advanced stage ovarian cancer reported to have undergone optimal surgical cytoreduction: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: We sought to determine the level of concordance among surgeons' assessment of residual disease (RD) and pre-treatment computed tomography (CT) findings among women who underwent optimal surgical cytoreduction for advanced stage ovarian cancer. METHODS: This is a post-trial ad hoc analysis of a phase 3 randomized clinical trial evaluating the impact of bevacizumab in primary and maintenance therapy for patients with advanced stage ovarian cancer following surgical cytoreduction. All subjects underwent imaging of the chest/abdomen/pelvis to establish a post-surgical baseline prior to the initiation of chemotherapy. Information collected on trial was utilized to compare surgeon's operative assessment of RD, to pre-treatment imaging. RESULTS: Of 1873 enrolled patients, surgical outcome was described as optimal (RD≤1cm) in 639 subjects. Twelve patients were excluded as they did not have a baseline, pretreatment imaging, leaving 627 participants for analysis. The average interval from surgery to baseline scan was 26days (range: 1-109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD>1cm in size. RD>1cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD>1.5cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD>1cm on pre-treatment CT (discordant) exhibited a significantly greater risk of disease progression (HR 1.30; 95% CI 1.08-1.56; p=0.0059). CONCLUSIONS: Among patients reported to have undergone optimal cytoreduction, 40% were found to have lesions >1cm on postoperative, pretreatment imaging. Although inflammatory changes and/or rapid tumor regrowth could account for the discordance, the impact on PFS and distribution of RD may suggest underestimation by the operating surgeon.

Preoperative predictors that impact the survival and outcome of patients undergoing secondary cytoreduction for ovarian cancer.

This study aimed to examine the factors affecting feasibility of optimal and complete secondary cytoreductive surgery (SCRS) and to characterise the prognostic factors that correlate with improved survival in patients who underwent SCRS. This is a retrospective single-institutional cohort study of patients who underwent SCRS for recurrent epithelial ovarian cancer (EOC). One hundred and forty-eight patients met inclusion criteria. Platinum sensitivity was associated with complete cytoreduction at SCRS. Factors associated with suboptimal cytoreduction (SOC) were age >55 years, serous histology, largest tumour implant size >4 cm, and SOC at primary surgery. Overall survival analysis showed significantly longer survival with complete cytoreduction compared to optimal and SOC. Surgical outcome of SCRS was an independent predictor of survival regardless of the outcome of primary cytoreduction. Location of the largest implant, DFI and timing of chemotherapy also impact on survival.

Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. METHODS: The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851. FINDINGS: Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1]). INTERPRETATION: The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. FUNDING: National Cancer Institute and Genentech.

CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study.

Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial.Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons.Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (P = 0.028), while BF achieves borderline significance (P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3-6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status (P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS.Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684-91. ©2017 AACR.

Group-based trajectory modeling of fear of disease recurrence among women recently diagnosed with gynecological cancers.

OBJECTIVE: Fear of cancer recurrence is an important clinical phenomenon and is associated with decrements in life domains. The study goals were to characterize patterns of global fear of recurrence (FOR) and 4 domains of fear (health, role, womanhood, and death worry) over time in women who were diagnosed with gynecological cancer and to identify demographic, medical, and psychological predictors of FOR. METHOD: One hundred eighteen women participating in the usual care arm of a randomized trial completed the Concerns about Recurrence scale as well as measures of depressive symptoms, cancer-specific distress, coping, coping efficacy, and social network responses at 4 time points. The majority of the sample was diagnosed with stage 3 ovarian cancer. RESULTS: Group-based trajectory modeling identified subgroups of women with high-stable (49.1%), high-decreasing (25.3%), and low-stable (25.5%) trajectories for global FOR. For role worries, 3 similar group trajectories were identified. For health worries, modeling identified subgroups with high-decreasing (19.1%) and low-increasing (80.9%) trajectories. For womanhood worries, modeling identified subgroups with high-increasing (15.7%) and low-decreasing (84.2%) trajectories. Young age, metastatic cancer, depression, cancer distress, holding back, and lower coping efficacy were associated with the high-stable global FOR and at least 1 domain of FOR. CONCLUSION: Almost half of the women recently diagnosed with gynecological cancer evidence persistently elevated FOR over the 6-month period postdiagnosis. Psychological interventions to reduce FOR may be more effective if they focus on teaching patients coping skills, as well as greater comfort expressing cancer-specific concerns to others.

The role of adjuvant radiation in lymph node positive endometrial adenocarcinoma.

OBJECTIVES: The purpose of this study was to examine the impact of adjuvant radiation on overall survival (OS) and cancer specific survival (CSS) in patients with lymph node (LN) positive endometrial cancer. METHODS: We analyzed all women diagnosed with FIGO stage IIIC endometrial adenocarcinoma in the Surveillance, Epidemiology, and End Results database from 2004 to 2012 (n=2177). Patients not undergoing surgery or with missing treatment information were excluded. Chi-squared tests were used to compare predictors of treatment received. Cox proportional hazards model and Kaplan-Meier method were used to assess OS and CSS. RESULTS: The median age was 60 (27-84) and the median follow-up was 31months (2-107). Adjuvant radiation was administered to 1248 (60.3%) patients. A total of 1363 (65.9%) patients had pelvic LN involvement while 658 (31.8%) had para-aortic involvement. The 3-year actuarial OS for patients with and without radiation was 80.5% and 67.6%, respectively (p<0.001). The 3-year actuarial CSS for patients with and without radiation was 83.4% and 73%, respectively (p<0.001). On multivariable analysis, receipt of radiotherapy remained associated with OS (HR 0.61 95% CI 0.51-0.74) and CSS (HR 0.65, 95% CI 0.53-0.80). After propensity matching, radiotherapy continued to be associated with an improved OS (HR 0.65 95% CI 0.54-0.78) and CSS (HR 0.65 95% CI 0.53-0.81). The addition of brachytherapy was not associated with OS or CSS. CONCLUSIONS: In this large population registry analysis, adjuvant radiation was associated with improved OS and CSS in patients with LN positive endometrial cancer. Prospective data is needed to confirm these findings.

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer.

BACKGROUND: A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS: We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS: A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS: Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).

Resilience, Positive Coping, and Quality of Life Among Women Newly Diagnosed With Gynecological Cancers.

BACKGROUND: Resilience has been linked to psychological adaptation to many challenging life events. OBJECTIVE: The goal was to examine 3 coping strategies--expressing positive emotions, positive reframing of the cancer experience, and cultivating a sense of peace and meaning in life--as potential mechanisms by which resilience translates to quality of life among women recently diagnosed with gynecological cancer. METHODS: This cross-sectional study utilized baseline data from women diagnosed with gynecological cancer participating in an ongoing randomized clinical trial (n = 281; mean age, 55 years; 80% were white). Participants completed measures of resilience, positive emotional expression, positive reappraisal, cultivating a sense of peace and meaning, and quality of life. Univariate and multiple mediation analyses were conducted. RESULTS: Greater resilience was related to higher quality of life (P < .001). Multiple mediation analyses indicated that the coping strategies, as a set, accounted for 62.6% of the relationship between resilience and quality of life. When considered as a set, cultivating a sense of peace and meaning had the strongest indirect effect (b = 0.281, SE = 0.073, P < .05). CONCLUSION: The findings suggested that resilient women may report higher quality of life during gynecological cancer diagnosis because they are more likely to express positive emotions, reframe the experience positively, and cultivate a sense of peace and meaning in their lives. IMPLICATIONS FOR PRACTICE: Interventions promoting a sense of purpose in one's life and facilitating expression of positive emotions may prove beneficial, particularly for women reporting higher levels of resilience.

Correlation of pelvic magnetic resonance imaging diagnosis with pathology for indeterminate adnexal masses.

OBJECTIVES: The aim of this study was to determine the accuracy of pelvic magnetic resonance imaging (MRI) diagnoses compared with the final pathology diagnoses for a series of women with indeterminate adnexal masses. MATERIALS AND METHODS: We performed a retrospective cohort study of women who underwent pelvic MRI with a diagnosis of an adnexal mass between June 2009 and 2010 after indeterminate ultrasound at our tertiary care institution. Chart abstraction was performed for demographic information and radiologic interpretations (benign or malignant) and favored a specific histologic subtype on MRI reports. The radiologic diagnoses were compared with the diagnoses by surgical pathology. RESULTS: Data from 237 female patients who underwent pelvic MRI were included, and 41.35% underwent surgical intervention for the adnexal mass. Pelvic MRI (n = 88) was determined to have a sensitivity of 95.0% and specificity of 94.1%. The predicted specific histologic subtype by MRI (n = 84) was accurate in 56 (98.25%) of 57 women with an anticipated benign diagnosis and in 23 (85.19%) of 27 women with an anticipated malignancy. The agreement between a benign diagnosis from MRI and benign final surgical pathology was 0.85 (95% confidence interval, 0.716-0.976). CONCLUSIONS: In our tertiary care center, MRI is used to further characterize indeterminate adnexal masses and can accurately differentiate benign versus malignant adnexal masses. The diagnosis on MRI was highly correlative with the final histopathology. The majority of the cohort (59%) were able to be managed expectantly based on reassuring results of the MRI. Magnetic resonance imaging offered diagnostic value, more detailed patient counseling, appropriate subspecialty referral, and surgical planning, as well as reassurance to pursue conservative management of benign masses by MRI.

Risk factors for GI adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced ovarian cancer: A Gynecologic Oncology Group Study.

PURPOSE: To evaluate risk factors for GI adverse events (AEs) within a phase III trial of bevacizumab in first-line ovarian cancer therapy. PATIENTS AND METHODS: Women with previously untreated advanced disease after surgery were randomly allocated to six cycles of platinum-taxane chemotherapy plus placebo cycles (C)2 to C22 (R1); chemotherapy plus bevacizumab C2 to C6 plus placebo C7 to C22 (R2); or chemotherapy plus bevacizumab C2 to C22 (R3). Patients were evaluated for history or on-study development of potential risk factors for GI AEs defined as grade ≥ 2 perforation, fistula, necrosis, or hemorrhage. RESULTS: Of 1,873 patients enrolled, 1,759 (94%) were evaluable, and 2.8% (50 of 1,759) experienced a GI AE: 10 of 587 (1.7%, R1), 20 of 587 (3.4%, R2), and 20 of 585 (3.4%, R3). Univariable analyses indicated that previous treatment of inflammatory bowel disease (IBD; P = .005) and small bowel resection (SBR; P = .032) or large bowel resection (LBR; P = .012) at primary surgery were significantly associated with a GI AE. The multivariable estimated relative odds of a GI AE were 13.4 (95% CI, 3.44 to 52.3; P < .001) for IBD; 2.05 (95% CI, 1.09 to 3.88; P = .026) for LBR; 1.95 (95% CI, 0.894 to 4.25; P = .093) for SBR; and 2.15 for bevacizumab exposure (aggregated 95% CI, 1.05 to 4.40; P = .036). CONCLUSION: History of treatment for IBD, and bowel resection at primary surgery, increase the odds of GI AEs in patients receiving first-line platinum-taxane chemotherapy for advanced ovarian cancer. After accounting for these risk factors, concurrent bevacizumab doubles the odds of a GI AE, but is not appreciably increased by continuation beyond chemotherapy.

Paget Cells in Endometrial and Endocervical Curettings in a Patient With Recurrent Vulvar Paget's Disease.

INTRODUCTION: Paget's disease of the vulva is a rare malignancy primarily affecting Caucasian women in their seventh to eighth decades. Most patients experience an indolent disease course and undergo surgical excision for disease control. Although progression to invasive adenocarcinoma is rare, recurrence is common because of the difficulty of achieving negative surgical margins. CASE PRESENTATION: We report a case of a 73-year-old woman with a long-standing history of recurrent vulvar Paget's disease who presented with postmenopausal bleeding. Workup revealed extensive endocervical involvement by Paget's disease, resulting in Paget cells on endocervical curettage, as well as endometrial curettage (because of cervical contamination). CONCLUSION: Extensive endocervical involvement by vulvar Paget's disease can occur despite multiple reexcisions and topical therapy. The presence of Paget cells on endometrial and endocervical curettings, particularly in patients without visible vulvar or cervical lesions, should raise suspicion of endocervical involvement and prompt further evaluation of disease extension.

A phase II trial of thalidomide in patients with refractory uterine carcinosarcoma and correlation with biomarkers of angiogenesis: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate the efficacy and adverse events of thalidomide in previously-treated, measurable, persistent or recurrent carcinosarcoma of the uterus, and to explore associations between angiogenic markers with patient demographics and clinical outcome. METHODS: Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. Endpoints included progression-free survival (PFS)≥6 months (primary), toxicity, response, overall PFS and survival. Pre- and post-treatment plasma were evaluated for a panel of angiogenic biomarkers and assessed against clinical outcomes. RESULTS: Of 55 enrolled patients, 45 were evaluable for toxicity and survival. Two patients (4%; 90% CI 1-13%) experienced a partial response, and 8 (18%; 90% CI 9-30%) had PFS≥6 months. Median PFS was 1.9 months and median survival was 5.9 months. Grade 2-3 sensory neuropathy was noted in 6 patients, and 4, 3, and 3 patients experienced grade 3 sedation, fatigue, and constipation, respectively. Three patients had grade 4 adverse events (2 thromboembolic, 1 anemia). High pre-treatment VEGFA levels were associated with poorer PFS and survival. CONCLUSIONS: Treatment with thalidomide met the protocol specified goal of prolonging PFS at 6 months. However, based on results with newer agents, the activity was insufficient to support further investigation. Association between pre-treatment VEGFA and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine carcinosarcoma.

Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission.

PURPOSE: In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Immunotherapy may have potential for consolidation therapy. EXPERIMENTAL DESIGN: This randomized open-label phase I/II trial evaluated responses of patients with advanced ovarian cancer in remission for vaccination with monocyte-derived dendritic cells (DC) loaded with Her2/neu, hTERT, and PADRE peptides, with or without low-dose intravenous cyclophosphamide. All patients also received pneumococcal vaccine and were randomized to cyclophosphamide 2 days prior to first vaccination. Blood samples were analyzed by ELISPOT and flow cytometry. RESULTS: Of 11 patients, 2 recurred during vaccination. Nine received all 4 doses: 3 patients recurred at 6, 17, and 26 months, respectively, and 6 have no evidence of disease at 36 months. No grade 3/4 vaccine-related toxicities were noted. The 3-year overall survival was 90%. Patients receiving cyclophosphamide showed a non-significant improvement in survival over controls. Patients receiving cyclophosphamide had a transient reduction in neutrophils, but no change in total lymphocytes or regulatory T cells. Modest T-cell responses to Her2/neu and hTERT were seen post-vaccine by IFN-γ ELISPOT. Patients demonstrated below normal responses to the diphtheria conjugate protein CRM197, a component of the pneumococcal vaccine. CONCLUSIONS: In this setting, peptide-loaded DC vaccination elicits modest immune responses, but survival is promising. Pneumococcal vaccination revealed substantial immune suppression, even in patients in remission. Rational design of consolidative strategies for ovarian cancer will need to overcome tolerance and immunosuppression.

A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer.

OBJECTIVE: Ten percent of ovarian cancer is attributed to hereditary syndromes, most commonly to mutations in the BRCA1 or BRCA2 genes. These cancers are characterized by a prolonged sensitivity to platinum agents in spite of presentation at advanced stages. We hypothesized that women with BRCA-associated ovarian cancer would also show a high response rate to pegylated liposomal doxorubicin (Doxil). METHODS: A retrospective cohort study was conducted to compare the response rate, progression-free, and overall survival among women with BRCA-associated or sporadic ovarian cancer who were treated with Doxil. RESULTS: A response to Doxil was seen in 13 of 23 patients with BRCA mutations (56.5%; 3 by RECIST criteria and 10 by CA125 levels) compared with only 8 of 41 women with non-hereditary cancers (19.5%; 2 by RECIST criteria and 6 by CA125 levels; p=0.004). This was associated with an improved progression-free and overall survival as measured from the time of Doxil administration. Notably, platinum sensitivity did not directly correlate with a response to Doxil. CONCLUSIONS: Women with BRCA-associated ovarian tumors demonstrate a greater sensitivity to cytotoxic therapy with Doxil than has previously been reported in unselected cases.

Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: a gynecologic oncology group study.

PURPOSE: Intraperitoneal chemotherapy has shown a survival advantage over intravenous chemotherapy for women with newly diagnosed optimally debulked epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. However, significant toxicity has limited its acceptance. In an effort to reduce toxicity, the Gynecologic Oncology Group conducted a Phase I study to evaluate the feasibility of day 1 intravenous (IV) paclitaxel and intraperitoneal (IP) cisplatin followed by day 8 IP paclitaxel on an every 21-day cycle. METHODS: Patients with Stage IIB-IV epithelial ovarian, fallopian tube, primary peritoneal carcinomas or carcinosarcoma received paclitaxel 135mg/m(2) IV over 3h followed by cisplatin 75mg/m(2) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8 of a 21 day cycle with 6 cycles planned. Dose-limiting toxicity (DLT) was defined as febrile neutropenia or dose-delay of greater than 2 weeks due to failure to recover counts, or Grade 3-5 non-hematologic toxicity occurring within the first 4 cycles of treatment. RESULTS: Twenty of 23 patients enrolled were evaluable and nineteen (95%) completed all six cycles of therapy. Three patients experienced a DLT consisting of infection with normal absolute neutrophil count, grade 3 hyperglycemia, and grade 4 abdominal pain. CONCLUSIONS: This modified IP regimen which administers both IV paclitaxel and IP cisplatin on day one, followed by IP paclitaxel on day eight, of a twenty-one day cycle appears feasible and is an attractive alternative to the intraperitoneal treatment regimen administered in GOG-0172.

Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study.

OBJECTIVE: Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers. METHODS: Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1-3 prior regimens were treated with 25mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall's tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome. RESULTS: Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%-38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90% CI 3.7%-23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS. CONCLUSIONS: Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.

A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study.

OBJECTIVE: This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles. METHODS: Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175mg/m(2) paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles. RESULTS: Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required. CONCLUSIONS: The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose.

Vaginal intraepithelial neoplasia (VAIN) after radiation therapy for gynecologic malignancies: a clinically recalcitrant entity.

OBJECTIVES: Vaginal dysplasia is associated with prior radiation therapy (RT) for gynecologic malignancies. We reviewed our institution's experience with VAIN in patients who were treated with radiation therapy for a gynecologic malignancy. METHODS: A retrospective review of patients treated for VAIN was performed. All cases of patients followed and treated for VAIN after radiation therapy were identified (n=10), along with a cohort of patients with VAIN who did not have radiation therapy (n=23). RESULTS: Mean follow-up after initial diagnosis of VAIN was 37.6 months (range: 12 to 72). Cytologic screening events after diagnosis of VAIN (n=105) showed that patients with prior RT were more than twice as likely to have recurrent dysplasia (OR 3.625, 95% CI=from 1.454 to 9.0376) after treatment. Of patients who recurred, the mean time to first recurrence was 12.3 months in cases and 15.3 months in controls, which was not statistically significant (p=0.31). Screening practices at our institution ranged from 3 month to 12 month intervals. 3 patients in the RT group and 1 patient in the control group developed invasive squamous cell cancer of the vagina. CONCLUSIONS: Vaginal dysplasia after radiation therapy is more refractory to treatment than dysplasia not associated with radiation therapy, more likely to recur after surgical and ablative therapy, and may also be more likely to progress to invasive cancer. These data support the need for further study to determine the optimal follow-up screening interval and whether aggressive surgical or ablative treatment stems disease progression in this clinical scenario.