Joan L. Walker

Long-Term Follow-Up and Overall Survival in NRG258, a Randomized Phase III Trial of Chemoradiation Versus Chemotherapy for Locally Advanced Endometrial Carcinoma

This randomized phase III trial aimed to determine whether treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for four cycles (chemoradiotherapy [C-RT]) increased recurrence-free survival (RFS) and overall survival (OS) when compared with carboplatin and paclitaxel for six cycles (chemotherapy [CT]) in locally advanced endometrial cancer (UC). Previously reported results showed that C-RT did not improve RFS compared with CT. Here we report the final OS analysis. Patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage III-IVA UC or stage I/II serous or clear cell UC and positive cytology were enrolled. The primary objective was RFS. Secondary objectives were OS, toxicity, and quality of life. Cumulative probabilities of OS were estimated using the Kaplan-Meier method. Subgroup analyses of treatment effect for FIGO stage, age, race, gross residual disease, histology, lymph-vascular space invasion, and body mass index were performed. In total, 813 patients were randomly assigned (407 C-RT and 406 CT). The median follow-up was 112 months. Median OS was not achieved in either arm. The stratified hazard ratio for death comparing C-RT versus CT was 1.05 (95% CI, 0.82 to 1.34, log-rank two-sided P value = .72). None of the factors analyzed predicted OS benefit from C-RT. Although C-RT reduced the rate of local recurrence compared with CT, it did not increase OS or RFS in stage III/IVA UC.

A Surgical Window Trial Evaluating Medroxyprogesterone Acetate with or without Entinostat in Patients with Endometrial Cancer and Validation of Biomarkers of Cellular Response

Abstract Purpose: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma. Patients and Methods: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21–24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response. Results: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008). Conclusions: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.

ROCC/GOG-3043: a randomized controlled trial of robotic versus open surgery for early-stage cervical cancer

The Laparoscopic Approach to Cervical Cancer trial is the only randomized trial to date addressing the role of surgical approach in cervical cancer; however, this non-inferiority trial of minimally invasive surgery vs an open approach in patients undergoing radical hysterectomy for early-stage cervical cancer did not meet its primary end point of 4.5-year disease-free survival and was terminated early because of significantly worse disease-specific survival, overall survival, and locoregional recurrence in the minimally invasive surgery cohort. Our trial compares 3-year disease-free survival after robotic-assisted or abdominal radical or simple (in select cases) hysterectomy in early-stage cervical cancer. We hypothesize that disease-free survival is non-inferior after robotic-assisted vs abdominal radical or simple hysterectomy. This multi-center, randomized non-inferiority trial conducted through the Gynecologic Oncology Group has specified surgeon qualification criteria. It requires a pelvic magnetic resonance imaging scan in all patients before enrollment and will use 1:1 randomization to assign patients to robotic-assisted or abdominal hysterectomy. All surgeons must use specified tumor-containment techniques in both arms. It does not allow trans-cervical uterine manipulators. Patients with early-stage (2018 International Federation of Gynecology and Obstetrics stages IA2-IB2) cervical cancer. Histologic types are limited to squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. Pelvic magnetic resonance imaging must confirm a tumor that is 4 cm or less without definitive extra-cervical spread. A simple hysterectomy is allowed in select cases after trial study principal investigator review. The primary end point is the 3-year disease-free survival between robotic-assisted or abdominal hysterectomy. The trial will randomly allocate 840 patients, with planned interim analysis for futility (oncologic safety) after we have randomly allocated 370 and 640 patients. 2030. ClinicalTrials.gov identifier: NCT04831580.

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

PURPOSE In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable < 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

Cervical Precancers and Cancers Attributed to HPV Types by Race and Ethnicity: Implications for Vaccination, Screening, and Management

AbstractBackgroundRacial and ethnic variations in attribution of cervical precancer and cancer to human papillomavirus (HPV) types may result in different HPV vaccine protection, screening test coverage, and clinical management.MethodsPooling data from 7 US studies, we calculated the proportional attribution of precancers and cancers to HPV types using HPV DNA typing from diagnosis. All statistical tests were 2-sided.ResultsFor all racial and ethnic groups, most cases of cervical intraepithelial neoplasia grade 3 (CIN3) (84.2%-90.8% of 5526) and squamous cell carcinoma (SCC) (90.4%-93.8% of 1138) were attributed to types targeted by the 9-valent vaccine. A higher proportion of CIN3s were attributed to nonvaccine HPV types among non-Hispanic Black women (15.8%) compared with non-Hispanic Asian or Pacific Islander (9.7%; P = .002), non-Hispanic White (9.2%; P < .001), and Hispanic (11.3%; P = .004) women. The proportion of SCCs attributed to 9-valent types was similar by race and ethnicity (P = .80). A higher proportion of CIN3s were attributed to nonvaccine HPV35 among non-Hispanic Black (9.0%) compared with non-Hispanic Asian or Pacific Islander (2.2%), non-Hispanic White (2.5%), and Hispanic (3.0%; all P < .001) women. Compared with CIN3, the proportion of SCCs attributed to HPV35 among non-Hispanic Black women (3.2%) was lower and closer to other groups (0.3%-2.1%; P = .70).ConclusionThe 9-valent HPV vaccine will prevent nearly all cervical precancers and invasive cancers among major racial and ethnic groups in the United States. Adding HPV35 to vaccines could prevent a small percentage of CIN3s and SCCs, with greater potential impact for CIN3s among Black women. HPV screening tests target high-risk HPV types, including HPV35. Future genotyping triage strategies could consider the importance of HPV35- and other HPV16-related types.

Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study

PURPOSE The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 ( P = .24). CONCLUSION Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

A Trial of Robotic Versus Open Hysterectomy Surgery in Cervix Cancer

This is a randomized controlled trial to compare survival for patients who undergoe robotic assisted laparoscopy versus open hysterectomy and lymph node assessment for the treatment of early stage cervical cancer.

Ruxolitinib Phosphate, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This phase I/II trial studies the side effects and the best dose of ruxolitinib phosphate when given together with paclitaxel and carboplatin and to see how well they work in treating patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate together with paclitaxel and carboplatin may be a better treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel and carboplatin alone.

Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

This randomized phase III trial studies carboplatin, paclitaxel, and bevacizumab to see how well they work compared to carboplatin, paclitaxel, and placebo in treating patients with stage III or stage IV ovarian epithelial, primary peritoneal, or fallopian tube cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether carboplatin, paclitaxel, and bevacizumab are more effective than carboplatin, paclitaxel, and placebo in treating ovarian epithelial, primary peritoneal, or fallopian tube cancer.