ABSTRACT Objective In order to understand the patient's perspective in regards to meaningful surrogate clinical trial endpoints and the impact of treatment-related toxicity, and quality of life, we ...surveyed women with gynecological cancers to ascertain their preferences. Methods A 28-question anonymous online survey was posted on the OCNA website ( www.ovariancancer.org ). Survey questions included demographic factors, tumor data, and patients' preference regarding side effects and therapy endpoints. Data was analyzed for frequency and percentage of each response. Student t-test, Fisher's exact test and Wilcoxon rank sums were preformed. Results There were 1413 survey responses. Participants reported that for a new agent to be meaningful, the minimum extension of progression-free survival (PFS) and overall survival (OS) should be five or more months, 77% and 85% of the time, respectively. Most subjects (55%, n = 612) were interested in an agent that would keep tumor growth relatively static without change in OS. Addressing the impact of adverse aspects from a hypothetical new agent as a function of response, there was significant migration (p < 0.0001) to acceptance of greater toxicity and cost under the scenario of a 5–6 months OS gain, despite three-fold higher neurotoxicity, as compared to a PFS gain of 3–4 months/no OS gain without toxicity. Response patterns weren't altered by recurrence status. Conclusions Herein, we show that magnitude of outcome is a desired effect, even given the prospect of significant toxicity and cost. However, these preferences appear to differ between those with primary and recurrent disease.
Abstract Objective Despite significant morbidity, surgical cytoreduction is the standard of care for ovarian cancer. We examined the outcomes of cytoreductive surgery to determine if there are groups ...of patients in which the morbidity is so substantial that alternate treatment strategies are warranted. Methods The Nationwide Inpatient Sample was used to identify women who underwent surgery for ovarian cancer from 1998 to 2007. The effect of age, number of radical procedures performed, and clinical characteristics on morbidity and mortality were examined. Results A total of 28,651 women were identified. The complication rates increased with age from 17.1% in those < 50 years of age to 29.7% in women age 70–79 and to 31.5% in those ≥ 80 (p < 0.05). The number of extended procedures performed was also a predictor of morbidity; complications increased from 20.4% for women with 0 procedures to 34.0% for 1 and 44.0% for ≥ 2 procedures (p < 0.0001). In multivariable analysis age, comorbidity, and the number of procedures performed were the strongest predictors of outcome. The morbidity associated with additional procedures was greatest in the elderly. Medical complications in women < 50 years of age occurred in 10.2% of those who underwent 0 radical procedures vs. 23.7% in those who underwent 2 or more procedures. For women ≥ 80 years, complications were noted in 18.3% for 0 procedures, and 33.3% for 2 or more procedures. Conclusion The morbidity of cytoreduction is greatest in elderly women where the effects of age and the number of radical procedures performed have an additive effect on complication rates.
GAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase ...1b study (NCT03639246) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D).
Eligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival.
No dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach.
AVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial.
•The combination of AVB-500 plus chemotherapy was safe and tolerable with no DLTs identified.•At the AVB-500 RP2D (15 mg/kg), AVB-500+PAC demonstrated better clinical activity than AVB-500+PLD.•Patients with no prior bevacizumab had greater clinical response than those with prior bevacizumab and historical control.•An exposure-response relationship was identified for AVB-500 trough levels >13.8 mg/L exhibiting greater clinical response.•A pretreatment serum biomarker may identify patients who benefit from AVB-500 in combination with chemotherapy.
Objective We examined the use, safety, and economic impact of same-day discharge for women undergoing laparoscopic hysterectomy. Study Design We identified women in the Perspective database who ...underwent laparoscopic hysterectomy from 2000 through 2010. Discharge was classified as same-day, 1 day, and ≥2 days. Multivariable models were used to examine predictors of same-day discharge, reevaluation, and cost. Results Among 128,634 women, 34,070 (26.5%) were discharged on the day of surgery. Same-day discharge increased from 11.3% in 2000 to 46.0% by 2010 ( P < .0001). The rate of reevaluation within 60 days was 4.0% for those discharged same day, 3.6% after a 1-day stay, and 5.1% for patients whose stay was ≥2 days ( P < .0001). In a multivariable model, patients discharged on postoperative day 1 were less likely to require reevaluation (risk ratio, 0.89; 95% confidence interval, 0.82–0.96), but costs were $207 (95% confidence interval, $179–234) greater. Conclusion Same-day discharge after laparoscopic hysterectomy is safe and associated with decreased cost.
Previously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we ...provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study.
HRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS. OS and RFS from time of randomization (immediately prior to maintenance therapy) and from debulking tissue procurement time points were analyzed by Kaplan-Meier (KM) and restricted mean survival time (RMST) analysis.
OS for Vigil treated patients at 3 years has not yet reached median OS time point (95% CI 41.6 months to not achieved) compared to 26.9 (95% CI 17.4 months to not achieved) in placebo treated patients (HR 0.417 p = 0.020). Three year RFS also showed benefit to Vigil (stratified HR 0.405, p = 0.011) and no long term toxicity to Vigil was observed. Three year OS for Vigil of 70% vs. 40% for placebo from time of randomization was observed (p = 0.019). RMST analysis was also significant for OS (45.7 vs. 32.8 months, p = 0.008) and RFS (p = 0.025).
In conclusion, results suggest durable activity of Vigil on RFS and OS and support further evaluation of Vigil in HRP ovarian cancer.
•Treatment options for HRP ovarian cancer are limited and associated with significant toxicity and limited clinical benefit.•Previously, Vigil has shown both safety and efficacy in the BRCA wild type, homologous recombination proficient patients.•Continued 3 year follow up has shown Vigil demonstrates durable clinical benefit to prolong OS and RFS in HRP patients.
The optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in ...progression-free survival as monotherapy maintenance treatment in the frontline setting versus active surveillance. Furthermore, preclinical and early clinical studies have shown that PARP inhibitors and immune checkpoint inhibitors have synergistic antitumor activity and may provide an additional therapeutic option for patients in this population.
In women with newly diagnosed ovarian, fallopian tube, or peritoneal cancer, we wish to assess the efficacy of frontline maintenance treatment with the PARP inhibitor rucaparib versus placebo following response to platinum-based chemotherapy (ATHENA-MONO), and to assess the combination of rucaparib plus nivolumab (a programmed death receptor 1 (PD-1)-blocking monoclonal antibody) versus rucaparib alone (ATHENA-COMBO).
(1) Maintenance therapy with rucaparib monotherapy may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting. (2) The combination of nivolumab plus rucaparib may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting compared with rucaparib alone.
ATHENA is an international, randomized, double-blind, phase III trial consisting of two independent comparisons (ATHENA-MONO and ATHENA-COMBO) in patients with newly diagnosed platinum-sensitive ovarian cancer. Patients are randomized 4:4:1:1 to the following: oral rucaparib+ intravenous nivolumab (arm A); oral rucaparib + intravenous placebo (arm B); oral placebo+ intravenous nivolumab (arm C); and oral placebo + intravenous placebo (arm D). The starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. ATHENA-MONO compares arm B with arm D to evaluate rucaparib monotherapy versus placebo, and ATHENA-COMBO evaluates arm A versus arm B to investigate the effects of rucaparib and nivolumab in combination versus rucaparib monotherapy. ATHENA-MONO and ATHENA-COMBO share a common treatment arm (arm B) but each comparison is independently powered.
Patients ≥18 years of age with newly diagnosed advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer who have achieved a response after completion of cytoreductive surgery and initial platinum-based chemotherapy are enrolled. No other prior treatment for ovarian cancer, other than the frontline platinum regimen, is permitted.
The primary endpoint is investigator-assessed progression-free survival by Response Evaluation Criteria in Solid Tumors v1.1.
Approximately 1000 patients have been enrolled and randomized.
The trial completed accrual in 2020. While dependent on event rates, primary results of ATHENA-MONO are anticipated in early 2022 and results of ATHENA-COMBO are anticipated to mature at a later date.
This trial is registered at clinicaltrials.gov (NCT03522246).
To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian ...cancer (PROC).
This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review.
Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29;
= .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27;
= .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu-like symptoms such as fever and chills.
The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.
The COVID‐19 pandemic changed health‐care operations around the world and has interrupted standard clinical practices as well as created clinical research challenges for cancer patients. Cancer ...patients are uniquely susceptible to COVID‐19 infection and have some of the worst outcomes. Importantly, cancer therapeutics could potentially render cancer patients more susceptible to demise from COVID‐19 yet the poor survival outcome of many cancer diagnoses outweighs this risk. In addition, the pandemic has resulted in risks to health‐care workers and research staff driving important change in clinical research operations and procedures. Remote telephone and video visits, remote monitoring, electronic capture of signatures and data, and limiting sample collections have allowed the leadership in our institution to ensure the safety of our staff and patients while continuing critical clinical research operations. Here we discuss some of these unique challenges and our response to change that was necessary to continue cancer clinical research; and, the impacts the pandemic has caused including increases in efficiency for our cancer research office.
The COVID‐19 pandemic has resulted in important changes in cancer clinical research operations and procedures. This commentary discusses some of these unique challenges and our response to change that was necessary to continue cancer clinical research; and, the impacts the pandemic has caused including increases in efficiency for our cancer research office.
Ovarian cancer causes more deaths than any other cancer of the female genital tract. Despite improvements in management and treatment, survival remains low in patients with extensive disease at ...presentation, which usually leads to eventual recurrence. Treatment of recurrence remains challenging. Although the use of secondary cytoreduction to treat recurrent disease has become widespread, its utility remains unproven.
This systematic review examines all the relevant electronic literature. An electronic literature search was conducted in the PubMed, MEDLINE, and EMBASE databases from January 1980 through December 2019.
Several relevant retrospective studies have been published, and these unanimously suggest that secondary cytoreduction is associated with an increase in progression-free and overall survival after relapse. Despite sound statistical methods, these studies are unfortunately limited by significant confounding inherent to the retrospective approach and by selection bias, given that healthier patients with less disease have historically been selected for surgery. Data from clinical trials are currently evolving. Early data from DESKTOP III demonstrate improved progression-free survival with secondary cytoreduction, whereas GOG-0213 found no difference in progression-free or overall survival.
Secondary cytoreduction remains a viable treatment option for select patients for now, but this is entirely dependent on the highly anticipated overall survival results of DESKTOP III and SOC 1.
Objective We examined the effect of radiation on survival for early-stage uterine carcinosarcomas and leiomyosarcomas. Study Design The surveillance, epidemiology, and end results database was used ...to identify patients with stage I/II carcinosarcomas and leiomyosarcomas. Logistic regression and Cox models were developed to determine radiation use and survival. Results Among 1819 women with carcinosarcomas and 1088 women with leiomyosarcomas, radiation was administered to 667 of the patients (37%) with carcinosarcomas and to 235 of the patients (22%) with leiomyosarcomas. In a multivariate model, adjuvant radiation reduced the risk of death by 21% in women with carcinosarcomas (hazard ratio, 0.79; 95% CI, 0.7-0.9). Radiation reduced mortality rates in patients with carcinosarcomas who had not undergone node dissection but had only a marginal effect on survival in node-negative women. Adjuvant radiation had no effect on survival for early-stage leiomyosarcomas (hazard ratio, 1.1; 95% CI, 0.9-1.4). Conclusion Adjuvant radiotherapy improves survival for select patients with early-stage carcinosarcomas but is of limited value for leiomyosarcomas.
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