Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018).

PURPOSE: 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). METHODS: 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. RESULTS: 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; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .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. CONCLUSION: 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 past, present, and future of opioid prescribing: Perioperative opioid use in gynecologic oncology patients after laparotomy at a single institution from 2012 to 2021.

Objective: To describe the evolution of perioperative opioid management in gynecologic oncology patients after open surgeries and determine current opioid over-prescription rates. Methods: Part one of this two-part study was a retrospective chart review of adult patients who underwent laparotomy by a gynecologic oncologist from July 1, 2012 to June 30, 2021, comparing changes in clinical characteristics, pain management and discharge opioid prescription sizes between fiscal year 2012 (FY2012) and 2020 (FY2020). In part two, we prospectively surveyed patients after laparotomy in 2021 to determine opioid use after hospital discharge. Results: 1187 patients were included in the chart review. Demographic and surgical characteristics remained stable from FY2012 to FY2020 with differences notable for increased rates of interval cytoreductive surgeries for advanced ovarian cancer and decreased rates of full lymph node dissection. Median inpatient opioid use decreased by 62 % from FY2012 to FY2020. Median discharge opioid prescription size was 675 oral morphine equivalents (OME) per patient in FY2012 and decreased by 77.7 % to 150 OME in FY2020. Of 95 surveyed patients in 2021, median self-reported opioid use after discharge was 22.5 OME. Patients had an excess of opioids equivalent to 1331 doses of 5-milligram oxycodone tablets per 100 patients. Conclusion: Inpatient opioid use in our gynecologic oncology open surgical patients and post-discharge opioid prescription size significantly decreased over the last decade. Despite this progress, our current prescribing patterns continue to significantly overestimate patients' actual opioid use after hospital discharge. Individualized point of care tools are needed to determine an appropriate opioid prescription size.

A Phase IB Trial of the PI3K Inhibitor Alpelisib and Weekly Cisplatin in Patients with Solid Tumor Malignancies.

The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. Significance: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.

Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial.

OBJECTIVE: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors. METHODS: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety. RESULTS: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations. CONCLUSIONS: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

Struma ovarii with atypical features and synchronous primary thyroid cancer: a case report and review of the literature.

PURPOSE: To present a case of struma ovarii with a typical features and synchronous primary thyroid carcinoma and review the available literature to guide diagnosis and management of these tumors. METHODS: We present a case from our hospital of a 55-year-old woman who had an adnexal mass with features concerning for papillary thyroid carcinoma and was ultimately determined to be struma ovarii with atypical features. Subsequent thyroid imaging and biopsy revealed a primary cervical thyroid carcinoma. We performed a PubMed search of published English language articles using the search terms "malignant struma ovarii," "metastatic struma ovarii," "struma ovarii with malignant transformation," "struma ovarii papillary thyroid carcinoma," "struma ovarii follicular thyroid carcinoma," and "struma ovarii with concurrent primary thyroid carcinoma." RESULTS: Literature review included 104 studies with a total of 195 patient cases. The average age at presentation was 44.9 years. 25.1% of patients had metastatic disease at presentation, and 6.2% had synchronous primary carcinomas; all of which were located in the thyroid. CONCLUSIONS: Thyroid carcinoma arising in struma ovarii or mature cystic teratoma should prompt clinical evaluation and imaging of the thyroid given the possibility of synchronous primaries, metastases, and recurrence.

Afatinib use in recurrent epithelial ovarian carcinoma.

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.

Alcohol Abuse Decreases Pelvic Control and Survival in Cervical Cancer: An Opportunity of Lifestyle Intervention for Outcome Improvement.

PURPOSE: We examined the incidence and the effect of alcohol abuse on pelvic control (PC), disease-free survival (DFS), and overall survival (OS) in locally advanced cervical cancer patients undergoing definitive radiation therapy (RT). METHODS: Between 2007 and 2013, 95 patients treated with RT were reviewed, and the tumor characteristics, the RT dose, the treatment time, chemotherapy, and the number of cycles were recorded. The association between alcohol abuse and DFS, OS, and the duration of PC was analyzed using multivariable Cox proportional hazards models. RESULTS: Of the 95 patients with an average age of 54.8 years (range, 27 to 91 y), 30% were FIGO stage 1B1, 1B2, 2A, 52% stage 2B, 3A; and 18% stage 3B; 86% of the patients were treated with weekly cisplatin chemotherapy. Alcohol history showed that 10 (10.5%) patients met the CDC criteria for heavy alcohol use. With a mean follow-up time of 2 years, 85 patients (88.5%) achieved PC and 86 patients (90.5%) were free of distant metastasis. A total of 82 patients (86.3%) were alive at the last follow-up. When controlling for the total treatment time, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; hazard ratio [HR], 6.19; 95% confidence interval [CI]: 1.73, 22.18), OS (P=0.001; HR, 6.68; 95% CI: 2.10, 21.26), and PC (P=0.029; HR, 3.10; 95% CI: 1.13, 8.56) on univariable analysis. On multivariable analysis, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; HR, 10.57; 95% CI: 2.07, 53.93) and OS (P=0.001; HR, 10.80; 95% CI: 2.57, 45.40). CONCLUSIONS: In this small hypothesis-generating series of patients with heavy alcohol use, the data support the association that heavy alcohol use increases the risk of cancer recurrence and mortality. Additional research is required to better define the patient- and treatment-related factors that may be targeted for intervention.

Synchronous uterine adenocarcinoma and leiomyosarcoma: A rare case report causing a clinical conundrum.

INTRODUCTION: Synchronous gynecologic primary cancers are uncommon. When present, the most frequent malignancies consist of endometrial and ovarian carcinomas. Here we report an exceedingly rare case of concurrent uterine adenocarcinoma and leiomyosarcoma. CASE PRESENTATION: A 60 year-old female presented with four years of postmenopausal bleeding. An endometrial sampling showed grade 2 endometrioid adenocarcinoma. She proceeded with hysterectomy that contained an anterior endometrial mass and a posterior myometrial mass. The final pathology demonstrated concurrent uterine adenocarcinoma and leiomyosarcoma. DISCUSSION: To the best of our knowledge, this is the third reported case of simultaneous uterine adenocarcinoma and leiomyosarcoma. As this presentation is infrequent with limited literature, this caused a clinical management conundrum. Unfortunately, the follow-up PET scan suggested possible recurrence or metastasis three months after the surgery. CONCLUSION: Simultaneous uterine adenocarcinoma and leiomyosarcoma is an exceptionally rare event. As the experience is limited, a multidisciplinary approach in managing these patients may be the best option currently available.

Use of psychosocial services increases after a social worker-mediated intervention in gynecology oncology patients.

The purpose of this study was to determine whether the introduction of psychosocial services to gynecologic oncology outpatients by a social worker increases service use. During the initial six weeks (phase I), patients were referred for psychosocial services by clinic staff. During the second six weeks (phase II), a nurse introduced available services to each patient with a brochure. During the final 12 weeks (phase III), a social worker introduced services to each patient. The authors then compared psychosocial service referral rates. The sample included 196 patients. During phase III, the probability of a patient-initiated referral increased 3.4-fold (95 percent confidence interval [CI] [1.1, 10.4], p = .04) compared with baseline; the probability of any referral rose 2.7-fold (95 percent CI [1.1, 6.3], p = .03). The mean time to referral decreased from 79.4 days at baseline to 3.9 days during phase III (p < .001). The phase III intervention was accomplished only in 34 patients (39 percent) because of scheduling conflicts. Of these, eight requested referral, resulting in a 24 percent patient-initiated referral rate after meeting with a social worker. The introduction of psychosocial services by a social worker to gynecologic oncology outpatients increases referral rates and expedites evaluation.

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

OBJECTIVE: This 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). METHODS: Eligible 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 10 mg/kg every other week and temsirolimus 25 mg 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. RESULTS: Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63 years, 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 16.9 months, respectively. CONCLUSION: Combination 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.

Changing demographics of cervical cancer in the United States (1973-2008).

OBJECTIVE: To describe changes in the cervical cancer population. METHODS: The SEER database 9 registries from 1973 to 2008 were queried to perform a retrospective cohort study of women with invasive cervical cancer. Estimated annual percent change (EAPC) in incidence rates and 95% confidence intervals (CI) over the entire study period were compared according to age, stage, race, and cell type (squamous [SCC] and adenocarcinoma [ACA]). Proportions and odds ratios (OR) were calculated for patients diagnosed during the second half (1990-2008) compared to first half (1973-89) of the study period. RESULTS: 40,363 women with cervical cancer were entered into SEER. The EAPC are falling fastest among those with localized disease (-2.5%; 95% CI -2.8 to -2.1), age≥50 (-3.0%; 95% CI=-3.2 to -2.8), and black women (-3.8%; 95% CI=-4.1 to -3.6). The odds of a newly diagnosed cervical cancer patient having advanced disease are 10% higher, being less than age 50 are 37% higher, and being Asian or Pacific Islander are 68% higher in the second time period as compared to the first. CONCLUSIONS: In the US, the population with cervical cancer is changing. Patients are presently significantly more likely to be pre-menopausal, Asian or Pacific Islander, and more frequently have non-squamous histology than previously. These progressive and cumulative changes could be due to the disparate impact of current population based screening and prevention strategies. Understanding the implications of these evolving population characteristics may facilitate planning targeted studies and interventions for cervical cancer prevention, screening and treatment in the future.

Cardiovascular disease is the leading cause of death among endometrial cancer patients.

OBJECTIVE: To evaluate the causes of death among women with endometrial cancer. METHODS: SEER registries from 1973-1988 were queried to perform a retrospective cohort study of women with invasive epithelial endometrial cancer. Causes of death were compared according to grade and stage. RESULTS: 33,232 women with incident cases of endometrial cancer had died at the time of last follow up. Overall, women were most likely to die from cardiovascular disease (35.9%, 95% CI 35.3-36.3%), followed by other causes, other malignancies, and endometrial cancer. Women with low grade localized cancer were most likely to die of cardiovascular disease, while women with high grade advanced cancer were least likely to die of cardiovascular disease and most likely to die of endometrial cancer. For the entire population, risk of death from cardiovascular causes surpasses the risk of death from endometrial cancer 5 years after diagnosis. CONCLUSIONS: Higher risk of cardiac death among endometrial cancer patients likely reflects the high probability of curative cancer treatment and the prevalence of cardiac disease and risk factors. As the probability of dying of endometrial cancer decreases with time, the probability of dying of cardiovascular disease increases. Interventions and investigations aimed at addressing risk factors for cardiovascular disease may have the greatest potential to improve survival for women diagnosed with endometrial cancer and should feature prominently in treatment and survivorship plans.

Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo.

Antiestrogen therapies arrest susceptible estrogen receptor (ER)-positive breast cancers by increasing p27. Since Src phosphorylates p27 to promote p27 proteolysis, Src activation observed in up to 40% of ER-positive cancers may contribute to antiestrogen resistance. In this article, we show that treatment with the Src-inhibitor saracatinib (AZD0530) together with ER-blocking drugs increased breast cancer cell cycle arrest via p27. Saracatinib and fulvestrant together more effectively increased p27, reduced Ki67, and impaired MDA-MB-361 xenograft tumor growth in vivo than either of the drugs alone. In contrast, saracatinib monotherapy rapidly gave rise to drug resistance. Since combined ER and Src inhibition delays development of resistance in vivo, these data support further clinical investigation of saracatinib in combination with fulvestrant for women with ER-positive breast cancer. Proteomic analysis revealed striking bypass activation of the mTOR pathway in saracatinib-resistant tumors. mTORC1 activation also arose following long-term culture of ER-positive breast cancer lines in the presence of saracatinib. These data indicate the utility of proteomic analysis of drug-resistant tumors to identify potential means of drug resistance. The use of mTOR kinase inhibitors with saracatinib may subvert drug resistance and prove to be more effective than saracatinib alone.

A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer.

OBJECTIVES: This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. METHODS: Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. RESULTS: Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). CONCLUSIONS: The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).