Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

Ultrastaging of 'negative' pelvic lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer who developed non-vaginal recurrences.

OBJECTIVE: Evidence on micrometastases and isolated tumor cells as factors associated with non-vaginal recurrence in low- and intermediate-risk endometrial cancer is limited. The goal of our study was to investigate risk factors for non-vaginal recurrence in low- and intermediate-risk endometrial cancer. METHODS: Records of all patients with endometrial cancer surgically managed at the Mayo Clinic before sentinel lymph node implementation (1999-2008) were reviewed. We identified all patients with endometrioid low-risk (International Federation of Gynecology and Obstetrics (FIGO) stage I, grade 1 or 2 with myometrial invasion <50% and negative peritoneal cytology) or intermediate-risk (FIGO stage I, grade 1 or 2 with myometrial invasion ≥50% or grade 3 with myometrial invasion <50% and negative peritoneal cytology) endometrial cancer at definitive pathology after pelvic and para-aortic lymph node assessment. All pelvic lymph nodes of patients with non-vaginal recurrence (any recurrence excluding isolated vaginal cuff recurrences) underwent ultrastaging. RESULTS: Among 1303 women, we identified 321 patients with low-risk (n=236) or intermediate-risk (n=85) endometrial cancer (median age 65.4 years; 266 (82.9%) stage IA; 55 (17.1%) stage IB). Of the total of 321, 13 patients developed non-vaginal recurrence (Kaplan-Meier rate 4.7% by 60 months; 95% CI 2.1% to 7.2%): 11 hematogenous/peritoneal and two para-aortic and distant lymphatic. Myometrial invasion and lymphovascular space invasion were univariately associated with non-vaginal recurrence. In these patients, the original hematoxylin/eosin slides review confirmed all 646 pelvic and para-aortic removed lymph nodes as negative. The ultrastaging of 463 pelvic lymph nodes did not identify any occult metastases (prevalence 0%; 95% CI 0% to 22.8% considering 13 patients; 95% CI 0% to 0.8% considering 463 pelvic lymph nodes). CONCLUSION: There were no occult metastases in pelvic lymph nodes of patients with low- or intermediate-risk endometrial cancer with non-vaginal recurrence. Myometrial invasion and lymphovascular space invasion appear to be associated with non-vaginal recurrence.

A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Optimizing the treatment of ovarian cancer: Neoadjuvant chemotherapy and interval debulking versus primary debulking surgery for epithelial ovarian cancers likely to have suboptimal resection.

OBJECTIVE: To: a) identify prognostic factors in patients with epithelial ovarian cancer treated with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS), and b) compare post-surgical survival between patients treated with NACT/IDS for presumed unresectable disease and stage IIIC/IV patients who underwent suboptimal primary debulking surgery (PDS). METHODS: This was a retrospective study of consecutive stage IIIC or IV patients undergoing IDS after NACT at Mayo Clinic from January 2007 to December 2013. A subset of patients receiving NACT/IDS for the indication of unresectable disease were matched 1:1 on age and stage to a cohort of patients who underwent suboptimal PDS between 2003 and 2011. Hazard ratios and corresponding 95% confidence intervals were estimated from Cox proportional hazards models. RESULTS: We identified 87 patients treated with NACT/IDS: the median OS and PFS following surgery was 2.4 and 1.0years, respectively. Factors associated with significantly worse OS were older age (adjusted HR 1.60 per 10-year increase in age, 95% CI 1.18, 2.16) and elevated CA-125 before IDS (adjusted HR 2.30 for CA-125 >35U/mL, 95% CI 1.25, 4.23). Number of adjuvant chemotherapy cycles administered did not have a significant effect on survival. In the matched cohort analysis of presumed unresectable cases undergoing NACT/IDS vs suboptimal PDS cases (n=45 each), the NACT/IDS group had a significant OS advantage (HR 0.53; 95% CI 0.32, 0.88), and fewer patients experienced a 30-day postoperative Accordion grade 3/4 complication (11% vs 36%, P=0.01). CONCLUSIONS: Younger age and normalization of CA-125 prior to IDS are associated with improved survival with NACT/IDS. For primary EOC where resection to residual disease of 1cm or less is unlikely, NACT/IDS is associated with improved survival and reduced perioperative morbidity compared to PDS. As these patients are likely best served by NACT/IDS, more reliable predictors of resectability would be valuable.

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.

Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary?

OBJECTIVE: The objective of this study was to determine the cardiac safety of high cumulative doses of pegylated liposomal doxorubicin (PLD) in patients with gynecologic malignancies and the need for routine evaluation of left ventricular ejection fraction (LVEF). METHODS: Data were collected for all patients treated with PLD with at least one evaluation of LVEF with either Multi-Gated Acquisition (MUGA) scan or echocardiogram from January 2006 to May 2012. Evaluation of LVEF was used to detect PLD-related cardiac toxicity (defined as a decline in LVEF of greater than 10% compared to baseline measurements). RESULTS: A total of 141 patients were included. Twenty-two patients were treated with a cumulative dose of 500 mg/m(2) or more, and five patients with 1000 mg/m(2) or more. Ten patients (7%) had a reduction in LVEF of greater than 10%, 38 had no significant change or increase in LVEF throughout the duration of treatment, and 93 did not require a follow-up evaluation of LVEF. The LVEFs of two patients dropped below 50% at cumulative doses of 1110 mg/m(2) and 1670 mg/m(2); one began with a baseline of 52%. CONCLUSIONS: Only one patient had a clinically significant decrease in LVEF at a cumulative dose of 1670 mg/m(2), suggesting that PLD does not carry a significant risk of cardiotoxicity, as evidenced by the stability of LVEF even after treatment with large cumulative doses. Routine surveillance of LVEF does not seem to be necessary or cost effective in the absence of other risk factors.

Physician opinions regarding elective bilateral salpingectomy with hysterectomy and for sterilization.

STUDY OBJECTIVE: To gather opinions about the benefits and concerns of performing bilateral salpingectomy without oophorectomy during hysterectomy for benign indications and as a sterilization procedure. DESIGN: Survey study (Canadian Task Force classification III). SETTING: Practicing physicians in US institutions that have obstetrics and gynecology residency programs listed on the FREIDA website were surveyed electronically. INTERVENTION: A validated, standardized questionnaire designed to gather opinions about bilateral salpingectomy performed during hysterectomy or for sterilization was administered via SurveyMonkey to practitioners of obstetrics and gynecology. MEASUREMENTS AND MAIN RESULTS: Results were compiled and presented as percentages of total responders. A total of 234 surveys were returned. Fifty-four percent of physicians perform bilateral salpingectomy during hysterectomy, most commonly to reduce the risks of cancer (75%) and repeat operation (49.1%). Of the 45.5% of physicians who do not perform bilateral salpingectomy during hysterectomy, most (69.4%) believe there is no benefit. Fifty-eight percent of practitioners believe that bilateral salpingectomy is the most effective method of sterilization after age 35 years but choose this method only in patients in whom one sterilization procedure has failed or because of tubal disease. Only 7.2% of surgeons prefer it as an interval sterilization procedure. CONCLUSION: Most practitioners believe that bilateral salpingectomy is beneficial. Most also believe that bilateral salpingectomy is the most effective sterilization procedure; however, only 7.2% use this method as an interval procedure. More data are needed to evaluate the prophylactic effect of bilateral salpingectomy against postoperative sequelae.

Investigation of factors affecting the efficacy of 3C23K, a human monoclonal antibody targeting MISIIR.

MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients. We selected two high expressing models and two low expressing models for in vivo testing. One xenograft model using an MISIIR over-expressing SKOV3ip cell line (Z3) was a positive control. The primary endpoint was change in tumor size. The secondary endpoint was final tumor mass. We observed no statistically significant differences between control and treated animals. The lack of response could be secondary to a number of variables including the lack of known biomarkers of response, the low membrane expression of MISIIR, and a limited ability of 3C23K to induce ADCC in PDX models. Further study is needed to determine the magnitude of ovarian cancer response to 3C23K and also if there is a threshold surface expression to predict response.

The role of surgery in recurrent endometrial cancer.

INTRODUCTION: Endometrial cancer is a common gynecologic malignancy in the United States, and the recurrence rate depends on the disease stage at diagnosis. Recurrence can affect several areas and follow different patterns. AREAS COVERED: The role of surgery at the time of recurrence is not clearly defined. In this review, we fully describe the current evidence available. In particular, we describe how surgical treatment might be recommended for 1) vaginal or pelvic recurrences; 2) retroperitoneal or localized intra-abdominal recurrence, when a maximal cytoreductive effort is more likely to be successful; or 3) isolated distant recurrences when microscopically tumor-free margins can be achieved. Expert commentary: Cases should be evaluated individually, considering factors such as comorbidities, risks of intervention, and impact of treatment on quality of life.

New-onset congestive heart failure with gemcitabine in ovarian and other solid cancers.

OBJECTIVE: To assess clinical features that may predispose individuals taking gemcitabine to new-onset congestive heart failure. METHODS: A retrospective chart review was conducted with 156 female patients, 51 with ovarian cancer and 105 with breast, lung, pancreas, and bladder cancer, all of whom had received gemcitabine. Patients with new-onset congestive heart failure were compared with patients without new-onset congestive heart failure with the use of Wilcoxon rank-sum test for continuously distributed data and the Fisher exact test for proportions. RESULTS: Seven patients developed new-onset congestive heart failure (4.5%) during their treatment, which was significantly greater than that reported previously (0.76%). Patients with new-onset congestive heart failure did not differ from other patients in the study for age, weight, gravidity, parity, body mass index, and type of cancer. They also did not differ in history of myocardial infarction, hypertension, prior episodes of congestive heart failure, prior treatment with adriamycin, or use of tobacco. However, diabetes mellitus and coronary artery disease were more common, and all patients who developed new-onset congestive heart failure received >17,000 mg/m of gemcitabine. The incidence of new-onset congestive heart failure in this study is significantly higher than previously reported with the use of gemcitabine. CONCLUSIONS: The single-most predictive risk factor for new-onset congestive heart failure in this cohort of patients is the receipt of a minimum dose of 17,000 mg/m. Therefore, additional follow-up may be necessary for all patients receiving >15,000 mg/m of gemcitabine to screen for potential new-onset congestive heart failure.

Simultaneous occurrence of well differentiated papillary mesothelioma and endometrioid ovarian cancer: A case report.

► We present a case of endometrioid ovarian cancer with concomitant well differentiated papillary mesothelioma of the peritoneum. ► Endometrioid ovarian cancer with concomitant well differentiated papillary mesothelioma is an extremely rare surgical finding of uncertain prognostic significance. ► Treatment with carboplatin and gemcitabine was given with no evidence of disease six months after diagnosis.

Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis.

BACKGROUND: Normal adult articular cartilage is thought to be avascular and aneural. OBJECTIVE: To describe neurovascular structures at the osteochondral junction and in osteophytes in tibiofemoral osteoarthritis (OA) displaying a range of severity of cartilage changes. METHODS: Articular surfaces were obtained from 40 patients at total knee joint replacement surgery for tibiofemoral OA (TKR) and seven patients post mortem (PM). Antibodies directed against CD34 (vascular endothelium), protein gene product 9.5 (pan-neuronal marker), substance P and calcitonin gene-related peptide (sensory nerves) and C-flanking peptide of neuropeptide Y (sympathetic nerves) were used to localise blood vessels and nerves by immunohistochemistry. Severity of OA cartilage changes was graded histologically. RESULTS: TKR and PM samples displayed a range of OA cartilage changes including tidemark breaching by vascular channels. Sympathetic and sensory nerves were both present within vascular channels in the articular cartilage, in both mild and severe OA. Perivascular and free nerve fibres, and nerve trunks were observed within the subchondral bone marrow and within the marrow cavities of osteophytes. Sensory and sympathetic nerves displayed similar distributions in each region studied. CONCLUSION: Vascularisation and the associated innervation of articular cartilage may contribute to tibiofemoral pain in OA across a wide range of structural disease severity.