Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

Independent psychometric validation of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24).

The endometrial cancer (EC)-specific Quality of Life module of the European Organization for Research and Treatment of Cancer (EORTC QLQ-EN24), was developed and validated in one study. We independently validated and assessed the psychometric properties of the instrument. Two hundred and eight women with EC before surgery, during adjuvant treatment and follow-up; in three different cancer centres completed the EORTC QLQ-C30 and the EN24. The questionnaire's completion rate was 100%, except sexuality items, that were answered by 35% of patients. All item-scale correlations for the multi-item scales exceeded the .4 criterion and correlated well with their own scale, while correlations with the other scales were low. The internal consistency of all multi-item scales were satisfactory (Cronbach's alpha coefficients ranging from .77 to .97). Discriminance for single-item scales was low. The QLQ-EN24 module discriminated well between clinically different patients, and there were no differences in quality of life questionnaire scales between patients with body mass index ≤30 when compared to those with >30. This validation study supports the reliability, as well as convergent and divergent validity of the EORTC QLQ-EN24. The module is a useful instrument for the assessment of QOL in patients with EC. However, data concerning sexuality should be interpreted with caution.

Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS: This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS: One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION: Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER: NCT00262847.

Viewing the immune checkpoint VISTA: landscape and outcomes across cancers.

BACKGROUND: Optimizing immune checkpoint inhibitor (ICI) therapy may require identification of co-targetable checkpoint pathways via immune profiling. Herein, we analyzed the transcriptomic expression and clinical correlates of V-domain immunoglobulin suppressor of T-cell activation (VISTA), a promising targetable checkpoint. PATIENTS AND METHODS: RNA sequencing was carried out on 514 tissues reflecting diverse advanced/metastatic cancers. Expression of eight immune checkpoint markers [lymphocyte-activation gene 3 (LAG-3), tumor necrosis factor receptor superfamily 14 (TNFRSF14), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), programmed death-ligand 2 (PD-L2), B- and T-lymphocyte attenuator (BTLA), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), cytotoxic T-lymphocyte antigen 4 (CTLA-4)], in addition to VISTA, was analyzed, along with clinical outcomes. RESULTS: High VISTA RNA expression was observed in 32% of tumors (66/514) and was the most common highly expressed checkpoint among the nine assessed. High VISTA expression was independently correlated with high BTLA, TIM-3, and TNFRSF14, and with a diagnosis of pancreatic, small intestine, and stomach cancer. VISTA transcript levels did not correlate with overall survival (OS) from metastatic/advanced disease in the pan-cancer cohort or with immunotherapy outcome (progression-free survival and OS from the start of ICI) in 217 ICI-treated patients. However, in ICI-treated pancreatic cancer patients (n = 16), median OS was significantly shorter (from immunotherapy initiation) for the high- versus not-high-VISTA groups (0.28 versus 1.21 years) (P = 0.047); in contrast, VISTA levels were not correlated with OS in 36 pancreatic cancer patients who did not receive ICI. CONCLUSION: High VISTA expression correlates with high BTLA, TIM-3, and TNFRSF14 checkpoint-related molecules and with poorer post-immunotherapy survival in pancreatic cancer, consistent with prior literature indicating that VISTA is prominently expressed on CD68+ macrophages in pancreatic cancers and requiring validation in larger prospective studies. Immunomic analysis may be important for individualized precision immunotherapy.

New paradigms in the surgical and adjuvant treatment of ovarian cancer.

Advanced stage epithelial ovarian cancer is difficult to treat. Despite advances in surgical resection and adjuvant chemotherapy the majority of patients suffer from disease recurrence. In an effort to improve oncologic outcomes, including progression free and overall survival, novel surgical paradigms and chemotherapeutic techniques have emerged over the past decade. An emphasis has been placed on achieving maximal surgical cytoreduction (defined as no visible residual disease) at completion of surgery, in combination with intra-peritoneal (IP) chemotherapy, as well as hyperthermic IP chemotherapy (HIPEC). This review article will discuss the evolution of surgical cytoreduction in the treatment of advanced stage epithelial ovarian cancer, as well as the development of adjuvant treatments that increasingly utilize the biologic advantage provided by microscopic residual disease.

A retrospective review of the effect of surgeon specialty on the management of 190 benign and malignant pediatric and adolescent adnexal masses.

STUDY OBJECTIVE: To investigate the impact of operating surgeon specialty on rates of ovarian preservation, and to explore differences in surgical management when malignant lesions are identified. DESIGN: Retrospective study. SETTING: Education and research hospitals. PARTICIPANTS: Between January 1, 2003 and January 1, 2009, all female patients ≤ 20 years of age undergoing surgery with pathologically confirmed ovarian or fallopian tube tissues removed were evaluated. INTERVENTIONS: Demographic, operative, and pathologic data were abstracted. MAIN OUTCOME MEASURES: Rates of ovarian preservation with benign lesions, and rates of appropriate surgical staging when malignant lesions were identified. RESULTS: The mean age was 11.9 ± 4.4 years. Malignant lesions were larger than benign masses, 17.3 ± 7.1 cm versus 8.8 ± 7.1 cm respectively (P < .001). Torsion was associated with oophorectomy with a relative risk (RR) of 1.86 and 95% confidence interval (CI) of 1.35-2.57 (P = 0.033). Postmenarchal patients were less likely to undergo ovarian sacrificing procedures (RR 0.62, 95% CI 0.45-0.84, P < .001). The relative risk of incomplete surgical staging with malignant lesions was reduced in the presence of a gynecologic oncologist (RR 0.14, 95% CI 0.02-0.89, P = .003). CONCLUSION: Ovarian conservation should be prioritized in cases with benign lesions, whereas complete and accurate surgical staging is imperative when malignancy is identified.