Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer.

BACKGROUND: Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS: We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS: Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS: In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).

Survival with Cemiplimab in Recurrent Cervical Cancer.

BACKGROUND: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. METHODS: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. RESULTS: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. CONCLUSIONS: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer.

BACKGROUND: Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis. RESULTS: In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively). CONCLUSIONS: Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.).

Ezabenlimab (BI 754091), an anti-PD-1 antibody, in patients with advanced solid tumours.

BACKGROUND: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours. STUDY DESIGN: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1). RESULTS: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days. CONCLUSIONS: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings.

Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the KEYNOTE-826 study, the addition of the anti-PD-1 monoclonal antibody pembrolizumab to chemotherapy with or without bevacizumab improved overall survival and progression-free survival (primary endpoints) versus placebo plus chemotherapy with or without bevacizumab, with manageable toxicity, in patients with persistent, recurrent, or metastatic cervical cancer. In this Article, we report patient-reported outcomes (PROs) from KEYNOTE-826. METHODS: KEYNOTE-826 is a multicentre, randomised, phase 3 trial in 151 cancer treatment centres in 19 countries. Eligible patients were aged 18 years or older with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy (previous radiosensitising chemotherapy was allowed) and not amenable to curative treatment and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) centrally by means of an interactive voice response system in a double-blind manner to receive either pembrolizumab 200 mg or placebo every 3 weeks intravenously for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 plus cisplatin 50 mg/m2 or carboplatin area under the curve 5 mg/mL per min, intravenously) with or without bevacizumab 15 mg/kg every 3 weeks intravenously. Randomisation (block size of 4) was stratified by metastatic disease at diagnosis, planned bevacizumab use, and PD-L1 combined positive score. Patients, investigators, and other study personnel involved in study treatment administration or clinical evaluation of patients were unaware of treatment group assignments. PRO instruments were the EORTC Quality-of-Life-Core 30 (QLQ-C30), the EORTC cervical cancer module (QLQ-CX24), and the EuroQol-5 dimension-5 level (EQ-5D-5L) visual analogue scale, each collected before treatment at cycles 1-14 and every other cycle thereafter. Primary endpoints were overall survival and progression-free survival per RECIST version 1.1 by investigator review. Change from baseline in QLQ-C30 global health status (GHS)-quality of life (QoL) was a prespecified secondary endpoint and was assessed in the PRO full analysis population (all patients who received at least one dose of study treatment and completed at least one post-baseline PRO assessment). Other PRO analyses were protocol-specified exploratory endpoints. The study is registered with ClinicalTrials.gov, NCT03635567, and is ongoing. FINDINGS: Between Nov 20, 2018, and Jan 31, 2020, of 883 patients screened, 617 were randomly assigned (pembrolizumab group, n=308; placebo group, n=309). 587 (95%) of 617 patients received at least one dose of study treatment and completed at least one post-baseline PRO assessment and were therefore included in the PRO analyses (pembrolizumab group, n=290; placebo group, n=297). Median follow-up was 22·0 months (IQR 19·1-24·4). At week 30, QLQ-C30 completion was 199 (69%) of 290 patients in the pembrolizumab group and 168 (57%) of 297 patients in the placebo group; compliance was 199 (94%) of 211 and 168 (90%) of 186, respectively. The least squares mean change in QLQ-C30 GHS-QoL score from baseline to week 30 was -0·3 points (95% CI -3·1 to 2·6) in the pembrolizumab group and -1·3 points (-4·2 to 1·7) in the placebo group, with a between-group difference in least squares mean change of 1·0 point (95% CI -2·7 to 4·7). Median time to true deterioration in GHS-QoL was not reached (NR; 95% CI 13·4 months-NR) in the pembrolizumab group and 12·9 months (6·6-NR) in the placebo group (hazard ratio 0·84 [95% CI 0·65-1·09]). 122 (42%) of 290 patients in the pembrolizumab group versus 85 (29%) of 297 in the placebo group had improved GHS-QoL at any time during the study (p=0·0003). INTERPRETATION: Addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect health-related quality of life. Along with the efficacy and safety results already reported from KEYNOTE-826, these data support the benefit of pembrolizumab and the value of immunotherapy in patients with recurrent, persistent, or metastatic cervical cancer. FUNDING: Merck Sharp & Dohme.

Grade and Estrogen Receptor Expression Identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at a Very Low Risk of Disease-Specific Death.

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC.

Surgical margin status in relation to surgical approach in the management of early-stage cervical Cancer: A Canadian cervical Cancer collaborative (4C) study.

OBJECTIVE: Surgical margin status in women undergoing surgery for early-stage cervical cancer is an important prognostic factor. We sought to determine whether close (<3 mm) and positive surgical margins are associated with surgical approach and survival. METHODS: This is a national retrospective cohort study of cervical cancer patients treated with radical hysterectomy. Patients with stage IA1/LVSI-Ib2(FIGO 2018) with lesions up to 4 cm at 11 Canadian institutions from 2007 to 2019 were included. Surgical approach included robotic/laparoscopic (LRH), abdominal (ARH) or combined laparoscopic-assisted vaginal/vaginal (LVRH) radical hysterectomy. Recurrence free survival(RFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Chi-square and log-rank tests were used to compare groups. RESULTS: 956 patients met inclusion criteria. Surgical margins were as follows: negative (87.0%), positive (0.4%) or close <3 mm (6.8%), missing (5.8%). Most patients had squamous histology (46.9%); 34.6% had adenocarcinomas and 11.3% adenosquamous. Most were stage IB (75.1%) and 24.9% were IA. Mode of surgery included: LRH(51.8%), ARH (39.2%), LVRH (8.9%). Predictive factors for close/positive margins included stage, tumour diameter, vaginal involvement and parametrial extension. Surgical approach was not associated with margin status (p = 0.27). Close/positive margins were associated with a higher risk of death on univariate analysis (HR = non calculable for positive and HR = 1.83 for close margins, p = 0.017), but not significant for OS when adjusted for stage, histology, surgical approach and adjuvant treatment. There were 7 recurrences in patients with close margins (10.3%, p = 0.25). 71.5% with positive/close margins received adjuvant treatment. In addition, MIS was associated with a higher risk of death (OR = 2.39, p = 0.029). CONCLUSION: Surgical approach was not associated to close or positive margins. Close surgical margins were associated with a higher risk of death. MIS was associated with worse survival, suggesting that margin status may not be the driver of worse survival in these cases.

Molecular subtype stratified outcomes according to adjuvant therapy in endometrial cancer.

OBJECTIVES: Recent data support the predictive implications of molecular subtype assignment in endometrial cancer (EC). Our objective was to retrospectively assess clinical outcomes according to adjuvant treatment received within EC molecular subtypes. METHODS: Clinical outcomes (disease-specific and progression-free survival DSS/PFS) of EC patients from a single institution and population-based cohorts that had undergone molecular classification were assessed with respect to adjuvant therapy received and 2016 ESMO risk group. RESULTS: 2472 ECs were assessed; 184 (7.4%) POLEmut, 638 (25.8%) MMRd, 1223 (49.5%) NSMP and 427 (17.3%) p53abn. N = 774 (34.6%) of the cohort were ESMO 2016 high risk and 109 (4.8%) were advanced or metastatic. In patients with MMRd EC, assessed across and within stage, there was no observed benefit in DSS or PFS with the addition of chemotherapy +/- radiation compared to radiation alone in ESMO high risk (p = 0.694) or ESMO high, advanced, metastatic risk groups combined (p = 0.852). In patients with p53abn EC, adjuvant chemotherapy given with radiation was associated with significantly longer DSS compared to radiation alone in ESMO high risk (p = 0.007) and ESMO high, advanced and metastatic risk groups combined (p = 0.015), even when restricted to stage I disease (p < 0.001) and when compared in serous vs. non-serous histotypes (p = 0.009). CONCLUSIONS: Adjuvant chemotherapy is associated with more favorable outcomes for patients with p53abn EC, including stage I disease and non-serous histotypes, but does not appear to add benefit within MMRd ECs for any stage of disease, consistent with PORTEC-3 molecular subanalysis. Prospective trials, assessing treatment efficacy within molecular subtype are needed, however these 'real-world' data should be considered when discussing adjuvant treatment with patients.

A plain language summary of results from the GARNET study of dostarlimab in patients with endometrial cancer.

WHAT IS THIS SUMMARY ABOUT?: Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study. WHAT WERE THE RESULTS?: The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects. WHAT DO THE RESULTS MEAN?: The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients.

Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification.

OBJECTIVES: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. METHODS: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. RESULTS: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). CONCLUSION: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

A prospective comparison of costs between robotics, laparoscopy, and laparotomy in endometrial cancer among women with Class III obesity or higher.

BACKGROUND AND OBJECTIVES: To compare the immediate operating room (OR), inpatient, and overall costs between three surgical modalities among women with endometrial cancer (EC) and Class III obesity or higher. METHODS: A multicentre prospective observational study examined outcomes of women, with early stage EC, treated surgically. Resource use was collected for OR costs including OR time, equipment, and inpatient costs. Median OR, inpatient, and overall costs across surgical modalities were analyzed using an Independent-Samples Kruskal-Wallis Test among patients with BMI ≥ 40. RESULTS: Out of 520 women, 103 had a BMI ≥ 40. Among women with BMI ≥ 40: median OR costs were $4197.02 for laparotomy, $5524.63 for non-robotic assisted laparoscopy, and $7225.16 for robotic-assisted laparoscopy (p < 0.001) and median inpatient costs were $5584.28 for laparotomy, $3042.07 for non-robotic assisted laparoscopy, and $1794.51 for robotic-assisted laparoscopy (p < 0.001). There were no statistically significant differences in the median overall costs: $10 291.50 for laparotomy, $8412.63 for non-robotic assisted laparoscopy, and $9002.48 for robotic-assisted laparoscopy (p = 0.185). CONCLUSION: There was no difference in overall costs between the three surgical modalities in patient with BMI ≥ 40. Given the similar costs, any form of minimally invasive surgery should be promoted in this population.

Oncologic outcomes in the era of modern radiation therapy using FIGO 2018 staging system for cervical cancer.

BACKGROUND: The recently published ASTRO cervical cancer guidelines recommend the use of modern radiotherapy. Imaging is now incorporated in the updated FIGO 2018 staging with a new stage IIIC. This study aims to evaluate the oncologic outcomes and predictors of survival using FIGO 2018 staging in a cohort of patients treated in an era of high-precision image-guided radiotherapy. METHODS: We performed a retrospective cohort study of 216 adult cervical cancer patients treated with definitive chemoradiotherapy between 2010 and 2018. Eligible patients had non-metastatic cervical cancer treated at a single academic institution. All patients had pre-treatment MRI and CT/PET. Treatment protocol consisted of external beam intensity-modulated radiotherapy and 3D image-guided brachytherapy. Kaplan-Meier curves were used for survival analysis. Multivariate cox proportional-hazards model was performed to identify potential prognostic factors. RESULTS: Median age at diagnosis was 50 and median BMI was 26.4 kg/m2. Median follow-up time was 44.3 months. Five-year overall survival (OS), disease-free survival and loco-regional disease-free survival rates were 76.8%, 68.5% and 82.6%, respectively. FIGO 2018 showed better OS discrimination compared to FIGO 2009 classification. OS was increasingly worse with positive pelvic and para-aortic nodes (p < 0.001). In a multivariate prediction model, performance status (p = 0.044) and FIGO 2018 classification (stage III p = 0.016; stage IVA p = 0.010) were predictors of mortality; FIGO 2018 classification (stage III p = 0.003; stage IVA p = 0.001) was a predictor of any recurrence; MRI tumor diameter (p ≤ 0.001) and nodal metastases (p = 0.024) were predictors of loco-regional recurrence. CONCLUSIONS: Integration of state-of-the-art imaging in cervical cancer staging and in radiotherapy planning leads to good loco-regional control rates, however distant recurrence remains an important issue. FIGO 2018 staging better reflects patient prognosis, highlighting the need for new treatment strategies for stage IIIC cervical cancer.

Factors associated with an increased risk of recurrence in patients diagnosed with high-grade endometrial cancer undergoing minimally invasive surgery: A study of the society of gynecologic oncology of Canada (GOC) community of practice (CoP).

BACKGROUND: Minimally invasive surgery (MIS) is a standard surgical approach for comprehensive surgical staging in women with endometrial cancer. As rates and complexity of MIS are steadily increasing, it is important to identify potential risk factors which may be associated with this approach. This study evaluates the impact of local factors on the risk of disease recurrence. METHODS: A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) who underwent MIS between 2012 and 2016 at eight Canadian centers. Data was collected from medical records. The 75th percentile was calculated for estimated uterine volume and weight. All recurrences were categorized into two groups; intra-abdominal vs. extra-abdominal. To search for significant covariates associated with recurrence-free survival a Cox proportional hazard model was performed. RESULTS: A total of 758 patients were included in the study. Intra-uterine manipulator was used in 497 (35.8%) of patients. Vaginal lacerations were documented in 9.1%. Median follow-up was 30.5 months (interquartile range 20-47). There were 157 who had disease recurrence (20.71%), including 92 (12.14%) intra-abdominal and 60 (7.92%) extra-abdominal only recurrences. In univariate analysis myometrial invasion, LVI, stage, uterine volume and weight > 75th percentile and chemotherapy were associated with increased risk of intra-abdominal recurrence. In multivariable analysis only stage, and specimen weight > 75th percentile (OR 2.207, CI 1.123-4.337) remained significant. Uterine volume, and weight were not associated with increased risk of extra-abdominal recurrences. CONCLUSION: For patients diagnosed with HGEC undergoing MIS, extracting a large uterus is associated with a significantly increased risk for intra-abdominal recurrence.

Clinical activity and safety of the anti-PD-1 monoclonal antibody dostarlimab for patients with recurrent or advanced dMMR endometrial cancer.

This document provides a short summary of the GARNET trial which was published in JAMA Oncology in October 2020. At the end of this document, there are links to websites where you can find more information about this study. The trial enrolled adult participants with advanced solid tumors. This report is restricted to patients with a particular type of endometrial cancer that has a deficient mismatch repair (dMMR) status. Patients received a trial treatment called dostarlimab (also known by the brand name Jemperli). In the US, dostarlimab is approved as a single therapy in adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after platinum-based chemotherapy. In the EU, dostarlimab is approved as a single therapy in adult patients with recurrent or advanced dMMR/microsatellite instability-high (MSI-H) endometrial cancer that has progressed on or after treatment with a platinum-containing regimen. The GARNET trial looked at dostarlimab given intravenously to patients with dMMR endometrial cancer from 7 countries. The trial showed that dostarlimab was successful in shrinking the tumor in 42% of these patients. In general, the percentage of participants who experienced medical problems (referred to as side effects) was low and within expectations for this type of treatment. ClinicalTrials.gov NCT number: NCT02715284. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here.

Effect of mannitol on acute kidney injury induced by cisplatin.

PURPOSE: Acute kidney injury (AKI) is a frequent dose-limiting toxicity induced by cisplatin. Mannitol has been used in hydration protocols to mitigate this adverse event but its role remains controversial. The aim of this study is to define the impact of mannitol on AKI in patients receiving cisplatin. METHODS: This retrospective observational study was conducted in cancer patients who received at least one dose of cisplatin between September 2010 and December 2016 at the Centre hospitalier de l'Université de Montréal. The primary outcome of this study was the comparison of all grade cisplatin-associated AKI between hydration protocols with or without mannitol. RESULTS: A total of 1821 patients were included of which 658 received mannitol whilst 1163 received hydration alone. The risk of all grade cisplatin-associated AKI was significantly lower for the mannitol group (Hazard Ratio (HR) = 0.62; 95% CI [0.42, 0.89]). This result was mainly driven by gynecologic (HR = 0.50), upper gastrointestinal (HR = 0.32), urinary tract malignancies (HR = 0.29) and lymphoma (HR = 0.33). No significant difference was seen for head and neck (HN), lung, germ cells and other cancers. However, HN cancers patients receiving mannitol had fewer grade 2 and 3 AKI. Significantly fewer AKI events were observed in HN, lung, upper gastrointestinal and urinary tract cancer when mannitol was added for cisplatin dose <75 mg/m2. CONCLUSION: Although the results were generally driven by a decrease of grade 1 AKI for most cancers, the greatest benefit of mannitol was seen with cisplatin doses lower than 75 mg/m2 and should probably be reinstated in this setting.

Neoadjuvant radiotherapy and brachytherapy in endometrial cancer with gross cervical involvement: a CHIRENDO research group study.

BACKGROUND: Historically, radical hysterectomy followed by adjuvant radiotherapy has been offered to patients with endometrial cancer who have gross cervical involvement; however, this approach is known to carry considerable morbidity. Neoadjuvant radiotherapy followed by extra-fascial hysterectomy has been proposed as an alternative treatment but has been poorly studied to date. OBJECTIVE: To evaluate the locoregional control rate associated with neoadjuvant radiotherapy followed by extra-fascial hysterectomy. METHODS: A retrospective cohort study of 30 patients with endometrial cancer with gross cervical involvement treated between May 2006 and January 2016 was performed. Eligible patients were those aged >18 years with non-metastatic endometrial adenocarcinoma and gross cervical disease treated with curative intent at the Centre hospitalier de l'Université de Montréal. Treatment protocol consisted of pelvic neoadjuvant radiotherapy and high-dose rate brachytherapy followed by extra-fascial hysterectomy. Kaplan-Meier curves were used for survival analysis. RESULTS: The median age was 60 (range 37-82) and median body mass index was 32 kg/m2 (range 16-55). Twenty-four (80%) patients were diagnosed with a positive cervical/endocervical biopsy. Clinical staging confirmed 36.7% (n=11) as stage II, 20% (n=6) stage IIIB, 30% (n=9) stage IIIC1, and 13.3% (n=4) stage IIIC2. Seventy-seven per cent (n=23) of patients had an endometrioid histology. Locally advanced disease was identified by imaging alone in six patients. Rates of parametrial, adnexal, vaginal, and nodal invasion were 10% (n=3), 6.7% (n=2), 13.3% (n=4), and 43.3% (n=13) at diagnosis, respectively. All patients completed pelvic radiotherapy (13.3% extended field) and 90% received brachytherapy. Twenty per cent (n=6) of surgeries were performed using minimal invasive technique. On surgical specimen, 63.3% (n=19) had complete cervical response, 90% (n=27) had negative margins, and 10% (n=3) had residual nodal involvement. Median follow-up time was 62 months (range 1-120). Six recurrences were identified; all except one involved distant failure, and two with locoregional failure. Five-year locoregional control rate, disease-free, overall, and disease-specific survival were 90.5%, 78.5%, 92.6%, and 96.2%, respectively. Two patients (6.7%) had grade 3+ acute radiation-related complications (all grade 3). Grade 3+ post-operative morbidity was noted in 2 (6.7%) patients. CONCLUSIONS: Neoadjuvant radiotherapy followed by extra-fascial hysterectomy offers good locoregional control with low treatment-related morbidity in patients with endometrial cancer with overt cervical involvement.

Green versus blue: Randomized controlled trial comparing indocyanine green with methylene blue for sentinel lymph node detection in endometrial cancer.

OBJECTIVE: To ascertain the increase in detection rate of sentinel lymph node (SLN) associated with the use of indocyanine green (ICG) in comparison with methylene blue dye in women with endometrial cancer. METHODS: For this randomized controlled trial, all patients underwent SLN mapping after injection of blue dye on one side of the cervix and ICG on the other side. Randomization was for the side (right vs. left) on which ICG was used so that each patient's contralateral hemipelvis (HP) served as a control to her ipsilateral HP. We performed a two-tailed, normal-approximate McNemar test for paired-matched data. The primary endpoint was the difference in SLN detection rate for each HP according to the dye used. RESULTS: This trial included 132 patients, and 46 patients underwent robotic-assisted surgery while 86 had standard laparoscopic surgery. Successful detection of SLN was 90.9% using ICG and 64.4% using blue dye (p < 0.0001). There were no differences in the duration of the SLN procedure (median 10 min per HP) and number of SLN per HP (mean 1.2) according to the dye used. The SLN detection rates for either dye were very similar whether the surgical approach was robotic (mean BMI 45) or laparoscopic (mean BMI 29). Crossover of dye to the contralateral HP was present in 3% of cases. CONCLUSION: The use of ICG instead of blue dye results in a 26.5% (95% CI 17.4%-35.6%) increase of SLN detection rates per HP in women with endometrial cancer.

Prospective cohort study comparing quality of life and sexual health outcomes between women undergoing robotic, laparoscopic and open surgery for endometrial cancer.

OBJECTIVE: To evaluate patient-reported outcomes (PROs) between women treated by laparoscopic, robotic and open approaches for endometrial cancer. METHODS: Prospective cohort study comparing PRO at baseline, short- (1 and 3 weeks) and long-term (12 and 24 weeks) follow-up postoperatively. Quality of life (QOL) measures were the Functional Assessment of Cancer Therapy (FACT-G), EuroQol Five Dimensions (EQ-5D), and Brief Pain Inventory (BPI). Sexual health measures were the Female Sexual Function Index (FSFI) and the Sexual Adjustment and Body Image Scale for Gynecologic Cancer (SABIS-G). RESULTS: 468 eligible patients (laparotomy = 92, laparoscopy = 152, robotic = 224) were recruited. There were no significant differences between the laparoscopy and robotic groups for any PRO (P > 0.05). At short-term follow-up, patients who underwent minimally invasive surgery (robotic or laparoscopy) had significantly higher FACT-G (P < 0.0001) and EQ-5D (P < 0.0001) scores, with less pain (P = 0.02) and improved pain interference (P = 0.0008), than patients undergoing laparotomy. At long-term follow-up, there were sustained improvements in the FACT-G (P = 0.035) and the health state EQ-5D visual analogue scale (P = 0.022). Surgical approach had no impact on sexual health (P > 0.05); however the mean FSFI score for the entire cohort met clinical cut-offs for sexual dysfunction. CONCLUSION: Minimally invasive approaches result in improved QOL beyond the short-term postoperative period, with benefits noted up to 12 weeks after surgery. This prolonged QOL advantage provides further evidence that MIS should be the standard surgical approach for women with early stage endometrial cancer.