Relationship between frailty and nutrition: Refining predictors of mortality after primary cytoreductive surgery for ovarian cancer.

OBJECTIVE: We aimed to examine the interplay between frailty and nutritional status on 90-day mortality after primary cytoreductive surgery (PCS) for ovarian cancer (OC). METHODS: Patients with OC who underwent PCS from 1/2/2006-4/30/2018 at a single institution were identified. Frailty index (FI) includes 30 items and is calculated summing across all the item scores and dividing by the total; frailty was defined as FI ≥0.15. Nutritional status was considered impaired when preoperative serum albumin was <3.5 g/dL. Logistic regression was used to analyze the association between FI (continuous) and albumin status (binary) and 90-day postoperative mortality. RESULTS: A total of 533 patients (mean age, 64.4 years) were included, the majority were stage IIIC disease and serous histology. Albumin was <3.5 g/dL in 87 patients (16.3%) and 113 patients (21.2%) were considered frail. Median FI was 0.07 (IQR 0.03, 0.13). Postoperative 90-day mortality occurred in 24 patients (4.5%). Mortality within 90 days was higher amongst patients with low albumin (12/87, 13.8%), regardless of frailty status (13.8% [9/65] non-frail and 13.6% [3/22] frail patients). Ninety-day mortality in patients with normal albumin (n = 446) was over twice as likely in frail versus non-frail patients (5.5% [5/91] vs. 2.0% [7/355], respectively, p = 0.08). A model to assess 90-day mortality that included both FI and low albumin significantly improved the overall discrimination compared to low albumin alone (AUC 0.76 vs. 0.68 p = 0.03). CONCLUSION: Our findings suggest that frailty and nutrition are both related to 90-day mortality. Preoperative interventions to improve functional and nutritional characteristics are needed.

Evaluating nutrition in advanced ovarian cancer: which biomarker works best?

BACKGROUND: Advanced epithelial ovarian cancer (OC) patients often present with malnutrition; however, the ideal nutritional evaluation tool is unclear. We aimed to evaluate the role of preoperative albumin, Prognostic Nutritional Index [PNI], neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR] as independent predictors of severe postoperative complications and 90-day mortality in OC patients who underwent primary cytoreductive surgery to identify the ideal tool. METHODS: OC patients who underwent surgery at Mayo Clinic (2003-2018) were included; biomarkers were retrospectively retrieved and established cut-offs were utilized. Outcomes included severe complications (Accordion grade ≥ 3) and 90-day mortality. Univariate and multivariable logistic regression models were performed. Biomarkers were evaluated in separate models adjusted for age and American Society of Anesthesiologists (ASA) score for 90-day mortality, and adjusted for age, ASA score, stage, and surgical complexity for severe complications. RESULTS: Albumin <3.5 g/dL, PNI < 45, NLR > 6 and PLR ≥ 200 were univariately associated with 90-day mortality (all p < 0.05) in 627 patients that met inclusion criteria. Each marker remained significant in adjusted models with albumin having the highest OR: 6.04 [95% CI:2.80-13.03] and AUC (0.83). Univariately, PNI <45, NLR >6, and PLR ≥200 were significant predictors of severe complications(all p < 0.05), however failed to reach significance in adjusted models. Albumin was not associated with severe complications. CONCLUSION: All biomarkers were associated with 90-day mortality in adjusted models, with albumin being the easiest predictor to attain clinically; none with severe complications. Future research should focus less on methods of nutritional assessment and more on strategies to improve nutrition during OC tumor-directed therapy.

Defining success after surgical treatment of stress urinary incontinence.

BACKGROUND: A consensus standardized definition of success after stress urinary incontinence surgical treatment is lacking, which precludes comparisons between studies and affects patient counseling. OBJECTIVE: This study aimed to identify optimal patient-centric definition(s) of success after stress urinary incontinence surgical treatment and to compare the identified "more accurate" treatment success definitions with a commonly used composite definition of success (ie, no reported urine leakage, negative cough stress test result, and no retreatment). STUDY DESIGN: We evaluated 51 distinct treatment success definitions for participants enrolled in a previously conducted randomized trial of stress urinary incontinence treatments concomitantly performed with sacrocolpopexy (NCT00934999). For each treatment success definition, we calculated the mean (SD) of participant-assessed symptom improvement and participant-assessed surgical success scores with an 11-point Likert scale among those achieving success and failure. The "more accurate" treatment success definition(s) were identified by measuring the magnitude of the mean difference of participant assessments with Hedges g values. The treatment success definitions with the highest Hedges g values were considered "more accurate" treatment success definitions and were then compared with the composite definition of success. RESULTS: The percentage of participants who had treatment success (6.4% to 97.3%) and Hedges g values (-4.85 to 1.25) varied greatly according to each treatment success definition. An International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score ≤5, Urogenital Distress Inventory-6 score ≤33.3, and a no/mild stress urinary incontinence response on Urogenital Distress Inventory-6 question 3 had the highest Hedges g values and were considered the top 3 "more accurate" treatment success definitions. Paradoxically, treatment success definitions that required a negative cough stress test result or no persistent urinary leakage greatly reduced the ability to differentiate between participant-assessed symptom improvement and surgical success. When the "more accurate" treatment success definitions were compared with the composite definition, patients with failed treatment according to the composite definition had lower Urinary Impact Questionnaire-7 scores and a higher proportion of survey responses indicating complete satisfaction or some level of satisfaction and very good/perfect bladder condition. In addition, the composite definition had considerably fewer favorable outcomes for participants than did the top 3 "more accurate" treatment success definitions. CONCLUSION: Successful outcomes of stress urinary incontinence surgical treatments for women undergoing concurrent sacrocolpopexy varied greatly depending on the definition used. However, stringent definitions (requiring complete dryness) and objective testing (negative cough stress test result) had decreased, rather than increased, participant-assessed symptom improvement and surgical success scores. The "more accurate" treatment success definitions better differentiated between participant-assessed symptom improvement and surgical success than the composite definition. The composite definition disproportionately misidentified participants who reported minor symptoms or complete/partial satisfaction with their outcome as having treatment failures and yielded a considerably lower proportion of women who reported favorable outcomes than did the top 3 "more accurate" treatment success definitions.

Incidence of venous thromboembolism in patients with advanced stage ovarian cancer undergoing neoadjuvant chemotherapy: Is it time for thromboprophylaxis?

OBJECTIVES: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment. METHODS: This retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution. Risk factors were compared between patients with versus without VTE between EOC diagnosis and 180 days after ICS. Bleeding complications were compared between patient who received a DOAC versus non-DOAC. RESULTS: VTE cases occurred amongst 33 of the 154 (21.4%) patients with 4 (2.6%) concurrent with EOC diagnosis, 9 (5.8%) between EOC diagnosis and NACT start, 13 (8.4%) between NACT start and ICS, and 7 (4.5%) within 180 days after ICS. There were no statistically significant differences in risk factors assessed (age, body mass index, functional status, histology, Khorana score, and smoking history) between patients with versus without VTE. Eleven patients (33.3%) received a DOAC for VTE treatment. There were no significant differences in number of intraoperative blood transfusions (p = 0.38), blood loss (p = 0.95), or bleeding complications (p = 0.53) between patients treated with a DOAC versus a non-DOAC. CONCLUSION: There is a high incidence of VTE events (21.4%) in patients with advanced stage EOC undergoing NACT. Two-thirds of the VTEs may have been prevented with thromboprophylaxis as they occurred between EOC diagnosis and ICS. These data support consideration of thromboprophylaxis in all patients with advanced stage EOC undergoing NACT.

Mohs surgery for female genital Paget's disease: a prospective observational trial.

BACKGROUND: Extramammary Paget's disease recurs often after traditional surgical excision. Margin-controlled surgery improves the recurrence rate for male genital disease but is less studied for female anatomy. OBJECTIVE: This study aimed to compare surgical and oncologic outcomes of margin-controlled surgery vs traditional surgical excision for female genital Paget's disease. STUDY DESIGN: We conducted a prospective observational trial of patients with vulvar or perianal Paget's disease treated with surgical excision guided by Mohs micrographic surgery between 2018 and 2022. The multidisciplinary protocol consisted of office-based scouting biopsies and modified Mohs surgery followed by surgical excision with wound closure under general anesthesia. Modified Mohs surgery cleared peripheral disease margins using a moat technique with cytokeratin 7 staining. Medial disease margins (the clitoris, urethra, vagina, and anus) were assessed using a hybrid of Mohs surgery and intraoperative frozen sections. Surgical and oncologic outcomes were compared with the outcomes of a retrospective cohort of patients who underwent traditional surgical excision. The primary outcome was 3-year recurrence-free survival. RESULTS: Three-year recurrence-free survival was 93.3% for Mohs-guided excision (n=24; 95% confidence interval, 81.5%-100.0%) compared to 65.9% for traditional excision (n=63; 95% confidence interval, 54.2%-80.0%) (P=.04). The maximum diameter of the excisional specimen was similar between groups (median, 11.3 vs 9.5 cm; P=.17), but complex reconstructive procedures were more common with the Mohs-guided approach (66.7% vs 30.2%; P<.01). Peripheral margin clearance was universally achieved with modified Mohs surgery, but positive medial margins were noted in 9 patients. Reasons included intentional organ sparing and poor performance of intraoperative hematoxylin and eosin frozen sections without cytokeratin 7. Grade 3 or higher postoperative complications were rare (0.0% for Mohs-guided excision vs 2.4% for traditional excision; P=.99). CONCLUSION: Margin control with modified Mohs surgery significantly improved short-term recurrence-free survival after surgical excision for female genital Paget's disease. Use on medial anatomic structures (the clitoris, urethra, vagina, and anus) is challenging, and further optimization is needed for margin control in these areas. Mohs-guided surgical excision requires specialized, collaborative care and may be best accomplished at designated referral centers.

Not all stage I and II endometrial cancers are created equal: Recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy alone in all subgroups of early-stage high-intermediate and high-risk endometrial cancer.

OBJECTIVE: To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC). METHODS: We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors. RESULTS: Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology. CONCLUSIONS: Observation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.

Appropriate triage allows aggressive primary debulking surgery with rates of morbidity and mortality comparable to interval surgery after chemotherapy.

OBJECTIVE: Morbidity and mortality (M/M) after primary debulking surgery (PDS) is often cited as a rationale for neoadjuvant chemotherapy and interval debulking surgery (IDS). We tested if using an evidence-based algorithm to identify patients fit for surgery would reduce M/M after PDS to that seen after IDS. METHODS: We included women who underwent PDS or IDS for advanced epithelial ovarian cancer (EOC) (1/2012-7/2016) guided by the use of a prospective triage algorithm. Outcomes were compared after applying inverse-probability of treatment weighting (IPTW) to adjust for covariate imbalance. RESULTS: Of 334 included patients, 232 (69.5%) underwent PDS and 102 (30.5%) were triaged to IDS. Relative to IDS group, PDS patients were younger (63.9 vs 67.5 years, P=0.01), were less likely to have low albumin (16.8% vs. 32.4%, P<0.001), had longer median operative times (315 vs 263 min, P <0.001), more high complexity surgeries and fewer low complexity surgeries (27.2% vs. 11.8% and 18.5% vs 36.3% respectively, P<0.001). The rates of the following outcomes were comparable for PDS and IDS, respectively: successful cytoreduction (complete, 62.5% vs 66.7%, P=0.47 and optimal, 95.3% vs 98.0%, P=0.36), 30-day grade 3+ complications (IPTW-adjusted 18.3% vs. 12.9%, P=0.22), 90-day mortality (IPTW-adjusted, 2.2% vs. 3.8%, P=0.42), length of hospitalization (P=0.29), and postoperative chemotherapy delivery (P=0.83). 3-year overall survival was higher for PDS group (IPTW-adjusted 64.1% vs. 42.6%, P=0.001). CONCLUSIONS: Use of our validated triage strategy allowed us to offer 70% of women with advanced EOC PDS surgery. Despite more complex surgery, M/M after this approach is low and comparable to IDS, with similar rates of complete resection and superior OS. Use of a validated triage system should be utilized when considering PDS vs neoadjuvant chemotherapy.

PP2A and E3 ubiquitin ligase deficiencies: Seminal biological drivers in endometrial cancer.

OBJECTIVE: PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes. METHODS: After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene-specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated. RESULTS: A PIK3CA, PTEN, or PIK3R1 mutant (-mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P = .10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53-mu and CIP2A expression (P < .001) but was not associated with PFS (P = .24). PIK3CA expression was significantly different between those with CIP2A-H and CIP2A low (-L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P < .01). CIP2A-H or PPP2R1A-mu mitigates PP2A kinase dephosphorylation, and FBXW7-mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A-H and PPP2R1A-mu (PP2A impairment) and FBXW7-mu (E3UL impairment) were associated with compromised PFS (P < .001) and were prognostically discriminatory for PIK3CA-mu and PIK3CA CNV-H tumors (P < .001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%). CONCLUSION: PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA-mu, PTEN-mu, and PIK3R1-mu and PIK3CA CNV.

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

OBJECTIVE: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded. RESULTS: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months). CONCLUSIONS: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

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.

Adjuvant chemotherapy in early-stage endometrioid endometrial cancer with >50% myometrial invasion and negative lymph nodes.

OBJECTIVE: The role of adjuvant chemotherapy as an addition or alternative to radiotherapy for early-stage high-risk endometrioid endometrial cancer is controversial. This study aimed to investigate the role of adjuvant chemotherapy in early-stage high-risk endometrioid endometrial cancer. METHODS: We identified patients with stage I or II endometrioid grade 2 or 3 endometrial cancer with myometrial invasion >50% and negative lymph nodes after pelvic with or without para-aortic lymphadenectomy at four institutions (USA and Italy). Associations between chemotherapy and cause-specific and recurrence-free survival were assessed with Cox proportional hazards models. Hematogenous, peritoneal, and lymphatic recurrences were defined as 'non-vaginal'. RESULTS: We identified 329 patients of mean (SD) age 66.4 (9.8) years. The median follow-up among those alive was 84 (IQR 44-133) months. The 5-year cause-specific survival was 86.1% (95% CI 82.0% to 90.4%) and the 5-year recurrence-free survival was 82.2% (95% CI 77.9% to 86.8%). Stage II (vs stage IB) was associated with poorer cause-specific and recurrence-free survival. A total of 58 (90.6%) of 64 patients who had chemotherapy had 4-6 cycles of platinum-based regimen. In adjusted analysis, we did not observe a statistically significant improvement in cause-specific survival (HR 0.34; 95% CI 0.11 to 1.03; p=0.06) or non-vaginal recurrence-free survival (HR 0.36; 95% CI 0.12 to 1.08; p=0.07) with adjuvant chemotherapy. Sixteen of 18 lymphatic recurrences (88.9%; 3/5 pelvic, all 13 para-aortic) were observed in the 265 patients who did not receive adjuvant chemotherapy. Among stage II patients, no deaths (100% 5-year recurrence-free survival) were observed in the eight patients who received adjuvant chemotherapy compared with 66% 5-year recurrence-free survival in the 34 patients who did not. CONCLUSION: Although we observed that adjuvant chemotherapy was associated with improved oncologic outcomes in early-stage high-risk endometrioid endometrial cancer, the associations did not meet conventional levels of statistical significance. Further research is warranted in this relatively uncommon subgroup of patients.

Frailty is a determinant of suboptimal chemotherapy in women with advanced ovarian cancer.

OBJECTIVE: To evaluate the relationship between frailty and chemotherapy delivery among women with epithelial ovarian cancer (EOC). METHODS: We included women who underwent primary debulking surgery (PDS) for stage IIIC/IV EOC between 1/2/2003 and 12/30/2011, received adjuvant chemotherapy at our institution, and had data available to calculate a frailty deficit index. Frailty was defined as a frailty deficit index ≥0.15. Relative dose intensity (RDI) of chemotherapy was calculated as the percentage of the standard dose that was administered, and compared between frail and non-frail using the Wilcoxon rank-sum test. RESULTS: Failure to receive chemotherapy following PDS was twice as common among frail vs. non-frail women (26.7% vs 14.2%, p = 0.001). Of the 169 women who received chemotherapy at our institution, 17.2% (29/169) were frail. Frail women were older (mean, 67.9 vs 62.3 years, p = 0.01), had higher BMI (mean, 29.6 vs 25.7 kg/m2, p = 0.003), and were less likely to complete 6 cycles of chemotherapy (75.9 vs. 93.6%, p = 0.008). Using an RDI cutoff of 85%, frail women were less likely to have adequate doses of carboplatin (15.8 vs. 66.2%, p < 0.001) and paclitaxel (57.9 vs. 80.5%, p = 0.07) despite no differences in dose delays (34.5 vs. 42.1%), dose reductions (65.5 vs. 68.6%), and severe neutropenia (44.8 vs. 39.3%). After adjusting for age, frailty was associated with shorter progression-free (HR 1.58, 95% CI: 0.99-2.50) and overall survival (HR 2.14, 95% CI: 1.35-3.41). CONCLUSION: Frail women with EOC were less likely to receive chemotherapy or the optimal dose of chemotherapy after PDS despite no evidence of treatment-related toxicity. Frail EOC patients demonstrated shorter progression-free and overall survival. Further studies are needed to explore the association between frailty, chemotherapy, and survival.

Multicenter study comparing oncologic outcomes after lymph node assessment via a sentinel lymph node algorithm versus comprehensive pelvic and paraaortic lymphadenectomy in patients with serous and clear cell endometrial carcinoma.

OBJECTIVES: To compare survival after nodal assessment using a sentinel lymph node (SLN) algorithm versus comprehensive pelvic and paraaortic lymphadenectomy (LND) in serous or clear cell endometrial carcinoma, and to compare survival in node-negative cases. METHODS: Three-year recurrence-free survival (RFS) and overall survival were compared between one institution that used comprehensive LND to the renal veins and a second institution that used an SLN algorithm with ultra-staging with inverse-probability of treatment weighting (IPTW) derived from propensity scores to adjust for covariate imbalance between cohorts. RESULTS: 214 patients were identified (118 SLN cohort, 96 LND cohort). Adjuvant therapy differed between the cohorts; 84% and 40% in the SLN and LND cohorts, respectively, received chemotherapy ± radiation therapy. The IPTW-adjusted 3-year RFS rates were 69% and 80%, respectively. The IPTW-adjusted 3-year OS rates were 88% and 77%, respectively. The IPTW-adjusted hazard ratio (HR) for the association of surgical approach (SLN vs LND) with progression and death was 1.46 (95% CI: 0.70-3.04) and 0.44 (95% CI: 0.19-1.02), respectively. In the 168 node-negative cases, the IPTW-adjusted 3-year RFS rates were 73% and 91%, respectively. The IPTW-adjusted 3-year OS rates were 88% and 86%, respectively. In this subgroup, IPTW-adjusted HR for the association of surgical approach (SLN vs LND) with progression and death was 3.12 (95% CI: 1.02-9.57) and 0.69 (95% CI: 0.24-1.95), respectively. CONCLUSION: OS was not compromised with the SLN algorithm. SLN may be associated with a decreased RFS but similar OS in node-negative cases despite the majority receiving chemotherapy. This may be due to differences in surveillance.

Role of adjuvant therapy in stage IIIC2 endometrial cancer.

OBJECTIVE: The role of the different types of adjuvant treatments in endometrial cancer with para-aortic node metastases is unclear. The aim of this study was to report oncologic outcomes after adjuvant therapy in patients with stage IIIC2 endometrial cancer. METHODS: This retrospective single-institution study assessed patients with stage IIIC2 endometrial cancer who underwent primary surgery from January 1984 to December 2014. All patients had hysterectomy (±salpingo-oophorectomy) plus lymphadenectomy (para-aortic nodes, ±pelvic nodes). We included all patients with stage III endometrial cancer and documented para-aortic lymph node metastases (International Federation of Obstetrics and Gynecologists stage IIIC2). We excluded patients who did not provide consent, who had synchronous cancer, or who underwent neoadjuvant chemotherapy. Follow-up was restricted to the first 5 years post-operatively. Cox proportional hazards models, with age as the time scale, was used to evaluate associations of risk factors with disease-free survival and overall survival. RESULTS: Among 105 patients with documented adjuvant therapy, external beam radiotherapy was administered to 25 patients (24%), chemotherapy to 24 (23%), and a combination (chemotherapy and external beam radiotherapy) to 56 (53%) patients. Most patients receiving chemotherapy and external beam radiotherapy (80%) had chemotherapy first. The majority of relapses had a distant component (31/46, 67%) and only one patient had an isolated para-aortic recurrence. Non-endometrioid subtypes had poorer disease-free survival (HR 2.57; 95% CI 1.38 to 4.78) and poorer overall survival (HR 2.00; 95% CI 1.09 to 3.65) compared with endometrioid. Among patients with endometrioid histology (n=60), chemotherapy and external beam radiotherapy improved disease-free survival (HR 0.22; 95% CI 0.07 to 0.71) and overall survival (HR 0.28; 95% CI 0.09 to 0.89) compared with chemotherapy or external beam radiotherapy alone. Combination therapy did not improve prognosis for patients with non-endometrioid histology (n=45). CONCLUSIONS: In our cohort of patients with stage IIIC2 endometrioid endometrial cancer, those receiving chemotherapy and external beam radiotherapy had improved survival compared with patients receiving chemotherapy or external beam radiotherapy alone. However, the prognosis of patients with non-endometrioid endometrial cancer remained poor, regardless of the adjuvant therapy administered. Distant recurrences were the most common sites of failure.

Should mucosal bowel invasion in ovarian cancer be assigned to FIGO stage IV disease?

OBJECTIVES: The FIGO staging consensus agreement from 2012 indicates that bowel mucosal invasion for epithelial ovarian cancer (EOC) should be assigned to stage IV disease. Finding no evidence justifying this recommendation, we examined the impact of recto-sigmoid colonic invasion on survival based on depth of invasion. METHODS: Patients having recto-sigmoid resection to achieve complete gross resection for stage IIIC/IV EOC between 2003 and 2011 were included. For this study, mucosal invasion alone was not considered as stage IV. Degree of bowel invasion was defined as: serosal/subserosal vs. muscularis/submucosa/mucosa. Patients with only mesenteric invasion were excluded. Intraperitoneal disease (IP) dissemination patterns were defined as pelvic, lower abdomen, upper abdomen, and miliary disease. Comparisons between groups were evaluated using the log-rank test for progression-free and overall survival (PFS, OS) and the chi-square test for IP dissemination pattern. RESULTS: Eighty-five patients were included with a mean age of 64.5 years. Most cases were serous (87.1%) and stage IIIC (83.5%). There were 53 (62.4%) patients with serosal/subserosal and 32 (37.6%) with muscularis/submucosa/mucosa invasion. Although not statistically significant, PFS and OS both favored cases with deeper invasion (muscularis/submucosa/mucosa vs. serosal/subserosal invasion: median PFS, 33.5 vs. 18.2 months, p = 0.34; median OS, 82.3 vs. 51.5 months, p = 0.46). When comparing patterns of disease dissemination, we observed that patients with serosal/subserosal invasion (vs. those with deeper invasion) tended to have more upper abdominal or miliary disease (67.9% vs. 48.4%, p = 0.08). CONCLUSIONS: Depth of recto-sigmoid colon wall invasion does not have prognostic significance. Our observations do not support assignment to a higher FIGO stage (IV) based solely on this factor.

Frailty in ovarian cancer identified the need for increased postoperative care requirements following cytoreductive surgery.

OBJECTIVES: We sought to examine the relationship between frailty and complicated postoperative courses, including intensive care unit (ICU) admission and non-home discharge, in patients with advanced ovarian cancer (OC) undergoing primary debulking surgery (PDS) for curative intent. METHODS: Patients were identified from a retrospectively collected database at a single institution between 1/1/2003-12/31/2011. A frailty index was derived from 30 items representing comorbidities and activities of daily living, each scored as 0, 0.5, or 1, and calculated as the total summated score divided by the total number of non-missing items. Frailty was defined as an index ≥0.15. Associations with binary outcomes were assessed using logistic regression. RESULTS: A total of 535 patients met inclusion criteria. Frail patients were older, mean age 67.8 versus 63.2 years (p < 0.001), but there was no difference in grade, stage, or serous histology. Almost half of the frail patients (48.9%, 64/131) were admitted to the ICU compared to 20.5% (83/404) of non-frail patients. Frailty remained an independent predictor of 30-day ICU admission (adjusted odds ratio (aOR) 3.20, 95% CI: 2.03-5.06) in a multivariable model including age, preoperative albumin, surgical complexity, and residual disease. Frail patients were also more likely to have a non-home discharge (24.2% vs. 7.0%). Frailty independently predicted non-home discharge (aOR 2.58, 95% CI: 1.35-4.93) after adjusting for age, BMI, and stage. CONCLUSION: Frailty is a measurable, objective clinical syndrome that has impact on postoperative outcomes in advanced OC and should be considered when decision-making about treatments and counseling patients.

Using an evidence-based triage algorithm to reduce 90-day mortality after primary debulking surgery for advanced epithelial ovarian cancer.

OBJECTIVE: To evaluate the impact of an evidence-based triage algorithm to decide between primary debulking surgery (PDS) and neoadjuvant chemotherapy followed by interval debulking surgery (NACT/IDS) for advanced epithelial ovarian cancer (EOC). METHODS: Surgical morbidity and mortality (M/M) after PDS for stage IIIC-IV EOC at Mayo Clinic after implementation of the triage algorithm (contemporary cohort, 2012-July 2016) were compared to that of a historic PDS cohort (2003-2011). RESULTS: Mean age of the 232 women who met inclusion criteria in the contemporary cohort was 63.9 years. We observed a 71% decrease in 90-day mortality from 8.9% to 2.6% (P = 0.002) between the contemporary and historic cohorts. Accordion grade 3+ postoperative complications within 30 days after surgery decreased from 22.3% to 18.3% (P = 0.19). Among those with a grade 3+ complication, 90-day mortality rates decreased from 28.3% in the historic cohort to 2.4% in the contemporary cohort (P < 0.001) suggesting patients were better able to tolerate complex surgery. When compared to the historic PDS cohort, oncologic outcomes were also improved in the contemporary PDS cohort. Complete as well as optimal (residual disease ≤1 cm) cytoreduction rates increased (45.5% vs. 62.5% and 84.5% vs. 95.3%, respectively, P < 0.001), and the proportion of women starting chemotherapy within 42 days of surgery increased (57.4% vs. 69.8%, P = 0.001). Three-year overall survival was 53% in the historic cohort and 66% in the contemporary cohort (P < 0.001). CONCLUSIONS: Use of the Mayo triage algorithm for EOC was associated with reduced 90-day mortality after PDS and improved oncologic outcomes. Surgical risk assessment is a critical aspect of treatment planning in the primary management of EOC and should be incorporated into practice.

Beyond prophylaxis: Extended risk of venous thromboembolism following primary debulking surgery for ovarian cancer.

OBJECTIVE: To determine the incidence and risk factors for venous thromboembolism (VTE) within six months after primary debulking surgery (PDS) for epithelial ovarian cancer (EOC). METHODS: In a historical cohort, we estimated the cumulative incidence of clinically diagnosed VTE within 6 months among consecutive women who underwent PDS for EOC at a single institution from 1/1/2003 to 12/31/2011. We evaluated perioperative variables as potential risk factors of VTE within 6 months during the postoperative period using univariate and multivariable Cox proportional hazards models. RESULTS: Among 860 women without an immediate history (past 30 days) of a VTE, the cumulative incidence of VTE was 7.5% (95% CI, 5.7-9.3) by 30 days and 13.8% (95% CI, 11.4-16.2) by 6 months following surgery. Macroscopic residual disease (adjusted HR 1.99 [95% CI 1.35-2.94] vs microscopic), increasing estimated blood loss (1.25 [1.05-1.49] per doubling), longer hospital length of stay (3.00 [1.57-5.75]), and experiencing a cardiac event within 30 postoperative days (2.72 [1.55-4.80]) were independently associated with subsequent VTE within 6 months. In-hospital VTE prophylaxis included heterogeneous approaches; dual prophylaxis did not impact 30-day or 6-month VTE rates. CONCLUSIONS: VTE occurred in 1 in 7 women with EOC within 6 months of PDS-a substantial risk of VTE that extends into the adjuvant chemotherapy period. Novel prophylactic measures should be explored in these women at high risk for VTE.

Mesenchymal molecular subtype is an independent predictor of severe postoperative complications after primary debulking surgery for advanced ovarian cancer.

OBJECTIVE: To evaluate the contribution of molecular subtype to 30-day postoperative complications and 90-day mortality after primary debulking surgery (PDS) in advanced stage high-grade serous ovarian cancer (HGSOC). METHODS: Patients with stages III-IV HGSOC undergoing PDS from 1994 to 2011 with available molecular subtyping were included. Residual disease (RD) status was categorized as 0, 0.1-0.5, 0.6-1.0, or >1 cm. Surgical complexity scores were calculated as high, intermediate, or low as previously published. Postoperative complications were graded according to the modified Accordion classification 0-4 scale; severe was defined as grade ≥3. Molecular subtypes were derived from Agilent 4 × 44k tumor mRNA expression profiles and categorized as mesenchymal (MES) or non-mesenchymal (non-MES). Logistic regression modeling was used to assess associations. RESULTS: Of 329 patients, 68.7% were stage IIIC, 80.5% had RD ≤1 cm, 28.0% had MES subtype, and 19.5% had a grade 3-4 complication; 90-day mortality was 5.8%. In univariate analysis, patients with MES subtype were more likely to have severe complications compared to non-MES (31.5 vs. 14.8%; OR 2.66, 95% CI 1.51-4.69; p < 0.001). MES subtype remained an independent predictor of complications (adjusted OR 2.14, 95% CI 1.17-3.92; p = 0.01) in a multivariable model which included ASA score, preoperative albumin, and surgical complexity. There was no statistical difference in 90-day mortality in patients with MES compared to non-MES subtype (7.6 vs. 5.1%; OR 1.54, 95% CI 0.59-4.05; p = 0.38). CONCLUSIONS: MES subtype is an independent predictor of severe postoperative morbidity and adds to the potential use of pre-operative molecular testing in planning primary treatment of patients with advanced ovarian cancer.

Models to predict outcomes after primary debulking surgery: Independent validation of models to predict suboptimal cytoreduction and gross residual disease.

OBJECTIVE: Treatment planning requires accurate estimation of surgical complexity (SC) and residual disease (RD) at primary debulking surgery (PDS) for advanced ovarian cancer (OC). We sought to independently validate two published computed tomography (CT) prediction models. METHODS: We included stage IIIC/IV OC patients who underwent PDS from 2003 to 2011. Two prediction models which included imaging and clinical variables to predict RD > 1 and any gross RD, respectively, were applied to our cohort. Two radiologists scored CTs. Discrimination was estimated using the c-index and calibration were assessed by comparing the observed and predicted estimates. RESULTS: The validation cohort consisted of 276 patients; median age of the cohort was 64 years old and majority had serous histology. The validation and model development cohorts were similar in terms of baseline characteristics, however the RD rates differed between cohorts (9.4% vs 25.4% had RD >1 cm; 50.7% vs. 66.6% had gross RD). Model 1, the model to predict RD >1 cm, did not validate well. The c-index of 0.653 for the validation cohort was lower than reported in the development cohort (0.758) and the model over-predicted the proportion with RD >1 cm. The second model to predict gross RD had excellent discrimination with a c-index of 0.762. CONCLUSIONS: We are able to validate a CT model to predict presence of gross RD in an independent center; the separate model to predict RD >1 cm did not validate. Application of the model to predict gross RD can help with clinical decision making in advanced ovarian cancer.