Enhanced recovery after surgery (ERAS®) society guidelines for gynecologic oncology: Addressing implementation challenges - 2023 update.

BACKGROUND: Despite evidence supporting its use, many Enhanced Recovery After Surgery (ERAS) recommendations remain poorly adhered to and barriers to ERAS implementation persist. In this second updated ERAS® Society guideline, a consensus for optimal perioperative care in gynecologic oncology surgery is presented, with a specific emphasis on implementation challenges. METHODS: Based on the gaps identified by clinician stakeholder groups, nine implementation challenge topics were prioritized for review. A database search of publications using Embase and PubMed was performed (2018-2023). Studies on each topic were selected with emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded by an international panel according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: All recommendations on ERAS implementation challenge topics are based on best available evidence. The level of evidence for each item is presented accordingly. CONCLUSIONS: The updated evidence base and recommendations for stakeholder derived ERAS implementation challenges in gynecologic oncology are presented by the ERAS® Society in this consensus review.

Outcomes of enhanced recovery after surgery (ERAS) in gynecologic oncology - A systematic review and meta-analysis.

OBJECTIVE: To assess the benefit of Enhanced Recovery After Surgery (ERAS) on length of stay (LOS), postoperative complications, 30-day readmission, and cost in gynecologic oncology. METHODS: A systematic literature search was performed in MEDLINE, EMBASE, Cochrane Register of Controlled Trials, and Web of Science for all peer-reviewed cohort studies and controlled trials on ERAS involving gynecologic oncology patients. Abstracts, commentaries, non-controlled studies, and studies without specific data on gynecologic oncology patients were excluded. Meta-analysis was performed on the primary endpoint of LOS. Subgroup analyses were performed based on risk of bias of the studies included, number of ERAS elements, and ERAS compliance. Secondary endpoints were readmission rate, complications, and cost. RESULTS: A total of 31 studies (6703 patients) were included: 5 randomized controlled trials, and 26 cohort studies. Meta-analysis of 27 studies (6345 patients) demonstrated a decrease in LOS of 1.6 days (95% confidence interval, CI 1.2-2.1) with ERAS implementation. Meta-analysis of 21 studies (4974 patients) demonstrated a 32% reduction in complications (OR 0.68, 95% CI 0.55-0.83) and a 20% reduction in readmission (OR 0.80, 95% CI 0.64-0.99) for ERAS patients. There was no difference in 30-day postoperative mortality (OR 0.61, 95% CI 0.23-1.6) for ERAS patients compared to controls. No difference in the odds of complications or reduction in LOS was observed based on number of included ERAS elements or reported compliance with ERAS interventions. The mean cost savings for ERAS patients was $2129 USD (95% CI $712 - $3544). CONCLUSIONS: ERAS protocols decrease LOS, complications, and cost without increasing rates of readmission or mortality in gynecologic oncology surgery. This evidence supports implementation of ERAS as standard of care in gynecologic oncology.

An international multidisciplinary consensus statement on the prevention of opioid-related harm in adult surgical patients.

This international multidisciplinary consensus statement was developed to provide balanced guidance on the safe peri-operative use of opioids in adults. An international panel of healthcare professionals evaluated the literature relating to postoperative opioid-related harm, including persistent postoperative opioid use; opioid-induced ventilatory impairment; non-medical opioid use; opioid diversion and dependence; and driving under the influence of prescription opioids. Recommended strategies to reduce harm include pre-operative assessment of the risk of persistent postoperative opioid use; use of an assessment of patient function rather than unidimensional pain scores alone to guide adequacy of analgesia; avoidance of long-acting (modified-release and transdermal patches) opioid formulations and combination analgesics; limiting the number of tablets prescribed at discharge; providing deprescribing advice; avoidance of automatic prescription refills; safe disposal of unused medicines; reducing the risk of opioid diversion; and better education of healthcare professionals, patients and carers. This consensus statement provides a framework for better prescribing practices that could help reduce the risk of postoperative opioid-related harm in adults.

Evidence-based wound classification for vulvar surgery: Implications for risk adjustment.

OBJECTIVES: The correct wound classification for vulvar procedures (VP) is ambiguous according to current definitions, and infection rates are poorly described. We aimed to analyze rates of surgical site infection (SSI) in women who underwent VP to correctly categorize wound classification. METHODS: Patients who underwent VP for dysplasia or carcinoma were collected from the National Surgical Quality Improvement Program database (NSQIP). SSI rates of vulvar cases were compared to patients who underwent abdominal hysterectomy via laparotomy, stratified by the National Academy of Sciences wound classification. Descriptive analyses and trend tests of categorical variables were performed. RESULTS: Between 2008 and 2016, 2116 and 31,506 patients underwent a VP or TAH, respectively. Among VP, 1345 (63.6%), 364 (17.2%), and 407 (19.2%) women underwent simple vulvectomy, radical vulvectomy, or radical vulvectomy with lymphadenectomy, respectively. The overall rate of SSI for VP was higher than that observed for TAH (5.6% vs. 3.8%; p < 0.0001). While patients undergoing TAH displayed a corresponding increase in the rate of SSI with wound type (type I: 3.4%; type II: 3.8%, type III: 6.8%; type IV 10.6%; p < 0.001), no such correlation was observed for simple VP (type I: 3.3%, type II: 3.0%; type III: 3.2%; type IV: 0%; p = 0.40). On the other hand, a non-significant correlation was observed for radical VP (type I: 4.0%, type II: 10.1%; type III: 14.3%; type IV: 20.0%; p = 0.08). The overall rate of SSI in patients undergoing any radical VP was similar to patients undergoing hysterectomy with a type IV wound (10.1% vs 10.6%, p = 0.87). CONCLUSION: Patients undergoing VP are at high risk of infection. Simple vulvectomy should be classified as a type II and radical vulvectomy as a type III wound. These recommendations are important for proper risk adjustment.

Vaginal vs. robotic hysterectomy for patients with endometrial cancer: A comparison of outcomes and cost of care.

OBJECTIVE: To compare outcomes and cost for patients with endometrial cancer undergoing vaginal hysterectomy (VH) or robotic hysterectomy (RH), with or without lymphadenectomy (LND). METHODS: Patients undergoing planned VH (and laparoscopic LND) or RH (and robotic LND) between January 2007 and November 2012 were reviewed. Patients with stage IV disease, synchronous cancer, synchronous surgery, or treated with palliative intent were excluded. Patients were objectively triaged to LND per institutional protocol based on frozen section. Outcomes were compared between VH and RH groups matched 1:1 on propensity scores. RESULTS: VH was planned in 153 patients; 60 (39%) had concurrent LND while 93 (61%) were low risk and did not require LND. RH was planned in 398 patients; 225 (56%) required concurrent LND and 173 (44%) did not. Among 50 PS-matched pairs without LND, there was no significant difference in complications, length of stay, readmission, or progression free survival. However, median operative time was 1.3h longer and median 30-day cost $3150 higher for RH compared to VH (both p<0.001). Among patients requiring LND, 42 PS-matched pairs were identified. Median operative time was not different when pelvic and para-aortic LND was performed, and 12min longer in the VH group for pelvic LND alone (p=0.03). Median 30-day cost was $921 higher for RH compared to VH when LND was required (p=0.08). CONCLUSION: Utilization of vaginal hysterectomy for endometrial cancer results in similar surgical and oncologic outcomes and lower costs compared to RH and should be considered for appropriate patients with a low risk of requiring LND.

A prospective algorithm to reduce anastomotic leaks after rectosigmoid resection for gynecologic malignancies.

OBJECTIVE: Determine whether a standardized protocol for temporary bowel diversion after rectosigmoid resection (RSR) for cytoreduction can reduce the rate of anastomotic leak (AL). METHODS: A prospective quality improvement project for patients undergoing RSR during debulking surgery from 07/2013 to 01/2016 was conducted. Patients with any of the following underwent temporary diversion: preoperative albumin ≤3.0g/dL, prior pelvic radiation, RSR plus additional large bowel resection (LBR), anastomosis (AS) ≤6cm from the anal verge, failed leak test or contamination of the pelvis with stool. The AL rate was compared to the historic AL rate from 01/04-06/11. RESULTS: Seventy-seven patients underwent RSR, with 27 (35.1%) receiving diverting stomas vs. 25/309 (8.1%) in the historic cohort. Additional LBR (33.3%) and AS at ≤6cm from anal verge (26.3%) were the most common indications for diversion. No AL was observed among diverted patients. If one AL which occurred following protocol violation (failed leak test but not diverted) is excluded, the theoretical AL rate is 1.3% (1/77) vs. 7.8% (24/309; P=0.039) in the historic cohort. Not excluding this case, the AL rate was 2.6% (2/77) vs. 7.8% (P=0.11). Short-term outcomes following primary surgery were not different between diverted and non-diverted patients. Stoma-related complications were observed in 7/27 (25.9%) patients, primarily related to dehydration. Reversal surgery was successfully performed in 24/75 (88.9%) patients. CONCLUSIONS: Criteria-based temporary bowel diversion for patients undergoing RSR for gynecologic cancer reduced the AL rate. Diversion was associated with acceptable morbidity and high reversal rate.

Management of endometrial cancer: issues and controversies.

Although endometrial cancer (EC) is the most common gynecologic cancer in developed countries, several aspects of its management are still controversial. In particular, the need to perform lymphadenectomy represents an important matter of discussion. Because of the discordant results in the literature, it is still not possible to draft any definitive conclusions regarding the therapeutic value of lymph node dissection. The present review discusses the role of lymphadenectomy in the setting of EC, risk factors for lymphatic spread, identification of patients at risk for lymph node dissemination, and the current evidence for adjuvant therapies in patients with positive nodes. Reasons for the difficulty in demonstrating any therapeutic value of pelvic and para-aortic lymphadenectomy are also discussed.

Risk-scoring system for the individualized prediction of lymphatic dissemination in patients with endometrioid endometrial cancer.

OBJECTIVE: To develop a risk-scoring system (RSS) for the prediction of lymphatic dissemination after hysterectomy in endometrioid endometrial carcinoma (EC). METHODS: Patients who underwent surgery from 1/1/1999-12/31/2008 were evaluated. Patients with non-endometrioid histology, stage IV with macroscopic extrauterine disease, or receiving adjuvant therapy (excluding brachytherapy) without pelvic and/or paraaortic (P/PA) lymphadenectomy (LND) were excluded. Lymph node dissemination was defined as nodal metastasis when P/PA LND was performed or P/PA lymph node recurrence after negative LND or when LND was not performed. Logistic regression analysis was used to identify predictors for lymphatic dissemination and develop a RSS and nomogram. The RSS was assessed for calibration and verified for discrimination. RESULTS: Overall, 883 patients were assessed of which 521 (59.0%) underwent P/PA LND and 57 (10.9%) had positive lymph nodes. Of patients who did not undergo P/PA LND (N=362) or had negative nodes (N=464), 10 (1.2%) patients had P/PA lymph node recurrence. Myometrial invasion, tumor diameter (TD), FIGO grade, cervical stromal invasion and lymphovascular space invasion were significant on univariable analysis. All preceding variables were included in a multivariable logistic model. A parsimonious model and an alternative full model not including TD were considered. The full model with TD (illustrated in nomogram) had the highest predictive ability (concordance index 0.88). CONCLUSION: Our RSS allows accurate quantification of the probability of lymphatic dissemination and can be used as an adjunct to clinical decision-making after hysterectomy in the absence of staging. TD is an important component of the RSS and should be routinely assessed.

Evaluating the prognostic significance of preoperative thrombocytosis in epithelial ovarian cancer.

OBJECTIVE: Preoperative thrombocytosis has been implicated as a negative prognostic marker for epithelial ovarian cancer (EOC). We assessed whether thrombocytosis is an independent risk factor for EOC recurrence and death. METHODS: Perioperative patient characteristics and process-of-care variables (National Surgical Quality Improvement Program (NSQIP)-defined) were retrospectively abstracted from 587 women who underwent EOC staging between 1/2/03-12/29/08. Thrombocytosis was defined as platelet count > 450 × 10(9)/L. Disease-free survival (DFS) and overall survival (OS) were determined using Kaplan-Meier methods. Associations were evaluated with Cox proportional hazards regression and hazard ratios (HR). RESULTS: The incidence of preoperative thrombocytosis was 22.3%. DFS was 70.8% and 36.0% at 1 and 3 years. OS was 83.3% and 54.3% at 1 and 3 years. Ascites, lower hemoglobin, advanced disease, and receipt of perioperative packed red blood cell transfusion were independently associated with thrombocytosis. Older age and the presence of coronary artery disease were associated with lower likelihood of thrombocytosis. Overall, thrombocytosis was an independent predictor of increased risk of recurrence. Among early stage (I/II) cases, there was a 5-fold increase in the risk of death and nearly 8-fold risk of disease recurrence independently associated with thrombocytosis. CONCLUSION: Preoperative thrombocytosis portends worse DFS in EOC. In early stage disease, thrombocytosis is a potent predictor of worse DFS and OS and further assessment of the impact of circulating platelet-derived factors on EOC survival is warranted. Thrombocytosis is also associated with extensive initial disease burden, measurable residual disease, and postoperative sequelae. Preoperative platelet levels may have value in primary cytoreduction counseling.

Risk factors that mitigate the role of paraaortic lymphadenectomy in uterine endometrioid cancer.

OBJECTIVE: Paraaortic lymph node (PA) dissemination in endometrial cancer (EC) is uncommon and a systematic infrarenal PA dissection carries morbidity. Our objective was to identify a subgroup of EC patients who may potentially forego PA lymphadenectomy (LND). METHODS: The study endpoint (PA Metastasis or Recurrence; PAMR) was defined as detection of metastasis to PA nodes (among those with any type of PA LND) or PA recurrence within 2 years (among patients without PA LND or those with negative nodes in the context of an inadequate (<5 nodes) PA LND). Patients with non-endometrioid histology, stage IV disease, synchronous cancers, gross extrauterine or gross adnexal disease, neoadjuvant therapy, or insufficient follow-up were excluded. Multivariable logistic regression analysis identified predictors of PAMR. RESULTS: Of the 946 patients, PAMR was observed in 4% (36/946). Multivariable analysis identified positive pelvic nodes (odds ratio (OR) 24.2; p<0.001), >50% MI (OR 5.3; p<0.001) and lymphovascular space invasion (LVSI) (OR 3.7; p=0.005) as the only three independent predictors of PAMR. When all three factors were absent (77% of study cohort), the predicted probability of PAMR was 0.6%. If intraoperative frozen section is not available on pelvic lymph nodes and LVSI, omitting PA LND in all patients with ≤ 50% MI would affect 84% (792/946) of the total cohort, with a 1.1% risk of PAMR (9/792). CONCLUSION: The majority of patients with endometrioid EC may potentially forgo PA LND with expected reductions in surgical morbidity and cost. This cohort may be identified by a combined absence of: positive pelvic nodes, >50% MI and LVSI.

Risk of postoperative venous thromboembolism after minimally invasive surgery for endometrial and cervical cancer is low: a multi-institutional study.

OBJECTIVE: To determine the 30-day prevalence of venous thromboembolism (VTE) after minimally invasive surgery (MIS) for endometrial (EC) and cervical cancers (CC). METHODS: A retrospective cohort study at two large tertiary care centers between 2006 and 2011. Patients having MIS for EC or CC were included. Cases converted to laparotomy were excluded. The primary outcome measure was clinically diagnosed VTE within 30 days of operation. RESULTS: Of the 558 patients, 90% had EC and 10% had CC. Modalities of hysterectomy included robotic (88%), vaginal (9%), and laparoscopic (3%). A total of 66% had pelvic and 35% had paraaortic lymphadenectomy. The VTE prophylaxes were sequential compression devices (100%) and heparin (39%). There were no VTE events during hospital stay (95% CI, 0.0%-0.7%). The 30-day prevalence of VTE was (0.5%; 95% CI, 0.1%-1.6%). The hitherto recommended risk criteria for giving extended 30-day thromboprophylaxis by the American College of Obstetrics and Gynecologists (ACOG) or by the American Society of Clinical Oncology (ASCO) did not predict risk of VTE in our population. CONCLUSIONS: The prevalence of VTE in EC and CC undergoing MIS is very low. The existing 30-day risk prediction models proposed by the ACOG and ASCO stem from open surgery patients and do not appear to apply to MIS patients. Certainly, we found no evidence supporting the use of extended prophylactic heparin in this setting. Further research is urgently needed to define the role of any duration of thromboprophylaxis in MIS patients with endometrial or cervix cancer.

Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer.

OBJECTIVE: Since 1999, patients with low risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. Here we prospectively assess survival, sites of recurrence, morbidity, and cost in this low risk cohort. METHODS: Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Classification. Thirty-day cost analyses were expressed in 2010 Medicare dollars. RESULTS: Among 1393 consecutive surgically managed cases, 385 (27.6%) met inclusion criteria, accounting for 34.1% of type I EC. There were 80 LND and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5% vs. 19.3%; P<0.001). The prevalence of lymph node metastasis was 0.3% (1/385). Over a median follow-up of 5.4 years only 5 of 31 deaths were due to disease. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was $15,678 for LND cases compared to $11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was $327,866 to $439,990, adding an additional $1,418,189 if all 305 non-LND cases had undergone LND. CONCLUSION: Lymphadenectomy dramatically increases morbidity and cost of care without discernible benefits in low-risk EC as defined by the Mayo criteria. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be standard of care.

Incidence and factors associated with synchronous ovarian and endometrial cancer: a population-based case-control study.

OBJECTIVE: To estimate the incidence of synchronous endometrial cancer (EC) and ovarian cancer (OC) in the female population, among all women with EC, and in women under 50 years of age with EC, and to identify factors associated with synchronous EC/OC. METHODS: All cases of synchronous EC/OC and EC diagnosed in women residing in Olmsted County, Minnesota between 1/1/1945 and 12/31/2008 were identified. Incidence was estimated using the population denominator from decennial census data, corrected for hysterectomy prevalence. A case-control study using 15 identified cases (EC/OC) and 45 controls (EC alone) was performed. RESULTS: The incidence of synchronous EC/OC and EC (age-adjusted to the 2000 US female total and corrected for hysterectomy prevalence) in 1945-2008 was 0.88 and 30.3 per 100,000 person-years, respectively. Among women under 50 years of age, the corrected incidence of EC/OC and EC was 0.51 and 5.1 per 100,000 person-years, respectively. Among all women with EC, 3.1% had a synchronous OC compared to 9.4% of women under 50 years of age with EC. Patients with synchronous EC/OC were more likely than those with EC alone to present with a pelvic mass (57.1% vs. 8.9%, p<0.001). Patients with EC alone were more likely to have used oral contraceptive pills (OCPs) than synchronous EC/OC cases (22.7% vs 0%; Odds ratio, 0.10; 95% CI, <0.01-0.87). CONCLUSION: Although the incidence of synchronous EC/OC in the general population is lower than previously reported, nearly 1 in 10 women diagnosed with EC under 50 years of age will have a synchronous OC.

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

Transvaginal colonic extraction following combined hysterectomy and laparoscopic total colectomy: a natural orifice approach.

A major advantage of laparoscopic colectomy is the limited incision. We describe an innovative technique in which the entire colon is extracted transvaginally to avoid any abdominal extraction incision in a female patient with hereditary nonpolyposis colon cancer who required total colectomy and hysterectomy. This novel technical approach is feasible and safe, eliminates the need for any extraction abdominal incision, and may be considered in patients requiring concurrent abdominal colectomy and hysterectomy.

Surgical management and adjuvant therapy for patients with uterine clear cell carcinoma: a multi-institutional review.

OBJECTIVE: To assess the role of surgical staging, adjuvant therapy, and cytoreduction in uterine clear cell carcinoma (UCCC). METHODS: A retrospective review was conducted at 2 major gynecologic cancer centers of all primary UCCC between 1982 and 2004. RESULTS: UCCC was confirmed in 99 patients. The 5-year overall survival (OS) was 79%, 77%, 47%, and 21% for stages I-IV respectively. 69 patients had no gross evidence of extra-uterine disease, but 36 (52%) were upstaged at surgery. For those 22 patients with stages I and II disease who had a systematic lymphadenectomy (LND) (> 20 lymph nodes), no lymphatic (LF), peritoneal (PF), or hematological (HF) failures were noted. Radiation (RT) improved PFS (67 vs. 36%, p=0.02), and reduced pelvic sidewall recurrences (18 vs. 53%, p=0.04) and vaginal failures (VF) (7 vs. 35%, p=0.04) for 45 patients at risk for LF (positive nodes or suboptimal LND). 39 patients with stages IIIC and IV disease were separately analyzed. Patients with no visible residual disease after cytoreduction had a significant improvement in median PFS (17 vs. 7 months, p<0.001), and OS (40 vs. 18 months, p=0.02) compared to patients with any residual disease after surgery. CONCLUSION: Comprehensive surgical staging with a systematic LND is essential to accurately define early stage UCCC. Vaginal brachytherapy may be adequate adjuvant therapy for stages I and II UCCC confirmed by systematic LND. Patients at risk for LF appear to benefit from pelvic RT. An effort at cytoreduction to no visible residual disease should be made in advanced UCCC when feasible.

Telomerase activity in sex cord-stromal tumors of the ovary.

OBJECTIVE: Telomerase is a ribonucleoprotein that protects chromosomes from degradation and end-to-end fusions by maintaining telomere length. Studies have shown that telomerase is present in 95% of gynecologic malignancies and in 88% of epithelial ovarian carcinomas but undetectable in benign tissue. The aim of this investigation was to determine whether telomerase is present in sex cord-stromal tumors and whether telomerase activity is indicative of patient outcomes. METHODS: Forty-five consecutive sex cord-stromal ovarian tumors were analyzed by using reverse transcription-polymerase chain reaction for expression of human telomerase, human telomerase reverse transcriptase, and telomerase activity. RESULTS: Of the 29 patients with malignant cell types (granulosa cell, Sertoli-Leydig cell, and steroid cell tumors), 21 of the 28 patients (75%) available for follow-up had recurrence, with a mean follow-up of 86 months (95% CI, 36-157 months). The telomerase repeat amplification protocol assay had a sensitivity of 74% and specificity of 94% for malignancy. Patients with telomerase-positive tumors had a mean disease-free interval of 66.5 months; for those with telomerase-negative tumors the interval was 90 months. In addition, patients with telomerase-positive tumors were more likely to be dead from disease or alive with disease than those without telomerase activity, and they showed trends toward requiring a larger number of surgical procedures for the treatment of their disease. However, these trends were not statistically significant. CONCLUSION: Although activation of telomerase is clearly an important step in carcinogenesis, it is unlikely to be helpful in the clinical management of sex cord-stromal tumors of the ovary.