Open vs minimally invasive radical trachelectomy in early-stage cervical cancer: International Radical Trachelectomy Assessment Study.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005-2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20-42) years for open surgery vs 31 (18-45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0-31) mm for open surgery and 12 (0.8-40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20-16.70) years for open surgery and 3.1 years (0.02-11.10) years for minimally invasive surgery (P<.001). At 4.5 years, 17 of 358 patients (4.7%) with open surgery and 18 of 288 patients (6.2%) with minimally invasive surgery had recurrence (P=.40). The 4.5-year disease-free survival rates were 94.3% (95% confidence interval, 91.6-97.0) for open surgery and 91.5% (95% confidence interval, 87.6-95.6) for minimally invasive surgery (log-rank P=.37). Post hoc propensity score analysis of recurrence risk showed no difference between surgical approaches (P=.42). At 4.5 years, there were 6 disease-related deaths (open surgery, 3; minimally invasive surgery, 3) (log-rank P=.49). The 4.5-year overall survival rates were 99.2% (95% confidence interval, 97.6-99.7) for open surgery and 99.0% (95% confidence interval, 79.0-99.8) for minimally invasive surgery. CONCLUSION: The 4.5-year disease-free survival rates did not differ between open radical trachelectomy and minimally invasive radical trachelectomy. However, recurrence rates in each group were low. Ongoing prospective studies of conservative management of early-stage cervical cancer may help guide future management.

Investigating the effect of optimal cytoreduction in the context of platinum sensitivity in high-grade serous ovarian cancer.

INTRODUCTION: The survival benefits of surgical cytoreduction in ovarian cancer are well-established. However, the surgical outcome has never been assessed while controlling for the efficacy of chemotherapy. This leaves the possibility that cytoreduction may not be beneficial for patients whose cancer does not respond well to adjuvant treatment. We sought to answer whether surgical cytoreduction independently improves overall survival when controlling for chemotherapy outcome. MATERIAL AND METHODS: We performed a retrospective case-control study using our institution's ovarian cancer database to evaluate the effect of optimal cytoreduction on advanced stage, high-grade serous ovarian cancer. Patients' characteristics were compared using both univariate and multivariate regression modeling to assess for independent predictors of overall survival. RESULTS: A total of 470 patients were assessed for inclusion; 234 responders to chemotherapy and 98 nonresponders. Significant survival characteristics were identified and included in the multivariate analysis. Independent predictors of survival in the multivariate analysis were age, responder status, optimal cytoreduction, neoadjuvant chemotherapy, and number of chemotherapy cycles. Kaplan-Meier survival curves showed improved survival for both patients who responded to chemotherapy and for those undergoing optimal cytoreduction (p < 0.001). We also demonstrated improved survival for patients receiving optimal cytoreduction among both nonresponders and responders (p < 0.001). CONCLUSIONS: Our analysis shows that patients who undergo optimal cytoreduction have an overall survival benefit regardless of their response to chemotherapy. Therefore, cytoreduction should be considered in all patients, even in those with advanced disease, if an optimal result can be achieved. This study was underpowered to assess patients who received neoadjuvant chemotherapy as a separate subgroup, but the order of treatment was controlled for in the overall analysis.

The impact of tumor fragmentation in patients with stage I uterine leiomyosarcoma on patterns of recurrence and oncologic outcome.

OBJECTIVE: To evaluate the impact of tumor fragmentation on oncologic outcomes in patients with stage I uterine leiomyosarcoma (uLMS). METHODS: We identified all patients diagnosed with stage I uLMS presenting to our institution within three months of primary surgery, 1/2000-1/2019. Patients with recurrent disease were excluded. The non-morcellated group had total hysterectomy without documented specimen fragmentation; the morcellated group, total hysterectomy with documented specimen fragmentation. We defined fragmentation as manual fragmentation or morcellation (via power morcellator or otherwise) of the specimen in peritoneal cavity or vagina. Appropriate statistical analyses were performed. RESULTS: 152 patients met inclusion criteria. 107 (70%) underwent total hysterectomy (non-morcellated); 45 (30%) underwent morcellation. Median age at diagnosis for the entire cohort was 55 years (range 30-91). Median follow-up was 42.1 months (range 1.1-197.8). 40 (26.3%) patients had primary surgery at our institution, 112 (73.7%) at an outside hospital. In total 110 (72.3%) recurred: 72/107 (67.2%) non-morcellated; 38/44 (86.3%) morcellated. Median progression-free survival (PFS) for non-morcellated versus morcellated was 13.8 (95%CI 9.2-20.2) versus 7.3 months (95%CI 3-13.1), HR 1.5 (95%CI 1.02-2.24); P = 0.04. Median overall survival (OS) for non-morcellated versus morcellated was 82.1 (95%CI 52.4-122) versus 47.8 months (95%CI 28.5-129.6), HR 1.1 (95%CI 0.67-1.82); P = 0.7. Among patients with recurrence, 69.4% of non-morcellated recurred at hematogenous sites only, 18.1% recurred in peritoneum only; 28.9% of morcellated recurred at hematogenous sites, 63.2% in peritoneum. Race, lymphovascular invasion, postoperative chemotherapy, were independently associated with PFS. Mitotic index was independently associated with OS. CONCLUSIONS: Tumor fragmentation/morcellation was associated with significantly higher risk of recurrence and a nearly 4-fold increase in peritoneal recurrence. Prognostic biomarkers remain important in predicting oncologic outcomes, independent of fragmentation or treatment.

Non-exenterative surgical management of recurrent endometrial carcinoma.

OBJECTIVE: To examine the role of non-exenterative secondary cytoreductive surgery (SCS) compared with non-surgical treatments and identify predictors of improved survival for patients with recurrent endometrial cancer (EC). METHODS: All patients undergoing primary surgical management for EC 1/1/2009-12/31/2017 who subsequently developed recurrence were retrospectively identified. Survival was determined from date of diagnosis of first recurrence to last follow-up and estimated using Kaplan-Meier method. Differences in survival were analyzed using Log-rank and Wald tests, based on Cox Proportional Hazards model. RESULTS: Among 376 patients with recurrent EC, median time to recurrence was 14.3 months (range, 0.2-102.2), post-recurrence median survival 29 months, median follow-up 29.2 months (range, 0-116). Sixty-one patients (16.2%) received SCS, 257 (68.4%) medical management (MM) (chemotherapy and/or radiation therapy), 32 (8.5%) hormonal therapy, 26 (6.9%) no further therapy. Patients selected for SCS were younger, had more endometrioid histology, more stage I disease at initial diagnosis, no residual disease after primary surgery, longer interval to first recurrence or progression, and the longest OS (57.6 months) (95% CI, 33.3-not reached). On multivariate analysis SCS was an independent predictor of improved survival. Among the 61 SCS patients, age < 70 at time of initial diagnosis, and endometrioid histology, were associated with improved post-relapse survival univariately (p = 0.008, 0.03, respectively). CONCLUSIONS: While MM was the most common treatment for first recurrence of EC, patients selected for surgery demonstrated the greatest survival benefit even after controlling for tumor size, site, histology, stage, time to recurrence. Careful patient selection and favorable tumor factors likely play a major role in improved outcomes. Surgical management should be considered whenever feasible in medically eligible patients, with additional consideration given to our suggested criteria.

Incidence of pelvic lymph node metastasis using modern FIGO staging and sentinel lymph node mapping with ultrastaging in surgically staged patients with endometrioid and serous endometrial carcinoma.

OBJECTIVE: We report the incidence of occult nodal metastasis in patients who underwent primary surgical staging for apparent early endometrioid or serous endometrial cancer with bilateral SLN mapping and enhanced pathology. Occult ovarian metastasis rates were also reported. METHODS: Patients with clinical stage I serous or endometrioid endometrial cancer who underwent primary staging surgery with successful bilateral SLN mapping from 1/2005-12/2018 were retrospectively evaluated. Rates of isolated tumor cells (ITCs), micro- and macrometastatic nodal disease, and occult ovarian involvement were reported. RESULTS: Of 1044 patients, 959 had endometrioid and 85 serous carcinoma. There were no positive SLNs among 510 patients with noninvasive FIGO grade 1/2 endometrioid carcinoma and < 1%ITCs. Grade 1: 4.5%(9/202) with inner-half and 10%(6/62) with outer-half myoinvasion had positive SLNs. Grade 2: rates were 4%(3/76) and 20%(8/41), respectively. Grade 3: 5%(1/20) with noninvasive, 3%(1/31) with inner-half, and 24%(4/17) with outer-half myoinvasion had positive SLNs. ITC incidence increased with depth of myoinvasion-25% of deeply invasive grade 1/2 and 18% of deeply invasive grade 3 tumors. Four (10%) of 41 patients with noninvasive serous endometrial carcinoma had ITCs or positive SLNs. There were no occult ovarian metastases with grades 1/2 disease, 2/68 (3%) with grade 3 disease, and 2/85 (2%) with serous endometrial carcinoma. CONCLUSION: Ultrastaging SLNs may be unwarranted in low-grade noninvasive endometrioid cancer but valuable in noninvasive serous carcinoma. Occult ovarian metastasis is uncommon in early endometrial carcinoma and occurs in 2-3% of high-risk histologies. Further research is needed to determine ITC significance, particularly with regard to adjuvant treatment.

A prospective multicenter international single-arm observational study on the oncological safety of the sentinel lymph node algorithm in stage I intermediate-risk endometrial cancer (SELECT, SEntinel Lymph node Endometrial Cancer Trial).

BACKGROUND: In the primary treatment of apparent uterine-confined endometrial carcinoma, pelvic ± para-aortic lymphadenectomy has been considered the standard of care. Although some retrospective data suggest that the sentinel lymph node algorithm without complete lymphadenectomy can be used without jeopardizing oncologic outcome, prospective data are lacking. PRIMARY OBJECTIVES: To assess the 36 month incidence of pelvic/non-vaginal recurrence in women with pathologically confirmed stage I intermediate-risk endometrioid endometrial carcinoma who have bilateral negative pelvic sentinel lymph nodes. STUDY HYPOTHESIS: We hypothesize that patients with stage I, intermediate-risk endometrioid endometrial carcinoma who have bilateral negative pelvic sentinel lymph nodes will demonstrate a pelvic/non-vaginal recurrence rate comparable to historical estimate of stage I, intermediate-risk endometrioid endometrial carcinoma patients (estimated 2.5%). TRIAL DESIGN: This prospective multicenter single-arm observational study will follow women with stage I, intermediate risk endometrioid endometrial adenocarcinoma who have undergone successful hysterectomy, bilateral salpingo-oophorectomy, and bilateral sentinel lymph node biopsies, for recurrence. All patients will undergo lymphatic mapping using indocynanine green and will either receive no adjuvant treatment or vaginal brachytherapy only. Patients will be followed for 36 months. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients will be enrolled in the study cohort if all the following criteria are met: (i) at time of surgery: hysterectomy with bilateral adnexectomy, and successful bilateral pelvic sentinel lymph node mapping; (ii) on final pathology: pathologic stage I, intermediate-risk endometrioid endometrial carcinoma (grade 1 or grade 2 with ≥50% myometrial invasion, or grade 3 with <50% myometrial invasion), negative pelvic peritoneal cytology, and bilateral sentinel lymph nodes negative for malignancy; (iii) recommended adjuvant treatment: vaginal brachytherapy or no adjuvant treatment. PRIMARY ENDPOINT: Incidence of pelvic/non-vaginal recurrence at 36 months. SAMPLE SIZE: 182 patients for study cohort ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual will be completed in 2023 with results reported in 2026. TRIAL REGISTRATION: NCT04291612.

Surveillance patterns of cervical cancer patients treated with conization alone.

OBJECTIVES: To determine surveillance patterns of stage I cervical cancer after cervical conization. METHODS: A 25-question electronic survey was sent to members of the Society of Gynecologic Oncology. Provider demographics, surveillance during year 1, years 1-3, and >3 years after cervical conization, use of pelvic examination, cytology, Human papillomavirus testing, colposcopy, and endocervical curettage were queried. Data were analyzed. RESULTS: 239/1175 (20.1%) responses were collected over a 5-week study period. All providers identified as gynecologic oncologists. During year 1, 66.7% of providers perform pelvic examination and 37.1% perform cytology every 3 months. During years 1-3, 61.6% perform pelvic examination and 46% perform cytology every 6 months. At >3 years, 54.4% perform pelvic examination every 6 months and 43% perform annual pelvic examination. 66.7% of respondents perform cytology annually, and 51.9% perform annual Human papilloma virus testing. 85% of providers do not offer routine colposcopy and 60% do not offer endocervical curettage at any point during 5-year follow-up. 76.3% of respondents screen patients for Human papilloma virus vaccination. CONCLUSIONS: To date, there are no specific surveillance guidelines for patients with stage I cervical cancer treated with cervical conization. The most common surveillance practice reported is pelvic examination with or without cytology every 3 months in year 1 and every 6 months thereafter. However, wide variation exists in visit frequency, cytology, and Human papillomavirus testing, and there is a clear trend away from using colposcopy and endocervical curettage. These disparate surveillance practices indicate a need for well-defined, uniform surveillance guidelines.

Comparison of minimally invasive versus open surgery in the treatment of endometrial carcinosarcoma.

OBJECTIVE: The aim of this study was to compare perioperative and oncologic outcomes between minimally invasive and open surgery in the treatment of endometrial carcinosarcoma. METHODS: We retrospectively identified all patients with newly diagnosed endometrial carcinosarcoma who underwent primary surgery via any approach at our institution from January 2009 to January 2018. Patients with known bulky disease identified on preoperative imaging were excluded. The χ2 and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival, and compared using the log rank test. RESULTS: We identified 147 eligible patients, of whom 37 (25%) underwent an open approach and 110 (75%) underwent minimally invasive surgery. Within the minimally invasive group, 92 (84%) of 110 patients underwent a robotic procedure and 14 (13%) underwent a laparoscopic procedure. Four minimally invasive cases (4%) were converted to open procedures. Median age, body mass index, operative time, stage, complication grade, and use of adjuvant treatment were clinically and statistically similar between groups. Median length of hospital stay in the open group was 4 days (range 3-21) compared with 1 day (range 0-6) in the minimally invasive group (p<0.001). The rates of any 30-day complication were 46% in the open and 8% in the minimally invasive group (p<0.001). The rates of grade 3 or higher complications were 5.4% and 1.8%, respectively (p=0.53). Median follow-up for the entire cohort was 30 months (range 0.4-121). Two-year progression-free survival rates were 52.8% (SE±8.4) in the open group and 58.5% (SE±5.1) in the minimally invasive group (p=0.7). Two-year disease-specific survival rates were 66.1% (SE±8.0) and 81.4% (SE±4.1), respectively (p=0.8). CONCLUSIONS: In patients with clinical stage I endometrial carcinosarcoma, minimally invasive compared with open surgery was not associated with poor oncologic outcomes, but with a shorter length of hospital stay and a lower rate of overall complications.

Integrated Clinical and Genomic Models to Predict Optimal Cytoreduction in High-Grade Serous Ovarian Cancer.

Advanced high-grade serous (HGSC) ovarian cancer is treated with either primary surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval surgery. The decision to proceed with surgery primarily or after chemotherapy is based on a surgeon's clinical assessment and prediction of an optimal outcome. Optimal and complete cytoreductive surgery are correlated with improved overall survival. This clinical assessment results in an optimal surgery approximately 70% of the time. We hypothesize that this prediction can be improved by using biological tumor data to predict optimal cytoreduction. With access to a large biobank of ovarian cancer tumors, we obtained genomic data on 83 patients encompassing gene expression, exon expression, long non-coding RNA, micro RNA, single nucleotide variants, copy number variation, DNA methylation, and fusion transcripts. We then used statistical learning methods (lasso regression) to integrate these data with pre-operative clinical information to create predictive models to discriminate which patient would have an optimal or complete cytoreductive outcome. These models were then validated within The Cancer Genome Atlas (TCGA) HGSC database and using machine learning methods (TensorFlow). Of the 124 models created and validated for optimal cytoreduction, 21 performed at least equal to, if not better than, our historical clinical rate of optimal debulking in advanced-stage HGSC as a control. Of the 89 models created to predict complete cytoreduction, 37 have the potential to outperform clinical decision-making. Prospective validation of these models could result in improving our ability to objectively predict which patients will undergo optimal cytoreduction and, therefore, improve our ovarian cancer outcomes.

Bacterial, Archaea, and Viral Transcripts (BAVT) Expression in Gynecological Cancers and Correlation with Regulatory Regions of the Genome.

Bacteria, archaea, and viruses are associated with numerous human cancers. To date, microbiome variations in transcription have not been evaluated relative to upper female genital tract cancer risk. Our aim was to assess differences in bacterial, archaea, and viral transcript (BAVT) expression between different gynecological cancers and normal fallopian tubes. In this case-control study we performed RNA sequencing on 12 normal tubes, 112 serous ovarian cancers (HGSC) and 62 endometrioid endometrial cancers (EEC). We used the centrifuge algorithm to classify resultant transcripts into four indexes: bacterial, archaea, viral, and human genomes. We then compared BAVT expression from normal samples, HGSC and EEC. T-test was used for univariate comparisons (correcting for multiple comparison) and lasso for multivariate modelling. For validation we performed DNA sequencing of normal tubes in comparison to HGSC and EEC BAVTs in the TCGA database. Pathway analyses were carried out to evaluate the function of significant BAVTs. Our results show that BAVT expression levels vary between different gynecological cancers. Finally, we mapped some of these BAVTs to the human genome. Numerous map locations were close to regulatory genes and long non-coding RNAs based on the pathway enrichment analysis. BAVTs may affect gynecological cancer risk and may be part of potential targets for cancer therapy.

DNA Mismatch Repair-deficient Endometrial Carcinosarcomas Portend Distinct Clinical, Morphologic, and Molecular Features Compared With Traditional Carcinosarcomas.

Uterine carcinosarcomas (UCSs) are aggressive neoplasms composed of high-grade malignant epithelial and mesenchymal elements with most (∼90%) showing TP53 abnormalities. A subset, however, shows mismatch repair deficiency (MMR-D). We sought to describe their clinical, morphologic, and molecular features. Clinicopathologic data of MMR-D UCSs were recorded including age, stage, follow-up, mismatch repair and p53 immunohistochemistry (IHC), MLH1 promoter methylation status, and germline alterations, TP53 mutation status, microsatellite instability and mutational burden by massively parallel sequencing. Seventeen (6.2%) MMR-D were identified among 276 UCSs. Of MMR-D UCSs, the median age was 60 years. mismatch repair IHC loss is as follows: MLH1/PMS2 65%, MSH2/MSH6 18%, MSH6 12%, and PMS2 6%. MLH1 promoter methylation and Lynch syndrome was identified in 47% and 12% of cases, respectively. Cases with p53 IHC showed the following patterns: wild-type 70%, aberrant 20%, and equivocal 10%. Of cases with sequencing, 88% were hypermutated and microsatellite instability high. High-grade endometrioid, undifferentiated, and clear cell carcinoma was present in 53%, 41%, and 6% of cases, respectively and 47% also showed a low-grade endometrioid component. Most patients presented at an early stage (67%) and upon follow-up, 18% died of disease, 65% showed no evidence of disease, while 18% are alive with disease. Patients with MMR-D UCS are younger than the reported median age (70 y) for traditional UCS and most do not show p53 abnormalities. Low-grade endometrioid and undifferentiated carcinoma were seen in approximately half of all cases. Although UCSs have a high tendency for early extrauterine spread, most patients in our cohort presented at an early stage and at follow-up were no evidence of disease. MMR-D UCSs display distinct clinical, morphologic, and molecular features compared with traditional UCSs.