Andra Nica

Effect of fragmentation of surgery and adjuvant treatment in high-grade nonendometrioid endometrial cancer: a population-based cohort study

Fragmented care (FC) occurs when patients receive treatment across several different hospitals. Regionalization of surgery for patients with high-grade endometrial cancer means that patients must travel longer distances to receive care; these patients often require adjuvant treatment after surgery. To determine whether the fragmentation of surgery and adjuvant treatment impacts survival in patients with high-grade nonendometrioid endometrial cancer. This population-based retrospective cohort study included patients diagnosed between 2003 and 2017 with high-grade nonendometrioid endometrial cancer who received adjuvant treatment postoperatively. Nonfragmented care was defined as receiving surgery and adjuvant treatment at the same institution. The primary outcome was overall survival. We identified 1795 patients, of whom 583 (32.5%) had FC. Patients with nonfragmented care were more likely to have had surgery by a gynecologic oncologist (92.4 vs 58.8%, P<.001), surgical staging (66.6 vs 44.8%, P<.001), and less travel for surgery (mean 30.8 km vs 93.7 km, P<.001). They were less likely to receive chemotherapy (26.3 vs 30%, P<.001) and chemoradiation (38.4 vs 41.3%, P<.001). Median survival was 9 years. There was no significant difference in overall survival between patients who received FC and nonfragmented care; 92.4% and 93.5% of the patients in the FC and nonfragmented care groups were treated at a specialized gynecologic oncology center for at least part of their treatment (surgery, adjuvant treatment, or both). We have previously shown that regionalization of surgery in high-grade endometrial cancer is associated with improved survival. Fragmentation of surgery and adjuvant treatment in this population does not have an adverse effect on survival. After receiving surgical treatment with a gynecologic oncologist, these patients may receive adjuvant treatment closer to home to decrease financial and travel burden.

Assessing para‐aortic nodal status in high‐grade endometrial cancer patients with negative pelvic sentinel lymph node biopsy

Abstract Objective To determine the accuracy of pelvic sentinel lymph node biopsy (SLN) in detecting positive para‐aortic (PA) lymph nodes in high‐grade uterine cancer, and to determine the recurrence rate in patients with high‐grade uterine cancers who did not receive adjuvant chemotherapy based on negative pelvic SLNs. Methods This was a retrospective cohort study of patients with newly diagnosed, high‐grade endometrial cancer who underwent surgery, including pelvic SLNs with or without PA node dissection, at a tertiary care institution between 2015 and 2020. Baseline demographics, surgical management, pathology data, and outcomes were analyzed using descriptive statistics, and survival analysis. Results Postoperative histology of the 110 patients meeting inclusion criteria was 45.5% grade 3 endometrioid, 36.4% serous, 10.9% clear cell, and 7.3% carcinosarcoma. On final pathology, 63.7% were stage 1, and 23.6% were stage 3C with positive nodes. A total of 63 patients (57.3%) had a PA lymph node dissection (56 bilateral, 7 unilateral) in addition to the pelvic SLN. Among this group, 5.8% (95% confidence interval 1.2%–16.0%) had a positive PA node despite a negative pelvic SLN. Among those with a negative pelvic SLN and no adjuvant chemotherapy ( n  = 75), the rate of distant recurrence was 14.7%, and 3‐year recurrence‐free survival was 71.9%. Conclusion The rate of isolated PA node metastasis in high‐grade endometrial cancers despite a negative pelvic SLN may be significantly higher than the accepted rate of isolated PA node metastasis in low‐grade endometrial cancer. This supports adjuvant treatment decisions continuing to incorporate primary tumor pathology and molecular classification.

Outcomes after the regionalization of care for high-grade endometrial cancers: a population-based study

In June 2013, Ontario Health (Cancer Care Ontario), the agency responsible for advancing cancer care in Ontario, Canada, published practice guidelines recommending that gynecologic oncologists at tertiary care centers manage the treatment of patients with high-grade endometrial cancers. This study examines the effects of this regionalization of care on patient outcomes. This study aimed to evaluate the impact of the regionalization of surgery for high-grade endometrial cancer on patient and treatment outcomes. In this retrospective cohort study, patients diagnosed with nonendometrioid high-grade endometrial cancer from 2003 to 2017 were identified using province-wide administrative databases. To allow 6 months for knowledge translation, 2 periods were defined, with January 1, 2014, as the cutoff. Methods for segmented regression were used to test the effect of the guidelines. Multivariable Cox proportional hazards regression was used to evaluate whether regionalization of care had an impact on patient survival. There were 3518 patients with nonendometrioid high-grade endometrial cancer identified. The case mix as represented by patient comorbidities and the disease stage distribution did not differ significantly between the 2 regionalization periods. There was a significant increase (69%-85%; P<.001) in the proportion of primary surgeries performed by gynecologic oncologists after regionalization, which was not explained by secular trends. After regionalization, the proportion of patients who had surgical staging (50%-63%; P<.001) and the proportion of patients who received adjuvant treatment (65%-71%; P<.001) increased significantly. After adjusting for age, stage, and comorbidities, there was a decrease in the hazard of mortality (hazard ratio, 0.85 [95% confidence interval, 0.73-0.99]; P=.04) after regionalization. The publication of a regionalization policy for the treatment of high-grade endometrial cancers in Ontario led to an increase in the proportion of surgeries performed by gynecologic oncologists. This also translated into a significant improvement in patient survival.

Impact of lymphadenectomy and intra-operative tumor rupture on survival in early-stage mucinous ovarian cancers

Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer with scarce literature guiding its management. We aimed to investigate the optimal surgical management of clinical stage I mucinous ovarian carcinoma by examining the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival. We conducted a retrospective cohort study of all pathology-reviewed invasive mucinous ovarian carcinomas diagnosed between 1999 and 2019 at two tertiary care cancer centers. Baseline demographics, surgical management details, and outcomes were collected. Five-year overall survival, recurrence-free survival, and the association of lymphadenectomy and intra-operative rupture on survival were examined. Of 170 women with mucinous ovarian carcinoma, 149 (88%) had clinical stage I disease. Forty-eight (32%; n=149) patients had a pelvic and/or para-aortic lymphadenectomy, but only 1 patient with grade 2 disease was upstaged due to positive pelvic lymph nodes. Intra-operative tumor rupture was documented in 52 cases (35%). On multivariable analysis, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2 (0.6-8.0); p=0.3) or recurrence-free survival (HR 1.3 (0.5-3.3); p=0.6), or lymphadenectomy with overall survival (HR 0.9 (0.3-2.8); p=0.9) or recurrence-free survival (HR 1.2 (0.5-3.0); p=0.7). Advanced stage was the only factor that was significantly associated with survival. In clinical stage I mucinous ovarian carcinoma, systematic lymphadenectomy has low utility, as very few patients are upstaged and recurrence typically occurs in the peritoneum. Furthermore, intra-operative rupture does not appear to independently confer a worse survival, and therefore these women may not benefit from adjuvant treatment based on rupture alone.

Survival after minimally invasive surgery in early cervical cancer: is the intra-uterine manipulator to blame?

Minimally invasive radical hysterectomy is associated with decreased survival in patients with early cervical cancer. The objective of this study was to determine whether the use of an intra-uterine manipulator at the time of laparoscopic or robotic radical hysterectomy is associated with inferior oncologic outcomes. A retrospective cohort study was carried out of all patients with cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) International Federation of Gynecology and Obstetrics 2009 stages IA1 (with positive lymphovascular space invasion) to IIA who underwent minimally invasive radical hysterectomy at two academic centers between January 2007 and December 2017. Treatment, tumor characteristics, and survival data were retrieved from hospital records. A total of 224 patients were identified at the two centers; 115 had surgery with the use of an intra-uterine manipulator while 109 did not; 53 were robotic and 171 were laparoscopic. Median age was 44 years (range 38-54) and median body mass index was 25.8 kg/m After controlling for adverse pathological factors, the use of an intra-uterine manipulator in patients with early cervical cancer who underwent minimally invasive radical hysterectomy was not an independent factor associated with rate of recurrence.

Advances in Vulvar Cancer Biology and Management

PURPOSE Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC. DESIGN We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC. RESULTS Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV–) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV–/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design. CONCLUSION Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.

Phase II activity trial of high-dose radiation and chemosensitization in patients with macrometastatic lymph node spread after sentinel node biopsy in vulvar cancer: GROningen INternational Study on Sentinel nodes in Vulvar cancer III (GROINSS-V III/NRG-GY024)

Standard treatment of early-stage vulvar cancer is a radical, wide, local excision of the primary tumor and a sentinel lymph node (SLN) procedure for the groins. An inguinofemoral lymphadenectomy is no longer necessary for patients who have a negative SLN or micrometastasis ( To investigate the safety of replacing inguinofemoral lymphadenectomy by chemoradiation in patients with early-stage vulvar cancer with a macrometastasis (>2 mm) and/or extracapsular extension in the sentinel node. Combination of 56 Gy of radiation to the inguinal site and concurrent cisplatin chemotherapy without completion inguinofemoral lymphadenectomy will be feasible and safe, with low groin recurrence rates. This is a single-arm, prospective phase II treatment trial with stopping rules for unacceptable groin recurrences. Eligible patients will receive 56 Gy of radiation to the involved inguinal site and chemotherapy with concurrent cisplatin. Eligible patients undergoing sentinel node procedure will have stage I, unifocal, invasive (>1 mm depth of invasion) squamous cell carcinoma of the vulva with tumor size 2 mm in the sentinel node and/or extracapsular extension, or more than one sentinel node with micrometastasis ≤2 mm. Groin recurrence rate in the first 2 years after primary treatment. 157 patients with macrometastases in their SLN. January 1, 2029. NCT05076942.

Cervical conization and lymph node assessment for early stage low-risk cervical cancer

There has been a contemporary shift in clinical practice towards tailoring treatment in patients with early cervical cancer and low-risk features to non-radical surgery. The objective of this study was to evaluate the oncologic, fertility, and obstetric outcomes after cervical conization and sentinel lymph node (SLN) biopsy in patients with early stage low-risk cervical cancer. We conducted a retrospective review in patients with early cervical cancer treated with cervical conization and lymph node assessment between November 2008 and February 2020. Eligibility criteria included patients with a histologic diagnosis of invasive squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage IA1 with positive lymphovascular space invasion (LVSI), stage IA2, or stage IB1 (≤2 cm) with less than two-thirds (<10 mm) cervical stromal invasion. A total of 44 patients were included in the analysis. The median age was 31 years (range 19-61) and 20 patients (45%) were nulliparous. One patient had a 25 mm tumor while the remaining patients had tumors smaller than 20 mm. Eighteen (41%) patients had LVSI. Median follow-up was 44 months (range 6-137). A total of 17 (39%) patients had negative margins on the diagnostic excisional procedure, and none had residual disease on the repeat cone biopsy. Three (6.8%) patients had micrometastases detected in the SLNs and underwent ipsilateral lymphadenectomy; all remaining non-SLN lymph nodes were negative. Six (13.6%) patients required more definitive surgical or adjuvant treatment due to high-risk pathologic features. There were no recurrences documented. Three patients developed cervical stenosis. The live birth rate was 85% and 16 (94%) of 17 patients had live births at term. Cervical conization with SLN biopsy appears to be a safe treatment option in selected patients with early cervical cancer. Future results of prospective trials may shed definitive light on fertility-sparing options in this group of patients.

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

PURPOSE Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. METHODS This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype–specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS. RESULTS With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P &lt; .001; and 82% v 24%, P &lt; .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS. CONCLUSION Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Rates of genetic consultation in high‐grade serous ovarian cancer patients in the era of PARP inhibitor therapy: A population‐based study

AbstractObjectiveThe American Society of Clinical Oncology recommends all patients with high‐grade serous ovarian carcinoma (HGSC) undergo germline genetic testing. Genetic consultation rates in Ontario, Canada, only reached 13.3% in 2011. In 2016, PARP inhibitor maintenance therapy became available in Ontario for BRCA‐positive HGSC patients. Given expanding treatment options, we re‐examined genetic consultation rates among HGSC patients.MethodsThis retrospective cohort study identified patients diagnosed with HGSC between 2012 and 2019 using population‐based administrative data from Ontario. Genetics consultations were identified using Ontario Health Insurance Plan billing codes. Consultation rates over time were analyzed using Cochran–Armitage trend test and segmental regression analysis. Multivariable analysis identified factors associated with attending genetics consultation.ResultsThis study included 4645 HGSC patients. The mean age was 64.2 years (±SD 12.3); 56.3% had stage 3–4 disease. Overall, approximately 35% attended genetics consultations. The genetic consultation rate per year increased significantly from 21.6% to 42.6% (P &lt; 0.001). Shorter times between diagnosis and genetics consult were observed after PARP inhibitors became available (68.1 vs 34.1 weeks, P &lt; 0.001). Patients treated at designated cancer centers (odds ratio [OR] 2.11, P &lt; 0.001), diagnosed in later years (OR 1.33, P &lt; 0.001), and from higher income groups (P &lt; 0.05) were more likely to attend genetics consultation; older patients were less likely (OR 0.98, P &lt; 0.001). After PARP inhibitors became available, consultation rates plateaued (P &lt; 0.001).ConclusionsBetween 2012 and 2019, genetic consultation rates improved significantly among HGSC patients; however, a large proportion of patients never attended consultation. Further exploration of barriers to care is warranted to improve consultation rates and ensure equitable access to care.

Association of body mass index and length of stay in patients undergoing minimally invasive surgery for uterine cancer: a National Surgical Quality Improvement Program (NSQIP) study.

Body mass index (BMI) has been associated with length of stay and post-operative complications; however, minimally invasive surgery has been proposed to mitigate this. Using real-world data of patients undergoing minimally invasive surgery for uterine cancer, we investigated the association between BMI and length of stay. Among patients discharged the same day, we explored post-operative complications associated with BMI. This was a National Surgical Quality Improvement Program retrospective cohort study including patients who underwent minimally invasive surgery for uterine cancer from 2013 to 2022. We performed a multi-variable Poisson regression to assess the association between BMI and length of stay, adjusting for a priori selected patient-level factors. In patients discharged the same day after surgery, we performed multi-variable linear regression to assess associations between BMI and the following post-operative complications: wound disruption, blood transfusion, surgical site infections, urinary tract infection, pneumonia, sepsis, deep vein thrombosis, pulmonary embolism, renal insufficiency, myocardial infarction, stroke/cerebrovascular accident, and re-admission, return to the operating room, and death within 30 days. A total of 33,307 patients were included. Their median BMI was 34.2 kg/m In patients undergoing minimally invasive surgery for uterine cancer, BMI was not associated with a clinically significant increase in length of stay, and in those discharged the same day, BMI was not associated with post-operative complications. Minimally invasive surgery for uterine cancer should be considered standard of care regardless of patient BMI, and same-day discharge for patients with elevated BMI is safe.

Groningen International Study on Sentinel Nodes in Vulvar Cancer-III

Vulvar cancer patients with SN-metastasis \> 2mm will receive chemoradiation instead of an inguinofemoral lymphadenectomy.

FDG-PET and Circulating HPV in Patients With Cervical Cancer Treated With Definitive Chemoradiation (II)

Nearly all cervical cancers are caused by the human papilloma virus (HPV), which can be detected in cancer tissue by laboratory tests. There is evidence that the virus can also be detected from a blood sample to monitor the effects of treatment. Previous studies have shown that a special test called 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET-CT) at 3 months after treatment may predict survival in cervical cancer. The purpose of this study is to see how well the FDG-PET Scan and blood tests for HPV can detect leftover cervical cancer cells after treatment. This study is not a particular form of treatment and patients will receive standard of care treatment.

Liquid Biopsy Evaluation and Repository Development at Princess Margaret

The objective of this protocol is to develop an institution-wide liquid biopsy protocol that will establish a common process for collecting blood and corresponding archived tumor specimens for future research studies at the University Health Network's Princess Margaret Cancer Centre. Circulating cell-free nucleic acids (cfNA), including cell-free DNA (cfDNA) and cell-free RNA (cfRNA), are non-invasive, real-time biomarkers that can provide diagnostic and prognostic information before cancer diagnosis, during cancer treatment, and at disease progression. Cancer research scientists and clinicians at the Princess Margaret are interested in incorporating the collection of peripheral blood samples ("liquid biopsies") into research protocols as a means of non-invasively assessing tumor progression and response to treatment at multiple time points during a patient's course of disease.