Glaser, Gretchen

PURPOSE To compare mortality risk among long-term survivors of high-grade serous ovarian cancer (HGSOC) with that of the general US population and to examine how mortality and recurrence trends have evolved under changing treatment approaches. MATERIALS AND METHODS This is a retrospective cohort study including patients with histologically confirmed HGSOC treated at a single referral cancer center from 1991 to 2022. Mortality risk, expressed as standardized mortality ratios (SMRs, ratio of observed deaths in the study population to expected deaths in an age-matched US population), was assessed at diagnosis and yearly on patients without events (disease persistence, recurrence, or death from any cause). RESULTS A total of 2,074 consecutive patients were included. The median follow-up was 12.5 years (IQR, 11.7-13.8). Most patients were stage III (1,396, 69.2%), 1,299 (62.8%) underwent primary cytoreductive surgery, and 1,688 (87.4%) received platinum-taxane as first-line therapy. At diagnosis, the mortality rate was 7.40 times higher than that in the general population (95% CI, 7.04 to 7.77). By 7 event-free years, the 95% CI for the SMR included 1 for the first time, and at 10 years, the SMR was 1.05 (95% CI, 0.72 to 1.49), indicating no statistically significant excess mortality compared with the general population. In those event-free at 10 years, the 5-year cumulative incidence of ovarian cancer–related deaths (8.2% [95% CI, 4.2 to 16.0]) was comparable with that of non–ovarian cancer–related deaths (6.3% [95% CI, 2.9 to 13.8]). CONCLUSION In this cohort, mortality risk steadily declined for patients who remained event-free, approaching that of the general population by 7 years after diagnosis. These results emphasize the importance of individualized, long-term follow-up to address both recurrence risk and survivorship needs.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vaginal Cancer outline the recommended diagnostic workup, staging considerations, and treatment options for this rare malignancy. Because vaginal cancer is uncommon and shares many biologic and clinical characteristics with cervical cancer, several management recommendations, particularly systemic therapy, are extrapolated from evidence and practices established for cervical cancer. This guideline excerpt summarizes key components of management, including diagnostic evaluation and workup, principles of staging, pathology considerations, radiation therapy principles, and primary treatment recommendations for both early-stage and advanced disease. It also details approaches to manage relapses, including locoregional recurrence and distant metastases, and provides an in-depth overview of systemic therapy recommendations for vaginal cancer.

Purpose of review The aim is to summarize the role of sentinel lymph node biopsy (SLN) in surgical staging for endometrial cancer (EC). Recent findings The value of SLN in EC staging continues to be demonstrated in all clinically uterine-confined disease, as SLN matches or improves the diagnostic accuracy of pelvic±para-aortic lymphadenectomy (PLD ± PALD) while reducing recovery time, surgical complications, and risk of lower extremity lymphedema. High diagnostic accuracy allows recommendation of appropriate adjuvant therapy, and recent studies have shown that even patients with high-risk histology may undergo SLN as opposed to PLD ± PALD provided this is combined with appropriate imaging. Debate about the necessity of any lymph node assessment in patients with certain low-risk features continues, with a preponderance of evidence pointing toward universal SLN in patients undergoing surgical staging for EC. In patients with negative SLN and intermediate risk uterine factors, molecular profiling is recommended to augment information gained through surgical assessment. Summary EC surgical staging with SLN is considered standard practice in clinically uterine-confined disease. This approach allows precise treatment recommendations without PLD ± PALD related side effects. The integration of molecular profiling with EC surgical staging will accelerate the benefits of therapeutic advances in EC.

Abstract: Lymphedema is a prevalent, incurable, and morbid condition with the potential to degrade the health and quality of life of patients living with cancer and beyond cancer. Effective long term control requires coordination by an interdisciplinary team to ensure that lymphedema progression, complications, and related disablement are detected and appropriately addressed. This review provides an overview of lymphatic function and lymphedema pathogenesis with focused discussion of the unique characteristics of cancer related lymphedema (CRL) including natural history, clinical presentation, and risk factors for onset and progression. Surgical practice changes and supportive evidence for lymph node sparing and lymphatic reconstruction for CRL prevention are described. The review outlines evaluations to diagnose, stage, and monitor CRL, and characterizes evidence for current CRL prevention and management practices, including surgeries to restore lymphatic function. Multimodal management with complete decongestive therapy remains first line treatment for CRL, though patient-specific customization might be required to optimize patients’ clinical response and quality of life as outlined in the review.

e15125 Background: Endometrial cancer (EC) is the most common gynecologic malignancy, with endometrioid being the most prevalent histology. Approximately 75% of high-grade endometrioid tumors are TP53 wild-type. During studies testing a novel combination of the PARP inhibitor rucaparib and TOP1 poison SN38 in high-risk primary patient serous and serous-like ECs, a subset of non-serous ECs with normal p53 expression showed unexpected synergy. This suggests broad efficacy in EC, warranting in vivo studies to assess tolerability and efficacy. Given potential overlapping toxicity, a novel formulation, pegylated SN38 (PLX038A), was tested. Methods: Primary patient tumors (n=4) were treated with rucaparib (0µM-25 µM) and SN38 (0µM-0.5 µM) in 3D cell culture experiments. RealTime Glo assessed viability after 3-5 days of drug exposure. Combination indices were determined using the Chou-Talalay method. Tolerability and efficacy were assessed in female SCID-beige mice (n=45) injected with intraperitoneal EC PDX tumors. Mice were randomized to controls, PLX038A (15 mmol/µmol IP, every 14 days), rucaparib (150 mg/kg daily gavage), or combination (same dose and schedule) for 8 weeks. Tolerability was assessed by daily animal weight and total condition score (TCS) from 1 (emaciated, non-ambulatory) to 13 (obese). Weight change more than -20% or TCS < 5 defined moribund criteria. Weekly ultrasound measurements assessed tumor response. Results: All four primary patient tumors exhibited synergy, with a combination index less than 1. Moribund criteria were not met in any mice across all cohorts. The average percent weight change and lowest TCS across cohorts were: rucaparib (-8.51%, min/max -19 to +14%; TCS 6.25, range 5-8, n=8), PLX038A (-3.97%, min/max -19 to +5%; TCS 6.8, range 6-9, n=10), the combination (-5.52%, min/max -15 to +1.8%; TCS 7.18, range 6-8, n=11), and control (+1.61%, range -6 to +8%; TCS 6.5, range 6-7, n=4). Scores were similar between groups, but the slightly lower TCS in the rucaparib cohort was associated with higher tumor burden from ineffective therapy. Tumors in the rucaparib monotherapy group grew similarly to controls. In contrast, the combination therapy cohort exhibited significant regression below baseline during treatment. Conclusions: These findings suggest that the combination of rucaparib and SN38 (PLX038A) is effective in EC primary patient tumor organoids and PDXs with wild-type TP53. No significant negative physiological effects on animal TCS and weight change were observed. No drug-related toxicity was observed in mice receiving combination treatment. Mice receiving combination treatment displayed significant tumor regression below baseline compared to both single agents and control. These data support future exploration of this combination therapy in ECs.

Endometrial cancer (EC) patients make up the second largest group of female cancer survivors. Patient-reported outcomes (PROs) including quality of life (QOL) and sexual function and satisfaction (SF and S) are critical facets of survivorship. This prospective, longitudinal study assesses associations between baseline characteristics and PROs after treatment. Herein, we report the baseline clinical characteristics and PROs prior to treatment initiation. Outcomes post-treatment over time will be reported separately. Patients with planned surgery for EC were prospectively enrolled in 2019–2021 and administered the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC Module (EN24), Patient-Reported Outcomes Measurement Information System (PROMIS), and the Mayo Clinic lower extremity lymphedema (LEL) questionnaire. This study enrolled 198 patients with a mean (SD) age of 63.6 (9.8) years and body mass index of 35.5 (8.3) kg/m2. No significant differences in the PROs for the QOL were seen when compared to the reference means (SD) except for the lower interest in sexual activity (31.9 (9.8) vs. 47.5 (SE0.70)) and lower fatigue (21.3 (19.8) vs. 31.7 (25.9)). Increased obesity was associated with an increased likelihood of LEL (p < 0.01) and multiple QOL scales, including poorer global health status (p < 0.01) and physical functioning (p < 0.01). Prior to treatment initiation for EC, the patients had a similar QOL compared to that of the general population. The patients with increasing obesity, a known risk factor for EC, had worse overall global health status and physical functioning. A better understanding of these QOL measures is imperative for earlier identification and intervention of patients at risk of chronic impairments from EC treatment.

Endometrial cancer (EC) is the most diagnosed gynecologic malignancy, and its incidence and mortality are increasing. The prognosis is highly dependent on the disease spread. Surgical staging includes retroperitoneal evaluation to detect potential lymph node metastases. In recent years, systematic lymphadenectomy has been replaced by sentinel lymph node (SLN) biopsy and ultrastaging, allowing for the detection of macrometastases, micrometastases, and isolated tumor cells (ITCs). Micrometastases and ITCs have been grouped as low-volume metastases (LVM). The reported prevalence of LVM in studies enrolling more than one thousand patients with apparent early-stage EC ranges from 1.9% to 10.2%. Different rates of LVM are observed when patients are stratified according to disease characteristics and their risk of recurrence. Patients with EC at low risk for recurrence have low rates of LVM, while intermediate- and high-risk patients have a higher likelihood of being diagnosed with nodal metastases, including LVM. Macro- and micrometastases increase the risk of recurrence and cause upstaging, while the clinical significance of ITCs is still uncertain. A recent meta-analysis found that patients with LVM have a higher relative risk of recurrence [1.34 (95% CI: 1.07–1.67)], regardless of adjuvant treatment. In a retrospective study on patients with low-risk EC and no adjuvant treatment, those with ITCs had worse recurrence-free survival compared to node-negative patients (85.1%; CI 95% 73.8–98.2 versus 90.2%; CI 95% 84.9–95.8). However, a difference was no longer observed after the exclusion of cases with lymphovascular space invasion. There is no consensus on adjuvant treatment in ITC patients at otherwise low risk, and their recurrence rate is low. Multi-institutional, prospective studies are warranted to evaluate the clinical significance of ITCs in low-risk patients. Further stratification of patients, considering histopathological and molecular features of the disease, may clarify the role of LVM and especially ITCs in specific contexts.

Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m2, BEV 30–70 mg/m2). Pharmacokinetic analyses were performed. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

e17518 Background: Morbidity and mortality for patients with cervical cancer has improved significantly over the past few decades with modern multimodal therapy. However, neuroendocrine carcinoma of the uterine cervix (NCUC), which accounts for 1-2% of cervical cancers, remains a deadly subtype. In this study, we combine data from Mayo Clinic (MC) and the University of Iowa Hospitals and Clinics (UIHC) to provide information on tumor characteristics, treatment, and outcomes. Methods: The electronic medical record was reviewed for patients with NCUC from MC and UIHC. Data on diagnosis, treatment, and outcomes were collected through chart review. Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included median survival, survival at 1 year after surgery, and survival at 1 year by first line chemotherapy agent. Kaplan-Meier survival analysis was used to estimate median PFS, median survival, and OS. Fisher’s test analysis was used to calculate survival at 1 year after surgery and by first line chemotherapy agent. Results: There were 62 patients (MC: 26, UIHCC: 36) with NCUC stage I-IV (stage I: 29, stage II: 9, stage III: 7, stage IV: 14, unknown: 3). Median age of diagnosis was 47 years (range 21-77 years). By subtype, 47 were small cell (76%), 9 were large cell (15%), and 6 were unknown/undetermined (9%). The initial treatment modalities for each patient are outlined in the table. 28 patients had complete/partial response or stable disease from first line treatment, while 10 patients had disease progression. Of the patients who initially responded or had stable disease, 16 later progressed (57%) with a median time to progression of 15 months. Median follow up was 65.1 months with a median OS of 28.5 months. Median survival for those with stage I was 40.9 months, stage II: 54.6 months, stage III: 8.75 months, and stage IV: 11.7 months. There was a significant difference in overall survival at 1 year between those who received surgery and those who did not in stage I/II ( p = 0.01). There was no significant difference in overall survival at 1 year for those who received surgery in stage III/IV. There was no statistical difference in survival at 1 year for carboplatin or cisplatin in combination with etoposide as first line chemotherapy agent. Conclusions: NCUC is an aggressive malignancy that is usually progressive despite multimodal therapy. Our study demonstrated a median overall survival of 28.5 months and 5-year survival rate of 21%. Our study showed a survival benefit at 1 year for those who receive surgery with stage I/II NCUC. There was no significant survival benefit at 1 year between carboplatin or cisplatin in combination with etoposide as first line agent.[Table: see text]