Opinion statement
Pelvic exenteration is a radical surgery, but oftentimes, it is the last curative option for patients with recurrent gynecologic malignancies who have exhausted more conservative ...therapies. Mortality and morbidity outcomes have improved over time, but there are still significant peri-operative risks. Considerations before pursing pelvic exenteration must include the likelihood of oncologic cure and patients’ fitness to undergo such a procedure, particularly given the high rate of surgical morbidity. Pelvic sidewall tumors have been a traditional contraindication for pelvic exenteration due to the difficulty in obtaining negative margins, but the use of laterally extended endopelvic resection and intra-operative radiation therapy allows for more radical resection of recurrent disease. We believe that these procedures to achieve R0 resection can expand the use of curative-intent surgery in recurrent gynecologic cancer, but require the surgical expertise of colleagues in orthopedic and vascular surgery and collaboration with plastic surgery for complex reconstruction and optimization of post-operative healing. Surgery of recurrent gynecologic cancer including pelvic exenteration, requires careful patient selection, pre-operative medical optimization and prehabilitation, and thorough counseling to optimize outcomes, both oncologic and peri-operative. We believe the creation of a well-developed team, including surgical teams and supportive care services, can lead to the best patient outcomes and improved professional satisfaction amongst providers.
Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins ...reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.
Abstract Objectives To assess the impact of muscle composition and sarcopenia on overall survival in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). Methods Women with ...stage IIIC/IV EOC who underwent PDS with curative intent between 1/1/2006 and 12/31/2012 were included. Patient variables and vital status were abstracted. Body composition was evaluated in a semi-automated process using Slice-O-Matic software v4.3 (TomoVision). Skeletal muscle area and mean skeletal muscle attenuation were recorded. Associations with overall survival were evaluated using Cox proportional hazards models and recursive partitioning. Results We identified 296 patients and 132 (44.6%) were classified as sarcopenic. The average mean skeletal muscle attenuation of the entire cohort was 33.4 Hounsfield units (HU). A multivariate model of overall risk of death included histology, residual disease, and mean skeletal attenuation. Among patients without residual disease, overall survival, but not progression free survival was significantly different between patients with low versus high mean skeletal attenuation (median survival, 2.8 vs. 3.3 years). Among patients with residual disease, overall survival was significantly different between patients with low versus high mean skeletal attenuation ≥ 36.40 vs. < 36.40 HU (median survival, 2.0 vs. 3.3 years). Conclusions Sarcopenia and low mean skeletal muscle attenuation are common in women undergoing PDS for advanced EOC. These factors are associated with poorer outcomes, and can be used in preoperative risk stratification and patient counseling. Further research into body composition and whether this risk factor can be altered via nutrition or fitness in this population is warranted.
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).
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).
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).
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.
•Both primary debulking (PDS) & neoadjuvant chemotherapy (NACT) are ideal approaches for different ovarian cancer patients•Choice between NACT and PDS should be based on risk of surgical morbidity and mortality•Use of our triage algorithm to choose between PDS and NACT reduces 90 day mortality after PDS•Use of our triage algorithm also improved residual disease and ability to start chemotherapy within 42 days of surgery.
Abstract
In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby ...patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.
We investigated the impact of sarcopenia on adjuvant chemotherapy dosing in advanced epithelial ovarian cancer (EOC). The chemotherapy dosing and toxicity of 173 eligible patients who underwent ...cytoreductive surgery and adjuvant chemotherapy at a single institution were analyzed. Patients with a skeletal muscle index less than 39 cm
/m
measured on a CT scan were considered sarcopenic. Sarcopenic and non-sarcopenic patients were compared with regard to relative dose intensity (RDI), completion of scheduled chemotherapy, toxicity, and survival. A total of 62 (35.8%) women were sarcopenic. Sarcopenic women were less likely to complete at least six cycles of chemotherapy (83.9% vs. 95.5%,
= 0.02). The mean RDI for both carboplatin (80.4% vs. 89.4%,
= 0.03) and paclitaxel (91.9% vs. 104.1%,
= 0.03) was lower in sarcopenic patients compared to non-sarcopenic patients. Despite these differences in chemotherapy, there was no difference in neutropenia or median overall survival (3.99 vs. 4.57 years,
= 0.62) between the sarcopenic and non-sarcopenic women, respectively. This study highlights the importance of considering lean body mass instead of body weight or surface area in chemotherapy dosing formulas for sarcopenic women with advanced EOC. Further research is needed to optimize chemotherapy strategies based on individual body composition, potentially leading to improved dosing strategies in this population.
•There are multiple disease and treatment related barriers to participating in an exercise based prehabilitation program.•Patients with advanced ovarian cancer are interested and motivated to take ...part in prehabilitation despite barriers.•The oncology care team has notable influence on a patient’s motivation and willingness to participate in prehabilitation.
Prehabilitation may modify frailty and increase resilience in a subset of ovarian cancer patients; however there is low adherence to most programs. Our aim was to investigate potential barriers and facilitators of prehabilitation during neoadjuvant chemotherapy (NACT). We identified 15 patients who underwent NACT from 2016 to 2018. Patients underwent a semi-structured one-on-one interview. Transcripts were coded by 4 independent reviewers to identify emerging themes related to patients’ experience, functioning and exercise during chemotherapy. Data saturation occurred after 15 interviews. Patients had a mean age of 64 and were triaged to NACT for unresectable disease in 47% of cases. Patients were overall willing to participate in exercise during chemotherapy, including walking (93%), strength training (87%), and yoga or stretching (33%). Patients identified significant factors which would motivate them to exercise during treatment despite the stated barriers, including perceived benefit to overall health and well-being, improving cancer related outcomes and a supportive treatment community. In addition, the majority of patients cited advice from their physician to participate in an exercise program as highly motivating. Cancer and treatment related symptoms such as fatigue, pain, nausea and vomiting, and respiratory distress, as well as access to care, and social and mental barriers were most often identified by patients as barriers to exercise. Patients with advanced ovarian cancer demonstrated high motivation and willingness to exercise during chemotherapy, particularly when recommended by their healthcare team and when they believe there will be a direct benefit on treatment options or cancer cure.
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Small cell carcinoma of the ovary, hypercalcemic type is a rare disorder associated with a SMARC4A mutation.
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Prophylactic surgery may be helpful in reducing risk of disease, however penetrance is ...unknown.
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Prophylatic surgery in children can be considered with a fully multi-disciplinary approach.
Loss of heterozygosity in the
SMARCA4
gene is a hallmark feature of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), an aggressive ovarian cancer occurring in young adults and adolescents with an average age of 23 years and a median survival of less than fifteen months following diagnosis. Patients with germline pathogenic variants of
SMARCA4
have a genetic predisposition to developing this aggressive ovarian cancer, a condition called rhabdoid tumor predisposition syndrome type 2 (RTPS2). Given the limited efficacy of surveillance imaging for ovarian neoplasm and the absence of an identified biomarker for the progression of this disease, asymptomatic patients who are found to possess pathogenic variants of the
SMARCA4
gene following genetic testing are advised to consider risk-reducing bilateral salpingo-oophorectomy to eliminate the risk of SCCOHT. Given the reproductive impacts of this procedure, bioethical consultation must be considered when counseling patients with RTPS2, particularly for those who have not completed their desired course of family planning. In this report, we describe the bioethical considerations and outcomes for the case of a 6-year-old female with a pathogenic variant of
SMARCA4
who underwent risk-reducing bilateral salpingo-oophorectomy (RRBSO). To our knowledge, this is the first time that this procedure has been reported in a prepubertal individual for cancer prevention in a patient with RTPS2.
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