Abstract Objective To: a) identify prognostic factors in patients with epithelial ovarian cancer treated with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS), and b) compare ...post-surgical survival between patients treated with NACT/IDS for presumed unresectable disease and stage IIIC/IV patients who underwent suboptimal primary debulking surgery (PDS). Methods This was a retrospective study of consecutive stage IIIC or IV patients undergoing IDS after NACT at Mayo Clinic from January 2007 to December 2013. A subset of patients receiving NACT/IDS for the indication of unresectable disease were matched 1:1 on age and stage to a cohort of patients who underwent suboptimal PDS between 2003 and 2011. Hazard ratios and corresponding 95% confidence intervals were estimated from Cox proportional hazards models. Results We identified 87 patients treated with NACT/IDS: the median OS and PFS following surgery was 2.4 and 1.0 years, respectively. Factors associated with significantly worse OS were older age (adjusted HR 1.60 per 10-year increase in age, 95% CI 1.18, 2.16) and elevated CA-125 before IDS (adjusted HR 2.30 for CA-125 > 35 U/mL, 95% CI 1.25, 4.23). Number of adjuvant chemotherapy cycles administered did not have a significant effect on survival. In the matched cohort analysis of presumed unresectable cases undergoing NACT/IDS vs suboptimal PDS cases (n = 45 each), the NACT/IDS group had a significant OS advantage (HR 0.53; 95% CI 0.32, 0.88), and fewer patients experienced a 30-day postoperative Accordion grade 3/4 complication (11% vs 36%, P = 0.01). Conclusions Younger age and normalization of CA-125 prior to IDS are associated with improved survival with NACT/IDS. For primary EOC where resection to residual disease of 1 cm or less is unlikely, NACT/IDS is associated with improved survival and reduced perioperative morbidity compared to PDS. As these patients are likely best served by NACT/IDS, more reliable predictors of resectability would be valuable.
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.
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.
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.
We previously reported an algorithm that identifies women at high risk of postoperative morbidity & mortality (M/M) as a tool to triage between neoadjuvant chemotherapy and primary surgery for ...epithelial ovarian cancer (EOC). We sought to independently validate its performance using multicenter data.
Women who underwent surgery for stage IIIC/IV EOC between 1/1/2014 and 12/31/2017 were identified from the National Surgical Quality Improvement Program database and classified as “high risk” or “triage appropriate” using our algorithm. Outcomes were compared between triage appropriate and high-risk women using the chi-square test.
1777 women met inclusion criteria; the mean age was 62.6 years and 81.9% had stage IIIC disease. Nationally, the surgical complexity scores were low (69.8% low, 25.2% intermediate and 5.0% high). “High risk” women had 2-fold higher rate of severe 30-day complication or death (6.2% vs 3.5%; p = 0.01), a 3-fold higher rate of 30-day mortality (1.4% vs 0.5%; p = 0.08), and a higher risk of death following a severe complication (11.1% vs. 0%, p = 0.11). A sensitivity analysis excluding women with unknown albumin who didn't meet other high risk criteria showed similar results: severe 30-day complications or death (6.2% vs 3.5%; p = 0.02) and 30-day mortality (1.4% vs 0.3%; p = 0.04) for “high risk” vs “triage appropriate” women.
Primary cytoreductive surgery to minimal residual disease remains the goal for EOC. We verify that our algorithm can identify women at risk of M/M using national multicenter data, despite a low complexity surgical setting and using 30-day mortality (vs. 90-day). Objective surgical risk assessment for ovarian cancer should be standard of care and can be incorporated into practice using the Mayo triage algorithm.
•The Mayo triage algorithm identifies women at highest risk of morbidity & mortality (M/M) after cytoreductive surgery.•Ability of our algorithm to identify women at risk of M/M after cytoreduction is verified using national multicenter data.•Given the reproducible findings, our algorithm can be applied to ovarian cancer management in varied clinical settings.
The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study ...examined the use of pafolacianine for real-time detection of folate receptor-positive ovarian cancer.
This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light.
From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor-positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7;
< .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4;
< .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported.
This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.
We aimed to examine the interplay between frailty and nutritional status on 90-day mortality after primary cytoreductive surgery (PCS) for ovarian cancer (OC).
Patients with OC who underwent PCS from ...1/2/2006–4/30/2018 at a single institution were identified. Frailty index (FI) includes 30 items and is calculated summing across all the item scores and dividing by the total; frailty was defined as FI ≥0.15. Nutritional status was considered impaired when preoperative serum albumin was <3.5 g/dL. Logistic regression was used to analyze the association between FI (continuous) and albumin status (binary) and 90-day postoperative mortality.
A total of 533 patients (mean age, 64.4 years) were included, the majority were stage IIIC disease and serous histology. Albumin was <3.5 g/dL in 87 patients (16.3%) and 113 patients (21.2%) were considered frail. Median FI was 0.07 (IQR 0.03, 0.13).
Postoperative 90-day mortality occurred in 24 patients (4.5%). Mortality within 90 days was higher amongst patients with low albumin (12/87, 13.8%), regardless of frailty status (13.8% 9/65 non-frail and 13.6% 3/22 frail patients). Ninety-day mortality in patients with normal albumin (n = 446) was over twice as likely in frail versus non-frail patients (5.5% 5/91 vs. 2.0% 7/355, respectively, p = 0.08). A model to assess 90-day mortality that included both FI and low albumin significantly improved the overall discrimination compared to low albumin alone (AUC 0.76 vs. 0.68 p = 0.03).
Our findings suggest that frailty and nutrition are both related to 90-day mortality. Preoperative interventions to improve functional and nutritional characteristics are needed.
•Albumin is a strong predictor of poor outcomes after surgery for advanced ovarian cancer irrespective of frailty status.•Patients who are either frail or nutritionally impaired are at risk for 90-day mortality after cytoreductive surgery.•Individualized prehabilitation strategies should be investigated to improve preoperative patient status.
The purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery.
Patients ...were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m
for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics.
Of 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard (
= .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37;
= .05). There was no significant difference in median overall survival (52.5
59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67;
= .31). These analyses were exploratory.
HIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.
To assess the impact of frailty as measured by a frailty deficit index (FI) on outcomes in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS).
Women with Stage IIIC/IV EOC ...who underwent PDS between 1/1/2003–12/31/2011 were included. Medical records were reviewed for patient characteristics and outcomes. The FI includes 30 items scored at 0, 0.5 or 1 and is calculated by summing across all the item scores and dividing by the total. Frailty was defined as a FI ≥0.15. Associations were assessed using logistic regression and Cox proportional hazards regression.
Of the 535 studied, 78% had stage IIIC disease and mean (SD) age was 64.3 (11.3) years. Median FI was 0.08, and 131 patients (24.5%) were considered frail with FI ≥0.15.
Compared to non-frail patients, frail patients were more likely to have an Accordion grade 3+ complication (28.2 vs. 18.8%; odds ratio (OR): 1.70, 95% CI: 1.08–2.68) and more likely to die within 90days of surgery (16.0 vs. 5.2%; OR: 3.48, 95% CI: 1.83–6.61). After adjusting for known risk factors, these associations remained significant, adjusted OR (aOR): 1.62, 95% CI: 1.00–2.62; aOR: 2.60, 95% CI 1.32–5.10; and aOR: 0.57, 95% CI 0.34–0.97, respectively.
Overall survival (OS) for the entire cohort was 39.6months (m). OS was shorter in the frail versus non-frail (median 26.5 vs 44.9m, p<0.001). Frailty was independently associated with death (adjusted hazard ratio: 1.52, 95% CI: 1.21–1.92) after adjusting for known risk factors.
Frailty is a common finding in patients with EOC and is independently associated with worse surgical outcomes and poorer OS. Routine assessments of frailty can be incorporated into patient counseling and decision-making for the EOC patient beyond simple reliance on single factors such as age.
•Frailty is easily measured and common in advanced epithelial ovarian cancer.•Frailty is associated with higher rates of peri-operative morbidity and mortality.•Frail patients with ovarian cancer have shorter survival than non-frail patients.
To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and ...high-risk endometrial cancer (EC).
We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors.
Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology.
Observation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.
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