Surgical and oncologic outcomes of hyperthermic intraperitoneal chemotherapy for uterine leiomyosarcoma: A systematic review of literature.

OBJECTIVE: To examine the perioperative and survival outcomes in women with disseminated peritoneal uterine leiomyosarcoma (uLMS) who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A comprehensive systematic review of literature was conducted using multiple public search engines, PubMed, Scopus, and the Cochrane Library, in compliance with the PRISMA guidelines. Women with disseminated peritoneal uLMS treated with CRS-HIPEC were analyzed. Perioperative morbidity and mortality rate as well as oncologic outcomes related to CRS-HIPEC were assessed. RESULTS: Ten studies met the inclusion criteria from 2004 to 2020, including 8 case series (n=28) and 2 original articles (n=47). Of the 75 patients, 68 (90.7%) were women with uLMS whereas 7 women were non-uLMS. Of these, 64 (85.3%) had recurrent disease, and 39 (52.0%) received chemotherapy or radiotherapy prior to CRS-HIPEC. The perioperative mortality rate was 4.0% (intraoperative 1.3%, and postoperative 2.7%), and postoperative complications (grade ≥3) rate ranged 21.4-22.2%. With regard to HIPEC regimens (n=75), cisplatin was most frequently used (n=55, 73.3%) followed by melphalan (n=17, 22.7%) and others (n=3, 4.0%). Among the two observational studies, the median overall survival after CRS-HIPEC treatment was 29.5-37 months. In one limited comparative effectiveness study (n=13), albeit statistically non-significant CRS-HIPEC was associated with higher progression-free survival versus CRS alone (3-year rates, 71.4% versus 0%, P=0.10). When the HIPEC regimens were compared, melphalan use was associated with decreased uLMS-related mortality compared to a cisplatin-based regimen, but the association was not statistically significant (hazard ratio 0.35, 95% confidence interval 0.04-3.05, P=0.35). CONCLUSION: Effectiveness of CRS-HIPEC for disseminated peritoneal uLMS is yet to be determined. As interpretation of the available data on survival is limited due to small sample sizes or the lack of an active comparator, further study is warranted to examine the safety and survival effect of CRS-HIPEC in disseminated peritoneal uLMS.

Outcomes of incidentally detected ovarian cancers diagnosed at time of risk-reducing salpingo-oophorectomy in BRCA mutation carriers.

OBJECTIVE: Prior data suggested that women with incidentally detected occult invasive ovarian cancer (OIOC) at the time of risk-reducing salpingo-oophorectomy (RRSO) for BRCA mutation may have poorer prognoses than would be expected based on disease stage. We sought to evaluate prevalence and outcomes of patients with OIOC in a tertiary referral center. METHODS: Patients with BRCA mutation undergoing RRSO from 01/2005 to 05/2017 were identified, and their records reviewed. Women with incidentally detected OIOC were included; those with clinical features raising preoperative suspicion for malignancy were excluded. RESULTS: 548 patients with BRCA mutation who underwent RRSO were identified. 26 (4.7%) had an OIOC (median age 55 years; range 42-75); 15(58%) patients, BRCA1; 9(34%), BRCA2; 2(8%) had a mutation in both genes. All OIOCs were high-grade serous: 10 (38%) Stage I; 8 (31%) Stage II; 8(31%) Stage III. 24(92%) patients received adjuvant platinum/taxane therapy. Of Stage III patients, 4 (50%) were identified intraoperatively; the remaining 4 (50%) had microscopic nodal disease on final pathology only. At median follow-up of 67.3 months (28-166) no Stage I patients have recurred; 2 Stage II and 6 Stage III patients recurred. 5-year progression-free survival (PFS) was 72% (95%CI, 50.2-85.7%); median PFS for the cohort was 129 months (95%CI, 75.3-not estimable). 5-year disease-specific survival (DSS) was 96% (95%CI, 76-99%); median DSS not reached. CONCLUSION: Consistent with prior reports, almost 5% of patients had an OIOC at RRSO. The majority with early-stage disease had excellent PFS and DSS outcomes, as would be expected based on disease stage.

Management of recurrent granulosa cell tumor of the ovary: Contemporary literature review and a proposal of hyperthermic intraperitoneal chemotherapy as novel therapeutic option.

Granulosa cell tumors of the ovary (GCT) are the most common type of sex cord stromal tumors. Although most of patients are diagnosed at early stage and has favorable 5-year overall survival rate, 16-23% of GCT ultimately develop recurrent disease. Recurrences are characterized by disseminated peritoneal metastasis. The treatment options include systemic chemotherapy, secondary CRS or palliative localized radiation therapy have not yet standardized due to the rarity of disease. Aggressive CRS followed up by hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to provide benefit in other peritoneal disease but limited data available for recurrent GCT. We have a case of recurrent Adult-type GCT (AGCT) who was treated with CRS followed by HIPEC with mitomycin C and doxorubicin. The patient has no evidence of recurrence for approximately 11 years. An electronic search of the PubMed database with the following search terms: GCT, HIPEC showed that there were total 21 patients with recurrent GCT treated in seven different studies and 13 of 21 (61.9%) patients had no evidence of disease during follow-up ranging from 6 to 100 months. Three patients (14.2%) died of the disease. Six studies used cisplatin for HIPEC. At least 76.2% (16 of 21, data not available for five patients) had complete cytoreduction with total 16 cases of perioperative complications but no perioperative mortality was observed. Although further investigation is needed, we propose that CRS and HIPEC can be an effective therapeutic option for recurrent GCT at experienced institutions.

Prevalence of viral DNA in high-grade serous epithelial ovarian cancer and correlation with clinical outcomes.

INTRODUCTION: Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. OBJECTIVE: To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. METHODS: Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. RESULTS: Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. CONCLUSIONS: The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.

Feasibility and safety of planned early discharge following laparotomy in gynecologic oncology with enhanced recovery protocol including opioid-sparing anesthesia.

Objective: This study aims to evaluate the feasibility and safety of planned postoperative day 1 discharge (PPOD1) among patients who undergo laparotomy (XL) in the department of gynecology oncology utilizing a modified enhanced recovery after surgery (ERAS) protocol including opioid-sparing anesthesia (OSA) and defined discharge criteria. Methods: Patients undergoing XL and minimally invasive surgery (MIS) were enrolled in this prospective, observational cohort study after the departmental implementation of a modified ERAS protocol. The primary outcome was quality of life (QoL) using SF36, PROMIS GI, and ICIQ-FLUTS at baseline and 2- and 6-week postoperative visits. Statistical significance was assessed using the two-tailed Student's t-test and non-parametric Mann-Whitney two-sample test. Results: Of the 141 subjects, no significant demographic differences were observed between the XL group and the MIS group. The majority of subjects, 84.7% (61), in the XL group had gynecologic malignancy [vs. MIS group; 21 (29.2%), p < 0.001]. All patients tolerated OSA. The XL group required higher intraoperative opioids [7.1 ± 9.2 morphine milligram equivalents (MME) vs. 3.9 ± 6.9 MME, p = 0.02] and longer surgical time (114.2 ± 41 min vs. 96.8 ± 32.1 min, p = 0.006). No significant difference was noted in the opioid requirements at the immediate postoperative phase and the rest of the postoperative day (POD) 0 or POD 1. In the XL group, 69 patients (73.6%) were successfully discharged home on POD1. There was no increase in the PROMIS score at 2 and 6 weeks compared to the preoperative phase. The readmission rates within 30 days after surgery (XL 4.2% vs. MIS 1.4%, p = 0.62), rates of surgical site infection (XL 0% vs. MIS 2.8%, p = 0.24), and mean number of post-discharge phone calls (0 vs. 0, p = 0.41) were comparable between the two groups. Although QoL scores were significantly lower than baseline in four of the nine QoL domains at 2 weeks post-laparotomy, all except physical health recovered by the 6-week time point. Conclusions: PPOD1 is a safe and feasible strategy for XL performed in the gynecologic oncology department. PPOD1 did not increase opioid requirements, readmission rates compared to MIS, and patient-reported constipation and nausea/vomiting compared to the preoperative phase.

Long-term outcomes after cytoreductive surgery and HIPEC for morcellated uterine leiomyosarcoma; A case series.

Uterine leiomyosarcoma (uLMS) is a rare aggressive malignant mesenchymal tumor with high risk of recurrence and poor prognosis regardless of stage. It is often diagnosed postoperatively following myomectomy, hysterectomy or supracervical hysterectomy for presumed benign disease. Primary surgery at the diagnosis of uLMS is considered to affect outcomes. If the tumor was morcellated, the oncologist will encounter special problems that require knowledgeable management of peritoneal metastases. We previously reported that six patients who successfully underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) plus early postoperative intraperitoneal chemotherapy (EPIC) to manage the disease dissemination that must occur following morcellation. This is a study for long-term outcome of these patients. Six patients were treated with an absence of grade IV adverse events and no mortality. The median Peritoneal Cancer Index (PCI) was 18 and complete cytoreduction without peritoneal metastases visualized within the operative field at the completion of the surgical procedure (CC-0) was achieved in all patients. One patient was diagnosed leiomyomatosis peritonealis postoperatively. Among five patients who were confirmed uterine leiomyosarcoma, the 3-year overall survival was 40.0% and 5-year overall survival was 20.0% with the median follow-up of 18 months (range 5-73 months). The patient with PCI 0 at the time of CRS showed no evidence of disease (NED) at 73 months. We believe that prophylactic CRS contributed her favorable outcome. Therapeutic options for patients with uLMS post-morcellation are limited. Currently, CRS and HIPEC plus EPIC followed by adjuvant systemic chemotherapy may be considered an option for treatment. Further studies in a larger number of patients are needed.

ADAMTS16 mutations sensitize ovarian cancer cells to platinum-based chemotherapy.

Ovarian cancer is one of the most lethal malignant tumors in women. The prognosis of ovarian cancer patients depends, in part, on their response to platinum-based chemotherapy. Our recent analysis of genomics and clinical data from the Cancer Genome Atlas demonstrated that somatic mutations of ADAMTS 1, 6, 8, 9, 15, 16, 18 and L1 genes were associated with higher sensitivity to platinum and longer progression-free survival, overall survival, and platinum-free survival duration in 512 patients with high-grade serous ovarian carcinoma. Among the ADAMTS mutations, ADAMTS16 is the most commonly affected gene in ovarian cancer. However, the functional role of these mutations in ovarian cancer cells is largely unknown. We performed in vitro studies to compare the functional effects of the six identified ADAMTS missense mutations on the platinum sensitivity of ovarian cancer cells. We also used a well-characterized in vivo mouse model to evaluate the response of ovarian cancer cells with ADAMTS16 mutations to platinum-based therapy. Our results showed that exogenously expressed ADAMTS16 missense mutations inhibited cell growth or sensitized tumor cells to cisplatin and inhibited tumor growth in vivo. Orthotopic xenograft experiments showed that mice injected with ovarian cancer cells that exogenously expressed ADAMTS16 mutations had a better response to cisplatin treatment. Thus, these functional studies provide evidence that mutations of ADAMTS16 actively contribute to therapeutic response in ovarian cancer.

Association of Somatic Mutations of ADAMTS Genes With Chemotherapy Sensitivity and Survival in High-Grade Serous Ovarian Carcinoma.

IMPORTANCE: Chemotherapy response in the majority of patients with ovarian cancer remains unpredictable. OBJECTIVE: To identify novel molecular markers for predicting chemotherapy response in patients with ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: Observational study of genomics and clinical data of high-grade serous ovarian cancer cases with genomic and clinical data made public between 2009 and 2014 via the Cancer Genome Atlas project. MAIN OUTCOMES AND MEASURES: Chemotherapy response (primary outcome) and overall survival (OS), progression-free survival (PFS), and platinum-free duration (secondary outcome). RESULTS: In 512 patients with ovarian cancer with available whole-exome sequencing data, mutations from 8 members of the ADAMTS family (ADAMTS mutations) with an overall mutation rate of approximately 10.4% were associated with a significantly higher chemotherapy sensitivity (100% for ADAMTS-mutated vs 64% for ADAMTS wild-type cases; P < .001) and longer platinum-free duration (median platinum-free duration, 21.7 months for ADAMTS-mutated vs 10.1 months for ADAMTS wild-type cases; P = .001). Moreover, ADAMTS mutations were associated with significantly better OS (hazard ratio [HR], 0.54 [95% CI, 0.42-0.89]; P = .01 and median OS, 58.0 months for ADAMTS-mutated vs 41.3 months for ADAMTS wild-type cases) and PFS (HR, 0.42 [95% CI, 0.38-0.70]; P < .001 and median PFS, 31.8 for ADAMTS-mutated vs 15.3 months for ADAMTS wild-type cases). After adjustment by BRCA1 or BRCA2 mutation, surgical stage, residual tumor, and patient age, ADAMTS mutations were significantly associated with better OS (HR, 0.53 [95% CI, 0.32-0.87]; P = .01), PFS (HR, 0.40 [95% CI, 0.25-0.62]; P < .001), and platinum-free survival (HR, 0.45 [95% CI, 0.28-0.73]; P = .001). ADAMTS-mutated cases exhibited a distinct mutation spectrum and were significantly associated with tumors with a higher genome-wide mutation rate than ADAMTS wild-type cases across the whole exome (median mutation number per sample, 121 for ADAMTS-mutated vs 69 for ADAMTS wild-type cases; P < .001). CONCLUSIONS AND RELEVANCE: ADAMTS mutations may contribute to outcomes in ovarian cancer cases without BRCA1 or BRCA2 mutations and may have important clinical implications.