Hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin induces distinct transcriptomic changes in ovarian tumor and normal tissues.

OBJECTIVE: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues. METHODS: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting. RESULTS: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues. CONCLUSIONS: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors.

Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Implementation of Evidence-Based Presurgical Testing Guidelines in Patients Undergoing Ambulatory Surgery for Endometrial Cancer.

PURPOSE: The aim of this quality improvement intervention was to evaluate the safety and cost savings of presurgical testing (PST) guidelines for patients undergoing hysterectomy for endometrial pathology in the ambulatory setting. METHODS: Evidence-based presurgical testing (PST) guidelines were developed by a multidisciplinary team. These guidelines were implemented on the gynecologic surgery service of a comprehensive cancer center in January 2016. All patients with a diagnosis of endometrial pathology who underwent ambulatory surgery during the specified time periods were included in this analysis. A pre-post analysis was performed (preperiod, July 2014-December 2015; postperiod, July 2016-December 2017). Rates of completed presurgical tests and perioperative adverse events were compared between time periods. Cost savings related to the reduction in PST were calculated using the direct cost of testing and reported in percentage cost reduction. RESULTS: A total of 749 hysterectomies were completed in the preperiod and 775 in the postperiod. After implementation of PST guidelines, complete blood counts, coagulation testing, comprehensive metabolic panels, chest x-rays, and electrocardiograms were reduced by 13.4%, 78.1%, 36.8%, 39.0%, and 15.5%, respectively (all P < .001). Rates of perioperative cardiopulmonary adverse events (0% v 0%) and hematologic adverse events (3.3% v 2.0%; P = .10) were stable between time periods. There were no deaths within 90 days of surgery. There was a 41.4% reduction in direct costs related to PST in the postperiod. CONCLUSION: The use of evidence-based PST guidelines for patients with endometrial pathology undergoing hysterectomy in the ambulatory setting is safe and cost-effective. A multidisciplinary approach is essential for successful development and implementation.

Factors influencing the adoption of the sentinel lymph node technique for endometrial cancer staging: an international survey of gynecologic oncologists.

OBJECTIVE: To explore the factors influencing adoption of the sentinel lymph node (SLN) technique for endometrial cancer staging among gynecologic oncologists. METHODS: A self-administered, web-based survey was sent via email (April 20 through May 21, 2017) to all members of European Society of Gynecologic Oncologists, International Gynecologic Cancer Society, and Society of Gynecologic Oncologists. Surgical and pathologic practices related to SLN and reasons for not adopting this technique were investigated. RESULTS: Overall, 489 attending physicians or consultants in gynecologic oncology from 69 countries responded: 201 (41.1%), 118 (24.1%), and 117 (23.9%) from Europe, the USA, and other countries, respectively (10.8% did not report a country). SLN was adopted by 246 (50.3%) respondents, with 93.1% injecting the cervix and 62.6 % using indocyanine green dye. The National Comprehensive Cancer Network SLN algorithm was followed by 160 (65.0%) respondents (USA 74.4%, Europe 55.4%, other countries 71.4%). However, 66.7% completed a backup lymphadenectomy in high-risk patients. When SLN biopsy revealed isolated tumor cells, 13.8% of respondents recommended adjuvant therapy. This percentage increased to 52% if micrometastases were detected. Among the 243 not adopting SLN, 50.2% cited lack of evidence and 45.3% stated that inadequate instrumentation fueled their decisions. CONCLUSIONS: SLN with a cervical injection is gaining widespread acceptance for staging of endometrial cancer among gynecologic oncologists worldwide. Standardization of the surgical approach with the National Comprehensive Care Network algorithm is applied by most users. Management of isolated tumor cells and the role of backup lymphadenectomy for 'high-risk' cases remain areas of investigation.

Neoadjuvant chemotherapy and primary debulking surgery utilization for advanced-stage ovarian cancer at a comprehensive cancer center.

OBJECTIVE: The aim of this study was to evaluate the use of neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) before and after results from a randomized trial were published and showed non-inferiority between NACT and PDS in the management of advanced-stage ovarian carcinoma. METHODS: We evaluated consecutive patients with advanced-stage ovarian cancer treated at our institution from 1/1/08-5/1/13, which encompassed 32 months before and 32 months after the randomized trial results were published. We included all newly diagnosed patients with high-grade histology and stage III/IV disease. Associations between the use of NACT and clinical variables over time were evaluated. RESULTS: Our study included 586 patients. Median age was 62 years (range, 30-90); 406 patients (69%) had stage III disease, and 570 (97%) had disease of serous histology. Twenty-six percent (154/586) were treated with NACT and 74% (432/586) with PDS. NACT use increased significantly from 22% (56/256) before 2010 (at which point the results of the randomized trial were published) to 30% (98/330) after 2010 (p=0.037). Although patients who underwent PDS were more likely to experience grade 3/4 surgical complications than those who underwent NACT, those selected for PDS had a median OS of 71.7 months (CI, 59.8-not reached) compared with 42.9 months (CI 37.1-56.3) for those selected for NACT. CONCLUSIONS: In this single-institution analysis, the best survival outcomes were observed in patients who were deemed eligible for PDS followed by platinum-based chemotherapy. Selection criteria for NACT require further definition and should take institutional surgical strategy into account.

Is It Time to Centralize Ovarian Cancer Care in the United States?

PURPOSE: The purpose of this article was to broadly review the most up-to-date information pertaining to the centralization of ovarian cancer care in the United States (US) and worldwide. METHODS: Much of the present literature pertaining to disparities in, and centralization of, ovarian cancer care in the US and internationally was reviewed, and specifically included original research and review articles. RESULTS: Data show improved optimal debulking rates, National Comprehensive Cancer Network (NCCN) guideline adherence, and overall survival rates in higher-volume, more specialized hospitals, and amongst higher-volume providers. CONCLUSIONS: Patients with invasive epithelial ovarian cancer, especially those with higher stages (III and IV), are better served by centralized care in high-volume hospitals and by high-volume physicians, who adhere to NCCN guidelines wherever possible. More research is needed to determine the policy changes that can increase NCCN guideline adherence in low-volume hospitals and low-provider caseload scenarios. Policy and future research should be aimed at increasing patient access, either directly or indirectly, to high-volume hospital and high-volume providers, especially amongst Medicare, lower socioeconomic status, and minority patients.

Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer.

OBJECTIVE: According to national surveys, the use of intensity-modulated radiation therapy (IMRT) in gynecologic cancers is on the rise, yet there is still some reluctance to adopt adjuvant IMRT as standard practice. The purpose of this study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. METHODS: From 1/2004 to 12/2009, 34 patients underwent radical hysterectomy and pelvic lymph node dissection (28 median nodes were removed) for early stage cervical cancer. Median dose of postoperative pelvic IMRT was 50.4 Gy (range, 45-50.4). All patients received concurrent cisplatin. RESULTS: With a median follow-up of 44 months, 3 patients have recurred; 1 vaginal recurrence, 1 regional and distant, and 1 distant. The 3- and 5-year disease-free survival (DFS) was 91.2% (95% CI, 81.4-100%) and overall survival (OS) was 91.1% (95% CI, 81.3-100%). All failures and all deaths were in the high-risk group (n=3/26). There was 32.3% G3-4 hematologic toxicity, 2.9% acute G3 gastrointestinal toxicity, and no acute G3 or higher genitourinary toxicity. There were no chronic G3 or higher toxicities. CONCLUSIONS: Oncologic outcomes with postoperative IMRT were very good, with DFS and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. Toxicity was minimal even in the setting of an aggressive trimodality approach. Data from this study and emerging data from the Phase II RTOG study (0418) demonstrate the advantages of postoperative IMRT in early stage cervical cancer.

Pediatric radical abdominal trachelectomy for anaplastic embryonal rhabdomyosarcoma of the uterine cervix: an alternative to radical hysterectomy.

Rhabdomyosarcoma arising in the female genital tract carries 5-year survival in excess of 80%, but lifelong infertility may be a consequence of local control strategies. We present the technique and outcome for a fertility-sparing, radical abdominal trachelectomy in a 12-year-old girl with anaplastic, embryonal rhabdomyosarcoma involving the uterine cervix. The patient had presented to our center after the piecemeal resection of a uterine cervical mass; because of concern about microscopic residual disease, we classified her as group II-A according to the Intergroup Rhabdomyosarcoma Study system. Staging studies excluded the presence of distant disease. The patient received 4 cycles of multiagent chemotherapy and then underwent radical abdominal trachelectomy, with removal of the uterine cervix, parametria, vaginal cuff, and regional lymph nodes. Microscopically, the specimen showed treatment effect and no residual tumor. Regional nodes were negative. Radical abdominal trachelectomy, which has not been previously reported for rhabdomyosarcoma, has appeared to secure local disease control in this case while preserving the patient's future fertility potential. In properly selected cases of rhabdomyosarcoma of the uterine cervix, where involvement of the uterus proper is not present, radical abdominal trachelectomy may be an attractive fertility-sparing alternative to radical hysterectomy.

Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches.

OBJECTIVE: Over the past 12 years, the primary management of endometrial cancer at a comprehensive cancer center has undergone changes characterized by the increased use of laparoscopic surgery with comprehensive staging resulting in a decreased reliance on postoperative adjuvant whole pelvic radiation therapy (WPRT). The purpose of this study was to analyze the results of these changes. MATERIALS AND METHODS: Between 1/93 and 12/04, 1312 patients underwent surgery for endometrial cancer consisting of either abdominal or laparoscopic hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO or LAVH/BSO). Pelvic and para-aortic lymph node dissection was performed at the discretion of the attending physician. Postoperative adjuvant treatment employed in patients with high-risk features consisted mainly of WPRT+/-intravaginal radiation therapy (IVRT). Total direct medical charges incurred from 10 days prior to surgery through 75 days after surgery were determined with charges converted to direct medical costs, taking into account inflationary changes. RESULTS: The median age at diagnosis for all patients was 62 years (range, 21-93 years), with a median follow-up of 31.6 months (range, 0-140 months). There was a significant increase in LAVH/BSO versus TAH/BSO (P<0.001) until 2001 when we began participating in a national randomized trial of laparoscopic versus abdominal surgery. In addition, there was a significant increase in the percentage of patients undergoing lymph node dissection as well as the median number of nodes removed (P<0.001). This was associated with a significant decrease in the use of WPRT during 1993-1998 versus 1999-2004 (P<0.001). The use of IVRT remained the same during these time periods. There was no significant difference in 1-, 2-, or 5-year survival for patients treated in either time period. Cost data were available from 1995 to 2004. There was a significant increase in the median total direct medical costs when comparing periods 1995-1998 with 1999-2004 (P<0.001), although the median cost of pelvic radiation therapy was lower in the later time period. CONCLUSION: Over a 12-year period, the primary management of endometrial cancer changed to include an increased use of laparoscopy and comprehensive surgical staging and a decrease in the use of postoperative adjuvant WPRT, with no appreciable negative effect on overall survival.