Is increased chronological age a contraindication to debulking surgery for elderly patients with advanced ovarian cancer?

We collected data of elderly patients aged 65 years and older who underwent debulking surgery for advanced ovarian cancer in order to explore the impact of old age on surgical outcomes and complications. A total of 120 patients were classified as follows: group 1, 65-69 years (n = 58); group 2, 70-74 years (n = 38); group 3, 75-79 years (n = 17); group 4, ≥80 years (n = 7). There were no differences in most of the characteristics, surgical extent and outcomes, and postoperative complications between the four groups, whereas polypharmacy was more common (6 vs. 5-16; p=.02) and operation time was shorter (median, 194 vs. 285-330 min; p=.02) in group 4. Factors related to frailty rather than age, polypharmacy, preoperative albumin level, estimated blood loss and transfusion increased the risk of postoperative complications. Thus, the impact of old age on surgical extent, outcomes and postoperative complications may be minimal in elderly patients with advanced ovarian cancer. Impact StatementWhat is already known on this subject? Optimal debulking surgery is a significant factor in improving the prognosis of ovarian cancer but it is not easy to perform such radical surgery on elderly patients in fear of increasing surgical morbidity and mortality. Some studies suggest that underlying comorbidities may be a stronger contributing factor to increasing such risk rather than old age although there is not enough evidence yet.What do the results of this study add? Through this study, we could see that increased age is not the determining cause of increased morbidity and mortality in elderly patients who undergo optimal debulking surgery in ovarian cancer. There are other aspects describing a patient's health status that can predict prognosis better rather than age.What are the implications of these findings for clinical practice and/or further research? Old age need not be a contraindication when performing optimal debulking surgery in elderly patients with advanced ovarian cancer.

The Clinical Desire for Pressurized Intraperitoneal Aerosol Chemotherapy in South Korea: An Electronic Survey-based Study.

BACKGROUND/AIM: To evaluate the clinical desire for pressurized intraperitoneal aerosol chemotherapy (PIPAC) in South Korea. PATIENTS AND METHODS: We performed an online survey on surgical oncologists between November and December 2019 using a questionnaire consisting of 20 questions. RESULTS: A total of 164 respondents answered the questionnaire. Among those specialized in ovarian cancer, pseudomyxoma peritonei, and malignant mesothelioma 41.7-50% preferred PIPAC for the curative treatment of primary diseases, whereas 32.7-33.3% majoring in colorectal and hepatobiliary cancers chose it for the palliative treatment of recurrent diseases. Furthermore, 66.7-95.2% considered PIPAC appropriate for the cancers they specialized in, and 76-78.7% expected a treatment response of more than 50% and considered grade 1 or 2 complications acceptable. Most respondents answered the reasonable costs to purchase and implement PIPAC once at between 1,000,000-5,000,000 South Korean Won (KRW). CONCLUSION: Most Korean surgical oncologists expected relatively high tumor response rates with minor toxicities through the repeated implementation of PIPAC.

Disparities between Uptake of Germline BRCA1/2 Gene Tests and Implementation of Post-test Management Strategies in Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients.

BACKGROUND: To assess the rate of germline BRCA gene tests in epithelial ovarian cancer (EOC) patients and uptake of post-test risk management strategies in BRCA1/2-mutated patients. METHODS: Institutional databases were searched to identify patients who were diagnosed with epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) between 2009 and 2019 in two academic hospitals. Retrospective review on medical records was performed to collect clinico-pathologic variables, including performance of germline BRCA gene test and its results, as well as conduct of breast cancer screening tests and cascade testing. If annual mammography +/- breast ultrasonography was performed, it was considered that regular breast cancer surveillance was done. RESULTS: A total of 840 women with EOC were identified during the study period. Of these, 454 patients (54.0%) received BRCA gene testing and 106 patients (106/454, 23.3%) were positive for BRCA1/2 mutations. The rate of BRCA tests has markedly increased from 25.8% in 2009-2012 to 62.7% in 2017-2019. Among the 93 patients with BRCA1/2 mutation without previous personal breast cancer history, 20 patients (21.5%) received annual mammography with or without breast ultrasonography for regular surveillance. Among the 106 BRCA1/2-mutated EOC patients, cascade testing on family members was performed only in 13 patients (12.3%). CONCLUSION: Although BRCA1/2 gene tests have been substantially expanded, the uptake of post-test risk management strategies, including breast cancer screening for BRCA1/2-mutated patients and cascade testing for family members, has remained low. Strategies to increase its uptake and education about the importance of post-test risk managements are needed.

Solution to prevent tumor spillage in minimally invasive radical hysterectomy using the endoscopic stapler for treating early-stage cervical cancer: Surgical technique with video.

Gynecologic oncologists had originally preferred minimally invasive surgery (MIS) over laparotomic surgery for patients with early-stage cervical cancer until the Laparoscopic Approach to Cervical Cancer (LACC) trial reported a worse prognosis and more loco-regional recurrence in patients treated with MIS. Although some controversy remains, experts suggested that tumor cell spillage and aggravation may have been caused by intra-corporeal colpotomy, usage of uterine elevators, maintenance of Trendelenburg position, and tumor irritation by capnoperitoneum during surgery. Thus, we introduce a surgical procedure with some steps added to the conventional MIS radical hysterectomy for preventing tumor spillage during the surgery, which is currently being evaluated in terms of safety and efficacy through a prospective, multicenter, single-arm, phase II study, entitled "Safety of laparoscopic or robotic radical surgery using endoscopic stapler for inhibiting tumor spillage of cervical neoplasms (SOLUTION trial: NCT04370496)".

SERPINB11 Expression Is Associated With Prognosis of High-grade Serous and Clear Cell Carcinoma of the Ovary.

BACKGROUND/AIM: To evaluate the role of serine protease inhibitor B11 (SERPINB11) expression as a prognostic biomarker in high-grade serous carcinoma (HGSC) and clear cell carcinoma of the ovary (CCC). MATERIALS AND METHODS: We obtained tumor tissues from patients with HGSC (n=145) and CCC (n=59). We evaluated immunohistochemically the expression of SERPINB11 and investigated whether SERPINB11 expression affects platinum-resistance and the prognosis of HGSC and CCC. RESULTS: High expression of SERPINB11 was more common in CCC than in HGSC (57.6% vs. 28.3%; p<0.01), and SEPRINB11 expression did not correlate with platinum-resistance of HGSC and CCC. High expression of SERPINB11 was associated with worse progression-free survival and overall survival with marginal significance in HGSC; no relation between SERPINB11 expression and the prognosis of CCC was found. CONCLUSION: SERPINB11 expression maybe a prognostic biomarker for HGSC.

Preservation of the ovarian reserve and hemostasis during laparoscopic ovarian cystectomy by a hemostatic agent versus suturing for patients with ovarian endometriosis: study protocol for randomized controlled, non-inferiority trial (PRAHA-2 trial).

BACKGROUND: Endometriosis (EMS) can be implanted everywhere, especially in pelvic organs. EMS can be asymptomatic, but it can result in pelvic pain and infertility by inducing local inflammation and pelvic adhesion. The prevalence of EMS is about 10% in reproductive-age women and higher in women with pelvic pain or infertility. For young patients with ovarian EMS, laparoscopic ovarian cystectomy is effective in relieving pelvic pain and preventing local recurrence. However, there is a concern that the ovarian reserve would decrease after the operation because of the removal of a part of the normal ovarian tissue and thermal damage during hemostasis, which depends on the types of hemostasis such as bipolar electrocoagulation, suturing, and the use of a hemostatic agent. In this study, we aim to evaluate the protective effect for the ovarian reserve and hemostasis between a hemostatic agent and suturing during laparoscopic ovarian cystectomy for patients with ovarian EMS. METHODS: This study is a randomized controlled, non-inferiority trial, where a total of 90 patients with ovarian EMS will be randomly assigned to the experimental (hemostatic agent) and control (suturing) groups. In the control group, a barbed suture will be applied for hemostasis, whereas a hemostatic agent will be applied in the experimental group. If two methods are insufficient, bipolar electrocoagulation will be applied for complete hemostasis. As the primary endpoint, the reduction rate of serum anti- Müllerian hormone (AMH) levels reflecting the ovarian reserve will be compared between the two groups 12 weeks after surgery. As secondary endpoints, we will compare the reduction rate of AMH level 48 weeks after surgery, the time required to complete hemostasis, the success rate of hemostasis within 10 min, and adverse events associated with operation. DISCUSSION: We expect that the protective effect for the ovarian reserve and hemostasis may be comparable between the two methods, suggesting that a hemostatic agent may be preferred considering that it is easy to use during laparoscopic ovarian cystectomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04643106 . Registered on 22 November 2020.

Development of rotational intraperitoneal pressurized aerosol chemotherapy to enhance drug delivery into the peritoneum.

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5-2124.9 vs. 161.7-1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5-392.7 vs. 116.9-240.1 µm; 291.2-551.2 vs. 250.5-362.4 µm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Laterally Extended Endopelvic Resection Versus Chemo or Targeted Therapy Alone for Pelvic Sidewall Recurrence of Cervical Cancer.

BACKGROUND: Laterally extended endopelvic resection (LEER) has been introduced for treatment of pelvic sidewall recurrence of cervical cancer (PSRCC), which occurs in only 8% of patients with relapsed cervical cancer. LEER can only be performed by a proficient surgeon due to the high risk of surgical morbidity and mortality, but there is no evidence as to whether LEER is may be more effective than chemo or targeted therapy alone for PSRCC. Thus, we aimed to compare the efficacy and safety between LEER and chemo or targeted therapy alone for treatment of PSRCC. METHODS: We prospectively recruited patients with PSRCC who underwent LEER between December 2016 and December 2019. Moreover, we retrospectively collected data on patients with PSRCC who received chemo or targeted therapy alone between January 2000 and December 2019. We compared treatment-free interval (TFI), progression-free survival (PFS), treatment-free survival (TFS), overall survival (OS), tumor response, neurologic disturbance of the low extremities, and pelvic pain severity in the different patient groups. RESULTS: Among 1295 patients with cervical cancer, we included 28 (2.2%) and 31 (2.4%) in the prospective and retrospective cohorts, respectively. When we subdivided all patients into two groups based on the median value of prior TFI (PTFI, 9.2 months), LEER improved TFI, PFS, TRS and OS compared to chemo or targeted therapy alone (median, 2.8 vs. 0.9; 7.4 vs. 4.1; 30.1 vs. 16.9 months; P ≤ 0.05) in patients with PTFI < 9.2 months despite no difference in survival in those with PTFI ≥ 9.2 months, suggesting that LEER may lead to better TFI, PFS, TRS and OS in patients with PTFI < 9.2 months (adjusted hazard ratios, 0.28, 0.27, 0.44 and 0.37; 95% confidence intervals, 0.12-0.68, 0.11-0.66, 0.18-0.83 and 0.15-0.88). Furthermore, LEER markedly reduced the number of morphine milligram equivalents necessary to reduce pelvic pain when compared with chemo or targeted therapy alone. CONCLUSION: Compared to chemo or targeted therapy alone, LEER improved survival in patients with PSRCC and PTFI < 9.2 months, and it was effective at controlling the pelvic pain associated with PSRCC. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02986568.

Clinical Phenotypes of Tumors Invading the Rectosigmoid Colon Affecting the Extent of Debulking Surgery and Survival in Advanced Ovarian Cancer.

We classified clinical phenotypes based on tumor separability from the rectosigmoid colon and then evaluated the effect of these clinical phenotypes on surgical outcomes and prognosis of advanced ovarian cancer. We collected data of patients with stage IIIB-IVB disease who either underwent visceral segmental serosectomy (VSS) or low anterior resection (LAR) during maximal debulking surgery. All patients were divided into the following, according to the resection types of tumors involving the rectosigmoid colon: the focal (tumor-involved length <18 cm) and separable (FS) group that received VSS, the focal and inseparable (FI) that received LAR, or the diffuse (tumor-involved length ≥18 cm) group (D) that also received LAR. A total of 83 patients were included in FS (n=44, 53%), FI (n=18, 21.7%), and D (n=24, 25.3%) groups. FS and D groups with more extensive tumors were related to wider extent of surgery and more tumor infiltration except for bowels, whereas FI and D groups with more invasive tumors were associated with wider extent of surgery, more tumor infiltration to bowels, longer operation time, more blood loss, more transfusion, longer hospitalization, and higher surgical complexity scores. Moreover, FS and FI groups showed better progression-free survival than D group, whereas FS group demonstrated better overall survival than FI and D groups. Clinical phenotypes based on tumor separability from the rectosigmoid colon may depend on tumor invasiveness and extensiveness in advanced ovarian cancer. Moreover, these clinical phenotypes may affect surgical outcomes and survival.

Narrative review of liver mobilization, diaphragm peritonectomy, full-thickness diaphragm resection, and reconstruction.

Epithelial ovarian cancer is the most lethal among gynecologic cancers. Despite advances in research efforts to cure this disease, the recurrence and survival rates have not significantly improved. Primary cytoreductive surgery and adjuvant chemotherapy are the standard treatment options for patients with epithelial ovarian cancer. Two randomized trials recently introduced neoadjuvant chemotherapy followed by interval cytoreductive surgery as an alternative treatment option. In any case, the size of the residual tumor after surgery is the most important prognostic factor for patients with ovarian cancer. With the improvement of surgical techniques in gynecologic oncology, cytoreductive surgery is now performed for the pelvic area and entire abdomen. Currently, surgical resectability of a mass spreading into the upper abdomen is the most important factor for achieving optimal cytoreduction. In this study, we explain the procedure of a cytoreductive surgery, involving the resection of a tumor located in the upper abdomen. We aimed to review and describe the surgical techniques involved in liver mobilization, diaphragm peritonectomy, and full-thickness diaphragm resection and reconstruction. Further, we have assessed the postoperative care involved and discussed complications that may possibly arise along with suggestions to avoid them based on the review of previous literature on the subject.

Rotational intraperitoneal pressurized aerosol chemotherapy in a porcine model.

Peritoneal carcinomatosis (PC) commonly represent drug resistance to intravenous (IV) chemotherapy in advanced or recurrent disease of solid tumors. For improving the prognosis of PC, intraperitoneal (IP) chemotherapy has been introduced in the clinical setting, and phase III trials proved the superiority of IP chemotherapy to IV chemotherapy, in particular, in advanced ovarian cancer. However, increased toxicities by IP chemotherapy lead to reduced cycles of chemotherapy, which does not guarantee its effectiveness. Moreover, hyperthermic IP chemotherapy after cytoreductive surgery also showed improved survival compared to IV chemotherapy in advanced ovarian cancer. Nevertheless, limited distribution and diffusion of drugs, and grade 3 or 4 renal and hepatic toxicity of 20% preclude the expansion of its application. On the other hand, pressurized intraperitoneal aerosol chemotherapy (PIPAC) is known to show the effect by delivering drugs to the parietal and visceral peritoneum in the form of aerosol under the abdominal pressure of 12 mmHg induced by laparoscopic system. Although low dose equivalent to about 1% dose of resistant drugs for IV chemotherapy and normothermia are used in PIPAC, it may improve tumor response and quality of life by repetitive application of PIPAC due to the increased distribution and penetration depth of drugs. However, the heterogeneous distribution of drugs is still the major limitation of PIPAC because the nozzle is placed at the possible outlying position to the tumor-bearing tissues during laparoscopic surgery. Therefore, we developed a novel prototype for PIPAC, rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) system because rotation of the nozzle and change of spray direction can contribute to homogenous distribution of drugs, and compared the distribution of drugs between PIPAC and RIPAC in a porcine model mimicking human body. As a result, RIPAC was more effective than PIPAC in terms of the distribution of drugs into the visceral and parietal peritoneum.

Vaginal delivery after robot-assisted uterine artery-preserving radical trachelectomy for early-stage cervical cancer.

Radical trachelectomy is conducted in women with early stage cervical cancer who strongly desire fertility preservation. To improve fertility outcomes, the preservation of the uterine artery has been suggested, which can be feasible by minimally invasive surgery using laparoscopy or robots. Although cesarean delivery is required for maternal and fetal health, vaginal delivery is a concern due to the fast delivery process of risk of preterm labor. We report a case of a 32-year-old nulliparous woman with stage IB1 cervical cancer who underwent robot-assisted uterine artery-preserving radical trachelectomy for improving fertility. This case is meaningful because she delivered by vaginal delivery after incision of the fibrotic ring at the level of uterovaginal anastomosis because delivery proceeded too quickly prior to the preparation of the cesarean delivery.

Evaluation of a Novel Prototype for Pressurized Intraperitoneal Aerosol Chemotherapy.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been suggested as an alternative option for treating peritoneal carcinomatosis (PC). Even with its clinical advantages, the current PIPAC system still suffers from limitations regarding drug distribution area and penetration depth. Thus, we evaluated the new PIPAC system using a novel prototype, and compared its performance to the results from previous studies related with the current MIP® indirectly because the system is currently not available for purchase in the market. The developed prototype includes a syringe pump, a nozzle, and controllers. Drug distribution was conducted using a methylene blue solution for performance test. For penetration depth evaluation, an ex-vivo experiment was performed with porcine tissues in a 3.5 L plastic box. Doxorubicin was sprayed using the novel prototype, and its penetration depth was investigated by confocal laser scanning microscopy. The experiment was repeated with varying nozzle levels from the bottom. The novel prototype sprays approximately 30 µm drug droplets at a flow rate of 30 mL/min with 7 bars of pressure. The average diameter of sprayed region with concentrated dye was 18.5 ± 1.2 cm, which was comparable to that of the current MIP® (about 10 cm). The depth of concentrated diffusion (DCD) did not differ among varying nozzle levels, whereas the depth of maximal diffusion (DMD) decreased with increasing distance between the prototype and the bottom (mean values, 515.3 µm at 2 cm; 437.6 µm at 4 cm; 363.2 µm at 8 cm), which was comparable to those of the current MIP® (about 350-500 µm). We developed a novel prototype that generate small droplets for drug aerosolization and that have a comparably wide sprayed area and depth of penetration to the current MIP® at a lower pressure.

Phase 1b Trial of Biweekly Intravenous Pexa-Vec (JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus in Colorectal Cancer.

Fifteen patients with treatment-refractory colorectal cancer were enrolled on a phase 1b study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia designed to selectively replicate in cancer cells. Pexa-Vec was administered intravenously every 14 days, at dose levels of 1 × 10(6), 1 × 10(7), or 3 × 10(7) plaque-forming units (pfu)/kg. The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacokinetics and pharmacodynamics as well as antitumor activity. Patients were heavily pretreated (mean 4.5 lines of therapy). All patients received at least two Pexa-Vec doses (median = 4; range = 2-4). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The most common adverse events were grade 1/2 flu-like symptoms, generally lasting <24 hours. During the first and last cycles, genome pharmacokinetics were unchanged. Infectious pfu could be detected in plasma up to 2 hours after cycle 1 and up to 30 minutes after cycle 4 (when antivaccinia antibody titers are known to have peaked). Ten patients (67%) had radiographically stable disease. Given the acceptable safety profile of multiple intravenous Pexa-Vec infusions in patients with treatment-refractory colorectal cancer, further trials evaluating efficacy of intravenous Pexa-Vec, as monotherapy or in combination with chemotherapeutic agents, is warranted in this patient population.