Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancer: A meta-analysis.

BACKGROUND: The value of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery (CRS) for epithelial ovarian cancer (EOC) is controversial and its use remains experimental in most national and international guidelines. We wished to systematically evaluate all available evidence. METHODS: A comprehensive review of data from MEDLINE, EMBASE, and Cochrane Library databases was conducted from the first report on HIPEC in EOC till April 3, 2022. Progression-free survival (PFS) and overall survival (OS) were compared between the HIPEC and control groups. This meta-analysis was registered with PROSPERO (CRD42021265810). RESULTS: Fifteen studies (10 case-control studies and 5 randomized controlled trials [RCTs]) were included in the present meta-analysis. Based on the time interval between the last systemic chemotherapy exposure and timing of CRS +/- HIPEC, all studies and patients' cohorts we classified into recent (<6 months; n = 9 studies/patients cohorts) and non-recent (≥6 months, n = 8 studies/patients cohorts) chemotherapy exposure groups. In the recent chemotherapy exposure group, HIPEC was associated with improvement of both PFS (HR, 0.585; 95% CI, 0.422-0.811) and OS (HR, 0.519; 95% CI, 0.346-0.777). On the contrary, in the non-recent chemotherapy exposure group, HIPEC failed to significantly affect PFS (HR, 1.037; 95% CI, 0.684-1.571) or OS (HR, 0.932; 95% CI, 0.607-1.430). Consistent results were observed in subsequent sensitivity analyses. CONCLUSION: Our present meta-analysis demonstrates that the value of HIPEC at CRS for EOC appears to depend on the timing of the last systemic chemotherapy exposure. Future trials are awaited to define the role of HIPEC in EOC.

Quality of life outcomes from the randomized trial of hyperthermic intraperitoneal chemotherapy following cytoreductive surgery for primary ovarian cancer (KOV-HIPEC-01).

OBJECTIVE: To investigate the health-related quality of life (HRQOL) related to hyperthermic intraperitoneal chemotherapy (HIPEC) following primary or interval cytoreductive surgery for primary ovarian cancer. METHODS: Between 2010 and 2016, a total of 184 patients were randomly assigned to receive cytoreductive surgery with HIPEC (n=92) or without HIPEC (n=92). Quality of life (QOL) assessment was evaluated at baseline (before surgery); on postoperative day 7; after the 3rd and 6th cycle of adjuvant chemotherapy; and at 3, 6, 9, and 12 months after randomization. Patient-reported QOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (EORTC-QLQ-C30), ovarian cancer questionnaire modules (QLQ-OV28), and the MD Anderson Symptoms Inventory (MDASI). RESULTS: Of the 184 patients enrolled, 165 (83/92 in the HIPEC group and 82/92 in the control group) participated in the baseline QOL assessment. There were no statistically significant differences in functional scales and symptom scales in QLQ-C30; symptom scales, including gastrointestinal symptoms QLQ-OV28; and severity and impact score in MDASI between the 2 treatment groups until 12 months after randomization. CONCLUSION: HIPEC with cytoreductive surgery showed no statistically significant difference in HRQOL outcomes. Thus, implementation of HIPEC during either primary or interval cytoreductive surgery does not impair HRQOL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01091636.

Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer: A Randomized Clinical Trial.

Importance: Ovarian cancer has the highest mortality rate among gynecologic malignant tumors. Data are lacking on the survival benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with ovarian cancer who underwent primary or interval cytoreductive surgery. Objective: To assess the clinical benefit of HIPEC after primary or interval maximal cytoreductive surgery in women with stage III or IV primary advanced ovarian cancer. Design, Setting, and Participants: In this single-blind randomized clinical trial performed at 2 institutions in South Korea from March 2, 2010, to January 22, 2016, a total of 184 patients with stage III or IV ovarian cancer with residual tumor size less than 1 cm were randomized (1:1) to a HIPEC (41.5 °C, 75 mg/m2 of cisplatin, 90 minutes) or control group. The primary end point was progression-free survival. Overall survival and adverse events were key secondary end points. The date of the last follow-up was January 10, 2020, and the data were locked on February 17, 2020. Exposures: Hyperthermic intraperitoneal chemotherapy after cytoreductive surgery. Main Outcomes and Measures: Progression-free and overall survival. Results: Of the 184 Korean women who underwent randomization, 92 were randomized to the HIPEC group (median age, 52.0 years; IQR, 46.0-59.5 years) and 92 to the control group (median age, 53.5 years; IQR, 47.5-61.0 years). After a median follow-up of 69.4 months (IQR, 54.4-86.3 months), median progression-free survival was 18.8 months (IQR, 13.0-43.2 months) in the control group and 19.8 months (IQR, 13.7-55.4 months) in the HIPEC group (P = .43), and median overall survival was 61.3 months (IQR, 34.3 months to not reported) in the control group and 69.5 months (IQR, 45.6 months to not reported) in the HIPEC group (P = .52). In the subgroup of interval cytoreductive surgery after neoadjuvant chemotherapy, the median progression-free survival was 15.4 months (IQR, 10.6-21.1 months) in the control group and 17.4 months (IQR, 13.8-31.5 months) in the HIPEC group (hazard ratio for disease progression or death, 0.60; 95% CI, 0.37-0.99; P = .04), and the median overall survival was 48.2 months (IQR, 33.8-61.3 months) in the control group and 61.8 months (IQR, 46.7 months to not reported) in the HIPEC group (hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). In the subgroup of primary cytoreductive surgery, median progression-free survival was 29.7 (IQR, 17.2-90.1 months) in the control group and 23.9 months (IQR, 12.3-71.5 months) in the HIPEC group, and the median overall survival was not reached in the control group and 71.3 months (IQR, 45.6 months to not reported) in the HIPEC group. Conclusions and Relevance: The addition of HIPEC to cytoreductive surgery did not improve progression-free and overall survival in patients with advanced epithelial ovarian cancer. Although the results are from a subgroup analysis, the addition of HIPEC to interval cytoreductive surgery provided an improvement of progression-free and overall survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01091636.

Phase I/II clinical trial of modulated electro-hyperthermia treatment in patients with relapsed, refractory or progressive heavily treated ovarian cancer.

OBJECTIVE: To determine the maximal tolerated dose (MTD) of modulated electro-hyperthermia (mEHT) treatment and to reveal whether mEHT treatment is feasible and effective as second-line therapy in recurrent and progressive ovarian cancer. METHODS: Patients were treated with mEHT with dose escalation during the first cycle (two sessions each week for three weeks) to determine the MTD. Additional cycles were carried out with the determined dose. Dose limiting toxicity (DLT) was defined grade ≥ 2: skin burns and inability to endure the hyperthermic state of the study. The Fact-O quality of life scale was used to assess health-related well-being. RESULTS: Nineteen patients with recurrent and progressive ovarian cancer were enrolled. In the first cycle of mEHT treatment, no patient developed DLT with applied power up to 110 W, 130 W, and 150 W/day; the 150 W was the maximal applied power. Stable disease was observed in only one patient (12.5%). With median progression of 4.0 months (range, 2-17 months), 18 patients (95%) demonstrated disease progression. With median overall survival of 8.0 months (range, 2-32 months), 18 patients (95%) had died. Physical well-being scores were significantly decreased over the study period, although social, emotional, and functional well-being scores did not significantly change. CONCLUSIONS: The mEHT treatment was feasible in patients with recurrent or progressive ovarian cancer without any complication and optimal dose of mEHT treatment was up to 150 W for 1 hour/day.

Development and Validation of Ovarian Symptom Index-18 and Neurotoxicity-4 for Korean Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

PURPOSE: The purpose of this study was to develop Korean versions of the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy (NCCN-FACT) Ovarian Symptom Index-18 (NFOSI-18) and FACT/Gynecologic Oncology Group (FACT-GOG) Neurotoxicity 4-item (NTX-4), evaluating their reliability and reproducibility. MATERIALS AND METHODS: In converting NFOSI-18 and NTX-4, the following steps were performed: forward translation, backward translation, expert review, pretest of preliminary format, and finalization of Korean versions (K-NFOSI-18 and K-NTX-4). Patients were enrolled from six institutions where each had completed chemotherapy for ovarian, tubal, or peritoneal cancer at least 1 month earlier. In addition to demographics obtained by questionnaire, all subjects were assessed via K-NFOSI-18, K-NTX-4, and a Korean version of the EuroQoL-5 Dimension. Internal structural validity and reliability were evaluated using item internal consistency, item discriminant validity, and Cronbach's α. To evaluate test-retest reliability, K-NFOSI-18 and K-NTX-4 were readministered after 7-21 days, and intraclass correlation coefficients (ICCs) were calculated. RESULTS: Of the 250 women enrolled during the 3-month recruitment period, 13 withdrew or did not respond, leaving 237 (94.8%) for the analyses. Mean patient age was 54.3±10.8 years. Re-testing was performed in 190 patients (80.2%). The total K-NFOSI-18 and K-NTX-4 scores were 49 (range, 20 to 72) and 9 (range, 0 to 16), respectively, with high reliability (Cronbach's α=0.84 and 0.89, respectively) and reproducibility (ICC=0.77 and 0.84, respectively) achieved in retesting. CONCLUSION: Both NFOSI-18 and NTX-4 were successfully developed in Korean with minimal modification. Each Korean version showed high internal consistency and reproducibility.

Current practices of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies: an international survey of oncologic surgeons.

BACKGROUND: The goal of the study was to investigate the current clinical practices among oncologic surgeons regarding cytoreductive surgery (CRS) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From September to October 2016, an online questionnaire surveyed the oncologic surgeons by email. The questionnaire included 20 multiple-choice questions of the following: eligibility for the CRS with HIPEC procedure, perioperative staging and surgery skill, assessment of residual tumors, and method used for intraperitoneal HIPEC. RESULTS: The response rate was 16% (34/217). The majority of respondents (68%) worked at a university hospital. All respondents indicated that mesenteric invasion is the most crucial factor affecting treatment decision. Most surgeons (79%) used the Sugarbaker's staging system to intraoperatively measure the extent of peritoneal invasion. The methods used to measure the extent of miliary pattern of residual tumor spread, and the amount of residual tumor after electrocauterization varied among the surgeons. Most responders (65%) used the closed system of HIPEC. CONCLUSIONS: Despite the fact that CRS HIPEC is the standard treatment for PSM, the clinical practices are very different according to each clinical situation. Nevertheless, mesenteric invasion was found to be the most important factor impacting the treatment decision-making by the majority of responders.

Survival outcomes after extensive cytoreductive surgery and selective neoadjuvant chemotherapy according to institutional criteria in bulky stage IIIC and IV epithelial ovarian cancer.

OBJECTIVE: To investigate the survival outcomes in patients with bulky stage IIIC and IV ovarian cancer, treated by primary debulking surgery (PDS) and selective use of neoadjuvant chemotherapy (NAC) according to institutional criteria. METHODS: Medical records for advanced ovarian cancer patients who were treated at National Cancer Center (NCC) between December 2000 and March 2009 were retrospectively reviewed in the comprehensive cancer center. Bulky stage IIIC and IV ovarian cancer cases were included. Current NCC indication for NAC is determined based on patients' performance status and/or computerized tomography (CT) findings indicating difficult cytoreduction. After NAC, all traces of regressed metastatic ovarian cancer, potentially including chemotherapy-resistant cancer cells, were surgically removed. RESULTS: Of the 279 patients with bulky stage IIIC and IV, 143 (51%) underwent PDS and 136 (49%) received NAC. No gross residual and residual tumor measuring ≤1 cm was achieved in 66% and 96% of the PDS group and 79% and 96% of the NAC group, respectively. The median progression-free survival (PFS) and overall survival (OS) time were 20 months and not reached, but might be estimated more than 70 months in the PDS group and 15 and 70 months in the NAC group, respectively. CONCLUSION: Extensive cytoreductive surgery to minimize residual tumor and selective use of NAC based on the institutional criteria could result in improved survival outcomes. Until further studies can be done to define the selection criteria for NAC after surgery, institutional criteria for NAC should consider the ability of the surgeon and institutional capacity.

Morusin induces cell death through inactivating STAT3 signaling in prostate cancer cells.

STAT3 has been recognized as an efficacious drug target for prostate cancer because of its constitutive activation in this fatal disease. We recently identified the root bark of Morus alba Linn. as a potential STAT3 inhibitor among 33 phytomedicines traditionally used in Korea. Morusin, an active compound isolated from the root bark of Morus alba, has shown anti-oxidant and anti-inflammatory effects. In the present study, we examined whether morusin has a potential as an anti-cancer agent in prostate cancer. We found that morusin suppressed viability of prostate cancer cells, but little effect in normal human prostate epithelial cells. Morusin also reduced STAT3 activity by inhibiting its phosphorylation, nuclear accumulation, and DNA binding activity. In addition, morusin down-regulated expression of STAT3 target genes encoding Bcl-xL, Bcl-2, Survivin, c-Myc and Cyclin D1, which are involved in regulation of apoptosis and cell cycle. Furthermore, morusin induced apoptosis in human prostate cancer cells by reducing STAT3 activity. Taken together, these results suggest that morusin could be a potentially therapeutic agent for prostate cancer by reducing STAT3 activity and inducing apoptosis.

Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells.

Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G(0)/G(1) apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up-regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF-7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IκBα in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.

Web-based tailored education program for disease-free cancer survivors with cancer-related fatigue: a randomized controlled trial.

PURPOSE: To determine whether an Internet-based tailored education program is effective for disease-free cancer survivors with cancer-related fatigue (CRF). PATIENTS AND METHODS: We randomly assigned patients who had completed primary cancer treatment within the past 24 months in any of four Korean hospitals and had reported moderate to severe fatigue for at least 1 week to participate in a 12-week, Internet-based, individually tailored CRF education program or to receive routine care. We based the program on the CRF guidelines of the National Comprehensive Cancer Network (NCCN) and incorporated the transtheoretic model (TTM). At baseline and 12 weeks, we used the Brief Fatigue Inventory (BFI) and Fatigue Severity Scale (FSS) as primary outcomes and the Hospital Anxiety and Depression Scale (HADS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) for secondary outcomes. RESULTS: We recruited 273 participants and randomly assigned 136 to the intervention group. Compared with the control group, the intervention group had an improvement in fatigue as shown by a significantly greater decrease in BFI global score (-0.66 points; 95% CI -1.04 to -0.27) and FSS total score (-0.49; 95% CI, -0.78 to -0.21). In secondary outcomes, the intervention group experienced a significantly greater decrease in HADS anxiety score (-0.90; 95% CI, -1.51 to -0.29) as well as global quality of life (5.22; 95% CI, 0.93 to 9.50) and several functioning scores of the EORTC QLQ-C30. CONCLUSION: An Internet-based education program based on NCCN guidelines and TTM may help patients manage CRF.

Decursin prevents cisplatin-induced apoptosis via the enhancement of antioxidant enzymes in human renal epithelial cells.

Adverse effects, nephrotoxicity and hepatotoxicity, of anticancer drugs such as cisplatin have limited the usage for cancer therapy. Therefore, development or identification of supplement agents in anticancer drugs is attractive to reduce side effects and enhance antitumor activity. Here, we found that decursin isolated from Angelica gigas showed protective effects of cisplatin-induced damage in normal human primary renal epithelial cells (HRCs). We found that decursin significantly blocked cisplatin-induced cytotoxicity by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in HRCs. Further, we found that decursin inhibited sub-G1 and cell death by suppression of cleavage of caspase-3, -9 and poly(ADP-ribose) polymerase (PARP) induced by cisplatin treatment in HRCs. Importantly, decursin effectively restored the activities of Cu/Zn superoxide dismutase (SOD), catalase and glutathione peroxidase in cisplatin-treated HRCs. Taken together, our findings demonstrate that decurcin prevents cisplatin-induced cytotoxicity and apoptosis through the activation of antioxidant enzymes in HRCs and suggest further that combination of decursin might suppressed adverse effects of anticancer drugs in cancer patients.

Hyperthermic intraperitoneal chemotherapy after extensive cytoreductive surgery in patients with primary advanced epithelial ovarian cancer: interim analysis of a phase II study.

BACKGROUND: The objective of the current study was to evaluate the toxicities and treatment response of intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced epithelial ovarian cancer. METHODS: Intraoperative HIPEC (cisplatin 75 mg/m(2), 41.5 degrees C, 90 min) was performed in 30 patients with residual tumor of <1 cm after cytoreductive surgery between January 2007 and February 2008. All the patients received adjuvant chemotherapy with combination platinum and taxane. Adverse events and responses to primary treatment were evaluated and scored as follows: grade I, observation; grade II, medical treatment; grade III, intervention; and grade IV, reoperation or admission to the intensive care unit. RESULTS: No deaths or grade IV morbidities were observed. One hundred seven adverse events were identified in 30 patients (grade I, 40; grade II, 46; grade III, 21). The most common adverse events affected the hematologic system (n = 26), followed by the gastrointestinal system (n = 23). Most adverse events were anemias requiring transfusion and nausea/vomiting requiring medication. Twenty-eight patients (93%) experienced complete remission, and two patients (7%) had progressive disease. CONCLUSION: HIPEC after extensive cytoreductive surgery for ovarian cancer is a procedure with acceptable morbidity that patients can tolerate. More follow-up is needed to determine the effect of HIPEC on survival.

Calpain 6 supports tumorigenesis by inhibiting apoptosis and facilitating angiogenesis.

Since calpain 6 is overexpressed in uterine cervical cancer tissue compared to normal tissue, we sought to define the role of calpain 6 during tumorigenesis. We overexpressed calpain 6 or inhibited calpain 6 in human cervical cancer cells (HeLa cells) and human umbilical vein endothelial cells (HUVECs), and measured cisplatin-mediated apoptosis and VEGF-mediated angiogenesis. The results indicated that calpain 6 supported tumorigenesis by inhibiting apoptosis and facilitating angiogenesis. To our knowledge, this result is the first evidence implicating calpain 6 in tumorigenesis, and it reveals calpain 6 as a novel therapeutic target for certain types of cancers.