Cytoreductive surgery and HIPEC for malignant ascites from colorectal cancer - a randomized study.

INTRODUCTION: The efficacy of different timings of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites caused by peritoneal carcinomatosis of colorectal cancer (CRC) is not well defined. The study aims to investigate the clinical efficacy and safety of different timings of CRS with HIPEC for malignant ascites caused by peritoneal carcinomatosis from CRC. MATERIALS AND METHODS: This was a preliminary randomized controlled study performed at the Intracelom Hyperthermic Perfusion Therapy Center of the Cancer Hospital of Guangzhou Medical University (China) from December 2008 to December 2016. The patients were randomized to: CRS, followed by HIPEC (CRS+HIPEC; n = 14), and ultrasound-guided HIPEC, followed by CRS 1 to 2 weeks later (HIPEC+ delayed cytoreductive surgery (dCRS) group, n = 14). The endpoints were complete remission rate of ascites, successful complete CRS rate, and overall survival. RESULTS: Malignant ascites in all patients showed complete remission; the total effective rate was 100%. Complete CRS was not feasible in any patient. The median follow-up of the 2 groups was 41.9 and 42.3 months in the CRS+HIPEC and HIPEC+dCRS groups, respectively. Overall survival was 14.5 (95%CI: 7-19 months) and 14.3 months (95%CI: 4-21 months) (P > .05). The adverse effects of HIPEC were manageable. CONCLUSIONS: CRS+HIPEC and HIPEC+dCRS have the same efficacy in controlling malignant ascites caused by CRC and peritoneal carcinomatosis. The timing of CRS and HIPEC does not prolong the survival of patients with peritoneal carcinomatosis from CRC, even when a complete CRS is not feasible.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients With Malignant Ascites Secondary to Unresectable Gastric Cancer.

BACKGROUND: To compare the efficacy of 3 chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into 3 groups and treated by laparoscopic HIPPC with 1 of the 3 following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin (L-OHP), Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the 3 groups. RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months and the median survival was 7.5 months for all patients. Patients in the Ra/L-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/L-OHP group and Ra/MMC group is significantly longer than Ra/DDP group (P<0.05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky performance scale, and incidence rate of port-site metastases among the 3 groups. CONCLUSIONS: Laparoscopy-assisted HIPPC provide modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutical combination of Ra/L-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

Development of a high-precision bladder hyperthermic intracavitary chemotherapy device for bladder cancer and pharmacokinetic study.

BACKGROUND: Bladder hyperthermic intracavitary chemotherapy (HIVEC) has good effectiveness for bladder cancer, but conventional HIVEC systems lack precision and convenient application. To test the safety of a new HIVEC device (BR-TRG-II-type) in pigs and to perform a preliminary clinical trial in patients with bladder cancer. METHODS: This device was tested on six pigs to optimize the temperature and time parameters. Then, 165 patients (HIVEC after transurethral resection (TUR), n = 128; or HIVEC, n = 37) treated between December 2006 and December 2016 were recruited. Mitomycin C (MMC) was the chemotherapeutic agent. A serum pharmacokinetic study was performed. The primary endpoints were tumor recurrence, disease-free survival (DFS), and cumulative incidence rate (CIR) during follow-up. The adverse effects were graded. RESULTS: The animal experiment showed that 45 °C for 1 h was optimal. HIVEC was successful, with the infusion tube temperature stably controlled at about 45 °C, and outlet tube temperature of about 43 °C in all patients, for three sessions. Serum MMC levels gradually increased during HIVEC and decreased thereafter. The mean DFS was 39 ± 3.21 months (ranging from 8 to 78 months), and the DFS rate was 89.1% during follow-up. No adverse events occurred. CONCLUSION: The use of the BR-TRG-II-type HIVEC device is feasible for the treatment of bladder cancer. Future clinical trials in patients with different stages of bladder cancer will further confirm the clinical usefulness of this device. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1900022099 (registered on Mar. 252,019). Retrospectively registered.

Thermo-chemotherapy inhibits the proliferation and metastasis of gastric cancer cells via suppression of EIF5A2 expression.

PURPOSE: Thermo-chemotherapy (TCT) is a new approach for the treatment of cancer that combines chemotherapy with thermotherapy. In the present study, we investigated the relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and TCT sensitivity in gastric cancer (GC) to further illuminate the molecular mechanism underlying the effect of TCT on GC. METHODS: A TCT cell model was constructed, and EIF5A2 was silenced or overexpressed by infection with a lentivirus expressing either EIF5A2 or EIF5A2 shRNA. Then, RT-qPCR, Western blotting, and immunohistochemistry assays were performed to evaluate the changes in the expression levels of EIF5A2, c-myc, vimentin, and E-cadherin. Cell proliferation and xenograft assays were conducted to evaluate the effect on cell proliferation. Finally, wound-healing and Transwell invasion assays were performed to evaluate the effects on migration and invasion. RESULTS: TCT reduced EIF5A2 expression at both the mRNA and protein levels. It also inhibited cell proliferation, migration, and invasion, downregulated the expression of c-myc and vimentin, and increased the expression of E-cadherin in both MKN28 and MKN45 cells. Silencing of EIF5A2 enhanced the above effects of TCT on MKN28 and MKN45 cells, while overexpression of EIF5A2 had the opposite effects. In addition, EIF5A2 overexpression weakened the inhibitory effect of TCT on tumor growth in vivo as well as the effects on c-myc, vimentin, and E-cadherin. CONCLUSION: TCT inhibits GC cell proliferation and metastasis by suppressing EIF5A2 expression. Our results provide new insights into our understanding of the molecular mechanism underlying the effects of TCT in GC.

Mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death.

Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined. The relationships between tumor growth regression, expression of autophagy-related genes, and reactive oxygen species production were evaluated. Tumor size and wet weight of hyperthermia + chemotherapy group was significantly decreased relative to values from hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group ( F = 6.92, p < 0.01 and F = 5.36, p < 0.01, respectively). Reactive oxygen species production was significantly higher in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. The expression levels of Beclin1 and LC3B were significantly higher, while those of mammalian target of rapamycin were significantly lower in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. Tumor growth regression was consistent with changes in reactive oxygen species production and expression of autophagy-related genes. N-acetyl-L-cysteine inhibited changes in the expression of the autophagy-related genes and also suppressed reactive oxygen species production and tumor growth. Hyperthermia + chemotherapy increase expression of autophagy-related genes Beclin1 and LC3B, decrease expression of mammalian target of rapamycin, and concomitantly increase reactive oxygen species generation. These results strongly indicate that mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death.

Bladder intracavitary hyperthermic perfusion chemotherapy for the prevention of recurrence of non-muscle invasive bladder cancer after transurethral resection.

Preventing the recurrence of non-muscle invasive bladder cancer (NMIBC) post-transurethral resection (TUR) remains challenging. The aim of the present study was to investigate the effectiveness and safety of bladder intracavitary hyperthermic perfusion chemotherapy (BHPC) for prevention of NMIBC recurrence post-TUR. Between December 2006 and December 2014, 53 patients with NMIBC who underwent TUR were randomly assigned to receive BHPC (BHPC group, 28 patients) or intravesical chemotherapy alone (chemotherapy group, 25 patients) at the Intracelom Hyperthermic Perfusion Therapy Center of Guangzhou Medical University Cancer Hospital (Guangzhou, China). BHPC was performed by combining perfusion-based hyperthermia with chemotherapeutic agent mitomycin C (MMC) in the bladder, and the chemotherapy group of patients received bladder MMC perfusion. The concentration of MMC in the perfusion fluid and serum were assessed at different time-points. Tumor recurrence, disease-free survival (DFS), and side-effects were recorded and compared between the 2 groups. Results revealed that BHPC was performed smoothly, at ~44̊C in the bladder cavity. Patients tolerated BHPC, and no side-effects were observed. Both BHPC and intravesical chemotherapy achieved a high MMC concentration in the bladder perfusion liquid, but low MMC concentration in the serum, although serum MMC concentrations in the BHPC group were significantly higher (P<0.05). The tumor recurrence rate was significantly lower (10.7 vs. 28.0%; P=0.02) and the DFS period was significantly longer (37±1.2 vs. 19±0.9 months; P=0.001) in the BHPC group than in the chemotherapy group. Our results demonstrated that BHPC is safe and effective for preventing NMIBC recurrence post-TUR and prolongs DFS.

Hyperthermic Intraperitoneal Perfusion Chemotherapy and Cytoreductive Surgery for Controlling Malignant Ascites From Ovarian Cancer.

BACKGROUND: Malignant ascites, a complication often seen in patients with ovarian cancer (OC), is difficult to treat, but hyperthermic intraperitoneal chemotherapy (HIPEC) has a good efficacy. OBJECTIVE: The aim of this study was to assess the efficacy of cytoreductive surgery (CRS) combined with HIPEC for controlling malignant ascites from OC. MATERIALS AND METHODS: From December 2009 until December 2014, 53 patients with OC and malignant ascites were treated with CRS and HIPEC. Patients in good health condition were treated with CRS followed by HIPEC (CRS + HIPEC), and patients in poor health condition were treated initially with B-mode ultrasound-guided HIPEC followed by delayed CRS upon improvement of their health condition (HIPEC + delayed CRS). Resolution of ascites, complete CRS, overall survival, and disease-free survival were analyzed. RESULTS: All patients showed ascites regression. The total objective remission rate was 100%, even for patients in the poor condition group before CRS. Complete CRS was successful in 30 (88.23%) of 34 patients in the good condition group, and 17 (89.47%) of 19 patients in the poor condition group (P > 0.05). Median disease-free survival and median overall survival were 21 and 39 months in the good condition group, and 22 and 38 months in the poor condition group, respectively (P > 0.05). CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy is effective at controlling ascites in patients with OC, even for patients in poor condition before CRS, or when complete CRS is not feasible. Furthermore, the regression of ascites appears not to be dependent on complete resection.

Autophagic death induced by thermo­chemotherapy in gastric cancer cells results from the reactive oxygen species pathway.

Gastric cancer is the third leading type of cancer and has the third leading cancer­associated mortality in China. The mechanism of thermo­chemotherapy in gastric cancer cells remains to be elucidated. The present study aimed to investigate the role of autophagic cell death in the thermo­chemotherapy of gastric cancer. The current study included four groups: An empty control group, a hyperthermia group, a chemotherapy (oxaliplatin) group, and a thermo­chemotherapy group. Cell viability was analyzed by the MTS assay. Production of intracellular reactive oxygen species (ROS) was quantified by flow cytometry. Autophagy­associated proteins, Beclin 1, microtubule­associated protein 1A/1B­light chain (LC3B) and mammalian target of rapamycin (mTOR), were determined by western blot analysis. The results indicated that thermo­chemotherapy markedly increased intracellular ROS production, and decreased mitochondrial membrane potential. The transmission electron microscopy results indicated that thermo­chemotherapy induced production of autophagic bodies. In addition, thermo­chemotherapy­induced cell damage at the cellular and animal levels indicated a notable increase in the expression of the autophagy­associated genes, LC3B and Beclin 1. A negative correlation between mTOR expression and autophagy was also identified, which demonstrates that thermo­chemotherapy induces autophagic cell death by activating the autophagy­associated signaling pathways. The results of the present study demonstrated that the ROS level is important in autophagic death of the gastric carcinoma cells, and the increased ROS level, induced by thermo­chemotherapy treatment, induced autophagy in gastric carcinoma cells.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients with Malignant Ascites Secondary to Unresectable Gastric Cancer.

BACKGROUND: To compare the efficacy of three chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into three groups and treated by laparoscopic HIPPC with one of the three following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin [trans-(±)-diaminocyclohexane oxalatoplatinum (l-OHP)], Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the three groups. RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months, and the median survival was 7.5 months for all patients. Patients in the Ra/l-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/l-OHP group and Ra/MMC group was significantly longer than in the Ra/DDP group (P < .05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky Performance Scale, and incidence rate of port-site metastases among the three groups. CONCLUSIONS: Laparoscopy-assisted HIPPC provides modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutic combination of Ra/l-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

Different sequential approaches of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in treating ovarian cancer with malignant ascites.

BACKGROUND AND OBJECTIVES: Treatment for malignant ascites in advanced ovarian cancer (OC) patients remains controversial. The objective of this study was to investigate the efficacy of combined continuous circulatory hyperthermic intraperitoneal chemotherapy (HIPEC) preceded or followed by cytoreductive surgery (CRS) for malignant ascites in OC patients. METHODS: Female OC patients (n = 32) with malignant ascites were divided based on stable (n = 17) or unstable (n = 15) vital signs. Stable patients were treated with CRS immediately followed by HIPEC (CRS + HIPEC). Unstable patients were treated using B-mode ultrasound-guided HIPEC followed by delayed CRS upon vital sign stability (HIPEC + dCRS). All patients were followed up until death or until December 2012. RESULTS: Median follow-up was 29 months. All patients showed ascite regression [objective remission rates (ORR) = 100 %]. Among stable patients, CRS + HIPEC was successful in 14/17 (83.4 %). Among unstable patients, HIPEC + dCRS was successful in 13/15 (86.7 %). Median survival times were 19 and 17 months in the stable and unstable groups, respectively. No significant differences in CRS rates, ascites ORR, Karnofsky performance status scores, or survival rates were observed between groups (P > 0.05). CONCLUSION: Cytoreductive surgery with immediate HIPEC and HIPEC with dCRS, determined by vital sign stability, may lead to similar outcomes in OC patients with malignant ascites.

Intrapleural hyperthermic perfusion using distilled water at 48 °C for malignant pleural effusion.

BACKGROUND: To evaluate the feasibility, safety and preliminary efficacy of B-ultrasound-guided continuous circulatory intrapleural hyperthermic perfusion (IHP) with distilled water (DW) at 48 °C, for the treatment of malignant pleural effusion (MPE). METHODS: Prospective, randomized interventional study in China (from December 2008 to December 2011) in adults with MPE originating from disseminated pleural tumor. EXCLUSION CRITERIA: thoracotomy or surgical resection, limited encapsulated pleural effusion or extensive pleural adhesions. Patients were randomly divided into DW (12 patients; B-ultrasound-guided IHP with 48 °C DW) and PSS-C (11 patients; B-ultrasound-guided IHP with 45 °C physiological saline solution and cisplatin) groups. Patients were followed up for assessment of objective MPE remission rate, Karnofsky performance scale (KPS) scores and survival duration. RESULTS: Pleural effusion was controlled in 100 % of patients, and mean KPS score was increased by 40 % after therapy. Patients' median survival times in the DW and PSS-C groups were 13.0 and 12.9 months, respectively. No serious clinical complications were observed. There were no significant differences between groups in the total objective MPE remission rate, mean KPS score change or median survival time, demonstrating the achievement of significant clinical efficacy with our modified IHP. CONCLUSION: Intrapleural hyperthermic perfusion with 48 °C DW is feasible, easy to perform and relatively safe. This method may offer excellent local control for patients with MPE secondary to disseminated pleural lesions.

Multivariate comparison of B-ultrasound guided and laparoscopic continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy for malignant ascites.

OBJECTIVE: Clinical efficacy of B-ultrasound-guided and laparoscopy-assisted continuous hyperthermic intraperitoneal perfusion chemotherapy (CHIPC) for treatment of malignant ascites was investigated. METHODS: Sixty-two patients with malignant ascites induced by ovarian or gastrointestinal cancers were randomly treated with B-ultrasound-guided CHIPC (therapeutic group) or laparoscopy-assisted CHIPC (control group) performed at the same center. Hospitalization costs and surgical duration were evaluated. Follow-up was conducted for 21 months with B-ultrasound or computed tomography at least once per month for assessment of ascites amount and tumor progression. Clinical efficacy was assessed by modified World Health Organization criteria. Survival time, Karnofsky performance score (KPS) of quality of life (QOL), and complications were recorded for all patients. RESULTS: Overall condition, primary disease type, and ascites amounts were comparable between groups. Significantly shorter mean duration of perfusion catheter placement (35 vs. 85 min) and mean hospitalization cost (36,000 vs. 55,000 ¥/patient) were observed in the therapeutic group than the control group (P < 0.01). Significantly different KPS scores were not observed before or after CHIPC (23.13 vs. 22.64 %) in both groups (P > 0.05). No significant differences in objective remission rates of malignant ascites (93.75 vs. 93.34 %), median survival times (9 vs. 8 months), or stamp hole metastasis rates (18.75 vs. 18.15 %) were observed between groups (P > 0.05). CONCLUSIONS: B-ultrasound-guided and laparoscopy-assisted CHIPC have similar clinical efficacy for improving QOL and prolonging patient survival. B-ultrasound-guided CHIPC may, however, shorten operation times and reduce hospitalization costs, making the treatment available to a broader patient population, although port hole metastasis remains an issue.

B ultrasound-guided hyperthermic intraperitoneal perfusion chemotherapy for the treatment of malignant ascites.

To minimize invasive surgery, we employed B ultrasound to guide the placement of the catheters used in continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy (CHIPC) in malignant ascites treatment. Thirty-two patients with malignant ascites were treated with CHIPC guided by B-mode ultrasound. Ascites were originally from ovarian cancer (11 cases), gastric cancer (10 cases), colorectal cancer (9 cases) and pancreatic cancer (2 cases). The CHIPC was carried out at 43˚C for 90 min with 0.9% saline solution as a carrier containing cisplatin and doxorubicin or mitomycin-C as therapeutic reagents depending on the type of the primary tumor. The therapeutic efficacy, postoperative complications and survival period of these patients were assessed with follow-up examinations. Among all participates to be assessed with ascites, 26 and 4 patients showed complete remission (CR) and partial remission (PR) respectively, with an objective remission rate (ORR) of 93.75%. The KPS scores were elevated by 23.1±9.0 after 3 sessions of ultrasound guided CHIPC and the quality of life (QOF) of patients was significantly improved (p<0.01). The median survival time was 9 months and 18 patients survived between 3 and 30 months after CHIPC treatment. Additionally, patients with different types of cancers significantly differed in the survival time (p<0.01). A novel approach of using B ultrasound guided CHIPC for the treatment of malignant ascites demonstrated satisfactory outcomes. The approach shows benefit in minimizing invasive surgery, improving the patient QOF and prolonging survival time.