The approval process for hyperthermic intraoperative intraperitoneal chemotherapy

AimsTo clarify the requirements for Food and Drug Administration approval in the United States for hyperthermic intraoperative intraperitoneal chemotherapy administration. Also, to review the status of the approval process in Europe.MethodsThe obstacles to be overcome for approval by the Food and Drug Administration for a new drug approval and for a new device approval were reviewed. Drugs approved in the past were examined for their potential for current application in this technology.ResultsThe likelihood that the approval of a heater circulator along with the approval for specific chemotherapy agents for heated intraoperative intraperitoneal chemotherapy was judged to be remote. Rather, the continued use of “homemade heater circulators” and the off-label use of appropriate chemotherapy agents augmented by heat will continue to be the standard of care. The European community currently has several heater circulators approved for hyperthermic intraoperative intraperitoneal chemotherapy administration. These devices have been specifically approved for oncologic indications.ConclusionsContinued research and development of heated intraoperative intraperitoneal chemotherapy is necessary. As the requirement for prevention and treatment of the peritoneal surface component of gastrointestinal and gynecologic oncology expands, new investigations into the approval process in the United States will be necessary. Publication of results from institutions pioneering these new treatment strategies will, of necessity, continue.     

大肠癌术后腹腔低渗温热化疗

目的研究腹腔低渗温热化疗对大肠癌术后腹腔内及肝转移的预防效果.方法收集自1996年7月～1999年12月大肠癌手术病例,随机分为两组A组腹腔低渗温热化疗组.B组常规静脉化疗组.观察腹腔复发率、肝转移率、生存率.结果A组腹腔复发率7.5%(4/53),肝转移率5.7%(3/53),1年、2年生存率分别为96.8%(60/62)、88.7%(55/62).B组腹腔复发率11.8%(6/51),肝转移率15.7%(8/51),1年、2年生存率分别为82.8(48/58)、74.1%(43/58).结论腹腔低渗温热化疗对预防大肠癌术后腹腔内复发、肝转移、提高生存率有显著疗效.     

胃癌患者术中腹腔热灌注化疗的临床研究

目的：探讨胃癌根治术中一次性腹腔温热灌注化疗的临床疗效。方法：将术中行一次性腹腔温热灌注化疗的50例胃癌患者（治疗组）与未行此方法治疗的100例患者（对照组）的腹腔游离癌细胞检出率及预后等情况进行对比。结果：治疗组的温热灌注液游离癌细胞检出率为7．4％；对照组冲洗液的癌细胞检出率为30．8％。治疗组与对照组术后两年内腹腔复发率分别为14．6％和38．7％（P〈0．01）。治疗组术后1、2、3年生存率分别为100％、79％和60％；对照组则为95．1％、50．2％和35．2％，两组2、3年生存率比较，差异有显著性（P〈0．01）。结论：一次性腹腔温热灌注化疗简便、高效、安全，具有杀灭腹腔游离癌细胞的作用，可降低患者术后腹腔复发率和提高生存率。     

胃癌患者术中腹腔热灌注化疗的临床研究

目的:探讨胃癌根治术中一次性腹腔温热灌注化疗的临床疗效.方法:将术中行一次性腹腔温热灌注化疗的50例胃癌患者(治疗组)与未行此方法治疗的100例患者(对照组)的腹腔游离癌细胞检出率及预后等情况进行对比.结果:治疗组的温热灌注液游离癌细胞检出率为7.4%;对照组冲洗液的癌细胞检出率为30.8%.治疗组与对照组术后两年内腹腔复发率分别为14.6%和38.7%(P＜0.01).治疗组术后1、2、3年生存率分别为100%、79%和60%;对照组则为95.1%、50.2%和35.2%,两组2、3年生存率比较,差异有显著性(P＜0.01).结论:一次性腹腔温热灌注化疗简便、高效、安全,具有杀灭腹腔游离癌细胞的作用,可降低患者术后腹腔复发率和提高生存率.     

腹腔热灌注化疗治疗进展期胃肠癌的疗效与安全性的Meta分析

目的:评价腹腔热灌注化疗（intraperitoneal hyperthermic perfusion chemotherapy,IHPC）治疗进展期胃肠癌的疗效与安全性。方法:检索Cochrane Library、PubMed、中国知网、中国生物医学文献数据库、中国科技期刊数据库和万方数据库等,辅以其他检索,收集单一IHPC或IHPC联合全身静脉化疗（intravenous chemotherapy,IC）对比IC治疗进展期胃肠癌的随机对照试验（randomized controlled trials,RCTs）。本文采用Cochrane系统评价手册推荐的标准和RevMan5.3软件对纳入文献进行质量评价和数据分析。结果:纳入29篇RCTs,共2 685例患者。Meta分析结果:IHPC 组的有效缓解率、完全缓解率、1生存率、3生存率和5年生存率高于IC组,OR和95%CI分别为（2.88,2.25~3.69）、（2.16,1.57~2.98）、（2.10,1.54~2.88）、（2.80,2.19~3.58）和（2.71,1.81~4.05）,其差异均有统计学意义（P＜0.000 01）。同时,IHPC组复发率、远处转移率及肝转移率低于IC组,其差异均有统计学意义（P＜0.05）。就安全性而言,两组胃肠道反应、腹痛、腹泻、肝脏损害、肠梗阻、神经毒性发生率的差异均无统计学意义（P＞0.05）;但白细胞减少、腹胀及肾脏损害的发生率差异均有统计学意义（P＜0.05）。结论:与IC相比,IHPC或IHPC+IC治疗胃肠癌的疗效较好,安全性可接受,但仍需要更大的多中心RCT研究来证实,以利于今后IHPC疗法在临床中更好的应用。     

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.     

Evaluation of the risk of contamination of surgical personnel by vaporization of oxaliplatin during the intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC).

AIMS: To evaluate if oxaliplatin is likely to vaporize under HIPEC conditions and to see if it could be a source of pulmonary contamination for surgeons. METHODS: Three oxaliplatin concentrations (230, 460 and 920 mg oxaliplatin/l), 3 heating temperatures (41, 43 and 45 degrees C) and 3 bubbling durations (30, 60 and 90 min) were tested. Drug vaporization was evaluated by using inductively coupled plasma mass spectrometry (ICP-MS) to analyze platinum concentrations in the trap solutions. RESULTS: At all concentrations of oxaliplatin solutions, heating temperatures and bubbling trap periods, the quantities of vaporized platinum were always insignificantly lower than 1 microg/l. CONCLUSIONS: The experimental risk of pulmonary contamination of hospital staff during HIPEC procedure appears to be negligible. However a monitoring study with an analysis of samples of the operating theatre and urine from surgical personnel should be carried out to confirm these conclusions.     

Postoperative infections in cytoreductive surgery with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis

BACKGROUND: Peritoneal carcinomatosis is a common evolution of many abdominal and pelvic malignancies. Over the last decade novel therapeutic approaches have emerged combining cytoreductive surgery with perioperative intraperitoneal chemotherapy. Aim of our study was to assess frequency, sites, and organisms of postoperative infections in this surgery and to evaluate associated risk factors and clinical outcome. METHODS: Retrospective study of postoperative infection in 30 patients undergoing combined cytoreductive surgery and hypertermic intraoperative chemotherapy in an oncologic surgery in Rome, between June 2001 and December 2004. RESULTS: Twenty-nine postoperative infections were recorded in 11 patients (36.7%; 2.6 infections per patient), including 13 surgical site infections, 8 clinical sepsis, 6 bloodstream infections, and 2 pneumonias. At multivariate analysis, total peritonectomy was found as independent variable associated to postoperative infection. Mortality rates were 36.4% and 5% among patients with and without postoperative infections, respectively (P = 0.04). Four of the 5 patients with invasive candidosis died. CONCLUSIONS: Peritonectomy procedures have an high risk of postoperative infections, prolonged hospital stay, and high morbidity and mortality. The increasing role of this surgery for the treatment of peritoneal carcinomatosis should strengthen the need for a careful evaluation of possible risk factors for postoperative infections, including the role of colonizing organisms.     

Shielding considerations for an operating room based intraoperative electron radiotherapy unit

The leakage radiation characteristics of a dedicated intraoperative radiotherapy linear accelerator have been measured on a machine designed to minimize the shielding required to allow it to be placed in an operating room suite. The scattering foil design was optimized to produce a flat beam for the field sizes employed while generating minimal bremsstrahlung contamination over the available energy range. More lead shielding was used in the treatment head than is used in conventional accelerators. A small amount of borated polyethylene shielding was also employed since neutron production was present at measurable levels. The room shielding installed in the operating room was demonstrated to be adequate to treat at least 20 patients each month to an average dose of 20 Gy. The worst case exposure was found to be 73% maximum permissible exposure. Administrative control was required for adjoining areas when calibrations and maintenance were performed.     

进展期胃癌术后腹腔热灌注化疗的研究进展

胃癌为临床常见恶性肿瘤之一, 外科手术是其重要治疗方案, 进展期胃癌患者术后5年生存率较低, 而术后癌灶复发成为影响患者预后的重要因素。随着国内医学水平不断发展, 腹腔热灌注化疗技术得以不断改进, 其在进展期胃癌患者术后辅助治疗中的应用日益广泛, 长期临床实践表明预防性运用腹腔热灌注化疗可明显降低进展期胃癌术后复发率并提高其5年生存率, 在改善患者生存质量及总体临床疗效方面的作用明确。本文旨在对中国进展期胃癌术后腹腔热灌注化疗的临床应用进展进行综述。      

The impact on postoperative outcomes of intraoperative fluid management strategies during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

BackgroundThe impact of intraoperative fluid management during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on postoperative outcomes has been poorly investigated. This study aimed to retrospectively evaluate the impact of intraoperative fluid management strategy on postoperative outcomes and survival.Methods509 patients undergoing CRS and HIPEC at Uppsala University Hospital/Sweden 2004–2017 were categorized into two groups according to the intraoperative fluid management strategy: pre-goal directed therapy (pre-GDT) and goal directed therapy (GDT), where a hemodynamic monitor (CardioQ or FloTrac/Vigileo) was used to optimize fluid management. Impact on morbidity, postoperative hemorrhage, length-of-stay and survival was analyzed.ResultsThe pre-GDT group received higher fluid volume compared to the GDT group (mean 19.9 vs. 16.2 ml/kg/h, p < 0.001). Overall postoperative morbidity Grade III-V was higher in the GDT group (30% vs. 22%, p = 0.03). Multivariable adjusted odds ratio (OR) for Grade III-V morbidity was 1.80 (95%CI 1.10–3.10, p = 0.02) in the GDT group. Numerically, more cases of postoperative hemorrhage were found in the GDT group (9% vs. 5%, p = 0.09), but no correlation was observed in the multivariable analysis 1.37 (95%CI 0.64–2.95, p = 0.40). An oxaliplatin regimen was a significant risk factor for postoperative hemorrhage (p = 0.03). Mean length of stay was shorter in the GDT group (17 vs. 26 days, p < 0.0001). Survival did not differ between the groups.ConclusionWhile GDT increased the risk for postoperative morbidity, it was associated with shortened hospital stay. Intraoperative fluid management during CRS and HIPEC did not affect the postoperative risk for hemorrhage, while the use of an oxaliplatin regimen did.     

腹腔热灌注化疗在胃癌治疗中的应用研究

目的研究腹腔热灌注化疗对胃癌的治疗效果.方法选行规范根治术的胃癌病人70例,随机分为:术后腹腔内热灌注化疗组(A组,n=35)和全身化疗组(B组,n=35),观察两组病人在治疗过程中肝、肾功能、体温、血细胞计数改变及术后生存率等.结果 B组病人术后所出现的毒副反应人数和程度都较A组多且重;术后1、3、5年A组生存率分别为88.5﹪、65.4﹪、53.8﹪,B组为73.3﹪、36.7﹪、26.7﹪.A组术后3、5年的生存率均明显高于B组,差异有显著性意义(P＜0.05).结论腹腔热灌注化疗能明显提高胃癌术后病人的生存率和生存质量.     

Chemotherapy for intraperitoneal use: a review of hyperthermic intraperitoneal chemotherapy and early post-operative intraperitoneal chemotherapy

Peritoneal spread of tumors is a major problem in cancer management. Patients develop a marked deterioration in quality of life and shortened survival. This is in part due to bowel obstructions, marked ascites, and overall increase debilitation. Standard medical management has shown to be inadequate for the treatment of these problems. Surgery can palliate symptoms, however, it is unable to be complete at the microscopic level by a significant spillage of tumor cells throughout the abdomen. Chemotherapy can have some improvement in symptoms however it is short lived due to poor penetration into the peritoneal cavity. The role of intraperitoneal chemotherapy is to maximize tumor penetration and optimize cell death while minimizing systemic toxicity. Hyperthermic intraperitoneal chemotherapy (HIPEC) and early post-operative intraperitoneal chemotherapy (EPIC) are two treatment methods that serve this role and have been shown to improve survival. This review will discuss different chemotherapies used for both of these treatment options.     

腹腔热灌注化疗的研究进展

腹膜是腹腔恶性肿瘤的常见转移部位,腹膜表面的血液供应很少,加之血浆-腹膜屏障的存在,使得静脉化疗药物很难到达腹膜表面.腹腔热灌注化疗则可直接作用于腹膜,从而有效地治疗腹膜转移癌及其引起的恶性腹水.本文将不同的腹腔热灌注化疗方法进行了分类,并综述了近几年腹腔热灌注化疗的研究进展.     

Investigations on safety of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with Mitomycin C

AIMS: Previous safety monitoring of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with Mitomycin C (MMC) did not demonstrate any detectable safety hazard to the personnel. Nevertheless, those results have been discussed controversially because of the methodological problems employed in the evaluation of potential exposure. We re-evaluated possible safety hazards of HIPEC by applying different monitoring strategies. METHODS: We monitored air samples in the operation room during HIPEC. In addition, we measured MMC in plasma of the surgeon with a newly developed analytical method. All samples were analysed by HPLC-UV at 360nm. The permeability of the gloves was tested using two in vitro techniques: diffusion cells and a glass cell chamber. In-use and worst-case exposure scenarios were imitated for in vitro experiments. RESULTS: The analysis of the air samples (n=3) could not detect any MMC. We found no drug above the limit of detection (1microg MMC/L) in the plasma samples of the surgeons (n=5). A breakthrough of latex glove material was detected in only one (worst-case exposure scenario) of 40 diffusion cell experiments. CONCLUSIONS: Established methods of safety monitoring could not reveal any detectable risk on in-use exposure conditions. The wearing of doubled latex gloves should prevent the surgeon from dermal exposure to MMC during HIPEC.     

Identifying the incidence of respiratory complications following diaphragmatic cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy

Clinical and Translational Oncology - In patients with peritoneal carcinomatosis (PC), the incidence of respiratory complications following cytoreductive surgery (CRS) and hyperthermic...     

Laparoscopic intraperitoneal hyperthermic chemotherapy for palliation of debilitating malignant ascites.

AIM: To report the use of laparoscopic Intraperitoneal Hyperthermic Chemotherapy (LIPHC) in the treatment of malignant ascites. METHODS: From September 2001 to December 2003, 14 patients between the age of 56 and 78years were treated. Ascites was from gastric cancer (5 cases), colorectal cancer (3 cases), ovarian cancer (3 cases), breast cancer (2 cases) and peritoneal mesothelioma (1 case). The LIPHC was carried out at 42 degrees C for 90 min with 1.5% dextrose solution as a carrier. Chemotherapy was cisplatin and doxorubicin or mitomycin depending on the type of primary tumor. The drains were left in situ after surgery and removed when perfuse drainage ceased. RESULTS: Ascites was controlled in all the treated cases. A CT scan performed in follow-up showed a small, clinically undetectable, fluid accumulation in the pelvis of one patient. CONCLUSIONS: This method resulted in benefit for those peritoneal carcinomatosis patients with debilitating malignant ascites who were excluded from cytoreductive surgery. Proficiency in laparoscopic staging procedures and experience in the management of carcinomatosis and intraperitoneal hyperthermic chemotherapy (IPHC) are required for the success of the procedure.