Treatment results of peritonectomy combined with perioperative chemotherapy for colorectal cancer-patients with peritoneal carcinomatosis

Operation results of 81 colorecatal cancer-patients with peritoneal carcinomatosis (PC) treated with peritonectomy plus perioperative chemotherapy are reported. The patients who had the following evidences are considered to be eligible for peritonectomy: 1) No evidence of N3 lymph node involvement, 2) No evidence of hematogenous metastasis, 3) No progressive disease after preoperative chemotherapy, 4) No severe co-morbidities or no poor general condition. Complete cytoreduction resection is aimed for removing all macroscopic tumors by peritonectomy using electrosurgical techniques. The completeness of cytoreduction (CC scores) after peritonectomy is classified into the following 4 criteria: CC-0-no peritoneal seeding was exposed during the complete exploration, CC-1-residual tumor nodules are less than 2.5 mm in diameter, CC-2-nodules are between 2 .5 mm and 25 mm in diameter, CC-3-nodules are greater than 25 mm in diameter, CC-2 and CC-3 are regarded as incomplete cytoreduction. Operation time and blood loss were 237 ± 124 min. (799-90 min) and 1,598 ± 1,411 mL (6,500-20 mL), respectively. Postoperative complications developed in 37( 46%) patients. The patients received CC-0/ -1 resection survived significantly longer than those of CC-2/ -3 group. The patients with PCI ≤ 10 survived significantly longer than those with PCI≥ 11. CC and PCI scores are the independent prognostic factors. The relative risk for death of CC-2/-3 group was 4.6-fold higher than that of CC-0/ -1 group. Accordingly, peritonectomy is indicated for patients with PCI score≤ 10.     

腹膜转移癌内科治疗新进展

腹膜转移癌因发现较晚且预后差,目前正成为研究热点。随着细胞减灭术及腹腔热灌注治疗的推广,部分经选择的患者获益。针对不同肿瘤的不同时期,大量的临床研究显示,用药选择、用药时机、用药方法方面均取得进展,尤其是加压腹腔内气溶胶化疗的使用减轻了治疗相关不良反应,并提高了疗效。本文就近年来腹膜转移癌的内科治疗进展进行阐述。     

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with gastric cancer and peritoneal carcinomatosis

Background

Gastric Cancer (GC) with Peritoneal Carcinomatosis (PC) has long been regarded as a terminal disease. Over the past two decades, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has changed the traditional concept of peritoneal metastases from being a systemic disease, to being considered a locoregional dissemination.

Prevention of peritoneal carcinomatosis recurrence with a prostaglandin synthesis inhibitor, indomethacin

Carcinomas produce large amounts of prostaglandin (PG) E2, which play an important role in suppression of non-specific cellular immune reaction in tumor-bearing individuals. PG synthesis inhibitor can restore the immune activity against tumors. The anti-tumor activity of indomethacin was investigated in CDF1 mice (BALB/c X DBA/2) implanted intraperitoneally with mouse colon adenocarcinoma 26 (5 X 10(5) or 2 X 10(5) cells) in a model study to prevent peritoneal recurrence after surgery for gastrointestinal cancers. Oral administration of indomethacin (0.002% water solution as drinking water) depressed and inhibited the disseminated tumor growth in the abdominal cavity, and prolonged the survival time, resulting in 30-50% cures of mice. The treatment combined with a small intraperitoneal dose of Picibanil (OK-432) (0.5 mg/kg twice weekly), which activates macrophages in the abdominal cavity, cured 90% of mice. An intraperitoneal dose of 16,16-dimethyl-PGE2 (5 micrograms/mouse, daily) reduced the anti-tumor activity of indomethacin. The results suggest that indomethacin treatment relieved the endogenous(tumor cell- and macrophage-produced) PGE2-mediated immunosuppression. It is postulated that PG-synthesis inhibitor in combination with chemotherapeutic agents, immunotherapeutic agents and low dose radiation, may provide a good therapeutic tool to prevent the development of peritoneal carcinomatosis, particularly in the cases having a small number of residual cancer cells or micrometastases in the abdominal cavity after surgery.     

Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy

BACKGROUND:

Peritoneal carcinomatosis (PC) from nonovarian malignancies long has been regarded as a terminal disease. Over the past decade, new locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved that have demonstrated improved survival.

METHODS:

A retrospective, multicenter cohort study was performed in French‐speaking institutions to evaluate toxicity and principal prognostic factors after cytoreductive surgery and PIC (hyperthermic intraperitoneal chemotherapy [HIPEC] and/or early postoperative intraperitoneal chemotherapy [EPIC]) for PC from nongynecologic malignancies.

RESULTS:

The study included 1290 patients from 25 institutions who underwent 1344 procedures between February 1989 and December 2007. HIPEC was performed in 1154 procedures. The principal origins of PC were colorectal adenocarcinoma (N = 523), pseudomyxoma peritonei (N = 301), gastric adenocarcinoma (N = 159), peritoneal mesothelioma (N = 88), and appendiceal adenocarcinoma (N = 50). The overall morbidity and mortality rates were 33.6% and 4.1%, respectively. In multivariate analysis, patient age, the extent of PC, and institutional experience had a significant influence on toxicity. The overall median survival was 34 months; and the median survival was 30 months for patients with colorectal PC, not reached for patients with pseudomyxoma peritonei, 9 months for patients with gastric PC, 41 months for patients with peritoneal mesothelioma, and 77 months for patients with PC from appendiceal adenocarcinoma. Independent prognostic indicators in multivariate analysis were institution, origin of PC, completeness of cytoreductive surgery, extent of carcinomatosis, and lymph node involvement.

CONCLUSIONS:

A therapeutic approach that combined cytoreductive surgery with PIC was able to achieve long‐term survival in a selected group of patients who had PC of nonovarian origin and had acceptable morbidity and mortality. The current results indicated that this treatment should be centralized to institutions with expertise in the management of PC. Cancer 2010. © 2010 American Cancer Society.     

Intracavital chemotherapy for peritoneal and pleural carcinomatosis with lipid-formulated anticancer agents

A clinical pilot study of intracavital chemotherapy with anticancer agents dissolved in lipids for malignant effusion in pleural and peritoneal cavity was performed. Seven patients with pleural or peritoneal metastases were treated with a cocktail of anticancer agents dissolved in Lipiodol individually administered via the intracavitary route. All the patients revealed cytological and physical improvement. Five patients responded completely and two responded partially; four patients were able to be discharged from hospital and no serious side effects were observed. Thus, this therapeutic tactic of using oily anticancer agents appeares to be promising for control of pleural and peritoneal carcinomatoses.     

胃肠道恶性肿瘤腹膜转移热灌注化疗研究进展

腹腔内热灌注化疗（IPHC）可提高大肠癌、胃癌等胃肠道恶性肿瘤腹膜转移患者的生存率，但对不同分期、不同部位来源腹膜转移患者的效果有所区别，且有部分患者对IPHC耐受性较差。因此需要严格掌握适应证和禁忌证。IPHC常用的药物有奥沙利铂、顺铂、丝裂霉素C等，具体方法不同机构常有所差别，尚有待标准化。     

腹腔热灌注化疗治疗结直肠癌腹膜癌

结直肠癌局域性进展可形成腹膜癌,大约10％的患者初诊即发现腹膜癌,有4％～19％的患者在根治术后随访期发生腹膜癌,25％～35％的复发患者以腹膜癌为唯一表现。全身化疗对此类腹膜癌只是姑息性治疗,中位生存期不足6个月。缩瘤术加腹腔热灌注化疗则可清除宏观和微观癌细胞。荷兰癌症中心的Ⅰ、Ⅱ、Ⅲ期临床试验总结分析表明,接受完全缩瘤术加腹腔热灌注化疗者的中位生存期可达42．9个月,1、3、5年生存率分别是95％、56％和43％,明显高于传统治疗方法,已成为英国、法国、意大利、荷兰、西班牙和澳大利亚等国的标准治疗。     

腹腔热灌注化疗治疗结直肠癌腹膜癌

结直肠癌局域性进展可形成腹膜癌，大约10％的患者初诊即发现腹膜癌，有4％～19％的患者在根治术后随访期发生腹膜癌，25％～35％的复发患者以腹膜癌为唯一表现。全身化疗对此类腹膜癌只是姑息性治疗，中位生存期不足6个月。缩瘤术加腹腔热灌注化疗则可清除宏观和微观癌细胞。荷兰癌症中心的Ⅰ、Ⅱ、Ⅲ期临床试验总结分析表明，接受完全缩瘤术加腹腔热灌注化疗者的中位生存期可达42．9个月，1、3、5年生存率分别是95％、56％和43％，明显高于传统治疗方法，已成为英国、法国、意大利、荷兰、西班牙和澳大利亚等国的标准治疗。     

In vivo effects of cavitation alone or in combination with chemotherapy in a peritoneal carcinomatosis in the rat.

Cavitation (volume oscillations and collapse of gas bubbles), as generated by a co-administration of shockwaves (SW) and microbubbles (SWB), induces cytotoxicity in vitro. Moreover, cavitation potentiates the effects of Fluorouracil (FUra) on colon cancer cells. We aimed at reproducing such effects in vivo. A peritoneal carcinomatosis was induced in BDIX rats by intraperitoneal (IP) injection of DHDK12PROb cells. Cavitation was produced by various SW regimens (250 to 750SW) combined with bubbles (air/gelatin emulsion) infused through an IP catheter. In two consecutive experiments, microtumours (day 3 after cell injection) were submitted to various combinations of cavitation and/or Fluorouracil (FUra) and Cisplatinum (CDDP) at either high or low doses. After 30 days, 100% of control animals were dead or presented carcinomatosis with ascites, vs 60% after FUra 5 mg kg dy, day 4 through 8, and 0% after 250 SWB, day 4 and 6 + FUra 5 mg kg dy, day 4 through 8 (P < 0.001); similar differences were found with CDDP. Survival after low dose FUra + SWB was comparable to high dose FUra (25 mg kg dy day through 8) and was improved as compared to low-dose FUra alone. Only a high dose FUra + SWB schedule induced 40% long term (> 150 days) disease-free survival, but also a higher undesirable toxicity (40% toxic deaths within 1 month). It is concluded that cavitation is cytotoxic in vivo and that it potentiates the effects of FUra and CDDP in this animal model.     

Hypotonic intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in mice.

The intraperitoneal (i.p.) administration of cisplatin (CDDP) is one of the most effective therapies for cancers that are confined to the abdominal cavity. However, the effect of fluid osmolarity on the therapeutic efficacy of i.p. administration of CDDP has not been well established. In the current study, hypotonic (154 mosmol 1-1), isotonic (308 mosmol 1-1) and hypertonic (616 mosmol 1-1) solutions of CDDP were prepared for an evaluation of their therapeutic efficacy in an experimental system. After i.p. administration, uptake of CDDP in vivo by tumor cells in hypotonic solution was significantly greater than in isotonic or hypertonic solution. The 50% lethal dose (LD50) value of CDDP in hypotonic solution (12.1 mg kg(-1)) was lower than that in isotonic solution (16.9 mg kg(-1)) and than that in hypertonic solution (28.6 mg kg(-1)). However, when a dose equal to one-half of the LD50 was administered in each solution to mice with i.p. tumours, survival of mice given the CDDP in hypotonic solution was significantly prolonged as compared with the survival of the other mice. These results demonstrate that the therapeutic efficacy of i.p. CDDP in mice is augmented when the drug is administered in hypotonic solution.     

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.     

Biliary cystadenocarcinoma with peritoneal carcinomatosis

An autopsy report of a patient with a hugh biliary cystadenocarcinoma arising in the right lobe of the liver is presented. The tumor had been though to be benign, but peritoneal carcinomatosis developed 18 months after the operation. Autopsy revealed marked peritoneal dissemination of mucinous adenocarcinoma, apparently a result of peritoneal seeding of hepatic cystadenocarcinoma, which was presumed to be triggered by cyst aspiration performed during the operation. Experience indicates that surgical procedures on cystic liver disease should be carried out carefully, considering the possible existence of malignancy.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in treatment of gastric cancer with peritoneal carcinomatosis

Although gastric cancer with peritoneal carcinomatosis is associated with poor prognosis and is generally treated with palliative systemic therapy,recent studies have shown that cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may prove to be an efficacious treatnent option.In addition to reviewing the natural history of gastric cancer with peritoneal carcinomatosis,this mini-review examines literature on the efficacy of CRS and HIPEC as compared to chemotherapy and surgical options.Both randomized and nonrandomized studies were summarized with the emphasis focused on overall survival.In summary,CRS and HIPEC are indeed a promising treatment option for gastric cancer with peritoneal carcinomatosis and large randomized clinical trials are warranted.     

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes

The effect of chemotherapy on peritoneal carcinomatosis (PC) of gastric cancer remains unclear. Recently, the intraperitoneal (IP) administration of taxanes [e.g., paclitaxel (PTX) and docetaxel (DOC)] during the perioperative period has shown promising results. Herein, we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results. IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h. The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects, making it ideal for IP chemotherapy. There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy (SPIC). In SPIC, patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery (CRS) until disease progression. Usually, a taxane dissolved in 500-1000 mL of saline at ordinary temperature is administered through an IP access port on an outpatient basis. According to phase I studies, the recommended doses (RD) are as follows: IP DOC, 45-60 mg/m²; IP PTX [without intravenous (IV) PTX], 80 mg/m²; and IP PTX (with IV PTX), 20 mg/m². Phase II studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%. A phase III study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011. The prognosis of patients who underwent CRS was better than that of those who did not; however, this was partly due to selection bias. Although several phase II studies have shown promising results, a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.     

减瘤术联合术中腹腔内温热化疗治疗消化道肿瘤腹膜转移

消化道恶性肿瘤腹膜转移在临床十分常见,预后极差。近年来,减瘤术联合术中腹腔内温热化疗方案治疗效果满意。现综述如下。