Indication of peritonectomy for peritoneal dissemination

A total of 521 patients with peritoneal carcinomatosis (PC) were treated by peritonectomy and perioperative chemotherapy. Each of the 95, 58, 316, 31, 10 and 11 patients were from gastric, colorectal, appendiceal, ovarian, small bowel cancer and mesothelioma, respectively. The distribution and volume of PC are recorded by the Sugarbaker peritoneal carcinomatosis index (PCI). Peritonectomy was performed with a radical resection of the primary tumor and all gross PC with involved organs, peritoneum, or tissue that was deemed technically feasible and safe for the patient. The postoperative major complication of grade 3 was found in 14%, and total 30-day mortality was 2.7%. The survival of gastric cancer patients with a PCI score ≤ 6 was significantly better than those with a PCI score ≥ 7. In appendiceal neoplasm, patients with PCI score less than 28 showed significantly better survival than those with PCI score greater than 29. The survival of colorectal cancer patients with a PCI score ≥ 11 was significantly poorer than those with a PCI score ≤ 10. Among the various prognostic factors in appendiceal neoplasm and gastric cancer patients, CC-0 complete cytoreduction was the most important independent prognostic factor. Peritonectomy is done to remove macroscopic disease and perioperative intraperitoneal chemotherapy to eradicate microscopic residual disease aiming to remove disease completely with a single procedure. Peritonectomy combined with perioperative chemotherapy may achieve long-term survival in a selected group of patients with PC. The higher mortality rate underlines this necessarily strict selection that should be reserved to experienced institutions.     

Effective therapy for peritoneal dissemination in gastric cancer

Peritoneal dissemination is the most frequent cause of death from gastric cancer, accounting for death in 20% to 40% of patients. Preoperative intraperitoneal chemotherapy, peritonectomy, intraoperative chemohyperthermic perfusion, and early postoperative intraperitoneal chemotherapy are treatment modalities specifically designed to eliminate peritoneal dissemination and progression. Preoperative intraperitoneal chemotherapy is for containment of peritoneal free cancer cells, and also may facilitate complete eradication of visible peritoneal dissemination by peritonectomy. Further, complete cytoreduction can be achieved more often when peritonectomy is included in the surgical treatment of gastric cancer with peritoneal dissemination. Phase III data shows prolonged survival attributed to complete cytoreduction. Aggressive cytoreduction of peritoneal dissemination by peritonectomy can reduce residual tumor burden to micrometastases on the peritoneal surface that can be treated by intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. Among all these modalities, surgical cytoreduction is probably the most important for survival benefit. If the surgical cytoreduction is visibly incomplete, prolonged survival cannot be expected, despite subsequent treatment. The surgeon's goal is to reduce the cancer cell burden to a microscopic level. Continued refinement of phase II studies is needed for maximal benefit and to standardize the technical and chemotherapeutic options of each modality.     

Photodynamic therapy using nanoparticle loaded with indocyanine green for experimental peritoneal dissemination of gastric cancer

Although there have been multiple advances in the development of novel anticancer agents and operative procedures, prognosis of patients with advanced gastric cancer remains poor, especially in patients with peritoneal metastasis. In this study, we established nanoparticles loaded with indocyanine green (ICG) derivatives: ICG loaded lactosomes (ICGm) and investigated the diagnostic and therapeutic value of photodynamic therapy (PDT) using ICGm for experimental peritoneal dissemination of gastric cancer. Experimental peritoneal disseminated xenografts of human gastric cancer were established in nude mice. Three weeks after intraperitoneal injection of the cancer cells, either ICGm (ICGm‐treated mice) or ICG solution (ICG‐treated mice) was injected through the tail vein. Forty‐eight hours after injection of the photosensitizer, in vivo and ex vivo imaging was carried out. For PDT, 48 h after injection of the photosensitizer, other mice were irradiated through the abdominal wall, and the body weight and survival rate were monitored. In vivo imaging revealed that peritoneal tumors were visualized through the abdominal wall in ICGm‐treated mice, whereas only non‐specific fluorescence was observed in ICG‐treated mice. The PDT reduced the total weight of the disseminated nodules and significantly improved weight loss and survival rate in ICGm‐treated mice. In conclusion, ICGm can be used as a novel diagnostic and therapeutic nanodevice in peritoneal dissemination of gastric cancer.     

Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. A novel multidisciplinary treatment combining bidirectional chemotherapy [neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)], peritonectomy, hyperthermic intraperitoneal chemoperfusion (HIPEC) and early postoperative intraperitoneal chemotherapy has been developed. In this article, we assess the indications, safety and efficacy of this treatment, review the relevant studies and introduce our experiences. The aims of NIPS are stage reduction, the eradication of peritoneal free cancer cells, and an increased incidence of complete cytoreduction (CC-0) for PC. A complete response after NIPS was obtained in 15 (50%) out of 30 patients with PC. Thus, a significantly high incidence of CC-0 can be obtained in patients with a peritoneal cancer index (PCI) ≤ 6. Using a multivariate analysis to examine the survival benefit, CC-0 and NIPS are identified as significant indicators of a good outcome. However, the high morbidity and mortality rates associated with peritonectomy and perioperative chemotherapy make stringent patient selection important. The best indications for multidisciplinary therapy are localized PC (PCI ≤ 6) from resectable gastric cancer that can be completely removed during a peritonectomy. NIPS and complete cytoreduction are essential treatment modalities for improving the survival of patients with PC from gastric cancer.     

ICAM-2 gene therapy for peritoneal dissemination of scirrhous gastric carcinoma.

PURPOSE: Human scirrhous gastric carcinoma develops peritoneal dissemination with high frequency, and the prognosis of patients with peritoneal metastasis is poor. There have been few reports of an immunogene therapy for peritoneal dissemination. Intercellular adhesion molecule (ICAM)-2 is a second ligand of leukocyte function-associated antigen-1, which functions as a costimulatory molecule for effector cells. In the present study, we examined whether ICAM-2 transfection using adenovirus vector is effective gene therapy for peritoneal metastasis of gastric cancer. EXPERIMENTAL DESIGN: We constructed an adenovirus vector, AdICAM-2, that encodes the full-length human ICAM-2 gene under control of the cytomegalovirus promoter. This vector expresses high levels of ICAM-2 on the human gastric cancer cell line OCUM-2MD3, which has high peritoneal metastatic ability in nude mice. We investigated the antitumor effects of gene transfer of ICAM-2 using the adenovirus vector AdICAM-2 in vitro and in vivo. RESULTS: ICAM-2 expressed on OCUM-2MD3 cells by AdICAM-2 demonstrated significantly high adhesiveness to and cytotoxicity against peripheral blood mononuclear cells in vitro compared with the control adenovirus vector AdlacZ. Intratumoral injection of AdICAM-2 significantly inhibited the growth of s.c. tumor. Mice with peritoneal metastasis survived for a significantly longer time after AdICAM-2 injection, compared with injection of AdlacZ. Histopathological findings revealed that many natural killer cells infiltrated the peritoneal metastatic lesions after AdICAM-2 injection. CONCLUSIONS: These findings suggest that transduction of ICAM-2 into cancer cells enhances the adhesion and activation of natural killer cells, resulting in a reduction of peritoneal metastasis. ICAM-2 transfection using adenovirus vector might be an effective form of gene therapy for peritoneal metastasis of gastric cancer.     

The effect of continuous hyperthermic peritoneal perfusion using high-dose cis-diamminedichloroplatinum for peritoneal dissemination of gastric cancers

A continuous hyperthermic peritoneal perfusion using high-dose cis-diamminedichloroplatinum (CDDP) and its antidote, sodium thiosulfate, was applied to eight patients with peritoneal metastasis from gastric cancers. Two of eight patients showed partial response and the rate of decrease of ascites was 38%. Renal failure and leukopenia were observed in one and two patients, respectively, but no severe or lethal dysfunction was observed and all were tolerated. These results showed that CDDP exerted anti-tumor effects on peritoneal metastasis from gastric cancers when used in high doses in combination with hyperthermia.     

晚期上皮性卵巢癌腹膜播散模式及腹膜切除范围

根据晚期上皮性卵巢癌（epithelial ovarian cancer,EOC）患者腹膜播散模式和腹膜切除范围的最新研究进展,分析评估肿瘤细胞减灭术（cytoreductive surgery,CRS）中行全壁腹膜切除术（total parietal peritonectomy,TPP）和内脏腹膜广泛切除术的前瞻性研究初步结果。在手术期间看似“正常”的腹膜中,隐匿性疾病的发生率较高,这可能是疾病复发的来源。腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy,HIPEC）主要作用于微小病灶和手术过程中脱落到腹腔内的游离癌细胞,从而降低复发风险;与单纯CRS相比,HIPEC联合CRS在无进展生存率和总生存率上均显示出优势。彻底根除这种隐匿性疾病的唯一方法为腹膜切除,TPP与内脏腹膜广泛切除术可能是治疗这种隐匿性疾病最有效的策略。TPP的术后并发症可接受,TPP可延长无进展生存率和总生存率,且TPP后铂类耐药复发的发生率远低于既往结果。      

Subtotal peritonectomy with chemohyperthermic peritoneal perfusion for peritonitis carcinomatosa in gastrointestinal cancer

Treatment for peritonitis carcinomatosa in gastrointestinal cancer remains to be established though it is one of the commonest causes of cancer death. Subtotal peritonectomy (SP) with chemohyperthermic peritoneal perfusion (CHPP) was developed for the new therapeutic strategy for peritoneal dissemination in gastrointestinal cancer in our department. SP includes resection of stomach, colon, small bowel, spleen, gall bladder, and parietal peritoneum. CHPP was carried out by heated saline containing 25 mg/l cisplatin, 10 mg/l mitomycin C, and 20 mg/l etoposide. Intraperitoneal temperature was maintained at 42 degrees C for 60 min. Fifteen gastric cancer and three colon cancer patients with severe peritoneal dissemination underwent these procedures. The averages of operating time, intraoperative bleeding volume, and total perioperative transfused blood volume were 9 h, 4400 ml, and 5600 ml, respectively. The patients estimated as complete resection and residual disease by histopathological study numbered 11 and 7. There was no treatment-related deaths though bleeding occurred in 5 patients; perforation in 2 patients; and abscesses in 2 patients. The 1-year survival rate (1ysr) and the 2-year survival rate (2-ysr) of all the patients were 57% and 21%, respectively. The 1-ysr and the 2-ysr of the patients who underwent complete resection were 67% and 40% significantly greater than the 43% and 0% of the patients who had residual tumors (p=0.02). The combination therapy of SP and CHPP is feasible in spite of its morbidity and has great possibilities in complete resection of peritoneal dissemination and prolongation of patient's survival.     

Cytoreductive surgery and sandwich therapy with chemohyperthermic peritoneal perfusion and intra-aortic chemotherapy for peritoneal dissemination in gastric cancer

Cytoreductive resection (RST), chemohyperthermic peritoneal perfusion (CHPP) and/or intra-aortic chemotherapy (IA-chemo) were performed for peritoneal dissemination in gastric cancer. Ninety-six patients with peritoneal dissemination were grouped into tubercular (TB), 40; nodular (ND), 31; diffuse (DF) type, 19; and others, 6, respectively, by the gross findings. Sixty-three patients underwent RST. Fifty-nine patients received CHPP by 10-liter heated saline. Thirty patients underwent intra-aortic catheterization for the IA-chemo. The 1-year and 2-year survival rate (1-ysr and 2-ysr) of the RST(+) group were 47% and 10% significantly greater than the 9% and 0% of the RST(-) group (p<0.001). The 1-ysr and 2-ysr of the CHPP(+) group were 37% and 11% significantly greater than the 27% and 0% of the CHPP(-) group (p=0.04). In the TB type the 1-ysr and 2-ysr of the former was 43% and 8% significantly greater than the 15% and 0% of the latter (p=0.04). But there was no significant difference in survival time between the CHPP(+) and the CHPP(-) group in the ND type (p=0.22) or in the DF type (p=0.42). The 1-ysr and 2-ysr of the IA-chemo(+) group were 49% and 19% significantly greater than the 27% and 2% of the IA-chemo(-) group (p<0.01). In the DF type the 1-ysr and 2-ysr of the former was 50% and 33% significantly greater than the 8% and 0% of the latter (p=0.02). However, there was no significant difference in survival time between the IA-chemo(+) and the IA-chemo(-) group in the TB type (p=0.06) or in the ND type (p=0.50). Moreover, the effect of the combination therapy of CHPP and IA-chemo (the sandwich therapy, SDW) were examined. The 1-ysr and 2-ysr of the SDW(+) group were 49% and 22% significantly greater than the 24% and 0% of the SDW(-) group (p=0.002). The sandwich therapy should be performed in addition to cytoreductive surgery for improvement of prognosis in the patient with intractable peritoneal dissemination.     

Long-term results of peritonectomy on the patients with peritoneal carcinomatosis

Peritonectomy was done for 125 patients with peritoneal carcinomatosis (PC): 19-pseudomyxomaperitonei (PMP), 15-appendiceal carcinoma (AC), 20-colorectal cancer, 67-gastric cancer, 2-small bowel cancer and 2-peritoneal mesothelioma. Cytoreduction by the standard techniques was done in 130 patients with PC. Complete cytoreduction (CC-0) was achieved in 85 of 125 (68%) patients, who have undergone peritonectomy, but was performed only in 28 of 130 (21%) by the standard surgical techniques. CC-0 could be done to patients with peritoneal cancer indices (PCI) of less than 14. A Cox model showed that significant prognostic factors are CC-0, and the patients were younger than 66 years old. Accordingly, peritonectomy increased the incidence of CC-0, and may have improved the prognosis of patients with PC. Peritonectomy is recommended for patients with PMP, AC and colorectal cancer. In gastric cancer, it is indicated for patients with PCI less than 14.     

Functional analysis of peritoneal lymphoid tissues by GFP expression in mice--possible application for targeting gene therapy against peritoneal dissemination

It is important to develop an efficient adjuvant therapy for the prevention of the postoperative peritoneal recurrence of gastrointestinal cancers such as gastric cancer or pancreatic cancer. Milky sports (MS) are peritoneal lymphoid tissues broadly distributed on the peritoneal tissues such as the omentum, mesentery, or Douglas pouch, and are the selective implantation sites of disseminated cancer cells. In this study, we introduced GFP gene into various cancer cell lines and host-derived cells such as peritoneal macrophages and dendritic cells by adenovirus vetor and injected them i.p. into mice. We then investigated the sites of GFP expression on the peritoneum by fluorescence microscopy. The results showed that green fluorescence was detected specifically for the MS sites that stained black with activated carbon particles (CH40), despite the differences in the cell type injected. These findings indicate that 1) the physioanatomical characteristics of MS may play an essential role in the formation of the initial disseminated lesions at MS, and 2) the host-derived cells accumulating near MS may be available as carriers of a therapeutic gene in intraperitoneal gene therapy against peritoneal dissemination.     

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.     

Neoadjuvant chemotherapy for gastric cancer with peritoneal dissemination

An early detection and treatment of gastric cancer with peritoneal dissemination are rather difficult so that a clinical trial has been neglected. Therefore, we introduced a pre-operative peritoneal lavage diagnosis for gastric cancer patients with serosa-invaded tumors. Neoadjuvant chemotherapy was introduced to patients with positive cytology and with no non-curative factors except peritoneum. The neoadjuvant chemotherapy followed by surgery was done safely. The patients with the disappearance of CY and P factors due to neoadjuvant chemotherapy had a better prognosis than those with positive results of CY or R However, many of the patients with negative results from peritoneum eventually suffered a peritoneal recurrence. We started another protocol study with S-1 and an intra-peritoneal chemotherapy using docetaxel. The efficacy in the protocol result will be expected.     

Effectiveness of intraperitoneal chemotherapy using new-aged drugs for the peritoneal dissemination of gastric cancer

We evaluated the effectiveness of intraperitoneal chemotherapy for peritoneal dissemination of gastric cancer. A total of 104 patients with primary gastric cancer with peritoneal dissemination were enrolled in this study. In 72 of the 104 patients with gastrectomy performed, 5 patients underwent CDDP-ip (50-100 mg/100-200 ml), 16 patients underwent CHPP (CDDP 300 mg, MMC 30 mg, ETP 150 mg/8 l/42-43 degrees C/60 min), and 17 patients underwent CMV-ip (CDDP 150 mg, MMC 20 mg, ETP 100 mg/1 l/60 min). The prognosis of patients who underwent CMV-ip was significantly better than those who received other therapies. In 26 patients with severe peritoneal dissemination who were treated with TS-1 (60 mg/m2) and taxane-ip (docetaxel 40-60 mg/body or paclitaxel 120-180 mg/body), 9 of 18 responders performed complete cytoreduction. The median survival time (MST) in these 9 patients was 944 days and a 2-year survival rate was 63%. A multimodal therapy consisting of systemic chemotherapy, intraperitoneal chemotherapy and complete cytoreductive surgery may provide good prognosis to the gastric cancer patients with peritoneal dissemination.     

Risk factors for peritoneal dissemination of colorectal cancer

BACKGROUND AND OBJECTIVES: The aim of this study was to clarify the risk factors associated with positive peritoneal dissemination (PPD) of colorectal cancer (CRC). METHODS: From June 2000 to September 2002, 143 CRC patients who underwent elective curative (79.0%) or non-curative (21.0%) open laparotomy were prospectively studied. Clinical evaluations including classical factors, colonoscopic evaluation, intraoperative evaluation, and pathological features were recorded. PPD was diagnosed when macro- (MAPD) or microscopic peritoneal dissemination (MIPD) was evident. Positive peritoneal cytology from initially existing ascites or washing lavage indicated MIPD. Various factors were analyzed with univariate (Chi-square test) and then multivariate analyses (logistic regression test) to search for the risk factors of PPD. RESULTS: Overall, MIPD, MAPD, and PPD were found in 2.8%, 6.3%, and 9.1%, respectively. Univariate analysis identified age (< or =59 years), CA19-9 (> or = 34.6 U/ml), poor differentiation, circumferential involvement (> or = 3 quadrants), ascites volume (>80 ml), pN+, and pT4 as risk factors of PPD. PPD did not occur in patients with well-differentiated tumors, less circumferential involvement (< 2 quadrants), or no lymph node metastasis. After multivariate analysis, CA19-9 (Odds ratio (95% CI), 8.6 (1.7-43.1)), pT4 (9.0 (1.3-61.0)), and age (5.26 (1.1-25.0)) remained significant risk factors. CONCLUSION: CA19-9 (> or = 34.6 U/ml), pT4, and age (< or =59 years) were significant risk factors of PPD.     

Effectiveness of continuous hyperthermic peritoneal perfusion for the peritoneal dissemination of gastric cancer

We investigated the effectiveness of continuous hyperthermic peritoneal perfusion (CHPP) for the peritoneal dissemination of gastric cancer. A total 124 patients with advanced gastric cancer were enrolled in this study. Prophylactic CHPP (P-CHPP) was performed in 45 patients who had macroscopic serosal invasion without peritoneal dissemination, and 79 patients without CHPP were a control group. Therapeutic CHPP (T-CHPP) was performed in 21 patients with peritoneal dissemination, and 52 patients without CHPP were a control group. There was no significant difference in 5 year survival between patients treated and not treated with P-CHPP. Univariate analysis showed that location of tumor, tumor diameter, and lymph node metastasis influenced prognosis, but there was no prognostic factor in the Cox proportional regression hazard model. There was no significant difference in 5-year survival between patients treated and not treated with T-CHPP. Univariate analysis showed that degree of peritoneal dissemination and adjuvant chemotherapy influenced prognosis, and the Cox proportional regression hazard model showed that the macroscopic types and degree of peritoneal dissemination affected prognosis. In the patients with CHPP, the incidences of respiratory failure and renal failure were each statistically greater than in the patients undergoing CHPP.