进展期胃癌术中腹腔热灌注化疗临床研究

目的探讨进展期胃癌术中腹腔热灌注化疗对防治腹膜转移的疗效及安全性。方法对40例进展期胃癌患者进行回顾性分析,热化疗组(实验组)20例行根治性手术联合术中腹腔热灌注化疗(H IPEC),采用奥沙利铂350 mg溶于右旋糖酐4000 m l中,加热至41.5℃~42.5℃腹腔内循环灌注40~60 m in;选择同期单纯根治性手术治疗的20例胃癌患者作为对照组,对比分析两组患者的临床指标及预后。结果热化疗组仅少数病例治疗后出现短期血压降低、心率增快及肝肾功能、凝血功能指标异常,两组并发症发生率无明显差异;术后腹腔种植转移率热化疗组为5.0%(1/20),对照组15.0%(3/20);1,2年生存率热化疗组分别为90.0%(18/20)和75.0%(15/20),对照组分别为80.0%(16/20)和60.0%(12/20)。结论 H IPEC可有效防治腹膜转移、提高生存率,且并发症少,可作为进展期胃癌术中的辅助治疗。     

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.     

The prognostic value of positive peritoneal lavage cytology and the prevention of peritoneal dissemination after colorectal surgery

Peritoneal washing cytology during surgery was done in 745 patients with colorectal cancer. The positive washing cytology rate was 49/745 (6.6%). The peritoneal recurrence rates were 12/22 (54.5%) and 8/682 (1.3%) among patients with positive and negative peritoneal washing, respectively (p < 0.0001). The 5-year survival rate is 89.4% of the patients with positive cytology and 38.2% with negative cytology. The patients with positive cytology have a significantly lower survival rate than the negative one (p < 0.0001). Eleven patients of the positive cytology received intraperitoneal administration of MMC. Peritoneal dissemination occurred in 3/11 (27.3%) of the MMC treated group and 9/11 (81.8%) in the untreated group (p = 0.030). Our results indicated that intraperitoneal administration of MMC was an effective method of preventing peritoneal dissemination after resection of colorectal cancer.     

Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case–control study

BackgroundCytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer.Patients and methodsA matched case–control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis; matching was according to the peritoneal cancer index score. Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival, disease-free survival, morbidity, mortality, and clinicopathological parameters were compared.ResultsMedian overall survival was 36.5 months in the HIPEC group and 23.9 months in the SPIC group (P = 0.01). Median disease-free survival for these groups was 22.8 (HIPEC) and 13.0 months (SPIC; P = 0.02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group.ConclusionHIPEC was associated with improved overall survival and disease-free survival compared with SPIC at similar morbidity and mortality, suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis.     

我国进展期胃癌围手术期行预防性腹腔热灌注化疗的研究进展

胃癌是我国最常见的恶性肿瘤之一, 术后5年生存率仅为10%~49%, 术后腹膜复发是影响其生存率的主要原因。腹腔热灌注化疗经过20多年的研究和发展, 已得到了充分的认识和较好的临床应用效果。预防性应用腹腔热灌注化疗有助于减少术后复发率, 提高胃癌的5年生存率, 改善生存质量, 提升胃癌的总体疗效。本文对近年来我国对进展期胃癌AGC行预防性腹腔热灌注化疗(hyperthermic intraperitonral chemotherapy, HIPEC)的临床开展情况作一综述。      

Impact of Tumor Angiogenesis in Peritoneal Mesothelioma After Radical Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy

Peritoneal mesothelioma is one of the peritoneal surface malignancies where long-term survival is a reality after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Tumor angiogenesis has been shown to be of prognostic significance on survival in mesothelioma. We investigated the impact of survival of patients with peritoneal mesothelioma following CRS and HIPEC to determine the impact of tumor angiogenesis on survival after this radical surgical treatment. Paraffin sections of 23 patients who were treated with CRS and HIPEC were retrieved for immunohistochemical analysis. The immunostaining was performed using monoclonal mouse anti-human antibodies (VEGF-C and CD31) on an autostainer (Autostainer Plus; Dako, Inc.). The intensity of the stains were quantified using the Image-Pro Plus (IPP) 4.5 (Media Cybernetics, Silver Spring, MD). VEGF expression and microvessel density (MVD) using CD31 staining were studied. The median survival was 94 months with a 3-year survival rate of 51%. There was no impact on patient’s age, sex, peritoneal cancer index, tumor histopathology and survival outcomes between patients with low or high MVD and VEGF expression. After CRS and HIPEC, our results demonstrate that the prognostic significance of tumor angiogenesis is negated, highlighting the potential importance of other co-contributory mechanisms in mesotheliomagenesis and undergoing radial treatment.     

Extensive cytoreductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin

Peritoneal seeding from colorectal cancer has a very poor prognosis and is relatively resistant to systemic chemotherapy. We performed a phase I/II trial to investigate the feasibility and effectiveness of extensive cytoreductive surgery in combination with intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. 29 patients with peritoneal carcinomatosis of colorectal origin without evidence of distant metastases underwent cytoreductive surgery and intra-operative HIPEC with mitomycin-C (MMC), followed by systemic chemotherapy with 5-fluorouracil (5-FU)/leucovorin. Surgical complications occurred in 11 patients (38%). One patient died directly related to the treatment, resulting in a mortality rate of 3%. MMC toxicity existed mainly of leucocytopenia (in 15 patients; 52%). After a median follow-up of 38 months (range 26-52 months) we found a 2- and 3-year survival rate (Kaplan-Meier) of 45 and 23%, respectively. Extensive cytoreductive surgery and HIPEC is feasible in patients with peritoneal seeding of colorectal cancer. First results suggest that a higher median survival could be achieved compared with conventional palliative surgery and systemic chemotherapy, therefore a randomised phase III study is now being conducted.     

Intraperitoneal chemotherapy in gastric cancer patients with peritoneal dissemination

Peritoneal dissemination is one of the non-curative factors in gastric cancer and colon cancer. Although many treatments have been conducted for peritoneal dissemination, no standard chemotherapy has yet been established. For sometime we had used continuous hyperthermic peritoneal perfusion (CHPP)for peritoneal dissemination in gastric cancer and colon cancer. CHPP has a marked survival benefit for scirrhous type gastric cancer patients without liver metastasis. Patients with prophylactic CHPP have significantly better prognoses than those without prophylactic CHPP, and therapeutic CHPP has a survival benefit for gastric cancer patients with slight to moderate peritoneal dissemination (P 1-2). But CHPP has no significant prognostic benefit for gastric cancer patients with severe peritoneal dissemination (P 3). Therefore, a new cancer treatment is needed for those patients. On the other hand, many kinds of anticancer agents, including cisplatin, via intraperitoneal (ip) administration have been tried thus far for peritoneal dissemination therapy. Especially, intraperitoneal taxane anticancer agent is very effective for the treatment and local control of severe peritoneal dissemination in gastric cancer. A phase I/II study of taxane anticancer agents via ip administration should be tried in gastric cancer patients with peritoneal dissemination.     

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Long term oncologic outcomes from the international PSOGI registry

The laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS + HIPEC) in highly selected patients was previously reported from the PSOGI registry with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to update this international PSOGI registry with a larger cohort of patients and a longer follow-up period.MethodsAn international registry was designed through a networking database (REDCAP®). All centers performing L-CRS + HIPEC were invited through PSOGI to submit data on their cases. Variables such as demographics, clinical outcomes, and survival were analyzed.ResultsA total of 315 L-CRS + HIPEC cases were provided by 14 worldwide centers. A total of 215 patients were included in the L-CRS + HIPEC group. The median peritoneal cancer index (PCI) was 3 (3–5). The median length of stay was 7 days (5-10) and the major morbidity (Clavien-Dindo ≥3) was 6.1% after 30 days. The 5-year disease-free survival (DFS) per tumor origin was: 94% for PMP-LG, 85% for PMP-HG, 100% for benign multicyst peritoneal mesothelioma (MPM), 37.4% for colonic origin, and 54%(at 3 years) for ovarian origin. The 5 years overall survival (OS) per tumor origin was: 100% for PMP-LG, PMP-HG and MPM; 61% for colonic origin, and 74% (at 3 years) for ovarian origin.In addition, a total of 85 patients were analyzed in the laparoscopic risk-reducing HIPEC (L-RR + HIPEC). The median length of stay was 5 days (4–6) and the major morbidity was 6% after 30 days. The 5-year DFS per tumor origin was: 96% for perforated low grade appendiceal mucinous neoplasm (LAMN II) and 68.1% for colon origin. The 5 years OS per tumor origin was: 98% for LAMN II and 83.5% for colonic origin.ConclusionsMinimally invasive CRS + HIPEC is a safe procedure for selected patients with peritoneal carcinomatosis in specialized centers. It improves perioperative results while providing satisfactory oncologic outcomes. L-RR + HIPEC represents a promising strategy that could be evaluated in patients with high risk of developing peritoneal carcinomatosis into prospective randomized trials.     

高精度持续循环腹腔热灌注化疗联合静脉化疗治疗卵巢癌的临床研究

目的：探讨高精度持续循环腹腔热灌注化疗（HIPEC）联合静脉化疗治疗卵巢癌的临床疗效。方法入组卵巢癌患者198例,分为2组,其中治疗组120例（HIPEC 联合紫杉醇＋奥沙利铂方案静脉化疗组）、对照组78例（紫杉醇＋奥沙利铂方案静脉化疗组）。观察2组患者的生存时间、病死率、复发率、生活质量及化疗毒副反应。结果治疗组患者术后1 a、2 a、3 a 病死率及复发率明显低于对照组,而平均生存时间高于对照组（P ＜005）。结论 HIPEC 联合静脉化疗能有效降低卵巢癌患者术后复发率及病死率,提高生活质量,延长其生存时间。     

倾向性评分匹配评估肿瘤细胞减灭术联合腹腔热灌注化疗治疗晚期卵巢癌的疗效

  目的  探讨传统减瘤术与肿瘤细胞减灭术（cytoreductive surgery,CRS）联合术中腹腔热灌注化疗（hyperthermic intraperitone-al chemotherapy,HIPEC）治疗上皮性卵巢癌腹膜转移（peritoneal carcinomatosis of epithelial ovarian cancer,EOCPC）的疗效。  方法  收集2004年5月至2019年5月186例于首都医科大学附属北京世纪坛医院行手术切除的卵巢癌患者的临床病理资料,采用倾向性评分匹配（propensity score matching,PSM）2:1匹配后,纳入133例EOCPC患者,分为行传统减瘤术80例为对照组、行CRS+HIPEC53例为研究组,并行亚组分析。比较两组中位生存期（median overall survival,mOS）。  结果  研究组患者mOS显著长于对照组（87.3个月vs.25.2个月,P=0.002）,5年生存率为对照组2.5倍（46.5% vs.18.3%,P=0.003）,3、4年生存率均为对照组1.9倍（70.0% vs.36.7%,P=0.016）。亚组分析显示,达到满意肿瘤细胞减灭研究组mOS较对照组显著延长（118.1个月vs.70.7个月,P=0.024）;未达到满意肿瘤细胞减灭研究组mOS显著长于对照组（87.3个月vs.23.1个月,P=0.028）。  结论  标准化、规范化CRS+HIPEC为治疗EOCPC的必要措施,可为患者带来显著的生存获益。      

Review of a personal experience in the management of carcinomatosis and sarcomatosis

BACKGROUND: Peritoneal surface malignancy can result from seeding of gastrointestinal cancer or abdomino-pelvic sarcoma; it can also occur as a primary disease, such as peritoneal mesothelioma. In the past, this clinical situation was treated only with palliative intent. METHODS: An aggressive approach to peritoneal surface malignancy involves peritonectomy procedures, perioperative intraperitoneal chemotherapy and knowledgeable patient selection. The clinical assessments necessary for valid clinical judgements include the cancer histopathology (invasive vs expansive progression), the preoperative abdominal and pelvic CT, the peritoneal cancer index and the completeness of cytoreduction score. Proper patient selection is mandatory for optimizing the results of treatment. RESULTS: In a series of phase II studies, appendiceal tumors with peritoneal seeding became the paradigm for success with an 85% long-term survival in selected patients. Carcinomatosis from colon cancer had an overall 5-year survival of 50% with selected patients. Also, sarcomatosis patients overall had a 40% 5-year survival in selected patients. Peritoneal mesothelioma showed a 36% 5-year survival. In all malignancies, early aggressive treatment of minimal peritoneal surface dissemination showed the greatest benefit. CONCLUSIONS: Oncologists must accept responsibility for knowledgeable management of peritoneal surface dissemination of cancer because a curative approach has been demonstrated in large phase II studies and all historical controls show 0% long-term survival. Adjuvant phase III studies with perioperative intraperitoneal chemotherapy in diseases where peritoneal surface spread occurs are indicated.     

Clinical evaluation of intra-peritoneal hyperthermic perfusion under hypothermic general anesthesia for advanced gastric cancer

Right after surgery, intra-peritoneal hyperthermic perfusion (IPHP) was performed under hypothermic general anesthesia for 41 gastric cancer patients with peritoneal dissemination or serosal invasion. The control group consisted of 40 patients given surgery alone. With respect to the direct antitumor efficacy of IPHP, there were no cancer cells in the peritoneal lavage from Douglas' pouch and, ascitic effusion disappeared in all patients with peritoneal dissemination. The 1- and 3-year survival rates for the IPHP group were 68% and 39%, whereas those of the control group were 30% and 0%, respectively. The survival rates for the IPHP group were better than those for the control group, with a statistically significant difference of p = 8.1 x 10(-7). As to prevention of recurrence, the incidence of peritoneal dissemination for the IPHP group was lower at p = 0.002 than the control group.     

Comparative analysis of perioperative intraperitoneal chemotherapy regimen in appendiceal and colorectal peritoneal carcinomatosis

Background

Perioperative intraperitoneal chemotherapy (PIC) is delivered by intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). The relative survival benefits of each or both regimens are explored in this large series of patients undergoing cytoreduction at a single institution.

Methods

Patients with a complete (CCR0) or optimal (CCR1) cytoreduction who received intraperitoneal chemotherapy for appendiceal and colorectal peritoneal carcinomatosis were included for analysis. PIC regimens were delivered according to the treatment protocol. Standardized statistical analyses were performed.

Results

Of 262 patients, 98 patients (37%) had colorectal peritoneal carcinomatosis, 108 patients (41%) had low-grade pseudomyxoma peritonei and 56 patients (21%) had appendiceal peritoneal carcinomatosis. For pseudomyxoma peritonei, recurrence-free survival (RFS) did not vary with PIC regimen, 5-year survival was 86% in the HIPEC and EPIC group and 64% in the HIPEC or EPIC group (P = 0.070). For appendiceal peritoneal carcinomatosis, RFS and overall survival (OS) did not vary with PIC regimen. For colorectal peritoneal carcinomatosis, the median RFS was 33 months in the HIPEC and EPIC group, 19 months in the HIPEC alone group and 20 months in the EPIC alone group (P = 0.046). OS did not vary with PIC regimen.

Conclusion

From our experience, without compromising the perioperative morbidity and mortality, PIC consisting of HIPEC and EPIC appears to be associated with potential survival benefits of improved OS in pseudomyxoma peritonei and RFS in colorectal peritoneal carcinomatosis.     

Preliminary trial of adjuvant surgery for advanced gastric cancer

In patients with stage IV gastric cancer, systemic chemotherapy is the key treatment. Combination chemotherapy (cis-diamminedichloride platinum plus S-1 and docetaxel plus S-1) results in long-term survival in clinical practice. In selected cases, additional (adjuvant) surgery may result in further long-term survival. This study aimed to evaluate the efficacy of adjuvant surgery following the response to chemotherapy for advanced gastric cancer. Based on response to chemotherapy, the indications for adjuvant surgery (surgery after the response to chemotherapy) are that resection is expected to be curative rather than palliative, provided that no other distant metastases occur. The study included 20 advanced gastric cancer patients who had undergone gastrectomies after the response to the combination chemotherapy of docetaxel and S-1, between September 2003 and December 2008 at Hiroshima University Hospital. At a median follow-up of 980 days, the median overall survival was 855 days. A 2- and 3-year survival was observed in 80 and 54.9% of patients, respectively, following macroscopic curative surgery. In the palliative group, the median overall survival was 510 days, but a 3-year survival was not observed. In the partial response group, the median overall survival was 865 days and a 3-year survival was observed in 37% of patients. One-year survival was not observed in the stable disease group. The patient survival in the partial response group was statistically more prolonged than in the stable disease group. The median overall survival in patients with liver metastasis was 865 days, while that in patients with peritoneal dissemination was 510 days. In conclusion, adjuvant surgery may be effective in gastric cancer patients diagnosed as stage IV by means of liver or distant lymph node metastasis, except in cases of peritoneal dissemination.     

Repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: Analysis of survival outcomes

Background

Cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) is the procedure of choice in patients with peritoneal dissemination from appendiceal cancer. Although recurrence rates are 26%–44% after first CRS/HIPEC, the role of repeated CRS/HIPEC has not been well defined. We hypothesize that patients undergoing multiple CRS/HIPEC's have meaningful long term survival.

Methods

A retrospective study of a prospective database of 294 patients with peritoneal carcinomatosis (PC) was conducted, of these 162 had PC of appendiceal origin. Twenty-six of these patients underwent 56 CRS/HIPEC. Survival and outcomes was analyzed.

Results

The percentage of patients with pre-surgical PCI scores ≥20 for the first, second, and third CRS/HIPEC was 65, 65, and 25%, respectively. Complete cytoreduction (CC 0-1) at first, second, and, third surgeries was 96, 65 and 75%, respectively.The mean operating time was 10.1 h. There was no 30-day peri-operative mortality. Following the first, second, and third CRS/HIPEC 27, 42, and 50% experienced grade III complications, respectively.Mean follow up was 51, 28, and 16 months from the first, second, and third CRS/HIPEC, respectively. Overall survival rate for the first CRS/HIPEC was 100, 83, 54, and 46% at years 1, 3, 5 and 10, respectively; from the second CRS/HIPEC 91, 53, and 34% at 1, 3, and 5 years, respectively; and from the third CRS/HIPEC was 75% at one year.

Conclusion

Repeat CRS/HIPEC can lead to meaningful long term survival rates in patients with appendiceal peritoneal carcinomatosis with morbidity and mortality similar to those of the initial CRS/HIPEC.     

长链非编码RNA HOXA-AS3在结肠癌组织中的表达及与临床预后的关系

目的:观察长链非编码RNA HOXA-AS3（lncRNA HOXA-AS3）在结肠癌组织中的表达并探究其与临床预后的关系。方法:选取2012年01月至2014年02月本院外科行手术治疗的94例结肠癌患者癌变及癌旁结肠组织冻存标本,采用实时定量PCR（RT-qPCR）法检测癌组织和癌旁组织中lncRNA HOXA-AS3的表达水平,采用单因素方差分析其与结肠癌患者临床病理参数的关系;采用Kaplan-Meier生存曲线分析lncRNA HOXA-AS3表达水平与结肠癌患者5年生存率的关系;采用COX多因素回归分析影响结肠癌患者不良预后的危险因素。结果:与癌旁组织比较,结肠癌组织中lncRNA HOXA-AS3表达水平明显升高（P＜0.05）;lncRNA HOXA-AS3在结肠癌组织中的表达水平与患者年龄、性别、病理类型无关（P＞0.05）,与TNM分期、肿瘤直径、分化程度、淋巴结转移有关（P＜0.05）。lncRNA HOXA-AS3高表达组结肠癌患者5年生存率（60.98%）明显低于低表达组（94.34%）（χ2=16.41,P＜0.05）。COX回归分析结果显示,lncRNA HOXA-AS3高表达、TNM分期和淋巴结转移是影响结肠癌患者预后的独立危险因素（P均＜0.05）。结论:lncRNA HOXA-AS3在结肠癌组织中高表达,且与患者TNM分期、肿瘤直径、分化程度、淋巴结转移及5年生存率有关,其表达变化可能与结肠癌的发生、发展进程有关,有潜力成为结肠癌预后评估的新型生物指标及潜在治疗靶标。     

Strategy for patients with cytology positive and peritoneal dissemination from gastric cancer

The aim of this study was to evaluate the strategy for patients with cytology positive and peritoneal dissemination from gastric cancer. Thirty eight of POCY1, three of P1, eight of P2 and thirty six of P3 from advanced gastric adenocarcinoma at staging laparoscopy were studied. Gastrectomy after staging laparoscopy was performed in 10 patients (Surgery group). NAC following gastrectomy after staging laparoscopy was performed in 31 patients (NAC group) in POCY1, P1. The overall response rate was 29%, twenty of the 31 patients (65%) in the NAC group revealed no free cancer cells at the operation. The overall 5-year survival rate in 41 patients of POCY1, P1 was 15%. There was a significant deference in the overall survival curves between Surgery and NAC groups. The overall 2-year survival rate in 44 patients of P2, P3 was 9%. NAC for patients with positive cytology could lead into free cancer cells at a high rate, but not to improve their prognoses. An intensive chemotherapy including intra-abdominal chemotherapy should be necessary for these patients.