Gastrectomy, peritonectomy, and perioperative intraperitoneal chemotherapy: the evolution of treatment strategies for advanced gastric cancer

Gastric cancer disseminates by hematogenous, lymphatic, and transcoelomic routes. For maximal containment of the malignant process, perioperative intraperitoneal chemotherapy is necessary in two groups of patients in whom the primary cancer can be resected. Those patients who have been resected for cure and have a high likelihood of microscopic residual disease require intraperitoneal chemotherapy. This includes all T3 and T4 patients, and patients with N2 nodes present. A series of randomized and nonrandomized clinical studies have established the benefits of perioperative intraperitoneal chemotherapy in this group of patients. Patients with stage IV disease who are able to undergo a palliative resection require these treatments if peritoneal seeding is observed. Systemic chemotherapy is largely ineffective for peritoneal seeding, while intraperitoneal chemotherapy is most likely to produce a response with small volume, surgically debulked carcinomatosis. In addition, intraperitoneal chemotherapy can eliminate the future development of debilitating ascites. Sufficient data are available from the gastric cancer literature to support the use of these combined treatments on a routine basis if the primary cancer is resectable and gastrointestinal function can be reestablished.     

进展期胃癌根治性术后腹腔内化疗的疗效评价

目的:观察进展期胃癌根治性手术后腹腔内化疗的疗效。方法:选择Ⅱ-Ⅲ期的根治性胃癌手术后病人64例,随机分成两组,分别为全身化疗+腹腔内化疗组和全身化疗组,统计两组的三年复发率、三年生存率。结果:治疗组三年复发率为18.75％,对照组为43.33％(P<0.05),治疗组三年生存率为84.38％,对照组为60％(P<0.05)。结论:全身静脉化疗结合腹腔内化疗治疗进展期胃癌手术后病人的疗效优于单纯全身静脉化疗。     

Laparoscopic distal gastrectomy and hyperthermic intraperitoneal chemotherapy in the treatment of advanced gastric cancer: a retrospective case-matched study on perioperative outcomes

BackgroundThis study aimed to assess the safety and efficacy of laparoscopic distal gastrectomy (LDG) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gastric cancer (AGC).MethodsIn this case-matched study, we retrospectively reviewed the database of 223 patients with AGC who underwent LDG in Tangdu Hospital from April 2016 to February 2019. Among all participants, 177 patients underwent LDG alone and 46 underwent LDG with HIPEC. We matched total of 138 (1:2) patients from the LDG + HIPEC group (n 46) and the LDG group (n 92) for gender, age, date of operation, and tumor-node-metastasis (TNM) stage of tumor.ResultsThere was no significant difference in the Clavien-Dindo classification of complications between LDG alone and LDG + HIPEC patients. Further analysis showed the morbidity of gastroparesis to be significantly increased in LDG + HIPEC patients. At the same time, we found that the operation time, the time to 1st flatus, and hospital stay were longer in LDG + HIPEC patients and the incidence of abdominal recurrence 2 years after operation was significantly higher in the LDG group than the LDG + HIPEC group.ConclusionsThe combination of LDG with intraoperative HIPEC is a safe and feasible method for AGC and HIPEC will limit the recovery of gastrointestinal functions. In addition, during the follow-up of our study, although there was no statistical difference between the two groups in abdominal recurrence at 2 years after surgery, a decreasing trend of abdominal recurrence in LDG + HIPEC patients could be seen in comparison to LDG patients.     

康莱特联合氟尿嘧啶腹腔化疗治疗晚期胃癌

目的:观察康莱特联合氟尿嘧啶腹腔化疗治疗晚期胃癌的临床疗效及副作用.方法:康莱特200ml,静滴,d1-21,氟尿嘧啶1.0g,腹腔灌注,d1,8,15,28天为一周期,共2-6周期,2周期后评价疗效.结果:33例患者总有效率为27.27%(9/33),疾病控制率为66.67%(22/33),中位疾病进展时间为4.1月,临床受益反应评价有效者占78.79%(26/33).结论:康莱特联合氟尿嘧啶腹腔化疗治疗晚期胃癌疗效好,毒性低.     

Neutropenia following perioperative intraperitoneal chemotherapy

INTRODUCTION: The purpose of this retrospective report was to evaluate clinical features associated with profound neutropenia in patients with peritoneal carcinomatosis who were treated with heated intraoperative intraperitoneal chemotherapy (HIIC) followed by early postoperative intraperitoneal chemotherapy (EPIC). Common clinical denominators for significant neutropenia were analyzed. MATERIALS AND METHODS: A retrospective study of all available clinical data of six patients with postoperative neutropenia out of a total of 242 was undertaken. All patients underwent cytoreductive surgery, HIIC with mitomycin C (n = 4) or cisplatin (n = 1) and EPIC with 5-fluorouracil (5-FU) for 4 (n = 1) or 5 (n = 5) days. RESULTS: All six patients presented with hematologic toxicity of WHO criteria grade 4; four of them died postoperatively. Two of the patients who died, and one who did not die, developed bowel perforations. Five patients had prior chemotherapy with 5-FU; three of them had toxic side effects. All patients were overweight, and three patients were anemic preoperatively. The neutropenia presented with fever, leukopenia and thrombocytopenia on postoperative days 10-15. The leukocyte count courses showed a pattern suggesting the 5-FU as the cause of leukopenia. There was no consistent warning signal for predicting severe neutropenia. DISCUSSION: Neutropenia following cytoreductive surgery combined with HIIC and EPIC has a high mortality (66%). Patients who are at special risk and should have a dose reduction include patients who had toxicities from prior chemotherapy, who present with obesity and anemia. The groups have an increased risk of developing postoperative profound neutropenia. This condition can result in a prohibitively high mortality and morbidity rate. Therefore, reduced doses of chemotherapy in selected patients are necessary to prevent this condition from developing.     

Hyperthermic intraperitoneal chemotherapy in serosa-invasive gastric cancer patients

BackgroundEvaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) in reducing metachronous peritoneal metastases (MPM) risks in patients with resectable serosa-invasive gastric cancer.Materials & methodsBetween 2008 and 2016, 154 patients with gastric cancer (stage IIB-IIIC) were randomly assigned to two groups: 76 patients underwent HIPEC (cisplatin 50 mg/m² + doxorubicin 50 mg/m², 42 °C, 1 h) combined with radical surgery (HIPEC group) and 78 patients underwent only radical surgery (control group).ResultsEvaluation of HIPEC toxicity showed neither toxic complications of IV-V degree nor haematological toxicity (according to CTCAE v. 4.03). There was no significant difference in the rate of complications between the two groups (p = 0.254). There was a more frequent disease progression in the control group than in the HIPEC group: 42/55 patients (76.4%) vs. 36/68 patients (52.9%), respectively (p = 0.009). At the same time a significant decrease in the rate of MPM was observed after HIPEC administration as compared with surgery alone – 16/68 (12.8%) vs. 39/55 (27.6%) (p < 0.001). 3-year progression-free survival was 47% (95% CI 36–61)) in the HIPEC group and 27% (95% CI 17–43) in the control group – p = 0.0024.The N-stage, HIPEC procedure, type of surgery and interaction between HIPEC treatment and age were independent prognostic factors.ConclusionsHIPEC appears to be helpful in improving treatment results in radically operated gastric cancer patients.     

Comprehensive management of resectable gastric cancer: requirement for optimal clearance, containment and perioperative intraperitoneal chemotherapy

Peritoneal spread is a major cause of treatment failure and mortality in gastric cancer, even before this malignancy spreads to extraabdominal sites. Conventional adjuvant treatment options have failed in solving this problem to date. As shown in randomized controlled clinical trials, perioperative intraperitoneal chemotherapy can change the natural history of gastric cancer resected for cure, preventing the development of peritoneal carcinomatosis and improving long-term survival. A surgical approach that maximizes clearance and containment of the malignancy is required for this success. Additional reports have shown the value of intraperitoneal chemotherapy associated with cytoreductive surgery in the treatment of selected cases with established peritoneal spread. Surgeons treating gastric cancer patients need to realize that perioperative intraperitoneal chemotherapy becomes an integral part of the surgical treatment of this disease, for which they should accept responsibility.     

Large volume intraperitoneal chemotherapy as treatment for the peritoneal carcinomatosis from gastric cancer]

Gastric cancer sometimes spread to peritoneal surfaces in the absence of lymphatic or hematogenous metastases. For the treatment of peritoneal carcinomatosis, we applied large volume intraperitoneal chemotherapy (L.V.I.C.). In L.V.I.C., drugs were administered with large volume of saline through the reservoir buried in the subcutaneous tissue of the abdominal wall. We used mitomycin C (MMC), 5-fluorouracil (5-FU) and CDDP and examined the pharmacokinetics of these drugs when they were administered by this method to the patients of peritoneal carcinomatosis. A marked pharmacokinetic advantage was observed when 5-FU and CDDP were administered. AUC of these drugs were much larger than that of MMC. In vitro sensitivity test (SDI test) was useful for the selection of adequate drugs for each patient. On this method, drugs were distributed widely in the abdominal cavity and the patients could be taken this treatment repeatedly as out-patient. L.V.I.C. seems to fulfill the need for a safe, effective and acceptable delivery system of intraperitoneal chemotherapy.     

Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.     

Catheter-related Complications in Postoperative Intraperitoneal Chemotherapy for Gastric Cancer

Objective： To analyze catheter-related complications during postoperative Intraperitoneal chemotherapy （IPCT） for gastric cancer. Methods： From December 2003 to April 2007, 80 patients with gastric cancer were treated with postoperative IPCT using central venous catheters （CVCs）, during which the complications that occurred in association with CVCs were documented and analyzed. Results： Catheter-related complications were seen in 10 out of the 80 patients, yielding a total complication rate of 12.5%. Main complications included abdominal pain （3.8%）, local infection （1.3%）, catheter obstruction （2.5%）, leakage （2.5%） and dislocation （2.5%）. All patients successfully finished their IPCT, the success rate was 100%. There occurred no severe complications or treatment-related deaths. Conclusion： It is convenient and safe to carry out postoperative IPCT for gastric cancer using CVCs, which, with a low catheter-related complication rate, should be recommended for more clinic use.     

Preoperative intraperitoneal chemotherapy for patients with serosa-infiltrating gastric cancer

BACKGROUND AND OBJECTIVES: Serosa-infiltrating gastric cancer poses a high risk for peritoneal recurrence. This study examined the feasibility and efficacy of preoperative intraperitoneal (i.p.) chemotherapy for such cancer. METHODS: Patients with serosa-infiltrating tumors, diagnosed by conventional examinations as well as by staging laparoscopy, were enrolled in this study. Those with unresectable T4 tumors, visible peritoneal metastasis or distant organ metastasis were excluded. Twenty-five eligible patients received preoperative i.p. chemotherapy, which consisted of i.p. injection of 20 mg of mitomycin C on day 1 and 10 mg of cisplatin for 5 days, followed by surgery. RESULTS: Of the 25 patients, 24 underwent gastrectomy with lymph node dissection and 1 underwent palliative gastrojejunostomy. The curability of the surgery was curability A in 6, B in 16, and C in 3. Preoperative T stages (T3 in 21 and T4 in 4) were downstaged postoperatively (T1 in 1, T2 in 10, T3 in 11, and T4 in 3). The 1- and 2-year overall survival was 83.3 and 51.3%, respectively. The median survival time was 24.4 months. The toxicity of the preoperative treatment was tolerable and no serious postoperative complication was seen. CONCLUSIONS: Preoperative i.p. chemotherapy seems to be a safe and effective therapy for serosa-infiltrating gastric cancer. Randomized clinical trials comparing preoperative i.p. chemotherapy followed by surgery and surgery alone are needed.     

The rationale of perioperative intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies

In summary, the use of perioperative intraperitoneal chemotherapy is a rational and scientifically sound treatment option for patients with peritoneal carcinomatosis. By delivering chemotherapeutic agents directly into the peritoneal cavity in the perioperative period, after cytoreductive procedures resulting in minimal residual tumor load, the cytotoxicity, efficacy, and safety of these agents can be maximized. The use of this treatment strategy in the intraoperative or perioperative period ensures that the efficacy of the chemotherapeutic agents is not reduced by limitations of abdominal compartmentalization and scarring. Treating patients under hyperthermic conditions may confer an additional benefit. Although the use of perioperative chemotherapy or hyperthermic intraperitoneal chemotherapy is not yet part of the standard of care for the treatment of advanced abdominal malignancies, both basic science and clinical investigations have confirmed the validity of these regimens. Further clinical studies in a cooperative group setting are necessary to prove the efficacy of perioperative intraperitoneal chemotherapy in both the treatment and prevention of peritoneal surface 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.     

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.     

胃癌腹腔灌注化疗的临床研究现状

我国胃癌发病率和死亡率均居肿瘤第一位,腹腔内复发转移是胃癌根治术后复发的主要形式和导致患者死亡的主要原因之一。腹腔灌注化疗（IPC）,能否预防与阻止腹膜扩散、淋巴转移和减少或杀死腹腔脱落癌细胞,减少术后腹腔转移,从而延长患者生存期,提高生活质量,一直是胃癌治疗领域研究的课题。文章针对胃癌IPC的理论基础、临床应用以及存在的问题等方面进行综述。     

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。     

晚期胃癌静脉合并腹腔化疗近期疗效观察

目的：观察并评价静脉合并腹腔化疗治疗晚期胃癌的近期疗效及毒副反应。方法：用ELF方案（CF、5－Fu、VP16）静脉滴注加DDP腹腔化疗61例晚期胃癌病人，观察并记录近期疗效和毒副反应。结果：全组患者总有效率为57.4%，其中CR率为9.8%，毒副反应较轻，主要为白细胞下降发生率为95.1%，血小板下降发生率为27.8%。结论：静脉加腹腔化疗治疗晚期胃癌疗效肯定，毒副反应轻，值得临床研究应用。     

十全大补汤配合腹腔化疗对进展期胃癌术后的影响

目的:探讨腹腔化疗配合中药十全大补汤在进展期胃癌术后的临床价值。方法:观察进展期胃癌根治性手术后患者78例,随机分成两组,即全身化疗+腹腔内化疗+十全大补组(治疗组)和全身化疗组(对照组),观察两组患者术后的1年、2年、3年复发率和生存率。结果:治疗组的3年复发率为21.75%,对照组为41.33%(P<0.05);治疗组3年生存率为58.38%,而对照组为39.6%(P<0.05)。结论:全身静脉化疗结合腹腔内化疗并配合十全大补汤治疗进展期胃癌手术后患者的疗效优于单纯全身静脉化疗。     

Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy

A new strategy currently under evaluation in patients with peritoneal carcinomatosis from gastrointestinal and gynecologic cancers is perioperative intraperitoneal chemotherapy. Although results to date show benefit to carefully selected groups of patients, continued local-regional failure is seen in many treated patients. Continued clinical and laboratory research efforts to improve local-regional effects are desired. The chemotherapeutic agents that have been used in the past or are currently being tested were reviewed. Their pharmacologic properties and clinical features were collected from the medical literature and are reviewed in the text. An organized presentation of available data concerning the drugs available for perioperative intraperitoneal chemotherapy for peritoneal surface malignancy was made. From this review, new possibilities for improved doses, schedules, and drug combinations for perioperative intraperitoneal chemotherapy may become important in future clinical studies. Continued optimal utilization of intraperitoneal chemotherapy treatments in the operating room with hyperthermia or normothermic treatment in the early postoperative period is desirable. Innovative treatment strategies can improve the outcome of patients with peritoneal surface malignancy.     

Cancer chemotherapy of unresectable primary gastric cancer

The criteria for cancer chemotherapy of gastric cancers proposed by the Japanese Research Society for Gastric Cancer is introduced with several effective cases. Three subtypes of judgment method--namely, measurable lesions, non-measurable but evaluable by X-ray or endoscopy, and diffuse infiltrating lesions are applied according to the shape and effect of primary foci. Measurable lesions in a case such as aPR should be recorded in metric notation, using a ruler or calipers on X-ray films. bPR is a case when chemotherapy of primary foci is markedly effective with a flattening of the randwall or polypoid part and a shrinkage of cancerous ulceration, but the size of a primary lesion is not decreased. cPR is a case when an expansion of affected site by more than 100% is proved by gastric radiogram or endoscopic image on primary focus in Borrman type 4, a synonym of gastric scirrhous clinically.