Safety And Efficacy Of Intraperitoneal Hyperthermic Perfusion Chemotherapy Following Laparoscopic Surgery For Gastric Cancer Patients With Peritoneal Metastasis

Background and source:Gastric cancer is the world’s second leading cause of death from cancer, and its morbidity and mortality rate stay in the forefront of disease in our country, so it’s a major disease which seriously threatens people’s health. Under the situation which lacks early endoscopic screening, there are a huge number of patients with advanced gastric cancer combined with peritoneal metastasis. The peritoneal carcinomatosis from local disseminations of advanced gastric cancer is an advanced type which is extremely difficult to controlled, lots of attempts have been made by domestic and foreign scholars, but the overall effect is still not ideal, so there is no standard treatment at present. Some patients need to accept palliative resection of gastric cancer, because combined with related obstruction, bleeding and perforation, it can relieve symptoms and reduce tumor at the same time, provide favorable conditions for further treatments after operation. Because the laparoscopic operation has the advantages of small trauma and quick recovery, some domestic experienced institutions have started the implementation of laparoscopic palliative resection of gastric cancer. But it has limited function to improve the prognosis that operating palliative resection of gastric cancer alone, it often need to combine with other complex treatments to control peritoneal metastasis lesions as far as possible, it is an option that early postoperative sequential intraperitoneal hyperthermic perfusion chemotherapy. Intraperitoneal chemotherapy belongs to high selectivity local chemotherapy, it has obvious pharmacokinetic advantages, and it has been applied in clinical practice in the world with the continuous improvement of equipment and accumulation of experience, the effect has been confirmed to a certain extent by academic circle. As the basis drugs of systemic chemotherapy for gastric cancer, DDP (cisplatin) and 5-Fu (5-fluorouracil) act with different mechanism and times, but they have the characteristics of wide antitumor spectrum without cross resistance, combination of the two drugs has synergistic effect to some extent. Therefore, combination of the two drugs is often chosen as the protocol of intraperitoneal hyperthermic perfusion chemotherapy. But some scholars believe that intraperitoneal hyperthermic perfusion chemotherapy will bring high risk to patients in treatment process, increasing attention to the safety of it. During 2010 March to 2013 October, there was 37 patients with peritoneal metastasis of gastric cancer in out unit underwent intraperitoneal hyperthermic perfusion chemotherapy using cisplatin and 5-fluorouracil after laparoscopic palliative resection. Different from other studies in intraperitoneal chemotherapy combined with open operation, this study with the characteristics of our unit chose the patients with peritoneal metastasis of gastric cancer after laparoscopic palliative resection to adapt to the rapid development trend of minimally invasive techniques, and the 37 cases of peritoneal metastasis of gastric cancer were used as the data source of our study. And the research was funded by the gastric cancer research fund projects of our department in recent years, include: Guangdong Province Science and Technology Plan (2012A030400012), Guangzhou Major Livelihood and Technological Special (201300000087), Ministry of Health Public Welfare Fund of Health Industry (201402015) and National Clinical Key Specialty Construction Project. It was analyzed the recent efficacy、Karnofsky Performance Status(KPS) evaluation、adverse reactions、complications、peripheral blood electrolyte and related indexes of inflammation of these patients.Objective and significance:To explore the safety and efficacy of intraperitoneal hyperthermic perfusion chemotherapy after laparoscopic palliative resection of gastric cancer. Different from other studies in intraperitoneal chemotherapy combined with open operation, this study with the characteristics of our unit choose the patients with peritoneal metastasis of gastric cancer after laparoscopic palliative resection to adapt to the rapid development trend of minimally invasive techniques, in order to explore the safety and efficacy of intraperitoneal hyperthermic perfusion chemotherapy after laparoscopic palliative resection of gastric cancer, provide reference of treatment for the patients underwent laparoscopic operation combined with intraperitoneal chemotherapy, and share experiences with peers.Methods and contents:General data37 cases were all inpatients(2010 March-2013 October),male:21 cases,female:16 cases, age:between 24 to 71years,median age:50.5 years.BMI:16.0-29.7 Kg/m2,average:21,2Kg/m2.All cases were confirmed peritoneal metastasis of gastric cancer by histopathology, poorly differentiated adenocarcinoma:21 cases(56.8%),moderately differentiated adenocarcinoma:9 cases(24.3%),signet ring cell carcinoma:7 cases(18.9%).ECOG scores were all< 3,0:10 cases(27%),1:16 cases(43.2%),2:9 cases(24.3%),3:2 cases(5.4%). Karnofsky Performance Status scores were all> 50,50:2 cases(5.4%),60:10 cases(27%),70:13 cases(35.1%),80:7 cases(18.9%),90:3 cases(8.1%),100:2 cases(5.4%).One or more complication:5 cases(13.5%).All patients have signed the informed consent.TreatmentsAll cases were successfully completed with laparoscopic palliative resection for gastric cancer, set three silica gel tubes with multi side holes for drainage after operation in facies diaphragmatica hepatis, splenic fossa and pelvic cavity, fixed through right upper, left upper and left lower abdominal wall respectively. The first intraperitoneal hyperthermic perfusion chemotherapy begin in 48 hours after operation, then once every 2 days, total of 4 times. Connect the extracorporeal circulation pipeline to the hyperthermic perfusion chemotherapy machine. (Type: BR-TRG-1, Guangzhou Baorui Medical Technology Co; Ltd), install the temperature measuring device. Physiological saline 2000ML,cisplatin 100mg and 5-fluorouracil 1000mg are added into perfusion bag, start the pump and heating system, connect the drainage to the extracorporeal circulation pipeline when the temperature of chemotherapy liquid reach stably at 38℃.The perfusion speed is set to 500 mL/min, gradually warm adjust temperature to adaptation of patients, maintain the temperature at 43℃ for 60min.At the end, abdominal residual liquid is not allowed to exceed 1500ML,closed circulation pipeline and remove its connection with drainage pipe which is then connected with a low negative pressure drainage bag. A perfusion doctor is in charge of monitoring ECG of every patient every time of treatment, record axillary temperature(T),heart rate(P),blood pressure(BP),blood oxygen saturation and condition change of patients in half an hour before and after treatment, make necessary further treatment. Fasting blood tests were done at the morning of the first treatment and the next morning of the last. The observation period of recent efficacy and of Karnofsky performance status is 2 months after operation.Evaluation criterionsEvaluation of short term efficacy:according to the RECIST (1.1 version) solid tumor evaluation standard, combined with the examination of CT, MR, X-ray, angiography, and so on, classified to complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).The effective rate of tumor remission in this study is defined as the proportion of CR+PR in all cases. The score of Karnofsky performance status(KPS):according to its criteria, significant improvement:the increase of KPS score after treatment is>20 more than before, improvement:the increase≥10,stability:the increase<10,progress:decrement of KPS score. The efficacy rate of Karnofsky performance status in this study is the proportion of improvement and stability in all cases. Evaluation of adverse reaction: according to the criterion of World Health Organization(WHO) in acute and subacute adverse reaction of tumor’s treatment, classified to 0(no), Ⅰ (mild), Ⅱ (moderate), Ⅲ(severe) and IV(life-threatening) five grades.Statistical methodsWe used SPSS 16.0 software (SPSS Company) for statistical analysis. Count data was expressed as n(%),quantitative data was expressed as x±s, data before and after treatment were compared by paired samples t test, P<0.05,the differences were significant.ResultsShort term efficacyOf 37 cases,18 were complete response,4 partial responses,8 were stable disease and 7 were progressive disease. The effective rate of poorly differentiated adenocarcinoma was 61.9%(13/21),that of moderately differentiated adenocarcinoma was 66.7%(6/9),that of signet ring cell carcinoma was 42.9%(3/7),the total effective rate was 59.5%(22/37).It was effective for most cases that intraperitoneal hyperthermic perfusion chemotherapy after laparoscopic palliative resection of gastric cancer. The effective rate between signet ring cell carcinoma and moderately/poorly differentiated adenocarcinoma was not significant (42.9/63.3, P=0.833)Evaluation of Karnofsky performance statusesComparing the all cases’score of Karnofsky performance status before and after treatment^ significant improved(16.2%),13 improved(35.1%),10 cases were stable(27.0%) and 8 progressed(21.6%),effective(improved and stable) rate was 78.4%,26 cases increased appetite(70.3%),21 cases increased weight(56.8%).Most of the cases’Karnofsky performance status, appetite and weight improved, that has a positive significance to improve quality of life of the patients with metastasis of advanced gastric cancer.Adverse reaction and complicationThe time window of observation on adverse reaction was from the first intraperitoneal hyperthermic perfusion to 24 hours after the last treatment. The most common adverse reaction was abdominal pain (32.4%),mild pain mostly, and mostly cases relieved without any treatment. But there were cases with moderate abdominal pain,2 cases (5.4%) with severe abdominal pain which was alleviated by general painkiller discontinued treatment. There was no case with abdominal pain which was persistent and difficult to control. We suggest giving general sedative or analgesic drugs to the patients of weak constitution or pain tolerance ability according to the circumstances, it can improve these patients’comfort. The peripheral white blood cells of 2 cases decreased significantly, from normal to 2.68×109/L and 2.44×109/L separately, that alleviated after application of leukogenic drugs. The increase of peripheral blood total bilirubin, alanine aminotransferase, urea nitrogen, creatinine and the decrease of peripheral blood hemoglobin happened in varying degrees, most were of I degree. The incidence of fever, nausea, vomiting or reduce of peripheral blood platelet was low. The incidents of bleeding, diarrhea, hematuria, allergies, rash, catheter obstruction or fall off, severe infection of cut or abdominal, damage of nervous or cardiopulmonary system were not happened, associated with intraperitoneal perfusion, had not happened. There were no significant changes of axillary temperature, pulse, blood pressure, oxygen saturation between half an hour before and after the treatment of intraperitoneal hyperthermic perfusion (P>0.05).With regard to the complications, there were 2 cases (5.4%) with intestinal obstruction,1 case (2.7%) with double pneumonia,1 case (2.7%) with reflux esophagitis,1 case (2.7%) with lower extremity deep venous thrombosis in the observation period. All the case above relieved after expectant treatment, chemical peritonitis and refractory intestinal obstruction had not appeared in the observation period.Changes of peripheral blood electrolytes and inflammatory indicatorsPeripheral blood electrolyte and inflammatory indicators were compared before and after the treatment, the results showed the ions of potassium, sodium, chlorine, magnesium declined in different degrees, the differences were statistically significant(all<0.05).After the treatment,7 cases’(18.9%) K+ were between 3.0 and 3.5mmol/L,2 cases’(5.4%) were under 3.0mmol/L,4.12mmol/L to 2.98mmol/L and 4.26mmol/L to 2.92mmol/L respectively.8 cases’(21.6%) Na+ were 130～ 135mmol/L,3 cases’(8.1%) were 120-130mmol/L.11 cases’(29.7%) Mg2+ were lower than 0.7mmol/L.Results show that intraperitoneal hyperthermic perfusion chemotherapy adopting cisplatin and 5-fluorouracil regimens maybe had some influences on human peripheral serum ions including Na+, K+, CL-, Mg2+, hypokalemia appeared in 9 cases. This reminds us to pay great attention to elderly patients with heart diseases, their ions above should be monitored regular and treated promptly. Of course, there may be several reasons of electrolyte imbalance, including early postoperative diet management, fluid replacement, internal environment instability, which were not related to intraperitoneal hyperthermic perfusion chemotherapy. But it should not be excluded that chemotherapy drugs especially cisplatin may have an effect on renal function of some patients. The serum concentration of Ca2+, P-and glucose had no statistical significance. The indicators of inflammation, including white blood cell count, neutrophil percentage and C reactive protein concentration, had no statistical significance comparing before and after the treatment.Conclusions:The modality of IHPEC adopting cisplatin plus 5-fluorouracil regimen following laparoscopic palliative resection for advanced gastric cancer is technical feasible and safe, which may improve the quality of life.