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Intraperitoneal Chemotherapy in gastric cancer.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

August 2001.     Review Article.        To the updating

Kim and Bae underline that a major problem after surgery for serosa-invasive gastric carcinoma is early postoperative peritoneal metastasis, which is encountered in more than 60% of patients. And despite the recent advances in surgical procedures and adjuvant chemotherapies, no satisfactory outcomes are available, because of residual micrometastases or free-floating carcinoma cells already existing in the peritoneal cavity. Furthermore extensive lymph node dissection may, in itself, be responsible for opening lymphatic channels and spreading viable tumour cells.
The authors report a prospective but nonrandomized controlled clinical analysis of 103 patients with serosa-invasive gastric carcinoma, carried out to evaluate the beneficial effect of surgery plus intraperitoneal hyperthermo-chemo-perfusion (IHCP) with MMC on the prevention and treatment of postoperative peritoneal metastases, and on survival.
Complete cytoreductive surgery plus IHCP is effective for preventing and treating peritoneal metastases in serosa-invasive gastric carcinoma patients,especially those in stage III. However in patients in stage IV with distant metastases there are some limitations for the treatment of peritoneal metastase because of other combining factors.

In future IHCP could be employed in patients selected by new methods that predicts peritoneal metastases at the time of surgery ( CEA mRNA with reverse transcription-polymerase chain reaction -RT-PCR- in peritoneal washings ) ( 1 ). The sensitivity for the prediction of peritoneal dissemination by cytology and MMP-7 RT-PCR assay are 46% and 33%, but the combination analysis using both parameters improves the sensitivity rate with 62%. Logistic regression analysis reveales that the cytological examination and MMP-7 RT-PCR assay are independent predictors of peritoneal dissemination ( 20 ).

Fujimoto et al report the results of a prospective randomized study ( 141patients enrolled ) of the prophylactic efficacy of the IHPC treatment with MMC combined with aggressive surgery, on the peritoneal recurrence of advanced gastric carcinoma with serosal invasion (stage II and III gastric cancer). The target of the IHPC treatment is free tumor cells in the abdominal cavity and micrometastases on and just beneath the peritoneal surface ( 2 ).
In fact macroscopic or microscopic peritoneal spread is present in 40 % of patients with stage II and III, and is associated with a significant survival disadvantage ( 4 ).
Both the peritoneal recurrence rate and long-term survival are significantly improved in the surgery plus HIPEC group; the postoperative morbidity rate ( 3% ) is not increased. Interestingly the hepatic recurrence rate is not different between the two groups, despite the fact that during HIPEC treatment the liver is exposed to MMC. ( 2 ).

In the Fujimoto study postoperative morbidity does not differ between the surgery group and the surgery plus HIPEC group; postoperative morbidity and death may therefore relate mainly to the extent and duration of surgery, and not to the hyperthermic perfusion itself. The author underlines that the prehyperthermic hypothermia and cimetidine drip infusion effectively protect the peritoneo-serosal surface against the hot perfusate. Moreover the catheter duodenostomy can obtain sufficient decompression in the upper alimentary tract after subtotal or total gastrectomy, with regard to the risk of leakage of the duodenal stump and esophagojejunostomy ( 2 ).

There are some different techniques, for example the so called continuous hyperthermic peritoneal perfusion technique may be performed following temporary closure of the abdomen, or with an open abdomen technique in which the abdomen is covered with a plastic sheet and drug vapour is evacuated to protect the operating room personnel. In the latter technique there is a better drug distribution by continuous manipulation of the abdominal organs. Closed perfusion on the other hand has the advantage of permitting an increase intraabdominal pressure that might lead to increased convection-driven drug penetration of macromolecular agents .Intestinal anastomoses are usually constructed after the perfusion in order to facilitate uniform distribution of heat and drug ( 8 ).
For more details about the "open coliseum technique" see the web site of PH Sugarbaker and colleagues, .
Moreover the intraabdominal temperature and perfusion time are also different ( 7 ).
Surgery and IPCH can be performed simultaneously or IPCH can be performed 15-30 days after surgery ( 16 ).
Fujimara et al introduced the concept of the expanded peritoneal cavity in an attempt to provide additional space for the peritoneal contents to float freely in the perfusate. They used an acrylic cylinder called a peritoneal cavity expander. The surgical wound is closed around the cylinder and the abdominal cavity remains open through the cylinder.The intestine floats in the perfusate and the surgeon's hand stirs the perfusate to secure even distribution ( 10 ).
Tsiftsis et al expand the peritoneal cavity by producing an artificial ascites with the abdominal cavity closed, in most cases infusing isotonic sodium chloride solution at approximately 3.5L/m2 body surface area. This technique is more efficient regarding heat loss; it prevents evaporation of the drug, decreases the risk for contamination and maintains a tight surgical field ( 11 ).

According to Esquivel and colleagues opinion, when the closed abdomen technique is used, its perioperative toxicity seems to be related to the hemodynamic and cardiac function changes associated with increased body temperature and increased intra-abdominal pressure. The hemodynamic and cardiac function changes are characterized by an increased heart rate, increased cardiac output and decreased effective circulating volume with the urinary output tending to decrease as therapy progresses.
Heated intraoperative intraperitoneal chemotherapy with the open abdomen coliseum technique induces a hyperdynamic circulatory state with an increased intravenous fluid requirement and avoids changes because of increased intra-abdominal pressure. Hemodynamic and cardiac stability, as documented by normal blood pressure and adequate urinary output, can be achieved by liberal intravenous fluids and frequent urinary output determination ( 9 ).
Another problem is the peritoneal damage induced by continuous hyperthermic peritoneal infusion, causing protein and fluid loss during and after CHPP. Peritoneum reacts to irritation by vascular dilatation and increased vascular permeability, with exudation of protein-rich plasma into the peritoneal cavity. Shido et al. affirm that the peritoneal damage by CHPP is not caused by hyperthermia but by the peritoneal perfusion with saline solution containing anticancer drugs. In fact the acidity of saline solution (ph 6.0) and anticancer drugs are irritating factors ( 7 ).

To conclude recent advances in surgical technique with the introduction of peritonectomy procedures, have allowed surgeons to completely remove all visible tumour ( 12 ).
The effects of regional (intraperitoneal chemotherapy) can be maximized by heated intraoperative intraperitoneal chemotherapy, that achieves high peritoneal concentrations with limited systemic absorption ( 13, 14 ).
The first aim is to wash out free intraperitoneal cancer cells and to damage peritoneal metastases by simultaneously heating and exposure to anticancer drugs.
The best indications of IPCH seem to be peritoneal carcinomatosis with small malignant granulations (stage I and II), and peritoneal carcinomatosis in patients for whom debulking surgery (granulation exeresis or local peritonectomies) appears to be possible.
However at least five problems remain : 1) the homogeneous diffusion of heat and drugs inside the abdominal cavity; 2) the indications for iterative IPCH; 3) the use of multidrug therapy with IPCH, as is done in systemic chemotherapy; 4) the importance of debulking surgery associate with IPCH; 5) the use of IPCH as an adjuvant therapy for patients with digestive tract cancers and serosal erosion ( 16 ).

Yu and colleagues underline a survival benefit in patients with resection of stage IV and stage III gastric cancer followed by early postoperative intraperitoneal mitomycin C and 5 fluorouracil (normothermic chemotherapy).
The fundamental feautures of stage III or IV gastric cancer are involvement of the serosal surface of the stomach and regional lymph nodes. Intraoperatively without frozen section examination surgeons can predict with reasonable accuracy only the presence of serosal invasion. Alternatively frozen section examination of regional lymph nodes may be utilized, although it does not preclude sampling errors and misdiagnoses due to limitations of the technique. Special attention must be paid to excluding T1 or T2 tumours ( 17, 18 ).

Several univariate and multivariate analyses reveal that the histologic types of advanced gastric cancer show significantly related recurrence patterns. A recent multivariate analyses reveals that the diffuse type of gastric cancer is the major risk factor for peritoneal dissemination whereas the intestinal type of gastric cancer is the major risk factor for hematogenous recurrence ( 19 ).


1) Jin Young Kim and Hoon Sik Bae. A controlled clinical study of serosa-invasive gastric carcinoma patients who underwent surgery plus intraperitoneal hyperthermic-chemo-perfusion (IHCP). Gastric Cancer 2001 4: 27-33.

2) S Fujimoto et al. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. Cancer 1999; 85:529-34.

3) S Fujimoto et al. Improved mortality rate of gastric carcinoma patients with peritoneal carcinomatosis treated with intraperitoneal hyperthermic chemoperfusion combined with surgery. Cancer 1997; 79: 884-91.

4) Kodera Y et al. Peritoneal washing cytology: prognostic value of positive findings in patients with gastric carcinoma undergoing a potentially curative resection. J Surg Oncol 1999; 72: 60-4.

5) YonemuraY et al. Prophylaxis with intraoperative chemoyperthermia against peritoneal recurrence of serosal invasion-positive gastric cancer. World J Surg 1995; 19: 450-5.

6) YonemuraY et al. Effects of intraoperative chemoyperthermia in patients with gastric cancer with peritoneal dissemination. Surgery 1996; 119: 437-44.

7) A Shido, S Ohmura, k Yamamoto, T Kobayashi, T Fujimura, Y Yonemura. Does hyperthermia induce peritoneal damage in continuous hyperthermic peritoneal perfusion? World J Surg 24, 507-511, 2000.

8) W P Ceelan et al. Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer. British Journal of Surgery 2000, 87, 1006-1015.

9) J Esquivel, F Angulo, Rebecca K Bland, CRNA, Arvil D Stephens, BS and Paul H Sugarbaker. Hemodynamic and cardiac function parameters during heated intraoperative intraperitoneal chemotherapy using the open "Coliseum Technique".Annals of Surgical Oncology 2000, 7 (4):296-300.

10) Fujimara T, Yonemura T, Fushida S et al. Continuous hyperthermic peritoneal perfusion for the treatment of peritoneal perfusion for the treatment of peritoneal dissemination in gastric cancers and subsequent second-look operation. Cancer 1990; 65: 65-71.

11) Dimitris Tsiftsis et al. Peritoneal expansion by artificially produced ascites during perfusion chemotherapy. Arch Surg 1999; 134: 545-549.

12) Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995; 221: 29-42.

13) Jaquet , Sugarbaker PH et al. Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5 fluorouracil: pharmaco-kinetics studies. Oncology 1998; 55: 130-8.

14) PH Sugarbaker. Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and treatment of peritoneal carcinomatosis and sarcomatosis. Seminars in Surgical Oncology 1998; 14: 254-61.

15) C Christophi et al. The treatment of malignancy by hyperthermia. Surgical Oncology 7, 1999, 83-90.

16) A C Beaujard, FN Gilly et al. Intraperitoneal chemohyperthermia with mitomicin C for digestive tract cancer patients with peritoneal carcinomatosis. Cancer 2000; 88: 2512-19.

17) W YU, I Whang, Ho Young Chung, Andrew Averbach, Paul H Sugarbaker. Indications for early postoperative intraperitoneal chemotherapy of advanced gastric cancer: results of a prospective randomized trial. World J Surg. 25, 985-990, 2001.

18) W Yu et al. Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer. Annals of Surgery 1998, 228, 3, 347-354.

19) S Shimoyama et al. Type oriented intraoperative and adjuvant chemotherapy and survival after curative resection of advanced gastric cancer. World J Surg 23, 284-292, 1999.

20) Yonemura Y,Fujimura T, et al.Prediction of peritoneal micrometastases by peritoneal lavaged cytology and reverse transcriptase-polymerase chain reaction for matrix metalloproteinase-7 mRNA. Clin Cancer Res 2001 Jun; 7,(6):1647-1653

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