Treatment of cancerous ascites and radical gastrectomy with intraperitoneal hyperthermic double distilled water and cis-diaminodichloro-platinum perfusion

Zhi Xing Chen, Jia Ping Chen, Zhong Chen, De Shu Peng, Ji Xiang Zhen, Jian San Tan

Subject headings  gastrectomy;  stomach neoplasms;  ascites; cis-diaminodichloro-platinum; perfusion

Chen ZX, Chen JP, Chen Z, Peng DS, Zhen JX, Tan JS. Treatment of cancerous ascites and radical gastrectomy with intraperitoneal hyperthermic double distilled water and cis-diaminodichloro-platinum perfusion. China Nati J New Gastroenterol, 1997;3(4):246-248

Abstract

AIM  To study the effect of intraperitoneal hyperthermic double distilled water and cis-diaminodichloro-platinum (DDP) perfusio n in treatment of cancerous ascites and radical gastrectomy.

METHODS H₂₂ cancer cells (2¡Á10⁷ tumor cells each mouse) were injected into the peritoneal cavity of LACA mice. Five days after the injection, intraperitoneal perfusion of 37¡æ isotonic fluid (Group ¢ñ), simple hyperthermic (43¡æ) double distilled water (Group ¢ò), isotonic fluid (group ¢ó), DDP (group ¢ô) and hyperthermic double distilled water perfusion combined with DDP (group ¢õ) were performed. Based on the experiment from September 1991 through September 1993, intraperitoneal hyperthermic double distilled water perfusion with DDP was used to treat 32 advanced gastric cancer patients after radical gastrectomy.

RESULTS  In comparison with the control group, the cancer cells in the peritoneal cavity of LACA mice were almost completely destroyied, the ascites was markedly inhibited and the survival time was prolonged, the growth of peritoneal cancerous nodes was reduced in all groups, except the control group.Clinically, after one-year follow-up, all 32 patients with advanced carcinoma got satisfactory results, but the 2-year follow-up was not satisfactory.

CONCLUSION  The intraperitoneal hyperthermic double distilled water perfusion with DDP inhibited the occurrence of ascites in LACA mice, and prolonged the lifetime of gastric cancer patients after radical gastrectomy.



INTRODUCTION
The five-year survival rate of gastric carcinoma after radical gastrectomy is about 30%-40%. Among the causes of death peritoneal metastasis recourrence, accounts for about 50%. In recent years there were some reports^£Û1-4£Ýabroad, using intraperitoneal hyperthermic isotonic anticarcinogen fluid perfusion, but the longª²term result is uncertain. We used intraperitoneal hyperthermic double distilled water and cis-diaminodichloro-platinum (DDP) perfusion to prevent peritoneal metastasis and treat cancerous ascites.

MATERIALS AND METHOD

Materials
The LACA mice and ascites tumor cells(liver cancer cell ascites, H₂₂)were provided by the Cancer Institute of West-China University of Medical Sciences; double distilled water (DDW) and physiological saline were provided by our pharmaceutical department; DDP (2mL/tube, containing 10mg DDP) were products of Gejiu Biochemical Pharmaceutical Factory, Yunnan.

Methods
Intraperitoneal injection of 2¡Á10⁷ tumor cells (each mouse) was administered to 70 LACA mice (half male, half female, each weighing 22g to 24g) which were divided into 5 groups randomly. Five days after the injection, intraperitoneal perfusion of 37¡æ physiological saline 1.5mL^£Û5£Ý(group ¢ñ, control group), hyperthermic double distilled water (group ¢ò), isotonic fluid (group ¢ó), DDP (2.5mg/kg)^£Û6£Ý(group ¢ô), and hyperthermic double distilled water perfusion combined with DDP (group ¢õ) was performed. The management of different perfusion is shown in Table 1.
Table 1 The management of ascites cancer cells in LACA mice

+: management; -: without management.

Observation and analysis of indexes
Average survival days of mice and the quantity of ascites.
The exact death time of mice was recorded as soon as the death occurred, and a small incision was made on the abdominal wall, the ascitic fluid was carefully sucked, and collected and measured accurately.
Peritoneal cancer nodes examination.  An autopsy was made to observe the distribution, number and size of the cancer nodules and carefully recorded.
Number survival rate of tumor cells. The ascitic fluid was diluted with physiological saline, and stained with Tai-pan blue, and the living tumor cells and the total number were calculated.
Tumor cells under optical and electron microscopic observation. The smear was made by the precipitate after centrifugation, sectioned by ultra thin technic and HE stained by uranyl, acetate and lead citrate, and observed under both optical and electronic microscopy. F and Q tests were used for comparison.

RESULT

Ascites tumor cells and survival rate of tumor cells
Ascites appeared obviously within one week in the control group, while in the managed group, its appearance postponed, and the amount reduced. Four mice in group ¢õ had no ascites compared with the control group. All the other managed groups, except group ¢ó, showed a low number of tumor cells, with a significant difference (P£¼0.01).Compared with groups ¢ò and ¢ô,tumor cells in group ¢õ sharply decreased, and the survival rate also markedly reduced (Table 2).
Table 2  Ascites, tumor cells and survival rate of tumor cells in all groups

^bP£¼0.01, vs ¢ñ,^dP£¼0.01, vs ¢ò and ¢ó.

Survival days of mice
Except in Group ¢ó (P£¾0.05), the survival days of mice in other groups were remarkably prolonged. Compared with Groups ¢ò, ¢ó and ¢ô, mice in Group ¢õ showed significant difference in prolonged survival days (Figure 1).
    Growth of peritoneal cancerous nodes. Results are shown in Table 3.
Table 3  Detected peritoneal cancerous nodes in all groups

^aP£¼0.05, vs ¢ñ.
Light and electron microscopic observation of ascites tumor cells
Under the light microscope, tumor cells in Group ¢ñ were found large in number, gathering in clots with big and deeply stained nuclei. The tumor cells in Group ¢ó reduced in number. In Groups ¢ò and ¢ô, water-like degeneration and necrosis were found in some tumor cells. In Group ¢õ, tumor cells were sharply decreased, the rest tumor cells showed necrotic pathological changes, with cytoplasm dissolvation and nucleus disappearance. Under the electron microscope no tumor cells with complete structures were found in Group ¢õ.The tumor cells in Groups ¢ò and ¢ô showed degeneration in various degrees, with distension of mitochondria and nucleoplasm of tumor cells.
Figure 1  Survival days in all groups.^bP£¼0.01 vs ¢ñ, ^dP£¼0.01 vs ¢ò, ¢ô and ¢õ.

CLINICAL APPLICATION
Based on this experiment from September 1991 to September 1993, 60 cases of adva nced gastric cancer were divided randomly into two groups. One control  group (28 cases), treated with operation only and the other group (32 cases), with intraperitoneal perfusion of 43¡æ double distilled water combined with DDP (Cisª²platin).
    The abdominal cavity was opened on each patient in both groups, and perfused and washed with 200mL of 37¡æ normal saline which was then sucked out in order to search the detouched tumor cells.
    In the second group, before closing the abdomen, intraperitoneal perfusion of hyperthermic (44¡æ-46¡æ) sterile double distilled water 2500mL-3000mL, circulating perfusion for 30 minutes, then 700mL-1000mL of perfusate were remained in the abdomen, and added 300mg of DDP (200mg/m²)^£Û7£Ý, the abdomen could then be closed with a tube for drain. Postoperatively the tube was clamped for 4 hours and then let it open for drainage. At the same time of perfusion, rapid i.v. drip of 12g of sodium thiosulfate was administered within 20 minutes, followed by 24?g of sodium thiosulfate in 1000mL of 5% G.S. i.v. for about 8 hours^£Û8£Ý.
    In the second group 13 (48.1%) patients were found positive in detouched tumor cells among 27 patients examined. All the 13 patients became negative after treatment. In the first group (control group), 9 cases were positive and 6 cases remained positive postoperatively.ª¥
        Postoperative follow-up showed that the one-year survival rate of the prevention group was 96.9% (31/32) and of the control group 46.1% (13/28) difference being statistically significant (P£¼0.01); and two-year survival rate 75.0% (24/32) and 42.9% (12/28), difference being not statistically significant (P£¾0.05).
    The incidence of complications of intraperitoneal perfusion was 65.6% (21/32), including nausea 43.8% (14) vomiting 25.0% (8/32). These were mild, and easily relieved by paspertin or cndansetron zofran. The serun creatinine and urea nitrogen determined after perfusion, were higher than before operation, but still within normal limits. Six patients had slight decrease of WBC after perfusion but all above 3.0¡Á10⁹. Liver function tests were normal, no peritoneal nerve injury, delayed healing of incision, anastomotic leakage, or intestinal adhesion occurred.

DISCUSSION
When the serosa of the gastric tumor is invaded, the tumor cell may detach spontaneously or by manipulation during operation to the free peritoneal cavity or the pelvic fossae^£Û9£Ý. Kaibara^£Û3£Ýreported that the five-year survival rate in patients free from peritoneal metastasis was 51.4% and on the other hand only 18.7% in these with peritoneal metastasis. Thus it is important to prevent and treat the peritoneal metastasis.
    The thermochemotherapy is able to eliminate the recurrence of the excision site and the peritoneal seeding. Kaibara^£Û3£Ý reported that it might raise the 5-year survival rate.
    In our experiment, on the fifth day after intraperitoneal injection of H₂₂ cancer cells into the peritoneal cavity of LACA mice, the tumor cells had continuous division and proliferation, and seeding, then intraperitoneal perfusion of hyperthermic (43¡æ) hypotonic (double distiled) combined with DDP, was compared with perfusion of normal temperature hypotonic fluid, isotonic fluid and DDP. The result showed that the solution of hyperthermic hypotonic water containing DDP had best effect, probably because of their synergic action.

REFERENCES
1  Fujimoto S, Shrestha Rd, Kokubun M. Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric
    cancer patients with peritoneal seeding. Ann Surg, 1988;208(2):36-41
2  Koga S, Hamazo ER, Maeta M. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic
    peritoneal perfusion with mitomycin C. Cancer, 1988;61(1):232-237
3  Kaibara N. Hyperthermic peritoneal perfusion conbined with anticancer chemotherapy as prophylactic treatment of peritoneal
    recurrence of gastric cancer. Hepato-Gastroenterology, 1989;36(2):75-78
4  Fujimura T, Yonemura Y, Fushida S. Continuous hyperthermic peritoneal perfusion for the treatment of peritoneal
    dissemination in gastric cancers and subsequent second-look operation. Cancer, 1990;65(1):65-71
5  Xu SY. Pharmacological experimental methodology, 2nd ed. Beijing: People s  Health Publishing House, 1991:1424-1430
6  Trave F, Rustum YM, Boransen T. Synergistic antitumor activity of cisplatin (DDP) and 5-fluorouracil (Fura 0 in mice bearing
    leukemic L1210 cells. Proc Annual Meeting of Association of Cancer Am Res, 1985;26:322 (meeting abstract)
7  Xu SY. Clinical guidance of administration drug. 1st ed. Hefei:  Anhui Publishing House of Science and Technology, 1989:8-10
8  Howell SB, Pfeifle CE, Wang WE. Intraperitoneal cis-diaminodiochloroplatinum with systemic thiosulfate protection.
    Cancer Res, 1983;43(2):1426-1430
9  Litsuka Y, Kaneshima S, Tanida O. Intraperitoneal free cancer cells and their viability in gastric cancer.
    Cancer, 1979;44(1):1476-1480

¹Department of Surgery, First Affiliated Hospital, Westª²China University of Medical Sciences, Chengdu 610041, China
²Department of Pathology, Fourth Affiliated Hospital, Westª²China University of Medical Sciences, Chengdu 610041, China
*Supported by the Sichuan Provincial Health Bureau (94F0132).
Correspondence to Dr. Zhi Xing Chen, male, born on 1961-12-25 in Langzhong City, Sichuan Province, graduated from West China University of Medical Sciences as a postgraduate in 1993, attending surgeon, mainly devoted to the studies of diagnosis and treatment of the gastroenteric tumors, having 10 papers published.
Tel:+86¡¤28¡¤5551255 ext. 26808
Received  1996-07-20   Revised  1997-09-09