Ram Dhoj Shrestha

Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding

Fifteen patients with far-advanced gastric cancer were given surgical treatment followed by intraperitoneal hyperthermic perfusion (IPHP) with mitomycin C (MMC) and misonidazole (MIS), a thermosensitizing drug. Immediately after extensive resection of the abdominal tumors, a 2-hour IPHP was performed at the inflow temperature of 44.7 to 48.7 C, using equipment designed for treatment of cancerous peritoneal seeding as a closed circuit, and under hypothermie general anesthesia at 30 to 31 C. In nine of the 15 patients with peritoneal seeding and/or ascites, cancerous ascites was absent after this treatment. In all cases, repeated cytologie examinations of the lavage from Douglass pouch were negative. The postoperative courses were uneventful except for Patients 1 and 10, in whom slight leakage occurred. All patients were discharged and are in good health at the time of this writing, 7.2 ± 4.6 months after the treatment. The Case 4 Patient recently died in a traffic accident. In all patients, transient hepatic dysfunction and hypoproteinemia occurred after the operation. This extensive surgery combined with IPHP using MMC and MIS was well tolerated and is a safe antitumor treatment for gastric cancer with peritoneal dissemination. Neurotoxicity due to MIS was nil.

Positive results of combined therapy of surgery and intraperitoneal hyperthermic perfusion for far-advanced gastric cancer.

To evaluate the clinical efficacy of intraperitoneal hyperthermic perfusion (IPHP) for far-advanced gastric cancer, particularly with peritoneal seeding, we investigated the survival times of 59 patients who underwent distal subtotal gastrectomy, total gastrectomy, or total gastrectomy combined with concomitant resection of some of the remaining intra-abdominal organs. In all the 30 patients given IPHP, no cancer cells were present posthyperthermically in the lavage from the Douglas pouch. The 30 patients given IPHP lived longer than the 29 patients not given IPHP (p = 0.001), with a 1-year survival rate of 80.4% in the former group compared to 34.2% in the latter. With respect to a comparison of survival time of patients with peritoneal seeding, 7 patients not given IPHP had a 6-month survival rate of 57.1% and did not survive more than 9 months, whereas 20 patients given IPHP had 1- and 2-year survival rates of 78.7% and 45.0%, respectively; here the difference was significant (p = 0.001). The IPHP and control groups without peritoneal metastasis included 10 and 22 patients, respectively, and the 1-year survival rates are 85.4% and 45.3%, respectively. The survival rates of the former exceeded those of the latter, with p = 0.015 by the generalized Wilcoxon test. Thus this combined therapy offers the promise of extended survival for patients with far-advanced gastric cancer.

Effects of intra-arterially infused biodegradable microspheres containing mitomycin C

We prepared biodegradable microspheres containing about 5% mitomycin C (MMC) and of 45 ± 8 μm in diameter. These preparations were infused into the rat hepatic artery as a preclinical model of intra‐arterial infusion treatment for patients with inoperable hepatic tumor. The leaked MMC levels in the hepatic vein decreased below the assay limitation 2 hours after conventional MMC injection, whereas in the case of MMC microsphere the leaked drug levels were maintained at almost the same concentration for over 2 hours after infusion. The entrapped period of MMC microspheres within the hepatic artery was at least 2 weeks, and the necrobiotic foci due to antitumor effects of the condensed MMC released from the microspheres were observed in the area fed by these entrapped arterioles. This phenomenon was never observed in the case of conventional MMC and placebo microspheres. Intra‐arterial infusion of MMC microspheres may be a promising clinical treatment for patients with malignant hepatic tumor.

A clinical pilot study combining surgery with intraoperative pelvic hyperthermochemotherapy to prevent the local recurrence of rectal cancer

Intraoperative pelvic hyperthermochemotherapy (IOPHC) with mitomycin C (MMC) was prescribed for 14 patients with resectable advanced rectal cancer in an attempt to prevent a postoperative local recurrence. Immediately after rectal amputation and extended lymphadenectomy, IOPHC was performed using physiologic saline containing 40 micrograms/mL of MMC at 45.5 +/- 0.6 C for 90 minutes, with an apparatus devised for IOPHC. At the end of IOPHC, the esophageal temperature was 37.2 +/- 0.8 C and cooling was not required. Antitumor efficacy and complications in the IOPHC group were compared with findings in 12 rectal cancer patients who underwent surgery only within the same period of time. Operation time was not prolonged with IOPHC treatment. In cytologic examinations of the pelvic lavage just before IOPHC treatment, viable cancer cells were detected in 6 of the 14 patients but were never detected in the postoperative exudate drained from the pelvic cavity. Of the 12 patients in the control group, 2 had a local recurrence, while in the IOPHC group there was no local recurrence for 16.9 +/- 9.7 months at this writing. Postoperative complications did not differ between the groups. This IOPHC treatment is a favorable method in eradicating cancer cells for postoperative local recurrence of rectal cancer.

Prevention of scald injury on the peritoneo-serosal surface in advanced gastric cancer patients treated with intraperitoneal hyperthermic perfusion

In attempts to avoid the side-effects derived from a scald on the peritoneo-serosal surface during intraperitoneal hyperthermic perfusion (IPHP) for advanced gastric cancer, a randomized study using cimetidine, a histamine H2-receptor antagonist, was carried out on 18 patients with advanced gastric cancer. Cimetidine, 50 mg/kg, was administered intravenously and immediately before IPHP. The background characteristics of the patients and the types of surgical treatment used were almost the same between each group of patients, whether or not cimetidine was given. The perfusion time in the cimetidine and control groups was 123 +/- 9 and 117 +/- 9 min, respectively. The inflow and outflow temperatures of the perfusate were 46.3 +/- 0.4 and 44.2 +/- 0.1 degrees C in the cimetidine group, respectively, whereas in the control group the temperatures were 46.0 +/- 0.3 and 44.1 +/- 0.2 degrees C, respectively. In the nine patients who were given cimetidine, the histamine concentrations in the peripheral blood increased significantly, compared to those in the nine controls; this resulted from the release of histamine into the circulating blood. Higher concentrations of protein were observed in the post-hyperthermic intraperitoneal exudate of the control group for 3-24 h after IPHP and, consequently, post-hyperthermic hypoproteinaemia was remarkable in the control group. These data suggest that when pre-IPHP cimetidine was prescribed for patients with gastric cancer treated with IPHP, the peritoneo-serosal surface was protected from scald injury and the side-effects of IPHP were reduced.

Intra-arterial administration of heated albumin microspheres containing mitomycin C to rabbits with VX-2 tumor

In an attempt to enhance antitumor effects, we prepared heated albumin microspheres containing mitomycin C (MMC). These MMC microspheres have an average diameter of 45±8 μm and contain about 5 per cent of MMC. The intra-arterial MMC microsphere treatment, for albino rabbits with implanted VX-2 tumor, increased remarkably the tissue MMC levels, compared to that with conventional MMC, and resulted in conspicuous antitumor efficacy. This approach to antitumor chemotherapy should be effective for selected patients with malignant tumor receiving a blood supply from an end-artery.

Metabolic changes in cimetidine treatment for scald injury on the peritoneo-serosal surface in far-advanced gastric cancer patients treated by intraperitoneal hyperthermic perfusion

Since pretreatment with cimetidine results in the prevention of scald injury on the peritoneo-serosal surface caused by intraperitoneal hyperthermic perfusion (IPHP) for advanced gastric cancer, the diverse influence of IPHP on patients who were either given or not given cimetidine was studied both during and after IPHP treatment. Cimetidine 50 mg/kg was injected intravenously into 12 patients immediately prior to IPHP. There were no statistical background differences between the cimetidine and control groups (those not given cimetidine). The inflow and outflow temperatures of the hyperthermic perfusate in the control and cimetidine groups were 46.1±0.1°C and 44.1±0.1°C and 46.3±0.1°C and 44.2±0.04°C, respectively. Either the pre-IPHP hypothermia or IPHP in the control group resulted in a considerable increase in serum noradrenaline and adrenaline. The intravenous administration of cimetidine led to a stransient but moderate drop in the mean blood pressure as well as a delayed appearance of high concentrations of noradrenaline and adrenaline, induced by high concentrations of circulating histamine released with cimetidine. These results suggest that the sympathetic nervous responses were activated either by hypothermia or hyperthermia. The transient hypotension and delayed increases of both serum catecholamines were attributed to a marked increase in circulating histamine, released with the intravenous cimetidine.

Enhanced antitumor efficacy with a combination of hyperthermochemotherapy and thermosensitization with polyamine antimetabolites in nude mice

In an attempt to enhance the antitumor effects of hyperthermochemotherapy, methylglyoxal-bis-guanylhydrazone (MGBG) and alpha-difluoromethylornithine (DFMO) were used in combination with hyperthermochemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) against human gastric cancer (ST-2) xenotransplanted into nude mice. After priming with DFMO and MGBG, ACNU was given ip and subsequently, a 23 minute-hyperthermia was carried out by placing the leg with the tumor into a water bath of a temperature of 43.5±0.1°C. The second hyperthermic treatment was given in the same manner after 48 hours. MGBG and DFMO were administered for 4 successive days from the previous day of the first hyperthermia. In mice treated with DFMO plus MGBG, either tumor growth or tumor tripling time was much the same as in the control, while in mice given MGBG, DFMO plus heat, there was a diminution in tumor growth. Hyperthermia together with MGBG, DFMO plus ACNU brought about remarkable antiproliferative effects on ST-2 tumor growth, compared to three regimens with MGBG, DFMO plus heat, MGBG, DFMO plus ACNU, as well as ACNU plus heat. These data suggest that a combination of MGBG with DFMO leads to a favorable thermosensitization to the antitumor efficacy of ACNU.

The presence of an aberrant type of human chorionic gonadotropin in patients with gastric or colorectal cancer

Beta subunits of human chorionic gonadotropin (β-hCG) and human chorionic gonadotropin-like substance (hCGLS) were measured radioimmunologically in the serum and malignant tissue from patients with gastrointestinal cancer. Since serum β-hCG and hCGLS correlate closely to those in cancer tissues, it is assumed that these two gonadotropins originate from cancer tissues. The serum hCGLS levels in 54 patients with gastrointestinal cancer were significantly higher, when compared with the findings in 19 healthy volunteers and 10 peptic ulcer patients. The frequency of high levels of serum hCGLS accounted for 71 per cent of those with operable gastric cancer, 44 per cent of those with inoperable gastric cancer, 100 per cent of those with operable colorectal cancer, and 67 per cent of those with inoperable colorectal cancer. On the contrary, serum β-hCG levels did not differ between the volunteers and the cancer patients. In the 17 sera and 15 cancer tissues assayed, β-hCG did not correlate to hCGLS. Moreover, the high levels of β-hCG in cancer patients occurred in only 1/14 (7.1 per cent) of the assayed serum, and in 5/14 (35.7 per cent) of the cancer tissue. The increased production of these two hCGs may result from neoplastic trans-fromation of an unrestrained fetal genome responsible for hCG production during gestation. It is assumed that the increased producibility of a defective hCG, i.e., an aberrant hCG such as hCGLS, is characteristic of malignant tumors.

Combined therapy of polyamine antimetabolites and antitumor drugs for human gastric cancer xenotransplanted into nude mice.

Antitumor therapies using polyamine antimetabolites combined with 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3(2-chloroethyl)-3-nitrosourea (ACNU) or fluorinated pyrimidines for human gastric cancer xenotransplanted into nude mice were studied to determine inhibiting post-therapeutic regrowth of the tumor after cessation of antitumor treatments with polyamine antimetabolites alone. ACNU 20 mg/kg, fluorinated pyrimidine, 5-FU 52.8 mg/kg and 5′-deoxy-5-fluorouridine (5′-DFUR) 100 mg/kg as well as polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) 1000 mg/kg and methylglyoxal-bis-guanylhydrazone (MGBG) 50 mg/kg were given intraperitoneally for 5 successive days. When DFMO and MGBG were combined with ACNU, the post-therapeutic regrowth was definitely inhibited, while combined treatments with 5-FU or 5′-DFUR did not inhibit the regrowth. Post-therapeutic DNA biosynthesis was suppressed in mice given DFMO, MGBG plus ACNU. On the contrary, in mice treated with DFMO, MGBG plus 5-FU or 5′-DFUR, suppression of DNA biosynthesis was not observed. Tumor tissue spermine levels in the DFMO, MGBG plus 5-FU or 5′-DFUR group remained unchanged, compared to those in the DFMO + MGBG group. In mice given DFMO, MGBG plus ACNU, however, spermine levels were markedly depressed; and the ACNU alone depressed also the tissue spermine levels. These different results between nitrosourea and fluorinated pyrimidines may relate to mechanisms of action of these antitumor drugs.