Yukio Kitsukawa

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.

A study of survival in patients with stomach cancer treated by a combination of preoperative intra‐arterial infusion therapy and surgery

Since 1968, there have been 62 patients with stomach cancer seen in the First Department of Surgery of Chiba University. Treatment consisted of preoperative intra‐arterial chemotherapy and surgery. The chemotherapy entailed continuous infusion for 15 to 20 hours. The survival rates were analyzed with particular emphasis on the degree of serosal invasion of the stomach. The overall survivals at the end of 3 years were 54.2% for the treated patients, and 37.1% for the controls: and at the end of 5 years, 33.3% of the treated patients were living as compared to 29.7% of the control patients. In patients without serosal invasion, the survival rates were higher for those treated than for the controls for the first 2 years. At the end of 3 years, the 39 patients treated for serosal invasion had a survival rate of 46.8% vs. 29% in the controls: and at 5 years, 32.2% of the treated patients vs. 23.7% in the controls. The survival rates for the treated patients with cancerous infiltration of other organs were about the same as those for the corresponding control patients.

Long-term survivors of colorectal cancer with unresectable hepatic metastases.

Five patients with colorectal cancer and unresectable synchronous liver metastases have survived for over five years at this writing. Four of the five had multiple metastases over both lobes, as diagnosed preoperatively, and the other had multiple metastases in the right lobe not evident preoperatively. The primary foci were excised completely in four patients. For one patient with multiple metastases limited to the right lobe, the postoperative cancer chemotherapy prescribed was intravenous mitomycin C (MMC; 12 mg) and oral ftorafur (a derivative of 5-FU) for a total dose of 291 gm over 63 weeks. The remaining four patients underwent postoperative intra-arterial infusion therapy with the average total dose of 20.5 mg of MMC plus 5600 mg of 5-FU; subsequently, they received protracted chemotherapy with oral ftorafur of 354 gm as an average, with little or no side effects. In these four patients, duration of intra-arterial treatment was an average of 3.2 weeks, and the subsequent oral treatment continued for an average of 85 weeks. Recent hepatic echography and CEA determinations show these patients to be free from intrahepatic metastasis.

Further investigations of immunoreactive carcinoembryonic antigen (CEA) in colorectal cancer patients with particular emphasis on the correlation between immunoreactive CEA levels in tissue, feces and blood

Immunoreactive carcinoembryonic antigen (IR-CEA) levels in colorectal cancer and mucosal tissues, feces and blood were measured in 14 colorectal cancer patients to study the correlation. IR-CEA levels in colorectal cancer tissues were about 30 times higher than those in colonic mucosal tissues. The correlation coefficient between IR-CEA levels in the tumor tissue and serum was 0.654 (p<0.02). We assumed that the total tumor IR-CEA levels were the product of the tumor IR-CEA level, by the estimated tumor weight. The correlation coefficient between the serum IR-CEA level and total tumor IR-CEA level was 0.750 (p<0.001). When the patients were divided into two groups with more and less a total tumor IR-CEA level of 65,000 ng, respectively, the statistical difference in serum IR-CEA levels was p<0.001. The differences in fecal IR-CEA levels between these two groups, however, are statistically insignificant (p<0.3). We assumed that there was a positive correlation between the IR-CEA levels in blood and tumor from the consideration that circulating IR-CEA orginates from the metabolic imbalance of its production in colorectal cancer tissues over its degradation in the liver. Moreover, it is essential to consider that the fecal IR-CEA levels may be influenced by the following three factors: the intraluminal direct release of CEA from tumor, no degradation process of CEA in the gut lumen, and the intraluminal transport rate of colonic contents.

Clinical evaluation of prolonged chemotherapy combined with induction of hepatic drug-metabolizing enzymes as an adjuvant for treating patients with gastric cancer

A clinical trial of a protracted adjuvant cancer chemotherapy was carried out on 207 patients with operable gastric cancer, from April, 1977, in the First Department of Surgery, Chiba University Hospital and two closely related hospitals. These patients were given intravenously 0.4 mg/kg and 0.2 mg/kg of mitomycin C on the day of operation and the next day, respectively, and then 16 mg/kg intravenously of Futraful (FT-207) daily from the 10th postoperative day until discharge, followed by oral administration of FT-207, 12 mg/kg, for 24 to 36 months after discharge. Two mg/kg of phenobarbital and 30 mg/kg of glutathione were administered randomly to half the number of patients (induction group) to induce hepatic drug-metabolizing enzymes. Significantly higher levels of serum 5-Fluorouracil (5-FU) released from FT-207 were found in the induction group than in the controls. Five-year overall survival rates in the induction and control groups revealed no difference. However, the survival rates in Stage III patients in the induction group were significantly superior in the 3–5 postoperative years, compared to those in the Statge III of the control group, while Stage I, II and IV patients apparently received no benefit from this induction treatment.

Comparative efficacy of antitumor treatment for liver metastases from colorectal cancer

A retrospective study of 37 colorectal cancer patients with synchronous liver metastases was made. Of these patients, 6 who had undergone primary tumor removal were treated with considerable success by hepatic arterial infusion of 5-FU and mitomycin C. Ten patients who underwent primary tumor excision were treate by oral chemotherapy using fluorinated pyrimidines. These patients survived about 23 months. On the other hand, 12 patients after primary tumor removal without cancer chemotherapy survived for about 10 months. Six patients without antitumor treatment for both primary tumor and hepatic metastasis survived about 5.2 months. The overall results of this study suggest that intrahepatic arterial infusion is of practical importance for hepatic metastases from colorectal cancer and that oral chemotherapy is indeed effective for selected patients.

In vitro sensitivity test of stomach cancer tissues by the use of metal grid method

Ninety-nine specimens obtained from 53 patients with stomach cancer were cultured for about 3 days by means of the stainless steel grid method. In vitro effects of antitumor drugs on the cancer cells were evaluated autoradiographically or biochemically using a liquid scintillation counter to measure the uptake of3H-thymidine. The radioactivity of the labeled tumor cells of both control fragments and fragments affected by drugs varied greatly among individual tumors. Therefore, the in vitro efficacy of antitumor drugs was represented as a comparison with that of control fragments. Positive correlation between in vitro tests and the clinical effects of antitumor drugs was observed in the specimens of 18 cases.

Stimulation of Protein, RNA, and Nucleotide Synthesis in Lymphocytes After Abdominal Surgery Is Not Affected by Postoperative Amino Acid Supply

The effects of abdominal surgery on protein, RNA, and de novo purine nucleotide synthesis in lymphocytes, and modification of these changes by postoperative amino acid supply, were investigated in 24 patients undergoing cholecystectomy (n = 12) or removal of gastric cancer (n = 12). Mono-nuclear cells were isolated from the peripheral venous blood and incubated with radioactive tracers in vitro. Protein and RNA synthesis, as measured using [14C] glycine and [3H]uridine, respectively, increased postoperatively. Nucleotide synthesis determined by the incorporation of radioactivity from [14C] glycine into nucleotides increased simultaneously. The concentration of 5-phosphoribosyl 1-pyrophosphate (PRPP) estimated by the incorporation of [14C]adenine into nucleotides also increased. These changes were greater and of longer duration in patients with cancer operation than in those with cholecystectomy. In neither case were they affected by the amount of amino acid intake, or increases in energy intake. These results suggest that abdominal surgery stimulates protein and ribonucleic acid (RNA) synthesis in lymphocytes. Increased RNA synthesis may be ensured by increased synthesis of nucleotides, and increased PRPP concentrations appear to regulate the rate of nucleotide synthesis. The responses are apparently dependent upon the severity of surgery, but unrelated to the amount of amino acid supplied postoperatively.