Treatment of implanted peritoneal cancer in rats by continuous hyperthermic peritoneal perfusion in combination with an anticancer drug.

To study the feasibility of combined hyperthermic and anticancer drug treatment for peritoneal cancer, we devised a continuous hyperthermic peritoneal perfusion system in combination with mitomycin C. The model uses i.p.-transplantable rat ascites hepatoma 100B cells. Hyperthermic peritoneal perfusion alone or combined with mitomycin C was performed after i.p. inoculation of the tumor cells into rats. In rats treated with combined peritoneal perfusion (41.5 degrees) and mitomycin C, the mean survival times were significantly prolonged as compared to those of rats treated with peritoneal perfusion at 41.5 degrees alone. Our results suggest that combined hyperthermic peritoneal perfusion and mitomycin C treatment may represent a therapeutic and prophylactic treatment for peritoneal metastasis after gastric cancer surgery in humans.

Diagnostic accuracy of combination of assays for immunosuppressive acidic protein and carcinoembryonic antigen in detection of recurrence of gastric cancer.

Two tumour markers, immunosuppressive acidic protein (IAP) and carcinoembryonic antigen (CEA), were assayed in gastric cancer patients. Levels of IAP and CEA were measured simultaneously in the preoperative and postoperative periods. The usefulness of the combined assay of these markers for detection of recurrence of cancer was investigated in terms of sensitivity, specificity and diagnostic accuracy. Sensitivity was not high (69.2%), but specificity and diagnostic accuracy were 96.7% and 86.9%, respectively. In cases with metastases in the liver, sensitivity (100.0%), specificity (100.0%) and diagnostic accuracy were high. In cases of peritoneal dissemination, these indices were low. The combination assay of IAP and CEA appears to be useful for detection of recurrence of gastric cancer, especially in patients with liver metastases.

CA72-4 compared with carcinoembryonic antigen as a tumour marker for gastric cancer.

Serum levels of a newly identified, tumour-associated antigen, CA72-4, were measured in 86 patients with histologically proven gastric carcinoma. Preoperative levels of CA72-4 in serum tended to be higher with increased dissemination of the cancer. Elevated levels of CA72-4 (above 5.0 U/ml) were significantly more frequent than those of carcinoembryonic antigen (CEA) (above 5.6 ng/ml) in patients with stage III or IV (P less than 0.01) carcinoma, in patients with Borrmann type 4 (P less than 0.01), and in patients with peritoneal metastasis (P less than 0.01). No correlation was seen between serum levels of CA72-4 and those of CEA. Serum levels of CA72-4 were lower 1 month after gastrectomy in 25 of 39 patients with resected cancers. In each of 4 patients with recurrence, lower levels of CA72-4 after gastrectomy were replaced by elevated levels on detection of the recurrence of cancer. These results indicate that CA72-4 is highly specific to gastric cancer and may be more reliable as a tumour marker than CEA for gastric cancer.

Cytological evaluation of the effects of chemotherapy on metastatic liver cancer.

We present a method for the cytological evaluation of the therapeutic effects of various treatments on unresectable metastasis in the liver from colorectal cancer. A degeneration index (DI) for cancer cells obtained by aspiration was determined in 17 patients before and after treatment. The relationships of the rate of tumor reduction and of the post-treatment survival period to the treatment-induced changes in DI were studied. The treatment-induced change in DI was represented by the difference between the pretreatment DI and the posttreatment DI. The treatment-induced change in DI was significantly correlated with the rate of tumor reduction (r = 0.794, P < 0.001). The survival rate was significantly higher in patients with higher changes in DI than in patients with lower changes (P < 0.05). The change in the DI of cancer cells seems to be a useful parameter for evaluating the effects of chemotherapy on unresectable liver metastases from colorectal cancer.

Effects of microwave tissue coagulation on the livers of normal rabbits: a comparison of findings of image analysis and histopathological examination.

The livers of normal rabbits were subjected to microwave tissue coagulation (MTC), and comparison was made of the subsequent time-course changes in tissue observed on MRI, CT and histopathological examination. 16 rabbits were used. MTC was performed with a 21 gauge needle electrode inserted into the liver at laparotomy. 1-2 h after thermal coagulation, a region with slightly lower attenuation than that of surrounding normal liver parenchyma was observed on CT, and no enhancement was detected. With MRI, change from high signal intensity to iso-signal intensity from the inner zone to the margin was found on T1 weighted images (T1WI), and heterogeneous high signal intensity was observed on T2 weighted images (T2WI). On Gd-DTPA enhanced MRI, no enhancement occurred. 1-4 weeks after coagulation, the cellular structure at the site of coagulation was lost on histological examination, and the tissue became necrotic. On CT, homogeneous water density was observed, and no enhancement was detected. With MRI, regions of iso- or slightly low signal intensity were observed on T1WI, and regions of heterogeneous high to low signal intensity were seen on T2WI. After 1 week, a granulation layer consisting mainly of fibrous tissue developed, and a ring-shaped enhancement was observed in the low signal intensity region on T1WI and in the high signal intensity region on T2WI. The ring-shaped enhancement was also noted on CT. MRI appears to be useful for observation of time-course changes following MTC therapy because of its sensitivity in the detection of tissue changes.

Gastric leiomyoblastoma in childhood.

A case of gastric leiomyoblastoma in a 7-year-old girl, who underwent partial gastrectomy combined with complete removal of perigastric lymph nodes, is reported. Characteristics of the behavior and prognosis of gastric leiomyoblastomas in childhood are discussed in a review of the world literature.

Hyperthermic peritoneal perfusion combined with anticancer chemotherapy as prophylactic treatment of peritoneal recurrence of gastric cancer.

We have conducted a clinical trial to evaluate the effectiveness of continuous hyperthermic peritoneal perfusion with mitomycin C (CHPP-M) as prophylactic treatment of peritoneal recurrence of gastric cancer. Between January 1983 and October 1985, 82 patients with macroscopic serosal invasion but no macroscopic peritoneal metastasis undergoing potentially curative resection of gastric cancer, were divided into two groups by random sampling: 42 patients were scheduled to receive CHPP-M, while 40 would not receive such treatment. The CHPP-M was administered immediately after closure of the abdomen following gastric resection, while the patient was still on the operating table under general anesthesia. The 5-year survival rate (71.5% of the patients in the CHPP-M group was higher than that (59.7%) of those in the control group. Although postoperative follow-up periods are not long enough, the longer survival obtained in the patients treated with CHPP-M should be emphasized, since no effective means of preventing peritoneal recurrence of gastric cancer is so far available.

Intrahepatic cholangiocarcinoma with a long-term survival of 12 years after surgical resection: report of a case and review of the literature.

The prognosis of primary liver cancer, especially cholangiocarcinoma, is extremely poor. A long term, 12 years survivor of intrahepatic cholangiocarcinoma arising in a local dilatation of the intrahepatic bile duct is presented. A 40-year-old male patient was presented with recurrent upper abdominal pain, fever, and jaundice. Computed tomography revealed a localized duct dilatation, and ultrasound clearly demonstrated a tumor mass arising within the bile duct. At surgery in March, 1982, the tumor mass was resected and histologically confirmed as a well differentiated papillary adenocarcinoma arising. In March, 1994, the patient is alive and cancer-free, 12 years after surgical resection. To our knowledge, there has been no report on a patient surviving more than 10 years after initial treatment. This case suggests that a localized cystic dilatation of the intrahepatic-bile duct on imaging modalities may harbor a bile duct carcinoma, and this in turn may contribute to early diagnosis of carcinomas and improved long term survival.

[Application of heat combined with antineoplastic agent administration in the treatment of cancer (with special reference to malignancy of the digestive system)].

Recently, there is a renewed interest in the efficacy of hyperthermia in human cancer therapy. Based on the results of our experimental studies, we treated far-advanced cancer patients with extracorporeally induced total-body hyperthermia (TBHT) or continuous hyperthermic peritoneal perfusion (CHPP). In the TBHT combined with anticancer chemotherapy, a partial remission was observed in 4 (25.0%) of 16 far-advanced cancer patients. However, the improvement of survival time was unsatisfactory. The CHPP combined with anticancer chemotherapy was performed in 23 gastric cancer patients with peritoneal dissemination. In 6 of them, subjective complaints were improved, but the remarkable prolongation of survival time was not obtained. If in the future hyperthermochemotherapy is performed for cancer recurrence in early stage, more favourable results may be expected.

[Hyperthermia adjunct to surgery in the treatment of scirrhous carcinoma of the stomach].

In approximately 80% of patients with scirrhous carcinoma of the stomach, recurrence of cancers occurs even after potentially curative resection, and recurrence most frequently occurs in the form of peritoneal metastasis. Such recurrence may be attributable to possible intraperitoneal dissemination of malignant cells already present at the time of surgery. We performed intraoperative peritoneal cytology on patients with scirrhous carcinoma of the stomach. Free cancer cells were demonstrated in the Douglas cavity in 16 of 32 (50%) patients who underwent potentially curative gastrectomy. The postoperative 5-year survival rate was 23% in patients without detectable free cancer cells in the peritoneal cavity, compared with only 9% in patients with microscopic evidence of intraperitoneal free cancer cells. Therefore, we have applied hyperthermic continuous peritoneal perfusion (CHPP) on patients with scirrhous carcinoma of the stomach in order to develop a surgical adjuvant therapy effective for the prevention of recurrence of peritoneal involvement. The results obtained so far from our study have shown an increased 3-year survival rate of patients undergoing potentially curative gastrectomy, but no improvement of therapeutic outcome in terms of postoperative 5-year survival.

[Clinical results and problems of total-body hyperthermia].

The clinical results and problems of extracorporeally-induced total-body hyperthermia (TBHT) for recurrent cancer were presented. A total of 105 hyperthermic treatments were performed in 38 patients who had had unsuccessful conventional systemic anticancer chemotherapy. Partial response was observed in 10 of 29 evaluable patients (37%). In analysing the anticancer effects of TBHT according to cancer site, a high efficacy was observed in patients with their main tumor in the lung, liver and lymph nodes. The anticancer effects were most enhanced when TBHT was performed in combination with cis-diamminedichloroplatinum (II) and 5-fluorouracil. In order to augment the anticancer effects of TBHT, the choice of combined agent(s) and administration timing are important. A useful method for determining the thermochemosensitivity of individual cancer cells to agents selected for drug treatment is the human tumor stem cell assay. Further, the usefulness of angiotensin II-induced hypertensive chemotherapy during TBHT for augmenting selective drug delivery to cancer tissues is stressed.

[Significance of full-thickness chest wall resection as a local treatment for sternum metastasis of breast cancer].

Bone metastasis of breast cancer generally tends to be multiple. However, breast cancer frequently metastasizes to the sternum as solitary metastasis. Resection of the sternum was reported to be an effective surgical technique for sternum metastasis which could not be remarkably improved by chemo-endocrine therapy and locoregional recurrent breast cancer invading the skin. A first patient was diagnosed with sternum metastasis invading the skin 44 months after radical mastectomy for breast cancer of stage II. A second patient had breast cancer of stage IV simultaneously with metastases to the sternum and the lung. Only the lung metastasis was successfully controlled by chemo-endocrine therapy, but the sternum metastasis was progressive, following radical mastectomy. Both patients manifested solitary bone metastases and underwent full-thickness chest wall resection. The defect of the chest wall was reconstructed with the mucocutaneous flap using the dorsal latissimus muscle in case 1 and with the abdominal rectus muscle in case 2. Twenty months after the resection of the sternum, the first patient suffered from supraclavicular lymph node metastasis, and the multidisciplinary treatment including radiation therapy was indicated. This therapeutic procedure was effective, and the patient survived for 63 months after resection of the sternum. The second patient has made good progress for six months in maintaining complete remission with chemo-endocrine therapy. These findings suggested that surgical resection was a useful local treatment for solitary sternum metastasis.

[Therapeutic results and pharmacokinetics of combined used anticancer drug in intraperitoneal hyperthermo-chemotherapy (CHPP)].

Continuous hyperthermic peritoneal perfusion (CHPP) was performed after curative gastrectomy for the patients with serosally invading gastric cancer to control their peritoneal recurrence. In the randomized control study of this prophylactic CHPP, using 10 l of physiological saline with 100 mg of mitomycin C or 150 mg of cisplatin (CDDP) at 42 degrees C, better post-operative survival was obtained in the CHPP group than the control group, two-year survivals were 83% in the CHPP and 70% in the control. Through the evaluation of time-concentration curve of free-Pt in serum, the side effects of CDDP in the CHPP treatment were considered to be almost equal to that of 25 mg of CDDP in the intravenous injection. In the experiments using rats, the concentration of Pt in the peritoneal tissue after CHPP was three times higher than that after intravenous injection of 2 mg of CDDP. These three results, better survival, less side effects and higher drug concentration of the peritoneal tissue, support the reasonableness of CHPP.

[Intraoperative interstitial microwave therapy for recurrent hepatocellular carcinoma of the caudate lobe: a case report].

Microwave tissue coagulation (MTC) therapy was given patients with recurrent hepatocellular carcinoma (HCC) of the caudate lobe of the liver, in which radical surgery for deteriorated liver function was impossible. A total of 40 MTC sessions was applied to two tumors under laparotomy. MTC was administered for 20 seconds in each session. Microwave energy output was 70 watts for 15 mm needle-electrodes and 100 watts for 30 mm electrodes. Alpha-fetoprotein levels in serum had decreased after surgery. Abdominal computed tomography showed no blood flow whatsoever in tumors undergoing MTC. There are fewer limits to the sites and angles for insertion of electrodes under laparotomy. Thus, the surgical approach provides access to all parts of the liver for treatment. We conclude that intraoperative MTC is highly effective in tumor necrosis, and can be a useful local treatment for nonresectable HCC.

[Intra-hepato-arterial chemotherapy combined with hyperthermic treatment: clinical results of metastatic cancer of the liver and effects on correct (but not at all necessary) hepatic blood flow].

In treating cancerous metastases to the liver, we combined hyperthermic treatment with chemotherapy via the intra-hepato-arterial injection (IHAI) of cis-diamminedichloroplatinum (II) plus 5-fluorouracil. The subjects were 14 patients having metastases to the liver: 3 from gastric cancer and 11 from colorectal cancer. In metastases of colorectal origin, the response rate (partial response) was 55%; the 1-year survival rate was 80%; the 50%-survival period was 23 months. The response rate and the 50%-survival period in metastases of gastric origin were 67% and 11 months, respectively. When IHAI chemotherapy was combined with hyperthermic treatment, antitumor effects were generated in 3 of 6 metastatic patients from colorectal cancer, who had received no benefit from the IHAI chemotherapy alone. Better results were produced by thermochemotherapy than by IHAI chemotherapy alone. Hepatic blood flow, which influences the antitumor effect of hyperthermic treatment or chemotherapy, was measured using the 133Xe clearance method. Over the long term, the hepatic blood flow, especially that of the portal-venous route, showed a decreasing tendency after repeated sessions of the present regimen. This fact suggests the increased retainability of arterial-injected carcinostatics in cancerous tissues.

[Short-term intensive chemotherapy (STIC) combined with intravenous hyperalimentation in advanced stomach cancer].

A short-term intensive chemotherapy (STIC) consisting of large dose of mitomycin C (MMC), tegafur (FT-207), streptococcus preparation picibanil (OK-432) and Krestin (PSK), combined with IVH was performed in 72 patients with advanced gastric cancer. Thirty-three patients were unresectable and 39 patients were recurrent. In this modality, an intensive chemotherapy was able to carry out, maintaining, or increasing in host immunologic parameters and body weight in spite of their disturbed condition in oral food take. Partial response was obtained in 10 of 51 evaluable cases (19.6%) and the survival period on STIC was superior to that on controls. However, no significant difference was observed between the two groups. Four patients had become to be able to take full oral food again by STIC and resulted in the removal of IVH. Hyperglycemia and septicaemia induced by IVH were observed in 9 of 72 patients (12.5%), one died of septicaemia. Full attention should be paid in the management of IVH for patients with advanced cancer.

[Hepatic arterial chemotherapy combined with hyperthermia or arterial embolization in unresectable liver tumor].

Fifty-four patients with unresectable malignant liver tumors (14 of hepatocellular carcinoma, 40 of metastasis to the liver from gastric or colo-rectal cancer) were treated with intra-hepato-arterial (IHA) injections of cis-diamminedichloroplatinum (II) (CDDP) plus 5-fluorouracil (5-FU). In 32 of the patients, the liver tumors were detected synchronously with the diagnosis of the primary cancers, which were resected palliatively. Therapeutic schedules consisted of bolus injections of CDDP (50 mg/body/week) and 5-FU (250 mg/body/day) [Regimen I], and CDDP (50 mg/body/10-14 days) and 5-FU (100 mg/body/day) [Regimen II]. In 48 patients treated with IHA chemotherapy only, a partial response (PR) was obtained in 6 of 14 (43%) evaluable patients for Regimen I and in 11 of 30 (37%) patients for Regimen II. The dose-limiting factor for treatment with CDDP was bone marrow toxicity, but this toxicity was remarkably alleviated in Regimen II without any decrease in antitumor effectiveness. In 13 patients, other modalities, such as total-body hyperthermia (4 patients), radiofrequency capacitive local hyperthermia (5), and temporary arterial embolization (4), were combined with IHA chemotherapy. PR was obtained in 7 of 13 (54%) patients with the combined therapy. This combined therapy was efficacious in 7 patients in whom no desired results were obtained by IHA chemotherapy only. The survival rate was 50% at 12 months. IHA chemotherapy with CDDP plus 5-FU, especially when according to Regimen II, appears to be a strongly recommended strategy for treatment of unresected primary or metastatic liver tumor. Further, addition of the hyperthermia or the arterial embolization might enhance the antitumor effect of IHA chemotherapy.

[Clinical results and problems of total-body thermochemotherapy].

The clinical results and problems of extracorporeally-induced total-body thermochemotherapy (TBHT) for recurrent cancer are presented. A total of 127 hyperthermic treatments were performed in 45 patients who had undergone unsuccessful conventional systemic anticancer chemotherapy. Partial response was observed in 11 of 34 evaluable patients (32%). In analysing the anticancer effects of TBHT according to cancer site, a high efficacy was observed in patients with their main tumor in the lung, liver and lymph nodes. The anticancer effects were most enhanced when TBHT was performed in combination with cisplatin and 5-fluorouracil. In order to augment the anticancer effects of TBHT, the choice of combined agents and administration timing are important. A useful method for determining the thermochemosensitivity of individual cancer cells to agents selected for drug treatment is the human tumor clonogenic assay. Furthermore, the usefulness of angiotensin II-induced hypertensive chemotherapy during TBHT for augmenting selective drug delivery to cancer tissue is stressed.

[Effects of prophylactic intraportal chemotherapy on liver function, blood profile and survival in patients with colo-rectal cancer].

Postoperative intraportal anti-cancer chemotherapy was used for 51 patients with curatively resected colorectal cancer who were selected in the randomized controlled study to evaluate its inhibitory effect on liver metastasis from colo-rectal cancer. In cases of intraportal chemotherapy, 30 mg of Mitomycin-C (in 3 doses) and 5 mg/kg (B.W.)/day (1985-1986) or 3 mg/kg/day (1987-1988) of 5-FU was injected through the catheter inserted into the portal vein during postoperative 14 days. In cases of the control group (58 patients), the same doses of the drugs were injected into the peripheral vein during the same term. Six patients with recurrences were observed in the intraportal chemotherapy group, and 3 of them had liver metastases. In the control group, more liver metastases were observed (5 of 7 recurrences were liver metastases). Intraportally injected 5 mg/kg/day of 5-FU slightly disturbed the liver function. The averages of the serum GOT, GPT and gamma-GTP level of these cases were higher than those of the control cases. Three mg/kg/day of intraportally injected 5-FU had no influence on the liver function. There were no differences in the incidence of leukocytopenia or thrombocytopenia between the two groups.

[Serum levels of mitomycin C following a high-dose continuous hyperthermic peritoneal perfusion].

Valid therapeutic means have not been established for treatment of disseminated peritoneal metastasis of carcinoma. Continuous hyperthermic peritoneal perfusion (CHPP) with high-dose of mitomycin-C (MMC) was applied to 26 patients with peritoneal metastasis from gastric, rectal or ovarian cancers. Levels of MMC in the sera and in the perfusate were measured. The results obtained were: 1. Approximately a half of the dose of MMC added into the perfusion fluid was recovered. 2. When perfused with 100 mg of MMC, the maximum serum concentration of MMC was equivalent to 1/3 of the maximum serum level when injected with 10 mg of MMC intravenously. Therefore, MMC which could not be detected in CHPP seemed to be retained in the abdominal cavity. 3. Bone marrow inhibition caused by CHPP was observed in only 2 of 26 patients. 4. The total dose of 300 mg of MMC, consisting of the maximum dose of 100 mg each, is acceptable in CHPP without any severe side effect. 5. CHPP exerts antitumor effects when utilizing hyperthermia and a high-dose of MMC on the disseminated peritoneal foci of carcinoma.