Post-operative adjuvant chemotherapy for colorectal cancer with 5-fluorouracil (5-FU) infusion combined with 1-hexylcarbamoyl-5-fluorouracil (HCFU) oral administration after curative resection.

BACKGROUND: Although surgical resectability is an important prognostic factor, recurrences are commonly noted in advanced colorectal cancer patients, even after apparently curative surgery. Since such recurrences cannot be cured, better adjuvant chemotherapies are urgently required. PATIENTS AND METHODS: We studied the effect of post-operative chemotherapy using oral administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) with 5-fluorouracil (5-FU) infusion for curatively-resected Stage IIIa and IIIb colorectal cancers. This study was prospectively randomized and controlled and 314 (97.8%) out of 321 patients were determined to be candidates for statistical assessment. Group A and Group B received 5-FU intravenous injection at, respectively, 333 mg/m2 and 1000 mg/m2 body surface area/24 hours continuously for 72 hours beginning on post-operative day 0 and day 6, with oral HCFU 300 mg daily for 52 weeks beginning 2 weeks after surgery. RESULTS: There were no differences in overall 5-year survival or disease-free survival between Group A and Group B. A retrospective subset analysis. however, suggested that the protocol of Group B tended to yield better 5-year survival (68.3%) for rectal cancer than that of Group A (58.8%). CONCLUSION: Inductive therapy with high-dose 5-FU in combination with oral HCFU appears to be beneficial as adjuvant chemotherapy for advanced rectal cancer with lymph node metastasis.

[Interim report of JFMTC study no. 20 on the effectiveness of high dose CDDP plus 5-FU regimen as an adjuvant therapy for far-advanced cancer of the stomach].

This interim analysis of the JFMTC study as of May, 1998 covers 321 gastrectomized patients with far-advanced stomach cancer from 135 institutions between November, 1993 and March, 1996. The intensive therapy group (I-group) received CDDP i.p. administration on resective surgery with 70 mg/m2 followed by CDDP i.v. of 80 mg/m2 (day 1, i.v.), accompanying 5-FU of 350 mg/m2/day (day 1-5, c.v.i.) in the 4th, 8th and 12th weeks. The I-group was randomly compared with the standard therapy group (S-group) of MMC of 6 mg/m2 i.v. in the 4th, 8th and 12th weeks and UFT of 3-4 capsules daily for postoperative one year. The results obtained were that 1. adverse reactions were found more in the I-group than in the S-group, particularly notable in the decrease in blood cells, loss of appetite and nausea/vomiting, and incidence of grade 3 or more being 13% (neutrophile leukocytes), 26% and 21%, respectively; 2. there was no significant difference between I- and S-groups in terms of 3-year survival or disease-free survival rates. (JFMTC: Japanese Foundation of Multidisciplinary Treatment for Cancer).

[Usefulness of percutaneous low output microwave tissue coagulation therapy for solitary liver cancer].

The possible use of percutaneous transhepatic low output microwave tissue coagulation therapy (PMCT) using ultra-sonography under local anesthesia for solitary liver cancer was studied. The subjects were 13 patients having primary or metastatic liver cancer with solitary liver tumor less than 3 cm in diameter, including 7 hepatocellular carcinomas and 6 metastatic liver cancers. PMCT was performed continuously 3 times at an output of 30 watts for 30 seconds at a time. Tumors less than 3 cm in diameter were completely coagulated by irradiation from 2 to 6 times, judging by enhanced CT. No tumor recurrence was recognized in the coagulation area. However, in two cases of metastasis from pancreatic carcinoma, multiple metastases were found at another site in the liver by 2 months after PMCT. Thus, the results suggest that PMCT is a useful therapy for small liver tumor as a local control.

Clinical evaluation of adjuvant chemoradiotherapy with CDDP, 5-FU, and VP-16 for advanced esophageal cancer.

OBJECTIVES: The aim of this study was to evaluate the efficacy of adjuvant chemoradiotherapy following surgery in patients with advanced esophageal cancer. SUBJECTS AND METHODS: We followed the cases of 57 such patients treated at our hospital, involving 19 who received adjuvant chemoradiotherapy (CR group), 19 who received radiotherapy alone (R group), and 19 who did received neither (N group). In the CR group, chemotherapy, consisting of cis-diaminodichloroplatinum (CDDP), 5-fluorouracil (5-FU), and etoposide (VP-16), was combined with radiotherapy was administered from 4 weeks after surgery. Concurrent radiotherapy was started at 3 weeks after esophagectomy. CDDP at 50 mg/m2 was administered on days 1 and 7.5-FU at 500 mg/m2 and VP-16 at 60 mg/m2 were administered on days 3, 4, and 5. Thirteen patients (68.4%) were treated with more than 2 cycles of chemotherapy combined with radiation. RESULTS: Side-effects of severe anorexia (grade 3) and leukocytopenia (< 1900/microliter) were observed in 47% and 39% of the patients, respectively. However no treatment-related death was observed. The 5-year-survival rate was 25.2%, 18.9%, and 15.8%, in the CR group, R group, and N group, respectively. The recurrence rate was 66.7% in the CR group, which was higher than in the matched control groups (46.2% in the N group and 54.5% in the R group), but with no a significant difference. CONCLUSION: These results suggested that adjuvant chemoradiotherapy did not contribute to improvement in prognosis for these patients with advanced esophageal cancer.

[Usefulness of percutaneous microwave tissue coagulation therapy for solitary liver cancer].

The possible use of percutaneous transhepatic microwave tissue coagulation therapy (PMCT) using ultra-sonography under local anesthesia for solitary liver cancer was studied. The subjects were 8 patients having primary or metastatic liver cancer with solitary liver tumor less than 4 cm in size, consisting of 2 hepatocellular carcinomas, and 6 metastatic carcinomas. PMCT was performed continuously 3 times at the output of 30 watts for 30 seconds at a time. Tumors less than 3 cm in size were completely coagulated by irradiation from 2 to 5 times judged by enhanced CT. No recurrence of tumor was recognized in the coagulation area. But in some cases, multiple metastases were found at another site in the liver by 3 months after PMCT. Thus, the results suggest that PMCT is a useful therapy for small liver tumor as a local control.

Selection of adjuvant chemotherapy for gastric cancer using objective criteria.

Precise prediction of recurrence risks is of importance in the selection of adjuvant chemotherapy. A proportional hazards regression analysis was performed to seek objective criteria for 234 gastric cancer patients. The analysis showed that a high level of carcinoembryonic antigen (CEA) in peritoneal washing (100 ng/g protein) was an independent risk factor for peritoneal recurrence, and a high MMP9 (92 KD type IV collagenase) level in serum was a powerful indicator of hematogenous recurrence. In addition, the PHREG analysis in 1453 gastric cancer patients showed that MF therapy (mitomycin C i.v. + fluoropyrimidine derivatives) and PF therapy (Cisplatin i.p. + fluoropyrimidine derivatives) might be effective in the prevention of hematogenous and peritoneal recurrence after a curative operation, respectively. Based on these findings, a recurrence type-oriented adjuvant chemotherapy, i.e., PF therapy for high CEA group and MF therapy for high MMP9 group, was designed. The retrospective analysis showed significant survival benefit in stage III gastric cancer patients who underwent a curative operation. The 5-year survival rate was 67%, while that of the historical control was 46%. Prediction of recurrence type using CEA levels in peritoneal washings and MMP9 levels in sera may be of value in the selection of a proper population of patients for PE or MF therapy after gastrectomy. The selection system of adjuvant chemotherapy using such objective criteria may improve the prognosis of gastric cancer patients and keep their good quality of life through the selection of proper candidates and by eliminating patients in no need of therapy.

[Progress of adjuvant chemotherapy in colon cancer].

There have been no life-prolonging effects of surgical adjuvant chemotherapy with 5-FU alone or in combination with chemotherapeutic drugs, so surgical resection has been considered a standard therapy for colorectal cancer. Recently, clinical trials of modulation therapy with 5-FU and leucovorin showed higher efficacies in advanced colorectal cancer, and significant prolongations of survival time and disease-free interval were reported in a randomized trial of 5-FU and leucovorin for postoperative adjuvant therapy of resected colon cancer. Moreover, in a scientifically well controlled randomized study with 5-FU and levamisole, the significance of this regimen for Dukes C colon cancer has been shown for standard adjuvant chemotherapy.

Clinical usefulness of an ATP heat sensitivity test using endoscopic biopsy materials from esophageal cancer patients.

The usefulness of a heat sensitivity test which involved performing an ATP assay on endoscopic biopsy materials for predicting the clinical response to hyperthermia was investigated in esophageal cancer patients. Following in vitro heat treatment of FM3A tumor cells, the heat sensitivity detected by ATPA was significantly correlated with that in the colony-forming assay, and the percent inhibition of the ATP level in the tumor cells was correlated with in vivo tumor growth. The heat sensitivity of the biopsy materials evaluated by ATPA correlated well with that of the resected specimens in 18 esophageal cancer patients, while the clinical response to thermal therapy was well predicted by the heat sensitivity of the biopsy materials evaluated by ATPA in seven of the patients. These results indicate that the heat sensitivity test conducted by performing an ATPA on endoscopic biopsy materials could be a useful indicator for predicting the clinical response to thermal therapy.

Chemotherapy combined with or without hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial.

From 1990 to 1991, 40 patients with squamous cell carcinoma of the thoracic oesophagus were admitted to our institutions and chemotherapy (oil Bleomycin p.o. and CDDP d.i.v.) either combined with or without hyperthermia was performed, in a prospective randomized trial carried out to investigate the effects of hyperthermia. The two groups (group A, consisting of 20 patients given chemotherapy alone; and group B, made up of 20 given chemotherapy with hyperthermia) were comparable with regard to various prognostic factors. Following the above treatment regimens, an oesophagectomy was done in 16 and 17 patients from groups A and B, respectively. A subjective improvement of dysphagia was seen in 8 (40.0%), and in 14 patients (70.0%), while a radiographic improvement was recognized in 5 (25.0%) and 10 cases (50.0%) in groups A and B, respectively. In the resected specimen of 16 (group A) and 17 patients (group B), histopathological evidence of the effectiveness of the treatments were recognized in 3 (18.8%) and 7 (41.2%) from groups A and B, respectively. Excluding the cases of superficial carcinoma (T1 tumour), histologic effectiveness of the treatments were recognized in 2 (14.3%) and 7 (58.3%) in groups A and B, respectively (p < 0.05). There was no difference in the occurrence of side effects between the groups. Therefore, the clinical and pathological effects were favourable in the hyperthermia combined with chemotherapy group, especially in the cases with advanced oesophageal cancer.

[Intra-arterial infusion chemotherapy of cisplatin (CDDP)-lipiodol suspension using implantable injection port for unresectable liver cancer patients].

Intra-arterial CDDP-Lipiodol infusion chemotherapy using an implantable port was effective in 10 unresectable liver cancer patients, including 7 hepatocellular and 3 metastatic cases. CDDP-Lipiodol suspension (10 mg of CDDP/1 ml of Lipiodol) was administered at the dose of 25 mg/m2 of CDDP biweekly from 2 to 9 times. The clinical responses were defined as 4 PR (40%), 5 NC (50%), including 3 MR, and 1 PD (10%). The efficacy rate was 40%. The level of AFP and CEA was reduced in all PR and NC cases except one. Side effects were nausea (70%), low-grade pyrexia (50%), abdominal pain (30%), and liver dysfunction (20%), but they were tolerable and transient.

A new experimental trial using repeated heating every 24 hours for local hyperthermic therapy with bleomycin in vivo.

This report presents the effect of repeated heating every 24 hrs using bleomycin (BLM) which, although seemingly contrary to the usual agreement that hyperthermia should be carried out with a long interval due to thermotolerance, holds many possibilities. FM3A cells on the foot pad of C3H mouse were immersed in a heated water bath at 43 and 44 degrees C for 30 min. The effect of repeated heating was appreciated by an improved growth curve and 50 day survival compared to mice which received heating twice with a 96-hr interval. Repeated heating every 24 hrs 5 times with BLM suppressed tumor growth significantly as compared to heating twice with a 96-hr interval without BLM. The longest survival time was obtained by the repeated heating with BLM among all protocols. There is therefore a good possibility that more effective results could be obtained clinically by repeated heating over a short period.

Antitumor effect of KW2149, a new mitomycin derivative, administered by different modalities.

The effectiveness of a new mitomycin derivative, KW2149, against human tumors was evaluated by the 4 days subrenal capsule assay (SRCA) and the nude mice screening assay (NMSA). Evaluation by the SRCA showed a 50% response rate at a maximum dose of 3.8 mg/kg for 3 consecutive days. When evaluated by NMSA, the response rate was 100, 75 and 25% after the intermittent administration of 7.5, 5.6 and 4.5 mg/kg (q4dx3) respectively. Although the efficacy was reduced when mice were administered a single dose equivalent to the intermittent one, the new analog was along more effective than MMC administered by either modality.

[Submucosal injection of lipiodol-bleomycin in esophageal cancer].

Submucosal injection of Lipiodol-bleomycin (BLM) for esophageal cancer is complementary to CT scan in preoperative determination of the depth of the cancerous invasion in the esophageal wall. This procedure was performed not only for diagnosis but also as a preoperative therapy in 109 cases with esophageal cancer in Hiroshima University Hospital. The Lipiodol-BLM suspension was prepared by mixing 45 mg BLM and 5 ml Lipiodol on a clean bench. The mixture was usually injected into the submucosal layer of the esophagus using fiberscopy 12 days before the operation. BLM concentration was measured in the primary tumor, normal esophageal tissue around the tumor and regional lymph nodes in the specimen in 14 cases. As a result, a low level of BLM had been maintained in these tissues for a long time. The concentration of the primary tumor was 4 times higher than that of the normal esophageal tissue. In order to predict the side effects of BLM, such as pulmonary fibrosis, the change in serum BLM level was measured in 12 cases. Serum BLM decreased to an unmeasurable level 24 hours after the injection. Thus, the submucosal injection of lipiodol-BLM for esophageal cancer seems to be promising for a targeting cancer chemotherapy.

Bypass operation for advanced esophageal cancer--an analysis of 93 cases.

From 1973 to 1987, 235 patients with esophageal squamous cell carcinoma were treated at Hiroshima University. Of these patients, 121 (51.5 per cent) were submitted to esophagectomy, 93 (39.6 per cent) to bypass surgery and 21 (8.9 per cent) to either exploratory or no surgery. In this report, the 93 cases who underwent bypass surgery were analysed. Ten patients died within thirty days after their operation (10.8 per cent) and there were 33 cases of hospital death (35.5 per cent). Following the bypass surgery, 49 (59.0 per cent) cases were able to tolerate over 50 per cent of their normal oral intake and 22 cases (26.5 per cent) were able to tolerate between 25 per cent and 50 per cent. For twelve cases (14.6 per cent), however, oral ingestion proved impossible up until the time of death due to such complications as leakage. The overall survival rates were 44.3 per cent at 6 months, 12.7 per cent at 1 year and 2.8 per cent at 5 years, respectively. Two cases survived for over 5 years. Hyperthermia was applied in combination with chemotherapy from 1981, however, no case survived for over one year without radiation therapy. Recently, radiation plus hyperthermia is being performed in combination with immunochemotherapy.

[Multidisciplinary treatment of unresectable liver cancer].

From January 1984 to December 1987, 63 unresectable liver cancers (22 hepatocellular carcinoma and 41 metastatic liver cancer) were treated with multidisciplinary therapy: partial resection of liver, hepatic arterial infusion, coagulation therapy using microwave tissue coagulator and intratumoral injection of the liver. The median survival period was 5-7 months, and the clinical response rate was 21.6% in these therapies, but there was no statistically significant difference between the treatments. Recently, we usually use degradable starch microspheres (DSM) with anticancer agents in hepatic arterial infusion. Adriamycin + DSM was administered for hepatocellular carcinoma, and Mitomycin C + DSM was used for metastatic liver cancer. The regimens were used for 12 cases, 6 of hepatocellular carcinoma and 6 of metastatic liver cancer, with a response rate of 50%, respectively. We also undertook chemosensitivity tests for liver cancer. The coincidence of clinical response with results of chemosensitivity tests was above 50%. In future, we shall use the most effective anticancer agents for individual tumors with DSM in arterial infusion.

[Clinical studies on a rapid screening assay for anticancer agents with nude mice and isotopic evaluation].

A rapid method using nude mice has been established as an in vivo model for assessing the chemosensitivity of individual human tumors, in which the final evaluation is made with 3H-thymidine (3H-TdR) incorporation into the treated tumor. In 234 of 289 cancers, the chemosensitivity of anticancer agents was evaluated by this method. This assay proved to be feasible in a sufficiently high percentage of human primary tumors (81.0%). The rate of positive sensitivity against all tumors was 23.8% for MMC, 12.3% for 5-FU, 29.1% for CPM and 23.5% for ADM, respectively. The sensitivity of anticancer agents varied according to the type of cancer. Correlation between the sensitivity test and the end results after chemotherapy in cases of inoperable gastrointestinal cancers was investigated, prospectively. Out of 19 cases, the 50% survival time of 11 patients treated with sensitive agents was longer than that of 8 patients treated with insensitive agents. From a prospective-correlative study carried out on 25 patients, this assay appeared to be correlated with clinical response (overall agreement, 76.0%) with specific agreements of sensitivity and resistance of 37.5% and 94.1%, respectively. From these results, it seems reasonable to conclude that this sensitivity test using a human/nude mouse system is a useful screening assay for revealing appropriate agents for the treatment of patients with cancer.