In twenty-nine cases of primary breast cancer preoperative treatment using CPA and FT-207 (or 5-FUDS) was performed to determine their efficacy. Daily dose of each anticancer drugs was as follows: CPA 50-200 mg, FT-207 200-600 mg, 5-FUDS 200 mg, p.o.. The total doses were CPA 1.8 g, FT-207 5.0g, 5-FUDS 3.4 g in average. In 11 cases (37.9%) reduction in tumor size was obtained. According to Ohboshi's criteria, over Grade II a effect was seen in 5 cases (17.2%), while Grade III effect was not seen in any of the cases. Effective cases were more frequently observed among those which received CPA at 25 mg/kg or more, or FT-207 (5-FUDS) at 80 mg/kg or more. Main side effects were G. I tract symptoms such as anorexia and nausea. To obtain definitive conclusion on the clinical significance of use of CPA and FT-207 (5-FUDS) as preoperative chemotherapy for breast cancer, further studies are required.

A randomized controlled study by envelope method was carried out with the purpose of evaluating effects and side effects of levamisole in patients with resectable stomach cancer. The patients were randomly allocated to the treatment either with control or levamisole according to the indication of the envelope opened at least 3 days prior to surgery. The control group was treated with Mitomycin C (day 0, 20 mg day 1, 10 mg, one shot i.v.) and 5-FU(150 mg/day, p.o.). The levamisole group was treated with Mitomycin C, 5-FU and levamisole. Levamisole was administered at a daily dose of 150 mg for 3 consecutive days before surgery, and the 3 consecutive days administration schedule was repeated every fortnight for one year after surgery. Four hundred and forty-six patients were entered in this trial. However, with the exclusion of 104 patients as exceptions and dropouts, the total eligible patients were 342, consisting of 167 in the control group and 175 in the levamisole group. The effects were evaluated by comparing the disease-free interval or the survival time of both groups. There was no significant difference in the disease-free interval and survival. In this study, we have not yet reached the conclusion that levamisole is effective in prolonging disease-free interval and survival time, because high survival rates are still maintained in both groups for 2 years after surgery. The final conclusion would be drawn with the follow-up results in the future.

The effects of levamisole used in combination with Mitomycin C and Tegafur in patients with resectable stomach cancer were investigated in 10 cooperative institutes. The patients were randomly allocated to the treatment with either control or levamisole by envelope method. Levamisole group was treated with Mitomycin C (day 0, 20 mg, day 1, 10 mg, one shot i.v.), Tegafur (600 mg/day, p.o.) and levamisole (150 mg/day, p.o.). Levamisole was administered 3 consecutive days prior to surgery, and 3 consecutive days every fortnight after surgery. The control group was administered Mitomycin C and Tegafur. The both drugs were administered by the same method as above. Two hundred and twenty-two patients were entered in this trial. However, with the exclusion of 67 patients, the eligible patients were 155, consisting of 77 in the control group and 78 in the levamisole group. In stage III patients, the disease-free interval and survival time were significantly prolonged in the levamisole group compared to the control group (generalized Wilcoxon test p less than 0.05). The side effects were observed a little more frequently in the levamisole group. However, there was no significant difference. From this result, it can be considered that levamisole is effective in delaying recurrence and in prolonging survival time of the patients when used in combination with adjuvant chemotherapy after resection of stomach cancer.

The purposes of this work were twofold: firstly to determine whether intratumor chemoimmunotherapy was more effective than either treatment alone or systemic therapy and; secondly to study how the intratumor therapy affected on the development of the tumor-specific immunity. Inbred male C3H/He mice and mouse ascited hepatoma 134 (MH 134) of C3H origin were used as host-tumor system. Mitomycin C was used as the chemotherapeutic agent and BCG as the immunopotentiating agent. Intratumor treatment of MMC + BCG led to complete cure in 85 percent of the mice. The lymph node metastases were markedly inhibited in the group treated with MMC + BCG compared to the groups treated with MMC alone or BCG alone. The growth of rechallenged tumor was investigated; 79% of mice treated with MMC + BCG were immune to rechallenge, whereas 57% of mice treated with BCG alone. The number of PFC and DTH against SRBC of the mice treated with MMC intraperitoneally significantly decreased compared to that treated with MMC intratumorally.

This study was conducted to determine efficacy of FT-207 to prevent hematogenous peri-operative metastasis of lung cancer. A total of 16 patients consisting of 10 with squamous cell cancer, 6 with adenocarcinoma were evaluated in this study. The protocol of this study consisted of the pre-and peri-operative chemotherapy, giving 1000 mg of FT-207 suppository daily for 10 days. 5-FU plasma concentration in the systemic circulation during surgery was 0.01 mcg/ml. 5-FU tissue concentration of the normal lung was 0.07 mcg/g, and cancerous tissue (squamous cell ca 0.11 mcg/g, adenocarcinoma 0.12 mcg/g), and lymph nodes 0.15 mcg/g. It was found in this study that the pre-and peri-operative adjuvant chemotherapy with FT-207 was effective to prevent operation-induced hematogenous metastasis of lung cancer.

The pancreatic duct cell adenocarcinoma induced by di-isopropanol nitrosamine could be easily and repeatedly transplanted into the subcutaneous or pancreatic tissues of the homologous animals. We established a tumor bearing animal design in which tumor tissues were transplanted simultaneously into subcutaneous and pancreatic tissues. At the first week after the transplantation, the animals were divided into three groups: In FT group FT-207 was given at a dose of 15 mg/kg/day, in UFT group FT-207 and uracil were given at a dose of 3 mg/kg/day and; 6.7 mg/kg/day (molar ratio; 1:4), respectively and in control group a solvent of FT-207 was given. In all groups the drugs were administrated orally for ten days. The size of tumors transplanted in subcutaneous and pancreatic tissues increased more slowly in FT and UFT groups, as compared with that of control group. The inhibitory effect on tumor growth observed in UFT group was more striking than that in FT group. No major side effects were observed in all groups. At the fourth weeks after subcutaneous and intrapancreatic transplantation, the animals were divided into two groups: In FT group FT-207 was given at a dose of 30 mg/kg and in UFT group FT-207 and uracil were given at a dose of 30 mg/kg and 67.2 mg/kg, respectively. In both groups the drugs were given orally, and at one hour after the administration all the animals were killed to determine 5-FU concentration in various tissues. The 5-FU concentrations of subcutaneous and intrapancreatic transplanted tumor tissues were significantly higher in UFT group than those in FT group. UFT therapy, therefore, seems to be hopeful for the treatment of human pancreatic cancer.

CAM is a derivative compound of mycophenolic acid produced by Penicillium brevicompactum, and is a new oral Purine antagonistic anticancer agent. The Phase I study was carried out cooperatively in ten hospitals. The results are as follows: The administration method was single administration and the starting dose was 200 mg/m2 (1n). The dose level was escalated according to varied Fibonacci formula. The number of total cases was thirty-one: three cases at 1n level, four at 2n, six at 3.3n, six at 7n and seven at 9n. Side effects were observed in five of thirteen cases over 7n dose levels, such as nausea, vomiting, anorexia and diarrhea. Leukopenia was developed in only one case at 7n dose level. Other side effects such as anemia, thrombocytopenia, and disturbances of liver function and renal function were not observed. It was estimated from above results that a dose limiting factor of CAM is nausea and vomiting. A subtoxic dose was 7n (1,400 mg/m2) and a maximum tolerated dose was 9n (1,800 mg/m2) which corresponded to 2,200-3,000 mg as a single administration.

This study, based on a co-operative group project involving 4 major medical institutes in Japan presents the first survey of malignant melanoma (MM) patients (157 cases) where an attempt was made to systemically evaluate the distribution of primary MM, and the response to DAV-chemoimmunotherapy. The distribution of primary MM in Japan is unique in a sense that the MM involving the lower extremities occupied more than 50% of the total male and female cases. The commonest type and site of involvement is the acrolentiginous MM involving the plantar area (30%). The regimen of our group included the combination of DTIC, VCR and ACNU, a new nitrosourea with or without immunoadjuvants OK-432, PSK, or NK-421). By a historical comparison, the DAV-treated group showed a better prognosis in the survival rates of overall (Stages I-IV) and disseminated (Stages III-IV) patients than those of the non-DAV group. However, the effect of combined immunoadjuvants was not statistically significant, though OK-432 showed a significant inhibition of lymphopenia which always occurred during DAV therapy.

The current status of treatment for multiple myeloma was reviewed. Recently, the response rate and survival for patients with multiple myeloma have improved with an introduction of combination chemotherapy. The addition of prednisolone to the regimen including alkylating agents clearly improved a response rate by 20% and extended survival by approximately 5 months. More recently, the use of multiple-drug combinations, such as VMCP and VMCBP schedules, seems to yield the best response rate. However, current improvements in survival of myeloma patients cannot be attributed fully to improved chemotherapy on the basis of the findings that the annual incidence and the number of patients with low tumor burden increase progressively, and the patients in the early stage of the disease have a high value for the incidence of long survival. Furthermore, earlier diagnosis, a low frequency of severe renal failure, and superior control of infections may likely influence the duration of survival. In order to cure the malignant tumor disease, it is necessary to eradicate every viable tumor cell in the host. Unfortunately, the most recently utilized combination chemotherapy has shown little evidence of permanent cure of multiple myeloma, even in patients with low tumor burden, i.e., effective treatment with currently available agents causes only an initial 1-2 log fall in the total body myeloma cell mass and an additional treatment does not reduce the residual tumor cell mass. Therefore, further studies of new drugs with major activity against plasma cell myeloma are expected.

Forty years ago, nitrogen mustard was first used in the treatment of a group of six patients with neoplastic diseases, including lymphosarcoma and Hodgkin's disease at Yale University. Since then different kinds of chemotherapeutic agents have been discovered, which clinical efficacy was reviewed as a single agent and in combination. Especially over the past two decades, the management of malignant lymphoma has improved significantly with combination chemotherapy. Now there are several potentially curative regimens, such as MOPP therapy for Hodgkin's disease, and MOPP (or C-MOPP), CHOP (or HOP), BACOP and COMLA for diffuse histiocytic lymphoma. There are recent trends to include methotrexate in combination and to use two non-cross-resistant regimens alternatively (CVP/ABP, MOPP/ABVD) for improving complete remission rate and remission duration. Treatment for favorable histologies, and clinical features and treatment of adult T-cell leukemia lymphoma were also briefly reviewed.

A case of erythroleukemia coexistent with pulmonary emphysema is reported. A 67-year-old male was admitted to our hospital in May 1981, with a few year history of cough, sputum and fatigue. He had already been diagnosed as having pulmonary emphysema and moderate anemia. On physical examination, except for pallor, no other findings were remarkable. The initial hematological examination showed hemoglobin, 9.6 g/dl, red cell count, 251 x 10(4)/microliters, platelet count, 7.3 x 10(4)/microliters, white cell count, 2600/microliters with neither myeloblasts nor erythroblasts. A sternal marrow aspiration revealed 21% myeloblasts and 40% erythroblasts including 7.5% megaloblastoids. Periodic Acid Schiff staining was strongly positive for a part of erythroblasts. A chest X-P finding was typical for pulmonary emphysema. Pulmonary function was moderately damaged. He was started on chemotherapy with AAAP (ACNU 50 mg/d i.v. drip over 4 hr x 4d, adriamycin 20 mg/d i.v. push x 4d, Methotrexate 20 mg i.v. push x 4d). The first course of AAAP brought him a complete remission with both disappearance of myeloblasts and erythroid precursors with megaloblastoid nuclei in the marrow and the normalization of white cell count and platelet count in the blood. He was discharged in September 1981 after completion of a consolidation chemotherapy with AAAP. Since then, he received two courses of AAAP as an intensification chemotherapy and has been in complete remission for more than 13 months. His pulmonary function has not been affected and no myocardial damage has been seen throughout AAAP therapy. Thus, AAAP therapy seems to be an excellent chemotherapy even for an aged patient with erythroleukemia.

Chemotherapy for chronic myelogenous leukemia is divided into two parts; chronic phase and blastic phase. The most distinguished new attempt for chronic phase in recent years in the former was the L-15 protocol, intensive multicombination chemotherapy by Clarkson and his group, which destroyed a large fraction of the leukemic population and permitted repopulation of the marrow with predominantly Ph1-negative cells in about half of the patients. However, most of the complete remissions were of short duration. On the other hand, much progress has been made in the chemotherapy for blastic phase cases. Using a combination chemotherapy of vincristine and prednisolone, over one-third of the patients with CML in blastic crisis have achieved a complete remission. Survivors over one year from the blastic crisis are rapidly increasing in recent years. Chemotherapy for chronic lymphocytic leukemia at the stage III of Rai's staging is recommended to start with chlorambucil, cyclophosphamide or corticosteroids.

Present status of chemotherapy for acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) was reviewed. In ALL, a 2-drug combination consisting of vincristine and prednisone (VP) obtained an overall complete remission rate of approximately 50% and when daunomycin or adriamycin was added to the regimen, the overall remission rate escalated to approximately 70%. Furthermore, L-asparaginase appeared to have a similar activity to the anthracyclines in combination with VP. Thus, VP plus one of these agents seemed to be a recommendable inductive chemotherapy against ALL. In CLL, remission rates obtained by the use of chlorambucil alone were ranged from 45 to 69%, while a 2-drug combination consisting of chlorambucil and prednisone obtained remission rates ranging 38 to 80%. Thus, the combination appeared to have superiority over chlorambucil alone. When this first line chemotherapy fails to obtain remissions, a 3-drug combination consisting of cyclophosphamide, vincristine and prednisone is worthwhile to try as a second line treatment.

Two advantages of the present therapeutic approach were described. Firstly, a selective deposition of lipiodol in tumor tissue was verified, thus more precise and accurate diagnosis by X-rays was possible either by CT or plain X-ray film. Secondly, pronounced accumulation of smancs in tumor tissue was observed, which established highly effective chemotherapy of unresectable hepatoma of 22 cases and 12 other cases based on (a) decrease in alpha-fetoprotein (86%), (b) tumor size (95%) and histology. Drug was given via the hepatic artery mostly 3-4 mg in 3-4 ml of lipiodol once every 3 to 4 weeks. Most patients have experienced a total dose of 6-8 mg in two cycles, but drug activity lasted more than 3 weeks. Neither hematosuppression nor anaphylaxis was observed. Major side effect was transient fever (38-39 degrees C) in about 50% of the cases which lasted no more than one week. Other minor side effect was abdominal pain during or after arterial infusion which lasted for about 20 min. Liver function was affected very slightly if any. Mild leukocytosis was observed in 65% of the patients.

The antitumor effect and side effects of oral high-dose Medroxyprogesterone acetate (MPA) therapy were studied in 110 patients with advanced or recurrent breast cancer. MPA in 200 mg tablets was consecutively administered at a daily dose of 600, 800, 1,000, 1,200, 1,600, 1,800 or 2,400 mg. The overall response rate was 32/110 (29.1%), and the highest response rate was obtained in the 1,200 mg group (38.2%). The response rate by the site of lesion was higher in the soft tissues and also in bone metastases. Side effects such as moon face, vaginal spotting and abnormal glucose tolerance was mild and tolerable. Accordingly, from the antitumor effect and side effects, the optimal dose was considered to be 1,200 mg a day. Furthermore, as MPA therapy increases appetite and body weight of patients without causing myelopoietic depression, this drug could be used successfully in combination with other chemotherapeutic agents.