Radiation therapy in patients with unresectable hepatocellular carcinoma.

From April 1978 through December 1989, a total of 17 patients with unresectable hepatocellular carcinoma (HCC) were treated with radiation therapy alone or radiation therapy in conjunction with percutaneous ethanol injection (PEI), transarterial infusion chemotherapy (TAI), or transarterial embolization (TAE) at the National Medical Center Hospital. The median survival of all patients was 13.8 months. The survival values determined at 1, 2, and 3 years were 58.8%, 26.1%, and 9.8%, respectively. Only the pretreatment liver function affected the survival value. Between patients who did not have liver cirrhosis (LC) as well as those who had LC of Child's class A and patients who had LC of Child's class B or C, the differences observed in the 1-year survival value and the median duration of survival were statistically significant (P < 0.05). The serum cholinesterase (ChE) level seemed to be a good indicator of liver function during the radiation therapy. A field size of 150 cm2 and a total dose of 5000 cGy (TDF 82) seemed to be well tolerated by patients who did not have LC and those who had LC of Child's class A. The field size determined whether patients with poor liver function such as LC of Child's class B or C would develop severe hepatic deterioration after undergoing radiation therapy.

Radiotherapy of cholangiocarcinoma: the roles for primary and adjuvant therapies.

A total of 22 patients with cholangiocarcinoma who had been treated with external radiotherapy between 1978 and 1989 were analyzed. Of the 22 patients, 18 had cancer of the hepatic hilus (Klatskin) and 4 had intrahepatic biliary cancer; all but 2 of the subjects had advanced disease. In all, 16 patients underwent primary irradiation for unresectable tumors, 4 were subjected to adjuvant irradiation after gross tumor resection, and 2 received preoperative irradiation followed by gross tumor resection. The mean initial irradiation dose was 52.0 Gy (range, 26-78 Gy). The TDF (time-dose-fractionation) for the entire course of radiotherapy ranged from 49 to 154 (mean, 100). The median survival of all patients was 10 months, and the cumulative 1-year survival value was 37.7%. The external radiotherapy proved to be effective in the treatment of cholangiocarcinoma in terms of palliation and survival.

[Therapeutic efficacy of postoperative irradiation on carcinoma of the breast].

From July 1973 to October 1983, 77 patients received mastectomy followed by postoperative irradiation at National Medical Center Hospital. The patients were classified as follows: 9 cases as stage I, 30 cases as stage II, 28 cases as stage IIIa, 7 cases as stage IIIb and 2 cases as stage IV. Irradiation fields were the parasternal and supraclavicular region. The axis of the irradiation fields to parasternal and supraclavicular regions were set up at 3.5 cm from the surface of the body and they were irradiated separately. The irradiation fields were about 0.5 cm apart from each other. Parasternal region contained bilateral parasternal lymphnodes. In some cases, the centersplit was used to prevent the radiation myelopathy. Prophylactic irradiation to axilla was performed by electron beam from October 1974 to September 1977. Prophylactic irradiation to chest wall has not been done since 1973. The five and ten years survival rates of stage II were 93.2% and 86.3%, stage IIIa were 61.9% and 55. 7%, Stage IIIb were 71.4% and 35.7%. The rate of the local recurrence at the supraclavicular region was 0% as stage I, 6.7% as stage II, 0% as stage IIIa and 14.3% as stage IIIb. Among the cases with regional lymphnode involvement at the time of mastectomy, the rate of local recurrence at the supraclavicular region was 6.7% in prophylactic irradiation group and it was significantly lower than in non-prophylactic irradiation group (11.5%) (p less than 0.05). The rate of local recurrence to chest wall was 0% as stage I, 6.7% as stage II, 8.0% as stage IIIa and 42.9% as stage IIIb.(ABSTRACT TRUNCATED AT 250 WORDS)

[Lipiodol transcatheter arterial chemoembolization for non-resectable hepatocellular carcinoma--multicenter cooperative study].

A cooperative group study was carried out on the effect of Lipiodol transcatheter arterial chemo-embolization (L-TACE) for non-resectable hepatocellular carcinoma (HCC). Thirty-seven hospitals in Japan participated in this study and a total of 157 eligible patients included 138 males and 19 females with an average age of 60.3 y.o. In the chemo-embolization, Lipiodol mixed with 20-50 mg/m2 of doxorubicin (adriamycin) was given through a catheter, and this was followed by embolization with gelatin sponge. Effect of additional oral 5-FU (150-200 mg/day) was also studied as an open trial. Levels of serum alpha-feto protein decreased at 10 days after L-TACE, and this decrease lasted for 5 weeks. CR was observed in one patient, PR in 33, MR in 24, NC in 66 and PD in 16. The response rate was 24.3%. Cumulative one-year, two-year and three-year survival rates were 56.0%, 30.8% and 26.4%, respectively. It was concluded that higher survival rates after L-TACE were observed when (1) patients had better functional reserves of the liver, (2) HCC was in the less advanced stage and (3) L-TACE was carried out more than twice. A reduction of the tumor size after L-TACE did not necessarily mean a good prognosis for the patients. There was no significant difference in the survival rate between the patients taking or not taking 5-FU.

Effects of transcatheter arterial chemoembolization with oral chemotherapy on hepatic neoplasms.

An investigation was carried out into the effects of lipiodol-transcatheter arterial chemoembolization (L-TACE) therapy on hepatocellular carcinoma (HCC) and metastatic liver cancer, as well as the effects of oral 5-fluorouracil administration after L-TACE. For L-TACE, lipiodol mixed with adriamycin (doxorubicin) was injected through a catheter inserted into the tumor feeding artery and this was followed by embolization with a gelatin sponge. Twenty national hospitals throughout Japan participated in this multicenter co-operative open trial. A total of 102 patients became the subjects of study, including 75 HCC patients, 12 metastatic liver cancer patients treated with L-TACE, and 15 HCC patients who had hepatectomy after L-TACE. In 22% of the HCC patients and in 42% of the metastatic liver cancer patients, the tumor size was reduced by more than 50% after L-TACE. 73% of the 63 HCC patients showed a more than 50% reduction of the levels of serum alpha-fetoprotein. Although the survival rates of the HCC patients who had a hepatic resection were better than those who had not, there was no statistically significant difference between the survival rates of the HCC patients and those of the metastatic liver cancer patients treated with L-TACE. The survival rates of the HCC patients after L-TACE did not change as a result of oral 5-fluorouracil administration. It was therefore concluded that L-TACE is an effective way of treating both HCC patients and metastatic liver cancer patients, and that repeated L-TACE should be considered for some patients whose serum levels of alpha-fetoprotein rose again after L-TACE. Further follow-up studies will be needed to discover the effects of oral chemotherapy after L-TACE.

Hepatic irradiation in primary and metastatic liver cancer.

Between December 1973 and September 1987, 21 patients with primary liver cancer and 41 patients with metastatic liver cancer were treated with external irradiation, intra-arterial infusion chemotherapy and/or transarterial embolization (TAE) at the National Medical Center Hospital, the National South Kyushu Central Hospital and the National Kure Hospital. Of the patients with primary liver cancer, 13 cases were treated with intra-arterial infusion chemotherapy (30-40 mg adriamycin or 10 mg mitomycin C) and hepatic irradiation. Eight cases were treated by TAE and hepatic irradiation. In the Child A group, the survival period of the chemotherapy + hepatic irradiation cases (mean: 608 days) was longer than that of the TAE + hepatic irradiation cases (mean: 216 days). The median survival period of all the cases was 7.0 months (mean: 10.9 months). For 16 of the 21 patients (who had absorbed over 40 Gy), the median survival period was 11.9 months (mean: 11.7 months). For 5 of the 21 patients (who had absorbed below 40 Gy), the median survival period was 4.3 months (mean: 7.9 months). Of the patients with metastatic liver cancer, the median survival period was 7.2 months (mean: 8.0 months). For 22 of the 41 patients (who had absorbed over 40 Gy), the median survival was 7.9 months (mean: 12.6 months). For 19 of the 41 patients (who had absorbed below 40 Gy), the median survival period was 1.7 months (mean: 2.6 months). The pretreatment serum GOT (glutamate oxaloacetate transaminase) levels and the pretreatment Karnofsky performance status index were the factors governing the prognosis of the cases with metastatic liver cancer, while toxicity was generally mild.

[Effect of intra-thoracic administration of an immune modulator (OK-432) with anti-cancer drugs (ADR and MMC)].

Fourty-three patients with pleuritis carcinomatosa have been treated with an intra-thoracic administration in four distinct ways: Adriamycin alone, OK-432 alone, the combination of Adriamycin with OK-432, or the combination of Mitomycin C with OK-432. Judging from an evaluation of the subsequent chest X-rays, the prognosis of the cases which received the combination therapy of the two drugs was significantly better to that of the others. There were no significant differences between cases with primary lung cancer and those with other cancers. As for the side effects after the administration, there were no side effects, such as the trouble the renal function or liver function, other than fever and a decrease in the W.B.C.

[Study of abscopal effect and cellular infiltration of tumor nests using less-fractionated, large-dose radiation].

As reported by several authors, abscopal effect and favorable cellular infiltrations into the tumor nest caused by irradiation suggest the existence of cell immunity in the host. In our present study, as first step to elucidate the mechanism of the fact mentioned above, effects of radiation with a single dose irradiation was estimated in terms of the increase of survival rate and the inhibition of pulmonary metastasis, i.e. abscopal effect in the mice of irradiated tumor burden. Therefore, we examined the resected and pulmonary specimen after irradiation histopathologically. We also examined the effects of the administration of immune modulator PSK and OK-432. Results; 1) Increase of survival rate and inhibition of pulmonary metastasis were observed in groups of mice with inoculated tumor and with again inoculated tumor treated by a single dose irradiation, compared to either the control groups. 2) Also administration of immune potentiator with radiation enhanced the survival rate and inhibition of pulmonary metastasis in all experimental protocols. 3) Remarkable cellular infiltrations of tumor nest after irradiation were observed, and these cellular infiltrations suggest participation of immunoreaction. In the group of using immune modulator, the cellular infiltrations were observed more remarkable than the other groups. 4) Optimal radiation dose was proved to be 30 Gy in this study.

[Preoperative radiotherapy of brain tumors].

Irradiation prior to radical surgical removal has been performed 51 times in 48 cases of brain tumor over the last 7 years. Through this procedure, all cases have attained good results in both clinical and CT evaluations. In the course of radiotherapy, various doses of corticosteroids and/or ventricular drainage were applied to prevent dangerous brain swelling and hydrocephalus. Total radiation doses were 40-50 Gy in primary cases and 30-40 Gy in recurrent cases. Through this preoperative radiotherapy, tumors showed reduction of their feeding vessels (78.9%) on angiography and/or became necrotized with cyst formation. This facilitated case of surgery and permitted radical resection of these tumors (41%). Especially, in cases of germ cell tumors of mixed type and medulloblastomas, this procedure permitted radical resection in 75% and 100% of cases, respectively. Among glioblastomas and grade 3 astrocytomas, 21.7% were radically resected and the patients involved showed a good relative survival rate. This method may actually facilitate radical cure of malignant brain tumors soon.

[Preoperative radiotherapy of carcinoma of the stomach and breast].

Sixty-one patients with gastric cancer and thirty-seven with breast cancer who had undergone preoperative radiotherapy were analysed retrospectively for assessment of various radiotherapeutic effects and prognosis. Most of the sixty-one patients with gastric cancer were found to be stage III or more with borderline operable lesions on admission. Of the sixty-one patients, sixteen were evaluated postoperatively to be stage I by histopathological examination. The 3-year survival rate in these sixteen patients was an admirable 60%. Of the thirty-seven patients with breast cancer, the 3-year survival rate among twenty-four in Stage III exceeded 90%. This survival rate is very high in comparison with other reports. For radiotherapy we adopted a less-fractionated irradiation method with a large dose instead of the conventional fractionated one. This irradiation method has not only a direct radiotherapeutic effect, but also produces a favorable effect on the host's immunocompetence. For gastric cancer, twice weekly treatment with 5 Gy and 3 Gy per week, and irradiation twice with 20 Gy and 10 Gy for breast cancer were very suitable preoperative irradiation doses.

[Diagnosis and treatment of metastatic bone tumor in the field of radiology].

From 1973 December to 1986 September, we have experienced 2,500 cases of radiation treatment, of which 237 cases have been with bone metastasis. X-ray CT was examined on the 19 cases to detect the bone metastasis. The detective rate was 89.5% with bone scintigram alone improved to 94.7% with both bone scintigram and X-ray CT. Serum Alkali phosphatase (Al-p) were measured after and before radiation treatment on 147 cases. Values of Al-p increased on 64.6% cases measured and when values of Al-p were decreased after radiation treatment, good treatment effects were showed. Electron microscope disclosed that Al-p has existed around cell membrane of metastatic tumor cell. We considered there is a correlation between increment of Al-p in blood and contents of Al-p in bone metastatic tissues. Judgement of effects of radiation treatments were scored by three grades of pain relieving on 217 cases. Effective rate showed 87.5%. Effective rate increased by using high dose rates irradiation with small fraction. Effective cases in relieving pain had longer survival than less ones. 26 cases which could not walk due to spinal cord paresis were treated by irradiation only or irradiation with decompression surgery. Walk recovery rate was 33% by radiation treatment only, on the other hand, by treatment with decompression surgery, it was 20%. Regarding as side effect, radiation myelopathy hardly occurred about 50 Gy (conventional irradiation method). We think if longer survival time is hoped, about 50 Gy is needed.

[Diagnosis and treatment of bone metastasis].

Diagnosis and treatments of bone metastasis were reviewed with clinical experiments in National Medical center Hospital. As for diagnosis of bone metastasis, early detection of bone metastasis was significantly improved by using bone scintigrams recently progressed. But the results of reviews suggest the possible improvements in diagnosis of bone metastasis. X-CT (X-ray Computed Tomography) for diagnosis of bone metastasis is advantages in three dimensional delineation of the extend and spread of bone lesions in bone marrow over bone scintigram. MRI (magnetic resonance imaging) has clinically been developed since 1981, does not directly represent bone structures but soft tissues in bone marrow, giving useful information concerning changes and spread of metastatic bone tumor not only inside the bone but also around it. MRI is now in technical progress and expected some improvements, could be expected in early diagnosis of bone metastasis. Regarding as treatment, we have individually to choose from radiotherapy, hormonal therapy, chemotherapy, surgical therapy according to clinical circumstances and does themselves. Radiation treatment is widely approved not only much effective in relieving the pains from bone metastasis, but also it is considered at the first choice in treatment of the spinal cord paresis by vertebral metastasis, because of frequently bringing good therapeutic effects.

[A clinical study of radiotherapy with HCFU for advanced and recurrent breast cancers. Radiation and HCFU Study Group for breast cancer].

We have investigated the usefulness of combination therapy with radiation and HCFU for advanced and recurrent breast cancer according to a clinical controlled multicenter trial from 1982 to 1984. One hundred cases were registered and 82 of them were available. Treatment sites were the lymph nodes, skin, bone and lung, and the overall response rate was 58% in CR and 19% in PR, while the duration of remission was 18 weeks in CR. Side effects were found in 10% of the patients. Combination therapy with radiation and HCFU may be useful in multimodal treatment for advanced recurrent breast cancer.