[A case of postoperative multiple hepatic metastasis from esophageal cancer successfully treated by surgical resection and hepatic arterial infusion chemotherapy].

A 66-year-old male who underwent radical resection for esophageal cancer (stage IV) was diagnosed with multiple hepatic metastasis 1 year and 3 months after the surgery. He underwent hepatic resection and received systemic chemotherapy (FAP: 5-FU, ADR, CDDP), as the post-operative adjuvant therapy. One year and 3 months later, there was a huge recurrence in the residual liver and hepatic arterial infusion chemotherapy (FAP) was performed. The recurrent lesion disappeared completely after 3 sessions of arterial infusion chemotherapy. The arterial infusion chemotherapy was continued in the outpatient clinic and the recurrent lesion is well controlled. At present, this patient has returned to social life, 2 years and 3 months after the hepatic resection. The utility of hepatic arterial infusion chemotherapy and hepatectomy for postoperative multiple hepatic metastasis from esophageal cancer was shown in the present case.

Prognostic factors for recurrence in stage II and III gastric cancer patients receiving a curative resection and postoperative adjuvant chemotherapy.

Prognostic value of clinicopathologic factors and biologic markers was analyzed in 185 patients who received a curative resection and adjuvant chemotherapy of pathologically confirmed stage II or III gastric cancer. No difference was found between the chemotherapeutic regimens according to the frequency of recurrence, but tumor type, histology, depth of invasion, nodal metastasis, and lymphatic and venous invasion were significantly different between recurrent (n=62) and non-recurrent (n=123) patients. However, the degree of lymphatic dissection and the patterns of biological markers (DNA ploidy, p53 staining and PCNA labeling) were not different. Hepatic metastasis and venous invasion were more frequent on patients recurring within one year, compared to those who recurred later. Multivariate analyses showed that depth of invasion, level 2 lymph node metastasis and tumor histology were risk factors for recurrence. Pathologic factors were more important for predicting recurrence than biological markers.

Squamous cell carcinoma of the esophagus infiltrating the respiratory tract is less sensitive to preoperative concurrent radiation and chemotherapy.

BACKGROUND: The prognosis of upper thoracic esophageal cancer is poor when compared with middle and lower thoracic esophageal cancer because the tumor easily infiltrates the respiratory tract and surgical en-bloc resection is difficult. Recently, preoperative chemoradiation therapy has been shown to lead to down-staging of the disease and improve prognosis. But the benefit of this therapy for tumors infiltrating the respiratory tract remains unknown. STUDY DESIGN: Fifty-six patients with thoracic esophageal cancer infiltrating neighboring organs, but with no hematogeneous metastasis, were given preoperative concurrent chemotherapy (5-fluorouracil and cisplatin) and radiation (40 Gy) therapy. When a clinical response was observed, making a curative resection potentially possible, patients were scheduled for esophagectomy with extended lymphadenectomy. Patient prognosis with respect to the organs infiltrated by the tumors was estimated by calculating survival curves using the Kaplan-Meier method and comparing the curves by the log-rank test. RESULTS: The prognosis was significantly poorer for patients with tumors infiltrating the respiratory tract (T) or aorta plus respiratory tract (A + T) than for patients with tumors infiltrating the aorta alone (A) or other organs (Oth) (p < 0.05 for Oth versus T; p < 0.05 for Oth versus A + T; p < 0.0001 for A versus T; p < 0.0001 for A versus A + T by log-rank test). Patients positive for respiratory tract invasion (T, T + A), compared with those negative for respiratory tract invasion (A, Oth), showed a poorer clinical response to chemoradiation (3.0%, 45.5%, 39.4%, and 9.1% versus 4.3%, 82.6%, 4.3%, and 8.7% in complete response (CR), partial response (PR), nonresponse (NC) and progressive disease (PD), respectively, p = 0.0156) and surgical resectability (36.4% vs. 87.0%, p = 0.0003). Histologic effectiveness (8.3%, 50.0%, and 41.7% versus 25.0%, 70.0%, and 5.0% in grade 3, grade 2, and grade 1, respectively, for patients with respiratory tract invasion versus those without it, p = 0.0189) and histologic stages (8.3%, 8.3%, 8.3%, 8.3%, 25.0%, and 41.7% versus 20.0%, 0%, 15.0%, 25.0%, 40.0%, and 0% in pathologic CR, stage I, stage IIA, stage IIB, stage III, and stage IV, respectively, for patients with respiratory tract invasion versus those without it, p = 0.0496) were significantly better in patients negative for respiratory tract invasion; the percentages of patients with lymph node metastasis did not differ significantly between the two groups. Comparison of the recurrence patterns showed that local failure was most common in patients with respiratory tract invasion, and distant failure was the leading cause of recurrence in patients without it. CONCLUSIONS: Because the prognosis of patients with thoracic esophageal cancer infiltrating the respiratory tract is extremely poor, partially because of the low local effectiveness of preoperative concurrent chemotherapy and radiation therapy, caution is needed when deciding on salvage surgery.

Selective augmentations of intratumoral 5-fluorouracil concentration by local immunotherapy with OK-432 and fibrinogen.

PURPOSE: Pyrimidine nucleoside phosphorylase is an enzyme that converts 5'-deoxy-5-fluorouridine into its active metabolite, 5-fluorouracil. In colorectal cancer tissue pyrimidine nucleoside phosphorylase has been proven to be produced by macrophages in the cancer stroma despite presence of the cancer cells. We reported that local immunotherapy with OK-432 and fibrinogen induced aggregation of macrophages in the cancer stroma and enforced their pyrimidine nucleoside phosphorylase expression. Thus it was hypothesized that if colon cancer were treated with 5'-deoxy-5-fluorouridine, the 5-fluorouracil concentration in cancer tissues would be enhanced by local immunotherapy. The present study was conducted to investigate whether local immunotherapy for colon cancer could increase the intratumoral 5-fluorouracil concentration in patients given chemotherapy with 5'-deoxy-5-fluorouridine. METHODS: Twenty patients with resectable colorectal cancer were examined in this study. They were given 5'-deoxy-5-fluorouridine (600 mg/day) orally for seven days preoperatively. Nine randomly selected patients underwent intratumoral injection of OK-432 mixed with fibrinogen, which was performed on the third preoperative day (OK-432 and fibrinogen plus 5'-deoxy-5-fluorouridine group); eleven patients were given oral 5'-deoxy-5-fluorouridine only (5'deoxy-5-fluorouridine group). The 5-fluorouracil concentration in tumor tissue and normal colon mucosa tissue was measured, and the influence of the local immunotherapy was assessed. RESULTS: The 5-fluorouracil concentration in the cancer tissue was increased by the local immunotherapy, whereas that in the normal colon mucosa was not influenced. Thus, the influence of local immunotherapy was selective to the cancer tissue where the mixture of OK-432 and fibrinogen was injected. CONCLUSION: In patients with colorectal cancer, selective high 5-fluorouracil concentration in the cancer tissue could be achieved by a combination of 5'-deoxy-5-fluorouridine and local immunotherapy with a mixture of OK-432 and fibrinogen.

[Transarterial immuno-embolization therapy in patients with hepatocellular carcinoma].

Surgical resection, transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) are effective for hepatocellular carcinoma (HCC), but the recurrence rate is high. We have devised a new therapy of transarterial immuno-embolization (TIE) with OK-432, fibrinogen and thrombin, and 2 cases are reported. Case 1: A 78-year-old Japanese male with HCC (diameter, 4 cm in subsegment 5) received TIE. The tumor size was markedly decreased, and the patient survived for more than 3 years without recurrence. Case 2: A 61-year-old Japanese male with HCC (diameter, 4.5 cm in segment 5) received hepatic subsegmentectomy following TIE. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells in the main tumor. Tumor recurrence had developed three times thereafter, but was effectively treated by TIE. TIE may be an effective therapy for HCC.

Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a comparison of epirubicin and doxorubicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan.

A randomized, controlled clinical trial was conducted to compare the use of epirubicin (EPI) and doxorubicin (DOX) in Lipiodol (Laboratoire Guerbet, Roissy-Charles-de-Gaulle Cedex, France)-transcatheter arterial chemoembolization as a treatment of hepatocellular carcinoma. One hundred ninety-two hospitals participated, and 415 patients were enrolled in the study during the period between October 1989 and December 1990. The patients were randomly allocated to group A (EPI) or group B (DOX) by a centralized telephone registration. The actual doses of EPI and DOX were 72 mg/body and 48 mg/body, respectively. The 1-, 2-, and 3-year survival rates were, respectively, 69%, 44%, and 33% for group A and 73%, 54%, and 37% for group B. There were no statistically significant differences (P = .2296, log-rank test). When each group of patients was classified retrospectively into high-risk and low-risk subgroups based on the severity index calculated by the Cox regression model from the significant prognostic factors (the pretreatment tumor size, the pretreatment serum alpha-fetoprotein level, tumor encroachment, and Child's classification), the survival curve of the low-risk DOX subgroup was significantly superior to that of the low-risk EPI subgroup (P = .0182). However, there was no significant difference between the high-risk subgroups (P = .4606). The change in the serum alpha-fetoprotein level, the extent of Lipiodol accumulation in the tumor, and the extent of tumor reduction after the treatment did not show any significant differences between the groups. The white blood cell count in group B showed a tendency to decrease slightly more than in group A at 3 weeks after Lipiodol-transcatheter arterial chemoembolization. In conclusion, there was no statistically significant difference between the survival curves of the EPI and DOX groups in Lipiodol-transcatheter arterial embolization treatment of hepatocellular carcinoma.

Hepatocellular carcinoma: efficacy of transcatheter oily chemoembolization in relation to macroscopic and microscopic patterns of tumor growth among 100 patients with partial hepatectomy.

PURPOSE: To evaluate the efficacy of transcatheter oily chemoembolization (TOCE) for hepatocellular carcinoma (HCC) on the basis of microscopic and macroscopic findings postembolization. METHODS: HCCs ranging in size from 0.5 to 13 cm (mean 3.6 cm) were obtained from partial hepatectomies of 100 consecutive patients who had undergone TOCE between 20 and 246 days (mean 59.5 days) prior to surgery. The efficacy of TOCE was assessed on the basis of the necrotic to live cell ratio of the tumors. The microscopic pattern of tumor growth was grouped into expanding type (complete capsule formation) and replacing type (incomplete or no capsule). There were five types of macroscopic groupings: single nodule, single nodule with extranodular growth (SNE), contiguous and noncontiguous multinodular, and massive growth type. RESULTS: Among 79 cases with the expanding type, 29 (37%) had 100% HCC necrosis, but none with 100% necrosis were in the replacing type. By macroscopic grouping, the efficacy of TOCE decreased from the single nodule type (50% of patients had 100% necrosis) to the SNE type (21%), and the other types (9%). CONCLUSION: TOCE appears to be most efficacious for HCC with the expanding growth pattern and HCC forming single nodules. Poor results are to be expected in HCC of replacing growth type and multinodular or massive growth types.

Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma--a comparison between L-TAE with farmorubicin and L-TAE with adriamycin: preliminary results (second cooperative study). Cooperative Study Group for Liver Cancer Treatment of Japan.

A randomized controlled clinical trial was conducted to compare the use of farmorubicin (FARM) and adriamycin (ADR) in Lipiodol transcatheter arterial chemoembolization (L-TAE) as a treatment of hepatocellular carcinoma. In all, 192 hospitals participated, and 415 patients were enrolled in the study during the period from October 1989 through December 1990, and their data were collected. The patients were randomly allocated to group A (FARM) or group B (ADR) by a central telephone registration. Several clinical characteristics were slightly worse in group A than in group B, but there was no statistically significant difference. The actual doses of FARM and ADR were 72 mg/body and 48 mg/body, respectively. Additional treatments, including repeated TAE or surgery, were given to 248 patients. The 1- and 2-year survival rates were 69% and 44% for group A and 74% and 57% for group B, respectively. The difference was marginally significant (P value in the log-rank test, 0.038). When each group of patients was classified into two subgroups, i.e., high-risk and low-risk categories, based on the severity index calculated by the Cox regression model from significant prognostic factors, the ADR subgroup was significantly superior to the FARM subgroup in the low-risk category, but there was no significant difference between the subgroups in the high-risk category. The change in the serum alpha-fetoprotein level, the extent of Lipiodol accumulation in the tumor, and the extent of tumor reduction did not show any significant difference between the groups. At the above-mentioned doses, ADR seemed to have efficacy almost the same as or slightly superior to that of FARM in L-TAE for the treatment of hepatocellular carcinoma.

[Efficacy of transarterial immuno-embolization therapy (TIE) in operable patients with hepatocellular carcinoma].

The efficacy of transarterial immuno-embolization therapy (TIE) was examined in six operable patients with hepatocellular carcinoma (HCC). We administered OK-432, fibrinogen (30 mg/ml) and thrombin (1 U/ml) through a catheter which was inserted into the tumor-feeding artery. In all patients with a high level of tumor markers (AFP and PIVKA-II), the level decreased promptly to less than the pretreatment level after TIE therapy. The therapy has not caused any serious side effects. No disturbance of the coagulation-fibrinolysis system due to TIE was observed in any patient. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells around tumor cell nests, and lytic necrosis as well as coagulation necrosis of the main tumor and the intrahepatic metastases. Our results indicate that TIE may be an effective and promising modality for HCC patients.

Detection of viable tumor cells in hepatocellular carcinoma following transcatheter arterial chemoembolization with iodized oil. Pathologic correlation with dynamic turbo-FLASH MR imaging with Gd-DTPA.

To evaluate the effect of transcatheter arterial chemoembolization (TACE) with iodized oil for hepatocellular carcinoma (HCC), dynamic turbo-fast low angle shot (turbo-FLASH) (TR/TE/flip angle/TI, 8.5/4.6/10/200) MR imaging with gadopentetate dimeglumine was performed in 10 patients with HCC after TACE with iodized oil and before partial hepatectomy. Immediately after 0.05 mmol/kg b.w. of gadopentetate dimeglumine was administered intravenously, 10 images were obtained in the first 20 s (early phase). Then, one image every 30 s from 1 to 3 min (late phase), and images at 5 min and 7 min (delayed phase) were obtained serially. In the early phase, HCC showed no enhancement in 5 patients, partial hyperintense enhancement in 4, and total hyperintense enhancement in one. Viable regions of the tumor, evaluated at histopathology, showed hyperintense enhancement relative to the surrounding liver parenchyma in the early phase, while necrotic regions showed no enhancement. Both viable and necrotic regions showed lower signal intensities than the surrounding liver parenchyma in both late and delayed phases. By using dynamic turbo-FLASH MR imaging, we were able to accurately evaluate the effect of TACE with iodized oil for HCC in 8 of the 10 patients. In 2 patients, in whom small viable cells were seen in the HCC, viable regions could not be detected with our technique. It is concluded that turbo-FLASH dynamic MR imaging was useful for evaluating the effect of TACE for HCC.

Treatment of hepatocellular carcinoma by chemoembolization: evaluation with 3DFT MR imaging.

OBJECTIVE: We evaluated the usefulness of an MR imaging technique that used dynamic three-dimensional Fourier transformation (3DFT) fast imaging with steady-state precession (FISP) with gadopentetate dimeglumine for detecting viable regions of hepatocellular carcinoma following transcatheter arterial chemoembolization with iodized oil (Lipiodol). Images obtained with the 3DFT FISP technique were directly correlated with hepatectomy specimens. SUBJECTS AND METHODS: Dynamic 3DFT FISP MR imaging was performed after transcatheter arterial chemoembolization and before partial hepatectomy in 10 patients with 10 tumors of hepatocellular carcinoma. Imaging parameters were 20/8/30 degrees (TR/TE/flip angle) with a slab thickness of 21-75 mm and seven or 15 partitions. 3DFT FISP images were obtained at the slice level where a tumor had been detected on T1- and/or T2-weighted spin-echo MR images before, just after (early phase), and 1 and 2 min after (late phase) IV administration of gadopentetate dimeglumine (0.1 mmol/kg). We directly compared the dynamic MR images of the 10 patients with the gross and microscopic findings. RESULTS: On early-phase images, tumors of hepatocellular carcinoma showed no enhancement in three patients and partial intense enhancement in seven. Viable regions of the tumor showed intense enhancement relative to the surrounding liver parenchyma in the early phase, whereas necrotic regions showed no enhancement in either the early or the late phase. Both viable and necrotic regions had lower signal intensities than did the surrounding liver parenchyma in the late phase. By using dynamic 3DFT MR imaging, we were able to accurately assess the effect of transcatheter arterial chemoembolization with iodized oil in nine of the 10 patients. However, in one patient in whom microscopically viable cells were seen in the capsule of the carcinoma, viable regions could not be detected with our technique. CONCLUSION: Dynamic 3DFT MR imaging was useful in differentiating viable regions of hepatocellular carcinoma from necrotic regions following transcatheter arterial chemoembolization with iodized oil.

Response to transcatheter oily chemoembolization in hepatocellular carcinoma 3 cm or less: a study in 50 patients who underwent surgery.

The response of 50 patients who underwent hepatectomy for hepatocellular carcinoma measuring 3 cm or less (at the time of surgery) to transcatheter oily chemoembolization was evaluated. The response was assessed in 5 categories, A: complete necrosis (100%), B: necrosis of at least 95%, C: at least 80%, but less than 95%, D: at least 50% but less than 80%, and E: less than 50% of the tumor cells. Response A was observed in 19 patients (38%), B in 7 (14%), C in 9 (18%), D in 7 (14%), and E in 8 (16%). These results were classified with respect to the histological degree of tumor differentiation, the WHO histological classification, the microscopic patterns of tumor growth, and macroscopic classification. The response was evaluated in relation to the histological grade of tumor differentiation and the WHO histological classification in all categories of response except response A, and there was no significant difference between the categories. The response was obviously better with the expansive type than with the replacing type. Single nodular type lesions were more responsive than the single nodular type lesions with extranodular growth and the contiguous multinodular type. Pretreatment estimation of the microscopic patterns of tumor growth and macroscopic classification appears to be valuable in predicting prognosis.

[The efficacy of transarterial immuno-embolization therapy in patients with hepatocellular carcinoma].

The efficacy of transarterial immuno-embolization therapy (TIE) was investigated in 7 patients with multiple hepatocellular carcinoma (HCC). We administered OK-432 (10 KE), fibrinogen (30 mg/ml) and thrombin (1 U/ml) as a new treatment for HCC with intrahepatic metastasis. In all patients with a high level of AFP, the AFP level decreased promptly less than the pretreatment level after TIE therapy. High fever in all cases, epigastralgia in 6 cases and appetite loss in 3 cases were observed after TIE therapy. Our results indicate that this therapy may be a safe and effective method in HCC patients with intrahepatic metastasis.

Limitation of transcatheter arterial chemoembolization using iodized oil for small hepatocellular carcinoma. A study in resected cases.

The radiologic and histologic findings are presented of the resection of 14 small hepatocellular carcinomas (HCC), less than 2 cm in maximum diameter, after transcatheter arterial chemoembolization (TCE) using iodized oil. The effect of TCE on small HCC depended on the morphologic type of the tumors. When no extracapsular invasion of tumor cells occurred, TCE was extremely effective against encapsulated tumors. However, in nine of the 14 resected specimens, viable tumor cells remained in or around the tumor. The authors suggest that small HCC are not always curable with TCE alone and that a multi-disciplinary approach is necessary for patients with small HCC.

Treatment of hepatocellular carcinoma by segmental hepatic artery injection of adriamycin-in-oil emulsion with overflow to segmental portal veins.

Hepatocellular carcinoma was treated with slow injection of an emulsion containing 40 to 60 mg of adriamycin and 3.5 to 12 ml of Lipiodol into the portal vein via a segmental hepatic artery. During and after the injection, the portal branches of the segment were demonstrated. Six patients with resectable hepatocellular carcinoma received this treatment, which in 3 of them was followed by embolization with Gelfoam of the segmental artery. In these 3, all main tumors and daughter nodules became completely necrotic, but some infarction developed in the non-tumorous area. Those without Gelfoam had complete necrosis of all daughter nodules, but incomplete response of the main tumor. This combined treatment may be recommended for patients with localized lesions which are nonresectable due to cirrhosis, or for other reasons.

Necrosis of portal tumor embolus of hepatocellular carcinoma by lipiodol transcatheter chemo-embolization. A case report.

We describe a case of hepatocellular carcinoma in which a tumor embolus in the portal vein and 3 of 4 intrahepatic metastases were necrosed completely by Lipiodol transcatheter chemo-embolization (Lipiodol-TCE). Tumor emboli in the portal vein and intrahepatic metastases usually cannot be necrosed by conventional transcatheter chemo-embolization alone, because small nodules such as intrahepatic metastases and tumor emboli in the portal vein are supplied blood from the portal vein. However, in this case, Lipiodol-TCE was effective against tumor emboli in the portal vein and intrahepatic metastases.

[Transarterial segmental hepatic chemo-embolization in patients with hepatocellular carcinoma].

We can administer a Lipiodol-adriamycin emulsion transarterially into the portal vein, because more than a certain amount of Lipiodol injected into the hepatic artery enters the portal vein through arterioportal communications without arterioportal shunting. When Gelfoam embolization is followed by portal venous administration of this emulsion, hepatic chemoembolization is performed from both artery and portal vein simultaneously. But this chemoembolization must be in a limited area of the liver, since such treatment of the whole liver is lethal. We encountered a segmental hepatic chemoembolization in four patients with hepatocellular carcinoma by the catheterization of a hepatic segmental artery. In two cases operated after segmental chemoembolization, complete necrosis was certified in the main tumor and daughter nodules. Hepatic segmental atrophy and infarctions were also noted in the treated segment. In two non-operated cases, hepatic segmental atrophy and excellent antitumor effects were demonstrated by CT and radioisotope liver scan. Thus, we call this treatment "transarterial partial hepatectomy".

[Preoperative chemo-embolization for treatment of hepatocellular carcinoma].

A multidisciplinary treatment for hepatocellular carcinoma including preoperative chemo-embolization with resection treatment was introduced. Recent attempts at combining lipiodol with chemo-embolization have been quite promising. An ideal multidisciplinary treatment should include an effective device using the transportal approach.