Masahiro Yoshino

Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group.

PURPOSE A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. PATIENTS AND METHODS From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. RESULTS A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CONCLUSION CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.

Evaluation of the prognosis for small hepatocellular carcinoma based on tumor volume doubling time. A preliminary report

The relationship of tumor volume doubling time to length of patient survival was investigated for 15 patients with small hepatocellular carcinoma smaller than 4.5 cm in diameter. The mean tumor volume doubling time of these 15 nodules was 102 ± 77 days (mean ± SD; range 41 to 305 days) before the initiation of a specific treatment for cancer. These doubling times tended to correlate with mitotic indexes of the tumors and the patients could be divided into two groups according to the therapeutic modalities used. Patients in Group A received systemic chemotherapy without response or nonspecific treatments for cancer. In this group, there was a positive correlation between tumor volume doubling time and survival length (r = 0.8812; P < 0.025). Patients in Group B either received hepatectomy after transarterial embolization or systemic chemotherapy or received hepatectomy alone. In this group, early death occurred in patients who had shorter tumor volume doubling times. Three surgically treated patients in Group B were evaluated as having survived for a significantly long period as assessed from their tumor volume doubling times. These results indicate that tumor volume doubling time is one of the determining factors of survival length in patients with hepatocellular carcinoma, and, therefore, can be used in the evaluation of therapeutic efficacy.

Bone metastasis in hepatocellular carcinoma

Bone metastasis was observed in 16.1% or in 14 of 87 male autopsy cases of hepatocellular carcinoma. The primary tumor within the liver was located in the right lobe in all but one case. There were six patients who first presented with signs attributable to bone metastasis, and lung metastasis subsequently became evident in five of them. These 6 patients lived significantly longer as compared with 8 other patients with bone metastases and 73 patients without. The possible route by which hepatocellular carcinoma cells were carried to the bone is discussed.

Clinical significance of monitoring serum levels of 5-fluorouracil by continuous infusion in patients with advanced colonic cancer.

SummarySerum concentrations of 5-fluorouracil (5-FU) given by continuous infusion to 19 patients with advanced colonic cancer were measured by an HPLC method, and steady-state concentration (SSc), area under the curve (AUC72) and total body clearance (Cl) were calculated as pharmacokinetic parameters. The serum level of 5-FU rapidly increased, reaching a plateau within 2 h after the start of administration. There were positive correlations between the dose and both SSc (r = 0.578,P <0.01) and AUC72 (r = 0.558,P <0.05). When the patients were divided into toxic and non-toxic groups according to the degree of toxicity, the values for SSc and AUC72 in the toxic group were significantly higher than those in non-toxic patients. The Cl value in the toxic group was also significantly different from that in the non-toxic group when data were calculated on a log scale. Furthermore, no differences in these parameters between effective and non-effective groups were detected when the patients were divided into two groups according to anti-neoplastic responses. These results indicate that increased serum concentration does not always provide therapeutic benefits to patients receiving continuous infusions of 5-FU.

Needle Tract Implantation of Hepatocellular Carcinoma and Pancreatic Carcinoma after Ultrasound-guided Percutaneous Puncture: Clinical and Pathologic Characteristics and the Treatment of Needle Tract Implantation

Tumor implantation along the needle tract following percutaneous procedures under ultrasonographic guidance for hepatocellular carcinoma (HCC) and pancreatic carcinoma (PC) has been well documented. The purpose of the present study was to investigate the correlation between the procedure, the pathologic differentiation of the primary tumor, and the treatment after implantation. Between July 1992 and March 2000, HCC patients (n = 372) who underwent biopsy, percutaneous ethanol injection (PEI) therapy and percutaneous microwave coagulation therapy (PMCT) and PC (n = 73) patients who underwent biopsy were retrospectively studied. Needle tract implantation was found in six of the HCC patients (1.6%) and one of the PC patients (1.4%). The interval to diagnosis ranged from 5 to 25 months (mean ± SD 11.2 ± 7.6 months) in the HCC patients. The needle tract implantation was evident for all procedure types in these patients (two after PEI alone, two after both biopsy and PEI, and one after PMCT) and for each degree of pathologic differentiation of the primary tumors (well differentiated in one, moderately differentiated in two, and poorly differentiated in one). Each implanted tumor was surgically resected, with no recurrence at the focal lesion. These results suggest that needle tract implantation develops regardless of the procedure or the pathologic differentiation of the primary tumor, and that surgical resection might be effective for controlling these implanted lesions.

Evaluation of Contrast Enhancement Patterns in Pancreatic Tumors by Coded Harmonic Sonographic Imaging With a Microbubble Contrast Agent

Objective. The purpose of the study was to assess patterns of primary pancreatic lesions by contrast‐enhanced sonography for differentiating ductal carcinomas from other pancreatic tumors. Methods. One hundred six consecutive patients with pancreatic masses, consisting of 83 ductal carcinomas, 7 endocrine carcinomas, 5 intraductal papillary mucinous tumors, 3 cases of autoimmune‐related pancreatitis, 3 solid pseudopapillary tumors, 2 cases of chronic pancreatitis, 1 serous cystadenoma, 1 osteoclastoid giant cell tumor, and 1 follicular lymphoma, were examined by contrast‐enhanced sonography with coded harmonic imaging in a phase inversion harmonic technique. The contrast enhancement patterns were assessed, and specimens removed during pancreatectomy were subjected to pathologic examination. Results. Internal tumoral vascularity was detected in 47 (56.6%) of the 83 ductal carcinomas. Vascular image spreading and homogeneous staining throughout the tumors were observed in all endocrine carcinomas. Two of the 5 intraductal papillary mucinous tumors were positive for enhancement effects. Enhancement effects were observed in all 3 cases of autoimmune‐related pancreatitis, but the degree varied. There was a significant correlation between the intensity of enhancement effects and the ratio of patent vessels in the tumors (P < .05). Conclusions. Vascularity was detected by contrast‐enhanced sonography in only about half of the ductal carcinomas, confirming the difficulty in distinguishing those tumors from other pancreatic tumors. There was a correlation between the patency of the vessels in the tumors and their vascularity.

Hepatic artery embolization for inoperable hepatocellular carcinoma; prognosis and Risk Factors

SummaryDuring a 7-year period in our hospital, 69 patients with inoperable hepatocellular carcinoma (HCC) underwent 111 courses of transcatheter hepatic artery embolization (TAE) and/or chemoinfusion with lipiodol. Patient survival was 0.5–37 months following therapy and the factors affecting prognosis were evaluated. Survival rates at 1, 2 and 3 years after TAE were 53%, 24% and 15%, respectively. Survival rates at 1, 2 and 3 years in relation to tumor size were 100%, 100% and 100% in 5 patients (tumor size <2 cm in diameter), 81%, 33% and 16% in 23 patients (2.1–5.0 cm), and 35%, 9% and 0% in 41 patients (>5.1 cm). An analysis of prognostic factors showed that the size of the main tumor significantly influenced the prognosis following TAE (P<0.01), whereas the frequency of TAE, intrahepatic metastasis and the degree of liver dysfunction showed a slight correlation (P<0.1). These results suggest that TAE has a significant potential for becoming the first choice of treatment for patients with small multiple HCCs (<2 cm), provided that neither severe hepatic dysfunction nor a tumor thrombus in the main portal vein is present.

A Phase II Study of Cisplatin in Patients with Biliary Tract Carcinoma

A phase II study of cisplatin was performed in 13 previously untreated patients with unresectable biliary tract carcinoma. The drug was given intravenously at a dose of 80 mg/m2/day once every 4 weeks. Of 13 patients evaluated, 1 showed partial response lasting 3 months, while no patients showed complete response. Of 9 patients, whose serum level of carcinoembryonic antigen (CEA) was high (> or = 10 ng/ml) before treatment, 4 showed > or = 50% reduction in serum CEA level after treatment. The current study indicates that cisplatin does not have significant antitumor activity against biliary tract carcinoma.

Chemotherapy in the treatment of advanced gallbladder cancer

Objective: To clarify the role of chemotherapy for advanced gallbladder cancer (GBC). Methods: We reviewed 89 GBC patients: 21 admitted before 1997 were treated with a combination of cisplatin, epirubicin, and 5-fluorouracil (CEF); 25, admitted subsequently, received a combination of 5-fluorouracil, doxorubicin and mitomycin (FAM), and the remaining 43, ineligible for these trials, received supportive care. We investigated the relation between pretreatment clinical variables and long-term survival in these 89 subjects, and analyzed whether chemotherapy could favor longer survival. Results: There were no significant differences in survival time between the chemotherapy groups, whereas the response rate to the CEF regimen was 4-fold higher than to the FAM regimen (32 vs. 8%). Subgroup analysis suggested that chemotherapy favored longer survival in patients with a performance status (PS) of 0 or 1, but not in patients with a PS of 2. Cox regression analysis suggested a significant hazard reduction by chemotherapy in patients with a PS of 0 or 1, but not in patients with a PS of 2. Conclusions: GBC patients with poor PS should not be treated with chemotherapy at present. It is essential to design good clinical trials and develop more effective chemotherapy regimens.

Intraoperative and conformal external-beam radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic carcinoma

Chemoradiotherapy is widely used for patients with locally advanced pancreatic carcinoma. The purpose of this study was to clarify the efficacy and feasibility of chemoradiotherapy with more intensive radiotherapy in these patients, using a combination of intraoperative radiotherapy (IORT), conformal external‐beam radiaotherapy (EBRT), and protracted 5‐fluorouracil (5‐FU).