[Multicenter phase II study of pre-administered uracil/tegafur (UFT) plus gemcitabine for unresectable/recurrent pancreatic cancer].

Our objective was to evaluate the efficacy and toxicity of the pre-administration of UFT (uracil/tegafur: prodrug of 5-FU) and GEM combination therapy for unresectable/recurrent pancreatic cancer in the outpatient setting. UFT (250mg/m(2)/day) was orally administered from day 1 through day 6 and from day 8 through 13, and GEM (800mg/m(2), div/30 min) was administered on day 7 and 14, with a one-week rest every 3 weeks based on results of the previous phase I study. Thirty-six pts (24 male, 12 female) were enrolled (median age, 63.8 yrs). There were 8 partial responses (25%). Eighteen pts (56%) had stable disease, and 6 pts (19%) had a progression. The median survival time was 7. 0 months( range 1.5 -66). Grade 3 toxicities were leucopenia (17%), thrombocytopenia (3%), nausea (3%), and liver dysfunctions(3%). There were no Grade 4 toxicities. Pre-administered UFT plus GM is a promising treatment for unresectable/recurrent pancreatic cancer in the outpatient setting.

[Induction of liaison-clinical pathway for patients with gastric cancer undergoing adjuvant chemotherapy using S-1 after curative gastrectomy].

The efficacy of adjuvant chemotherapy using S-1 for one year after curative surgical treatment for patients with gastric cancer of stage II or III was reported as the result of randomized controlled trial named ACTS-GC in 2007. Therefore the number of patients undergoing this adjuvant chemotherapy is predicted to be rapidly increasing in near future. On the other hand, the government promotes to construct the liaison-clinical pathway for patients with major carcinoma as a policy in 2007. According to these two backgrounds, liaison-clinical pathway for patients with gastric cancer undergoing adjuvant chemotherapy using S-1 after curative gastrectomy has been induced in our institute from November 2007. Not only alliance among doctors, nurses and pharmacologist in our institute but also communication with clinic is important to construct and manage this pathway. Three patients have been undergoing this pathway until now. All of them are satisfied with this pathway because of reliable feelings supported by intensive alliance between our institute and local clinic.

[A trial of TS-1 administration on the basis of the pharmacokinetic study for an advanced gastric cancer patient with impaired renal function].

TS-1 is an antitumor drug including 5-chloro-2,4 dihydroxypyridine (CDHP), which inhibits dihydriopyrimidine dehydrogenase (DPD) activity selectively in metabolism of 5-FU. However, TS-1 therapy tends to increase adverse events for patients with impaired renal function due to excessively high blood concentration of 5-FU, because CDHP is mainly excreted into the urine. In a 67-year-old male with advanced gastric cancer, renal dysfunction occurred during TS-1 administration as its adverse event. We studied the pharmacokinetics of 5-FU, which were analyzed on the T1/2 value and the AUC (0-infinity) of 5-FU with a single and consecutive TS-1 administration, and estimated an optimal TS-1 administration regimen for this patient. The regimen is 60 mg/body/day given in one divided dose for 28 days consecutively followed by 14 days rest. This regimen enabled a continuation of TS-1 treatment for the patient. In conclusion, individual dose adjustment using pharmacokinetic study of 5-FU might be beneficial to patients with impaired renal function.

[A case of pseudo aneurysm of common hepatic artery related to hepatic arterial infusion chemotherapy].

A 87-year-old male underwent the extended hepatic left lobectomy and the partial hepatectomy (S7, S8) for liver hepatic metastasis from the rectal cancer in March 2003. The reserver was implanted by the GDA-coil method from the right femoral artery, and WHF was enforced 10 times. Epigastric and back pain appeared from January 2004. The pain became strong gradually. MRI and CT scan were examined after hospitalization. These imaging tests showed the pseudo aneurysm of common hepatic artery. Therefore, an emergency angiography was performed, and pseudo aneurysm of the common hepatic artery was embolized with 36 metallic coils. After the embolization, the pain had disappeared suddenly. The patient was discharged the 7th day after embolization. Hepatic arterial infusion chemotherapy is considered safe with respect to blood and non blood toxicity, which was compared with systemic chemotherapy. However, there were also complications like this case, and caution is required.

[A case of peritoneal dissemination disappeared by CPT-11 + TS-1 combination chemotherapy].

A patient is a 35-year-old man. By a diagnosis of descending colon cancer, descending colon ablative operation and D1 lymph node dissection were performed on April 22, 2004. It was P3H0N1SE, Stage IV in perioperative findings. Abdominal CT showed peritoneal dissemination of 1.7 cm at the right under the abdominal wall wound and 1.2 cm in the rectovesical pouch on May 18, 2004. CPT-11 + TS-1 combination chemotherapy was started on June 22nd. In the five weeks of the combination chemotherapy, continuous infusion of CPT-11 (150 mg/body day 1 and 15) was twice administered, and oral administration of TS-1 (120 mg/body/day) was given for 3 weeks (day 1-21). Peritoneal dissemination disappeared after the two-course end, and we judged it as CR. Furthermore, we were certain that we obtained CR after the three course end. The adverse event was only neutropenia of grade 1. The fourth course was not administered, but recurrence has not been observed. Abdominal CT showed no recurrence on March 3, 2005 since the combination chemotherapy ended 6 months ago.

Ki-67 and CEA expression as prognostic markers in Dukes' C colorectal cancer.

This study investigated the relationship between clinicopathological or immunohistochemical factors and postoperative prognosis for Dukes' C colorectal cancer. Short-term survivors died from cancer within 2 years of surgery, whereas long-term survivors were disease-free for over 10 years. The groups differed in Ki-67 antigen and CEA expression in colon cancer, and CEA expression in rectal cancer that was limited to the metastatic lymph nodes. The immunohistochemical scores were higher in short-term survivors. Our data suggest that the characteristics of metastatic lymph nodes are important as a predictor of the aggressiveness of tumor behavior and that the expression of Ki-67 antigen or CEA there may be a useful indicators of patients' survival in Dukes' C colorectal cancer.

Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor agent in animal model and in patients with impaired renal function.

PURPOSE: S-1 is a novel oral fluorouracil antitumor drug that combines tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the DPD inhibitory effect and lead to increased 5-fluorouracil (5-FU) concentrations. We sought to determine the influence of impaired renal function on the pharmacokinetics of S-1 in an animal model and in patients with gastric cancer. METHODS: An experimental renal failure model induced by cisplatin was developed in rabbits, and plasma concentrations of FT, 5-FU, CDHP and Oxo were determined after S-1 injection. Four patients with various degrees of renal impairment with unresectable gastric cancer were recruited to the study, and the pharmacokinetics in these four patients were analyzed following single and consecutive S-1 administrations. RESULTS: In experimental renal failure, plasma clearance of CDHP and 5-FU was retarded corresponding to the degree of renal impairment and there was a close correlation between creatinine clearance (CLcr) and plasma CDHP and 5-FU clearance. In the single administration study, half standard dose was used in three patients (CLcr > or = 50 ml/min) and one-third in the other (CLcr <50 ml/min). In patients with CLcr more than 75 ml/min, C(max), T(max), AUC((0-infinity)), and T(1/2) of 5-FU and CDHP were not different between single and consecutive administrations. In contrast, in patients with mild and moderate renal dysfunction (CLcr 55 and 36 ml/min, respectively), the T(1/2) values of CDHP with consecutive administrations (7.6 and 15.3 h, respectively) were longer than the values with single administration (4.6 and 8.2 h, respectively). The T(1/2) of 5-FU was 5.7 h with single administration and 8.5 h with consecutive administration in patients with moderate renal impairment. The AUC((0-infinity)) of 5-FU with consecutive administrations (3089.7 ng.h/ml) was far greater than with single administration (430.4 ng.h/ml). There was also a strong correlation between CLcr and plasma CDHP clearance. Based on the pharmacokinetics following multiple consecutive administrations, S-1 administration resulted in no severe adverse reactions in any of the four patients. CONCLUSIONS: CDHP clearance was prolonged in the presence of renal impairment, leading to a delayed T(1/2), and high AUC of 5-FU. These findings demonstrate that administration of S-1 to patients with impaired renal function may need individualized dosing and pharmacokinetic monitoring.

[A case of lymph node recurrence after curative operation of type 4 gastric cancer, successfully treated with TS-1].

A 74-year-old male underwent left upper abdomen excision (LUAE) and D3 lymph node dissection for type 4 gastric cancer. Nine months after the surgery, abdominal computed tomography (CT) revealed paraportal lymph node recurrence (#8p), 22 mm in size. One hundred mg/body/day of TS-1 was administrated for 14 days, followed by 7 days rest, as one course. A complete response was obtained after the second course. This treatment was stopped after the 11 course because the patient suffered prolonged grade 1 fatigue. The patient has been in good health without a recurrence for 1 year and 5 months after the recurrence. Adverse effects included rash (grade 1), diarrhea (grade 2), fatigue (grade 2) and neutrophils neutropenia (grade 2).

[Limits of surgical therapy for pulmonary metastasis from breast cancer].

Sixteen cases of first pulmonary metastasis from breast cancer were reexamined. There was no significant difference between the operated and non-operated cases. The prognoses of both groups were unfavorable due to aggravation of the lung, including the pleural focus or other distant metastases. We found a surgical benefit in only selected cases such as comparatively advanced breast cancers with long disease-free intervals, and cases in which the differentiation with the primary lung cancer was difficult. We recommend a mildly invasive operation using video-assisted thoracic surgery in these cases.

[A case of metastatic gastric cancer treated with CDDP plus TS-1 and surgical resection].

UNLABELLED: Advanced gastric cancer (AGC) with liver metastasis has a poor prognosis. We encountered a case of AGC with multiple liver metastasis treated with chemotherapy and surgery. CASE: A 54-year-old male. He was admitted to our hospital with epigastric pain. Gastrointestinal fiberscope examination revealed gastric cancer. A CT scan showed regional and para-aortic lymph node (LN) swelling and multiple hepatic metastasis in the left hepatic lobe. The serum CEA level was 100.6 ng/dl. He was administered 4 courses of CDDP (100 mg (day 8 i.v.)) plus TS-1 (120 mg/day day 1-21 p.o.). After the chemotherapy, CT showed a reduction of liver metastasis and disappearance of the LN swelling. The serum CEA levels were normalized. Distal gastrectomy, partial hepatectomy, and microwave coagulation therapy were performed. After operation, he was administered 4 courses of CDDP/TS-1 additionally. Surgery may be one of therapeutic option for AGC with liver metastasis that has responded to chemotherapy, as in the present case.

[Two cases of resection of synchronous bilobar multiple liver metastases from colorectal cancer after hepatic arterial infusion chemotherapy].

We report 2 cases of synchronous bilobar multiple liver metastases from colorectal cancer which are hepatectomised following a hepatic arterial infusion chemotherapy. Both cases were considered unresectable metastases before chemotherapy. Case 1: A 55-year-old male, with rectal cancer and multiple hepatic metastases, was performed a low anterior resection. Hepatic arterial infusion chemotherapy (5-FU 1 g/m2 5h qw) and systemic chemotherapy (5-FU/LV) were administered. Twelve months after the first surgery, hepatectomy was performed. Case 2: Right hemicolectomy was performed on a 66-year-old male, with cancer of the transverse colon and multiple hepatic metastases. Hepatic arterial infusion chemotherapy was administered 38 times. Thirteen months after the first surgery, hepatectomy and MCT were performed. Even among the cases of unresectable hepatic metastases from colorectal cancer, there are some in which resection is possible followed by hepatic arterial infusion chemotherapy. Re-evaluation for hepatectomy is needed for the cases where hepatic arterial infusion chemotherapy is administered.

[A case responding to weekly paclitaxel therapy as second-line chemotherapy for gastric cancer previously treated with TS-1].

A 58-year-old male patient with the recurrence of para-aortic lymphnodes after TS-1 treatment was treated by a weekly infusion of paclitaxel as second-line chemotherapy. Paclitaxel was administered at a weekly dose of 70 mg/m2/day for three weeks followed by a one week interval. After 2 courses, the tumor was reduced, and the reduction was judged as PR. Moreover, after 5 courses, the tumor was more remarkably reduced and the reduction was judged as CR. The grade 2 leukopenia, neutropenia, and grade 1 alopecia were observed as adverse events. Recently, we treated 11 patients of advanced or recurrent gastric cancers with measurable lesions, using the weekly paclitaxel therapy after TS-1 treatment. The response rate was 36.4%. The median duration of PR was 130 days. Therefore, a weekly paclitaxel regimen was considered to be one of the promising regimens for advanced or recurrent gastric cancer as the second-line chemotherapy after TS-1 treatment.

[Distilled water pleurodesis for two breast cancer patients suffering from carcinomatous pleurisy].

Pleural effusion of carcinomatous pleurisy is relatively common and a significant problem in recurrent breast cancer patients. It's very important to control it to keep a good quality of life for those patients. Two recurrent breast cancer patients, suffering from carcinomatous pleurisy and dyspnea due to pleural effusion, were treated with distilled water. As they have been treated with many kinds of hormonal therapy or chemotherapy for their several distant metastases, the performance status of these therapies has not been good. After one or two distilled water pleurodesis, pleural effusion was well controlled and dyspnea had disappeared. No adverse events, such as high fever and chest pain concerning this distilled water therapy were experienced. Taking its efficacy and a rarity of adverse events, distilled water plerodesis is a useful treatment for pleural effusion of carcinomatous pleurisy.

[Long-term outcome of advanced hepatocellular carcinoma that received transarterial hepatic chemotherapy].

Nineteen patients with far advanced hepatocellular carcinoma received transarterial hepatic chemotherapy. Twelve patients were Child-Pugh A, 2 were B, and 2 were C. Seventeen patients had portal vein thrombus, and 2 patients had extra-hepatic metastasis. Among the 19 patients, 13 received low-dose CDDP and 5-FU, and 5-FU with interferon was performed in 2. Lipiodol chemotherapy with epirubicin and MMC was performed after first-line chemotherapy, following the evaluation of the progressive disease. The 1- and 3-year survival rates in all cases were 42.5% and 18.2%, respectively. Of the 18 patients evaluated for response, 1 showed complete response, 2 showed partial responses, 8 had stable disease, and 7 progressed. Median survival time of CR, PR and SD patients was 14.2 months. A multivariate analysis identified CLIP score and therapeutic effect as independent predictors for mortality. It is concluded that transarterial hepatic chemotherapy was very useful for far advanced hepatocellular carcinoma.

[Surgical indication and significance of local therapy for first pulmonary metastases from colorectal cancer].

We often observe pulmonary metastases in patients following advanced colorectal cancer, especially rectal cancer. The prognoses of LM3 patients and patients with histological v2 factor in the primary site were unfavorable. Surgery was not indicated in these cases. Some patients experienced rapid progression during the standby period for surgery. For the surgery group, we recommend systemic reexaminations after several months. Pulmonary resections for metastatic colorectal cancer are beneficial to the selected patients and 5-year survival rate was 52.6%. New pulmonary relapses were also encountered which were the cause of death among the surgical patients. Close follow-up and multimodal therapy including surgery contributed to longer survival for postoperative pulmonary metastatectomy patients with colorectal cancer.

[A case of spinal infarction related to hepatic arterial infusion chemotherapy].

A 65-year-old male underwent iliocecal excision and hepatic posterior segmentectomy for cecum cancer and synchronous liver hepatic metastasis in September and October 2001, respectively. A reservoir was implanted by the GDA-coil method from the right femoral artery in November, and WHF (5-FU 1,000 mg/m2) was administered 8 times. Because of the remnant liver recurrence, WHF was restarted in April 2002. Left leg paralysis appeared suddenly after the 3rd administration. Heparin and urokinase were administrated continuously after hospitalization. Also, liver function tests showed a worsening condition. The bile duct necrosis in the liver was examined with abdominal CT scan. The anti-coagulation therapy was changed to an oral drug on the 7th day after hospitalization. The liver function tests normalized gradually. Although the rehabilitation for leg paralysis performed during hospitalization was continued after discharge from the hospital, the patient is unable to walk and uses a wheelchair. Hepatic arterial infusion chemotherapy is considered safe for blood and non-blood toxicity compared with systemic chemotherapy. However, there are also complications as in this case, where QOL is reduced remarkably, and caution is required.

[A case report of hepatocellular carcinoma with portal thrombus responding to hepatic arterial infusion chemo-lipiodolization].

A 73-year old man with multiple hepatocellular carcinomas underwent 4 transarterial chemoembolizations, but a tumor thrombus appeared in the left portal vein. The tumor sizes in segments 4 and 5 were 4.0 cm and 2.4 cm, respectively. The serum levels of AFP and PIVKA-II were 14,991 ng/ml and 15,944 mAU/ml, respectively. The tumor was 5-FU palpable in the epigastric region. Four ml of SMANCS and 4 ml of Lipiodol were injected to proper hepatic artery using the Seldinger technique. In addition, epirubicin (20 mg), MMC (4 mg) and Lipiodoi (2 ml) were injected into a proper hepatic artery via a reservoir every 3 weeks. The tumor was not palpable, and the tumor markers were markedly reduced after 2 months. The evaluation of response to the treatment was a partial response 3 months and 6 months later. Chemo-lipiodolization was very useful for advanced hepatocellular carcinoma with portal vein thrombus.

Management of hepatic arterial infusion port following prophylactic regional chemotherapy in patients who have undergone curative resection of colorectal liver metastases.

PURPOSE: Although hepatic arterial infusion (HAI) is widely performed as a prophylactic chemotherapy for patients who have undergone a curative resection of a metastatic liver tumor from colorectal cancer, the optimal management of implantable ports and catheters after the cessation of such adjuvant therapy remains to be elucidated. METHODS: The survival and recurrence rate of 30 patients who received adjuvant regional chemotherapy following a hepatectomy were examined. The outcomes of the 15 patients who were regularly administered heparin into the port to prevent its occlusion were also analyzed. RESULTS: With a median follow-up period of 38.1 months, local recurrence in the residual liver was observed in only 5 patients (17%), and the 3-year hepatic disease-free survival was as high as 82%. Out of the 15 patients who received heparin injection, the ports were successfully maintained in only 6 patients (40%) at from 8.8 to 24.7 months (median, 10.8 months) postoperatively, and 69% of the implantable ports were maintained without occlusion for 12 months. Furthermore, a second course of regional chemotherapy was carried out in only one patient, while a repeat hepatectomy was performed instead of chemotherapy in the other patients with hepatic recurrence. CONCLUSIONS: Because HAI remarkably reduced the degree of relapse in the residual liver, there is no benefit in maintaining the port after discontinuing the chemotherapy. Heparin administration via the same port after a cessation of the prophylactic HAI chemotherapy is not justified, and it is desirable to remove the implanted catheter when possible.

Surgery for gastric cancer increases plasma levels of vascular endothelial growth factor and von Willebrand factor.

BACKGROUND: Angiogenesis and hemostatic activation are important factors in tumor progression and metastasis. Because surgical intervention induces tissue hypoxia and hemostatic activation, we analyzed the effect of gastric surgery on the plasma concentrations of vascular endothelial growth factor (VEGF), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). METHODS: Plasma VEGF, sP-selectin, and vWf concentrations were measured in 14 patients with gastric cancer before operation and on postoperative day 1 (POD 1). Correlations between disease stage and the effect of surgical intervention were analyzed. RESULTS: The plasma concentrations of these three factors did not correlate with the disease stage. Plasma levels of sP-selectin did not change after operation (before surgery, 87.6 +/- 34.1 ng/ml; on POD 1, 101.1 +/- 48.1 ng/ml; P = 0.123). Plasma VEGF and vWf concentrations were significantly elevated on POD 1 (VEGF, 33.3 +/- 20.5 pg/ml before surgery and 61.9 +/- 35.6 pg/ml on POD 1; P = 0.0013; vWf, 164 +/- 31.1% before surgery and 211.1 +/- 66.1% on POD 1; P = 0.027). CONCLUSION: Because VEGF and vWf are involved in angiogenesis, tumor-platelet adhesion, and tumor-endothelial cell adhesion, surgical intervention could influence tumor growth and metastasis.

Poor prognosis associated with thrombocytosis in patients with gastric cancer.

BACKGROUND: Thrombocytosis is commonly associated with malignant disease and has recently been suggested to be a poor prognostic indicator in patients with lung cancer and gynecological cancers. The prevalence of thrombocytosis in patients with gastric cancer was reviewed, and its association with poor prognosis was investigated. METHODS: Platelet count (PLT) and hemoglobin concentrations (Hb) were reviewed in 369 consecutive patients with histologically verified gastric cancer from 1994 to 2000. Differences between categories were analyzed with analysis of variance, and survival was compared by using the log-rank test on the Kaplan-Meier life table. Multivariate Cox regression analysis was used to evaluate whether thrombocytosis is an independent prognostic marker. RESULTS: Thrombocytosis was found in 42 patients, and anemia was found in 200 patients. PLT was negatively correlated with Hb. Mean PLT was significantly increased in patients with noncurative operations. There was a positive correlation between the depth of tumor invasion and PLT. One- and 3-year survival expectancies in patients with or without thrombocytosis were 52.4% and 23.4% and 85.7% and 72.9%, respectively. PLT was identified as an independent prognostic factor after lymph node metastasis and depth of tumor invasion. CONCLUSIONS: Thrombocytosis is an independent prognostic indicator of survival in patients with gastric cancer.