A pilot study of docetaxel-carboplatin versus paclitaxel-carboplatin in Japanese patients with epithelial ovarian cancer

Background It has been reported that a docetaxel-carboplatin combination as first-line chemotherapy for ovarian cancer showed a level of progression-free survival similar to that of paclitaxel-carboplatin while reducing neurotoxicity and improving quality of life. We investigated the recommended doses of docetaxel-carboplatin in Japanese patients with ovarian cancer and conducted a comparative study of docetaxel-carboplatin versus paclitaxel-carboplatin. Methods Thirty-nine patients with ovarian cancer were enrolled in this study and 38 patients were evaluated. We conducted a dose-escalation study using a docetaxel dose of 70 mg/m² and carboplatin AUC 5 and 6. In the comparative study, patients received either docetaxel 70 mg/m² and carboplatin AUC 5 or paclitaxel 175 mg/m² and carboplatin AUC 5. Progression-free survival, survival rate at 2 years, response rate, toxicity, and quality of life were investigated. Results In the dose-finding study, we determined the recommended doses as docetaxel 70 mg/m² and carboplatin AUC 5. In the comparative study, the two arms showed similar progression-free survival. Grade 4 neutropenia occurred more frequently in the docetaxel-carboplatin group (84.6%) than in the paclitaxel-carboplatin group (43.8%), while sensory neurotoxicity was less frequent in the docetaxel-carboplatin group (53.8%) than in the paclitaxel-carboplatin (68.8%) group. There were significant differences in the quality-of-life data in favor of docetaxel-carboplatin. Conclusion We determined the recommended doses of docetaxel-carboplatin for Japanese patients with ovarian cancer to be docetaxel 70 mg/m² and carboplatin AUC 5. In the comparative study, we suggest that the docetaxel-carboplatin combination is effective and well tolerated as first-line chemotherapy for Japanese patients with ovarian cancer.     

Phase I study of cisplatin analogue nedaplatin, paclitaxel, and thoracic radiotherapy for unresectable stage III non-small cell lung cancer

BACKGROUND: The standard treatment of unresectable stage III non-small cell lung cancer is concurrent chemoradiotherapy in patients in good general condition, but where the optimal chemotherapeutic regimen has not been determined. METHODS: Patients with unresectable stage III non-small cell lung cancer received nedaplatin (80 mg/m2) and paclitaxel on day 1 every 4 weeks for 3-4 cycles and concurrent thoracic radiotherapy (60 Gy/30 fractions for 6 weeks) starting on day 1. The dose of paclitaxel was escalated from 120 mg/m2 in level 1, 135 mg/m2 in level 2 to 150 mg/m2 in level 3. RESULTS: A total of 18 patients (14 males and 4 females, with a median age of 62.5 years) were evaluated in this study. Full cycles of chemotherapy were administered in 83% of patients in level 1, and in 50% of patients in levels 2 and 3. No more than 50% of patients developed grade 4 neutropenia. Transient grade 3 esophagitis and infection were noted in one patient, and unacceptable pneumonitis was noted in three (17%) patients, two of whom died of the toxicity. Dose-limiting toxicity (DLT), evaluated in 15 patients, noted in one of the six patients in level 1, three of the six patients in level 2 and one of the three patients in level 3. One DLT at level 2 developed later as radiation pneumonitis. Thus, the maximum tolerated dose was determined to be level 1. The overall response rate (95% confidence interval) was 67% (41-87%) with 12 partial responses. CONCLUSION: The doses of paclitaxel and nedaplatin could not be escalated as a result of severe pulmonary toxicity.     

Effect of platinum combined with irinotecan or paclitaxel against large cell neuroendocrine carcinoma of the lung

BACKGROUND: The efficacy of chemotherapy in patients with large cell neuroendocrine carcinoma of the lung (LCNEC) remains unclear. METHODS: Of 42 consecutive patients with LCNEC, 22 with measurable disease receiving chemotherapy were enrolled as the subjects of this study. The clinical characteristics and objective responses to chemotherapy in these patients were analysed retrospectively. RESULTS: The distribution of the disease stage in the patients consisting of 21 males and one female (median age: 67 years; range: 47-78 years) was as follows: stage IIB (n = 1), stage IIIA (n = 1), stage IIIB (n = 5), stage IV (n = 8), and post-operative recurrence (n = 7). Chemotherapy consisted of cisplatin and irinotecan (n = 9), a platinum agent and paclitaxel (n = 6), paclitaxel alone (n = 1), cisplatin and vinorelbine (n = 1), cisplatin and docetaxel (n = 1), and a platinum and etoposide (n = 4). The objective response rate in the 22 patients was 59.1% (95% CI, 38.1-80.1). An objective response was obtained in five of the nine patients receiving irinotecan and five of the seven patients receiving paclitaxel. The progression-free survival, median overall survival and 1-year survival rates were 4.1 months (95% CI, 3.1-5.1), 10.3 months (95% CI, 5.8-14.8) and 43.0% (95% CI, 20.7-65.3), respectively. The median overall survival of the patients treated with irinotecan or paclitaxel was 10.3 months (95% CI, 0-21.8), and the 1-year survival rate of these patients was 47.6% (95% CI, 20.4-74.8). CONCLUSION: Our results suggest that irinotecan and paclitaxel may be active against LCNEC.     

A feasible study of docetaxel/nedaplatin combined chemotherapy for relapsed or refractory esophageal cancer patients as a 2nd-line chemotherapy

As a 2nd-line treatment for relapsed or refractory esophageal cancer patients after chemoradiotherapy, we performed a combination chemotherapy of DOC/CDGP for 11 patients.Intravenous drip infusion of DOC 30 mg/m(2)and CDGP 30 mg/m(2)on days 1, 8 and 15, and 4 weeks treatment was assumed as 1 cycle.We treated 8 of 11 patients with more than 2 cycles, and 4 of 8 patients were treated with radiation therapy (RT). The effects by RECIST revealed partial response (PR) in 2 patients (50%), stable disease (SD) in 1 patient and progress disease (PD) in 1 patient without RT, and PR in 3 patients and not effective in 1 patient with RT, respectively. There was no treatment-related death nor adverse event of grade 4. The Hematological toxicities of leukopenia of grade 3 were observed in 3 patients. Non-hematological toxicites more than grade 3 were not observed. The combination chemotherapy of DOC/CDGP was concluded to be safe and effective for relapsed or refractory esophageal cancer patients as a 2nd line treatment.     

Transcatheter arterial embolization for the continuous bleeding from duodenal carcinoma--a case report

We report a case of duodenal carcinoma with continuous bleeding that was successfully treated with transcatheter arterial embolization using gelatin sponge particles. The case was a woman in her 70's who had a curative surgical resection for sigmoid colon cancer with liver and lung metastases, hepatic arterial infusion chemotherapy and radiofrequency ablation for liver metastasis in the past. She was admitted to our hospital because of liver abscess and anemia. Upper gastrointestinal endoscopy revealed active bleeding from a duodenal tumor. The biopsy of the specimens was made and showed duodenal adenocarcinoma. The patient was considered to be inoperable because of the liver abscess and transcatheter arterial embolization of an anterior superior pancreaticoduodenal artery through an inferior pancreaticoduodenal artery was performed for the continuous bleeding from duodenal carcinoma not completely treated by endoscopic hemostasis or frequent transfusion. After the tumor embolization anemia was improved and partial response was obtained by systemic chemotherapy of mFOLFOX6. Transcatheter arterial embolization for a continuous bleeding from duodenal carcinoma is a feasible and effective method as a noninvasive therapy when it is unabled to be treated by surgical resection or endoscopic therapy.     

A case of multiple liver metastases from rectal cancer in poor performance status successfully treated with hepatic arterial infusion chemotherapy plus CPT-11

Hepatic arterial infusion (HAI) chemotherapy is one of the strategies for cases in poor performance status. This is a case report of multiple liver metastases from rectal cancer in poor performance status successfully treated with HAI plus CPT-11. A 59-year-old man who had rectal cancer, multiple liver metastases and para-aortic LN metastasis underwent a laparoscopic rectal anterior resection. He denied receiving postoperative chemotherapy and selected alternative therapy at another clinic. Four months later, he visited our hospital. His liver metastasis and performance status got worse, so HAI of 5-FU 1250 mg/m2 for 5-hour weekly (weekly high-dose 5-FU: WHF) was started at first. After 3 courses, his status improved, so systemic chemotherapy was added. HAI (WHF: 1000 mg/m2) plus CPT-11 (100 mg/m2) was effective, and liver metastases showed a significant reduction (PR) on abdominal CT. HAI plus CPT-11 was effective for a patient of the poor performance status with unresectable liver metastasis.     

The efficacy of transcatheter embolization of severe arterioportal shunts in hepatocellular carcinoma

Transcatheter arterial embolizations of severe arterioportal shunt (A-P shunt) were performed with steel coils in 3 patients with hepatocellurlar carcinoma (HCC) as shown below. Case 1: A 56-year-old man with HCC associated with portal hypertension (esophageal varices and ascites abnominal pain), portal vein tumor thrombus and severe A-P shunt was performed in critical conditions. Case 2: A 51-year-old man with HCC, lung and adrenal gland metastases was accompanied with severe portal hypertention caused by A-P shunt and was in a harmful condition similar to case 1. Case 3: A 68-year-old woman with HCC associated with autoimmune hepatitis was performed a hepatic resection. Then multiple intrahepatic recurrences appeared 6 months later. A-P shunt made impossible to detect the feeding artery of tumor. After embolization of A-P shunt, esophageal varices and ascites resolved, and abdominal pain improved in cases 1 and 2. In addition, embolization enabled to perform transcatheter arterial chemoembolization in case 3. This procedure is a useful tool to improve various symptoms due to A-P shunt and to continue treatments for HCCs.     

Induction of interleukin-8 (CXCL-8) by tumor necrosis factor-alpha and leukemia inhibitory factor in pancreatic carcinoma cells: Impact of CXCL-8 as an autocrine growth factor

Pancreatic carcinoma is one of the most lethal of the gastrointestinal malignant tumors. Chronic inflammation leads to cancer development and progression. Interleukin-8 (CXCL-8) is a CXC chemokine, which plays an important role in neutrophil chemotaxis and activation. We previously reported that CXCL-8 was produced by a variety of human carcinoma cells and tissues, and that CXCL-8 promoted proliferation in pancreatic carcinoma cells (SUIT-2). In the present study, we analyzed whether various cytokines affect cell proliferation by CXCL-8 expression in pancreas carcinoma cells. All examined pancreatic carcinoma cells expressed CXCL-8 and TNFRII mRNA constitutively in RPMI-1640 medium without FBS. TNF-alpha, LIF, IL-1beta, IL-6, IL-8, or IFN-beta enhanced the expression of CXCL-8 mRNA, but IL-10 did not in Hs-700T cells. Actinomycin D suppressed and cycloheximide augmented CXCL-8 mRNA which was induced by TNF-alpha or not. The half-life of CXCL-8 mRNA was 36.5 min by TNF-alpha and 35.2 min by no stimulation. In our previous study, LIF promoted cell growth in Hs-700T cells. LIF induced CXCL-8 mRNA in a dose- and time-dependent manner. Addition of recombinant CXCL-8 did not induce cell growth of Hs-700T. Anti-CXCL-8 IgG significantly suppressed cell growth. CXCL-8 would act as an autocrine growth factor in Hs-700T cells, which expressed CXCL-8 mRNA highly without stimulation. Curcumin (diferuloylmethane), NF-kappaB inhibitor, suppressed cell proliferation in Hs-700T cells. These results suggest that CXCL-8 plays a pivotal role in progression of pancreatic cancer, and its expression is influenced by inflammatory cytokines in pancreatic tumor microenvironment.     

Investigation of optimal schedule of concurrent radiotherapy with S-1 for oral squamous cell carcinoma

In the present study, we examined the appropriate schedule of S-1 medication in the combination with radiation by investigating the safety, the clinical efficacy, and antitumor effects on tumors in nude mice. In the patients with oral squamous cell carcinoma (OSCC), S-1 was given orally according to a 4-week application followed by 2-week rest regimen (4-week regimen), or a 2-week application followed by a 1-week rest regimen (2-week regimen). Radiation was given (2 Gy/day; 5 days/week) for a total of 60 Gy. In nude mouse models, human oral cancer cell lines were used as subcutaneous xenografts in nude mice. The mice were treated by S-1 (10 mg/kg) and radiation (1 Gy) with a 4-week regimen or a 2-week regimen. Apoptotic cells were detected by TUNEL method. In the patients with OSCC, the response rate with the 4-week regimen was 100% and the response rate with the 2-week regimen was 92.3%. However, a high frequency of adverse effect was found in the 4-week regimen when compared to the 2-week regimen. Grade 3 toxicity of leukopenia, neutropenia and stomatitis were seen in 3 cases, grade 3 toxicity of anorexia and nausea were seen in 2 cases, and grade 3 toxicity of decrease of hemoglobin level, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 4-week regimen. On the other hand, grade 3 toxicity of stomatitis, anorexia, nausea, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 2-week regimen. In nude mouse models, the 2-week regimen was more effective than the 4-week regimen. In addition, significant increase in the percentage of apoptotic cells was observed in the tumors treated with the 4-week regimen when compared with the tumors treated with the 2-week regimen. No loss of body weight was observed in mice treated with the 2-week regimen during the experimental period. These results suggested that the 2-week regimen might reduce adverse effects, and enhance therapeutic effects compared to the 4-week regimen. Briefly, this 2-week regimen may be a useful concurrent chemo-radiotherapy improving the quality of life (QOL) of patients with OSCC.     

An antisense oligonucleotide to HSP47 inhibits paraquat-induced pulmonary fibrosis in rats

The most common cause of death from poisoning by the widely used, but highly toxic herbicide paraquat is respiratory failure from pulmonary fibrosis, which develops through pathological overproduction of extracellular matrix proteins such as the collagens. Heat shock protein (HSP47) is a collagen-specific molecular chaperone that assists in the posttranslational modifications of procollagens during collagen biosynthesis. We investigated whether treatment with an HSP47-antisense oligonucleotide would inhibit paraquat-induced pulmonary fibrosis in Wistar rats. Rats randomized into three groups (control, paraquat, and paraquat+antisense). Paraquat (20 mg/kg/day) (n=16) or a saline control (n=10) was administered to groups of Wistar rats. Intratracheal administration of the antisense oligonucleotide (100 nmol/kg in saline) was performed after the initial paraquat treatment (n=16). Treatment with paraquat alone induced pulmonary fibrosis in the entire group, while treatment with the antisense oligonucleotide alone did not produce any substantial change in lung histology. Administration of antisense oligonucleotides produced a substantial reduction in paraquat-induced pulmonary fibrosis. An immunoblot analysis confirmed that the HSP47-antisense oligonucleotide inhibited HSP47 production. These findings indicate that the HSP47-antisense oligonucleotide inhibited paraquat-induced pulmonary fibrosis and pneumopathy in rats.