First clinical pharmacokinetic dose-escalation study of sagopilone, a novel, fully synthetic epothilone, in Japanese patients with refractory solid tumors.

PURPOSE: Sagopilone has recently been identified and preferentially used for the treatment of taxane-resistant cancer. The purpose of this dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics (PK) of sagopilone in refractory solid tumors. METHODS: A total of 17 Japanese patients received sagopilone in this Phase I study. Sagopilone was given as a 30-min intravenous infusion once every 3 weeks (one course) with an initial dose of 12.4 mg/m(2) up to 22.0 mg/m(2) for a maximum of 6 courses. RESULTS: The maximum tolerated dose (MTD) was determined to be 16.5 mg/m(2). The major dose-limiting toxicity (DLT) was peripheral sensory neuropathy. The PK data demonstrated that sagopilone did not accumulate after repeated administration. Two patients had stable disease (SD) over a period of 12 weeks. CONCLUSIONS: Our study demonstrated clinically favorable safety, tolerability, and efficacy of sagopilone, which will help define the treatment of advanced tumors in more extensive clinical trials.

A retrospective study of definitive chemoradiotherapy for elderly patients with esophageal cancer.

OBJECTIVE: The efficacy and safety of definitive chemoradiotherapy (CRT) for elderly patients with esophageal cancer have not been fully elucidated yet. We conducted a retrospective comparison of the outcomes of CRT between elderly and nonelderly patients with Stage II-III (non-T4) esophageal cancer. METHODS: There were 33 elderly (aged over 71) patients and 145 nonelderly (aged under 70) patients who fulfilled the selection criteria. The treatment consisted of the continuous infusion of fluorouracil (5-FU) and the intravenous infusion of cisplatin (CDDP) combined with 60 Gy of radiation. RESULTS: Although the CR rate was almost identical between the 2 groups (63.6% vs. 63.4%, respectively), the recurrence rate after CR was higher in the elderly patients group than in the nonelderly patients group (47.6% vs. 33.7%, P = 0.32). The elderly patient group showed a significantly inferior survival in comparison to the nonelderly patient group with a median survival time (14.7 months vs. 35.1 months, P = 0.01). Discontinuations at the end of CRT were more frequent in the elderly patient group than in the nonelderly patients (57.6% vs. 17.3%, P = 0.01). In addition, over Grade 3 hematologic adverse events were more frequently observed in elderly patients than in nonelderly patients. There were no obvious differences in patients who died of causes other than primary disease. CONCLUSION: This retrospective analysis revealed a significantly inferior efficacy even in selected elderly patients. Although improving the dose intensity of CRT should be desirable even in elderly patients, it seems to be difficult because of more substantial toxicity in elderly patients.

[Therapeutic agents for disorders of bone and calcium metabolism--Denosumab, a fully human monoclocal antibody-targeting RANKL as a therapy for cancer-induced bone diseases].

Receptor activator of nuclear-kappaB ligand (RANKL) is a protein expressed by oseoblastic stromal cells, binds to receptor activator of nuclear factor-kappaB (RANK) and is the primary mediator of osteoclast differentiation, activation, and survival. RANKL is responsible for osteoclast-mediated bone resorption in a broad range of conditions and play a key role in establishment and propagation of skeletal disease in patients with advanced cancer. Denosumab is a fully human monoclonal antibody that binds RANKL with high affinity and specificity and inhibits RANKL-RANK interaction, mimicking the endogenous effects of osteoprotegerin, a soluble RANKL decoy receptor. In the phase 1 clinical trials in healthy post menopausal women and patients with multiple myeloma or breast cancer with bone metastasis including Japanese (except for multiple myeloma) showed that single and multiple subcutaneous injection of denosumab caused rapid and sustained suppression of markers of osteoclastic bone resorption with favorable safety profiles. Currently, the larger global clinical trials to investigate the effect of this agent for the treatment of cancer-induced bone disease as well as osteoporosis are underway.

Phase I/II study of oxaliplatin with weekly bolus fluorouracil and high-dose leucovorin (ROX) as first-line therapy for patients with colorectal cancer.

BACKGROUND: Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD. METHODS: The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m2) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m2) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). RESULTS: A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied. CONCLUSIONS: Oxaliplatin (85 mg/m2) with weekly bolus 5-FU (400 mg/m2) and high-dose l-LV (250 mg/m2) is recommended for further phase III studies in patients with metastatic colorectal cancer.

Depressed-type (0-IIc) colorectal neoplasm in patients with family history of first-degree relatives with colorectal cancer: A cross-sectional study.

AIM: To investigate the correlation of depressed-type (0-IIc) colorectal neoplasm and family history of first-degree relatives (FDR) with colorectal cancer (CRC). METHODS: This cross-sectional study was conducted from June 2000 to October 2002 at National Cancer Center Hospital East. Eligible patients undergoing initial total colonoscopy were surveyed regarding family history of CRC among FDR by a questionnaire prior to colonoscopic examinations. All endoscopic findings during colonoscopy were recorded and the macroscopic classification of the early stage neoplasm/cancer was classified into two types (0-IIc vs non 0-IIc). Odds ratios (OR) and 95% confidence intervals (CI) were calculated by univariate and multivariate logistic regression to estimate the association between macroscopic features and clinicopathological data including gender, age, and family history of FDR with CRC. RESULTS: The OR of an association between family history of FDR with CRC and overall early stage neoplasm adjusted by gender and age was 1.85 (95% CI: 1.31-2.61, P = 0.0004), that for non 0-IIc neoplasm was 1.71 (95% CI: 1.22-2.41, P = 0.0017) and for 0-IIc colorectal neoplasm was 2.78 (95% CI: 1.49-5.16, P = 0.0031). CONCLUSION: Our study shows a significant association between a family history of FDR with CRC and 0-IIc colorectal neoplasm. When patients with a family history of FDR with CRC undergo colonoscopy, colonoscopists should check carefully for not only polypoid, but also depressed-type (0-IIc) lesions.

Epstein-Barr virus involvement is a predictive factor for the resistance to chemoradiotherapy of gastric diffuse large B-cell lymphoma.

Primary gastric diffuse large B-cell lymphomas are generally well controlled by non-surgical treatment with combination chemotherapy followed by radiotherapy. We have previously reported that over 90% of patients achieved complete response (CR) with this therapeutic strategy: three cycles of cyclophosphamide, adriamycin, vincristine and prednisone followed by radiotherapy (40.5 Gy). Although the CR rate was very high, some patients still showed resistance to this combination therapy. In order to clarify the factors related to therapy resistance, we examined the relationship between Epstein-Barr virus (EBV), which was examined using an in situ hybridization technique, and the patients' clinical courses. Out of the 50 patients, four were EBV positive; over half of lymphoma cells were positive for EBV by in situ hybridization. Of the three EBV-positive patients, two showed progressive disease and one achieved partial response (PR). Two of the patients died of disease progression. The other patient achieved CR, but the lymphoma recurred with distant metastasis in the cerebellum 3 months after remission. In the present study, eight patients did not achieve CR or they relapsed, four patients showed progressive disease, one patient achieved PR, and three patients achieved CR with recurrence. Therefore, half of these unfavorable patients were EBV positive. This finding strongly indicated that EBV-associated gastric diffuse large B-cell lymphomas frequently show resistance to standard chemoradiotherapy, although some other adverse factors remain unclear.

Distribution and prevalence of colorectal hyperplastic polyps using magnifying pan-mucosal chromoendoscopy and its relationship with synchronous colorectal cancer: prospective study.

BACKGROUND AND AIM: Patients with multiple (hyperplastic polyposis) or large hyperplastic polyps (HPs) predominantly in the right-sided colon, have been reported to have an increased risk of colorectal cancer (CRC). This prospective study was conducted to clarify the distribution of various sized HPs using magnifying pan-mucosal chromoendoscopy and its relationship with synchronous CRC. METHODS: Patients eligible for this study had an initial total colonoscopy. Indigo carmine dye was sprayed throughout the whole colon and rectum, and diagnoses were made using magnifying colonoscopy. RESULTS: A total of 263 patients were enrolled, and a total of 3060 HPs were observed in 226 (86%) patients. The prevalence of patients with intermediate size (> or = 6 mm) HPs was 8.7% (n = 23) and that of patients with large HPs (> or = 10 mm) was 0.8% (n = 2). Of 3060 HPs, the numbers of diminutive (< 6 mm), intermediate size and large HPs were 3020, 38 and two, respectively, and 5.0%, 42.1% and 100% of these were located in the right-sided colon, respectively. Synchronous CRC was observed in 64 (24%) of 263 patients. Compared to patients without HPs, patients with intermediate size HPs showed a significant increase in odds ratio (OR) for synchronous CRC (OR = 4.9: 95% CI [1.3-18.2]), but there was no significant association between synchronous CRC and patients with diminutive or large HPs. CONCLUSIONS: Compared to diminutive HPs, intermediate size and large HPs were predominantly located in the right-side colon. Moreover, intermediate size HPs were significantly correlated with synchronous CRC.

Japanese multicenter phase II study of CHOP followed by radiotherapy in stage I-II, diffuse large B-cell lymphoma of the stomach.

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by radiotherapy is regarded as standard care for localized aggressive lymphoma; however, prospective confirmation of its applicability to localized primary gastric lymphoma is inadequate, and most patients in Japan have been initially treated with gastrectomy. We conducted a multicenter phase II study to evaluate the feasibility and efficacy of the non-surgical treatment. Eligibility criteria required primary gastric diffuse large B-cell lymphoma, stage I-II(1), age 20-75, performance status 0-1 and adequate organ function. Treatment consisted of three cycles of CHOP followed by radiotherapy 40.5 Gy. Fifty-five patients were enrolled between December 1999 and February 2003, and 52 eligible patients were analyzed. Patient characteristics were as follows: median age, 61 years; 28 men, 24 women; 36 with stage I, 16 with stage II(1); 47 with a low International Prognostic Index (IPI) and five with a low-intermediate IPI. All but one patient completed planned treatment. No serious complications including massive hemorrhage or perforation were observed. A complete response was achieved in 48 of the 52 patients (92%, 95% confidence interval: 82-98%) and progressive disease in three. Two patients underwent salvage gastrectomy due to disease persistence or recurrence. With a median follow-up period of 28 months, 2-year progression-free and overall survivals were 88 and 94%, respectively. CHOP followed by radiotherapy is safe and highly effective in localized gastric diffuse large B-cell lymphoma. This organ-preserving treatment should be considered as a very reasonable therapeutic option.

[Controversies in the treatment of esophageal cancer from the viewpoint of medical oncology].

Recent advances in non-surgical treatments such as endoscopic mucosal resection (EMR) and chemoradiotherapy (CRT) have provided various advantages with clinically meaningful impacts in the treatment of esophageal cancer. EMR is a standard treatment for mucosal cancer and is being investigated for use in combination with CRT for submucosal cancer. Definitive CRT has also reported to results in survival mostly comparable with surgery in the loco-regional stage. A randomized trial comparing surgery alone with definitive CRT in stage I disease is also planned. In patients with T4 disease, it appears that CRT is becoming a standard. However, various issues and limitations remain with non-surgical treatments. To improve treatment results, closer collaboration between surgeons and radiation oncologists is necessary.

Long-term toxicity after definitive chemoradiotherapy for squamous cell carcinoma of the thoracic esophagus.

PURPOSE: To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus. PATIENTS AND METHODS: Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age

Efficacy and safety profile of S-1 in patients with metastatic gastric cancer in clinical practice: results from a post-marketing survey.

BACKGROUND: S-1(TS-1), a novel oral fluoropyrimidine, has been commercially available for gastric cancer in Japan. A nationwide post-marketing survey for safety was carried out after its approval. The aim of this analysis was to evaluate the efficacy and safety profile of this agent in clinical practice for patients with advanced gastric cancer registered in the postmarketing survey from our institution. METHODS: Between April 1999 and April 2000, a total of 51 chemo-naive patients were registered in the survey from the National Cancer Center Hospital East. S-1 was administered at 80 mg/m2/day for 4 weeks, followed by a 2-week rest, repeated every 6 weeks until disease progression, unacceptable toxicity, or the patient's refusal. RESULTS: Of the 51 patients, 41 (80%) fulfilled the criteria of the guidelines determined by the company as appropriate patients for the drug administration. The median number of treatment courses was five. Toxicities were generally mild: grade 3 or 4 toxicities were seen in 10% or fewer patients, and no treatment-related deaths occurred. In the 47 patients with evaluable lesions, there were 2 complete responses and 18 partial responses, with a response rate of 43%. With a minimum follow-up of 2 years, median survival time and 2-year survival were 11.1 months and 33%, respectively. The majority of the 17 2-year survivors had diffuse-type histology and peritoneal metastasis and achieved an objective response. CONCLUSION: S-1 appears to be safe and highly active, with favorable longterm survival in patients with metastatic gastric cancer, particularly in those with diffuse-type histology and peritoneal metastasis.

Pilot study of transcatheter arterial chemoembolization with degradable starch microspheres in patients with hepatocellular carcinoma.

We prospectively evaluated the efficacy and safety of transcatheter arterial chemoembolization (TACE) with microembolization material, degradable starch microspheres (DSMs), and epirubicin, for treatment of multifocal hepatocellular carcinoma (HCC). Seventeen patients with multifocal HCC were treated. At the first treatment, DSMs were injected alone to determine the dose for embolization of the hepatic artery in each patient. After 4 weeks, TACE was performed every 4 to 6 weeks with a mixture of DSMs and epirubicin at a dose of 40 mg/m2. A necrotic area of more than 50% was produced in 6 patients by DSMs alone, and in 11 patients by TACE. The overall response rate was 52.9% (2 complete and 7 partial responses). The duration of the responses ranged from 4 to 21 months (median: 9 months). Common toxicities were transient abdominal pain, nausea/vomiting, fever, and leukopenia. In four patients, grade III or IV toxicity was observed as gamma-glutamyl transpeptidase elevation. TACE with DSMs had tumor necrosis efficacy with acceptable toxicity. The median survival time was 21.7 months, and the 2-year survival rate was 45.3%. Further investigation of the effects of DSM treatment on survival should be carried out.

Three novel single nucleotide polymorphisms in UGT1A10.

Three novel single nucleotide polymorphisms (SNPs) were found in the UDP-glucuronosyltransferase (UGT) 1A10 gene from 24 Japanese patients with various cancers who were administered the anti-tumor drug, irinotecan (CPT-11). The detected SNPs were as follows: 1) SNP, MPJ6_U1A003; GENE NAME, UGT1A10; ACCESSION NUMBER, AF297093; LENGTH, 25 bases; 5'-CAGATGCCATGAC/TTTTCAAGGAGAG-3'. 2) SNP, MPJ6_U1A004; GENE NAME, UGT1A10; ACCESSION NUMBER, AF297093; LENGTH, 25 bases; 5'-CCTAGAAATAGCC/TTCTGAAATTCTC-3'. 3) SNP, MPJ6_U1A030; GENE NAME, UGT1A10; ACCESSION NUMBER, AF297093; LENGTH, 25 bases; 5'-GGTTGTAGTCATG/ACCAGAGGTGAGT-3' All the three SNPs were located in exon 1 and their frequencies were all 0.021. Among these SNPs, MPJ6_U1A003 and U1A030 resulted in amino acid alterations, T202I and M59I, respectively. The third SNP, MPJ6_U1A004, introduced a synonymous amino acid change (A231A).