Protocol of a phase II study investigating the efficacy and safety of trifluridine/tipiracil plus ramucirumab as a third-line or later treatment for advanced gastric cancer.

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m2) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer.

Phase II multi-institutional prospective randomized trial comparing S-1 plus paclitaxel with paclitaxel alone as second-line chemotherapy in S-1 pretreated gastric cancer (CCOG0701).

BACKGROUND: The aim of this study was to explore whether a combination of S-1 and paclitaxel offers any benefit over paclitaxel alone to patients pretreated by S-1. METHODS: Gastric cancer patients who developed progression during S-1-based first-line chemotherapy or had recurrence during postoperative adjuvant chemotherapy by S-1 were randomly assigned to receive second-line treatment either by weekly administration of paclitaxel at 80 mg/m(2) three times every 4 weeks or daily oral S-1 (80 mg/m(2)) for 2 weeks plus paclitaxel (50 mg/m(2)) given on days 1 and 8, every 3 weeks (S-1 plus paclitaxel). The primary endpoint was progression-free survival (PFS) at 4 months after the initiation of treatment. RESULTS: A total of 78 patients were eligible for efficacy analyses-40 were assigned to the paclitaxel group and 38 to the S-1 plus paclitaxel group. PFS at 4 months was similar between the groups (50 % for paclitaxel vs 55 % for S-1 plus paclitaxel, P = 0.641). There were no differences between the groups either in progression-free survival (4.6 vs 4.6 months, respectively, P = 0.526), overall survival (10.0 vs 10.0 months, respectively, P = 0.464), or overall response rate (27 vs 22 %, respectively, P = 0.767). The incidences of grade 3 or 4 hematological and non-hematological toxicities were also equivalent between the two groups (25 vs 26 % and 24 vs 26 %, respectively). CONCLUSIONS: No benefit of S-1 administration beyond progression was shown when paclitaxel was selected as the key drug for second-line chemotherapy.

CPT-11 as a second-line treatment for patients with advanced/metastatic gastric cancer who failed S-1 (CCOG0702).

BACKGROUND: In Japan, CPT-11 is often used to treat unresectable gastric cancer in the second-line setting. However, evidence regarding benefit of second-line chemotherapy remains sparse, especially after failing S-1. METHODS: A phase II study to evaluate the efficacy and safety of weekly administration of CPT-11 at a dose of 100 mg/m(2) after failing a S-1-containing first-line treatment was planned with response rate as a primary end point. UGT1A1*6, *27, and *28 genotyping were performed in all cases, and those found to have either homozygous for *28, homozygous for *6, heterozygous for both *6 and *28, and heterozygous for *27 were rendered ineligible for the phase II trial. RESULTS: Two patients of homozygous for *28, two patients of homozygous for *6, and one patient of heterozygous for *27 were found among 39 recruited patients. The median number of courses delivered was 3 courses. The overall response rate was 15.4 % and disease control rate was 65.4 %. The median time to treatment failure was 87.5 days and median overall survival was 268 days. Twenty-two (73 %) of 30 valuable patients experienced protocol-specified skip of treatment and 8 (30 %) of patients could continue treatment with dose reduction. ≥G3 neutropenia was found in 30 % and ≥G3 anorexia and diarrhea were found in 23 and 17 %, respectively. CONCLUSION: Weekly CPT-11 at 100 mg/m(2) showed moderate response among gastric cancer patients who were refractory to S-1, but the disease control rate seemed meaningful. Even after selection of patients by UGT1A1 polymorphism of *6, *27, and *28, severe toxic events could not be prevented completely.

A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric Cancer (CCOG0302 study).

BACKGROUND: Although paclitaxel was given triweekly in phase II trials prior to its approval for gastric cancer in Japan, it is currently more often delivered by a weekly schedule in the second-line setting. PATIENTS AND METHODS: A phase II trial with response rate as the primary end-point was conducted. Patients with metastatic or unresectable gastric adenocarcinoma who had measurable lesions and had disease progression with the front-line chemotherapy were treated by weekly administration of paclitaxel at a dose of 80 mg/m2. RESULTS: Forty-five patients were accrued and 44 were assessable for response. Partial responses were observed in 7 patients (16%). Stable disease was documented in further 14 patients (48%). Median progression-free survival of all patients enrolled was 2.6 months and median overall survival was 7.8 months. Toxicity was mild and manageable, the most frequent > or = grade 3 toxicity being neutropenia occurring in 16% of the patients. CONCLUSION: With modest response rate, favorable toxicity profile, and progression-free or overall survival similar to those of more intense combination regimens, weekly paclitaxel remains a rational therapeutic option for gastric cancer refractory to the first-line chemotherapy.

S100A2 overexpression is frequently observed in esophageal squamous cell carcinoma.

BACKGROUND: We previously detected that deltaNp63, a human p53 homologue, is an oncogene amplified in squamous cell carcinomas (SCC) including esophageal SCC. Subsequently, we examined global patterns of gene expression in cancer cells following deltaNp63 gene introduction using an oligonucleotide microarray approach. We identified S100A2, a Ca2+-binding protein, as a novel downstream mediator of deltaNp63. MATERIALS AND METHODS: In this study, we examined S100A2 expression in esophageal SCC cell lines and primary SCCs using Northern analysis. RESULTS: We found that 2 out of 8 (25%) cell lines and 14 out of 30 primary esophageal cancers (47%) showed S100A2 gene overexpression compared to paired normal tissues. To examine a possible relationship between S100A2 overexpression and clinicopathological features, we proceeded with statistical analysis. S100A2 overexpression was significantly-associated with higher age in esophageal SCC (p=0.0434). Interestingly, S100A2-overexpressing cancers showed a trend toward preferentially developing lymph node metastases and distant metastases (p=0.111 and 0.178, respectively). CONCLUSION: These results suggested that S100A2 might be related to the progression of esophageal SCC.

Aberrant methylation of SOCS-1 was observed in younger colorectal cancer patients.

UNLABELLED: BACKGROUND Recently, it was demonstrated that sup-pressor of cytokine signaling-1 (SOCS-1) was frequently silenced by methylation of its CpG island inhuman hepatocellular carcinoma (HCC). To define the role of SOCS-1 in the tumorigenic pathway of the colorectum, we examined the methylation of SOCS-1 in tumors of colorectal cancer patients. METHODS: We examined 74 colorectal cancer patients, using a methylation-specific polymerase chain reaction (PCR;MSP) for SOCS-1 CpG island in primary tumors. RESULTS: Aberrant methylation of the SOCS-1 CpG island was detected in 6 of the 74 (8%) colorectal cancer specimens. No corresponding normal colorectal tissues showed SOCS-1 methylation. We then analyzed the correlation between the clinicopathological features and SOCS-1 aberrant methylation and found that younger age was significantly related to SOCS-1 methylation (P = 0.048). CONCLUSIONS: These findings suggested that SOCS-1 may act as a tumor suppressor in at least some colorectal cancers and that SOCS-1 methylation may be a particular phenomenon related to a nearly onset of colorectal cancer.

Identification of S100A2 as a target of the DeltaNp63 oncogenic pathway.

PURPOSE AND EXPERIMENTAL DESIGN: It has been proved recently that DeltaNp63 may play an oncogenic role in the tumorigenic pathway of squamous cell cancers. To gain additional insight into this pathway, we examined global patterns of gene expression in cancer cells after DeltaNp63 gene introduction using the oligonucleotide microarray approach. RESULTS: We found that S100A2 might be a target of the DeltaNp63 pathway. To confirm the data obtained from oligonucleotide microarray, we then examined the interaction of DeltaNp63 to S100A2. S100A2 induction was strictly dependent on DeltaNp63 expression by DeltaNp63 transgene and Northern analysis. DeltaNp63 transactivated the S100A2 promoter, and significantly more fold changes were seen in DeltaNp63-introduced cells than in p53-introduced cells, suggesting that DeltaNp63 may be a novel stimulator of the S100A2 promoter. CONCLUSION: Taken together, this evidence would seem to suggest that S100A2 is a novel downstream mediator of DeltaNp63.

A cancer-prone case with a background of methylation of p16 tumor suppressor gene.

PURPOSE AND EXPERIMENTAL DESIGN: To date, the presence of p16 gene promoter methylation associated with loss of protein expression has been demonstrated frequently in digestive tract cancers. In this study, we tested for the methylation status of p16 promoter in normal tissue specimens using the methylation-specific PCR technique to examine whether p16 methylation already existed in the background of tumors. RESULTS: Aberrant promoter methylation of p16 gene was detected in 1 of 40 esophageal and 1 of 69 gastric and no colorectal epithelium specimens, and these 2 specimens were derived from the same patient. We also found the same methylation change in both tumor and blood cell DNA. CONCLUSION: These results suggested that the p16 gene was inactivated by methylation in normal background cells of this patient and that other additional factors may promote tumor development in his esophageal and gastric tissues.