Tumor immune-gene expression profiles and peripheral immune phenotypes associated with clinical outcomes of locally advanced pancreatic cancer following FOLFIRINOX.

BACKGROUND: A comprehensive analysis of peripheral immune cell phenotypes and tumor immune-gene expression profiles in locally advanced pancreatic cancer patients treated with neoadjuvant chemotherapy in a phase II clinical trial was carried out. METHODS: Patients were treated with neoadjuvant modified folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin (mFOLFIRINOX) followed by surgery and adjuvant gemcitabine at the Asan Medical Center. Correlations between survival outcomes and baseline peripheral immune cells and their changes during preoperative chemotherapy were analyzed. Patients who had surgery were divided into two groups according to achievement of disease-free survival >10 months (achieved versus failed). Differential expression and pathway analysis of immune-related genes were carried out using the Nanostring platform, and immune cells within the tumor microenvironment were compared by immunohistochemistry. RESULTS: Forty-four patients were treated in the phase II clinical trial. Higher baseline CD14+CD11c+HLA-DR+ monocytes (P = 0.044) and lower Foxp3+CD4+ T cells (P = 0.02) were associated with poor progression-free survival of neoadjuvant mFOLFIRINOX. During the preoperative chemotherapy, PD-1 T cells significantly decreased (P = 0.0110). Differential expression and pathway analysis of immune-genes from the resected tumor after neoadjuvant treatment revealed transforming growth factor-ß pathway enrichment and higher expression of MARCO (adjusted P < 0.05) associated with early recurrence. Enrichment of the Th1 pathway and higher peritumoral CD8+ T cells (P = 0.0103) were associated with durable disease-free survival from surgery (>10 months) following neoadjuvant mFOLFIRINOX. CONCLUSIONS: Our results identify potential immune biomarkers for locally advanced pancreatic cancer and provide insights into pancreatic cancer immunity.

Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group.

PURPOSE: To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. EXPERIMENTAL DESIGN: Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. RESULTS: Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1-25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19-52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without. CONCLUSIONS: Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.

A Phase II Trial of UFT-E and Oral Leucovorin in Advanced Colorectal Cancer.

PURPOSE: To determine the efficacy and toxicity of UFT-E plus oral calcium leucovorin in the treatment of patients with advanced colorectal cancer. MATERIALS AND METHODS: Forty-three patients with advanced, bidimensionally measurable colorectal adenocarcinoma were enrolled in the trial. No patients had received prior palliative chemotherapy. The patients that had received previous adjuvant chemotherapy were enrolled when more than 6 months had elapsed after the completion of adjuvant therapy. Patients were treated with 300 mg/m2/day of UFT-E (tegafur-based) plus 90 mg/day of leucovorin administered orally in three divided daily doses, every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two or three courses of therapy. RESULTS: Thirty-six of forty-three patients were evaluable for response; seven dropped out due to infection, toxicity and patients' refusal. Ten patients had partial responses and one patient complete response (response rate, 31%; 95% confidence interval, 16~46%). The median response duration for the UFT-E plus leucovorin regimen was 28 weeks. Grade III toxicity was seen in one case, with diarrhea. CONCLUSION: This oral regimen proved effective and well tolerated. This schema also avoided inconveniences, such as hospitalization and the use of infusion pumps, which are associated with 5-FU infusion regimens. The regimen used showed minimal toxicity, especially in the upper digestive tract, with good patient compliance.

Adjuvant (cisplatin, etoposide, and 5-fluorouracil) chemotherapy after curative resection of gastric adenocarcinomas involving the esophagogastric junction.

Gastric adenocarcinomas involving the esophagogastric junction represent a particular therapeutic problem because they lie in the border area between two body cavities: the thorax and the abdomen. The prognosis of gastric adenocarcinomas involving esophagogastric junction is poor because there is widespread lymphatic metastasis, making curative resection difficult. Even in patients with localized disease who are potentially curable, the 5-year survival rate is approximately 20% with curative resection only, somewhat lower than for those with cancer elsewhere in the stomach. The authors conducted a pilot study to evaluate the safety and possible efficacy of adjuvant chemotherapy with cisplatin, etoposide, and 5-fluorouracil (PEF) after curative resection of gastric adenocarcinoma involving esophagogastric junction. Three cycles of adjuvant PEF chemotherapy with cisplatin (20 mg/m2/day intravenously on days 1-5), etoposide (100 mg/m2/day intravenously on days 1, 3, and 5), and 5-fluorouracil (800 mg/m2/day continuous intravenous infusion on days 1-5) were given every 3 weeks after curative resection of gastric adenocarcinoma involving the esophagogastric junction. Between November 1989 and June 1995, a total of 50 patients with postoperative stage II, IIIA, or IIIB disease entered this trial. In 14 of 50 patients (28%), the disease recurred during the follow-up of 4-83 months (median 26 months). Disease-free survival was 4-83+ months (median 48 months), and the actuarial 5-year disease-free survival rate was 48% (95% CI: 41% to 55%). Overall survival was 4-83+ months (median 62 months), and the actuarial 5-year survival rate was 54% (95% CI: 40% to 68%). The prognostic factor analysis showed that the postoperative N stage and the interval between surgery and chemotherapy affected disease-free survival and overall survival. The toxicities of PEF adjuvant chemotherapy were leukopenia, nausea/vomiting, and alopecia, but they were mostly mild and reversible except in one patient who died because of treatment-related sepsis. Adjuvant chemotherapy with three cycles of PEF regimen was well tolerated and seems to be a promising treatment for gastric adenocarcinoma involving the esophagopstric junction, in comparison with previous treatments. To define the efficacy of adjuvant PEF chemotherapy for gastric adenocarcinoma involving esophagogastric junction, prospective randomized trials are warranted.