Mitsukuni Suenaga

Circulating tumor cells as a surrogate marker for determining response to chemotherapy in patients with advanced gastric cancer

The purpose of this study was to quantify circulating tumor cells (CTCs) in advanced gastric cancer (AGC) patients, and to demonstrate the role of CTCs in cancer therapy. This study investigates the hypothesis that CTCs can predict clinical outcomes in patients with AGC. From November 2007 to June 2009, 52 patients with AGC were enrolled into a prospective study. The chemotherapy regimen was an S‐1‐based regimen (S‐1 with or without cisplatin) or paclitaxel. CTCs of whole blood at baseline, 2 weeks, and 4 weeks after initiation of chemotherapy, were isolated and enumerated using immunomagnetics. Patients with ≥4 CTCs at 2‐week points and 4‐week points had a shorter median progression‐free survival (PFS) (1.4, 1.4 months, respectively) than those with the median PFS of <4 CTCs (4.9, 5.0 months, respectively) (log‐rank test; P < 0.001, P < 0.001, respectively). Patients with ≥4 CTCs at 2‐week points and 4‐week points had shorter median overall survival (OS) (3.5, 4.0 months, respectively) than those with the median PFS of <4 CTCs (11.7, 11.4 months, respectively) (log‐rank test; P < 0.001, P = 0.001, respectively). In conclusion, this study demonstrates that CTC measurement may be useful as a surrogate marker for determining response to S‐1‐based or paclitaxel regimens in AGC.

Circulating tumor cells as a surrogate marker for determining response to chemotherapy in Japanese patients with metastatic colorectal cancer

The purpose of this study was to investigate the potential of circulating tumor cells (CTC) as a surrogate marker of the clinical outcome in metastatic colorectal cancer (mCRC) patients in order to identify Japanese patients responsive to oxaliplatin‐based chemotherapy. Between January 2007 and April 2008, 64 patients with mCRC were enrolled in this prospective study. The treatment regimen was oxaliplatin‐based chemotherapy. Collection of CTC from whole blood was performed at baseline and at 2 and 8–12 weeks after initiation of chemotherapy. Isolation and enumeration of CTC was performed using immunomagnetics. Patients with ≥3 CTC at baseline and at 2 and 8–12 weeks had a shorter median progression‐free survival (8.5, 7.3 and 1.9 months, respectively) than those with <3 CTC (9.7, 10.4 and 9.1 months, respectively) (log‐rank test: P = 0.047, P < 0.001 and P < 0.001, respectively). Patients with ≥3 CTC at 2 and 8–12 weeks had a shorter median overall survival (10.2 and 4.1 months, respectively) than those with <3 CTC (29.1 and 29.1 months, respectively) (P < 0.001 and P = 0.001, respectively). A spurious early rise in carcinoembryonic antigen level was observed in 11 patients showing a partial response. In contrast, no rise in early CTC level was observed among responders. Our data support the clinical utility of CTC enumeration in improving our ability to accurately assess treatment benefit and in expediting the identification of effective treatment regimens for individual Japanese patients. (Cancer Sci 2011; 102: 1188–1192)

Irinotecan plus cisplatin for therapy of small-cell carcinoma of the esophagus: report of 12 cases from single institution experience.

BACKGROUND Esophageal small-cell cancer is a rare disease, and standard therapy has not yet been established. METHODS A total of 12 esophageal small-cell carcinoma patients were treated with CPT-11 (70 mg/m(2)) on Days 1 and 15 and CPT-11 plus CDDP (80 mg/m(2)) on Day 1 with each cycle repeated every 4 weeks at our institution. RESULTS A total of 46 chemotherapy courses were given (median, 3.5). There were two complete responses and eight partial responses. The median survival time was 417 (97-1626) days, and three patients were still alive for >40 months. Grade 4 neutropenia was observed in two patients, Grade 4 anemia in one patient, Grade 3-4 diarrhea in three patients and Grade 3-4 hyponatremia in three patients. Other adverse reactions seen were mild with no treatment-related deaths observed. CONCLUSIONS To our knowledge, this is the first report of the series of more than 10 patients with small-cell carcinoma of the esophagus treated with the same chemotherapy regimen. The combination of CPT-11 and CDDP appears to be effective therapy of this disease with acceptable toxicity profile. We believe that this regimen is one of the options to be considered for treatment of esophageal small-cell carcinoma.

Circulating endothelial progenitors and CXCR4‐positive circulating endothelial cells are predictive markers for bevacizumab

Bevacizumab plus chemotherapy is a standard option in the treatment of metastatic colorectal cancer (mCRC). The aim of this study was to investigate the potential of circulating endothelial cell progenitors (CEPs) and phenotypical circulating endothelial cells (CECs) as surrogate markers of clinical outcome in mCRC patients to identify responders to bevacizumab in combination with chemotherapy.

Safety, Efficacy and Pharmacokinetics of Neratinib (HKI-272) in Japanese Patients with Advanced Solid Tumors: A Phase 1 Dose-escalation Study

OBJECTIVE Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. METHODS Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. RESULTS Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. CONCLUSIONS The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

Chemotherapy for small-bowel Adenocarcinoma at a single institution

PurposeSmall-bowel adenocarcinoma (SBA) is rare. No standard chemotherapy for this type of cancer has yet been established. At Cancer Institute Hospital (CIH), the chemotherapy regimen used for colorectal cancer is initially used for patients with SBA, followed by that used for gastric cancer.MethodsPatients with advanced or recurrent SBA who had been treated with chemotherapy in CIH were retrospectively analyzed. The first-line treatments were fluoropyrimidines used alone or in combination with other drugs, such as 5-fluorouracil plus leucovorin (FL), UFT-E, or TS-1. The second-line treatment was irinotecan (CPT-11) monotherapy.ResultsFluoropyrimidine-based regimens, mainly FL, were used for 10 patients. Seven patients received the second-line CPT-11 regimen. Disease control was seen in five patients (50%) with the first-line chemotherapy and in three (43%) with the second-line. The median overall survival time was 12 months (range 3–39). The treatments were generally tolerated. Gastrointestinal symptoms were the most common adverse effects.ConclusionsFluoropyrimidines as the first-line and CPT-11 as the second-line chemotherapy yielded low response, although the adverse effects were mild. The FOLFOX and FOLFIRI regimens such as those used for metastatic colorectal cancer are potential alternative strategies. Extensive trials are needed to develop standard chemotherapy with new drugs.

Anal canal carcinoma with Pagetoid spread: report of a case.

A 70-year-old man with a history of colon polyps was found to have a semipedunculated polyp in the anal canal. The patient was asymptomatic. The lesion was 14 mm in diameter and located 5 mm from the dentate line. Histological examination of biopsy specimens revealed well-differentiated adenocarcinoma of the anal canal. During transanal local excision of the tumor, an abnormality of the perianal skin was recognized. Although intraoperative frozen section of the perianal skin did not show malignancy, permanent sections of the perineal skin revealed Pagets cells in the epidermis. Pathological examination of the anal canal carcinoma revealed submucosally invasive well-differentiated adenocarcinoma with a positive distal surgical margin. Thus, we performed additional wide local excision of the perianal skin including the distal margin of the previous local excision. Pathological examination revealed continuance within the epidermis between the anal canal adenocarcinoma and Pagets cells in the perianal skin lesion. Scattered Pagets cells also formed some glandular structures. Thus, we concluded that the perianal skin lesion was Pagetoid spread of anal canal adenocarcinoma. This report shows that the perianal skin should be examined carefully in patients with anal canal carcinoma.

Predictors of the Efficacy of FOLFIRI plus Bevacizumab as Second-Line Treatment in Metastatic Colorectal Cancer Patients

PurposeFluoropyrimidine-based chemotherapy plus bevacizumab (BV) is the standard treatment for metastatic colorectal cancer (mCRC). The aim of this study was to investigate the efficacy of BV plus FOLFIRI (5-fluorouracil, leucovorin, irinotecan) as second-line treatment in mCRC patients refractory to first-line oxaliplatin-based chemotherapy, and determine potential predictive factors affecting survival.MethodsThirty-four consecutive patients were included in this retrospective study. All patients received FOLFIRI plus 5 mg/kg BV until progression or unmanageable toxicity occurred. Clinical factors and KRAS status were evaluated as potential biomarkers of efficacy.ResultsThe overall response was 23.5%. The median progression-free survival (PFS) and time-to-treatment failure (TTF) were 248 and 221 days, respectively. The median overall survival (OS) was 651 days. A univariate analysis revealed that normal thrombin antithrombin complex, alkaline phosphatase, lactate dehydrogenase, and carbohydrate antigen 125 (CA125) levels at baseline were associated with better PFS, TTF, and OS. A multivariate analysis showed that only the CA125 level at baseline was an independent negative predictor of both PFS and OS. KRAS status was not identified as a predictor.ConclusionsThe results of this study suggest that FOLFIRI plus BV is a viable option in second-line treatment for mCRC refractory to first-line FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone, and indicate that CA125 might be a predictive biomarker for the outcome.

Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer.

Regorafenib is an oral multi-kinase inhibitor used as salvage therapy for metastatic colorectal cancer (mCRC). We tested whether serum cytokine levels are associated with clinical outcome in the mCRC patients receiving regorafenib. Serum samples were collected before treatment start, day 21, and progressive disease, and eleven angiogenic and inflammatory cytokine serum levels were examined. Fifty-four patients of a total of 62 enrolled patients were eligible for the analyses. The chemokine ligand 5 (CCL5) levels ≤ cut-off value (59959 pg/ml) at baseline was associated with relative tumor shrinkage (P = 0.021), better progression-free survival (PFS) (P = 0.036) and overall survival (OS) (P = 0.019). Vascular endothelial growth factor A (VEGF-A) levels showing a decrease on day 21 were significantly associated with a better PFS (P = 0.021). CCL5 levels ≤ cut-off was associated with any grade hand-foot skin reaction (HFSR) (P = 0.025) and thrombocytopenia (P = 0.013). Low chemokine ligand 2 levels at baseline were associated with grade 2 ≤ HFSR. High angiopoietin-2 and basic fibroblast growth factor (bFGF) levels at baseline were associated with grade 3 ≤ total bilirubin increase and transaminases increase, respectively. Low bFGF levels at baseline were associated with grade 3 ≤ hypertension. No correlation with severe events was observed. Baseline serum CCL5 levels and decrease of the serum VEGF-A levels may serve as potential predictive markers for survival or treatment-specific toxicities in mCRC patients receiving regorafenib.

RAS mutation is a prognostic biomarker in colorectal cancer patients with metastasectomy.

Studies have demonstrated a relationship between clinical outcomes after curative resection for colorectal cancer (CRC) and gene mutations of the EGFR pathway; however, no studies have examined metastatic CRC (mCRC) patients with metastasectomy. The aim of this study was to evaluate the relationship between gene mutations of EGFR pathway and clinical outcomes after metastasectomy in mCRC patients. A total of 1,053 patients histopathologically confirmed CRC received a genotyping test for the EGFR pathway from February 2012 to October 2013. Detailed information was obtained through review of medical records. Gene mutations of EGFR pathway were analyzed by Luminex assay. Overall survival (OS) and recurrence free survival were estimated by the Kaplan‐Meier method and the log‐rank test was used to compare the survival outcomes by gene mutation status. A total of 132 patients received metastasectomy. The frequencies of KRAS exon 2, KRAS exon 3.4, NRAS, BRAF, and PIK3CA mutations were 38.6% (51/132), 3.6% (5/132), 5.1% (7/132), 5.1% (7/132), and 8.7% (12/132), respectively. With a median follow‐up of 84.1 months (57.2—NA) for a survivor, the 4‐year OS rate was 65.6% for mCRC with RAS mutation, and 81.3% for mCRC with wild‐type RAS (p < 0.05). We observed a statistically significant correlation for only the RAS mutation and OS. In multivariate analysis, RAS mutation and liver metastasis were independent factors for shorter OS. There were no significant differences between gene mutations of EGFR pathway and recurrence free survival. RAS mutation in mCRC metastasectomy patients was associated with shorter overall survival.