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Purpose The purpose of this study was to evaluate the rate of pathologic complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation therapy (CRT) with leucovorin (FL) versus irinotecan/S-1 (IS). Methods and Materials Patients with resectable LARC (clinical stage T3/4, lymph node positive, or both) were randomly assigned to receive preoperative radiation (45-50.4 Gy in 25 to 28 daily fractions) and concomitant chemotherapy either with a bolus injection of FL (400 mg/m 2 /day 5-fluorouracil and 20 mg/m 2 /day leucovorin) for 3 consecutive days every 4 weeks for 2 cycles (FL group) or with 40 mg/m 2 irinotecan on days 1, 8, 15, 22, and 29, and 35 mg/m 2 S-1 twice on the day of irradiation (IS group). Curative surgery was performed approximately 4 to 8 weeks after the completion of CRT. The postoperative chemotherapy regimen was FL with a primary endpoint of a pCR rate evaluation. Results One hundred forty-two eligible patients were randomly assigned, and the median follow-up duration was 43.8 months (95% confidence interval, 40.8-46.8 months). One hundred thirty-three patients (93.7%) of 142 underwent total mesorectal excision; pCR was achieved in 11 (16.7%) of 66 patients in the FL group and 17 (25.8%) of 67 patients in the IS group ( P =.246). When good responders were defined as patients with Mandard grades 1 and 2, the rate of good responders was significantly higher in the IS group than in the FL group (54.6% vs 36.4%, respectively, P =.036). The preoperative rates of grade 3 and 4 toxicities were higher in the IS group (7.0%) than in the FL group (1.4%, P =.095). The 3-year disease-free survival was not significantly different between the 2 groups (79.7% vs 76.6%, respectively, P =.896). Conclusions IS-based preoperative CRT did not increase pCR rate, but it did increase acute toxicities compared with standard 5-FU treatment. Therefore, further investigation is needed.

We investigated the usefulness of a clinical risk scoring system (CRS) for guiding management and defining prognosis for patients with colorectal liver met"astases (CLM).We retrospectively analyzed data about the correlation between outcomes and Fong's CRS from 1989 to 2010 for patients treated for CLM at the Severance Hospital.Of 566 patients, 232 received adjuvant treatment after liver resection. Of these patients, 185 (81%) had a low CRS (0-2) and 47 (19%) had a high CRS (3-5). Stratification into high and low CRS allowed significant distinction between Kaplan-Meier curves for outcome. The 5-year survival rate was 88.5% and 11.5% among patients with a low and high CRS, respectively (P 0.001). Seventy patients with initially unresectable CLM underwent liver resection after tumor downsizing by induction chemotherapy. Shifting of the CRS from high to low (8 patients; 11.4%) improved disease-free survival and overall survival.High CRS is associated with worse survival after resection in resectable and unresectable disease. The CRS may be used for risk assessment when recommending oncological surgical timing in initially unresectable disease and treatment options for perioperative or adjuvant treatment in resectable disease.

Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting.Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798.KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16).The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed.Merck KGaA.

Background and purpose The aim of this study is to evaluate the efficacy and safety of preoperative radiation therapy combined with S-1 and irinotecan (SI) in LARC. Materials and methods Patients were considered LARC if they had a T3/T4 lesion or node positive. Weekly doses of 40mg/m 2 irinotecan were intravenously administered once per week during weeks 1–5 of radiotherapy. S-1 (70mg/m 2 ) was given from Monday to Friday in all weeks of radiotherapy. 3-D conformal radiotherapy was given at daily fractions of 1.8Gy for 5days for a total dose of 50.4 (45+5.4)Gy. Surgery was performed 4–6weeks following the completion of chemoradiation. Results Between June 2006 and November 2007, 43 pts were enrolled. The stage was: cT3 24 patients, cT4 6 patients; 28 patients were cN+. Forty-one patients completed the chemoradiation and 42 patients underwent operation: a low anterior resection was performed in 36 patients, a total colectomy in 1 patient, and an abdominal perineal resection in 5 patients. T downstaging was observed in 50%; 23 N+ patients became N− (55%). The complete pathological response was observed in 9 patients (21%). The 3-year locoregional failure rate, distant failure rate, disease-free survival, and overall survival were 9.5%, 18.6%, 72.1%, and 94.3%, respectively. Only three patients experienced G3 diarrhea; one had G3 sepsis and two had septic shock. Hematological toxicity (G3–G4) was observed in five patients. Conclusions This study demonstrated the efficacy of preoperative CRT with S-1 and irinotecan with 21% of complete response. However, prompt recognition and management of infection is needed to use it in patients with locally advanced rectal cancer.

It has been suggested that vasculogenesis by endothelial progenitor cells (EPC) as well as angiogenesis play an important role in the production of blood vessels in neoplasm. The present study was designed to isolate and characterize the EPC in gastric cancer patients as a tumor specific angiogenesis marker. The cells derived from CD34 positive PBMC presented with a cobblestone appearance at 28 days, revealing differentiation into endothelial cells. They were also positive to the LDL-uptake reaction, showing that they have biological endothelial cell functions. These cells demonstrated tube formation, showing their ability to participate in neovascularization. The cells derived from CD34 positive PBMC expressed CD133 and demonstrated telomerase activity, showing the stem cell character. In xenograft model, EPC derived from CD34 positive PBMC mobilized mainly into tumor area after being injected through tail vein. With isolation, ex vivo amplification and characterization of EPC from gastric cancer patients receiving chemotherapy, endothelial progenitor cells may be used as a candidate prognostic and predictive biomarker for cancer.

We investigated whether the level of bone marrow-derived progenitor cells and mature endothelial cells could be used as predictors of clinical outcome in patients receiving taxotere-based chemotherapy for advanced gastric cancer. Peripheral blood mononuclear cells were obtained from 49 gastric cancer patients who received taxotere combined with 5-FU and leucovorin and prophylactic G-CSF treatment. To categorize the cells, the cell markers CD34, vWF, P1H12, and CD31 were stained. Changes in these cells were examined before and after chemotherapy, and the clinical significance of these changes to response prediction and prognosis were investigated. Before the second cycle of chemotherapy, the number of CD34 + /vWF + and CD34 + cells was higher in non-responders as compared to the responders. Patients with ⩾6.2 CD34 + /vWF + cells/ml had a shorter progression free survival (3.7 months) as against patients with + /vWF + /ml (6.0 months, p = 0.076). Patients with ⩾5.8 CD34 + cells/ml had shorter progression free survival (4.0 months) than patients with + cells/ml (6.1 months, p = 0.046). In an ex vivo pharmacokinetic study, the maximum inhibition ( I max ) for HUVEC and YCC3 cells was 13.0 ± 6.6% and 74.0 ± 2.0%, respectively. The time to reach I max ( T max ) was 72 h in all HUVEC cells and 0.5 hours in YCC3 cells. We suggested that CD34 + /vWF + and CD34 + cells can be used as a biomarker for prediction and CD34 + cells for prognosis.

To investigate the patterns of local failure and the risk factors predictive of local failure and to establish the dose-response relationships influencing the probability of local control in patients with Stage I and II angiocentric T-cell or natural killer (NK)/T-cell lymphoma who were treated with radiotherapy (RT) alone.We retrospectively reviewed the data from 102 patients with Ann Arbor Stage I and II angiocentric T-cell or NK/T-cell lymphoma who underwent RT alone to a median dose of 45 Gy (range, 20-70 Gy) between 1976 and 1998. The patterns of local failure, risk factors predictive of local failure, dose-response relationships, and survival data were analyzed. Because of the protean feature of local recurrences, the sites of local failure were allocated to one of three categories: true recurrence (TR), marginal recurrence (MR), and elsewhere recurrence (ER).Despite a higher complete remission rate (72%) after RT, 60 patients experienced treatment failure, including local failure in 48 (47%), regional failure in 3 (3%), and systemic failure in 28 (27%). The patterns of local failure were TR in 42, MR in 3, and ER in 5 patients. The median time to recurrence for TR/MR was shorter than that for ER (1 month for TR/MR vs. 12 months for ER). Patients with TR/MR had a more unfavorable prognosis than those experiencing ER (2-year survival rate after salvage treatment: 6% for TR/MR vs. 80% for ER; p0.01). The dose-response curve was sigmoid in shape within the range of 20-54 Gy, which followed the plateau at doses in excess of about 54 Gy. A positive correlation was observed in the dose-response curve for the probability of local control (p = 0.017, logistic regression analysis). The overall 5-year actuarial survival and local recurrence-free survival rate for all patients was 42% and 53%, respectively. Achievement of complete remission was the most statistically significant risk factor predictive of TR/MR and the most important prognostic factor.Our data confirm that local failure remains the major obstacle for patients who receive RT alone and that achievement of complete remission is a particularly important determinant of treatment success. Although dose escalation up to54 Gy cannot entirely reduce the incidence of TR/MR, we believe it is important to identify an appropriate subset of patients for whom an additional boost dose may be beneficial. Given the high rate of local failure, an investigational approach should be conducted to supplement RT using radiosensitizers or more effective chemotherapeutic agents in future trials.

The plasminogen activation system plays a crucial role during cancer invasion and metastasis. In the solid tumor, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and uPA receptor (uPAR) are considered as prognostic factors. In this study, we have investigated whether secretion of the uPA, PAI-1 and uPAR from the primary breast cancer tissue can be detected in the blood of the patients using the ELISA assay. We have found that the plasminogen activation system (uPA, PAI-1, uPAR) of tumor tissue is activated from the early stage of breast cancer. However, only a number of metastatic lymph nodes was a prognostic factor in multivariate analysis for relapse. The blood level of the plasminogen activation system correlated with that of tissue in an order of uPAR (r(2)=0.61; P=0.001), uPA (r(2)=0.35; P=0.001) and PAI-1 (r(2)=0.11; P=0.001). We conclude that the total uPAR level of cancer tissue can be substituted by that which is detected in the blood for further clinical applications.

We studied biological phenotypes of gastric cancer cell lines based on a novel heparin-binding growth/differentiation factor (midkine (MK)) expression. MK expression was found in 67% (6/9) of the gastric cancer cell lines and 56% (14/25) of the primary cancer tissues. Gastric cancer cell lines with MK expression showed higher colony forming activity in soft agar assay and endothelial cell growth stimulatory effect in cross-feeding assay than cells which did not express MK. However, urokinase-type plasminogen activator (uPA) expression and tumor invasiveness did not correlate with MK expression. Growth of MK expressing cells was inhibited by a heparin-binding blocking agent, pentosan polysulfate (PPS). In cancer tissues, MK expression correlated with tumor size, suggesting in vivo autocrine and paracrine activity. This proliferation promoting activity of MK can be targeted by an anti-heparin binding agent as a biotherapy model in gastric cancer.

Introduction Aflibercept is a recombinant human fusion protein that acts as a decoy receptor preventing VEGF-A, VEGF-B, and PlGF from interacting with their receptors. The phase 3 VELOUR study demonstrated a statistically significant survival benefit with the combination of aflibercept + FOLFIRI in metastatic colorectal cancer (mCRC) patients who had progressed during or after prior oxaliplatin-based chemotherapy. Modified (m) FOLFOX6 is an established first-line regimen for patients with mCRC. Preclinical and clinical evidence supported the evaluation of aflibercept + mFOLFOX6 for the first-line treatment of patients with mCRC. An mFOLFOX6 study arm was included as a calibrator; the study was not powered for a statistical comparison. Methods The primary endpoint was progression-free survival rate at 12 months (PFS12). A secondary objective was to explore biomarkers. Patients with previously untreated mCRC, ECOG PS 0-2, and adequate organ function were randomized 1:1 to receive aflibercept 4 mg/kg + mFOLFOX6 (A) or mFOLFOX6 (B), every 2 weeks, and were stratified by ECOG PS (0-1/2), prior adjuvant therapy (yes/no), and metastases confined to liver (yes/no). Patients were to be treated to disease progression. PFS12 rate and objective response rate were assessed according to RECIST criteria by an Independent Review Committee blinded to treatment allocation. Results From March 2009 to April 2010, 236 patients (median age, 62.5 years; male, 61% PS 0-1, 97.5% prior adjuvant therapy, 10.2% liver metastases only, 28.4%) were randomized to A (n = 119) or B (n = 117). Baseline characteristics were similar in both arms. PFS12 was 25.8% (95% CI: 17.2-34.4) for A and 21.2% (95% CI: 12.2-30.3) for B. Response rate was 49.1% (95% CI: 39.7-58.6) in arm A and 45.9% (95% CI: 36.4-55.7) in arm B, and median PFS was 8.48 months (95% CI: 7.89-9.92) in arm A and 8.77 months (95% CI: 7.62-9.27) in arm B. Overall survival data had limited maturity, with less than 43% death events in each arm. Grade 3-4 adverse events with >5% higher incidence in arm A relative to arm B were hypertension, proteinuria, neutropenia, diarrhea, and infections. Biomarker data will be presented at the meeting. Conclusion In this phase 2 study, PFS12 with aflibercept + mFOLFOX6 appeared to be similar to mFOLFOX6, although the study was not powered for comparison. The biomarker analyses and clinical interpretation will be presented at the meeting. The safety profile of aflibercept was consistent with that seen in prior studies.