bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of dUTP nucleotidohydrolase (dUTPase) and thymidylate synthase (TS) in stage III colon cancer patients treated with either bolus 5-FU or infusional 5-FU in the adjuvant setting: Results of a translational study of the PETACC-2 trial.
Authors: Stoehlmacher J. , Kohne C. , Mauer M. , Goekkurt E. , Lutz M. P. , Aust D. E. , Carrato A. , Bedenne L. , Popov I. , Ladner R. D.
Published: February 2017

417

Background: Pts with stage III colon cancer have been treated with either infusional 5-FU or bolus 5- FU in the adjuvant setting (PETACC-2 trial). DUTPase and TS demonstrated potential as predictive markers for 5-FU efficacy in pts with advanced colorectal cancer. Here we aimed to explore whether TS or dUTPase protein levels may predict recurrence of disease for stage III colon pts treated with 5-FU.

Methods: Tumor (T) blocks of 324 pts were analyzed for protein expression of dUTPase and TS. For analysis monoclonal antibodies DUT415 and TS106 were used. T were evaluated by two investigators as follows. Only nuclear staining for both, TS and dUTPase, was analyzed. If tumor cells (TC) showed a nuclear dUTPase expression in >10% of cells, the sample was scored positive. Positive nuclear staining for >20% of TC, when using the TS antibody, determined a positive sample.

Results: Analysis for dUTPase was successful in 308 samples (95.1%, 308/324). 263 out of those 308 pts showed a positive dUTPase expression (85.3%). 297/324 samples (91.7%) could be evaluated for TS. In the TS group 62.3% (185/297) showed a positive expression for TS protein. In 281 cases analyses were successful for both TS and dUTPase. We observed a significant association between dUTPase and TS expression with a majotity of 71.4% (172/241) dUTPase positive T also being positive for TS as compared to 32.5% (13/40) of dUTPase negative T that showed positivity for TS protein expression (p< 0.0001). Of pts with dUTPase positive T 64.7% showed no recurrence of disease as compared to 44.7% of those with dUTPase negative T 5 years after completion of therapy (HR 0.61 [95% CI 0.36, 1.03], p=0.06). No associations between TS and DFS were observed. Both TS and dUTPase expression did not correlate with OS in this patient cohort.

Conclusions: High TS protein levels appeared to be significantly correlated with high protein levels of dUTPase in stage III colon cancer pts. Neither dUTPase nor TS protein levels appeared to be significantly associated with DFS or OS of stage III colon cancer pts that received adjuvant chemotherapy with 5-FU.

No significant financial relationships to disclose.
Evaluation of antiproliferative and apoptotic effects of the rational combination of the MEK1/2 inhibitor selumetinib (AZD6244) and inhibitors of the hedgehog pathway in colorectal cancer (CRC) cell lines.
Authors: Spreafico A. , Tentler J. J. , Tan A. , Pitts T. M. , Kachaeva M. I. , Selby H. M. , Eckhardt S. G.
Published: February 2017

422

Background: The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. Hyperactivation of this pathway due to mutations in KRAS have been reported in up to 50% of CRC cases. Clinical trials have shown that KRAS patients do not benefit from therapies targeting EGFR, highlighting the need for new therapeutic options. Utilizing differential gene array analyses, we have identified the hedgehog (HH) signaling pathway as a potential mediator of resistance to AZD6244. Based on these results, we tested the rational combination of selumetinib and the HH inhibitor, cyclopamine against human CRC cell lines.

Methods: CRC cell lines were exposed to varying concentrations of selumetinib and cyclopamine. For AZD6244, cell lines with IC50≤ 0.1 μM were considered extremely sensitive (ES) and those with IC50≥ 1μM were deemed extremely resistant (ER). Four KRAS mutant cell lines (2ES, 2ER) were selected for combination studies. The antiproliferative effects were assessed using the sulforhodamine B (SRB) cell viability assay, and potential synergy was evaluated using the Chou and Talalay method. Apoptosis was analyzed using bioluminescent caspase 3/7 detection.

Results: In all four cell lines tested, synergistic antiproliferative effects of selumetinib and cyclopamine were observed, including resistant lines to selumetinib. We observed significant induction of apoptosis when cell lines were exposed to the combination treatment, independent of their responsiveness to selumetinib in the SRB assay.

Conclusions: Treatment of KRAS mutant CRC cell lines with selumetinib and cyclopamine resulted in synergistic inhibition of proliferation, regardless of sensitivity to selumetinib. Interestingly, a significant increase in apoptosis was observed in response to the combination, which may explain the synergy observed by the combination index (CI). In vivo analyses of this combination in cell lines and human CRC explants are ongoing to further validate these results. These preclinical data may suggest a rational combination strategy for patients with KRAS mutant CRC.

No significant financial relationships to disclose.
Use of circulating tumor cells to predict response to chemotherapy in patients with advanced gastric cancer.
Authors: Matsusaka S. , Chin K. , Mizunuma N. , Ogura M. , Suenaga M. , Ozaka M. , Takagi K. , Oba M. , Mishima Y. , Hatake K.
Published: February 2017

43

Background: 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. The purpose of this study was to identify CTC threshold proposal for determining response to chemotherapy in AGC.

Methods: From November 2007 to June 2009, fifty-two patients with AGC were enrolled into a prospective study. All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital and provided informed consent. The study population consisted of patients of aged 18 years or older with histologically proven AGC. Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2; adequate organ function. The subjects were five patients treated with S-1 (40 mg/m2, twice daily, days 1-28, repeated every 6 weeks), twenty-six patients treated with S-1 plus CDDP (S-1 40 mg/m2, twice daily, days 1-21, CDDP 60 mg/m2, day 8, repeated every 5 weeks), and twenty-one patients treated with paclitaxel (80 mg/m2, weekly). CTCs of whole blood at baseline, two weeks and four weeks after initiation of chemotherapy, were isolated and enumerated using immunomagnetics.

Results: Patients with ≥4 CTCs at two-week points and four-week points had a shorter median PFS (1.4, 1.4 months, respectively), than those with the median PFS of <4 CTCs (4.9, 5.0 months, respectively) (p<0.001, p<0.001, respectively). Patients with ≥4 CTCs at two-week points and four-week points had shorter median OS (3.5, 4.0 months, respectively) than those with the median PFS of <4 CTCs (11.7, 11.4 months, respectively) (p<0.001, p=0.001, respectively). In univariate analysis, PS, treatment regimen, Line of chemotherapy, and CTC levels at 2 weeks and 4 weeks predicted PFS and OS. In order to evaluate the independent predictive effect of chemotherapy, multivariate Cox regression analysis was carried out. CTC levels at 2 weeks and 4 weeks were the strongest predictors.

Conclusions: A threshold of lower than 4 CTC/7.5 ml at 2 weeks and 4 weeks was a significant predictor of the outcome for AGC patients treated with S-1 based regimen or paclitaxel regimen.

No significant financial relationships to disclose.
Analysis of BRAF and KRAS mutations in colorectal cancer and rectal carcinogenesis via fluorescent allele-specific PCR.
Authors: Stover D. G. , Cushman-Vokoun A. M. , Vnencak-Jones C. L. , Berlin J.
Published: February 2017

436

Background: Molecular analysis has become increasingly relevant in the evaluation of colorectal carcinomas. Mutations in Ras-MAPK pathway proteins KRAS (present in 30-40% of colorectal cancer) and BRAF (10-14% of colorectal cancer) or mismatch repair (MMR) enzymes can impact response to therapy and/or can assist in defining hereditary predisposition. High frequency microsatellite instability (MSI) in colorectal cancer is associated with improved outcomes. Targeted therapies against BRAF and other components of the Ras-MAPK signaling pathway are becoming important aspects of treatment in colorectal and other cancers.

Methods: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted between 1/07 and 3/09 for MSI testing based on family history and/or histologic features. DNA samples were screened for the BRAF V600E mutation and 7 KRAS mutations in codons 12 and 13 using fluorescent allele specific PCR with capillary electrophoresis. Clinical data was collected via chart review.

Results: 58 males and 53 females were studied. The incidence of KRAS and BRAF mutations among the 111 samples was 49.5% and 6.3%, respectively. KRAS G12D and G12V were the most common mutations, representing 57% of total KRAS mutations. Dually positive KRAS and MSI tumors exclusively demonstrated G12D and G13D mutations. KRAS and BRAF mutations were mutually exclusive. Rectal cancers did not show evidence of BRAF V600E mutation (p=0.04). KRAS, BRAF, and MSI status did not correlate with survival, however pre-operative and post-operative carcinoembryonic antigen (CEA) levels were significantly associated with survival both in univariate and multivariate analyses.

Conclusions: We demonstrate that BRAF V600E mutation is significantly associated with colon cancer and not rectal cancer, suggesting that BRAF mutations are not relevant in rectal carcinogenesis. Correlation between specific KRAS mutation and outcome may require larger populations.

No significant financial relationships to disclose.
Simultaneous protection against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR-signaling blockade by oncogenic RAS.
Authors: Schuler M. H. , Breitenbuecher F. , Trarbach T. , Brandau S. , Schmid K. W. , Kasper S.
Published: February 2017

440

Background: Monoclonal antibodies against the epidermal growth factor receptor (EGFR) have improved treatment options for colorectal cancer (CRC), but tumors harboring RAS mutations are resistant. Full molecular understanding of RAS-mediated protection is key to the development of sensitization strategies.

Methods: We have used cell culture and murine CRC transplant models to study whether RAS solely imposes resistance by compensating EGFR signaling blockade, or additionally interferes with antibody-dependent cellular cytotoxicity (ADCC).

Results: Both clinically approved anti-EGFR antibodies, cetuximab and panitumumab, were equally cytotoxic in CRC cells in vitro. Interestingly, cetuximab, a chimeric IgG1 antibody capable of triggering ADCC, was more effective than panitumumab (human IgG2) in murine CRC transplant models in vivo. The advantage of cetuximab in vivo was completely abolished by leukocyte depletion following total body irradiation. Moreover, oncogenic RAS neutralized the in vivo therapeutic activity of cetuximab and panitumumab to the same extent. Mechanistically, RAS conferred antibody resistance by upregulation of BCL-XL, which was overcome by cotreatment with a BH3 mimetic. In support, RAS-mutant primary human CRCs exhibited increased BCL-XL expression as detected by immunohistochemistry.

Conclusions: RAS-mutant CRCs escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacologic modulation of RAS downstream effectors, such as BCL-XL, can restore sensitivity to antibody effector mechanisms.

[Table: see text]
Evaluation of serum CXCL5 as a serum marker for prognosis of colorectal cancer patients.
Authors: Kawamura M. , Toiyama Y. , Tanaka K. , Yasuda H. , Fujikawa H. , Saigusa S. , Inoue Y. , Miki C. , Yamaguchi M. , Kusunoki M.
Published: February 2017

442

Background: CXCL5 is known as CXC chemokine which promotes angiogenesis related to cancer. However, the function of serum level of CXCL5 (sCXCL5) has not been fully studied in colorectal cancer. The purpose of this study was to evaluate the relationships between preoperative sCXCL5 and clinicopathological features and prognosis in colorectal cancer.

Methods: This was a single-institution, retrospective study. Preoperative serum samples of 250 colorectal cancer patients (between 1998 and 2007, median age: 65.3 years, male 159/female 91) were available for the study, and 33 normal serum was examined and used as a control. sCXCL5 level was assayed using a commercially available enzyme-linked immunosorbent assay kit, and analyzed statistically.

Results: Mean level of sCXCL5 was significantly higher in colorectal cancer patients than in control group (p=0.013). Patients with liver metastases had significantly higher sCXCL5 level than those without metastases (p=0.0086), and in logistic analysis, sCXCL5 was an independent marker for predicting liver metastasis (p=0.040). Overall survival of patients with elevated sCXCL5 level was significantly worse than those with lower sCXCL5 (p=0.0006).

Conclusions: Preoperative sCXCL5 level was increased in colorectal cancer patients compared to in healthy volunteer and elevated sCXCL5 was correlated with liver metastasis and poor prognosis for overall survival in colorectal cancer patients. Elevated sCXCL5 has been proposed as a useful predictive marker for liver metastasis and overall survival in colorectal cancer.

No significant financial relationships to disclose.
Relationship of pro-angiogenic factor Cyr61to colorectal cancer development and prognosis.
Authors: Baek M. , Bae S. , Jeong D.
Published: February 2017

446

Background: Angiogenic factorCysteine-rich 61 (Cyr61) is a member of the CCN protein family that has been implicated in diverse biological processes such as cell adhesion, proliferation, angiogenesis, and tumorigenesis. An altered expression of Cyr61 is found to be associated with several human cancers. However, the correlation of expression of Cyr61 protein and clinical features of colorectal cancer remains unknown.

Methods: Cyr61 expression in colorectal cancer and normal tissues was evaluated by Western blot analysis. Immunohistochemical staining was carried out using tissue microassay (TMA) to examine the expression status of Cyr61. Correlations of Cyr61 over-expression with various clinicopathologic factors were also determined. Statistical analysis was performed to explore the links between expression of the Cyr61 and clinicopathological parameters.

Results: On Western blot analysis Cyr61 up-regulation was observed in colorectal cancer tissues (17/21, 80.9%). In 234 colorectal cancers, tumor tissue microarray revealed significantly up-regulated Cyr61 protein expression in colorectal cancer tissues versus normal tissues adjacent to tumor. Cyr61 expression was high in 136 of 234 cases of colorectal carcinomas (58.1%). Cyr61 over-expression was significantly associated with TNM stage (p=0.012) and regional lymph node involvement (p=0.018). Kaplan-Meier survival analysis showed that over-expression of Cyr61 was related to poor survival of colorectal cancer patients (p=0.031). But significant associations were not found between CYR61 expression versus tumor grade, age and gender.

Conclusions: Our results suggest that Cyr61 is highly expressed in colorectal carcinomas and Cyr61 may play a role in the progression of colorectal cancers. Also, Cyr61 might be a new molecular marker to predict the prognosis and serve as valuable targets for therapeutic intervention of patients with colorectal carcinoma.

No significant financial relationships to disclose.
Clinicopathological correlation of beclin-1 expression in human colon cancer.
Authors: Choi S. , Lim S. J. , Kim B. s. , Lee J. J. , Kang W.
Published: February 2017

464

Background: We investigated the expression of beclin-1 and bcl-2 in human colon cancer tissue by immunohistochemical analysis using a tissue microarray in relation to other prognostic factors.

Methods: Tissue samples from 78 cases of invasive colon cancer were used for the present study. A positive control for bcl-2 expression was small lymphocytes in the mantle zone. Immunohistochemical staining for beclin-1 and bcl-2 was evaluated according to intensity and proportion. The intensity score was determined as 0 (no staining), 1 (weak), 2 (moderate) and 3 (strong). The proportion score was determined as 1 (< 30% of tumor cells) and 2 (≥ 30% of tumor cells). The intensity score and proportion score were multiplied together for a total score. Total scores were as follows: 0-1 (negative) and 2-6 (positive).

Results: The normal colonic epithelium showed weak to no beclin-1 expression. Positive beclin-1 expression and positive bcl-2 expression of colon cancer cells was observed in 48 cases (61.5%) and 10 cases (12.8%), respectively. beclin-1 expression was significantly correlated with lymph node metastasis (p = 0.035) Bcl-2 expression in colon cancer cells showed no significant correlation with clinocopathologic factors studied. Beclin-1 expression was not correlated with bcl-2 expression in colon cancer cells (p = 0.348).

Conclusions: In conclusion, we have characterized the expression of beclin-1 in human colon cancer and the relationship with bcl-2 protein. Our results suggest that it seems reasonable to assume that beclin-1 might play a role in the development of colorectal cancer.

No significant financial relationships to disclose.
Clinicopathological analysis of KRAS mutation in an Irish population.
Authors: Teo M. , O'Reilly S. , Moylan E. , Power D. G.
Published: February 2017

467

Background: Clinical trials have shown that tumor KRAS status predicts response to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). We sought to compare distribution of wild-type and mutated KRAS in an Irish population and identify clinicopathologic correlates.

Methods: From our prospectively maintained database we retrospectively identified patients with mCRC and documented KRAS status between Jan 2007 to June 2010. Medical notes were examined for patient demographics and disease characteristics. Variables were extracted and compared using unpaired t test and chi2 test.

Results: 52 patients were identified, 29 (55.8%) with mutated (mt) and 23 (44.2%) with wild type (wt) KRAS from tumor tissue. Males accounted for 61.5% (n=31). Median age at diagnosis of metastatic disease for the KRASmt group was 66.4 years (range 56.7-82.1) and for the KRAS wt group was 64.2 years (40.1-76.8), p= 0.08. 21 (72.4%) of the KRASmt group and 16 (69.6%) of the KRASwt group had metastatic disease at presentation (p=0.81). For patients who presented initially with localised disease, time to development of metastases was 22.5mo (range 14-37.6) for the KRASmt group and 16.7mo (3.2-123.7) for the KRASwt (p=0.30). 21 (72.4%) of KRASmt and 17 (74.1%) of KRASwt tumors had left-sided primary (p = 0.84) with equal numbers of primary tumor resection in both groups. There was no statistical difference in TN-stage or the presence of liver metastases. Numbers of patients with KRASmt tumors with one, two and three or more different sites of metastases was 22 (75.9%), 5 (17.2%), and 2 (6.9%), and in KRASwt tumors there was no significant difference: 18 (78.3%), 4 (17.4%), and 1 (4.3%), respectively (p = 0.93). Median CEA at diagnosis for both groups were 19.7 μg/l (range 1.2-5958) and 6.1 (1.3-696.9; p = 0.11).

Conclusions: We found that the ratio of KRASmt to KRASwt tumours in an Irish population is comparable to that in large international trials. Our analysis revealed no association between KRAS status and clinicopathologic variables. The inclusion of BRAF status, not readily available in our institution, may help define poor prognosis tumors. At present there is no validated molecular biomarker that is superior to standard clinicopathologic variables.

No significant financial relationships to disclose.
Quality of life during rehabilitation: Rectal cancer patient and partner experiences with altered bowel function.
Authors: Boucher J. , Piperdi B. , Lundquist D.
Published: February 2017

468

Background: In 2010, the American Cancer Society has estimated rectal cancer affects over 39,670 adult patients in the United States. Five-year disease-free survival for rectal cancer patients with stage II/III disease ranges from 60-70%. Current gaps exist regarding long-term effects after treatment including altered bowel function and health-related quality of life (HR-QOL) concerns from rectal cancer patient and partners' perspectives both individually and together during rehabilitation and as cancer survivors. The purpose of this study was to: (1) describe the experiences of adult rectal cancer patients and their partners during rehabilitation from cancer treatment, including long- term effects; (2) examine health-related quality of life (HR-QOL) issues for rectal cancer patients and their partners including well-being and coping during their rehabilitation and as survivors.

Methods: A qualitative descriptive study for a planned sample of 20 adult rectal cancer patients, stage II/III, and their partners from an academic health science hospital and cancer center has been conducted. Twelve patients and their partners have currently completed face to face semi-structured interviews. Patient participants were at least 6 months to 5 years post treatment. Qualitative descriptive design used purposive sampling to obtain broad information on rectal cancer patients' and partners' perspectives for content analysis.

Results: Preliminary findings have revealed unexpected difficulties; chronic bowel function alterations; symptom unpredictability; nutrition intolerances; patient/partner adjustments; social concerns in going places, reactions by friends, work and financial strains; and, acceptance in living with it or chronic life changes as survivors. Partners acknowledged their own needs for information and support to assist their spouse or significant other. Further rich, thick descriptions will be presented in presentation of findings for 20 patient and partner responses.

Conclusions: Survivorship follow-up regarding these concerns should be emphasized for rectal cancer patients and their partners to formalize interventions for study to enhance HR-QOL well-being.

No significant financial relationships to disclose.
Intratumoral immune reaction: A novel paradigm for cancer.
Authors: Galon J. , Mlecnik B. , Kirilovsky A. , Bindea G. , Tosolini M. , Fridman W. , Pages F.
Published: February 2017

471

Background: To date the anatomic extent of tumor (TNM classifications) has been by far the most important factors to predict the prognosis of cancer patients. However, the impact of immune responses and tumor escape on patient prognosis in human cancer is poorly understood.

Methods: We analyzed large retrospective cohorts of colorectal cancer patients.

Results: We showed that tumors from human colorectal cancer with a high density of infiltrating memory and effector memory T-cells (T-EM) are less likely to disseminate to lymphovascular and perineural structures and to regional lymph-nodes (New Engl J Med, 2005). We showed that the combination of immune parameters associating the nature, the density, the functional orientation and the location of immune cells within the tumor was essential to accurately define the impact of the local host immune reaction on patients prognosis (Science, 2006). We proposed to define these immune criteria as “immune contexture.” Analysis of patients with early-stage colorectal cancer confirmed the major role of cyotoxic effector T cells in predicting the prognosis of the patients (J Clin Oncol, 2009). Investigation of the primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response. We described four major immune coordination profiles within primary tumors depending on the balance between tumor escape and immune coordination. Recent advances analyzing mechanisms responsible for lymphocytic infiltration will be discussed.

Conclusions: The density and the immune-cell location within the tumor have a prognostic value that is superior of those of the TNM classifications. Tumor invasion is statistically dependent on the host-immune reaction.

No significant financial relationships to disclose.
A randomized, multicenter phase III trial of bevacizumab plus capecitabine as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer.
Authors: Yalcin S. , Uslu R. , Dane F. , Yilmaz U. , Zengin N. , Buyukunal E. , Buyukberber S. , Camci C. , Sencan O. , Kilickap S.
Published: February 2017

474

Background: Colorectal cancer is one of the most frequent malignancies, second to breast cancer in women and third to lung cancer and prostate cancer in men. The aim of this study in first-line metastatic colorectal cancer (mCRC) was to achieve a better progression-free survival (PFS) and less risk of toxicity by administrating bevacizumab (BEV) + capecitabine + oxaliplatin (XELOX) for 6 cycles, stop oxaliplatin and go with maintenance therapy (BEV + capecitabine) until progression.

Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 patients (pts) was calculated to achieve 80% power to detect an increase of 1.5 months in median PFS between Arm A (9.5 months) and Arm B (11.0 months) with a standard deviation of 3.9 months and significance level of 0.05 using a 10% drop-out rate.

Results: A total of 122 pts were randomized. No significant differences were found in demographic characteristics between the two arms. Median treatment period was 6.1 (range 0.7–13.4) and 6.8 (range 0.7–12.4) months in Arms A and B, respectively. Interim analysis showed no statistically significant differences in median PFS and ORR between arms (see table). Tolerability was also acceptable in both arms with grade 3/4 diarrhoea in 7.7% vs. 8.2%, weakness in 15.2% vs. 8.4%, hand-foot syndrome in 6.3% vs. 9.4%, and neuropathy in 2.8% vs. 4.6% of pts in Arms A and B, respectively.

Conclusions: BEV + capecitabine as maintenance therapy following induction BEV + XELOX is non-inferior to continuous BEV + XELOX until progression. While this study is ongoing, these interim findings suggest that maintenance therapy with BEV + capecitabine is an appropriate option following induction BEV + XELOX in pts with mCRC.

[Table: see text]

[Table: see text]
Do cancer centers need to assess quality and outcomes? Introducing a customized ACS-NSQIP for oncology (Onc-NSQIP).
Authors: Bilimoria K. Y. , Wang X. , Cohen M. E. , Hall B. L. , Richards K. , Merkow R. P. , Pisters P. W. , Ko C. Y.
Published: February 2017

475

Background: To identify quality improvement opportunities, hospitals can use ACS NSQIP to compare their risk-adjusted performance to other hospitals. However, Cancer Centers have few opportunities to compare their outcomes to similar hospitals for oncologic operations. Our objective was to develop an oncology-specific version of ACS NSQIP (Onc-NSQIP) and determine whether it could be useful for Cancer Centers.

Methods: From ACS-NSQIP (2006-2009), patients undergoing major colorectal (n=34,858; 221 hospitals) and pancreatic (n=7,667; 65 hospitals) as well as esophageal, gastric, and soft tissue operations for malignancy were identified. Risk-adjusted postoperative outcomes were assessed with regression models adjusting for demographics, comorbidities, and operative procedure. Relative rankings of NCI-designated Comprehensive Cancer Centers in ACS NSQIP among the other ACS NSQIP hospitals were compared.

Results: Cancer Center outcomes varied widely for colorectal and pancreas. For overall colorectal morbidity, Cancer Centers were ranked in the top third (n=4), middle third (n=7), and bottom third (n=10). For colorectal 30-day mortality, Cancer Centers were ranked in the top (n=14), middle (n=3), and bottom third (n=4). For overall pancreatic morbidity, Cancer Centers were ranked in the top (n=5), middle (n=7), and bottom third (n=7). For pancreatic 30-day mortality, Cancer Centers were ranked in the top (n=5), middle (n=6), and bottom third (n=8). Similar results were observed for colorectal and pancreas for DVT/PE, SSI, reoperation, and length of stay. Onc-NSQIP models were comparable to standard ACS NSQIP models. At least some Cancer Centers were statistical outliers for most outcomes (P<0.05). Results were similar for other malignancies.

Conclusions: Cancer Center outcomes varied as much as other ACS NSQIP hospitals, demonstrating need for quality assessment. Without standardized risk-adjusted outcomes comparisons, Cancer Centers cannot accurately assess their outcomes to identify quality improvement targets. ACS NSQIP's new platform allows customization so hospitals can compare surgical oncology-specific risk-adjusted processes and outcomes.

No significant financial relationships to disclose.
Effects of ASA404, a vascular disrupting agent, on tumor growth of gastric cancer in an experimental model.
Authors: Lang S. A. , Moser C. , Jung E. M. , Pfister K. , Geissler E. K. , Schlitt H. J.
Published: February 2017

48

Background: A functional vascular system is essential for growth of solid malignancies including gastric cancer. For establishment and maintenance of such a vascular system endothelial cells (ECs) and pericytes (e.g. vascular smooth muscle cells, VSMC) are required. We hypothesized that targeting tumor vasculature with the vascular disrupting agent (VDA) ASA404 (Novartis Oncology) reduces tumor growth in a model of gastric cancer.

Methods: Gastric cancer (GC) cell lines, ECs and VSMCs were used for experiments. Effects of ASA404 on growth of GC, EC and VSMC were assessed by MTT assays. Impact of ASA404 (20 mg/kg on day 1, 5, 9) in combination with paclitaxel (10 mg/kg on day 1 and 7) on tumor growth was assessed in a subcutaneous tumor model. Treatment was started when tumors reached a size of approximately 200 mm3. Tumors were measured and harvested on day 23 for IHC analyses. Effect of ASA404 on blood perfusion of tumors during therapy was monitored by contrast-enhanced ultrasound (CEUS).

Results: In vitro ASA404 impaired growth of ECs and VSMCs upon stimulation with condition media from gastric cancer cells. No direct effect on tumor cells was observed. In vivo, treatment with ASA404 led to marked decrease of tumor perfusion and an increase of necrosis as determined by CEUS. Furthermore, combination of ASA404 with paclitaxel showed significant reduction of tumor growth compared to controls (p < 0.05). In addition, tumor vascularisation and tumor cell proliferation were significantly reduced as determined by CD31-positive vessel area and BrdU-positive cells (p < 0.05).

Conclusions: Combination of the VDA ASA404 with paclitaxel impairs tumor growth and perfusion of gastric cancer in an experimental model. Hence, targeting tumor vasculature with ASA404 appears to be a promising strategy for therapy of gastric cancer.

No significant financial relationships to disclose.
Deferral of rectal surgery following a continued response to preoperative chemoradiotherapy (Watch and Wait) study: A phase II multicenter study in the United Kingdom.
Authors: Yu S. K. , Brown G. , Heald R. J. , Chua S. , Cook G. , Barbachano Y. , Chau I. , Wotherspoon A. , Tait D. M.
Published: February 2017

489

Background: Neoadjuvant chemoradiotherapy (CRT) and surgical resection are standard components of therapy for patients locally advanced rectal cancer (T3,T4 or N+) in UK. In 15%-30% of patients treated pre-operatively with CRT will develop pathological complete response (CR). The time from completion of CRT to maximal tumour response is as yet unknown. This study is the first prospective study to attempt to identify the percentage of patients who can safely omit surgery and the safety of deferred surgery in patients who achieve clinical complete response post CRT. Of the 59 patients required for the study, this provides an update on 19 patients entered.

Methods: Patients with locally advanced rectal cancer requiring neoadjuvant treatment are identified in the multidisciplinary meet (MDT). Patients undergo CRT using a minimum of 50.4Gy in 28 # daily conformal CT planned CRT with concomitant Capecitabine at 825mg/m2 BD. MRI pelvis and body CT are repeated 4 weeks post CRT and rediscussed at MDT. If there is a good partial response or CR, patients are considered for Deferral of Surgery Study. Based on the pre treatment clinical staging, patients are considered for adjuvant chemotherapy as per NICE guidance. At any point of the study, if there is histology proven tumour regrowth or progression, patient undergo surgery.

Results: 10 (53%) patients remain in CR. 6 (32%) patients underwent surgical resection with clear margin after detection of tumour regrowth at from 2-23 months post CRT. 5 out of 6 of the patients with tumour regrowth underwent PET CT as per protocol, and all tumour regrowth in those 5 patients were detected by PET CT, i.e. FDG avid disease. The pathological stages on these 6 patients were ypT2N0 CRM negative in 5 and ypT3N0 CRM negative in 1. 3 (15%) patients with tumour regrowth refused surgery.

Conclusions: In the 19 recruited patients, all the patients with tumour regrowth underwent surgical resection with clear margins. PET CT appears a useful tool for detecting tumour regrowth. The median time for tumour regrowth is 17.5 months post CRT. The trial will be successful if at least 11/59 patients are able to safely omit surgery. Accrual of patients continues.

No significant financial relationships to disclose.
Review of completed and ongoing trials of capecitabine-based adjuvant therapy in patients with early-stage colon cancer.
Authors: Cassidy J. , Scotto N. , Diaz-Rubio E.
Published: February 2017

495

Background: Capecitabine is an established alternative to 5-FU in gastrointestinal cancers. In metastatic colorectal cancer, capecitabine is non-inferior to 5-FU and capecitabine + oxaliplatin (XELOX) is non-inferior to FOLFOX4. Capecitabine is also an effective adjuvant treatment for early-stage colon cancer. Here we review the evidence available from completed studies of adjuvant capecitabine and describe ongoing trials in this setting.

Methods: The X-ACT trial included 1,987 patients (pts) with resected stage III disease receiving either capecitabine (n=1,004) or bolus 5-FU/LV (n=983). NO16968 included 1,886 pts with resected stage III disease receiving either XELOX (n=944) or 5-FU/LV (n=942). The primary efficacy endpoint of both trials was DFS. Other large phase III trials of capecitabine in high-risk stage II/stage III pts include AVANT (XELOX + bevacizumab vs. FOLFOX4 ± bevacizumab), QUASAR2 (capecitabine vs. capecitabine + bevacizumab), SCOT (capecitabine or 5-FU/LV + oxaliplatin 12w vs. 24w), and a Japanese study of single-agent capecitabine.

Results: In X- ACT, capecitabine was at least equivalent to 5-FU/LV in terms of DFS (HR=0.88; 95% CI, 0.77–1.01) and OS (HR=0.86; 95% CI, 0.74–1.01). In a preplanned multivariate analysis, capecitabine led to significantly superior DFS (p=0.02) and OS (p=0.02) vs. bolus 5-FU/LV [Twelves et al. WCGIC 2010]. In NO16968, DFS was significantly superior for XELOX vs. 5-FU/LV (HR=0.80; 95% CI, 0.69–0.93; p=0.0045) [Haller et al. ECCO-ESMO 2009]. There was a trend towards improvement in OS with XELOX (HR=0.87; 95% CI, 0.72–1.05; p=0.1486); follow-up is ongoing. Capecitabine-based therapy had an acceptable safety profile in both trials [Twelves et al. NEJM 2005; Schmoll et al. JCO 2007]. Data have yet to be reported from the AVANT, QUASAR2, SCOT and Japanese trials, although results from these trials in over 15,000 pts are awaited with interest.

Conclusions: Adjuvant capecitabine is non-inferior to 5-FU/LV when given as monotherapy and superior to 5-FU/LV when given in combination with oxaliplatin. Capecitabine should be considered as a standard component of adjuvant treatment regimens for pts with stage III disease.

[Table: see text]
Survival outcomes based on race in gastric carcinoma: A SEER database analysis.
Authors: Didwaniya N. , Edmonds R. J. , Silberstein P. T. , Subbiah S.
Published: February 2017

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Background: Gastric cancer is one of the leading causes of cancer related deaths worldwide with the incidence declining in the United States. However the prognosis remains poor with variable survivals being reported among different races. We analyzed the effect of race on patterns of disease presentation and survival rates using the Surveillance, Epidemiology, and End Results (SEER) database.

Methods: A total of 9,851 patients were diagnosed with gastric cancer from year 2004 to 2007 were identified from SEER database. Age, race, TNM staging, grade, treatment modalities utilized and cancer specific survival was collected.

Results: Out of 9,851 patients, 64.63% were white, 12.17% were black, and 13.04% were Asian-Pacific islanders. Median age was 73 years for whites, 70 years in blacks, and 71 years in Asians. Sex distribution amongst races was more or less similar with 58.83% of whites, 59.47% of blacks, and 54.24% of Asians being men. 23.62% of whites had T1 lesions, 28.10% had T2, 19.58% were T3 and 28.70% had T4 lesions. 26.76% of blacks presented with T1 lesions, 26.63% with T2, 16.08% with T3 and 30.53% with T4. 18.69% of Asians had T1 lesions, 26.84% with T2, 23.44% had T3 and 31.03% had T4 lesions. 37.80% of whites, 36.70% of blacks, and 44.44% of Asians had lymph node involvement. Tumor grade was similar among all races. Surgery was performed in 31.49% of whites, 33.13% of blacks, and 40.48% of Asians. 14.68% of whites, 14.10% of blacks, and 19.43 % of all Asians underwent radiation therapy. Median overall survival in localized disease was 44 months, 43 months and 98 months (p < 0.0001) while in regional disease it was 16 months, 15 months and 23 months in whites, blacks and Asians respectively (p < 0.0001). Median survival in distant disease was 4 months in both whites and blacks; it was 5 months in Asians (p < 0.0001).

Conclusions: Cancer-specific survival in gastric carcinoma is significantly better in localized, regional and metastatic disease in Asians when compared to whites and blacks independent of T stage, grade, nodal involvement and treatment modalities utilized. The reason for this observation is unclear, exposure and genetic factors are potential causes and this needs to be investigated.

No significant financial relationships to disclose.
Gene-expression profiles related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells.
Authors: Chang H. , Rha S. Y. , Jeung H. , Ahn J. , Jung J. , Kim T. , Kwon H. , Kim B. , Chung H. C.
Published: February 2017

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Background: We evaluated the cytotoxic effects of combining of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, with taxanes in human gastric cancer cell lines, and evaluated the pre-treatment difference of gene profile to identify genes that could potentially mediate the cytotoxic response.

Methods: Twenty-five gastric cancer cell lines with 22K gene expression data were treated with SAHA and paclitaxel or docetaxel, and the synergistic interaction between the drugs was evaluated in vitro using the combination index (CI) method. We performed significance analysis of microarray (SAM) to identify chemosensitivity-related genes in gastric cancer cell lines that were concomitantly treated with SAHA and taxane. We generated a correlation-matrix between gene expression and CI values to identify genes whose expression correlated with a combined effect of taxanes and SAHA.

Results: Taxane and SAHA combination had a synergistic cytotoxic effect against taxane-resistant gastric cancer cells. We selected 49 chemosensitivity-related genes, which were commonly identified in paclitaxel and docetaxel combined with SAHA, via SAM analysis. Among them, nine common genes (SLIT2, REEP2, EFEMP2, CDC42SE1, FSD1, POU1F1, ZNF79, ETNK1, and DOCK5) were extracted from the subsequent correlation-matrix analysis.

Conclusions: Taxane and SAHA combination could be efficacious for the treatment of gastric cancer. The genes which were related with the synergistic response to taxane and SAHA could serve as surrogate biomarkers to predict the therapeutic response in gastric cancer patients. We are researching to determine the expression of the nine genes in malignant human gastric cancer tissue and to correlate them with clinical information.

No significant financial relationships to disclose.
Prospective assessment of symptoms and quality of life in localized rectal cancer patients receiving chemoradiotherapy.
Authors: Herman J. M. , Griffith K. A. , Narang A. K. , Zalupski M. M. , Azad N. S. , Chan J. , Olsen L. , Efron J. , Lawrence T. S. , Ben-Josef E.
Published: February 2017

504

Background: Neoadjuvant conformal chemoradiotherapy (CRT) is an important component of treatment for locally advanced rectal cancer, yet its morbidity has not been well characterized using quality of life (QOL) instruments. The present study attempts to establish a baseline distribution of QOL scores before, during, and after CRT and to correlate these changes with symptoms.

Methods: Patients undergoing 3-4 field neoadjuvant CRT for localized rectal cancer were prospectively enrolled at two institutions. Fifty patients completed the QOL instruments at three time points: pretreatment, week 4 of treatment, and 1 month post-treatment. QOL information was captured using three validated questionnaires, the EORTC QLQ-30, QLQ-38, and QLQ-29. Additionally, institutional symptom inventories and CTCAE toxicity data were collected.

Results: Average age was 59.2 years and 72% were men. During CRT, patients had a statistically significant decline in global QOL (70 to 60, p = 0.0024), which normalized (71) following completion of treatment. During therapy, patients also experienced a significant increase in GI symptoms (21 to 27, p = 0.028), urinary symptoms (16 to 30, p < 0.0001), male sexual dysfunction (23 to 34, p = 0.013), and chemotherapy related side effects (8 to 20, p = 0.0001). While these measures returned to baseline 1 month post-CRT, overall sexual function (25 vs. 37, p = 0.0062) and sexual enjoyment (53 vs. 67, p = 0.0070) remained persistently low compared to pretreatment levels. Diarrhea (27%) and proctitis (22%) were the most common grade 3 toxicities. Those patients who experienced grade 3 toxicity during treatment showed markedly decreased global QOL (mean difference = 34).

Conclusions: While rectal cancer patients experienced impaired QOL during neoadjuvant CRT, the vast majority of measures normalized one month after treatment. In contrast, significantly decreased sexual function and enjoyment persisted. This data can be used as a baseline to compare future neoadjuvant conformal CRT regimens and/or assess the toxicity and QOL of new RT modalities such as intensity modulated radiation therapy.

No significant financial relationships to disclose.
Predicting pathologic response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer using FDG PET/CT.
Authors: Shanmugan S. , Arrangoiz R. , Nitzkorski J. R. , Yu J. Q. , Li T. , Konski A. A. , Farma J. M. , Sigurdson E. R.
Published: February 2017

505

Background: Pathologic complete response (pCR) after neoadjuvant chemoradiation has been observed in 15% to 30% of patients with locally advanced rectal cancer. The utility of FDG PET/CT scans in the management of patients with stage II or III rectal cancer is not well defined. The objective of this study is to determine if FDG PET/CT can be used to predict pCR and disease-free survival in patients receiving neoadjuvant chemoradiation with locally advanced rectal cancer.

Methods: A retrospective chart review was conducted in patients with endorectal ultrasound-staged T3 to T4 rectal tumors who underwent preoperative and postoperative FGD PET/CT imaging. All patients were treated with neoadjuvant chemoradiotherapy (CRT). Maximum standardized uptake value (SUV) of each tumor was recorded. Logistic regression was used to analyze the association of pre-CRT SUV, post-CRT SUV, % SUV change, and time between therapy and surgery in comparison to pathological complete response. Kaplan-Meier estimation was used to look for significant predictors of survival.

Results: Seventy patients (mean age 62; 42M:28F) with preoperative stage T3Nx (n = 60) and T4Nx (n = 10) underwent pre-CRT and post-CRT FDG PET/CT scans between November 2002 and March 2009. All patients underwent definitive surgery after therapy with standard pathologic evaluation.The pCR rate was 26%. Median pre-CRT SUV was 10.5 while the median post-CRT SUV was 4.05. Patients with pCR had a lower mean post-CRT SUV compared to those without pCR (2.7 vs. 4.5, p = 0.02). Median SUV decrease was 61% (range 6% to 95%) and was significant in predicting pCR (p = 0.004). Patients with a pCR had a greater time interval between neoadjuvant therapy and surgery (median 57 days vs. 50 days) than those without (p = 0.05). Furthermore, patients with post-CRT SUV < 4 had a lower local recurrence rate compared to those with post-CRT SUV > 4 (p = 0.03). Patients with SUV decrease > 61% had improved overall survival at mean follow-up of 39 months than those without (p = 0.01).

Conclusions: PET/CT can predict response to neoadjuvant chemoradiation in patients with locally advanced rectal cancer. Pre-CRT SUV was the only predictor of disease-free survival.

No significant financial relationships to disclose.
A phase I study of neoadjuvant chemoradiotherapy with S-1/oxaliplatin in patients with gastric cancer.
Authors: Lee D. , Lee J. , Lim D. , Kim S. , Park S. , Park J. , Park Y. , Lim H. , Kang W.
Published: February 2017

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Background: To determine the maximum tolerated dose (MTD) of concurrent radiotherapy with S-1 and oxaliplatin, and antitumor activity of the combination treatment in patients with gastric cancer.

Methods: This was a phase I, escalating multiple-dose tolerability trial. S-1 and oxaliplatin were administered concurrently with radiotherapy for 4 weeks before surgery. The dose escalation scheme is provided in the table below. S-1 was continuously administered during radiotherapy and oxaliplatin was administered weekly for 4 weeks during radiotherapy.

Results: From March 2009 to June 2010, twelve patients were entered at two dose levels. The most common dose-related grade 1 and 2 adverse events were nausea, vomiting, anorexia and abdominal pain. Two of six patients treated at level 1 developed DLT (disabling abdominal pain, stomach perforation). The dose of S-1/oxaliplatin was reduced to 30 mg/m2 bid and 40 mg/m2 (Level -1). There one DLT (vomiting and anorexia, grade 3) observed in the expanded cohort of 6 patients at Level -1. Among 12 patients, 1 patient demonstrated pathological CR after neoadjuvant chemoradiation therapy.

Conclusions: Neoadjuvant CCRT with S-1/oxaliplatin was well tolerated, at a dose 30 mg/m2 bid for S-1 and 40 mg/m2 for oxaliplatin that at which antitumor activity was seen. Phase II study is planned to investigate further the efficacy, tolerability and optimal dose.

[Table: see text]

No significant financial relationships to disclose.