bluuebunny/crossref_metadata_2025 huggingface dataset:
Second-line chemotherapy with capecitabine (CAP) and oxaliplatin (OX) in patients with pancreatic or biliary tree adenocarcinoma (ADC).
Authors: Mane J. , Iruarrizaga E. , Rubio I. , Fonseca E. , Iza E. , Casas R. , Marrodan I. , Martinez M. , Fernandez R. , Carrera S.
Published: February 2017

308

Background: Pancreatic and biliary tree ADC represent poor prognostic tumors. Gemcitabine is usually considered the first- line chemotherapy and after that no standard treatment has been established. CAP and OX have demonstrated some activity in metastatic (M1) and locally advanced (LA) pancreatic cancer, and the combination of these drugs confers additional benefit as well. We conducted this study in order to establish the efficacy of this schedule on pancreatic and biliary tree ADC.

Methods: Pts with M1 or LA pancreatic or biliary tree ADC with progression to one previous chemotherapy treatment were included. Performance status≤2, age≥18 years and adequate renal and hepatic function were selected. Schedule of chemotherapy: CAP 1000 mg/m2 bid on days 2 to 15 and OX 130 mg/m2 on day 1 of a 3-week cycle. RECIST criteria were used for assessment of response and NCI-CTCAE v 3.0 for toxicity.

Results: Between April 2006 and March 2010, 40 pt were included. Male/female: 29/11. Mean age: 60.7 years (37-74). Pancreatic/biliary: 23/17. PS 0/1/2: 3/27/10. LA/ M1: 1/39. Mean number of cycles: 2.50 (1-10). Disease response per pt, partial/ stable disease/progression/not evaluated: 1/9/21/9. Tumor control (partial/stable disease): 10 pt (22%). Hematologic toxicity (grade1/2/3/4) (%) per pt: neutropenia 5/2.5/7.5/0; thrombocytopenia 15/5/2.5/5; anemia 42.5/10/52.5/0. Nonhematologic toxicity (grade 1/2/3) (%) per pt: asthenia 10/45/17.5; emesis 22.5/15/2.5.; anorexia 12.5/35/7.5; diarrhea 7.5/12.5/5; neurotoxicity 42.5/17.5/2.5; hand-foot syndrome 5/2.5/2.5. One toxic death was reported. Median time to progression: 15 weeks (95% CI 6.6-23.3). Median survival time: 19 weeks (95% CI 10.4-27.5). For pts with PS0 or 1 median overall survival was 23 weeks (95% CI 6.3-39.6) and for pts with PS2 was 8 weeks (95% CI 5.3-1.6) (p 0.004).

Conclusions: Advanced pancreatic and biliar ADC have unfavorable prognosis. After first-line treatment, CAPOX shows a tolerable toxicity and some activity and it can represent an alternative on selected pretreated pts.

No significant financial relationships to disclose.
Do bisphosphonates increase esophageal cancer risk? A meta-analysis.
Authors: Ditah I. C. , Janarthanan S. , Tageja N.
Published: February 2017

31

Background: Oral bisphosphonates are known to cause severe esophagitis in some users. This has lead to some authors speculating that they may also increase the risk of esophageal cancer. However, studies investigating the association have yielded inconsistent results. The aim of this work is to summarize available data on the magnitude and direction of the association in a meta-analysis.

Methods: A standardized search was independently conducted by two investigators from January 1990 through September 2010 on Medline and PubMed. Identified articles that met the exposure and outcome definition were manually reviewed for any additional references. Only full articles that provided risk estimates for the association were eligible for inclusion. The most adjusted risk estimates were abstracted independently by the two authors and synthesized using the random-effects model. A stratified analysis by study design has also been done. All studies were evaluated for publication bias before analysis.

Results: Five studies, three case-controls and two cohort studies were eligible for analysis. The combined risk estimate for esophageal cancer was 0.86 (95% CI: 0.62, 1.09). This result remained consistently nonsignificant among the case control studies with a risk estimate of 1.26 (95% CI: 0.94, 1.57). However, there was a significant decrease in the risk of esophageal cancer among the cohort studies with a risk ratio of 0.35 (95% CI: 0.00, 0.71). There was no heterogeneity among the studies by study design. No evidence of publication bias was found, even by study design.

Conclusions: This meta-analysis shows that the evidence in support of an association between bisphosphonates and esophageal cancer is lacking. Large studies with appropriate comparison groups, adequate follow-up, robust characterization of the exposure and information on potential confounders are warranted to determine whether bisphosphonates increase esophageal cancer risk.

No significant financial relationships to disclose.
Bleeding events and eligibility requirements in studies evaluating an antiangiogenic agent in hepatocellular carcinoma (HCC).
Authors: Duffy A. G. , Greten T.
Published: February 2017

310

Background: The presence of cirrhosis means an increased baseline potential risk of bleeding in patients with HCC. With the establishment of sorafenib as a standard of care option this risk is further increased. Bleeding events might potentially become a bigger problem, when sorafenib is combined with other vascular targeting agents. Therefore standardized eligibility criteria across clinical trials are needed.

Methods: We performed a review of all available studies evaluating an antiangiogenic agent either alone or in combination with another agent. The following variables were recorded: demographics, eligibility criteria re: platelet count, coagulation, CP status, endoscopic requirements, hemorrhagic events (any grade). Data tabulated and descriptive statistical analysis employed.

Results: 30 studies were identified since 2005 involving a total of 2,416 pts. 19 studies were available as published manuscripts. 11 of the studies involved sorafenib, 8 bevacizumab, 4 sunitinib with the remainder involving other agents (brivanib, lenalidomide, TSU68, Linifanib, ramicirumab).Eligibility criteria range re: platelet count 40 – 150; INR 1 – 2.3; No study was identified which mandated endoscopy to outrule varices, apart from one study which did so after the occurrence of 2 variceal bleeds. Serious hemorrhagic event up to 13%.

Conclusions: While the risk of hemorrhagic event in studies evaluating an antiangiogenic agent appears to be within an acceptable range, there are no standardized across-study eligibility criteria for this “at risk” population in terms of platelet count, prothrombin time, or endoscopic requirements. Future studies will need to address this issue in more detail, particularly when multiple vascular targeting agents are combined.

No significant financial relationships to disclose.
Cancer prevention among residents: Practice and patterns.
Authors: Akogbe G. O. , Anumenechi N. , Ezigbo C. A.
Published: February 2017

33

Background: At least a third of all cancer cases are preventable. Prevention offers the most cost-effective long- term strategy for the control of cancer; especially in resource deprived areas of the world. Tobacco is the single largest preventable cause of cancer in the world today. Dietary modification is another important approach to cancer control. Infectious agents are responsible for almost 22% of cancer death in the developing world and 6% in industrialized countries. This number is on the rise as result of HIV/AIDS pandemic, life style change and malnutrition. Residents constitute a very important arm of specialized cares in tertiary health institutions. They are the “gate-keepers” who are often the first to come in contact with patients that will benefit from cancer preventive measures. The purpose of this study is therefore, to examine the awareness, attitude and practice of cancer prevention by residents.

Methods: Randomly selected residents from the major clinical oncology departments answered questionnaire that addressed these cancer prevention domains; awareness of behavioral modification and early screening, discussing cancer prevention with patients, and participating in screening for common cancer risk factors.

Results: 77 out 100 questionnaire distributed were completed and returned; 77% response rate. 97% of the respondents are aware of cancer preventive measures but only 73% of these discussed the measures with patients. 9% of the respondents do not advise patient to quit smoking/not to smoke, only 22% advocate protection against sun, 23% do not advocate for early screening, and only 25% of the respondents themselves are screened for any of the common cancer risk factors while 74% are not.

Conclusions: There is significant awareness of cancer prevention measures but not all put this knowledge to practice. Only a quarter of the respondents are themselves screened. Further studies are needed to determine interventions that can improve resident's attitude to cancer prevention in resource deprived economy with rising prevalence of cancer. With improved training opportunities for cancer control among professionals, more cancers will be diagnosed via early screening and detection.

No significant financial relationships to disclose.
Quality of life in patients with pancreatic cancer during neoadjuvant chemotherapy using gemcitabine and bevazizumab: A pilot study.
Authors: Fitzal F. , Schindl M. , Wrba F. , Koelblinger K. , Goetzinger P. , Kornek G. , Sahora K. , Gnant M. , Kuehrer I.
Published: February 2017

330

Background: Neoadjuvant chemotherapy (nCT) for pancreatic cancer is increasing due to the fact that 75% of patients diagnosed with pancreatic cancer are borderline or non-resectable. The use of antibodies may improve the efficacy of nCT. The influence on quality of life is not clear.

Methods: We prospectively evaluated quality of life in patients comparing nCT with gemcitabine (1000mg/m2; 1, 8, 15 for 4 cycles) and bevacizumab (nCT-GA; n=8) with patients with (aCT-G, n=15) or without adjuvant gemcitabine (noCT; n=14) using the EORTC-QLQ PAN26 modul. We also included patients operated due to benign disease as a control group (B; n=15). Quality of life was measured before as well as 3-7 months after surgery.

Results: 52 patients were included in the study. There was no difference between the four groups before surgery in overall quality of life sores (p=0.280). Overall quality of life was also not impaired three months after surgery in any group (nCT-GA: 45 ± 23 vs. 65 ± 23 p=0.196; aCT-G: 42 ± 16 vs. 58 ± 22 p=0.104; noCT: 42 ± 16 vs. 49 ± 24 p=0.462; B: 60 ± 22 vs. 58 ± 21 p=0.894). There were no statistic significant differences between the four groups three to seven months after surgery (p=0.578). Similar function scores such as appetite loss, digestive symptoms or others did not differ significantly.

Conclusions: Chemotherapy with or without bevacizumab seems to be well tolerated. The similar appetite score in patients comparing malignant (±chemotherapy) with benign disease is of importance as weight loss is a bad prognostic marker in pancreatic cancer patients. Thus, chemotherapy with or without bevacizumab may be safe in this respect. Further prospective trials with larger patient numbers are needed.

[Table: see text]
Effect of age on likelihood of treatment and outcome in pancreatic cancer.
Authors: Wheeler A. A. , Dale P. S. , Nicholl M. B.
Published: February 2017

332

Background: Pancreatic cancer is a disease primarily diagnosed in elderly patients; however, a significant number of young patients will also be affected. We hypothesized young patients with pancreatic cancer would be treated more aggressively and therefore have better prognosis.

Methods: A retrospective review of a prospectively maintained cancer database was queried for all patients treated for pancreatic cancer at our institution. Age 50 years was selected to stratify pancreatic cancer patients as young or old.

Results: Of 320 pancreatic cancer patients identified from the database, 56 (18%) were ≤ 50 years old. Exocrine cancer was the most common histology (90%). Young patients were significantly more likely to have an endocrine cancer (23% vs. 7%, p<0.001). For all tumor histologies, there was no difference between young and old patients regarding stage, grade, or likelihood curative intent surgery; however, young patients were more likely to receive chemotherapy (59% vs. 40%, p=0.008) and radiation therapy (27% vs. 15%, p=0.03). There was a trend toward improved overall survival in young patients (23.9 months vs. 13.8 months, p=0.06). When only exocrine pancreatic cancers were considered, there was no difference between young and old patients regarding stage, grade, location, or likelihood of undergoing surgical treatment. In this group, young patients were again more likely to receive chemotherapy (65% vs. 40%, p=0.002) and radiation therapy (35% vs. 16%, p=0.003). There was no difference in overall survival between young and old patients with exocrine pancreatic cancer.

Conclusions: A considerable number of patients with pancreatic cancer are ≤ 50 years old. Exocrine cancers are the most common pancreatic neoplasm regardless of age; however endocrine tumors are more common in young patients. Despite more frequent use of adjuvant treatment in exocrine pancreatic cancer patients ≤ 50 years old, there is no improvement in overall survival. Significant improvements in pancreatic cancer survival are not dependent on aggressive use of adjuvant therapies, but await the development of new treatment strategies.

No significant financial relationships to disclose.
Resectable pancreatic small cell carcinoma: The experience of two institutions and review of the literature.
Authors: Winter J. M. , Narang A. K. , Mansfield A. S. , Herman J. M. , Cameron J. L. , Laheru D. , Eckhauser F. E. , Olson M. , Miller R. C. , Andersen D. K.
Published: February 2017

333

Background: Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC.

Methods: Six patients with pancreatic SCC at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data was analyzed, and the literature on pancreatic SCC was reviewed.

Results: Median age at diagnosis was 50 years (range 27-60). Half of the patients were male, and half were known smokers. All six masses were limited to the pancreatic head. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There was no perioperative mortality, although three patients had postoperative complications. All six patients received adjuvant chemotherapy therapy, five of whom were given cisplatin and etoposide. Of these five patients, three were known to have received radiation, while the remaining two had a plan for radiation at an outside facility. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date.

Conclusions: Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed improved survival rates when compared to prior experiences with both resected and unresectable cases. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation.

No significant financial relationships to disclose.
Sorafenib versus cytotoxic chemotherapy for patients with advanced hepatocellular carcinoma: A retrospective, single-institution study.
Authors: Lee S. , Yoon S. , Shin S. , Choi H.
Published: February 2017

339

Background: Prior to the sorafenib era, most of the advanced hepatocellular carcinoma (HCC) patients had to rely only on conventional cytotoxic chemotherapy. But the introduction of sorafenib in 2008 had given HCC patients additional option for their treatment. However, given that sorafenib has been a nonreimbursable drug under the Korea public health system, most of treatment strategy has largely been determined by patients' affordability of the drug rather than by difference in efficacy and toxicity of the two treatments. Therefore, we compared the efficacy and toxicity of the two treatments by observing HCC patients.

Methods: From January 2002 to December 2009, 173 patients with unresectable HCC had been retrospectively analyzed. Among them, 44 (25.4%) had been treated with sorafenib and the remaining had received cytotoxic chemotherapy. We evaluated objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity profiles.

Results: The median OS of sorafenib group was 23.0 weeks (95% CI, 8.1-37.9) vs. 43.6 weeks (95% CI, 34.0-37.9) for cytotoxic chemotherapy group. The median PFS for sorafenib group was 11.1 weeks (95% CI, 6.5-15.8) versus 12.4 weeks (95% CI, 8.1-16.7) for cytotoxic chemotherapy group. However, the difference in both findings had not been statistically significant (p=0.105 and p=0.496, respectively). ORR and DCR for sorafenib group were 2.3% and 52.3% versus 6.2% and 43.4% for cytotoxic chemotherapy group, respectively. Patients treated with chemotherapy had shown higher frequencies of grade 3 or 4 neutropenia, 19.7%, (vs. 0% for sorafenib). However, the group with sorafenib had reported a higher rate of all grade dermatologic toxicities such as hand-foot skin reaction, rash and pruritus.

Conclusions: Our analysis indicates that efficacy of conventional chemotherapy is not inferior to that of sorafenib. Further research including novel target agent and cytotoxic chemotherapy is needed to improve clinical outcomes for advanced HCC.

No significant financial relationships to disclose.
Laparoscopic hepatic resection: Favorable short-term outcomes for colorectal cancer metastases of the left hemiliver.
Authors: Enestvedt C. K. , Diggs B. S. , Sheppard B. C. , Orloff S. , Billingsley K. G.
Published: February 2017

347

Background: Recent reports demonstrate the feasibility of laparoscopic liver resection for patients with benign and malignant conditions. We hypothesized that patients who underwent laparoscopic resections for colorectal cancer (CRC) metastases of the left liver would have short-term outcomes similar to those who had open surgery.

Methods: A retrospective review compared laparoscopic left liver resections for CRC metastases to open controls for the years 2005-2010. There were two anatomic left hepatectomies in each group, with lesser segmentectomies in the remainder. Demographic information, pathology, tumor characteristics, procedure related factors, complications, and mortality were assessed. Univariate analysis was performed with significance of p<0.05.

Results: Nine patients had laparoscopic resection during the study period, with 1 case converted to open (11%). There were no differences in demographics, tumor factors, margins, or major complications (Table). The laparoscopy group had significantly lower intraoperative blood loss and shorter length of stay compared to the open group. There were no deaths in either group.

Conclusions: In this select group of patients undergoing resection of the left hemi-liver for CRC metastases, short-term outcomes favored the laparoscopic approach. Long- term data regarding disease recurrence and survival are needed in this group of patients. These results indicate that surgeons should consider laparoscopic resection of the left liver whenever technically feasible in the setting of CRC metastases.

[Table: see text]

No significant financial relationships to disclose.
Positron emission tomography (PET) with 89Zr-labeled trastuzumab (89Zr-trastuzumab): Monitoring HER2 expression in HER2-positive gastric cancer in vivo.
Authors: Janjigian Y. Y. , Villegas N. T. , Holland J. P. , Shah M. A. , Divilov V. , Kelsen D. P. , Lewis J. S.
Published: February 2017

35

Background: The ToGA study established HER2 is a target in the treatment of gastric cancer. Trastuzumab pharmacokinetics and organ distribution is varied in each patient and is heavily affected by the extent of tumor load (Oude Munnink, JCO 2010). 89Zr-trastuzumab HER2 PET can be used to image that variability and may aid in detection and staging of HER2-positive tumors. We are implementing 89Zr-radiolabeled trastuzumab PET in vivo for imaging of HER2-positive gastric cancer and for future non-invasive assessment of HER2 inhibition with a dual irreversible HER1/HER2 inhibitor, BIBW-2992.

Methods: 89Zr (t1/2 = 3.17 days) was prepared via the 89Y(p,n)89Zr transmutation with high radiochemical yields (1.52±0.11 mCi/μAh) and purity (>99.99%). Trastuzumab was functionalized with the tris-hydroxamate chelate, desferrioxamine B (DFO) and radiolabeled with [89Zr]Zr-oxalate at room temperature. 89Zr-trastuzumab PET experiments in athymic nu/nu mice bearing sub-cutaneous NCI-N87 (HER2+) and/or SNU1 (HER2-) tumors were conducted. NCI-N87 gastric cancer cells were treated with BIBW-2992.

Results: 89Zr-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity of 2.82±0.05 mCi/mg. In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87±7. In vivo biodistribution experiments revealed high and specific uptake in HER2-positive tumors after 72 h (85.2±11.1% ID/g) with retention of activity for over 120 h. No uptake was seen in HER2-negative gastric cancer xenografts. In vitro, BIBW-2992 demonstrates dose dependent growth inhibition in the HER2+ gastric cancer cell line.

Conclusions: 89Zr-trastuzumab provides quantitative and highly-specific delineation of HER2-positive gastric cancer. In vivo studies of BIBW2-2992 in gastric cancer with 89Zr-trastuzumab HER2 PET response assessment are underway. A Phase I study of 89Zr-trastuzumab PETin HER2-positive patients is to open at MSKCC imminently.

No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) as a predictive and prognostic marker in patients with advanced colorectal cancer (aCRC): The MRC COIN trial experience.
Authors: Adams R. A. , James M. D. , Smith C. G. , Wilson R. H. , Fisher D. , Kenny S. L. , Kaplan R. S. , Stoerkel S. , Maughan T. S. , Jasani B.
Published: February 2017

359

Background: KRAS mutation has been shown to be a more effective (though negative) biomarker for selection of patients for EGFR targeted therapy in aCRC. However, positive EGFR immunohistochemistry (IHC) remains a license requirement and was an inclusion criterion in most trials to date. The MRC COIN trial recruited 2445 pts into 3 arms of oxaliplatin + fluoropyrimidine +/- cetuximab without prior EGFR assessment. This trial provides a unique opportunity to definitively examine the role of EGFR IHC as prognostic and predictive marker and potentially the evidence required to remove this assessment from the license for this drug.

Methods: Formalin-fixed paraffin embedded (FFPE) tissue was stained retrospectively for EGFR using Dako kit in a national reference lab. Results were assessed by 3 reviewers (BJ, SS, RA) using digital imaging software in a blinded fashion, then by BJ/SS providing consensus for discrepancies. EGFR scoring was assessed as a prognostic variable in association with selected patient, tumor and biochemical data. Cut off points examined for +ve vs -ve tumours, in terms of total tumour cells demonstrating membrane staining, were: 0% vs >0%; <10% vs ≥10%; <20% vs ≥20%.

Results: EGFR IHC was adequately assessed for 1621 pts (66% of randomised), 22% were negative (0%) and 78% positive (>0%), balanced across arms. EGFR was not prognostic for PFS within KRAS wt pts at the standardized cut off point 0% vs >0% HR=1.11 95% CI 0.91-1.36 p=0.31 but was at <10% vs ≥10% (HR=1.27 95% CI 1.07-1.52 p=0.008) this was robust to other prognostic variables. No effect was seen for overall response or survival. There was no prognostic effect for the KRAS mutant group. In the 1065 assessable pts randomised to +/- cetuximab, no evidence of EGFR IHC as a predictive marker for response or survival outcomes was observed for the addition of cetuximab to chemotherapy (OS HR=1.11 95% CI 0.70-1.75 p=0.66; PFS HR=0.95 95% CI 0.64-1.43 p=0.82).

Conclusions: Extensive assessment of samples from this trial suggest a role for EGFR IHC as a prognostic marker in KRAS wt aCRC but refute the predictive value embedded within the licence for cetuximab used in combination with chemo in first-line therapy.

[Table: see text]
GCC expression in lymph nodes (LNs) as a significant determinant of recurrence in stage II colon cancer (CC) patients (pts).
Authors: Sargent D. J. , Shi Q. , Bot B. M. , Resnick M. B. , Meyers M. O. , Goldar-Najafi A. , Clancy T. E. , Gill S. , Siemons G. O. , Fradet Y.
Published: February 2017

369

Background: A multi-center prospectively specified retrospective study Validating Indicators to Associate Recurrence (VITAR) is assessing the relationship between guanylyl cyclase C (GCC) gene expression in formalin fixed LNs and recurrence risk in stage II CC pts not treated with adjuvant chemotherapy. Here we report the preplanned initial analysis performed with 241 pts.

Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs tissues from untreated stage II CC pts diagnosed from 1999-2006 with at least 10 LN examined blinded to clinical outcomes. Cox regression models examined the relationship between GCC nodal status and the prespecified primary endpoint of recurrence risk.

Results: Twenty-ninepts (12%) had a disease recurrence or cancer death, median follow-up was 60 months and median LNs examined was 15. The ratio of the number of GCC+ LNs over the total number of informative LNs (LNR) significantly predicted higher recurrence risk for 84 pts classified as high risk (HR, 2.38; p=0.02). The estimated 5-yr recurrence rates were 10% and 27% for the low and high risk group, respectively. After adjusting for age, T stage, number of LNs assessed, and MMR status, the significant association remained (HR, 2.61; 95% CI, 1.17-5.83; p=0.02). In a subset of 181 pts with negative margin, T3 tumor only and ≥12 LN examined, the GCC LNR had a HR for recurrence of 5.06 (95% CI 1.61-15.91, p=0.003), translating into 5-yr recurrence rates of 4% among low risk pts and 27% for the high-risk group.

Conclusions: Our results suggest that GCC expression in LNs is a significant determinant of recurrence in appropriately staged CC pts not treated with adjuvant chemotherapy. The validation component of the study is ongoing.

[Table: see text]

[Table: see text]
Hypertension (HTN) as a potential biomarker of efficacy in patients (pts) with gastrointestinal stromal tumor (GIST) treated with sunitinib (SU).
Authors: George S. , Lechner T. , Li S. , Cohen D. P. , Demetri G. D.
Published: February 2017

38

Background: HTN is a class effect of VEGF signaling pathway inhibitors. SU is a multitargeted inhibitor of VEGFRs and other receptor tyrosine kinases. Associations between SU-induced HTN and efficacy endpoints (OS, PFS, TTP, and ORR) in pts with imatinib-resistant/intolerant GIST from 2 prospective clinical trials were investigated retrospectively.

Methods: This analysis included pooled data from 319 pts who received SU and had post-baseline blood pressure (BP) data available. Tumor response data were based on investigator assessments. Most pts (87%) received SU 50 mg/d on the standard 4-wk-on/2-wk-off schedule. BP was measured on the first and last day of dosing in each treatment cycle at a minimum. HTN was defined as max or mean SBP ≥ 140 or DBP ≥ 90 mmHg. OS, PFS, and TTP were estimated by Kaplan—Meier methods and compared between pts with vs. without HTN using the log-rank test. The influence of prognostic risk factors was analyzed using a Cox proportional hazards model.

Results: 233 and 187 pts (73% and 59%) had ≥ 1 HTN episode as defined by max SBP and DBP, respectively. Efficacy results significantly favored pts who developed HTN on SU based on max SBP or DBP (eg, median OS for pts with HTN [max SBP] was 89.4 weeks vs. 53.1 weeks for pts without HTN [p = 0.0001]). Using HTN onset as a time-dependent covariate, HTN defined by max DBP was a significant predictor of prolonged TTP and PFS, and HTN defined by both max SBP and DBP was a significant predictor of prolonged OS (p < 0.05). In multivariate analysis, HTN defined by max SBP or DBP was a significant independent predictor of improved OS, PFS, and TTP (p < 0.0001). Analysis of any-grade and grade ≥3 cerebrovascular, ocular, cardiac, and renal AEs in pts with/without HTN is ongoing and will be presented. Clinical outcomes were not compromised in pts treated with anti-HTN medications.

Conclusions: SU-associated HTN was significantly and independently associated with improved clinical outcomes, supporting the hypothesis that HTN is a biomarker for antitumor efficacy in pts with GIST treated with SU. Serial BP monitoring and standard use of anti-HTN medications, which were not shown to compromise efficacy, are recommended during SU therapy.

[Table: see text]
Presentation, management, and outcome of the pregnant female with colorectal cancer.
Authors: Kachikwu E. L. , Leong L. A. , Lai L. L.
Published: February 2017

389

Background: Most patients diagnosed with colorectal cancer (CRC) are older than 60 years old. However, there remains a population of women of reproductive age (17-49) who develop CRC. Few publications have described the presentation, management and outcome of patients who initially present while pregnant.The objective of this study is to assess the presentation, management and outcome of women aged 17-49 with a particular focus on the pregnant patient. Presenting symptoms, time from presentation to diagnosis, management of disease, and overall survival were the main endpoints of this study.

Methods: A retrospective chart review was conducted of 72 women aged 18-49 who were treated for CRC between 2005 and 2009 at a single institution. We compared the non-pregnant women (n = 66, group A) with the pregnant women (n = 6, group B).

Results: The median age at presentation was 43 and 36.5 years in group A and group B, respectively. All six patients in group B presented with significant anemia, severe abdominal pain, and bright red blood per rectum during pregnancy while 25% of group A were asymptomatic. Although all 6 of the group B patients presented while pregnant, five patients were diagnosed in the postpartum period. Only 1/6 patients were diagnosed while pregnant, in the 3rd trimester. Median time from presentation to diagnosis was 10 days in group A, and 175 days in group B. Definitive treatment for the group B women included resection with C-section (n = 1), resection followed by systemic chemotherapy (n = 3), and resection only (n = 2). 72% of group A and 100% of group B patients presented with advanced disease (stages III and IV). Median overall survival for the entire cohort was 24.4 months; 26.1 months for group A and 7.8 months for group B. There was one long-term survivor amongst the group B patients (5.3 years), who has had two recurrences.

Conclusions: Overall, the majority of women aged 18-49 presented with advanced stages of CRC. Specifically, 5/6 pregnant women presented with stage IV disease. Given that many of the symptoms of CRC mimic symptoms of pregnancy, a higher index of suspicion of CRC may minimize the delay in diagnosis, decrease the proportion of higher stage cancers, and improve the cancer outcome in this cohort of patients.

No significant financial relationships to disclose.
Development of a new stool biomarker ELISA for the early detection of colorectal cancer.
Authors: Luka J. , Arlen P. M. , Bristol J. A.
Published: February 2017

390

Background: An ELISA was developed using NPC-1C, a novel antibody that reacts with an antigen expressed specifically by human colorectal and pancreatic tumor tissues and cell lines. The target antigen that NPC-1C recognizes was shown to be related to MUC5AC, a member of the mucin family of glycoproteins. NPC-1C reacts with neither normal tissues from healthy donors (rare, weak binding to normal colon and esophagus), nor cell lines derived from other tumor types, thereby providing the basis for a proof of concept comparative evaluation with stool from normal healthy donors.

Methods: An ELISA that uses NPC-1C antibody as both capture and detection reagent was developed. Samples of stool collected during colonoscopy from colorectal cancer patients (n = 4), stool from people with small polyps (n = 4), stool from people with multiple polyps (n = 2), stool from people with large polyps (n = 3), and stool from healthy adults (n = 13) were applied to the ELISA. A soluble extract of stool was prepared by detergent lysis and centrifugation. The level of NPC-1C-specific MUC5AC antigen measured in this ELISA was compared among all groups.

Results: Preliminary results demonstrated that healthy people did not express NPC-1C antigen in their stool. The signal in the assay was similar to background levels (average 723 units). In contrast, people with small polyps had higher levels (average 3,819 units); people with multiple polyps expressed higher levels (average 7,369 units); people with large polyps had even higher levels (average 10,189 units); and colon cancer patients had the highest levels (average 175,983 units), more than 240 times the level of MUC5AC-related antigen compared with healthy people.

Conclusions: The proof of concept has been established to correlate the level of NPC-1C reactive antigen, measured by a novel stool-based ELISA, with colon cancer disease progression. The level of NPC-1C-specific MUC5AC detected increased concomitantly with the number and size of polyps observed during colonoscopy, and reached the highest levels in patients with colon cancer. Our goal is to apply this ELISA test for early noninvasive diagnostic screening for colorectal cancer, an area of still largely unmet need.

[Table: see text]
Use of preoperative liver biopsy to predict livers that have avoided chemotherapy-induced liver injury.
Authors: Belghiti J. , Genser L. , Fuks D. , Dokmak S. , Faivre S. J. , Paradis V.
Published: February 2017

393

Background: Liver parenchymal damage caused by neoadjuvant chemotherapy may increase the surgical risk. The aim of the present study was to assess the performance of preoperative liver biopsy (PLB) in predicting the status of the liver parenchyma at the time of resection.

Methods: Among 40 patients who underwent liver resection after neoadjuvant chemotherapy for colorectal liver metastases (CLM) in 2009, 28 had percutaneous PLB from 2 to 6 weeks after onset of the treatment. Patients underwent a mean number of 9 cycles of chemotherapy (range 4-22). Chemotherapy included oxaliplatin (n=22), irinotecan (n=10), and bevacizumab (n=12). PLB and surgical specimens were compared according to the presence and rate of steatosis, sinusoidal obstruction syndrome (SOS) and chemotherapy-associated steatohepatitis (CASH).

Results: Surgical specimen analysis showed steatosis in 12 (43%) patients (ranging from 5 to 80%), SOS in 12 patients (43%) and CASH in 1 patient (3%). The sensitivity, specificity, positive predictive value and negative predictive value of PLB for steatosis were 67%, 81%, 73% and 77%, respectively. It was 50%, 94%, 86% and 71%, respectively for SOS and 0%, 100%, 0% and 96%, respectively for CASH. Performance of PLB was not related to the type of chemotherapy. Among the 28 patients, 8 patients had no abnormalities on PLB. In 7 of them, surgical specimen analysis was considered normal.

Conclusions: The accuracy of PLB in predicting chemotherapy- induced liver injury appears to be low. It is useful, however, given its high specificity when the PBL is normal, for encouraging hepatic resection without delay.

No significant financial relationships to disclose.
Use of co-expression of HGF and c-Met to predict peritoneal dissemination established by autocrine HGF/c-Met signaling in gastric cancer.
Authors: Toiyama Y. , Tanaka K. , Yasuda H. , Saigusa S. , Fujikawa H. , Mohri Y. , Inoue Y. , Miki C. , Tabata T. , Kusunoki M.
Published: February 2017

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Background: Epithelial mesencymal transition (EMT) promotes facilitates migration and invasion of epithelial tumour cells. EMT is induced by growth factors implicated in theses process such as hepatocyte growth factor (HGF). Our aim of this study is whether HGF/c-Met pathway is associated with metastasis of gastric cancer (GC), especially in peritoneal dissemination (PD).

Methods: HGF and c-Met expression and EMT related molecules were evaluated using real-time PCR and immunohistochemistry in GC tissues. The role of HGF/c-Met pathway for EMT and anoikis was determined and c-Met TKI (SU11274) was tested for their ability to block HGF-induced biological effects in vitro and vivo.

Results: In HGF(-)c-Met(+) GC cells,recombinant HGF promoted EMT phenotype characterized by morphology, impaired E-cadherin and induction of Vimentin. HGF promoted cell growth, invasiveness, migration ability and inhibition of anoikis. SU11274 blocked HGF-induced EMT and the biological effects in vitro. In contrast of HGF(+)c-Met(+) GC cells, HGF exposure was not affected biological outcome of EMT and anoikis but SU11274 blocked biological effect as same as in HGF(-)c-Met(+) GC cells. In vivo, HGF(+)c-Met(+) GC cell line only established PD and SU11274 intraperitoneally caused an inhibition of PD growth. Clinically, HGF expression was significantly positive correlated with c-Met expression in GC specimens. Increased HGF and c-Met demonstrated a significantly associated with poor prognosis and can predict PD, respectively. Furthermore, HGF was one of the independent factors for predicting PD. Immunohistochemical analysis showed HGF and c-Met were predominantly co-expressed in cancer cell of both primary GC and PD.

Conclusions: We have demonstrated that HGF/c-Met pathway as an inducer of EMT and anoikis inhibition in GC cell. Co-expression of HGF and c-Met implicates its potential to promote PD in GC. Blocking the autocrine HGF/c-Met pathway may be clinically useful for the treatment of PD in GC.

No significant financial relationships to disclose.
The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan/cetuximab.
Authors: Scartozzi M. , Mandolesi A. , Giampieri R. , Zaniboni A. , Galizia E. , Giustini L. , Silva R. R. , Berardi R. , Bearzi I. , Cascinu S.
Published: February 2017

404

Background: Preclinical data suggested that in presence of HER3 altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. HER3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER3 expression and clinical outcome in KRAS wild-type advanced colorectal cancer receiving cetuximab and irinotecan.

Methods: We retrospectively analyzed immunoreactivity for HER3 in KRAS wild-type advanced colorectal cancer patients receiving irinotecan-cetuximab.

Results: Eighty-four advanced KRAS wild- type colorectal cancer patients were available for HER3 analysis. Forty patients (48%) showed HER3 negative colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER3 positive. In HER3 negative and HER3 positive tumors we observed a partial response in 17 (42%) and 8 (18%) patients respectively (p = 0.04). Progressive disease was obtained in 11 (35%) and 26 (53%) patients with respectively HER3 negative and positive tumor (p = 0.007). No differences were observed for stable disease. Median PFS was 6.3 months in patients showing HER3 negative tumors and 2.8 months for those who had HER3 overexpressing tumors (p < 0.0001). Median overall survival was 13.6 months in patients showing HER3 negative tumors and 10.5 months for those who had HER3-expressing tumors (p = 0.01).

Conclusions: HER3 proved to be a predictive factor for clinical outcome in KRAS wild-type colorectal cancer patients treated with cetuximab. Combined HER3 and KRAS analysis may represent an effective strategy for a better selection of responding colorectal tumors. Furthermore besides identifying colorectal cancer patients refractory to EGFR directed treatment, HER3 overexpression may also represent a potential biological indicator for the development of a new class of antineoplastic agents in this setting.

No significant financial relationships to disclose.
Association of circulating cytokine and angiogenic factors (CAFs) with outcomes to second-line FOLFOX plus bevacizumab or cediranib in metastatic colorectal cancer.
Authors: Kopetz S. , Tran H. T. , Cunningham D. , Mookerjee B. , Pike L. , Jurgensmeier J. , Heymach J.
Published: February 2017

406

Background: Chemotherapy combined with inhibitors of VEGF signaling is associated with improved outcomes, but biomarkers of therapeutic benefit have been elusive. Cediranib (Ced) is an oral VEGFR tyrosine kinase inhibitor that has been investigated as a treatment for metastatic colorectal cancer (mCRC).

Methods: 215 patients with progressive disease and no prior VEGF inhibitor therapy were enrolled in a randomized phase II study of FOLFOX + Ced 20mg/d, Ced 30mg/d or bevacizumab (Bev) 10mg/kg (Cunningham D, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4028). 36 CAFs were analyzed at 3 time points (baseline, wk 4, wk 8). Groups were dichotomized by median CAF value. Hazard ratios (HRs) were estimated from a Cox model with a single term.

Results: Data were available for > 85% patients for each CAF. When pooled across all arms, several baseline CAFs including VEGF, interleukin (IL)-2Rα, IL-8 and PDGF were associated with improved PFS (Table). Low and high baseline CAF subgroups were evaluated for potential predictive CAFs. Pts with elevated baseline IL-8 did better with Ced 30mg/d than Bev (HR 0.6 for PFS, CI 0.3-1.0) while low IL-8 was associated with greater benefit from Bev than Ced (HR 2.1, CI 1.0 to 4.2). For Ced 20mg/d, PFS HRs were 0.9 (CI 0.5, 1.6) and 1.7 (CI 0.9, 3.2) for elevated and low baseline IL-8 respectively. Hepatocyte-growth factor (HGF) demonstrated a similar relationship, while a trend for the inverse association was seen with IP-10. Distinct patterns of cytokine modulation were seen between Ced and Bev during the 8 wks, including decreases of sVEGFR2, IL-13 and increases in osteopontin.

Conclusions: Several potential prognostic factors for second-line mCRC therapy were identified including VEGF and IL-8. Further work in larger placebo-controlled studies is required to further evaluate predictive markers for VEGF signaling inhibitors.

[Table: see text]

[Table: see text]
Use of genetic variants in formyl peptide receptor 2 (FPR2) to predict tumor recurrence in stage II colon cancer.
Authors: Zhang W. , Labonte M. J. , Yang D. , Ning Y. , Gerger A. , Bohanes P. O. , Winder T. , El-Khoueiry A. B. , Iqbal S. , Lenz H.
Published: February 2017

408

Background: The formyl peptide receptor (FPR) is a G-protein-coupled receptor (GPCR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides. Recent studies found that it is selectively expressed in highly malignant gliomas and contributes to tumor growth and angiogenesis by mediating tumor cell chemotaxis, proliferation and production of chemokines and VEGF. Previously we demonstrated that polymorphisms in the VEGF pathway predict tumor recurrence in adjuvant colon cancer. Here we tested the hypothesis that two genetic variants in the FPR2 gene (rs17834679 and rs17694990) may predict tumor recurrence in a cohort of adjuvant colon cancer patients.

Methods: Between 1992 and 2007, blood samples were obtained from 234 adjuvant colon caner patients (109 with stage II and 125 with stage III) at the USC medical facilities. Genomic DNA was extracted from peripheral blood and two potentially functional genotypes (rs17834679 and rs17694990) within the FPR2 gene were determined utilizing the PCR-RFLP technique. The median follow-up was 4.4 years (range: 0.3- 16.8). Ninety of 234 patients (38.5%) developed tumor recurrence with a 3-year probability of 0.34 ± 0.05.

Results: In multivariable Cox proportional hazards regression analysis, FPR2 polymorphism rs17834679 was significantly associated with time to tumor recurrence (TTR) in stage II colon cancer (adjusted P = 0.027). Patients with CC genotype were at greatest risk of developing tumor recurrence (adjusted hazard ratio [HR]: 2.819 [95%CI: 1.127-7.051]) compared to those with GC and GG genotypes. In the dominant inheritance model, patients with any G allele had longer TTR (16.8 years+, median was not reached) compared to those with CC genotype (median TTR 5.4 years [95%CI: 3.2-10.7]; p=0.007, log-rank test). There are no significantly associations between FPR2 polymorphisms and TTR in stage III colon cancer.

Conclusions: Polymorphisms in the FPR2 gene may serve as molecular markers for tumor recurrence in stage II colon cancer, indicating that the analysis of genetic variants of FPR2 may help to identify patient subgroups at high risk for tumor recurrence.

No significant financial relationships to disclose.
Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response observed in adenocarcinoma.
Authors: Ilson D. , Janjigian Y. Y. , Shah M. A. , Tang L. H. , Kelsen D. P. , Campbell J. , Fuqua L.
Published: February 2017

41

Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial combining sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We are studying single agent sorafenib in a phase II trial with the primary endpoint to assess progression free survival (PFS). Secondary endpoints include response and therapy tolerance.

Methods: Patients (pts) with measurable metastatic E and GEJ cancer with no more than 3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months.

Results: Sixteen of 35 pts have been accrued and 14 are currently evaluable. 13 male, 3 female, median KPS 80%, age 58, GEJ 7, E 9, squamous 2, adenocarcinoma (AC)14. An ongoing complete response (11+ months) was observed in a pt with biopsy proven metastatic neck lymphadenopathy (E primary AC, recurrence after prior chemoradiotherapy and surgery). A second pt (GEJ AC) had protracted stable disease in bulky celiac node disease (15+ months). Grade 3 toxicity was limited to skin rash (1 pt), hand foot reaction (1 pt), and fatigue (1 pt). Only 3 of 14 pts (21%) had early disease progression at 2 months or less. Median PFS 4 mos, 4 patients (29%) continue on therapy for more than 7 months. The majority of tumors tested positive for phospho-erk by immunohistochemistry (11/14, 79%).

Conclusions: The observation of a durable complete response and protracted stable disease to sorafenib in E cancer is remarkable. Further accrual continues to define PFS. Supported by a grant from Bayer.

[Table: see text]