bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolerability and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in patients with borderline-resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAURPC).
Authors: Blazer Marlo A. , Wu Christina Sing-Ying , Goldberg Richard M. , Phillips Gary S. , Schmidt Carl Richard , Muscarella Peter , El-Dika Samer S , Walker Jon P , Krishna Somashekar Gopala , Groce J. Royce , Wuthrick Evan John , Williams Terence M , Efries David , Smith Yahna T. , Mathey Kris , Wagner Mandy , Reardon Josh , Ellison Edwin Christopher , Bloomston Mark , Bekaii-Saab Tanios S.
Published: February 2017

275

Background: FOLFIRINOX exhibits a meaningful improvement in outcome measures in metastatic pancreatic cancer, making it an interesting regimen for BRPC and LAURPC. However, its use remains prohibitive due to toxicity. In this study, we examine the outcomes of mFOLFIRINOX as a neoadjuvant strategy for patients with BRPC and LAURPC. Methods: This is a retrospective analysis of a prospectively maintained database of patients who received mFOLFIRINOX for BRPC or LAURPC at Ohio State University. mFOLFIRINOX is as follows: irinotecan at 165 mg/m2; oxaliplatin at 85 mg/m2; 5-fluorouracil (5FU) at 2,400 mg/m2 over 46 hours and pegfilgrastim on day 4 of each 2-week cycle. Cases were thoroughly reviewed by a multidisciplinary team prior to initiation of therapy and at each restaging scan. The primary outcomes of this analysis were resection rate and grade 3/4 (G3/4) toxicities. Results: Since 1/1/2011, 43 patients (20 BRPC; 23 LAURPC) have received mFOLFIRINOX. Patients received gemcitabine-based chemoradiation (36 Gy in 15 fractions) only if their best response was stable disease after 4 months of mFOLFIRINOX. At the time of this abstract, 39 patients are evaluable for primary outcome. Overall resection rate was 53.8% including 45% of patients with initially unresectable disease. R0 resection was achieved in 85.7% of the surgeries. See table for more results. The rate of G3/4 toxicity was remarkably low with no episodes of febrile neutropenia, G3/4 neutropenia or thrombocytopenia. Toxicities lead to dose reductions in 46% of patients. Conclusions: Neoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen as part of an integrated, multimodality strategy in BRPC and LAURPC leading to high resection rates and high R0 resection frequency. [Table: see text]
Neoadjuvant therapy for pancreatic cancer in patients older than age 75.
Authors: Miura John Thomas , Krepline Ashley N , Duelge Kaleb D , George Ben , Ritch Paul S. , Erickson Beth , Thomas James P. , Mahmoud Anna , Quebbeman Edward J , Turaga Kiran , Johnston Fabian McCartney , Christians Kathleen K. , Gamblin T. Clark , Evans Douglas B. , Tsai Susan
Published: February 2017

287

Background: Multiple treatments in series may be difficult for older patients (pt) to tolerate. We sought to examine the outcomes associated with neoadjuvant therapy in older pt with resectable (R) or borderline resectable (BLR) pancreatic cancer (PC). Methods: Pt ≥75 years (O) with those <75 (Y) with R or BLR PC receiving neoadjuvant therapy from 2008-2012 were identified. Clinicopathologic and treatment data were abstracted. Completion of all therapy was defined as the receipt of neoadjuvant therapy followed by surgical resection. Results: We identified 77 (42.5%) R and 104 (57.5%) BLR pt; 29 (16%) were ≥ 75 years. Higher Charlson Comorbidity Index (CCI) (median CCI 4 vs. 2, p<0.01) and more hospitalizations during neoadjuvant therapy (50% vs. 28%, p=0.04) were associated with O vs. Y pt. Older pt were less likely to complete all therapy as compared to Y pt (72.4 vs. 89.5%, p<0.01). Poor performance status was the most common reason for failure to complete all therapy in O vs. Y pt (17.2% vs. 0.7%; p<0.01). Higher CCI (OR 0.25; 95% CI: 0.08-0.74, p=0.01) and higher clinical stage (OR 0.17; 95%CI: 0.06-0.48, p<0.01) were associated with failure to complete all therapy. Of the 138 pt that completed all therapy, no significant differences in complication rates (15 vs. 15.3%, p=0.33), median length of hospital stay (10 vs. 9 days, p=0.29), 30 day readmission rates (10 vs. 11.9%, p=0.81), or median overall survival (24.3 mo vs. 36.7 mo, p=0.20) were observed between O vs. Y pt. Conclusions: After neoadjuvant therapy, 25% of pt ≥ 75 years of age will not undergo surgical resection. The most common reason for not completing all therapy is a decline in performance status. Whether neoadjuvant therapy improves the selection of older pts who should not undergo an operation or prevents successful resection of pt who may have tolerated an operation is unclear. With evolving paradigms of treatment sequencing, the management of PC pt with advanced age will require further assessment.
Efficacy and safety of FOLFIRINOX in patients with metastatic pancreatic cancer.
Authors: Metges Jean Philippe , Ramée Jean François , Douillard Jean-Yves , Boucher Eveline , Faroux Roger , Guerin-Meyer Veronique , Cumin Isabelle , Miglianico Laurent , Le Roux Catherine , Dupuis Olivier , Porneuf Marc , Lam You Heng , Achour Nacredine , Etienne Pierre-Luc , Cojocarasu Oana , Corbinais Stephane , Deguiral Philippe , Geslin Guillaume , Campion Loic , Grude Francoise
Published: February 2017

305

Background: FOLFIRINOX, one of the gold standard in metastatic pancreatic cancer as first-line therapy for patients under 76 years with PS 0-1, good haematological and renal function and a subnormal bilirubin level (Prodige 4 criteria), was analysed in Brittany (B) and Pays de la Loire (PL) in routine clinical practice. Methods: Our aim is to evaluate the use of Folfirinox between July 2010 and December 2012 in B/PL. Results: Data of 340 patients have been studied (198 men, median age 63 years [29-81]). 208 patients were metastatic at diagnosis (liver 67%). 62 primary tumors were resected and 51 patients had received previous adjuvant chemotherapy (gemcitabine, n=48). The median progression free survival PFS and overall survival OS were respectively 6.80 months IC95% [6.18-7.43] and 10.97 months IC 95% [9.56-11.83]. Patients could be divided into 4 groups : Group 1 composed of patients treated according to Prodige 4 trial (n=242), Group 2 1st line metastatic patients with at least one Prodige 4 non-eligibility criterion (n=25), Group 3 locally advanced patients (n=59) and Group 4 by Folfirinox in 2ndline (n=14). The median number of cycles was 9 [1-27] in Group 1 and 6 [1-12] in Group 2. Clinical benefit was 65% (group 1) vs 56% (group 2). During treatment, 81% of patients had a dose adjustment (Group 1) vs 72% (Group 2) and 32% vs 40% presented grade III/IV toxicity (mostly neuro- or haematotoxicity). Median PFS were respectively in Group 1 vs Group 2 : 6.54 months IC95% [5.98-7.29] vs 4.14 [1.68-6.21] (p=0.0107) and median OS :10.91 months IC 95% [8.94-12.02] vs 7.0 IC95% [4.01-11.20] (p=0.0166). For Group 3 and 4, median OS were respectively 11.24 months [10.0-15.01] vs 11.50 [4.83-14.09]. Others results will be shown at the meeting. For Group 1, stopping treatment before progression induced significatively better median PFS and OS than going on treatment until progression : PFS : 8.25 IC95[7.52-8.74] vs 3.48. IC95 [3.09-4.44] (p<0.0001) and OS : 12.78 months IC95 [11.60-15.54] vs 7.62 IC95 [6.44-9.49] (p<0.0001). Conclusions: Our results for Group 1 are relatively consistent with those of Prodige 4: objective response rate (39% vs 32%), PFS (6.5 vs 6.4 months) and OS (10.9 vs 11.1 months). Non eligibity for Prodige 4’s criteria decreases PFS and OS significantly.
A randomized phase I/II study of everolimus, irinotecan, and cetuximab versus capecitabine and oxaliplatin in gemcitabine-resistant patients with pancreatic cancer.
Authors: Bjerregaard Jon Kroll , Ladekarl Morten , Farr Katherina Podlekareva , Vestermark Lene Weber , Jensen Helle Anita , Pfeiffer Per
Published: February 2017

337

Background: Little evidence exists on 2nd line therapy for gemcitabine resistant patients. The combination of oxaliplatin (Ox) and 5-FU has shown efficacy in small trials. We wanted to establish a tolerable dose of the combination of irinotecan, cetuximab and everolimus(ICE), and test it vs. the combination of capecitabine (Cap) and Ox in a randomized phase I/II setting. Methods: Patients were initially recruited in a 3+3 dose finding design with an expanded MDT cohort. After establishing MDT; patients were randomized between ICE (at MDT-1) and CapOx (Cap: 1250 mg/m2 BID and Ox: 70 mg/m2q14d). Patients that progressed could cross-over to the other arm. (NCT01042028). Results: Between January 2010 and November 2012, 40 patients were recruited. Due to DLT toxicity (mainly mucositis) at dose level 1 of the phase I trial, the protocol was amended and patients were treated at dose level -1. Ten patients were safely treated at this dose. The final dose for everolimus was 2.5 mg q1d, for irinotecan 180 mg/m2 q14d and 500 mg/m2q14d for cetuximab. At this dose level patients were randomized to either ICE or CapOx. Planned accrual was 90 patients, but due to the emergence of FOLFIRINOX and slow accrual, the study was terminated after randomization of 26 patients. One patient died before randomization. Median PFS for the ICE regime was 3.8 months (2.5-7.8), CapOx 3.5 (1.7-5.3) p=0.72. Median OS for ICE was 7.7 (4.5-11.8) and for CapOx 4.5 (2.2-7.4) p=0.04. Six patients crossed from CapOx to ICE, and 3 patients from ICE to CapOx upon progression. RR for ICE was 25% (5-57), CapOx 29% (8-58). Toxicity grade 3+ in the ICE regime was acne-like-rash (20%), fatigue (16%), infection (16%) and emboli (12%). CapOx was associated with grade 3+ neuropathy (21%), emboli (14%), pain (21%) and PPE (14%). Conclusions: The triple combination of ICE displayed similar PFS but significantly increased OS compared to CapOx. Both regimes displayed cancer activity with acceptable response rates. Toxicity was manageable. Due to early termination no solid conclusions can be drawn. Selected patients may benefit from dual-targeted therapy. Clinical trial information: NCT01042028.
The relationship between systemic inflammation-based prognostic scores and body composition analysis in colorectal cancer patients.
Authors: Douglas Euan , Richards Colin H. , Roxburgh Campbell S. D. , Horgan Paul G. , Mcmillan Donald C.
Published: February 2017

407

Background: Weight loss in cancer is increasingly recognised as part of syndrome associated with chronic activation of the systemic inflammatory response (McMillan DC, 2009). The aim of the present study was to examine the relationship between systemic inflammation based prognostic scores (SIBPS) and CT measured parameters of body composition in patients with primary operable colorectal cancer (CRC). Methods: 303 patients with primary operable CRC who underwent resection with curative intent (2003-2012) were studied. Image analysis of CT scans was used to measure total fat index (cm2/m2), subcutaneous fat index (cm2/m2), visceral fat index (cm2/m2) and skeletal muscle index (cm2/m2). SIBPS included the Glasgow Prognostic Score (mGPS), Neutrophil: Lymphocyte ratio (NLR), Platelet: Lymphocyte Ratio (PLR), Prognostic Index (PI), and Prognostic Nutritional Index (PNI). Results: In all patients there was a significant association between lower BMI and skeletal muscle index and an elevated systemic inflammatory response, as measured by the mGPS (p=0.028 and p<0.001), NLR (p=0.004 and p=0.002), and PNI (p=0.001 and p=0.022). In male patients there was a significant association between lower BMI, total fat mass and skeletal muscle index and an elevated systemic inflammatory response, as measured by the mGPS (p= 0.027, p=0.048 and p=0.001), NLR (p=0.002, p=0.034 and p=0.003), and PNI (p=0.003, p<0.001 and p0.048). In female patients total body fat was associated with the PLR (p=0.001) and PNI (p=0.009) but only the mGPS (p=0.007) and the PI (p=0.013) were associated with reduced skeletal muscle. Conclusions: The present study highlights a consistent association between lower BMI and skeletal muscle mass and the presence of a systemic inflammatory response. These results are consistent with the hypothesis that chronic activation of the systemic inflammatory response results in the loss of lean tissue and that ultimately compromises survival in patients with CRC. McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12:223-6.
Association between ColDx assay result and recurrence-free interval in stage II colon cancer patients on CALGB (Alliance) 9581.
Authors: Niedzwiecki Donna , Frankel Wendy , Venook Alan Paul , Ye Xing , Friedman Paula N. , Goldberg Richard M. , Mayer Robert J. , Colacchio Thomas Anthony , Kennedy Richard D. , Davison Timothy , O'Brien Eamonn J. , Mulligan Jude , Johnston Patrick G. , Harkin D. Paul , Schilsky Richard L. , Bertagnolli Monica M. , Innocenti Federico
Published: February 2017

455

Background: Only 15-25% of pts with stage II colon cancer (CC) experience recurrence and conventional staging methods neither allow accurate identification of low (L) and high-risk (H) subgroups nor predict benefit of adjuvant chemotherapy. The ColDx assay (Almac Diagnostics) is a 634-probeset gene expression signature shown to be independently prognostic for recurrence-free interval (RFI). The objective of this study was to assess the ability of ColDx to classify stage II CC pts at L- and H-risk of relapse. Methods: This validation study was conducted using formalin fixed paraffin embedded biospecimens and clinical data from CALGB 9581, a phase III trial of edrecolomab v. observation in pts with normal risk, stage II CC. 1,454 CALGB 9,581 pts met eligibility criteria. A case-cohort sampling design was used to randomly select (RS) 514 pts from 901 eligible pts with available tissue; supplemented by 49 non-RS recurrent pts (total 563). Risk status for each pt was based on a positive or negative ColDx score using a pre-specified cutpoint, 0.4377. The Self Prentice method was used to test the association between ColDx categories and RFI (distant recurrence or death due to primary disease). Results: Initial results in 563 pts were erroneous due to a quality failure in a batch of reagent. 524 samples were re-labeled, re-ordered, and re-assayed using reagents that passed quality control (36 samples had insufficient material; 95 failed ColDx QC). Final analysis comprised 393 pts, 360 RS (58 events; 16%); 33 non-RS events. 216 pts (55%) were predicted H (62 events); 177 (45%) pts were predicted L (29 events). H pts exhibited significantly worse RFI (univariable hazard ratio (HR), 2.0; 95% CI, 1.3-3.3; p < 0.01). ColDx remained significant after adjustment for prognostic factors; HR, 2.1 (95% CI, 1.3-3.4; p < 0.01). Conclusions: The ColDx assay result is associated with RFI in the CALGB 9,581 sub-sample and is independent from other prognostic factors, including MSI. Further investigation is needed to establish the role of this classifier in guiding treatment decisions in this patient population.
Molecular subtyping of colorectal cancer to identify a mesenchymal tumor type that might benefit from TGF-beta pathway inhibition.
Authors: Salazar Ramon , Roepman Paul , Willems Stefan M. , Brunen Diede , Kellner Udo , Midgley Rachel A , Bernards Rene , Simon Iris M.
Published: February 2017

456

Background: Currently, most colorectal cancer (CRC) patients receive chemotherapy treatment, even though many patients do not benefit. Therefore, a better understanding of the biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for all other patients. Methods: A molecular subtype classification was developed using full genome expression data of 188 stage I-IV CRC patients and validated in 543 stage II and III patients. Subtypes were correlated to clinical factors, prognosis and treatment benefit (stage III). To determine whether TGF-β signaling is elevated in the tumors, 78 patient biopsies were analyzed for p-SMAD2/3 expression using immunohistochemistry. To analyze the effect of TGF-β activation, we studied the effects of MED12 suppression in SKCO-1 CRC cells under treatment with Cisplatin, Oxaliplatin or 5-FU. Results: We developed a diagnostic test that allows the classification of colorectal cancer tumors into different intrinsic molecular subtypes (A-, B-, C-type). The heterogeneity of these subtypes is largely based on 3 biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes resulting in a high mutation frequency associated with MSI, and cellular proliferation. Especially the C-type (~15% of CRC tumors) is of clinical interest, as C-type patients have the worst outcome, a mesenchymal phenotype and show no benefit from chemotherapy treatment in our patient set or a public dataset. The C-type subgroup has elevated TGF-β signaling, as shown by TGF-beta and TGF-beta receptor over-expression (TGFB1, p=0.0012; TGFBR1, p=0.0005) and increased phopho-SMAD2/3 staining in the tumor cells (1.9-fold, p=0.0002). In cell line experiments, we show that up-regulation of TGF-β signaling by MED12 knockdown resulted in resistance against chemotherapy by preventing apoptosis. Conclusions: The molecular subtypes differ largely in prognosis and response to chemotherapy. A treatment strategy combining standard drugs with agents suppressing TGF-β signaling might benefit C-type patients.
Comparison of ColoPrint risk classification with clinical risk in the prospective PARSC trial.
Authors: Salazar Ramon , Capdevila Jaume , Rosenberg Robert , de Waard Jan Willem , Glimelius Bengt , Bibeau Frederic , Klaase Joost , Van der Hoeven Jacobus JM , Midgley Rachel A , Chang George J. , Bachleitner-Hofmann Thomas , Asano Michio , Ziebermayr Reinhard , Levine Edward Allen , Deck Kenneth B. , Sington Jamie , Law Wai Lun , Shbeeb Imad , Stork Lisette , Marshall John
Published: February 2017

465

Background: The 18-gene expression profile, ColoPrint, has been developed and validated for identifying risk of recurrence in patients with early-stage colon cancer (CC). In a pooled stage II validation study ColoPrint identified 63% of patients as Low Risk with a 3-yr recurrence-free survival (RFS) of 93% while High Risk patients had a 3-yr RFS of 82% with a HR of 2.7 (p=0.001). PARSC is a prospective study for the assessment of recurrence risk in stage II CC patients using ColoPrint. ColoPrint classification is compared to NCCN risk classification. Methods: The study enrolled 468 patients with histologically proven stage II CC from 31 institutes in Europe, the United States, and Asia between October 2008 and May 2013. Synchronous tumors were excluded. ColoPrint results were not disclosed to the physician and patient. Treatment was at the discretion of the physician, adhering to NCCN approved regimens or a recognized alternative. A McNemars test is performed to compare ColoPrint with NCCN risk classification. A p value ≤ 0.05 indicates the two tests differ significantly. Results: ColoPrint classified 320 (68%) patients as Low Risk and 148 (32%) as High Risk. 89 patients (19%) received adjuvant chemotherapy. In the ColoPrint Low Risk group, 57 (18%) patients received adjuvant chemotherapy while 32 (22%) of ColoPrint High Risk patients received chemotherapy. According to NCCN high risk factors (T4, high grade (exclusive of MSI-H), lymphovascular/perineural invasion, perforation/obstruction, <12 nodes examined, positive margins) 234 (50%) patients were NCCN Low Risk and 234 were NCCN High Risk. 72 (31%) of the NCCN Low Risk patients are ColoPrint High Risk. 158 (68%) of the NCCN High Risk patients are ColoPrint Low Risk. MSI-status was assessed in 86 (18%) patients of which 29 were MSI high and 57 were MSS. All MSI high were classified as ColoPrint Low Risk. Conclusions: The PARSC study is the first prospective study to compare genomic and clinical risk assessment and we observed marked differences between NCCN risk classification and ColoPrint. The clinical validity of these methods will be based on the outcomes at 3 and 5 years. Clinical trial information: NCT00903565. [Table: see text]
The relationship between tumor cell density in the pretreatment biopsy and survival after chemotherapy in OE02 trial esophageal cancer patients.
Authors: Hale Matthew D. , Nankivell Matthew Guy , Mueller Wolfram , West Nicholas P. , Stenning Sally Patricia , Wright Alexander I. , Treanor Darren , Langley Ruth E. , Ward Lindsay C. , Allum William H. , Cunningham David , Hayden Jeremy D. , Grabsch Heike I.
Published: February 2017

49

Background: Neoadjuvant chemotherapy (chemo) followed by surgery is the standard treatment for UK patients with resectable oesophageal cancer [OeC] since the OE02 trial (Allum et al. J. Clin. Oncol, 2009), yet some patients receive no benefit from chemo. We investigated whether tumour cell density (TCD) in the pre-chemo biopsy can predict patient benefit from chemo among OE02 patients. Methods: Hematoxylin and eosin stained diagnostic biopsy slides from 281 OE02 trial OeC patients reflective of the whole trial population based on patient characteristics and survival (70% adenocarcinoma, surgery alone: n=141; chemo followed by surgery: n=140) were digitized. TCD (percentage of epithelial tumor cells/viable tumor mass) was quantified by point counting and cut offs for overall survival analyses were identified. The relationship between TCD and clinicopathological data and its predictive value (heterogeneity of treatment effect) were assessed. Results: TCD ranged between 16-99% with 85% of cases in the 25-75% range. TCD was initially divided into tertiles. The treatment hazard ratio (HR) was examined within each tertile showing evidence of heterogeneity with clear benefit from chemo seen only in the middle tertile. Cut offs were refined through examination of treatment HR within TCD quintiles. Treatment HRs were 1.25 (95%confidence interval 0.66, 2.35), 1.94 (1.39, 2.71) and 0.65 (0.36, 1.18), respectively, for TCD <40% (n=46), 40-70% (n=183) and >70% (n=52), suggesting that only patients with 40-70% TCD benefit from neoadjuvant chemo (HR>1 favours chemo, heterogeneity p=0.006). Low Mandard tumor regression grade (1-3 versus 4-5) was related to a lower biopsy TCD (median: 47% versus 56%, p=0.0402). Conclusions: TCD appears to be able to predict survival benefit from neoadjuvant chemo in OeC patients and is associated with tumour regression. Our result requires validation in an independent dataset to confirm its potential clinical utility. If validated, TCD measurement in the diagnostic biopsy could be used to determine which OeC patients would benefit from neoadjuvant chemo versus those who would benefit most from management with surgery alone.
The effect of postoperative morbidity on survival after resection for gastric adenocarcinoma: Results from the U.S. Gastric Cancer Collaborative.
Authors: Jin Linda X. , Moses Lindsey E. , Yan Yan , Squires Malcolm Hart , Weber Sharon M. , Bloomston Mark , Poultsides George A. , Votanopoulos Konstantinos I. , Pawlik Timothy M. , Hawkins William G. , Linehan David , Strasberg Steven M. , Archer Alexandra W. , Ejaz Aslam , Kooby David A. , Schmidt Carl Richard , Swords Doug S. , Worhunsky David J. , Maithel Shishir Kumar , Fields Ryan C. ,   US Gastric Cancer Collaborative
Published: February 2017

5

Background: The negative impact of postoperative complications (POCs) on survival is well documented for many cancer types, but has not been well described in gastric cancer. Here, we evaluated the effect of POCs on survival after surgery for gastric cancer in a cohort of patients from a multi-institutional database. Methods: Patients who underwent surgery with curative intent for gastric adenocarcinoma between 2000-2012 from participating institutions of the U.S. Gastric Cancer Collaborative were analyzed. Patients who died within 30 days of surgery were excluded. Ninety-day postoperative complication data were collected. Survival probabilities were estimated by Kaplan-Meier analysis and compared using the log-rank test. Results: A total of 853 patients from seven institutions met inclusion criteria. Median follow-up was 32 months. The overall complication rate was 40% (n=344). The most frequent complications were: infectious (25%, including surgical site infection [8%]), and anastomotic leak (6%). 7% of patients underwent reoperation during the same hospitalization. Five-year overall survival (OS) for patients without perioperative complications was 54%, compared with 39% for patients with POCs (p=0.001). Disease free survival (DFS) at five years was 61% for patients without POCs compared to 49% in patients with POCs (p=0.002). Patients without POCs were significantly more likely to receive adjuvant therapy (55% vs 42%; p<0.001). Conclusions: In a large, multi-institutional cohort, POCs were associated with decreased survival in patients undergoing surgery for gastric adenocarcinoma. This may be due, in part, to the negative impact of complications on the receipt of adjuvant therapy. Efforts aimed at reducing perioperative morbidity are important not only for short-term surgical outcomes, but also for enhancing long-term oncologic outcomes in patients with gastric cancer. [Table: see text]
Identification of epigenetic silencing of GCNT2 expression by comprehensive real-time PCR screening in colorectal cancer.
Authors: Nakamura Kazunorii , Sawaki Horomichi , Yamashita Keishi , Watanabe Masahiko , Narimatsu Hisashi
Published: February 2017

506

Background: Glycoprotein expression profile has been proved to be dramatically altered in human cancers, however specific glycogenes which are aberrant in expression in cancer cells has not been fully identified. Recent accumulated evidence supported notion that the reduced expression of tumor suppressor genes is explained by DNA promoter methylation in human cancer. Methods: We used Comprehensive Real time PCR system (CRPS) for glycogenes (189 genes) to identify genes aberrantly expressed in colorectal cancer tissues (CRC) as compared to the corresponding normal mucosa tissues. GCNT2 was of particular interest among the identified genes in CRC. Results: (1) GCNT2 harbors 3 isoforms which have different promoter regions. (2) All of the 3 isoforms of GCNT2 genes were remarkably decreased in CRC as compared to the corresponding normal mucosa, and each isoform expression was strongly associated with other 2 isoforms in primary cancer tissues by TaqMan real time PCR (R = 0.99-995, p < 0.0001). (3) Among the 5 CRC cell lines (DLD1, HCT116, CACO2, LOVO), those which were silenced in expression were reactivated by demethylating agents such as 5-aza-2’ deoxycytidine and trichostatin A. (4) Promoter region of the variant 2 of GCNT2 was consistent with its silenced expression in CRC cell lines by cloned sequence, so we examined DNA methylation status of the promoter of the GCNT2 variant 2 in 50 primary cancer tissues and the corresponding normal tissues. Quantitative MSP revealed that almost half of normal tissues have methylation as high as tumor tissues, while, in the primary CRC with less methylation in the corresponding normal tissues, DNA methylation was higher in primary CRC tissues than in the corresponding normal tissues. Finally, GCNT2 variant 2 stable transfection induced expression of other 2 isoform variants. Conclusions: We identified novel methylation gene GCNT2 among the glycoenes. Glycoenes that were altered in genomic or epigenetic manner have been few, so GCNT2 may play a critical role in cancer progression through glycan change.
SoMore trial: Early metabolic response assessment of a sorafenib (SOR) and capecitabine (CAP) combination in chemorefractory metastatic colorectal cancer (mCRC).
Authors: Deleporte Amélie , Hendlisz Alain , Garcia Camilo , Delaunoit Thierry , Maréchal Raphael , Peeters Marc , Holbrechts Stephane , Van Den Eynde Marc , Houbiers Ghislain , Filleul Bertrand , Van Laethem Jean-Luc , Rolfo Christian Diego , Diaz Marie , Lhommel Renaud , Demolin Gauthier , Moreau Michel , Ameye Lieveke , Paesmans Marianne , Piccart-Gebhart Martine J. , Flamen Patrick
Published: February 2017

524

Background: The SOR-CAP combination has shown clinical activity in several phase I-II trials involving metastatic breast cancer and mCRC patients (pts). SoMore aims to substantiate the combination’s effects in mCRC refractory to all medications and the predictive value of early metabolic response (MR) on survival. Methods: SoMore (EUDRACT 2010-023695-91) has 2 coprimary objectives: 1) to demonstrate an overall survival (OS) rate at 6 months (mths) > 30%, and 2) to compare OS between pts with and without MR. CAP was given at 1700 mg/m²/day (D), 2 weeks out of 3. SOR was administered at 600mg/D for the first cycle, then at 800mg/D until progression or unacceptable toxicity. FDGPET-CT was performed at baseline and before the 2nd cycle. MR analysis was centralized and blinded for the investigators. Results: From February to October 2011, 92 eligible pts were prospectively recruited in 6 Belgian centers: M/F: 54%/46%; ECOG PS 0/1: 55%/45%; median age: 61. A median of 5 treatment cycles were given (0-28+). Grade 3-4 toxic reactions were reported in 61.2%, mainly fatigue (18%), hand-foot skin reaction (14%) and diarrhea (11%), but no toxic death. 6.9% of the pts stopped therapy due to toxicity. 6 mths OS was 71% (95% CI: 61%-79%), significantly >30% (p<0.001). 47% of the 79 pts evaluable for metabolic assessment showed homogeneous MR (HMR) of all metastatic lesions, 32% mixed MR and 21% homogeneous non-MR. Median overall OS and PFS of the intent-to-treat population and of pts with and without HMR are shown in the table below. Hazard ratio for HMR was 0.34 (95% CI, 0.21 to 0.56) p-value <0.001 for PFS and 0.59 (95% CI, 0.37 to 0.96) p-value 0.03 for OS. Conclusions: These data suggest robust efficacy for the SOR-CAP combination in heavily pretreated mCRC, associated with high but manageable toxicity. Early MR assessment, by detecting unresponsive lesions within the whole body tumoral load, is able to capture the pts’ likelihood of benefit, opening the path to personalized medicine. Clinical trial information: NCT01290926. [Table: see text]
A randomized, open-label phase II study of efatutazone in combination with FOLFIRI as second-line therapy for metastatic colorectal cancer (mCRC).
Authors: Marshall John , Shuster Dale Edward , Goldberg Terri Robin , Copigneaux Catherine , Chen Shuquan , Zahir Hamim , Dutta Dipen , Saleh Mansoor N. , Pishvaian Michael J. , Varela Mirta Susana , Palazzo Felipe , Lazaretti Nicolas , Costa Cassia , Loredo Eugenia , Leon Jorge , Von Roemeling Reinhard W.
Published: February 2017

535^

Background: Efatutazone, a highly-selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has shown efficacy and manageable toxicity in phase I trials in solid tumors, including CRC. This study evaluated efatutazone in combination with chemotherapy for second-line mCRC. Methods: Patients (pts) from the United States and Latin America with mCRC progressing after first-line therapy not containing irinotecan were stratified by Eastern Cooperative Oncology Group (ECOG) status (0/1 vs. 2) and randomized 1:1 to efatutazone + FOLFIRI (E+F) or FOLFIRI alone (F). Treatment was administered in 4-week cycles until disease progression (PD), unacceptable toxicity, or consent withdrawal. Efatutazone (0.5 mg) was administered orally, twice daily; FOLFIRI (irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 1200 mg/m2/d x 2 days) was administered intravenously once every 2 weeks immediately after efatutazone. The primary end point, progression-free survival (PFS) rate at week 16, was assessed locally according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. Results: Characteristics of the 100 randomized pts were generally well balanced between the E+F and F treatment arms: median age, 59.7 vs. 58.3 years; male, 56% vs 56%; and ECOG 0/1, 98% vs. 92%. Across the arms, more pts discontinued due to PD than toxicity: 49% vs. 19%, respectively. While PFS rate at week 16 was 60% vs. 67% for the E+F vs F arms (p = 0.30), overall, PFS was somewhat longer with E+F than with F (hazard ratio [HR], 0.87; 90% [confidence interval [CI], 0.57–1.32) with medians of 4.4 vs. 4.2 months, respectively. The objective response rate also favored E+F over F (20% vs. 14%). Overall survival was not significantly different (HR, 0.95; 90% CI, 0.65–1.38). Fluid retention, which was managed with diuretics, was more frequent with E+F than with F: 86% vs. 12% (grade 3/4: 12% vs. 0%). Hematologic adverse events, including neutropenia (66% vs. 20%; grade 3/4: 44% vs. 12%) and febrile neutropenia (14% vs 0%), were more common with E+F than with F. Conclusions: Efatutazone minimally improved efficacy of FOLFIRI for CRC and increased neutropenia and fluid retention. Clinical trial information: NCT00967616.
Right (R) or left (L) primary site of colorectal cancer and outcomes for metastatic colorectal cancer (mCRC): Results from the south Australian registry of mCRC.
Authors: Price Timothy Jay , Beeke Carol , Padbury Robert , Maddern Guy , Roder David , Moore James , Townsend Amanda Rose , Roy Amitesh , Hocking Christopher , Karapetis Christos Stelios
Published: February 2017

596

Background: Previous reports have described differences in biology and outcome based on whether the primary is R or L sided. Possible differences in response to biological agents have also been reported based on side of primary lesion (SY Brule et al., JCO31, 2013 (supp #3528). Methods: We explored the SA mCRC registry to assess if there were any differences in patient characteristics, treatment received and outcomes based on whether the primary was R (caecum to transverse colon) or L (splenic flexure to rectum) sided (JA Bufill, Ann Int Med. 113, 1990, 779-788). KM was used for survival outcomes and Cox proportional hazards regression modeling was used to assess defined prognostic markers. Results: 2,877 patients were analysed. 33% had R sided primary. Major differences between R and L respectively are as follows; Female 51.3% vs. 37.9% (p = <0.0001), Med age 75.8 yrs vs. 70.5yrs (p = <0.0001), poorly differentiated pathology 34.3% vs. 20.8% (p = <0.0001), KRAS mutation 48% vs. 37% (p = 0.023), and liver surgery 10.5% vs. 16.3% (p = <0.0001). Analysis of chemotherapy (defined as either cytotoxic and/or molecular-targeted) revealed similar rates of first-line therapy, but differences in rates of therapy beyond first-line R vs. L respectively; second-line 46% vs. 60.4%, third-line 17% vs. 30%, fourth-line 7% vs. 13%. There was however no difference in single agent vs. combination first-line therapy. The median overall survival (mOS) for the entire group R vs. L was 9.6 vs. 20.3 months (p <0.0001). For the group who had active therapy defined as chemotherapy (+/- metastasis resection), mOS was R 18.2 months vs. L 29.4 months (p <0.0001). For those (n = 123) who underwent liver resection (+/- chemotherapy) mOS was 6.2 years for both R and L (p = 0.32). Patients who were treated with only chemotherapy, the mOS was 10.7 mths vs. 15.3 mths for R v L (p = 0.0005). Conclusions: Patients with R sided primary have more negative prognostic factors and indeed have inferior outcomes when compared with those with a L sided primary. This did not appear to be the case for patients who were suitable for hepatic surgery.
Toward personalized treatment for gastroesophageal adenocarcinoma (GEC): Strategies to address tumor heterogeneity—PANGEA.
Authors: Catenacci Daniel Virgil Thomas , Polite Blase N. , Henderson Les , Xu Peng , Rambo Brittany , Liao Wei-Li , Hembrough Todd A. , Zhao Lei , Xiao Shu-Yuan , Hart John , Karrison Theodore , Dignam James J. , Kindler Hedy Lee
Published: February 2017

66

Background: GEC is the second highest cause of cancer mortality worldwide. The promise of ‘personalized’ cancer care with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized molecular heterogeneity within GEC (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) through space (primary tumor to metastatsis) and time (resistance to treatment) - a hurdle to advancing GEC treatment. Current trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic aberrations with adequate power. Accrual difficulties to GEC trials are exacerbated by low frequencies of molecular ‘oncogenic drivers.’ Oncogenic drivers of GEC including MET and others have even less frequent genomic activation than HER2. To address this challenge, there is need for novel clinical trial designs/strategies implementing novel technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for predefined treatment priority algorithms given multiple aberrations observed within any one individual. Finally, access to multiple therapeutic agents are required to be available for treatment. Intra-patient heterogeneity may be addressed by post-treatment biopsy. Methods: We present a novel trial design 'Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma' for metastatic GEC, integrating medium throughput proteomic/genomic assays with a practical biomarker assessment/treatment algorithm. Analysis of 50 GEC patients was performed to determine feasibility/timing of testing and treatment assignment into 5 major molecular categories. Results: 50 GEC tumors had biomarker assessment and mock treatment assignment within 60 days, revealing HER2 (26%), MET (30%), FGFR2 (8%), EGFR (20%), KRAS/PI3K (26%). Conclusions: Comprehensive molecular profiling of FFPE tissue was feasible and timely. Tumors were classified into major molecular subgoups. PANGEA is a compromise between the number of potential treatment categories and feasibility of conducting such a trial.
A phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC).
Authors: Faivre Sandrine J. , Santoro Armando , Kelley Robin Kate , Merle Philippe , Gane Ed , Douillard Jean-Yves , Waldschmidt Dirk , Mulcahy Mary Frances , Costentin Charlotte , Minguez Beatriz , Papappicco Pasqua , Gueorguieva Ivelina , Cleverly Ann , Desaiah Durisala , Lahn Michael M. , Ameryckx Sophie , Benhadji Karim A. , Raymond Eric , Giannelli Gianluigi
Published: February 2017

LBA173

Background: TGF-β signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety, antitumor activity, and overall survival (OS) in HCC patients with elevated AFP treated with LY. Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/off (28 days=1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-β and E-cadherin) for each dose. AFP responders were defined as >20% decline from baseline. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK). Available data from interims are presented. Results: 109 patients were enrolled (Arm A=37; B=72). Baseline characteristics were (Arm A/B): median age 61/63 years; PS=0, 60%/53%; Child-Pugh A 97%/88%; etiology: hepatitis C 30%/38%, hepatitis B 27%/24%, alcohol 24%/25%. Overall, 78%/83% of patients had received prior SF; 57%/53% had AFP >400 ng/mL. Median TTP was 12.0 weeks (90% CI: 6.6, 12.6) in the overall population (Arm A/B, 12.1/10.0 weeks). In SF-naive patients, TTP was 18.3 weeks (90% CI: 6.6-42.4). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-β1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >20% occurred in 24% of patients. Based on the latest interim, median OS was 36 weeks. In AFP responders, median OS was 93.1 weeks vs 29.6 weeks in non AFP responders (Log Rank p=0.0006). Four patients discontinued treatment due to AEs. Most common grade 3/4 related AEs were: neutropenia (n=3), fatigue (n=2), and anemia (n=3). Preliminary PK analysis (n=51) demonstrated moderate interpatient exposure variability (42%). Conclusions: Based on the manageable toxicity profile, the evidence for biomarker responses, analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC. Both TTP and overall survival in AFP responding patients is promising.
Effect of KRAS and NRAS mutational status on first-line treatment with FOLFIRI plus cetuximab in patients with metastatic colorectal cancer (mCRC): New results from the CRYSTAL trial.
Authors: Ciardiello Fortunato , Lenz Heinz-Josef , Kohne Claus-Henning , Heinemann Volker , Tejpar Sabine , Esser Regina , Beier Frank , Stroh Christopher , Duecker Klaus , Van Cutsem Eric
Published: February 2017

LBA443

Background: The phase III CRYSTAL study showed patients with unresectable KRAS exon 2, codon 12 and 13, wild-type (wt) mCRC (n = 666) to benefit from the addition of cetuximab to FOLFIRI first-line. Progression-free survival (PFS), overall survival (OS) times and response rate (RR) were significantly better in patients who received FOLFIRI plus cetuximab, compared with FOLFIRI alone. Recent retrospective analyses of studies involving EGFR-targeted monoclonal antibody therapy have suggested that patients with KRAS and NRAS mutations in other codons were unlikely to benefit from the addition of an EGFR-targeted agent. Thus, the impact of these additional KRAS and NRAS mutations on the efficacy and safety of FOLFIRI plus cetuximab treatment is under investigation in patients from the CRYSTAL study. Methods: KRAS (eight mutations on exons 3 [codons 59 and 61] and 4 [codons 117 and 146]) and NRAS (18 mutations on exons 2 [codons 12 and 13], 3 [codons 59 and 61] and 4 [codons 117 and 146]) mutation detection is ongoing using BEAMing (Beads, Emulsions, Amplification, and Magnetics) with a mutation detection cut-off of 0.1%. Tumor genomic DNA samples from 541 randomized patients with KRAS exon 2 wt disease (81% of KRAS wt patient population) and tumor material available are currently being screened. Treatment arms will be compared using two-sided log-rank tests for PFS and OS, and the Cochran–Mantel–Haenszel (CMH) test for response. Results: RAS mutation status is currently available from 192 patients (28.8% ascertainment) with further RAS assessment ongoing. Currently 63.5% of the samples are RAS wt and 36.5% are new RAS mutations. Conclusions: Updated information on the full RAS mutation dataset of up to 400 samples combined with the clinical data will be presented and implications for patient care discussed.
A phase I study of the multikinase inhibitor cabozantinib (C) plus docetaxel (D) and prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H. , Shah Avani Atul , Ojemuyiwa Michelle A. , Madan Ravi Amrit , Apolo Andrea Borghese , Dawson Nancy Ann , Arlen Philip M. , Theoret Marc Robert , Wright John Joseph , Chen Clara , Trepel Jane B. , Couvillon Anna , Chun Guinevere , Harold Nancy , Steinberg Seth M. , Price Douglas K. , Gulley James L. , Figg William Douglas , Dahut William L.
Published: February 2017

108

Background: Cabozantinib (C) is a multikinase inhibitor of c-Met, vascular endothelial growth factor receptor two and RET. C has shown activity in metastatic castrate resistant prostate cancer (mCRPC), with resolution of bone lesions on bone scan (BS), regression of soft tissue/visceral disease (STD), reductions in circulating tumor cells and bone biomarkers. Combining docetaxel (D) with other agents, without overlapping toxicities, can target different cellular signaling pathways necessary for tumor survival. Methods: Patients (pts), with no prior D for CRPC, receive a fixed dose of D (75 mg/m2 IV day one of each 21 day cycle) and prednisone (P) (5 mg po q12 hours) with C at three escalating dose levels: 20 mg, 40 mg, or 60 mg (all po daily). Using a standard three-plus-three design, three to six pts are treated at each dose level until the maximum tolerated dose (MTD) has been defined. Results: Thirteen pts have been accrued; four on dose level one, six on dose level two, and three on dose level three. Median age 69 (45 to 84). Four pts have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of zero and nine pts have a PS of one. Median Gleason score is nine (7 to 10). Median on-study prostate-specific antigen (PSA) is 129.2 ng/mL (0.01-508.5 ng/mL). Median cycles is six (1 to 17). Grade 1 adverse events (AEs), possibly related to C; dysgeusia (4/12), oral mucositis (4/12), increased ALT (3/12), and epistaxis (3/12). Grade 2 AEs; nausea (2/12), hand/foot syndrome (2/12), fatigue (2/12), dysgeusia (2/12), oral mucositis (2/12), hypophosphatemia (2/12), and anemia (2/12). Grade 3 AE is hypophosphatemia (2/12). Grade 4 AE is neutropenia (1/12). MTD of C is 60 mg. Of nine evaluable pts, six have bone only disease. Of these six, three pts have PSA declines of less than 30% with improvement on BS (two pts) or stable BS (one pt). The other three pts have PSA declines of greater than 30% and bone scan improvement. Three pts have STD and bone disease; one patient had a PSA decline of greater than 30% with improvement on BS and SD by CT scan. One patient had an increase in PSA of less than 30% with improvement on BS and CT. The third pt had PD by CT and an increase in PSA equal to 30%. PFS probability at six months is 90.0% and is 67.5% at eight months and beyond. Conclusions: The addition of C to D and P, has an acceptable toxicity profile. CT scan and BS improvements did not correlate with PSA declines in all pts. An expansion cohort will combine D plus P with C at the MTD (60 mg) to determine clinical benefit. Clinical trial information: NCT01683994.