bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUNSHINE: Randomized double-blind phase II trial of vitamin D supplementation in patients with previously untreated metastatic colorectal cancer.
Authors: Ng Kimmie , Nimeiri Halla Sayed , McCleary Nadine Jackson , Abrams Thomas Adam , Yurgelun Matthew B. , Cleary James M. , Rubinson Douglas Adam , Schrag Deborah , Allen Jill N. , Zuckerman Dan Sayam , Miksad Rebecca A. , Chan Emily , Constantine Michael , Weckstein Douglas , Faggen Meredith Gail , Thomas Christian A. , Kournioti Chryssanthi S. , Mackintosh Christopher , Zheng Hui , Fuchs Charles S. 
Published: September 2018

3506 Background: In prospective observational studies of mCRC patients, higher plasma levels of 25-hydroxyvitamin D have been associated with improved progression-free (PFS) and overall survival (OS), but the role of vitamin D supplementation in the treatment of mCRC is unknown. Methods: SUNSHINE was a multi-center double-blind phase II randomized controlled trial in previously untreated mCRC patients. Patients were eligible if they had histologically confirmed mCRC, no prior therapy for metastatic disease, ECOG PS 0-1, and were not taking vitamin D >2,000 IU/day x 1 year. All subjects received standard treatment with mFOLFOX6 + bevacizumab with 1:1 randomization to concurrent: HiVitD (vitamin D3 po 8,000 IU/d x 2 wks as loading dose followed by 4,000 IU/d) or LowVitD (standard vitamin D3 400 IU/d) until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was PFS, with the sample size designed to provide 80% power to detect a HR of 0.66 for PFS at a 1-sided alpha=0.2. Results: From April 2012 to November 2016, 139 patients were randomized. Median age was 54 yrs (range 24-82), 57% were male, 77% were white, and 7% had received prior adjuvant chemo. Baseline characteristics were balanced between arms except ECOG PS = 0 was 42% vs. 60% in HiVitD vs. LowVitD. Median follow-up was 16.1 mos (range 0-45.9) and median compliance with VitD capsules was 98%. Patients randomized to HiVitD experienced longer PFS than those receiving LowVitD (median PFS, 12.4 vs. 10.7 mos, respectively; log rank P=0.03). After multivariate adjustment for prognostic variables, HR was 0.66 (95% CI, 0.45-0.99, 2-sided P=0.04). Comparing HiVitD vs LowVitD, RR was 58% vs. 63% ( P=0.54) and disease control rate was 100% vs. 94% ( P=0.05). The most common grade 3-4 toxicities were as expected for FOLFOX-bevacizumab, and none were related to vitamin D. Currently, 14 patients are still actively receiving treatment, and OS data are not yet mature. Conclusion: SUNSHINE met its prespecified primary endpoint, with patients randomized to HiVitD experiencing longer PFS compared to those randomized to LowVitD. A larger confirmatory phase III randomized trial appears warranted. Clinical trial information: NCT01516216.
Statistical modeling of CALGB 80405 (Alliance) to identify influential factors in metastatic colorectal cancer (CRC) dependent on primary (1o) tumor side.
Authors: Furchtgott Leon , Swanson David , Hayete Boris , Khalil Iya , Wuest Diane , Rich Kelly , Nixon Andrew B. , Niedzwiecki Donna , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary , Ou Fang-Shu , Lenz Heinz-Josef , Innocenti Federico , Venook Alan P. ,   Alliance for Clinical Trials in Oncology
Published: September 2018

3528 Background: CALGB 80405 is a phase III clinical trial of FOLFOX and FOLFIRI w/ randomly assigned cetuximab or bevacizumab. Novel machine learning approaches to the study dataset provide valuable insights into CRC prognosis and management of CRC progression. Methods: Using a Monte Carlo Bayesian Generalized Linear Model analytical platform, we built an ensemble of models for overall survival (OS). We used 99 baseline and demographic variables, including 1904 patients w/ 1o side and 949 w/ KRAS wild-type status. Building an ensemble of predictive models reduces risk of overfitting, estimates model uncertainty and identifies key variables by model consensus as measured by ensemble frequency (freq). We fit gender and 1o side (L vs R) stratum-specific models to examine differences in drivers of disease in those strata. Results: 1o side (avg Cox hazard ratio = 0.89, R side reference), ECOG performance status (1.30, reference level 0), AST concentration (1.01), peripheral neutrophil percentage (1.01) and local primary and abdominal site of disease indicators (1.22; 1.26) were key variables predictive of OS ( > 75% freq). In 1o side stratum-specific models, urine protein level (1.61), treatment intent (0.75, nonpalliative as reference) and hemoglobin concentration (0.85) were more associated w/ L side progression (freq > 85% in L stratum model, < 20% in R), while liver and lung sites of disease (2.3; 1.09) were more associated w/ R side progression (freq > 65% in R stratum model, < 20% in L). Predictors of 1o left-sidedness included age (avg log odds ratio = 0.02), hemoglobin (0.41), and abdominal (3.79) and liver (0.68) sites of disease. Modest differences in disease prognostic factors existed between genders: women more influenced by metastatic status, age, liver site of disease and creatinine level; men more influenced by urine protein level and prior diabetes. Conclusions: 1o side plays a central role in potentially explaining both variation in OS and differences in drivers of OS. Availability of these measures at baseline enables better sense of disease course at initiation of treatment. Support: U10CA180821, U10CA180882, Eli Lilly & Co., Genentech, Pfizer Clinical trial information: NCT00265850.
“CHARTA”: FOLFOX/Bevacizumab vs. FOLFOXIRI/Bevacizumab in advanced colorectal cancer—Final results, prognostic and potentially predictive factors from the randomized Phase II trial of the AIO.
Authors: Schmoll Hans-Joachim , Meinert Fabian Maximilian , Cygon Franziska , Garlipp Benjamin , Junghanss Christian , Leithäuser Malte , Vogel Arndt , Schaefers Michael , Kaiser Ulrich , Hoeffkes Heinz-Gert , Florschütz Axel , Rüssel Jörn , Kanzler Stephan , Edelmann Thomas , Forstbauer Helmut , Goehler Thomas , Hannig Carla , Hildebrandt Bert , Steighardt Jörg , Stein Alexander 
Published: September 2018

3533 Background: FOLFOXIRI/Bevacizumab (Bev) is superior to FOLFIRI/Bev in the TRIBE trial (F Loupakis, NEJM 2014). The CHARTA trial was developed parallel to TRIBE with the same 4-drug-protocol but vs. FOLFOX/B ev as control arm. Methods: From 7/11 to 12/14 250 patients were randomized, including ECOG 0-2, ≥ 1 measurable lesion > 1cm, stratified by ESMO-Group 1,2,3 (HJ Schmoll, Ann Oncol 2012). Induction: 6 months, maintenance Capecitabine+Bev until progression or max.12 months, at P reinduction by investigators decision. 25% dose reduction was allowed in cycle 1 + 2 on the investigator’s discretion. Primary EP: significant improvement of PFS-rate @ 9 months (p<0.1, 2-sided Fisher’s-exact test); secondary EP: RR, PFS, OS, toxicity. Results: 241 pts. (1 not elig., 8 prot. violation) are evaluable after a follow up of 31.4 (0.1-51) months. m/f: 65%/35%, age 61y (21-82), ECOG 0-1/2: 96%/4%. The Primary Endpoint was met: PFS @ 9 months 56% vs. 68%, p= 0.086. PFS was improved: 9.8 vs. 12.0 months, HR 0.7 (ns.), identical to TRIBE with 9.7 vs. 12.1 months. Response rate (A/B): CR: 5%/5%, CR/PR 60%/70%, SD 25%/21%, PD 14%/9%. Final OS will be available at the meeting. Toxicity was low to moderate without major differences except ° ¾ diarrhea (12%/16%) and neutrophils (14%/20%). Clinical/molecular prognostic or predictive factors are equally distributed (stratification by ESMO groups) (see table). There are major, but mostly not significant differences in RR/ PFS in most subgroups, however, not strong enough to safely identify patients with high potential to benefit from the 4-drug combination. Therefore, a multivariate analysis to model a common prognostic and predictive risk score is ongoing and will be presented at the meeting. Conclusion: “CHARTA” supports the superiority of FOLFOXIRI/Bev. A combined prognostic and predictive classification is required to better select those patients with most potential benefit from the 4-drug combination. Clinical trial information: NCT01321957. [Table: see text]
Phase II trial of the autophagy inhibitor hydroxychloroquine with FOLFOX and bevacizumab in front line treatment of metastatic colorectal cancer.
Authors: O'Hara Mark H. , Karasic Thomas Benjamin , Vasilevskaya Irina , Redlinger Maryann , Loaiza-Bonilla Arturo , Teitelbaum Ursina R. , Giantonio Bruce J. , Damjanov Nevena , Reiss Kim Anna , Rosen Mark Alan , Heitjan Daniel F , Troxel Andrea B. , Amaravadi Ravi K. , O'Dwyer Peter J. 
Published: September 2018

3545 Background: Colorectal cancer (CRC) cells can become resistant to chemotherapy and anti-angiogenic therapy through autophagy. The antimalarial agent hydroxychloroquine (HCQ) is a potent inhibitor of autophagy, and in vivo studies in CRC cell models show significant decrease tumor volume when these autophagy inhibitors were combined with oxaliplatin and bevacizumab. We previously reported safety with HCQ 600mg BID in combination with standard front-line FOLFOX and bevacizumab in a Phase I study in metastatic CRC patients. We report the results of a single-arm phase II trial of patients with previously untreated stage IV CRC with good performance status and adequate hematologic and biochemical indices. Methods: Patients were treated with standard doses of mFOLFOX6 and bevacizumab with HCQ 600mg BID. Imaging was obtained every 2 months. Results: 37 patients were enrolled, 62% male, 89% Caucasian, median age 61, 65% ECOG PS 0, and 73% colon primary. Twenty-eight patients were evaluable for response as 2 patients did not start therapy and 7 patients withdrew prior to first response assessment. The ORR was 68% with an 11% CR rate. The median time to response was 3.1 months. Responses were independent of genomic aberrations within tumor tissue, specifically KRAS, TP53, BRAF, and PIK3CA. Median PFS and duration of response were not interpretable given that only 25% of patients came off trial for progression; all other patients withdrew to pursue surgery or liver embolization therapy, to receive therapy elsewhere, or due to toxicity associated with chemotherapy. The 1 year OS rate was 74%, and median OS has not been reached. The most common G3 or higher adverse events included neutropenia (31%), fatigue (11%), thromboembolism (9%), and cardiac events (9%). HCQ-attributable side effects included G1-3 insomnia (26%), G1-3 anxiety (20%), G1 visual disturbances (11%) and G3 allergy (3%). The majority of patients had increase in both LC3 and p62 in peripheral blood mononuclear cells and exhibited an increase in autophagosomes within the cytosol by electron microscopy. Conclusions: These data are promising and further evaluation in a randomized controlled trial is planned. Clinical trial information: NCT01206530.
Safety and feasibility of adding tumor debulking to palliative chemotherapy in multi-organ metastatic colorectal cancer: The ORCHESTRA trial.
Authors: Gootjes Elske C. , van der Stok Eric P. , Bakkerus Lotte , Buffart Tineke E , Zonderhuis Barbara M , Meijerink Martijn R. , Haasbeek Cornelis J , van de Ven Peter M , Ten Tije Albert J. , De Groot Jan Willem , Radema Sandra A , Meerten Esther Van , Nuyttens Joost , Verhoef Cornelis , Verheul Henk M.W. 
Published: September 2018

3553 Background: For selected patients with oligometastatic colorectal cancer (mCRC), local treatment of metastases is standard of care based on retrospective reports showing long term survival rates. Local treatment of metastases is technically feasible in an increasing number of patients with multi-organ mCRC. It is unknown if patients with extensive disease will benefit from tumor debulking when added to first line palliative chemotherapy. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival (OS) benefit from tumor debulking in patients with multi-organ mCRC. Methods: Patients with multi-organ mCRC were eligible if > 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. All patients received oxaliplatin based chemotherapy ± bevacizumab. In case of stable disease or response at first evaluation (9 weeks), patients were randomized to continuation of chemotherapy or tumor debulking followed by chemotherapy. Adverse events were reported. If patient withdrawal after randomization was < 10%, the study was deemed feasible. Study continuation was based on the interim report on safety and feasibility after inclusion of 100 (of 478) patients. Results: Patients were randomized to the standard (N = 43) or intervention arm (N = 45). No patients withdrew after randomization. In 6.8% of patients debulking was not performed due to progressive disease (N = 5) or death (N = 1) prior to local treatment. Two patients had no lesions left to treat, 37 patients underwent tumor debulking. In 15 patients (40%) 21 serious adverse events related to debulking were reported, 83.7% of patients had no SAEs or recovered within 30 days. Postoperative 90-day mortality was 2.7% (N = 1). Chemotherapy was resumed in 86.5% of patients, median time to restart was 12.7 weeks (SD 5.6) and 78.4% completed ≥24 weeks of chemotherapy. Conclusions: Tumor debulking is feasible and safe and does not prohibit administration of palliative chemotherapy in the majority of patients with multi-organ mCRC. The ORCHESTRA trial will continue accrual to determine whether the aim of > 6 months OS benefit from tumor debulking will be achieved. Clinical trial information: NCT01792934.
Age as a predictive and prognostic factor for targeted therapy treatment in metastatic chemorefractory colorectal cancer (CRC): An analysis of NCIC CTG CO.17 and CO.20.
Authors: Wells Connor , Siu Lillian L. , Shapiro Jeremy David , Tu Dongsheng , Jonker Derek J. , Karapetis Christos Stelios , Simes John , Liu Geoffrey , Price Timothy Jay , Tebbutt Niall C. , O'Callaghan Christopher J. 
Published: September 2018

3555 Background: There is minimal data on the efficacy and improvement of quality of life (QoL) of these targeted therapies, like cetuximab, in elderly CRC patients (≥70yo). We analyzed outcomes from two randomized phase III clinical trials from the Canadian Clinical Trials Group, CO.17 and CO.20. Methods: CO.17 and CO.20 were retrospectively analyzed. CO.17 compared cetuximab (CETUX) with best supportive care (BSC), CO.20 compared CETUX + brivanib (BRIV) with CETUX + placebo. Key eligibility criteria were similar between each trial. Patients were dichotomized by age (≥70yo/ < 70yo) for comparisons. Outcomes included overall survival (OS), progression free survival (PFS), adverse events (AEs), and QoL deterioration. In CO.17, only patients with wild type K-RAS were included in analysis. Multivariate analysis with Cox regression controlled for additional variables. Results: 980 patients were included in this analysis. 257 (26.2%) were ≥70yo at the time of enrollment. In CO.17, OS and PFS were similar between young and elderly patients treated with CETUX (OS 9.7m vs 8.0m, p = 0.45; HR 0.73 95%CI 0.39-1.37). Compared to the BSC arm, elderly patients treated with CETUX had a non-significant increase in OS (8.0m vs 5.1m, p = 0.11). In patients treated with CETUX, grade 3/4 AEs were similar between age groups, however elderly patients had a faster deterioration in global QoL than younger patients (3.6m vs 5.7m p = 0.046). In CO.20, younger patients had longer OS than elderly (9.2m vs 7.6m, p = 0.02; HR 0.81 95% 0.68-0.97, p = 0.02). AEs in the BRIV+CETUX arm were higher in the elderly than young (88% vs 77%, p = 0.03). Both young and elderly treated with BRIV+CETUX had more rapid decreases in global QoL than the CETUX arm. Conclusions: Age was neither prognostic nor predictive of response to targeted therapy in the single agent CO.17 trial. In CO.20, age conferred a worse prognosis. Elderly patients who are eligible for clinical trials may garner similar survival benefits as younger patients with single agent therapy, but may not derive the same improvement in QoL.
Effect of postoperative morbidity on survival after cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis in a series of 700 cases.
Authors: Eveno Clarisse , Schiavone Roberto , Pocard Marc , Andre Thierry , Caballero Marie-Josee , Gayat Etienne 
Published: September 2018

3565 Background: Major morbidity (MM) after cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) is associated with worsening of disabilities and length of the hospital stay. This study aimed to identify MM prognostic factors and to measure its impact on oncological outcomes. Methods: A post-hoc analysis of a prospective cohort of 734 patients with peritoneal metastasis (PM) from 2006 to 2015 was undertaken. Five hundred and two patients who had complete CRS and HIPEC for PM were included. Results: Major morbidity was identified in 31% (156/502) of CRS/HIPEC procedures, including 67 hemorrhagic complication (13.3%), 87 anastomotic leaks (17.4%), 121 reoperation (24.1%), and 65 pulmonary complication (12.9%). The multivariate predictors of MM were American Society of Anesthesiologists (ASA) score (ASA 3 vs. 1-2, 0R 95%CI: 3.58 [1.54 – 8.34]), origin of PM colorectal adenocarcinoma vs. other, OR 95%CI: 1.62 [1.06 – 2.48]), type of HIPEC drug (oxaliplatin vs. other, OR 95%CI: 2.85 [1.28 – 6.32]), number of anastomosis (no vs. at least 1, HR 95%CI: 1.85 [1.19 – 2.88]), blood transfusion (OR 95%CI: 1.84 [1.05 – 3.23]) and length of surgery longer than the median value (OR 95%CI: 1.88 [1.22 – 2.91]). The in-hospital mortality rate for the entire cohort was 1.7% (9/502). Rate of adjuvant chemotherapy after CRS/HIPEC was comparable between the two groups (70.3% vs. 72.4%, p = 0.64). The median duration of follow-up was 18 months. The MM group had worst OS and DFS comparing non-MM (Hazard ratio and 95% confidence interval at 3.48 [1.90 ; 6.35] and 1.91 [1.43 ; 2.57], respectively). Conclusions: Major morbidity after CRS/HIPEC for peritoneal metastasis is a source of significant reoperation and longer hospital and intensive care unit stay; with a decrease in overall survival and disease free survival even after complete CRS. Preoperative ASA score, number of anastomoses, colorectal origin of PM, HIPEC with oxaliplatin, blood transfusion and length of surgery are independent predictors of MM for CRS/HIPEC patients.
Association of immune markers and Immunoscore with survival of stage III colon carcinoma (CC) patients (pts) treated with adjuvant FOLFOX: NCCTG N0147 (Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Hermitte Fabienne , Heying Erica N , Benson Al Bowen , Gill Sharlene , Goldberg Richard M. , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Sargent Daniel J. , Galon Jerome , Alberts Steven R. 
Published: September 2018

3579 Background: Tumor infiltrating lymphocytes (TIL) indicate a host immune response that may influence survival. Immunoscore was developed using CD3+ and CD8+density and location in primary CC pts with pooled stages, varying treatment and follow-up. We determined if individual immune markers and/or Immunoscore are prognostic in resected stage III CC pts (N=600). Methods: CD3+ and CD8+ T-cell or CD20+ B lymphocyte density in central tumor (CT) and invasive margin (IM) was evaluated by immunostaining and quantified by image analysis. Immunoscore was calculated on a scale of I0 to I4 with high densities of CD3+ and CD8+in both CT and IM scored as I4; low densities scored as I0. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for covariates. Results: Data for CD3+, CD8+ and CD20+ were generated (N=595). Higher density of CD3+ CT, CD3+ IM and CD8+ IM were associated with longer DFS adjusting for covariates (Table). CD3+ IM had the strongest association with DFS, and was stronger in left-sided (HRadj.=0.81, 95% CI, 0.70-0.94, padj.= 0.0049) vs right-sided (HRadj.=0.93, 95% CI, 0.85-1.0 padj.=0.52) tumors (pinteraction=0.039). Higher density of CD3+ IM was associated with older age (p=0.034), T1/2 (p<.0001), N1 (p=0.017), right-sided (p=0.013), high TILs (p=0.0008), and deficient MMR (p=0.0003). Using a prior Immunoscore risk stratification, higher scores were associated with better DFS (HR.=0.62, CI, 0.44-0.87, p=0.006) (Table). Conclusions: Densities of CD3+ and CD8+, especially at IM, are individually prognostic in FOLFOX-treated pts. Association of CD3+IM with prognosis differed by primary CC site. Immunoscore was strongly prognostic, and this result provides validation in a clinical trial cohort. [Table: see text]
Arginine methylation of EGFR in circulating tumor cells: A new biomarker for predicting resistance to anti-EGFR agents.
Authors: Korphaisarn Krittiya , Chou Chao-Kai , Xia Weiya , Clarke Callisia , Davis Jennifer S , Liao Hsin-Wei , Crosby Shadarra , Manuel Shanequa , Wu Ji , Menter David , Hung Mien-Chie , Kopetz Scott 
Published: September 2018

3590 Background: Arginine methylation of the epidermal growth factor receptor (meEGFR) increases binding affinity of EGF and other EGFR ligands, reduces the efficacy of anti-EGFR agents in vivo, and is reported to have a role in predicting response to anti-EGFR agents. This study aimed to investigate the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients (pts) treated with anti-EGFR agents using blood-based testing. Methods: 15 mL of blood were collected from mCRC pts with documented disease progression following anti-EGFR treatment (Rx). Circulating tumor cells (CTCs) were isolated using antibody (ab)-independent micro-fluidic cassette-based technology (Parsortix system), which separates CTCs on the basis of size and deformability. CTCs were identified based on negative staining for CD45ab and positive staining for EpCAMab. meEGFR was identified based on positive staining for me-R198/200ab on CTCs. Associations between meEGFR-CTCs and total CTCs with progression free survival (PFS) were determined by Kaplan-Meier method and compared by the log-rank test. Results: A total of 47 mCRC pts were prospectively included in this study. CTCs were identified in 30 out of 47 cases (64%). Of those 30, meEGFR-CTCs were identified in 19 cases (63%). Mean total CTCs and meEGFR-CTCs counts were 3.6 (range 0-52) and 2.3 (range 0-30) cells per 7.5ml, respectively. There was no association between meEGFR-CTCs and clinic-pathological features (age, sex, tumor site & grade), line of anti-EGFR Rx, previous irinotecan used, or NRAS, BRAF, PIK3CA, and MSI status. However, in RASwt/BRAFwtmCRC pts, high levels of meEGFR ratio (defined as > 0.25 meEGFR-CTCs per total CTCs) was associated with significantly inferior PFS with anti-EGFR Rx (median PFS 5.4 mo vs. 8 mo, HR 3.4, 95% CI of 1.5-7.9, P = 0.004). By contrast, high levels of total CTCs ( > 3 cells/per 7.5 ml) had no impact on PFS with anti-EGFR Rx. Conclusions: We have successfully isolated CTCs from mCRC pts’ blood using Parsortix system. Elevated levels of arginine methylated EGFR is associated with a shorter PFS with anti-EGFR-based Rx. Assessment of meEGFR-CTCs may provide a “liquid biopsy” biomarker for reduced efficacy from anti-EGFR Rx.