bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronomodulated hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil (5-FU), and oxaliplatin (l-OHP) plus intravenous (iv) cetuximab (Cet) (Chrono-Optiliv) in patients with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) after treatment failure (European Phase II trial NCT 00852228).
Authors: Bouchahda Mohamed , Karaboué Abdoulaye , Etienne-Grimaldi Marie-Christine , Chatelut Etienne , Innominato Pasquale F. , Paintaud Gilles , Ricca Luana , Vibert Eric , Ajavon Yves , Awad Sameh , Castaing Denis , Focan C. N. J. , Milano Gerard , Morere Jean Francois , Adam Rene , Levi Francis ,   ARTBC International
Published: March 2020

3606 Background: Hepatic artery triplet chronotherapy is an effective salvage therapy for pretreated LM-CRC (Bouchahda et al. Cancer 2009). The combination of iv Cet with chrono or conventional triplet HAI allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, and median progression-free (PFS) and overall survival (OS) of 8.7 and 25.7 months respectively, despite prior chemotherapy (Lévi et al. ASCO-GI 2013). Purpose: To relate tolerability and efficacy of Chrono-Optiliv to pharmacokinetics (PK). Methods: 18/64 registered patients received iv Cet (500 mg/m²) and chrono HAI of Irinotecan (180 mg/m²), 5-FU (2800 mg/m²), and l-OHP (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks reviews. The systemic exposure to the 4 drugs was determined on 1st course in 11 pts, through 16 samples over 56h. Results: 8F, 10M, aged 33-72 years had good PS (0/1: 83%/17%), a median of 7 LM-CRC (2-50) in 6 segments (1-8) with median largest diameter of 47 mm (15-130). LM-CRC were bilateral in 13 pts (72%); 10 pts (56%) got Chrono-Optiliv as 3rd-4th line. Main grade 3-4 toxicities were neutropenia (56%), abdominal pain (44%), diarrhea and fatigue (22%). The rate of objective responses was 50% [26.9-73.1], and that of R0-R1 33.3% [11.5 -55.1], resulting in median PFS and OS (months) of 12.6 [8.8 -16.1] and 21.9 [7.4-36.4] respectively. Plasma PK revealed the expected Cet levels and a relevant systemic exposure to the HAI drugs, with median trapezoidal AUC’s of 12.4 µg*mn/mL (2.6-38.5) for SN-38, 142 µg*mn/mL (96- 434) for 5-FU and 100 µg*mn/mL (37-189) for free l-OHP. A significant correlation was found between free l-OHP AUC and abdominal pain (p=0.016) and between SN38 AUC and both neutropenia (p=0.018) and response (p=0.028). Conclusions: The significant systemic exposure to the HAI drugs together with iv Cet could explain efficacy and lack of early progression on Chrono-Optiliv. The results call for upfront testing of optimized Chrono-Optiliv. Clinical trial information: NCT 00852228.
Quality of life (QOL) and toxicity among patients in CALGB 80405.
Authors: Naughton Michelle Joy , Schrag Deborah , Venook Alan Paul , Niedzwiecki Donna , Anderson Roger T. , Lenz Heinz-Josef , Grubbs Stephen S. 
Published: March 2020

3611 Background: CALGB 80405, a phase III trial, was originally designed to compare toxicity and overall survival of metastatic colorectal patients treated with standard chemotherapy (choice of FOLFOX or FOLFIRI) and either: 1) Bevacizumab; 2) Cetuximab; or 3) both Bevacizumab and Cetuximab. Because Cetuximab causes a prominent acneiform skin rash, adverse effects on QOL were anticipated and assessed in a QOL companion. Methods: The QOL companion enrolled the first 518 consenting patients randomized to CALGB 80405 between 10/2005-9/2007, the majority prior to amendments that eliminated the dual biologic arm and restricted participation to patients with KRAS wttumors. QOL was assessed at baseline, 6 weeks, and 3, 6 and 9 months post-randomization, using the EORTC QLQ-30 and the Dermatology-Specific Quality of Life (DSQL) Scale. We hypothesized that patients receiving Cetuximab would have lower satisfaction with appearance, reduced social functioning and lower overall QOL at 3 months, (a primary assessment point). Results: Patients had a mean age of 59, were predominantly male (58%), performance status 0 (62%), and non-Hispanic White (85%). 83% completed a 3 month assessment. There were no differences in global health functioning (p=0.164) or other items/subscales of the EORTC at 3 months by treatment arm. However, significant differences were found across arms in skin symptoms (p<.0001), limitations in social activities due to skin condition (p=0.008), and concerns about appearance (p<.0001), as measured by the DSQL. Patients randomized to Bevacizumab reported fewer skin symptoms, fewer social limitations and appearance concerns than patients receiving Cetuximab alone or Cetuximab + Bevacizumab. The choice of chemotherapy (FOLFOX or FOLFIRI) had no bearing on these results. Conclusions: Global QOL, as well as physical, role, social and emotional functioning, were not significantly different across treatment arms. However, Cetuximab recipients reported greater symptoms and QOL concerns relating to their skin than those receiving Bevacizumab alone. Interventions to more adequately address skin problems from Cetuximab treatment are warranted. Participants are still being followed to determine survival differences between the biologics. Clinical trial information: NCT00265850.
Genomic classifier (ColoPrint) to predict outcome and chemotherapy benefit in stage II and III colon cancer patients.
Authors: Kopetz Scott , Jiang Zhi-Qin , Overman Michael J. , Rosenberg Robert , Salazar Ramon , Tabernero Josep , Stork Lisette , Li Ying , Simon Iris , Chang George J. , Maru Dipen M. 
Published: March 2020

3612 Background: Although benefit of chemotherapy in stage II and III colorectal cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and validated in independent validation studies (JCO 2011, Ann Surg 2013). Methods: In this study, ColoPrint was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center. Frozen tissue specimen, clinical parameters and follow-up data (median follow-up 64 months) were available. Stage II patients from this study were pooled with patients from previous studies (n=416) and ColoPrint performance was compared to clinical risk factors described in the NCCN Guidelines 2013. Results: In the MDACC patient cohort, ColoPrint classified 56% of stage II and III patients as being at Low Risk. The 3-year Relapse-Free-Survival (RFS) was 90.5% for Low Risk and 78.1% for High Risk patients with a HR of 2.42 (p=0.025). In uni-and multivariate analysis, ColoPrint and stage were the only significant factors to predict outcome. Low Risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (91% 3-year RFS for treated patients, 90% for untreated patients) while ColoPrint High Risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70% 3-year RFS in untreated patients (p=0.037). In the pooled stage II dataset, ColoPrint identified 63% of patients as Low Risk with a 3-year RFS of 93% while High Risk patients had a 3-year RFS of 82.3% with a HR of 2.7 (p=0.001). In the univariate analysis, no clinical factor reached statistical significance. Using clinical high risk factors as described in the NCCN guidelines as classification, 56% of patients were classified as low risk with a 3-year RFS of 90.3% while high risk patients had a 3-year RFS of 87.7% with a HR of 0.6 (p=0.63). Conclusions: ColoPrint significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.
Accent-based nomograms (NGs) to predict time to recurrence (TTR) and overall survival (OS) in stage III colon cancer (CC).
Authors: Renfro Lindsay A. , Grothey Axel , Saltz Leonard , André Thierry , Labianca Roberto , Alberts Steven R. , Loprinzi Charles L. , Yothers Greg , Sargent Daniel J. ,   Adjuvant Colon Cancer Endpoints (ACCENT) Group
Published: March 2020

3618 Background: Current prognostic tools and staging systems in CC use relatively few patient (pt) characteristics; including additional covariates may improve prediction. Using the large ACCENT database, we constructed clinically based NGs for OS and TTR in stage III CC that better separate pts into risk groups compared to AJCC v7 staging. Methods: 15,936 stage III pts accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, BMI, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number/location of primary tumors (any multiple versus single left, right, or transverse), and treatment (5FU variations vs. 5FU with oxaliplatin or irinotecan). Missing data (<18%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions included if p < 0.001. Final models were internally validated via bootstrapping for corrected calibration and C-indices for survival data. NG-defined risk tertiles were compared to AJCC v7 stage III for observed 3-year (yr) TTR and 5-yr OS for a subset of 7400 pts with complete data. Results: All variables were statistically and clinically significant for OS; age and race did not predict TTR. No meaningful interactions existed. NGs for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, vs. 0.58 and 0.59 for AJCC. NG risk tertiles were better separated than AJCC groups, (3-yr TTR, 5-yr OS below), with fewer mid-risk NG pts. Removing treatment from NGs did not affect performance (C=0.66 for OS and 0.65 for TTR). Conclusions: The proposed ACCENT NGs are internally valid and have the potential to aid prognostication, decision-making, and patient/physician communication in pts with stage III CC. [Table: see text]
Predicting overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT): The British Columbia Cancer Agency (BCCA) mCRC score.
Authors: Chen Leo , Gresham Gillian , Cheung Winson Y. , Kennecke Hagen F. , Renouf Daniel John 
Published: March 2020

3624 Background: The prognosis of individual pts with mCRC can be highly variable. Our objective was to develop a scoring system to improve the prognostication of mCRC pts at baseline assessment. We also further explored the impact of palliative resection (PR) of the primary tumor on OS. Methods: Pts diagnosed with mCRC from 2006 to 2008, referred to 1 of 5 regional cancer centers in British Columbia were retrospectively reviewed. Pts with prior early stage CRC who relapsed with mCRC were excluded. Multivariate stepwise selection was performed using significant variables from univariate analysis. Patients were assigned a composite risk score (range 0-15) based on their baseline variables, and then separated into quartiles for OS using cut-point analysis and Kaplan Meier methods. A secondary propensity score matched analysis was performed to obtain hazard ratios (HR) for death in order to control for baseline differences between pts who underwent PR and those who did not. Results: A total of 505 mCRC pts were included: median age 63 (range 22-86), 58% male, 75% ECOG 0-1, 58% colon primary, 34% >1 metastatic site, and 46% smokers. In this cohort, 81% of the population underwent PR. ECOG 2-3, no primary resection, colon primary, >1 metastatic site, CEA level >4 ng/ml, male gender, and smoker were significant in the multivariate model and subsequently assigned a score. Median OS varied significantly depending on the composite risk score (table). After ECOG PS, PR of the primary was the second strongest prognostic factor (HR 2.3, 95%CI 1.6-3.3). To further explore this, a propensity score matched analysis was performed adjusting for age, gender, ECOG and receipt of chemotherapy. Prognosis continued to be more favorable in the PR group with a median OS of 17 vs. 7.9 months (HR 0.66, 95% CI 0.50-0.86, p=0.0019). Conclusions: In this population based analysis, the BCCA mCRC score was a simple and effective method to improve prognostication for mCRC pts. PR of the primary was associated with significantly longer OS. [Table: see text]
A phase I study of sorafenib with FOLFIRI as first-line therapy for metastatic colorectal cancer (mCRC): Safety and efficacy results.
Authors: Maroun Jean Alfred , Jonker Derek J. , Cripps M. Christine , Asmis Timothy R. , Goel Rakesh , Goodwin Rachel Anne , Marginean Horia 
Published: March 2020

3633 Background: Phase I dose escalation to a maximum planned dose (MPD) o determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended-phase-II-dose (RP2D) and preliminary efficacy of sorafenib and FOLFIRI (irinotecan reduced-dose) in metastatic colorectal cancer (mCRC) patients. Methods: Starting doses: irinotecan 80 mg/m2 iv d1, sorafenib 400 mg po twice daily (bid, continuous), starting day 2. Escalations based on toxicity observed at the previous dose level (DL) up to: irinotecan 100 mg/m2 and sorafenib 800 mg bid. DLT was evaluated within the 1st study cycle (1 cycle = 2 FOLFIRI treatments). Results: 5 cohorts were concluded. All 16 ECOG PS 0-1 patients (9/7 men/women; 2/14 rectal/colon) with median age of 64, discontinued study: 10 (62%) disease progression, 4 (25%) toxicity, 1 curative surgery, 1 comorbidities. The dose levels of irinotecan (mg/m2, day1) and sorafenib (mg/day, bid, day 2-28) studied were DL1-80/400, DL2-80/600, DL3-90/600, DL4-100/600 and DL5-100/800, repeated every 4 weeks, 3 patients/DL. No DLT was observed. The MTD was not reached at the MPD (DL5). The most common ≥Gr2 treatment related adverse events (AEs) were: neutropenia 81%, HFS 69%, leucopenia 50%, fatigue 38%, anemia 31%, constipation 31%, nausea/vomiting 31%, mucositis 31%, diarrhea 25%, hypophosphatemia 25%. The most severe treatment related AEs were: Gr4: neutropenia 2 (12.5%); pulmonary embolism 1 (6%); Gr3: HFS 9 (56%), neutropenia 3 (19%), leucopenia 3 (19%), hypophosphatemia 3 (19%). Objective response rate was 56% (9 of 16 patients, 95%CI; 33-77%). Response duration was 13 months (95%CI; 5-17). Median progression-free survival and overall survival were 11 months (95%CI; 6-17) and 25 months (95%CI; 15-34), respectively. Conclusions: Combination therapy with S and modified FOLFIRI in these patients is well tolerated and demonstrates clinical efficacy at the MPD. The MTD was not reached at the MPD. Future research of this combination is warranted. Supported by Bayer Healthcare Pharmaceuticals. Clinical trial information: NCT00780169.
Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates.
Authors: Von Hoff Daniel D. , Ervin Thomas J. , Arena Francis P. , Chiorean E. Gabriela , Infante Jeffrey R. , Moore Malcolm J. , Seay Thomas E. , Tjulandin Sergei , Ma Wen Wee , Saleh Mansoor N. , Harris Marion , Reni Michele , Ramanathan Ramesh K. , Tabernero Josep , Hidalgo Manuel , Van Cutsem Eric , Goldstein David , Wei Xinyu , Iglesias Jose Luis , Renschler Markus Frederic 
Published: March 2020

4005^ Background: nab-paclitaxel (nab-P; 130 nm albumin-bound paclitaxel) has demonstrated both single-agent activity and synergy with gemcitabine (G) in preclinical models of pancreatic cancer (PC). nab-P + G also demonstrated promising efficacy in a phase I/II study in metastatic PC (J Clin Oncol. 2011:4548-4554), warranting a phase III study of nab-P + G vs G for metastatic PC. Methods: 861 patients (pts) with metastatic PC and a Karnofsky performance status (KPS) ≥ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 days 1, 8, and 15 every 4 weeks or G alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥ 2). The primary endpoint was OS; secondary endpoints were PFS and ORR by independent review. Results: The median age was 63 years (range 27 - 88). KPS was 100 (16%), 90 (44%), 80 (32%), and 70 (7%). Pts had advanced disease with liver metastases (84%), ≥ 3 metastatic sites (46%), and CA19-9 ≥ 59 × ULN (46%). nab-P + G was superior to G for all efficacy endpoints: median OS was 8.5 vs. 6.7 mo (HR 0.72; 95% CI, 0.617 - 0.835; P = 0.000015); median PFS was 5.5 vs. 3.7 mo (HR 0.69; 95% CI, 0.581 - 0.821; P = 0.000024), and ORR was 23% vs. 7% (P = 1.1 × 10−10) by RECIST v1.0. Metabolic response by PET in 257 patients was 63% for nab-P + G vs 38% for G (P = 0.000051). CA19-9 response (≥ 90% decrease) was 31% for nab-P + G vs. 14% for G (P < 0.0001). Grade ≥ 3 AEs with nab-P + G vs. G included neutropenia (38% vs. 27%), fatigue (17 % vs. 7%), diarrhea (6% vs 1%), and febrile neutropenia (3% vs. 1%). Grade ≥ 3 peripheral neuropathy (PN) occurred in 17% vs. 1% of pts who received nab-P + G vs. G, respectively; for nab-P + G, PN improved to grade ≤ 1 in a median 29 days, and 44% of patients resumed nab-P treatment. The median duration of treatment was 3.9 mo for nab-P + G and 2.8 mo for G. Conclusions: MPACT was a large, international study performed at community and academic centers. nab-P + G was superior to G across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens. Clinical trial information: NCT00844649.
JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer.
Authors: Fukutomi Akira , Uesaka Katsuhiko , Boku Narikazu , Kanemoto Hideyuki , Konishi Masaru , Matsumoto Ippei , Kaneoka Yuji , Shimizu Yasuhiro , Nakamori Shoji , Sakamoto Hirohiko , Morinaga Soichiro , Kainuma Osamu , Imai Koji , Sata Naohiro , Hishinuma Shoichi , Nakamura Takayuki , Kanai Michio , Hirano Satoshi , Yoshikawa Yukinobu , Ohashi Yasuo 
Published: March 2020

4008 Background: Adjuvant chemotherapy with gemcitabine (G) has been standard treatment for resected pancreatic cancer (PC). In the GEST study, S-1 (S) had shown non-inferiority to G in overall survival (OS) for unresectable PC. The aim of this phase III study is to investigate non-inferiority of S to G on OS as adjuvant chemotherapy for resected PC. Methods: Patients (pts) after macroscopically curative resection of PC with an ECOG PS of 0-1 and adequate organ functions were randomly assigned to G (1000 mg/m2, iv, d1, 8 and 15, q4w, for 6 courses) or S (80/100/120 mg/day based on BSA, po, d1-28, q6w, for 4 courses) with balancing by surgical margins (R), nodal status (N) and institution. Primary endpoint was OS. With 180 pts per arm, the study had 80% power to prove non-inferiority with a margin of hazard ratio (HR) 1.25 on the basis of expected HR 0.87, with 0.05 two-sided alpha. Secondary endpoints were relapse-free survival (RFS), safety, and quality of life (EQ-5D). One interim analysis was planned after 180 deaths. Results: From 4/2007 to 6/2010, 385 pts were enrolled from 33 hospitals in Japan. 378 pts (G/S: 191/187) were included in the full analysis set. Pts characteristics (G/S) were well balanced (PS0: 67%/70%, R0: 86%/88%, N0: 38%/36%). Based on the interim analysis with 205 OS events, IDMC recommended to publish the results. OS at 2-years were 53% for G and 70% for S. HR for S to G was 0.56 (95% CI, 0.42-0.74, p<0.0001 for non-inferiority, p<0.0001 for superiority). On subgroup analysis, HRs for R0/R1, N0/N1 pts were 0.57 (95% CI, 0.42-0.78)/0.53 (0.27-1.05), 0.48 (0.28-0.83)/0.58 (0.41-0.80), respectively. RFS at 2-years were 29% for G and 49% for S. HR of relapse for S to G was 0.56 (95% CI, 0.43-0.71, log-rank p<0.0001). Incidences of grade 3/4 toxicities in G/S were leukopenia 39%/9%, hemoglobin decrease 17%/13%, thrombocytopenia 9%/4%, elevated AST 5%/1%, fatigue 5%/5%, and anorexia 6%/8%. Relative dose intensity of G/S was 84%/97%. EQ-5D QOL score in S was significantly better than that in G (p<0.0001). Conclusions: S-1 adjuvant chemotherapy is shown non-inferior, and furthermore, even superior to GEM. S-1 is considered as the new standard treatment for resected PC pts. Clinical trial information: UMIN000000655.
Vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led phase II randomized study.
Authors: Cohen Deirdre Jill , Christos Paul J. , Kindler Hedy Lee , Catenacci Daniel Virgil Thomas , Bekaii-Saab Tanios B. , Tahiri Sanaa , Janjigian Yelena Yuriy , Gibson Michael K. , Chan Emily , Rajdev Lakshmi , Urba Susan , Wade James Lloyd , Kozuch Peter , Love Erica , Vandris Katherine , Takebe Naoko , Hochster Howard S. , Sparano Joseph A. ,   New York Cancer Consortium
Published: March 2020

4011 Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m2, LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/ m2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts enrolled at 20 sites between 10/09-2/12. 123 pts eligible for analysis (V/P 60/63). Pt characteristics (V/P): median age 58/62; ECOG PS 0: 24 (40%) / 30 (48%); male 39 (65%) / 52 (83%); GEJ 37 (62%) / 39 (61%); diffuse or mixed histology 19 (32%) / 10 (16%), recurrent disease 10(17%) / 16 (25%). Median number of FOLFOX cycles 10/11. Most common Grade ≥3 toxicities: (% pts V/P) neutropenia 50/32 (p=0.07), neuropathy 19/13 (p=0.49), fatigue 15/10 (p=0.50), thrombosis 14/11 (p=0.92), anemia 10/10 (p=0.99), hemorrhage-GI 8/11 (p=0.77), hypokalemia 10/5 (p=0.76), nausea 8/8 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in intent to treat population 7.3/8.0 mo (95% CI 4.6-10.1/5.1-11.0; p=0.64) and median OS 11.5/14.9 mo (95% CI 9.6-13.4/11.3-18.4; p=0.23). Overall RR (%) 35/35 (p=0.99). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06. Clinical trial information: NCT00982592.