bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual patient data (IPD) analysis of progression-free survival (PFS) versus overall survival (OS) as an endpoint for metastatic colorectal cancer (mCRC) in modern trials: Findings from the 16,700 patients (pts) ARCAD database.
Authors: Shi Qian , De Gramont Aimery , Buyse Marc E. , Grothey Axel , Schmoll Hans-Joachim , Seymour Matthew T. , Adams Richard A. , Saltz Leonard , Goldberg Richard M. , Punt Cornelis J. A. , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Diaz-Rubio Eduardo , Porschen Rainer , Tebbutt Niall C. , Fuchs Charles S. , Souglakos John , Falcone Alfredo , Sargent Daniel J. ,   for the ARCAD Group
Published: March 2020

3533 Background: PFS has previously been established as a surrogate for OS based on IPD from first-line mCRC trials conducted before 1999. As mCRC treatment (trt) has advanced in the last decade and OS has increased from 1 to 2 years, this surrogacy required re-examination. Methods: IPD from 16,762 pts, median age 62, 62% male, 53% ECOG PS 0 were available from 22 1st line mCRC studies conducted from 1997-2006; 12 tested targeted (anti-angiogenic and/or anti-EGFR) regimens. The relationship between PFS (first event of progression or death) and OS was evaluated at patient-, trt-arm-, and trial-levels using correlation (corr.) coefficients and R2 (closer to 1 the better) from weighted least square (WLS) regression of arm-specific survival rates and trial-specific hazard ratios (HRs), estimated using Cox and Copula bivariate models. The concordance of significance (CoS) of the treatment effects (TEs) on both endpoints was calculated. Results: 44% pts received a targeted regimen. Median PFS was 8 and OS was18 months. The corr. between PFS and OS was modest at all three levels with low CoS in TE comparisons (see Table). Analyses limited to trials testing targeted trts, non-strategy trials, or superiority trials did not improve surrogacy. Conclusions: In modern mCRC trials, where survival post-first progression exceeds time to first progression, PFS TEs do not reliably predict TEs on OS. Nonetheless, until alternative endpoints of clinical benefit can be validated, PFS remains a relevant primary endpoint for 1st line mCRC trials, as our data demonstrate that the ability for any agent to produce an OS benefit from a single line of therapy is challenging. [Table: see text]
Effect of oxaliplatin-containing neoadjuvant chemotherapy on tumor volume in locally advanced rectal cancer and sensitivity of surviving tumor cells to radiotherapy.
Authors: Flatmark Kjersti , Hole Knut Hakon , Saelen Marie Gron , Abrahamsen Torveig Weum , Fleten Karianne Giller , Roe Kathrine , Dueland Svein , Seierstad Therese , Ree Anne Hansen 
Published: March 2020

3547 Background: The use of oxaliplatin (OXA) is well established in adjuvant and palliative treatment of colorectal cancer (CRC), but its role in neoadjuvant treatment of locally advanced rectal cancer (LARC) is controversial. Data from the ACCORD 12/0405, STAR-01 and NSABBP R-04 trials suggest no additional clinical benefit of adding OXA to fluoropyrimidine-based preoperative chemoradiotherapy (CRT) in LARC. However, the possibility of reducing risk of systemic recurrence and the use of OXA-containing neoadjuvant chemotherapy (NACT) in liver metastasis warrant further clarification of the role of OXA in neoadjuvant treatment of LARC. Methods: We report results from a non-randomized phase II trial of neoadjuvant treatment of 72 LARC patients, receiving two courses of the Nordic FLOX regimen prior to CRT (25 x 2 Gy; weekly OXA; daily capecitabine). Tumor volumes were calculated from MRI scans taken before and after NACT and 4 weeks after CRT completion. Using OXA resistant human CRC cell lines, the impact of previous OXA exposure on radiosensitivity (1-5 Gy) was examined. Results: Median baseline tumor volume was 16.6 cm3 (1.1-293 cm3). All tumors, except one, responded to NACT, leaving a median tumor volume of 5.3 cm3 (0.2-157 cm3), representing a median volume reduction of 63%. In all but three patients, additional tumor volume reduction was observed following subsequent CRT (median tumor volume 5.3 cm3; 0.02-119 cm3; median volume reduction of 68%). Exposure of cell lines to increasing concentrations of OXA resulted in resistance towards the drug. OXA resistant models exhibited increased radiosensitivity compared to OXA sensitive counterparts. Conclusions: OXA-containing NACT led to substantial tumor volume reduction. Additional tumor volume reduction was observed in almost all cases, suggesting that pretreatment with OXA-containing NACT did not preclude tumor response to CRT. Results from experimental models rather suggest that pretreatment with OXA might enhance radiosensitivity of surviving OXA resistant cells. Taken together, our results are in favor of continued exploration of OXA-containing NACT in LARC. Clinical trial information: NCT00278694.
Survival after resection plus intra-operative radiofrequency ablation (IRFA) to treat colorectal liver metastases (CLM): Results of an international collaborative study.
Authors: Evrard Serge , Diallo Abou , Brouste Veronique , Lalet Caroline , Desolneux Gregoire , Mathoulin-Pelissier Simone , Kissmeyer-Nielsen Peter , Mortensen Frank , Poston Graeme John , Staettner Stefan , Konstantinidis Ioannis , DeMatteo Ronald P. , D'Angelica Michael Ian , Allen Peter J. , Jarnagin William R. , Fong Yuman 
Published: March 2020

3558 Background: Adding IRFA to parenchymal resection to treat CLM is gaining increasing acceptance in specialized HPB teams treating complex, bilobar disease. Objectives were to confirm the promising results of the prospective CLOCC and ARF2003 trials on a larger international scale. Methods: Four centers combined their clinical databases regarding IRFA for CLM. Demographics, treatments, CLM characteristics, complications (Clavien-Dindo), local recurrence, and survivals (liver progression-free, LPFS, relapse-free, RFS and overall, OS) were analyzed. Results: 280 patients (38% female, median age 61y) received resection plus IRFA over 2001-2011. 205 had synchronous CLM (73%) and 247 bilateral (88%). 227 patients received pre-operative chemotherapy (173 one line, 37 two lines, 10 three lines, 7 missing); 189 received post-operative chemotherapy (103 one line, 46 two lines, 40 three lines). Median number of tumors resected was 2 (range 1-19) and ablated 2 (1-12). Median size (mm) of largest CLM ablated per patient was 8.5(0.1-50). 96 patients experienced complications: 29 G1, 19 G2, 35 G3, 10 G4, and 3 deaths. 48 patients had local recurrence of ablated CLM. 155 patients developed new CLM, 165 extra-hepatic metastases, and 119 patients died during follow-up. One-year, 3-year and median (months) RFS, LPFS and OS were respectively: RFS 41%(95CI35-47), 14%(95CI9-19), 9m (95CI8-11); LPFS 53%(95CI47-59), 31%(95CI25-37), 15m (95CI11-19); OS 90%(95CI85-93), 58%(95CI51-65), 40m (95CI37-50). Median follow-up was 38m (95CI34-49). Conclusions: In this difficult-to-treat group, survival results were good and comparable with rates reported after resection only. IRFA complements resection, enabling to treat more patients, and offers the advantage of sparing healthy parenchyma.
Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.
Authors: Pant Shubham , Hart Lowell L. , Bendell Johanna C. , Infante Jeffrey R. , Jones Suzanne Fields , Mohyuddin Adil , Murphy Patrick , Patton Jeffrey , Penley William Charles , Thompson Dana Shelton , Burris Howard A. 
Published: March 2020

3564 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3+3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 pts were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n= 6). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44+). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.
On-treatment progression-free survival analysis of ziv-aflibercept/FOLFIRI treatment within 28 days of end of treatment in metastatic colorectal cancer: Updated efficacy results from the VELOUR study.
Authors: Ferry David , Kim Tae Won , Guren Tormod Kyrre , Desai Jayesh , Villanueva Luis Marcelo , Andria Michael L. , Van Cutsem Eric , Macarulla Teresa 
Published: March 2020

3573 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent ziv-aflibercept (known as aflibercept outside the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate vs placebo/FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive ziv-aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test and were stratified by Eastern Cooperative Oncology Group performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment analysis showed significantly increased PFS for patients treated with ziv-aflibercept/FOLFIRI compared with placebo/FOLFIRI (Table). More patients were censored in the ziv-aflibercept arm due to adverse events. Conclusions: The on-treatment PFS analysis demonstrates a significantly improved treatment effect of the addition of ziv-aflibercept to FOLFIRI (HR=0.55) over what was observed in the primary analysis suggesting that continuing treatment with ziv-aflibercept up to disease progression provides additional benefit. Clinical trial information: NCT00561470. [Table: see text]
Results of a phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim (PEG) in patients (pts) receiving first-line FOLFOX or FOLFIRI and bevacizumab (B) for colorectal cancer (CRC).
Authors: Pinter Tamas , Abella Esteban , Cesas Alvydas , Croitoru Adina , Decaestecker Jochen , Gibbs Peter , Hotko Yevhen , Jassem Jacek , Kurteva Galina Petrova , Novotny Jan , O'Reilly Seamus , Salek Tomas , Mo May F. , Choi L. Mi Rim , Blanke Charles Davic 
Published: March 2020

3575 Background: The literature reports that adding biologics to chemotherapy (ctx) may increase the incidence of clinically significant neutropenia. his trial was conducted to evaluate the efficacy of PEG in reducing the incidence of febrile neutropenia (FN) in pts with locally-advanced (LA) or metastatic (m)CRC receiving first-line treatment with either FOLFOX/B or FOLFIRI/B. Methods: Key eligibility: ≥ 18 years old; measurable, nonresectable CRC per RECIST 1.1. Pts were randomly assigned 1:1 to either placebo or 6 mg PEG ~24 h after ctx/B. The study treatment period included four Q2W cycles, but pts could continue their assigned regimen until progression. Pts were stratified by region (North America vs rest of world), stage (LA vs mCRC), and ctx (FOLFOX vs FOLFIRI). Estimated sample size (N = 800) was based on the expected incidence of grade 3/4 FN (primary endpoint) across the first 4 cycles of ctx/B, powered for PEG superiority over placebo. Other endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 845 pts were randomized (Nov 2009 to Jan 2012) and received study treatment; 783 pts completed 4 cycles of ctx/B. Median age was 61 years; 512 (61%) pts were male; 819 (97%) had mCRC; 414 (49%) received FOLFOX, and 431 (51%) received FOLFIRI. Grade 3/4 FN (first 4 cycles) for placebo vs PEG was 5.7% vs 2.4%; OR 0.41; p = 0.014. A similar incidence of other ≥ grade 3 adverse events was seen in both arms (28% placebo; 27% PEG). See table for additional results. Conclusions: PEG significantly reduced the incidence of grade 3/4 FN in this pt population receiving standard ctx/B for CRC. Follow-up is ongoing. Clinical trial information: NCT00911170. [Table: see text]
Risk of second primary cancers after treatment for locoregional rectal cancer.
Authors: Nangia Chaitali Singh , Taylor Thomas H. , Tsang Walter , Wong Jason , Carmichael Joseph , Karnes William , Zell Jason A. 
Published: March 2020

3578 Background: The risk of second primary colorectal cancers among rectal cancer patients has been described, but little is known about the risk of non-colorectal malignancies that may occur in the field of radiation. We attempted to quantify the risk, using data from the large population-based California Cancer Registry (CCR). Methods: We analyzed the CCR data for surgically-treated locoregional rectal cancer cases, diagnosed during the period 1988–2009. We excluded cases with second primary tumor (SPT) diagnosed within 12 months of initial diagnosis . Radiation treatment used was external beam radiation therapy. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated to evaluate risk as compared to the underlying population after matching for age, sex, ethnicity, and time. Results: Of the study cohort of 13,418 rectal cancer cases, 1572 cases of SPTs were observed . The SIR was increased for small intestine cancer among cases receiving radiation treatment (4 cases observed vs. 1.01 cases expected; SIR=3.94, 95% CI 1.07-10.10) but not among cases lacking radiation treatment (4 observed vs. 4.45 expected; SIR=0.90, 5% CI 0.24-2.30). Among females treated with radiation, the SIR was increased for uterine cancer (12 observed vs. 5.59 expected; SIR=2.15, 95% CI 1.11 to 3.75) but not among cases lacking radiation therapy (23 observed vs. 26.17 expected; SIR=0.88, 95% CI 0.56-1.32). Among males receiving radiation treatment, the SIR for prostate cancer was decreased (23 observed vs. 69.78 expected; SIR=0.33; 95% CI 0.21 to 0.49) but of borderline significance among males lacking radiation therapy (243 observed vs. 276.97 expected; SIR=0.88, 95% CI 0.77-0.99). No significant differences were observed for cancers of the vagina, cervix, ovary, kidney, bladder, penis, testes, or leukemia based on prior radiation treatment for rectal cancer. Conclusions: Patients receiving pelvic radiation for treatment of rectal cancer have a subsequently higher than expected incidence of small intestine and uterine cancer. The incidence of prostate cancer appears to fall after pelvic radiation. These unexpected findings suggest complex relationships associated with radiation treatment for rectal cancer and SPT risk.
A phase II, randomized, double blind comparison of calcium aluminosilicate clay (CASAD) versus placebo (dibasic calcium carbonate) for the prevention of diarrhea in patients (pts) with metastatic colorectal cancer (mCRC) treated with irinotecan (I).
Authors: Kee Bryan K. , Slack Rebecca , Crocenzi Todd S. , Wong Lucas , Esparaz Benjamin , Overman Michael J. , Glover Katrina Y. , Morris Jeffrey , Fisch Michael 
Published: March 2020

3600 Background: CASAD is a naturally occurring calcium montmorrilonite clay that serves as a cation exchange absorbent. One of the active metabolites of Irinotecan is SN-38, which is adsorbed by CASAD in vitro. The study hypothesis was that oral CASAD would reduce the rate of grade 3/4 diarrhea in mCRC patients treated with irinotecan. Methods: The study is a multicenter, prospective, randomized, double blinded placebo-controlled phase II trial. One hundred patients receiving I-based chemotherapy were randomized equally between CASAD (1000 mg po 4x daily) and placebo in order to have 75% power to detect a difference in the proportions of patients with grade 3/4 diarrhea within 6 weeks at a 1-sided 5% significance level. We also compared symptom burden using the MDASI questionnaire summed over the 13 symptom items for weeks 0, 3, 5, and 6. Results: Between 5/2009 and 5/2012, 100 patients were randomized in a 1:1 ratio between study arms. Median age 57 yrs, 54% male, 74% Non-Hispanic White, 93% performance status 0 or 1. Serious diarrhea was less frequent than expected based upon prior studies with Irinotecan. In evaluable patients, no significant difference in the rate of G3/4 diarrhea was seen (the primary endpoint): CASAD arm: 7/43 pts (16%), Placebo arm: 3/32 pts (9%), p=0.70. The rate of any diarrhea among all pts was also similar: CASAD arm 64% vs. Placebo arm 70%. The rate of study dropout was 14% in CASAD and 38% for placebo (p=0.01; 2-sided). No differences were found in symptom burden or individual symptom items or serious adverse events. Conclusions: Compared with placebo, CASAD use was safe but ineffective in preventing diarrhea in mCRC patients treated with irinotecan-containing chemotherapy regimens. There were no favorable or unfavorable signals in terms of the patient experience related to symptoms, but there were significantly more dropouts in the placebo arm. Future CASAD trials are focused on active treatment of diarrhea. Clinical trial information: NCT00748215.
Prospective analysis of the early modulation of plasma amphiregulin (AR) during treatment with cetuximab and irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients (pts).
Authors: Cremolini Chiara , Loupakis Fotios , Antoniotti Carlotta , Fioravanti Anna , Orlandi Paola , Salvatore Lisa , Canu Bastianina , Schirripa Marta , Masi Gianluca , Di Desidero Teresa , Marmorino Federica , Bergamo Francesca , Zoratto Federica , Bocci Guido , Falcone Alfredo 
Published: March 2020

3602 Background: The potential role of AR tissue levels in the prediction of benefit from anti-EGFRs in mCRC pts was suggested by retrospective series. Preclinical and preliminary clinical experiences showed a modulation of plasma EGFR ligands during the treatment with cetuximab. Previous data by our group evidenced that a significant increase of plasma AR occurred one hour after the administration of cetuximab and higher increases were associated with worse clinical outcome in KRAS and BRAFwt irinotecan-refractory mCRC pts receiving cetuximab and irinotecan. Methods: We designed a prospective confirmatory study in the same setting of mCRC pts. To detect a HR for PFS of 2.3 for pts with high AR levels one hour after the administration of cetuximab (1hr-AR) compared to those with low levels, with two-sided a=0.05 and b=0.2, 45 events were required. The median value was adopted as cut-off. Plasma AR levels were assessed by means of validated ELISA kits. Results: Forty-nine KRAS and BRAFwt pts were included. A significant early increase of AR levels was observed (median increase +24.7%; median levels of baseline AR and 1hr-AR: 18.06 and 24.06 pg/mL, respectively; Wilcoxon signed rank test, p<0.0001). At a median follow-up of 20.4 mos, median PFS and OS were 4.6 and 12.1 mos, respectively. No differences in PFS or OS were observed according to 1hr-AR levels (median PFS 5.5 vs 4.6 mos, HR: 0.76 [95%CI:0.40-1.32], p=0.322; median OS: 15.6 vs 13.4 mos, HR:0.77 [95%CI:0.36-1.62], p=0.485). Conclusions: This prospective experience confirms that AR early increases one hour after the administration of cetuximab. Underlying biological mechanisms should be investigated. Nevertheless, this modulation of AR does not predict clinical outcome. Our work underlines the need to prospectively validate retrospective findings in independent series, to assess their reliability. Clinical trial information: 2008-003160-19.
Chemotherapy first, followed by chemoradiation (CRT) and then surgery, in the management of locally advanced rectal cancer (LARC).
Authors: Cercek Andrea , Goodman Karyn A. , Hajj Carla , Weisberger Emily , Segal Neil Howard , Reidy Diane Lauren , Stadler Zsofia Kinga , Wu Abraham Jing-Ching , Weiser Martin R. , Paty Philip , Guillem Jose G. , Nash Garrett Michael , Temple Larissa K. F. , Garcia-Aguilar Julio , Saltz Leonard 
Published: March 2020

3605 Background: Standard pre-op CRT and post-op chemo for LARC delays the start of optimal systemic therapy by 18-22 weeks. To more promptly address micrometastases that could lead to distant failure, and supported by evidence of excellent primary tumor response to FOLFOX, we began offering FOLFOX as initial treatment for patients (pts) with high-risk LARC. More recently, we have begun offering all planned FOLFOX prior to CRT and surgery. Methods: We obtained an IRB waiver to review records of all clinical stage II/III RC pts treated with initial FOLFOX followed by CRT and total mesorectal excision (TME) at our institution between 2007 and 2012. Of approximately 300 rectal pts treated with CMT, 61 received some or all of their planned FOLFOX as initial therapy. Results: The median age of these 61 pts was 52 years, 54% male. At diagnosis, 84% had T3N1-2 or T4N0-1 tumors and 16% had T3N0 tumors. Of these, 57 received induction FOLFOX (median 7 cycles) then received pre-op CRT, while 4 pts achieved an excellent response to chemotherapy alone, declined CRT, and went directly to TME. Twelve pts did not undergo surgery; 9 had a complete clinical response and elected to be managed non-operatively; 1 refused recommended surgery despite incomplete tumor regression, 1 had surgery deferred due to comorbidities, and 1 developed distant metastatic disease prior to planned surgery. Of the 61 patients, 19 (31%) had either a pathCR (14) or a complete clinical response (5) leading to non-operative management. Of the 49 pts who underwent TME, all had R0 resections and 23 (47%) had tumor response >90%, including 13 (27%) with pathCR. Of the 28 patients who received all 8 cycles of initial FOLFOX, 8 achieved a pathCR (29%) and 3 achieved a complete clinical responses (11%), managed non-operatively. All patients completed therapy as planned. There were no SAEs requiring delay in treatment during either FOLFOX or CMT. Conclusions: FOLFOX before CRT results in substantial tumor regression, a high rate of delivery of all planned therapy, and a substantial rate of pathCRs. Chemo and CMT before planned TME provides a favorable opportunity for consideration of non-operative management.