bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive pharmacogenetic profiling of advanced colorectal cancer.
Authors: Madi Ayman , Fisher David , Maughan Tim , Colley James , Meade Angela M. , Maynard Julie , Humpreys Vikki , Wasan Harpreet , Adams Richard A. , Idziaszczyk Shelley , Harris Rebecca , Nichols Laura L. , Kaplan Richard S. , Cheadle Jeremy
Published: March 2020

3509

Background: Inherited genetic factors may influence a patient’s response to, and side effects from, chemotherapy and biological therapies. Here, we sought to generate a comprehensive inherited pharmacogenetic profile for advanced colorectal cancer (aCRC). Methods: We analysed 260 potentially functional coding region and promoter variants in genes within the 5-FU, capecitabine, oxaliplatin, EGFR and DNA repair pathways in 2183 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy ± cetuximab (from the MRC COIN and COIN-B trials). Primary outcomes assessed were 12-week response, skin rash (SR) (for those receiving cetuximab), dose-reduction or delay in treatment due to any toxicity and peripheral neuropathy (PN). Results: For variants with minor allele frequencies >20%, we had >85% power to detect an effect on response / toxicity with an OR of 1.3. In patients treated with chemotherapy + cetuximab, 5 and 4 coding region variants in the EGFR pathway were associated with response and SR, respectively. The most significant associations were with variants in members of phosphatidylinositol 3-kinase regulatory subunit. In patients treated with chemotherapy ± cetuximab, 8 coding region variants in the 5-FU, capecitabine, oxaliplatin or DNA repair pathways were associated with response, 8 with any toxicity and 5 with PN. The most significant associations for response were with variants in DNA repair genes and, for any toxicity, with common variants in DPYD. Conclusions: Our study highlights the difficulty in identifying inherited biomarkers for the treatment of aCRC - despite using samples from the largest reported randomised trial for aCRC, with considerable power to detect alleles of small effects, none of the associations remained significant after rigorous correction for multiple testing.
A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study.
Authors: Takahari Daisuke , Yamada Yasuhide , Matsumoto Hiroshi , Baba Hideo , Yoshida Kazuhiro , Nakamura Masato , Yoshida Motoki , Iwamoto Shigeyoshi , Takinishi Yasutaka , Sakata Yuh , Morita Satoshi , Shimada Yasuhiro , Komatsu Yoshito , Sasaki Yasutsuna , Satoh Taroh , Takahashi Keiichi , Mishima Hideyuki , Muro Kei , Watanabe Masahiko , Sugihara Kenichi ,   SOFT Study Group
Published: March 2020

3519

Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX+Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6+Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6+Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX+Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40−60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate non-inferiority of SOX+Bev with a 2.5-month margin (hazard ratio, HR = 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming >388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle = 2 weeks) of mFOLFOX6+Bev and 8 cycles (1 cycle = 3 weeks) of SOX+Bev (range: 1−16). Median PFS was 11.5 months (95% CI: 10.7−13.2) with mFOLFOX6+Bev and 11.7 months (95% CI: 10.7−12.9) with SOX+Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860−1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6+Bev and 61.5% with SOX+Bev. Grade 3/4 toxicities (%) with mFOLFOX6+Bev/SOX+Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX+Bev is non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6+Bev. Clinical trial information: JapicCTI-090699.
Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II and III included in the MOSIAC study.
Authors: Flejou Jean-François , André Thierry , Chibaudel Benoist , Scriva Aurelie , Hickish Tamas , Tabernero Josep , Van Laethem Jean-Luc , Banzi Maria , Maartense Eduard , Shani Adi , Carlsson Göran , Scheithauer Werner , Papamichael Demetris , Moehler Markus , Landolfi Stefania , Demetter Pieter , Duval Alex , Lee Mark , Colote Soudhir , De Gramont Aimery
Published: March 2020

3524

Background: The MOSAIC study (André T, N Engl J Med, 2004) demonstrated that adding oxaliplatin to adjuvant 5FU and LV improved three-year disease-free survival (DFS) in stage II and III resected CC. Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study (Zaanan A, Ann Oncol 2010). Methods: Of the 2,246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1,019 pts were obtained. Thirty-three samples with insufficient tumor tissue were excluded from this translational study. MMR status was determined by immunohistochemistry (IHC) analysis of the protein products of MLH1, MSH2, PMS2, and MSH6 genes. Results: A total of 986 pts (44%) were evaluable for MMR status and MMR status was not evaluable for 1,260 pts (56%). Relapse-free survival (RFS), DFS and overall survival (OS) were similar in both, MMR and MMR not evaluable population. Ninety (9.1%) and 896 (90.9%) pts had dMMR and proficient MMR (pMMR) CC, respectively. Of the patients with 90 dMMR CC, 45 pts had stage II and 45 stage III. Hazard Ratios (HRs) for stage II and III dMMR are 0.52 (0.21–1.28) for RFS, 0.52 (0.24–1.14) for DFS, and 0.45 (0.19–1.05) for OS, respectively. HR for stage III dMMR are 0.56 (0.19–1.61) for RFS, 0.51 (0.18–1.41) for DFS, and 0.44 (0.15–1.34) for OS, respectively. HR for stage II dMMR are 0.64 (0.11–3.70) for RFS, 0.60 (0.17–2.09) for DFS, and 0.52 (0.13–2.10) for OS, respectively. Conclusions: Analyses ofcolon cancerMMR status in pts included in the MOSAIC study support the use of FOLFOX4 in pts with dMMR stage III cancer. Clinical trial information: NCT00275210. [Table: see text]
Gene expression profiles and tumor locations in colorectal cancer (left vs. right vs. rectum).
Authors: Maus Martin K. H. , Hanna Diana L. , Stephens Craig , Grimminger Peter Philipp , Epstein Melinda , Astrow Stephanie H. , Yang Dongyun , Loupakis Fotios , Hsiang Jack , Zeger Gary , Wakatsuki Takeru , Barzi Afsaneh , Lenz Heinz-Josef
Published: March 2020

3527

Background: Recent data suggests that CRC from different locations show distinct genetic profiles. Right-sided tumors have a worse prognosis and may have less benefit from targeted therapies. We investigated the tumor locations and genetic profiles (KRAS and BRAF mutation status and ERCC1, TS, EGFR and VEGFR2 mRNA expression) in 580 CRC tumors. Methods: FFPE tumor specimen from 580 patients with advanced CRC adenocarcinoma were microdissected and DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the mRNA expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. These values were analyzed according to tumor location (left vs. right vs. rectum). Results: BRAF mutations were significantly more common in the right colon (15%), followed by rectum (3.8%) and left colon (2.5%). KRAS mutations occurred at similar frequencies throughout the colon. Gene expression of ERCC1 was significantly higher in right-sided than left-sided colon tumors in KRAS wild-type colon cancers. The highest expression levels for all genes were seen in rectum. These differences reached significant levels for ERCC1 (rectum vs. right and rectum vs. left, p<0.001), TS (rectum vs. left, p<0.036) and VEGFR2 (rectum vs. right and rectum vs. left, p<0.001). Conclusions: Tumor location in CRC is associated with specific mutation and expression profiles. Differences in chemosensitivity may be explained by mutation status and mRNA levels in right vs. left CRC. Rectum cancers showed a distinct genetic profile when compared to colon which indicates different tumor biology and may be related to differences in the microflora.
Location of colon cancer (right-sided [RC] versus left-sided [LC]) as a predictor of benefit from cetuximab (CET): NCIC CTG CO.17.
Authors: Brule Stephanie Yasmin , Jonker Derek J. , Karapetis Christos Stelios , O'Callaghan Christopher J. , Moore Malcolm J. , Wong Ralph , Tebbutt Niall C. , Underhill Craig , Yip Desmond , Zalcberg John Raymond , Tu Dongsheng , Goodwin Rachel Anne
Published: March 2020

3528

Background: RC and LC differ with respect to biology, pathology, and epidemiology. Further, recent SEER data suggests a mortality difference between RC and LC that varies by stage: stage II and III RC having lower and higher mortality, respectively. We examined if the primary tumour site can also predict for outcome in pre-treated, chemotherapy refractory, metastatic colon cancer (MCC). We compared RC vs. LC as a predictor for efficacy of EGFR inhibition with CET. Methods: Using CO.17 (CET vs. BSC), we coded the primary tumour site for 399 pts as RC (cecum to transverse colon) or LC (splenic flexure to rectosigmoid). Fisher’s exact test assessed the association between site of cancer and baseline characteristics. Univariate and multivariate analyses of overall survival (OS) and progression free survival (PFS) by site of cancer were performed using Cox regression models. Results: Pts with RC (150/399) had more poorly differentiated tumours, mutant KRAS status, and peritoneal rather than liver and lung metastases, and they more often entered the study less than two years after initial diagnosis. Among pts receiving BSC, tumour location (RC vs. LC) was not prognostic for PFS (HR 1.07 [0.79, 1.44], p=0.67) or OS (HR 0.96 [0.70, 1.31], p=0.78). Among pts with KRAS wild type tumour status, site of cancer was a predictor of benefit from CET, with much greater PFS observed for LC (interaction p=0.002). Conclusions: In refractory MCC, tumour location within the colon (RC vs. LC) is not a prognostic factor, but is a strong predictor of PFS benefit from CET therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition. [Table: see text]
Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial.
Authors: Schmoll Hans-Joachim , Haustermans Karin , Price Timothy Jay , Nordlinger Bernard , Hofheinz Ralf , Daisne Jean-Francois , Janssens Jozef , Brenner Baruch , Schmidt Peter , Reinel Hans , Hollerbach Stephan , Caca Karel , Fauth Florian W.B. , Hannig Carla , Zalcberg John Raymond , Tebbutt Niall C. , Mauer Murielle E. , Messina Carlo G. M. , Lutz Manfred P. , Van Cutsem Eric ,   for the EORTC GITCG, AIO, AGITG, EORTC ROG, BGDO, FFCD
Published: March 2020

3531

Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves disease-free survival (DFS) in locally advanced rectal cancer. We present results of the early secondary endpoints. Methods: Between 11/2008 and 09/2011, patients with rectal cancer within 12 cm from the anal verge, T3/4 and/or node-positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable after preoperative CRT, were randomly assigned to receive 5 weeks of preoperative CRT (45 Gy in 25 fractions) with capecitabine (825 mg/m² twice daily), followed by 6 cycles of adjuvant CT with capecitabine (1000 mg/m2twice daily/days 1-15 every three weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m²/days 1, 8, 15, 22, 29) and after surgery (130 mg/m²/day 1, every three weeks) (arm 2). Additional RT before surgery (5.4 Gy/days 36-38) using the same fields or as a boost with capecitabine was an option. Primary endpoint is DFS. Results: 1094 patients were randomized (547 in each arm). 98% and 92% of patients, respectively, received at least 45 Gy of preoperative RT in arm 1 and arm 2. More than 90% of full dose concurrent CT was delivered in 91% and 63% of patients, respectively, in arm 1 and arm 2. Preoperative grade 3/4 toxicity occurred in 15.1% of patients in arm 1 vs. 36.7% in arm 2; 1 vs. 3 patients died before surgery. R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The pCR rate (ypT0N0) was equal in both arms with 11.3% in arm 1 and 13.3% in arm 2 (p=0.31). The anal sphincter was preserved in 70% vs. 65% (p=0.09) in arm 1 and 2. Postoperative complications were not different between arms (38% vs. 41%; 5 vs. 4 patients died following surgery). Definitive numbers will be presented at the congress. Conclusions: The addition of oxaliplatin to preoperative fluoropyrimidine-based CRT led to decreased treatment compliance and increased toxicity, but did not improve surgical outcome. Clinical trial information: NCT00766155.
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.
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]