bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06).
Authors: Koeberle Dieter , Betticher Daniel C. , Von Moos Roger , Dietrich Daniel , Brauchli Peter , Baertschi Daniela , Matter-Walstra Klazien , Winterhalder Ralph C. , Borner Markus M. , Anchisi Sandro , Moosmann Peter , Kollar Attila , Saletti Piercarlo , Roth Arnaud , Frueh Martin , Kueng Marc , Popescu Razvan A. , Schacher Sabina , Hess Viviane , Herrmann Richard 
Published: March 2020

3503 Background: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after stop of first-line chemotherapy. Methods: In an open-label, phase 3 multicenter study conducted in Switzerland, patients with unresectable metastatic colorectal cancer having non-progressive disease after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned in a 1:1 ratio to continuing bevacizumab (7.5 mg/kg every 3 weeks) or no treatment. CT scans were done every 6 weeks between randomization and disease progression. The primary endpoint was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significant level of 10% and a statistical power of 85%. Results: The per-protocol population comprised 262 patients. Median follow-up is 28.6 months (range, 0.6-54.9 months). Median TTP was 17.9 weeks (95% CI 13.3-23.4) for bevacizumab continuation and 12.6 weeks (95% CI 12.0-16.4) for no continuation; HR 0.72 (95% CI 0.56-0.92). Median progression free-survival and overall survival, both measured from start of first-line treatment, was 9.5 months and 24.9 months for bevacizumab continuation and 8.5 months (HR 0.73 (95% CI 0.57 - 0.94)) and 22.8 months (HR 0.87 (95% CI 0.64 – 1.18)) for no continuation. Median time from randomization to second-line treatment was 5.9 months for bevacizumab and 4.8 for no continuation. Grade 3-4 adverse events in the bevacizumab continuation arm were uncommon. Conclusions: Non-inferiority could not be demonstrated. The 95% confidence intervals for the TTP HR indicate superiority of bevacizumab continuation after stop of first-line chemotherapy. The median differences in TTP and in time between randomization and start of second-line treatment were of moderate magnitude being less than 6 weeks. The results of an accompanying cost analysis will be presented at the meeting. Clinical trial information: NCT00544700.
A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study.
Authors: Primrose John Neil , Falk Stephen , Finch-Jones Meg , Valle Juan W. , Sherlock David , Hornbuckle Joanne , Gardner-Thorpe James , Smith David , Imber Charles , Hickish Tamas , Davidson Brian , Cunningham David , Poston Graeme John , Maughan Tim , Rees Myrrdyn , Stanton Louise , Little Louisa , Bowers Megan , Wood Wendy , Bridgewater John A. 
Published: March 2020

3504 Background: Resection of liver metastases from colorectal cancer with or without neoadjuvant chemotherapy is the standard of care. The EPOC study (Nordlinger et al, Lancet 2008) randomised patients between surgery and surgery with chemotherapy and demonstrated an improvement in 3 year progression free survival (PFS) of 7·3% (from 28·1% to 35·4%). As a rational extension to the EPOC study data, the New EPOC study evaluates the benefit of cetuximab, an EGF receptor antibody, in addition to standard chemotherapy in patients with operable liver metastases. Methods: 272 patients were randomised between February 2007 and November 2012 into the New EPOC study. Eligible patients were required to be k-RAS wild type, have operable liver metastases and to be sufficiently fit for chemotherapy and surgery. Patients with the primary tumour in situ, and those who required short course rectal radiation were eligible. Patients were randomised to receive a fluoropyrimidine and oxaliplatin plus or minus cetuximab for 12 weeks before, then 12 weeks following surgery. Patients who had been treated with adjuvant oxaliplatin could receive irinotecan and 5 – fluorouracil. Results: Following a recommendation from the Independent Data Monitoring Committee on 19/11/2012, the New EPOC study was stopped when the study met a protocol pre-defined futility analysis. With 45.3% (96/212) of the expected events observed, progression free survival was significantly worse in the cetuximab arm (14.8 vs 24.2 months, HR (95%CI) 1.50037 (1.000707 to 2.249517) p< 0.048). The result of a pre-planned analysis excluding the 23 patients treated with irinotecan based chemotherapy was similar (15.2 vs 24.2 months, HR 1.565546 (1.014967-2.414793) P<0.043). Conclusions: Although the data are immature, the accumulation of more events is unlikely to change this result. In patients with resectable liver metastases and K-RAS wt tumours the addition of cetuximab to chemotherapy is not beneficial. Clinical trial information: ISRCTN22944367.
Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: Results of the GERCOR DREAM phase III trial.
Authors: Tournigand Christophe , Chibaudel Benoist , Samson Benoit , Scheithauer Werner , Lledo Gérard , Viret Frederic , André Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , de Gramont Aimery ,   GERCOR
Published: March 2020

3515 Background: The primary analysis of DREAM demonstrated that a maintenance therapy (MT) with bevacizumab (Bev) + EGFR TKI erlotinib (E) significantly improved progression-free survival (PFS) after a 1st-line Bev-based induction therapy (IT) in patients (pts) with unresectable mCRC. Methods: Pts were randomized to MT after an IT with FOLFOX-bev or XELOX-bev or FOLFIRI-bev between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/d ; arm B) until PD or unacceptable toxicity. Primary endpoint was PFS on MT. Secondary endpoints included PFS from inclusion, overall survival (OS) and safety. The impact of KRAS tumor status on treatment efficacy was evaluated in an exploratory analysis. Results: 700 pts were registered and 452 pts were randomized (228 in arm A, 224 in arm B). KRAS status was available for 413/452 (91%) pts. The median duration of MT was 3.6 m. Results for MT are presented below (Table). In the registered population, median OS was 24.9m (22.5 – 27.3). Conclusions: Maintenance treatment with bev + erlotinib increases PFS over maintenance with bev alone in pts with mCRC but does not prolong OS. Further follow-up will determine the impact of 2nd or 3rd line anti-EGFR Mabs in this study. Contrasting with anti-EGFR Mabs, KRAS tumor status is not mandatory to select pts with mCRC for treatment with erlotinib. Clinical trial information: NCT00265824. [Table: see text]
Tumor-related and treatment-related colostomy-free survival (CFS) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance 5FU/CisP chemotherapy (CT) in squamous cell carcinoma of the anus (SCCA): Results of ACT II.
Authors: Glynne-Jones Robert , Kadalayil Latha , Meadows Helen , Cunningham David , Samuel Leslie M. , Geh Ian , Lowdell Charles , James Roger David , Beare Sandy , Begum Rubina , Ledermann Jonathan A. , Sebag-Montefiore David ,   on behalf of the ACT II Study Group
Published: March 2020

3532 Background: Concurrent CRT is standard treatment for patients (pts) with SCCA. We explore tumor- and treatment-related CFS in a phase III trial (ACT II), which mandated standardised radiation fields and a uniform dose (50.4Gy in 28 daily fractions of 1.8Gy). Methods: The ACT II trial (940 pts) compared both CisP (n=468) versus MMC (n=472) combined with 5-FU/CRT, and 2 cycles of maintenance CT (Maint, n=448) versus none (No-maint, n=446). We investigated the association between CFS and baseline factors (age, sex, T stage, size of tumour, nodal status) and treatment using Cox regression. CFS events included baseline colostomies not reversed at first follow up after treatment and post-treatment colostomies. Results: Median follow-up (all pts) was 5.1 years. Median age: 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%). Of 884 evaluable patients only 20/118 (17%) baseline colostomies were reversed within 8 months, and 37 later. 112 pts had a post-treatment colostomy due to persistent disease (98) or morbidity (14). The 5-year CFS rates by stage were 86% T1, 77% T2, 57% T3 and 47% T4; 72% N0, 60% N+; by treatment arm 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/No-maint respectively. The 5-year CFS rates were 72% and 60% for N0 and N+ respectively. The most significant predictors of colostomy in multivariable Cox regression analyses were T stage, sex and baseline haemoglobin (p<0.001 for all). Men were more at risk than women (adjusted HR 1.64; 95% CI: 1.26, 2.14). Age, site of primary or treatment did not impact on CFS. Although significant in univariate analysis, nodal status did not influence CFS when adjusted for other baseline factors. Conclusions: In the largest trial in anal cancer, neither the type of CRT (5FU/CisP vs. 5FU/MMC) nor maintenance chemotherapy improved CFS. 34% (61/177) of all colostomies were baseline fashioned prior to treatment and never reversed after all treatments. The major predictive factors for CFS were T stage, sex and haemoglobin levels. Clinical trial information: NCT00025090.
Cetuximab and chemotherapy in the treatment of patients with initially “nonresectable” colorectal (CRC) liver metastases: Long-term follow-up of the CELIM trial.
Authors: Folprecht Gunnar , Gruenberger Thomas , Bechstein Wolf , Raab Hans-Rudolf , Weitz Juergen , Lordick Florian , Hartmann Joerg Thomas , Lang Hauke , Trarbach Tanja , Stoehlmacher-Williams Jan , Liersch Torsten , Ockert Detlev , Jaeger Dirk , Steger Ulrich , Suedhoff Thomas , Kohne Claus-Henning 
Published: March 2020

3538 Background: CRC liver metastases can be resected after downsizing with intensive chemotherapy schedules, with a strong correlation between the response and resection rates. Cetuximab plus chemotherapy has been shown to increase the rates of tumor response and resection of liver metastases. (Van Cutsem et al, JCO 2011). Methods: Patients (pts) with technically non-resectable and/or with > 4 liver metastases were randomized to treatment with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated regarding resectability every 2 months. Resection was offered to all patients who became resectable during the study. K-ras and b-raf status were retrospectively evaluated. Data on tumor response and resection were reported earlier (Folprecht et al, Lancet Oncol 2010). Overall and progression free survival were analyzed in December 2012. Results: Between Dec 2004 and March 2008, 56 pts were randomized to arm A, 55 to arm B. For the current analysis, 109 pts were evaluable for overall survival (OS), and 106 patients for PFS. The median OS was 35.7 [95% CI: 27.2-44.2] months (arm A: 35.8 [28.1-43.6], arm B: 29.0 [16.0-41.9], HR 1.03 [0.66-1.61], p=0.9). The median PFS was 10.8 [9.3-12.2] months (Arm A: 11.2 [7.2-15.3], Arm B: 10.5 [8.9-12.2], HR 1.18 [0.79-1.74], p=0.4). Patients with R0 resection had a better OS (median: 53.9 [35.9-71.9] mo) than patients without R0 resection (27.3 [21.1-33.4] mo, p=0.002) and a better PFS (median 15.4 [11.4-19.5] and 8.9 [6.7-11.1] mo in R0 resected and not R0 resected pts, p<0.001). The 5 year survival in R0 resected patients is 46.2% [29.5-62.9%]. Conclusions: This study confirmed a favourable long term survival of patients with initially “nonresectable” CRC liver metastases treated in a multidisciplinary approach of neoadjuvant chemotherapy with cetuximab and subsequent metastasectomy in pts who became resectable. Clinical trial information: NCT00153998. [Table: see text]
A phase II study of combination epigenetic therapy in metastatic colorectal cancer (mCRC): A phase II consortium (P2C)/Stand Up 2 Cancer (SU2C) study.
Authors: Azad Nilofer Saba , El-Khoueiry Anthony B. , Mahoney Michelle R. , Adkins Douglas , Flynn Patrick J. , Bahary Nathan , Kim George P. , Pitot Henry Clement , Erlichman Charles , Donehower Ross C. , Herman James Gordon , Baylin Stephen , Ahuja Nita ,   P2C
Published: March 2020

3539 Background: Therapy with decitabine and entinostat (ENT: HDAC inhibitor) shows synergistic effect in re-expression of tumor-suppressor genes and growth inhibition in CRC cell lines and in vivo studies. Methods: We conducted a phase II, multi-institutional study of SQ 5-azacitidine (AZA) and oral ENT in mCRC pts. A 28 day cycle included: AZA at 40 mg/m2 d1-5 and 8-10 with ENT 7 mg d3 and 10. Initial eligibility criteria included: ECOG PS 0-1, good end organ function, and biopsiable disease for cohort A (CoA). An interim analysis indicated that toxicity which crossed pre-specified safety boundary was secondary to disease. A 2nd cohort B (CoB) with eligibility restrictions: <2 prior regimens in KRAS-mutated CRC pts, <3 prior regimens if KRAS wild-type, and liver disease limited to <30% of volume was accrued. Serial tumor biopsies and research blood were collected to assess for methylation/expression changes in circulating tumor DNA and biopsies, respectively. The primary endpoint was response as measured by RECIST criteria using a 2-stage Simon design. Results: 47 pts were initially enrolled (24 CoA, 23 CoB). Pts received a median of 2 cycles on both cohorts (1-16 CoA, 2-6 CoB). Pts had a median of 4 prior therapies for CoA (range 2-9) and 3 for CoB (range 2-6). Gr 4 AEs attributable to treatment for CoA included hyperglycemia (1) and hypokalemia (1); other common Gr 3 AEs included anemia (3), decreased lymphocytes (7), fatigue (3), and nausea (3). CoB pts experienced grade 3 chest pain (1), neutropenia (2), leucopenia (2), urinary tract obstruction (1), and hypophosphatemia (1). No responses have been observed. Results of translational objectives will be presented at the meeting. Conclusions: SQ AZA and ENT therapy does not have clinical activity as defined by confirmed response in aCRC. Follow-up for survival, response to subsequent therapy, and correlative analysis are ongoing. Supported in part by N01-CM-2011-00099. Clinical trial information: NCT01105377. [Table: see text]
Use of RAS pathway activation or KRAS mutation status to predict cetuximab response in CRC patient-derived xenografts.
Authors: Li Henry , Chen Dawei , Guo Sheng , Cai Jie , Chen Yiyou , Wery Jean-Pierre 
Published: March 2020

3544 Background: Cetuximab was approved for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) without patient stratification. Subsequent retrospective clinical studies resulted in an exclusion criterion for patients with KRAS mutations at codons 12 and 13. However, only a fraction of patients with wtKRAS benefit from the treatment. Recent analyses indicated that patients with KRAS mutation at codon 13 can also benefit. We set out to investigate whether KRAS mutations, or any other factors, are good biomarkers for CRC-cetuximab therapy patient stratification. Methods: We have established patient derived xenografts (PDX) from treatment-naive Asian CRC patients to discover biomarker predictive of cetuximab response. We conducted a clinical trial style study (“patient avatar trial”) of cetuximab using a randomly selected cohort of 26 EGFR+ PDXs. The antitumor activities were analyzed against KRAS mutation status and a published expression-signature. Results: We identified 12/26 (~46%) as cetuximab responders and 14/26 non-responders (defined by 50% tumor growth inhibition threshold). All 14 non-responders are mutated for one or more of KRAS, BRAF (V600E), EGFR, AKT and PIK3CA oncogenes. In contrast, 5/11 responders analyzed are wild-type for all these genes. Importantly, 5/11 responders have activating KRAS mutations at codons 12/13, contradictory to the currently practiced clinical exclusion criteria, but consistent with more recent clinical findings. Most interestingly, the observed cetuximab activity in this cohort of 26 PDXs has a surprisingly strong correlation to a published RAS pathway score. Conclusions: Our results indicated strong predictive power of cetuximab-CRC-PDX trial and RAS signature, and warrant prospective clinical studies for further confirmation.
Stereotactic body radiotherapy response and local control rates for hepatic oligometastases.
Authors: Goodman Ben , Johnson Cynthia S , Gebregziabher Netsanet , Maluccio Mary A. , Helft Paul R. , Chiorean E. Gabriela , Cardenes Higinia Rosa 
Published: March 2020

3546 Background: Stereotactic body radiation therapy (SBRT) is a non-invasive, effective technique in the treatment of hepatic oligometastases from solid tumors. We present response and local control rates from our single institution experience. Methods: We treated 79 metastatic liver lesions from 64 different patients using stereotactic body radiation therapy. One colorectal cancer patient was treated three times and four patients were treated twice. Among the 79 metastatic liver lesions treated, 85% had prior chemotherapy. The primary cancer site included: Colorectal 66%, Non-colorectal GI 14%, Breast 6%, Ovarian 5%, NSCLC 3%, and other 6%. The mean GTV size was 37.3 (cc). The mean GTV diameter was 3.1 (cm). The median total dose was 54 (Gy) with the minimum and maximum total dose being 30 and 60 (Gy). Results: The overall local control rate was 94.2%, with estimates at 12, 24, 36, and 48 months being 96.1%, 87.9%, 87.9% and 87.9% following SBRT treatment. When comparing colorectal cancer patients vs all other primary cancer sites, the one year local control rate was 93.4% and 100%. The two and three year local control rates for colorectal cancer vs other primary cancer sites were 84.9% vs 90.9%. Best response was examined as a 4 level response (CR,PR,SD,PD) per the RECIST criteria. Overall, 67% of patients had a response, and less than 3% of patients had progression with SBRT treatment. For colorectal cancer patients, 79% had a response to treatment. Only 21% of colorectal cancer patients did not respond, however, the majority of these patients still had stable disease following treatment. Non-colorectal primary site cancers had a response in 50% of the lesions following SBRT treatment. The remaining 50% of non-colorectal primary cancers were stable following SBRT treatment and none progressed. The median dose for CR, PR, or SD was 54 Gy. The median dose for patients with progressive disease was less than 50 Gy. The observed CTC toxicities were limited with mostly grade 1-2 toxicity and only two grade 4 and one grade 5 toxicity. Conclusions: Stereotactic body radiation therapy is an effective treatment option for patients with hepatic oligometastases with a limited toxicity profile.
Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and ziv-aflibercept or placebo in mCRC patients who progressed on prior oxaliplatin treatment.
Authors: Ruff Paul , Lakomy Radek , Prausová Jana , Van Hazel Guy A. , Moiseyenko Vladimir , McKendrick Joseph , Boelle Emmanuelle , Castan Remi , Macarulla Teresa , Van Cutsem Eric 
Published: March 2020

3574 Background: VELOUR, a large, international, randomized, placebo (pbo)-controlled study, compared efficacy and safety of FOLFIRI with ziv-aflibercept (known as aflibercept outside the United States) or with pbo in 1,226 metastatic colorectal cancer patients who received prior oxaliplatin treatment. Ziv-aflibercept demonstrated statistically significant, clinically meaningful improvements in median overall survival (OS) (13.5 vs 12.06 mos; hazard ratio [HR]=0.817, P=0.0032), progression-free survival, and response rate. This analysis estimates treatment effect and safety over time course of the study. Methods: HRs by 6-mo time periods were estimated using piecewise Cox proportional hazard model. NCI-CTCAE v3.0 was used to grade adverse event (AE) severity. Results: HR improved over time (Table), consistent with survival curves that continue to separate past the median time point, indicating that the magnitude of ziv-aflibercept treatment effect continues to increase over time. Incidence of grade 3 AEs (45.1% vs 62.0%) was higher in the ziv-aflibercept/FOLFIRI arm; incidences of grade 4 AEs were 17.4% (pbo) vs 21.4% (ziv-aflibercept). More common AEs only occurred in a small proportion of ziv-aflibercept/FOLFIRI cycles (eg, grade ≥3 hypertension and diarrhea occurred in 3.6% and 2.8% of cycles, respectively). The majority of grade 3/4 AEs occurred in early treatment (first 3-4 cycles). Most patients experienced only a single episode of grade ≥3 AEs with ziv-aflibercept/FOLFIRI. Importantly, AEs in VELOUR did not impact patients’ ability to receive chemotherapy. Conclusions: Treatment with ziv-aflibercept/FOLFIRI showed continuous, consistent improvement in OS over time. While combined grade 3/4 AEs were higher with ziv-aflibercept, AEs occurred early in treatment in a small proportion of total cycles; the majority were single-episode in nature. Clinical trial information: NCT00561470. [Table: see text]
Detection of the BRAFV600E protein in human colon carcinomas by a mutation-specific antibody.
Authors: Smyrk Thomas C. , Tougeron David , Thibodeau Stephen N. , Singh Shalini , Muranyi Andrea , Shanmugam Kandavel , Grogan Thomas M. , Alberts Steven R. , Shi Qian , Sinicrope Frank A. ,   North Central Cancer Treatment Group
Published: March 2020

3576 Background: BRAF encodes a serine-threonine kinase that is a downstream effector of activated RAS. A point mutation (V600E) in BRAF occurs in a subset of colorectal cancers (CRCs) and is associated with adverse outcome and may predict non response to anti-EGFR antibodies. Detection of a BRAFV600E mutation in a CRC with microsatellite instability indicates a sporadic origin and excludes Lynch Syndrome. While BRAFV600E mutation status is determined using a DNA-based assay, antibodies against the BRAFV600E protein have recently been developed. We examined mutant BRAFV600E protein expression and its concordance with mutation status. Methods: Primary stage III colon carcinomas (50 BRAFV600E mutation carriers and 25 wild-type cases) were studied from a completed phase III adjuvant trial comparing FOLFOX +/- cetuximab (NCCTG N0147). In archival resection specimens, immunohistochemistry (IHC) was performed using a pan-BRAF antibody and a V600E mutation-specific antibody raised against an immunogenic synthetic peptide derived from the internal region of the BRAFV600E protein. BRAFV600E mutations in codon 15 were analyzed in extracted DNA using a multiplex, allele specific PCR–based assay. BRAF staining was scored independently by two pathologists blinded to mutation status. Results: In primary colon carcinomas stained with a pan-BRAF antibody, diffuse cytoplasmic staining for BRAF proteins was detected in 74 of 75 carcinomas with one case deemed non-evaluable. Using the mutation-specific BRAFV600E antibody, diffuse cytoplasmic staining was detected in 49 of 74 tumors without appreciable heterogeneity of expression. Among these 49 tumors expressing mutant BRAFV600E proteins, all (100%) were found to carry a BRAFV600E mutation according to a DNA-based assay. In contrast, absent BRAFV600E staining was observed in all 25 tumors that were found to have wild-type copies of BRAFV600E detected using a PCR-based assay. Conclusions: For the detection of mutant BRAFV600E, complete concordance was found between IHC and a DNA-based method in colon carcinomas. This finding supports the use of IHC as a simplified strategy to screen CRCs for mutant BRAFV600E proteins in routine clinical practice to inform clinical decision-making.