bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.
Authors: Tougeron David , Lecomte Thierry , Pages jean-Christophe , Collin Christine , Villalva Claire , Ferru Aurelie , Tourani Jean Marc , Silvain Christine , Levillain Pierre , Karayan-Tapon Lucie
Published: March 2020

3520

Background: Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are standard components of treatment algorithms in metastatic colorectal cancer (mCRC). It is already well established that only patients with wild-type KRAS tumors benefit from treatment with an anti-EGFR agent. Pyrosequencing is now used for a precise determination of KRAS mutation burden and a conservative cutoff of 10% was defined as the lower limit of quantification for the assignment of mutation status. Up to now, the impact of low-signal KRAS mutations below 10% on the response to anti-EGFR therapy in mCRC has not been evaluated. Methods: All consecutive patients treated by anti-EGFR for a mCRC between January 2006 and June 2011 have been retrospectively analyzed by pyrosequencing using the therascreen KRAS Pyro Kit (Qiagen). All patients were defined wild-type (WT) for KRAS status using direct sequencing. The PFS data were plotted as Kaplan–Meier curve and compared by the log-rank test. Results: A total of 141 patients treated by anti-EGFR for a mCRC were included in the study. Mean age was 64.1 ± 14.8 years and a majority of patients had synchronous metastases (68.6%). Patients benefited from anti-EGFR in first-line chemotherapy (30.7%), second-line (22.9%), third-line (35%) or later (11.4%). Majority of patients benefited from anti-EGFR combined with cytotoxic chemotherapy (91.4%), mostly irinotecan (78.6%). Using pyrosequencing, 117 tumors had a KRAS WT status and 24 tumors had low-signal mutation, between 2 and 10% (KRAS lowMT). Response rate according RECIST criteria were 13.6% versus 35.4% partial response, 13.6% versus 37.2% stabilization and 72.7% versus 27.1% progression (p<0.01), for KRAS lowMT versus KRAS WT respectively. The PFS was respectively 2.6 ± 0.2 months for KRAS lowMT versus 6.0 ± 0.5 months for KRAS WT (p=0.024). Overall survival was not different between the two groups (27.4 months versus 33.0 months, p=0.4). Conclusions: Patients with tumors harboring KRAS lowMT benefit less of anti-EGFR therapy than patients with tumor harboring KRAS WT. While these results invite to consider low-signal tumors as positives, generalization awaits a large prospective trial.
Randomized phase III study of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients (pts) with stage III colon cancer (CC): Final results of Japan Clinical Oncology Group study (JCOG0205).
Authors: Shimada Yasuhiro , Hamaguchi Tetsuya , Moriya Yoshihiro , Saito Norio , Kanemitsu Yukihide , Takiguchi Nobuhiro , Ohue Masayuki , Kato Takeshi , Takii Yasumasa , Sato Toshihiko , Tomita Naohiro , Yamaguchi Shigeki , Akaike Makoto , Mishima Hideyuki , Kubo Yoshiro , Mizusawa Junki , Nakamura Kenichi , Fukuda Haruhiko
Published: March 2020

3524

Background: NSABP C-06 reported the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) in disease-free survival (DFS) in stage II/III CC. Although adjuvant FOLFOX for stage III is standard care in US or EU, its toxicity and cost is major problem. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofoloinate (l-LV) in stage III CC. Methods: Pts were randomized to 3 courses of 5-FU/l-LV (5-FU 500 mg/m2, l-LV 250 mg/m2, on days 1, 8, 15, 22, 29, 36, q8w), or 5 courses of UFT/LV (UFT 300 mg/m2/day, LV 75 mg/day, on days 1–28, q5w). Primary endpoint was DFS. Sample size was 1,100, determined with one-sided alpha of 0.05, power of 0.78, and non-inferiority margin of hazard ratio (HR) of 1.27. Owing to interim analyses, the multiplicity-adjusted alpha and confidence coefficient of CI in the final analysis were 0.0433 and 91.3%. Results: Between Feb 2003 and Nov 2006, 1,101 pts (1,092 eligible) were randomized to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median follow-up was 72.0 months, median age: 61, colon/rectum: 67%/33%, number of positive nodes <3/4<: 73%/27%, stage IIIa/IIIb: 75%/25%. The HR of DFS was 1.02 (91.3% CI, 0.84–1.23) and non-inferiority of UFT/LV was demonstrated (P=0.0236). Incidences of G3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% ALT elevation in UFT/LV. In the 2 arms (5-FU/l-LV, UFT/LV), diarrhea (9.6%, 8.5%) and anorexia (4.0%, 3.7%) were similar. G3/4 diarrhea was one-third less and G3/4 ALT elevation was three times more common than those in C-06. No treatment-related death was reported. Conclusions: Adjuvant UFT/LV is demonstrated to be non-inferior to standard 5-FU/l-LV in DFS. Five-year OS (87.5%) is favorable to 69.6% in C-06, possibly due to D3 dissection and stage migration. UFT/LV should be an oral treatment option for stage III CC. [Table: see text]
Do we need adjuvant therapy in rectal cancer with complete pathologic response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal excision?
Authors: Pereira Verónica , Sosa Aarón , Reig Óscar , Victoria Iván , Féliz Luis Roberto , Ayuso Juan Ramón , Bombí Josep Antoni , Castells Antoni , Conill Carles , Cuatrecasas Miriam , Delgado Salvadora , Fernández-Esparrach Gloria , Ginés Àngels , Lacy Antonio , Miquel Rosa , Pagés Mario , Pineda Estela , Garcia-Albeniz Xabier , Gallego Rosa , Maurel Juan
Published: March 2020

3536

Background: Neoadjuvant chemo-radiotherapy (CRT) is the standard of care for patients (pts) with u>T3 by endoscopic ultrasound (EUS) rectal cancer. Although pts with complete pathological response (ypT0N0) fare well in multiple series, there is uncertainty of whether it’s due to the induction (CRT), due to the adjuvant chemotherapy (ACT) or due to the combination of both therapies. We have evaluated long-term outcomes in CRT-treated pts. Those with ypT0N0, were not treated with ACT. Methods: Pts with u>T3 rectal cancer, received neoadjuvant chemotherapy (225mg/m2/day 5-fluorouracil (FU)) in continuous infusion (CI) per 5 weeks (wks) and concomitant radiotherapy (45 Gy). Laparoscopic surgery (LAP) was planned after an interval of 5-8 wks. Pts achieving ypT0N0 were no treated with ACT. Pts with ypT>1 or N1 were treated with 3 gr/m2 FU in 48 hour CI and LV 200 mg/m2 every 2 wks x 6 cycles. Results: From November 2000 to November 2008, a cohort of 173 pts were treated with induction CRT and 167 pts underwent total mesorectal excision (LAP, n=158, open surgery n=9). Complete pathological response was achieved in 26/167 pts (15.5%). After a median follow-up of 58.3 months, pts with ypT0N0 have a 5-year disease-free survival and overall survival rate of 96% (95% CI 76 to 99%) and 100% (95% CI not estimable) respectively. Conclusions: Using these results, a clinical trial comparing observation versus adjuvant therapy in ypT0N0 after standard CRT, would need to enroll 3088 pts to show a HR of 0.75 in favor of ACT after 5 years of follow-up (alpha=.05, beta=.2). In case that the true DFS lied in the lower bound of the 95% CI, 636 patients would be needed under the same assumptions. These results do not support the administration of ACT to ypT0N0 patients.
KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI and bevacizumab.
Authors: Schirripa Marta , Loupakis Fotios , Cremolini Chiara , Yang Dongyun , Labonte Melissa Janae , Zhang Wu , Salvatore Lisa , Wakatsuki Takeru , El-Khoueiry Rita , Antoniotti Carlotta , Aprile Giuseppe , Maus Martin Karl Herbert , Lucchesi Sara , Allegrini Giacomo , De Vita Fernando , Zhang Hua , Giamas Georgios , Stebbing Justin , Falcone Alfredo , Lenz Heinz-Josef
Published: March 2020

3546

Background: Kinase suppressor of Ras (KSR) 1 is a scaffolding protein regulating the Raf/Mek/ERK cascade. Preclinical data showed that KSR1 could increase estrogen receptor transcriptional activity after exposure to estrogens. Recent retrospective analyses suggested a possible role for KSR1 rs2241906 C/T polymorphism in predicting the outcome of patients with mCRC. Methods: MCRC patients receiving first-line FOLFIRI+bevacizumab prospectively enrolled in a translational research program were selected on the basis of KRAS and BRAF mutational status availability. KSR1 rs2241906 polymorphism was analyzed on DNA extracted from peripheral blood by means of PCR and direct sequencing. Taking into account the connection between estrogen pathway and KSR1, subgroup analyses according to gender were pre-planned. Results: 287 patients were included. Main patients’ characteristics were the following: M/F=175/112; median age=62 (range 26-79); ECOG-PS 0/1-2=240/47; synchronous/metachronous disease=213/74; Köhne score (low/intermediate/high/data missing)=122/129/22/14; KRAS-BRAF mutational status (wt-wt/mut-wt/wt-mut)= 123/146/18. In the overall KRAS-BRAF wt population, KSR1 polymorphism did not affect the outcome. The analysis performed according to gender showed that in the KRAS-BRAF wt population females with KSR1 rs2241906 T/- achieved a significantly better PFS (median 15.9 mos) in comparison to C/C variant carriers (median 8.8 mos) (HR=0.44 [95%CI 0.21-0.91], p=0.010); meanwhile males with T/- showed a worse PFS in comparison to those carrying the C/C variant (HR=1.92 [95%CI 1.05-3.53], p=0.021). These results were significant also in a multivariate model and a significant interaction of gender with PFS according to KSR1 allelic variants was demonstrated (p=0.004). Conclusions: This prospectively conceived pharmacogenetic study confims the role of KSR1 polymorphisms in affecting the outcome of mCRC KRAS-BRAF wt patients. In particular, these results indirectly indicate that estrogenic stimulation could affect the proliferation of KRAS-BRAF wt CRC cells through an interaction with KSR1. Preclinical investigations to further explore this preliminary hypothesis are ongoing.
An 18-gene blood-based IVD test for colorectal cancer early detection with high sensitivity and specificity.
Authors: Xu Ye , Xu Qinghua , Ye Xun , Wu Fei , Liu Fang , Yang Li , Cai Guoxiang , Tan Cong , Meng Xia , Cai SanJun , Du Xiang
Published: March 2020

3551

Background: Colorectal cancer (CRC) is often curable particularly diagnosed at early stages. Different screening strategies are in place in various counties. However, the compliance rate with current CRC screening recommendations remains poor. A simple blood-based IVD test would represent an interesting alternative. We previously reported a 100-gene signature for early detection of CRC using microarray technology. Based on this result, we have developed a new blood test with real-time PCR technology. Methods: 144 CRC cases and 153 Controls were enrolled. A total of 52 genes were selected as candidate markers to be transferred from microarray to real-time PCR. The gene expression profiles from 100 CRC cases and 100 Controls were used as a training set for signature discovery. Signature identification process was conducted by Minimum Redundancy Maximum Relevance (mRMR) feature selection method and Support Vector Machine (SVM) classification algorithm under the Leave-One-Out Cross Validation (LOOCV) framework. The optimal size of signature was determined by a stepwise inclusion selection procedure which started with one gene and repeatedly added genes one by one until all genes were included. The performance of each N-gene signature by the LOOCV was estimated and used to determine the best size of signature. Results: The gene expression profiles measured by microarray and real-time PCR technology were highly comparable and resulted in a significant correlation in term of fold change ratio between CRC cases and Controls (Pearson’s Correlation Coefficient = 0.95). An 18-gene signature was identified and validated in an independent validation set with 44 CRC cases and 53 Controls. The performance of 18-gene signature in the validation set reached 88.7% accuracy (95%CI: 0.80-0.94), 88.6% sensitivity (95%CI: 0.75-0.96), and 88.7% specificity (95%CI: 0.76-0.95). Conclusions: Our new results demonstrated the feasibility of technology transfer from microarray to real-time PCR. The blood test could be offered to individuals who are unwilling or unable to undergo colonoscopy to increase the CRC screening compliance rate. Meanwhile, its high specificity could also help to avoid unnecessary colonoscopies.
Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy.
Authors: Alonso-Espinaco Virginia , Marmol Maribel , Alonso Vicente , Escudero Pilar , Horndler Carlos , Ortego Javier , Gallego Rosa , Garcia-Albeniz Xabier , Jares Pedro , Cuatrecasas Miriam , Lozano Juan Jose , Castells Antoni , Maurel Joan
Published: March 2020

3553

Background: Metastatic colorectal cancer (mCRC) patients (pts), with BRAF tumor mutation (V600E) present poor overall survival (OS). RAC1b, a RAC1 spliced variant, is overexpressed in CRC, and impairs apoptosis by activation of nuclear-factor-KB. Because RAC1b and BRAF (V600E) are significantly associated in CRC (Matos et al, 2008), we evaluated if RAC1b/RAC1 mRNA expression ratio (RNA ER) was an independent prognostic factor in mCRC. Methods: We analyzed tumor samples from 186 mCRC pts, treated in first-line therapy with FOLFOX or CAPOX in three Spanish hospitals. We examined BRAF (V600E) mutational status by allelic discrimination, RAC1b/RAC1 expression ratio by mRNA RT-PCR (quantitative real time polymerase chain reaction) and mismatch repair (MMR) deficiency by microsatellite instability (MSI) analysis. We assessed whether these biomarkers were independently predictive of response rate (RR), progression free survival (PFS) or OS. Results: 88% of samples were informative for BRAF, 75% for MMR status and 85% for RAC1b/RAC1 (RNA ER). BRAF (V600E) was found in 7%, MSI-H in 5% and high >0.9-fold RAC1b/RAC1 (RNA ER) in 20% of pts. Five of 11 pts (46%) with BRAF mutation had high RAC1b/RAC1 (RNA ER) compared with 25/144 (18%) without BRAF mutation (p=0.036). All pts with BRAF mutation were MMR and none of the MSI-H pts, showed high RAC1b/RAC1 (RNA ER). Patients with low RAC1b/RAC1 (RNA ER) and BRAF WT had higher response rate (68% vs 43%; p=0.035). Response rate were not different according BRAF mutation (64% WT vs 63% mutant) (p=NS). The multivariate regression analysis identified ECOG PS (HR: 4.2 (CI 1.4-12.7) as a significant variable for PFS and LDH levels (HR: 2.26 (CI 1.3-3.8), PS (HR: 3.85 (CI 1.5-9.8) and high RAC1b/RAC1 (RNA ER) (HR: 2.6 (CI 1.1-5.9) for OS in WT BRAF pts. Conclusions: High RAC1b/RAC1 (RNA ER) constitutes a marker of poor OS and a potential marker of acquired chemo-resistance in WT BRAF mCRC pts treated with first-line oxaliplatin-based therapy.
Post-progression survival (PPS) according to treatment line, type, and time in phase III trials in advanced colorectal cancer (ACC).
Authors: Buyse Marc E. , Saad Everardo D. , Matheson Alastair
Published: March 2020

3557

Background: Since post-progression therapy influences overall survival (OS), PPS is of interest as a determinant of OS. We quantified the relationship between several median times to event in ACC: progression-free survival (PFS), PPS and OS. We looked for factors with an impact on these times. Methods: We searched PubMed for phase III trials published between January 1998 and December 2010 in 12 leading journals. PPS is the difference between median OS and median PFS or time to tumor progression. The statistics of interest (median times [PFS, OS and PPS] and the ratio of PPS/OS) were compared using t-tests. Results: We retrieved 70 trials that yielded 71 comparisons and 156 arms (one trial was factorial) involving 38,504 patients. Trials from the period 2005-10 enrolled more patients than trials from the period 1998-2004 (medians of 246 vs 174 per arm; P=.026). PPS could be calculated for 60 trials and 135 arms (Table). Treatment type did not have an impact on any statistic. Treatment line had a significant impact on all times and on the ratio of PPS/OS, although the difference on the latter statistic was small. Treatment period had a significant impact on all times but not on the ratio of PPS/OS. Conclusions: None of the factors examined have a major impact on the ratio of PPS/OS. This suggests that in ACC, gains in PFS are translated into proportional gains in OS, one of the conditions required for PFS to be considered a surrogate for OS. [Table: see text]
Phase II study of combination therapy with S-1 and cetuximab in patients with KRAS wild-type unresectable colorectal cancer who had previously received irinotecan, oxaliplatin, and fluoropyrimidines (KSCC0901).
Authors: Kobayashi Kazuma , Emi Yasunori , Kakeji Yoshihiro , Takahashi Takao , Oki Eiji , Akagi Yoshito , Tsuji Akihito , Kodera Yasuhiro , Yoshida Kazuhiro , Baba Hideo , Shimada Mitsuo , Ogata Yutaka , Shimokawa Mototsugu , Tokunaga Shoji , Natsugoe Shoji , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: March 2020

3558

Background: Anti-epidermal growth factor receptor (anti-EGFR) antibodies alone or in combination with irinotecan (Iri) can be considered standard third-line therapy for KRAS wild-type (wKRAS) unresectable colorectal cancer (UNCRC). However, some UNCRC patients (pts) cannot tolerate Iri-containing therapy. S-1, an oral fluorouracil (FU) derivative, enhances the anti-tumor effect by inhibiting dihydropyrimidine dehydrogenase activity and reducing digestive toxicity. Combination therapy with cetuximab (C-mab) may restore 5-FU resistance in 5-FU–resistant CCs. Therefore, we examined the efficacy of S-1+C-mab therapy in wKRAS UNCRC pts, who had previously received Iri, oxaliplatin (OX), and FUs. Methods: The study design was multicenter, single-arm, open-label phase II study. The major inclusion criteria were written informed consent; histologically proven CRC and clinically proven UNCRC; presence of measurable lesions; previous therapy with Iri, OX, and 5-FU; documented progressive disease after 5-FU–based chemotherapy; wKRAS tumors; age ≥ 20 years; performance status (PS) 0–1; and adequate organ function. The treatment protocol was as follows: weekly durable intravenous (DIV) C-mab administration at 400 mg/m2 (day 1) and 250 mg/m2/week (except day 1) and oral administration of 80 mg/m2/day S-1 on days 1–28 of each 42-day cycle. The primary endpoint was progression-free survival (PFS). A sample size of 39 was planned for a threshold PFS of 3.5 months and expected value of 6.0 months, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: One patient was ineligible; 38 pts (PS 0/1, 32/6; 1/2/>3 prior chemotherapy regimens, 4/23/11) were enrolled from 10/2009 to 12/2010. The median PFS (central review) was 5.5 months (90% CI: 4.4 – 5.7); median overall survival (OS), 13.1 months; and the best ORR, 36.8%. The most common grade 3–4 adverse events were neutrophils, hypokalemia, rash, and dry skin. Conclusions: This study showed that S-1+C-mab may be a promising and well-tolerated treatment choice of wKRAS UNCRC, who had previously heavily treated by Iri, OX and FUs.
Phase II study of dacarbazine for metastatic colorectal cancer with determined MGMT status.
Authors: Amatu Alessio , Sartore-Bianchi Andrea , Bencardino Katia , Moutinho Catia , Marrapese Giovanna , Belotti Alessandro , Gambaro Alessandra , Cassingena Andrea , Venturini Filippo , Giacobbe Felicia , Sporchia Andrea , Lauricella Calogero , Schiavo Roberta , Esteller Manel , Siena Salvatore
Published: March 2020

3570

Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O6-guanine in DNA. Roughly 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents exert their antitumor activity by DNA methylation at the O6–guanine site, inducing base pair mismatch; therefore, activity of these compounds may be enhanced in CRCs lacking MGMT (Esteller, 2004; Pegg, 1990). Despite anecdotal reports about activity of dacarbazine in CRC (Shacham-Shmueli, 2011) no clinical trials assessed monotherapy with dacarbazine for metastatic CRC. Methods: We conducted a phase II study of dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines and cetuximab or panitumumab if KRAS WT), PS=0-1, with adequate organ function, and measurable disease as per RECIST criteria assessed by CT scans at baseline and every 8 weeks. All patients had tumor tissue assessed for MGMT as promoter hypermethylation. Patients received dacarbazine 250 mg/m2 i.v. d1-4, q21 until PD or untolerable toxicity (with a maximum of 6 cycles in case of SD). We employed a Simon, two-stage design to determinate if the ORR of dacarbazine treatment would be ≥ 10%. Secondary endpoints were association of response/resistance with loss of expression of MGMT, PFS and disease control rate. Results: In the first stage, from June 2011 to November 2011 we enrolled 40 pts (male 68%, median age 67 y [range 29-81], PS=0 50%, KRAS mut 55%). Pts received a median of 3 cycles [range 1-11]. Toxicities included (All Grades/Grade 3-4 %): fatigue (58/5), constipation (38/0), nausea/vomiting (35/0), anemia (20/2.5), platelet count decrease (10/5). 36 pts were evaluable for objective response. Overall, 2 pts (5%) achieved PR and 5 pts (12.5%) had SD. All pts with PR had tumors with MGMT promoter hypermethylation. Conclusions: Having exceeded the boundaries of futility (at least 2 objective responses in the first stage), the trial proceeds to the second stage, enrolling 28 more patients. Analysis of MGMT promoter hypermethylation and association with sensitivity/resistance is performed at the end of the second stage.
A phase II study of high-dose cetuximab plus irinotecan in colorectal cancer patients with KRAS-wild type tumors who progressed on prior standard dose cetuximab and irinotecan.
Authors: Fora Ahmad Ali , McMahon Jeanne A , Wilding Greg , Groman Adrienne E. , Ma Wen Wee , Romano Karen S. , Fakih Marwan
Published: March 2020

3582

Background: Prior clinical data suggest a dose-related response to cetuximab (cmab) when combined with irinotecan in patients (pts) with KRAS WT tumors who do not develop grade ≥ 2 rash with standard cmab dosing. However, the investigation of higher doses of cmab in the setting of acquired or innate resistance to standard dose cmab has not been previously investigated. We conducted a phase II clinical trial of high-dose cmab plus irinotecan in KRAS WT pts who progressed on standard-dose cmab plus irinotecan. Methods: Pts who progressed within 4 weeks from receiving a minimum of 6 weeks of standard dose cmab plus irinotecan were included in this study. Cmab was administered at 500 mg/m2/week and irinotecan was administered at the same dose/schedule on which each individual patient previously progressed. All pts received doxycyline 100 mg PO bid starting day 1 of treatment. 12-week PFS rate was the primary endpoint. The regimen was considered interesting if 7/36 patients had stable disease or response at 12 weeks. The study was closed early after meeting its primary endpoint. Results: 20 pts were treated on study: median age 65.5 yrs (44-84), 14 pts were males. 8 pts had grade ≥ 2 hypomagnesaemia (3 grade 3 and 2 grade 4), 6 pts had grade ≥ 2 skin rash (1 grade 3, 0 grade 4), and 4 pts had grade ≥ 2 diarrhea (1 grade 3, 0 grade 4). 1 pt had a confirmed PR and 12 pts had a SD (at 6 weeks). In 9 pts, SD was confirmed at 12 weeks (3 pts> 24 weeks). Median PFS and OS were 2.8 and 6.6 months, respectively. The 1-year survival was 25%. Conclusions: High-dose cmab plus irinotecan is well tolerated with an acceptable rate of diarrhea and skin toxicities but with an increased rate of grade 3-4 hypomagnesemia. The prolonged disease stabilization and single response suggest that resistance to standard dose cmab plus irinotecan can be overcome by cmab dose escalation. The identification of predictive markers of response from dose escalation will be necessary to implement this strategy selectively in KRAS WT colorectal cancer patients.
FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutant metastatic colorectal cancer patients.
Authors: Salvatore Lisa , Loupakis Fotios , Cremolini Chiara , Schirripa Marta , Masi Gianluca , Antoniotti Carlotta , Fornaro Lorenzo , Sensi Elisa , Lupi Cristiana , Bergamo Francesca , Lonardi Sara , Zagonel Vittorina , Fontanini Gabriella , Falcone Alfredo
Published: March 2020

3585

Background: BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC) patients, leading to a median PFS of 4-6 months with first-line conventional treatments. Recently, results from a retrospective exploratory analysis suggested that an up-front intensive treatment with FOLFOXIRI plus bevacizumab could improve the outcome of BRAF mutant mCRC. Methods: Fifteen consecutive BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab were included in a validation set. The primary endpoint was 6-months progression free rate (6m-PFR). Secondary endpoints were: overall survival, response rate and the pooled analysis of all main outcome parameters in both the exploratory and validation set. Results: In the validation set, 11 out 15 patients included were progression-free at 6 months, for a 6m-PFR of 73.3%. Primary endpoint was met. At a median follow-up of 21.6 months, median progression-free survival was 9.2 months while median OS has not yet been reached. In the pooled data analysis of the validation set and the initial retrospective cohort 24 out 25 total patients were evaluable for response: partial or complete response was obtained in 17 (68%) and in 1 (4%) patient, respectively, for an overall response rate of 72%. At a median follow-up of 34.1 months, the pooled set of patients showed a median PFS of 11.8 months and a median OS of 23.8 months. Conclusions: These data suggest that FOLFOXIRI plus bevacizumab could be a reasonable option for the first-line treatment of BRAF mutant metastatic colorectal cancer patients.
Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial.
Authors: Fernandez-Martos Carlos , Estevan Rafael , Salud Antonia , Pericay Carles , Gallen Manuel , Sierra Enrique , Serra Javier , Pera Miguel , Maurel Juan , Delgado Salvadora , Safont M. José , Roig Jose Vicente , Aparicio Jorge , Feliu Jaime , Garcia Damian , Vera Ruth , Suarez Javier , Alonso Vicente , Martin-Richard Marta , Brown Gina
Published: March 2020

3586

Background: Retrospective data suggest that RT might not be needed in all patients with stage II/III RC. Modern systemic therapy might have local efficacy similar to chemoradiation (CRT). Methods: A multicenter phase II trial was undertaken to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with T3 middle third rectal adenocarcinoma. Eligible patients (pts) had measurable disease at the baseline and candidate for R0 total mesorectal escision (TME) with intermediate-risk defined by pelvic MR a) T3 with distal border of tumor > 5 cm from the anal verge and below the sacral promontory. b) tumor ≥2 mm from the mesorectal fascia. Pts received 4 cycles of Cap 2000 mg/m2 (d1-14), Ox 130 mg/m2 (d1) and B 7.5 mg/kg (d1) every 3 weeks (last cycle without B). Pts undergo re-staging with MR. One radiologist reviewed all pre- and post-treatment MR scans independently. Pts without progression proceed to TME 4-6 weeks from the last cycle. If progression, pts were to be referred for pre-op cap/RT followed by TME. 1º Endpoint: Tumor Response (RECIST). Design: Simon 2-stage; 28 pts 1st stage and 46 pts 2nd stage. We report data on the planned analysis of pts included for 1st stage. Results: 28 eligible pts (10F/18M) were enrolled from 7/09-5/11. Tumor response, compliance and toxicity details are shown in table below. Two pN2 pts received postop Cap/RT. Conclusions: Neoadjuvant CAPOX-B is active and safe. Early parameters of efficacy are encouraging and seem similar to those observed with CRT. [Table: see text]
Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients with locally advanced, K-ras-mutated rectal cancer (LARC): A phase I/II trial (SAKK 41/08).
Authors: Von Moos Roger , Koeberle Dieter , Winterhalder Ralph C. , Cathomas Richard , Inauen Roman Ignaz , Zwahlen Daniel Rudolf , Roth Arnaud , Helbling Daniel , Gautschi Oliver , Baertschi Daniela , Kuehne Reto , Von Briel Thomas , Grzesiczek Anja , Samaras Panagiotis , Kollar Attila , Klingbiel Dirk , Zaugg Kathrin
Published: March 2020

3595

Background: 40% of patients (pts) with LARC present with K-ras mutation. Sor is an inhibitor of ras/raf and of VEGFR. Furthermore Sor has radiosensitizing effects. These facts build a strong rationale to use Sor in combination with preoperative RT and Cape in pts with K-ras mutant tumors. Methods: Pts with K-ras mutated mrT3-4 and / or mrN+, M0 disease were recruited in cohorts of 7 pts per dose level (DL). Dose limiting toxicity (DLT) was defined as any G3 or higher non hematological toxicity (tox) or haematological tox during ≥ 7 days, which are possibly, probably or definitely related to trial treatment occurring during and up to 4 weeks after last administration. If ≤ 2 out of 7 pts experienced a DLT, then the next cohort was treated at a higher dose level. If > 2 out of 7 pts suffered from a DLT, this DL would be considered too toxic and a dose level below would be tested in the next cohort. The highest dose level with ≤ 2 out of 7 pts experienced a DLT would be recommended for the phase II part. In all dose levels RT was given in 25 fractions at 1.8Gy (45Gy). Results: In 8 centers in Switzerland a total of 21 pts in 3 cohorts have been treated in the phase 1 study. After observing severe skin toxicity and diarrhea (2 pt with skin toxicity G3, one patient (pt) with diarrhea G3 plus hand-foot syndrome (HFS) (G3)) an amendment was implemented to reduce the Sor dose from 400mg BID to once daily. In DL 1 after the amendment, 2 pts experienced a DLT (enteritis G3, dermatitis G3). Two pts in DL 2 suffered from a DLT (cystitis G3 plus HFS G3, cardiac ischemia G3). Further non dose-limiting G3 toxicities after the amendment were lymphopenia (G3) (1pt, DL 2) and hypocalcaemia (G3) (1 pt, DL 2). No Grade 4 toxicity was seen. DL 2 is the recommended dose for phase II. Conclusions: After reducing the Sor dose to 400mg once daily, neoadjuvant treatment with Sor in combination with full dose Cape and RT was tolerable and the toxicities manageable. [Table: see text]
Treating patients with colorectal liver metastasis: A national decision-making analysis to understand choice of therapy.
Authors: Pawlik Timothy M , Nathan Hari , Cosgrove David , Laheru Dan , Diaz Luis A. , Herman Joseph M. , Edil Barish H , Hirose Kenzo , Wolfgang Christopher Lee , Choti Michael A. , Schulick Richard D.
Published: March 2020

3596

Background: Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. Methods: Physicians completed a national web-based survey that consisted of varied CLM case scenarios. Respondents choose among 3 treatment strategies: immediate liver resection(LR), preoperative chemotherapy followed by surgery(C→LR), or palliative chemotherapy (PC). Data were analyzed using multinomial logistic regression, yielding relative risk ratios (RRR). Results: Of 219 respondents, 79% practiced at academic centers and 63% were in practice ≥10 years. Median number of cases evaluated was 4/month. Surgical training varied: 51% surgical oncology (SO), 44% hepatobiliary/transplant (HB/LT), 5% no fellowship. While each factor impacted choice of CLM therapy, the relative impact differed (p<0.01). Synchronous CLM presentation increased the choice of C→LR (OR 4.27) and PC (OR 3.10) versus LR (p<0.001). For patients with more extensive intrahepatic disease (i.e., 5 tumors, both lobes) respondents strongly favored C→LR (OR 5.12) and PC (OR 9.60) versus LR (p<0.001). The presence of hilar lymph-node disease was associated with a strong aversion to LR with surgeons more likely to choose C→LR (OR 8.92) or PC (OR 49.9) (p<0.001). Interestingly, even the presence of a resectable solitary lung metastasis strongly deterred choice of LR with respondents favoring C→LR (OR 4.43) or PC (OR 6.97) (p<0.001). While other factors such as patient age, tumor size, and extent of resection impacted choice of therapy, the relative size of these effects was modest. After controlling for clinical factors, surgeons with more years in practice were more likely to choose LR (RRR 1.4). SO-trained surgeons were more likely than HB/LT-trained surgeons to choose C→LR (RRR 2.5) or PC (RRR 4.15)(p<0.001). Conclusions: This is the first study to define the relative impact of key clinical factors on choice of therapy for CLM. While clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.
Phase II study of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: A trial of the Eastern Cooperative Oncology Group (E3204).
Authors: Cohen Steven J. , Feng Yang , Landry Jerome Carl , Staley Charles A. , Whittington Richard , Sigurdson Elin R. , Nimeiri Halla Sayed , Verma Udit N. , Benson Al Bowen
Published: March 2020

3605

Background: Oxaliplatin and bevacizumab potentiate the antitumor activity of fluoroyprimidines and radiotherapy in preclinical and clinical studies of colorectal cancer. This phase II trial evaluated the efficacy of the preoperative combination of capecitabine, oxaliplatin, and bevacizumab with radiotherapy in rectal cancer. Methods: Eligibility: resectable T3/T4 adenocarcinoma of the rectum ≤ 12 cm. from anal verge. Preoperative treatment was capecitabine (825 mg/m² bid M-F), oxaliplatin (50 mg/m² weekly), bevacizumab (5 mg/kg D1,15,29), and pelvic external beam radiotherapy (50.4 Gy/28 fractions). Surgery was performed within 6-8 weeks. Within 12 weeks of surgery, patients received 12 cycles of FOLFOX + bevacizumab (5 mg/kg) Q2 weeks. Pathologic complete response (path CR) was the primary endpoint. Secondary endpoints included resection rate and toxicity. Results: Fifty-seven patients (pts) enrolled from 7/06 to 5/10 and 54 were eligible. Clinical staging: T3/4 (50/4), NX0/1/2 (2/16/31/5). Most common grade 3/4 non-hematologic toxicities during treatment were rectal pain (9), fatigue (8), and diarrhea (7). Two patients died of aspiration. Nine pts had early postsurgical complications (9 wound infections, 6 dehiscence, 1 abscess) and 23 had late surgical complications (23 non-healing wounds, 12 dehiscence, 5 bowel obstruction/ileus, 2 abscess). Pathologic staging: T0/1/2/3 (11/3/15/19), N0/1/2 (32/10/7). Nine pts had path CRs (17%, 90% CI:[9%-27%]. Surgery was LAR (38) and APR (11). Twenty-two pts did not receive postoperative chemotherapy (39%), 16 due to adverse events. Five local recurrences have been reported. RFS and OS data are immature. Conclusions: The addition of oxaliplatin and bevacizumab to capecitabine and radiotherapy for locally advanced rectal cancer resulted in downstaging for the majority of pts but did not improve the pathologic complete response rate compared to historical controls. The combination resulted in significant early and late postsurgical complications.
Six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III (Dukes' C) colon cancer: Initial safety report for the open-label randomized phase III study (JFMC37-0801).
Authors: Kunieda Katsuyuki , Sadahiro Sotaro , Mishima Hideyuki , Hamada Chikuma , Saji Shigetoyo , Sakamoto Junichi , Sato Toshihiko , Hirai Takashi , Maeda Atsuyuki , Yoshida Kazuhiro , Akamatsu Hiroki , Ohue Masayuki , Ohta Naohiro , Kinugasa Yusuke , Fujii Shoichi , Hasegawa Junichi , Tamagawa Koji , Yamaguchi Shigeki , Tomita Naohiro
Published: March 2020

3607

Background: The standard treatment duration of adjuvant chemotherapy (CT) in patients (pts) with stage III colon cancer is 6 months. On the other hand, no clinical trial showed the optimal treatment duration of oral chemotherapeutic agents in adjuvant setting for colon cancer. Sargent et al have reported that 83% of recurrences in stage II and III pts have occurred within the first 3 years after surgery and peak was observed around one year after surgery. Therefore, to clarify the benefit of 12 months administration of Capecitabine, we designed randomized phase III trial for a comparison of 6 months treatment and 12 months treatment of capecitabine as adjuvant CT for stage III colon cancer. Methods: JFMC37 is a multicenter, randomized Phase III trial. Patients with fully resected Stage III colon or recto sigmoid cancer were eligible. Capecitabine was administered orally as tablets, 2,500 mg/m²/day for 14 days followed by a 7-days rest. Treatment is continued to 8 cycles (6 months) in arm A (A) or 16 cycles (12 months) in arm B (B). Patients were randomized 1:1 to A or B. Data size was estimated by disease free survival as primary endpoint. The statistical design is based on superiority hypothesis; 5-yrs DFS is 60% in arm A, 67% in arm B ;unilateral α=0.05, 1-β=0.8;and planed accrual is 1200 pts. Results: Between September 2008 to December 2009, 1304 patients were enrolled and then randomized. Both arms were well balanced for mean age: (A) 64.1, (B) 63.8; ECOG PS (%0/1): (A) 95.0/5.0, (B) 97.1/2.9; involvement of lymph nodes (%N0/N1/N2): (A) 77.1/19.9/3.1, (B) 76.6/19.7/3.7. Treatment completion rate for A and B were 68.2% and 43.4%. Incidences of serious adverse events (SAEs) over 1% were neutropenia: (A) 2.6%, (B) 3.8%, diarrhea: (A) 2.9%, (B) 2.1%, loss of appetite: (A) 1.3%, (B) 1.0%, fatigue: (A) 1.8%, (B) 1.2%, hand-hoot syndrome: (A) 16.4%, (B) 22.1%. Conclusions: There were no obvious differences in SAEs between arm A and arm B. Although twelve months of capecitabine showed a tendency to increase G3/4 hand-foot syndrome, we concluded that incidence of SAEs were acceptable and comparable to previously report.
A population-based study of the effect of FDG PET/CT in the management of liver-limited colorectal adenocarcinoma (CRC) metastases.
Authors: Ho Maria Yi , Parhar Tarnjit , Wilson Don , Cheung Winson Y. , Lim Howard John
Published: March 2020

3610

Background: PET/CT scans are publically funded in British Columbia for staging in liver limited metastatic CRC. However, past studies have been equivocal about the utility of PET/CT as some report as high as a 20-30% change in management while others report <10% change in management. Our primary objective was to assess the effect of the addition of PET/CT to CT scanning for the management of liver limited colorectal cancer. Methods: Patients who underwent PET/CT scan for de novo liver limited metastatic disease from 2005-2011 in the province of British Columbia were identified using the PET/CT database. Patients recently completed or currently on chemotherapy were excluded. We determined the concordance rates between CT and PET/CT scans with respect to the extra-hepatic disease, the number of lesions in the liver and the location of liver lesions. Results: 349 patients were identified. The most common indications for PET/CT scans after an initial CT scan were: detection of extrahepatic disease (77%), confirmation of the malignant nature of the liver lesions (8%) and the extent of extrahepatic disease (15%). PET/CT and CT were discordant in 39% of cases for the extent of metastatic disease. PET/CT revealed extrahepatic disease in 27% of the cases for which CT only detected liver limited disease. In contrast, 13% of patients were downstaged when CT liver lesions were demonstrated not to be FDG avid. Concordance of PET/CT and CT scans on the number and location of liver lesions was 52% and 85%, respectively. PET/CT revealed additional number of liver lesions and multilobar disease in 26% and 12% of cases, respectively. Furthermore, the median time between PET/CT and CT were 64.3 days and 64.1 days for concordant and discordant cases (p=0.88). Conclusions: PET/CT scans provided additional information compared to CT scans which could have implications for surgical management. Our study supports the utility and public funding of PET/CT in addition to CT in patients with potentially surgically curable metastatic CRC involving the liver.
Neoadjuvant treatment of colorectal liver metastases (CRLM) with drug eluting beads trans-arterial chemoembolization (DEBIRI-TACE): A multi-institute phase II study in resectable metastases.
Authors: Jones Robert Peter , Malik Hassan Zakria , Fenwick Stephen W , Byrne Clare , Terlizzo Monica , O'Grady Elizabeth , Stremitzer Stefan , Gruenberger Thomas , Poston Graeme John
Published: March 2020

3613

Background: Perioperative chemotherapy confers 3-year progression free survival advantage following resection of CRLM and good pathologic response is associated with improved overall survival. However, systemic neoadjuvant chemotherapy can increase postoperative morbidity and mortality. TACE using preloaded Irinotecan eluting beads gives sustained delivery of drug directly to tumor, thereby maximising response and reducing systemic exposure. This study examined the feasibility and safety of neoadjuvant DEBIRI-TACE before CRLM resection. Methods: Patients with resectable CRLM received single DEBIRI-TACE (up to 200mg) 1 month pre-hepatectomy. Primary end-point: tumor resectability, secondary end-points: safety, radiologic response (RECIST) and pathologic tumor response. Results: TACE attempted in 49 patients, successful in 40. Reasons for failed TACE included consent withdrawal (n=2), bilobar disease (n=2), tumour involving gallbladder wall (n=1), suspected hepatoma (n=1), arterial access difficulty (n=2), contrast medium allergy (n=1). Post-TACE complications: 1 acute pancreatitis (3%); 4 post-embolization syndromes (10%). Imaging at 4 weeks post-TACE (30 patients): complete response 0/40 (0%); partial response 1/40 (3%); stable disease 19/40 (48%); ‘progressive’ disease 10/40 (25%). 40 patients proceeded to surgery, 38 underwent hepatectomy (2 peritoneal disease, resectability rate 95%). 30-day post-operative mortality 5% (n=2), neither death TACE related (1 intraoperative pneumomediastinum, 1 aspiration pneumonia). 63 lesions (median 2 per patient) targeted with TACE. Histology: no residual disease 17%; 1-49% residual disease 59%; >50% residual disease 22%; no response 2%. Conclusions: Resection after neoadjuvant DEBIRI-TACE for CRLM is feasible and safe. Single treatment with DEBIRI-TACE resulted in tumor pathologic response similar to that seen after protracted systemic chemotherapy.
Efficacy and safety of bevacizumab in metastatic colorectal cancer (mCRC): Pooled analysis from randomized controlled trials (RCTs).
Authors: Tebbutt Niall Christopher , Hurwitz Herbert , Kabbinavar Fairooz , Giantonio Bruce J. , Guan Zhongzhen , Mitchell Lada , Waterkamp Daniel , Tabernero Josep
Published: March 2020

3614

Background: Bevacizumab (BV) with chemotherapy (CT) is a standard treatment for mCRC. This analysis pooled individual patient data from the clinical databases of seven RCTs (phase II or III) of BV in 1st- or 2nd-line treatment to further define clinical outcomes, including within subgroups. Methods: Patient data were pooled from 1st-line (AVF2107, NO16966, ARTIST, AVF2192, AVF0780, AGITG MAX) and 2nd-line (ECOG E3200) trials. All analyses were based on the intent-to-treat population. Overall and progression-free survival estimates (OS, PFS) were calculated by Kaplan-Meier methods. To assess differences in time to response variables by treatment arm (CT vs BV + CT), stratified random (overall) and fixed (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs), with each study included as a stratum. Results: Of the 3,763 pooled patients (CT [n=1773]; BV + CT [n=1990]), 58.8% were male, 39.6% were ≥65 years, and 45.7% had an ECOG performance status ≥1. OS and PFS were statistically significantly increased in BV-treated patients vs control patients. Safety data in this pooled analysis were consistent with the profile of BV from the individual studies. Conclusions: The addition of bevacizumab to CT resulted in statistically significant improvements in survival outcomes for mCRC patients in the overall analysis, with PFS benefit extending across subgroups defined by CT intensity, CT regimen, and KRAS status. [Table: see text]
Clinicopathologic and molecular associations of PIK3CA and PTEN mutation in colorectal cancer.
Authors: Day Fiona Lee , Desai Jayesh , Jorissen Robert N , Gibbs Peter , Mouradov Dmitri , Li Shan , Sieber Oliver
Published: March 2020

3623

Background: The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated in the development of colorectal cancer (CRC), however a systematic analysis of pathway members and their association with clinical, pathological and other molecular features has been lacking. Methods: We determined the prevalence of PIK3CA (exons 9, 20) mutations in a large cohort (n=1092) of community-based patients (pts) with stage I-IV CRCs. A subset (n=744, 68%) were also tested for mutation in PTEN (exons 3,4,5,6,7,8), PTEN LOH and CIMP. All tumors were characterised for MSI, KRAS and BRAF mutations, and annotated for clinico-pathologic features and patient outcomes in a prospectively-recorded database. Detected novel PIK3CA exon-specific correlates were further explored in a combined analysis integrating the data of other published cohorts (total n=3677). Results: PIK3CA mutations occurred in 11.6% of primary tumors and were associated with older pt age (p=0.009), proximal site (p<0.001), lower lymphovascular invasion (p=0.018) and KRAS mutation (p<0.001), but not with gender, tumor stage or differentiation. Direct comparison of PIK3CA exon 9 and 20 mutations in the combined analysis (mixed effect logistic regression) finds both at increased frequency in KRAS-mutant tumors (p=0.098 for difference); however PIK3CA exon 20 mutations uniquely correlated with BRAF mutation (p=0.002 for difference), MSI (p<0.001) and CIMP-high status (p=0.031). PTEN mutations were present in 5.8% of tumors and associated with proximal site (p=0.013), mucinous histology (p=0.013), MSI (p<0.001), CIMP-high (p<0.001), and BRAF mutation (p<0.001). There was a trend toward mutation of both PIK3CA and PTEN and strong selection for two hits to PTEN (mut/mut or mut/LOH, p<0.001). In our cohort neither PIK3CA or PTEN mutation were associated with pt survival outcomes. Conclusions: In CRC, common mutations in the PI3K signaling pathway are universally associated with proximal site, however display unique gene- and exon-specific associations with tumor histology, MSI, CIMP, KRAS and BRAF mutation. These need to be considered when exploring targeted therapeutic options for pts with CRC.