bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2 study of temozolomide in patients affected by pretreated metastatic colorectal cancer with MGMT promoter methylation.
Authors: Calegari Maria Alessandra , Monterisi Santa , Inno Alessandro , Orlandi Armando , Basso Michele , Cassano Alessandra , Santini Daniele , Martini Maurizio , Cenci Tonia , de Pascalis Ivana , Barbaro Brunella , Camarda Floriana , Colosimo Cesare , Larocca Luigi Maria , Tonini Giuseppe , Gori Stefania , Barone Carlo Antonio
Published: March 2017

629

Background: Presently few options are available for pts with mCRC who failed standard treatments and prognosis remains grim. MGMT promoter methylation is a frequent and early event in CRC tumorigenesis. This epigenetic silencing is a predictor of response to the alkylating drug TMZ in glioblastoma. Preclinical evidences and a couple of clinical cases showed TMZ activity in pts affected by mCRC with MGMT silencing. We designed a study to evaluate the efficacy and safety of TMZ in pts with refractory mCRC harboring MGMT promoter methylation. While the trial was ongoing three analogous studies, reporting discordant results, were published. Methods: This was a 3-institutional, single arm, phase 2 trial, planned according to a 2-stage Simon’s optimal design. The primary endpoint was ORR. Secondary outcomes included DCR, OS, PFS and safety. A first cohort of 21 pts was accrued: if more than 1 response was observed a second cohort of 20 pts would be enrolled; if 4 or fewer responses were observed by the end of stage two, then no further investigation would be warranted. MGMT promoter methylation was assessed on archival tissue samples by MS-PCR. Patients affected by MGMT methylated mCRC, who failed 2 or more prior treatments, received TMZ, provided by TEVA Pharmaceutical Industries, at a dose of 150-200 mg/mq/day once a day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 pts were screened and 80 showed MGMT promoter methylation, among those 42 met the inclusion and exclusion criteria and were enrolled. ORR was 10% with no CR and 4 (10%) PR. SD was achieved in 9 (22%) pts, accounting for a DCR of 32%. At a median FU of 9 months all pts experienced PD and 88% died. Median PFS and OS were 2.6 months (95% CI 2.1-3.2) and 7.1 months (95% CI 5.1-9.2) respectively. Overall, any-grades AEs were reported in 75.6% pts, most of them were G1-2 (84%). The most frequent AE were nausea (56%) and platelet count decreased (39%). 4 pts discontinued study treatment due to AE. No SAE neither toxic death was recorded. Conclusions: The study did not meet its primary endpoint, however an interesting DCR (32%) and 4 PR were achieved. The role of TMZ in mCRC treatment remains still controversial and might warrant further analysis. Clinical trial information: 2012-002766-13.
Characterization of the number and site of APC mutations in sporadic colorectal cancer.
Authors: Joseph Ranjit , Little Paul , Hayes David N. , Lee Michael Sangmin
Published: March 2017

630

Background: Truncating mutations in the adenomatous polyposis coli ( APC) gene are well-described events in the carcinogenesis of colorectal carcinomas (CRC) and may impact one or both APC alleles. These aberrations often fall within the mutation cluster region (MCR) of the APC gene to preserve a “just right” number of beta-catenin binding sites in the resulting mutant APC protein. Further clinical and genotypic characterization of CRCs based on number and site of mutations in APC determined using modern next generation sequencing methods is needed. Methods: Next generation sequencing of 70 CRC tumors was performed at a single institution via UNCseq to determine mutations in a panel of 247 oncogenes and tumor suppressors, including APC. RNASeq, DNA sequencing, and clinical characteristics from 224 colon and rectal cancer samples in The Cancer Genome Atlas (TCGA) project were also obtained. Results: In the UNCseq cohort, 58 patients (83%) had at least one inactivating APC mutation, and 33 (47%) had two mutations. Of those with at least one mutation, 81% had a mutation in the MCR (residues 1281-1556), but only 5/33 (15%) with two mutations had both in the MCR. In the TCGA cohort, 162 (72%) had at least one inactivating APC mutation, and 52 (23%) had two mutations. Of those with at least one mutation, 59% had a mutation in the MCR, but only 3/52 (6%) with two mutations had both in the MCR. Gene expression of APC was higher in those with no APC mutations vs. 1-2 mutations (p = 0.015), but was not significantly different between those with one vs. two mutations (p = 0.29). The absence of APC mutations was associated with microsatellite instability (p < 0.001) and with right-sided primary tumors (p = 0.001 by chi-square). Conclusions: CRCs have high frequency of biallelic APC mutations, and the majority of tumors with APC mutations had a single mutation within the MCR region of the APC gene. These genotypic factors may impact tumor biology and clinical features.
Combination of TLR9 agonist lefitolimod/MGN1703 with checkpoint inhibitors for cancer immunotherapy.
Authors: Schmidt Manuel , Kapp Kerstin , Volz Barbara , Oswald Detlef , Wittig Burghardt
Published: March 2017

634

Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. Lefitolimod/MGN1703 is a covalently-closed dumbbell-like immune surveillance reactivator (ISR) with a broad immunomodulatory potential. After promising data from a phase II trial (IMPACT) as maintenance therapy after first-line induction chemotherapy in patients with metastatic colorectal cancer lefitolimod is recently evaluated in a phase III trial in mCRC patients (IMPALA). Methods: It was previously shown that lefitolimod can reduce tumor growth in several murine tumor models. Since the mode-of-action of lefitolimod starts upstream of the initiation points of checkpoint inhibitors aCTLA-4 or aPD-1/aPD-L1 a combinatory approach may result in an enhanced anti-tumor effect. Therefore, we employed two syngeneic murine tumor models: One with s.c. inoculation of CT26 cells and another with s.c. A20 cell challenge. Multiple doses of lefitolimod were injected s.c. or i.tu. Results: In the colon carcinoma CT26 model i.p. injection of aPD-L1 had no effect on the tumor growth, whereas peritumoral injection of lefitolimod led to a slowed tumor growth. The tumor growth was further inhibited by the combination (tumor growth inhibition, TGI - aPD-L1: no, lefitolimod: 28%, combination: 48%) resulting in prolonged survival of the mice. This combinatory effect was even more pronounced in the lymphoma A20 model: Injections of anti-PD-1 (i.p.) or lefitolimod (i.tu.) alone had a moderate anti-tumor effect which was vastly increased by the combination (TGI - aPD-1: 46%, lefitolimod: 50%, combination: 99%). Conclusions: In conclusion, we showed that lefitolimod, a member of dSLIM family of TLR9 agonists and an ISR, can enhance the limited anti-tumor effects of checkpoint inhibitors in pilot studies in murine colon carcinoma and lymphoma tumor models in vivo. These data show the promising potential for the combination with checkpoint inhibitors. In fact, a clinical trial in cooperation with MD Anderson evaluating the benefit of lefitolimod in combination with ipilimumab is currently ongoing.
A survey of medical oncologist’s opinions and perceptions regarding the management of dermatologic toxicities among mCRC patients treated with panitumumab in the United States.
Authors: Lowe Kimberly , Bergstresser Rachel , Hool Kristina , Kafatos George , Garawin Tamer , McNamara Michelle , Kelsh Michael Anthony , Collins Seth , Bach Bruce A. ,   Skin Tox
Published: March 2017

639

Background: Dermatologic toxicity can be a limiting factor for the use of anti-EGFR therapy such as panitumumab. There is a paucity of real world data regarding the management of dermatologic toxicity among metastatic colorectal cancer (mCRC) patients treated with panitumumab in the United States (U.S.). The objective of this study is to describe oncologist's opinions regarding timing of skin rash management in relation to the initiation of treatment and perceptions regarding rash management strategies. Methods: A total of 125 oncologists were recruited from a national database via a third independent party. Eligible oncologists (i.e.: licensed and practicing oncologist who had treated at least three new or continuing mCRC patients with panitumumab in the last year) completed an online survey to report their opinions regarding the grade and type of dermatologic toxicities seen and their perceptions about management strategies for mCRC patients who are treated with panitumumab. The timing of rash management initiation was defined as pre-emptive (prior to the appearance of the rash) or reactive (after any signs of skin rash). Results: Based upon their collective experience, oncologists expect that 44% of patients will develop acneiform rash while on treatment. More than half (58%) of the oncologists reported they did not follow any practice guidelines regarding the management of dermatologic toxicities. The oncologists reported that they pre-emptively initiated the management of dermatologic toxicities in 53% of their patients. Skin moisturizer and sunscreen were reported to be the most critical preemptive management approach, while skin moisturizer, over-the-counter topical steroids, and oral antibiotics were reported to be the most critical reactive management tools for Grades 1, 2, and 3, respectively. Conclusions: Despite evidence from randomized controlled trials, a majority of oncologists do not follow guidelines for dermatologic management of EGFR-I rash. There is a clear need for better physician education and awareness of mitigation strategies for skin toxicity management in mCRC patients treated with panitumumab.
A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy.
Authors: Townsend Amanda Rose , Hardingham Jennifer , Tebbutt Niall C. , Karapetis Christos Stelios , Singhal Nimit , Joshi Rohit , Yeend Sue , Cooper Pamela , Dorward Hilary , Price Timothy Jay
Published: March 2017

643

Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P < 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 & p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.
BRAF +/- MEK inhibition in patients (pts) with BRAF-mutant (mut) metastatic colorectal cancer (mCRC): The Sarah Cannon Research Institute UK’s experience.
Authors: Uccello Mario , Moschetta Michele , Mak Gabriel , Martynyuk Nataliya , Hauser Joana , Bassett Sian , Voskoboynik Mark , Lemech Charlotte , Rafii Saeed , Arkenau Hendrik-Tobias
Published: March 2017

645

Background: Activating V600 BRAF mutations are detectable in around 10% of mCRC pts and are associated with poor prognosis. Low response rates have been reported with anti-BRAF monotherapy in this subset of pts while encouraging data exist on enhanced MAPK pathway inhibition with combination therapy (anti-BRAF + anti-MEK and/or anti-EGFR). Methods: We performed a pooled analysis of BRAF-mut mCRC pts enrolled into different phase 1 trials involving the use of anti-BRAF monotherapy alone (Group A) or in combination with a MEK inhibitor (Group B) at therapeutic doses between June 2012 and August 2016. Demographic, baseline, toxicity and efficacy data were retrospectively reviewed. Results: Twenty BRAF-mut mCRC pts were identified in either Group A (n = 13) or Group B (n = 7). All pts had an ECOG performance status ≤ 1. Median age was 54 years (range 33-74). The primary tumor was right-sided in 10 (50%) pts, left-sided in 9 (45%) pts, and unknown in 1 (5%) subject. Median number of previous treatment lines was 1 (range 1-4). The disease control rate was 55%, with 3 (15%) pts experiencing partial response (PR) and 8 (40%) with stable disease. No complete responses were observed, 8 (40%) pts had progressive disease and 1 subject was considered not evaluable. All PRs were achieved in Group B and had duration of 2-4 months (mo). Median PFS was 3.73 mo (95% confidence interval [CI] 3.06-6.79) in the overall population, and showed a trend favoring the combination arm (2.80 mo for Group A vs. 5.03 mo for Group B, hazard ratio 0.71 [CI 0.26-1.95], p = 0.503). Most common toxicities were skin-related side effects (n = 10; 50%), myalgia/arthralgia (n = 5; 25%), nausea (n = 3; 15%), and pyrexia (n = 3; 15%). Grade 3/4 toxicities were uncommon and manageable: neutropenia (n = 1; 5%), hypophosphatemia (n = 1; 5%), pyrexia (n = 1; 5%), and abdominal pain (n = 1; 5%). Conclusions: Our cohort of pts treated with BRAF +/- MEK inhibitors showed a favorable safety profile. An encouraging activity level was found in the combination arm. In line with existing literature data, our findings supporting further development of combined MAPK inhibition in V600-positive mCRC.
Sequencing cell free DNA in patients receiving selective internal radiation therapy for colorectal liver metastases.
Authors: Winter Helen , Kaisaki P , Carter Rebecca , Cutts Anthony , Greenhalgh Tessa , Schuh Anna , Sharma Ricky A. , Taylor Jenny C
Published: March 2017

646

Background: Tumour heterogeneity is a key determinants of cancer resistance. Serial sampling of cell free (cf)DNA may detect evolving somatic mutations. Monitoring cancers after therapies e.g. selective internal radiation therapy (SIRT) require new biomarkers as RECIST imaging was developed to assess response to chemotherapy and may not reflect tumour changes due to new therapeutic strategies. The utility of cfDNA to detect recurrence and predict response is emerging. The objective of this study was to sequence serial cfDNA samples from patients with liver predominant metastatic disease receiving SIRT, and explore the feasibility of using this method to detect evolution of somatic mutations after high dose radiation. Methods: A prospective imaging biomarker study was performed in patients with colorectal liver metastases (CRLM) receiving SIRT. Plasma was extracted and frozen within 4 hours at 3 time points: baseline, 4 and 10 weeks after SIRT. Ion Torrent Amplicon sequencing was performed using cancer hotspot panel v.2. Sequencing of primary tumours was obtained by pyrosequencing. Results: Twenty-four patients with CRLM were recruited from March – Dec 2015, and 18 had cfDNA extracted for sequencing at a minimum of two time points. Ion Torrent amplicon sequencing of baseline cfDNA showed high concordance with formalin-fixed paraffin-embedded (FFPE) tumour samples. Serial cfDNA sequencing in a patient with partial response by imaging, detected 22% KRAS G12C mutation at baseline, which decreased to 1.5% by 4 weeks, then was undetectable 10 weeks after SIRT. Sequencing of another patient’s cfDNA revealed persistence of KRAS G13D and a truncating APCmutation at both 4 and 10 weeks after SIRT, consistent with the patient’s progressive disease. Conclusions: Cell-free DNA is emerging as a biomarker in colorectal cancer. Our measurements of mutational status in baseline cfDNA and FFPE samples show high concordance. This study reports that serial cfDNA sequencing detects changes in mutational status and specific mutations following high dose radiation to the liver. This adds to the evidence of cfDNA as a tool to detect evolution of somatic mutations following therapy.
CEA response and depth of response (DpR) to predict clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus oxaliplatin-based chemotherapy: A sub-analysis of the JACCRO CC-05/06 trials.
Authors: Sunakawa Yu , Ichikawa Wataru , Tsuji Akihito , Denda Tadamichi , Segawa Yoshihiko , Negoro Yuji , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Tanioka Hiroaki , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Takeuchi Masahiro , Fujii Masashi , Nakajima Toshifusa
Published: March 2017

648

Background: Carcinoembryonic antigen (CEA) decrease was faster and greater in cetuximab (cet) treatment than bevacizumab treatment and correlated with prolonged survival in mCRC pts receiving FOLFIRI plus cet (Michl M, et al. Ann Oncol 2016). We investigated if the CEA decrease is a surrogate for DpR reported to be associated with clinical outcomes. Methods: This study evaluated the association between the percentage of CEA decrease or DpR and clinical outcomes in pts with KRAS exon 2 wild-type from 2 phase II trials of 1st-line therapy; JACCRO CC-05 of cet plus FOLFOX ( n= 57, UMIN000004197) and CC-06 of cet plus SOX ( n= 61, UMIN000007022). The association was analyzed using Spearman’s rank correlation coefficient. The cut-off value of 75% CEA decrease was used for CEA response to discriminate CEA responders according to the previous report. The DpR was defined as the percentage of tumor shrinkage at the nadir as compared with the baseline values. Results: In total of 113 pts of the 2 trials in the full analysis set, 92 were eligible for analyses of both CEA and DpR. In the population consists of 92 evaluable pts, median progression-free survival (PFS) was 9.1 months, and median overall survival (OS) was 36.2 months. Median CEA decrease was 67.4% and median time to CEA nadir was 2.8 months similar to median time to DpR of 3.0 months. The DpR was associated with PFS and OS (rs= 0.56; P< 0.0001, rs= 0.39; P= 0.0090, respectively); moreover, CEA decrease correlated with PFS (rs= 0.56, P< 0.0001) as well as OS (rs= 0.35, P= 0.019). CEA responders showed significantly longer PFS [11.8 vs. 5.5 months; hazard ratio (HR) 0.46; 95% Cl, 0.28–0.73; P= 0.0009] and numerically longer OS (36.2 vs. 23.5 months; HR 0.57; 95% CI, 0.30-1.05; P= 0.072) than CEA non-responders. The CEA decrease was statistically significantly associated with DpR (rs= 0.44, P< 0.0001). Conclusions: Our study demonstrates that DpR and CEA response both correlated with clinical outcomes of 1st-line treatment with cet plus oxaliplatin-based chemotherapy. The CEA decrease may serve as a surrogate for DpR in 1st-line cet treatment.
Molecular profiling of adenocarcinoma of esophagogastric junction.
Authors: Suh Yun-Suhk , Na Deukchae , Kim Euihyun , Lee Ju-Seog , Chae Jeesoo , Min Jimin , Choi Boram , Kong Seong-Ho , Lee Hyuk-Joon , Kim Jong-Il , Lee Charles , Kim Woo Ho , Yang Han-Kwang
Published: March 2017

65

Background: Biologic understanding of adenocarcinoma of esophagogastric junction (AEJ) and similarity to gastric or esophageal adenocarcinoma has been long standing controversial issue, especially according to Siewert classification. The purpose of our study is to evaluate molecular characteristics of AEJ compared to esophageal (EAC) or upper third gastric adenocarcinoma (UT) using next generation sequencing. Methods: We analyzed classifier genes between EAC and body/fundus gastric adenocarcinoma (GCBF) from The Cancer Genome Atlas (TCGA) cohort. Based on classifiers, class prediction model was developed with Bayesian compound covariate predictor (BCCP). According to Siewert classification, SNUH cohort is comprised of each 16 pairs of tumors and normal gastric mucosae of AEJII, III and UT groups for which whole exome and transcriptome sequencing was carried out. SNUH cohort (n = 48) and AEJ/cardia cancer of TCGA cohort (n = 48) were tested using class prediction model. Results: Between EAC (n = 78) and GCBF (n = 102) in TCGA cohort, we identified 5,520 differentially expressed genes ( P< 0.001), and chose each top and bottom 200 genes using fold-change rank as classifiers for prediction model. Cross validation for prediction model revealed 90.2% of sensitivity and 89.7% of specificity. AEJ/Cardia cancer in both cohorts showed spectrum transition of predictor gene expression, and 75% in TCGA cohort (AEJ/Cardia) and 81.2% in SNUH cohort (AEJ) is classified as GCBF type using cut-off as 0.5 of BCCP. In SNUH cohort, 68.8% of AEJII , 80.0% of AEJIII sparing gastroesophageal junction (GEJ) and all AEJIII involving GEJ was classified as GCBF type. GCBF type shows significantly higher proportion of undifferentiated and diffuse type than EAC. Conclusions: Molecular prediction using BCCP revealed spectrum transition of AEJ, and 75-81.2% of AEJ/cardia cancer was classified as GCBF. Especially, 68.8 of AEJII and more than 80.0% of AEJIII can be considered as GCBF irrespective of involvement of GEJ.
C-jun N-terminal kinase dependent autophagic cell death in cancer cells induced by Zanthoxylum fruit extract from Japanese pepper.
Authors: Kono Toru , Nozaki Reo , Bochimoto Hiroki , Watanabe Tsuyoshi , Oketani Kaori , Sakamaki Yuichi , Okubo Naoto , Nakagawa Koji , Takeda Hiroshi
Published: March 2017

653

Background: Natural products constitute a promising resource for drug development including an anticancer drug. Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) is an important component of Daikenchuto, which is a form of Japanese traditional medicine. Recently, we have reported that Daikenchuto has an anticancer activity in vivo, however precise mechanism is still unclear. Therefore, we investigated the potential anticancer activity of ZFE as an inducer of autophagic cell death (ACD). Methods: ZFE powder was provided by Tsumura (Japan). We investigated the effect of ZFE on the morphology of six types of human cancer cells and normal cells by using phase contrast microscopy and electron microscopy. Knockdown of autophagy-related gene 5 (ATG5), which is an essential gene for autophagy, by transfecting small interfering RNA was performed and confirmed by quantitative RT-qPCR and Western blot analysis. Effect of bafilomycin A1 (Baf A1), an inhibitor of vacuolar type H+-ATPases, on the anticancer activity of ZFE was investigated. Western blot analysis revealed LC3-II levels, a marker of autophagy. Results: ZFE caused remarkable autophagy-like cytoplasmic vacuolization with the inhibition of cell proliferation and subsequent induction of cell death in human cancer cell lines, DLD-1, HepG2 and Caco-2 cells but not in A549, MCF-7 or WiDr cells. ZFE increased LC3-II protein levels. Suppression of an ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, ZFE increased the phosphorylation of c-jun N-terminal kinase (JNK) in cancer cells which can be induced cell death by ZFE and JNK inhibitor SP600125 attenuated both vacuolization and cell death induced by ZFE. Instead, ZFE-induced cell death was neither apoptosis nor necrosis according to the morphological perspective and the marker of apoptosis or necrosis. And normal intestinal cell was not affected by ZFE. Conclusions: ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.
Updated efficacy, safety, and biomarker analyses of STEAM, a randomized, open-label, phase II trial of sequential (s) and concurrent (c) FOLFOXIRI-bevacizumab (BV) vs FOLFOX-BV for first-line (1L) treatment (tx) of patients with metastatic colorectal cancer (mCRC).
Authors: Hurwitz Herbert , Tan Benjamin R. , Reeves James Andrew , Xiong Henry Q. , Somer Bradley G. , Lenz Heinz-Josef , Hochster Howard S. , Scappaticci Frank , Palma John F. , Mancao Christoph , Lee John J. , Nicholas Alan , Sommer Nicolas , Bendell Johanna C.
Published: March 2017

657

Background: STEAM (NCT01765582) assessed efficacy and safety of 1L cFOLFOXIRI-BV and sFOLFOXIRI-BV vs FOLFOX-BV. Updated efficacy, safety, and exploratory biomarker data are reported. Methods: 280 tx-naive pts with mCRC were randomized 1:1:1 to BV-containing (5 mg/kg q2w) arms (cFOLFOXIRI, sFOLFOXIRI [alternating FOLFOX and FOLFIRI every 4 weeks {q4w}], or FOLFOX) in a 4–6 month (mo) induction phase, followed by maintenance. Primary objectives include progression-free survival (PFS). Secondary objectives include overall survival (OS). Tumor-relevant biomarker evaluations were exploratory. Results: Median PFS significantly improved and median OS showed a positive trend with cFOLFOXIRI-BV vs FOLFOX-BV. PFS significantly improved with cFOLFOXFIRI-BV vs FOLFOX-BV in BRAF wild type (WT); there was a positive trend in RAS WT and mutant (MUT) pts; no tx difference observed in BRAF MUT pts. In the safety pop., (n = 271), 88% had Grade ≥ 3 tx emergent AEs: 91% cFOLFOXIRI-BV; 87% sFOLFOXIRI-BV; 86% FOLFOX-BV. Conclusions: Improved PFS and a positive trend in OS were observed for cFOLFOXIRI-BV vs FOLFOX-BV. A positive PFS trend was seen in RAS WT and MUT pts, with significantly improved PFS in BRAF WT. The small number of BRAF MUT pts precluded estimation of tx effects. AEs for all 3 txs were consistent with previous reports. Clinical trial information: NCT01765582. [Table: see text]
Unresectable colorectal cancer liver metastases treated with radioembolization: Updated survival analysis of the MORE study.
Authors: Kennedy Andrew S. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Eduardo , Kaiser Adeel , Nutting Charles W. , Rose Steven C. , Wang Eric , Savin Michael
Published: March 2017

666

Background: In December 2011, the Metastatic Colorectal Cancer Liver Metastases Outcomes after Radioembolization (MORE) study retrospectively analyzed 606 patients with unresectable colorectal liver metastases treated with radioembolization using Y-90 resin microspheres. At a median follow-up of 8.6 months, 503 of these patients had died. Here, we summarize survival outcomes from extended follow-up of the remaining patients through September 1, 2016. Methods: Extended survival surveillance was abstracted from patient charts and public records. Survival time was compared for prognostic variables using Kaplan-Meier estimates. Results: Survival data were analyzed for 574 of 606 patients with median follow-up of 9.5 months (IQR 12.9 months). Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Additional death dates were obtained on 71 patients, and median survival was 10.0 months (95% CI 9.2-11.8) -versus 9.6 (95% CI 9.0-11.1) months originally reported. Data confirm ECOG PS, disease stage, extent of liver involvement, liver function, metachronous metastasis, and prior chemotherapy as predictors of post-radioembolization survival. Conclusions: Long-term follow-up confirms the originally reported prognostic factors for survival and that radioembolization offers a favorable survival benefit for patients with unresectable colorectal cancer liver metastases, even among those who already received 3 or more lines of chemotherapy. [Table: see text]
Baseline creatinine clearance as an indicator of severe adverse events associated with oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer: Safety analysis of the phase III Japanese ACHIEVE trial.
Authors: Nakamura Masato , Kotaka Masahito , Eto Tetsuya , Manaka Dai , Hasegawa Junichi , Takagane Akinori , Kato Takeshi , Munemoto Yoshinori , Nakamura Fumitaka , Bando Hiroyuki , Taniguchi Hiroki , Gamoh Makio , Shiozawa Manabu , Yamanaka Takeharu , Mizushima Tsunekazu , Sakamoto Junichi , Saji Shigetoyo , Ohtsu Atsushi , Mori Masaki , Yoshino Takayuki
Published: March 2017

667

Background: The phase III ACHIEVE trial (JFMC47), a project of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA), was established to prospectively analyze data from several randomized trials to test whether 3-month (arm 3) oxaliplatin-based adjuvant (FOLFOX4, mFOLFOX6, or XELOX) treatment is non-inferior to 6-month (arm 6) treatment in terms of disease-free survival in patients (pts) with stage III colon cancer. It aims to reveal the association between baseline characteristics and ≥ grade 3 adverse events (AEs) related to XELOX and mFOLFOX6, particularly focusing on the role of baseline creatinine clearance (CCr) on ≥ grade 3 AEs. Methods: This association was assessed using the Cox proportional hazards model. Results: During 2012–2014, 1,313 pts were randomized from 244 centers; 1,301 were included in the intention-to-treat population. Among the safety population (N = 1,277; 642, arm 3; 635, arm 6), the overall incidence of ≥ grade 3 AEs was 29% in arm 3 and 43% in arm 6 (p < 0.0001). Neuropathy of ≥ grade 2 was more frequent in arm 6 than in arm 3 (37% vs. 14%; p < 0.0001). Regarding the fluoropyrimidine backbone, grade 3–4 neutropenia was more with mFOLFOX6 than XELOX (30% vs. 12%), whereas grade 3–4 anorexia (2% vs. 5%) and grade 3–4 diarrhea (1% vs. 6%) were more with XELOX. Multivariate analysis, including treatment duration, regimen, CCr ( < 50 vs. > 50 mL/min), age, and sex, showed that CCr had a statistically significant impact on the occurrence of ≥ grade 3 AEs (hazard ratio = 0.44, p < 0.0001). Pts with CCr < 50 may have had more frequent ≥ grade 3 AEs independent of other factors, such as age. Conclusions: Grade 3 or higher AEs related to XELOX or mFOLFOX6 may be associated with the degree of CCr. Clinical trial information: UMIN 000008543.
Exploratory analysis of left- versus right-sided colorectal carcinoma in RAISE: A randomized, double-blind, phase 3 trial of ramucirumab (RAM) + FOLFIRI versus placebo (PBO) + FOLFIRI.
Authors: Portnoy David Craig , Obermannova Radka , Bodoky Gyorgy , Prausová Jana , Garcia-Carbonero Rocio , Ciuleanu Tudor-Eliade , Garcia Alfonso Pilar , Cohn Allen Lee , Van Cutsem Eric , Yamazaki Kentaro , Yoshino Takayuki , Lonardi Sara , Kim Tae Won , Yamaguchi Kensei , Grothey Axel , O Connor Juan Manuel , Hsu Yanzhi , Ferry David , Nasroulah Federico , Tabernero Josep
Published: March 2017

668

Background: Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2. Overall survival (OS) and progression-free survival (PFS) in 2nd line FOLFIRI based treatment for metastatic colorectal cancer (mCRC) were improved with RAM therapy versus PBO in the RAISE trial. Recent work suggests mCRC primary tumor location is both prognostic and predictive; with improved OS and therapy-specific sensitivity observed in left (L)- vs right (R)-sided tumors. Given these findings, the RAISE trial data was subjected to post-hoc analysis to determine if sidedness influenced RAM efficacy. Methods: Primary tumor site was obtained. L-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum, while R-CRC included transverse, ascending colon and cecum. OS/PFS in L and R subgroups were analyzed via Kaplan-Meier method and unstratified log-rank test (treatments within subgroup), unstratified Cox proportional hazards model (estimate hazard ratio [HR] and 95% CI), and Wald test (treatment-by-subgroup interaction). Results: Tumor location was available for 1012/1072 (94%) patients, 699 L- and 313 R-CRC. Baseline characteristics were balanced between arms. RAM treatment enhanced L-CRC median OS by 2.5 mo (median 14.5 vs 12.0 mo) with a HR (95% CI) = 0.807 (0.675, 0.965), P = 0.019; compared to a 1.1 mo increase in median OS in R-CRC vs PBO (12.7 vs 11.6) with a HR (95% CI) = 0.971 (0.750, 1.258), P = 0.823; and, RAM enhanced L-CRC median PFS by 1.6 mo (6.0 vs 4.4 mo) and HR (95% CI) = 0.776 (0.664, 0.906), P = 0.001 compared to a 1.1 mo increase in median PFS R-CRC vs PBO (5.6 vs 4.5) with a HR (95% CI) = 0.855 (0.674, 1.084), P = 0.197. The treatment-by-subgroup interaction for both OS and PFS was not significant ( P = 0.276, 0.578, respectively). Conclusions: Despite L-CRC patients having longer OS/PFS and a seemingly stronger RAM treatment effect than R-CRC, the non-significant interaction test cannot verify sidedness as being predictive of RAM efficacy. The current study confirms ramucirumab benefits mCRC patients regardless primary tumor location. Clinical trial information: NCT01183780.
Association of delayed commencement of adjuvant chemotherapy (AC) with inferior survival in colon cancer patients with stage II and III diseases: A national population-based cohort study.
Authors: Kim Ik Yong , Kim Young Wan
Published: March 2017

669

Background: To evaluate factors affecting the delay ( ≥ 8 weeks) of AC and the impact of chemotherapy delay on survival in patients with colon cancer(CC). Methods: The study cohort consisted of patients with stage II and III colon cancer, diagnosed between January 1, 2011 and December 31, 2012, who underwent curative resection and AC at all hospitals registered in the Korean Health Insurance Review and Assessment Service (HIRA). Detailed clinical data are from monitoring and evaluation of quality of colon cancer care. Results: Among 5355 patients, 154 (2.9%) received AC more than 8 weeks after surgery. Based on multivariate analysis, risk factors associated with AC delay ≥ 8 weeks were: older age [65 to 74 years (hazard ratio, HR = 1.48) and 75 years (HR = 1.69), p = 0.0354], medical aid status in health security system (HR = 1.76, p = 0.0345), emergency surgery (HR = 2.43, p = 0.0002), and chemotherapy with fluoropyrimidine (HR = 1.49, p = 0.0373). Independent prognostic factors for inferior OS included AC delay ≥ 8 weeks (HR = 1.49, p = 0.0365), older age [65 to 74 years (HR = 1.94) and 75 years (HR = 3.41), p < 0.0001], TNM III stage (HR = 2.46, p < 0.0001), emergency surgery (HR = 1.89, p < 0.0001), ASA score with 3 or higher (HR = 1.50, p < 0.0001), and higher transfusion amount (HR = 1.09, p = 0.0392). OS rates in patients with stage II / III CCs according to delay of AC using 8 weeks cutoff showed inferior OS in the delayed chemotherapy group (p = 0.008).Detailed OS rates were 97.81% at 1 year, 93.77% at 2 year, 89.62% at 3 year, and 85.79% at 4 year in the chemotherapy group within 8weeks. In the delayed chemotherapy group ≥ 8 weeks, OS rates were 96.1% at 1 year, 87.66% at 2 year, 80.98% at 3 year, and 80.2% at 4 year. Conclusions: This national population-based cohort study shows that delayed commencement of AC, defined as ≥ 8 weeks, is associated with inferior OS in CC patients with stage II / III. To reduce the proportion of patients receiving delayed AC, multidimensional aspects such as health insurance status or age should be considered. Based on our results, the time of commencement of chemotherapy can be incorporated as another quality indicator for colon cancer care.
Nintedanib (N) plus best supportive care (BSC) versus placebo plus BSC for the treatment of patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies: Health-related quality of life (HRQoL) results of the Phase III LUME-Colon 1 study.
Authors: Lenz Heinz-Josef , Tabernero Josep , Yoshino Takayuki , Lonardi Sara , Falcone Alfredo , Limón Mirón María Luisa , Saunders Mark P. , Sobrero Alberto F. , Park Young Suk , Ferreiro Monteagudo Reyes , Hong Yong Sang , Tomasek Jiri , Taniguchi Hiroya , Ciardiello Fortunato , Sassi Mouna , Peil Barbara , Hastedt Claudia , Studeny Matus , Van Cutsem Eric
Published: March 2017

671

Background: N is a multiple angiokinase inhibitor (including VEGFR, PDGFR and FGFR). A randomised Phase III study, LUME-Colon 1 (NCT02149108), evaluated the efficacy and safety of N in pts with refractory mCRC after failure of standard therapies. LUME-Colon 1 showed a statistically significant improvement in PFS (HR [95% CI] 0.58 [0.49–0.69]; p < 0.0001) but no difference in OS (HR [95% CI]: 1.01 [0.86–1.19]; p = 0.8659). Here, we report the HRQoL outcomes. Methods: 768 pts with mCRC adenocarcinoma refractory to standard chemotherapy were randomised 1:1 to receive either N (200 mg bid) + BSC or P (bid) + BSC in 21-day courses until disease progression or undue toxicity. HRQoL was assessed every 21 days using the EORTC QLQ-C30 instrument; the main endpoints of interest were the differences in mean scores up to median follow-up time (treatment difference, TD) for physical functioning (PF) and global health status/QoL (QL) scales using a longitudinal model, with 95% CIs and associated p-values adjusted for baseline stratification factors. Time to deterioration (TTD) of scores and status change ( ≥ 10 point change from baseline) were also assessed. Results: Compliance with questionnaire completion was high ( > 85% in first 12 cycles). Mean baseline (N vs P) PF (80 vs 80) and QL (65 vs 65) scale scores were balanced between treatment arms. The mean TD favoured N vs P for PF scale scores (TD 2.66 [95% CI: 0.97–4.34]; p = 0.0020) and QL scale scores (TD 1.61 [95% CI: −0.04–3.27]; p = 0.0555). TTD of PF (HR 0.84; 95% CI: 0.69–1.03; p = 0.0904) and QL (HR 0.90; 95% CI: 0.75–1.08; p = 0.2674) scores were not significantly different between treatment groups, although the percentage of patients with improved PF (17.2% vs 11.8%; p = 0.0462) and QL scores (30.3% vs 21.6%: p = 0.0102) were both significantly higher for N vs P. Conclusions: In LUME-Colon 1, patient reported outcomes confirmed that overall HRQoL was not impaired by treatment with N. There was evidence for improvement of PF and QL with N vs P, corresponding to the significant increase in PFS observed. Clinical trial information: NCT02149108.
Oral adjuvant chemotherapy using uracil-tegafur (UFT) with leucovorin (LV) after resection of colorectal cancer liver metastases: Long-term survival results of the phase III UFT/LV study.
Authors: Hasegawa Kiyoshi , Saiura Akio , Takayama Tadatoshi , Miyagawa Shinichi , Yamamoto Junji , Bandai Yasutsugu , Teruya Masanori , Yoshimi Fuyo , Kawasaki Seiji , Koyama Hiroto , Oba Masaru , Takahashi Michiro , Yamashita Suguru , Mizunuma Nobuyuki , Matsuyama Yutaka , Watanabe Toshiaki , Makuuchi Masatoshi , Kokudo Norihiro ,   The UFT/LV Study Group
Published: March 2017

672

Background: Surgical resection has been accepted as the standard therapy for colorectal cancer liver metastases (CRLM), however, high recurrence incidence even after curative resection remains a severe problem. The 1st analysis of the UFT/LV trial showed that oral UFT/LV for 6 months significantly prolonged relapse-free survival (RFS) after resection for CRLM (Kobayashi A et al. ASCO 2014, Hasegawa K et al. PlosOne 2016 E-pub). To further evaluate the impact of the UFT/LV therapy on overall survival (OS), we performed the 2nd analysis under longer follow-up period, as have been scheduled by the protocol. Methods: Patients undergoing curative resection of CRLM were randomly assigned to either UFT/LV or surgery alone (control) group. In the UFT/LV group, 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75 mg/day for 28 days followed by 7 days rest in one cycle) were administered. Results: Between 2004 and 2010, a total of 180 patients were enrolled to this trial, among whom 3 patients were ineligible for analysis. Median follow-up of the 2nd analysis was 6 years. The 5y-OS rate in the UFT/LV group was 65.3%, which was slightly better than the control group (62.2%) without statistical significance. The hazard ratio for death in the UFT/LV relative to the control was 0.86 (95% confidence interval: 0.54-1.38, P = 0.54). The OS curves of the 2 groups were identical within 4 years after resection, however, the OS curve of the UFT/LV group seemed to go higher than the control group. The 5y-RFS rate in the UFT/LV group was 36.2%, which was significantly better than that in the control group (32.3%), as have been shown by the 1st analysis. Conclusions: The results of the 2nd analysis suggested that oral UFT/LV adjuvant chemotherapy might be also useful to prolong OS, as have been confirmed for RFS. This regimen can be recommended as an alternative choice after hepatic resection for CRLM. Clinical trial information: C000000013.
Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): Interim data from MyPathway.
Authors: Hurwitz Herbert , Raghav Kanwal Pratap Singh , Burris Howard A. , Kurzrock Razelle , Sweeney Christopher , Meric-Bernstam Funda , Vanderwalde Ari M. , Spigel David R. , Bose Ron , Fakih Marwan , Swanton Charles , Guo Shuangli , Bernaards Coen , Beattie Mary Stanley , Sommer Nicolas , Hainsworth John D.
Published: March 2017

676

Background: Among recent advances in precision medicine, HER2 has emerged as a potential therapeutic target for advanced colon cancer. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. We present updated data for an expanded cohort of patients with HER2-amplified/overexpressed mCRC receiving HER2-targeted therapy with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is a multicenter, open-label, phase IIA study. Patients in this analysis had treatment-refractory HER2-amplified/overexpressed mCRC by gene sequencing, FISH, or IHC. Patients received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate. The cutoff date was July 31, 2016. Results: Of 34 patients with mCRC enrolled, 32 have had ≥1 tumor assessment. At a median follow-up of 5.2 (range 0.7–18.3) months from treatment initiation, 12 patients had partial responses (PR), with stable disease (SD) for >4 months in 3 additional patients (Table). The safety profiles were consistent with the product labels. Conclusions: Interim data show that HER2-targeted therapy with pertuzumab + trastuzumab, a chemotherapy-free regimen, is active in heavily pretreated HER2-amplified/overexpressed mCRC. The ORR was 37.5%, responses were durable (median 11.1 months), and the CBR was 46.9%. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
BBI608-224: A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) administered with panitumumab in KRAS wild-type patients with metastatic colorectal cancer.
Authors: Larson Tim , Ortuzar Waldo Feliu , Bekaii-Saab Tanios S. , Becerra Carlos , Ciombor Kristen Keon , Hubbard Joleen Marie , Edenfield William Jeffery , Shao Spencer H. , Grothey Axel , Borodyansky Laura , Xu Bo , Li Wei , Li Youzhi , Li Chiang , Khan Waheed
Published: March 2017

677

Background: Napabucasin a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. In a phase 1 study, napabucasin monotherapy was well tolerated with encouraging signs of anti-tumor activity at the RP2D of 500 mg BID. Methods: The current open-label, multi-center study includes phase II expansion in pts with refractory, K- Raswt mCRC to confirm safety and anti-tumor activity of napabucasin administered orally at 480mg BID in combination with panitumumab (6mg/kg bi-weekly). Results: 72 pts were enrolled, 48 pts were evaluable by RECIST of which 7 (15%) and 41 (85%) had 2 or >3 prior treatment lines, respectively. Of the 48 evaluable pts, 64.6% (31/48) were previously treated with an anti-EGFR agent. No new adverse events (AEs) were observed and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Among 48 pts enrolled who received RECIST evaluation, Disease Control Rate (DCR) was observed in 25 pts (52.1%) of which 3 pts achieved PR (6%) and 22 pts achieved SD (45%). Among 31 pts previously treated with anti-EGFR therapy, DCR was observed in 15 pts (48%) compared with DCR of 59% observed in 10 out of 17 anti-EGFR naïve pts receiving a scan. Conclusions: This phase II study confirmed that napabucasin can be safely combined with panitumumab at full dose and shows encouraging anti-tumor activity in pts with K- Ras wt mCRC, regardless of prior anti-EGFR exposure, suggesting that napabucasin may sensitize pts to repeat anti-EGFR therapy. Clinical trial information: NCT01776307. [Table: see text]
Evolution in multimodality management of locally advanced rectal cancer.
Authors: Roxburgh Campbell SD , Strombom Paul , Lynn Patricio B , Cercek Andrea , Saltz Leonard , Gollub Marc Jeffrey , Crane Christopher H , Wu Abraham Jing-Ching , Shia Jinru , Vakiani Efsevia , Smith Jesse Joshua , Temple Larissa K. F. , Nash Garrett Michael , Guillem Jose G. , Paty Philip , Garcia-Aguilar Julio , Weiser Martin R.
Published: March 2017

684

Background: This study reports the evolving multimodality management of locally advanced rectal cancer (LARC) and associated outcomes at a high volume center. Methods: Patients with Stage II/III LARC <15cm from the anal verge evaluated by the colorectal surgery service were identified from a prospective database. Clinical management including neoadjuvant therapy (NT) and surgical treatment along with pathologic and perioperative outcomes were collected. Results: Between June 2009 and March 2015, 798 patients were evaluated and received NT for LARC. Majority were staged cT3/T4 (84%) or cN+ (78%), and 635 had surgery within 26wks following NT. Reliance on MRI staging increased from 57% to 98% during the study period (P < 0.001). There was increased usage of total NT (NEO) with pre-op chemotherapy (CT) and chemoradiotherapy (CRT) (17% to 76%, p < 0.001) with a concomitant decrease in use of CRT alone (77% to 16%, p < 0.001) and post-op CT (70% to 15%, p < 0.001). The proportion undergoing surgery beyond 8wks after NT rose from 41% to 62% (P < 0.001) and beyond 8 wks after CRT rose from 45% to 72% (p < 0.001). The percentage of patients not undergoing resection by 26wks (nonoperative management) rose from 12% to 27%, P < 0.001). Minimally invasive surgery (MIS) increased from 33% to 71% (P < 0.001); in 2014-15 98% of MIS was robot-assisted. Over the study period there was a decrease in LOS (mean 8.1 to 6.5 days, p < 0.001), grade III-V complications (13% to 7%, p < 0.05), surgical site infections (25% to 8%, p < 0.001), and anastomotic leak (11% to 3%, p < 0.05). The proportion undergoing ileostomy closure within 15 wks rose from 7% to 73% (P < 0.001). Involved CRM rates decreased from 9% to 3% (P < 0.01). TNM downstaging increased from 62% to 74% (p = 0.002). Complete response rates (clinical and pathologic) at 26wks was 26% in 2009-10 and 32% in 2014/5 (p = 0.067). Conclusions: Over the past decade, there has been a shift to MRI staging, total NT (NEO), and MIS rectal resection at 8-12 weeks. This has been associated with higher response rates, shorter LOS, and fewer complications.