bluuebunny/crossref_metadata_2025 huggingface dataset:
Apatinib in combination with S-1 as first-line treatment in patients with advanced gastric cancer: A phase II clinical trial.
Authors: Zhang Chuantao , Liu Zimin , Zhou Na , Zhang Jianli , Zhu Jingjuan , Lv Hongying , Li Tianjun , Hou Helei , Liu Dong , Cong Jing , Jiang Man , Liu Kewei , Cui Zhumei , Zhou Yanbing , Zhang Xiaochun
Published: January 2019

71

Background: Apatinib is a standard therapy for advanced gastric cancer in third-line setting. However, the efficacy and safety of apatinib plus S-1 as first-line therapy is unknown. Here, we conducted a single center study to evaluate the efficacy and safety of it. Methods: In this phase II trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between August 24, 2016 and Sept 25, 2017, at a single centers in P.R. China. The patients enrolled were assigned to S-1 plus apatinib, S-1 (40 mg m-2 depending on patient's body surface area) was given orally, twice daily for 2 consecutive weeks, followed by a 1-week rest period, and apatinib 500 mg was given once daily, every 3-week cycle. The primary endpoint was overall survival(OS). Secondary endpoints were progression-free survival(PFS), time to progress (TTP), objective response rate (ORR) and safety. On disease progression, patients had the option to receive single-agent apatinib every 3 weeks.This trial is registered with ClinicalTrials.gov , number NCT02525237. Results: Thirty eligible patients, median age 63 years (range 40-76) and median performance status 1 (ECOG 0-2) ,were enrolled, 9 patients have no evaluation or withdrew consent. Therefore, of the 21 patients the median PFS and TTP were 5.34±1.83 months [1.76–8.92] and 1.34±0.08 months[1.18–1.51], respectively. Additionally, one(4.76%) patient had a complete response, one (4.76%)patients had partial responses, 11 patients had stable disease, and 9 patients had progress of disease. The objective response rate(ORR)and the disease control rate(DCR) were 9.52%(2/21) and 57.14%(12/21),respectively. Until Sept 25.2017,the primary endpoint(OS) had not been reached. We recorded grade 3 or 4 adverse events including elevated bilirubin and/or transaminase, fatigue, abdominal pain, thrombocytopenia,et al. There were no treatment-related deaths. Conclusions: First-line chemotherapy with S-1 plus apatinib in patients with advanced gastric cancer did not reach its primary objective. However, it holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer. Clinical trial information: NCT02525237.
A 20-year comparison of definitive chemoradiation with 5-FU versus capecitabine in anal cancer patients treated at Stanford.
Authors: Pumpalova Yoanna S , Kozak Margaret M. , von Eyben Rie , Fisher George A. , Kunz Pamela L. , Chang Daniel Tandel , Haraldsdottir Sigurdis
Published: January 2019

710

Background: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. The objective of this retrospective study was to compare outcomes and toxicities in non-metastatic anal cancer patients undergoing definitive radiotherapy (RT) at Stanford combined with capecitabine/mitomycin (CM) versus 5-FU/mitomycin (FM). Methods: We included all non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997 – 2016. Patients who received cisplatin or induction chemotherapy were excluded. Patient charts were reviewed and cause of death determined from the cancer registry. Fisher’s exact test was used to compare nominal parameters, Mann-Whitney U test for continuous variables. Gray’s test for equality was used to compare recurrence and colostomy incidence, and Log-rank test to compare disease-specific and overall survival. Results: Sixty-eight patients were treated at Stanford. Twenty-nine received FM and RT, 12 received standard 5-FU and 17 received low-dose continuous 5-FU; 39 patients received CM and RT. Median age was 59.5 years, and 56% were female. There was no difference in the 3-year overall and disease-specific survival between the FM and CM groups (81.5% v 90.5% p = 0.262; 88.1% v 96.0% p = 0.229). Incidence of recurrence was equivalent between the two groups (13.8% v 10.6%, p = 0.927) but patients in the combined FM group recurred earlier (6.9 v 20 months, p = 0.004) and distant recurrences were only seen in the CM group. Colostomy rates were higher in the FM group (14.6% v 2.8%, p = 0.082); all colostomies in the FM group were in patients receiving continuous 5-FU. Toxicities were similar between the two groups. The most common grade 2 or higher toxicities were dermatitis (77%), anal pain (77%), diarrhea (54%), stomatitis (19%), and nausea (22%). Conclusions: Overall and disease-specific survival and recurrence rates were equivalent between FM and CM groups. Recurrence patterns differed with loco-regional recurrences and higher colostomy rates in the FM group, while most recurrences in the CM group were distant.
Down expression of activin A receptor type 2A in relation to metastatic potential and prognosis of patients with colon cancer.
Authors: Zhuo Changhua , Hu Dan , Lin Xiandong , Chen Ying , Zheng Xiongwei , Yang Chunkang
Published: January 2019

712

Background: The ACVR2A (activin A receptor type 2A) is a membrane receptor in TGF-β signal pathway, which is involved in the regulation of cell proliferation, migration and apoptosis. The expression profiles and biological functions of ACVR2A in colon cancer is largely unknown so far. Methods: ACVR2A expression was investigated using GSE39582 database and two validation cohorts. The in vitro study of the cell proliferation and migration of human colon cell lines was also performed. Results: In GSE39582 database (n = 497), lower mRNA expression of ACVR2A was identified as an inferior prognostic factor by linear regression analysis. In one validation cohort of 15 stage IV patients, the mRNA expression of ACVR2A was significantly reduced in metastatic lesions and primary tumors compared with adjacent normal controls (P = 0.001). In another validation cohort of tissue microarray (TMA) cohort consisting 193 cases, reduced ACVR2A expression was correlated with advanced N stage (P = 0.001) and positive lymphovascular invasion (P = 0.005). Strong correlations between lower ACVR2A mRNA or protein expression and worse survival were also observed in GSE39582 database and TMA validation cohort (all P< 0.05). Moreover, our in vitro studies showed a remarkable increase of cell migration in cell ACVR2A knockdown cells. Conclusions: Taken together, our findings indicate that loss of ACVR2A has an important role in cancer progression and distant metastasis, and may serve as a prognostic marker in patients with colon cancer. Keywords: Activin a receptor type 2A (ACVR2A), Colon Cancer, tissue microarray, Metastasis, Cell proliferation, Cell migration
Dynamic monitoring HER2 amplification of circulating DNA in metastatic colorectal cancer patients treated with cetuximab.
Authors: Chen Zhi-Yu , Liu Rujiao , Guo Weijian , Zhu Xiaodong , Zhao Xiaoying , Qiu Lixin , Zhang Xiaowei , Huang Mingzhu , Zhang Wen , Zhang Zhe , Li Wenhua
Published: January 2019

714

Background: Addition of cetuximab has shown clinical benefit in RAS and BRAF wild-type (wt) patients with metastatic colorectal cancer (mCRC). Human epidermal growth factor receptor 2 ( HER2) amplification was reported to be one of the resistance mechanisms to cetuximab. We investigated whether monitoring of HER2 amplification in circulating DNA allows early detection of progression and informs about resistance to cetuximab. Methods: We analyzed HER2 amplification in circulating DNA by 8 week-interval using droplet digital polymerase chain reaction (ddPCR) from 30 RAS and BRAF wt patients, who progressed after failure of cetuximab-containing regimens between Jul 2015 and Jun 2017. Results: 16.7% (5/30) of patients exhibited dynamic fluctuations of HER2 amplification in plasma, one of whom was found to be positive for HER2 amplification in matched tumor tissue sample using FISH. Two patients had HER2 and c-MET co-amplification. All 5 primary sites were left side, 4 rectums and 1 descending colon. 3 patients received cetuximab as first line therapy, whereas 2 patients in the 2nd line setting. Among these 5 patients, changes in circulating DNA levels showed good agreement with changes in tumor volume. Furthermore, quantifications of HER2 amplification showed obvious increase with an average lead time of 2 months compared with CT documented progress. But interestingly, there was no difference in progression-free survival (PFS) between these 5 patients and the others without HER2 amplification (p > 0.05). Conclusions: Plasma HER2 amplification detected by ddPCR was showed dynamic changing over time and would predict resistance to cetuximab-containing treatment. Average 2 months lead time was observed and need to validate in the further study.
Effect of MMP-13 degraded SPARC on type I collagen and its biomarker potential in colorectal cancer.
Authors: Kehlet Stephanie Nina , Harling Henrik , Jørgensen Lars N , Karsdal Morten A , Willumsen Nicholas
Published: January 2019

717

Background: Increased collagen deposition and remodeling of the extracellular matrix has been shown to play a role in the pathology of gastrointestinal cancer (GC). The matricellular protein SPARC (secreted proteome acidic and rich in cysteine) binds collagens and hereby regulates collagen fibrillogenesis. Matrix metalloproteinase (MMP) mediated cleavage of SPARC, increases the affinity for collagens up to 20-fold. SPARC has been shown to be overexpressed in GC patients and associated with GC cell invasion and metastasis. Increased expression and cleavage of SPARC might therefore be implicated in GC pathology by increasing collagen deposition. Here, we present the development and validation of a competitive enzyme-linked immunosorbent assay (ELISA) quantifying a specific MMP-13 generated fragment of SPARC - a cleavage site involved in increased collagen affinity. The biomarker potential of this fragment was examined in serum from colorectal cancer (CRC) patients and healthy controls. Moreover, we evaluated the ability of cleaved SPARC to prevent type I collagen degradation in vitro. Methods: A monoclonal antibody was raised against a MMP-13-generated neo-epitope of SPARC and a competitive ELISA assay (SPARC-M) was developed and technically validated. Serum levels were assessed in CRC patients (n=50) and healthy controls (n=30). The ability of cleaved SPARC to prevent collagen degradation was investigated using an ELISA assay measuring type I collagen degradation by MMP-9. Results: SPARC-M was technically robust and specific for SPARC cleaved by MMP-13. The fragment was elevated in CRC patients when compared to healthy controls (p=0.0097). When MMP-13 degraded SPARC was incubated with type I collagen and MMP-9, type I collagen degradation was completely inhibited suggesting that SPARC increases collagen deposition by preventing collagen degradation. Conclusions: SPARC-M was significantly elevated in CRC patients compared to healthy controls suggesting biomarker potential. Biologically, cleaved SPARC may prevent type I collagen degradation hereby leading to a pro-tumorigenic environment. Larger clinical studies are needed to validate the clinical use of this biomarker in GC.
Single nucleotide polymorphisms (SNPs) in COL4A2, PPP1R17, and ARHGAPP44 and prognostic value in metastatic colorectal cancer (mCRC).
Authors: Townsend Amanda Rose , Asher Rebecca , Price Timothy Jay , Lee Chee Khoon , Dorward Hilary , Gebski Val , Tomita Yoko , Tebbutt Niall C. , Hardingham Jennifer
Published: January 2019

720

Background: Our previous study has identified COL4A2, PPP1R17 and ARHGAP44 SNPs using whole exome sequencing with potential prognostic significance (Townsend et al. ASCO GI 2017). COL4A2 encodes a subunit of type IV collagen, the C-terminal of which is an inhibitor of angiogenesis. We assessed prognostic impact of these variants in patients from the phase III MAX study (capecitabine +/- bevacizumab (+/- mitomycin C)). An analysis of predictive effect on bevacizumab was also undertaken. Methods: DNA was extracted from archival macrodissected formalin fixed paraffin embedded tumor tissue and genotyped using Agena Bioscience MassARRAY system (AGRF). Univariate association of variant group (WT versus mutation (MT)) with progression free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier curves and Cox regression models. Logistic regression models were used to assess association with response rate (RR). A cox regression model with treatment, variant status and their interaction investigated if variants were predictive of bevacizumab effect. Results: Of the available 145 of 471 (31%) patients in the MAX study, 25 (17%) had COL4A2 MT, 29 (20%) PPP1R17 MT, 14 (10%) ARHGAP44 MT. Patient demographics were comparable across treatment groups and outcomes similar to whole study population. On univariate analysis median PFS was numerically longer for WT vs MT in all 3 variants, but these differences were not significant (COL4A2 WT 8.4m v MT 6.0m, p=0.09; PPP1R17 WT 7.8m v MT 7.5m, p=0.76; ARHGAP44 WT 8.2m v MT 6.5m, p=0.86). There was also no significant association between variant type and OS. Multivariate analysis for COL4A2 MT v WT showed no significant difference in PFS or OS (HR 1.42; 95% CI 0.91-2.22, p=0.13 and HR 1.33; 95% CI 0.85-2.1, p=0.21). There was no association between treatment response and variant status. Variant status was not predictive of bevazicumab efficacy for treatment response, PFS or OS. Conclusions: There was no significant prognostic or predictive impact of novel gene variants in patients treated with bevacizumab. This may be due to small numbers of MT variants in this study and further studies in larger populations may be useful.
Regorafenib tolerance and outcomes in inner-city minority colorectal cancer population.
Authors: Ahmed Ahmed Tarig , Malapati Sindhu Janarthanam , Yim Barbara , Singh Sunny R K , Gupta Shweta
Published: January 2019

722

Background: Regorafenib (REG) is an oral multikinase inhibitor used for treatment of metastatic colon cancer after progression on fluorouracil, oxaliplatin and irinotecan therapy. The FDA approval was based on CORRECT trial showing improvements in progression-free survival (PFS) and overall survival (OS). Another trial (CONCUR) showed similar results. However, these trials included predominantly Whites and Asians. Our study aimed to evaluate treatment outcomes in the underserved, mainly African Americans and Hispanics. Methods: Cook County hospital is the 3rd largest public hospital in the US. All patients with an order for REG were identified from our pharmacy database. Charts were retrospectively reviewed for cancer stage, age, ethnicity, previous treatments, PFS and OS. Patients with non-colorectal cancer, incomplete data, no evidence of REG usage were excluded. Statistical analysis was done by t-test on subgroups. Results: A total of 42 patients were screened and 30 were included in the study. A comparison of outcomes with CORRECT and CONCUR trials is presented in Table 1. Our study patients, despite being less heavily pre-treated, had a worse OS compared to the clinical trials, with similar PFS. There was a trend towards better PFS and OS in women in our study of 4.3 and 4.8 months compared to men with 1.9 and 3.3 months respectively (p = NS). Six (20%) patients discontinued REG due to intolerance within a median of 1.2 months. The intolerant patients had a significantly higher median BMI of 31 compared to 24.9 for patients who continued the medication to progression (p = 0.019). Conclusions: Compared to CORRECT and CONCUR trials, population of predominantly AA and Hispanics showed a trend towards worse OS despite being less heavily pre-treated indicating worse outcomes in minorities treated with REG. Women showed better PFS and OS compared to men in our study. Patients unable to tolerate REG had significantly higher BMI, indicating a need to study dosing in this subgroup. [Table: see text]
Evaluation of outcomes over time (1998-2009) of patients (pts) with stage III colon cancer receiving adjuvant FOLFOX: Analysis of 7,230 patients from MOSAIC, C07, C08, N0147, AVANT, and PETACC8 trials in the ACCENT Database.
Authors: Salem Mohamed E. , Yin Jun , Goldberg Richard M. , Pederson Levi , Wolmark Norman , Alberts Steven R. , Taieb Julien , Marshall John , Lonardi Sara , Yoshino Takayuki , Kerr Rachel , Yothers Greg , Grothey Axel , Andre Thierry , De Gramont Aimery , Shi Qian
Published: January 2019

724

Background: Adjuvant FOLFOX is the standard of care for pts with stage III colon cancer and a platform to test new agents. Improvements in supportive care and development of newer treatments for metastatic disease impact the overall outcome of pts treated with adjuvant therapy. We examined the trend of disease-free survival (DFS), survival after recurrence (SAR), and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of colon cancer pts enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated by adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T/N stage, tumor sidedness and histologic grade. Results: In total, 7,230 pts (stage II [n = 1122]; stage III [n = 6,108]) were identified; 32% and 68% were treated in the old and new era, respectively. Stage III pts enrolled in the new era were significantly younger, more likely to have T4/N2 disease, higher tumor grade, and left-sided tumors. After adjusting for pt characteristics, no difference in DFS was seen over time. However prolonged SAR and OS were observed in pts treated in the new era (Table). 5yr OS increased from 76% to 80% over time. Median SAR improved from 14.8 to 26.4 months. Conclusions: Stage III colon cancer pts who received adjuvant FOLFOX experienced significant improvements in SAR and OS—but not DFS—over time. In view of the improvements in OS and nearly doubled SAR, the optimal duration of OS follow-up to evaluate the benefits of adjuvant therapy (currently 5 years) should be reassessed, and ACCENT investigators are planning to conduct these additional analyses using their large pooled-trial database. [Table: see text]
Efficacy outcomes with bevacizumab added to chemotherapy (bev+CT) compared with chemotherapy alone (CT) in left- and right-sided tumors in metastatic colorectal cancer (mCRC).
Authors: Loupakis Fotios , Hurwitz Herbert I. , Saltz Leonard , Arnold Dirk , Grothey Axel , Nguyen Quynh Lan , Osborne Stuart , Yau Linda , Talbot Jonathan , Srock Stefanie , Lenz Heinz-Josef
Published: January 2019

726

Background: Primary tumor location is an important prognostic factor in mCRC. Efficacy differences with EGFR antibodies by tumor location show a predictive effect (Arnold et al. Ann Oncol 2017). Two first-line (1L) pivotal bev trials showed the prognostic value of sidedness (Loupakis et al. J Natl Cancer Inst 2015). In this exploratory study, further analysis of the predictive effect of bev is presented. Methods: Data from two randomized phase III studies (NO16966 [NCT00069095], AVF2107g [NCT00109070]) of bev+CT vs CT-alone as 1L treatment for mCRC were analyzed retrospectively. Patients (pts) with sidedness information available were included; pts from NO16966 (part 1) randomized to CT only were excluded. Sidedness was identified by case report forms. Results: Sidedness was determined in 1590 pts (27% Right and 73% Left) out of 2214 pts total (Table). In the pooled analysis, PFS improved with bev+CT compared to CT only in both right-sided (HR=0.75; 95% CI 0.61, 0.93) and left-sided (HR=0.76; 95% CI 0.67, 0.86) mCRC with similar magnitude of benefit in both sides. OS also improved with bev+CT in right-sided (HR=0.82; 95% CI 0.65, 1.03) and left-sided (HR=0.85; 95% CI 0.74, 0.98) pts. Conclusions: This exploratory subgroup analysis of two pivotal studies indicates that the effect of bev is independent of tumor location in mCRC patients. Survival outcomes. Clinical trial information: NCT00069095 and NCT00109070. [Table: see text]
Outcomes over time (1998-2009) of stage II colon cancer patients (pts) receiving adjuvant FOLFOX: Pooled analysis of 1,122 pts in the ACCENT database.
Authors: Salem Mohamed E. , Yin Jun , Goldberg Richard M. , Pederson Levi , Wolmark Norman , Alberts Steven R. , Taieb Julien , Marshall John , Lonardi Sara , Yoshino Takayuki , Kerr Rachel , Yothers Greg , Grothey Axel , Andre Thierry , De Gramont Aimery , Shi Qian
Published: January 2019

728

Background: Adjuvant FOLFOX therapy for stage II patients remains controversial, and selection criteria are imprecise. We examined the trend of disease-free survival (DFS: time to recurrence or death, whichever occurs first); time to recurrence (TTR: time to recurrence, censored at death without recurrence); survival after recurrence (SAR); and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of pts with stage II colon cancer enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated using adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by multivariate Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T stage, number of lymph nodes (LNs) examined, tumor side, and histologic grade. Results: In total, 1,122 pts with stage II were identified; 71% and 29% were treated in the old and new era, respectively. Pts enrolled in the new era were significantly younger and more likely to have higher tumor-grade and right-sided tumors compared to old era. More pts in the new era (71%) had ≥12 LNs examined compared to the old era (53%). After adjusting for potential confounding effects, no difference in DFS, TTR, SAR or OS between old and new eras was found (Table). Although median SAR increased from 13.6 to 26 months over time, this was not statistically significant, likely due to lack of power. An increased TTR over time (HRadj. 0.41, padj.= 0.002) was observed in pts with ≥12 LNs examined (3-yr TTR: 92% in old era vs. 96% in new era), but not pts with <12 LNs examined (pinteraction = 0.04). Conclusions: In stage II colon cancer pts who received adjuvant FOLFOX, no significant increase of DFS or OS was observed over time. However TTR was longer only in pts with ≥12 LNs examined. [Table: see text]
Three versus six months adjuvant oxaliplatin plus fluoropyrimidine chemotherapy for patients with stage III colon cancer: The Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant (IDEA) chemotherapy project.
Authors: Souglakos John , Boukovinas Ioannis , Xynogalos Spyros , Kakolyris Stylianos , Ziras Nikolaos , Vaslamatzis Michael , Ardavanis Alexandros , Athanasiadis Athanasios , Androulakis Nikolaos E. M. , Kentepozidis Nikolaos K. , Christopoulou Athina , Makrantonakis Paris , Varthalitis Ioannis I. , Christofyllakis Charalampos , Emmanouilides Christos E. , Mavroudis Dimitrios , Prinarakis Efthimios , Kalisperi Aggeliki , Hatzidaki Dora , Georgoulias Vassilis
Published: January 2019

730

Background: The IDEA international collaboration aimed to combine data from 6 randomized trials to investigate whether a 3-month (3m) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month(6m) for 3-year disease free survival (DFS)in stage III colon cancer (CC). Methods: HORG-IDEA randomized patients between 3Mand 6M of CT with mFOLFOX6 or CAPOX. DFS was estimated using the Kaplan–Meier method and described using 3 years DFS rate. Results: In total708 patients were randomized between May 2009 and October2015, 354in each arm. Among them the basic characteristics was: median age 63.9 years; mFOLFOX6: 41.8% and CAPOX 58.2%, N1: 74.9%, N2: 25.2%; T1-3: 86.4%, T4: 13.6%. DFS median follow-up was 54.2 months. There were 214 DFS events (109in 3M and 105 in 6M arm) leading to a 3-year DFS rate of 73.2% in the 3M vs. 74.9% in the 6M (HR = 1.03; 95%CI 0.80–1.43, p = 0.622).For patients receiving mFOLFOX6, 3-year DFS rate was 71.8% in the 3M vs.77.7% in the 6M (HR = 1.18; 95%CI 0.74–1.88 p = 0.478). For patients receiving CAPOX 3-year DFS rate was 74.7% in the 3M vs. 74.8% in the 6M (HR = 0.99; 95%CI 0.69–1.45 p = 0.994).94.2% and 78.0% of pts completed 3 and 6 months of CT, respectively. Overall, 96.9% and 89.5% of patients completed 3 months (arm A) and 6 months (arm B) of CT, respectively. Median oxaliplatin doses intensity were 97.3% in 3M and 73.2% in 6M (505.0 and 738.3 mg/m2).Overall maximum neuropathy during treatment grade 2/3-4 was 23.9/5.9%in 3M and38.7/13.7%in 6M; p < 0.0001. In addition, worst grade 2/3-4 diarrhea was 11.1/4/0 in 3M and in 12.3/7.36M; p = 0.03. Conclusions: Since the HORG-IDEA study was designed in order to contribute patients in the IDEA project, the result on the study should be interpreted together with those of the whole IDEA project. Nevertheless, the results of the HORG-IDEA study are in line with those of the whole IDEA project, indicating that the results are depended on the administered adjuvant regimen, and the choice of regimen and duration should be depended on tumor characteristics and patient preference. Clinical trial information: NCT01308086.
Age, gender, and performance status effects on efficacy of 3 versus 6 months of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for stage III colon cancer: Phase III ACHIEVE trial as part of the IDEA collaboration.
Authors: Kato Takeshi , Yoshino Takayuki , Yamanaka Takeharu , Kotaka Masahito , Manaka Dai , Eto Tetsuya , Hasegawa Junichi , Takagane Akinori , Nakamura Masato , Munemoto Yoshinori , Nakamura Fumitaka , Bando Hiroyuki , Taniguchi Hiroki , Gamoh Makio , Shiozawa Manabu , Saji Shigetoyo , Maehara Yoshihiko , Mizushima Tsunekazu , Ohtsu Atsushi , Mori Masaki
Published: January 2019

731

Background: ACHIEVE, a part of the IDEA collaboration, was a multicenter trial randomizing patients with stage III resected colon cancer to either 3 versus 6 months of mFOLFOX6/CAPOX. The primary endpoint was disease-free survival (DFS). We previously reported that the hazard ratios (HRs) of 3 versus 6 months duration in this study according to risk stage (low-risk [T1-3 and N1] or high-risk [T4 or N2]) and regimen (mFOLFOX6 or CAPOX) as well as in overall population were consistent with those observed in the whole IDEA. Methods: ACHIEVE enrolled 1313 patients in Japan between August 2012 and June 2014, out of whom 1291 pts were analyzed for efficacy analysis. As of June 2017, 291 DFS events were observed with a median follow-up time of 39 months. The HR of DFS in the overall population was 0.95 (0.76—1.20) with a 3-year DFS of 80% in 3 months arm and 78% in 6 months arm. In the current study, we investigated subgroup analyses for DFS including age, gender, and ECOG performance status (PS). Results: Outcomes of subgroup analyses are summarized in the Table. With regard to HRs and upper bound on the confidence intervals, the trend of 3 months arm being slightly inferior to 6 months arm in patients with an age of ≥70, female gender, and an ECOG PS of 1; however, there was no evidence of significant interaction across treatment duration and the subgroups. Conclusions: The treatment duration effect did not depend on age, gender, and ECOG PS. Further results according to risk stage and regimen will be presented. Clinical trial information: UMIN 000008543. [Table: see text]
The consensus molecular subtypes of colorectal cancer as a predictive factor for chemotherapies against metastatic colorectal cancer.
Authors: Okita Akira , Takahashi Shin , Ouchi Kota , Inoue Masahiro , Yamada Yasuhide , Ishioka Chikashi
Published: January 2019

736

Background: Since treatment options of chemotherapy for metastatic colorectal cancer (mCRC) have been diversified, biomarkers which could predict efficacy of chemotherapies are needed for optimal treatment. In this study, we analyzed the association of the treatment outcomes by several chemotherapies and the consensus molecular subtypes (CMS), which was developed from large-scale comprehensive gene expression analysis of colorectal cancer (Guinney J et al. Nat Med 21:1350-6, 2015). Methods: A total of 193 patients with previously treated mCRC were classified in 4 subtypes, CMS1 to CMS4 by using the microarrays data of primary tumors and the “CMS classifier” package for the R software. Then the association between the subtypes and the treatment outcomes was analyzed retrospectively. Results: The193 cases were classified into 21 CMS1, 53 CMS2, 69 CMS3 and 50 CMS4. The molecular characteristics of each subtype such as mutation status of KRAS and BRAF genes, and DNA methylation status were consistent with those of the previous study. First-line chemotherapies of the 193 patients were oxaliplatin (OX)-based treatment (121 patients), irinotecan (IRI)-based treatment (59 patients) and others (13 patients). In CMS4, the median progression-free survival (PFS) of the IRI-based group was significantly longer than that of the OX-based group (21.8 months vs. 10.5 months, p < 0.01). The median overall survival (OS) and objective response rate of the IRI-based group were also better than that of the OX-based group in CMS4. Among 193 patients, 103 were RAS wild-type and treated with anti-EGFR antibody. The effect of the anti-EGFR treatment was low in CMS1 (median PFS: 2.4 months, p < 0.01, median OS: 5.7 months, p < 0.01) and whereas was high in CMS2 (median PFS: 8.0 months, p = 0.05, median OS: 26.6 months, p = 0.02). CMS significantly correlated with PFS and OS after anti-EGFR treatment by univariate analysis. However the most useful predictive biomarker was a DNA methylation status by multivariable analysis. Conclusions: The biological characteristics of CMS may affect the therapeutic effect of anti-cancer agents in mCRC and, therefore, might be a new predictive factor of anti-cancer treatment.
The influence of hospital and surgeon volume on survival and local control in rectal cancer: Long-term results of the CAO/ARO/AIO-94 trial.
Authors: Sprenger Thilo , Beissbarth Tim , Sauer Rolf , Fokas Emmanouil , Hohenberger Werner , Liersch Torsten , Rödel Claus , Ghadimi Michael
Published: January 2019

738

Background: The association of hospital and surgeon volume with the outcome of rectal cancer patients is under debate. In this study the long-term influence of the hospital as well as the surgeon volume on overall survival and local recurrence were investigated. Methods: In a post-hoc analysis of the randomized phase III CAO/ARO/AIO-94 trial after a follow-up of more than 10 years, 799 patients with locally advanced rectal cancers were evaluated. Survival and local recurrence rates were stratified by the hospital recruitment volume (≤20 vs. 21-90 vs. > 90 patients) and by the surgeon volume (≤10 vs. 11-50 vs. > 50 procedures). Results: Patients treated in „high-volume“ hospitals had a longer overall survival than those treated in hospitals with medium or low treatment volume (p = 0.03). The surgeon volume was significantly associated with decreased local recurrences (p = 0.01) but had no influence on overall survival. The effect of neoadjuvant chemoradiation on local control was the strongest in patients being operated by medium-volume surgeons. Conclusions: Patients with locally advanced rectal cancers might benefit from treatment in in specialized high-volume hospitals. In particular, the surgeon volume had significant influence on local control.
The impact of primary tumour resection and sidedness in patients with synchronous metastatic colorectal cancer (mCRC): Findings from the South Australian Metastatic Colorectal Cancer Registry (SAMCRC).
Authors: Klevansky Myron , Vatandoust Sina , Dykes Lukah , Padbury Rob , Price Timothy Jay , Roder David , Moore James , Piantadosi Cynthia , Roy Amitesh , Karapetis Christos
Published: January 2019

739

Background: The benefit of primary tumour resection (PTR) in patients with synchronous mCRC is not clear. The influence of tumour location on PTR benefit is also uncertain. Methods: SAMCRC is a population based registry collating data from all patients in South Australia diagnosed with mCRC from February 2006. We examined outcomes according to whether the primary colorectal tumour was excised within 3 months of diagnosis or remained in situ; we also examined whether outcomes were affected by tumour side (right v left). Registry data was included for patients with synchronous metastic adenocarcinoma from colon or rectum. Exclusion criteria included metastasectomy, tumour resection within 7 days or death within 3 months of mCRC diagnosis. Kaplan Meier analysis was used for Survival. Tumour sidedness and PTR were analysed with a multivariate Cox proportional hazards model. Survival was measured from the landmark date (3 months from date of diagnosis). Results: 2575 patients with synchronous mCRC have entered the database, of which 1869 patients were eligible for the PTR analysis. 50.2% (n = 938) underwent PTR. 481 patients (51.3%) of the PTR analysis group had left-sided primary tumours whilst 436 had right sided tumours (46.5%) which was significant (p < 0.001). 63% of the PTR cohort were male (n = 1006). Site and age metastases were included in the multivariate analysis. PTR was associated with improved survival from landmark compared to no resection (15.0 mo vs 11.2 mo, 95% CI 15.0 – 16.3 vs 11.2 – 12.3, p = 0.031). In the entire synchronous mCRC group, left-sided tumours (62.1%) had a longer median survival (17.8 mo vs 10.4 mo, 95% CI 15.7 – 19.5 vs 10.4 – 11.7 p = < 0.001). An interaction test was performed for sidedness and was not significant. Conclusions: PTR was associated was associated with improvement in survival in this large population based registry. This finding did not differ signifcantly between right and left sided tumours. Survival was superior for patients with left sided tumours, in keeping with established data. Criteria for selection of patients with mCRC who benefit from PTR need to be defined.
MET-amplification (MET-amp) in relation to aggressive biology in esophagogastric cancer (EGC): An analysis of clinical outcomes of MET-amp vs non-MET-amp EGC.
Authors: Hong Theodore S. , Hwang Katie L. , Clark Jeffrey W. , Lennerz Jochen K , Shui Amy , Zheng Hui , Szymonifka Jackie , Corcoran Ryan Bruce , Heist Rebecca Suk , Russo Andrea Lyn , Parikh Aparna Raj , Borger Darrell R. , Blaszkowsky Lawrence Scott , Faris Jason Edward , Murphy Janet E. , Azzoli Christopher G. , Mullen John Thomas , Ryan David P. , Iafrate A. John , Kwak Eunice Lee
Published: January 2019

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Background: c-MET gene amplified ( MET-amp) tumors have been identified as a rare but targetable subset of esophagogastric cancer (EGC). In a phase I study, patients with MET-amp EGC had a 50% response rate to the oral MET inhibitor AMG 337, with some responses exceeding a year (Kwak EL, GI ASCO 2015). We evaluate clinical characteristics and outcomes were evaluated in patients with MET amplified esophagogastric cancer to facilitate identification of patients and establishment of treatment paradigms. Methods: Patients with metastatic MET amplified EGC were identified. MET-amplification was identified by fluorescent in situ hybridization (FISH) on paraffin-embedded tissue, with a gene to control ratio of > 2.2 defined as positive. Clinical characteristics, treatment factors, and survival were recorded. A group of metastatic non- MET amplified patients identified during the same time period who had undergone tumor genotyping and treatment at our institution was evaluated as a comparison group. Results: 21 patients were identified with metastatic MET amplified EGC and 65 patients with metastatic non- MET amplified EGC. The majority of MET amplified tumors occurred in the distal esophagus. 4 patients had co-amplification of HER2, 1 patient had PIK3CA mutation and 1 patient had a TP53 mutation. Compared to non- MET amplified tumors, MET-amplified tumors were more likely to have poorly differentiated tumors. There was no difference in initial sites of metastatic disease. Progression-free survival (PFS) for first line therapy was substantially shorter for patients with MET (6.5 mo vs 14.3 mo, p = 0.0033). MET amplified patients trended towards a shorter overall survival (OS) as well (12.3 mo vs. 20.1 mo, p = 0.0523). Conclusions: MET amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Given the efficacy seen with MET inhibition, patients need to be tested and identified early and directed to appropriate MET-targeted clinical trials.
VOICE trial: Final results from multicenter phaseII study of assessment of clinical efficiency and safety in capecitabine plus intermittent oxaliplatin together with bevacizumab as first-line therapy for patients with advanced colorectal cancer.
Authors: Kosugi Chihiro , Koda Keiji , Denda Tadamichi , Ishibashi Keiichiro , Ishida Hideyuki , Seike Kazuhiro , Sakata Naoto , Yanagisawa Shinji , Miyazaki Akinari , Takayama Wataru , Koike Naoto , Matsubara Hisahiro , Yamazaki Masato , Shimizu Hiroaki , Shuto Kiyohiko , Mori Mikito , Narushima Kazuo
Published: January 2019

740

Background: The FOLFOX with bevacizumab (B-mab) has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and OPTIMOX1 study suggested that stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. The CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we accessed the efficacy and safety of the combination of intermittent CapeOx + B-mab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, No Peripheral neuropathy ( < Grade 1). Patients received CapeOX (oxaliplatin 130mg/m2, capecitabine 2000mg/m2 + B-mab 7.5mg/kg) q3 weeks for 5 cycles, maintenance without oxaliplatin for 5 cycles, and reintroduction CapeOX + B-mab for 5 cycles until progression. Primary endpoint was Progression Free Survival (PFS). Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female (33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance Capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 14.7months (95%CI, 8.6–19.5) and Median TTF was 12.3 months (95%CI, 10.3–14.3). Best overall response rate was 48.0%. Oxaliplatin reintroduction rate was 57.4%. Main grade 3/4 toxicity were: neutropenia (1 pt), anemia (1 pt), peripheral neuropathy (1 pt), allergic reaction of oxaliplatin (1 pt), deep vein thrombosis (1 pt), nausea (1 pt), hand-foot syndrome (1 pt), and hypertension (1 pt). Conclusions: This study met its primary endpoint PFS. CapeOx intermittent oxaliplatin indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerate and effective for first line therapy in mCRC, and maintenance duration for 5 cycles, was reasonable. Clinical trial information: UMIN000005732.
Sidedness, mutations, and survival in stage IV colon cancer: A U.S. population-based study.
Authors: Lin Albert Y. , Kahl Amanda , Gribovskaja-Rupp Irena , West Michele , Lynch Charles F , Charlton Mary E.
Published: January 2019

742

Background: Despite recent diagnostic and therapeutic advances in colon cancer (CC), it remains one of the leading causes for cancer-related deaths worldwide. At time of diagnosis, 20% of CC patients (PTS) present with de novo stage IV. In recent years, clinical trials have identified sidedness and several molecular biomarkers (MBM), such as microsatellite instability high (MSI-H), KRAS and BRAF mutations, as prognostic and predictive factors for treatment response in stage IV CC. However, their impact and interactions in the population-based setting remain elusive. Methods: The National Cancer Institute’s 2014 Patterns of Care study included a sample of 1,444 stage IV CC PTS from Surveillance, Epidemiology, and End Results registries, and captured MSI, BRAF and detailed chemotherapy information not available in the public-use dataset. Demographic, tumor, molecular and treatment data were compared using chi-square tests. Cox proportional hazards models were used to compare overall survival (OS) across subgroups of demographic, tumor, MBM and treatment characteristics. Results: Compared to left-sided (L) CC, PTS diagnosed with right-sided (R) CC tend to be older (median age: 65 vs 60, respectively; p < 0.001), more females (54% vs 44%, p = 0.001), African Americans (25% vs 22%, p = 0.001), have poorly or undifferentiated tumors (27% vs 15%, p = 0.001), and harbor MSI-H (14% vs 7%, p = 0.018), KRAS (52% vs 36%, p < 0.001) or BRAF (29% vs 11%, p = 0.001) mutations. FOLFOX, with or without bevacizumab, accounted for > 50% of the first-line regimens. Multivariable Cox proportional hazards models revealed the following poor risk factors: right-sidedness, poorly or undifferentiated tumor, no surgery, no chemotherapy, no cetuximab/panitumumab or no bevacizumab therapy. In separate models for LCC and RCC among those tested for KRAS (n = 689), treatment with bevacizumab was associated with lower odds of death in both models (p < 0.05). Cetuximab/panitumumab were nearly significantly associated with lower odds of death in LCC (p = 0.06) but not RCC (0.35). Conclusions: Right-sidedness is a poor prognostic factor in stage IV CC. Regardless of sidedness, stage IV CC PTS can benefit from surgery, chemotherapy, or bevacizumab.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS), progression free survival (PFS) and disease control rate (DCR) in patients with metastatic colorectal cancer (mCRC) from the RECOURSE study.
Authors: Argiles Guillem , Yoshino Takayuki , Ohtsu Atsushi , Mayer Robert J. , Winkler Robert , Amellal Nadia , Fougeray Ronan , Kanehisa Akira , Van Cutsem Eric
Published: January 2019

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Background: Elevated neutrophil-to-lymphocyte (NLR) ratios may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types. Trifluridine/tipiracil (FTD/TPI also known as TAS-102) compared with placebo significantly improved OS (median: 7.1 vs.5.3 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) [0.58;0.81], p < 0.0001), PFS, and DCR in the phase 3 RECOURSE study, conducted in patients with refractory mCRC. A post-hoc analysis was conducted to assess correlation between clinical outcomes and baseline NLR (in blood) in RECOURSE. Methods: A retrospective review on 782/800 patients, with available NLR, was performed on OS, PFS, and DCR in two subgroups of patients with low ( < 3) or high (≥ 3) NLR at baseline. Based on literature, the cutoff value of 3 was chosen as the number of patients was similar in each NLR subgroup. Between-group comparison was performed using a stratified Cox’s proportional hazard model for OS and PFS, and Fisher’s Exact test for DCR. Results: The median value of NLR at baseline was similar in each group, FTD/TPI (N = 519): 4.4 ± 6.3, placebo (N = 263): 4.7 ± 6.5. Almost 60% of patients in each group had high NLR. In the low NLR vs. high NLR subgroup, there were differences at baseline for ethnic origin (Asian: 45% vs.29%), ECOG PS 0 (69% vs. 49%), and number of metastatic sites ≥ 3 (32% vs. 46%). The median OS [95 % CI] was statistically significantly higher in the low vs. high NLR subgroup: 8.4 [7.8;9.5] vs. 5.3 [4.7;5.7] months, HR = 0.49, 95% CI [0.41;0.59], p < 0.0001. Irrespective of NLR, all patients benefited from FTD/TPI vs. placebo. The results of PFS and DCR were statistically significantly better in the low NLR vs. high NLR subgroup. The multivariate Cox analysis for OS with the interaction test between treatment groups and NLR showed that NLR is not a predictive factor (p = 0.15). Conclusions: In this retrospectively analyzed mCRC population, NLR was shown to be an independent prognostic factor. Further research is warranted to assess if NLR can be a stratification factor in mCRC clinical trials. Clinical trial information: NCT01607957.
Panitumumab versus cetuximab in patients with wild-type KRAS exon 2 metastatic colorectal cancer who received prior bevacizumab therapy: A combined analysis of individual patient data from ASPECCT and WJOG6510G.
Authors: Taniguchi Hiroya , Yamanaka Takeharu , Sakai Daisuke , Yamazaki Kentaro , Muro Kei , Peeters Marc , Price Timothy Jay
Published: January 2019

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Background: The ASPECCT (Price T, et al. Eur J Cancer 2016) and WJOG6510G (Sugimoto N, et al. ASCO-GI 2017) trials demonstrated noninferiority of panitumumab (Pmab), compared with cetuximab (Cmab), regarding the overall survival (OS) for chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). However, the subgroup analyses of both trials revealed a longer survival with Pmab than Cmab in patients who previously received bevacizumab (Bev). We performed a combined analysis of both trials using individual patient data. Methods: In both trials, patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to CPT-11- or L-OHP-based chemotherapy were randomized to receive Pmab or Cmab monotherapy (ASPECCT) or in combination with CPT-11 (WJOG). The patient subgroup with prior Bev was eligible for enrollment in this analysis. Results: In the combined data of 374 patients, 185 patients were enrolled in the Pmab arm (ASPECCT, 126; WJOG, 59) and 189 patients in the Cmab arm (ASPECCT, 132; WJOG, 57). The patient characteristics were well-balanced in both arms. Of the 374 patients, 341 (91%) and 369 (99%) had the OS and progression-free survival (PFS) events, respectively. The median OS was 12.8 months in the Pmab arm and 10.1 months in the Cmab arm ( P = 0.0031; the log-rank test stratified by trial). The hazard ratio (HR) for OS was 0.72 (95% confidence interval [CI], 0.58–0.90). The median PFS in the Pmab and Cmab arms were 4.7 and 4.1 months, respectively (P = 0.0207). HR for PFS was 0.79 (95% CI: 0.64–0.97). Response rates in the Pmab and Cmab arms were 23% and 16%, respectively (P = 0.114). Although the incidence of skin toxicities was similar, the infusion reaction was observed more in the Cmab arm (any grade, 1.1% vs 8.6%), whereas hypomagnesemia was noted more in the Pmab arm (48% vs 33%). Conclusions: This combined analysis demonstrated that Pmab significantly prolonged OS and PFS compared with Cmab, raising the potential that Pmab is the more reliable anti-EGFR option for patients with wild-type KRAS exon 2 metastatic colorectal cancer who previously received Bev.