bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective, randomized study of low molecular weight as supplemental therapy in metastatic colorectal cancer patients treated with FOLFIRI regimen and target agents.
Authors: Tsai Hsiang-Lin , Tai Chi-Jung , Huang Ching-Wen , Wang Jaw-Yuan
Published: March 2017

746

Background: Fucoidan is recently studied for its anti-cancer and anti-inflammatory effects. It also has been used as food supplements in Asia for many years. This study is the first prospective, randomized trial to compare the clinical outcomes and adverse events in metastatic colorectal cancer (mCRC) patients, who are treated with FOLFIRI regimen and target agents as the first line setting with or without low molecular weight Fucoidan (LMF). Additionally, the study also aimed to evaluate the inhibitory effect of LMF in EGFR-KRAS-BRAF-ERK signaling pathway. Methods: A total of 54 patients with mCRC were randomly divided into a study group (28 cases, 4g BID oral low molecular weight Fucoidan powder) and a control group (26 cases, 4g BID oral placebo powder). The supplements were given for 6 months during the therapeutic period. The primary endpoint was the disease-control rate (DCR), and the secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and adverse effects between the two groups. MTT cell viability assay and western blotting analysis were used to evaluate synergic effect of LMF plus 5-FU or Cetuximab on Caco-2, SW620 and HCT-15. Results: 54 mCRC patients were enrolled, including 28 patients in the study group and 26 patients in the control group. The DCR was 92.8% vs. 69.2% in study and control group respectively ( P = 0.026) in median follow up time of 11.5 months. The PFS was 15.93 ± 1.20 vs. 10.80 ± 1.06 months ( P = 0.075), ORR was 60.7% vs. 46.2% ( P = 0.284) and OS was 18.04 ± 0.91 vs. 12.96 ± 0.83 months ( P= 0.092). There were no statistical differences in adverse effects between two groups. In vitrostudy, LMF plus 5-FU or Cetuximab showed synergic cytotoxic effect (maximal 24% increase) through the inhibition of the expression of p-EGFR, p-ERK and p-Akt. Conclusions: The preliminary results show that LMF as supplemental therapy in mCRC patients may improve DCR. In vitro, Fucoidan showed the synergic cytotoxic effect with 5-FU or Cetuximab. The possible mechanism may involve the inhibition effect of Fucoidan in phosphorylation of EGFR-KRAS-BRAF-ERK signaling pathway.
Effect of multidisciplinary tumor conference on clinical management of rectal cancer.
Authors: Karagkounis Georgios , Stocchi Luca , Lavery Ian C. , Liska David , Gorgun Emre , Amarnath Sudha , Khorana Alok A. , Kalady Matthew
Published: March 2017

749

Background: Presentation of rectal cancer cases at a multidisciplinary tumor conference (MTC) is a required standard for the newly formed National Accreditation Program for Rectal Cancer. However, its impact on clinical decision-making remains incompletely defined. Our aim was to determine the frequency and manner in which MTC changed the management of patients with rectal cancer at a tertiary academic center. Methods: All rectal cancer cases presented at the weekly Colorectal Cancer MTC between July 2015 and June 2016 at a single institution were prospectively included. Patient demographics and clinical information were recorded. The presenting physician completed a uniform written questionnaire outlining their plan before and after the MTC discussion, and any changes in management as a result of the discussion. Imaging and pathology were reviewed for each case at MTC and consistency with prior interpretation was recorded. Results: 234 unique initial rectal cancer cases were included. Survey responses were obtained for 212 cases (90.6%). The mean patient age was 58.3 years. 37 patients (15.8%) presented with Stage IV disease and 20 (9.4%) had locally recurrent cancer. There was a documented change in plan as a result of the MTC discussion in 70 of 212 (33%) cases surveyed, including 22 cases (10.4%) in which the presenting physician had a “definitive plan” prior to the MTC. Changes in management included a change in therapy or change in therapy sequence in 45 cases (64%), and recommendation of further evaluation in 26 cases (37%). Change in management following MTC did not vary by surgeon experience: it occurred in 31.4%, 37.2% and 29.8% of cases presented by surgeons with < 10, 10-20, and ≥ 20 years of experience respectively (Chi-square p= 0.71). The imaging or pathology review at MTC resulted in a different interpretation than previously reported in 23% and 12% of cases, respectively. Conclusions: MTC changes clinical management for a significant portion of rectal cancer patients at a tertiary care center, independent of the presenting surgeons’ years of clinical experience. Our results highlight the utility of multidisciplinary rectal cancer care and support the MTC standard for the National Accreditation Program for Rectal Cancer.
Comparison of early tumor shrinkage between oxaliplatin plus S-1 and cisplatin plus S-1 in first-line chemotherapy with advanced gastric cancer.
Authors: Osumi Hiroki , Takahari Daisuke , Shinozaki Eiji , Chin Keisho , Ogura Mariko , Nakayama Izuma , Matsushima Tomohiro , Wakatsuki Takeru , Ichimura Takashi , Suenaga Mitsukuni , Yamaguchi Kensei
Published: March 2017

75

Background: Early tumor shrinkage (ETS) is regarded as predictive marker in metastatic colorectal cancer. In the phase III study comparing oxaliplatin plus S-1 (SOX) to cisplatin plus S-1 (SP) in patients with advanced gastric cancer (AGC), although response rates were almost same between two groups, ETS wasn’t evaluated. Therefore, in AGC, it is controversial whether ETS is predictive or not and which is more suitable regimen, especially as neo adjuvant chemotherapy (NAC). The aim of this study is to compare ETS in SOX with SP and to evaluate the relationship between ETS and clinical outcomes in AGC. Methods: We retrospectively enrolled consecutive 469 patients (SOX 128, SP 341) with histopathologically confirmed HER2 negative AGC treated as 1st-line chemotherapy or NAC in our institution between January 2010 and June 2016. ETS was defined relative change in the sum of the longest diameters of target regions at week 8 (±4) compared to baseline. (Cut-off: 20%). Tumor response was assessed computed tomography using the RECIST 1.1. Patients with peritoneal metastasis and/or bone metastasis without target region were excluded in this study. Results: 192 patients (SOX 60, SP 132) were included in this study. Median tumor shrinkage between SOX and SP were 30% (min-35%, max77%) and 21% (min-89%, max73%), respectively ( p= .16). The ratio of ETS between SOX and SP was 53.3% and 50.7%, respectively ( p= .75). ETS > 20% was associated with longer OS and PFS when compared with ETS≦20% in SOX group. (ETS > 20% vs≦20%: OS 15.3 vs 10.1 months, HR 0.47 p= .03 PFS 7.6 vs 4.2 months, HR 0.58 p= .09) On the other hand, ETS > 20% was associated with significantly longer PFS only when compared with ETS≦20% in SP group and significant independent predictive factor. (ETS > 20% vs≦20%: OS 15.7 vs 10.9 months, HR 0.79 p= .29 PFS 7.7 vs 4.0 months, HR 0.57 p= .01) In multivariate analysis, ETS remained significant independent predictive factor for PFS in SP group (HR 0.53, p= .006). Conclusions: The ratio of ETS was similar between SOX and SP. ETS may be an early-on-treatment predictor in AGC.
Nonagenarian patients with metastatic colorectal cancer: Results from the South Australian metastatic colorectal cancer registry.
Authors: Price Timothy Jay , Karapetis Christos Stelios , Piantadosi Cynthia , Padbury Robert , Roy Amitesh Chandra , Maddern Guy , Gonzalo Tapia Rico , Moore James , Roder David , Townsend Amanda Rose
Published: March 2017

752

Background: With improved healthcare we now face an ageing population worldwide. More patients with metastatic colorectal cancer (mCRC) will present at advanced age. Patients with mCRC now have the potential of living longer due to surgery, chemotherapeutic agents and monoclonal antibodies. Australian data (2011) indicated 1.3% of the population are aged over 90 years*. Medical oncologists are now being referred patients in their 90’s and the optimal management for this group is unknown. Methods: The population based South Australian Clinical Registry for mCRC includes all patients with metastatic CRC diagnosed since the 1st February 2006. We examined cancer characteristics, treatments administered and outcomes for patients aged > 90 years. Results: 130 patients of 4199 (3%) were aged 90 years or older. The median age was 92.1 years (range 90-104.8 years). 61% were female, 70% presented with synchronous disease. Organ involvement was as follows; 58% liver, 32% lung, 8% peritoneal and 7% bone. Primary site was: right 46%, left 28%, rectum 20%, unknown 6%. Only 4 patients had KRAS testing (all WT). 44.6% overall have had no surgery for their CRC primary. 24% of those with synchronous disease at diagnosis had resection of primary lesion and 3% had stoma formed for palliation. One patient had lung resection for metastasis. Only 4 patients received systemic therapy (age range 90-93). Lines of therapy delivered; one in 2 patients, two lines in one and 4 lines in one. Aside single agent 5FU, combination therapy (oxaliplatin/FU+/- bevacizumab) was given to two patients and cetuximab single agent in 2 (WT one, unknown one). The median survival overall was 3 months (95% CI 1.4-4.6 months). Two year survival was 10%. Conclusions: This analysis gives us some insight into the management of the very old. Female sex and right sided cancers are more frequent. Systemic therapy is rarely offered and the outlook is poor. Further research to understand whether active therapy is possible or warranted in this age group should be considered. *http://www.abs.gov.au/ausstats/abs@.nsf
A phase I/II study of nintedanib and capecitabine in refractory metastatic colorectal cancer.
Authors: Boland Patrick McKay , Fakih Marwan , Attwood Kristopher , Robins Melissa , Iyer Renuka V. , Ma Wen Wee
Published: March 2017

759

Background: Refractory metastatic colorectal cancer patients (mCRC) have a poor prognosis with median survival of 4-6 months. Nintedanib is a TKI which inhibits VEGFR, PDGFR, and FGFR with preclinical efficacy in bevacizumab resistant CRC. This phase I/II study sought to evaluate the recommended phase II dose (RP2D) and efficacy of nintedanib and capecitabine in refractory mCRC patients. Methods: Key eligibility criteria included histologically proven mCRC, ECOG PS of 0 or 1, progression/intolerance to a fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR therapy for RAS wt patients. Prior regorafenib, uncontrolled hypertension ( ≥ 160/90), recent clinically significant thrombosis/hemorrhage, or prior intolerance to capecitabine were exclusionary. Doses were escalated across 2 planned dose levels (DL) in a standard 3+3 design, with escalating doses of capecitabine. DLT observation window was the first 3 weeks after dosing. The primary endpoint was establishment of the RP2D. Results: 10 patients were enrolled across 2 dose levels. 1 patient withdrew consent and was replaced. 5 (50%) were PS 0. No grade 4 or 5 AEs were observed. No DLTs were observed. 2/10 (20%) of patients experienced a grade 3 AE, including hyperbilirubinemia (10%), AST elevation (10%), diarrhea (10%), dehydration (10%), and weakness (10%). The most common treatment-related AEs included palmar-plantar eythrodysesthesia (PPE) (50%), diarrhea (40%), stomatitis (30%), nausea (20%), vomiting (20%), and fatigue (20%). The RP2D was determined to be capecitabine 1000 mg/m2 divided bid and nintedanib 200 mg bid. PK data will be presented. Conclusions: Treatment was well tolerated. Most of the observed AEs were grade 1 or 2, without a marked difference between DLs. PPE was readily managed with dose adjustments. The phase II study is ongoing at the RP2D. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Clinical trial information: NCT02393755.
Tumor-size-based endpoints as surrogates for overall survival in the ARCAD Advanced Colorectal Cancer Database.
Authors: Burzykowski Tomasz , Coart Elisabeth , Saad Everardo D. , Sargent Dan , Zalcberg John Raymond , Shi Qian , Sommeijer Dirkje Willemien , Buyse Marc E.
Published: March 2017

766

Background: Tumor-size-based endpoints such as depth of response have recently become a focus of investigations related to search for early on-treatment predictive markers for patients with colorectal cancer (Piessevaux et al. 2013; Cremolini et al., 2015; Heinemann et al., 2015). We evaluate the use of time-to-nadir (TTN) and depth-of-nadir (DoN) as potential surrogates for overall survival (OS). Methods: We have used the data from trials included in the ARCAD Advanced Colorectal Cancer Database. We have considered three sets of treatment comparisons: comparisons involving only chemotherapy agents (CT); involving anti-angiogenesic agents (ANG); and involving anti-EGFR agents (EGFR). For each of the sets separately, we applied a two-stage modelling approach (Renard et al. 2002) to jointly analyze the relative change of tumor size versus baseline (RCTS) and OS. In particular, in the first stage, a joint model for the repeated measurements of RCTS and OS was fitted to the data. Based on the model, treatment effects on OS and RCTS were estimated. Treatment effects on OS were expressed as log-hazard-ratios, while the effects on RCTS were expressed in terms of differences in the time-to-nadir (TTN) and in the depth of nadir (DoN). In the second stage, a linear regression was fitted through the estimated treatment effects on TTN/DoN and OS. The coefficient of determination (R2), computed by using the comparison-specific sample-size as weights, was used to quantify the strength of association between the treatment effects on TTN/DoN and OS. In particular, values of R2 larger than 0.75 were considered as indicating a good surrogate. Results: The CT set included 18 comparisons with 5726 pts. in total. For the treatment effects on TTN and OS, the value of R2 was estimated to be equal to 0.31, while for DoN and OS, it was equal to 0.01. For the ANG set (11 comparisons, 3964 pts.) the values of R2 were equal to 0.26 and 0.21, respectively, while for the EGFR set (16 comparisons, 4687 pts.) they were equal to 0.10 and 0.45, respectively. Conclusions: These preliminary results suggest that TTN and DoN are not good surrogates for OS in advanced colorectal cancer. More detailed analyses are ongoing and will be presented at the meeting.
Tumor sidedness, adjuvant chemotherapy (AC), and other factors affecting survival in patients with stage II colon cancer (CC-II).
Authors: Mukkamalla Shiva Kumar Reddy , Huynh Donny V. , Somasundar Ponnandai Sadasivan , Rathore Ritesh
Published: March 2017

768

Background: The role of AC in CC-II is not well defined due to lack of conclusive randomized trial data. This updated analysis using National Cancer Database (NCDB) addresses the overall survival (OS) benefit from AC in CC-II using more refined and case appropriate population cohort. Methods: NCDB was queried for patients diagnosed with CC-II from 2004-2008 with survival information through 2013. Only those patients with pathologically confirmed CC diagnosis were included. Patients undergoing any surgical procedure less than a partial colectomy were excluded. Pearson Chi-square test, Kaplan Meier survival curves and Cox proportional hazards model were used for statistical analysis. Results: A cohort of 36,630 patients was identified for analysis. Elderly patients received less frequent AC (p < 0.0001) and AC was associated with an improved 5-year OS with no difference noted in outcomes from single or multi-agent regimens. AC was an independent predictor of OS regardless of age, gender, race, comorbidity index, insurance status, income level, year of diagnosis, tumor sidedness, tumor grade, adequacy of lymph node evaluation, pathologic tumor (pT) status, colectomy type, margin involvement or academic level of treating institution. In multivariate analysis, right-sided cancers had better survival outcomes compared to left-sided cancers (HR 0.91; p < 0.0001). Conclusions: This study validates previous findings of improved OS from AC in CC-II while addressing some of the shortcomings of prior retrospective studies. Only patients with CC-II without any other primary cancer diagnoses were included. To our knowledge this is the most uptodate analysis of AC in CC-II which includes cases diagnosed up to 2008. Our study found similar improvement in 5-year OS irrespective of chemotherapy regimen. Interestingly, improved OS was seen in right sided tumors compared to left sided tumors, in contrary to that seen with metastatic colon cancer (Venook et al). [Table: see text]
Clinical efficacy and safety of regorafenib (REG) in the treatment of metastatic colorectal cancer (mCRC) in daily practice in Germany: Interim results of the prospective multicentre noninterventional RECORA study.
Authors: Schulz Holger , Janssen Jan , Strauss Uwe P. , Langen Markus , Frey Marcel , Fiala-Buskies Sabine , Bokemeyer Carsten
Published: March 2017

769

Background: In 2013 REG was approved for mCRC based on the results achieved in the CORRECT trial. However, prospective data from daily practice use are still scarce. Methods: RECORA is investigating efficacy and safety of REG in routine clinical care in Germany. Male/female mCRC patients (pts) ≥ 18 years for whom the decision was taken to treat with REG in its approved indication were enrolled. Primary objective was overall survival (OS). Secondary objectives included progression-free survival time (PFS), time-to-progression (TTP), disease control rate (DCR), and incidence of treatment-emergent adverse events (TEAE). Results of a planned interim analysis with data cut-off 11 July 2016 are presented. Results: 480 pts were enrolled at 90 sites between 10/13 and 07/16; 458 pts were included in this interim analysis for safety, 457 for efficacy. Mean/median age was 67 years, 61% of pts were male, baseline ECOG PS was 0 in 20%, 1 in 61%, 2 in 18%, and 3 in 1% of pts, 62% had a primary colon cancer, 46% had KRAS mutated tumors at diagnosis, 23% had mets in the liver only, 9% in the lung only, and 22% in both lung and liver. Median OS was 5.6 months (mos) (95% CI 5.2-6.6) based on 277 deaths, median PFS was 3.2 mos (95% CI 2.9-3.5) based on 337 progression or death events, median TTP was 4.5 mos (95% CI 3.8-5.4) based on 195 progressions, DCR was 29.9% based on 234 tumor evaluations. There were no significant differences in OS in subgroups according to age ( < 65/ ≥ 65), sex, KRAS status, number of prior treatment lines, and site of mets; whereas OS was significantly different in subgroups according to ECOG PS (ECOG 0/1 vs. 2), primary tumor site, and time from initial diagnosis ( < 18/ ≥ 18 mos). Mean duration of treatment was 2.7 mos. TEAE grade ≥ 3 occurred in 23.7% of pts, in 17.3% REG related. A serious TEAE was recorded in 47.8% of pts, in 8.3% considered as REG related. Overall, 26.6% died of an AE, in 0.4% REG related. 23.8% of pts received another anti-tumor therapy after REG was stopped. Conclusions: RECORA showed clinical benefit and acceptable tolerability for REG in this interim analysis. OS was in the range of the pivotal study. Clinical trial information: NCT01959269.
Intermittent maintenance treatment with bevacizumab in patients with metastatic colorectal cancer: A single centre experience.
Authors: Cerchiaro Eleonora , Squadroni Michela , Sauta Maria Grazia , Bonomi Maria , Brena Federica , Ripa Cristina , Barile Rosalba , Salvini Piermario , Ceresoli Giovanni Luca , Beretta Giordano D.
Published: March 2017

776

Background: The main objective of care in patients with metastatic colorectal cancer (mCRC) is survival prolongation preserving the quality of life (QoL). Optimal duration of chemotherapy after induction treatment is still a matter of debate, such as the treatment strategies that could be adopted (intermittent versus continuous maintenance chemotherapy). Methods: In this monoinstitutional retrospective study we evaluated 70 patients (pts) diagnosed with mCRC with stable or responsive disease after chemotherapy with Bevacizumab (12 courses of FOLFIRI-Bevacizumab) as first or second-line treatment. We observed three groups: group A (20pts): maintenance therapy with de Gramont-Bevacizumab 2 months on/2 months off until disease progression (intermittent strategy); group B (30 pts): no maintenance treatment; group C (20 pts): induction treatment exclusively as first line followed by continuous maintenance with de Gramont-Bevacizumab. Results: Median progression free survival (PFS) was 21 months in Group A (range: 10-51 months), 9 months in Group B (range 6.6-12.9 months), 11 months in groups C (range 10.4-13.3 months), the difference resulted significant among group in favor of intermittent strategy (p = 0.006). Median OS was 60.6 months (range: 35.6-96.2 months) in group A, 27.2 months (range 19.5-39.9 months) in group B and 23.6 months in group C (range: 19.1-31 months); p = 0.0011. The most frequent adverse events of all grades were: hypertension, neutropenia, thrombocytopenia, diarrhea, asthenia. No toxic death was observed. Adverse events (AEs) of all grades were more frequent in group C (15% Grade 3-4), comparing with Group A and B (10% Grade 3-4 AEs) Conclusions: According to our retrospective analysis, intermittent maintenance treatment with chemotherapy and Bevacizumab appears to be a feasible strategy in pts with stable or responsive disease. PFS and OS resulted longer in patients treated with intermittent strategy comparing with other groups. The study has at least three bias: selection of patients, small sample size and retrospective nature, however we can conclude that intermittent strategy could improve patients outcome with an acceptable toxicity profile.
Bevacizumab in addition to chemotherapy first-line for right-side metastatic colorectal cancer: A cost-effectiveness analysis.
Authors: Chen Gong , Liu Maobai , Li Te , Wu Bin
Published: March 2017

777

Background: To test the cost-effectiveness of bevacizumab treatment compared with cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for patients with right-side metastatic colorectal cancer (mCRC). Methods: A Markov model was developed to Chinese clinical practice. The model incorporated clinical and utility data from published literatures, resource utilization and unit prices based on local charge. The lifetime horizontal was used and sensitivity analyses were carried out to test the robustness of the model results. The impact of patient assistance program (PAP) was also evaluated in scenario analyses. Results: Baseline analysis showed that the addition of cetuximab gained additional 0.232 QALYs with more $60,371 relative to bevacizumab therapy, resulting in an ICER of $259,775 /QALY. When PAP was available, the incremental cost decreased to $24,161, which yielded an ICER of $60,371 /QALY, which indicated that the strategy was not cost-effective at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China ($22,200/QALY). Sensitivity analyses found that the costs of bevacizumab was the most influential parameter. Conclusions: Bevacizumab treatment for right-side mCRC is not a cost-effective option in comparison with standard chemotherapy in Chinese context.
Updated analysis: A retrospective cohort study evaluating the safety and efficacy of regorafenib in patients with metastatic colorectal cancer—HGCSG1401.
Authors: Ota Yumiko , Yuki Satoshi , Harada Kazuaki , Yoshida Shuntaro , Tsuji Yasushi , Kobayashi Yoshimitsu , Hatanaka Kazuteru , Okuda Hiroyuki , Sasaki Takahide , Dazai Masayoshi , Konno Jun , Ohta Tomoyuki , Honda Takuya , Ishiguro Atsushi , Muto Osamu , Sato Yasushi , Kato Sosuke , Onodera Kei , Sakata Yuh , Komatsu Yoshito
Published: March 2017

778

Background: The CORRECT trial revealed the safety and efficacy of regorafenib (REG) for patients (pts) with colorectal cancer including Japanese. REG was approved in Japan in March 2013. However, there are few studies exploring the efficacy and safety of REG in a large number of patients, particularly in daily practice. Methods: We analyzed 173 pts who received REG from May 2013 in the multi-institutional retrospective study (HGCSG1401). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR), and Kaplan-Meier method for progression free survival (PFS) and overall survival (OS). Results: Patients’ characteristics were as follows; male/female 98/75, median age 66 (range 29-87), ECOG PS (0/1/2/3) 58/96/18/1, KRAS Exon2 wild/mutant 98/74 (1 patient ; KRAS Exon2 status was not tested). The initial starting dose was 160 mg (n = 145, 83.8%), 120mg (n = 22, 12.7%), and 80mg (n = 6, 3.5%) respectively. Dose reductions were required in 73 pts (42.2%); 38 pts (22.0%) discontinued therapy due to AEs. The common ≥ grade 3 AEs ( ≥ 15%) were palmar-plantar erythrodysesthesia syndrome (n = 48; 27.7%), hypertension (n = 34; 19.7%), proteinuria (n = 24; 19.2%) and AST increased (n = 24; 13.9%). RR and disease control rate (DCR) were 1.3% and 29.6%, respectively. Median PFS and median survival time (MST) were 2.1 and 6.3 months. In an analysis on relationship between ECOG PS (PS 0-1 vs. PS 2-3) and efficacy, median PFS was 2.3 vs. 1.2 months (HR 3.598, p < 0.001), and MST was 7.0 vs. 2.1 months (HR 4.751, p < 0.001). Conclusions: The efficacy of REG in pts with PS 0–1 was similar to the previous report; however, REG was not effective in patients with PS 2–3. In adverse events, hypertension and liver dysfunction were expressed more frequently than previously reported. We will continue the analysis of the factors associated with liver dysfunction and prognostic/predictive factors.
The risk factors for vomiting and nausea in patients with oxaliplatin-based chemotherapy: Subgroup analysis of SENRI trial.
Authors: Nishimura Junichi , Kudo Toshihiro , Takemoto Hiroyoshi , Komori Takamichi , Kim Ho Min , Ota Hirofumi , Suzuki Rei , Ikenaga Masakazu , Ikeda Masataka , Yamamoto Hirofumi , Satoh Taroh , Hata Taishi , Takemasa Ichiro , Mizushima Tsunekazu , Doki Yuichiro , Mori Masaki
Published: March 2017

779

Background: We previously reported, in the SENRI trial, usefulness of aprepitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In this study, we assessed the risk factors for CINV in colorectal cancer patients who received Oxaliplatin-based chemotherapy. Methods: A total of 370 patients was analyzed as for the rate of vomiting, and significant nausea in overall phase. We also assessed the proportion of CINV in patients divided by gender. Results: First, we analyzed the risk factors for vomiting and nausea. Female gender and aprepitant use were associated with the incidence of vomiting and significant nausea. Significantly more women suffered from vomiting than men (84.5 % vs. 92.9 % in women and men, respectively; P= 0.0001). The rate of no nausea, complete response, complete protection, and total control was also lower in women. The rate of use of rescue therapy was significantly higher in women. We compared the rate of CINV between aprepitant and control groups and found that, in women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group. Conclusions: Gender and no aprepitant use were risk factors of CINV in colorectal patients who received oxaliplatin-based chemotherapy.Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen. Clinical trial information: NCT01344304.
Methionine gamma-lyase-encapsulated into red blood cells (ERY-MET) antitumor activity in gastric carcinoma.
Authors: Bourgeaux Vanessa , Sénéchal Karine , Aguera Karine , Gay Fabien , Horand Françoise
Published: March 2017

78

Background: Methionine (Met) requirement is a cancer specific–metabolic defect that seems a promising target, especially in gastric cancers. Methionine gamma–lyase (MGL), a pyridoxal–5′–phosphate (PLP)–dependent enzyme, is an emerging approach consisting in tumors Met starvation via systemic Met depletion. ERY-MET is a new therapeutic product overcoming the short in vivo half-life of free MGL by its encapsulation into Red Blood Cells (RBCs). Indeed, ERY-MET works as a bioreactor degrading Met that passively diffuses inside the RBC. In addition, entrapped MGL activity can be controlled by supplying Vitamin B6 (PN), the precursor of MGL’s cofactor (PLP), converted inside RBCs. ERY-MET anti-tumor activity was evaluated in vivo in NMRI nudemice bearing subcutaneous gastric carcinoma. Methods: First, in vitro sensitivity of NCI-N87 and AGS human gastric cell lines to free MGL was assessed by IC50 determination using CCK–8 assay. MGL encapsulated into mouse RBCs by hypotonic dialysis was injected once in CD1 mice to determine PK-PD parameters with or without PN supplementation. The anti-tumor activity of weekly ERY-MET injections (x5) at 116 IU/kg ± 25% was assessed with or without PN supplementation in female NMRI nudemice (n = 10/group) xenografted with NCI-N87 cells. Met depletion was determined 6 days after each cumulative injection while tumor growth was followed twice a week by caliper measurement. Results: In vitro studies showed that NCI-N87 as well as AGS cell lines displayed a sensitivity to free MGL with IC50 of 0.35 ± 0.01 and 0.12 ± 0.02 IU/mL, respectively. ERY-MET with daily PN supplementation significantly increased active MGL half-life in vivo (from < 24h to 8–9 days). ERY-MET induced 80% inhibition of tumor growth at day 45 (p < 0.0001). Response rate obtained was 76% of treated mice (15/20). Besides, PN supplementation induced a slow-down of tumor growth during the supplementation period and improved ERY-MET efficacy. Conclusions: Theses results suggest that ERY-MET can induce tumor growth inhibition in mice bearing human gastric adenocarcinoma and that its effect can be regulated by PN supplementation. As such, ERY-MET seems a promising anti-tumor drug to treat gastric cancers.
ECOG performance status as a predictor of adjuvant chemotherapy (AC) toxicities in stage III colorectal cancer (CRC) patients.
Authors: Watanabe Akie , Yang Charlie , Cheung Winson Y.
Published: March 2017

789

Background: Toxicities acquired from AC can greatly impact quality of life. ECOG performance status is a clinical factor that is frequently considered in AC treatment decision-making, but its associations with common toxicity outcomes remain unclear. Methods: We reviewed a cohort of 371 CRC patients treated with adjuvant monotherapy (Capecitabine) or combination therapy (FOLFOX or CAPOX) within 12 weeks of curative resection at the British Columbia Cancer Agency, and determined the associations between ECOG (0, 1, ≥ 2) and toxicity outcomes. We also categorized toxicities into early, intermediate, or late based on their time of onset. Results: Among 371 patients, median age was 65 years, 52% were men, and 45%, 41%, and 14% were ECOG 0, 1, and ≥ 2, respectively. In this cohort, 41% received monotherapy and 59% received combination therapy. There was a trend of decreased toxicity for specific side effects, such as nausea, vomiting, and diarrhea, with each additional treatment cycle. For monotherapy, ECOG was found on univariate analyses to be associated with several toxicities including early onset hand foot syndrome and early onset anemia (both P < 0.05). When compared to ECOG 0, multivariate analyses showed that patients with worse ECOG were more likely to develop early hematological toxicities (ECOG 1, OR 2.75, 95% CI 1.01-7.49, P= 0.04; ECOG ≥ 2, OR 4.38, 95% CI 1.24-15.49, P= 0.02). ECOG ≥ 2 patients also had higher odds of experiencing late hematological toxicities (OR 4.52, 95% CI 1.05-19.52, P= 0.04) and neuropathy (OR 5.73, 95% CI 1.25-26.14, P= 0.02). In univariate analyses of combination therapy, ECOG was associated with early gastrointestinal and late hematologic toxicities (both P < 0.05). On multivariate analyses, however, ECOG was predictive of only early hematologic toxicities (ECOG 1, OR 2.13, 95% CI 1.05-4.32, P= 0.04; ECOG ≥ 2, OR 3.85, 95% CI 1.18-12.6, P= 0.03). Further analyses did not show any consistent correlations between ECOG and other toxicity outcomes. Conclusions: Although specific toxicities appear to decrease with each successive cycle of AC, poor ECOG is associated with an increased likelihood of certain side effects that can further inform AC discussions.
The efficacy and safety of CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy in patients with metastatic colorectal cancer: A multi-center, single-arm, phase II study (CCOG-0902 study).
Authors: Sunakawa Yuuki , Nakayama Goro , Ishigure Kiyoshi , Yokoyama Hiroyuki , Uehara Keisuke , Kanda Mitsuro , Murotani Kenta , Fujii Tsutomu , Kodera Yasuhiro
Published: March 2017

795

Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Clinical trial information: UMIN000006478.
Evaluation and response of mucin pools in primary rectal cancer tissue during chemoradiotherapy (CRT).
Authors: Miyakita Hiroshi , Sadahiro Sotaro , Saito Gota , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki
Published: March 2017

798

Background: Mucinous carcinoma (MC) has been defined as carcinoma with > 50% of tumor volume showing mucin pool (MP). The incidence of MC had been reported to be 4 to 12% of colorectal cancer and to be less effective for chemotherapy and CRT. The incidence of MC was 3 to 8% in rectal cancer treated with surgery alone and 13 to 24% in patients treated with CRT. These findings suggest that MP may be induced by CRT in some patients. We therefore compared the degree of MP in MRI findings before CRT, after CRT and in resected specimens. Methods: The study group comprised 205 patients with rectal cancer who received CRT (40 to 45 Gy) from 2006 through 2014. MPs on MRI were evaluated using T2-weighted fast-spin echo images, and the MP area ratios on maximum cross-section of the primary tumor were calculated. An MP area ratio of 0% was designated as class 0, 1 to 9% as class I, 10 to 29% as class II, 30 to 50% as class III, and 50% or higher as class IV. Results: On MRI before CRT, the MP area ratio was class 0 in 181 patients (88%), class I in 11 (5%), and class II or higher in 13 (6%). On MRI after CRT, the MP area ratio was class 0 in 186 patients (91%), class I in 4 (2%), and class II or higher in 15 (7%). The prevalence of MP classes did not change appreciably. The MP class evaluated on MRI before and after CRT changed by 2 or more levels in only 2 patients, both of whom had marked tumor shrinkage. Among 175 patients with an MP area ratio of class 0 or I in the resected specimens, the MRI findings after CRT were consistent with the findings of the resected specimens. However, the MP area ratio was underestimated by 2 or more levels on MRI in 14 (47%) of 30 patients who had an MP area ratio of class II or higher. A pathological complete response (pCR) was obtained in 24 patients (12%), all of whom had an MP area ratio of class 0 or I on MRI before CRT. No patient with an MP area ratio of class II or higher before CRT had a pCR. Conclusions: The degree of MP evaluated on MRI did not change during CRT. In patients who had an MP area ratio of > 10% in their resected specimens, the evaluation of MP on MRI was often underestimated. Patients with an MP area ratio of > 10% before CRT had a poor response to CRT, with no pCR.
Using adjacent to tumor samples as normal controls in molecular investigations: Are we missing the earliest biomarkers?
Authors: Barra Williams Fernandes , Moreira Fabiano , Ribeiro-dos-Santos Arthur , Santos Sidney , Santos Andrea KCR , Demachki Samia , Assumpcao Monica B , Khayat Andre Salim , Assumpcao Carolina Barauna , Anaissi Ana Karyssa , Ishak Geraldo , Hage Pedro Antonio Mufarrej , Assumpção Paulo P
Published: March 2017

80

Background: Recently, some papers aiming to warn the scientific community regarding possible misinterpretation due to using adjacent to tumor sample tissues as normal controls were published The main motivation for these alerts was the observation of important molecular alterations in tissues nearby a cancer, although been collected from non-tumor areas. Nevertheless the cancer field hypothesis has been recognized many years ago; this concept was not incorporated to current practice in molecular investigations. In this work we aim to investigate potential implications of using adjacent to tumor sample tissues as normal controls. Methods: Gastric Cancer (GC) and Adjacent Tissues (AT) paired fresh samples of 16 patients, and 16 samples from non-cancer patients (NC) were analyzed. miRNA sequencing was performed using Illumina Miseq platform. Statistical analysis was performed in R using DESeq2 tool to identify differential expressed miRNAs. Results: Comparing GC with NC tissue samples, we observed 21 miRNAs differentially expressed (p-value < 0.05 and |Log2(Fold-Change)| > 2), eight were down-regulated and 13 were up-regulated in GC. Comparing AT with NC tissue samples, 16 miRNAs were differentially expressed, two were down-regulated and 14 were up-regulated in AT. In both comparisons, GC and AT samples clustered together and clearly separated from NC samples. Comparing GC with AT samples, hsa-miR-196a-5p was significantly down-regulated in GC. Conclusions: AT tissues harbor molecular alterations distinguishing them from non-cancer patient’s samples. Combined analyses of the groups clearly demonstrated that AT resembles much more cancer profile than NC patient’s tissue prolife. Using AT samples as controls might impair the discovery of possible initial molecular events identifiable exclusively by using samples from non-cancer patients. The current strategy of molecular investigation must be revised.
Clinical trials versus clinical practice in colorectal cancer: Equivalent populations?
Authors: Magdaleno Cremades Alejandra , Ors Castaño María del Carmen , Ballester Espinosa María , Llopis Cuquerella Marta , Ramirez Belloch María del Rocío , Boix Aracil Vicente , Gómez González Lucía , Morales Giménez Roberto , Asensio Martinez Elena , Gallego Plazas Javier
Published: March 2017

802

Background: Clinical trials are criticized due to inclusion of selected populations. The aim of this analysis is to compare populations included in clinical trials which justify treatment recommendations in stage III and IV colorectal cancer (CRC) to patient populations in our area. Methods: Data related to age, sex, primary tumor and stage of CRC patients consecutively diagnosed in Vega Baja Hospital and Elche University General Hospital were collected. Also data regarding the same variables were collected from the publications of clinical trials which justify adjuvant treatment in stage III colon cancer and combination treatment with chemotherapy and targeted therapies in stage IV CRC. Results: We analyzed 249 patients with stage III colon cancer and 237 patients with stage IV CRC from our area. In our experience, 56.6% of stage III colon cancer were males, and median age was 66.2 years (23 - 91), with 41.8% ≥ 70 years. In clinical trials supporting adjuvant treatment 54 - 56.1% of patients were males, and median age was 59 - 61 years (19-83), with 14 - 21.7% ≥ 70 years. In our experience 64.4% of stage IV CRC patients were males, and median age was 67.2 years (38-89), 76.4% primary tumor in colon. In clinical trials supporting combination treatment with chemotherapy and targeted therapies 60-67% of patients were males, and median age was 59.2 – 62 years, primary tumor in colon 57.9 – 81% (Table). Conclusions: Patient populations included in clinical trials which support standard treatment in CRC are younger to those in our area. This fact, added to the restrictions based on inclusion and exclusion criteria of clinical trials, justify the qualification of “selected” to these populations not being representative of our clinical practice. [Table: see text]
Genomic-directed therapy of gastrointestinal cancers by comprehensive genomic profile (CGP): Clinical and genomic characteristics at the John Theurer Cancer Center (JTCC).
Authors: Gonzalez Velez Miguel , Duma Narjust , Jaramillo Restrepo Valentina , Lopez-Zertuche Pablo , Parrondo Ricardo Daniel , Mariotti Veronica , Kothadia Sejal , Boseski Beth , Jennis Andrew , Gutierrez Martin
Published: March 2017

803

Background: The routine use of comprehensive genomic profiling (CGP) has led to better genomic characterization, more personalized treatments and higher enrollment in clinical trials for many solid cancers. The aim of this study was to evaluate the clinical and genomic prolife of patients (pts) with gastrointestinal cancers (GIC) with the use of a CGP assay and their potential therapeutic benefit at a large comprehensive cancer center. Methods: We retrospectively analyzed 83 consecutive pts with GIC that had CGP at the JTCC between 01/2014-09/2016. Demographics, CGP results, and clinical characteristics were studied. Clinically relevant genomic alterations (CRGAs) were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA), and were defined as alterations linked to approved therapies and those under evaluation in genotype-driven clinical trials. Results: 83 pts with GIC were analyzed. 46.9% males and 53.0% females. The median age at diagnosis was 58.5 years. 73 (88%) patients were stage III/IV at diagnosis. Tumors consisted of colorectal (36%), gastric (24%), pancreatic (12%) and cholangiocarcinoma (6%). All the pts were found to have at least one genomic alteration (GA). CRGAs were identified in 63 (76%) of cases, with an average of 2 per pt. The most frequently identified GAs were TP53 43 (29.9%), APC 24 (16.7%), KRAS 31 (21.5%), ARID1A 12 (8.3%), PIK3CA 11 (7.6%), and SMAD4 11 (7.6%). Of the 63 pts with CRGAs, 23 (36%) received one of the therapies suggested by the NGS assay, and 9 (14%) were enrolled in a clinical trial. Conclusions: The use of CGP assay identified a high frequency of CRGAs in GIC pts. The assay provided information for genomic-directed therapy in 36% of the patients. The routine use of CGP in GIC may lead to pts receive more personalized treatments. The potential benefit of selected targeted therapies in individual cases suggests that larger studies of treatment guided by routine CGP in gastrointestinal malignancies are warranted.
Relations of changes in serum carcinoembryonic antigen (CEA) levels before and after chemoradiotherapy (CRT) and after surgery to histological response and outcomes in patients with locally advanced rectal cancer (LARC).
Authors: Saito Gota , Sadahiro Sotaro , Miyakita Hiroshi , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki
Published: March 2017

804

Background: Multidisciplinary treatment had been a standard of care for locally advanced rectal cancer. Serum CEA had been reported as one of the predictive factors to CRT, however, serum CEA levels may change after CRT and surgery. We examined the relations of serum CEA before CRT, after CRT, and after surgery to histological response and outcomes. Methods: The subjects were 149 patients with cStage II or III adenocarcinoma of the rectum who underwent surgery after CRT from 2005 through 2013. A total dose of 40 to 45 Gy with concurrent oral UFT or S-1 was delivered. Surgery was performed 6 to 8 weeks after CRT. A serum CEA > 5 ng/mL was defined as positive. Patients with negative serum CEA before CRT were designated as group 1. Patients with positive serum CEA before CRT that became negative after CRT were designated as group 2. Patients with positive serum CEA after CRT that became negative after surgery were designated as group 3, and patients with positive serum CEA after CRT as well as after surgery were designated as group 4. The median follow-up period of the survivors was 60.4 months. Results: The numbers of patients in Groups 1, 2, 3, and 4 were 55 (37%), 41 (28%), 37 (25%), and 16 (11%), respectively. The incidences of pCR, T downstaging, and N downstaging did not differ significantly among the groups (p = 0.094, 0.060, and 0.346). Rates of marked regression (TRG Grade 1 or 2) were 55% in Group 1, 42% in Group 2, 16% in Group 3, 25% in group 4. The rates were significantly higher in groups 1 and 2 (p = 0.001).5y DFS was 76% in group 1, 75% in group 2, 77% in group 3, and 48% in group 4 and was significantly lower in group 4 (p = 0.024). 5y OS was 88% in group 1, 91% in group 2, 85% in group 3, and 68% in group 4 and was significantly lower in group 4 than that in groups 1 and 2 (p = 0.03, 0.019). Conclusions: In patients with rectal cancer who received CRT, changes in serum CEA levels before and after CRT and after surgery were intimately related to the histological response of the primary lesion. Patients who continued to have positive serum CEA levels after surgery had poor outcomes, strongly suggesting the presence of occult distant metastasis.