bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment strategy for metastatic colorectal cancer (mCRC) treated with chemotherapy plus biological targeted agent: Is strategy with biological targeted agent based on the primary tumor lesion possible?
Authors: Sagawa Tamotsu , Hamaguchi Kyoko , Uemura Naomi , Tamura Fumito , Fujikawa Koshi , Sato Yasushi , Takahashi Yasuo
Published: January 2019

769

Background: The data from randomized trials suggested that primary tumor location (PTL) could represent a prognostic and predictive factor in mCRC patients, particularly during treatment with anti- EGFR therapy. However, it remains unclear whether anti-EGFR is effective for right- sided primary tumors (RT). Methods: Single-institution, retrospective, case-control study was reviewed. A total of 110 patients with mCRC were enrolled between January 2011 and December 2016. We evaluated the association between PTL and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy (FOLFOX/CapeOX or FOLFIRI/IRIS) plus cetuximab(Cmab) or bevacizumab(Bmab). The impact of PTL for Cmab and Bmab groups was analyzed, respectively. Results: 76 patients presented Left-sided primary tumors (LT) and 34 patients RT. Median PFS, median OS, and ORR were numerically superior in our study patients with LT compared with patients with RT (PFS, L vs R, 13.0 vs 6.8 M, p = 0.0040; OS, 36.2 vs 19.0 M, p = 0.002; ORR, 67.1 vs 44.1 %, p = 0.022951). In the Cmab group, LT were significantly superior to RT in terms of OS (L vs R, 56.3 vs11.3 M, p = 0.0057). Likewise, in the Bmab group, OS showed differences between the LT and RT (L vs R, 27.8 vs 19.7 M, p = 0.0116). In LT, Cmab group were significantly superior to Bmab group in terms of the OS (C vs B, 56.3 vs 27.8 M p = 0.0428). Conversely, in RT, the survival times showed no differences between Cmab and Bmab group (C vs B, 11.3 vs 19.7 M, p = 0.6555). Furthermore, while early tumor shrinkage(ETS) was associated with favorable outcome in patients with RT who treated Cmab, non-ETS represented a less favorable survival (ETS vs non-ETS, NR vs 11.3 M, p = 0.0335). ETS was a predictor for survival benefit acquired from Cmab treatment for patients with RT with wild-type KRAS/RAS tumors. Conclusions: Our study suggests the conclusion that patients with LT with KRAS/RAS wild-type should be preferentially treated with Cmab. By contrast, in RT, chemotherapy plus Bmab may be effective, but optimal treatment has yet to be defined and ETS may be able to predictive of benefit acquired from Cmab.
Prevalence and correlates of critical malnutrition (CMN) among gastrointestinal (GI) and non-GI participants in phase I/II (P1/2) clinical trials.
Authors: Jain Rishi , Handorf Elizabeth , Khare Vipin , Blau Matthew , Chertock Yana , Clinton Steven K. , Hall Michael J.
Published: January 2019

770

Background: Patients (pts) with cancer, in particular GI malignancies, are vulnerable to CMN from both tumor-related digestive symptoms and treatment-related toxicity (TRT). CMN is associated with poor cancer outcomes, including reduced quality of life, poor treatment tolerance and decreased survival. P1/2 trial participants are not routinely screened for CMN or potentially associated psychological and physical activity impairments. Methods: Baseline assessments of nutrition (PG-SGA), distress (NCCN-DT), anxiety (HADS-A), depression (HADS-D), and sedentary lifestyle (SL, Godin-LTQ) were conducted in pts beginning a P1/2 trial. CMN was defined as a PG-SGA score of ≥9. Statistical significance was determined by Fisher’s exact test. A regression model was used to identify a composite predictor of CMN. Results: 100 pts (87% P1, 13% P2) were enrolled. Results of assessments are shown in Table 1. 39% of pts had CMN and 52% had a SL. CMN was more common in non-whites (p = 0.05) and those on P1 trials (p = 0.073). No differences were noted by age, gender, or prior lines of therapy. CMN was strongly associated with depression (p < 0.001) and SL (p < 0.001). 31 pts had GI malignancies [CRC (15), pancreas (8), and other (8)]. CMN was more prevalent in GI pts than non-GI (61% vs 29%, p = 0.004). When evaluating the predictive value of commonly used clinical indicators for CMN such as BMI ( < 25), weight loss (WL) past 2 weeks, or WL past month, having 2/3 of these indicators was the optimal cut-point predictor of CMN (76% sensitivity, 85% specificity). TRT data collection is ongoing. Conclusions: CMN and SL are highly prevalent in P1/2 trial pts, particularly in those with GI cancers and minorities. CMN is strongly associated with depression and SL. A composite clinical indicator (BMI + WL) may be most useful in screening for CMN. Urgent nutritional interventions in these participants may be warranted in light of magnified mortality and toxicity risks. [Table: see text]
Neoadjuvant chemotherapy and high dose intensity modulated radiotherapy followed by rectal sparing TEM for distal rectal cancer.
Authors: Parikh Kinjal , DeNittis Albert S. , Marks Gerald J. , Zeger Erik L. , Cho David , Marks John
Published: January 2019

771

Background: For distal rectal tumors, abdominoperineal resection (APR) may achieve a complete resection; however is associated with significant morbidity. Full thickness local excision (FTLE) via transanal endoscopic microsurgery (TEM) may provide disease control with fewer complications. Additionally, Intensity Modulated Radiation Therapy (IMRT) may minimize toxicity by limiting small bowel exposure to radiation. We report on 14 years of prospective data from Lankenau Medical Center for distal rectal cancer pts treated with neoadjuvant chemotherapy and high dose IMRT followed by FTLE via TEM. Methods: From 2002 to 2016, 44 pts were treated for cT1(n = 4), cT2 (n = 24), cT3 (n = 16), N0, M0 distal rectal cancer using IMRT at 5580 cGy along with concurrent 5FU-based chemotherapy, followed by FTLE. Local recurrence (LR), disease free survival (DFS) and overall survival (OS) was reported using Kaplan-Meier survival analysis. Results: At the time of FTLE complete pathological response was achieved in 18 pts, good response in 25 pts, and 1 pt with poor response. Median time to follow-up is 58 months. 3 of 44 pts (6.8%) had isolated local recurrence, all achieving local control with surgical salvage. Mean DFS is 10.68 years (95% CI 8.77 to 12.60). Mean OS is 11.78 years (95% CI 9.99 to 12.58). 34 pts (77%) are currently alive with NED. 6 pts developed metastatic disease, 5 of whom died, and one who was surgically salvaged. 5 pts died from causes outside of their malignancy. In adjusted analysis, DFS was strongly associated with pathologic response to chemoradiotherapy (p = 0.025). Post-operative Grade I-II complications noted in 17 pts, all managed with conservative measures; Grade III occurred in 2 pts. No pts required a diverting colostomy. Conclusions: Neoadjuvant high dose IMRT and chemotherapy followed by FTLE to treat distal rectal cancers is well tolerated and effective. Local excision surgery may provide excellent tumor control and improved quality of life in appropriately selected pts. A randomized clinical trial is needed to compare it to standard surgery. Also a dose escalation study with IMRT may allow for improvement in pathologic response without increasing toxicity.
Randomized phase II trial of CapOX plus bevacizumab versus CapIRI plus bevacizumab as first-line treatment in Japanese patients with metastatic colorectal cancer (CCOG-1201).
Authors: Sasahara Masahiro , Nakayama Goro , Ishigure Kiyoshi , Yokoyama Hiroyuki , Uehara Keisuke , Ishiyama Akiharu , Matsui Takanori , Nakayama Hiroshi , Kobayashi Daisuke , Umeda Shinichi , Sunagawa Yuki , Murotani Kenta , Ando Yuichi , Kodera Yasuhiro
Published: January 2019

781

Background: The aim of this randomized, multicenter, non-comparative phase II trial was to investigate the efficacy and safety of capecitabine/oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine/irinotecan (CapIRI) plus BEV as a first-line treatment in Japanese patients with metastatic colorectal cancer (mCRC). Methods: Patients with untreated mCRC were randomly assigned to the following treatment arms; CapOX/BEV arm (bevacizumab 7.5mg/kg and oxaliplatin 130 mg/m2 on day 1, and oral capecitabine 1000 mg/m2 bid on day 1-14, every 3 weeks) and CapIRI/BEV arm (bevacizumab 7.5mg/kg and irinotecan 200 mg/m2 on day 1, and capecitabine 800 mg/m2 bid on day 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 107 patients were enrolled. The intent-to-treat population comprised 52 patients in CapOX/BEV arm and 51 patients in CapIRI/BEV arm. The ORR was 58% in CapOX/BEV arm and 57% in CapIRI/BEV arm ( p= 0.545). The median tumor shrinkage rate (DpR) was 36.0% (range, -24.0 to 100%) and 36.7% (range, -26.0 to 100%), respectively (p = 0.399). Median PFS was 12.4 months (95% confidence interval [CI], 10.6–14.3 months) in CapOX/BEV arm and 11.5 months (95% CI, 9.6–13.4 months) in CapIRI/BEV arm (hazard ratio [HR], 1.145; 95% CI, 0.760–1.725; p= 0.517). The median OS was 26.6 months (95% CI, 21.5–31.8 months) and 28.7 months (95% CI, 19.6–37.9), respectively (HR, 1.206; 95% CI, 0.0.733–1.907; p= 0.461). The frequency of hematological and non-hematological adverse events (≥grade3) were 10% and 27% in CapOX/BEV arm, and 16% and 27% in CapIRI/BEV arm, respectively. Conclusions: Both regimens, CapOX plus BEV and CapIRI plus BEV, could be equally feasible first-line treatment for Japanese patients with mCRC. Clinical trial information: UMIN_000007545.
Impact of age and frailty on survival in older adults with squamous cell carcinoma of the anus.
Authors: Yokom Daniel , Alibhai Shabbir M.H. , Puts Martine , Brierley James D. , Kim John , Krzyzanowska Monika K.
Published: January 2019

786

Background: Patients with anal cancer (AC) can achieve long-term disease control with chemoradiation (CRT), however, the treatment has serious adverse effects. Most patients with AC are ≥65 but little is known about cancer outcomes in this population. Frailty measures have been proposed to determine the risk of treating older adults. The purpose of this study was to evaluate the impact of age and frailty on outcomes in patients with AC. Methods: A retrospective review was performed of patients age ≥65 with non-metastatic AC treated from 2007-2016 at Princess Margaret Cancer Centre. A 44-item Cumulative Deficit Score was constructed to quantify frailty as per the Rockwood model. The impact of age and frailty on treatment toxicity and overall survival (OS) was analyzed using multivariable logistic regression and survival models, respectively, adjusting for ECOG performance status (PS), stage and treatment modality. Results: Among 92 patients, median age was 72 and 42.4% were age ≥75. Seventy (76.1%) patients were treated with CRT and 17 with radical radiotherapy (RT). After a median follow-up of 34.9 mo (range 0.5-103.9) 34 patients died – 16 from metastatic AC, 16 from other or unknown causes, and 2 treatment-related deaths. For patients treated with CRT or RT (N = 87), 53 (60.9%) required treatment modification due to toxicity. Twenty patients (22.9%) had an emergency room visit or hospitalization. Frailty did not significantly increase the risk of toxicity in multivariable analysis (OR 1.9, 95% CI 0.35-10.8). Treatment with CRT increased the risk of toxicity compared to RT alone (OR 9.5, 95% CI 1.7-53.8). Patients ≥75 had shorter OS on univariable analysis (HR 1.9, 95% CI 1.0-3.8) but not on multivariable modeling (HR 1.5, 95% CI 0.72-3.4). Factors associated with shorter OS were increased frailty (HR 3.8 CI 1.4-10.2) and ECOG ≥2 (HR 3.9, 95% CI 1.7-9.1). There was good discrimination of the model with a C-statistic of 0.77. Conclusions: Older adults with AC experience a high rate of treatment toxicity especially with CRT relative to RT alone. OS was significantly associated with frailty as well as PS but not age. Frailty assessment may improve treatment planning and understanding survival for older patients with AC.
Potential drug cost impact of nivolumab (N) in Canada in patients with DNA mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).
Authors: Virik Kiran , Biagi James Joseph , Wilson Robert B
Published: January 2019

797

Background: The overall 5 year survival for mCRC remains poor (14%) despite the sequential use of chemotherapy and biologic agents. Immunotherapy is a promising treatment option in tumors with a high mutational burden. This includes mCRC DNA mismatch repair deficient tumors (dMMR). These have upregulation of immune checkpoints and a poorer prognosis. The CheckMate 142 phase II trial in pretreated dMMR mCRC patients showed durable responses and disease control across a number of subgroups including BRAF mutant tumors. The use of immunotherapy has an anticipated budgetary impact on health care systems within the context of this potentially funded utilization of N. Methods: An estimation of the N drug cost alone for new cases diagnosed in 2017 and treated upon relapse in Canada was undertaken. A cost estimate for N treatment in the first line of dMMR mCRC in relapses and de novo was undertaken should this be a future option. N cost per patient was calculated based on treatment indication, median number of cycles, standard dose/schedule. The analysis was performed in Canadian dollars ($) and assumed complete drug delivery and uncomplicated cycles. The cost of N was obtained from the pan Canadian Oncology Drug Review (pCODR) cost for N in lung cancer. The number of target patients and N utilization was derived from constructed schema to give a budget impact estimate. Results: Estimated N cost per treated patient is $91,667. The N drug cost for prior second line and third line relapsed chemotherapy treated patients respectively ranges from $23.6 Million (M) – $36.4M and $12.7M – $17.7M. For 1st line N: the cost of treating early stage dMMR CRC which subsequently recurs would be $49.1M and the cost for treatment of dMMR de novo mCRC would be $24.6M. A sensitivity analysis was performed. Conclusions: Immunotherapy drug costs in dMMR mCRC potentially add a substantial cost burden to the publicly funded Canadian healthcare system. As data evolves, longer duration of therapy and potential first line use will add further to the estimated budgetary impact.
Cardio-respiratory fitness and functional performance in patients with a recent diagnosis of colorectal cancer.
Authors: Alvarez-Bustos Alejandro , Gutierrez Sanz Lourdes Gutierrez , Nuñez García Beatriz , Soriano Maria , Fiuza-Luces Carmen , Ramos Javier , Sen Jorge D. , Sánchez-Ruiz Antonio Carlos , Gomez-Bravo Raquel , De La Puente Blanca , Lucia Alejandro , Ruiz-Casado Ana
Published: January 2019

804

Background: Physical capability describes the ability to do the physical tasks of everyday living. Oncologists usually evaluate physical capability through anamnesis generating a performance status (PS) score. Some authors have proposed the use of cardiorespiratory reserve, muscular strength and objective evaluation of physical activity to avoid the subjective, unreliable and non-reproducible condition of PS. Methods: Patients with a recent diagnosis of colorectal cancer who accepted to participate were evaluated at the hospital setting. Walking speed was evaluated through both one-mile walk test and six-minute walk test. VO2max was calculated through the Kilne formula. Muscular strength was measured through dynamometry (hand-grip) and “sit to stand” test. Physical activity was objectively evaluated with accelerometers. Fatigue was evaluated through the PERFORM questionnaire (12-60). ECOG was evaluated by the medical oncologist. Results: 100 pats were recruited between March 15 and Jul 17. ECOG O/1/2 (80/14/2). 40 (40 %) were metastatic. Mean age 66 (25-81), Sex M/F; 68/32. Conclusions: Objective evaluation of physical condition is feasible at the hospital setting. There were no differences in BMI, heart rate, fatigue, muscular strength and objective functional performance (weekly PA) between localized and metastatic CRC. In metastatic pts with an excellent ECOG-PS the time to walk one mile and the estimated VO2max could be more sensitive than ECOG to evaluate the functional capacity impairment. In pts with cancer the One- mile walk test could be superior to the Six-minute walk to estimate the cardiorespiratory fitness. The objective evaluation of physical condition is a useful additional tool to select pts for aggressive therapies. [Table: see text]
Metastatic colorectal cancer (mCRC) treatment patterns in the Medicare population.
Authors: Snider Jeremy , Wang Ed , Anderson Sibyl , Steelquist Jordan , Warnick Greg S , Fedorenko Catherine R. , Shankaran Veena , Ramsey Scott David
Published: January 2019

823

Background: Few studies have examined how patterns of care relate to clinical consensus guidelines for metastatic colorectal cancer (mCRC) in real-world settings. This study investigated treatment patterns around systemic therapies for older mCRC patients using SEER-Medicare data. Methods: We utilized data from a linkage of national Medicare claims data with records from the 12 Surveillance, Epidemiology, and End Results (SEER) regions for patients diagnosed with stage IV CRC between 2011 and 2014. Other inclusion criteria included adenocarcinoma histology, being > 65 years of age, and continuous Part A/B enrollment 12 months prior to diagnosis. We conducted bivariate analysis and multivariate modeling to evaluate the association between age, race, gender, SEER region, and comorbidity score with receipt of systemic therapy. We examined first and subsequent lines of therapy, and classified them as adherent or non-adherent to NCCN guidelines. Results: Of 102,461 CRC patients, 6,360 (6.2%) patients had evidence of metastatic disease and met all inclusion criteria. 3,155 (49.6%) received no systemic therapy. Of the 2,976 (46.8%) who received systemic therapy with identifiable regimens, FOLFOX/CAPOX was the most common 1L regimen (32.9%), followed by 5-FU or capecitabine alone (26.4%) – both identified as guideline-adherent therapies. Non-guideline adherent regimens (such as use of single-agent oxaliplatin or bevacizumab) were uncommon as 1L therapies (1.4%). 1,553 patients (52.2%) progressed to a 2L therapy, 715 (24.0%) progressed to a 3L therapy, and 320 (10.8%) to a 4L therapy. A large proportion of 2L (26.9%) and 3L (24.2%) treatments contained bevacizumab. 96 patients (3.2%) received regorafenib, representing 6.7% of 3L and 10.6% of 4L therapies. Patients who did not receive systemic therapy were older (mean age of 80.8 vs 74.9) and had multiple comorbidities (63.1% vs 48.4% with Klabunde score > 1). Conclusions: In a Medicare-insured mCRC cohort, patients generally received systemic therapy adhering to consensus guidelines. However, many patients did not receive systemic therapy – suggesting there may be delays in diagnosis and barriers to treatment which lower systemic therapy utilization.
Nivolumab versus nivolumab with ipilimumab versus trifluridine/tipiracil for metastatic microsatellite instability-high colorectal cancer: A modeling decision analysis.
Authors: Chu Jacqueline N. , Choi Jin G. , Ostvar Sassan , Torchia James A. , Reynolds Kerry Lynn , Gainor Justin F. , Chung Daniel C. , Clark Jeffrey W. , Hur Chin
Published: January 2019

829

Background: Microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients who have failed chemotherapy have shown response to checkpoint blockade. We investigate optimal third-line treatment in MSI-H mCRC with regard to overall survival, quality of life years gained (QALYs), and cost-effectiveness. Methods: A Markov Model was created for a base case of a 57 year old man with MSI-H mCRC refractory to two lines of chemotherapy. Treatments compared were nivolumab, nivolumab with ipilimumab, and trifluridine/tipiracil. Patients could remain stable, progress to fourth-line chemotherapy or palliative care, experience drug toxicity, die from age/sex mortality, or die from cancer over their simulated lifetimes. Transitions between health states were based on the CheckMate 142 and RECOURSE trials. Outcomes were survival or unadjusted life years, QALYs, and incremental cost-effectiveness ratios (ICERs). The willingness to pay threshold was $100,000/QALY. Results: Nivolumab with ipilimumab was the most effective strategy as it yielded more unadjusted life-years (4.24) and QALYs (2.53) compared to nivolumab (3.95 LY, 2.33 QALYs) and trifluridine/tipiracil (0.74 LY, 0.07 QALYs). However, nivolumab with ipilimumab was not cost-effective compared to nivolumab and neither treatment strategy was cost-effective compared to trifluridine/tipiracil. Sensitivity analysis found nivolumab monotherapy could be cost-effective with decrease in drug cost to $2000/dose. Conclusions: Our modeling analysis finds that both single and dual checkpoint blockade yield significantly increased overall survival and QALYs for MSI-H mCRC compared to third-line chemotherapy, but were not cost-effective because of nivolumab cost. Decreases in drug pricing and/or duration of maintenance nivolumab could make nivolumab monotherapy cost-effective. [Table: see text]
Patterns of care and outcomes with the addition of radiotherapy to surgery for stage I rectal adenocarcinoma.
Authors: Zhao Nan , Lin Chi
Published: January 2019

831

Background: The standard of care for stage I (T1/2N0M0) rectal adenocarcinoma is surgery alone. We investigated practice patterns and outcomes associated with administration of radiotherapy (RT) to surgery for stage I rectal adenocarcinoma. Methods: Using National Cancer Database from 2004 to 2014, 12494 patients with clinical stage T1-2N0M0 rectal adenocarcinoma who had definitive surgery were analyzed. 8265 received definitive surgery alone and 4229 received definitive surgery with preoperative or postoperative RT. Between groups, demographic, tumor and treatment characteristics were compared. Multivariate logistics regression was used to examine factors associated with the receipt of RT. Overall survival (OS) were estimated by Kaplan-Meier method; the log-rank test was used to compare survival curves. Cox proportional hazards modeling determined variables associated with death. Results: Of 12494 patients, 34% received RT; among them, 94% received chemotherapy (CT). Patients who received RT tended to be younger, male, diagnosed in early years, covered by Medicaid/Medicare/Not Insured, treated at community cancer program, a lower Charlson/Deyo score, a T2 clinical stage, a poorly differentiated or a larger tumor. Survival analysis revealed no difference in patients with or without RT (Median survival of 142 months vs. 137 months and 5 year OS of 79% vs. 82%, p = 0.50). Multivariate Cox models showed that variables significantly associated with increased hazard of death (p < 0.05) were older age (HR = 1.06), male gender (HR = 1.24) , Charlson/Deyo score 1 (HR = 1.54)/ Charlson/Deyo score 2 (HR = 2.29) (vs. Charlson/Deyo score 0), clinical T2 stage (HR = 1.15), pathological III/IV stage (HR = 4.16), poorly differentiated grade (HR = 1.38), Medicaid (HR = 1.70) /Medicare (HR = 1.24) /Not Insured (HR = 2.28) (vs. private insurance), community cancer program (HR = 1.17) and lower income (HR = 1.25). After adjusting for all above variables, RT or CT was not associated with improved OS. Conclusions: Addition of RT (with or without chemotherapy) to definitive surgery was not associated with survival advantage in stage I rectal adenocarcinoma.
ISO-CC-005: A phase I/II study of Modufolin (MTHF) in combination with 5-FU, irinotecan, and oxaliplatin ± bevacizumab in patients with metastasizing colorectal cancer.
Authors: Taflin Helena Anna , Ganlov Karin M E , Guren Tormod Kyrre , Papadimitrou Christos , Kentepozidis Nikolaos K. , Haux Johan , Pfeiffer Per , Carlsson Goran Ulf
Published: January 2019

838

Background: Chemotherapy treatment of Colorectal Cancer, often include 5-Fluorouracil (5- FU). 5-FU inhibits the enzyme thymidylate synthase (TS), stopping the supply of thymidine for DNA synthesis. 5-FU is always combined with a folate, which enhances the 5-FU effect. Marketed folates such as LV/L-LV are prodrugs needing enzymatic conversion. Modufolin is the natural, biologically active form of the folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability Methods: ISO-CC-005 is a multi-center, phase I/II study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. The study investigates safety and tolerability of Modufolin at 4 dose levels by analysing the number and severity of AEs, SAEs and DLTs. Efficacy is evaluated as ORR after four cycles of chemotherapy. Gene expression, deoxyuridine levels as an indirect marker of TS inhibition and time to death is also investigated. Three to six patients per cohort are included. All receives Modufolin twice every two weeks during at least four cycles of chemotherapy. Results: Today, 42 patients have been enrolled and 40 have initiated treatment. 13 are 1st line patients, 16 are in 2nd line, 10 are in 3rd line and 1 is in 5th treatment line. 19 SAEs have been reported in 12 patients, 3 of these were judged as at least possibly related to Modufolin. No SAE were judged as solely related to Modufolin. 31 patients have today been evaluated for efficacy. ORR 1st line patients (n=12) All 50% (6 PR, 6 SD) Patients with Modufolin dose ≥60 mg/m2 71% (5 PR, 2 SD) Patients with Modufolin dose ≥60 mg/m2 + oxaliplatin 100% (3 PR) Conclusions: The lack of need for metabolic activation makes Modufolin a better candidate than LV/L-LV for improved outcome of 5-FU-based chemotherapy regimens in mCRC. The ISO-CC-005 study evaluates Modufolin in combination with 5-FU, irinotecan, oxaliplatin ± bevacizumab in mCRC patients in 4 countries in Europe. The results, so far, for both safety and efficacy seems promising. Clinical trial information: NCT02244632.
Benefit of adjuvant treatment in stages II and III colon cancer: Experience at the Ramón y Cajal University Hospital.
Authors: Martinez Saez Olga , Barquín García Arantzazu Martínez , Saavedra Serrano Cristina , Corral de la Fuente Elena , Serrano Domingo Juan José , Martín Huertas Roberto , Villamayor Delgado Maria , LONGO FEDERICO , Reguera Puertas Pablo , Pachon Vanessa , Rodríguez Garrote Mercedes , Guillen Carmen , Carrato Alfredo , Ferreiro Monteagudo Reyes
Published: January 2019

842

Background: The standard adjuvant treatment for patients with stage III colon cancer is 6 months with fluoropyrimidines and oxaliplatin. The Intergroup Trial INT-0035 was the first large-scale study to demonstrate a significant reduction in the risk of death with adjuvant FU plus levamisole in patients with stage III colon cancer. In the MOSAIC study, the addition of oxaliplatin to fluoropyrimidines in patients with resected stage II to III colon cancer showed OS and DFS benefit of oxaliplatin. However, no significant benefit was observed in either DFS or OS in patients with stage II disease, therefore the benefit of adjuvant chemotherapy is still controversial in those patients. Methods: We retrospectively included patients with stages II and III colon cancer that were operated between 2009 and 2014 in the University Ramón y Cajal Hospital from Madrid. We calculate DFS and OS at 48 months and we perform a multivariable Cox model analysis to estimate the benefit of the chemotherapy in each stage. The model was further adjusted by including the following confounders: ECOG-PS, number or removed nodes ( < 12 or ≥ 12), grade and age. A covariate was considered a confounder factor if the difference between the adjusted and unadjusted coefficient of chemotherapy varied > 10%. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (281 stage II and 283 stage III). 259 received chemotherapy and 305 did not. The median follow-up in the entire cohort was 49 months. The median DFS and OS were not reached at the moment of the analysis. DFS and OS at 48 months were both 78.5%. Globally, chemotherapy did not improve DFS (HR 1.05, p: 0.83) but OS was significantly better (HR 0.47, p: 0.001). By stage, chemotherapy did not improve DFS in stage II (HR: 1.6, p: 0.2) nor OS (HR 0.76, p: 0.43). In stage III, chemotherapy showed a trend to improve DSF (HR: 0.61, p: 0.075) and did improve OS (HR: 0.31, p < 0.0001). Conclusions: The multivariable analysis showed a chemotherapy benefit in patients with stage III colon cancer, with a 39% reduction in the risk of recurrence and a 69% in the risk of death; however, in stage II patients these benefits were not found either in DFS or OS.
Liver and/or lung metastasectomy after cetuximab or bevacizumab+FOLFIRI chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Kim Sang-A , Kim Ji-Won , Suh Koung Jin , Kim Jin Won , Oh Heung-Kwon , Cho Jai Young , Kim Duck-Woo , Lee Keun-Wook , Cho Sukki , Kim Jee Hyun , Kim Kwhanmien , Kang Sung-Bum , Jheon Sanghoon
Published: January 2019

843

Background: Some mCRC pts who have liver and/or lung metastases (LLMs) could achieve cure after palliative chemotherapy and conversion surgery (CS) including metastasectomy. Though targeted agents including bevacizumab and cetuximab significantly improved outcomes in mCRC pts, the effect of targeted agents on cure rate after CS has not yet been thoroughly investigated. Methods: We analyzed clinical data of mCRC pts who initially had unresectable LLMs regardless of their size and number and underwent first-line cetuximab or bevacizumab+FOLFIRI. Pts who had metastasis other than liver and lung were excluded. Results: From January 2013 to May 2016, 87 pts (male, 56) were consecutively enrolled: liver-limited metastasis in 42 pts (48.3%), lung-limited metastasis in 17 pts (19.5%), and both liver and lung metastases in 28 pts (32.2%). Median age was 62 years (range, 37-85). K-RAS or N-RAS mutation was detected in 39 pts (46.4%) and B-RAF in 2 pts (3.1%) among mutation evaluated pts. Among them, 35 pts (40.2%) received cetuximab+FOLFIRI and the others (N = 52, 59.8%), bevacizumab+FOLFIRI. Median follow-up time was 20.0 months (range, 1.9-49.1). Response rate was 65.7% in the cetuximab group (CET) and 42.3% in the bevacizumab group (BEV) ( p= 0.032). Median progression-free survival was 19.1 months (95% confidence interval [CI], 11.2-27.1) in CET and 14.1 months (95% CI, 11.5-16.8) in BEV ( p= 0.249). CS was performed in 24 pts (27.6%) after median 8.7 months (range, 2.5-27.3) after initiation of chemotherapy. In CET, 11 pts (31.4%) including 8 pts with partial response (PR) and 3 pts with stable disease (SD) underwent CS and all (100%) attained R0. In BEV, 13 pts (25%) including 6 pts with PR and 7 pts with SD received CS and 11 of them (84.6%) achieved R0. Among pts with R0 resection, median disease-free survival (DFS) was 8.8 months (95% CI, 4.9-12.7) in CET and 3.2 months (95% CI, 0.0-7.4) in BEV ( p= 0.326). Conclusions: A substantial proportion of pts could receive CS after cetuximab or bevacizumab+FOLFIRI chemotherapy. CET tended to show higher rate of CS. However, the median DFS after R0 resection was not significantly different between the two groups.
Clinical differences and prognostic factors in right and left colon cancer.
Authors: Onate-Ocana Luis F. , Beltran Leonora , Gonzalez-Trejo Sagrario , Carrillo Jose F. , Herrera-Goepfert Roberto , Carmona-Herrera Doris , Aiello-Crocifoglio Vincenzo , Gallardo-Rincon Dolores , Ruiz Garcia Erika
Published: January 2019

846

Background: Clinical-Pathological and genomic differences between Right-colon cancer (RCC) and Left-colon cancer (LCC) have been reported, but there is not available information from Latin American countries. Methods: A retrospective cohort study was carried out in patients with RCC and LCC treated from January 1989 to December 2016, in a cancer referral center at Mexico City. Patients were assigned into groups according to the location of the neoplasm defined by colonoscopy. Comparison between groups was performed regarding demographic, clinical, histopathology or survival data, using the Student’s T or Squared chi tests, as appropriate. Multivariate analysis was performed employing the logistic regression model. Survival analysis was addressed using the Kaplan-Meier method, and results were compared using the Log rank test. Results: 1,619 patients were included in this analysis; 806 were women (49.8%) and 813 men (50.2%); mean age was 58.1 years old. RCC was registered in 871 cases (53.8%) and LCC in 748 (46.2%). RCC was significantly associated with low socioeconomic status, low body mass index (BMI), low hemoglobin, low serum albumin, and lower lymphocyte count than LCC. Distribution of TNM stages was similar between groups, as well as gender, age of presentation, comorbidities, surgical morbidity and mortality; 72.3% of RCC and 83.2% of LCC were well or moderately differentiated ( p< 0.0001). Mean lymph node retrieval was 19.3 (SD 14.6) for RCC and 15.7 (SD 13.1) for LCC ( p< 0.0001). Mean metastatic lymph node ratio was 0.19 for RCC and 0.21 for LCC ( p= 0.54). Median Overall survival (OS) was 5.55 years (95% CI 4.3–6.8) for RCC, and 3.28 years (95% CI 2.1–4.45) for LCC ( p= 0.052). Conclusions: Striking differences between RCC and LCC were found, mainly represented by anemia and immunonutritional variables. Moreover, OS is substantially better for RCC.
Early survival outcomes in stage I-III operated colon cancer patients from a low prevalence, lower-middle income country: The Indian experience.
Authors: Kothari Rushabh Kiran , Ostwal Vikas S. , Ramaswamy Anant , Gupta Tara Chand , Kumar Bairwa Sandeep , Kapoor Akhil , Kumar Amit , Ventrapati Pradeep , Ramadvar Mukta , Arya Supreeta , Kumar Suman , Patil Prachi , DeSouza Ashwin , Saklani Avanish
Published: January 2019

857

Background: Data regarding survival and outcomes in operated colon cancer patients from a lower-middle income and low prevalence nation like India is scarce. Methods: Patients who underwent curative resection for non-metastatic, non-rectal colon cancer from January 2013 to December 2016 were retrospectively analyzed from a prospectively maintained database for baseline demographics, disease characteristics, adjuvant chemotherapy, recurrence free survival (RFS) and overall survival (OS). RFS and OS were calculated by Kaplan Meier method. Results: 505 patients underwent resection in the pre-defined time-period. Median age of the patients was 53 years (range: 17 – 87) and 339 patients (67.3%) were male. Patients with stage I, stage II and stage III disease were 43(8.6%), 233(46.1%) and 217(42.9%), respectively, while 12 patients(2.4%) were not adequately staged, though non-metastatic. Right sided colon cancers were more prevalent as compared to left sided (56% vs. 44%) and 41 patients (8%) had signet ring adenocarcinoma on cytomorphology. Median number of nodes retrieved during surgery was 22 nodes(range:1-96 ). Adjuvant chemotherapy was planned for 406 patients (80.4%), with the common regimens used being capecitabine-oxaliplatin, capecitabine , 5-fluorouracil – oxaliplatin and 5-fluorouracil in 280 (55.2%), 80 (16%), 34 (7%) and 6 patients (1.2%), respectively. Planned adjuvant chemotherapy was completed in 334 patients(82.3%; n = 406) with 27 patients (6%) required dose reduction. 35 patients (7%) required permanent cessation of adjuvant treatment due to chemotherapy related toxicity. With a median follow up of 21.8 months (range: 0-56),estimated 3 year RFS for the entire cohort was 86.2% and estimated median OS was 95.2%. Estimated RFS in stage I, Stage II, stage III patients were 90.3%, 89.5% and 78% respectively (p-0.006). Conclusions: Early survival outcomes with Stage I-III colon cancers in a low prevalence country like India appears to be comparable or potentially superior to outcomes published from high prevalence countries. Adjuvant chemotherapy in Stage II and Stage III colon cancers in a real world scenario in India appears to be well tolerated.
Survival results of hepatectomy followed by adjuvant chemotherapy with three months of capecitabine plus oxaliplatin for colorectal cancer liver metastases: A multicenter phase II study.
Authors: Satake Hironaga , Hashida Hiroki , Tanioka Hiroaki , Miyake Yasuhiro , Yoshioka Shinichi , Watanabe Takanori , Matsuura Masato , Kyogoku Takahisa , Inukai Michio , Kotake Takeshi , Okita Yoshihiro , Hatachi Yukimasa , Yasui Hisateru , Kotaka Masahito , Kato Takeshi , Kaihara Satoshi , Tsuji Akihito
Published: January 2019

866

Background: Hepatic resection is one of the treatment strategies for resectable colorectal cancer liver metastases (CLM). The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable CLM is still unclear. Adjuvant chemotherapy consisting of capecitabine plus oxaliplatin (CapeOx) appears to be equivalent to FOLFOX in patients with stage III colon cancer. Furthermore, the IDEA collaboration reported that adjuvant chemotherapy with the three months of CapeOx after curative resection for stage III colon cancer has equivalent efficacy to adjuvant chemotherapy for 6 months. We conducted a multi-institutional, single-arm, phase II trial to confirm the feasibility of the three months of adjuvant CapeOx for post curative resection of CLM. Methods: Patients received one course of capecitabine followed by four courses of CapeOx for a total five courses (15 weeks) as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given with 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CapeOx consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. The primary endpoint was completion rate of adjuvant chemotherapy. We set a threshold completion rate of protocol treatment of 45% and an expected completion rate of 70%. Given a one-sided α of 0.1 and statistical power of 80%, a minimum of 25 patients was required. Results: From May 2013 to November 2015, Twenty-eight patients were enrolled from six institutions: median age 69.5y, 54% male, 78.5% left-sided primary. Of the patients, 15 were synchronous metastases and 13 were metachronous. The locations of the metastases were unilobar in 20 patients and bilobar in 8. The mean number of lesions resected was two (range, 1 to 4). Among the 28 patients, 20 (71.4%: 95% CI, 53.6 to 89.3%) completed the protocol treatment. The most common grade 3/4 toxicities were neutropenia (29%). No treatment related death was observed. With a median follow-up period of 36 months (range 15-53months), 3 year-relapse free survival was 75.3%. Conclusions: The three months of adjuvant CapeOx is tolerable for post curative resection of CLM. Clinical trial information: 000011164.
Clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for colorectal cancer.
Authors: Yagi Shusuke , Shinozaki Eiji , Chin Keisho , Suenaga Mitsukuni , Takahari Daisuke , Ogura Mariko , Ichimura Takashi , Wakatsuki Takeru , Ozaka Masato , Nakayama Izuma , MATSUSHIMA TOMOHIRO , Osumi Hiroki , Yamaguchi Kensei
Published: January 2019

867

Background: CAPOX as adjuvant chemotherapy is a standard care option for stage III and high risk stage II colorectal cancer(CRC). And then chemotherapy induced diarrhea (CID) is known as one of the dose-limiting toxicities for CAPOX. Although diverting ileostomy is useful for preventing serious complications of high risk anastomosis, it is well recognized that high ileostomy output is hard to manage. Furthermore, the effect of diverting ileostomy on CID of adjuvant chemotherapy is unclear. In this study, we addressed the clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for CRC. Methods: Patients who diagnosed with stage III colon cancer and stage II or III rectal cancer after curative surgery and received CAPOX as adjuvant chemotherapy during 2011- 2014 were reviewed retrospectively. We investigated the relationship between diverting ileostomy and dose intensity, toxicities and disease-free survival (DFS). Results: 112 patients (median age 60 years, 52% male, 69% colon cancer, 63% stage III, median follow-up 47 months) were enrolled in this study. Of 112 patients, 100 patients were received chemotherapy without ileostomy (non-ileostomy group: NIG) and 12 patients were received chemotherapy with ileostomy (ileostomy group: IG). 112 Patients received 870 chemotherapy cycles. All treatment related grade 3/4 adverse events were documented in 39% of patients in NIG and 33% of patients in IG (P = 0.77). Grade 3/4 of CID occurred in 8% of patients in NIG and 8% of patients in IG (P = 1). Grade 3/4 of neutropenia were recognized in 21% of patients in NIG and 17% of patients in IG (P = 1). Average relative dose intensity (RDI) in NIG were 75.7% and 85.8% for capecitabine and oxaliplatin, respectively. Average RDI of capecitabine and oxaliplatin in IG were 76.1% and 82.7%, respectively. Significant difference of RDI of capecitabine and oxaliplatin were not shown in comparison between NIG and IG (P = 0.93, P = 0.63). The 3-year DFS rate was 85.0% in NIG and 75.0% in IG. The HR for DFS for NIG compared to IG was 1.709 (95% CI, 0.49 to 5.95; P = 0.40). Conclusions: The presence of diverting ileostomy does not affect RDI of CAPOX as adjuvant chemotherapy.
A prospective multicenter trial of S-1 with lafutidine vs S-1 as adjuvant chemotherapy for gastric cancer in Japan: AEOLUS.
Authors: Machida Nozomu , Terashima Masanori , Taku Keisei , Daimon Takashi , Kimura Masashi , Sugimoto Akihisa , Yasui Hirofumi , Nozaki Isao , Fukushima Norimasa , Takagane Akinori , Kim Yongil , Takiguchi Nobuhiro , Takagi Masakazu , Misawa Kazunari , Kimura Taisei , Maeda Masato , Kanai Toshikazu , Ota Mitsuhiko , Yokoyama Hidetarou
Published: January 2019

91

Background: From the result of ACTS-GC study, adjuvant chemotherapy with S-1 for one year is standard therapy of gastric cancer in Japan. In this study, completion rate of pre-planned S-1 treatment was 65.8% and there is still room for improvement on this rate. Lafutidine is a H2 blocker and enhances submucosal blood flow via capsaicin-sensitive afferent neurons. Alleviating effect of lafutidine on toxicity of 5FU leading to discontinuation of adjuvant treatment could be expected. Methods: Patients with histologically confirmed stage II (excluding T1 cases), IIIA, or IIIB (Japanese Classification of Gastric Carcinoma 13th) who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 with lafutidine(L) or S-1 (S). All patients were given S-1 (40mg/m2) for 4 weeks with 2 weeks rest, repeated for 1 year after surgery. Patients of L group received lafutidine (20mg/day) every day for 1 year with S-1. The primary end point was treatment completion rate (TCR) of S-1. Definition of treatment completion was S-1 continuation for 1 year with over 70% planned dose. The secondary end points were toxicity (CTCAE v3.0) and relative total administration dose (RD) of S-1. Results: We randomly assigned 101 patients to the L group and 101 patients to the S group between February 2010 and December 2012 from 17 centers in Japan. After randomization, two patients were found to be ineligible in L group (the absence of cytologic examination of the peritoneal fluid, stageIB) and 1 in S group (allocation violation). TCR was 68.3% in the L group and 60.4% in the S group (p = 0.072, Cochran-Mantel-Haenzel test at a pre-specified one-sided significance level of 0.1). Adverse events of grade 3/4 excluding ineligible example was 30.0% in the L group, and 36.0% in the S group. Patients who require a dose reduction and/or delay of S-1 was 41.6% in the L group, and 51.5% in the S group. RD was 83.9% (range: 1.6-103.7) in the L group, and 84.0% (range: 1.7-103.8) in the S group. No any toxicity of lafutidine was observed. Conclusions: Lafutidine may increase a completion rate of adjuvant chemotherapy using S-1 within a 30% dose reduction for gastric cancer. This result need to be confirmed in double-blind placebo control study. Clinical trial information: UMIN000002703.
Nodal downstaging in gastric cancer in relation to survival when ypN0 is achieved.
Authors: Ikoma Naruhiko , Estrella Jeannelyn , Hofstetter Wayne Lewis , Das Prajnan , Ajani Jaffer A. , Fournier Keith F. , Mansfield Paul F. , Badgwell Brian D.
Published: January 2019

93

Background: The AJCC 8th edition introduced ypStage for patients with gastric cancer due to the increasing use of preoperative therapy. ypN0 patients have better survival than ypN+ patients; however, whether patients who had clinically positive nodal disease before preoperative therapy (cN+ ypN0) have similar survival to those who had “natural N0” (cN0 ypN0) disease is unknown. Methods: We reviewed an institutional database to identify patients with gastric adenocarcinoma who underwent potentially curative R0 resection after preoperative chemo- or chemoradiation therapy. Patients were categorized into 3 groups based on nodal status: natural N0 (cN0 ypN0), downstaged N0 (cN+ ypN0), and ypN+. Univariable and multivariable Cox regressions were performed to determine associations with overall survival (OS). Results: We identified 316 patients who met study criteria, including 74 (23%) patients with GEJ tumors; 56% were white and 62% were male. Preoperative chemoradiation therapy was given to 239 (76%). Ninety-four (30%) had natural N0, 93 (29%) had downstaged N0, and 129 (41%) had ypN+ disease. Of all patients, 136 (43%) patients died during a median follow-up of 3.1 y. Median OS was 7.7 y, and 5-year OS was 60.3%. OS did not differ in patients with natural N0 disease (5-y OS, 72%) and those with downstaged N0 disease (5-y OS, 69%) ( p = 0.776), even though the downstaged N0 group had more advanced baseline cT disease than did the natural N0 group ( p < 0.001). On multivariable analysis adjusting for other factors, including ypT category, OS did not differ between natural N0 and downstaged N0 patients (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.54-1.48; p = 0.666), but it was shorter in ypN+ patients (HR, 1.82; 95% CI, 1.15-2.87; p = 0.010). Sensitivity analyses also showed equivalent OS in the natural N0 and downstaged N0 groups within the ypT0-2 group ( p = 0.936) and the ypT3-4 group ( p = 0.608). Conclusions: In patients with gastric cancer who underwent preoperative therapy, we found similar OS in patients with natural N0 and those with downstaged N0 disease. As ypN+ patients had poor OS, achieving ypN0 status is an important hallmark demonstrating the effectiveness of preoperative therapy.