bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective, multi-center study of 5-fluorouracil (5-FU) therapeutic drug management (TDM) in metastatic colorectal cancer (mCRC) patients treated in routine clinical practice.
Authors: Salamone Salvatore J. , Jaehde Ulrich , Mueller Lothar , Link Karin , Holdenrieder Stefan , Bertsch Thomas , Ko Yon-Dschun , Kunzmann Volker , Suttmann Ingo , Braess Jan , Roessler Max , Moritz Berta , Kraff Stefanie , Miller Michael Craig , Wilhelm Martin
Published: March 2017

650

Background: Studies have demonstrated that body surface area (BSA)-based dosing of chemotherapy drugs leads to significant individual exposure variability with a substantial risk of under- or overdosing. This study was initiated to validate use of TDM to personalize 5-FU dosing in mCRC patients treated in routine clinical practice. Methods: 75 mCRC patients from 8 German medical centers received up to 6 administrations of infusional 5-FU according to either the AIO (n = 16), FOLFOX6 (n = 26) or FUFOX (n = 33) regimen. Initial infusional 5-FU dosing for all patients was based on BSA. Individual 5-FU exposure (AUC) was measured by an immunoassay using a blood sample drawn during each infusion. To achieve target AUC of 20 to 30 mg•h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle 5-FU AUC. Tumor markers CEA and CA19-9 were also measured before, during and after treatment. Primary objective was to confirm TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the 4th versus the 1st administration. Secondary objective was to determine whether 5-FU TDM reduced treatment-related toxicities compared to historical data. Results: Average 5-FU AUC at 1st administration was 18 + 6 mg•h/L, with 64%, 33% and 3% of the patients below, within or above target AUC range, respectively. By the 4th administration average 5-FU AUC was 25 + 7 mg•h/L (p < 0.001), with 54% patients within the target 5-FU AUC range (p = 0.0294). Compared to baseline levels, CEA and CA19-9 remained stable or decreased at the end of treatment in 82% and 84% of the patients, respectively. 5-FU-related grade 3-4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%) and mucositis (0.2%) were reduced compared to historical data inspite of 55% of patients having their doses increased. Conclusions: Personalization of 5-FU dosing via TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested lower 5-FU-related toxicities. Clinical trial information: 2011-003553-26.
KRAS testing practice in Denmark between 2009 and 2013.
Authors: Ording Anne Gulbech , Frøslev Trine , Spindler Karen-Lise Garm , McCusker Margaret Elizabeth , Cheng I-Ning (Elaine) , Sørensen Henrik Toft , Ehrenstein Vera
Published: March 2017

654

Background: Guidelines for managing patients with metastatic colorectal cancer (mCRC) were updated in Denmark in 2013, and anti-epidermal growth factor receptor (EGFR) inhibitors were promoted from third-line to first-line treatment for KRAS wildtype mCRC patients. As a result, more patients became eligible for EGFR antibody therapy. Weexamined KRAS testing practice among patients with mCRC who received systemic cancer treatment in Denmark during 2009-2013. Methods: We linked data from several population registries with nationwide coverage - the Danish Cancer Registry, the Danish National Patient Registry, and the Danish National Pathology Registry - to identify patients diagnosed with mCRC (primary or recurrent) between 2009 and 2013, their systemic cancer treatment, and their KRAS testing status. We obtained all KRAS test results through 2014 and calculated proportions of KRAS-tested patients by year of mCRC diagnosis. Results: There were 7,245 mCRC patients, among whom 4,272 (59%) had a record of systemic cancer treatment within 6 months of mCRC diagnosis and were included in the analysis. The proportion of men was 57%; median age at mCRC diagnosis was 67 years (range 20-94 years). Overall, 2,099/4,272 (49%) of the treated mCRC patients had a recorded KRAS test result, with similar proportions for patients with primary and recurrent mCRC. Among patients diagnosed with mCRC in 2009, the proportion with a recorded KRAS test result was 374/900 (42%). Corresponding proportions for patients diagnosed in 2010, 2011, 2012, and 2013 were 411/891 (46%), 457/870 (52%), 430/807 (53%), and 427/804 (53%). Conclusions: Among patients in Denmark diagnosed with mCRC who received systemic cancer treatment, the proportion of patients with a KRAS test result recorded in the Danish National Pathology Registry increased from 2009 to 2013. This may have resulted from increased testing or increased recording, or both.
CHARTA: FOLFOX+bevacizumab +/- irinotecan in advanced colorectal cancer (CRC)—Final results of the randomized phase II trial of the AIO (KRK 0209).
Authors: Schmoll Hans-Joachim , Garlipp Benjamin , Junghanss Christian , Leithaeuser Malte , Vogel Arndt , Schaefers Michael , Kaiser Ulrich , Hoeffkes Heinz-Gert , Florschütz Axel , Rüssel Jörn , Kanzler Stephan , Edelmann Thomas , Forstbauer Helmut , Goehler Thomas , Hannig Carla , Hildebrandt Bert , Steighardt Jörg , Meinert Fabian Maximilian , Cygon Franziska , Stein Alexander
Published: March 2017

658

Background: The 4-drug-regimen FOLFOXIRI+Bevacizumab (Bev) was superior to FOLFIRI+Bev (TRIBE F.Loupakis, NEJM 2014). CHARTA investigates the same 4-drug-regimen vs. FOLFOX+Bev. Methods: 250 patients were randomized from 7/11 to 12/14 to standard FOLFOX+Bev (A) vs. FOLFOXIRI+Bev (B), with dose/schedule as in TRIBE, 25% dose reduction in cycle 1 + 2, if necessary. Incl.criteria: ECOG 0-2, ≥ 1 measurable lesion > 1cm; stratified by ESMO-Group 1, 2, 3 (HJ Schmoll et. al., Ann Oncol 2012). Induction: 6 months, maintenance Capecitabine+Bev until progression or max. of 12 months, with reinduction by individual decision. Primary EP: significant improvement of PFS-rate at 9 months (p<0.1, 2-sided Fisher’s-exact test); secondary EP: RR- rate, PFS, OS, sec. resection. Results: Evaluable 241 pts. (1 not elig., 8 prot. violation); m/f: 65%/35%, age 61 yrs. (21-82), left/right: left A: 51, 5%, B: 48, 5%; right A: 45%, B: 55%; ECOG 0-1/2: 96% / 4%, ESMO-group 1/2/3: 29%/ 55%/ 16%. Primary endpoint was met: significantly improved PFS at 9 months 56% vs. 68% (p= 0,086). Preliminary PFS 9,76 vs. 12,0 months (HR 0.77, p=0.61), identical to TRIBE: 9.7 vs. 12.1. Response (A/B): CR: 5/5%, CR/PR 60/70%, SD 25/21%, PD 14/9%; sec. resection: 21/23%. Subgroup - analyses did not show significant differences, except CR / PR left/right (A/B): left 59/68%, right 63/73%; PFS (months) left 10.4/12 (HR 0.69, p=0.03), right: 8.2 /10.7); non-significant improvement in ESMO-group 3 (HR 0.51), RAS-wt (HR 0.67), Koehne-Score High risk HR 0.58; ECOG 1: HR 0.69. QL-Global- Health-Score: slightly worse in A, vs. improved in B. Dose-intensity <70%/ 70-90%/ >90% (A/B): 39/37%/ 18/26%/ 41%/36%; initial dose-reduction 17% of pts. Toxicity: low to moderate without major differences between A &B, except grade ¾ diarrhea 12/16%, neutrophils 14/20%, GI 12/20%. Conclusions: The 4-drug-regimen has superior activity with the same outcome as TRIBE and is well tolerated, without a negative effect of initial dose-reduction, and an improvement of global QoL-Score. Final PFS, OS data and detailed subgroup/multivariate analysis, including Quality of life data, will be presented. Clinical trial information: NCT01321957.
Metabolomic profling in gastric cancer tissues using time-of-flight mass spectrometry.
Authors: Kaji Sanae , Kusuhara Masatoshi , Makuuchi Rie , Yamakawa Yushi , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Kami Kenjiro , Ohashi Yoshiaki , Terashima Masanori
Published: March 2017

66

Background: To explore carcinogenic and prognostic biomarkers for gastric cancer, genomics, transcriptomics and proteomics approaches have been extensively applied;however, little has been investigated regarding the role of metabolomics profiles on progression and prognosis of gastric cancer. Therefore, in order to elucidate the role of metabolome on prognosis of gastric cancer, we investigated the metabolic profiles of gastric cancer tissue using time-of-flight mass spectrometry (TOFMS) Methods: A total of 162 patients with gastric cancer underwent gastrectomy from February 2010 to March 2013 were enrolled in this study. Cancer tissues (CA) and adjacent non-cancerous tissues (NC) were obtained from surgically resected sample and were snap-frozen in liquid nitrogen. The samples were then homogenized and then applied to capillary electrophoresis TOFMS (CE-TOFMS) The metabolomics dates were analyzed using principal component analysis (PCA) and hierachical clustering analysis(HCA) in order to compare the metabolic profiles of NC and CA. Metabolites date were further assessed according by the non-parametric Mann–Whitney U-test on the presence or absence of recurrence . Results: A total 96 metabolites were detected and quantified. PCA of the date well-distinguished CA from NC. In CA, lactate / pyruvate ratio was significantly higher, while adenylate energy charge was significantly lower than NC, which reaffirms the Warburug effect of cancer. Total glutathione and reducted glutathione/oxidized glutathione ratio in CA were significantly higher than in NC which possibly contributes to the homeostasis of redox status in CA. Intriguingly, in patients with recurrence, tumor concentrations of β-Ala, Asp, GDP and Gly were significantly lower than in those without recurrence. Conclusions: Metabolomic profiling clearly differentiated CA from NC. Considerably high lactate and amino acids levels expectedly highlighted the metabolome of tumors. Certain metabolite will be a candidate for biomarker in gastric cancer.
Nintedanib (N) plus best supportive care (BSC) versus placebo (P) plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to standard therapies: Subanalysis of the phase III LUME-colon 1 study in pts by prior regorafenib (R) treatment.
Authors: Lenz Heinz-Josef , Yoshino Takayuki , Argiles Guillem , Iveson Timothy , Sastre Javier , Harrison Mark , Lim Howard John , Tebbutt Niall C. , Peeters Marc , Satoh Taroh , Dittrich Christian , Sassi Mouna , Loembe Arsene-Bienvenu , Van Cutsem Eric
Published: March 2017

660

Background: N is a triple angiokinase inhibitor (including VEGFR, PDGFR and FGFR). LUME-Colon 1 (NCT02149108) evaluated the efficacy and safety of N in pts with metastatic CRC (mCRC) after failure of standard therapies and showed a statistically significant improvement in progression-free survival (PFS) (HR [95% CI]: 0.58 [0.49–0.69]; p < 0.0001) but no difference in overall survival (OS) (HR: 1.01 [0.86–1.19]; p = 0.8659). Here, we report results of a prespecified subanalysis in pts by prior R treatment. Methods: Eligible pts (aged ≥ 18 years; ECOG PS 0–1; mCRC adenocarcinoma refractory to standard treatments, including oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF and anti-EGFR in RAS wt) were randomised 1:1 to N (200 mg bid) + BSC or P (bid) + BSC. Prior R treatment was a stratification factor. Co-primary endpoints were PFS by central review and OS. Results: 768 mCRC pts were randomised; 285 (37%) had received prior R (N, n = 141; P, n = 144) and 483 (63%) were R naïve (N, n = 245; P, n = 238). Baseline characteristics were similar between the groups (pretreated vs naïve) except: race (Asian: 39% vs 19%), time from first diagnosis ( ≥ 36 months [m]: 67% vs 48%), time from onset of metastatic disease ( ≥ 24 m: 85% vs 64%). Median PFS (N vs P) was 1.5 vs 1.4 m (HR: 0.61 [0.47–0.79]) in prior R pts and 1.5 vs 1.4 m (HR: 0.62 [0.51–0.76]) in R-naïve pts (interaction p-value = 0.9245). Median OS (N vs P) was 6.5 vs 4.6 m (HR: 0.90 [0.69–1.17]) in prior R pts and 6.3 vs 6.6 m (HR: 1.09 [0.89–1.33]) in R-naïve pts (interaction p-value = 0.2529). N was tolerable in both subgroups; AEs leading to discontinuation (N vs P) occurred in 12% vs 8% of prior R pts and 16% vs 12% of R-naïve pts. The most frequent AEs with N were diarrhoea, nausea and vomiting in both subgroups. Conclusions: N demonstrated clinical activity in CRC regardless of prior R treatment; significant improvement in PFS compared to P was observed in both R-pretreated and R-naïve pts, supporting the concept of continuous antiangiogenic therapy. A slight improvement in OS was observed in R-pretreated compared to R-naïve pts. Clinical trial information: NCT02149108.
Efficacy/safety analysis of a phase 2 study of ruxolitinib (Rux) + regorafenib (Re) in patients (pts) with relapsed/refractory (r/r) metastatic colorectal cancer (mCRC).
Authors: Fogelman David R. , Bendell Johanna C. , Cubillo Antonio , Garcia Alfonso Pilar , Limón Mirón María Luisa , Nemunaitis John J. , Flora Daniel Blake , Borg Christophe , Mineur Laurent , Vieitez Jose M , Cohn Allen Lee , Saylors Gene Brian , Assad Albert , Switzky Julie C. , O'Neill Peter , Zhou Li , Kochenderfer Mark D.
Published: March 2017

663

Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did not improve OS/PFS over Re + Pb in S1/S2 (see Table). S1 was terminated for futility at interim analysis; S2 was terminated per sponsor decision. The number of events required for final efficacy analysis was reached in S1, not in S2. Most common non-hematologic AEs (Rux v Pb): palmar-plantar erythrodysesthesia syndrome (PPES; S1: 42% v 44%; S2: 58% v 47%), diarrhea (S1: 38% v 31%; S2: 39% v 27%), decreased appetite (S1: 37% v 36%; S2: 26% v 33%), fatigue (S1: 34% v 36%; S2: 41% v 44%), hypertension (S1: 21% v 26%; S2: 42% v 40%). Most common grade (G) 3/4 non-hematologic AEs: PPES (S1: 13% v 15%; S2: 17% v 13%) and hypertension (S1: 9% v 7%; S2: 22% v 16%). Most common G 3/4 hematologic AEs (new/worsening lab abnormalities): lymphopenia (S1: 13% v 8%; S2: 14% v 7%) and anemia (S1: 4% v 5%; S2: 9% v 4%). Conclusions: Rux + Re did not improve OS/PFS in mCRC pts over Re alone. There was a nonsignificant trend towards improved OS/PFS in S2. Rux 15-20 mg BID safety profile was consistent with previous studies in other tumors. Clinical trial information: NCT02119676. [Table: see text]
Right versus left: Impact of primary location on survival and cure in patients undergoing hepatic resection for metastatic colon cancer.
Authors: Creasy John M. , Sadot Eran , Groot Koerkamp Bas , Chou Joanne F. , Gonen Mithat , Kemeny Nancy E. , Cercek Andrea , Saltz Leonard , Balachandran Vinod P. , Kingham T. Peter , Allen Peter J. , DeMatteo Ronald P. , Jarnagin William R. , D'Angelica Michael Ian
Published: March 2017

664

Background: Recent prospective studies in metastatic colorectal cancer (mCRC) have demonstrated an association between left-sided primaries and improved overall (OS) and progression-free survival (PFS). Primary location (right vs left colon) has not been well studied in patients undergoing potentially curative hepatic resection. Methods: A single-institution database was queried for all initial hepatic resections for mCRC 1992-2004. Postoperative deaths and patients with no followup after 90 days were excluded. Primary location determined by chart review (Right = cecum to transverse; Left = splenic flexure to sigmoid). Rectal cancer (distal 16cm), multiple primaries, and unknown location were excluded. Kaplan Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with no recurrence or resected recurrence with at least 3 years of disease-free followup. Results: 907 patients were included with a median followup of 11 years. 578 patients (64%) had left-sided and 329 (36%) had right-sided primary. Median OS for patients with a left-sided primary was 5.2 years (95% CI: 4.6-6.0) versus 3.6 years (95% CI: 3.2-4.2) for right-sided (p = 0.004). The hazard ratio (HR) for right-sided tumors was 1.22 (95% CI: 1.02-1.45, p = 0.028) after adjusting for age, CEA > 200, DFI < 12 months, hepatic tumor > 5cm, > 1 tumor, lymph node status, margin, and extrahepatic disease. Recurrence-free survival (RFS) was marginally different stratified by primary location (p = 0.065). Estimated cure rates were 22% for left and 20% for right-sided tumors. Conclusions: Among patients selected for hepatic resection of metastatic colon cancer, left-sided primary tumors were associated with an improved OS but not RFS. This difference in OS was independent of common prognostic variables. Estimated cure rates were not statistically different. Patients with left-sided primary tumors display a prolonged clinical course after recurrence suggestive of more indolent biology. [Table: see text]
The prognostic impact of surgical complications after combined modality treatment of rectal cancer: Long-term results of the CAO/ARO/AIO-94 trial.
Authors: Sprenger Thilo , Beissbarth Tim , Fietkau Rainer , Raab Hans-Rudolf , Hohenberger Werner , Liersch Torsten , Rödel Claus , Ghadimi Michael
Published: March 2017

670

Background: The influence of major surgical complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is still debatable. The aim of this study was to evaluate the impact of surgical complications on oncological outcome in 823 patients with locally advanced rectal cancer treated within the phase III CAO/ARO/AIO-94 trial. Methods: Anastomotic leakages as well as wound healing disorders were prospectively evaluated and correlated with overall survival (OS) and the cumulative incidence of distant metastasis and local recurrence after a long-term follow-up of more than 10 years. Results: Anastomotic leakage after restorative rectal resection is significantly correlated with an impaired 10-year OS (51.0% vs. 65.2%, p = 0.02). Patients with abdominal or sacral wound healing disorders had a significantly reduced OS compared to those with sufficient wound healing (45.2% vs. 62.7%, p = 0.009). Patients developing any surgical complication (anastomotic leakage or/and wound healing disorder) had an impaired OS (50.6% vs 65.3%, p = 0.0002) as well as higher rates of distant metastases (65.3% vs. 72.7%, p = 0.03) and local recurrences (6.0% vs. 12.9%, p = 0.0007). In a multivariate cox regression model the only independent factors for restricted OS were lymph node metastases (p < 0.0001) and the occurrence of surgical complications (p = 0.008). Conclusions: Surgical complications are significantly associated with an adverse oncological outcome and reduced long-term OS in patients undergoing combined modality treatment for locally advanced rectal cancer.
Primary tumor location and survival in general population with metastatic colorectal cancer (mCRC).
Authors: Ahmed Shahid , Papneja Neha , Emara Mohamed Elsayed , Alvi Riaz , Asif Tehmina , Dorie-Anna Dueck , Le Duc , Zaidi Adnan , Haider Kamal , Kanthan Selliah , Iqbal Nayyer
Published: March 2017

674

Background: Recent evidence from clinical trials suggests that location of the primary tumor in patients with mCRC correlates with differential outcomes and patients with tumors originating in the right side of colon have inferior survival. This large population-based cohort study using individual patient data was performed to confirm this findings in general population with mCRC. Methods: A cohort of 1947 patients who were diagnosed with synchronous mCRC from 1992-2010 was studied. Ascending and transverse colon cancers were defined as right-sided tumors (RT) and remainder tumors were define as left-sided tumors (LT). Cox proportional multivariate analyses were done to determine prognostic significance of primary tumor location and to adjust other prognostic variables including age, Charlson comorbid index (CCI) and WHO performance status (PS) in patients treated with chemotherapy. Results: Median age was 70 years (IQR: 60-78) and M:F was 1.3:1. Mean CCI was 9.7±1.4 and 29% had WHO PS of > 1. 770 (39%) patients had RT and 37% had stage IVb disease. 908 (47%) received chemotherapy and of those 44% received modern chemotherapy. Significant differences were noted between the groups with RT and LT with respect to age, WHO PS, CCI, liver metastases, mucinous tumor, grade, smoking history, and primary tumor resection. Median overall survival of patients with RT was 14 (95%CI: 12.7-15.3) months compared with 20.5 (95%CI: 18.5-22.5) of patients with LT (p < 0.001). On multivariate analysis following variables were correlated with inferior survival: Right-sided tumors, hazard ratio (HR) 1.40 (95%CI: 1.20-1.60); no primary tumor resection, HR 1.60 (95%CI: 1.32-1.90); no metastasectomy, HR 2.40 (95%CI: 1.90-2.90); not using modern chemotherapy, HR 1.52 (95%CI: 1.31-1.80); leukocytosis, HR 1.44 (95%CI: 1.28-1.73); elevated CEA, HR 1.54 (95%CI: 1.30-1.90); WHO PS > 1, HR 1.30 (95%CI: 1.10-1.55); and stage IVb disease, HR 1.50 (95%CI: 1.17-1.86). Tests for interaction were negative. Conclusions: Our results confirm that patients with RT who received chemotherapy have inferior survival independent of other known prognostic variables. Future studies are required to understand underlying pathophysiology.
Neoadjuvant chemoradiation for locally advanced rectal cancer with fluoropyrimidine alone or intensified with oxaliplatin: A systematic review and meta-analysis.
Authors: Nadler Ashlie , Handorf Elizabeth , Sigurdson Elin R. , Meyer Joshua E. , Denlinger Crystal Shereen , Farma Jeffrey M.
Published: March 2017

678

Background: Improved outcomes have been demonstrated with the use of neoadjuvant fluoropyrimidine-based chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer. The addition of oxaliplatin in the adjuvant setting has also resulted in improved disease-free survival (DFS). A meta-analysis was performed to evaluate DFS and overall survival (OS) with the addition of oxaliplatin to standard neoadjuvant chemoradiation for locally advanced rectal cancer. Methods: A systematic literature review was performed. Randomized-controlled trials (RCTs) comparing the addition of oxaliplatin in the neoadjuvant setting (oxaliplatin group) to fluoropyrimidine-based chemoradiation (standard group) were included. The primary outcomes were DFS and OS; secondary outcomes were short-term surgical results, morbidity, and mortality. Results were combined using meta-analysis via linear mixed-effects models. Calculations were performed using R. Results: Of 73 studies identified, 4 reported DFS (n=3829) and 3 reported OS (n=2680). There was no difference in DFS between the standard and oxaliplatin groups amongst RCTs [HR 0.90 (0.64-1.26), p=0.5313]. There was no difference in OS [HR 0.93 (0.59-1.47), p=0.9894]. There was no significant heterogeneity between RCTs for primary outcomes. There was also no difference in pathologic complete response rate [OR 0.93 (0.77-1.14), p=0.4923), resection margin (R0) status [OR 1.01 (0.59-1.72), p=0.9846], circumferential resection margin status [OR 0.84 (0.50-1.41), p=0.5079], sphincter saving surgery rate [OR 0.87 (0.74-1.03), p=0.1103], grade 3-4 toxicity [OR 1.60 (0.88-2.92), p=0.1251], and 60-day mortality [OR 1.27 (0.50-3.25), p=0.6148]. There was significant heterogeneity between RCTs for R0 status, circumferential margin status, and grade 3-4 toxicity. Adjuvant treatment varied across studies. Conclusions: There are no short-term or long-term survival benefits with the addition of oxaliplatin to fluoropyrimidine-based chemoradiation in the neoadjuvant setting for locally advanced rectal cancer.
A multinational, randomized, phase III trial of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab as second-line therapy for metastatic colorectal cancer: Safety analysis of Asian XELIRI project (AXEPT).
Authors: Nakamura Masato , Kim Tae Won , Xu Rui-hua , Park Young Suk , Hong Yong Sang , Zhang Tao , Kato Takeshi , Cho Sang Hee , Wang Wei , Matsuoka Hiroshi , Han Sae-Won , Deng Yanhong , Makiyama Akitaka , Lee Keun-Wook , Ba Yi , Ota Mitsuyoshi , Iwasa Satoru , Morita Satoshi , Yamada Yasuhide , Muro Kei
Published: March 2017

681

Background: Several studies have shown that capecitabine plus irinotecan (XELIRI) has promising efficacy and safety in patients with metastatic colorectal cancer. AXEPT is a non-inferiority, phase III comparison of XELIRI with or without bevacizumab vs 5-fluorouracil/folinic acid plus irinotecan (FOLFIRI) with or without bevacizumab as second-line therapy in patients with metastatic colorectal cancer. Methods: We undertook an open-label, non-inferiority, randomized phase III trial in South Korea, China and Japan. Patients were randomized 1:1 to XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 twice daily for 2 weeks in a 3-week cycle) with or without bevacizumab 7.5 mg/kg or FOLFIRI with or without bevacizumab. The primary endpoint was overall survival. Results: From December 2013 to August 2015, 650 patients were enrolled and 625 (311 in FOLFIRI and 314 in XELIRI) were included to safety analysis at the cutoff dates on August 31, 2016. Patient baseline characteristics including KRAS status and UGT1A1 gene polymorphism were similar between the two treatment arms. Prior chemotherapy with oxaliplatin was given to 97.4% in both arms. The overall incidence of grade 3-4 toxicity was 73% in FOLFIRI arm and 53.2% in XELIRI arm. Whereas FOLFIRI was associated with more grade 3-4 neutropenia (43.7% vs 16.2%), leucopenia (13.5% vs 7.3%) and all grades anemia (80.4% vs 69.4%) than XELIRI, XELIRI was associated with more all grades hand-foot syndrome (34.1% vs 14.8%) and grade 3-4 diarrhea (7.0% vs 3.2%). There was no significant difference in febrile neutropenia (4.2% in FOLFIRI and 2.9% in XELIRI). The addition of bevacizumab did not alter safety profiles between XELIRI and FOLFIRI. There was a treatment-related death in FOLFIRI arm (0.3%). Conclusions: Both FOLFIRI and XELIRI were safe and well tolerated, though there were differences in the rates and toxicity profiles at which adverse events occur. Clinical trial information: NCT01996306. UMIN000012263.
Left versus right sided colorectal cancer: Teasing out drivers of disparity in outcomes in metastatic disease.
Authors: Lee Belinda , Mendis Shehara , Lee Margaret , Wong Rachel , Kosmider Suzanne , Shapiro Jeremy David , Yip Desmond , Steel Simone Anne , Nott Louise M. , Jennens Ross , Lipton Lara Rachel , Burge Matthew E. , Ananda Sumitra , Gibbs Peter
Published: March 2017

682

Background: Patients (pts) with metastatic colorectal cancer (mCRC) arising from a right sided colon cancer (RCC) have an inferior survival versus pts with a left sided primary (LCC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively collected data on consecutive mCRC pts at 32 sites (Australia and Hong Kong) from July 2009. LLC were defined as those distal to the splenic flexure. We analysed patient, tumour, treatment and outcome data. Results: Of 1763 patients, median age 67 years (range 18 – 100), 1201 patients (68.1%) had a LCC. RCC were more common in pts ≥ 70 years old (53.9% vs 38.5%, p < 0.01) and females (50.7%, p < 0.01). Where tested, KRAS (50.9% vs 41.5%, p < 0.01) and BRAF (19.1% vs 6.4%, p < 0.01) mutations were more common in RCC. Where tested, dMMR was more common in RCC (11.0% vs 3.2%, p < 0.01). Pts with a RCC more often had peritoneal metastases (25.9% vs 12.5%%, p < 0.01) and were less likely to have liver metastases (69.8% vs 77.9%, p < 0.01) or resection of metachronous metastases (31.8% vs 43.6%, p < 0.01). LCC more commonly received chemotherapy in the 1st (86.1% vs 80.3%, p = 0.02) and 2nd (49.7% vs 43.0%, p = 0.04) line setting. There was no difference in ECOG performance status or co-morbidity for LCC vs RCC. Overall survival for pts with a RCC was 20.6 months vs 27.9 months for LCC L-sided tumours (HR 1.395, p < 0. 0001). Conclusions: Our data confirms that pts with mCRC arising from a RCC have an inferior survival. This appears multifactorial due to associations with adverse clinical and molecular features, metastatic pattern, and less therapy, some of which are related. A multivariate analysis is being performed.
Impact of primary tumor location (TL) on outcomes of first-line (1L) FOLFOX-4 (F) ± cetuximab (cet) in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 3 TAILOR trial.
Authors: Qin Shukui , Xu Jian-Ming , Wang Liwei , Cheng Ying , Liu Tian Shu , Chen Jiongjie , Chen Wen-Feng , LI Jin
Published: March 2017

683

Background: In the RAS wt population of TAILOR, adding cet to 1L F significantly improved progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). In this subgroup analysis, we evaluate the impact of TL. Methods: TAILOR is a randomized phase 3 trial that includes a modified intention-to-treat (mITT) population of 393 pts from China with RASwt mCRC treated with F ± cet. The primary endpoint of TAILOR is PFS; key secondary endpoints include OS and ORR. TL was categorized in evaluable pts in the mITT population (left-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right-sided = appendix, cecum, ascending colon, hepatic flexure, ± transverse colon). Results: Efficacy data for the TL subgroups are summarized in the table. Additionally, the prognostic effect of TL (left- vs right-sided) within the treatment arms could be shown for PFS (HR = 1.72; p = .007), OS (HR = 1.84; p = .002), and ORR (OR = 0.40; p = .014) in the cet + F arm and PFS (HR = 1.97; p = .002), OS (HR = 1.43; p = .073), and ORR (OR = 0.41; p = .028) in the F arm. Regarding the potential predictive value of TL, the p values for the interaction between TL and treatment are: PFS (.676), OS (.339), and ORR (.986). Conclusions: In TAILOR, adding cet to 1L F clearly benefitted RAS wt pts with left-sided tumors in terms of PFS, OS, and ORR; for pts with right-sided tumors, the HRs for PFS and the ORs for ORR also consistently suggested a benefit showing a trend in favor of cet. Clinical trial information: NCT01228734. [Table: see text]
Phase I study of neoadjuvant 5-fluorouracil (5FU) chemoradiation (CRT) and trametinib in patients with locally advanced rectal cancers (LARC).
Authors: Wu Christina Sing-Ying , Williams Terence M , Wei Lai , Umar Hamida , Mikhail Sameh , Ciombor Kristen Keon , Noonan Anne M. , Roychowdhury Sameek , El-Dika Samer S , Krishna Somashekar , Upchurch Bennie , McCarthy Sean T , Arnold Mark , Harzman Alan , Abdel-Misih Sherif , Cirocco William , Traugott Amber , Bekaii-Saab Tanios S. , Wuthrick Evan John
Published: March 2017

685

Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m2/day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]
Immunoscore based on PD-L1/PD-1 and CD8+ T cells as prognostic marker for stage II/III gastric cancer.
Authors: Wen Ti , Qu Xiujuan , Li Yi , Li Zhi , Che Xiaofang , Fan Yibo , Wang Shuo , Xu Ling , Song Na , Liu Yunpeng
Published: March 2017

69

Background: PD-L1/PD-1 pathway has become an important target in tumor immunotherapy. However, the prognostic value of PD-L1/PD-1 for gastric cancer (GC) remains controversial due to the complexity of immune response. Therefore, comprehensive evaluation of PD-L1/PD-1 expression and CD8+T cells is necessary and superior to one factor in predicting survival. Methods: 166 patients with stage II-III GC were enrolled. Expression of PD-L1, PD-1, and CD8 protein in tumor tissues was examined by IHC staining, and their association with patient’s survival was analyzed by Kaplan-Meier method. Immunoscore classification was constructed using a scoring system, which was based on hazard ratios in a Cox proportional hazard analysis. Results: Expression of PD-L1 was found in 22.29% of immune cells (IC) and 38.55% of tumor cells (TC), while expression of PD-1 was found in 31.33% of IC. CD8High was detected in 41.57% patients. PD-L1+ and PD-1+ IC were both correlated with worse overall survival (OS) ( P=0.0009 and P=0.0004, respectively). In contrast, TC PD-L1+ was associated with better clinical outcomes, including Borrmann classification 0-1, lower AJCC stage, CD8High infiltration and better OS ( P<0.05). Furthermore, IC PD-L1, IC PD-1, CD8, and TC PD-L1 had independent prognostic significance after TNM stage adjustment, and we built an immunoscore system based on these immune factors. Patients with same stage could be further categorized into low-/median-/high-risk subgroups according to their immunoscores. Conclusions: Immunoscore based on comprehensive evaluation of PD-L1/PD-1 and CD8+ T cells can separate GC patients with same stage into different risk subgroups, and might provide suggestion for immunotherapy options in GC.
Effect of neoadjuvant IMRT for locally advanced rectal cancer on toxicity and pathologic response.
Authors: David John , Jabbour Salma , Gresham Gillian K. , Deek Mathew , Shant Thomassian , Robertson John M. , Kabolizadeh Peyman , Tuli Richard
Published: March 2017

693

Background: Neoadjuvant chemoradiation (NeoCRT) is standard of care for the treatment of locally advanced rectal cancer (LARC). Contemporary radiation techniques may reduce dose to normal organs at risk. Our purpose was to compare clinical outcomes and acute toxicities between standard 3D conformal (3D) and intensity modulated radiation therapy (IMRT). Methods: LARC patients (pts) treated at 4 large academic centers in the US between 2007 and 2016 were reviewed. Pts received 5FU-based NeoCRT concurrently with IMRT or 3D. Pathologic response (PR) was used as a surrogate for clinical outcome, and common terminology for adverse events version 4 was used to grade toxicities, summarized on a 1-5 scale. Toxicity rates were compared using chi-square analysis. Multivariable models were fit adjusting for age, gender, pre-tx CT to identify independent predictors of PR and toxicity. Results: 128 pts were analyzed: 60.1% male and 39.8% female, median age 57.7 years (Range 31-85). Clinical characteristics were similar across RT groups. The outcome of partial and complete PR was similar for IMRT and 3D (48.1%, 23.1% vs 32.2%, 23.7%*), respectively. After adjusting for gender, age, and pre-RT chemotherapy type, IMRT was significantly associated with increased odds for complete and partial response (OR: 2.9, 95%CI 1.2-7.2*). Additionally, IMRT was significantly associated with reduced rates of dehydration, dermatitis, rectal pain, rectal bleeding, diverting ostomy, and trend toward significance for decreased rates of fatigue (p = 0.07) and erythema (p = 0.06) (see table). Overall rates of grade 2 and higher toxicities were significantly reduced in IMRT vs. 3D after adjusting for confounders (OR: 0.27, 95% CI 0.08-0.87*). Conclusions: Neoadjuvant 5FU-based IMRT for LARC leads to reduced acute toxicities and improved PR compared to 3D. Given the challenges associated with prospective validation of these data, IMRT should be considered standard treatment for LARC.[Table: see text]
Survivorship after lower gastrointestinal cancer: Patient reported outcomes and planning for care.
Authors: Frick Melissa , Vachani Carolyn , Hampshire Margaret K. , Bach Christina , Arnold-Korzeniowski Karen , Metz James M. , Hill-Kayser Christine E.
Published: March 2017

695

Background: There is significant need for quality follow-up care to optimize long-term outcomes for the growing population of lower gastrointestinal (GI) cancer survivors. Patient-reported outcomes (PROs) provide valuable information regarding late- and long-term effects. Methods: Using a convenience sample from 1,129 colon, rectal and anal cancer survivors (n=792, 218, and 119, respectively) who utilized an Internet-based survivorship care plan (SCP) tool, we examined patient-reported demographics, treatment, and toxicity data. Responses from a follow-up survey were reviewed. Results: Median age of diagnosis was 51 years and median current age was 54 years. 81% of respondents were Caucasian and 58% were female. The most commonly reported late- and long-term effects for all survivors were neuropathy (65%), fatigue (56%), cognitive changes (49%), changes in GI function (43%), sexual dysfunction (22% in males, 43% in females), and radiation-induced dermatologic effects including changes in color/texture of skin (39%) and loss of flexibility in radiated areas (31%). The prevalence of these effects varied with length of time since treatment and treatment modality. Anal cancer patients reported a high prevalence of sexual dysfunction and radiation-induced dermatologic effects. Over 87% of users reported satisfaction levels of "good" to "excellent" using this tool, and 69% reported they intend to share SCP with their healthcare team. Conclusions: For lower GI cancer survivors, it is feasible to obtain PROs from an Internet-based survivorship tool. Survivors report a wide spectrum of late- and long-term side effects, which can be used to inform counseling at time of diagnosis, as well as help anticipate and respond to disease- and treatment-related sequelae during follow-up. We are among the first to report on PROs in anal cancer survivors. Further investigation on the impact of SCPs on healthcare communication and use is needed.
Predictive value of PET/CT for pathological complete response and survival in patients with locally advanced rectal cancer.
Authors: Sorenson Eric C , Choudhry Aruj J , Yu Jian Qin , Reddy Sanjay S. , Denlinger Crystal Shereen , Meyer Joshua E. , Farma Jeffrey M. , Sigurdson Elin R.
Published: March 2017

697

Background: A major challenge in identifying candidates for nonoperative management of locally advanced rectal cancer is predicting pathological complete response (pCR) following chemoradiation therapy (CRT). We evaluated the ability of pre- and post-CRT PET imaging to predict pCR and long-term prognosis. Methods: We retrospectively identified patients at our institution from 2002–2015 with locally advanced rectal cancer who underwent CRT, pre- and post-CRT PET imaging, and surgical resection. Logistic regression and Kaplan-Meier estimates were used to analyze the association of PET variables with tumor pCR and survival outcomes. Receiver operator characteristic curves were generated to define optimal cutoff points for predictive PET variables. Results: 140 patients matched the inclusion criteria. The pCR rate was 28%, and median follow-up time was 48 months. On multivariable analysis, pCR was associated with lower median post-CRT SUVmax(3.2 vs 5.2, p=0.009) and higher median SUV percent decrease (72 vs 58%, p=0.009). ROC curves were generated for SUV percent decrease (AUC=0.70) and post-CRT SUV (AUC=0.69) to estimate cutoff points for maximum specificity and sensitivity to predict pCR. Post-CRT SUV <4.3 and SUV percent decrease of >66% were equally predictive of pCR with a sensitivity of 65%, specificity of 72%, PPV of 44%, and NPV of 86%. Median 5-year OS and RFS were significantly improved for patients with post-CRT SUV <4.3 (OS, 86 vs 66%, p=0.01; RFS, 75 vs 52%, p=0.01) or SUV percent decrease of >66% (OS, 82 vs 66%, p=0.05; RFS, 75 vs 54%, p=0.01). Patients with stage III disease and a post-CRT SUV <4.3 were in effect downstaged, with a median 5-year OS equivalent to that of patients with stage II disease (Table 1; 86 vs 86%). Conclusions: PET/CT may be a useful modality in predicting pCR and overall survival in patients undergoing CRT for rectal cancer. Inclusion of pre-CRT PET does not appear to add prognostic value for pCR compared with post-CRT PET alone. Patients with a post-CRT SUV of >4.3 should not be considered for nonoperative management, as an estimated 86% of these patients will not have a pCR.
Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Jiang Di Maria , Sim Hao-Wen , Siu Lillian L. , Shapiro Jeremy David , Liu Geoffrey , Price Timothy Jay , Jonker Derek J. , Karapetis Christos Stelios , Strickland Andrew , Zhang Wenjiang , Jeffery Mark , Tu Dongsheng , Ng Siobhan , Sabesan Sabe S. , Shannon Jenny , Townsend Amanda Rose , Morgen Eric , Xu Wei , O'Callaghan Christopher J. , Chen Eric Xueyu
Published: March 2017

699

Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.
Using NSG recipient mice improves engraftment of gastric cancer patient derived xenografts.
Authors: Wang Sam C. , Zhu Min , Nassour Ibrahim , Shen Jeanne , Mansour John C. , Agarwal Deepak , Zhu Hao , Porembka Matthew R.
Published: March 2017

70

Background: Previous gastric cancer (GC) patient derived xenograft (PDX) studies reported engraftment rates inversely proportional to the immunocompromised states of recipient mice (nudes 17%, scid 27%, and NOD/ scid 34%). We tested highly immunocompromised NOD scidgamma (NSG) mice, which lack mature T cells, B cells, or functional natural killer cells, as recipients for low volume biopsies and post-treatment GC samples. Methods: Consent was obtained from GC patients who were scheduled to undergo esophagogastroduodenoscopy (EGD) and diagnostic laparoscopy as part of their disease management strategies. The following amounts of tumor were coated with Matrigel and inoculated into the flanks of NSG mice: EGD biopsies ~10 mg, post-treatment samples ~100 mm3, and peritoneal metastasis biopsies ~100 mm3. Tumors were serially measured and passaged when the greatest dimension reached 1.5 cm, or if there was overlying skin necrosis. Results: The engraftment rates were: EGD biopsies 48% (13 of 27 samples), post-resection samples 58% (7 of 12), and peritoneal metastases 11% (1 of 9). Median time to first passage was 10.1 weeks (range: 8.1 to 12.4) for EGD biopsies and 22.1 weeks (9.6 to 33.0) for post-treatment samples. Two (15%) engrafted EGD mice developed liver metastases, and one (7.7%) had axillary lymph node metastasis (AxLN). Three (47%) engrafted post-treatment mice had liver metastases and two (29%) had AxLN. Histology was generally maintained through passages and metastases with some loss of mucinous components. There were no associations between engraftment rate and any evaluated clinical or pathologic characteristics, including tumor response and overall survival. The tumor from the one patient who had a complete pathologic response after NAT did not engraft. Conclusions: Using highly immunocompromised NSG mice improved engraftment rates of GC PDX, even for challenging specimens such as endoscopic biopsies and post-treatment resection samples. Peritoneal biopsies did not engraft well. Tumor histology was generally maintained through passages. Studies comparing the expression profiles of serially passaged tumors to the original clinical samples are ongoing.