bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continued cetuximab in second-line treatment for patients with unresectable metastatic wild-type KRAS, NRAS, and BRAF colorectal cancer after disease progression during first-line cetuximab-based therapy.
Authors: Liu Ying , Wang Feng , Ma Ning , Xu Shuning , Qiao Lei , Li Ke , Kuang Gaizhen , Li Danyang , Liu Yangyang , Xiong Yanyan , Sun Mingming 
Published: February 2020

127 Background: Cetuximab plus chemotherapy is a first-line treatment option for metastatic RAS wild type colorectal cancer patients. Currently, no data are available on continuing cetuximab or changing bevacizumab as second-line therapy beyond first-line cetuximab-based chemotherapy. Methods: Patients (aged ≥18 years) with metastatic, histologically and genetically confirmed wild-type KRAS, NRAS and BRAF colorectal cancer progressing after first-line cetuximab plus chemotherapy were randomly assigned (1:1 ratio) to second-line chemotherapy with cetuximab (arm A) or with bevacizumab (arm B) 2·5 mg/kg per week equivalently. The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). The second endpoint was overall survival (OS). Results: 77 Patients (from July 1, 2016 to Sept 20, 2019, 77) were randomized (41 in arm A and 36 in arm B). ORR was 29.3% and 19.4% in Arm A and Arm B ( p= 0.31). PFS was 7.2 months (95% CI 5.2–9.2) for Arm A and 5.9 months (95% CI 5.1–6.7) for Arm B ( p= 0.677). OS was 18.5 months (95% CI 15.1–21.8) for Arm A and 17.5 months (95% CI 15.4–19·7) for Arm B ( p= 0.444). Patients with ECOG PS 0 had significantly longer PFS and OS than ECOG PS 1 in second-line therapy whether cetuximab or bevacizumab combined with chemotherapy. ECOG 0 group vs ECOG 1 group, PFS was 8.7 months vs 4.6 months (p = 0.00) and OS was 21.2 months vs 12.3 months (p = 0.00). Moreover, ETS may predict efficacy of second-line continued cetuximab. The most frequently grade 3–4 adverse events in both arms were neutropenia (19.4% VS 16.7%), diarrhea (7.5% vs 11.1%), and nausea(10% vs 13.9%). Conclusions: Continuing cetuximab or changing bevacizumab plus standard second-line chemotherapy in patients with metastatic wild-type KRAS, NRAS and BRAF colorectal cancer after first-line cetuximab plus chemotherapy have similar clinical benefits. ECOG score is an independent predictor of prognosis and second-line treatment efficacy for colorectal cancer.
Association of sarcopenia and myosteatosis with the systemic inflammatory response and tumor stage in patients undergoing surgery for colorectal cancer (CRC).
Authors: Abbass Tanvir , Dolan Ross , McSorley Stephen Thomas , Horgan Paul G. , McMillan Donald C. 
Published: February 2020

130 Background: There is now good evidence that sarcopenia and myosteatosis, measured as low skeletal muscle index (SMI) and low skeletal muscle density (SMD) from CT scans, are associated with poor survival in patients undergoing surgery for CRC. However, this is not clear whether this is as a result of tumour burden or chronic inflammation. Methods: The relationship between tumour stage, systemic inflammatory response using modified Glasgow prognostic score (mGPS), neutrophil lymphocyte ratio (NLR) and sarcopenia and myosteatosis using defined SMI/SMD was examined in 840 patients undergoing CRC resection from a prospectively maintained database. Results: The majority of patients were > 65 years of age (64.5%), male (55%) and did not have sarcopenia (51%) but had myosteatosis (65%). In those patients with a mGPS = 0 (n = 617), mGPS = 1 (n = 99), mGPS = 2 (n = 124), TNM stage of 0-I, II and III was not associated with sarcopenia (p = 0.260, p = 0.869 and p = 0.458 respectively) or myosteatosis (p = 0.136, p = 0.879 and p = 0.06 respectively). In those patients with TNM stage of 0-I (n = 202), stage II (n = 346) and stage III (n = 292), mGPS (0,1,2) was significantly associated with sarcopenia (p = 0.329, p = 0.001 and p = 0.002 respectively) and myosteatosis (p = 0.329, p < 0.001 and p = 0.001 respectively). In patients with TNM stage of 0-I, stage II and stage III, NLR was significantly associated with sarcopenia (p = 0.492, p = 0.299 and 0.027 respectively) and myosteatosis (p = 0.870, p = 0.012 and p = 0.019 respectively). Conclusions: Compared with tumour burden, the systemic inflammatory response (particularly mGPS) appears to have a greater influence on the development of sarcopenia and myosteatosis. These results have implications for the treatment of sarcopenia and myosteatosis in patients undergoing surgery for CRC.
Immunomodulatory effects of tumor treating fields (TTFields) on colon cancer models.
Authors: Voloshin Tali , Kaynan Noa , Davidi Shiri , Porat Yaara , Shteingauz Anna , Munster Mijal , Schneiderman Rosa S , Tempel-Brami Catherine , Zeevi Einav , Gotlib Karnit , Cahal Shay , Giladi Moshe , Kirson Eilon D. , Weinberg Uri , Kinzel Adrian , Palti Yoram 
Published: February 2020

136 Background: Tumor Treating Fields (TTFields) are clinically approved in glioblastoma and malignant pleural mesothelioma as an anti-mitotic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. We evaluated whether TTFields (150 kHz) induced colon cancer cell death can be perceived as immunogenic and suitable for combination with anti-programmed cell death protein 1 (anti-PD-1; immune checkpoint inhibitor) therapy. Methods: Murine colorectal carcinoma cells (CT-26) were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by assessing changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of eukaryotic translation initiation factor alpha (eIF2α), and secretion of ATP and high-mobility group box 1 (HMGB1). For in-vivo studies, CT-26 cells were subcutaneously implanted in BALB/c mice. The mice were treated with TTFields (150 kHz), anti-PD-1 (200 μg/mouse), or a combination of the 2 modalities. Tumor volume was monitored and flow cytometry analyses performed for phenotypic characterization of infiltrating immune cells. Results: We demonstrate that cancer cell death under TTFields application exhibited release of HMGB1, ATP secretion from cells, and ER stress leading to CRT translocation to the cell surface, all of which are signs of immunogenic cell death. The combined treatment of colon tumor-bearing mice with TTFields plus anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. We demonstrate significant increases in both CD8 and CD4 T-cells in tumors treated with combination therapy, and in CD8 in tumors treated with anti-PD-1 alone. Conclusions: Our results establish the potential of TTFields therapy to induce immunogenic cell death. We also demonstrate efficacy of concurrent application of TTFields and anti PD-1 therapy in mouse cancer models. These data suggest that TTFields plus anti-PD-1 combination treatment may achieve tumor control by further enhancing anti-tumor immunity.
Short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.
Authors: Shamseddine Ali , Zeidan Youssef , Khalifeh Ibrahim Moustafa , Kattan Joseph Gergi , Turfa Rim , Mukherji Deborah , Temraz Sally Naji , Jamali Faek , Shaib Yasser Hani , Soweid Assaad , Deeba Samer , Kreidieh Malek , El Husseini Ziad zuheir , Charafeddine Maya , Al Darazi Monita , Geara Fady B. 
Published: February 2020

139 Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer is becoming an accepted approach over the last few years with increasing pathologic complete response (pCR) and compliance of patients for chemotherapy in comparison with the current standard of care i.e., fluoropyrimidine based chemoradiation followed by surgery and adjuvant chemotherapy. Sequential use checkpoint inhibitors after radiation therapy (RT) has demonstrated synergistic effect in vivo leading to decrease in size of irradiated and non-irradiated secondary tumors outside the radiation field (abscopal effect). Methods: This is an investigator initiated; open-label, single-arm multicenter phase II study, adopting Simon’s two-stage aiming at evaluating the pCR rate and safety of using short-course radiation therapy (25 Grays in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus Avelumab (anti PDL1), then total mesorectal excision(TME) in patients with locally-advanced, potentially resectable rectal adenocarcinoma. Results: 13 out of 44 patients were accrued from 20, July till 28, Dec 2018 in the first stage of the study (30% from total sample size). They all met the inclusion criteria and received full protocol treatment. 12 out of the 13 completed TME. 1 of the 13 had progression of disease, so surgery was aborted and patient was dropped out the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33.0, 73.0) years. The first interim analysis revealed 3 patients (25%) achieved pCR (tumor regression grade: TRG = 0) out of 12 as compared to the historical control group with pCR of 16%. For the rest of the patients, 3 (25%) had major pathologic response rate (pRR) with TRG = 1 (< 10% viable cells is tumor bed).In total, 6 out of 12 patients (50%) had major pathologic response rate. As for safety, no serious adverse events of grade 3 and 4 were reported. Conclusions: Based on the first interim analysis results, incorporation of Avelumab and short course radiotherapy is tolerable in patients with locally advanced rectal cancer treated with TNT. The study will resume recruitment to reach the target accrual. Clinical trial information: NCT03503630.
Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.
Authors: George Ben , Van Cutsem Eric , Hochster Howard S. , Mayer Robert J. , Ohtsu Atsushi , Falcone Alfredo , Yoshino Takayuki , Doi Toshihiko , Ilson David H. , Arkenau Hendrik-Tobias , Benhadji Karim A. , Makris Lukas , Tabernero Josep , Shitara Kohei 
Published: February 2020

145 Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin <1.5 X ULN, or AST >ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957. [Table: see text]
Stereotactic radiotherapy (SRT) in oligometastatic (OM) colorectal cancer (CRC): Can we improve systemic therapy (ST) free interval?
Authors: Palhares Daniel Moore Freitas , Reis Figueiredo Renata , Marchetti Katia Regina , Pereira Allan Andresson Lima , Alves Teixeira Marcela , Faria Luiza , Gumz Brenda Pires , Gadia Rafael , Fernandes Gustavo Dos Santos 
Published: February 2020

154 Background: Metastatic colorectal cancer is common disease that is treated mainly with systemic chemotherapy with or without target therapy combined with local therapies when feasible. Patients with OM-CRC may benefit from local treatments, classically surgery, but more recently SRT is also showing to be effective. We aimed to access the benefit of SRT in patients (pts) with OM-CRC that where not candidates for surgery. Methods: This retrospective study evaluated all the pts with CRC from a single institution that did SRT for OM-CRC. SRT was done with 3D or IMRT/VMAT planning and daily volumetric image. 1-10 fractions were delivered aiming to keep BED > 100Gy10. Dose was decreased as necessary to respect the constraints and minimize toxicity. Progression free survival (PFS) was analyzed from SRT to first progression or death, ST-free survival (STFS) from SRT to the beginning on next ST line or death. Results: We evaluated 32 consecutive pts from Sep/2014 to Jul/2019. Forty-six courses of SRT where performed. Mean age was 56 ± 13y, 60% female and 65% had colon cancer. 52% had metastatic disease after radical treatment. 63% were off ST by the time of the SRT. SRT treatment sites were lung and liver in 28%, bones and lymph nodes 13%, and CNS 11%. 72% of pts had only 1 treated lesion and 70% did 1 SRT course. Most commonly used regimens were 3 x 10-18Gy (35%), 4 x 10-12Gy (15%) and 5 x 7-10Gy (22%). 37% of treatments had BED≥100Gy10 and 78% were done with IMRT/VMAT. With a median follow-up of 16.1m (IQR 8.2-32.7), the median PFS was 5.4m (95% CI 4.1-11.0) and STFS was 12.7m (95% CI 0.8-24.5). Patients with multiple SRT courses had longer interval between disease progression and starting the next ST line (median 2.2 vs 12.4m). Pts that where on ST holidays before SRT had higher STFS (HR = 0.24 95% CI 0.1-0.6, p = 0.001) probably due to selection bias (lower disease volume). The 3y OS was 71%, median was not reached. Conclusions: Local treatment with SRT for OM-CRC showed to be feasible and safe with promising PFS and OS that deserves further investigation. The median STFS superior to a year suggests that SRT can influence OM-CRC treatment positively, possible impacting quality of life and even treatment costs.
A cost-effectiveness analysis of pretreatment DPYD and UGT1A1 screening in patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI+bevacizumab (FOLFIRI+Bev).
Authors: Rivers Zachary , Stenehjem David D. , Jacobson Pamala , Lou Emil , Nelson Andrew , Kuntz Karen M 
Published: February 2020

168 Background: Variants in DPYD and UGT1A1 impact toxicities experienced by patients being treated with FOLFIRI+bev. Testing allows providers to preemptively adjust dosing, reducing the toxicity that patients experience. We assessed the cost-effectiveness of pre-treatment testing for variants in DPYD and UGT1A1 in patients with mCRC receiving FOLFIRI+bev. Methods: We developed a six-state Markov model to compare pre-treatment genetic testing to no testing. The genetic testing arm screened for UGT1A1 and DPYD using a multi-gene panel. Patients were dosed per proposed guidelines (Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group) and allowed dose reductions based on toxicity. In the no-test arm, patients received full doses of FOLFIRI+bev, and dose reductions based on toxicity. Costs included medications, clinic visits, and hospitalizations to treat the disease and adverse events, and were obtained from the literature, adjusted to 2019 $US. Quality-adjusted life years (QALYs) were used to assess effectiveness. We used a US health care system perspective with a 16 week horizon, the average length of time patients were exposed to FOLFIRI+bev in clinical trials. We conducted sensitivity analyses to determine the impact of uncertainty on outcomes. Results: Genetic testing cost $25,563, generating 0.21 QALYs. Standard of care cost $25,515, generating 0.20 QALYs. This resulted in an incremental cost-effectiveness ratio (ICER) of $4963 per QALY gained. Results were sensitive to costs of post-progression care, the probability of carrying UGT1A1 variants, and the impact of low-functioning DPYD variants on side effects. Conclusions: Pre-treatment testing for DPYD and UGT1A1 in patients receiving FOLFIRI+bev for mCRC is cost-effective, well below typical oncology ICERs of $50,000-100,000 per QALY. Further work is needed to characterize the impact of post-progression treatment and supportive care medications.
Biomarker analysis for UPCI 14-118: Phase II study of pembrolizumab in combination with azacitidine in patients with refractory metastatic colorectal cancer.
Authors: Kuang Chaoyuan , Park Yongseok , Bahary Nathan , Sun Weijing , Ohr James , Rhee John C. , Marks Stanley M. , Beasley H. Scott , Shuai Yongli , Lin Yan , Pai Reetesh K. , Krishnamurthy Anuradha , Zarour Hassane M. , Herman James , Chu Edward , Lee James J. 
Published: February 2020

173 Background: DNA mismatch repair (MMR) proficient colorectal cancer (CRC) is resistant to immune checkpoint therapy compared to MMR deficient CRC. DNA hypomethylating agents may promote anti-tumor immune response by re-expression of cancer-testis antigen and reactivating immune genes suppressed by DNA methylation. This trial tested whether epigenetic modulation by concurrent treatment with azacitidine could enhance the anti-tumor activity of pembrolizumab in mCRC. Methods: Phase II trial was conducted to evaluate activity, safety, and tolerability of pembrolizumab in combination with azacitidine in patients with previously treated pMMR metastatic CRC. Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg daily SQ injection on days 1-5 every 3 weeks. The primary endpoint of the study was ORR. Tumors were biopsied pre-treatment and on-treatment for biomarker studies. Results: 30 patients received at least one dose of therapy. One patient experienced a confirmed partial response, one experienced stable disease. ORR was 3% (1/30; 95% CI, 0.1-17%). Median PFS was 1.9 months, median OS was 6.3 months. Treatment was well tolerated with only one patient (3%) experiencing grade 3 adverse event. The patient with a PR had positive pre-treatment TILs, but no evaluable tumor from on-treatment biopsy. 2 of 6 patients who continued therapy despite PD on first restaging experienced temporary stabilization of disease later. 5 of 16 evaluable biopsy pairs demonstrated increased TILs on treatment compared to baseline; however, all of these patients experienced PD. 10 of 15 paired samples demonstrated decreased methylation of hypermethylated loci on-treatment. Clustering analysis demonstrated a correlation between pre-treatment methylation of immune activation genes with overall survival of the patients. Conclusions: Combining azacitidine and pembrolizumab is safe and tolerable for pMMR mCRC with only limited activity. DNA methylation and TIL changes are detectable after 3 cycles of therapy. DNA methylation of immune activation genes correlate with overall survival. RNA sequencing and peripheral immune cell flow cytometry are ongoing. Clinical trial information: NCT02260440.
Circulating miR-203 secreted from metastatic tissues could exacerbate myopenia in colorectal cancer patients.
Authors: Okugawa Yoshinaga , Toiyama Yuji , Hur Keun , Ide Shozo , Shimura Tadanobu , Fujikawa Hiroyuki , Yasuda Hiromi , Yokoe Takeshi , Hiro Junichiro , Ohi Masaki , Kusunoki Masato 
Published: February 2020

181 Background: Sarcopenia is commonly observed in advanced cancer patients with distant metastases. In addition, biological functions of microRNAs (miRNAs) in cell-to-cell communication by incorporating into neighboring or distal cells has been gradually elucidated in various diseases, including sarcopenia, have been established. Methods: First, we quantified miR-203 expression, a key miRNA involved in cell-to-cell communication, by qRT-PCR and in situ hybridization in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM) tissues. We further evaluated miR-203 levels using pCRC tissues and matched preoperative serum to clarify its clinical significance in independent 183 CRC patients. Second, we assessed psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using preoperative computed tomography imaging to clarify its clinical burden and correlations with miR-203 levels in CRC patients. Functional analysis of miR-203 overexpression was investigated in human skeletal muscle cells (SkMC), and cells were analyzed for proliferation and apoptosis. Expression of several, putative, miR-203-target genes was also validated in SkMC cells. Results: MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. In contrast to IMAC, decreased PMI significantly correlated with well-established disease development factors, and decreased PMI was an independent prognostic factor for both overall survival, and disease-free survival in CRC patients. Although tissue miR-203 expression did not significantly correlate with the body composition status, serum miR-203 expression negatively correlated with preoperative PMI level. Overexpression of miR-203 inhibited cell proliferation and induced apoptosis via downregulation of BIRC5 (Survivin) expression in SkMC cell. Conclusions: Assessment of serum miR-203 could be used for risk assessment of metastasis-related myopenia in CRC.