bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical efficacy and safety of regorafenib (REG) in the treatment of metastatic colorectal cancer (mCRC) in daily practice in Germany: Final results of the prospective multicentre non-interventional RECORA study.
Authors: Schulz Holger , Janssen Jan , Strauss Uwe P. , Langen Markus , Dworschak Kai Uwe , Fiala-Buskies Sabine , Bokemeyer Carsten 
Published: January 2019

748 Background: In 2013 REG was approved for mCRC based on the results achieved in the CORRECT trial. However, prospective data from daily practice use are still scarce. Methods: RECORA investigated efficacy and safety of REG in routine clinical care in Germany. Male/female mCRC patients (pts) ≥ 18 years for whom the decision was taken to treat with REG in its approved indication were enrolled. Primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival time (PFS), time-to-progression (TTP), disease control rate (DCR), and incidence of treatment-emergent adverse events (TEAE). Subgroup analyses for OS, PFS, TTP and safety were performed according to age, sex, ECOG PS, KRAS status, time from initial diagnosis, number of prior bevacizumab therapies, tumor location, and sites of metastases (mets). Results: 481 pts were enrolled at 90 sites between 10/13 and 07/16; 464 pts were included in the safety analysis, 463 for efficacy. Mean/median age was 67 years (range 30-89), 60% of pts were male, baseline ECOG PS was 0 in 20%, 1 in 61%, 2 in 18%, and 3 in 1% of pts, 63% had a primary colon cancer, 46% had KRAS mutated tumors at diagnosis, 75% had mets in the liver, 59% in the lung , and 42% in both lung and liver. Median OS was 5.8 months (mos) (95% CI 5.3-6.6), median PFS was 3.1 mos (95% CI 2.8-3.3), median TTP was 4.0 mos (95% CI 3.6-4.9), DCR was 26.7%. There were no significant differences in OS in subgroups according to age ( < 65/≥65), sex, KRAS status, prior bevacizumab therapy, and primary tumor site; whereas OS was significantly different in subgroups according to ECOG PS (ECOG 0/1 vs. 2) and time from initial diagnosis ( < 18/≥18 mos). TEAE grade ≥3 occurred in 57.5% of pts, in 19% REG related. A serious TEAE was recorded in 51% of pts, in 9% considered as REG related. Overall, 29% died of an AE, in 0.4% REG related. 24.4% of pts received further anti-tumor therapy after REG was stopped. Conclusions: RECORA, a non-interventional real-life setting study, showed clinical benefit and acceptable tolerability for REG in this final analysis. The OS achieved was in the same range as in the pivotal study. Clinical trial information: NCT01959269.
Cost-effectiveness of short course radiation therapy versus long-course chemoradiation for locally advanced rectal adenocarcinoma.
Authors: Raldow Ann C. , Lee Percy , Russell Marcia McGory , Hong Theodore S. , Ryan David P. , Wo Jennifer Yon-Li 
Published: January 2019

749 Background: Long-course chemoradiation (LCRT; 50.4 Gy in 28 fractions with concurrent chemotherapy) followed by surgery and adjuvant chemotherapy is the standard of care in the United States for locally advanced rectal cancer. However, many countries follow a protocol of short course radiation therapy (SCRT; 25 Gy in 5 fractions). The purpose of this study was to analyze the cost-effectiveness of SCRT versus LCRT. Methods: We developed a cost-effectiveness model simulating 10-year outcomes for 65-year-old patients treated with either SCRT or LCRT. For the base case analysis, we assumed 3D-conformal radiation treatment. We used probabilities, utilities and costs based on the literature and Medicare Fee schedules to determine the incremental cost-effectiveness ratio (ICER) of SCRT versus LCRT. We defined cost effectiveness at an ICER of $100,000/quality-adjusted life-year (QALY) or less. We assumed that SCRT would not result in tumor downstaging adequate enough to change rates of sphincter preservation, while LCRT resulted in higher rates of low anterior resection (LAR). To model preference-sensitive care, we conducted a two-way sensitivity analysis in which we simultaneously varied the utilities of the no evidence of disease states with LAR (NED-LAR) and abdominoperineal resection (APR; NED-APR). To model current practice, we repeated the analysis assuming 3D-conformal treatment for LCRT but intensity modulated radiation therapy (IMRT) for SCRT. Results: With an ICER of $351,731/QALY, SCRT was cost-effective as compared to LCRT. SCRT remained the cost-effective strategy with 3D-conformal treatment for LCRT but IMRT for SCRT (ICER of $314,022/QALY). On one-way sensitivity analysis, LCRT became the cost-effective approach when the utility of NED-APR was below 0.61. Two-way sensitivity analysis revealed that the cost-effective approach for a given patient depended on the utilities for the NED-LAR and NED-APR states. Conclusions: SCRT was the cost-effective strategy as compared to LCRT. However, the cost effectiveness of SCRT versus LCRT was sensitive to the utilities of NED-LAR and NED-APR, highlighting the importance of patient preference-sensitive care.
Phase II study of S-1 on alternate days combined with bevacizumab in elderly patients (aged ≥75 years) with metastatic colorectal cancer (mCRC).
Authors: Eto Tetsuya , Moriwaki Toshikazu , Ishida Hiroyasu , Endo Shinji , Yamamoto Yoshiyuki , Kuramochi Hidekazu , Sato Mikio , Tsuji Akihito , Bando Yoshiaki , Indou Shunju , Shimada Mitsuo , Amagai Kenji , Morimoto Masamitsu , Kobayashi Kazuma , Nishina Tomohiro , Hyodo Ichinosuke 
Published: January 2019

750 Background: The alternate-days administration of S-1 was suggested to reduce toxicities such as GI-related adverse events (AEs) or neutropenia maintaining efficacy in some previous reports. This phase II study was aimed to evaluate an alternate-day administration of S-1 combined with bevacizumab in untreated elderly patients with mCRC. Methods: The key eligibility criteria included age ≥75 years, first-line chemotherapy, measurable lesions, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, preserved organ function, and refusal of oxaliplatin- or irinotecan-containing regimen as the initial chemotherapy. Patients received 40 mg (body surface area [BSA] ≤1.25 m2), 50 mg (BSA > 1.25 to ≤1.50 m2), or (BSA > 1.50 m2) of S-1 orally, twice a day, on Monday, Wednesday, Friday, and Sunday every week. Bevacizumab of 7.5 mg/kg was administered every 3 weeks. Primary endpoint was progression-free survival (PFS). Expected median PFS was 8.5 months, and efficacy threshold was 5.0 months. The required sample size was calculated as 50 patients, with a 2-sided type I error of 10% and a power of 80%. Results: Of 54 enrolled patients, 50 patients for efficacy and 53 patients for safety were evaluated. The median age was 79 years (range, 75–88), and 56% had an ECOG PS of 0. The median follow-up time was 34.5 months (95% confidence interval [CI], 25.6–44.9). Median PFS was 8.1 months (95%CI, 7.4–10.1). Median overall survival was 22.8 months (95%CI, 16.9–28.5). The response rate and disease control rate were 44% and 88%, respectively. Grade 3 or more hematologic, non-hematologic, and bevacizumab-related AEs were observed in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Treatment-related death caused by cerebral infarction was observed in one patient. Conclusions: The primary endpoint was met. The alternate-days administration of S-1 combined with bevacizumab was well tolerated and effective in elderly patients with mCRC. Clinical trial information: UMIN000010402.
Safety of trifluridine/tipiracil (FTD/TPI) in elderly patients with metastatic colorectal cancer.
Authors: Mayer Robert J. , Hochster Howard S. , Cohen Steven J. , Winkler Robert , Makris Lukas , Grothey Axel 
Published: January 2019

752 Background: Elderly patients (≥65 yrs) with metastatic colorectal cancer (mCRC) are more likely to have comorbid conditions than younger patients ( < 65 yrs), limiting their therapeutic options. As previously reported (Mayer et al. J Clin Oncol 2017;35:abs 3559), FTD/TPI confirmed its clinical profile in mCRC in a real-world setting. Here, we report the safety and tolerability profile of FTD/TPI from the expanded-access program (EAP) in patients aged ≥65 yrs. Methods: Patients (≥18 yrs) with mCRC following ≥2 regimens of anticancer therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to this open-label EAP. Patients received FTD/TPI 35 mg/m2 twice daily for 5 days followed by 2 days’ rest for 2 weeks, with a 14-day rest period (28-day treatment cycle). Data were collected for therapy duration, treatment discontinuation, and adverse events (AEs). Results: Of 549 patients, 377 (68.7%) were aged < 65 and 172 (31.3%) were ≥65. The treatment duration of FTD/TPI was similar between < 65 and ≥65 yrs (Table). A lower proportion of those aged ≥65 had fatigue and nausea compared with < 65 (Table). However, the frequency of neutropenia and diarrhea was slightly increased in those ≥65 compared with < 65 (Table). One patient (0.6%) in the ≥65 group developed febrile neutropenia compared with 9 (2.4%) in the < 65 group, with no associated deaths in either group. Conclusions: This analysis from the EAP showed that the safety profile and treatment duration of FTD/TPI in patients aged ≥65 with mCRC were similar to those in patients aged < 65. FTD/TPI is well tolerated and can be considered in patients aged ≥65 with mCRC. Clinical trial information: NCT-02286492. [Table: see text]
Tumor platinum concentrations and pathological responses following preoperative cisplatin-containing chemotherapy in gastric or gastroesophageal junction cancer patients.
Authors: Cao Yanshuo , Chang Qing , Cabanero Michael , Zhang Wenjiang , Hafezi-Bakhtiari Sara , Hedley David W. , Darling Gail Elizabeth , Quereshy Fayez A. , Jang Raymond Woo-Jun , Elimova Elena , Knox Jennifer J. , Ornatsky Olga , Serra Stefano , Chen Eric Xueyu 
Published: January 2019

76 Background: Perioperative chemotherapy plus surgical resection is a standard of care for locally advanced gastric or gastroesophageal junction (GEJ) cancers. There is a wide range in tumor response following cisplatin-containing preoperative chemotherapy. We investigated the relationship between tumor platinum levels and pathological tumor responses in gastric or GEJ cancer patients following preoperative chemotherapy. Methods: Tumor and adjacent normal tissues were retrieved. Pathological responses were assessed per standard criteria. Tissue platinum concentrations were determined with high-performance liquid chromatography mass spectrometry. Platinum distribution in tissue components was evaluated with imaging mass cytometry. Tissue collagen content was evaluated using trichrome staining. Results: Ten patients were enrolled in this study. Nine patients received 3 cycles of preoperative chemotherapy and 1 received 2 cycles. The median cumulative cisplatin dose was 166.8 mg/m2 (range: 95.9–181.1 mg/m2). Surgery was performed at a median time of 49 days (range: 28–72 days) after the last cycle of chemotherapy. The mean platinum level in tumor tissue in patients with any response was 893 ± 460 pg, significantly higher than in those with no response [38.8 ± 8.8 pg (p = 0.007)]. The collagen content was significantly higher in patients with any response than in those with no response (37.4 ± 6.8% vs. 11.5 ± 8.6%, p < 0.05). Platinum preferentially bound to collagen. Conclusions: Platinum was detectable in surgical specimens up to 72 days after preoperative chemotherapy. Higher tumor platinum concentration correlated with improved pathological response. Collagen binding potentially explained the high interpatient variability in tumor platinum concentrations.
Baseline characteristics in the international, open-label, early-access program of trifluridine/tipiracil in previously treated metastatic colorectal cancer (phase IIIb).
Authors: Price Timothy Jay , Taieb Julien , Falcone Alfredo , Seitz Jean Francois , Wyrwicz Lucjan , Becquart Martin , Moreno Shanti , Mounedji Nadjat , Van Cutsem Eric 
Published: January 2019

761 Background: In the phase 3 RECOURSE trial, trifluridine/tipiracil (FTD/TPI, also known as TAS-102) significantly improved overall and progression-free survival versus placebo in patients (pts) with metastatic colorectal cancer (mCRC) progressing after all available standard therapies (Mayer et al. N Engl J Med 2015;372:1909-19). FTD/TPI is approved after regorafenib in the same setting for management of previously treated mCRC patients. A phase 3b early-access program (EAP) is ongoing to provide access to FTD/TPI for mCRC pts with similar eligibility criteria to assess safety profiles in real-world setting (EudraCT Number: 2016‐002311‐18). First pt was enrolled in Oct 2016. We describe the characteristics of pts included up to 7 March 2017. Methods: Eligible pts had histologically confirmed mCRC previously treated with, or not considered candidates for, available therapies. Other inclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 or 1. Pts planned to receive FTD/TPI (35 mg/m2 bid) orally on days 1–5 and 8–12 of each 28-day cycle. Results: A total of 298 pts from 7 countries had received at least 1 dose of treatment. Median age was 65 years (range 28–87); 65% were male; 98% were Caucasian (n = 264 out of 269). Among 271 pts, 40% and 60% had respectively ECOG PS 0 and 1 at baseline except 1 pt with PS 2. Primary site of disease was colon (55%, of which 27% right-sided and 61% left-sided); 33% have rectum as primary site; and not specified in 12%,52% had synchronous disease at diagnosis. Median time from initial diagnosis was 37 months (range 6–302) and from first metastasis was 32 months (range 1–180). 59% had RAS mutation (n = 164 out of 279). More than 95% received fluoropyrimidine and/or oxaliplatin and/or irinotecan, while 82%, 39% and 37% received anti-VEGF, anti-EGFR and regorafenib prior to study enroll, respectively. Conclusions: Analysis of the baseline characteristics shows a heavily pretreated mCRC population still seeking additional anti-cancer therapy. Optimal treatment sequencing in 3rd line is not yet established. Preliminary safety and efficacy results are anticipated in 2018. Clinical trial information: 2016-002311-18.
Predictive value of tumor growth rate during previous treatment for tumor response to regorafenib (REGO) and trifluridine/tipiracil (TFTD) in metastatic colorectal cancer (mCRC).
Authors: Kawakami Takeshi , Masuishi Toshiki , Kawamoto Yasuyuki , Omae Katsuhiro , Muranaka Tetsuhito , Nakatsumi Hiroshi , Yuki Satoshi , Komatsu Yoshito , Yamazaki Kentaro , Onozawa Yusuke , Yasui Hirofumi , Tajika Masahiro , Kadowaki Shigenori , Taniguchi Hiroya , Muro Kei 
Published: January 2019

766 Background: Although REGO and TFTD have been recognized as standard salvage treatments for patients (pts) with refractory mCRC, it is still unclear which drug should be used first. Tumor growth rate (TGR) during the pre-treatment period is associated with survival in lung and laryngeal cancer treated with chemoradiotherapy. However, little is known about the association between TGR during the pre-treatment period and tumor response to REGO and TFTD. Methods: We retrospectively analyzed the data of consecutive mCRC pts who were treated with REGO or TFTD at three institutions. We classified pts into slow-growing (SG) or rapid-growing (RG) groups according to TGR, and appearance of new lesions (NL+) or their absence (NL–) during the pre-treatment period. TGR was calculated as follows: TGR = (D1 − D0)/100D0 (CT1 − CT0), where CT1 is the date of computed tomography (CT) at progressive disease, CT0 is the date of CT before CT1, and Dn is the sum of target lesion diameters at CTn (according to RECIST version 1.1). SG was defined as NL– with a low TGR ( < 0.33), and RG was defined as NL− with a high TGR (≥0.33) or NL+, irrespective of TGR. Results: A total of 244 pts (RG/SG: 133/111, REGO/TFTD: 132/112) were eligible. The proportion of RG pts with a long duration from first-line chemotherapy and SG pts with elevated ALP was higher in the REGO group, while the proportion of SG pts with poor PS was higher in the TFTD group. The disease control rate (DCR) was similar in both groups (REGO 29% vs TFTD 23%, p = 0.556) among RG pts, while the DCR of TFTD was significantly better than REGO in SG pts In a multivariate analysis of predictive factors for DCR, drug selection was an independent factor for DCR in SG pts (odds ratio 3.51; 95% CI 1.33-9.27; p = 0.011). In RG group, DCRs of NL+ pts were worse than that of NL- pts (16% vs 36% in REGO group, p = 0.109; 9% vs. 31% in TFTD group, 0.108). Conclusions: TGR during the pre-treatment period would be helpful in selecting between REGO and TFTD, especially for pts with slow-growing tumors. Pts with appearance of new lesions may not benefit from either REGO or TFTD as salvage treatment.
Mucinous component assessed by magnetic resonance imaging in primary rectal cancer tissue before chemoradiotherapy and tumor response.
Authors: Miyakita Hiroshi , Sadahiro Sotaro , Saito Gota , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki 
Published: January 2019

768 Background: Mucinous carcinoma has been reported to have a lower survival rate, a poorer histologic response to preoperative chemoradiotherapy (CRT) than non-mucinous differentiated adenocarcinoma. Mucinous carcinoma was difficult to diagnose on biopsy because mucinous components are mainly located inside the tumor. We therefore compared MRI findings before and after CRT with histologic findings of resected specimens to investigate the predictive factor of response to CRT. Methods: The study group comprised 205 patients with locally advanced rectal cancer (LARC) who received CRT (40 to 45 Gy) from January 2006 through December 2014. T2-weighted fast-spin echo MRI was used to show the area ratio of mucin lakes (ML) to the maximum cut surface of the primary tissue. The presence or absence of ML and the area ratio of ML on the maximum cut surface were evaluated. Results: The histologic type on preoperative biopsy was well-differentiated or moderately differentiated adenocarcinomas in 202 patients (98.5%), poorly differentiated adenocarcinoma in 2 patients (1.0%), and mucinous carcinoma in only 1 patient (0.5%). ML area ratio on MRI before treatment was less than 20% in 194 patients (94.6%), 20% to 50% in 4 patients (2.0%), 50% or more in 7 patients (3.4%). In 11 patients with ML area ratio of 50% or more in resected specimen, mucinous carcinoma was diagnosed in only one patient (14.3%). The tumor shrinkage rate was 74% in patients with ML area ratio of less than 20%, 54.5% with ML area ration of 20% to 50%, and 56.4% with ML area ratio of 50% or more. (p = 0.002) The rate of T-downstaging was significantly greater in patients with ML area ratio of less than 20% than those with ML area ratio of 20% or more. (58% vs. 27%, p = 0.047) The rates of pCR were 13% and 0%, however, the difference was not significant. (p = 0.21) Conclusions: Mucinous carcinoma is difficult to diagnose on biopsy before chemoradiotherapy. The diagnosis of mucin lakes on MRI before treatment may be useful for predicting the response to CRT.
Effect of aberrant expression of miR-421, miR-29b_1_5p and miR-27b_5p on gastric adenoma development.
Authors: Kim Yu Jin , Kim Sang Woo , Lee Yong Chan , Kim Pumsoo 
Published: January 2019

77 Background: Gastric cancer (GC) is the fourth leading cause of cancer-related death in the world. Some gastric adenomas may progress to adenocarcinoma in a short time. Several studies have examined adenomas the intermediate step of gastric carcinoma development. MicroRNAs have an important role in progression of gastric cancer but less is known about their role in premalignant adenomas. Changes in the expression pattern of miRNAs can be informative and highly significant in the gastric adenoma-carcinoma sequence progression as well. However, to date precancerous lesions (such as adenomas) have been investigated less frequently than cancers compared to healthy tissues. The aim of the present study was to perform a miRNA microarray analysis of normal, low-grade dysplasia, and high-grade dysplasia using fresh frozen tissues. Changes in miRNA expression patterns were also verified from samples obtained from the same patients using TaqMan MicroRNA Assays. Methods: Human tissue samples were obtained from nine patients who underwent endoscopic submucosal dissection (ESD) due to gastric adenoma or early gastric cancer at Severance Hospital of Yonsei University. Tumor and non-tumor mucosa tissue in each patient were taken just before ESD using biopsy forceps and frozen in the nitrogen tank. The miRNA expression profiles were analyzed by Affymetrix Gene-Chip miRNA 4.0 array (Homo sapiens). qRT-PCR was performed using TaqMan MicroRNA Assays (Applied Biosystems). Results: There were 28 (up-regulation) and 10 (down-regulation) miRNAs which showed significantly different expression between control group and low-/high-grade dysplasia group. miRNAs showing altered expression in normal and low-/high-grade dysplasia by microarrays were selected, and the expression tendencies were detected by real-time PCR validation. Three miRNAs (miR-421, miR-29b-1-5p, miR-27b-5p) were selected the continually upregulated from normal to low-/high-grade dysplasia based qRT-PCR in tissue samples. Conclusions: We identified new, less known miRNAs (miR-421, miR-29b-1-5p, miR-27b-5p), with altered expression in different grade dysplasia compare with normal samples.
Association of SMAD4 gene mutation with incidence of peritoneal involvement in unresectable metastatic colorectal cancer.
Authors: Vicente Diego , Mizuno Takashi , Loehrer Andrew , Limani Preparim , Kopetz Scott , Vauthey Jean-Nicolas 
Published: January 2019

772 Background: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is involved in TGF- β and Bone Morphogenic Protein (BMP) signaling pathways. Dysregulation in these signaling pathways has been associated with carcinogenesis and poor prognosis in colorectal cancer (CRC). Recent evidence suggests that SMAD4 mutations in CRC may be associated ovarian metastasis, however, the link to peritoneal involvement has not been established. Methods: Patients with next generation sequencing of 50 cancer related genes and unresectable metastatic CRC were identified from a prospectively maintained medical oncology department database. Clinicopathological variables, metastatic sites, and genetic mutations were compared between patients with SMAD4 mutant and SMAD4 wild type patients. Multivariable analysis was then performed to evaluate for factors associated with peritoneal involvement. Results: 324 patients with unresectable metastatic CRC were identified and of these 36 (11%) were SMAD4 mutants. Clinicopathologic variables and additional cancer related gene mutations were similar between SMAD4 mutant and wild type patients. Patients with SMAD4 mutations were more likely to present with peritoneal metastatic disease (50% vs. 24%, p = 0.002) and less likely to present with hepatic metastasis (39% vs 59%, p = 0.021). Metastatic rates to the lungs, distant lymph nodes, and multiple metastatic sites at presentation were similar between the two groups. In patients with metachronous metastatic disease (n = 131), SMAD4 mutation patients demonstrated a trend towards shorter interval to metastatic recurrence (12 vs. 23 months, p = 0.059). During a median follow up of 26 months, SMAD4 mutation patients were more likely to develop peritoneal involvement at either presentation or in progression of disease (58 vs. 35%, p = 0.010). Multivariable analysis showed that compared to other mutations, only the SMAD4 mutation was associated with a higher risk of peritoneal metastasis (OR 2.5, 195% CI 1.2-5.6, p = 0.025). Conclusions: In patients with unresectable metastatic colorectal cancer, SMAD4 mutation is independently associated with peritoneal metastasis.