bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I dose-escalation trial of intraperitoneal oxaliplatin with systemic capecitabine and bevacizumab following cytoreduction in patients with peritoneal carcinomatosis from appendiceal or colorectal cancer.
Authors: Oza Aabha , Grierson Patrick , Glasgow Sean , Pedersen Katrina , Barman Stephen , Westbrook Thomas , Mutch Matthew G , Wang-Gillam Andrea , Suresh Rama , Morton Ashley , Marquez Samantha , Fleshman James W , Tan Benjamin R.
Published: January 2019

746

Background: Peritoneal carcinomatosis (PC) is the intraperitoneal spread of cancer. Optimal treatment for PC is controversial. Systemic chemotherapy offers limited benefit (Franko, 2011). Intraperitoneal (IP) chemotherapy following cytoreductive surgery (CRS) improves outcomes (Verwaal, 2008). Oxaliplatin (Ox), capecitabine, and bevacizumab are standard agents for the treatment of metastatic colorectal cancer (CRC). Evidence suggests benefit of IP Ox at high doses. However, the optimal dose of IP Ox combined with standard systemic therapy is unclear. Methods: We conducted an IRB-approved phase I dose-escalation study of IP Ox D1 at 25mg/m2-100mg/m2, with systemic bevacizumab D1 at 5mg/kg, and capecitabine 850mg/m2 BID for 7 days (cycle = 14 days), in patients with PC from appendiceal or CRC after CRS. The primary aim was to determine the recommended phase II dose (RP2D)/maximum tolerated dose (MTD) for this regimen. Dose limiting toxicities (DLTs) were assessed during cycle 1. DLTs included grade 3 or 4 non-hematological toxicities, or grade 4 hematological toxicities. Results: 18 patients (12 females, median age 56) were enrolled on the study. No DLTs were observed during cycle 1 in the first 4 cohorts. One DLT (abdominal pain) was observed in cohort 5. Another patient in cohort 5 experienced grade 3 abdominal pain soon after cycle 2, thus limiting repeated treatment for this cohort. Other toxicities included fatigue (72%), nausea (61%), peripheral neuropathy (50%), constipation (50%), mucositis (39%) and dizziness (39%). See table below for average # of cycles per cohort and responses. Conclusions: IP Ox combined with capecitabine and bevacizumab is feasible. Our recommended dose for IP Ox is 85 mg/m2 with systemic therapy (cohort 4). An expansion cohort is underway for this dose level. Based on these data, further investigation of IP Ox with systemic chemotherapy for PC is warranted. Clinical trial information: NCT01061515. [Table: see text]
Impact of primary tumor side (TS) on outcomes of once-every-2-weeks (q2w) cetuximab + first-line (1L) FOLFOX or FOLFIRI in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 2 APEC trial.
Authors: Price Timothy Jay , Shen Lin , Ma Brigette , Esser Regina , Chen Wen-Feng , Gibbs Peter , Lim Robert S.C. , Cheng Ann-Lii
Published: January 2019

747

Background: In the RAS wt population of APEC, q2w cetuximab combined with 1L FOLFOX or FOLFIRI achieved a best confirmed overall response rate (BORR), median progression-free survival (PFS), and median overall survival (OS) similar to those reported in prior 1L pivotal studies involving weekly (qw) cetuximab. In this hypothesis-generating subgroup analysis, we evaluated the impact of TS in APEC study patients with RAS wt mCRC. Methods: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region, with BORR as the primary endpoint. Patients with KRAS exon 2 wt tumors received q2w cetuximab + investigator’s choice of FOLFOX or FOLFIRI; subsequent analyses considered patients who were RAS wt ( KRAS/ NRAS, exons 2-4). TS was categorized in evaluable patients with RAS wt tumors (left [L]-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right [R]-sided = appendix, cecum, ascending colon, hepatic flexure, and transverse colon). Results: Among 167 patients with RAS wt mCRC, 159 were evaluable for TS; 130 (81.8%) had L-sided and 29 (18.2%) had R-sided mCRC. Baseline characteristics in the TS subgroups reflected the known differences between L- and R-sided mCRC. Efficacy data for the TS subgroups are summarized in the table. Conclusions: Consistent with prior 1L pivotal studies involving qw cetuximab, a prognostic effect of TS in patients receiving 1L q2w cetuximab was confirmed in APEC. BORR remained ≥50% in patients with R-sided mCRC, in line with prior evidence that use of cetuximab may be appropriate when tumor shrinkage/cytoreduction is the goal. These hypothesis-generating data also raise the possibility of synergy between cetuximab and, in particular, irinotecan for PFS and OS in patients with R-sided tumors, although numbers are small. Clinical trial information: NCT00778830. [Table: see text]
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.
Utilization rates and outcomes of short-course radiotherapy for nonmetastatic rectal adenocarcinoma for patients in the National Cancer Database.
Authors: Elhalawani Hesham , Allen Pamela , Abdel-Rahman Omar Mohammed , Holliday Emma Brey
Published: January 2019

774

Background: Short-course radiation therapy (SCRT) has been studied in European trials but is not often utilized in the US. We aim to describe the utilization and outcomes of SCRT compared to the more widely used long-course (LCRT) neoadjuvant regimen. Methods: The National Cancer Database (NCDB) was queried for patients treated with preoperative RT followed by surgical resection for non-metastatic rectal adenocarcinoma from 2004-2014. Patient, tumor and treatment-related characteristics were compared between those treated with SCRT (defined as patients receiving < 26 Gray (Gy) in < 7 fractions) and those treated with LCRT. Survivals were compared using the Log-Rank test. Univariate and multivariate Cox regression analyses were used for univariate analysis of factors associated with overall survival (OS). Results: 48898 patients were included for analysis: 48396 patients (99.0%) treated with LCRT and 502 (1.0%) treated with SCRT. Patients treated with SCRT were older (median [range] age 67 [21-90] vs 60 [18-90]; p < .001), had more comorbidities (Charlson/Deyo score 1+ N = 155 (30.9%) vs N = 9795 (20.2%); p < .001), had earlier T-stage (T1-2 N = 141 (28.1%) vs N = 5774 (11.9%); p < .001) and were more likely to be clinically node-negative (N = 324 (64.5%) vs N = 22701 (46.9%); p < .001). Patients treated with SCRT were more likely to be treated after 2009 (N = 303 (60.4%) vs N = 24834 (51.3%); p < .001) and were more often treated at an academic center (N = 318 (63.3%) vs N = 20375 (42.1%); p < .001). Patients treated with SCRT had a 2- and 5-year OS of 85.8% and 65.7%, respectively, compared with 90.9% and 73.5% in patients treated with LCRT (log-rank p < .001). On univariate analysis, receipt of SCRT was associated with worse OS (HR 1.40 95% CI 1.18-1.65; p < .001). However, when entered into a multivariate model including other patient and tumor-related factors, SCRT was actually associated with improved OS (HR 0.77 95% CI 0.59-1.00; p = .048). Conclusions: SCRT is utilized for approximately 1% of patients treated with preoperative treatment of non-metastatic rectal cancer in the US. The results of recently completed randomized trials may further inform patterns of practice in the US and abroad.
Impact of pelvis irradiation on toxicity of further oxaliplatin-based chemotherapy in rectal cancer.
Authors: Spalek Mateusz , Michalski Wojciech , Bujko Krzysztof , Wyrwicz Lucjan
Published: January 2019

777

Background: Radiotherapy is used in the neoadjuvant setting in majority of rectal cancer patients, while its effect on overall survival is limited mostly to patients with threatened resection margin. Preoperative pelvic irradiation might damage bone marrow. In consequence, relative dose intensity (RDI) and efficacy of further adjuvant or palliative CT might be reduced. The aim of the study was to assess whether radiation damage to the pelvic bone marrow influences the tolerance of further oxaliplatin-based CT. Methods: We have performed the cohort analysis of patients with adenocarcinoma of rectum or colon receiving FOLFOX-4 chemotherapy in adjuvant or palliative setting between 2011-2016. Oxaliplatin relative-dose intensity (RDI) within 8 weeks from the beginning of CT was calculated for each patient. The major factors, which can reduce oxaliplatin RDI, were analyzed independently (hemathological toxicity, neurological toxicity, occurrence of hypersensitivity reactions to oxaliplatin). The data regarding the first disruption of oxaliplatin dose within all planned courses of FOLFOX-4 was also collected. Results: 220 patients met eligibility criteria. 41 of them received neoadjuvant radio(chemo)therapy (study group), the remaining 179 patients were assigned to control group (n = 179). RDI did not differ significantly between irradiated and non-irradiated patients (p = 0.794). There were no statistically significant differences in observed oxaliplatin-related toxicities. The median time between the start of chemotherapy and the first disruption of oxaliplatin administration was also not statistically different between the two groups (p = 0.156). Conclusions: An impact of preoperative radio(chemo)therapy on RDI or tolerance of FOLFOX was not found in rectal cancer.
Clinicopathologic characteristics and impact of oophorectomy for ovarian metastases (ovmets) in colorectal cancer (CRC).
Authors: Ursem Carling Jade , Zhou Margaret , Paciorek Alan T , Atreya Chloe Evelyn , Ko Andrew H. , Zhang Li , Van Loon Katherine
Published: January 2019

779

Background: As overall survival (OS) with metastatic colorectal cancer (mCRC) and imaging modalities improve, detection of ovmets may be increasing. The ovary is often a sanctuary site for mCRC; however, there is a paucity of data to guide decision-making regarding the role for oophorectomy. Methods: This is a single-institution retrospective review of patients (pts) who received care for mCRC (incl. appendiceal primaries) with ovmets from 2009-2017. Pts were identified through a hospital-based cancer registry, provider recall, and pathology and radiology databases. Clinicopathologic and treatment data were abstracted. Cox proportional hazards models were used to evaluate for associations with OS. Results: Of 108 pts, median age was 50 (range 19-106), 62 (57%) were Caucasian, and 69 (64%) had ovmets at initial CRC diagnosis. Primary tumor location was left-sided in 54 (50%), right-sided in 27 (25%), appendiceal in 18 (17%), and unknown in 9 (8%). Median OS from diagnosis of mCRC was 29.6 months (mo) with median follow-up of 21.9 mo (range 0.77-172.47). Younger age, absence of signet-ring or mucinous features, well/moderately differentiated grade, and resection of primary tumor were associated with improved OS (p < 0.05). Of 83 (76%) pts who underwent oophorectomy median OS was 36.7 mo vs. 25 mo in those who underwent non-operative management (HR 0.54, 95% CI 0.31-0.94, p = 0.03). Among 94 pts with extra-ovarian disease, 70 (74%) underwent oophorectomy; however, no significant difference in median OS was detected vs. those who did not (30.9 vs 25.0 mo, p = 0.07). In a multivariate model, oophorectomy was not associated with OS (HR 0.63, 95% CI 0.29-1.36, p = 0.24). Conclusions: While ovmets have been previously reported as associated with a poor prognosis, the median OS for this cohort was comparable to existing OS data for mCRC pts. Although oophorectomy for ovmets from mCRC was associated with improved OS in univariate analysis, this effect was not significant in the presence of extra-ovarian metastases. Ovmets from mCRC remain a difficult challenge in clinical care. Oophorectomy may improve OS in select cases; however, further evaluation of predictors of benefit is needed.
Regorafenib in antiangiogenic-naive, chemotherapy-refractory advanced colorectal cancer: A phase IIb trial.
Authors: Riechelmann Rachel Pimenta , Leite Luiz Antonio Senna , Glasberg Joao , Bariani Giovanni Mendonca , Rivelli Thomas Giollo , Nebuloni Daniela R. , Puty Fabiola , Kappeler Christian , Pereira Kaline M. C. , Queiroz Marcelo A , Hoff Paulo Marcelo
Published: January 2019

782

Background: The oral multikinase inhibitor regorafenib improves overall survival in advanced colorectal cancer (CRC). The aim of this study was to investigate the safety and efficacy of regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory CRC. Methods: In this single-center, single-arm, phase 2b study, patients received regorafenib 160 mg/day for 3 weeks on/1 week off. Tumor response assessed by RECIST 1.1 and tumor metabolic response by [18F] fluorodeoxyglucose positron emission tomography (PET/CT) according to the European Organization for Research and Treatment of Cancer (EORTC) criteria were evaluated at week 8 (W8). PFS rate was defined as the percentage of evaluable patients alive without progression at W8. Safety was assessed until the cut-off date (May 2, 2017). Results: Overall, 59 patients (59.3% male; median age 58.0 yrs) received regorafenib (median dose 148.8 mg/day). The W8 PFS rate was 46.6% (95% CI 33.3% - 60.1%) and median PFS and OS were 3.6 and 7.5 months, respectively. Overall disease control rate (DCR) was 50.8% by RECIST and 62.7% by EORTC criteria (Table). Most common regorafenib-related grade ≥3 AEs were hypertension (35.6%), hand-foot skin reaction (HFSR) (25.4%) and hypophosphatemia (22.0%). One patient discontinued treatment due to drug-related HFSR. Conclusions: The W8 PFS rate and overall DCR support the anti-tumor activity of regorafenib in antiangiogenic-naïve, chemotherapy-refractory advanced CRC. Compared with the previous phase 3 CORRECT and CONCUR trials, the median PFS suggests a better outcome in this population. These data provide the basis for further investigation of regorafenib’s role in earlier treatment lines in metastatic CRC and on the use of PET/CT in tumor response assessment. Clinical trial information: NCT02465502. [Table: see text]
Efficacy of adjuvant chemotherapy after resection of pulmonary metastasis from colorectal cancer: A propensity score matching analysis.
Authors: Imanishi Mamiko , Yamamoto Yoshiyuki , Hamano Yukako , Yamada Takeshi , Moriwaki Toshikazu , Gosho Masahiko , Sakao Yukinori , Okumura Takehiro , Boku Narikazu , Kondo Haruhiko , Hyodo Ichinosuke
Published: January 2019

788

Background: A number of retrospective studies reported that 5-year survival rate was 30-60% in patients who underwent curative resection of pulmonary metastases (PM) from colorectal cancer (CRC), and PM-CRC resection was recommended in clinical practice. Efficacy of adjuvant chemotherapy after resection of PM remains unclear. Therefore, using a large-scale data obtained from patients who underwent R0 resection of PM in Japan, we investigated it with a propensity score-matching analysis. Methods: We retrospectively collected clinical data of 1237 patients who underwent metastasectomy of PM-CRC at 46 Japanese institutions from 2004 to 2008. Excluding non-curative resection, preoperative chemotherapies, extra-thoratic metastases, complications after surgery, and inadequate data, 530 patients’ data (surgery alone 269 and surgery with adjuvant chemotherapy 261) were used for the matching. Patient backgrounds affecting doctor’s recommendation of adjuvant chemotherapy and including commonly reported prognostic factors were adjusted, using a propensity score-matching method. Primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively. Results: After the matching with propensity-score, 167 patients for each group were selected. Patient backgrounds were balanced between both groups. Adjuvant chemotherapies were fluorouracil alone (67%), oxaliplatine-containing regimen (24%), irinotecan-containing regimen (7%) and others (2%). There were no significant differences between both groups in OS (HR 0.97, 95%CI 0.64-1.46, p = 0.88) and DFS (HR 0.99, 95%CI 0.75-1.32, p = 0.96). Conclusions: A propensity score-matching analysis did not show a survival benefit of adjuvant chemotherapy after resection of PM in patients with CRC. A large prospective observational study with high quality or randomized clinical trial is needed.
Comparative analysis of different maintenance regimens after first-line induction in patients with metastatic colorectal cancer.
Authors: Mohamed AMR , Abdallah Nadine , Ismail Hibah , Chen Wei , Jang Hyejeong , Smith Daryn W. , Akhras Alaa , Tesfaye Anteneh A. , Philip Philip Agop , Shields Anthony Frank
Published: January 2019

789

Background: Although, previous trials have demonstrated the benefits of maintenance chemotherapy for unresectable metastatic colorectal cancer (MCRC), the optimal maintenance regimen with acceptable safety profile is still undetermined. The primary objective of this meta-analysis was to compare the effectiveness of the most common clinically used maintenance regimens after first line therapy in MCRC. Methods: Among 52 prospective studies published 2009-2017, 14 were qualified for inclusion. Random-effect model was used for pooled effects within different categories include those with no maintenance treatment versus different maintenance regimens (Bevacizumab, capecitabine, bevacizumab plus capecitabine, bevacizumab plus erlotinib, and cetuximab). Primary endpoint was median progression free survival (PFS), and secondary endpoint was median overall survival (OS). All statistical tests were two-sided and p values < 0.05 were considered significant. Results: 14 studies with 3553 patients (57% males) were included in final analysis. Induction treatment was 5-FU or capecitabine - based chemotherapy with either oxaliplatin or irinotecan with or without bevacizumab. After stratifying for induction status, patients who did not receive treatment had worse PFS compared to maintenance treatment [pooled median PFS 3.52 months, 95% CI (2.97- 4.07) Vs 5.08 months, 95% CI (4.59- 5.57), z-test adjusted p-value 0.0005]. Among different maintenance regimens, capecitabine /bevacizumab combination showed better PFS [pooled median PFS 6.87 month, 95% CI (5.17- 8.57)], however the results were not significant (z test adjusted p-value 0.1383). No statistical significant difference in median OS between maintenance regimens. Conclusions: MCRC patients who did not receive maintenance treatment had shorter PFS. Although the superiority of bevacizumab plus capecitabine maintenance cannot be confirmed, there was a trend towards better PFS. This study suggests that bevacizumab plus capecitabine may be an appropriate maintenance option after first induction therapy depending on the tolerability and compliance with oral capecitabine.
Relations of carcinoembryonic antigen (CEA) staining of cancer tissue and serum CEA levels to histologic response in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (nCRT).
Authors: Saito Gota , Sadahiro Sotaro , Miyakita Hiroshi , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki
Published: January 2019

790

Background: Neoadjuvant chemoradiotherapy (nCRT) is a standard of care for LARC. The serum CEA level is a predictor of the response to nCRT; however, the relation between CEA production immunohistochemically evaluated in cancer tissue and treatment response remains unclear. Methods: The study group comprised 145 patients with clinical Stage II/III rectal cancer who received nCRT followed by surgery from 2005 through 2013. The radiation dose was 40 to 45 Gy. UFT- or S-1-based chemotherapy was given concurrently. Surgery was performed 6 to 8 weeks after the completion of radiotherapy. Immunohistological CEA staining patterns in biopsy tissue obtained before nCRT were evaluated. Specimens in which the luminal cell membrane or the cytoplasm was strongly stained were defined as staining positive. The histologic response was evaluated on the basis of the pathological complete response (ypCR) rate, T downstaging, tumor regression grade (TRG), and tumor shrinkage rate on MRI. Results: CEA staining in biopsy specimens and serum CEA levels were both negative in 17 patients (11.7%) and both positive in 72 patients (49.7%). There was no relation between the groups (p = 0.174). In patients with negative CEA staining, the rates of ypCR, T downstaging, marked regression, and mean tumor shrinkage were 24.3%, 51.4%, 45.9%, and 72.3%, respectively. In patients with positive CEA staining, these rates were 11.1%, 48.1%, 37.0%, and 72.8%, respectively. CEA staining of cancer tissue was not significantly related to the ypCR rate, T downstaging, a marked regression rate, or the tumor shrinkage rate on MRI (p = 0.060, p = 0.849, p = 0.436, and p = 0.874, respectively). Patients with negative serum CEA levels before nCRT had significantly higher rates of ypCR, T downstaging, marked regression, and tumor shrinkage on MRI than did patients with positive serum CEA levels (p = 0.014, p = 0.006, p = 0.002, and p = 0.014, respectively). Conclusions: Serum CEA levels before nCRT were a significant predictor of the histologic response to nCRT; in contrast, tissue CEA staining before nCRT was unrelated to the histologic response to nCRT.
The effect of dose escalation for large squamous cell carcinomas of the anal canal: A National Cancer Database study.
Authors: Prasad Rahul Neal , Elson Joshua , Kharofa Jordan
Published: January 2019

791

Background: Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (T3/T4) continue to have high rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to improve local control for large tumors. Methods: The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004-2013 with tumors > 5 cm in size. Adult patients with T3 or T4 squamous cell carcinoma who received definitive chemoradiation were included. Patients with prior resection were excluded. Higher dose was defined as > than or equal to 5940 Gy. Statistical analyses were performed using logistic regression, Kaplan-Meier, and Cox proportional hazards for overall survival (OS). Results: In total, 1349 patients were analyzed with 412 (30.5%) receiving higher dose radiation therapy (RT). Dose in the higher group ranged from 5940 – 7000 Gy. 5-year OS was 58% and 60% for higher and lower dose RT, respectively. On univariate analysis, higher dose RT (HR 0.998, CI 0.805 - 1.239, p = 0.9887) was not associated with a change in OS but older age (HR 1.484, CI 1.193 - 1.844, p = 0.0004), male sex (HR 1.660, CI 1.355 - 2.033, p < 0.0001), comorbidities (HR 1.496, CI 1.183 - 1.893, p = 0.0008), and long RT (HR 1.248, CI 1.016 - 1.533, p = 0.0347) were significantly associated with decreased OS. The results of multivariate analysis are shown in the Table. Conclusions: There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis, but differences in local control cannot be assessed through the NCDB. Males, elderly, and comorbid patients were particularly high-risk populations with poor chemoradiation survival outcomes. Reducing treatment breaks is important for improving outcomes. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials. [Table: see text]