bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of bevacizumab-based treatment in early-onset treatment-naïve metastatic colorectal cancer patients: An ARCAD database analysis.
Authors: Jin Zhaohui , Dixon Jesse G. , Hubbard Joleen M. , Eng Cathy , Lieu Christopher Hanyoung , Fiskum Jack , Saltz Leonard B. , Hurwitz Herbert I. , Venook Alan P. , Schmoll Hans-Joachim , Fuchs Charles S. , Hecht J. Randolph Randolph , Cremolini Chiara , Diaz-Rubio Eduardo , Punt Cornelis J. A. , Tebbutt Niall C. , Heinemann Volker , Yoshino Takayuki , De Gramont Aimery , Shi Qian 
Published: January 2022

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p<0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p<0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p<0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p<0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]
Temsirolimus (T) in patients (pts) with colorectal cancer (CRC) with PIK3CA mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Grem Jean L. , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Khalil Maged F. , Rogosin Shane O. , Salmon John Stuart , Cannon Timothy Lewis , Grantham Gina N. , Halabi Susan , Schilsky Richard L. 
Published: January 2022

106 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with PIK3CA mutation treated with T are reported. Methods: Eligible pts had advanced CRC with PIK3CA mutation reported by a genomic test performed in a CLIA-certified, CAP-accredited site selected lab, no standard treatment options, measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Use of T was approved by the TAPUR Molecular Tumor Board in each case. After antihistamine pre-treatment, T was administered at 25 mg IV over 30-60 minutes weekly until disease progression. Primary endpoint was disease control (DC), defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease at 16+ weeks (SD 16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, the study stops for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 10 pts (60% male) with CRC with PIK3CA mutation were enrolled from November 2017 to May 2020. All were eligible for efficacy and toxicity. Demographics and outcomes are summarized in Table. No objective responses (OR) were observed. 1 pt had SD of 16.1 wks duration for a DC rate of 10% (95% CI: 0%, 45%); the null DC rate of 15% was not rejected (p=0.80). 6 pts had at least one grade 3-4 adverse or serious adverse event (AE/SAE) at least possibly related to T, including acute kidney injury, dehydration, decreased platelet count hypertriglyceridemia, mucositis, neutropenia, and scrotal and penile edema. Conclusions: Monotherapy T does not have sufficient clinical activity in CRC pts with PIK3CA mutation for continued evaluation in this pt population. Other treatments should be considered for these pts, including treatments offered in clinical trials. Clinical trial information: NCT02693535. [Table: see text]
Modified FOLFIRINOX (mFOLFIRINOX) in high risk locally advanced rectal adenocarcinomas.
Authors: Prajapati Ramjas , Srinivas Sujay , Ostwal Vikas S , Bhargava Prabhat Ghanshyam , Engineer Reena , Krishnatry Rahul , Peelay Zoya , Desouza Ashwin Luis , Saklani Avanish , Ankathi Suman Kumar , Parulekar Manali , Ramaswamy Anant 
Published: January 2022

108 Background: There is limited data with regard to the use of modified 5-fluoroural-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX) in enabling resection and increasing survival of locally advanced rectal adenocarcinomas (LARC) with high-risk characteristics (T4b status, signet ring histology, etc.) post standard neoadjuvant long course chemoradiation (NACTRT) or short course radiation (SCRT) and chemotherapy. Methods: Patients with LARC from January 2018 to December 2020 receiving mFOLFIRINOX (5-Fluorouracil - 1800mg/m2 over 46 hours, Leucovorin 300mg, Irinotecan 135mg/m2, oxaliplatin 65mg/m2) post NACTRT/SCRT to facilitate curative local resection were evaluated. The primary endpoint was event free survival (EFS), where event was defined as disease progression or recurrence post resection after mFOLFIRINOX. Survivals were calculated using Kaplan-Meier analysis. Results: Forty-seven patients were evaluated with a median age of 33 years (Range:18-59), 45% T4b status, 94% radiological circumferential margin (CRM) involved (79% CRM positive post NACTRT/SCRT), 43% extramural venous invasion (n=33) and 36% signet ring histology. 62% had received prior NACTRT and 38% had received SCRT with chemotherapy before receiving mFOLFIRINOX. The most common grade 3 and grade 4 treatment related side effects included diarrhoea (7%), anaemia (4%) and infections (4%). Intended duration of mFOLFIRINOX or beyond was completed in 94% of patients. 60% of patients underwent curative local resection with R0 resection rates of 100% (n=28) and pathological complete response rates of 21%. The most common surgeries done were exenterations and abdominoperineal resections in 22% and 17% patients respectively. With a median follow up of 19 months, 25 patients had recurred or progressed for a median EFS of 20 months [95% confidence interval (CI): 15-24] while median overall survival was 55 months (95% CI: 24-86). Conclusions: Locally advanced rectal cancers with high-risk characteristics are a niche group of cancers with less-than-optimal outcomes post standard neoadjuvant strategies. mFOLFIRINOX appears to be well tolerated in this cohort of patients and enables conversion to curative local resection and potentially improves survival as well.
Perioperative and oncologic outcomes of hepatic artery infusion pump therapy at an expanding HAI program.
Authors: Sharib Jeremy , Liu Annie , Creasy John , Wildman-Tobriner Benjamin , Uronis Hope Elizabeth , Strickler John H. , Hsu David S. , Zani Sabino , Allen Peter J , Lidsky Michael 
Published: January 2022

120 Background: Hepatic artery infusion (HAI) is a liver directed therapy to treat unresectable or resected colorectal liver metastases (CRLM) and unresectable intrahepatic cholangiocarcinoma (ICC). Historically, HAI has only been performed at few specialized centers; however, there is increasing expansion to new centers. We previously reported safety outcomes of our index year of HAI therapy. We now report safety, feasibility, efficacy and oncologic outcomes for an expanded cohort of 62 patients in an established HAI program. Methods: Patients selected for HAI by multidisciplinary review were evaluated for demographics and perioperative outcomes. Objective hepatic response was calculated according to RECIST 1.1. Overall, hepatic and extrahepatic progression-free survival (PFS) were calculated by the Kaplan-Meier method on an intent-to-treat basis. Results: 62 patients were treated with HAI from November 2018-September 2021: 46 for unresectable CRLM, 8 as adjuvant HAI for resected CRLM, and 8 for unresectable ICC. Median age was 54.5 years (range 32-80), 58% were male, and 97% received prior chemotherapy (median 12 cycles, range 0-66). Hepatectomy (18, 29%) and/or colectomy/proctectomy (27, 43.5%) was performed concurrently with pump placement, and 19 (30.6%) were performed robotically. Median operating time was 265 minutes (range 130-526), estimated blood loss was 100 mL (range 22-1000) and length of stay was 5 days (range 1-19). HAI-specific complications occurred in 14% (Table). Floxuridine (FUDR) was initiated in 95% of patients a median of 18.5 days after surgery. Of the 38 patients who received HAI for unresectable CRLM and had measurable disease on imaging, 3- and 6-month hepatic disease control was achieved in 86% (8 partial response [PR], 22 stable disease [SD], 5 progressed [PD]) and 89% (1 complete response, 8 PR, 8 SD, 2 PD), respectively. For patients with at least 3 months follow-up, median PFS, hepatic PFS and extrahepatic PFS were 13 months, 13 months, and 13 months, respectively. Conclusions: HAI can be safely and effectively delivered to well-selected patients with CRLM and ICC. Response rates, disease control and PFS in heavily treated patients with unresectable CRLM comparable to high-volume centers can be achieved at new programs with appropriate expertise. These data support the mission of the newly formed HAI Consortium to critically evaluate efficacy and innovation in HAI therapy through multi-institutional collaboration and contemporary prospective trials.[Table: see text]
Efficacy of retreatment with oxaliplatin-based regimens in metastatic colorectal cancer patients: The RETROX-CRC retrospective study.
Authors: Mauri Gianluca , Amatu Alessio , Tosi Federica , Bencardino Katia , Bonazzina Erica , Gori Viviana , Ruggieri Lorenzo , Arena Sabrina , Bardelli Alberto , Marsoni Silvia , Siena Salvatore , Sartore-Bianchi Andrea 
Published: January 2022

127 Background: Oxaliplatin in association with fluoropyrimidines is universally considered one of the most effective drugs for colorectal cancer and the mainstay of front-line treatment of metastatic patients. In contrast the efficacy and safety profile of oxaliplatin based regimens in the late-care treatment space have been poorly and conflictingly reported. Methods: We identified a real-world cohort of metastatic colorectal cancer (mCRC) patients undergoing repeated oxaliplatin treatments in a single institution and retrospectively analysed their clinicopathological features to identify potential efficacy-predictive determinants of oxaliplatin response at retreatment (RETROX-CRC Study). Results: Out of 2,606 consecutive mCRC patients referred to Niguarda Cancer Center, 119 fulfilled the eligibility criteria of the study. The response rate (RR) and the disease control rate (DCR) after oxaliplatin retreatments were respectively 21.6% (95% CI 14.4-31.0%), and 57.8% (95% CI 47.7-67.4). A trend towards better RR and DCR was observed among patients who were exposed to oxaliplatin in the adjuvant setting, while a significantly poorer outcome was observed when two or more intervening treatments were delivered in between oxaliplatin exposures. Median progression-free survival (PFS) was 5.1 months (95% CI 4.3-6.1), significantly lower if oxaliplatin was re-administered beyond the third line (HR 2.02; 1.25-3.25; p=0.004). Safety data were reliably retrieved in 65 patients (54,6%). Of these 18.5% (12/65) and 7.7% (5/65) of them had G3-4 toxicities. Overall, toxicity was the cause of treatment discontinuation in almost a third of cases (28.6%; 34/119), with hypersensitivity reactions as the most prevalent reason for stopping treatment (58.8%; 20/34). Conclusions: In this large real-world series of 2,606 mCRC patients, less than 5% were re-treated with oxaliplatin. A late-disease control was achieved in almost 60% of patients, with a clinically acceptable sustained PFS and safety. Given the low performance of current standard drugs in late care of mCRC, retreatment with oxaliplatin might be considered a viable alternative especially if hopefully biology-based predictive markers for improving patient selection could be found.
Improved organ preservation with dose escalation using contact X-ray brachytherapy for good responders following external beam chemoradiotherapy: Long-term outcomes from a single institution.
Authors: Sun Myint Arthur , Rao Christopher , Dhadda Amandeep Singh , Wong Helen , Hershman Michael , Sripadam Rajaram , Pritchard Mark 
Published: January 2022

131 Background: We previously reported the benefit of Contact X-ray Brachytherapy boost (CXB) in achieving a higher clinical complete response (cCR) following partial response to external beam chemoradiotherapy (EBCRT). We now update our report on the organ preservation rate and long-term durability of the cCR in this cohort. Methods: Outcome data for rectal cancer patients referred to our institution from 2003 to 2012 were retrieved from an institutional database after an audit approval. These patients were referred after initial local multidisciplinary team discussion. All patients had EBCRT 45Gy/25/5 weeks with capecitabine 825mg/m2 (Mon-Fri). Those who respond well but has a small residual tumour were offered CXB boost of 90Gy in 3 fractions over 4-6 weeks as they were not suitable or unwilling to undergo completion surgery. Following treatment, patients had close 3 monthly follow-ups with DRE, endoscopy, and MRI in the first 2 years, then 6 monthly up to 5 years. Results: Of 345 consecutive patients with rectal cancer referred to us, 83 patients who responded well to EBCRT but with small suspicious residual disease (≤3 cm) were offered CXB boost. Median age was 72 years (range 36–87) and 58 (69.9%) were males. Initial MRI tumor stages were cT2 (n = 28), cT3 (n = 55) and 54.2% were node positive. The median follow up of surviving patients was 6.4 years (range 2-11 years). cCR was achieved after CXB boost in 53/83 (64%). After achieving cCR, 8/53 (15%) developed local regrowth. However, all patients successfully underwent curative surgery with R(0) resection rate of 24/30 (80%) and only 21/83 (25%) had stoma. Organ preservation was achieved in 62/83 (75%). 12/53 (14%) patients developed metastatic disease. At the end of the study period, 64/83(77%) were cancer free. Conclusions: Our long-term data suggests dose escalation with CXB boost following EBCRT can achieved high organ preservation rate with excellent long-term durable cCR. This approach can provide an alternative treatment option for elderly or comorbid patient patients who are not suitable for surgery. This can also be an option for some patients who wish to avoid surgery upfront after initial diagnosis. Those who needed surgery later for treatment failure can be salvage successfully. A phase 3 European randomised trial OPERA (Organ Preservation in Early Rectal Adenocarcinoma) was set up to evaluate this concept further.
Evaluation of efficacy and tolerance of radical radiotherapy and radiochemotherapy in treatment of locally advanced, unresectable rectal cancer.
Authors: Kraszkiewicz Małgorzata , Napieralska Aleksandra , Wydmanski Jerzy , Majewski Wojciech 
Published: January 2022

133 Background: Evaluation of tolerance and efficacy of two schemes of neoadjuvant treatment in patients with unresectable rectal cancer: radiochemotherapy and radiotherapy, including conventional and accelerated hyperfractionation. Methods: 145 patients (pts) with unresectable, locally advanced rectal cancer. Schemes used: radiotherapy (RT) in 73 (50%) or radiochemotherapy (CRT) in 72 (50%). In RT group conventional fractionation (CFRT) and hyperfractionated accelerated radiotherapy (HART). In CRT 54 Gy in 1.8 Gy fractions was given with two cycles of 5 Fu-LV chemotherapy in three or five day cycles. Results: Objective response (OR) in RT and CRT group was 60% versus 75%. Resection rate (RR) in RT and CRT: 37% versus 65%. Tumor mobility and laparotomy-based unresectability were significant factors for OR. Performance status, tumor mobility, neoadjuvant treatment method were significant for RR. Five-year LC in CRT versus RT: 68% versus 37%. Five-year OS: 52% versus 27%. CRT was independent positive prognostic factor for resection rate, local control. Tumor volume did not reach significance for any of the end points. Lenght of chemotherapy cycles (three or five days) did not reach significance for any of the endpoints. Toxicity was acceptable in both groups. CRT had best outcome in LC: 68% versus 42% in HART; and 25% in CFRT. Five-year OS was much better in CRT than in CFRT: 52% versus 17%. Conclusions: The results of treatment depend on performance status, patients age, tumor mobility and unresectability based on earlier laparotomy. The lack of influence of the tumor volume on all endpoints indicates the need for radical neoadjuvant treatment independently of tumor volume and underlines the key role of a proper surgical treatment. In patients not suitable for CRT, HART is optimal strategy for its better efficacy than CFRT.
High-risk gene expression in colorectal liver metastasis: Potential for novel therapies.
Authors: Medin Caroline , Turgeon Michael K. , Keilson Jessica M. , Dwivedi Bhakti , Herting Cameron , Maithel Shishir K. , Lesinski Gregory B. 
Published: January 2022

147 Background: Over half of patients with colorectal cancer (CRC) develop liver metastases. While immunotherapy is an emerging treatment of solid tumors, its use among CRC patients is limited. Furthermore, gene expression patterns of liver-specific CRC metastases remain unclear. The purpose of this study was to identify a high-risk gene expression profile for patients with colorectal liver metastasis (CRLM) to better inform prognosis and development of novel targeted therapies. Methods: Fifty-three FFPE CRLM samples from patients who underwent complete metastatectomy from 2009-2017 were examined. Expression profiling of extracted RNA was performed using NanoString Immuno-Oncology (IO360) 750-gene panel. Statistical analyses using cutoffs of absolute log 2-fold change≥1.5 and p-value≤0.05 were performed. Patients were analyzed by extremes of outcomes: survival time in the lowest quartile compared to those still alive at last follow-up. Results: Eight differentially expressed genes were associated with poor survival. Overexpressed genes included IL6R, CXCL2, C7, MGMT, PCK2, CSF1 and LILRB4 (Table). PLA2G2A was under-expressed. Conclusions: This study demonstrates differential gene expression associated with poor survival among patients with CRLM. Specific genes of interest include IL6R, MGMT, CSF1 and LILRB4. IL6R is a known effector in tumor proliferation via IL-6 signaling from tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs) and T-cells. MGMT repairs alkylating DNA damage and is implicated in carcinogenesis and response to chemotherapy. CSF1 promotes macrophage differentiation to M2 phenotype, suppressing inflammation and anti-tumor defense mechanisms. LILRB4 activation via MDSCs leads to T-cell inhibition. These overall suggest a myeloid-dominant tumor immune microenvironment and represent important potential therapeutic targets. Next steps include performing immunohistochemistry to validate findings at the protein level and investigate the tumor intrinsic role using human cell lines.[Table: see text]
The association between tumour sidedness, clinicopathological characteristics and outcomes in patients undergoing curative resection for colon cancer.
Authors: Golder Allan Matthew , Pennel Kathryn AF , Mansouri David , Horgan Paul G. , Roxburgh Campbell SD , Biankin Andrew V , Edwards Joanne , McMillan Donald C. 
Published: January 2022

148 Background: Right-sided colon cancer is associated with worse outcomes than left-sided disease, likely due to an association between tumour/host factors and tumour sidedness. The present study analyses the association between tumour sidedness, clinicopathological features and common mutations to better understand this discrepancy in outcomes. Methods: The association between tumour sidedness, clinicopathological characteristics and survival was examined within a cohort of patients undergoing curative surgery for TNM I-III colon cancer. Results: 3,419 patients were identified. 54% of cases were right-sided and associated with worse 3-year OS/CSS. On multivariate analysis for clinical factors: sex (OR 0.63), Systemic Inflammatory Grade (SIG), anaemia and differentiation (OR 0.80/0.31/0.57) were associated with T3 cancer sidedness and: sex, anaemia and differentiation (OR 0.61/0.46/0.57) were associated with T4 cancer sidedness. On further MVA including mutational factors anaemia/BRAF status remained significant in T3/T4 cancer respectively (OR 0.08/0.09). BRAF mutant status was associated with SIG in all patients/T3 disease (p=0.046/0.016). Conclusions: Worse outcomes seen in right-sided colon cancer are likely explained predominantly by factors including tumour stage, SIG, anaemia and BRAF mutational status. BRAF mutations are associated with the Systemic Inflammatory Response and further research is required to better understand this relationship taking into the tumour microenvironment, microsatellite instability.[Table: see text]