Clinical Colorectal Cancer

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ISSN / EISSN : 1533-0028 / 1938-0674
Published by: Elsevier BV (10.1016)
Total articles ≅ 1,369
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Kanan Alshammari, Kyaw L. Aung, Tong Zhang, Albiruni R.A. Razak, Stefano Serra, Tracy Stockley, Lisa Wang, Jessica Nguyen, Anna Spreafico, Aaron R. Hansen, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.004

Abstract:
Introduction: MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial. Methods: Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5mg oral daily and panitumumab 4.8mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) were collected and profiled using Oncomine Lung cfDNA assay. Results: Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression. Conclusion: The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.
, Giampiero Porzio, Katia Cannita, Olga Venditti, Antonio Avallone, Roberto Filippi, Lisa Salvatore, Giampaolo Tortora, Marta Ribelli, Olga Nigro, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.003

Abstract:
Background : Doublets plus anti-epidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. Methods : This multicentre, retrospective study is aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in left-sided RAS/BRAF wild-type mCRC patients treated in clinical practice in 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. Results : A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95%CI: 8.9 – 31.7) and 16.1 (95%CI: 12.1 – 36.8) months (p = 0.621), while median OS was 30.2 (95%CI: 14.4 – 69.5) and 38.1 (95%CI: 33.1 – 101.1) months (p = 0.0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (p = 0.016), while the secondary resection rate was 18.8% and 46.9% (p = 0.016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs 12.5%, p = 0.041). Conclusion : Although a doublet-EGFRi remains the recommended upfront regimen in left-sided RAS and BRAF wild-type mCRC patients, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.
, , Pina Ziranu, Chiara Cremolini, , Maria Banzi, Stefano Mariani, Nicole Liscia, Saverio Cinieri, Manuela Dettori, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.008

Caroline Vandeputte, Giacomo Bregni, Paraskevas Gkolfakis, , , Pashalina Kehagias, Chiara Senti, Elena Acedo Reina, Camille Van Bogaert, Amélie Deleporte, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.006

Abstract:
Background Regorafenib is a standard treatment for refractory metastatic colorectal cancer (mCRC). In view of the toxicity burden, significant research efforts have been made to increase the therapeutic ratio of this multikinase inhibitor. Predictive factors for treatment-related adverse events (TRAEs), however, are still lacking. Materials & Methods We assessed the association between a number of baseline clinical, laboratory and imaging parameters and the occurrence of TRAEs in 136 patients who had received regorafenib (160 mg/day, 3-weeks-on/1-week-off) in a prospective phase II clinical trial. Results Grade ≥2 TRAEs during the first cycle of treatment (84% vs 60%, p=0.002) and grade ≥3 TRAEs throughout the whole treatment (71% vs 53%, p=0.035) occurred more frequently in females, with sex being the only independent predictive factor of early and any-time toxicity (OR 3.4; 95% CI: 1.2-11.1, p=0.02 and OR 2.1; 95% CI: 1.0-4.4, p=0.045, respectively). Fatigue, anorexia, hypertension, and rash were reported significantly more frequently by females than males (p<0.04). Females were also more likely to suffer early (19% vs 5%, p=0.014) and any-time serious AEs (28% vs 9%, p=0.005), and to require early dose modifications (55% vs 37%, p=0.055). Conclusion This is the first study showing an association between sex and TRAEs during regorafenib treatment for mCRC. If confirmed in larger, independent series, these results could pave the way for the implementation of personalized regorafenib dosing strategies with the potential to optimize oncological outcomes while reducing toxicity and preserving quality of life.
L.P Guerrera, S Napolitano, V De Falco, , , , G Suarato, A Perrone, E Martinelli, F Ciardiello, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.005

Abstract:
Primary resistance is defined by the presence of activating mutations in BRAF and RAS genes before treatment initiation, while acquired resistance refers to the selection of pre-existing mutant clones or de novo acquisition of mutations under the pressure of anti EGFR treatment.•Testing mutations in RAS and BRAF genes as predictive biomarkers is mandatory.•Liquid biopsy has acquired growing importance and showed to be reliable when compared to tissue NGS.•Liquid biopsy offers a full overview of the genetic landscape of the disease, overcoming spatial and temporal heterogeneity, when compared to tissue biopsy.•Liquid biopsy can be used to capture the changes in biology of cancer cells under the selective pressure of targeted agents over time.•Using complementary techniques allows to increase the diagnostic power and the biological significance of the results.
Roberto Moretto, Daniele Rossini, , , Federica Perrone, Elena Tamborini, , Carlotta Antoniotti, Federica Marmorino, Veronica Conca, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.001

Abstract:
Background: A recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab +/- irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients. Patients and Methods: PARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety. Aim of the study: The aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.
, Babette I. Kuiper, Laurien M. Buffart, Martijn R. Meijerink, , Rutger-Jan Swijnenburg, Otto M. van Delden, , Jan J.J. de Vries, Jan Hein T.M. van Waesberghe, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.07.007

Abstract:
Background A uniform treatment strategy for patients suffering from early recurrence after local treatment of colorectal cancer liver metastases (CRLM) is currently lacking. The aim of this observational cohort study was to assess the potential survival benefit of repeat local treatment compared to systemic therapy in patients suffering from early recurrence of CRLM. Patients and Methods Patients who developed recurrent CRLM within twelve months after initial local treatment with curative intent were retrospectively identified in Amsterdam University Medical Centers between 2009-2019. Differences in overall and progression-free survival among treatment strategies were assessed using multivariable Cox regression analyses. Results A total of 135 patients were included. Median overall survival of 41 months [range 4 - 135] was observed in patients who received repeat local treatment, consisting of upfront or repeat local treatment after neoadjuvant systemic therapy, compared to 24 months [range 1 - 55] in patients subjected to systemic therapy alone (adjusted HR = 0.42 [95%-CI: 0.25 – 0.72]; p = 0.002). Prolonged progression-free survival was observed after neoadjuvant systemic therapy followed by repeat local treatment, as compared to upfront repeat local treatment in patients with recurrent CRLM within four months following initial local treatment of CRLM (adjusted HR = 0.36 [95%-CI: 0.15 – 0.86]; p = 0.021). Conclusion Patients with early recurrence of CRLM should be considered for repeat local treatment strategies. A multimodality approach, consisting of neoadjuvant systemic therapy followed by repeat local treatment, appeared favorable in patients with recurrence within four months following initial local treatment of CRLM. MicroAbstract Repeat local treatment should be considered in patients suffering from early recurrence of CRLM. A multimodality approach, consisting of neoadjuvant systemic therapy followed by repeat local treatment of CRLM, appeared favorable in patients with recurrence within four months. The optimal sequence and the role of systemic therapy in patient selection should be further clarified in prospective studies.
Published: 1 July 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.06.005

Abstract:
The standard treatment of locally advanced rectal cancer (LARC) comprises neoadjuvant chemoradiation followed by total mesorectal excision. This strategy provides low local recurrence rate, however distant recurrence is still an issue and may impact on survival rates. Novel approaches in the neoadjuvant setting have been tested to improve early and late outcomes, as well as to reduce treatment-related toxicity and morbidity. In this review, we discuss the current literature of neoadjuvant treatment in LARC, including total neoadjuvant methods, protocols for radiation delivery, chemotherapy regimen and efforts to add novel targeted therapies, selective withdrawal of surgery or radiotherapy, and future perspectives. Moreover, we highlight relevant issues that have emerged with these new treatment possibilities.
, Xiaoyu Xie, Zehua Wu, Huabin Hu, Yue Cai, Jianxia Li, Jiayu Ling, Miaomiao Ding, Weiwei Li,
Published: 1 June 2021
Clinical Colorectal Cancer; doi:10.1016/j.clcc.2021.06.004

Abstract:
Purpose To evaluate the predictive implications and prognosis of mucinous adenocarcinoma (MAC) in locally advanced rectal cancer (LARC) with intensified neoadjuvant treatment. Methods Individual patient data of LARC patients from 3 prospective clinical trials was analyzed. Neoadjuvant treatment regimens comprised chemoradiotherapy (CRT) with fluorouracil (5-FU) or mFOLFOX6, neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI. The postoperative pathological result, local recurrence and disease-free survival (DFS) were retrospectively analyzed in patients with MAC and adenocarcinoma (AC) with neoadjuvant treatment. Results Totally, 743 patients were recruited, with 620 patients eligible for analysis. Fifty-three (8.5%) patients were MAC. The pathological complete response (pCR) rate and tumor downstaging rate (ypStage 0-I) between MAC and AC patients was 7.5% vs. 22.0% (P = 0.01) and 20.8% vs. 48.7% (P< 0.001), respectively. Among patients receiving preoperative CRT with 5FU or mFOLFOX6, the pCR rate and tumor downstaging rate between MAC and AC patients was 11.1% vs. 27.3% (P=0.03) and 23.7% vs. 52.6% (P=0.001), respectively. Regarding neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI, the pCR rate and tumor downstaging rate was 0 vs.13.2% (P=0.11) and 11.8% vs. 42.5% (P=0.03) between MAC and AC group, respectively. With the median follow-up time of 38.9 months, the 3-year DFS and 3-year locoregional recurrence rate was 58.4% vs. 77.6% (P=0.02) and 26.0% vs. 5.7% (P=0.001) in the MAC and AC group, respectively. MAC (HR 1.85, 95% CI, 1.15-2.98), PNI (HR 3.23, 95% CI, 1.85-5.72) and LVI (HR 2.04, 95% CI, 1.02-4.08) were independent prognosis factors and were associated with worse DFS. Conclusions Patients with MAC of the rectum are associated with a lower pCR rate and tumor downstaging rate, higher incidence of local recurrence and poorer DFS with neoadjuvant treatment. Minor Abstract The predictive implication and prognosis of Mucinous adenocarcinoma (MAC) in locally advanced rectal cancer (LARC) with intensified neoadjuvant treatment strategies from 3 prospective clinical trials had been explored. The pathological complete response (pCR) rate and tumor downstaging rate (ypStage 0-I) between MAC and adenocarcinoma (AC) patients was 7.5% vs. 22.0% (P = 0.01) and 20.8% vs. 48.7% (P< 0.001), respectively. The 3-year disease-free survival (DFS) and 3-year locoregional recurrence rate was 58.4% vs. 77.6% (P=0.02) and 26.0% vs. 5.7% (P=0.001) in the MAC and AC group, respectively. MAC was a poor prognostic factor in LARC with neoadjuvant treatment.
Published: 1 June 2021
Clinical Colorectal Cancer, Volume 20; doi:10.1016/s1533-0028(21)00042-6

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