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, Anke Reinacher-Schick, Jürgen Weitz, Celine Lugnier, Anna-Lena Kraeft, Sarah Wisser, Daniela E. Aust, , Nikolas V Bubnoff, Michael Kramer, et al.
Published: 14 September 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.09.005

Abstract:
Background : Guidance regarding adjuvant treatment decisions in stage II colorectal cancer (CRC) remains uncertain due to lack of predictive clinical or molecular markers. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be a strong prognostic marker in early colon cancer. Patients and Methods : CIRCULATE enrols patients with stage II microsatellite stable CRC in Germany (AIO) and Austria (ABCSG). Within the AIO, screening is supported by ColoPredict Plus 2.0, a molecular registry and screening platform for interventional trials. Patient-specific mutations are centrally analysed by next generation sequencing in the resected primary tumour. A postoperative plasma sample subsequently screened for the specific mutation(s). ctDNA positive (ctDNApos) patients are randomised (1:2) to control (follow up) or chemotherapy (capecitabine, oxaliplatin added a investigator's choice). ctDNA negative (ctDNAneg) patients are randomised (1:4) to be followed-up within CIRCULATE (control group) or outside the trial. Patients in the control group remain blinded to the ctDNA results. The primary objective is to compare disease free survival (DFS) of ctDNApos patients with chemotherapy or control. To demonstrate a treatment effect with a hazard ratio of 0.617 (3 year DFS rates 42.5 % vs. 25 %), 231 ctDNApos and estimated 2079 ctDNAneg patients are randomised. Secondary aims include to compare overall survival and DFS in the ctDNApos and ctDNAneg patient cohorts and ctDNA kinetics. Conclusion : The CIRCULATE trial may establish ctDNA for adjuvant treatment decision in stage II colon cancer – and with the secondary objectives – support a ctDNA guided follow up in colon cancer stage II and beyond. Micro Abstract Circulating tumour DNA (ctDNA) is a prognostic biomarker of recurrence in patients with early stage and resected colorectal cancer. The CIRCULATE study evaluates the predictive value of ctDNA with respect to adjuvant treatment in colon cancer stage II. In total, 231 patients with detectable ctDNA (ctDNApos) post resection are randomised 2:1 to chemotherapy or to control (follow-up). Patients without detectable ctDNA (approx. 2079 patients) are randomized 1:4 into control or off-study. The primary endpoint is the disease free survival.
, Brunella Di Stefano, Michele Basso, Carmine Carbone, Floriana Camarda, Marta Ribelli, Annunziato Anghelone, Raffaella Vivolo, Maria Bensi, Maurizio Martini, et al.
Published: 14 September 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.09.002

Jeroen F. Schouten, Jeroen Willems, Stefan J.W.J. Sanders, Geert-Jan Creemers,
Published: 14 September 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.09.004

Abstract:
5-fluorouracil (5-FU) and its oral prodrug capecitabine belong to the group of the fluoropyrimidines and are among the most commonly applied anticancer drugs. More than 85% of 5-FU is inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). Thereby, DPD-deficient patients are at strongly increased risk for severe, life-threatening 5-FU-induced toxicity. Nowadays, pre-treatment screening for DPD-deficiency is becoming more commonly routinely applied. However, unlike DPYD genotype-guided dosing, dosing based on DPD phenotype remains largely uninvestigated. Plus, despite initial dose reduction in DPD-deficient patients, severe toxicity may still occur. New treatment options are therefore warranted. Trifluridine/tipiracil is a new anticancer drug registered for the treatment of metastatic colorectal cancer. Interestingly, in contrast to 5-FU, its pharmacokinetic pathway is completely independent of DPD. Thereby, trifluridine/tipiracil may offer a new treatment paradigm for the safe treatment of DPD-deficient colorectal cancer patients. Following a cohort-based search strategy, we identified six consecutive metastatic colorectal cancer patients with a genetically proven DPD deficiency and treated with standard-dose trifluridine/tipiracil. Treatment in all patients was generally well-tolerated and none of the patients developed grade ≥3 gastro-intestinal or hematological toxicity requiring any dose reductions. Thereby, assuming comparable efficacy, trifluridine/tipiracil may offer a new and safe treatment alternative for DPD-deficient metastatic colorectal cancer patients.
, 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: 25 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
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: 24 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
L.P Guerrera, S Napolitano, V De Falco, , , , G Suarato, A Perrone, E Martinelli, F Ciardiello, et al.
Published: 24 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
Caroline Vandeputte, Giacomo Bregni, Paraskevas Gkolfakis, , , Pashalina Kehagias, Chiara Senti, Elena Acedo Reina, Camille Van Bogaert, Amélie Deleporte, et al.
Published: 24 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
, Giampiero Porzio, Katia Cannita, Olga Venditti, , Roberto Filippi, Lisa Salvatore, Giampaolo Tortora, Marta Ribelli, Olga Nigro, et al.
Published: 18 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
Roberto Moretto, Daniele Rossini, , , Federica Perrone, Elena Tamborini, , Carlotta Antoniotti, Federica Marmorino, Veronica Conca, et al.
Published: 10 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
Published: 7 July 2021
Clinical Colorectal Cancer; https://doi.org/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.
, , Pina Ziranu, Chiara Cremolini, , Maria Banzi, Stefano Mariani, Nicole Liscia, Saverio Cinieri, Manuela Dettori, et al.
Published: 1 July 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.07.008

Abstract:
Background Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. Patients and Methods REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥6months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). Results 100 regorafenib-treated mCRC patients with OS≥6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95%CI:3.43-43.03). The absence of liver progression and of dose/schedule changes during the first four cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, p=0.0277and Exp(b)2.2000, p=0.0313) and PFS (Exp(b)2.1583, p=0.0065 and Exp(b)2.3036, p=0.0169). Patients with neither of these variables had a significantly improved OS (n=14, 20.8 months; 95%CI:12.967–55.267) versus others (n=86, 10 months; 95%CI:8.367–12.167; HR=0.4902, p=0.0045) and PFS (11.3 months, 95%CI:4.267–35.8 versus 3.9 months, 95%CI:3.167–43.033; HR=0.4648, p=0.0086). Conclusion These two factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial. Micro abstract The REALITY trial aimed to assess the association between clinical parameters and outcome, to define a panel identify long-term metastatic colorectal cancer survivors among regorafenib candidates. 100 regorafenib-treated patients with OS≥6 months were enrolled; absence of liver progression+treatment modifications led to improved OS (Δ10.8 months; p=0.0045) and PFS (Δ7.4 months, p=0.0086). These results might improve patient selection in clinical practice.
, Xiaoyu Xie, Zehua Wu, Huabin Hu, Yue Cai, Jianxia Li, Jiayu Ling, Miaomiao Ding, Weiwei Li,
Published: 26 June 2021
Clinical Colorectal Cancer; https://doi.org/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.
, Soe Yu Aung, Vanessa Wong, Catherine Dunn, Jeremy Shapiro, Azim Jalali, Rachel Wong, Margaret Lee, , Sumitra Ananda, et al.
Published: 24 June 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.06.003

Abstract:
Introduction: The optimal management of isolated distant lymph node metastases (IDLNM) from a colorectal primary, is not clearly established. We aimed to analyse the outcomes of patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Materials & Methods: Clinical data were collected and reviewed from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry, a prospective, comprehensive registry for metastatic colorectal cancer (mCRC) treated at multiple tertiary hospitals across Australia. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with disease at other sites. Results: Of 3408 mCRC patients diagnosed 2009-2020, with median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC at other sites, patients with IDLNM were younger (mean age: 62.1 vs 65.6 years, p=0.02), more likely to have metachronous disease (57.0% vs 38.9%, P <0.01), be KRAS wild-type (74.6% vs 53.9%, p<0.01) and BRAF mutant (12.9% vs 6.2%, P=0.01). Amongst mCRC patients with IDLNM, 24 (25.8%) received treatment with curative intent and had a significantly better overall median survival than those treated with palliative intent (73.5 months vs 23.2 months, P=0.01). These 24 patients had an overall median survival similar (62.7 months, P=0.82) to patients with isolated liver or lung metastases also treated with curative intent. Conclusion: Curative treatment strategies (radiotherapy or surgery), with or without systemic therapy, should be considered for mCRC patients with IDLNM where appropriate as assessed by the multidisciplinary team.
, P. Marks, J. Chapman, B. Miller, S. Baijal
Published: 10 June 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.06.001

Abstract:
Lynch syndrome, the most common hereditary colorectal cancer condition, is an autosomal dominant disease caused by a germline mutation in mismatch repair genes. Patients with Lynch syndrome are predisposed to multiple malignancies, mainly colorectal and endometrial cancers. Here we report a case of a 57 year old male patient with a known family history of Lynch syndrome, who developed a squamous cell carcinoma arising from an ileo-colic anastomosis on the background of a previously resected adenocarcinoma of the ascending colon. Pathological analysis of both tumours confirmed the loss of MLH1 and PMS2 with normal expression of MSH2 and MSH6 and no evidence of methylation of the MLH1 promotor. While Lynch syndrome is strongly associated with colorectal adenocarcinoma, the development of a squamous cell carcinoma of the bowel in this context is a rare occurrence with only one case previously reported in the literature. As patients with Lynch syndrome are predisposed to a spectrum of cancers, unusual presentations and rare histological subtypes may emerge. This case illustrates the importance of continued surveillance and repeat pathological analysis. It also highlights the need to offer such patients individualized treatment based on tumour biomarker status rather than histology.
Pasquale Vitale, Nicoletta Zanaletti, Vincenzo Famiglietti, , Andres Cervantes, , Elisabetta Fenocchio, Michela Milanesio, Pasquale Lombardi, Davide Ciardiello, et al.
Published: 9 June 2021
Clinical Colorectal Cancer, Volume 20, pp 227-235; https://doi.org/10.1016/j.clcc.2021.06.002

Abstract:
Introduction There have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice. Methods We performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs. Results One hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials. Conclusion The present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice.
, Pilar García-Alfonso, Michael Geissler, Claus-Henning Köhne, Marc Peeters, Timothy Price, Manuel Valladares-Ayerbes, Ying Zhang, Peter Burdon, Julien Taieb, et al.
Published: 25 May 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.05.007

Abstract:
Background In metastatic colorectal cancer (mCRC), there are limited data on associations between early tumor shrinkage (ETS), depth of response (DpR), and patient characteristics. Methods Data from patients with RAS wild-type mCRC who had participated in the PRIME (NCT00364013) and PEAK (NCT00819780) studies were analyzed retrospectively. ETS and DpR were assessed by baseline Köhne category/BRAF status (PRIME) and baseline tumor load (pooled PRIME and PEAK). Results Analysis populations included 436 to 665 patients. Patients' chances of achieving ETS ≥30% were 63.8%, 50.4%, and 41.9% in the low-, medium-, and high-risk Köhne categories, and 21.7% in those with BRAF mutations. Corresponding percentages for the highest DpR classification (71%–100%) were 47.7% (low risk), 23.6% (medium risk), 10.0% (high risk), and 4.2% (BRAF mutant). No clear relationship was observed between baseline tumor load and ETS or DpR. ETS ≥30% and higher DpR values were associated with statistically significant prolongation of median progression-free survival (PFS) and overall survival (OS). Conclusion Patients with mCRC categorized at baseline by the Köhne criteria as high risk or with BRAF mutations have lower chances of achieving ETS ≥30% or a high DpR. Conversely, baseline tumor load was not predictive of ETS or DpR. Favorable ETS or DpR is associated with improved PFS and OS. Micro In metastatic colorectal cancer (mCRC), there are limited data on associations between early tumor shrinkage (ETS), depth of response (DpR), and patient characteristics. We assessed ETS and DpR by baseline Köhne category and tumor load (n=648). Patients categorized as high risk or with BRAF mutations have lower chances of achieving ETS ≥30% or a high DpR. ETS ≥30% and high DpR were associated with prolonged survival. Baseline tumor load was not linked with achieving ETS ≥30% or high DpR.
Andria R. Morielli, Nawaid Usmani, Normand G. Boulé, Diane Severin, Keith Tankel, , Tirath Nijjar, Alysa Fairchild,
Published: 25 May 2021
Clinical Colorectal Cancer, Volume 20, pp 216-226; https://doi.org/10.1016/j.clcc.2021.05.004

Abstract:
BACKGROUND Neoadjuvant chemoradiation (NACRT) improves outcomes for rectal cancer patients, however, there are dose-limiting toxicities and only a 15-27% pathologic complete response (pCR) rate. Exercise may help manage toxicities and improve treatment response in this clinical setting but feasibility and early efficacy have not been established. EXERT was a phase II trial designed to establish the feasibility and safety of exercise in this clinical setting and provide the first evidence of efficacy. MATERIALS AND METHODS Rectal cancer patients scheduled to receive NACRT were randomly assigned to usual care (n=18) or exercise (n=18) involving supervised exercise during NACRT and unsupervised exercise after NACRT. The primary outcome was cardiorespiratory fitness (VO2 peak). Clinical outcomes included treatment toxicities, treatment completion, and treatment response. RESULTS Median attendance at supervised exercise sessions during NACRT was 82%, and median self-reported exercise post-NACRT was 90 minutes/week. From baseline to post-NACRT, VO2 peak increased by 0.4 ml∙kg−1∙min−1 in the exercise group and decreased by 0.8 ml∙kg−1∙min−1 in the usual care group (p=0.47). There were no significant differences between groups for grade 3/4 toxicities or treatment completion. The number of patients achieving a pCR or near pCR was 10 of 18 (56%) in the exercise group compared to 3 of 17 (18%) in the usual care group (p=0.020). CONCLUSION Exercise during and after NACRT is feasible for many rectal cancer patients and may improve pCR despite limited fitness improvements. Larger trials are warranted to confirm if exercise is an effective intervention for improving treatment outcomes in this clinical setting.
Francinne T. Tostes, Italo Fernandes, Vanderlei Segatelli, Donato Callegaro,
Published: 24 May 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.05.008

Abstract:
We report the case of a 44-year-old female with a prior diagnosis of Sjogren's Syndrome, who was treated for metastatic anal squamous cell carcinoma with second-line Pembrolizumab and has achieved a sustained partial response after a follow-up of 13 months. Comprehensive genomic profiling was remarkable for PD-L1 and PD- L2 amplification and a high tumor mutational burden (19 mutations per megabase). To the best of our knowledge, we present the first report to correlate PD-L1 and PD-L2 amplification with good outcomes of immune checkpoint inhibition in metastatic ASCC.
Bruna R.S. Mattos, Marcos P.G. Camandaroba, , Consuelo Diaz-Romero, Romina Luca, Guillermo Mendez, Iara K.F. Lustosa, Sinara F. Silva, , Virgilio S. Silva, et al.
Published: 23 May 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.05.005

Abstract:
Background HIV-positive patients are underrepresented in clinical trials of metastatic squamous cell carcinoma of the anal canal (mSCCA). We aimed to compare the clinical outcomes of mSCCA patients according to HIV-infection. Methods This was a retrospective multicenter cohort study of consecutive patients with mSCCA. All HIV-positive patients received antiretroviral therapy. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and response rate (RR). Results From January 2005 to December 2019, 113 patients were included: 20 (17.6%) had HIV infection. HIV-positive patients were younger at diagnosis, more frequently male and 20% (N=8) received exclusive best supportive care in comparison with 8.6% of HIV-negative patients (p = 0.13). Both groups were similar in terms of ECOG, patterns of metastatic disease and type of first-line chemotherapy. Five (25%) HIV-positive and 36 (38.7%) HIV-negative received second-line therapies (p = 0.24). RR and median PFS in first-line were similar between the group: 35% and 30.1% (p = 0.78) and 4.9 and 5.3 months (p = 0.85) for patients with and without HIV infection, respectively. In a median follow-up of 26 months, median OS was 11.3 months (95% confidence interval [CI]: 10.1 to 26.4) for HIV-infected patients vs. 14.6 (95% CI: 11.1 to 18.1) months for HIV-negative patients (p = 0.92). In the univariate analysis for OS, only ECOG performance status was significant. Conclusion HIV-positive mSCCA patients under antiretroviral therapy have similar oncological outcomes to HIV-negative patients. These patients should be included in trials of mSCCA.
, Fernanda A. Oliveira, Flora Lino, João Paulo S.N. Lima
Published: 23 May 2021
Clinical Colorectal Cancer, Volume 20, pp 265-272; https://doi.org/10.1016/j.clcc.2021.05.006

Abstract:
Background Liver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR to preoperative systemic therapy for CLM. Methods We systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase and LILACS for studies published between January 2004 and August 2019 that compared the pR to CT plus bevacizumab versus CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor response (pMiR). Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. Results Of the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab versus 686 CT alone). The addition of bevacizumab to CT increased the pCR rate, but it did not reach statistical significance (OR: 1.24, 95% CI 0.81 – 1.92, P=0.32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 – 3.25, P<0.001), and pMiR was significantly lower in the bevacizumab group (OR: 0.41, 95% CI 0.31 – 0.54, P<0.001). The analyses showed a low level of heterogeneity (I2=0-6%). Publication bias was not found. Conclusions This meta-analysis originally demonstrates that bevacizumab plus preoperative CT was associated with higher rates of pR in CLM. Anti-angiogenics might improve OS of CLM patients and should be evaluated in randomized clinical trials. Micro The benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR to bevacizumab plus chemotherapy versus chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.
, , Naziheh Assarzadegan, Hector Li Chang, Heather A.E. Dawson, Andrea Grin, Gordon G.A. Hutchins, Laura Magill, , Robert H. Riddell, et al.
Published: 13 May 2021
Clinical Colorectal Cancer, Volume 20, pp 256-264; https://doi.org/10.1016/j.clcc.2021.05.003

Abstract:
Background: Tumor budding (TB) is an adverse prognostic factor in colorectal cancer (CRC). International consensus on a standardized assessment method has led to its wider reporting. However, uncertainty regarding its clinical value persists. This study aimed to (1) confirm the prognostic significance of TB, particularly in stage II CRC; (2) determine optimum thresholds for TB risk grouping; and (3) determine whether TB influences responsiveness to chemotherapy. Methods: TB was assessed in CRC sections from 1575 QUASAR trial patients randomized between adjuvant chemotherapy and observation. Optimal risk group cutoffs were determined by maximum likelihood methods, with their influence on recurrence and mortality investigated in stratified logrank analyses on ‘exploratory' (n=504), ‘hypothesis testing' (n=478) and ‘final' (n=593) datasets. Results: The optimal threshold for high grade TB (HGTB) was 10+ buds/1.23 mm2. HGTB tumors had significantly worse outcome than those with lower TB: 10-year recurrence 36% vs 22% (risk ratio [RR]=2.00 [95%CI 1.62–2.45], 2p<0.0001) and 10-year mortality 50% vs 37% [RR=1.53; 95% CI 1.34-1.76], 2p<0.0001). The prognostic significance remained equally strong after allowance for other pathological risk factors, including stage, grade, lymphovascular invasion, and mismatch repair status. There was a nonsignificant trend towards increasing chemotherapy efficacy with increasing bud counts. Conclusions: TB is a strong independent predictor of recurrence. Chemotherapy efficacy is comparable in patients with higher and lower TB, hence absolute reductions in recurrence and death with chemotherapy should be about twice as large in patients with 10+ than <10 TB counts.
, Maxfield M. Frohlich, Edward Chu
Published: 12 May 2021
Clinical Colorectal Cancer; https://doi.org/10.1016/j.clcc.2021.05.002

Abstract:
Background Suboptimal completion of chemotherapy, which may involve reduced patient adherence, remains a serious issue and leads to reduced treatment efficacy. This study assessed the completion rates, risk factors for non-completion, and cost impact for non-completion in patients on capecitabine monotherapy (Cape) or capecitabine with oxaliplatin (CAPOX) for the adjuvant treatment of early-stage colon cancer. Methods Patients with a diagnosis of early-stage colon cancer between April 2013 and March 2017 were retrospectively identified. Treatment completion was evaluated. Multivariate logistic regressions analyses were used to assess the baseline factors associated with non-completion. Adverse events, costs, healthcare resource utilization, and cost impact for non-completion were investigated. Results A total of 673 patients met the eligibility criteria, of which 382 (57%) were treated with Cape and 291 (43%) with CAPOX. The overall completion rate for adjuvant therapy was 40% (Cape 46%; CAPOX 33%). Non-completion was associated with CAPOX treatment and higher healthcare costs within 6-months prior to chemotherapy. The 6-month unadjusted total healthcare costs were $44,444 for Cape and $71,247 for CAPOX. The non-chemotherapy costs were 41% higher for non-completers than completers in both treatment groups (p = 0.002). Conclusions The real-world completion rates for adjuvant capecitabine-based chemotherapy in early-stage colon cancer patients are low. Non-completion of therapy is associated with higher baseline healthcare costs. The non-chemotherapy costs are significantly higher in non-completers than completers, highlighting the financial burden of managing adverse events and pre-existing comorbidities, which may lead to early discontinuation of therapy. Effective strategies to optimize completion of oral chemotherapy may consider adherence monitoring. Microabstract Suboptimal completion of chemotherapy remains a serious issue and leads to reduced treatment efficacy. This retrospective database study included 673 patients with early-stage colon cancer and found that completion rate for adjuvant capecitabine-based therapy was only 40% (Cape 46%; CAPOX 33%). The non-chemotherapy costs were 41% higher for non-completers than completers.
, , Peter Gibbs, Stephen Ackland, , Niall C. Tebbutt, Timothy Price, Matthew Burge
Published: 10 May 2021
Clinical Colorectal Cancer, Volume 20, pp 245-255; https://doi.org/10.1016/j.clcc.2021.05.001

Abstract:
Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrates that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests this is an underutilised approach, particularly in younger and fitter patients. Established prognostic factors including patient age, performance status, tumor sidedness and biomarkers such as BRAF/RAS, are key in treatment selection; left sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less intensive regimens in the modern era, where the incorporation of biologic therapies has become routine, and where non-chemotherapy options are emerging as viable options for molecularly-defined patient subsets. Personalising the approach to first-line systemic therapy in metastatic colorectal cancer: is there a role for initial low intensity therapy in 2021 and beyond? A perspective from the Australasian Gastrointestinal Trials Group (AGITG)
, Winson Y. Cheung, , , Daniel J. Renouf, Derek Tilley, Patricia A. Tang, Chad G. Ball, Elijah Dixon,
Published: 19 April 2021
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2021.04.004

Abstract:
Introduction In resected colonic liver metastasis (CLM), randomized studies of oxaliplatin-based chemotherapy have demonstrated improvements in disease-free survival (DFS), but not overall survival (OS). Additionally, oxaliplatin regimens have not been compared to non-oxaliplatin chemotherapy. Despite limited evidence, perioperative chemotherapy is often used in the management of CLM. The primary aim of this study was to assess the impact of oxaliplatin chemotherapy regimens on OS in patients that have undergone resection of CLM in a real-world setting. Methods Patients who underwent resection of CLM in the provinces of Alberta and British Columbia, Canada were identified from 1996-2016. Perioperative (pre and/or post) systemic therapy was categorized as oxaliplatin or non-oxaliplatin-based chemotherapy or no chemotherapy. The primary and secondary outcomes were OS and DFS, respectively. Results 511 patients were identified who underwent R0 resection of CLM. A significant difference in median OS was identified among oxaliplatin, non-oxaliplatin and no chemotherapy groups of 100, 60 and 59 months, respectively (p=0.009). In multivariate analysis, patients who received oxaliplatin regimens had a lower risk of death (HR 0.68, 95% CI 0.51-0.92, p=0.012), while the non-oxaliplatin chemotherapy group did not (HR 0.88, 95% CI 0.65-1.20, p=0.422) compared to no chemotherapy. Conclusions In this multicenter, retrospective population based study, perioperative oxaliplatin-based chemotherapy is associated with improved OS in conjunction with R0 resection of CLM. Further studies should evaluate the optimal duration and sequencing of perioperative chemotherapy in relation to curative-intent surgical resection of CLM.
, , Andrew Briggs, Andrea Harkin, , John McQueen, Karen Allan, , , Bengt Glimelius, et al.
Published: 9 April 2021
Clinical Colorectal Cancer, Volume 20, pp 236-244; https://doi.org/10.1016/j.clcc.2021.04.001

Abstract:
Background The Short Course Oncology Treatment (SCOT) trial demonstrated non-inferiority, less toxicity, and cost-effectiveness from a UK perspective of 3 versus 6 months of oxaliplatin-based chemotherapy for patients with colorectal cancer. This study assessed the cost-effectiveness of shorter treatment and the budget impact of implementing trial findings from the perspectives of all countries recruited to SCOT: Australia, Denmark, New Zealand, Spain, Sweden, and the United Kingdom. Patients and Methods Individual cost–utility analyses were performed from the perspective of each country. Resource, quality of life, and survival estimates from the SCOT trial (N = 6065) were used. Probabilistic sensitivity analysis and subgroup analyses were undertaken. Using undiscounted costs from these cost–utility analyses, the impact on country-specific healthcare budgets of implementing the SCOT trial findings was calculated over a 5-year period. The currency used was US dollars (US$), and 2019 was the base year. One-way and scenario sensitivity analysis addressed uncertainty within the budget impact analysis. Results Three months of treatment were cost saving and cost-effective compared to 6 months from the perspective of all countries. The incremental net monetary benefit per patient ranged from US$8972 (Spain) to US$13,884 (Denmark). The healthcare budget impact over 5 years for the base-case scenario ranged from US$3.6 million (New Zealand) to US$61.4 million (UK) and totaled over US$150 million across all countries. Conclusion This study has widened the transferability of results from the SCOT trial, showing that shorter treatment is cost-effective from a multi-country perspective. The vast savings from implementation could fully justify the investment in conducting the SCOT trial.
, Guilherme Fialho Freitas, Daniel Negrini Batista, Otavio Augusto Noschang Moreira, Carla A.R. Dias, Tiago Biachi Castria, Jorge Sabbaga, Paulo M. Hoff
Published: 9 April 2021
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2021.04.002

Abstract:
Background Brain metastases (BMs) from colorectal cancer (CRC) are unusual; however, an increase in incidence has been reported. The evidence available on the subject is scarce, and a better understanding is warranted. We aimed to characterize the epidemiology and the outcomes of patients with BMs from CRC. Patients and Methods A cohort of patients with BMs from CRC was retrospectively evaluated. Patients were treated in a single center between May 2008 and April 2019. BMs were confirmed by brain computed tomography or magnetic resonance imaging. Results A total of 247 consecutive patients were evaluated. Most patients had a left-sided primary tumor (193, 78%) and at least two extra-cranial metastatic sites (194, 78%). Ninety-six patients (39%) were RAS wild-type; 68 patients (27%) were RAS mutated; and 83 patients (34%) were not characterized. Median time from the initial diagnosis to BMs was 27.6 months (interquartile range, 13.1-46.9). Regarding local therapy, 43 patients (17.4%) were treated with BM surgery alone, 76 patients (30.8%) with radiotherapy (RT) alone, and 58 patients (23.5%) with both surgery and RT. Median overall survival (OS) was 2.9 months (95% confidence interval [CI], 2.2-3.5). Six-month and 1-year OS rates were 29% (95% CI, 23-25) and 13.5% (95% CI, 9.2-18.6), respectively. In a multivariable analysis, BM surgery alone (hazard ratio [HR], 0.56; P = .018), RT alone (HR, 0.51; P = .001), and surgery plus RT (HR, 0.27; P< .001) were associated with superior OS, whereas Eastern Cooperative Oncology Group Performance Status 3 or 4 (HR, 2.01; P = .009) and male gender (HR, 1.46; P = .012) were negative prognostic factors. RAS status was not associated with OS. Conclusion BMs occur late during the course of colorectal cancer and are more common in patients with a left-sided primary tumor and a high volume of metastatic disease. BMs from colorectal cancer are still associated with an extremely poor prognosis; however, selected patients may benefit from treatment with surgical resection and radiotherapy.
, , Jeffrey R. Olsen, Matthew G. Mutch, , , , Matthew L. Silviera, Benjamin R. Tan, Andrea Wang-Gillam, et al.
Published: 7 April 2021
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2021.03.003

Abstract:
Purpose Short-course radiation therapy (SCRT) and non-operative management are two emerging paradigms for rectal cancer treatment. This is the first clinical trial to evaluate SCRT followed by chemotherapy as a non-operative treatment modality. Methods Patients were treated on the single-arm, Non-Operative Radiation Management of Adenocarcinoma of the Lower Rectum (NORMAL-R) study, of SCRT followed by chemotherapy in patients with non-metastatic rectal adenocarcinoma. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX x 8 or CAPOX x 5 cycles. Patients with clinical complete response (cCR) underwent non-operative surveillance. The primary endpoint was cCR at 1-year. Secondary endpoints included safety profile and anorectal function. Results From June 2016 and March 2019, 19 patients were treated with 21% stage I, 32% stage II, and 47% stage III disease. At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of nineteen patients are alive, all without evidence of disease. Patients with cCR vs without cCR had improved 2-year disease free survival (93% vs 67%, p=.006), distant metastasis free survival (100% vs 67%, p=.03), and overall survival (100% vs 67%, p=.03). Involved vs uninvolved circumferential resection margin on MRI was associated with less initial cCR (40% vs. 93%, p=.04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1-year was not different than baseline. There were no severe late effects. Conclusions Treatment with SCRT and chemotherapy resulted in high clinical complete response rate, intact anorectal function, and no severe late effects. NCT02641691. Microabstract Short-course radiation therapy results in higher pathologic complete response than long-course chemoradiation therapy in rectal adenocarcinoma. All definitive treatment experiences with non-operative intent have utilized long-course chemoradiation. This prospective clinical trial of 20 patients is the first experience of non-operative management with short-course radiation followed by chemotherapy. We observed a high clinical complete response rate with no severe late toxicity.
Published: 7 March 2021
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2021.03.001

Abstract:
Background : Combination therapy comprising fluoropyrimidine plus irinotecan with an angiogenesis inhibitor is widely used as a second-line treatment for metastatic colorectal cancer (mCRC). Materials and methods : This retrospective study evaluated the efficacy and safety of FOLFIRI (fluorouracil and irinotecan) plus ramucirumab (RAM), FOLFIRI plus aflibercept (AFL), IRIS (S-1 and irinotecan) plus bevacizumab (BEV), and CAPIRI (capecitabine and irinotecan) plus BEV with FOLFIRI plus BEV as control among mCRC patients who failed treatment with fluoropyrimidine and oxaliplatin plus BEV. Data were collected from a medical claim database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The primary outcome was time to treatment failure (TTF). Secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and safety. Results : Among 3,136 patients assessed, TTF was significantly shorter with FOLFIRI plus RAM (adjusted hazard ratio [HR], 1.40; 95% CI, 1.26–1.56; p<0.001) and FOLFIRI plus AFL (HR, 1.34; 95% CI, 1.09–1.66; p=0.002), and significantly longer with IRIS plus BEV (HR, 0.80; 95% CI, 0.70–0.92; p=0.002). TFST was significantly shorter with FOLFIRI plus RAM (HR, 1.32; 95% CI, 1.17–1.49; p<0.001); no significant difference in OS was observed. The incidences of neutropenia requiring granulocyte-colony stimulating factor were significantly lower with IRIS plus BEV and CAPIRI plus BEV. Conclusion : Regarding TTF, BEV seemed to be a favorable option compared with RAM and AFL when combined with FOLFIRI, and IRIS might be preferable compared to FOLFIRI when combined with BEV for patients who failed to respond to fluoropyrimidine, oxaliplatin, and BEV.
Yannick Eisele, Patrick M. Mallea, , , Christy A. Warby, Kate Buhrke, Tengda Lin, Juergen Boehm, Petra Schrotz-King, Sheetal Hardikar, et al.
Published: 27 February 2021
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2021.02.007

Abstract:
Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood. We examined associations between Fn abundance and clinicopathologic characteristics among n=105 treatment-naïve CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in pre-operative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models. Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n=22) were three-fold more likely to be diagnosed with rectal vs colon cancer (Odds Ratio, OR=3.01; 95% CI=1.06-8.57; P<0.05) after adjustment for patient sex, age, BMI, and study site. Patients with Fn-high abundance also had a five-fold increased risk of being diagnosed with rectal cancer vs. right-sided colon cancer (OR=5.32, 95% CI=1.23-22.98, P=0.03). There was no statistically significant association between Fn abundance with overall survival. Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naïve CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.
, Arvind Sabesan, , Sophie Dessureault, Julian Sanchez, Michael Schell, Iman Imanirad, Ibrahim Sahin, Hao Xie,
Published: 26 February 2021
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2021.02.006

Abstract:
Background The benefit of adjuvant chemotherapy (AC) is unclear in Stage II (T3N0/T4N0) rectal adenocarcinoma (RAC) after neoadjuvant chemoradiation (NCRT) and total mesorectal excision (TME). We aim to identify pathologic factors that influence overall survival (OS) and stratify patients into risk profiles to assess the AC benefit within each profile. Methods The NCDB for rectal cancer was utilized to identify patients with Stage II RAC who completed NCRT and TME. Cox multivariable analysis was used to identify pathologic predictors of 5-year OS, which were then used to construct a nomogram and stratify patients into low, intermediate, and high-risk subgroups. Propensity score matching was applied for the receipt of AC within each risk stratum, and Kaplan-Meier (KM) analysis was used to measure 5-year OS. Results 3,570 patients met inclusion criteria. Inadequate lymphadenectomy (<12), poor differentiation, involved distal margin, involved circumferential margin, perineural invasion, and absence of T-downstaging after NCRT were identified as unfavorable predictors of 5-year OS and were used to construct the nomogram. KM of the matched patients demonstrated the absolute 5-year survival benefits for each risk stratum as follows; 4% for low-risk (HR 0.869 [0.651-1.021]; p=0.062), 26% for intermediate-risk (HR 0.249 [0.133-0.468]; p<0.001), and 10% in high-risk patients (HR 0.633 [0.427-0.940]; p=0.024). Conclusions The survival benefit of AC for clinical stage II RAC following NCRT and TME is most pronounced among intermediate and high-risk patients as determined by our nomogram. Risk-adaptive AC may be appropriate for selected patients by integrating standard reported pathologic elements into the treatment plan. Micro Abstract The benefit of adjuvant chemotherapy in stage II rectal cancer following neoadjuvant chemoradiation and total mesorectal excision remains unclear. In this work, we devise a nomogram to better guide the clinical decision for adjuvant chemotherapy based on the predicted survival benefit.
Wei Zhang, Ana Acuna-Villaorduna, , Sorab Gupta, Shaomin Hu, Kim Ohaegbulam, Joseph Albanese, Meghan Kaumaya, Rachel Levy, Richard R. Hwang, et al.
Published: 19 February 2021
Clinical Colorectal Cancer, Volume 20, pp 161-169; https://doi.org/10.1016/j.clcc.2021.02.002

Abstract:
Background Immunotherapy has emerged as an effective and durable treatment modality for solid cancers. However, its use in colorectal cancer (CRC) is limited to deficient mismatch repair (dMMR) tumors. As such, assessing immune regulatory proteins from the B7-CD28 family, other than PD-1, PD-L1, and CTLA-4, is critical. This study aimed to evaluate the expression of novel protein regulators in a racially diverse population of patients with CRC. Methods A tumor microarray was created for 214 samples from a multiracial patient population with metastatic CRC, and expression of HHLA2, B7-H3, PD-L1, CK7, CK20, and CDX2 was determined. The expression pattern was scored as 0 to 12, based on tumor tissue prevalence and the intensity. Clinical information was obtained by chart review and vital statistics from the National Death Index. Associations between low and high expression groups for each protein by race/ethnic groups were assessed, and Kaplan–Meier curves were plotted to evaluate association with survival. Results The median age at diagnosis was 61 years, with a female predominance. The majority of the patients were diagnosed with de novo metastatic disease with left-sided, moderately differentiated tumors. There were no racial disparities in the expression of any protein. Overall, a high frequency of tumors had no expression of B7-H3 (62.5%) or PD-L1 (43.5%). Low expression of both PD-L1 and B7-H3 was a significant prognostic biomarker associated with better survival (median overall survival, 43.3 months vs. 24.6 months; P< .01). Conclusion In this multiracial tumor microarray of CRC samples, low PD-L1 and B7-H3 expression was associated with an improved prognosis. There was no significant variation among races with respect to the relevant CRC protein markers.
Ofer Margalit, Ben Boursi, Manel Rakez, André Thierry, , Norman Wolmark, Daniel G. Haller, Hans-Joachim Schmoll, Qian Shi, Einat Shacham-Shmueli, et al.
Published: 18 February 2021
Clinical Colorectal Cancer, Volume 20, pp 130-136; https://doi.org/10.1016/j.clcc.2021.02.001

Abstract:
Background The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. Patients were classified into low-risk and high-risk, suggesting low-risk patients may be offered only 3 months of treatment. In this study, we aimed to assess the benefit of oxaliplatin in the adjuvant setting per IDEA risk groups, using data from three large adjuvant phase III studies, namely, MOSAIC, C-07, and XELOXA. Methods Using the MOSAIC, C-07, and XELOXA previously published studies, we identified 2810 low-risk and 2124 high-risk patients with stage III colon cancer. We used Cox regression model to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. Based on design similarity and equivalent follow-up data, MOSAIC and C-07 were pooled, whereas XELOXA was analyzed separately. Subgroup analyses were also performed for T4 and/or N2 patients. Results Individuals with IDEA low- and high risk derived overall survival benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios of 0.79 (0.66-0.95) and 0.84 (0.71-0.99), respectively. Among individuals with IDEA high-risk, those with T4 disease did not gain overall survival benefit from addition of oxaliplatin with hazard ratio of 0.95 (0.71-1.27). Similar results were demonstrated using data from the XELOXA study. Conclusions IDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer. T4 disease may predict lack of benefit from oxaliplatin addition.
Published: 18 February 2021
Clinical Colorectal Cancer, Volume 20, pp 201-215; https://doi.org/10.1016/j.clcc.2021.02.003

Abstract:
Background Colorectal cancer is one of the most common malignancies in both men and women. Despite progress in the treatment of the disease, metastatic colorectal cancer remains lethal with a median survival slightly surpassing 2 years and commonly for some cases a more aggressive course. New therapies are urgently needed based on a better understanding of the molecular pathogenesis of the disease. Methods The focus of this investigation is the PIK3CA gene, encoding the alpha catalytic subunit of the enzyme phosphatidylinositol-3 kinase (PI3K). Publicly available data from 3 extensive published series of colorectal carcinomas were analyzed to define the molecular landscape of colorectal adenocarcinomas with and without mutations of PIK3CA. An analysis for discovery of associations with alterations in other critical genes and pathways involved in colorectal cancer was performed. The total mutation burden (TMB) and copy number alteration burden of colorectal cancers with and without mutations of PIK3CA, as well as prognostic implications of alterations of the gene for survival, were examined. Results Mutations in PIK3CA are observed in 20% to 25% of colorectal cancers. PIK3CA represents one of the most frequently mutated oncogenes in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β-catenin pathway. In addition, PIK3CA mutated colorectal cancers display a higher TMB than nonmutated cancers. Conclusion Frequent mutations of PIK3CA gene in colorectal carcinomas may represent an opportunity for targeted therapy combination development inhibiting both the PI3K kinase itself and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity, which could be augmented by other targeted therapies.
Kevin Biju, George Q. Zhang, Miloslawa Stem, Rebecca Sahyoun, Bashar Safar, , Jonathan E. Efron,
Published: 23 January 2021
Clinical Colorectal Cancer, Volume 20, pp 187-196; https://doi.org/10.1016/j.clcc.2021.01.002

Abstract:
Background Rectal cancer treatment is often multimodal, comprising of surgery, chemotherapy, and radiotherapy. However, the impact of coordination between these modalities is currently unknown. We aimed to assess whether delivery of nonsurgical therapy within same facility as surgery impacts survival in patients with rectal cancer. Methods A patient cohort with rectal cancer stages II to IV who received multimodal treatment between 2004 and 2016 from National Cancer Database was retrospectively analyzed. Patients were categorized into three groups: (A) surgery + chemotherapy + radiotherapy at same facility (surgery + 2); (B) surgery + chemotherapy or radiotherapy at same facility (surgery + 1); or (C) only surgery at reporting facility (chemotherapy + radiotherapy elsewhere; surgery + 0). The primary outcome was 5-year overall survival (OS), analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional-hazards models. Results A total of 44,716 patients (16,985 [37.98%] surgery + 2, 12,317 [27.54%] surgery + 1, and 15,414 [34.47%] surgery + 0) were included. In univariate analysis, we observed that surgery+2 patients had significantly greater 5-year OS compared to surgery + 1 or surgery + 0 patients (5-year OS: 63.46% vs 62.50% vs 61.41%, respectively; P= .002). We observed similar results in multivariable Cox proportional-hazards analysis, with surgery + 0 group demonstrating increased hazard of mortality when compared to surgery + 2 group (HR: 1.09; P< .001). These results held true after stratification by stage for stage II (HR 1.10; P= .022) and stage III (HR 1.12; P< .001) but not for stage IV (P= .474). Conclusion Greater degree of care coordination within the same facility is associated with greater OS in patients with stage II to III rectal cancer. This finding illustrates the importance of interdisciplinary collaboration in multimodal rectal cancer therapy.
, Ronac Mamtani, Mark H. O'Hara, Peter J. O'Dwyer, Ofer Margalit, Bruce J. Giantonio, Einat Shmueli, Kim A. Reiss, Ben Boursi
Published: 21 January 2021
Clinical Colorectal Cancer, Volume 20, pp 121-129; https://doi.org/10.1016/j.clcc.2021.01.001

Abstract:
Introduction The use of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has been increasing in recent years, but the long-term overall survival characteristics of this approach is currently unknown. Methods We performed a retrospective study of patients with clinical stage II/III rectal cancer within the National Cancer Database. Patients who received TNT (defined as chemotherapy, followed by CRT, followed by surgery) were propensity score matched to patients who received adjuvant therapy (defined as CRT, followed by surgery, followed by chemotherapy). We compared overall survival (OS) and rates of pathologic complete response (pCR) between the 2 arms. Results Of the 4300 patients in our cohort, 3502 (81%) received adjuvant therapy and 798 (19%) received TNT. At baseline, patients who received TNT were more likely to have higher clinical T and N stages (P< .001). The 5-year OS was 77% for both TNT and adjuvant therapy patients (hazard ratio [HR] 1.06, 95% confidence interval [CI], 0.88-1.28, P = .57). After propensity score matching and adjusting for potential confounders, there were no significant differences in OS (HRadj 1.00, 95% CI, 0.71-1.40, P = .99). After propensity score matching, there were higher pCR rates among TNT patients (16.1%) compared to adjuvant therapy patients (12.0%) (P = .037). Conclusion In this observational study, we found TNT was not associated with a lower OS compared to standard adjuvant chemotherapy. This finding potentially reassures clinicians choosing TNT as an alternative to adjuvant chemotherapy. However, future prospective data are needed to confirm these findings.
, Hans Prenen, Marissa Lam, , Samuel Tipping-Smith, Caroline Lum, Elizabeth Liow, Eva Segelov
Published: 4 January 2021
Clinical Colorectal Cancer, Volume 20, pp 29-41; https://doi.org/10.1016/j.clcc.2020.12.005

Abstract:
Locally advanced rectal cancer has a rising global incidence. Over the last 4 decades, advances first in surgery and later in radiotherapy and chemoradiation have improved outcomes, particularly with regard to local recurrence. Unfortunately, distant metastases remain a significant problem. In clinical trials of patients with stage II and III disease, distant relapse occurs in 25-30% of patients regardless of the treatment approach. Recent phase III trials have therefore focused on intensification of systemic therapy for localized disease, with an aim of reducing the distant relapse rate. Early results of trials of total neoadjuvant therapy with combination systemic therapy given in the neoadjuvant setting are promising; for the first time a significant improvement in the rate of distant relapse has been noted. Longer term follow up is eagerly awaited. On the other hand, trimodality therapy with chemotherapy, radiotherapy and surgery is toxic. Several trials are currently assessing the feasibility of a "watch and wait" approach, omitting surgery in those with complete response to neoadjuvant treatment, in an attempt to reduce the burden of treatment on patients. The future for rectal cancer patients is likely to be highly personalized, with more intense approaches for high risk patients and omission of unnecessary therapy for those who respond well to initial treatment. Biomarkers such as circulating tumor DNA will help to more accurately stratify patients into risk groups. Improvements in survival and quality of life are expected as the results of ongoing research become available throughout the next decade.
, Elizabeth Sakach, Urvi Patel, Marley Watson, Kevin Hall, Amber Draper, Christine Davis, Subir Goyal, , Mehmet Akce, et al.
Published: 22 December 2020
Clinical Colorectal Cancer, Volume 20, pp 153-160; https://doi.org/10.1016/j.clcc.2020.12.002

Abstract:
Introduction/Background The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing. Materials and Methods In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies. Results Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P< .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P< .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P< .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS. Conclusion Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.
, Alex J. Liu, , Timothy J. Hobday, Jonathan B. Ashman, Nitin Mishra, Tanios S. Bekaii-Saab, Thorvardur R. Halfdanarson, M. Bassam Sonbol
Published: 17 December 2020
Clinical Colorectal Cancer, Volume 20; https://doi.org/10.1016/j.clcc.2020.12.001

Abstract:
Introduction Anorectal neuroendocrine carcinomas (NEC) are uncommon malignancies with poor prognosis. Consensus guidelines exist for treating extrapulmonary NEC. However, limited data is available to guide treatment for anorectal NEC. In this study, we sought to review the clinical characteristics and outcomes of patients with NEC of the rectum and/or anus at Mayo Clinic. Patients and Methods This is a retrospective study of all patients with the diagnosis of NEC of the anus and/or rectum treated across Mayo Clinic sites since 2000. Baseline patient characteristics, tumor pathology, imaging profiles, treatment strategies utilized, and survival outcomes were analyzed. Kaplan-Meier analysis was used with a significance level of p<0.05. Results The study included a total of 38 patients with primary NEC of the anus and/or rectum. Median age at diagnosis was 55.5 years. Median follow up was 18.8 months. Fifteen patients had locoregional disease (LRD) at diagnosis. The remaining 23 had metastatic disease. Overall survival (OS) was significantly shorter in patients with LRD compared to those with metastatic disease at diagnosis (18.1 vs. 13.8 months; p=0.039). The majority of LRD patients were treated with concurrent chemoradiation therapy (n=11) and 10 underwent surgical resection of primary tumor. The majority of LRD patients (13/15) progressed with the majority of progressions being distant (11/15). Median PFS for LRD patients was 5.7 months (1-year PFS of 26.7%). Conclusion Anorectal NEC is an aggressive malignancy with poor prognosis requiring multidisciplinary discussion. In addition, the systemic nature of anorectal NEC with distant recurrences in LRD and poor outcomes in metastatic disease emphasizes the need to further develop better systemic treatment options that can potentially improve outcomes in NEC.
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