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Adjuvant Chemotherapy for Colorectal Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 63942

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Special Issue Editors

Dr. Francesco Sclafani

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Guest Editor

Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels 1000, Belgium; Université Libre de Bruxelles, Brussels, Belgium
Interests: gastrointestinal cancers; clinical research; translational research

Dr. Giacomo Bregni

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Co-Guest Editor

Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels 1000, Belgium;
Université Libre de Bruxelles, Brussels 1000, Belgium
Interests: colorectal cancer; molecularly targeted therapeutics; combination therapies

Special Issue Information

Dear Colleagues,

Management of colorectal cancer has substantially evolved over the last few decades. In addition to to the increased ability to dissect the biological complexity of this tumor, we have been able to gradually depart from the conventional “one-size-fit-all” approach and increasingly adopt molecular-based, risk-adapted treatment strategies. This paradigm shift, however, has especially concerned the management of advanced disease, whereas little progress has been made in the same direction with regard to the treatment of localized tumors. As a result, patient selection criteria and treatment strategies in the adjuvant setting have largely remained unchanged, with only some exceptions for rectal cancer.

Recently, we have witnessed a renewed awareness of the need to challenge the status quo in the management of early-stage colorectal cancer. Furthermore, significant interest has emerged for novel analytic techniques and risk-stratification tools that have the potential to represent real game changers in this context. Turning this premise into concrete advances in routine clinical practice is urgently needed, bearing in mind that approximately 75% of our patients present with nonmetastatic disease.

This Special Issue aims to provide readers with an overview of the current state of the art in the adjuvant chemotherapy treatment for colon and rectal cancers, as well as with valuable insights regarding the possible upcoming evolution of the same.

Dr. Francesco Sclafani
Dr. Giacomo Bregni
Guest Editors

Manuscript Submission Information

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Keywords

colon cancer
rectal cancer
adjuvant chemotherapy
neoadjuvant chemotherapy
immunotherapy
genomics
transcriptomics
circulating tumour DNA
surrogate endpoints

Published Papers (12 papers)

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Review

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22 pages, 937 KiB

Open AccessEditor’s ChoiceReview

ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm

by Mahendra Naidoo, Peter Gibbs and Jeanne Tie

Cancers 2021, 13(2), 346; https://doi.org/10.3390/cancers13020346 - 19 Jan 2021

Cited by 42 | Viewed by 6853

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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12 pages, 5477 KiB

Open AccessReview

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

by Federica Papaccio, Susana Roselló, Marisol Huerta, Valentina Gambardella, Noelia Tarazona, Tania Fleitas, Desamparados Roda and Andres Cervantes

Cancers 2020, 12(12), 3611; https://doi.org/10.3390/cancers12123611 - 03 Dec 2020

Cited by 30 | Viewed by 10933

Abstract

Most clinical practice guidelines recommend a selective approach for rectal cancer after clinical staging. In low-risk patients, upfront surgery may be an appropriate option. However, in patients with MRI-defined high-risk features such as extramural vascular invasion, multiple nodal involvement or T4 and/or tumors close to or invading the mesorectal fascia, a more intensive preoperative approach is recommended, which may include neoadjuvant or preoperative chemotherapy. The potential benefits include better compliance than postoperative chemotherapy, a higher pathological complete remission rate, which facilitates a non-surgical approach, and earlier treatment of micrometastatic disease with improved disease-free survival compared to standard preoperative chemoradiation or short-course radiation. Two recently reported phase III randomized trials, RAPIDO and PRODIGE 23, show that adding neoadjuvant chemotherapy to either standard short-course radiation or standard long-course chemoradiation in locally advanced rectal cancer patients reduces the risk of metastasis and significantly prolongs disease-related treatment failure and disease-free survival. This review discusses these potentially practice-changing trials and how they may affect our current understanding of treating locally advanced rectal cancers. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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18 pages, 950 KiB

Open AccessReview

Statistical Considerations for Trials in Adjuvant Treatment of Colorectal Cancer

by Everardo Delforge Saad and Marc Buyse

Cancers 2020, 12(11), 3442; https://doi.org/10.3390/cancers12113442 - 19 Nov 2020

Cited by 2 | Viewed by 2077

Abstract

The design of the best possible clinical trials of adjuvant interventions in colorectal cancer will entail the use of both time-tested and novel methods that allow efficient, reliable and patient-relevant therapeutic development. The ultimate goal of this endeavor is to safely and expeditiously bring to clinical practice novel interventions that impact patient lives. In this paper, we discuss statistical aspects and provide suggestions to optimize trial design, data collection, study implementation, and the use of predictive biomarkers and endpoints in phase 3 trials of systemic adjuvant therapy. We also discuss the issues of collaboration and patient centricity, expecting that several novel agents with activity in the (neo)adjuvant therapy of colon and rectal cancers will become available in the near future. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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31 pages, 1404 KiB

Open AccessReview

Recurrence Risk after Radical Colorectal Cancer Surgery—Less Than before, But How High Is It?

by Erik Osterman, Klara Hammarström, Israa Imam, Emerik Osterlund, Tobias Sjöblom and Bengt Glimelius

Cancers 2020, 12(11), 3308; https://doi.org/10.3390/cancers12113308 - 09 Nov 2020

Cited by 33 | Viewed by 4727

Abstract

Adjuvant chemotherapy aims at eradicating tumour cells sometimes present after radical surgery for a colorectal cancer (CRC) and thereby diminish the recurrence rate and prolong time to recurrence (TTR). Remaining tumour cells will lead to recurrent disease that is usually fatal. Adjuvant therapy is administered based upon the estimated recurrence risk, which in turn defines the need for this treatment. This systematic overview aims at describing whether the need has decreased since trials showing that adjuvant chemotherapy provides benefits in colon cancer were performed decades ago. Thanks to other improvements than the administration of adjuvant chemotherapy, such as better staging, improved surgery, the use of radiotherapy and more careful pathology, recurrence risks have decreased. Methodological difficulties including intertrial comparisons decades apart and the present selective use of adjuvant therapy prevent an accurate estimate of the magnitude of the decreased need. Furthermore, most trials do not report recurrence rates or TTR, only disease-free and overall survival (DFS/OS). Fewer colon cancer patients, particularly in stage II but also in stage III, today display a sufficient need for adjuvant treatment considering the burden of treatment, especially when oxaliplatin is added. In rectal cancer, neo-adjuvant treatment will be increasingly used, diminishing the need for adjuvant treatment. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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17 pages, 1631 KiB

Open AccessReview

Adjuvant Chemotherapy for Stage III Colon Cancer

by Julien Taieb and Claire Gallois

Cancers 2020, 12(9), 2679; https://doi.org/10.3390/cancers12092679 - 19 Sep 2020

Cited by 44 | Viewed by 11014

Abstract

In patients with stage III colon cancer (CC), adjuvant chemotherapy with the combination of oxapliplatin to a fluoropyrimidine (FOLFOX or CAPOX) is a standard of care. The duration of treatment can be reduced from 6 months to 3 months, depending on the regimen, for patients at low risk of recurrence, without loss of effectiveness and allowing a significant reduction in the risk of cumulative sensitive neuropathy. However, our capacity to identify patients that do really need this doublet adjuvant treatment remains limited. In fact, only 30% at the most will actually benefit from this adjuvant treatment, 50% of them being already cured by the surgery and 20% of them experiencing disease recurrence despite the adjuvant treatment. Thus, it is necessary to be able to better predict individually for each patient the risk of recurrence and the need for adjuvant chemotherapy together with the need of new treatment approaches for specific subgroups. Many biomarkers have been described with their own prognostic weight, without leading to any change in clinical practices for now. In this review, we will first discuss the recommendations for adjuvant chemotherapy, and then the different biomarkers described and the future perspectives for the management of stage III CC. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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12 pages, 439 KiB

Open AccessReview

Adjuvant Chemotherapy for Stage II Colon Cancer

by Sara Elena Rebuzzi, Guido Pesola, Valentino Martelli and Alberto Felice Sobrero

Cancers 2020, 12(9), 2584; https://doi.org/10.3390/cancers12092584 - 10 Sep 2020

Cited by 27 | Viewed by 4021

Abstract

In stage II colon cancer management, surgery alone has shown a high cure rate (about 80%), and the role of adjuvant chemotherapy is still a matter of debate. Patients with high-risk features (T4, insufficient nodal sampling, grading, etc.) have a poorer prognosis and, usually, adjuvant chemotherapy is recommended. The purpose of the present study is to highlight and discuss what is still unclear and not completely defined from the previous trials regarding risk stratification and therapeutic benefit of adjuvant chemotherapy. With all the limitations of generalizing, we make the effort of trying to quantify the relative contribution of each prognostic factor and the benefit of adjuvant chemotherapy for stage II colon cancer. Finally, we propose a decision algorithm with the aim of summarizing the current evidence and translating it to clinical practice. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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12 pages, 485 KiB

Open AccessReview

The Optimal Duration of Adjuvant Chemotherapy in Colon Cancer

by Maike Collienne and Dirk Arnold

Cancers 2020, 12(9), 2509; https://doi.org/10.3390/cancers12092509 - 03 Sep 2020

Cited by 7 | Viewed by 3279

Abstract

Adjuvant chemotherapy for colon cancer (UICC stage II and III) has been under investigation over the last 30 years, regarding treatment duration and regimens. In this review, choice of regimen, its duration, possible limitations and future perspectives are discussed. Monotherapy with 5-fluorouracil was followed by addition of oxaliplatin, resulting in improved 3-yr disease free survival (DFS) and overall survival (OS) rates, but also increased peripheral sensory neurotoxicity (PSN). The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration demonstrated less toxicity, especially PSN, when shortening treatment duration to 3 months. However, formally, the anticipated non-inferiority of 3 months with fluoropyrimidine (FP)/oxaliplatin over 6 months (at 3-yr DFS) was not met for all patients groups, although subgroup analyses showed non-inferiority with capecitabine/oxaliplatin (CAPOX) rather than with FOLFOX, and also in relation to the prognostic information (e.g., clinical low-risk group, pT1-3 N0). In addition, first data of newer parameters like Immunoscore^® and ctDNA show promising results as stratification parameters. Further investigations to better define clinical risk groups and prognostic factors are mandatory. Besides this, individual decision-making of treatment intensity (FP or FP/oxaliplatin) and duration should always consider patient characteristics and preferences, also given the absolute relatively small differences and their clinical relevance. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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22 pages, 350 KiB

Open AccessReview

Adjuvant Chemotherapy in Elderly Colorectal Cancer Patients

by Bengt Glimelius and Erik Osterman

Cancers 2020, 12(8), 2289; https://doi.org/10.3390/cancers12082289 - 14 Aug 2020

Cited by 12 | Viewed by 3472

Abstract

The value of adjuvant chemotherapy in elderly patients has been the subject of many overviews, with opinions varying from “not effective”, since randomized trials have not been performed, to “as effective as in young individuals”, based upon many retrospective analyses of randomized trials that have included patients of all ages. In the absence of randomized trials performed specifically with elderly patients, retrospective analyses demonstrate that the influence on the time to tumour recurrence (TTR) may be the same as in young individuals, but that endpoints that include death for any reason, such as recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS), are poorer in the elderly. This is particularly true if oxaliplatin has been part of the treatment. The need for adjuvant chemotherapy after colorectal cancer surgery in elderly patients is basically the same as that in younger patients. The reduction in recurrence risks may be similar, provided the chosen treatment is tolerated but survival gains are less. Adding oxaliplatin to a fluoropyrimidine is probably not beneficial in individuals above a biological age of approximately 70 years. If an oxaliplatin combination is administered to elderly patients, three months of therapy is in all probability the most realistic goal. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

22 pages, 379 KiB

Open AccessReview

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives

by Reetu Mukherji, John L. Marshall and Andreas Seeber

Cancers 2020, 12(8), 2001; https://doi.org/10.3390/cancers12082001 - 22 Jul 2020

Cited by 2 | Viewed by 2094

Abstract

The selection of treatment according to genomic alterations is a standard approach in metastatic colorectal cancer but is only starting to have an impact in the earlier stages of the disease. The status of genes like KRAS, BRAF, and MMR has substantial survival implications, and concerted research efforts have revolutionized treatment towards precision oncology. In contrast, a genomic-based approach has not changed the adjuvant setting after curative tumor-resection in the daily routine so far. This review focuses on the current knowledge regarding prognostic and predictive genomic biomarkers in patients with locally advanced nonmetastasized colorectal cancer. Furthermore, we provide an outlook on future challenges for a personalized adjuvant treatment approach in patients with colorectal cancer. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

14 pages, 321 KiB

Open AccessReview

Immunotherapy for Early Stage Colorectal Cancer: A Glance into the Future

by Romain Cohen, Qian Shi and Thierry André

Cancers 2020, 12(7), 1990; https://doi.org/10.3390/cancers12071990 - 21 Jul 2020

Cited by 9 | Viewed by 3658

Abstract

Immune checkpoint inhibitors (ICI) have reshaped therapeutic strategies for cancer patients. The development of ICI for early stage colorectal cancer is accompanied by specific challenges: (i) the selection of patients who are likely to benefit from these treatments, i.e., patients with tumors harboring predictive factors of efficacy of ICI, such as microsatellite instability and/or mismatch repair deficiency (MSI/dMMR), or other potential parameters (increased T cell infiltration using Immunoscore^® or others, high tumor mutational burden, POLE mutation), (ii) the selection of patients at risk of disease recurrence (poor prognostic features), and (iii) the choice of an accurate clinical trial methodological framework. In this review, we will discuss the ins and outs of clinical research of ICI for early stage MSI/dMMR CC patients in adjuvant and neoadjuvant settings. We will then summarize data that might support the development of ICI in localized colorectal cancer beyond MSI/dMMR. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

15 pages, 281 KiB

Open AccessReview

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy

by Guido Cavaletti and Paola Marmiroli

Cancers 2020, 12(6), 1370; https://doi.org/10.3390/cancers12061370 - 27 May 2020

Cited by 31 | Viewed by 5789

Abstract

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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10 pages, 240 KiB

Open AccessCommentary

Neoadjuvant Chemotherapy for Colon Cancer

by Marc T. Roth and Cathy Eng

Cancers 2020, 12(9), 2368; https://doi.org/10.3390/cancers12092368 - 26 Sep 2020

Cited by 14 | Viewed by 4833

Abstract

Early stage colon cancer is typically managed with surgical resection, although not all patients experience a durable remission. Adjuvant chemotherapy with a fluoropyrimidine, with or without oxaliplatin, is commonly utilized to increase the chance of cure, but its efficacy in the neoadjuvant setting is not well established. Preoperative chemotherapy has demonstrated safety and efficacy in other gastrointestinal malignancies, but there is a paucity of data from large, prospective randomized trials, although multiple are ongoing. In this review, we will discuss the theoretical risks and benefits, logistical difficulties, and available safety and efficacy data pertaining to the use of chemotherapy in locally advanced colon cancer. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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