Authors:

Andreas Koulouris

Demetris Papamichael

John Souglakos

Abstract

_European research has substantially advanced the management of colorectal carcinoma over the past two decades. This article reviews key studies and clinical trials that have shaped current clinical practice in both the adjuvant and metastatic setting. From the groundbreaking MOSAIC trial to the comprehensive IDEA collaboration, and from single-agent 5-Fluorouracil (5-FU) to the doublet combinations of FOLFOX and FOLFIRI regimens, to the addition of anti-EGFR or anti-VEGF targeted therapies, Europe's contributions have been pivotal. Neoadjuvant approaches are also under way, with more data anticipated to establish novel treatment strategies. Biomarker-based stratification of metastatic CRC (mCRC) already enables enhanced therapeutic tailoring and improves treatment outcomes. These advancements have improved survival rates while enhancing quality of life and have marked substantial achievements in gastrointestinal oncology. _

Introduction

Colorectal cancer (CRC) ranks as the third most frequent malignancy and the second leading-cause of cancer-related mortality worldwide. Metastatic CRC (mCRC) accounts for the majority of deaths ^[1]. Approximately 15-30% of patients are diagnosed with metastatic disease at the outset, and 20%-50% of those initially diagnosed with localised disease will eventually develop distant spread ^[2]. According to phase III clinical trials, the median overall survival (OS) for metastatic disease remained relatively stable for patients diagnosed between 2004 and 2012 at 22.6 months. However, there was a steady improvement for cases diagnosed between 2013 and 2015, reaching 28.8 months, further increasing to 32.4 months for those diagnosed between 2016 and 2019. Similarly, the 5-year survival rate rose from 15.7% for patients diagnosed between 2004 and 2006 to 26% for those diagnosed between 2013 and 2015 ^[3]. This OS improvement in phase III clinical trials represents the pinnacle of advancements in colorectal cancer treatment over the last two decades.

The prognosis and outlook of mCRC was dismal until the introduction and optimisation of fluoropyrimidine-based chemotherapy. 5-Fluorouracil (5-FU) was introduced in 1958, leading to improved 5-year survival outcomes for mCRC and decreased risk of recurrence for patients with resected colon cancer in the adjuvant setting when combined with folinic acid [leucovorin (LV)] ^{[4] [5]}. This antimetabolite was the only chemotherapeutic agent available for many years and led to an improvement of 1-year survival in mCRC patients.

Since 2000, multiple chemotherapeutic agents were integrated into standard clinical practice. During this odyssey of chemotherapy, numerous therapeutic advancements were pioneered mostly by European researchers. The most important examples are regimens combining Irinotecan, a semisynthetic topoisomerase inhibitor, as well as Oxaliplatin, a third-generation platinum compound inducing mitotic arrest through DNA adduct formation. These are now well-established therapeutic options for the management of CRC ^[6].

Systemic chemotherapy coupled with surgery, when feasible, comprise the cornerstone for curing mCRC ^[7]. European researchers and clinicians have been at the forefront of developing and optimizing chemotherapy regimens. This article explores the most important milestones in the development of systemic chemotherapy of CRC with an emphasis on European studies, in both the (neo)adjuvant and metastatic setting.

Resectable Colon Cancer

The standard adjuvant therapy for resected colon cancer was the combination of LV/5-FU for many years. In 2004 the Multicenter International Study of Oxaliplatin/5-FU/LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators including Professors Thierry André and Aimery de Gramont demonstrated superior efficacy for the addition of Oxaliplatin to bolus and infusional 5FU, thereby establishing a new benchmark in the adjuvant therapy for colon cancer ^[8]. The final results of the MOSAIC study confirmed that adding Oxaliplatin to LV5FU2 significantly improved 5-year disease-free survival (DFS) and 6-year OS in the adjuvant therapy of stage III disease thus establishing adjuvant FOLFOX as a standard of care in this setting ^[9].

Professor Aimery de Gramont was a Professor of Oncology at Saint-Antoine Hospital, Paris, France, since 1993 and served as Chief of Services from 2001 to 2014. Since 2014, he has been the Chief of Oncology Services at Institut Hospitalier Franco-Britannique, Paris. Thierry André is a Professor of Medical Oncology at Sorbonne Université in Paris and has been the Head of the Medical Oncology Department at Saint-Antoine Hospital, Assistance Publique Hôpitaux de Paris, since 2011. They are the founders and past presidents of the multidisciplinary oncology research group GERCOR, and their contributions in the evolution of treatment in CRC have been pivotal ^[9].

Since 2001, the Adjuvant Colon Cancer End Points (ACCENT) group's collaborations have substantially improved the efficacy of conducting trials for stage II and III colon cancer. The efforts of the Group have contributed to a better understanding of the disease prognosis and outlook but also refined the use of Oxaliplatin-based regimens. The ACCENT group was gradually formed with a view to addressing questions in colon cancer research through pooled analysis of clinical trials. In 2003, the ACCENT collaborative group was formally established after a meeting in Paris, France, leading to the initial set of 18 trials focusing on adjuvant chemotherapy in colon cancer. The ACCENT database was created in order to compile data from various adjuvant colon cancer trials ^[10]. Over the years, publications from ACCENT analyses have investigated numerous challenging issues. Some of the academic questions investiagted include adjuvant chemotherapy in older patients, evaluation of early prognostic and predictive models, factors impacting on time-dependent recurrence risk, benefits of Oxaliplatin on survival following recurrence and 3- year DFS as a surrogate for 5-year OS ^{[11] [12]}.

The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration was another landmark academic collaborative effort concerning the optimal management of CRC in the adjuvant setting. This large-scale analysis of pooled data from multiple national trials compared 3-month versus 6-months duration of either FOLFOX or CAPOX. The findings documented that a 3-month regimen was nearly as effective as a 6-month regimen for many patients, particularly those with lower-risk disease, while significantly reducing treatment-related toxicity. Overall survival results endorse the use of 3 months of adjuvant CAPOX for the majority of patients with stage III colon cancer. In addition to the substantial reduction in toxicity, this de-escalation of treatment is supported by a more tailored approach to chemotherapy duration, along with a reduction in inconvenience and treatment-associated expenditure, ultimately improving patient quality of life. Notably, the majority of investigators who participated in this effort were based in Europe, including the UK, France, Italy, and Greece ^[13]. In 2022, an ACCENT/IDEA pooled analysis of 11 trials confirmed these findings, indicating that if FOLFOX or CAPOX is given for 3 months and then the fluoropyrimidine continues for a further 3 months the outcomes are comparable to 6 months duration of the above regimens, but with less toxicity ^[14].

In 2023, a research group from Northern Europe, led by the Barling Professor of Surgery in Birmingham, United Kingdom (UK), Dion Morton, published the FOxTROT (Fluorouracil, Oxaliplatin, and Targeted Receptor pre-Operative Therapy) trial. This study investigated the use of a 6-week neoadjuvant chemotherapy regimen in resectable colon cancer. This innovative approach aimed to reduce tumour size and potentially eradicate micrometastatic disease before surgery, potentially improving surgical outcomes and survival rates. Preliminary results from the FOxTROT trial indicated improved pathological response rates and suggested survival benefits, yielding a 2-year duration of disease control (DDC) benefit. Consequently, six weeks of neoadjuvant chemotherapy results in lower postoperative recurrence risk and can be considered a treatment option for localised colon cancer ^[15]. The ongoing FOxTROT platform continues to explore strategies for new agents, potentially representing a paradigm shift in the treatment of colon cancer ^[16].

Metastatic Colorectal Cancer

The modern quest for optimal chemotherapy for patients with mCRC has been underway since the early 2000’s. Jean Yves Douillard, affiliated with the Centre René Gauducheau, Saint Herblain, France, conducted a pivotal study comparing the FOLFIRI regimen (Irinotecan with LV/5FU) to LV/5FU alone in patients with mCRC. The study demonstrated that FOLFIRI significantly improved response rates (RR), progression-free survival (PFS), OS, as well as quality of life. This established FOLFIRI as a standard treatment option in the metastatic setting, offering a more effective treatment for patients with advanced disease. Remarkably, it was the first therapeutic regimen for mCRC to dethrone 5-FU since 1958 ^[17].

In 2000, another groundbreaking study was published by Aimery de Gramont, which highlighted the superiority of the FOLFOX regimen over LV/5FU in the metastatic setting. The study showed significant improvements in RR and PFS for patients treated with FOLFOX, thereby solidifying the role of Oxaliplatin in combination therapies for mCRC ^[18].

The Hellenic Oncology Research Group (HORG) was the first research group to introduce a four-agent regimen in the first line setting of mCRC. FOLFOXIRI (Fluorouracil, Leucovorin, Oxaliplatin, Irinotecan) failed to demonstrate any superiority compared to FOLFIRI. However, the observed median OS was one of the highest reported in the literature until 2006 ^[19]. Conversely, in 2007 the Gruppo Oncologico Nord Ovest (GONO) showed significantly increased RR PFS and OS in patients with mCRC with an almost identical quadruplet regimen, particularly in those who were fit and able to tolerate the increased toxicity of this treatment, which includes a higher incidence of alopecia, diarrhoea, and neurosensory toxicity. Therefore, FOLFOXIRI represents a potential option for treating metastatic disease, providing a new therapeutic avenue for patients ^[20].

As a result of these trials, the chemotherapy landscape for mCRC underwent significant changes with the introduction of novel combination chemotherapy regimens in the early 2000s. However, the management of the associated increased toxicity presented a challenging issue, especially the associated oxaliplatin-related peripheral neuropathy. The OPTIMOX trials sought to address this issue. Christophe Tournigand, from the Saint-Antoine Hospital in Paris, France, designed the OPTIMOX1, a GERCOR study, in 2006 to tackle the cumulative neurotoxicity of Oxaliplatin. He introduced a new strategy of intermittent Oxaliplatin treatment based on FOLFOX7, a simplified LV/5-FU regimen with high-dose oxaliplatin. Their results indicated that oxaliplatin could be paused after six cycles within a FOLFOX regimen leading to a more favourable safety and toxicity profile. This strategy helped manage long-term side effects without significantly compromising the efficacy of maintenance treatment ^[21]. Benoist Chibaudel from the same Institution published the GERCOR OPTIMOX2 study 3 years later, aiming to further evaluate the optimal management of cumulative toxicity through chemotherapy discontinuation. However, the findings of this study revealed that chemotherapy discontinuation may be detrimental on DFS compared to a maintenance therapy strategy ^[22]. The Medical Research Council (MRC) FOCUS British trial sought to elucidate the optimal sequence of treatments for mCRC. Matt Seymour from the UK NCRI suggested that a staged approach of initial single-agent treatment upgraded to combination when required was not worse to up front first-line doublet chemotherapy ^[23].

In 2004, an important study using targeted therapy in mCRC was published by David Cunningham Professor of Medical Oncology at the Royal Marsden Hospital](@royal-marsden), London, UK. For the first time, a novel non-chemotherapeutic agent was tested for the treatment of mCRC. Cetuximab, an anti-Epidermal Growth Factor Receptor (anti-EGFR) monoclonal antibody inhibitor was evaluated as a second-line treatment in Irinotecan-refractory mCRC, showing clinically significant activity both as monotherapy as well as in combination with Irinotecan ^[24]. In 2008 the EPIC phase III study with Alberto Sobrero from Ospedale San Martino in Genova, Italy as the primary investigator (PI) demonstrated enhanced RR, PFS, and quality of life outcomes, when Irinotecan was combined with Cetuximab upon progression on first-line Oxaliplatin-based regimens ^[25]. The subsequent Crystal trial by Eric Van Cutsem from the University of Leuven in 2009 was the first study to introduce the combination of FOLFIRI with Cetuximab in the first-line treatment for Kristen rat sarcoma virus (KRAS) wild-type (wt) mCRC patients. Cetuximab plus FOLFIRI was beneficial to this subgroup compared to FOLFIRI alone in terms of PFS ^[26]. The pivotal phase III FIRE-3 trial shed light on the dilemma of incorporating Cetuximab or Bevacizumab into first-line chemotherapy regimens for mCRC. This German trial conducted by Volker Heinemann Professor at the University of Munich showed that FOLFIRI plus Cetuximab provided an OS benefit for KRAS exon 2 wt CRC compared to FOLFIRI plus Bevacizumab ^[27]. Seven years later, in 2021, the same collaborative group highlighted the crucial role of the anatomical site of CRC tumors in the optimal selection of targeted treatments. Among mCRC patients with left-sided tumors, FOLFIRI plus Cetuximab demonstrated a significantly higher overall RR and longer OS compared to FOLFIRI plus Bevacizumab [28]. Collectively, the EPIC, CRYSTAL, and FIRE-3 trials established the efficacy of targeted therapy in combination with chemotherapy, emphasizing the critical role of clinical features and molecular profiling in personalised cancer treatment ^{[24] [25] [28]}. An overview of pivotal trials on chemotherapy regimens for resectable and mCRC is shown in Table 1 and the timeline of Figure 1.

Figure 1. The chronicle of chemotherapy for resectable and metastatic colorectal cancer. ACCENT: Adjuvant Colon Cancer Endpoints; CT: chemotherapy; FOLFIRI: Fluorouracil, Leucovorin, and Irinotecan; FOLFOX: Fluorouracil, Leucovorin, Oxaliplatin; FOLFOXIRI: Fluorouracil, Leucovorin, Oxaliplatin, Irinotecan; FOxTROT: Fluorouracil, Oxaliplatin, and Targeted Receptor pre-Operative Therapy; GONO: Gruppo Oncologico Nord Ovest; IDEA: International Duration Evaluation of Adjuvant chemotherapy; IRI: Irinotecan; KRAS: Kirsten rat sarcoma virus; 1L: first line of treatment; 2L: second line of treatment; LV/5FU: Leucovorin, Fluorouracil; mCRC: metastatic colorectal cancer; mo: months; MRC: Medical Research Council; OX: Oxaliplatin; Tx: treatment; wt: wild-type.

Conclusions

In conclusion, European clinical research contributions in the form of clinical trials have been transformative for the management of CRC, significantly improving patient outcomes and survival rates. Future research and continuous collaboration will be essential in overcoming substantial remaining challenges and in order to keep improving outcomes and quality of life for CRC patients. As Konstantinos Kavafis reminds us in his poem "Ithaca", it is the journey that matters, full of experience, knowledge, and growth rather than the destination per se.

“And if you find her poor, Ithaka won’t have fooled you. Wise as you will have become, so full of experience, you’ll have understood by then what these Ithakas mean...”