Extending the continuum of care for metastatic colorectal cancer

The increase of therapeutic options for metastatic colorectal cancer (mCRC) in the last fifteen years has reinforced the continuum of care as the best approach to improve the patient’s survival and quality of life.

While today medical oncologists can build complex and more personalised treatment strategies by integrating sequential chemotherapies, surgery, targeted agents and local treatments across multiple lines of therapy, patient selection is imperative to ensure good outcomes. Recently, a step forward has been taken by the recognition that primary tumour side of mCRC has a prognostic and predictive value alongside molecular biomarkers such as KRAS, NRAS, BRAF, mismatch repair deficiency (dMMR) and HER2. This enables clinicians to finetune the first-line treatment of patients with left-side, RAS wild-type (wt) tumours which can now benefit from anti-EGFR agents in combination with chemotherapy (Ann Oncol. 2017 Aug 1;28(8):1713-1729). “Median survival has reached 40 months for these patients, which is an extraordinary result compared to the poor prognosis which did not exceed 12 months two decades ago,” highlights Eric Van Cutsem, Professor of Medicine, Digestive Oncology at University of Leuven (KUL) and University Hospitals Gasthuisberg, Leuven, Belgium, Co-Chair of the ESMO Gastrointestinal Cancers Congress 2024 taking place in Munich, Germany, from 26 to 29 June.

In the biomarker era of gastrointestinal cancer care druggable targets are increasingly being identified. A focus of research is now enhancing immunogenicity in mCRC to replicate the impressive results that have been achieved with the use of immunotherapy in the small cohort of dMMR/microsatellite instability-high (MSI-H) tumours, accounting for 4-5% of all mCRC. “Immunotherapy is now the standard of care for dMMR/MSI-H mCRC, and updates on the efficacy of immunotherapy combinations are expected from ongoing studies,” continues Van Cutsem. “However, we need to take steps forward in understanding the immunophenotypes in colorectal cancer and the interaction between cancer cells and the tumour microenvironment, to better integrate the immunotherapeutics into clinical practice alongside targeted treatments which act on single driver mutations.”

The barriers to precision oncology

Whereas the underlying principle of the continuum of care is that all patients receive the treatments for which they are eligible, access to precision oncology is highly heterogeneous across Europe, keeping targeted therapies out of reach for many. As an ESMO study revealed in 2023, in fact, small or large next-generation sequencing (NGS) panels and Tumour Mutational Burden are only occasionally available in routine practice in some high-income countries and limited to clinical trials or research in the majority of low- and middle-income countries.

Beyond implementing policies to address the gaps in infrastructure and funding for personalised treatment in oncology, more needs to be done to educate the patients themselves on the key role of molecular testing. “Unfortunately, as it resulted by some focus groups and surveys conducted, not all patients with colorectal cancer are aware of their biomarker status, so they are less active to search for clinical trials, and this impacts negatively on the treatment options they can have access to,” explains Zorana Maravic, CEO of Digestive Cancers Europe (DiCE) the non-profit umbrella organisation which unites patient organisations and collaborates with stakeholders dedicated to gastrointestinal cancers in the European region. Interestingly, patients’ awareness of what precision oncology can offer them seems to go in parallel with some practice-changing achievements which have improved the prognosis for some molecular subtypes. “This is the case of the community of patients with BRAF V600E–mutant mCRC who are very active and participate to clinical trials, and for whom there is now a treatment option after the failure of initial therapy,” points out Maravic, talking about the benefit of a chemotherapy-free regimen - the combination of encorafenib plus cetuximab - in terms of overall survival which has provided new hope to some patients (N Engl J Med. 2019 Oct 24;381(17):1632-1643).

Going beyond third line

Despite research in mCRC continuing to raise the bar in disease control, many new and emerging therapies are not curative, and a large proportion of tumours become resistant or refractory over time. After two lines of treatment, the reintroduction of chemotherapy and rechallenge with targeted agents have led to unsatisfactory results so far.

Last year, the treatment pathway for patients with refractory tumours was further enriched with the approval of trifluridine/tipiracil with bevacizumab - an anti-VEGF biological therapy - for mCRC previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, bevacizumab, and if RAS wt, an anti-EGFR therapy (N Engl J Med. 2023 May 4;388(18):1657-1667). “Although the median improvement in survival of three months can be considered a modest result, the use of this combination therapy in third line and beyond represents an opportunity for many patients progressing on first- and second-line standard doublet or triplet-based chemotherapies who generally retain a good performance status to undergo further lines of treatment,” comments Van Cutsem. He also mentions the encouraging efficacy and safety profile of fruquintinib, a highly selective, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3 in heavily pre-treated patients (Ann of Oncol. 2022; Vol 33, Issue S7), which received a positive opinion by the European Medicines Agency on 25 April.

The possibility to continue treatments beyond third or fourth line, however, must be carefully balanced with the patient’s expectations and preferences. “Most of the patients are not just looking for a prolongation of survival, but also maintaining an acceptable quality of life,” highlights Maravic. “Aggressive treatments often induce side-effects which severely interfere with daily activities and gradually erode physical and psychological well-being for patients with metastatic disease, so discouraging them from trying a new option offered by their clinicians.” According to Maravic, expanding the continuum of care should not be limited to further increase the therapeutic armamentarium: more efforts are needed to improve nutritional care and promote physical activity as well as emotional well-being. “Although engaging in physical activity, which should be customised on the condition and individual characteristics of each patient, might initially appear burdensome, research has demonstrated its beneficial impact on mental health, and in cancer patients it may reduce treatment side-effects such as fatigue,” she explains. “Nutritional support is often neglected despite patients with gastrointestinal cancers experience difficulties with feeding. And this is a sort of paradox, because being adequately fed may enable patients to feel better, remain in good conditions and stay longer on treatment, thus increasing their chances of living longer.”