Practical Notes on the Current ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer in Resource-Constrained Environments of Low- to Middle-Income Countries

Globally, colorectal cancer (CRC) is the third most prevalent cancer and is second only to lung cancer in cancer deaths [1]. In 2019, there were 2.1 million new CRC incident cases and 1.09 million deaths attributable to CRC, with East Asia being the worst affected [2]. Low- to middle-income countries (LMICs) account for the majority of CRC deaths, with most patients presenting with late-stage disease and unable to receive the requisite care [1]. This is highlighted by the finding that in South East Asia and Africa, cancer centers and departments are only available in 55% and 30% of countries, respectively [3]. As such, both short- and long-term outcomes for patients with CRC in LMICs are poor [4]. The incidence of CRC is expected to increase in LMICs, given shifting demographics and industrialization, placing additional burdens on current healthcare systems [4]. Given these resource constraints and more patients presenting with late-stage disease, what are the practicalities of implementing the recently published European Society for Medical Oncology (EMSO) consensus guidelines for managing patients with metastatic CRC in LMICs [6]? In this article, we discuss how oncologists in LMICs approach metastatic CRC management. Specifically, certain aspects of the current guidelines are examined and discussed in relation to the resource-constrained environments of LMICs.

Molecular pathology and biomarkers comprise the first section of the EMSO consensus guidelines. The progress being made in personalized medicine and targeted therapy has made molecular profiling of tumors a precondition to treatment [7]. There was no consensus among LMIC oncologists on whether broad panel-based sequencing should be used as an initial strategy for devising treatments. LMIC oncologists in favor point to the fact that this approach immediately provides the healthcare practitioner with the status of the tumor, which conveys both prognostic and predictive information. In addition, upfront broad panel sequencing opens up more treatment strategies and allows for a more personalized treatment regimen to be designed. LMIC oncologists who disagree with broad panel-based sequencing as an upfront strategy largely state the availability and cost of such testing in LMICs as limiting factors for its application. Furthermore, not all targeted therapies are accessible in LMICs, limiting the value of broad panel testing. Oncologists not in favor of broad panel-based sequencing also argue that alternative, more affordable panels are available should further characterization be required – these include KRAS, NRAS, BRAF (V600E), dMMR, and HER2. Equally important, LMICs may not have the budget for the expensive targeted therapies recommended based on the sequencing results. The ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) is a framework developed to rank genomic alterations as targets for cancer precision medicine and has six levels of clinical evidence for molecular targets [8]. The highest-ranked alterations are hotspot mutations in KRAS, NRAS, and BRAF. Considering that IHC or PCR determines microsatellite instability status, there is no need to test samples using multigene NGS in daily practice. Multigene NGS can be an alternative to PCR tests only if it does not generate extra cost compared with standard techniques.

With regard to RAS analysis and the recommendation for including all KRAS and NRAS exons, there was a favorable response by LMIC oncologists to incorporate analysis of these biomarkers as part of the analysis for all patients with metastatic CRCs. The results from such testing can affect the treatment strategy, contribute to a more cost-effective approach, and further prognosticate the clinical profile of the patient. However, some LMIC oncologists argue that in the context of a resource-constrained environment, often knowing the status of the KRAS and NRAS exons would not change the course of treatment as targeted drugs may not be available. Excluding analysis of these exons has been suggested if it reduces the overall cost of the analysis, as many patients are financially constrained. Since a disagreement arose around this issue, a consensus was to discuss with the patient pros of testing and the associated cost of the relevant target therapy-based testing on the final decision by the patient.

Fluoropyrimidine analog 5-fluorouracil (5-FU) is one of the most widely prescribed chemotherapeutics used mainly to treat CRC as part of adjuvant treatment or in cases of advanced disease. One drawback of 5-FU is therapy-related toxicity which affects 1 in 3 patients. Patients with a decreased function of the enzyme dihydropyrimidine dehydrogenase (DPD) are particularly at risk of severe and potentially life-threatening toxicity [9]. In the US, the cost of DPYD genotyping is approximately $174, and recent analysis in this setting looking at stage 3 colon cancer patients receiving adjuvant chemotherapy found genotyping to be a cost-effective strategy [10]. While testing for DPD deficiency is available, the current EMSO consensus guidelines suggest testing as an option, but it is not routinely recommended [6]. Most LMIC oncologists agree with these recommendations, stating that the test is expensive, not readily available, and prefer to apply testing on a case-by-case basis. In addition, patients with normal DPD activity can still develop significant 5-FU toxicity. While cost is an important consideration for genotyping, another aspect influencing the cost-effectiveness of testing is the frequency of risk alleles in the population as this impacts the availability of testing [11]. Should the cost of testing become affordable, LMIC oncologists would take advantage of the screening to predict toxicity and adjust dosages accordingly.

The third section of the EMSO consensus guidelines covers the treatment of metastatic disease. It has been reported that of mCRC patients treated with FOLFOX, FOLFIRI, or XELOX, nine in ten will experience at least one adverse drug reaction, and two-thirds will have one or more adverse events during the first line of treatment. Such events and the interventions to resolve them further increase the economic burden on the patient [12]. In LMICs, the cost of treatment is more often than not borne by the patient, in contrast to patients in upper- and upper-middle-income countries where treatment is covered [13]. In light of this, individualized treatment approaches are crucial in avoiding unnecessary toxicity. There was unanimous agreement among LMIC oncologists on involving patients in discussions around the individualization of treatment approaches. Such discussions would include clinical and patient factors, cost, efficacy, logistics, and side effects to devise the best treatment option and hopefully the best outcome for the patient. The financial capacity is a major factor in determining the extent to which the treatment is personalized.

The EMSO consensus guidelines covering metastatic disease, specifically maintenance therapy, state that initial induction therapy or a second-line therapy should be reintroduced at radiological or first signs of symptomatic progression on maintenance therapy. The prognosis of mCRCs and the activity of first-line treatments have been shown to be affected by the primary tumor site. A worse prognosis is often associated with right-side MRCs, whereas RAS wild-type mCRCs originating in the left colon have been found to be more sensitive to EGFR-based therapies than those arising on the right side. The current standard of care in mCRC first-line treatment is chemotherapy (either doublet or triplet combinations) together with targeted agents depending on RAS mutational status [14]. Most LMIC oncologists recommend reintroducing the initial induction therapy instead of introducing a second-line treatment, provided that the patient initially responded very well to this treatment and did not stop due to progression or significant toxicity.

In metastatic disease, where patients receive second-line combinations with targeted agents, LMIC oncologists were asked their opinion on the ESMO guidelines covering bevacizumab. Namely, should patients who received bevacizumab first-line be considered for treatment with bevacizumab beyond the progression, especially RAS-mutant patients? All but 1 respondent agreed that patients who received bevacizumab first-line could be considered for treatment with bevacizumab beyond progression. Restoring the normalcy of vasculature and inhibiting neovascularization remains a valuable strategy in patients with mCRC. The basis of this agreement among LMIC oncologists was that in such instances, clinical data support this strategy (improvements in overall survival), the chemotherapy should be changed (but not repeated) and not the targeted agent, bevacizumab is indicated as the first and second line of treatment in mCRC, and the anti-VEGF pathway continues to be functional beyond progression [15]. The argument against using bevacizumab in LMICs is that it conveys a small absolute benefit at a very high financial cost and with a (albeit very small) risk of severe side effects. Such treatment would more likely be favorably considered if the price were considerably lower. These opinions on cost are supported by Kizub et al. [16], who reported that improving the affordability of targeted therapy to LMICs, particularly in Sub-Saharan Africa, is crucial to expanding treatment access and patient outcomes.

In metastatic patients with RAS wt (BRAF wt) disease, the ESMO guidelines recommend that patients who received bevacizumab first-line should be considered for treatment with EGFR antibodies in combination with FOLFIRI/irinotecan. This recommendation would be put into practice by most oncologists working in LMICs, where EGFR antibodies are accessible. The reasons provided for their decision are that robust data support the recommendation. Unfortunately, it remains a reality that in most LMICs, EGFR antibody treatment is unaffordable.

In terms of the consensus recommendations on the use of cytotoxics and biologicals in the first- and subsequent-line treatment of patients with mCRC, LMIC oncologists employed various strategies. For patients with left-sided RAS wt disease, the treatment of choice followed the recommendations of a cytotoxic doublet plus an EGFR antibody. Chemotherapy used included oxaliplatin-based (FOLFOX) or irinotecan-based (FOLFIRI); however, there was a preference among LMIC oncologists for using FOLFOX as a treatment of choice. Regarding EGFR antibodies, panitumumab or cetuximab were used based on availability and affordability. In patients with right-sided RAS wt disease, the recommendations state that a cytotoxic triplet plus bevacizumab or a cytotoxic doublet plus an EGFR antibody are valid options. In LMICs, the treatment of choice varied among oncologists, with chemotherapy (FOLFOX/FOLFIRI) or the use of bevacizumab alone being choices. Some oncologists used the cytotoxic doublet and an EGFR antibody, particularly in young patients with ECOG 1–2. However, for most LMIC oncologists, the treatment of choice was a chemotherapy doublet in combination with bevacizumab. Finally, in patients with RAS-mutant or BRAF-mutant disease, the guidelines suggest that a cytotoxic doublet plus bevacizumab or cytotoxic triplet (in suitable patients) plus bevacizumab are the preferred options. This was supported by LMIC oncologists.

Overall, oncologists caring for patients in LMICs attempt to follow the recommendations set out by ESMO. The significant constraints, however, are the financial and accessibility barriers oncologists and patients face in managing metastatic CRC. Chemotherapy doublets and the central venous catheters and infusion pumps required to administer them require significant infrastructure, costs, and trained staff for their implementation. As a starting point, making these chemotherapy agents more widely available in LMICs would significantly impact outcomes in mCRC. The high cost of targeted agents and the molecular testing necessary to select them mean that they are only used in a very small proportion of patients in LMICs. Their implementation would be most meaningful in the context of more widely available cytotoxic chemotherapy.