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, 5]. 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.
Acknowledgment
The authors thank Dr. Guy Regnard, Cape Town, South Africa, for providing medical
writing support/editorial support.
Statement of Ethics
All papers must contain the following statements after the main body of the text and
before the reference list.
Conflict of Interest Statement
J.M. received speaker’s fees/honoraria and conference sponsorship from Lilly, Roche,
and Viatris. M.T., R.P., P.M., D.D., C.D., S.B., and E.A. have no conflicts of interest
to declare. A.O. is a speaker at AstraZeneca, Roche, J and J and Otsuka and principal
investigator for various phase III clinical trials involving AstraZeneca, Roche, and
Nanoray. M.B. is a consultant to Viatris and received financial support from Viatris.
S.D. received honoraria from Novartis, Pfizer, Lilly, AstraZeneca, Roche, MSD, BMS,
New Bridge, and Caris and received research funding from MSD, Amgen, and the Al Jalila
Foundation.
Funding Sources
There were no funding sources to declare.
Author Contributions
J.M., M.T., R.P., A.O., P.M., D.D., C.D., M.B., S.B., E.A., and S.D.: substantial
contributions to the conception of the work, revising it critically for important
intellectual content, final approval of the version to be published, and agreement
to be accountable for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately investigated and
resolved.