Resource Oriented Decision Making for Treatment of Metastatic Colorectal Cancer (mCRC) in a Lower-Middle Income Country: Egyptian Foundation of Medical Sciences (EFMS) Consensus Recommendations 2020

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, accounting for 9.2% of cancer-related deaths.¹ About 30% of patients present with metastatic disease at diagnosis, and around 50% of patients will relapse after potentially curative treatment.^2,3 Colorectal cancer is the sixth most common cancer in Egypt,⁴ around 40% of patients diagnosed below 45 years old.⁵

The median overall survival (OS) for mCRC patients significantly improved with the addition of irinotecan or oxaliplatin to fluoropyrimidine (5FU) chemotherapy backbone.^6,7 Patients currently are treated within a “continuum of care model” with sequential exposure to various agents including epidermal growth factor receptors inhibitors (Anti-EGFR), vascular endothelial growth factor inhibitors (Anti-VEGF), immunotherapy and targeted therapies. An incremental increase in median overall survival (OS) with sequential use of active agents reaching around 30 months compared to 11 months with 5FU alone.^8–10

Access to approved treatment options and modalities is variable among different countries and within the same country.^11–14 International oncology societies developed resource stratified clinical practice guidelines for mCRC,^11,15 and regional adaptation of international guidelines.¹⁶ National guidelines for each country adjusted according to its health system and policies were also developed.^17,18 Even with the guideline recommendations developed for limited resource countries, a gap between guidelines and everyday practice is usually noted.¹⁹ Practicing physicians in low and lower-middle income countries usually face clinical questions that require further modification of resource stratified guidelines.¹⁴

Egypt is a lower middle-income country according to the World Bank ranking.²⁰ The Egyptian healthcare system has a very complex structure, with governmental and non-governmental institutions providing healthcare services to cancer patients. A wide diversity in drug availability, reimbursement policies and access to health care facilities²¹ makes decision making difficult,²² the majority of institutions do not completely fit in the definitions of basic or limited resources provided by international guidelines.

Herein, the results of consensus recommendations for the treatment of patients with metastatic colorectal cancer developed by the Egyptian foundation of medical sciences (EFMS) are reported. The main objective is to offer resource-oriented guidance for physicians working in Egypt treating patients with mCRC. Aiming to improve quality of care and unification of clinical decisions through structured expert consensus-based recommendations tailored according to the national status, reduce variability in cancer care, clarify evidence gaps and identify research needs. We explored the possibility of dissemination and the applicability of EFMS recommendations in countries within the same income group as Egypt (Tunisia²³ and Morocco²⁴) as well as in a low income country (Sudan).²⁵

Materials and Methods

EFMS task force was formed in June 2019. A literature review was conducted between June 2019 and September 2019, Clinical practice guidelines published by scientific societies as well as practice-changing clinical trials reports were retrieved. Survey (1) questions and statements were generated covering four main sectors of recommendation: general principles guiding management of mCRC, local interventions in patients with metastatic disease including surgery, Initial Systemic chemotherapy for metastatic colorectal cancer, second-line treatment, and beyond. The task force selected the content expert panel members based on their publications or their leadership of GIT malignancies specialized units. The expert panel included 12 medical/clinical oncologists, 3 oncology surgeons, and 3 radio-diagnosis and interventional radiology experts. The panel represents various institutions and clinical practice settings, including university hospitals, specialized cancer centers and governmental health insurance facilities in different geographical areas.

On 20th September 2019, an in-person launching meeting with the content expert panel members was held. During the meeting, the panels endorsed the scope of the recommendations, approved the voting formats and questions, agreed on the deadlines, and launched the process.

A modified Delphi consensus development process was used to collect expert opinions.²⁶ In Survey (1), expert panel members were asked to give their feedback, comments, and references supporting their point of view on each proposed statement. Feedback was collected via email in January 2020. EFMS task force used the feedback on the survey (1) to formulate provisional statement recommendations of survey (2).

Survey (2) was circulated to the content expert members in April 2020 via email. The expert panel members were asked to give their feedback on a Likert scale from 1 to 5 based on their level of agreement with the recommendation as well as the clarity of recommendation (1=Strongly disagree, 2=Disagree, 3=neither agree nor disagree, 4=Agree and 5=strongly agree). Experts were asked to re-write unclear recommendations and give a reference supporting the feedback in case of disagreement or agreement with reservation. Survey (2) results were collected in August 2020. New data emerged in the duration between Survey (1) and the final voting, experts were asked to give their opinion including new data to the consensus recommendations and put it into the final voting process.

EFMS task force collected survey (2) results and analyzed the feedback. The recommendation was considered a reached consensus if the mean level of agreement was ≥4.5, near consensus 3–4.4, the recommendation was considered rejected if the mean level of agreement was ≤2.9. During all surveys, experts were asked to vote on some recommendations in two different resource-oriented settings (restricted resources and non-restricted resources) as defined in the Table 1.

Table 1 Resources Oriented Groups Definitions, Levels of Agreement and Types of Recommendations

The final voting round was done by a virtual conference held on the 25th of December 2020, including 46 recommendations that did not reach consensus in the survey (2), recommendations required rephrasing with major modification or based on newly released data during 2020. During this meeting, experts discussed the final form of recommendations and voted on the same Likert chart used in the survey (2) to re-evaluate the recommendations and give their opinion.

The task force used ADAPTE methodology to classify recommendation statements into 3 main types according to concordance with existing guidelines.²² The final recommendations were developed with the level of agreement and type specified for each recommendation as well as the resource group where the recommendation could be adopted and applied (Tables 2–5). Definitions of levels of agreement and recommendation type are shown in Table 1.

Table 2 Sector 1: Consensus Recommendation Statements on General Principles Guiding the Management of mCRC

Table 3 Sector 2: Consensus Recommendation Statements on Local Interventions in Patients with mCRC and the Role of Systemic Chemotherapy Combined with Surgery

Table 4 Sector 3: Initial (First Line) Systemic Chemotherapy for Metastatic Colorectal Cancer, Resection is Not a Goal

Table 5 Sector 4: Systemic Treatment in Second Line and Beyond

External review board with 3 experts representing a low-income country (Sudan) and lower-middle income countries (Morocco and Tunisia) were asked to assess the recommendations for applicability in their countries. Experts were asked to vote on the level of agreement with the recommendations using the same Likert scale previously utilized, applicability (applicable, not applicable, applicable in some centers) and the barriers preventing adaptation of the recommendations (budget/infrastructure/access).

The final manuscript was approved by all the panel members, target users review is planned after publication and dissemination of the recommendations. Feedback from stakeholders, decision-makers, and different institution representatives is encouraged to measure the applicability of the consensus-based recommendations in different healthcare facilities.

As per the Egyptian law of biomedical research, application to IRB is not requested as no human or animal subjects were included.

Results

Summary of the consensus recommendations with the level of agreement and type of recommendations are presented in Tables 2–5. Each sector is dedicated to answer a group of clinical questions covering a well-defined aspect of clinical practice. External review boards voting on applicability of recommendations for restricted resources are summarized in Table 6.

Table 6 External Review Board Voting on Level of Agreement and Applicability of EFMS Restricted Resources Recommendations in Each Country

Recommendations and Discussion

Sector (1): General Principles Guiding the Management of mCRC

This sector is dedicated to answer questions regarding the pivotal factors guiding treatment strategy planning and how to choose the proper treatment intensity for each patient. The first pivotal step in treatment strategy planning is evaluating patient fitness to treatment, by assessment of performance status using ECOG (Eastern cooperative oncology group) scale²⁷ and the overall health condition. No specific is age considered as an absolute contraindication for intensified chemotherapy. However, for patients above 65 (the median age of patients in most RCTs, range between 60–65), the panel recommends adopting the ASCO recommendation in using the CGA (comprehensive geriatric assessment) score for geriatric patients assessment.^28,29 CGA score is a decision aiding tool used to evaluate multiple aspects of general health status in the elder population receiving chemotherapy, including comorbidities, risk of fall, and cognitive functions.

Based on the ECOG PS scale and CGA score, patients should be classified into three main categories: fit for intensified treatment, fit for less intensified treatment, and patients not fit for any active treatment that requires only best supportive care (Recommendations 1.2.3, 1.2.4, and 1.2.5; Table 2). Treatment in patients with chronic renal failure under regular hemodialysis as patients with end-organ failure was discussed, dose adjustment and modified hemodialysis schedules could be used.³⁰ The panel prefers decision-making case by case based on expected survival with careful monitoring of adverse events.³¹

The second step in decision-making is classifying patients according to tumor characteristics (tumor burden, primary tumor anatomical site, and molecular profile). Patients with Oligometastatic disease represent a special group with a low disease burden and potentially good prognosis. The panel acknowledges the complexity of decisions in patients with Oligometastatic disease due to heterogeneity of this group of patients as well as vague definition.³² We choose to adopt the ESMO definition of Oligometastatic disease³³ (Recommendation 1.3.5).

Patients with solitary site metastases or Oligometastatic disease must be evaluated by MDT to classify mCRC patients according to resectability into resectable, potentially resectable or resection is not a goal.

The primary tumor site serves as a surrogate for the molecular profile of the tumor.³⁴ The panel agreed to adopt the definition of RT colon as the cecum, ascending, and transverse colon till splenic flexure.

The choice of the basic molecular markers panel should be guided by the resource group; only markers with known predictive roles should be requested. This recommendation applies to initial treatment and subsequent lines.

The third and final step is defining treatment intensity, the treatment decision should be resource oriented. The panel acknowledges that there is no clear cut-off point for defining acceptable or negligible clinical benefit with no cost-effectiveness studies available to guide decision making. The main factors used to differentiate between restricted and non-restricted resources are the availability of targeted agents and reimbursement policies for expensive drugs.

For patients treated in a restricted resources setting, chemotherapy doublets or triplets are considered intensified treatment. While in non-restricted resources, intensified treatment options include doublet or triplet plus targeted agents. In patients eligible for less intensified treatment, the panel chose to add FOLFIRI with reduced dose³⁵ to treatment options in restricted resources setting as well as single-agent capecitabine and modified dose FOLFOX. For the non-restricted resources, the panel considers adding 5FU/LV plus panitumumab followed by panitumumab maintenance in elder patients (above 70 years old) with LT sided RAS wild tumors as an acceptable option based on data from a Phase II trial (PANDA trial).³⁶

Sector 2: Local Interventions in Patients with mCRC and the Role of Systemic Chemotherapy Combined with Surgery

In sector 2, the panel tried to offer answers to questions about the role of local interventions in mCRC patients, when to use these interventions and for which patient.

The panel recommends MDT consultation for patients with oligometastatic disease as previously defined (Recommendation 1.3.5) and for patients with solitary site metastatic involvement “lung, liver or peritoneum”. If access to MDT is not possible, refer patients to a health care facility with experienced MDT to be evaluated. If complete resection with pathologically free margins is not possible, resection should not be attempted.³⁷

Local interventions including surgery could be offered to patients as a palliative measure or as a radical treatment with curative intent. The local interventions including RFA, TACE, and SBRT can offer long-term control for patients with a localized disease or small tumor burden “Oligometastatic disease”.

Organ-specific criteria for selecting patients with metastatic disease amenable for metastasectomy were approved by the surgery expert panel (Table 3, recommendation 2.3). Besides technical surgical criteria, patient and tumor characteristics should be evaluated before deciding the proper sequence of treatment modalities.

In selected patients, liver metastases resection can improve survival significantly with a 5-year median survival rate of 40% reported in some trials.³⁸ Fong’s criteria are used to select candidates for curative resection.³⁸

Based on oncological criteria, patients with resectable mCRC should be further classified into 1) patients with good oncological prognostic criteria 2) patients with an uncertain oncological outcome, 3) patients with a poor oncological outcome (Recommendations 2.2.1, 2.2.2, 2.2.3).

Long-term follow-up data from EORTC 40983 trial did not show a benefit in OS from the addition of perioperative chemotherapy to surgery.³⁹ The majority of patients in the EORTC 40983 trial had metachronous metastases (66%) with relatively long DFS after primary treatment. The panel agreed that the benefit of perioperative chemotherapy for patients with good oncological criteria is controversial; surgery should be the upfront modality. Adjuvant chemotherapy after R0 resection in this group of patients is not recommended as well.

Patients with synchronous metastatic disease are considered of “uncertain oncological outcome”, with short OS after resection compared to patients with a metachronous disease.⁴⁰ BRAF mutant tumors are of poor prognosis with a limited benefit of metastasectomy, but it is not considered an absolute contraindication for surgery.⁴¹ For these patients, perioperative chemotherapy is preferred in patients with initially resectable metastases. If a patient with uncertain oncological criteria or poor prognostic oncological criteria was submitted to surgery, the panel suggests adjuvant chemotherapy with FOLFOX/XELOX in this subset of patients. The JCOG0603 study results presented during ASCO 2020 showed significant improvement in DFS with the addition of adjuvant chemotherapy with no improvement in OS, patients with synchronous metastases represented 54% of the study population. On subgroup analysis, patients with a synchronous disease showed better DFS compared to metachronous disease.⁴²

The role of biologics (Anti-EGFR, Anti-VEGF) patients with resectable metastases is not proven with even detrimental effects in some trials,⁴³ thus it is not recommended as a part of peri-operative or adjuvant treatment.⁴⁴

The definition of “potentially resectable” metastatic disease is based mainly on consensus recommendations.³⁷ The surgical expert panel agreed on organ-specific criteria for considering patients “potentially resectable” (Recommendations 2.3.2, 2.3.4, 2.3.6, Table 2). Systemic treatment, in this case, is recommended to allow R0 resection. The choice of conversion therapy depends mainly on the molecular profile of the tumor (recommendation 2.6.1, Table 3).

FOLFOX, FOLFIRI are acceptable options as a conversion therapy in restricted resources and as a chemotherapy backbone in non-restricted resources, FOLFOXIRI with or without targeted agents could be an option in selected patients.^45,46 The panel has major concerns on the toxicity of FOLFOXIRI as conversion therapy and recommends it should be limited to restricted resources if access to targeted agents is not possible in selected patients with excellent PS.

In patients with RAS/BRAF wild tumors, anti-EGFR should be added even in restricted resources to improve the chances of R0 resection regardless of sidedness of the primary tumor.

The role of sidedness in selecting targeted therapy is controversial. NCCN guidelines restrict the administration of anti-EGFR to left-sided tumors⁴⁷ while Pan-Asian adapted ESMO guidelines recommend anti-EGFR in these patients regardless of sidedness.¹⁶ The panels choose to adopt the pan-Asian adapted ESMO recommendation based on superior ORR favoring anti-EGFR in a meta-analysis of 3 studies with head-to-head comparison of anti-EGFR vs anti-VEGF.⁴⁸

There was a debate on the value of bevacizumab as a treatment option in patients with right-sided RAS/BRAF wild tumors, the panel agreed on adding this regimen as a treatment option with reservations but with a level III of agreement, and it is considered as a less favorable option.

For RAS mutant tumors, doublet or triplet chemotherapy is acceptable with the addition of bevacizumab in non-restricted resources. In patients with BRAF mutant tumors, FOLFOXIRI plus bevacizumab is an acceptable treatment option. After R0 resection, no evidence supports the continuation of biologics.

Sector 3: Initial (First Line) Systemic Chemotherapy for Metastatic Colorectal Cancer, Resection is Not a Goal

When surgical resection is not the goal, factors guiding treatment choice should include: the molecular profile, sidedness, patient preference, patient motivation, and expected toxicity. How to use these factors to tailor treatment for each patient in different resource groups and what is the minimal acceptable level of cancer care to be offered in restricted resources centers were the main questions in this sector (Table 4).

Molecular profile and sidedness are the main factors used as predictive markers for response to targeted therapy with no specific role in selecting chemotherapy. The panel of essential biomarkers should be guided by the resource group to avoid unnecessary costs. The panel agreed on the necessity of extended RAS testing in any resource group as a predictive marker for response to Anti-EGFR agents.⁴⁹ There was a debate on adding BRAF testing in restricted resources, the voting results approved extended RAS/BRAF as an essential panel in restricted resources, with BRAF test used as a negative predictive biomarker denoting resistance to Anti-EGFR.⁵⁰ This recommendation was added to guide decision-making in some institutions with restricted resources as well as non-profit patient support organizations sponsoring targeted agents in selected patients with criteria specific to each facility. (Recommendation 3.1.6, Table 4). In the non-restricted resources group, the panel agreed on adding MSI testing to the previous panel.

The panel agreed that in absence of strong evidence, patients with Her2 amplified RAS/BRAF wild tumors should be treated as RAS/BRAF wild tumors in the first line, thus Her2 testing is not recommended.

Tumor localization or “sidedness” is considered a predictive factor for response to anti-EGFR in the first line as suggested by retrospective analysis of clinical trials.^51,52 No predictive markers are available for anti-VEGF or chemotherapy efficacy.

FOLFOX, FOLFIRI, XELOX, and FOLFOXIRI are all valid options as chemotherapeutic regimens in the restricted resources group or as a backbone with the addition of targeted therapy in non-restricted resources in fit patients willing to receive intensified therapy. In a meta-analysis for trials comparing FOLFOXIRI to FOLFIRI, higher response rates and better PFS with FOLFOXIRI was reported with a higher incidence of GIII/IV adverse events mainly neutropenia and diarrhea,⁵³ FOLFOXIRI should be used with caution and only in facilities with supportive care units.⁵⁴

The panel approved the current guidelines’ recommendations against the use of oral fluoropyrimidines in combination with irinotecan with reservation (level of agreement III). The reservation is based on a meta-analysis evaluating CAPIRI/XELIRI with or without bevacizumab compared to FOLFIRI, no significant difference in the incidence of adverse events was noted.⁵⁵

The maintenance treatment in restricted resources is controversial; limited benefit in PFS and absence of OS are the main criticism points to this treatment strategy.⁵⁶ Based on data from Two trials (OPTIMOX and CONcePT) evaluated the withdrawal and reintroduction of oxaliplatin upon progression with the maintenance with 5FU or capecitabine.^57,58 The recommendation approved was maintenance treatment with 5FU or capecitabine. (Recommendation 3.2.7, level of agreement II, Recommendation type B).

In non-restricted resources, treatment choice is based on molecular profile and sidedness. Patients fit for intensified treatment should be classified into RAS/BRAF wild left-sided tumors, RAS/BRAF wild right-sided tumors, BRAF mutant tumors regardless of sidedness, and patients with MSI-H tumors.

In RAS/BRAF wild left-sided tumors, FOLFOX or FOLFIRI in combination with anti-EGFR is the preferred option based on benefit in OS.⁵² Capecitabine-based and 5FU bolus chemotherapy backbone is not recommended in combination with anti-EGFR due to reduced efficacy.³³

In RAS/BRAF wild right-sided and RAS mutant tumors, FOLFOX, FOLFIRI, and XELOX in combination with bevacizumab is the preferred treatment choice. The main benefit of bevacizumab is offering clinical benefit in terms of PFS with no OS benefit.⁵⁹

For BRAF mutant patients, doublet or triplet chemotherapy in combination with bevacizumab are all acceptable options. The updated results of TRIBE2 trial showed a potential benefit of FOLFOXIRI plus bevacizumab in a small subgroup of patients with BRAF mutation.⁶⁰ In this subset of patients, triplet chemotherapy with bevacizumab in fit patients is the preferred option. The ANCHOR trial is ongoing investigating the role of adding BRAF inhibitor (encorafenib) in the first line.⁶¹

For MSI-H tumors, pembrolizumab showed significant improvement in PFS and response rates as first-line treatment.⁶² Single agent pembrolizumab presents an acceptable option, with long-term follow-up and OS data still pending.

Intensified treatment with triplet chemotherapy (FOLFOXIRI) combined with panitumumab was evaluated in phase II trial VOLFI, a numerical trend towards improved OS was noted.⁶³ The panel prefers waiting for more solid and long-term data before approving this treatment option, currently, it is not recommended.

For patients fit to less intensified treatment as defined in sector 1, treatment options in restricted resources include capecitabine single agent, FOLFOX/FOLFIRI with reduced dose according to PS and comorbidities. Patients under single agent capecitabine should be under treatment till disease progression or unacceptable toxicity.

In non-restricted resources, the panel adopted the currently available treatment options (Capecitabine/bevacizumab continued till disease progression or unacceptable toxicity) based on efficacy and safety data reported in AVEX trial in elderly patients above 70 years old not candidates for intensified therapy.^64,65

In patients receiving CAPOX-bevacizumab as induction therapy, de-escalation of chemotherapy and maintenance with CAP/Beva is recommended.⁶⁴

Sector 4: Systemic Treatment in the Second Line and Beyond

One of the most challenging clinical situations in restricted resources setting is the management of patients progressing on prior line of treatment. In sector 4, questions about the proper sequence of treatment and potential treatment options in later lines were discussed (Table 5).

Patients who received FOLFOX as initial treatment can receive FOLFIRI upon progression and vice-versa.⁶⁶ Irinotecan single agent may represent a treatment option in patients not eligible for FOLFIRI using the same criteria to define treatment intensity in the first line, but it should not be considered in fit patients due to inferior efficacy compared to a combination.⁶⁷ For patients who received first-line treatment with FOLFOXIRI, no clear evidence-based treatment options are available; the panel suggests these patients to be treated with treatment options approved for the third line.

The duration of treatment in patients receiving chemotherapy as the second line is not well defined, the panel agrees on either de-escalation in form of oxaliplatin withdrawal in patients receiving FOLFOX/XELOX or continuation without de-escalation in patients receiving FOLFIRI. Pre-defined treatment duration is also an acceptable option.

No additional molecular biomarkers are needed for treatment planning in the second line in restricted resources. For non-restricted resources, additional testing for Her2 overexpression⁶⁸ could be considered besides RAS/BRAF/MSI if not tested before the first line. Comprehensive genetic profiling may be considered in some institutions according to their inner fund policies.

No Phase III head-to-head trials were conducted to compare anti-EGFR to anti-VEGF in the second line, one phase II randomized trial showed comparable efficacy in terms of PFS and OS in patients with wild RAS.⁶⁹

Efficacy of anti-EGFR /FOLFIRI in the second line showed limited benefit in PFS and no improvement in OS compared to chemotherapy alone.^70,71 The predictive value of sidedness in choosing one targeted agent over another is not confirmed in second-line treatment with data from retrospective analysis suggesting better results when limiting the use of anti-EGFR to left-sided tumors.⁷² The panel considers anti-EGFR in the second line as a less preferable option, and to be limited to patients with left-sided tumors progressing on initial treatment with FOLFOX/XELOX with bevacizumab with RAS/BRAF wild tumors.

In patients treated initially with FOLFIRI and bevacizumab naïve, bevacizumab plus FOLFOX is a preferable treatment option.⁷³ In patients not previously exposed to irinotecan treated with FOLFOX as initial treatment, FOLFIRI plus aflibercept is a valid treatment option with improvement in OS by 1.8 months.^74,75 Ramucirumab is also another option that could be considered in combination with FOLFIRI.⁷⁶

In patients treated with bevacizumab at the first line, the panel discussed the treatment options including the continuation of bevacizumab beyond progression or switching to other anti-angiogenetic agents. The panel chose to adopt the ESMO recommendation of switching to aflibercept or ramucirumab plus FOLFIRI in rapid progressor patients defined as those progressing within less than 3–4 months of bevacizumab treatment in the first line.^16,33 The recommendation was approved by level of agreement III.

In restricted resources, the panel emphasizes the absence of evidence-based treatment options in patients who progressed on oxaliplatin and irinotecan-based treatments and considers best supportive care as the preferred modality. Treatment options for patients with maintained good PS and willing to receive active treatment are summarized in recommendation 4.4.4. The panel considers single-agent irinotecan in patients who did not recently receive irinotecan-based treatment, re-challenge with previously used regimens in earlier treatment lines, capecitabine as a single agent and IROX but as the least favorable treatment option with concerns on toxicity.

In non-restricted resources, the panel adopts international guidelines on considering both regorafenib and trifluridine/tipiracil (TAS-102) as acceptable treatment options in the third line,^16,33,47 with TAS-102 then regorafenib as the preferred sequence if the patient is still amenable for active treatment.

In patients with RAS/BRAF wild tumors who were never exposed to Anti-EGFR treatment, anti-EGFR agents could be considered in the third line as a single agent.^77,78 Reintroduction of anti-EGFR may be a reasonable option in patients who received anti-EGFR in first-line and exhausted previous lines of treatment, provided that more than 6 months after last anti-EGFR administration with response to treatment in the first line.^79–81

Other treatment options are now available including encorafenib/cetuximab in RAS wild BRAF mutant patients,⁸² Her2 targeting agents in patients with Her2 overexpression (trastuzumab plus lapatinib,⁸³ trastuzumab plus pertuzumab⁸⁴ or trastuzumab deruxtecan⁸⁵), and immunotherapy (single-agent nivolumab⁸⁶ or pembrolizumab⁸⁷ nivolumab plus ipilimumab combination⁸⁸). More phase III studies are required before considering these treatments as a standard of care. In heavily pre-treated patients, the main benefit of these agents was either improvement in response rates (RR) or in PFS.

External Review Board Voting

EFMS recommendations were assessed for applicability in low and lower-middle income countries in North Africa (Tunisia, Morocco and Sudan).

Recommendations were accepted with variable levels of agreement by external review board members (Table 6). Applicability varied between countries even within the same income group.

Proposed recommendations on defining treatment intensity in restricted resources as well as recommendations on principles of management for patients with Oligometastatic disease were accepted and applicable in all countries. SBRT plus FOLFIRI was agreed upon by all the review board, but not applicable in most countries due to lack of infrastructure.

Experts from Tunisia and Morocco asked to add a recommendation on routine DPD testing, DPD testing is performed as a routine test for all patients before initiating treatment with 5FU/capecitabine in Tunisia, while in Morocco it is performed in patients showing toxicity pattern suggestive of DPD deficiency as in Egypt. DPD test is available in very limited centers in Sudan.

Adding Anti-EGFR to chemotherapy backbone in RAS wild patients with potentially resectable tumors regardless of sidedness even in restricted resources was approved by the entire panel. However, access to Anti-EGFR is very limited in Sudan, FOLFOXIRI is considered more applicable as a conversion treatment option.

Adding BRAF to extended RAS test as a basic molecular profile before initiating first line treatment was also discussed. BRAF test is not sponsored in Tunisia and thus it is not performed routinely. Access to BRAF test is available in some centers in Morocco but not considered a standard of care.

The idea of intensifying chemotherapy with triplets in restricted resources was not agreed upon due to concerns on toxicity, triplets should be limited only to patients with PS 0 symptomatic patients with high tumor burden.

The concept of maintenance treatment instead of a total treatment breakdown was preferred by all the external panel members. However, each center should sort out the priorities and internal policies with priority to patients treated for cure in early stages. If resources are enough to give both, maintenance should be considered. If not, priority should be given to curative and early disease.

The panelists commented on restricting second line and beyond to patients with PS 0–11, they prefer offering treatment to patients with PS II with no residual toxicity from prior lines.

For third line, they highlighted the fact of absence of approved third line treatment options (trifluridine/tipiracil and regorafenib) from most facilities. Other suggested treatment options were accepted except IROX, due to toxicity concerns and absence of data on efficacy in later lines.

Conclusion

Colorectal cancer is a major health problem in Egypt and around the world.⁸⁹ EFMS developed these recommendations to be convenient with the Egyptian healthcare system, bearing in mind the complexity, fragmentation, and heterogeneity of health care policies between different facilities and institutions in Egypt.

The main limitation of this recommendation is the absence of cost-effectiveness studies for most therapeutic interventions. The grouping into restricted and non-restricted was based on availability and reimbursement policies of targeted agents. The absence of national data on some clinically important points (eg incidence of DPD deficiency) hurdled the development of recommendations for these points. Lack of clinical audit policies will pose a considerable challenge to assess and measure the impact of implementing the current recommendations.

The current recommendations highlighted the discrepancy in health care between restricted and non-restricted resources with expected survival loss and quality of life deterioration. Access to targeted agents in the first line is very limited, and access gets more limited at later lines of treatment.

Recommendations for treatment in the third line in restricted resources are all approved with level III approval due to concerns on efficacy and expected toxicity, all of them are between type B or type C based on a low level of evidence, eg IROX,⁹⁰ or based solely on expert opinion. With increased incidence among patients less than 45 years old. Patients with refractory disease failed on irinotecan and oxaliplatin-based treatment with maintained good PS and willing to receive active treatment is not an uncommon scenario. The current expanding treatment landscape will not be accessible to the majority of patients.

Heterogeneity in health care policies and available resources is noted even in the same country and between countries within the same income range. The lack of clinical practice recommendations tailored according to local status led to wide diversity of clinical care decisions offered to patients and with no supporting evidence. The need to harmonize clinical care options within each country is mandatory. National adaptation of international guidelines with variable degrees is an option to close possible gaps not covered by international guidelines.

The current consensus recommendations could be adopted and generalized in other countries with similar economic and health care status, as an example for management in middle low-income countries. External review by target consumers after dissemination and implementation is planned, aiming to guide the next version of the EFMS consensus recommendations.