Author:

Camilla Fiz

Abstract

In response to the growing disconnect between healthcare costs and clinical benefit, as well as the widening disparities in access to care across European nations, the European Society for Medical Oncology (ESMO) developed the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). This structured, validated tool assess the magnitude of clinical benefit of cancer therapies derived from clinical trials, assigning a standardised numerical score. The ESMO-MCBS was conceived to facilitate objective assessment of oncological treatments, thereby supporting clinicians, researchers, and policymakers in selecting optimal therapeutic strategies, designing robust clinical studies, and informing evidence-based health policy decisions. As advancements in cancer therapeutics have continued to accelerate, the ESMO-MCBS has undergone iterative refinement, shaped by systematic feedback and evolving scientific landscape.

Introduction

In the early 2010s, there was an urgent need to develop a tool to help clinicians, patients and health administrators to untangle the large number of cancer drugs available at the time. To address this need, ESMO introduced the ESMO-MCBS in 2015. The objective was to translate the complexity of the clinical benefit into a standardized score, thereby making it accessible and interpretable for a broad range of stakeholders. ESMO-MCBS was founded on a straightforward yet powerful principle: “The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost,” as was articulated in its seminal publication. However, a major challenge lay in defining what constitutes an acceptable level of clinical benefit and cost, all while maintaining a patient-centred approach at the core of the evaluation framework. Over time most of the initial premises have been met. To date, ESMO-MCBS is the only clinical benefit scale to be acknowledged by the World Health Organisation (WHO) as a screening tool to assist in the identification of cancer treatments that have potential therapeutic value that warrants full evaluation for the WHO Model Lists of Essential Medicines listing.

The issue of marginal medicine

“There is true waste in the health care system, including excessive administrative costs, misused and wasted material, and inefficiencies such as duplicate testing and unnecessary physician visits generated by uncoordinated care,” Ari Hoffman and Steven Pearson wrote in 2015 (Hoffman and Pearson 2009). At the time, they were respectively bio ethician at the National Institutes of Health in Bethesda, and president of the Institute for Clinical and Economic Review in Boston, and they were referring to the fragile health care condition in the United States. In 2009 cetuximab costed $80.00 to extend to just over a month the life of one patient with non-small cell lung cancer. To prolongate the life expectancy of 1 year, this price could shift even to $800.000. Far from demeaning the value of life, the scholars wanted to denounce the critical condition of what they called ‘marginal medicine’. With this expression they meant therapies without any evidence of a comparative net benefit, as compared to the existing alternative, and whose extremely high costs were not justified. A kind of marginal medicine was going on in Europe too.

In 2014 Courtney Davis, medical and political sociologist at the King’s College of London, claimed that in the United States as well as in Europe, chemotherapy regime was getting more aggressive (Davis 2015). That happened even near the end-of-life of cancer patients, causing the compromission of their quality of life and even a waste of resources. In addition to this, someone began questioning even innovative drugs, such as targeted therapies that were new to the market in those years. They were designed to kill cancer cells more precisely and produce fewer side effects than chemotherapy. As they were innovative and more sophisticated therapies, they also tended to cost more. Nevertheless, in some cases, survival rates at the population level didn’t seem to be improved as much after they were commercialised (Shah and Ghimire 2015). As for the situation at the time, Franco Cavalli, president of the Institute of Oncology Research (IOR), in Switzerland, wrote on The Lancet: “The cost of the new generation of drugs is getting out of all proportion to the added benefit” (Cavalli 2013).

The changing value of clinical benefit

If defining the real clinical benefit of new therapies was becoming very challenging was also due to the acceleration of drug approval process by government agencies, including US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Actually, drug approval can take a very long time, even years (Joppi et al. 2020), but this lengthy period is justified by its importance in evaluating and verifying outcomes of new agents from clinical trials, before they enter the market. Yet, EMA and FDA decided to speed it up in the mid-1990s allowing to replace the overall survival (OS) by surrogate parameters that get outcomes faster.

Generally, OS is considered the gold standard for defining the benefit of a therapy, as it measures the percentage of patients who survive 5 years after diagnosis or the outset of a particular treatment. Instead, surrogate parameters could be progression-free survival (PFS) and disease-free survival (DFS), which respectively calculate how long and how much patients survive without their disease coming back and getting worse. “These surrogate endpoints are radiological measurements that demonstrate a drug has biological activity, but do not reliably predict whether it will improve the outcomes that really matter to patients,” Davis alerted and later denounced the consequences of this accelerated process (Davis 2015; Davis et al. 2017). According to her and colleagues, the employment of surrogate parameters was the reason why clinical benefit was meaningful in just less than half cancer drugs approved by the EMA between 2009 and 2013.

The other side of medicine progress

Clearly, not all cancer treatments were so ineffective and unjustifiably expensive. Oncologic research was developing very fast with the introduction of targeted therapies, immunotherapy, radiotherapy and so on. Survival rates increased and mortality rates decreased for many tumour types (Our world in data 2021), including many children cancers, and stomach and colon-rectum cancers. But this rapid and enormous progress has also highlighted its problematic side.

Also, due to the extended increase in the average age of the population average age and in cancer incidence in Europe, marginal medicine became an issue in term of public expenditure in health care systems, more so in countries with lower spending capacity. By the late 1990s the health care Gross Domestic Product (GDP), that is the monetary measure of that market value, has risen and reached a peak in 2006 with an average level of 6,7% in Europe (Przywara, Bartosz 2010). In 2009, just the cost of anticancer drugs was estimated to almost €14 billion, the 27% of the total cancer-related health care expenditure, but not all countries could have the same chance to get the lasts and expensive therapies. The average cost per cancer drugs could vary considerably, ranging from €7-10 millions in Malta, Lithuania and Estonia, to around €1.660-3.000 billion in Italy, Germany and France (Luengo-Fernandez et al. 2013).

Giving the chance to judge independently

As a matter of fact, in the early 2010s both ESMO, with the ESMO-MCBS, and the American Society of Clinical Oncology (ASCO), with their ASCO value framework started conceiving scales to measure the clinical benefit of cancer drugs. At the time, ESMO was a well-established and respected organisation, approaching its 40th anniversary, which was subsequently celebrated in 2014. “We were aware of the significant differences in access to cancer medicine in European countries. With this project, we wanted to see whether we could define a scale that would help countries and other partners to decide which drugs they especially needed,” says Elisabeth De Vries, former chair of the ESMO Cancer Medicines Committee. “Our aim was to provide the means for independent evaluation of the most appropriate therapy for each clinical scenario”.

In 2013, De Vries served as co-chair of the ESMO-MCBS Task Force alongside Martine Piccart, Director of Medicine at the Jules Bordet Institute in Brussels, Belgium. Nathan Cherny, from the Shaare Zedek Medical Centre in Jerusalem, was the driving force behind the initiative, having shaped its vision and direction from the very beginning. The first draft was reviewed by more than 300 experts including members of ESMO and biostatisticians scattered in Europe and in the United States. This first version was sent out for the field testing amongst various stakeholders. While several discrepancies were observed during this field testing in evaluations by the reviewers, they were mostly due to errors in extracting, interpreting or applying data in the forms. “Over the course of 2 years, we repeated the drafting process multiple times with thirteen iterations in total”, De Vries tells. At last, in 2015 the final first version of the scale was established, and the pivotal manuscript was published in the journal Annals of Oncology (Cherny et al. 2015). For their contribution in designing and developing the scale, it is necessary to mention also Richard Sullivan, Urania Dafni, Martijn Kerst, Alberto Sobrero and Christoph Zielinski.

The value of a cancer drug in a number

From the outset, it was decided that due to the heterogeneity of treatment costs the ESMO-MCBS would focus solely on clinical benefit, without incorporating drug costs. This approach ensured that the scale could be universally applied, allowing patients, clinicians, and policymakers alike to interpret the scores within their own socio-economic contexts and make informed decisions accordingly. Maintaining independence from industry influence was a foundational principle, with patient benefit as the central objective. No pharmaceutical companies were involved in the development of the scale; their participation was limited to later stages for workshops and informational purposes only.

Additionally, the ESMO-MCBS Working Group chose to limit the initial version of the scale to treatments for solid tumours and to data derived from comparative, randomized clinical trials, specifically those comparing new agents with either standard-of-care treatments or placebo. Two distinct scoring systems were established: one ranging from A to C, applied to curative-intent therapies such as adjuvant and neoadjuvant treatments, as well as localized or metastatic disease; and another ranging from 1 to 5, used for non-curative therapies, including novel agents and maintenance treatments.

This initial phase of development was followed by a project to develop a visualisation of the ESMO-MCBS scores to illustrate the factors contributing to the final score. The visualization aims to consolidate all the different ESMO-MCBS evaluation forms into a unified graphical interface, increasing its user friendliness and understandability “I personally collaborated closely with experts to enhance the visual presentation,” De Vries recalls. “I came to realise just how challenging it is to distil all the components behind the score into something that can be easily visualised and understood by a broad audience.”

The first ones now, will later be last

Figure 1: An excerpt from the ESMO-MBCS scorecard website

For instance, entering ‘pazopanib’ into the ESMO-MCBS scorecard repository held on the ESMO website, you see a score of 4. This score is based on data from the COMPARZ phase III clinical trial, which compared pazopanib with sunitinib, both tyrosine kinase inhibitors, as a first line treatment in patients with metastatic renal cell cancer. Pazopanib received a score of 4 because it demonstrated non-inferior overall survival (OS) compared to f sunitinib, while offering reduced adverse advents and improved quality of life. This score would support the consideration of pazopanib over sunitinib, particularly in settings where socioeconomic factors influence treatment accessibility. However, treatment paradigms have evolved significantly since the early 2020s. Both pazopanib and sunitinib have largely fallen out of favour in the management of metastatic renal cell carcinoma, as immunotherapy and newer-generation tyrosine kinase inhibitors have become the preferred options. Despite this shift, pazopanib still retains a score of 4 on the ESMO-MCBS scorecard, identical to that of the immunotherapy combination lenvatinib and pembrolizumab. This is neither a paradox nor an error; rather, it reflects the scale’s design to assess clinical benefit within the context of the evidence available at the time of evaluation, independent of evolving treatment landscapes.

“The first ones now, will later be last.” In an editorial in 2022, members of the ESMO-MCBS Working Group quoted this sentence of the singer Bob Dylan to remind people to always consider the historical context of the scale’s scores. In their words: “The ESMO-MCBS score is a measure of the added benefit compared to the standard of care (SoC) at the particular time of study initiation” (Cherny et al. 2022). Although pazopanib has been superseded by newer therapies, it remains a preferable option over sunitinib. The score of 4 may still hold relevance, particularly for patients who lack access to the most recent treatment options. At the same time, the evolving nature of ESMO-MCBS scores underscores the importance of consulting both the scorecards and clinical experts to gain a comprehensive understanding of a treatment’s value within its current context. “To enhance clarity around a treatments clinical positioning we have recently linked scores to the ESMO Living Guidelines where relevant,” De Vries explains. “This is especially useful for countries or individuals making treatment decisions based on costs considerations. In such cases, maybe an older therapy might still offer substantial benefit at a significantly lower cost.”

A new version will always be needed

As oncology research has evolved, so too has the ESMO-MCBS. From the outset, the project welcomed community engagement through a dedicated email address on the ESMO website, allowing anyone to submit questions, suggestions, or concerns. “When we were drafting the scale, we made a concerted effort to review and incorporate all feedback,” De Vries notes. The initiative has also stimulated open dialogue within the scientific community, prompting editorials and responses from the ESMO-MCBS Working Group. As De Vries reflects, “I believe a scale like this will always invite commentary and there will always be a need for new versions.” Indeed, the ESMO-MCBS remains a dynamic, evolving tool, continuously refined in response to scientific progress and stakeholder input.

In 2017, the team guided by Urania Dafni, biostatistician at the School of Health Sciences at the University of Athens, in Greece, published a detailed statistical assessment of the scale (Dafni et al. 2017). In the same year, the experience of the past 2 years was summarised in the next version 1.1, that also included the ability to score single-arm studies (Cherny et al. 2017). Later in 2023 the ESMO-MCBS Working Group. collaborated with the European Organisation for Research and Treatment of Cancer (EORTC) developed a checklist to assess the robustness of QoL research to use for ESMO-MCBS grading. The implementation of the ESMO-MCBS QoL checklist will facilitate objective and transparent decision making on QoL data within the ESMO-MCBS scoring process (Oosting et al. 2023). During the same year, the scale was also extended to include a version of the scale specifically for haematological malignancies (Kiesewetter et al. 2023).

Celebrating 10 years of the ESMO-MCBS version 2 has been launched with this new version involving as previously a transparent process of extensive peer review, appeal and revision ensuring the accountability for reasonableness of the scores, making the scale a continued trusted decision-support tool.

Even more necessary

The application of the ESMO-MCBS has expanded significantly over time. It now plays a role in multiple domains ranging from inclusion in the ESMO Clinical Practice guidelines, educational workshops aimed at diverse stakeholders ranging from patients’ healthcare professionals to policymakers and pharmaceutical representative. In several countries, the scale has also been integrated into processes related to public resource allocation and Health Technology Assessment (HTA). Moreover, numerous researchers have employed the ESMO-MCBS in conjunction with other evaluative frameworks, including the ASCO Value Framework and the National Comprehensive Cancer Network (NCCN) Evidence Blocks, the latter introduced shortly after the former two. Although the ASCO initiative was discontinued several years ago, the continued existence of multiple assessment tools remains essential. These frameworks offer complementary methodologies and perspectives, enriching the evaluation of clinical benefit and supporting more nuanced, context-sensitive decision-making in oncology.

These types of tools are more essential today than they were a decade ago. Disparities in healthcare access and expenditure persist across European countries, while cancer incidence continues to rise. At the same time, the cost of anticancer drugs is steadily increasing, driven by the rapid and ongoing progress in oncology research. Recent breakthroughs in gene editing, RNA-based therapeutics, and precision medicine are reshaping the field, and we are only beginning to explore the transformative potential of artificial intelligence in cancer research. Precision oncology, in particular, has become increasingly complex due to the growing number of actionable genetic alterations and the widespread adoption of multi-gene sequencing in clinical practice. One emerging concern is the potential overestimation of the benefits of personalised therapies, which may also influence patients’ perceptions and experiences of their illness.

Building on the experience gained with the ESMO-MCBS, ESMO launched a new framework in 2018: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). This initiative aims to establish a common language among clinicians, researchers, patients, and industry stakeholders to guide the interpretation and prioritisation of molecular targets in precision cancer medicine.

References

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Other Research Centres

University Medical Centre Groningen, Groningen, The Netherlands

San Martino Polyclinic Hospital, Genoa, Italy