Author:

Letizia Gabaglio

Abstract

Europe's collaborative cancer research movement took root in the mid-1950s, drawing inspiration from similar efforts in the United States. However, unlike their American counterparts, European researchers faced significant funding challenges, as recounted by Silvio Garattini, a key figure in the formation of the European Group for Anticancer Chemotherapy (GECA). Despite these financial hurdles, the cross-border collaboration initiated during this period established a foundation for modern clinical research practices. With adequate financial support, this collaborative approach could still position Europe as a leader in impactful scientific discoveries that benefit patients.

Introduction

Over the course of the last century, clinical research in oncology has developed into the practice we know today. The turning points in its transformation were the introduction of clinical trials and the birth of collaborative research groups, which were essential to deal with the complexity of the work required by the new protocols. The first examples of this new way of working were born in the US in the mid-1950s. Less than 10 years later, the wave of renewal also reached Europe, with the birth of the European Group for Anticancer Chemotherapy (GECA). With the help of the testimony of Silvio Garattini, one of the founders of the first European cooperative group, we retrace the early years of that work in search of the spirit that inspired it and that should still guide European cooperative research today.

The Birth of the New Practice

Before World War II cancer therapy rested primarily on two modalities: surgery and radiation therapy. Chemotherapy emerged in the 1950s thanks to major programs to find anticancer drugs, such as the screening program sponsored by the National Cancer Institute’s Cancer Chemotherapy National Service Centers. Chemotherapy exemplified a more inventive and experimentalist mode that became common after World War II, and that, through the practice of trials, shaped the new subprofession of medical oncology (Pickstone, 2007) . Modern clinical research has its roots and bases its scientific nature on clinical trials: it is from the results of experiments designed according to universally shared standards that oncologists embraced a new style of practice (Keating, 2007). Another cornerstone of oncology research – which no one questions today – is its multicentre dimension, the idea that it is necessary to collaborate to bring together ideas, skills, patients, infrastructures. But it has not always been this way. It was only in the mid-1950s, with the introduction of large-scale clinical trials, that modern oncology began to take shape and a new way of conducting cancer research emerged, leading to the formation of collaborative groups of researchers.

The National Cancer Institute (NCI) played a crucial role in this process, conducting the first randomized cancer trial in 1954 and establishing two key groups: the Acute Leukemia Group A and the Acute Leukemia Group B. These groups later evolved into the Children's Cancer Study Group and the Cancer and Leukemia Group B (CALGB). The following year, the NCI formed the Eastern Solid Tumor Group, the first cooperative group for solid cancers. This group expanded significantly and is now known as the Eastern Cooperative Oncology Group (ECOG), with over 4,000 members. By the 1960s, most advanced cancer trials in North America were managed by the NCI's network of collaborative groups. These groups were not just new organizations; they represented a new model of collective scientific endeavor, with research distributed across different institutions (Keating, 2002).

The European Wave

In 1962, a group of 17 scientists from six European nations (Belgium, France, Germany, the Netherlands, Italy, and Switzerland) established the "European Group for Anticancer Chemotherapy" (GECA). This initiative was inspired by research conducted at the NCI in the United States. As Silvio Garattini, one of GECA's founders and the head of the Mario Negri Institute for Pharmacological Research in Milan, recalls: “during a research period in the United States, I learned about a program of the NCI aimed at establishing whether certain chemical substances had an antitumor effect. A general screening, never performed before, conducted on many substances. An idea that immediately seemed very interesting to me and that could be replicated in Italy”.

However, GECA was also born out of the realization that such complex research would be challenging for any single European nation to undertake independently. “When I discussed my idea with Georges Mathé, immediately found him available and from there we started to bring together other countries and scientists. Why, in fact, continue to seek collaborations with the US without first thinking of collaborating with European countries? This was the thought that drove us at the beginning, together with that of exploring a relatively new discipline at the time, antitumor chemotherapy”, continues Garattini. Together with Garattini and Mathé, then director of the Hematology Department of the Institut Gustave Roussy in Villejuif, the group of founders of the GECA included, among others, Henri Tagnon and Dirk van Bekkum.

The primary impetus for establishing GECA stemmed from the inherent limitations faced by individual European nations in conducting such complex research. These limitations manifested in several key areas:

• Financial constraints: Individual countries often lacked the necessary financial resources to procure the specialized research equipment and animal models crucial for effective investigation.

• Insufficient interdisciplinary collaboration: Comprehensive cancer research demands a multidisciplinary approach, necessitating seamless collaboration among a diverse range of experts, including pharmacists, biochemists, cell biologists, geneticists, immunologists, radiation biologists, virologists, clinicians, and statisticians. Such collaborative efforts were often challenging to establish and maintain within the confines of individual countries.

• Limited patient access: Clinical cancer trials frequently require a substantial number of participants. However, accessing enough eligible patients often proved problematic within the confines of a single hospital or even a single country.

As its name implies, GECA prioritized chemotherapy research, encompassing a broad spectrum of activities. These ranged from the initial evaluation of potential anti-cancer drugs to the rigorous testing of these agents in clinical trials. Individual GECA members took responsibility for different kind of tests, whose results underwent statistical treatment before being discussed by the group (Keating, 2012).

In 1966, GECA embarked on its clinical research journey by initiating studies on leukemia, lymphoma (then classified as hematosarcoma), and metastatic breast cancer. These early investigations served as a blueprint for subsequent clinical trials, establishing guidelines for study design that included optimal treatment approaches, rigorous assessment of treatment responses and toxicities. A primary aim was to foster consistency in the management of common malignancies within the European landscape, a pivotal step towards the implementation of randomized controlled trials (Monfardini, 2021).

Criticisms from the Scientific Community

However, the establishment of GECA did not receive unanimous acclaim. Critics argued that chemotherapy did not constitute genuine scientific inquiry, dismissing it as merely an empirical pursuit unduly influenced by the commercial interests of pharmaceutical companies.

In response, GECA countered these criticisms by emphasizing two key points:

• Clinical efficacy: Chemotherapy demonstrated significant success in treating cancers where traditional approaches like surgery and radiotherapy proved ineffective.
• Scientific advancement: The search for effective chemotherapeutic agents served as a powerful catalyst for fundamental research in biochemistry, organic chemistry, and molecular biology. These investigations not only yielded crucial insights into cancer biology but also contributed significantly to the overall advancement of these scientific disciplines.

The Lack of Funding

Within Europe, GECA continued to refine its operational methods and define its distinct identity within the broader landscape of cancer research institutions. This included navigating relationships with established organizations such as the International Union Against Cancer (UICC), which provided financial support, and the Co-ordinating Committee for Human Tumor Investigations, a recently launched pan-European initiative that had established study groups focused on human tumor biochemistry, cytogenetics, cell proliferation, and the role of hormones in cancer development.

"It was immediately clear that the main difference between us and the Americans was in research funding, which in Europe has always been lower than in North America, and this has marked the history of European collaborative groups for better or for worse. One of the reasons for the establishment of GECA, in fact, was precisely economic: the idea of pooling resources, which at the time were truly scarce", underlines Garattini.

While Europe lacked centralized research institutions comparable to the National Institutes of Health (NIH) and the NCI in the United States, the early members of GECA envisioned establishing a European counterpart. Consequently, they sought support for their initial endeavours from institutions such as the European Economic Community (established in 1957) and Euratom. A pivotal moment for the organization occurred in 1968 when GECA, in part to secure funding from Euratom, underwent a name change, becoming the European Organization for Research and Treatment of Cancer (EORTC).

From Chemotherapies to Multimodal Therapies

The name change signalled the broadening of the group’s activities to include other treatment modalities (e.g. immunotherapy) and research not immediately related to the screening program, although group members made it clear that their main focus would remain the development and testing of anticancer drugs and regimes (Keating, 2012). “Despite the name change and the shift in focus to clinical research, the funding problem was not solved, mainly due to national individualism: if there had been greater cohesion among researchers, perhaps the funding problem would have been solved. On the other hand, if research is not considered a priority, costs are classified as expenses and not as investments, and centres struggle to make ends meet, sharing becomes difficult, and everyone tries to take for themselves the little funding available, both at national and European level,” says Garattini, who led the Mario Negri Institute to collaborate directly with the National Cancer Institute in the context of studies on chemical products that could have an antitumor effect. “The funding that we had tried to collect through European collaboration came from the US. A more efficient and effective way to carry out our work,” comments the pharmacologist.

EORTC continued its work and evolved in an academic research organization which mission is to develop, conduct, coordinate, and stimulate translational and clinical research in Europe to improve the management of cancer and related problems by increasing survival and also improving patient quality of life (Meunier, 2012).

The Added Value of Collaborative Research

The collaborative research envisioned by GECA represented a solution to several problems: managing a huge amount of data to produce scientifically robust results, validating a series of substances quickly, finding the funding needed to test innovative hypotheses that were not tied to market needs, and much more. Not only that. Participation in research within collaborative groups has introduced a change in the way researchers must interpret their work, based on sharing projects and data and dividing tasks. “Collaborating is an enrichment from the point of view of skills, because it allows you to see how others tackle the same problem, but it also involves a structural adjustment because to participate in large collaborative studies you need to have a structure that includes the presence of dedicated personnel. It is truly an opportunity for growth, but it must be perceived as such by everyone: researchers, institute management and institutions”, says Garattini. “The fact is, today, that scientific research depends heavily on private funding, institutional investments are absent and therefore independent research is very little”.

Conclusion

Although European research is not as relevant today as Garattini had hoped when he founded GECA, for him there is still room to relaunch the initial ambition: to join forces - of numbers, because in Europe there are over 500 million people, and of skills, which are certainly not lacking in European countries - to carry out independent collaborative research. "Europe could really be the first power in oncology research, and not only that. The power of the data collected by national health systems, for example, is enormous, and could be used without costs (other than those of data anonymization). The presence of national health systems that provide treatments more or less free of charge would allow for large clinical studies. Compared to the US, the interest in the public good is structured within the health system and this is truly an advantage. In short, European oncology could really represent a power", concludes the pharmacologist.

Acknowledgements

We would like to thank Professor Silvio Garattini for the time he gave me and the revision of the text.

References >

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