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The European Organization for Research and Treatment of Cancer (EORTC), created in 1962, is an international nonprofit association dedicated mainly to clinical cancer research in Europe. The aims of the [...]

Improving cancer treatment is the mission of the EORTC's Regulatory Affairs Unit. The European Organisation for Research and Treatment of Cancer (EORTC) is an international nonprofit association, created in 1962 [...]

The European cancer burden is growing rapidly, with an estimated 2 million deaths a year according to the latest research. As almost half of cancers are diagnosed after the age of 65, and considering the aging European population, a tidal wave of cancer cases will sweep across Europe within the coming decades. Without major action, the additional number of annual cancer cases is expected to rise from 4.2 million to 5.2 million by 2040. If we are to reach plateauing numbers by 2040 (as a minimum goal), this would require 0.75% annual reduction in risk and 1% reduction in risk of death. These challenges call for attack from various angles, coordinated efforts, rational strategies, initiatives throughout the cancer trajectory, activities to reduce inequities, and implementation of evidence-based measures. In order to defeat the societal challenges of cancer through innovation, Europe will need to join forces and connect the European Commission and the member states, politicians and citizens, industries and patient associations. A cancer mission should thus unite the public and patient viewpoint to the perspective of cancer professionals. The authors describe a plan that has been agreed upon among some of the major European Cancer organizations and associations. This plan uses a cancer mission as a tool and must deliver robust medical evidence to patients and doctors through high-quality research delivering sustainable and affordable strategies for prevention, treatment, and follow-up.

For over 50years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article.

Imaging biomarkers (IBs) are used extensively in drug development and cancer research, but important differences exist between IBs and biospecimen-derived biomarkers. A tailored 'roadmap' is required for the development of new IBs to be used either in clinical research or for decision-making in healthcare. In this Consensus statement, a group of experts assembled by CRUK and the EORTC present 14 key recommendations for accelerating the clinical translation of IBs.

The current drug development procedures are far from optimal, owing to the continuous development of the health systems and the clinical research landscape. The European Organisation for Research and Treatment of Cancer proposes in this Perspective the use of collaborative molecular screening platforms (CMSPs) as a new approach for drug development. These CMSPs have the advantage of optimizing expertise of several partners and combining efforts alongside with cost-sharing models for efficient patient selection.

Introduction:Drug development is a complex and risky enterprise. Clinical development must be a thoroughly paced process sequenced by clinical and developmental questions logically ordered. Drug development parameters are changing due to better insights in system biology and mechanisms of actions. Therefore, there is a need to revisit how clinical trials are designed and sequenced.Areas covered:In the context of this paper, the development of glufosfamideis placed in perspective of possible new trends for more optimal drug development. Glufosfamide is an alkylating agent with a favorable safety profile as its metabolic activation does not lead to the release of toxic metabolites such as acrolein. In addition, its cellular uptake mediated through the transmembrane receptors of glucose makes it an attractive agent for the treatment of highly proliferative tumors cells. These observations have served the rationale to bring this agent to the clinic from Phase I up to Phase III with a focus on pancreatic cancer. The pathways for its development have been challenging due in part to the fact that there is no proof of mechanism-based study for any alkylating agent, even those used in the clinic.Expert opinion:Solid mechanism and translational research-based clinical trials providing evidence on the mechanism of action and how the agent interacts with the biology of the targeted disease are today an absolute requirement for the development of new agents. Optimal clinical trial design must complement system biology understanding so that ‘trials designed to learn' may give robust grounds to ‘clinical trials designed to conclude'.

International investigator-driven clinical trials (IDCTs) satisfy international standards for quality, achieve maximum efficiency, avoid duplication of effort, and realize effective and widespread implementation of research results into medical practice. This article focuses on specific intercontinental issues involving the development and conduct of IDCTs and reviews what is necessary for a successful international partnership, specifically, intergroup trials involving the European Organisation for Research and Treatment of Cancer (EORTC) and the US-based National Cancer Institute intergroup system. Through examples, it is shown that the lead group of an international intergroup IDCT must have the expertise and capabilities to work effectively in the international setting, establish working procedures, consider the regulatory environment and QA/QC in the trial setting, and secure the principles of academic independence.

The present article reviews the randomized trials contributing to the establishment of current standards for the treatment of head and neck cancer. It provides critical analysis of their methodology in order to facilitate future trial design.

The purpose of the clinical trial guidelines is to harmonise legislation in order to ensure consistency within Europe and thereby promote Europe’s attractiveness for clinical research while maintaining or improving the protection of subjects who agree to participate.

La directive essais cliniques avait pour but une harmonisation des législations afin de favoriser la cohérence du système européen et par la même l’attractivité de l’Europe en matière de recherche clinique tout en maintenant ou renforçant la protection des personnes qui acceptent d’y participer.

Background. XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of the present study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with ovarian cancer who had relapsed within 1 year after first-line chemotherapy with taxanes and platinum for advanced disease. Patients and methods. Patients received XR5000 at the dose of 3010 mg/m2through a 120-h central venous infusion every 3 weeks. Toxicity was graded according to the Common Toxicity Criteria (CTC), version 2.0. An independent panel assessed response every two cycles according to the World Health Organization (WHO) criteria. Gehan's rule was used for sample size determination. Results. Sixteen patients were enrolled; one patient was ineligible because of prior melphalan single agent treatment. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (eight patients), 1 (five patients), or 2 (two patients). The 15 eligible patients received 43 cycles of XR5000 (median 2, range 1–8). Hematological toxicity was mild with only one grade 3 anemia in one patient. Other drug-related toxicities never exceeded grade 3 and included fatigue (four patients), thrombosis (one patient), nausea (one patient), stomatitis (one patient) as well as dyspnea/cough (one patient). One patient who had refused further therapy and controls after the first cycle was not assessable for response evaluation. No objective responses were observed. Four patients experienced stable disease and 10 patients progressive disease. The median time to progression was 42 days (CI 95% 40; 54). Conclusions. The complete lack of any objective response does not justify further evaluation of XR5000 in patients with advanced ovarian cancer using this dose and schedule, although the therapy was generally well tolerated.

The availability of targeted anticancer drugs and the relative affordability of genomic analyses has led to a growing expectation among patients with cancer that they can receive personalized treatment based on the genomic signature of their tumour. Here, we discuss some of the challenges and steps needed to bring such approaches into routine practice.

Primary Cutaneous T-cell Lymphomas (CTCLs) are a heterogenous group of lymphomas, as outlined in the WHO classification. Due to the rarity of CTCL, very few prospective randomized trials have been performed for this disease. EORTC consensus recommendations for the treatment of early CTCL have been published, but treatment of advanced stage disease remains largely empirical, based on small non-randomized, uncontrolled studies with uncertain response data and limited chances to affect clinical practice.The CTCL platform has been designed by the EORTC Cutaneous Lymphoma Task Force to address critical unadressed questions to move forward the standards of care of CTCL in advanced stage disease. It was built following a sequential approach. Following a European consensus defining the key clincial questions to improve disease control in CTCL, ideas regarding the biology of the disease and all possible emerging targets which may lead to a better understanding of the disease were explored. The candidate targets were selected and prioritized by their scientific and clinical relevance. The maturity and relevance of agents in development to tackle these pathways and targets were analyzed. Methodologically and statistically robust clinical trials were designed to allow the enrollment of patients through the evolution of their disease. Endpoints and translational research programs that could address and help identify mechanisms of action and clinical efficacy were also evaluated as to feasibility and scientific relevance. This comprehensive process lead to the design of early phase randomized trials on solid scientific grounds with the use of innovative drugs. Study protocol 21081 is a multicenter, randomized, open-label, phase III study and is suitable for patients who have not previously had other intravenous chemotherapy, and are therefore relatively treatment-naïve. The accrual goal is 105 patients. The objective of this trial is to test the hypothesis that lenalidomide is able to increase progression free survival in patients achieving a complete (CR) or partial (PR) response after standardized debulking treatment. A sister protocol, 21082, is addressed to patients who have had previous chemotherapy. Patients in that study will be treated with the histone deacetylase inhibitor vorinostat, with or without the addition of the proteosome inhibitor bortezomib. The primary objective of this trial will be to determine if the combination of bortezomib plus vorinostat is more effective than a histone deacetylase inhibitor alone in terms of prolonging progression free survival.The presentation will address details of the disease biology which gave rise to these trials and the selection of innovative agents, the procedures of the strategy adopted and the challenges of designing methodologically valid trials addressing this rare disease.Ortiz-Romero: MSD: Consultancy; Ferrer: Honoraria.

Emerging technologies and progress in data processing allowed for new insights on gene expression, genomics and epigenomics, and mechanisms of cancer genesis and progression. The development of new therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Therefore, the methodology and the design of cancer clinical trials as well as the methods of their implementation are under profound changes. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. It has been questioned therefore whether clinical trials traditionally designed for specific tumor types could not re-visited towards trials gathering patients based on molecular features rather than pure pathology criteria. The complexity of the cancer biology being the result of so many different interactive mechanisms whether driving or not the process of cancer cells is an additional level of complexity to approach more inclusive clinical trial access. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. This paper questions the advantages and the limits of clinical trials performed across tumor types bearing similar selected molecular features and looks further into the feasibility of such histology agnostic trials.