Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper

Abstract

While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to stepwisely test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers .

Systemic therapy for selected skull base sarcomas: Chondrosarcoma, chordoma, giant cell tumour and solitary fibrous tumour/hemangiopericytoma

“…In this regard, an effort to improve the methodology of research in rare cancers is in place within the European community. 66 In addition, given the heterogeneity of sarcomas, an endeavour to centralise the treatment of sarcoma cases into reference centres or collaborative networks is also strongly requested, since it is a prerequisite to increase our chances to intensify clinical and translational research. …”

Emerging Opportunities for Target Discovery in Rare Cancers

“…Important additional topics, not reviewed herein, include challenges in funding rare cancer research and opportunities to accelerate the drug development process, including drug development incentives and redesign of clinical trial protocols (Panageas, 2015; Casali et al, 2015). …”

“…This evidence, which can be anecdotal, is in stark contrast to the multi-institutional cancer statistics studies routinely reported for common cancer types (National Cancer Institute, 2016b). Low incidence rates also make clinical trial recruitment for rare cancers extremely challenging, stalling efforts to test emerging therapeutic hypotheses (Casali et al, 2015; Tan et al, 2003). In basic research settings, a scarcity of rare tumor tissue and patient-derived models can preclude well-powered studies aimed at elucidating underlying biology (Boehm and Golub, 2015).…”

Management of GIST—go beyond imatinib: treat resistant subtypes

“…Innovative approaches to combine all the available evidence and the use of Bayesian approaches to quanti fy uncertainty will be instrumental to optimize efforts and the clinical decision-making, as suggested by the Rare Cancer Europe Consensus Panel in a series of recommendations to improve the clinical research on rare cancers. 10 In conclusion, although the ENESTg1 findings confirm imatinib as the first-line gold-standard of care in KIT/PDGFRA mutated metastatic GIST, the results highlight the need to shift our efforts on to finding other treatments for GIST subsets for which effective therapies are lacking, calling for molecularly designed trials. …”