Author:

Carla van Herpen

Abstract

Rare cancers are defined as those with an incidence of fewer than 6 per 100,000 people per year in Europe. This definition is used since 2011. Out of 260 cancers, which exist in total, 223 are rare. Nowadays, more than 4.3 million people with a diagnosis of rare cancer are living in the European Union. The prognosis of patients with a rare cancer is worse than that of patients with a non-rare cancer. Between 1995-1999 and 2015-2019, 5-year survival rates for rare cancers increased to a lesser extent (i.e., 6.4%) than for non-rare cancers (i.e., 13.2%). Rare cancers have common challenges, like a late diagnosis or delay in diagnosis, less expertise, fewer guidelines, a limited number of registered medications and fewer clinical studies. For improvement of care and prognosis in rare cancers working in networks, better diagnostics, the use of precison medicin and treatment in basket studies, development of studies with alternative designs and patient involvement are all of utmost importance.

Introduction

Definition and numbers

Rare cancers are defined as those with an incidence of fewer than 6 per 100,000 people per year in Europe (Gatta et al 2011), and fewer than 15 per 100,000 people per year in the US (Greenlee et al 2010). In contrast to the definition of rare cancers based on incidence, the definition of rare diseases is based on prevalence, i.e. those that affect fewer than 5 in 10,000 people. In this chapter we will focus on rare adult solid cancers. We will not discuss rare hematological malignancies, nor pediatric cancers. In 2008 the EU-funded project Surveillance of Rare Cancers in Europe (RARECARE), the multi-stakeholder effort RareCancers Europe, was founded; it involved patients, healthcare professionals, industry, the European Society for Paediatric Oncology (SIOP Europe) for paediatric cancers, and many others.

In 2011 results of an analysis of European population-based cancer registry data for patients with cancer diagnosed between 1988 and 2002 was performed by RARECARE (Gatta et al 2011). In that study, for the first-time rare cancers were defined as those with an incidence of less than six per 100,000 persons per year. 22% of all new cancers annually classify as rare cancers. Since 2011, this definition of rare cancers has been widely accepted. In a large-scale European study in 2017, the RARECARE project showed that out of 260 cancers, which exist in total, 223 are rare (Gatta et al 2017). Rare cancers accounted for 24% of all cancers diagnosed in the Europe during 2000-2007. The RARECARE project proposed a list of rare cancers, in which adult solid rare cancer entities were grouped into ten ‘domains’. This list was based on the International Classification of Diseases for Oncology (ICD-O), which incorporates topographical and histological labels) (Percy 2000).

Comparing incidences of rare cancers worldwide using the RARECARE definition demonstrates that rare cancers represent 24% of cancer diagnoses in Europe (period: 2000-2007), 20% of cancers in the United States (period: 2009-2013), 16-24% of cancers in Asia (period: 2011-2015), and 17% of cancers in Canada (period: 2006-2016) (DeSantis et al 2017; Gatta et al 2017) (Matsuda et al 2020) (Walker et al 2020)

In 2020, the Joint Action on Rare Cancers (JARC), launched by the EU in 2016, published a consensus paper in which all rare cancers were grouped within 12 families of rare cancers. Their new definition was more conservative, and leads to a lower percentage of rare cancers, i.e. 10%-20% of all cancer cases (Casali & Trama 2020). Potential implications of the adjusted partitioning and whether there will be widespread adherence to this proposed modification still has to be explored. A comparison of rare cancers as grouped within the RARECARE domains and within the JARC families is needed as a first step (de Heus et al 2022).

Examples of a rare cancer are sarcomas, thyroid cancer, brain tumours, head and neck cancer, salivary gland cancer, Merkel cell carcinoma testicular carcinomas and cholangiocarcinomas. Other decisions that were made in several consensus meetings between 2011 and 2024 were as follows. All malignancies in children and adolescents are rare, including leukaemias and lymphomas. Some cancers have a hereditary risk component, of which some are rare cancers while others belong to common entities (e.g. sarcomas and breast cancer, respectively, when occurring in a Li Fraumeni syndrome). Currently, there is no specific code for heredofamilial cancers. However, hereditary cancer syndromes may be recorded in rare disease registries. The decision was made not to single out subgroups of common cancers, such as the molecular ones. This was done because the basis for the list of rare cancers was the ICD-O. Likewise, clinical subgroups were not considered (e.g. inflammatory breast cancer was not singled out as an entity, though it is rare).

Amongst rare cancers, some are exceedingly rare, i.e. ultra-rare. Several definitions are used for ultra-rare cancers ranging from less than 2 to less than 0.2 per 100.000/year.

Nowadays, more than 4.3 million people with a diagnosis of rare cancer are living in the European Union (EU), as reported in a study by RARECARE (Gatta et al 2017) .

Prognosis in rare cancers

The prognosis of patients with a rare cancer is worse than that of patients with a non-rare cancer. In 2017 the RARECARE project has shown that in Europe, after 5 years, 63% of non-rare cancer patients are still alive, compared with only 49% of rare cancer patients; thus, the difference is as much as 14% (Gatta et al 2017). Recently, an analysis of epidemiology data of the from the Netherlands Cancer Registry was published: ‘The gap between rare and common cancers still exists’. Between 1995-1999 and 2015-2019, 5-year survival rates for rare cancers increased to a lesser extent (from 46.2% to 52.6%, i.e., 6.4%) than for common cancers (56.9% to 70.1%, i.e., 13.2%), and for most rare cancer domains compared to common cancer domains. Most rare cancer entities did not show an improvement in 5-year survival (de Heus et al 2022).

Challenges and solutions

Rare cancers have common challenges within health care for both clinicians and patient, which might be causes for the poorer and still not improving prognosis. Knowledge and expertise are not widely available, and information regarding rare cancers is limited, which may lead to misdiagnosis, delay in diagnosis, and/or lack of access to appropriate therapies. Scientific studies in rare cancer patients face difficulties as well, due to the small number of patients available for inclusion. A phase III study with hundreds of patients for non-rare cancers, such as breast, prostate or lung cancer, is quite feasible, but unfortunately, for the rare cancers, we cannot bring together hundreds of patients to conduct a phase III study. Furthermore, there are a limited number of guidelines and registered medications. Also, dedicated funding is an obvious difficulty. Limited marketing opportunities affect the motivation of pharmaceutical and other companies to develop new drugs in rare cancers.

European rare cancer agenda

In 2017 the European Rare Cancer Agenda 2030 was published in which the main recommendations of the Joint Action on Rare Cancers, were enshrined (JARC). Ten recommendations were made to be instrumental to the policy agenda on rare cancers in the European Union. Most importantly healthcare networking and clinical and research methodology are the two areas that could make the largest difference to improve care in rare cancers. These two areas give rise to much of the topics discussed in the “rare cancer agenda 2030”, which, in the end, was drafted in 2019 by many disease-based communities.

Networks

In 2017, the European Commission launched 24 European Reference Networks (ERNs) to improve the quality of care of patients with rare diseases. Four ERNs are dedicated to cancer: GENTURIS (for patients with rare genetic tumour risk syndromes), PAEDCAN (for paediatric cancers), EUROBLOODNET (for haematological malignancies), and EURACAN (for rare adult solid tumours) (Blay et al 2021). EURACAN includes ten clinical domains representing the ten different groups of rare adult solid cancers: sarcomas, rare gynaecological malignancies, rare urological malignancies, neuroendocrine neoplasms (NEN), rare gastrointestinal tract tumours, endocrine cancers, head and neck rare cancers, rare thoracic cancers, rare skin and eye tumours, and central nervous system –CNS- tumours, including subdomains for several of the domains. There were initially 67 full member centres across 16 countries, working closely with 14 patient advocacy groups (ePAGs) and 22 scientific societies and rare cancer networks to meet the objectives set within the first grant period (5 years). EURACAN has also recently expanded substantially with now (in 2024) 106 centres across 25 countries, 15 ePAGs and 24 associated partners and stakeholders (scientific societies, national rare cancer networks). In the last five years EURACAN promoted management in reference centres, and equal implementation of excellence and innovation in Europe and developed 22 clinical practice guidelines (CPGs). Additionally, fourteen information brochures translated in 24 EU languages were developed in collaboration with patient advocacy groups (ePAGs) and seventeen training sessions were organized. Nevertheless, connections to national networks in the 26 participating countries (106 centres), simplification of cross-border healthcare, international multidisciplinary tumour boards, registries and monitoring of the quality of care are still required (Blay et al 2024).

##Better diagnostics

Inherently, the diagnostic procedures for rare cancers parallel those employed for conventional cancers. These diagnostic modalities include a comprehensive array of techniques, including physical examination techniques such as pressure application, histological studies, fine needle aspiration cytology (FNAC), biopsy, X-ray imaging, and electron microscopy. Despite the effectiveness of these conventional diagnostic approaches in common cancers, their application encounters inherent limitations pertaining to accuracy and early detection in rare cancers. The resemblance in physical characteristics between common and rare cancers often results in the inadequate and inaccurate diagnosis of the latter. Modern diagnosis utilizing novel techniques has been playing an important role in the development of rare cancer diagnoses. The use of genome sequencing, RNA-Sequencing and Omics Analysis are all important and supports to diagnose rare cancers more rapidly. Also, the use of AI and digital pathology helps to diagnose patients with a rare cancer in an appropriate and faster way. All these new diagnostic tools will be gradually more used for rare cancer diagnosis during the coming years.

Molecular diagnostics and precision medicin

Because the number of treatment lines in recurrent and/or metastatic disease is limited in rare cancers, DNA genomic analysis or RNA analysis is used to detect drugable mutations, drugable fusion genes or microsatellite instability-high (MSI-H). These comprehensive genomic analyses, performed broadly in studies since 2010, guide to therapeutic options of which it is shown in basket studies that this can be beneficial for rare cancer patients (Horak et al 2021) (Hoes et al 2022). Patients with rare cancers can benefit from tumor-agnostic indications. In May 2017, the FDA granted accelerated approval to the anti-PD-1 mAb pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors that continued to progress after conventional treatment, based on the data from 149 patients with MSI-H or dMMR cancers enrolled across 5 clinical trials (Prasad et al 2018). This was the FDA’s first tissue-/site-agnostic approval, i.e., the first time the agency has approved a cancer treatment on the basis of a tumor’s specific genetic features regardless of its primary site.

Another tumor-agnostic targeted treatment is the use of Neurotrophic tyrosine receptor kinase (NTRK) inhibitors. NTRK gene fusions are an actionable biomarker for cancer therapy and can be found in over 25 different types of cancer, of which many are rare cancers (Thein et al 2024).

Studies with alternative designs

In principle, the difficulties of rare cancers in terms of clinical research are by definition related to the low number of patients (Casali et al 2015). This limits “statistical precision” in clinical, translational and outcome research.

The principle that a higher degree of uncertainty needs to be tolerated in rare cancers should be acknowledged in selecting the methodology of new clinical studies. In general, clinical studies should also be done when a lower statistical precision is likely, given available numbers, and their patient populations should be selected exclusively to maximize the chances of any new treatment to display its maximum efficacy, without widening eligibility criteria inappropriately. Newer designs non-randomized clinical, use of identifying a priori external (historical) controls, Bayesian designs, basket studies.

Patient involvement

The European Cancer Patient Coalition (ECPC) is Europe’s largest cancer patient umbrella organization. Established in 2003, as of 2019 ECPC represented over 450 cancer patient organizations in 46 countries, effectively acting as a united voice of cancer patients in Europe. ECPC has set up a Working Group on Rare Cancers (WGRC), with the mission to support the work of JARC. ECPC’s WGRC has grown to include over 60 rare cancer patient organizations as active members. ECPC counts on the expertise and collaboration of rare cancer patient organizations all over Europe to continuously represent the rare cancer patient community. ECPC previously contributed to the RARECAREnet project by collecting patient information materials on rare cancers. Furthermore, ECPC is the elected ePAG representative across all cancer domains for EURACAN.

Conclusion

The prognosis of patients with a rare cancer is worse than that for a common cancer and also increases less over the past 20 years. The attention for and research in rare cancers has increased in recent years, hopefully leading to truly better care and prognosis for these patients.

Table 1

The European Reference Network for Rare Adult Solid Cancers (EURACAN) groups rare cancers into ten domains based on the RARECARE classification. These domains are:

1. Rare cancer of the connective tissue (sarcomas)
2. Rare cancer of the female genital organs and placenta
3. Rare cancer of the male genital organs and urinary tract
4. Rare cancer of the neuroendocrine system
5. Rare cancer of the digestive tract
6. Rare cancer of the endocrine organs
7. Rare cancer of the head and neck
8. Rare cancer of the thorax
9. Rare cancer of the skin and eye melanoma
10. Rare cancer of the brain and spinal cord

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