RARE CANCERS

Expanding the network


In the last decade, international cooperative efforts have changed a lot in terms of how rare cancers are diagnosed, treated and managed. Networks such as Rare Cancers Europe and its recently launched Asia-Pacific counterpart Rare Cancers Asia are having a key role in improving standards of care globally. Despite the many successes, it is a long way ahead. What is yet to be done?

Rare cancers have always represented a challenge in oncology. Due to their low incidence — less than 6 newly-diagnosed cases per 100,000 persons per year — they may prove more difficult to diagnose, treat and manage, and the limited number of clinical trials together with a scarce interest from pharmaceutical stakeholders have affected the quality of care for long.


Despite these aspects still pose major barriers to what can be offered to patients in terms of options of treatment, cross-country cooperative efforts have significantly changed the paradigm of care in rare cancer. By raising awareness, the long-standing work of Rare Cancers Europe — a multi-stakeholder initiative established together with ESMO as founding partner in November 2008 to overcome the unique challenges faced by rare cancers community — has resulted today in rare cancer receiving more recognition and being on the European policy agenda. Having reached its 10th anniversary, RCE celebrated its achievements and discussed the remaining challenges ahead in a multi-stakeholder event held in the European Parliament in September 2018.


Building on the successes of RCE, ESMO last year launched Rare Cancers Asia (RCA) founded jointly with actors ranging from patient advocacy groups to research institutions and industry partners across Asia-Pacific. This new initiative will focus on supporting education, research and epidemiology in the Asian-Pacific cultural and socio-economic settings, and will benefit from the resources offered by European Reference Networks on rare cancers by collaborating and sharing experiences with Rare Cancers Europe. We spoke with different stakeholder representatives involved in RCE and RCA to gain their perspectives on the achievements so far and the goals ahead.

Paolo Casali
Istituto Nazionale dei Tumori, Milan, Italy; Co-founder of Rare Cancers Europe and Rare Cancers Asia
“We have put rare cancers on the EU policy agenda”

What major challenges were overcome in rare cancer care in the last decade?

The big achievements in medical and clinical oncology in general have also impacted the management of rare cancers. Although there are increasingly specific drugs with orphan status for rare cancers, many of the major cancer drugs in general have indications in rare cancers as well. However, even a drug like imatinib, which is indicated for the treatment of a few rare cancers, was developed effectively. This suggests that rare cancers are receiving more recognition and that drugs with indications in rare cancers are less “orphan” than previously.

What is the potential impact of the EU HTA draft Regulation on improving treatment options for rare cancer patients?

Health Technology Assessment (HTA) has become an important part of decision making on new drugs in most European countries, weighing evidence-based information with cost considerations. The EU draft regulation on HTA aims to decrease discrepancies at least by harmonising the assessment of evidence. This would be an important step forward.

After 10 years, what do you think are the main challenges ahead for RCE?

So far, RCE was instrumental in raising awareness and putting rare cancers on the European policy agenda. A EU Joint Action on Rare Cancers (JARC) is ongoing, while European Reference Networks have been deployed also on rare cancers, not only rare diseases. These were achievements. Now, we must go ahead addressing the major factors that can affect survival rates for rare cancers. These include the difficulties in carrying out clinical trials, due to the small number of patients with these cancers, as well as discrepancies in quality of care due to limited clinical expertise in the community.

“RCE was instrumental in raising awareness in Europe”

The EU cross-border healthcare directive led to the creation of 24 European Reference Networks (ERNs) for rare diseases. Importantly, 3 ERNs were created in 2017 specifically for rare cancers—EURACAN (rare adult solid cancers), PaedCan (paediatric cancers) and EuroBloodNet (haematological diseases and cancers). The implementation and growth of these ERNs for rare cancers has been vital in improving outcomes. ERNs are comprised of national centres of excellence across EU member states; these centres were already experienced in collaborating with each other in terms of research and now the hope is that they can collaborate in healthcare too.
This will lead to much greater improvements in quality care when each European country develops national networks with harmonised practices and links to ERNs, and these are integrated into these national health systems. This will allow patients to be referred to centres within their own country. However, developing national networks will likely be harder for some countries than others—for many countries ERNs have marked the first time they selected national centres of excellence for rare cancers. RCE is working with the JARC to help promote and support the development of national networks within European countries. Factors such as patient referral pathways and reimbursement for treatments carried out cross-border also remain issues to be overcome.

RCE and JARC intend to publish a summary of the JARC’s work after a 3-year collaboration, including a set of 10 key recommendations, honed by consensus from the original 39 political and stakeholder recommendations defined at the RCE’s inception in 2008. These 10 recommendations will become the new founding recommendations for RCE going forwards.

Do we need to do more to educate oncologists on rare cancers?

ESMO and the ERNs for rare cancers are working together to develop clinical practice guidelines for rare cancers. For example, on sarcoma, we now have ESMO-EURACAN-PaedCAN clinical practice guidelines, which hopefully will aid harmonisation of practices across national networks.


One of the challenges with educating the oncology community is that clinicians and healthcare professionals often do not get to put their new knowledge into practice for a long time due to the relatively few patients with these cancers. It is important to target the oncologists most likely to see patients with rare cancers. RCE is striving to develop a fellowship programme that will provide opportunities for young oncologists to travel to and learn from institutions within the ERNs for rare cancer. The overall aim is to create both medical education and career pathways for young oncologists interested in managing rare cancers, particularly rare adult solid tumours.

How can RCE and RCA work towards high-quality, sustainable cancer care?

RCA is a new initiative launched by ESMO at the end of 2018, which will build on the success of RCE, through collaboration and shared experience. In terms of collaborations between RCE and RCA, 3 initial projects are: 1) an educational programme on sarcoma that will share clinical experience and aim to harmonise pathological diagnosis and clinical practice for this group of rare tumours; 2) an epidemiological and translational research project on nasopharyngeal cancer—a rare cancer with striking epidemiological characteristics that is relatively rare in Europe yet relatively more common in Asia; and 3) harmonisation of data collection from cancer registries in Asia, particularly in terms of epidemiological data to estimate the incidence of rare cancers and compare it across selected Asian countries, as well as between Asia and Europe.

Annalisa Trama
Istituto Nazionale dei Tumori, Milan, Italy
“We can learn from each other on this Europe-Asia bridge”

Why was 2018 the right time to launch Rare Cancers Asia?

The launch of Rare Cancers Asia (RCA) in November last year represented a very important milestone for Asia-Pacific, and for Europe too, in diagnosing and treating rare cancers. The introduction of the European Reference Networks (ERNs) just two years ago highlighted the importance of their integration into the national healthcare systems of many EU countries, and we now have the knowledge to build the best framework to deal with the challenges posed by rare cancer management. By creating a Europe-Asia bridge, we aim to share what has been learnt so far between the two regions, and the continued support of ESMO together with all the different stakeholders involved will be crucial to the success of this venture.

What countries and registries are involved?

As a priority, RCA is currently working on a number of initial projects that were identified as requiring urgent attention, each involving a number of countries. One project is the development of a clinical/pathological web sarcoma board. Another project is looking to develop a better understanding of the underlying tumour biology of Epstein Barr Virus (EBV)-related nasopharyngeal cancer (NPC), which is rare in Europe but not in Asia, by means of high throughput processing of samples in both Europe and selected Asian countries with a high incidence of NPC. The study will further the understanding of this rare cancer and will facilitate the improvement of treatment options, possibly stratified by geographical region, based on tumour biology in Europe and Asia. The third project, and the one that I am coordinating, is an epidemiological study investigating the incidence and relevance of different rare cancers in the region. A key challenge is the lack of available data on rare cancers in the Asia-Pacific region, which makes it difficult to understand their extent and their impact. To improve the understanding of rare cancers, bearing in mind the diverse epidemiology of the region, RCA recognises the need to generate reliable regional epidemiological data by working with the available population-based cancer registries and building on the experience of the European projects, RARECARE and RARECAREnet. We have started to work with national population-based cancer registries from Japan, South Korea and Taiwan—with the presentation of the first results at ESMO Asia 2018—and hope in time to extend this to other countries.

Will data collection and interpretation be standardised across countries and with those of RCE to allow combination of data across the databases?

One of the biggest challenges faced in utilising data on a regional basis is how reliably the data from national registries can be combined. Guidelines for collection and analysis of data from population-based cancer registries, along with the mandatory use of the International Classification of Diseases for Oncology, ensure that reporting and disease classification are standardised at an international level. However, quality of data is equally important, and this can vary between areas, often as a result of resources, the healthcare organisation (for rare cancers, the expertise availability) and the healthcare information system. Programmes like the Global Initiative for Cancer Registry Development run by the International Agency for Research on Cancer (IARC) with different partners are trying to establish standardised registries, with a special focus on the Asia-Pacific region, and our study is not intended to duplicate work. Merging databases into a centralised resource is not an option for RCA, given data protection issues surrounding the exporting of data out of individual countries. Instead, we are exploring the use of a standardised analysis tool kit to allow each cancer registry to perform their own analyses.


Looking ahead, we hope to use distributed learning as a way of providing combined results without merging data in a common dataset, a process that requires good collaboration between national sources.

What challenges do you see in trying to harmonise diagnosis and clinical practice for rare cancers across the two continents?

Harmonising clinical practice between Europe and Asia is another challenge. We know that there is heterogeneity of clinical practice both within, as well as between, these regions.

"Harmonisation of clinical practice between Europe and Asia will be more likely if we can structure healthcare systems for rare cancers along similar lines in each country or region"

Central to these systems will be the expertise of the pathologists, which is fundamental to ensuring quality of diagnosis, and the use of a good multidisciplinary team. Collaboration is also important for education—which is a big problem in rare cancers—and centres that see few rare cancers can learn from those that treat more cases.

What are the potential benefits for EU and Asian cancer communities of the mutual exchange of information?

Asia will benefit from the long experience we have in rare cancers in Europe. And Europe will benefit too. For example, the data from the EBV-associated NPC in Asia should help us to understand whether the disease has a common biology across the continents or whether the pathophysiology differs between Europe and Asia and, therefore, requires a different treatment approach. Europe will also benefit from the advanced technological expertise of some Asian countries, which will be crucial to interpreting Big Data for rare cancers.

Francesco Pignatti
Oncology, Haematology, Diagnostics – Safety and Efficacy Sector at European Medicines Agency (EMA), Amsterdam, Netherlands
“We aim to facilitate the clinical development of promising therapies for rare cancers”

What has been done to address the need of rare cancer-specific study design at an EU level?

Special provisions exist to address the specificities of certain types of medicinal products and promote research in specific areas, including orphan medicinal products. For instance, the EMA provides a form of scientific advice specifically for orphan medicines called protocol assistance. This allows sponsors to get answers to their questions on the types of studies needed to demonstrate the medicine's quality, benefits and risks, and information on the significant benefit of the medicine. Recently, the Priority Medicines (PRIME) scheme was launched by the EMA to enhance support for the development of medicines that target an unmet medical need. Through PRIME, the EMA offers early and proactive support to medicine developers to optimise the generation of robust data on a medicine's benefits and risks and enable accelerated assessment of medicines applications.


Methodological and regulatory guidelines on drug development for small populations are also available.

"The EMA is committed to continuing discussions with rare cancer stakeholders and to provide advice during the drug development process in order to support vital innovation in the field of rare cancers."

An example of this commitment is the EMA and ESMO’s RCE initiative, which has been holding regular workshops to discuss drug development case studies to identify main challenges and possible methodological solutions as well as scientific and regulatory evidence requirements for rare diseases, with the aim of facilitating the clinical development of promising therapies for rare cancers.

How are “adaptive pathways” which aim to improve timely access for patients to new medicines helping to improve treatment of rare cancers?

Adaptive pathways can support medicine development in therapeutic areas where evidence generation is challenging, such as rare cancers. Also, adaptive pathways can bring multiple stakeholders together—regulators, health technology assessment (HTA) bodies, healthcare professionals and patients—to agree on a prospective plan to generate data on a medicine across its lifespan in areas of unmet medical need.


When assessing the evidence, regulators need to strike a balance between early access for patients affected by conditions with high unmet medical need versus having as complete information as possible on the benefits and risks. For instance, considering all therapeutic areas, out of 104 orphan medicinal products approved by 2015, 3 were approved on the basis of case studies or compassionate-use programmes and 9 were approved on the basis of published data only. For the 37 oncology products in this series, 11 were approved on the basis of non-randomised controlled trials and 2 were based solely on bibliographical data.


The EMA has recently published a report on an adaptive pathways pilot project. The pilot helped to identify a number of aspects for further reflection, including: the need for increased involvement of patients to assist in the selection of candidates for adaptive pathways; the definition of methodologically sound strategies of real-world evidence collection to support the assessment of both efficacy and effectiveness; and the potential involvement of payers—Member State organisations responsible for decisions on pricing and reimbursement—to provide input on pricing strategies. The EMA will further explore adaptive pathways in the context of its parallel advice with HTA bodies, which provides a framework to include additional stakeholders (e.g. patients and, if relevant, payers).

Kathy Oliver
International Brain Tumour Alliance, Surrey, UK
"We can become more engaged in international networks by volunteering our time to work with these organisations"

As a patient advocate, do you think Rare Cancers Europe has helped the management of rare cancers?

I’ve been involved in RCE for ten years through the International Brain Tumour Alliance (IBTA), which was one of the founding members of RCE. Over this time, RCE has significantly helped to raise awareness, in several ways, of the challenges surrounding rare cancers. I believe this will have a positive impact on how we research, treat and eventually cure these difficult diseases.


Firstly, an important European consensus position paper by RCE members on clinical trial methodology for rare cancers, published in 2015, allowed RCE to bring some of the challenges associated with these types of studies to the attention of the EMA. This led to in-depth discussions on regulatory issues relating to rare cancers.

"These efforts demonstrate that regulators do want to hear what RCE has to say and will hopefully consider our suggestions for improvements"

In terms of managing rare cancers, RCE plays a pivotal role in JARC and was a crucial partner in the establishment of EURACAN and ERNs such as PaedCan (for paediatric cancers) and EuroBloodNet (for rare haematological diseases, including blood cancers). ERNs facilitate virtual medical consultations, with the aim of ensuring timely, adequate and equal access to diagnosis and care for people with rare cancers in the EU.


RCE’s work has also provided patient advocates with some excellent resources, such as the Patient Advocacy Toolkit for Rare Cancers — a concise online guide that helps rare cancer patient advocacy organisations speak confidently about the challenges faced by their communities and provides a practical guide on how to convey key messages about rare cancers in the most effective ways.

Furthermore, RCE regularly deliver high-quality educational courses in rare cancers to healthcare professionals and patient advocates.

In your opinion, what challenges remain? And which is the biggest?

For patients with rare cancers, ERNs should help to address challenges of a timely and accurate diagnosis, help patients benefit from shared clinical expertise and promote better access to clinical trials. Remaining challenges to improving patient outcomes include the still substantial underfunding of rare cancer research, the need for better understanding of the epidemiology of rare cancers, increasing treatment options, and the long-term sustainability of well-established, multi-stakeholder, collaborative rare cancer networks. In addition, as our knowledge about cancer grows and common cancers are increasingly compartmentalised into rare subtypes, clinical trial designs will need to be adjusted to allow for significantly smaller trial populations.

How has the role of patient advocates changed in the last 10 years?

I think that one of the most significant changes is the level of specialist education that patient advocates can access to improve their knowledge and skills. For example, RCE and ESMO have been offering specialist training courses for patient advocates for some years now. The faculty on these courses comprises expert patient advocates and world-leading scientists and clinicians. This has greatly increased the level of knowledge that patient advocates now possess.

“Patient advocates in the rare cancer field need to be well informed about many aspects, including pre-clinical studies and clinical trials, safety issues, ethics, trial accrual procedures, statistics and other research topics”

Nowadays, patient advocates must be well-informed on every oncology-related aspect and also comfortable working within the regulatory arena, including understanding medicine approval processes, plus aspects such as benefit versus risk, patient reported outcomes measures and quality of life issues, and health technology assessment. These days, expert patient advocates participate in discussions about complex scientific and regulatory issues, they co-author scientific papers and they are speakers at major international oncology conferences in plenaries, workshops and panel debates. This degree of high-level involvement relies on a solid understanding of the various issues relevant to rare cancers.

How can patients be more engaged in international networks such as RCE and RCA and what would be the benefits?

Achieving success in rare cancers—such as better treatments, improved outcomes, good quality of life—requires international collaboration on a global scale. RCE has united healthcare professionals and patient advocates across Europe in the quest for these goals. RCA is set to do the same across the Asia-Pacific region of the world. By working together, there will be less waste of precious resources, more knowledge-sharing and less duplication of efforts.


Not only will advocates learn from their involvement but they will have the opportunity to provide their unique perspectives on what is really of value to people with rare cancers. Patients and patient advocates could also take advantage of educational courses offered by RCE and RCA in order to enhance their own knowledge and understanding.

How can patients/patient advocates work more closely with medical and regulatory bodies to improve outcomes?

Patients/patient advocates should actively seek engagement with medical and regulatory bodies. They should take advantage of as many educational opportunities as possible, to increase their understanding of the work and perspectives of these stakeholders. In addition, to achieve successful working relationships, it is important that patients/patient advocates and medical/regulatory bodies respect each other’s opinions, even though they may not always agree with them.