There is no internationally agreed definition of a rare cancer. In Europe, rare diseases are often defined as those with a prevalence of <50/100, In the US, the Orphan Drug Act defines rare cancers as those affecting <200,000 persons. 2 The estimated annual incidence rate of all rare cancers in Europe (based on the RARECARE definition of an incidence of <6/100,000/year) is about 108 per 100,000, corresponding to 541,000 new diagnoses annually or 22% of all cancer diagnoses. This is more than any single common cancer. About 4,300,000 patients are living today in the European Union with a diagnoses of a rare cancer, 24% of the total cancer prevalence. Unfortunately, the average outcome for patients with a rare cancer is inferior to those with more common cancers. 3 In an attempt to address this issue, the International Rare Cancers Initiative (IRCI) was established early in IRCI is a joint initiative between the National Institute for Health Research Cancer Research Network (NCRN), Cancer Research UK (CR-UK), the National Cancer Institute (NCI) and the European Organisation for Research and Treatment of Cancer (EORTC). International Rare Cancers Initiative Reference Background: Objectives: Facilitate the development of international clinical trials for patients with rare cancers in order to boost the progress of new treatments for these patients. Encourage the use of innovative methodologies to maximise the potential to answer research questions. Identify and overcome barriers to international trials to allow collaborative trials to run smoothly. Criteria for inclusion in IRCI: 1. Rarity A fixed rarity cut-off is not applied, but as a guide cancers with a total incidence of <2/100,000/year have been considered for inclusion. Occasionally, rare clinical scenarios have also been considered. To date, IRCI has excluded rare molecular sub-types of common cancers, however, a rare molecular sub-type could be considered if it is a distinct, prospectively identifiable rare sub-group with a strong rationale for separate research, rather than inclusion as a molecular stratum in a mainline trial. 2. Lack of existing trials No (or minimal) existing trial data and no existing trial. 3. Potential for an interventional trial Priority is given to cancers with potential for an interventional trial (usually randomised) (not an audit, registry or non-trial tissue collection). There needs, therefore, to be research treatments of genuine interest for investigation, and sufficient patients for an international trial to be feasible. 4. Enthusiastic champions Enthusiastic commitment from investigators. Methods: At the outset of the initiative clinical communities associated with each partner organisation were asked to identify rare cancers where there was enthusiasm for international collaborations and the potential for development of an interventional (preferably randomised) clinical trial. It was not possible to take forward every rare cancer type suggested, but where interests coincided in at least two of the partner organisations, and the IRCI Board could see potential for research development, IRCI groups were formed. IRCI organises face-to-face meetings and teleconferences to allow potential clinical trial designs to be discussed and developed. Wherever possible these face-to-face meetings are run alongside international conferences. Activity: Of the nine groups supported by IRCI to date, seven are actively developing 10 clinical trials for submission to appropriate funding bodies. Two groups, anaplastic thyroid cancer and fibrollamellar hepatocellular carcinoma decided that there is no immediate role for an interventional trial, however, preparatory work is underway. Future plans: Continue to facilitate the existing groups. Initiate new groups - an initial teleconference has taken place to discuss the possibility of developing international trials for relapsed Ewing’s sarcoma and Desmoplastic small round cell tumours. Consider engagement with other international groups. Continue discussions with industry. Co-ordinate a methodological meeting. ‘I would be delighted to work on this with CR-UK and believe that it [small bowel adenocarcinoma] would be a good choice for a rare cancer.‘ Dr Richard Wilson (Belfast City Hospital) Ocular melanoma Leads - Dr Richard Carvajal (US), Dr Ernie Marshall (UK), Professor Poulam Patel (EORTC ) A randomized phase II trial of MEK versus MEK + AKT Gynaecological sarcoma Leads - Professor Jean-Yves Blay (EORTC), Dr Helen Hatcher (UK), Dr Martee Hensley (US) 1. A phase III randomised trial of gemcitabine plus docetaxel followed by doxorubicin versus observation for uterus-limited, high grade uterine leiomyosarcoma (IRCI 001) 2. A randomized phase II study evaluating the role of maintenance therapy with pazopanib in High Grade Uterine Sarcoma (HGUS) after stabilization or response to chemotherapy following surgery or in metastatic first line treatment 3. Efficacy of aromatase inhibitors in stage III-IV or recurrent endometrial stromal sarcoma: a phase II trial Salivary gland cancer Leads - Dr Kevin Harrington (UK), Dr Alan Ho (US), Dr Lisa Licitra (EORTC) A randomised phase II study to evaluate the efficacy and safety of Chemotherapy (CT) versus androgen deprivation therapy (ADT) in patients with recurrent and/or metastatic, androgen receptor (AR) expressing, salivary gland cancer (SGCs) Small bowel adenocarcinoma Leads - Dr Rob McWilliams (US), Dr Arnaud Roth (EORTC), Dr Richard Wilson (UK) 1. The BALLAD study: A global study to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma 2. Global study to evaluate the role of bevacizumab in combination with chemotherapy for metastatic small bowel adenocarcinoma Thymoma Leads - Professor Frank Detterbeck (US), Professor Mike Lind (UK), Dr Sanjay Popat (EORTC) Randomized study of resected stage III invasive thymoma or stage II –III thymic carcinoma with or without postoperative radiation therapy Relapsed/metastatic anal cancer Leads - Professor Dirk Arnold (EORTC), Dr Al Benson (US), Dr Rob Glynne-Jones InterAAct: A phase II international multicentre randomized advanced anal cancer trial comparing cisplatin plus 5FU versus carboplatin plus weekly paclitaxel in patients with relapsed or metastatic disease Penile Cancer Leads –Dr Steve Nicholson (UK), Dr Curtis Pettaway (US), Dr Christine Theordore (EORTC) InPACT – International Penile Advanced Cancer Trial ‘I would be honoured to be part of this effort! There is a great need for collaborative trials in the disease [penile cancer].’ Dr Curtis Pettaway (MD Anderson Cancer Centre) References: 1. European parliament and council of the European communities. Decision no. 1295/1999/EC of the European parliament and of the council of 29 April 1999 adopting a programme of community action on rare diseases within the framework for action in the field of public health (1999–2003); Available from: 3. Gatta G, van der Zwan JM, Casali PG, Siesling S, Dei Tos AP, Kunkler I, Otter R, Licitra L, Mallone S, Tavilla A, Trama A, Capocaccia R, RARECARE working group. Rare cancers are not so rare: The rare cancer burden in Europe. Eur J Cancer, 2011, Nov;47(17): N Keat, K Law, M Seymour, J Welch, T Trimble, D Lacombe, A Negrouk