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The challenge of treating rare cancers in children

Rare cancers in children are treated by medicines developed for adults but in a lower dose after having the dose adapted for the paediatric population


Rare cancers in children are treated by medicines developed for adults but in a lower dose after having the dose adapted for the paediatric population


Marc Dooms
Senior orphan-drug pharmacist, University Hospitals Leuven, Belgium Email: [email protected]
Childhood cancer is much less common than adult cancer. The more common types of cancer in children (even babies) are acute leukaemia and tumours of the brain, while rarer forms include retinoblastoma, neuroblastoma, Wilms’ tumours, osteosarcoma and lymphoma. These rare neoplasms are treated with surgery, radiotherapy and chemotherapy. 
Newer forms of treatment such as proton beam therapy cause fewer severe side effects in paediatric cancer patients than conventional radiotherapy. Medicinal products used in the treatment of cancer in children today has been developed for the use in adults after having the dose adapted to the paediatric population. This dose adaptation needs to be individualised and is never standardised. The cancers in youngsters with a good prognosis under current standard multidisciplinary treatment are acute lymphoblastic leukaemia, lymphoma, retinoblastoma and renal tumours. 
Those with a poorer prognosis are acute myeloid leukaemia, CNS tumours, neuroblastoma, bone and soft tissue sarcomas.1,2 Some cancers in children do not occur in adults. The incidence in Belgium (11 million inhabitants of which 2 million are children under 18) is 224 boys/118 girls under 14 years of age and 90 boys/80 girls between 15 and 19 years old in 2013. That represents 512 cancers in 2 million youngsters (1 in 4000) per year and  the EU defines a condition as rare when the prevalence is not more than 1 in 2000. 
Orphan drugs are medicinal products intended for the in vivo diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition with a low incidence such as rare cancers in children. 
The European Medicines Agency authorised 119 orphan drugs with a marketing authorisation in all EU Member States: 40 (1 out of 3) of these medicinal products are labelled for the treatment of cancer such as rare forms of glioma, leukaemia, lymphoma, myeloma, neuroblastoma, osteosarcoma and thyroid cancer. Only eight of these orphan medicinal products authorised by the European Medicines Agency are labelled for use in cancer patients under the age of 18 years.
In 2007 the EU Paediatric Medicine Regulation was launched and benefited many childhood diseases but not cancer. Several of these orphan drugs have a rather high cost per year so reimbursement is an important issue for patient access. While authorisation is a European issue, reimbursement is left to the authority of the different national agencies in the Member States.3
Different social security systems among Member States results in significant inequalities in access to cancer treatment in youngsters. A faster reimbursement and a longer patent protection for an extension to the paediatric population has been a proposed in some EU Member States. 
Off-label use is the practice of using a medicine outside of its authorised indication, dose, route of administration or patient group. It plays an important role in the treatment of rare cancers since it may be of benefit to these patients when no other authorised treatment option is available. Most of the medicinal products used in the treatment of children with rare cancer are labelled not to be used in patients under the age of 18.4,5
But no on-label medicinal products exist for these young patients and there is a lot of evidence in the literature about their successful use. Off-label use is often not reimbursed as payers do not want to pay for a treatment when the medication is not proven to be safe and effective. 
Many of these treatments with orphan drugs are given by a parenteral route (18 orphan drugs for cancer) but oral administration (22 orphan drugs for cancer) will become more common in the future. This is of course more convenient for children but adherence to oral medication is always lower than the parenteral use. Some cytotoxic medications can even be administrated at home with the help of a qualified nurse.
The preparation of the medication for the parenteral route is always done in the safety cabinet of the hospital pharmacy under vertical laminar flow by trained pharmacy technicians. Compounding of the cytotoxic medication in to a more convenient galenical form is common practice (crushing tablets) but this unlicensed use poses problems of homogeneity, stability, efficacy and protection of the compounder.
Advanced Therapy Medicinal Products (ATMP) are medical products based on genes (gene therapy), cells (stem cells) and tissues (tissue engineering). As these innovative products are clearly medicines, the hospital pharmacist is the responsible person as for any other pharmaceutical product. No ATMPs are already approved for the use in children with rare cancers but clinical trials are ongoing.
When cure and care for infants with rare forms of cancer is not possible any more and when there is unbearable and irreversible suffering, a child can be helped to die in only one EU Member State under strict conditions. All material and medication needed will be dispensed by the hospital pharmacy. Also for palliative care high doses of morphine (oral or parenteral) are sometimes necessary that need to be compounded in the hospital pharmacy.
Clinical trials with infants are very difficult and even illegal in some EU Member States. There are major delays in starting clinical trials of oncology drugs for children while waiting for the drug to first show promise in adult cancer. Adaptive pathways can hopefully accelerate the use of  these pharmaceutical products in children.
Patient Reported Outcome such as quality of life versus survival will become more important in the registration procedure of medicines but in children the measurement of patient preferences will most frequently be reported by the parents. Clinical pharmacists on the paediatric ward can contribute to this activity but also to improve adherence to medication, report drug interactions, solve health literacy issues and perform seamless care.  
Expert centres (not necessarily university hospitals) are the best places to diagnose and treat children and adolescents with rare cancers. The European Union is currently developing some pilot projects aiming to build interconnected European Reference Networks, including the project ExPO-r-Net (European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment).
The concept of precision medicine will develop further to better predict treatment success and minimise side effects. A clinical pharmacist needs to be a member of a multidisciplinary team to dispense, compound and evaluate the medication (including stem cells) especially the follow-up of off-label use and long-term side effects in the survivors.  
Seven medical and scientific objectives need to be addressed to increase the cure rate and the quality of survivorship for children and young people living with cancer:
  1. Innovative treatments: safer and more effective new drugs and technologies (stem cells, gene therapy) as standard of care (including off-label use).
  2. Precision cancer medicine: biological characteristics of tumour and patient for better clinical decision-making.
  3. Tumour biology: faster translation from basic fundamental research to clinical practice. 
  4. Equal access: same quality in diagnosis, treatment (reimbursement) and follow-up for all patients. 
  5. Teenagers and young adults: specific needs in cooperation with adult oncology.
  6. Quality of survivorship: long-term side effects after cancer treatment.
  7. Causes of cancer: prevention wherever possible.
SIOPE (Societé Internationale Oncologie Pediatrie Europe) is a European organisation representing all professionals working in the field of childhood cancer to ensure the best possible care and outcome for all children and adolescents with cancer in Europe. ENCCA (European Network for Cancer Research in Children and Adolescents) was a EU FP7 project dedicated to effectively structure and enhance research collaboration within the field of paediatric oncology by promoting innovative methodologies and designs for clinical trials and improving the quality of their lives with particular emphasis on long-term treatment side effects. 
RCE (Rare Cancers Europe) is a multi-stakeholder initiative dedicated to put rare cancers on the European policy agenda. ITCC (Innovative Therapies for Children with Cancer) gathers 49 European Paediatric Oncology departments with expertise in conducting early phase trials in children and adolescents. CDDF (Cancer Drug Development Forum) facilitates interactions between all stakeholders in cancer drug development. 
ISOPP (International Society Oncology Pharmacy Practice) and ESOP (European Society Oncology Pharmacy) want to support the optimal treatment for cancer patients through education and training on the safe handling and administration of cytotoxic drugs, pharmaceutical care for the patients and spreading information on cancer to the general public. (Grand)parents and patient advocates have created Unite2Cure (Unite Against Childhood and Teenage Cancer) to contribute to faster access to better tolerated and more effective new drugs for young people with cancer.
Orphan drugs authorised for the use in children with cancer include: Busilvex (busulfan) as conditional treatment prior to conventional haematopoietic progenitor cell transplantation; Evoltra (clofarabine) for the treatment of acute lymphoblastic leukaemia; Glivec (imatinib) for the treatment of acute and chronic lymphoblastic leukaemia; Lysodren (mitotane) for the treatment of adrenal cortical carcinoma; Spectrila (asparaginase) for the treatment of acute lymphoblastic leukaemia; Tepadina (thiotepa) for the conditional treatment prior to hematopoietic progenitor cell transplantation; Unituxin (dinutuximab) for the treatment of neuroblastoma and Xaluprine (mercaptopurine) for the treatment of acute lymphoblastic leukaemia.
Key points
  • 1 out of 300 newborns will develop cancer before turning 20 years old.
  • 20 children and adolescents die of cancer every day.
  • There are 35,000 new cases of cancer in young people every year.
  • There are 300,000 European survivors of childhood cancer today.
  • Currently there are eight orphan drugs authorised for use in cancer patients under 18.


  1. Pizzo PA et al. Principles and Practice of Paediatric Oncology. Philadelphia PA, Wolters, Kluwer. 2016.
  2. Schneider DT. Rare tumours in children and adolescents. Dordrecht, Springer, 2012.
  3. Simoens S, Dooms M. Market access of orphan drugs: One size fits all? Hosp Pharm Eur 2012;62:59–63. 
  4. Field M, Shanley S, Kirk J. Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 2007;43(4):219–29.
  5. Pappo AS et al. Rare tumours in children: Progress through Collaboration. J Clin Oncol 2015;33(27):3047–54.

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