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Oral chemotherapy: developments in oral chemotherapy

PRACTICAL THERAPEUTICS
Mikael Daouphars PharmD PhD
Cancer Centre Henri Becquerel, Rouen, France
Jürgen Barth PharmD 
Justus-Liebig-Universität, Giessen, Germany
Klaus Meier PharmD
Heidekreis-Klinikum GmbH, Soltau, Germany
Oral cytotoxic drugs have been approved since the beginning of anti-tumoural chemotherapy. The first of these were alkylating agents, such as chlorambucil and melphalan, and antimetabolites, such as mercaptopurine and tioguanine. Since the end of the 20th century, more and more small molecule kinase inhibitors (smKIs) have been developed in the field of oncology. 
Growing awareness of oral chemotherapy-specific issues
With the availability of these novel therapeutic agents, patient-administered oral medications have played an increasing role in anticancer treatment. Advantages of using oral chemotherapies include increased control and convenience for the patient, potential increase in the quality of life, sustained medication exposure and potential reduction in travel costs and use of healthcare resources. However, multiple factors associated with oral chemotherapy can compromise patient safety and contribute to medication errors, contamination and inadvertent exposure to other individuals.(1) Take the case of a young woman who died by taking 200mg lomustine over seven days instead of 200mg every six weeks. Obviously, she was not informed about this exceptional dosing interval, either by her physician or by the pharmacist.(2) 
Besides several problems with reduced (chlorambucil, melphalan, procarbacine, nilotinib, sorafenib) or exaggerated (erlotinib, nilotinib, lapatinib, pazopanib) bioavailability in combination with food and interactions with nutritional components (melphalan + L-Leucin-rich food),(3) the intake of vitamins or related products can be harmful. A 51-year-old woman died due to the concomitant intake of 15mg folinic acid (which augments the pharmacodynamics of capecitabine) prescribed by her family physician.(4) Besides the well-known toxicities of the 'classic' cytotoxics, the 'new' smKIs show a broad range of new or uncommon side-effects. Almost all organs (skin, heart, liver, kidneys, gastrointestinal, thyroid gland) and blood pressure are affected by the inhibition of 'bystander' or 'off-target' kinases, and sometimes the so-called 'normal variant' of the mutated kinase is hit. For example, the fusion protein BCR/Abl is the molecular driver for a Philadelphia chromosome-positive chronic myeloid leukaemia, whereas Abl has protecting functions in contractile cardiomyocytes.(5) Other examples of targeted toxicity have been reviewed.(6) Emetogenic potential of oral cytotoxics should also be taken into consideration(7).
There has been much concern regarding patient adherence to medication in the cancer care setting over recent years. In general, rates of adherence to, and persistence with, oral cancer therapies range between 16% and 100% in adult populations.(8) Chronic myeloid leukaemia (CML) has provided an illustrative model of consequences of nonadherence to patient outcomes. Indeed, BCR-ABL transcript levels may be monitored to assess the quantity of residual leukaemia. Achieving a complete cytogenetic response (CCyR) is the major objective of therapy, because it is associated with prolonged survival. Poor adherence is the main reason for loss of CCyR and imatinib failure for CML patients on long-term therapy.(9)
Reasons for nonadherence in CML are both intentional and non-intentional, and many patients do not think that missing a few doses will affect their response, as shown by a recent study.(10)
Oral chemotherapy-specific issues are not confined to patients.(11) Despite their increased use, current practices for prescribing, coordinating, monitoring and dispensing these medications and educating patients in cancer centres can be improved.(12) Only a third of the centres provided special training or certification for those who educate patients about these oral medications. Nearly a quarter of centres had no formal process for monitoring patients' adherence. Few of the safeguards of infusion chemotherapy in routine use have been adopted for oral chemotherapy, and consensus about safe medication practices is lacking.(12) 
In an international survey by Kav and colleagues,(13) a significant difference was found between the countries regarding education, availability of guidelines/protocol, patient educational materials and involvement in patient education, and follow-up for patients receiving oral chemotherapy. Another study assessed community pharmacists' attitude toward and knowledge of oral chemotherapy in terms of drug indications, general dosing principles, drug interactions, adverse effects and special handling precautions.(14) Pharmacists reported a low awareness of safety precautions, and the average comfort in dispensing oral chemotherapy was 2.4 on a Likert-type scale of 1 (low) to 5 (high). Moreover, communication between community pharmacies and cancer centres could be improved.(12)
Such concerns over the safe supply and dispensing of oral chemotherapy in the community has led the NHS to issue a Safety Alert in January 2008. The alert entitled 'Risks of incorrect dosing of oral anticancer medicines' highlighted the potential for fatal outcomes if incorrect doses of oral anticancer medicines are prescribed, dispensed or administered.(15) A guideline from an international pharmacy panel has recently been published on the safe use of oral chemotherapeutic agents.(1)
Greater involvement of community healthcare professionals
Indeed, cancer medicines are one of the categories recently transferred from the hospital to community setting. Chemotherapy services in secondary care are facing capacity pressures, as the number of patients receiving chemotherapy grows, and it is anticipated that oral anticancer medicines used in patients with more stable disease would be most suitable for dispensing and supply in the community. Many historically hospital-only medicines have been available from the French Community Pharmacy for several years. It is the case in many other EU Member States (17 countries) and the trend is growing. 
Such developments imply, however, a strong coordination between hospital and ambulatory care. Community pharmacists have also to enter continuous education programmes to stay updated on the different cancers and their treatment. To promote the rational and safe use of oral chemotherapy and supportive treatments, and to encourage training of pharmacists, different initiatives have been implemented, such as those of the Pharmaceutical Group of the European Union (PGEU). Another ambitious programme has been set up in Germany to teach 20,000 community and hospital pharmacists how to support patients the best in taking oral cytotoxic drugs.
This initiative aims to reach the following goals for oncology patients:
  • on-site optimisation of oral chemotherapy and improvement of pharmaceutical care 
  • cost-effective and reliable care owing to professional collaboration of local physicians, pharmacists and other healthcare professionals at the right time
  • recognising and solving drug-related problems related to oral chemotherapy
  • enhancing the quality of life of oncology patients through a coordinated management of side-effects and interactions during and after therapy
  • providing new insight as a contribution to health services research and to encourage drug safety.
The UK has also been elaborating service specifications for primary care in oral anticancer medicine supply. Different service models have been considered, from level 1 (baseline service: supply ensuring compliance with the recommendations of the NHS Safety Alert), level 2 (specialised service, following the basics of national standards for chemotherapy verification (BOPA, 2010)), to level 3 (advanced service, with patient clinical assessment to ensure that it is safe to proceed with chemotherapy).(15)
In France, community pharmacists have recently been granted the right to provide reimbursed interventions to patients being treated by anticoagulants and, soon, those with asthma. Cancer patients may be eligible for such interventions in the future. 
Development of patient education in cancer care
Therapeutic patient education (TPE) has been implemented in chronic disease management for a few decades.(16) However, it is only recently that TPE has entered the field of cancer care, as the awareness of nonadherence issues with oral drugs in cancer patients has grown. Interventions may be educational, behavioural, affective or multidimensional. These can be provided by physicians, nurses, pharmacists and other healthcare professionals within a team.(8) Involvement of patients in the programmes' elaboration is paramount to ensure concordance between services and patients' expectations. Few studies showing the efficacy of TPE in oncology have been published so far. Use of daily pill boxes versus conventional pill bottles of capecitabine did not significantly improve patients' adherence.(17) But an intensified pharmaceutical care provision was shown to be beneficial to adherence to capecitabine in colorectal and breast cancer patients.(18) Prescriptions have to be clarified with patients, as under- or over-dosing may occur in error, and also without regard to administration rules.(11)
Patients need to develop the competence to supervise the side-effects of treatment. Indeed, a common reason for intentional non-adherence is dealing with the side-effects.(10) The management of side-effects and delayed reporting to the physician may be difficult and even harmful for some patients.(11) Initiatives to help patients in pill taking and side effects management have been also supported by pharmaceutical companies, such as financing of call centres. Although helpful for patients, such services should collaborate with the TPE team, if any, whether it is hospital- or (less often) community-driven. The Multinational Association for Supportive Care in Cancer (MASCC) has also developed a teaching tool for patients receiving oral agents for cancer, to assist healthcare providers assess and teach patients about their treatment.(19) There remains room for improvement for the training and rewarding of healthcare professionals in TPE.
Conclusions
As more and more oral chemotherapeutic agents become available, and as combinations of such therapies, whether cytotoxic or targeted, are considered, there is an increasing need for hospital and community pharmacists to be trained on patient counselling on adherence to treatment and managing side-effects at home.
Key points
  • Small molecule kinase inhibitors are not the "small, smart untoxic" anti-tumour therapeutics we may think.
  • All organs can be affected by toxicities – some of them are new or uncommon.
  • A good communication between patient and healthcare professionals (HCPs) is mandatory to achieve an adequate adherence and a limited/early detectable toxicity.
  • Patient education is paramount to ensure that the patient recognises and understands toxicities with the need for action.
  • A special training for HCPs is needed and in development in several EU countries.
References
  1. Goodin S et al. Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel. J Oncol Practice 2011;7(1):7–12. 
  2. Trent KC, Myers L, Moreb J. Multiorgan failure associated with lomustine overdose. Ann Pharmacother 1995;29(4):384–6. 
  3. Adair CG, McElnay JC. The effect of dietary amino acids on the gastrointestinal absorption of melphalan and chlorambucil. Cancer Chemother Pharmacol 1987;19(4):343–6. 
  4. Clippe C et al. Lethal toxicity of capecitabine due to abusive folic acid prescription? Clin Oncol 2003;15(5):299–300. 
  5. Force T et al. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature Rev Cancer 2007;7(5):332-44. 
  6. Barth J. Molekular zielgerichtete Therapien – gibt es sie wirklich? Krankenhauspharmazie 2008;29:288–301.
  7. Müller F, Jahn P, Jordan K. Antiemese – Aktualisierte leitliniengerechte Therapie Onkologie Heute;2009(6).
  8. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA: a cancer journal for clinicians 2009;59(1):56–66. 
  9. Ibrahim AR et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117(14):3733–6. 
  10. Eliasson L et al. Exploring chronic myeloid leukemia patients' reasons for not adhering to the oral anticancer drug imatinib as prescribed Leukemia Res 2011;35(5):626–30. 
  11. Regnier Denois V et al. Adherence with oral chemotherapy: results from a qualitative study of the behaviour and representations of patients and oncologists. Eur Journal Cancer Care 2011;20(4):520–7. 
  12. Weingart SN et al. Oral chemotherapy safety practices at US cancer centres: questionnaire survey. Br Med J 2007;334(7590):407. 
  13. Kav S et al. Role of the nurse in patient education and follow-up of people receiving oral chemotherapy treatment: an international survey. Supportive care in cancer. Official Journal of the Multinational Association of Supportive Care in Cancer 2008;16(9):1075–83. 
  14. O'Bryant CL, Crandell BC. Community pharmacists' knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc 2008;48(5):632–9. 
  15. Williamson S. Dispensing and supply of oral chemotherapy and systemic anticancer medicines in primary care. Royal Pharmaceutical Society 2011.
  16. Adherence to long-term therapies: evidence for action. World Health Organization, 2003.
  17. Macintosh PW et al. A comparison of patient adherence and preference of packaging method for oral anticancer agents using conventional pill bottles versus daily pill boxes. Eur J Cancer Care 2007;16(4):380–6.
  18. Simons S, et al. Enhancing adherence to capecitabine chemotherapy by means of multidisciplinary pharmaceutical care. Support Care Cancer 2011;19(7):1009–18. 
  19. Kav S et al. Development of the MASCC Teaching Tool for Patients Receiving Oral Agents for Cancer. Support Care Cancer 2010;18(5):583–90. 
European Conference of Oncology Pharmacy, Budapest (27-29th September 2012)
Plenary session on 27th September: "The age of oral chemotherapy: a time of opportunities and responsibilities for oncology pharmacists".

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