The evolution in the treatment of cancer has opened the world to new, innovative medicines that have brought hope to the management of a disease in which a diagnosis is almost synonymous with death to most people. With the benefits that have accrued from the use of these agents, however, inevitably comes many challenges. Drug toxicity is undeniably one of the most stubborn challenges that confront both the patient and the oncology practitioner (1). The wide range of toxicities exhibited by oral oncolytics, sometimes necessitate a hold or withdrawal of a potentially helpful drug due to suboptimal patient management; and in some cases, patient non-compliance (2). Toxicity of these agents at times may even contribute to the worsening of a patient’s condition (3, 4,). As such, the biggest concern for most practitioners is the implementation of a therapeutic strategy to minimize this toxicity while maximizing a drug’s efficacy (5, 6). The pharmacist occupies a unique niche in this reality by acting as a crucial link between the doctor and the patient. In this review, we examine the unique opportunity for pharmacists to direct oral oncolytics therapy towards greater patient benefit with less patient toxicity through the facilitation of education to both the prescriber and patient, drug selection, patient monitoring, and toxicity mitigation with reference to kidney and breast oral oncolytics.
Patient/Prescriber Education
Patient education is among the most effective means of promoting adherence to medications and improving outcomes. Among the aspects that the pharmacist has to stress when educating the patient are the absolute necessity of the patient to adhere to medication, the different methods and resources that can be taken advantage of to ensure such adherence as well as informing the patient of the different programmes that are available for education of the patient (7,8). Adherence is particularly an important issue because lack of it affects the efficacy of the medication (9,10). Among the issues that can lead to poor compliance to medications include poor eyesight, mental disability and lack of a proper social support network and polypharmacy. The fact that some patients may need to take drugs in a frequency upwards of four times in a day does not make things any easier for them. Several tools have been developed to help the patients track their use of medications and improve on adherence. Interventional tools, including a means for patients to note down and track their use of medications has been developed (11). Despite these efforts though, adherence still remains a huge problem, especially in those with chronic conditions, so that the pharmacist’s role in its mitigations is critical.
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An important factor in the education of patients is the discussion of the various drug interactions that may be encountered in the use of their drugs. Such interactions include drug-drug interactions as well as drug food interactions. The pharmacist, therefore, needs to explore the co-morbidities of the patients and the other drugs that they might be on, and review these against the oral cancer medications to avert possibly dangerous interactions (12). Warfarin is one of the drugs that potentially interacts with the oral oncolytics because of its effect on the liver enzymes, particularly the CYP 450 system (13). Because people with cancer are more likely than the general population to be on anticoagulants, the chances of encountering such interactions increase. Food-drug interactions include the use of grape fruit which has the potential to inhibit the enzymes which are drug metabolizers, leading to potentiation of the toxic effects of drugs (14). The pharmacist needs to make the patient aware of these interactions, among others, so as to take the necessary steps to avoid their consequences.
Patient education also needs to confront the issue of duration of therapy and the steps to be taken in the event the patient skips doses of the medication. Information about the duration of therapy is critical because the patients should be adequately informed so as to know what to expect (15). This can be seen as one way of improving compliance to the medication. The action to be taken in case doses are missed are also important, to mitigate against panic or further-non adherence from missed doses. Furthermore, some patients may elect to make up for the missed doses through combining doses, and this has a huge potential for toxicity (16). The pharmacist ought to educate the patients about these possibilities and what they must do in the event it happens.
Drug Selection and Patient Monitoring
Besides educating the patient, the pharmacist should also be able to explain to the prescribing physician all of the risks that are involved, assist in patient selection as well as the monitoring of such patients. By so doing, the pharmacist takes an active role in the management of these patients and averting toxicity while maximizing benefits. The selection of patients can be guided by various criteria that are available for determining physical performance scores and the general suitability of patients for chemotherapy (17, 18). The Eastern Cooperative Oncology Group (ECOG) patient performance status scales, for instance, have not only been found to be useful in the identification of patient that are fit for the use of such oral drugs as sorafenib, but also in prognostication purposes, finding applicability in a wide array of issues to do with a patients particular cancer situation (15,19). The National Comprehensive Cancer Center Guidelines as well as monographs such as Lexi Comp and UptoDate are useful tools in avoiding the harmful side effects and toxicities of the oral oncolytic agents. Lexicomp, for instance, provides useful information on various aspects of drug uses including the dosage, precautions and other correlates, which can then be transformed into more informed clients for the benefit of reduced drug toxicities.
Toxicity Mitigation
The various oral oncolytic agents may produce a wide range of toxicities, ranging from mild to life-threatening adverse effects (19). The pharmacist must be aware of these toxicities so as to advice the patient and the physician on the steps to take so as to maximize benefit for the patient. This opportunity for intervention as the last member of the healthcare team to interact with a patient has been a recognized. One of the methods measures that the pharmacist can put in place is medication reconciliation. In reconciliation, the list of medications of the patient is checked so as to avoid errors that may include omission, duplication, prescribing drugs that interact and other dosing errors (20). The value of reconciliation in averting drug toxicities or in the very least, reducing adverse outcomes is self-evident. Because many of the errors that occur in drug administration occur outside the hospital setting, reconciliation of medications for cancer patients is crucial if patient harm is to be averted. As much as 20% of the errors that can be cured by proper medication reconciliation are harmful to the patient (21), hence the need to correct them.
The pharmacist should also be at the forefront in identifying adverse effects and other drug related problems that might plague the patient, and act accordingly to mitigate them. A keen eye should be maintained for such complaints as diarrhoea while on medication, or acute chest pain, because these might be a harbinger for serious or even fatal outcomes with regard to toxicity while or such a drug as sorafenib for instance (22). The pharmacist, on identifying these adverse effects, will then liaise with the other stakeholders to come up with a plan to remedy the effects. Such decisions as dose modification, symptomatic treatment of the adverse effect or complete cancelation of the therapy as may be warranted, may be necessary in mitigating such toxicity.
Medication therapy management (MTM) is, therefore, an important tool for the avoidance of errors in patient medications and subsequent toxicities. Bertsch et al (23) demonstrated that the use of the MTM not only makes it possible to identify and intervene in errors, but also improves the relations between the pharmacist and the client, and overall patient satisfaction as well. It is, therefore, a useful tool especially in the case of oncolytic agent, to fast-track medication to ensure that they align with the interest of the best outcome for the patient. Linkage of the physician and the patient as well as strengthening inter-displinary relations is the culmination a responsibility that places the pharmacist in the unique position. These measures should be applied in tandem rather than singularly, to ensure that the best possible outcomes for the patient obtain. As the last person on contact with the patient, the pharmacist must take time to educate the patient and formulate a plan of action in the event the patient notices or develops adverse reactions.
Sorafenib belongs to a class of agents known as anti-angiogenesis multitargeted kinase inhibitors (VEGF TKI) which also include sunitinib, pazopanib, lenvatinib and cabozantanib. Its toxicity profile includes diarrhea, generalized body malaise, cardiovascular disease including hypertension and hand-foot and skin reaction (24). Cardiovascular disease caused by VEGF TKIs are particularly concerning because the risk of death in these patients is real (25). The risk of cardiac ischemia is ten-fold that of the untreated population, with one randomized control trial showing an incidence of up to 5% is users compared to a placebo group (26). The risk of development of left ventricular ejection fraction as well as that of coronary artery disease is also significantly increased with these therapies and so is the risk of developing heart failure. Overall, VEGF TKIs are associated with a 33% increase in the risk of cardiac events among patients. Even in the exclusion of death, these toxicities have the potential to reduce the quality of life of the patient considerably (27). For example, the hypertension that is caused by the use of VEGF TKIs may come with long term consequences making it necessary for patients to keep blood pressure diaries in order to optimize medical management. To avert the cardiovascular toxicity associated with the use of sorafenib, as an example, it is first important to apply caution when treating patients that already have pre-existing cardiac conditions. The other patients that do not have pre-existing conditions should also be monitored during the course of treatment (28). One way that this monitoring can be done is through the use of echocardiograms, electrocardiogram and where possible, the use of magnetic resonance imaging (29). Magnetic resonance imaging has been found to be particularly useful in identifying early stages of ischemia in the myocardial wall which can then be managed to avert further damage to the heart (26). Further, the risk of bleeding that accompanies the use of VEGF TKIs like sorafenib have been largely appreciated, with the anti-angiogenic properties that they confer also pre-disposing to higher rates of bleeding. Bleeding, occurring in 15% of the patients on sorafenib compared to 8% in the control groups complicates the management of other cardiac events such as ischemia because of the dilemma in the use of anticoagulants such as aspirin (30). This calls on the pharmacist to actively participate not only in the recognition of patients that are at an increased risk for bleeding such as those with advanced renal cell carcinoma with metastasis to the brain, but also in education of patients on the identification of such symptoms and reporting to healthcare setup. Education of patients in this regard will include telling them the signs that should alarm them if seen. Nose-bleeding, bleeding from gums, excessive menstrual bleeding in premenopausal women are among the signs that should warrant a visit to the doctor in such patients. In addition, signs of cardiac disease should also be explained to the patient by the pharmacist at the point of drug dispensing or via telephone if mail-ordered. Such include sudden chest pain, inability to breathe, palpitations, loss of consciousness, a feeling of impending doom among others. Signs of hypertension can also be made clear to the patient, and these include headache, generalized fatigue, palpitations, and dizziness among others (28). With a proper understanding of the risk of the development of such toxicities, it should be possible for the patient to seek medical attention as soon as they suspect having such problems.
Diarrhea is another common side effect that stems from the use of VEGF TKIs. The induced diarrhoea is mostly mild, but can be severe in a few cases, to the extent of leading to interruption of treatment including complete withdrawal of the drug (31). The mild cases that do not need withdrawal of the drug can, however be managed symptomatically through use of loperamide, monitoring electrolytes, diet control and rehydration. Many patients are able to have a resolution of their symptoms and continue the use of sorafenib without many challenges. When associated with upper GI discomfort and dyspepsia, symptomatic control can also be used to alleviate the symptoms. The pharmacist must be cognizant of the possibility of developing gastrointestinal discomfort in these patients, and act swiftly to control the symptoms or where necessary, hold the medication. Reassuring the patients that present with the symptoms is necessary in avoiding much worry among the patients and ensuring that compliance with the medications is maintained for the benefit of the patient.
Hand-foot skin reaction to the use of VEGF TKIs like sorafenib have the potential to reduce the quality of life of patients. For this reason, it is desirable for patients to be educated on methods to prevent the development of this condition and to manage it when it occurs. The pharmacist can play an active role in educating the patient about the need to keep the feet and hands moist, the use of thick socks and gloves, the use of emollients, protecting pressure points in the feet and hands as well as the avoidance of hot water in the management and control of hand-foot skin reactions (32). Identification of the popular rash that heralds the development if this condition is also critical for the patient to understand so as to seek medical help when this occurs.
Conclusion
The pharmacist plays a central role in the administration of oral oncolytic agents, their proper use and mitigation of adverse effects from their use. As the last person of contact with the patient, the pharmacist accesses a unique opportunity to influence reduced toxicity from the use of the drugs. Patient education, mitigation of the side effects as well as establishment of medication therapy management strategies are key to the execution of this role. Medications that are used in the treatment of kidney cancer offer insight into the way that the pharmacist can apply these strategies to reduce toxicity. The VEGF TKIs such as sorafenib depict a variety of side effects, ranging from mild to fatal, which call for the input of the pharmacist to mitigate. A collaborative environment is, however, necessary for the pharmacist to be able to execute these roles effectively, for the purpose of improved efficacy and reduced toxicity for the patient.
References
David Bailey, G. D. (2013). Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ .
Klempner, S. J. (12). Severe pazopanib-induced hepatotoxicity: clinical and histologic course in two patients. Journal of clinical oncology .
Gao, F. F. (2016). Tamoxifen induces hepatotoxicity and changes to hepatocyte morphology at the early stage of endocrinotherapy in mice. biomedical reports .
Lingling wang, H. M. (2015). Tamoxifen retinopathy: a case report. Springerplus .
Given, B. A. (2017). Oral Oncolytic Agents –A Need for Research to Enhance Patient Centered? Cancer Nursing .
Neyfield SG, G. M. (1996). Tamoxifen-associated eye disease. A review. Journal of Clinical Oncology .
Cabanilas, M. E. (2018). Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Seminars in oncology .
Saltz, L. B. (2008). Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of clinical Oncology .
Given, B. A. (2017). Oral Oncolytic Agents –A Need for Research to Enhance Patient Centered? Cancer Nursing .
Neha Chopra, U. R. (2017). Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies. journal of clinical and diagnostic research .
Elisio Costa, A. G. (2015). Interventional tools to improve medication adherence: review of literature. Patient Preference and Adherence , 1303-1314.
Maria Giuseppa Vitale, C. M. (2017). The impact of kidney function on the efficacy and safety of pazopanib in metastatic renal cell carcinoma (mRCC) patients: CORE-URO-01 study. journal of Clinical Oncology .
Klempner, S. J. (12). Severe pazopanib-induced hepatotoxicity: clinical and histologic course in two patients. Journal of clinical oncology .
David Bailey, G. D. (2013). Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ .
Javier Angulo, O. S. (2019). The Changing Therapeutic Landscape of Metastatic Renal Cancer. Cancers , 1227-1228.
Henriksen, J. (2020). Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes. Clinical genitourinary cancer , 62-68.
Dorff, T. B. (2009). Targeted therapy in renal cancer. Medical Oncology , 183-205.
Vivek Narayan, N. B. (2016). Axitinib in the treatment of renal cell carcinoma: patient selection and perspectives. International Journal of Nephrology and Renovascular Disease , 65-72.
Matteo Santoni, F. M. (2018). Immunotherapy in renal cell carcinoma: latest evidence and clinical implications. Drugs in context .
Barnsteiner, J. (2010). Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Pennsylvania: University of Pennsylvania.
Volpi, E. (2017). Medication Reconciliation During Hospitalization and in Hospital-Home Interface. Journal of Patient Safety .
Tracy Downs, M. S. (2009). RENAL CELL CARCINOMA: RISK ASSESSMENT FOR NEWLY DIAGNOSED PATIENTS. Journal of Clinical Oncology , 59-70.
Nathan Bertsch, R. B. (2016). Medication Therapy Management for Patieints Receiving Oral Chemotherapy. Hospital Pharmacy .
B Escuider, T. E. (2009). Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in. Journal of Clinical Oncology .
Candace Wu, K. S. (2017). Sorafenib-Associated Heart Failure Complicated by Cardiogenic Shock after Treatment of Advanced Stage Hepatocellular Carcinoma: A Clinical Case Discussion. Case Reports in Cardiology .
Saltz, L. B. (2008). Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of clinical Oncology .
Ye Li, Z. H. (2015). The Adverse Effects of Sorafenib in Patients with. Basic & Clinical Pharmacology & Toxicology , 216-221.
Maria Brose, C. F. (2014). Management of Sorafenib-Related Adverse Events: A Clinician’s Perspective. Seminars in Oncology .
Manuela Schmidinger, C. Z. (2016). Cardiac Toxicity of Sunitinib and Sorafenib in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology
Chao Dai, F. Z. (2018). Bleeding risk in cancer patients treated with sorafenib: A meta-analysis of randomized controlled trials. Journal of Cancer Research and Therapeutics , 928-956.
E C Lauritano, M. N. (2009). The pathogenic mechanisms of sorafenib-related diarrhea: Preliminary results. Digestive and Liver Disease .
Anca Chiriac, M. F. (2017). Grade III hand-foot skin reaction induced by sorafenib. Anais Brasileiros de dermatologica , 590-591.
