Dosing modifications of targeted cancer therapies in patients with special needs: Evidence and controversies

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Abstract

Targeted therapies have revolutionized the treatment of malignancies over the past decade. These agents are generally regarded to posses fewer systemic side effects than traditional cytotoxic chemotherapies. However, patients manifesting organ dysfunction or drug interactions with concurrent medications may require dosing modifications of their targeted therapies in order to reduce the risk of systemic toxicities or reduction of drug efficacies. Studies have shown that wide variations and controversies exist with regard to dosing modifications of drugs, due to the lack of well conducted studies and consensus. Hence, this review was conducted to review the literature on the dosing modification strategies, for 30 commercially available targeted cancer drugs, and to evaluate the current mainstay recommendations and controversies.

Introduction

Defined by the National Cancer Institute, targeted cancer therapies are drugs that block the growth and spread of cancer cells by interfering with specific molecules involved in tumor growth and progression [1]. Due to their unique mechanisms on targeting cancer cells, these therapies are generally regarded to possess fewer side effects than traditional cytotoxic chemotherapies [2], [3]. Similar to cytotoxics, however, side effects of targeted agents may be exaggerated if inappropriate dosages of these agents are being used.

In practice, majority of the dosing modifications of anticancer drugs are supported by drug product inserts and various medical drug information sources, and usually couple with clinical judgment from the practitioner. Among patients who manifest organ dysfunctions, dosing modifications are often empiric due to the lack of lucid recommendations from mainstream sources [4]. In addition, other characteristics may also affect dosing recommendations; these characteristics include a patient's smoking status and cytochrome P450 (CYP450) enzyme drug interactions (from polypharmacy), which may affect a patient's response to anticancer treatment. In those scenarios, dose adjustments are often warranted [5], [6], [7], [8].

It is important for healthcare professionals to keep themselves abreast with the various dose recommendations available for targeted cancer therapies. Studies have shown that wide variations and controversies exist with dosing recommendations issues in drug references and online drug databases [9], [10], [11]. Henceforth, this article was design to evaluate the current recommendations on dosing modifications of targeted cancer therapies.

Section snippets

Drugs selection

A search was conducted through the Food and Drug Administration (FDA) and National Cancer Institute websites to identify drugs that are classified as targeted cancer therapies. In this review, only targeted agents that are approved by FDA for anticancer treatments are included. Thirty drugs satisfy the inclusion criteria, and the agents include: arsenic trioxide, alemtuzumab, alitretinoin, bevacizumab, bexarotene, bortezomib, cetuximab, dasatinib, denileukin difitox, erlotinib, everolimus,

Results and discussion

A total of 472 relevant articles were identified, and 68 articles met the predetermined inclusion criteria. Based on the product inserts and selected articles, three tables containing the dosing recommendations were created and they were divided into “Dose adjustments in patients with hepatic and renal dysfunction” (Table 3), “Dose adjustments in smokers” (Table 4) and “Dose adjustments in presence of CYP450 drug interactions” (Table 5). Fig. 1 displays the flowchart for the inclusion–exclusion

Limitations and future work

A major limitation of this review is the lack of detailed recommendations and data with regard to dosage adjustments among patients with special health status for the 30 selected targeted anticancer drugs. A total of 24 of the discussed agents are commercially available for less than 10 years. In essence, these drugs are still considered new in the market. Hence, detailed recommendations to elaborate dose adjustment among patients with organ dysfunctions, cigarette smoking and existence of drug

Conclusion

This review has successfully captured a comprehensive overview of dose adjustment strategies among cancer patients using targeted therapies who also have underlying organ dysfunctions, smoking status and presence of CYP450 enzyme–drug interactions respectively, with the aim of aiding healthcare professionals in making sound clinical decisions with regard to dose adjustment. Nonetheless, it must be noted that every patient is different and cancer treatments are usually individualized to cater

Conflict of interest

The authors have no conflicts of interest that are directly relevant to the content of this study.

Reviewers

Judith Lees, B.Pharm., FISOPP, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia.

Jean-Charles Soria, M.D., Ph.D., Institut Gustave Roussy, Department of Medicine, 39, rue Camille Desmoulins, F-94805 Villejuif Cedex, France.

Acknowledgement

Authors would like to acknowledge the Department of Pharmacy, National University of Singapore for providing support for this project.

Dr. Alexandre Chan is an Assistant Professor at Department of Pharmacy, National Cancer Centre Singapore. He is also an Associate Consultant Clinical Pharmacist at Department of Pharmacy, National Cancer Centre Singapore. His research interest includes supportive care in cancer patients, clinical relevance of drug interactions in cancer patients and clinical pharmacy education.

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    Dr. Alexandre Chan is an Assistant Professor at Department of Pharmacy, National Cancer Centre Singapore. He is also an Associate Consultant Clinical Pharmacist at Department of Pharmacy, National Cancer Centre Singapore. His research interest includes supportive care in cancer patients, clinical relevance of drug interactions in cancer patients and clinical pharmacy education.

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