Cancer disproportionately impacts older individuals in the United States, with more than 50% of all cancer diagnoses occurring after the age of 65 years.1 At the point of a cancer diagnosis, these individuals are also likely to have several medical comorbidities2 that require the use of multiple medications, both prescription and over the counter (OTC), to support condition management. Having multiple comorbidities increases the risk for potentially inappropriate medication (PIM) use and adverse drug interactions due to the multiple medications used to manage these conditions. Polypharmacy, or the use of multiple medications, is classified as either appropriate (based on presenting conditions) or problematic, when there is high risk for adverse drug interactions.3
Standard antineoplastic therapies, including cytotoxic chemotherapy, biological immunotherapies, and hormonal agents, tend to increase the risk of drug interaction and adverse events in the geriatric population.4,5 Moreover, these cytotoxic agents are responsible for an array of side effects, many requiring pharmacological intervention. Managing the cascade of side effects from cancer treatments may require the use of drug therapies that are commonly recognized as PIM outside of the oncology care continuum but are indicated under these unique circumstances. These drug interactions can have an adverse impact on function and contribute to an array of complications in the geriatric population.
In 2016, there were an estimated 15.5 million cancer survivors living in the United States, more than 60% of whom were 65 years or older, and this prevalence is projected to grow to more than 73% of the survivorship population by 2040.6 The majority of these individuals will experience high comorbidity burden, often requiring complex pharmacological intervention. Rehabilitation providers should be aware of the impact of polypharmacy on older individuals with cancer and recognize how drug side effects and interactions can impact the onset and severity of functional impairments in this population. The purpose of this article is to provide a comprehensive review of common antineoplastic pharmaceutical agents, their side effects, and the potential drug interactions that may occur between these agents and those used to manage the comorbid conditions that commonly occur in older adults.
The specialized practice of geriatric oncology focuses on the needs of the older adult population of cancer survivors. For the purposes of this article, an individual is defined as a cancer survivor from the point of cancer diagnosis through the trajectory of their remaining lifespan.7 The needs of the geriatric population warrant special consideration for 2 specific reasons. First, cancer is a disease of age and older adults are not only more likely to develop cancer, they are also more likely to have age-related comorbidities that introduce more complexities and therefore require special consideration in developing cancer treatment care plans and follow-up care.8 Second, because of the rise in cancer survival rates over the last 3 decades, a large segment of the geriatric population has a history of past cancer treatments4 and is likely to experience late effects of these treatments that impact function, such as persistent pain, neuropathies, balance deficits, cardiotoxicities, cognitive deficits, and other musculoskeletal impairments.9 These persistent and late effects require both lifestyle and pharmacological interventions for optimal symptom and condition management.8,9 Furthermore, individuals who have completed antineoplastic medical treatments with chemotherapy, surgery, radiotherapy, and immunotherapies may be on longer term medical treatment interventions including hormonal drug therapies, corticosteroids, bisphosphonates, and other pharmacological agents that mitigate their risk for disease recurrence or temporize persistent disease.
Because of these complexities, specific focus and attention is drawn to the physical and functional assessment and supportive care needs of the geriatric oncologic population.10 Targeted approaches are recommended to improve assessment, intervention, and follow-up care specific to the needs of this population.11,12 A large part of the standard of care approaches for cancer disease management and cancer treatment side effect attenuation relies on pharmacological interventions.
Complexities of multiple medications in older adults
Older adults, in general, experience multiple comorbidities that require pharmacological management strategies. The American Geriatric Society recognizes the various issues derived from the use of polypharmacy in this population and has developed the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, a guideline for health care professionals that aims to improve recognition of inappropriate medication prescription and reduce the risk of adverse events related to PIMs.13
A challenge in geriatric oncology care, however, is that many of the medications deemed as “potentially inappropriate” by Beers Criteria are requisite in the treatment of cancer and in the management of cancer treatment-related side effects. This conundrum is addressed by the National Comprehensive Cancer Network (NCCN), which offers a guideline specific to older adult oncology practice.14 The NCCN guideline provides a comprehensive list of “medications that are of concern in older adults.”* There is significant agreement between both the NCCN guideline and Beers Criteria on both medications of concern, and also on best practice for clinical approach to medication management in the oncologic population. Both entities recommend clinical consideration by the health care provider that recognizes the known benefits and needs of the oncologic patient and balances that with the medication risks. Close monitoring for adverse events, with greater frequency of follow-up and greater attention to functional assessment, is recommended.15 Clinical providers should recognize that the use of these drugs will be prevalent in the geriatric oncology population and should have a sound understanding of the commonly used antineoplastic agents, their side effects, common pharmacological management of the side effects, and their interplay with comorbidity medication strategies.
Antineoplastic pharmacological agents interfere with cell division, leading to cell kill (cytocidal effects) or failure to replicate (cytostatic effects).16 These agents, however, are nonselective and their cytotoxic impact affects both healthy normal cells and malignant cells. Agents are delivered in a cyclic manner over a span of weeks to months or years in order to maximize the death of cancer cells and to allow for adequate recovery and survival of normal cells. In general, there is broad, multisystem impact from these agents. The general side effects of antineoplastic treatment are outlined in Table 1.
There are various classes of chemotherapeutic agents, immunotherapy and biological agents, and hormonal agents each with different impact on mechanisms of cell functions, such as cellular division, metabolism, and cell growth.17 These drugs are most effective when used in combination, as disruption to multiple cell functions over time accounts for greater success in eradicating cancer cells from the body. Many of the commonly used drug classes have distinct side effects that impact specific body structures and functions. Specific antineoplastic agents and their side effects are outlined in Table 2.
Because of the cyclic nature of antineoplastic treatments, the side effects are anticipated to occur most prevalently during the time period of drug delivery when systemic drug impact is greatest. Side effects, however, can be cumulative over time with additional cycles of drug delivery and may become persistent, leading to chronic conditions. Outside of cancer care, managing cascading side effects of drugs with additional drugs is not often recommended, instead the primary inciting medication should be removed or altered. However, in oncology this may not be possible as the inciting drug is needed to kill cancer cells. Therefore, side effects such as nausea, swelling, neuropathies, constipation, and others are routinely managed with additional medications.
An example of this cascade is seen with Taxane chemotherapy agents (paclitaxel, docetaxel). Taxanes are prevalent in cancer care as they are used to treat breast, ovarian, lung, bladder, prostate, melanoma, esophageal, and other solid tumors. Taxane agents are highly neurotoxic leading to peripheral neuropathies that can involve both sensory and motor impairment. While neuropathies are an anticipated side effect during drug administration, they can become more severe with progressive treatment cycles and may persist long after the completion of treatment.18 For some individuals, peripheral neuropathies significantly impact daily life disrupting fine motor tasks, inhibiting activities of daily living, and impairing mobility. To counteract this, medications such as gabapentin, an anticonvulsant, are commonly prescribed for neuropathic symptom management.19 Gabapentin has side effects, including some sedative effect. For patients undergoing or recovering from treatment for cancer, fatigue is already a commonly presenting symptom and the presence of drug-induced sedative effects can further compound symptoms and impairments. Additional treatment-related cascade examples include the following:
- - Vinca alkaloids (Vincristine, Vinblastine) used in treating acute leukemia, Hodgkin's and non-Hodgkin's lymphoma, and various types of sarcoma. These agents cause neurotoxicity that specifically affects the peristalsis of the bowel, resulting in constipation. Patients are often prescribed OTC and prescription-strength medications to relieve constipation. This cascade often results in diarrhea and can cause electrolyte imbalance putting the patient at further risk for dehydration and other metabolic deficiencies.
- - Hormonal drug therapies are used in hormonally driven breast, prostate, and ovarian cancer treatment and often cause symptoms of bone pain, especially in the back and long bones, as well as joint arthralgias. If these symptoms become intolerable, the patient can be switched to another medication within the class but most often medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed to mitigate the side effects. In an individual with a comorbid condition that requires anticoagulation therapy, there is significant risk for an adverse event as the NSAID may heighten anticoagulation and perpetuate a risk for bleeding.
In order for many patients to tolerate the antineoplastic therapies and effectively manage their cancer, polypharmacy is unavoidable. Although the few examples provided here speak to single-agent side effects and management, it is clinically prudent to assume that in the presence of multidrug cocktails, there will be multiple side effects and therefore multiple drug interventions leveraged to manage these side effects. Drug interactions should be anticipated and monitored.
Pharmacological management of side effects of cancer treatments
The use of drug interventions to manage side effects of antineoplastic drugs is critical to the success of oncology care. Maintaining chemotherapy dosing and cycle timing as close to regimen specificity is ideal. In many cases the only way to manage the rigors of the prescribed antineoplastic therapies is with careful pharmacological interventions that improve an individual's tolerance to cancer treatments and improve quality of life during cancer care. However, the use of additional drugs for managing the side effects of cancer treatment carries implications and risk for further drug interactions. Many of the medications used to manage the most common toxicities of antineoplastic therapies further alter body functions and can perpetuate a decline in functioning.
One of the most common side effects of many antineoplastic drugs therapies is nausea/vomiting (N/V). The key to treating N/V is prevention and there have been many therapeutic solutions that have come about in recent years. Unfortunately, current pharmacological options introduce side effects such as headache and constipation. In addition, they often are coprescribed with corticosteroids for maximum benefit that can potentiate further adverse effects. At times medications used to treat side effects can be so effective that they cause an opposite reaction to occur. For example, a patient experiencing diarrhea may be prescribed multiple antidiarrhea medications to prevent dehydration and electrolyte imbalance resulting in severe constipation.
Another example is the management of insomnia. Anxiety and insomnia are common symptoms experienced during treatment for cancer as patients are facing not only their mortality, but the stress of multiple medical appointments, struggling with side effect and their impact on daily function, and concerns regarding financial implications of their cancer medical care. Many patients are prescribed antidepressants, specifically benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). These drugs can have a sedative effect and impair cognition or exacerbate memory loss. Although these drugs are prescribed to help to improve an individual's quality of life, they may further complicate the common side effect referred to as “Chemo-Brain.” The Mayo Clinic describes Chemo-Brain as “a common term used by cancer survivors to describe thinking and memory problems that can occur after cancer treatment. Chemo brain can also be called chemo fog, chemotherapy-related cognitive impairment or cognitive dysfunction.”20 Individuals experiencing chemo-brain symptoms may also be taking medication for anxiety or insomnia, which may worsen delays in thinking and judgment, and increase sedation, malaise, and depression, which can negatively impact quality of life. In addition, both benzodiazepines and hypnotics, commonly used medications to manage insomnia, are identified as PIMs by the Beers criteria as they may present significant risk to older adults.13
Table 3 outlines many of the standard pharmacological strategies for side effect management and provides insight to their potential impact on function.13,14,16 The NCCN Medications of Concern is designated in Table 3 and should serve as a reminder to providers to assess for the presence of these drugs, recognize their indication in cancer care, and monitor for their functional impact.
Pharmacological considerations with preexisting comorbidities
The majority of older individuals undergoing therapy cancer may also have preexisting comorbidities, most commonly; diabetes mellitus (DM), hypertension (HTN), hypercholesterolemia, arthritis, depression, anxiety disorders, incontinence, frailty, osteopenia/osteoporosis, and memory and cognitive impairments.6 These conditions are commonly managed by a cadre of drug therapies and OTC medications.21 Drug doses are prescribed and carefully monitored and adjusted over time to ensure optimal condition management.
The introduction of antineoplastic therapies can cause physiological changes that necessitate drug dose alterations. For example, many antineoplastic agents result in thrombocytopenia which, at critical thresholds, increases the risk for bleeding. A patient who is closely managed with anticoagulant therapy, such as warfarin, will require oversight and intervention to ensure safe platelet levels and to mitigate risk for an adverse bleeding event.
Antineoplastic therapies can also lead to drug interactions that introduce further complication or exacerbation of an existing condition such as with blood glucose, necessitating medication alteration. For example, the use of corticosteroids inhibits the effectiveness of many insulin management interventions and may lead to elevations in blood glucose even when individuals are taking their medications regularly. Glucose management can be exceedingly challenging for patients with both type I and II diabetes through the duration of cancer treatment and warrants ongoing education and close oversight to alter dosages.
Best practice in identification and management of polypharmacy suggest that medication count is a predictor of risk for adverse events. While this is not inconsistent with risk stratification in the cancer population, rather than counting the sheer number of medications an individual is on; a prudent approach is to develop a clinical understanding of the side effects of commonly used antineoplastic drugs and the drug agents leveraged to manage their side effects. Balancing this with knowledge of the number PIMs will enable an understanding of the risk versus benefit of the drug usage and will enable appropriate monitoring for early identification of adverse effects. Individuals with multiple comorbidities should be monitored with greater frequency and have close contact with the oncology providers overseeing care.
The combined use of numerous antineoplastic agents with various side effects, the requisite use of pharmacological interventions to manage the side effects of these agents, combined with existing drug interventions for comorbidity management seems to lead to a near infinite number of possible risks for serious adverse drug interactions in the older population of cancer survivors. Add to this the routine use of OTC drugs and remedies such as herbal supplements and vitamins (which are beyond the scope of this article), the risks increase exponentially.
Health care providers in rehabilitation medicine should be acutely aware of the antineoplastic agents used for medical cancer treatment, additional pharmacological agents prescribed for side effects management, and the pharmacological management of existing comorbidities. Table 4 reviews common comorbidities and their pharmacological management strategies and describes the functional implications of how these interact with antineoplastic therapies.22–31
Drug interaction awareness in practice
Nearly one third of elderly cancer patients are exposed to severe drug interactions and PIMs.32 The oncologic population is more likely to be exposed to PIMs as they may be indicated for optimal disease management. Rehabilitation providers should use prudent assessment methods to understand the pharmacological agents in use and their side effects and potential interactions. Although caution should be used in interpreting the Beer's Criteria, as drug indications during cancer care are different, medication review and reconciliation efforts should be considered a part of standard patient evaluation and intake. Further, the rehabilitation provider should leverage their understanding of cancer-related pharmacological strategies to assess whether emerging impairments and functional limitations are the result of a potential drug side effect or whether there are elevated risk and need for monitoring and screening for impairment due to the risk of PIM adverse effects. There are several steps rehabilitation providers can take to optimize care and reduce risk.
First, providers should identify numerous resources that can provide them with up-to-date knowledge of commonly used antineoplastic agents and their known side effects. The Internet provides obvious accessibility to resources; however, providers should seek out reputable websites for information such as the National Cancer Institute† (NCI), the American Cancer Society‡ (ACS), the American Society of Clinical Oncology§ (ASCO), and the NCCN.** These sites provide information on current standard practice in oncology care and evidence-based guidelines for pharmacological intervention. Additionally, NCI and ACS have excellent patient-focused resources that can be used for educational purposes. Scientific research in the field of antineoplastic therapies is rapidly evolving and new drugs are being used in clinical trials and in standard clinical practice with great frequency necessitating an ongoing awareness.
Second, providers should have intimate awareness of an individual's functional status and employ methods to routinely screen high-risk individuals for treatment-related toxicities and late effects that negatively impact function. This approach enables early identification and awareness of pharmacologic-related adverse events, as the early manifestation of these events may present as changes in physical or cognitive functioning. In 2014, a consensus statement by the International Society of Geriatric Oncology recommended the use of a comprehensive geriatric assessment (GA) to detect functional impairments not identified in routine history or physical examination related to cancer treatment toxicities.12 They recommend the GA as a screening tool, as many components such as grip strength and gait speed are predictive of overall disability in this population.30,33
Prospective research using a GA tool in oncologic populations shows that it is more sensitive in identifying functional impairments than the current standard performance measures used in oncology practice.34Table 5 outlines the components of a GA, as studied by Jolly et al.34 There are numerous clinical measurement tools and patient-reported measures that are valid for use in this population. When choosing assessment tools, it is important to ensure that each domain is assessed. Clinical feasibility of this assessment method is very good, and the measures included have a strong evidence base.35,36 Since cancer care involves a protracted trajectory with an accumulated burden of morbidity throughout, an optimal framework for clinical assessment of function is one that starts at the point of diagnosis to obtain a baseline, and tracks an individual over the continuum of care to screen for changes in status indicative of emerging impairment.37 This approach in prospective surveillance is touted as an optimal rehabilitation model for identification of adverse events and enabling tailored interventions and that may improve function and prevent cancer treatment-related disabilities.38,39
Last, it is imperative that health care providers work comprehensively as an integrated team with the patient. Leveraging survivorship care plans and enabling optimal communication among interdisciplinary care teams promotes high-quality cancer care.40 Team members should have an understanding of the medical therapies prescribed, their anticipated side effects, and should share changes in the plan of care so that all team members are aware and able to monitor for adverse effects. Providers should be aware of the mechanisms for managing functional decline and should have resources in place to ensure optimal referral for appropriate interventions.41
Rehabilitation providers should have clear communication mechanisms with the cancer care team during the phases of cancer treatment to convey identified changes in functional status that may be associated with medication interactions. Once an individual completes active, medically directed cancer treatment follow-up care typically moves out of the sphere of oncology and into primary care. Over the course of survivorship, providers should continue to monitor for potential late effects of cancer treatments as well as the emergence of additional age-related comorbidities both of which may necessitate pharmacological management. Functional screening and assessment should continue proactively.
The complexities of cancer pharmacological therapies introduce the potential for significant drug interactions that impact an individual's function. Older adults have unique needs and risks for drug interactions due to common age-related, comorbid conditions. Rehabilitation providers should familiarize themselves with the current standards for managing polypharmacy in the oncologic population. A prospective approach to surveillance and monitoring of drug therapies and functional status is an ideal model for optimizing outcomes.
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