Potential drug interactions in elderly cancer patients

1. Introduction 

Only a few published studies have investigated potential drug interactions in elderly cancer patients. It has been reported that up to 80% of cancer patients aged over 65 years have comorbid conditions [1] and that the number of comorbidities increases with age. Consequently, these patients can be expected to take several concomitant medications. The majority of patients over 65 years of age take prescription medications and 39% regularly take five or more drugs [2]. The risk of drug-related toxicity is likely to increase with the increasing number of medications. Predictors of increased risk of drug interactions are increasing number of medications, the presence of certain types of tumors and the use of drugs for comorbid diseases. Predictors of inappropriate medication use in elderly populations include functional status, gender, ethnic origins, health literacy, cognitive impairment and adherence, but these factors have not been investigated in elderly cancer patients. Adverse drug reactions account for 10% of all hospital admissions over the age of 65, and 20% of admissions over the age of 80 [3], [4], [5]. It is therefore very important to be aware of these drug interactions, to detect them as early as possible and to prevent them.

The aim of this study was therefore to investigate the presence of a wide range of potential drug interactions in elderly patients treated in a tertiary cancer center by using the French national reference for the detection of paired drug interactions.

2. Methods 

3. Results 

3.1. Patients and polypharmacy 

Patient characteristics are shown in Table 1. The majority of participants were women (83%) with a median age of 79 years (range: 70–97). The most common cancer diagnosis was breast cancer (N=64), followed by colon cancer (N=7). Forty percent of patients were receiving specific cancer therapy at the time of the consultation, most commonly endocrine therapy. The most common treatment plan proposed at the end of the consultation was chemotherapy followed by surgery. Four hundred ninety-five medications were used, corresponding to 522 compounds (defined according to their INN). One patient did not receive any treatment, 6 patients received only one medication and no treatment information was available in the chart for one patient. Statistical analysis was therefore performed on the 97 patients who received 2 or more medications; 46.7% of these 97 patients received 5 or more medications see Table 2.

Table 1. Patient characteristics with health and functional status, N=105.

	Characteristics	N (%)
	Male	18 (17)
	Female	87 (83)
	Age, median (range)	79 (70–97)
	Diagnosis
	Breast cancer	64 (60.9)
	Lung cancer	6 (5.7)
	Colorectal cancer	7 (6.7)
	Cervical carcinoma	4 (3.8)
	Endometrial cancer	3 (2.8)
	Ovarian cancer	1 (0.9)
	Prostate cancer	2 (1.9)
	Choroidal melanoma	3 (2.8)
	Hematologic malignancy	2 (1.9)
	Other	13 (12.3)
	Presence of metastases	60 (57.1)

	Domains of health and functional status		N (%); mean±SE, [range]
	Functional status
	ADL	Independent	55 (58)
		Dependent (<4/6)	40 (42)
	IADL	Independent	46 (46)
		Dependent (<4/6)	54 (54)
	ECOG PS	0	12 (12.5)
		1	46 (47.9)
		2	31 (32.3)
		3	7 (7.3)
		4	0 (0)
	Nutrition
	Weight loss in the last 3 months >10%		7 (7.7)
	BMI (kg/m2)	Mean	23.8±0.47 [14.5–41]
		<18.5	14 (13.6)
		18.5–21.0	13 (12.6)
		21–23	20 (19.4)
		23–25	21 (20.4)
		25–50	35 (34)
	Mood
	Mini GDS (≥1 depressive symptom)		43 (53.1)
	Mobility
	≥2 falls in the last year		20 (19.8)
	Comorbidity (n evaluable)		9 (9)
	Diabetes (103)		49 (47)
	Hypertension (104)		3 (3)
	Chronic renal failure (101)		3 (3)
	Stroke (104)		2 (2)
	CHF (101)		14 (15)
	Coronary disease (95)		50 (61)
	Other (82)
	Number of comorbidities		11 (15.3)
	0		37 (51.4)
	1		24 (33.3)
	≥2
	Social support (caregiver present)		84 (83.1)
	Living in a nursing home		11 (10.6)

	Treatment plan proposed at baseline N=93	N
	Chemotherapy	51
	Chemotherapy+endocrine therapy	4
	Chemotherapy+radiotherapy	3
	Chemotherapy or surgery or endocrine therapy	1
	Surgery	2
	Radiotherapy±endocrine therapy	4
	Endocrine therapy	16
	Watchful waiting	11

Abbreviations: ADL: activities of daily living; IADL: instrumental activities of daily living; ECOG PS: eastern cooperative oncology group performance status; BMI: body mass index; mini GDS: mini geriatric depression scale [50], CHF: chronic heart failure

Table 2. Number of concomitant medications per patient.

The medications most commonly used were level II opioid analgesics, followed by benzodiazepines, benzodiazepine hypnotics, beta-blockers and proton pump inhibitors (see Table 3, Table 4).

Table 3. Top 10 pharmacotherapeutic groups used.

	Rank	% of prescriptions	Pharmacotherapeutic groups
	1	29.1	Level II opioid analgesics
	2	26.2	Benzodiazepines
	3	21.4	Hypnotic Benzodiazepines and others
	4	18.4	Beta-blockers
			Proton pump inhibitors
	5	17.5	HMG-CoA reductase inhibitor lipid-lowering drugs
	6	16.5	Non-opioid analgesic
			Diuretics
	7	13.6	Platelet aggregation inhibitors
			Antineoplastic, endocrine therapy and similar
			Bisphosphonates
			Minerals
	8	12.6	Cytotoxic drugs
			Calcium channel blockers
	9	11.6	Other antianginal drugs
			Serotonin reuptake inhibitor antidepressants
			Thyroid hormones
	10	10.7	Level III opioid analgesics
			H2 antihistamine antisecretory agents
			Angiotensin-converting enzyme inhibitors
			Vasoconstrictors

Table 4. Top 5 therapeutic fields.

	Therapeutic fields	Number of medications prescribed (% of all drug prescriptions)
	Cardiovascular	149 (28.7)
	Analgesics and anti-inflammatory	71 (13.7)
	Psychotropic medications	68 (13.1)
	Gastrointestinal medications	47 (9.1)
	Antineoplastic medications	43 (8.2)

3.2. Drug interactions 

Forty-five potential drug interactions were detected among the 97 patients who received 2 or more medications. These interactions actually occurred in only 32 patients, while no interactions were observed in 67% of cases (65/97). No contraindication was identified, 2 cases of concomitant use not recommended, 9 cases requiring certain precautions (20%) and 34 cases of concomitant medications to be taken into account were identified (see Fig. 1).

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Fig. 1. Drug–drug interactions: number and level.

The two cases requiring certain precautions corresponded to concomitant use of hydroxyzine and betahistine (potential antagonism) and concomitant use of ibuprofen and diclofenac associated with an increased risk of peptic ulcer and gastrointestinal bleeding.

The most common adverse drug reactions were respiratory distress and sedation in the case of overdose, increased bleeding risk and risk of masking of hypoglycemia (Fig. 2). These potential risks were not observed in these patents. The patients’ charts were retrospectively reviewed and no case of respiratory distress was observed during the 3 months following this consultation.

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Fig. 2. Drug–drug interactions: major risks.

4. Discussion 

Elderly patients present an increased risk of drug interactions. They frequently take many drugs and present several comorbidities. Several factors, such as interindividual variability, frailty and impaired homeostasis, increase the complexity of management of drug interactions in the elderly, but about one half of adverse drug reactions in the elderly can be prevented by better prescribing practices [8]. It is therefore essential to optimize drug prescription in the elderly. General practitioners are generally responsible for the medical care of the elderly, who tend not to consult specialists as frequently as younger adults [9]. The main risk factor for polypharmacy is the prescribing physician and the number of prescribing physicians [10], [11]. This factor must be taken into account [12], [13] in order to develop education programs for patients and physicians [14]. Some teams have developed and implemented a pharmacy automation system (robotics) to ensure medication safety [15], [16]. However, the essential role of pharmacists must not be underestimated [17]. Screening tools for Inappropriate Prescribing (IP) have been devised, mainly based on Beers’ Criteria [18], [19] and the Inappropriate Prescribing in the Elderly Tool (IPET) [20], but more up-to-date, systems-based and easily applicable criteria are needed in the routine clinical setting [8], [21], [22], [23], [24].

Many studies performed to estimate the prevalence of inappropriate medication use in elderly populations have reported inappropriate prescription rates of up to 40% [25]. Other studies have described drug interactions in oncology, either between specific cancer treatments [26], or between anticancer drugs and other medications, as in certain Canadian studies [27], or drug interactions unrelated to chemotherapy in cancer patients [4] or patients receiving supportive care [28]. The frequency of drug interactions is probably underestimated, as many studies are retrospective, without systematic recording of all medications and all interactions. Four percent of cancer-related deaths could be associated with drug interactions [29], but very limited data are available [30].

However, few drug interaction studies have been conducted in elderly cancer. The present study was conducted in a specific population, elderly cancer patients, who may present an increased risk, as they are likely to take more medications than the elderly population without cancer. The mean number of medications per patient in this population was 4.7. Elderly patients have been reported to take an average of two to five prescription medications, and polypharmacy is observed in 20–50% of these patients [31]. Another US survey of adult outpatients showed that the highest overall prevalence of medication use was observed among women aged ≥65 years: 94% used at least one drug weekly, 57% used five or more drugs and 12% used ten or more drugs weekly [32]. The term “polypharmacy” is often used to describe the use of five or more drugs [33], but other authors have defined polypharmacy as the use of more drugs than clinically indicated. In the absence of a clear definition, we decided to use the term polypharmacy to refer to the use of “multiple drugs”. Concomitant use of several drugs is known to increase the risk of adverse drug reactions and drug interactions [34], [35] and adverse drug reactions are known to be more frequent and more serious in the elderly [36]. Polypharmacy has been demonstrated to be a statistically significant predictor of hospitalization, nursing home placement, death, hypoglycemia, fractures, impaired mobility, pneumonia and malnutrition [37]. Approximately 5–10% of hospital admissions of elderly patients in general are related to adverse drug reactions [38], [39]. In the present study, drug–drug interactions were less frequent than expected: only 32 of the 97 patients taking 2 or more medications actually experienced a drug interaction. This low rate could be partly explained by the fact that these patients were outpatients. Another French study [40], performed in older adults, showed that one half of patients admitted to hospital had at least one potential drug–drug interaction and that this drug interaction led to an adverse event in one quarter of patients. A Canadian study [41] based on 112 newly diagnosed cancer patients aged 65 years and over found that 62% had a potential drug interaction, regardless of the degree of severity and 47% patients had a potential moderate/severe drug interaction. This higher rate is probably due to drug–patient interactions (impaired renal function or liver function, etc), which could not be analyzed in the present study.

The most common adverse drug reactions were respiratory distress and sedation due to concomitant use of analgesics, but in practice, this type of adverse reaction is unusual.

This study we did not analyze the consequences of polypharmacy, including poor adherence or increased risk of hospitalization. For example, the risk of falls or recurrent falls is doubled with the use of four or more medications [42] with a subsequent increased risk of hospitalization. Poor adherence to treatment regimens is a major concern and could be a leading cause of adverse drug reactions. Another limitation of this study is that no information on drug–patient interactions was available. The hepatic metabolism of many drugs is reduced, sometimes by about 30–50% [12] and decreased creatinine clearance is commonly observed in the elderly, often secondary to other diseases. Many drugs are metabolized to their active forms by hepatic cytochrome P450(CYP) and interactions with P450 inhibitors are often neglected [43]. For example, concomitant use of CYP 2D6 inhibitors, such as the commonly prescribed selective serotonin reuptake inhibitors, and tamoxifen in breast cancer may interfere with the efficacy of tamoxifen with a significant 1.9-fold higher breast cancer recurrence rate 2 years after initiating therapy [44] (unpublished data) but other studies have not demonstrated any association [45].

The dosages of all of these drugs were not studied and there is no evidence from clinical trials in favor of dose reduction of cancer treatments or other medications in the elderly. Although dose reduction may minimize adverse drug reactions, the efficacy of lower lowers is often unknown in this population. Elderly patients may present a different pharmacokinetic profile for many drugs, mainly because of altered elimination due to impaired renal or metabolic function [46]. Population pharmacokinetic studies are designed to estimate the statistical distribution of pharmacokinetic parameters for a given drug in a population of patients, in order to quantify the inter- and intra-individual variability of pharmacokinetics and to identify the sources of this variability. Population pharmacokinetic studies in the elderly would be useful to detect patients in whom pharmacokinetic parameters are sufficiently different from reference values to justify dose adjustment and would require very few samples per patient [47].

Another limitation of this study is the low rate of patients receiving chemotherapy, which could be a source of additional interactions (such as platinum and anti-inflammatory drugs) with a higher risk of toxicity in the case of hypoalbuminemia, commonly observed in elderly cancer patients. It would be interesting to conduct a prospective study of drug interactions in elderly cancer patients receiving chemotherapy. In a prospective pilot study designed to determine which elderly cancer patients are at risk of developing chemotherapy-related toxicity, Extermann et al. [48] showed that polypharmacy (3 or more medications) was associated with a lower dose intensity and with FACT-G change (Functional assessment of Cancer Treatment-General) but not with toxicity. However, few studies have examined the impact of polypharmacy on the safety and efficacy of chemotherapy. One study [49] showed that long-term anticonvulsant therapy increased the systemic clearance of several antileukaemic agents and was associated with lower efficacy of chemotherapy, but this study was performed in a pediatric unit and no specific study has been performed in elderly cancer patients.

In conclusion, elderly cancer patients are at high risk of drug interactions, but the prevalence of these interactions has not been well documented. A multidisciplinary approach with the participation of nurses, pharmacists, geriatricians, oncologists and general practitioners, is necessary to optimize drug therapy in elderly cancer patients.

Conflict of interest statement 

There are no financial disclosures from any authors.

Reviewers 

Etienne Chatelut, M.D., Institut Claudius-Regaud 20-24 rue du Pont Saint-Pierre, F-31052 Toulouse, France.

Stuart M. Lichtman, M.D., Memorial Sloan-Kettering Cancer Center, Department of Medicine, 650 Commack Road Commack, NY 11725, United States.