With advancements in cancer treatment, there are an estimated 3 million breast cancer survivors living in the United States.1 While statistics vary, estimates show that there is an approximate 15% to 28% incidence rate for lymphedema in breast cancer survivors, with an estimated 5% to 10% of women developing lymphedema after a modified radical mastectomy.2 Lymphedema typically develops within the first year of treatment of breast cancer but can develop 20 years after diagnosis.
RISK FACTORS FOR BREAST CANCER–RELATED LYMPHEDEMA
The following have been identified as risk factors for the development and exacerbation of breast cancer–related lymphedema (BCRL): axillary dissection, radiotherapy, obesity, extent of surgical revisions, infection of affected extremity, diabetes mellitus, traumatic injury of affected extremity, and/or excessive use of affected extremity.2–9
One item that is not included in this list as a potential risk factor for the development or exacerbation of lymphedema is medication. Little is known about the effect that certain medications have on a known diagnosis of lymphedema. Given that there are more than 900 medications that can cause fluid retention and edema as a side effect, there is a significant lack of literature outlining the effects of medications on secondary lymphedema, specifically lymphedema following breast cancer treatment.4 , 5 Knowing that BCRL causes substantial psychological and financial stress, clinicians need a greater understanding of medication's effect on BCRL.
An understanding of the basics of how edema develops is key to understanding secondary lymphedema. The distribution of water, carrying nutrients and waste, is determined by changes in hydrostatic pressure (pushing fluid) and osmotic pressure (pulling fluid) back and forth across the capillary wall.10 How this fluid moves is determined by 4 forces:
- Capillary hydrostatic pressure (blood pressure): Blood pressure assists fluid moving from the capillary space to the interstitial space; this assists in filtration.
- Plasma oncotic pressure: The pull of osmotic pressure on moving fluid from the interstitial space back into the capillary space; this opposes filtration.
- Interstitial hydrostatic pressure: Facilitating fluid movement from the interstitial space into the capillary space by a pushing force; this opposes filtration.
- Interstitial oncotic pressure: Facilitating fluid movement from the capillary space into the interstitial space by a pulling force; this assists in filtration.18
The ability of fluid to move smoothly back and forth across the capillary wall is referred to as net filtration, which can be best described by Starling's forces. In Starling's forces, net filtration is essentially the difference between the pressures favoring filtration and the pressures opposing filtration.10
Edema results from having too much fluid within the interstitial space, and fluid within this space is typically absorbed by the lymphatic system. Changes in forces altering net filtration can lead to increased edema. For example, changes in blood pressure (capillary hydrostatic pressure) as seen in congestive heart failure results in a plasma volume overload and increased capillary pressure and edema. Another example would be poor nutritional intake or liver diseases resulting in lowered albumin levels. Albumin, as with all plasma proteins, does not cross the capillary wall, which subsequently has a decreasing effect on oncotic pressure. This decrease in pressure results in fluid remaining within the interstitial space.10
The next step in filtration is the interstitial fluid being drained by the lymphatic system. Whenever there is an imbalance between capillary filtration and tissue (lymphatic) drainage, edema will result.10 Lymphedema occurs whenever there is normal capillary filtration, but the underlying lymphatic system is damaged.7 Individuals diagnosed with breast cancer who have undergone lymph node biopsy and/or removal and/or radiation will subsequently have underlying damage to lymphatic tissue. Therefore, individuals with a history of breast cancer will be at a higher risk for experiencing upper extremity lymphedema in their lifetime. This is secondary lymphedema. Secondary lymphedema in women with breast cancer can be attributed to lymph node dissection, radiation therapy (scarring and fibrosis), infection, chemotherapy damage (extravasation of a vesicant), and lymph node metastasis.2
Psychological Distress and Depression
BCRL can have a profound effect on a person's life. BCRL is often associated with a lower reported quality of life and psychological distress; fatigue, chronic pain, and limitations in overall mobility; higher rates of infection/cellulitis in the affected extremity; increased financial burdens; and increased constraints on time due to individuals attending therapy and performing associated self-care. A systematic review of literature conducted on 23 peer-reviewed research articles from 2004 to 2011 found that BCRL is associated with statistically significant decreased social well-being. This decrease in well-being correlates to negative self-identity or body image disturbances and psychological distress. In addition, people experiencing BCRL experience negative social effects related to increased financial restraints, isolation, and marginalization.11 Understanding the depth to which lymphedema can negatively impact an individual further emphasizes the need for research examining the role medications play in potentially exacerbating BCRL.
Women with BCRL are at a higher risk for depression and anxiety related to their lymphedema, especially if they already suffer from depression secondary to their diagnosis of breast cancer. Psychological distress and depression are associated with a diagnosis of breast cancer. An analysis of data from 4496 patients with cancer who took the Brief Symptom Inventory assessment, a 53-item measure of psychological distress, found that approximately 33% of patients with breast cancer (n = 1249) suffered from depression.12 Individuals who already suffer from depression and psychological distress are at increased risk for developing ongoing or worsening symptoms, and evidence shows that patients with breast cancer who have lymphedema suffer from psychological distress at higher rates than patients with breast cancer who do not have lymphedema.13
Negative Body Images
Furthermore, negative body image beliefs in women are more profound in those suffering from BCRL than in those who have suffered physical changes secondary to trauma. Researchers in Austria compared body image beliefs and quality-of-life indicators between 40 women who suffered from lymphedema and 40 women who had suffered from physical trauma.14 Using the Frankfurt Body Image Questionnaire and the German version of the Short Form-36 Health Survey, researchers found that women who suffered from lymphedema scored significantly lower than trauma patients in the following categories: health and physical well-being (p = .004); personal hygiene and outward appearance, consideration of physical efficiency (p = .065); sexuality (p = .000); physical self-acceptance (p = .000); physical acceptance by others (p = .006); and aspects of physical appearance (p = .020).14
BCRL also has a significant financial effect. A team of researchers examined productivity information for more than 550 000 employees and their spouses by looking at medical and pharmaceutical claims specific to lymphedema secondary to a breast cancer diagnosis. Of a total 1877 women with a breast cancer diagnosis, 108 had a diagnosis of BCRL.15 Overall results found that women who experienced lymphedema had a significant increase in medical expenses ($23 167 compared with $14 877) and were also twice as likely to have a diagnosis of lymphangitis or cellulitis.15
Return to Work
Along with the financial burden of lymphedema, women suffering from BCRL can also find returning to the workforce to be difficult. Using a descriptive phenomenological method, work experiences of 22 women who suffered from BCRL were examined in 66 in-depth interviews.16 The messages from the women not only demonstrate difficulties faced in the workforce but also significantly highlight ongoing psychological distress related to their lymphedema. Three themes emerged from findings: having a visible sign of BCRL; having physical limitations; and worrying versus feeling fortunate.16
Disability in the Work Place
For the women, having visible lymphedema caused more attention from their coworkers and women reported feeling viewed as having a disability.16 This view of having a disability caused the women to feel as though they were treated differently, and some subsequently wore clothes, to hide as much of the lymphedema, or compression garment, as possible. Sadly, one woman who worked as a waitress recounted the following incident:
My boss constantly reminded me that I'd better cover my hand well so that our customers would not be scared. I understand that people might lose their appetite if they see my swollen hand or they might think something worse. Every time I reminded myself to only use the other hand to put food on the table so that I don't give people the chance to compare. I am really stressed out to be reminded every day, as if I had something very disgusting.16 (p22)
Physical Limitations in the Work Place
For many women, having BCRL put physical limitations on their ability to perform their work. In describing their work performance, words such as “debilitating,” “disabled,” and “handicapped” were used.16 Some women felt frustrated or embarrassed by needing to ask for assistance from their peers. One woman, a hospital technician, described the following:
I cannot lift my patients just using my right arm. I have to ask people to help me to lift patients. Often, people are busy with their own work and I have to wait. It can be very depressing for women like me in the working field.16 (p23)
Fear of Job Loss
Women in the workforce with perceived or anticipated inability to complete all their required tasks due to lymphedema found themselves in a perpetual state of worry due to fear of being unable to work. One woman expressed this by stating,
As I type each day and see my hand swell up by the middle of the day, I cannot stop worrying that someday I might no longer be able to use my arm and hand if I continue my job. I am worried about my future.16 (p23)
Chronic Disease and Medication
As survival rates for breast cancer improve and survivors age, the risk these women face for developing a chronic disease(s) also increases. According to the World Health Organization, chronic diseases accounted for 60% of deaths in 2002, and estimates are that three-fourths of all deaths will be secondary to chronic diseases by 2020.17 Cardiovascular disease, cancer, chronic obstructive pulmonary disease, and type II diabetes are the 4 most common chronic diseases, and there is a worldwide call to action for successfully managing debilitating sequelae through medication management.
Unfortunately, chronic disease medication management may require certain classifications known to cause significant generalized and peripheral edema. Fluid retention could elicit, exacerbate, or impact lymphedema. A few examples of these medication classifications are calcium channel blockers, anticonvulsants/antineuralgics, chemotherapeutic agents, nonsteroidal anti-inflammatories, and antidiabetics.
In all, more than 900 medications potentially contribute to edema.4 , 5 However, very little research examines how specific medications influence a known diagnosis of lymphedema secondary to breast cancer or even potentiate a new diagnosis of lymphedema in a patient previously treated for breast cancer.
The purpose of this review is to outline the importance of examining the effect that certain medications may have on BCRL through providing examples of common medications/drug classifications that have known to produce increased peripheral edema in patients who already have a compromised limb due to edema and emphasizing the effect medications have on edema in some patient populations through previously reported case studies.
EDEMA RESULTING FROM MEDICATIONS
Certain types of drug therapy can result in an increase in peripheral edema. Typically, when a person develops edema secondary to a medication, swelling develops gradually with a generalized presentation throughout the body or it develops in limbs bilaterally. However, knowing that edema is caused by a disruption in the balance of capillary filtration and drainage, individuals with lymphatic damage to a particular limb will often develop this otherwise generalized edema unilaterally (in the affected limb). Both limbs might increase in size, but a limb with lymphatic or venous damage will often present larger in size.9 In 2008, Keeley4 , 5 identified several drug categories that can contribute to peripheral edema including calcium channel blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants/antineuralgics, antidepressants, antidiabetics, and cytotoxic agents. Many of these medications treat chronic diseases such as cardiac disease, cancer, and diabetes; these medications also treat the sequelae that can occur with chronic disease such as pain and depression.4 , 5
At the time of breast cancer treatment and diagnosis, many patients with breast cancer are exposed to medications that not only are necessary to treat their cancer but can also potentiate the risk of peripheral swelling. For example, docetaxel (a taxoid drug) is a chemotherapeutic agent used in the treatment of metastatic breast cancer. However, fluid retention is a common cumulative toxicity for this drug and this side effect can often limit both the dose and duration of treatment. Statistics show that 44% to 65% of patients treated with docetaxel experience significant fluid retention despite premedication.18 The pathophysiological mechanism for fluid retention in docetaxel, as with many taxoids, is thought to pertain directly to the capillary filtration/lymphatic drainage system. There appears to be a 2-step process for fluid retention beginning with (1) fluid congestion in the interstitial space (secondary to a toxic effect on capillary endothelium leading to capillary hyperpermeability); compounded by (2) inadequate lymphatic drainage.19 This combination of hyperpermeability and toxicity at the capillary endothelial level is specific to why patients should be premedicated with corticosteroids.19 , 20 Docetaxel and other taxoids are given to patients during their initial phases of a cancer diagnosis and recurrence and therefore could potentiate a new diagnosis of lymphedema that could later be affected by chronic disease medications.
Calcium Channel Blockers
Calcium channel blockers are medications commonly prescribed in the treatment and stabilization of many cardiac diseases. Some Food and Drug Administration–approved indications for calcium channel blockers include hypertension, angina, and certain dysrhythmias.21 Calcium channel blockers are commonly prescribed for aging populations, including patients with BCRL. Unfortunately, calcium channel blockers have been known to cause peripheral edema and, depending on the dose and specific drug, peripheral edema can have an incidence rate of anywhere from 5% to 70%.22 Calcium channel blocker–associated edema results from a disruption in capillary filtration flow. Essentially, there is precapillary dilation without compensatory dilation in the post–capillary circulation.9 This disruption in resistance “increases precapillary pressures to a degree that plasma is literally forced from the intravascular compartment into the interstitium.”22 (p291) In order for subsequent edema to develop, this movement of fluid in the capillary circulation must exceed the overall capacity of the lymphatic or venous draining system. It makes sense, then, that limbs with impaired lymphatic flow would succumb to edema more rapidly than unaffected limbs. Patients often present with unilateral edema secondary to calcium channel blockers, particularly in at-risk extremities. Of even greater interest, research shows that the phenomenon of edema with this medication tends to be higher in women and presents gradually, thereby making it difficult to attribute swelling to the calcium channel blocker. The most clinically effective way to manage this side effect is to either change the type of calcium channel blocker or cease this classification of drug all together. Diuretics show initial benefit but are not effective over time.23 Future research is needed into whether calcium channel blockers directly affect BCRL incidence or severity.
While calcium channel blockers cause swelling resulting from a disruption in flow of overall capillary filtrations, NSAIDs can influence sodium/water retention due to the drugs renal effect. NSAIDs could potentially increase tubular reabsorption of sodium, and individuals who are already at risk for edema (eg, underlying lymphedema) experience these symptoms more frequently than those without an underlying disease process or injury.24 It is estimated that fluid retention is seen in up to 25% of patients who are taking NSAIDs, and NSAIDs can make diuretic therapy less effective.24 These statistics are significant when we consider how often NSAIDs are either prescribed or taken over-the-counter.
Under the subheading of anticonvulsants are medications used to treat neuropathic pain (antineuralgics). Two common medications seen are pregabalin (Lyrica) and gabapentin (Neurontin). In addition to having properties for treating seizure disorders and neuropathic pain, these medications are prescribed for the treatment of sleep disorders and anxiety. Given the wide variety of uses for these medications, they are prescribed with increasing frequency for a variety of chronic conditions and their sequelae.25 , 26
Among women who have undergone surgery for breast cancer, the incidence of postoperative pain can be up to 50%. Often, this pain becomes chronic and treatment of surgery-induced neuropathic pain with daily pregabalin or gabapentin has become common practice among providers. However, the risk of fluid retention with this type of medication is high. With pregabalin, the prevalence of peripheral edema is reported up to 15% of the time.25 In a recent case study, a 76-year-old female patient underwent decompression surgery to her L1-S1 spinal segment in 2008. Postoperatively, the patient was prescribed 300 mg of pregabalin 2 times a day for the resulting neuropathic pain. By 2012, the patient condition continued to decline and was no longer mobile, and she was subsequently hospitalized for 53 days with a diagnosis of cellulitis and severe edema. The patient's pregabalin dose was titrated down and fully stopped within 1 week. After 10 days, the circumference of each calf had decreased, the wounds stopped draining, and they were beginning to heal.25 Although this appears to be a relatively extreme example, the case study clearly highlights the potential for delayed onset and recognition of medication-induced peripheral edema, in a manner similar to that reported by many women with BCRL.25
The specific medication that will be examined for antidepressants is trazodone, a tricyclic antidepressant that has fewer anticholinergic and cardiac side effects than other medications within the same classification. In 1985, 10 case studies reported on patients treated with trazodone who subsequently experienced fluid retention.27 None of the patients had any underlying cardiac conditions that could account for, or contribute to, this fluid retention. However, once the medication was stopped, patients' fluid levels returned to baseline.27
The mechanism of action causing fluid retention in patients taking trazodone is unclear. One possible explanation would be that trazodone lowers arterial blood pressure and decreases heart rate; this has an overall effect on lowering cardiac output. This lowered cardiac output could mimic heart failure and therefore produce those same symptoms.27 In 10 reported cases, none of the patients had any underlying cardiac conditions that could account for, or contribute, to this fluid retention.27 Another possible explanation would be that depending on the dose of the trazodone, it will act either as a serotonin antagonist or as an agonist. The 5-HT receptors mediate vasoconstriction, and either the antagonist or the agonist effects could be responsible for fluid retention. The authors reporting on the 10 cases of patients receiving trazodone concluded that while the exact mechanism of action remains elusive, trazodone dosing should be increased gradually in patients who have an underling disease process that predisposes them to edema or fluid retention.27 Again, this caution is relevant for the category of patients who are experiencing BCRL, and as previously reported, depression is common in women with BCRL.
According to the American Diabetes Association in 2012, a total of 29.1 million Americans had a diagnosis of diabetes, equating to approximately 9% of the population; this is up from approximately 8% of the population in 2010.23 Unfortunately, many medications used to treat diabetes cause peripheral edema, in particular rosiglitazone (Avandia) and pioglitazone (Actos). These medications are a type of thiazolidinediones, medications used in the treatment of type II diabetes. In patients who are taking a thiazolidinedione as singular therapy, edema is reported at an incidence rate of 5% to 10%. However, thiazolidinediones paired with daily insulin have an edema incidence rate of 15% to 20%.28 The mechanism of action for fluid retention in this patient population remains unclear, although more studies suggest that this fluid retention results from increases in tubular sodium and water retention.28
A case study reported on a 51-year-old African American man who had been diagnosed with type 2 diabetes and had been taking rosiglitazone for 26 months.29 Although the patient had been taking rosiglitazone for more than 2 years, he experienced a sudden onset of swelling in his right leg. Following a full examination, deep vein thrombosis was ruled out. Furosemide administration was not beneficial. The patient's wife subsequently consulted a Physician's Desk Reference and hypothesized that the swelling was likely secondary to the rosiglitazone, and she recommended that her husband stop taking it. Within days of discontinuing the drug, the swelling disappeared. In an effort to determine that this outcome was specific to the medication, a medication rechallenge was recommended (start taking rosiglitazone again); within 5 days, the edema returned and the medication was subsequently stopped.29
A possibility exists that that certain medications associated with edema and fluid retention may exacerbate BCRL, and discontinuing these medications might be the only effective remedy. Although it remains poorly studied, the effects of medications on BCRL are currently under investigation at an academic health sciences cancer center and school of nursing. Specific goals of the study include an examination of the relationship between known lymphedema and patterns or alterations in daily medication regimens and examining new cases of lymphedema based on medication regimens in breast cancer survivors.
Better understanding and awareness of concomitant medical therapy may help improve the diagnosis and management of BCRL. As longevity after breast cancer diagnosis continues to increase, women with BCRL will be exposed to varying types of medications across their lifespan, and each could have an effect on a current or new diagnosis of lymphedema. BCRL can have a profoundly negative effect on women for years following diagnosis. Through medication side effect profiles and case studies, edema associated with medications will often not subside until medications are either decreased or discontinued. Having a compiled list of medications that could contribute to BCRL will allow providers to initiate their own medication reconciliation with patients and improve outcomes in this disease process.
The authors thank Kimberly Butler, BS, and Dr Chi-Ren Shyu, University of Missouri Institute of Informatics and College of Engineering, for their efforts in the creation of a database that will allow for the cross-examination of associations between medications and limb volume changes.
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