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Screening for Chemotherapy Adverse Late Effects

Marchese, Victoria G. PhD, PT; Morris, G. Stephen PhD, PT; Gilchrist, Laura PhD, PT; Ness, Kirsten K. PhD, PT; Wampler, Meredith DPTSc, PT; VanHoose, Lisa PT; Galantino, Mary Lou PhD, MSCE, PT

doi: 10.1097/TGR.0b013e318219912a
Cancer Rehabilitation
Free

Chemotherapeutic agents are the primary treatment of many solid (breast, bone, brain, and lung) and hematological malignancies (leukemia, lymphoma, and multiple myeloma). Because these drugs are not specific for cancer cells, healthy, rapidly dividing cells can also be damaged by chemotherapeutic agents, and such damage manifests itself in the form of chemotherapy short- and long-term adverse effects. The increased survival rate for patients with cancer has led to the recognition that adverse effects associated with chemotherapy regimens may appear or persist months to years after chemotherapy has been completed. Therefore, the purpose of this article is to highlight the late adverse effects of the most common chemotherapeutic agents, present screening tools that can suggest the presence of these adverse effects, and then briefly describe rehabilitation considerations with case study examples.

Department of Physical Therapy, Lebanon Valley College, Annville, Pennsylvania (Dr Marchese); Penn State Hershey College of Medicine at The Pennsylvania State University, Hershey (Dr Marchese); MD Anderson Cancer Center, The University of Texas, Houston (Dr Morris); The College of St. Catherine, Minneapolis, Minnesota (Dr Gilchrist); Children's Hospitals Clinics of Minnesota, Minneapolis (Dr Ness); Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee (Dr Ness); POTENTRx, Seattle, Washington (Dr Wampler); University of Kansas Medical Center, Kansas City (Ms VanHoose); Richard Stockton College of New Jersey, Pomona (Dr Galantino); and University of Pennsylvania, Philadelphia (Dr Galantino).

Correspondence: Victoria G. Marchese, PhD, PT, Department of Physical Therapy, Lebanon Valley College, Annville, PA 17003 (marchese@lvc.edu).

The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Chemotherapeutic agents are the primary treatment for many solid (breast, bone, brain, and lung) and hematological malignancies (leukemia, lymphoma, and multiple myeloma). Most chemotherapeutic agents indiscriminately target rapidly dividing cells and cause cell death by damaging either the cell's genetic information or disrupting processes needed for cell division. These drugs are seldom given singly, but rather are typically administered in combination with other agents in an effort to maximize destruction of cancer cells, prevent the development of drug resistance, and allow the administration of higher drug doses. Chemotherapeutic agents are typically administered in multiple cycles and are often given in conjunction with surgery and/or radiation.1 Because these drugs are not specific for cancer cells, healthy, rapidly dividing cells can also be damaged by chemotherapeutic agents, and such damage manifests itself in the form of chemotherapy short- and long-term adverse effects.

The chemotherapy side effects or more appropriately adverse effects tend to resolve once chemotherapy is completed and are referred to as immediate adverse effects.18 However, some chemotherapy agents cause adverse effects that persist after completion of therapy or emerge months to years after completion of therapy. For the purpose of this manuscript, adverse effect is defined as “any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.”9 We will define late effects as therapy-related complications or adverse effects that persist or arise after completion of treatment.10 In addition, there are grading systems, such as the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) that provide unique clinical descriptions of severity for specific adverse events for use in scoring both acute and chronic conditions in patients with cancer and survivors of all ages.9

The increased survival rate for patients with cancer has lead to the recognition that adverse effects associated with chemotherapy regimes may appear or persist months to years after chemotherapy has been completed. These late effects often impact organs not initially involved in the original diagnosis, differ significantly from acute adverse effects, and may be responsible for or explain unanticipated or unusual symptoms. These late effects impact the cardiopulmonary, neuromuscular, musculoskeletal, and integumentary systems, causing impairments of body structure and function, activity limitations, and participation restrictions.7,1115 As such, physical therapists (PTs) must know and recognize the late effects of chemotherapeutic agents and be able to modify treatment plans accordingly. Therefore, the purpose of this manuscript is to highlight the late adverse effects of the most common chemotherapeutic agents, present screening tools that can suggest the presence of these adverse effects, and then briefly describe rehabilitation considerations with case study examples.

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CARDIOPULMONARY

Physical therapy examination/screening for the cardiopulmonary system

The first step in a cardiopulmonary screening or any other organ or system screening is to gather disease- and treatment-specific information. Such information may come from patient interviews or be abstracted from a medical chart. Examples of useful interview questions are contained in Table 1. However, we would like to emphasize that it is important to determine not only that the patient received chemotherapy, but also the specific drug(s), dose, and dates they received the drugs. Often, patient recollection of such specific information will diminish over time, so the information may need to be requested from the patient's medical oncologist. It can be overwhelming for busy clinicians to become familiar with every chemotherapy drug and its acute and late adverse effects. We have highlighted many commonly used drugs that have recognized late effects (Table 2); however, there are useful free tools such as www.chemocare.com that can provide PTs with more information. The clinician can search this Web site by drug (common or brand name) to find information about the type(s) of cancer a drug is commonly used to treat, its mechanism of action, common acute and late adverse effects, warning signs that would warrant a referral back to their physician, and patient self-care tips.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

Several chemotherapeutic agents, particularly anthracyclines, can cause late effects in the cardiovascular (CV) system (Table 3). A history of exposure to an anthracycline should alert the PT to possible CV disease. The current drug regimes of patients who have taken anthracyclines should be reviewed for drugs suggesting the presence of CV disease including statins, β1-adrenergic blockers (β-blockers), angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, and/or nitrates.16 Results of CV diagnostic tests, including echocardiograms, coronary angiograms, stress testing, radionuclide imaging studies, and pulmonary function tests, should be reviewed as they provide information about the status of the cardiopulmonary system.17 Cancer survivors should be screened for a variety of observable signs suggesting cardiopulmonary deficits (Table 4). Patient-reported symptoms that warrant further exploration include excessive fatigue; leg pain with exercise; sleeping in an upright or partially upright position (orthopnea); discomfort in the chest, neck, jaw, arms, or other areas either at rest or with activity; dizziness; and palpitations.18

TABLE 3

TABLE 3

TABLE 4

TABLE 4

Because many survivors participate in therapeutic activities/exercise that can stress the CV system, it is important for the PT to minimize associated risk for adverse events. Self-administered, patient-screening tools (Physical Activity Readiness Questionnaire and AHA/ACSM Health/Fitness Facility Preparticipation Screening Questionnaire) are effective in identifying those patients at high risk for an adverse CV event, and thus would benefit from medical consultation/clearance before participating in an exercise program.19 In addition, the American College of Sports Medicine has developed an algorithm for assessing patient risk for CV disease. This scheme is predicated on the presence or absence of known CV, pulmonary, and metabolic disease; the presence or absence of signs and symptoms of CV, pulmonary, and metabolic disease; and the presence or absence of CV disease risk factors. Identification of the level of CV risk defines the need for medical clearance and/or exercise stress testing prior to participation in an exercise program.20

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Physical therapy intervention

For those survivors of cancer who have known late adverse cardiac effects and have been medically cleared for exercise, participation in a low-to-moderate progressive exercise program is most often recommended.20 Importantly, correcting deconditioning associated with cardiac or pulmonary disease may be particularly necessary for those patients who come to physical therapy for noncardiac problems such as orthopedic or neurological issues. Because it is beyond the scope of this manuscript to provide specific exercise prescription information, the reader is referred to currently available exercise guidelines.20

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MUSCULOSKELETAL

Physical therapy screening/examination for the musculoskeletal system

Osteoporosis is the most common bone-related side effect of cancer treatment encountered by PTs. It is defined as a bone mineral density measurement that is ≥2.5 standard deviations below the average peak bone mass for a 20-year-old person of the same gender as determined by dual energy X-ray absorptiometry and predisposes the individual to an increased risk of fracture. Chemotherapeutic agents (alkylating agents, anthracyclines, and taxanes) and supportive care medications (corticosteroids) decrease bone mineral density by reducing bone formation and/or enhancing bone resorption (Table 5). Standard chemotherapy regimes used to treat premenopausal women for breast cancer places them at increased risk for developing osteoporosis prematurely because these agents often disrupt normal hormonal status by causing amenorrhea and ovarian failure.21,22 Aromatase inhibitors (AI) (eg, anastrozole, letrozole, and exemestane) also increase the risk for bone loss and fracture.23,24 Men receiving androgen depravation therapy for prostate cancer are also at risk for chemotherapy-induced osteoporosis.25 In addition, chemotherapeutic agents used to treat testicular cancers, leukemia, and ovarian cancers also increase the risk for osteonecrosis or generalized bone death.26 The Osteoporosis Pre-Screening Risk Assessment, a measure that uses age; sex; weight; and a history of low-impact fracture, early menopause, and/or corticosteroid exposure to predict osteoporosis risk, is a reliable and valid osteoporosis screening tool.27

More than 50% of breast cancer survivors treated with AI report arthralgia or joint pain.28 Screening for arthralgia in this and other survivor populations is important as this impairment may limit the functional capacity needed to actively participate in daily life. The Index of Osteoarthritis (WOMAC) of both the Western Ontario and McMaster universities and the Disabilities of the Arm, Shoulder and Hand questionnaire are useful in evaluating arthralgias-associated impairments and progress made by participation in rehabilitation.29,30

Cancer-related cachexia (muscle wasting, which results in weight loss) is a well-recognized acute effect of either the disease itself or of the chemotherapeutic agents used to treat it. Less commonly recognized are the unfavorable alterations in body composition that can occur in survivors of cancer.31 For example, posttreatment weight gain is problematic for survivors of cancer because such changes increase the risk of developing type 2 diabetes, CV disease, and cancer recurrence.32 Posttreatment weight gain is often worsened by the decrease in physical activity, which occurs in survivors.7 Anthropometric and body composition measures such as height, weight, waist and hip circumference measurements, skin fold measurements, and bioelectrical impedance assessments can be done quickly and allow for the calculations of other indices of body composition including body mass index. Physical activity levels can be captured with exercise logs, pedometers, accelerometers, and recall questionnaires.33

Treatment-related declines in muscle strength is also common and can appear months to years after treatment.34 For example, 22 of the 137 hematopoietic stem cell transplant survivors (16%) reported moderate to severe muscle weakness 10 years after the treatment.35 Both self-reports of muscle weakness and disability and clinical observations of functional loss or compensation should be addressed with assessment of muscle strength (manual muscle testing, hand-held dynamometry) and functional abilities (Timed-up and Go, Timed-Up and Down Stairs, 10 ft fast walk, 5-time sit-to-stand, tandem stance). The Timed Up and Go is recommended as one of 14 measures included in a cancer-specific geriatric assessment.36 Physical therapists should assess core strength and pelvic floor stability in all survivors, particularly survivors of gynecological and prostate cancer (Table 6).

TABLE 5

TABLE 5

TABLE 6

TABLE 6

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Physical therapy intervention

For those survivors of cancer who have known osteoporosis and have been medically cleared for exercise, weight-bearing exercise should be encouraged as they help to build or maintain bone.37 Flexion exercises and activities, which increase the likelihood of assuming a kyphotic postures, increase the risk for pathologic fractures in patients with osteoporosis and hence should be avoided. Pain and nutrition assessment is necessary prior to development of an exercise program.38 Exercise can cause an acute energy deficit that can result in weight gain or loss depending on an individual's compensatory response to this deficit.39 Aerobic and strengthening exercises are of known benefit in multiple cancer survivor populations because they positively impact fatigue, body composition, and declines in muscle strength.40 Other physical activities such as yoga and tai chi can also enhance flexibility, strength, and coordination.41

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NEUROMUSCULAR

Physical therapy screening/examination for the neuromuscular system

Central nervous system

Adjuvant chemotherapy compounds are well known for damaging the central nervous system, adversely affecting cognition, memory, concentration, motor control, and balance.42,43 Some chemotherapies are delivered directly into the central nervous system through an Ommaya shunt, whereas others are delivered peripherally. Even drugs received peripherally may adversely impact central nervous system function, particularly cognition, despite the protection provided by the blood-nerve barrier. Possible mechanisms for this damage includes direct or indirect chemical toxicity to neurons or other nonneuronal elements in the central nervous system, oxidative damage, and damage secondary to inflammatory and/or destructive autoimmune responses.44,45 Hurria et al46 found that older women undergoing chemotherapy perceived a decline in cognitive function extending from before starting chemotherapy to 6 months after completing chemotherapy.46 This decline was most pronounced in patients with preexisting memory complaints.46 Because of the implications of such changes, PTs are advised to at least screen for the presence and extent of these neurological impairments (Table 8).

The magnitude of cognitive impairments among cancer survivors varies with the nature and sensitivity of the rating instrument used and is likely tied to the patient's perception of his or her cancer experience.47,48 A recent study found that outcomes on instruments used for cognitive screening in patients with cancer were poorly correlated with the patients' perception of their cognitive impairments.48 Thus, evaluating cognitive function by using both objective measurements and self-report is important for PTs who suspect that cognitive issues are impacting treatment and patient daily activity.49

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Peripheral nervous system

Commonly used chemotherapeutic agents such as vinca alkaloids, platinum compounds, and taxanes can damage the peripheral nervous system, resulting in acute and chronic chemotherapy-induced peripheral neuropathy (CIPN) (Table 7). Although a definitive mechanism for CIPN has not been fully elucidated, it is believed that most neurotoxic chemotherapies disrupt neuronal metabolic processes, causing axonal degeneration and possibly cell death. Chemotherapy-induced peripheral neuropathy can occur in any of the 3 functional divisions of the nervous system: sensory, motor, and autonomic; however, patients complain most commonly of sensory deficits including tingling, numbness, cold sensitivity, and/or burning pain in the distal extremities.50,51 Weakness of the hand and foot muscles may also be present, and patients with CIPN may describe an increased frequency of trips/falls, muscle cramps, and activity-related muscle fatigue. Autonomic dysfunction from chemotherapy, is rare and has yet to be systematically studied, but impairments may include orthostasis, changes in urinary continence, and constipation.50 Although CIPN typically diminishes after treatment has been completed, adverse neurological effects may persist long after treatment has been completed.52 Cisplatin is particularly well known for causing persistent CIPN, a condition referred to as coasting.53

TABLE 7

TABLE 7

TABLE 8

TABLE 8

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Physical therapy screening/examination of peripheral nervous system

Clinical assessment of CIPN should include patient history, a detailed description of symptoms, and clinical measures of nerve function. Preexisting medical conditions such as diabetes, alcoholic neuropathy, or Charcot Marie Tooth disease will increase the likelihood of significant neuropathy.50,54 Questioning patients about symptoms of CIPN is an important component of the evaluation because CIPN symptoms are often underreported. Hence, clinicians must rely on active questioning rather than patient-volunteered information.38,55,56 Physical assessment should include examination of light touch and vibration thresholds, pin-prick sensitivity, distal muscle strength, and deep tendon reflexes. Tools, such as the clinical version of the Total Neuropathy Scale and the modified Total Neuropathy Scale exist that compile these individual findings into a composite score.57,58 Since neuropathic pain is not a major component of these scales, using a specific self-reported measure of this disabling symptom such as the Neuropathic Pain Scale or the Leeds Assessment of Neuropathy Symptoms and Signs may be warranted.59 A combination of the above-mentioned tools can assist the practitioner in both assembling the appropriate set of clinical assessments and monitoring for changes in nerve function over time.

Determining the contribution of CIPN to activity limitations and participation restrictions is an important part of the screening of these patients. Balance deficits and gait abnormalities have been reported in patients with CIPN, placing this population at greater risk of falls.58 The Berg Balance test, the Tinetti, and simple fall assessment tools may be used to document these restrictions.60,61 In addition, decreased hand function may limit participation in activities of daily living such as handwriting, dressing, and grooming, making both the screening for such deficits and referring to occupational therapy vitally important.51

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Physical therapy intervention for the neurologic system

Possible treatments for CIPN are diverse and, unfortunately, there is no conclusive evidence that available medical treatments are helpful in preventing CIPN or effective in treating persistent CIPN.62 Likewise, there is no conclusive evidence that physical therapy interventions can prevent or reverse peripheral nerve impairments due to CIPN. However, descriptive studies suggest that aerobic exercise or laser therapy may help those with peripheral neuropathy from diabetes and carpal tunnel compression.6365 Other treatment possibilities include addressing balance and gait restrictions; an integrative balance-retraining program; patient education in how to manage neuropathic pain symptoms, allodynia, and hyperalgesia; and fine motor retraining of the hand.50,66

Treatment interventions for persistent or worsening CIPN are generally tailored toward limiting activity limitations caused by gait and balance impairments. Improvement in distal muscle strength and range can often assist in improving gait abnormalities, but assistive devices and orthotics may be necessary. Balance training and teaching protective household adaptations are indicated to reduce the risk of falls in this population.50

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INTEGUMENTARY

Physical therapy screening/examination for the integumentary system

Cutaneous toxicities in response to chemotherapy are diverse and, in many cases, are associated with multiple agents (Table 9). Most of these reactions are acute and dissipate with removal of the offending agent. Alopecia, or hair loss, is the most recognized side effect of chemotherapy and occurs because chemotherapy agents interfere with replication in the hair matrix cells of the scalp.6771 Permanent hair loss is uncommon with chemotherapy alone, but may occur in individuals whose scalp has also been exposed to radiation.

TABLE 9

TABLE 9

Scar tissue formation following chemotherapy, although uncommon, may result from skin reactions occurring acutely. For example, acral erythema, or dysesthesia (also known as Burgdorf's syndrome, hand-foot syndrome, palmar-plantar erythrodyesthesia, or toxic erythema of the palms and soles), has been associated with alkylating agents, anthracyclines, antimetabolites, platinum compounds, taxanes, and exposure to vinca alkaloids. It is characterized by painful erythema and dysesthesias over the palms and soles and may be followed by edema, well-defined erythematous macules, blister formation, and superficial skin loss.70,7274

Extravasation of infused chemotherapeutic agents can occur when the needle punctures the vein. Older patients are at particular risk because of their brittle veins. Immediate effects include local inflammation, pain, tightness at the site of the injection; phlebitis in the infused vein (vesicants), and necrosis (vesicants) of the surrounding tissue. Long-term effects can include skin damage and scarring of the epidermis and underlying tissue. The use of a Power Port or Hickman line allows long-term access to larger veins, thus reducing peripheral vein stress and risk for extravasation. Irritants may induce local sclerosis or hyperpigmentation. Vesicants may induce tissue necrosis with severe acute and often long-term injury.70,75

Hyperpigmentation and discoloration of the skin, mucous membranes, nails, or hair may occur with chemotherapy administration and are likely the result of toxic effects of the chemotherapy agent on melanocytes. Nail changes also include ridging of and premature separation of the nail plate.70,76 Changes may be acute or permanent.68,70,71

Radiation recall reaction is an adverse skin reaction (inflammation) that occurs at a site of previous radiation exposure (months to years before) and in response to recent chemotherapy therapy. Recall reactions also occur at sites of previous chemotherapy extravasation or at previously used infusion sites.69,77,78

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Physical therapy intervention for the integumentary system

Physical therapy management of integumentary problems following chemotherapy may include wound care or scar management and should include education on skin protection when indicated.

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SUMMARY

Adverse effects of cancer and/or its treatment can last long after a cure has been achieved and treatment has ended or may only emerge long after treatment has ended. In either case, these late effects have the potential for complicating a patient's clinical picture, making it necessary for a treating PT to clearly understand both the patient's cancer history and the current ramifications of past cancer treatments. Using appropriate, valid, and reliable screening tools will allow the PT to quickly rule in or out late effects of cancer and chemotherapy, thus allowing for optimal treatment intervention from a multidisciplinary approach. This brief monograph has attempted to identify chemotherapy-specific late effects and methods of screening for those effects. Our hope is that this information will enhance PT services provided to this complex patient population.

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    Keywords:

    chemotherapy; outcome measures; physical therapy

    © 2011 Lippincott Williams & Wilkins, Inc.