A Focused Review of Safety Considerations in Cancer Rehabilitation

Abstract

Cancer and its treatments introduce various adverse effects that may impact survivors’ physical, cognitive and psychological functioning. Frequently both tolerance to activity and exercise are affected as well. Rehabilitation providers should have substantive knowledge about the effect of cancer progression and common side effects associated with anti-neoplastic treatment to safely integrate rehabilitation interventions. Rehabilitation may mitigate loss of function and disability; however, these patients are among the most medically complex that providers treat. This report provides a focused review that synthesizes the current evidence regarding disease progression and oncology-directed treatment side effects within the context of safety considerations for rehabilitation interventions throughout the continuum of cancer care. Descriptive information regarding the evidence for precautions and contraindications is provided so that rehabilitation providers can promote a safe plan of rehabilitation care. It is incumbent upon but also challenging for rehabilitation providers to stay up to date on the many advances in cancer treatment, and there are many gaps in the literature regarding safety issues. Although further research is needed to inform care, this review provides clinicians with a framework to assess patients with the goal of safely initiating rehabilitation interventions.

Introduction

Cancer and oncology-directed treatments introduce a variety of side effects that can adversely impact multiple body systems during and after disease treatment. ¹ Each disease treatment modality (e.g., surgery, chemotherapy, radiation) may individually or collectively introduce risk for a host of potential safety issues. Additionally, a complex array of biopsychosocial factors such as an individual’s pre-existing comorbidities, polypharmacy, and other lifestyle factors also impact and amplify risk for adverse side effects during treatment.

It is incumbent upon rehabilitation providers to be knowledgeable about safety issues related to the disease or progression of the cancer as well as side effects and serious adverse events associated with antineoplastic therapies that may impact care. Early identification and management of emerging adverse events may impact morbidity and survival.² The purpose of this report is to provide a focused narrative review of the current literature regarding safety with rehabilitation interventions for individuals with cancer with consideration for the disease process, side effects of disease treatment and associated precautions and contraindications.

Pre-treatment risk assessment

Pre-treatment risk assessment helps to identify potential safety problems and establish a patient’s baseline physical and functional status. Understanding the disease and treatment trajectory provides an opportunity to assess the potential risk for problems that may impact rehabilitation interventions. Prior to initiating antineoplastic therapies, an extensive medical work up is undertaken to diagnose, stage, and determine a treatment plan for the disease. Baseline imaging, laboratory, and other testing provides insight to various markers and system functions. In addition to a comprehensive medical history to identify existing co-morbidities and medication regimens, assessing functional measures is important in predicting mortality, disease free survival and prognosticating functional decline. An ideal construct for rehabilitation professionals is to obtain a comprehensive functional assessment prior to the initiation of any cancer-directed intervention as this may optimize performance outcomes during and after treatment³ and will help identify early functional status decline.⁴

Various models of pretreatment assessment and planning have been investigated and typically involve an interdisciplinary team-based approach. These include the prospective surveillance model, multi-modal prehabilitation, enhance peri-operative surgical recovery programs.⁵

Safety Considerations with Anti-Neoplastic Treatment Adverse Effects

During active oncology-directed treatment, various modalities are sequentially and sometimes concurrently delivered. Rehabilitation providers must be aware of post-surgical precautions and contraindications regarding movement and activity restrictions so that a plan of care can be developed that facilitates tissue healing, prevents restrictions in function, and optimizes functional status. These precautions however should be balanced with evidence-based mobilization and post-operative activity recommendations and informed by surgical precautions and guidance. Mobility and exercise participation in the acute post-operative stage of treatment may reduce the risk of adverse events,^6,7 impact overall length of stay,⁸ and reduce readmissions and complications in various cancer populations.^6,9

Chemotherapeutic interventions typically include multi-drug therapies administered cyclically over a standardized period of time. Chemotherapy side effects contribute to multi-system dysfunction and have considerable influence on the safe administration of a rehabilitation plan of care. Table 1 identifies common chemotherapy, immunotherapy, and hormonal drugs and side effectsⁱ that may be particularly relevant to rehabilitation specialists.

Table 1.

Common Chemotherapy Agents and Side Effects

Drug Category	Common Generic Drugs (brand name)	Side effects
Alkylating Agents	Cyclophosphamide Ifosfamide Melphalan Busulfan Thiotepa Carmustine Dacarbazine	Congestive heart failure Pericardial effusion Shortness of breath Dyspnea on exertion Pulmonary fibrosis Dizziness, confusion agitation Joint pain Anemia Renal failure
Anthracyclines	Danorubicin Doxorubicin (Adriamycin) Epirubicin Bleomycin	Cardiotoxicity Left ventricular dysfunction Congestive heart failure Cardiomyopathy Pulmonary fibrosis
Anti-Androgens	Flutamide (Eulexin) Nilutamide	Muscle wasting Osteoporosis Erectile dysfunction
Antimetabolites	5-flurouracil Capecitabine (Xeloda) Gemcitabine Fludarabine Methotrexate	Anemia Shortness of breath Skin rash/dermatitis
Aromatase Inhibitors	Letrozole (Femara) Anastrozole (Arimidex) Exemestane (Aromasin)	Joint arthralgias Osteopenia/Osteoporosis Hot flashes Weight gain Mood fluctuations
Cytoskeletal disruptors (Taxanes)	Paclitaxel (Taxol) Docetaxel (Taxotere) Abraxane	Peripheral neuropathy Cytopenia Acute myocardial infarction
Gonadotropin-releasing hormone agonist	GnRH-A (Cetrorelix)	Osteoporosis Weight gain Heart failure Heart disease
Luteinizing hormone agonist	Goserelin (Zoladex) Leuprolide (Lupron) Triptorelin (Trelstar)	Bone pain Sexual dysfunction Anemia Cognitive dysfunction
Kinase Inhibitors	Erlotinib (Tarceva) Lapatinib (Tykerb) Imantinib (Gleevac) Gefinitib (Iressa)	Hypertension Acute myocardial infarction Stroke DVT/PE* Interstitial lung disease Bradycardia
Monoclonal Antibodies	Trastuzumab (Herceptin) Alemtuzumab (Campath) Bevacizumab (Avastin)	Cytopenia Pulmonary inflammation Congestive heart failure Hypertension Reduced wound healing Skin rash
Platinum-based agents	Carboplatin Cicplatin Oxaliplatin	Neurotoxicity Ototoxicity Rhabdomyolysis
Retiniods	Tretinoin Alitretinion	Increased intracranial pressure DVT/PE
Selective Estrogen Receptor Modifiers	Tamoxifen (Nolvadex) Raloxifene (Evista)	Hot flashes Weight gain Cognitive and memory dysfunction DVT/PE Stroke
Topiosomerase Inhibitors	Irinotecan (Camptosar) Topotecan (Hycamtin)	Cytopenia Severe diarrhea and dehydration
Vinca Alkaloids	Vincristine (Oncovin) Vinblastine	Peripheral neuropathy Dyspnea Hypertension Angina Acute myocardial infarction

^*DVT=deep vein thrombosis; PE=pulmonary embolism

Hematological Compromise

Myelosuppression is a common side effect associated with nearly all chemotherapy and immunosuppressive agents, particularly corticosteroids, and thus present significant implications for rehabilitation interventions. Hematologic compromise can result in cytopenias which increase risk for infection, compromise metabolic function, and alter physiological responses to exercise in severe circumstances. Table 2 provides an overview of laboratory values and safety thresholds for consideration by the rehabilitation provider.

Table 2.

General Rehabilitation Considerations in the Context of Hematological Compromise^13,16,19

Blood Count	Rehabilitation Considerations
White Blood Cells	> 11.0 109/L: Symptom-based approach, monitor for fever < 4.0 109/L: Symptom-based approach, monitor for fever < 1.5 109/L (Neutropenia): Symptom-based approach, neutropenic precautions based on facility guidelines. Mild < 1.5 109/L Moderate 0.5 – 1.0 109/L Severe < 0.5 109/L
Platelets	< 150,000 cells/uL (Thrombocytopenia): Symptom-based approach, monitor tolerance to activity. > 50,000 cells/uL: Progressive exercise as tolerated, aerobic and resistive with monitoring for symptoms associated with bleeding. >30,000 cells/uL: Active range of motion exercises, moderate exercise, aquatic therapy based on immune status. > 20,000 cells/uL: Light exercise, walking, activities of daily living without strenuous effort;Assess fall risk and implement safety plan for falls prevention < 20,000 cells/uL: Understand transfusion status or plan of care, walking, light activities of daily living, symptom monitoring, precaution for falls.
Hemoglobin	Reference Values Male: 14 – 17.4 g/dL Female: 12 – 16 g/dL < 11 g/dL (anemia): Establish baseline vital signs; may be tachycardic or present with orthostatic hypertension; symptom-based approach to intervention, monitoring self-perceived exertion < 8 g/dL (severe anemia): Close monitoring of symptoms and vital signs with intervention; transfusion may or may not be indicated based on individual presentation; short periods of intervention, symptom-limited; education for energy conservation

The cancer population, as a cohort, has a higher rate of transfer to acute care hospital during inpatient rehabilitation and it is important to identify the risk factors for transfer.¹⁰ In a study by Guo et al of 98 individuals with cancer undergoing inpatient rehabilitation, hemoglobin levels, absolute neutrophil and platelet counts at the time of admission were not associated with acute care transfers.¹¹ In another study by Fu et al, 143 lymphoma patients undergoing inpatient rehabilitation, male gender, creatinine > 1.3, and hematopoietic stem cell transplantation were associated with higher rate of transfer to acute service hospitals.¹²

Anemia is a frequent complication of cancer and cancer treatment including chemotherapy and radiation.¹³ Worsening anemia reduces exercise tolerance and endurance leading to symptoms of fatigue, dizziness and hemodynamic instability.¹⁴ While aerobic capacity is improved with higher hemoglobin levels, it is unclear whether there is a level of hemoglobin below which functional outcomes are compromised.¹⁴ Precaution should be used in prescribing progressive resistive and moderate to high intensity aerobic exercise in individuals with severe anemia (hemoglobin ≤8 g/dL ).^15,16 Low intensity exercise may be beneficial to promoting improvements in blood counts. Rehabilitation professionals should monitor hemodynamic, functional, and exertional status as well as patient symptoms such as chest pain, lightheadedness, and inappropriate dyspnea.¹⁷

Thrombocytopenia occurs with myelosuppression therapies and impacts the red blood cell counts. Individuals with platelet counts below 10,000 k cells/uL are at significant risk for spontaneous hemorrhage and as per current guidelines will receive prophylactic transfusions.¹⁸ Those with counts below 20,000 k cells/uL are at increased risk and special consideration for rehabilitation intervention should be considered, generally activity is restricted to walking and activities of daily living.¹⁹ Individuals with counts >20,000 k cells/uL can complete light exercise with close symptom monitoring. In general, this includes maintaining blood pressures below 170/100 mmHg and screening the patient for symptoms of bleeding including bruising and bleeding around the gums.²⁰ Those with counts > 30,000 k cells/uL can engage in moderate exercise and light resistive exercise within tolerance.¹⁹

Chemotherapy induced neutropenia (absolute neutrophil count less than 500 mc/L) typically occurs 3–7 days following administration of chemotherapy at. Neutropenia predisposes patients to infection. Typical signs and symptoms of infection are often absent in neutropenia, and fever remains the earliest sign of occult infection. Primary sites of infection are the GI tract, sinuses, lungs and skin.²¹ Clinicians should practice hand hygiene with antimicrobial soap during every patient encounter. The use of barrier precautions such as gowns, gloves and masks are usually unnecessary, as patients are more likely to get infected with their own flora.²² The Centers for Disease Control guidelines advise against barrier protection except when “the risk of infection from healthcare providers is excessive”.²³ There is no compelling evidence that rehabilitation interventions are contraindicated due to neutropenia, but special consideration should be given to individuals experiencing side effects such as fatigue, malaise, dizziness or lethargy and rehabilitation therapy should be self-limited based on the patients preferences.¹⁶ Further consideration is warranted to prevent infection by reducing exposure to potential pathogens such as those found in public therapy spaces.²⁴ Neutropenic infections are a major cause of morbidity and mortality in individuals undergoing cancer treatment.²¹ Common infections include sepsis, cellulitis, pneumonia, urinary tract infections and colitis.^25,26 Rehabilitation providers should closely monitor at-risk patients for early signs and symptoms of infection so that medical management can be expedited when needed.²⁷

Hematological considerations are particularly important in patients undergoing Bone Marrow Transplantation (BMT). Pre-transplant induction treatment involves high dose chemotherapy, frequently with concurrent irradiation. BMT is typically undertaken after traditional antineoplastic therapies have failed to put an individual into remission. These patients are cytopenic at the time of transplant and remain so for weeks afterwards. There is additional concern as these individuals have a history of antineoplastic therapies that can result in other adverse effects such as neurotoxicities impacting peripheral nerve function, myopathy due to chronic corticosteroids use, prolonged immobility, nutrition deficits, and cognitive dysfunction.²⁸ Given the substantial need for rehabilitation services in this population, it is imperative to provide safe rehabilitation interventions. Dimeo et al suggest that exercise not only mediates better physical performance at discharge in this population, but a shorter duration of anemia, neutropenia, thrombocytopenia and length of hospitalization.²⁹

Cardiopulmonary Toxicity

Malignant tumors are more likely to involve the lungs than the heart—either as primary or metastatic disease. In advanced cancer, there may be significant compromise of pulmonary function due to metastatic disease. Individuals with advanced cancer may have cachexia with severe muscle wasting that may affect cardiac function as well (“cardiac cachexia”). Antineoplastic therapies such as chemotherapy and immunotherapy drugs, as well as radiation therapy to the chest wall, can impact cardiac and pulmonary function both during and after cancer-directed treatments.³⁰ Once of the most commonly used chemotherapy drug classes, anthracyclines, may have significant and irreversible impact on cardiac function, primarily resulting in reduce left ventricular function. Over time, this reduces overall ejection fraction and compromises long term cardiac function. Trastuzumab is a targeted drug that is frequently used in breast and other cancers and has well known potential for cardiac toxicity. The implications manifest in symptoms of systemic edema, shortness of breath, dyspnea, and lung congestion in severe cases. Bleomycin and methotrexate are agents that commonly lead to pulmonary compromise including pulmonary inflammation and fibrosis.

Exposure of the chest wall to radiation has the potential to adversely impact both cardiac and pulmonary function and may be progressive over time. Individuals receiving > 30 – 35 Gy exposure to the chest wall are at risk for radiation-associated heart damage.³⁰ These dose levels are typically eclipsed with standard breast, lung, and various Hodgkin’s treatments, elevating the risk in these populations. Radiation-related changes include structural damage to the myocardium, coronary arteries, valves, and the conduction system. These complications often lead to diastolic dysfunction and blood flow abnormalities. Cardiac changes typically manifest clinically at least 6 to 12 months following radiation, necessitating awareness and monitoring for symptoms of cardiovascular and pulmonary dysfunction. The impact on cardiac function however, can be identified even 20 years following the completion of radiation therapy, impacting long term morbidity and function.³¹

Vital sign monitoring throughout the duration of cancer-directed treatments is recommended. A baseline echocardiogram is usually obtained in individuals undergoing cardiotoxic chemotherapeutic regimens and may be repeated at various stages of treatment or post-treatment. Low intensity exercise, administered during chemotherapy cycles, may be protective against anthracycline-induced cardiotoxicity³² but recommendations regarding timing, frequency, intensity, and mode of exercise are lacking.³³ When prescribing exercise interventions for this population, risk factors such as dose scheduling, prior cardiac comorbidities and baseline vital signs should be considered. Edema monitoring is necessary to observe and differentially diagnose cardiopulmonary edema symptoms from the onset of lymphedema.

Late effects of cardiovascular compromise are especially prominent and warrant consideration in adult survivors of childhood and adolescent cancers. The deleterious impact on cardiac function is prevalent, nearly 50% demonstrate cardiac-related co-morbidity that compromises function 20 to 30 years after completion of treatment.³⁴

Rehabilitation providers seeking to implement a plan of care should be aware of the risk for reduced tolerance to exercise, altered baseline vital signs and altered physiological responses to rehabilitation interventions. Monitoring during rehabilitative interventions should include focus on patient self-report of tolerance to exercise via the Borg Scale, or another index. Observation for symptoms that may herald undetected cardiac dysfunction or exercise that is too vigorous for someone with known heart disease include excessive fatigue, sweating, or pallor changes with exercise or activity and severe shortness of breath.

Neurotoxicity

Chemotherapy induced peripheral neuropathy (CIPN) is a well-known complication with taxane-based as well as platinum-based chemotherapeutic agents. Acute presentation of neuropathies includes sensory manifestation in the distal extremities. The neuropathic changes are typically progressive with additive chemotherapy cycles. The progression of sensory changes presents in a stocking/glove pattern. In more severe cases motor disturbance is noted, primarily in the lower extremities.

While neuropathies occur during chemotherapy cycles, the symptoms tend to abate after the completion of treatment. However, persistent impact on sensation and proprioception are notable and are shown to have a negative impact on balance, gait, and mobility even > 5 years after the completion of treatment.³⁵ Individuals who receive neurotoxic doublets are at greater risk for persistent neuropathic impairment. Of importance is the evidence elucidating the significantly increased risk of falls in the population of individuals treated with neurotoxic chemotherapy agents. Fall risk is two to three times greater in the population of individuals with a history of receiving neurotoxic chemotherapeutic agents.³⁶

There are significant rehabilitation implications for the population of individuals treated with neurotoxic chemotherapeutic agents. Ideally a baseline assessment of sensation, strength, and balance is completed prior to initiating chemotherapy. Continued screening for balance change over time, observation of gait deviation and triage for rehabilitation intervention to manage emerging impairments is recommended.³⁷ Severe neuropathy with motor changes may impact safety and may necessitate intervention to mitigate balance deficits and enhance gait and stability.³⁸ A comprehensive falls prevention program is an effective strategy that should be proactively implemented to improve functioning.^39,40 Providing assistive devices and/or orthoses may be required to maintain patient safety.

Lymphedema

The natural history of lymphedema is typically a slow, progressive, swelling that appears asymmetrically in the limb s following lymphadenectomy or radiation therapy. New onset lymphedema is an important safety concern due primarily due to the risk of deep vein thrombosis, cancer recurrence or infection.⁴¹

Several studies have examined the safety of exercise on development and exacerbation of lymphedema and found that, under controlled circumstances, exercise does not exacerbate the condition nor have significant impact on worsening symptoms.^42–44 There is no strong evidence basis for the use of compression garments during exercise for prophylactic purposes, however early use of compression therapy in the presence of early, sub-clinical lymphedema is safe and effective.⁴⁵ Individuals with lymphedema should be advised to exercise with some form of compression on their limb to prevent fluid accumulation. Any signs of redness, erythema, pain, new onset or exacerbation of swelling should be referred for more extensive medical management. Cellulitis infections are common in individuals with lymphedema and require antibiotic therapy prior to continuation of rehabilitation interventions.

For individuals in whom lymph nodes have been resected as a standard part of cancer surgery, astute observation of any changes in the limb that indicate an emerging infection should be addressed. An individualized rehabilitation treatment plan should be developed for this at-risk population with precaution to avoid unnecessary strain and injury to the limb that may cause the onset of lymphedema.⁴⁵

Frailty

Frailty is a clinical syndrome found in those over the age of 65 and characterized by a loss of physiologic reserve secondary to reduced physiological capacity, weight loss, weakness, slow walking speed, self-reported exhaustion and low physical activity.^46,47 Because cancer occurs disproportionally among people over the age of 70, many cancer survivors have frailty symptoms compounded by the negative effects of cancer directed treatments.⁴⁸ Frailty is associated with falls, hospitalizations and increased mortality.⁴⁹ A recent study analyzing more than 12,000 patients ≥ 65 years found that the prevalence of falls was significantly higher post cancer treatment than pre-treatment among individuals with prostate and lung cancer and the prevalence of balance/walking problems were significantly higher post-diagnosis in non-Hodgkin’s lymphoma and breast, prostate and lung cancer.⁵⁰ Frail patients, specifically, pose a challenge to rehabilitation physicians who work with cancer survivors. Frailty has been associated with poorer rehabilitation outcomes and functional gains.

The Comprehensive Geriatric Assessment (CGA) has received attention as a comprehensive battery of tests that assess various domains of functioning and can be used to stratify patients into high versus low risk categories to predict their tolerance to cancer therapies and risk for side effects of chemotherapy.⁵¹ The CGA may be a more comprehensive and sensitive indicator to identify functional decline than the current performance status measures used in oncology practice.⁵² Interventions such as optimizing nutrition and muscle mass may delay frailty and are safe in the geriatric population.⁹ In a review of studies on exercise interventions in frail institutionalized adults, balance and functional training were shown to be effective in improving functional performance, activities of daily living and quality of life.⁵³

Osseous Fragility

Osteoporosis and secondary bone loss affect bone health in cancer survivors, most commonly in hormonally-driven breast and prostate cancer.^54,55 Osteoporosis worsens with prolonged exposure to hormonal therapies increasing fracture risk with increased duration of treatment.^56,57 Rehabilitation providers should identify meaningful changes over time that may suggest increased risk and should modify rehabilitative interventions to optimize safety. Weight bearing exercise may have a protective effect in mitigating bone density depletion during hormonal therapy interventions.⁵⁸

Bone metastases occur prevalently in the most commonly occurring cancers; breast, lung, and prostate.^59,60 Bone lesions often result in pain, spinal cord compression, fracture, and hypercalcemia reducing quality of life and limiting functional mobility.^61,62 While rehabilitative weight bearing activities can have a positive impact on bone density, mobilizing individuals with bone lesions is challenging due to pain and fracture risk during therapeutic exercise.⁶³

Metastatic lesions of the long bones and spine present the greatest risk of pathologic fractures making fracture risk assessment of great importance to rehabilitation providers.⁶⁰ A scoring system developed by Mirels et al⁶⁴ assigns a severity score to each of four factors associated with fracture; site, size, type of lesion, and the type of pain reported. (Table 3) This system enables an aggregate score that supports fracture risk stratification so that appropriate mobility interventions may be initiated.

Table 3.

Mirels Criteria

Score	Site of lesion	Size of lesion	Nature of lesion	Pain
1	Upper limb	< 1/3 of cortex	Blastic	Mild
2	Lower limb	1/3–2/3 of cortex	Mixed	Moderate
3	Trochanteric region	> 2/3 of cortex	Lytic	Functional

According to Mirels’ recommendation, prophylactic fixation is indicated for a lesion with a score of ≥ 9. A lesion with a score of ≤ 7 can be managed using radiotherapy and drugs. A score of 8 presents a clinical dilemma and requires clinical judgement of the criteria. Functional pain has been identified as the single best predictor of pathological fracture.⁶⁴

Another stratification system by Harrington suggests that lytic and blastic lesions in long bones can develop pathologic fractures when > 50% of the cortex is destroyed and lesions of the proximal femur are more likely to fracture if they are > 2.5 cm or if they are associated with avulsion of the lesser trochanter. Such lesions should be referred for prophylactic fixation.⁶⁵

Rehabilitation is indicated in the presence of bone metastases to maintain function and promote safety and fracture prevention with activities of daily living (ADLs).⁶⁶ Of importance are fall prevention strategies and education for safety with activities that require lifting and carrying heavy objects. A comprehensive mobility assessment is necessary, as sheer number of bone lesions and location of metastatic sites may not be associated with functional mobility loss in the short term.⁶⁷ Rehabilitation interventions are generally safe and effective and do not increase the risk for fractures.^66,68–70 General safety measures are outlined in Table 4 and target restricting excessive resistive, compressive, or rotational torque-like forces on an involved limb or region.⁷¹ Individuals with more severe fracture risk may benefit from offloading the affected limb and using assistive devices or orthoses to safely enhance function and mobility. Caregiver education should be emphasized in the rehabilitation care plan to optimize safety and function in the home environment.

Table 4.

General Safety Measures with Bone Metastasis

No manual muscle testing in affected limb

No progressive resistive exercises in affected limb

Offloading affected limb with assisted device

Avoid excessive spinal flexion, extension and rotation. Clarify need for bracing.

Monitor for increasing functional pain

Advanced Cancers

Functional impairments are prevalent in patients with advanced cancer and can lead to disability, increased caretaker dependency, and psychological distress.⁷² Safety considerations should be broadened and rehabilitation assessment should extend beyond the primary functional limitation as the multi-system impact from advanced cancer jeopardizes safe functioning.⁷³ Patients with advanced cancer often have a range of comorbid conditions and polypharmacy considerations and impact functioning and require a more complex rehabilitative prescription.^72,74

Cachexia is a common condition related to advanced cancer. Symptoms include marked weight loss, loss of lean muscle and muscle atrophy, fatigue, weakness, and loss of appetite which negatively impacts function. Sarcopenia is a condition of lean muscle loss and muscle atrophy. Sarcopenia may also be seen in advanced cancer populations but is a different condition than cachexia, although sarcopenia may be a component of cachexia not all individuals with sarcopenia are cachectic.⁷⁵ Sarcopenia can be identified by low muscle mass and reduced gait speed. This differentiation is important as exercise, in the absence of appropriate protein and energy balance may pose a risk for further functional decline in the cachectic population.⁷⁶ Rehabilitation interventions should be undertaken with insight and input from an interdisciplinary team that includes an understanding of nutritional support and inflammatory profiles of the patient balanced with physical activity and muscle training interventions.⁷⁷

Central and peripheral neural structures may be affected by a primary or metastatic tumor as well as oncology-directed treatment (e.g. chemotherapy). Neurological changes may be the first presenting sign of metastatic disease and warrant close follow up and triage for medical management. Neurological symptoms are often consistent with the spinal level or central location of the lesion. Patients may present with cognitive changes, memory loss, affective and personality changes, altered mental status, speech and word finding complications as well as sensory or motor dysfunction including radiculopathy or myelopathy.⁷⁸ Autonomic dysfunction may also occur related to chemotherapy or other anti-neoplastic treatment issues. Rehabilitation providers should monitor for any neurological status changes during and after intervention, and should monitor pain and vital sign changes during intervention. Caregiver education is also important as patients may have altered safety judgement, reduced reflexive reactions, poor visual acuity, and word finding issues that make it difficult to function independently.

Assessment for home modifications and adaptive equipment evaluations should be considered to help reduce the risk of falling and improve overall safety in the home. Education for compensatory strategies using assistive devices, orthotics, and wheelchairs can improve the safety of individuals while promoting optimal functioning. Partnering with palliative care services to develop patient centered protocols that span the oncologic spectrum, can combine rehabilitation interventions with the treatment of cancer related pain, anxiety, psychosocial and spiritual needs.⁷⁹

Safety Considerations with Rehabilitation Interventions

Exercise

Exercise has been extensively studied across the cancer care continuum including interventions pre-treatment^6,80,81, during active treatment^82,83, and following the completion of treatment.^82,84 Timing and type of exercise impacts various biological and physiological markers, psychosocial factors, and functional impairments differently.^82,85 Overall, tolerance to treatment and functional outcomes in a variety of cancer types are improved when exercise is initiated before or during cancer treatment.^6,44,81 Unique considerations are necessary based on the type of cancer and the body structures impacted by cancer-directed therapies.

Exercise training and maximal and sub-maximal exercise testing in persons with breast cancer is relatively safe.^{42,43,86–88} However, because 35–58% of breast cancer survivors report persistent shoulder and arm pain⁸⁹, it is important to minimize the risk of musculoskeletal injuries which may result from surgical intervention or hormonal therapies. Since women with breast cancer commonly receive cardiotoxic chemotherapeutic agents, awareness for cardiac compromise is warranted. Ideally, a tailored exercise program is developed and initially supervised by a rehabilitation provider.⁹⁰

Exercise interventions are generally safe during and after prostate cancer treatment.^69,91 Greater than 50% of individuals undergoing prostate cancer treatment will receive androgen deprivation therapy (ADT) to alter hormonal impact on tumor growth. ADT is associated with muscle mass depletion and bone density loss which directly impact safety with rehabilitation interventions. Aerobic and resistive exercise interventions mitigate the impact of ADT and promote restoration of muscle mass and mitigate bone density loss.⁹²

Numerous prehabilitation and rehabilitation trials have identified positive benefits of exercise as well as its safety and feasibility in the lung cancer population.⁹³ Exercise is generally well tolerated and beneficial in controlled clinical settings and evidence supports moderate intensity exercise for this population.^6,94,95 Vital signs, oximetry, and respiration should be closely monitored during exercise and individual interventions and testing should be self-limited by the patient.⁷⁴

Evidence supports exercise as a safe interventions in women during and after gynecological cancer treatment.^96,97 Lymphedema of the lower extremities may be associated with gynecological cancer and its treatment warranting consideration for lower extremity monitoring for individuals who have had inguinal lymph node dissection and/or radiation therapy.⁴¹

Exercise interventions such as walking, stationary cycle, resistance training and virtual reality appear to be safe for individuals with leukemia.^98–101 Exercise may be limited by complications of the cancer and its treatment such as infection, thromboembolic disease and hemorrhage.¹⁰² Aerobic and strength training exercises can be safely performed by persons with a stem cell transplant; however exercises should be less intense, progress slowly and avoid overtraining. ¹⁰³

Modalities and manual therapy

Physical modalities such as heat¹⁰⁴, cryotherapy¹⁰⁵, electrotherapeutic modalities^106–108, laser^109,110, and manual therapy^104,111 are used as adjuncts to reduce pain and facilitate tissue healing and to minimize pain during rehabilitation interventions.^105,112 Modalities and physical agents require astute understanding of the impact on cancer and the risk of promoting metastatic disease.^113,114 Numerous indications exist for the use of modalities in pain management but should be applied with precaution.¹⁰⁴ Table 5 summarizes contraindications of modalities in cancer survivors.

Table 5.

Modality Indications, Precautions and Contraindications for Cancer Survivors

Modality	Indication	Precaution	Contraindication
Heat	Pain relief Muscle relaxation Tissue extensibility	Impaired lymphatic function Scar tissue Open wounds or skin fragility	Unmanaged tumor/active disease Peripheral vascular disease (PVD) Severely impaired sensation Irradiated tissue
Ultrasound	Tissue extensibility Inflammation management	Impaired sensation Open wounds or skin fragility	Individuals with cancer or with a history of cancer
Cryotherapy	Pain relief Acute management of inflammation Hair loss management	Impaired sensation Open wounds or skin fragility	Ischemic tissue PVD Raynaud’s syndrome
Transcutaneous electrical nerve stimulation (TENS)	Sensory pain management Scar desensitization	Insensate tissue	Unmanaged tumor/active disease Over pacemaker Open wounds
Needle Electromyography (EMG)	Measures muscle response to nerve stimulation	Thrombocytopenia	None
Functional Electrical Stimulation (FES)	Restoration of muscle firing when nerve conduction is intact (e.g. ambulation, limb function, swallowing, pelvic floor retraining)	Poor skin condition or indurated tissue	Unmanaged tumor/active disease
Low Level Light Laser	Oral mucositis Scar tissue extensibility Lymphedema	Open wounds or skin fragility	Acute radiation dermatitis Unmanaged tumor/active disease
Manual Therapy	Pain relief Tissue extensibility Joint mobility Soft tissue and radiation fibrosis management Lymphatic stimulation	Impaired sensation Dysvascular tissue Open wounds or skin fragility	Acute radiation dermatitis Unmanaged tumor/active disease Bone fragility due to metastasis or osteoporosis
Spinal Manipulation	Spinal mobility and alignment Pain relief	Open wounds or skin fragility	Bone fragility due to metastasis or osteoporosis Radiculopathy, spinal stenosis, myelopathy Spinal cord compromise from tumor or lesion

Oncologic Emergencies

During the course of cancer treatment there may be signs of emergent conditions and the need for care to manage the sudden onset of serious adverse events. These oncologic emergencies should be recognized by rehabilitation providers in order to promote acute medical management so as to limit the impact on outcomes.

Morris et al categorized oncologic emergencies according to the mechanism of injury and organ system involved and outlined 3 categories of oncologic emergencies: 1)structural/mechanically induced, 2) metabolic, 3) hematological.¹⁷

Table 6 outlines the common presenting symptoms of the conditions associated with these categories of emergencies and their implications for rehabilitation providers.

Table 6.

Oncologic emergencies

Condition	Presenting Symptoms	Rehabilitation Implications
Structural or Mechanically Induced Oncologic Emergencies
Spinal Cord Compression (SCC)	Localized back pain, primarily in thoracic region. Thoracic pain escalating with lying supine, at night, with increased thoracic pressure during sneezing, coughing, or straining. Muscle weakness below the area of spinal involvement.	Worsening pain in a recumbent position helps to differentiate SCC from other forms of mechanical back pain. Pain is the most frequent presenting symptom. Identification of SCC prior to onset of motor or sensory loss improve functional mobility and mortality outcomes. Patients with SCC are at risk for urinary tract infections, VTE, decubitus ulcers, and pneumonia. Pain assessment should be routine in rehabilitation interactions with concomitant assessment of muscle strength and sensory changes.
Malignant pericardial effusion	Due to primary pericardial tumor (rare) or metastatic pericardial disease associated with lung, breast, esophageal, lymphoma, leukemia, and melanoma. Pericardial effusion results in increased intrapericardial pressure, reduced cardiac output and cardiac tamponade. Dyspnea, cyanosis, engorged neck veins, orthopnea, congested cough, fatigue, palpitations, and a drop in systolic blood pressure of > 10mm Hg during inspiration. Hypotensive, tachycardic, narrow pulse pressure, diaphoretic.	Frequent assessment of heart rate, hemodynamic status and respiratory status, including oximetry levels should be carried out during treatment. Assessment of skin color and temperature, capillary refill and peripheral pulses should be tracked. Awareness of mental status changes, confusion, or seizures is necessary due to reduced cerebral blood flow. Following a cardiac tamponade episode, patients should have medical clearance before re-engaging in rehabilitation care. Rehabilitation is indicated to provide strengthening and reconditioning activities, pulmonary hygiene, and postural positioning.
Superior Vena Cava Syndrome	Swelling in the upper thorax, face, neck. Jugular vein distention. In early stages edema is worse in the morning and improves throughout the day. Dyspnea, dry cough. Tachycardia, hypotension, cyanosis, cough, tachypnea, dyspnea. Central nervous system symptoms; confusion, headache and vision changes.	Onset is typically slow and progressive. Symptom recognition and observance of change over time will support differential diagnosis. Avoid valsalva maneuvers with activity and exercise. Heart rate response to activity may be impaired. Use Rate of Perceived Exertion (RPE) scale as a more sensitive self-reported measure during activity.
Metabolic Oncologic
Emergencies Hypercalcemia	Presentation may be vague and symptoms diffuse. Impact on nervous tissue and muscle tissue result in constipation, lethargy, fatigue, bone pain, abdominal pain, polyuria, muscle weakness, confusion, delirium.	Diagnostic testing includes serum ionized calcium levels. The rate of increase of calcium level is more important than the absolute serum calcium in correlating with symptoms. In severe conditions individuals are relatively unresponsive and rehabilitation may not be indicated. In mild to moderate conditions, weight-bearing activities are recommended along with general aerobic conditioning. Consider assistive devices for safety with ambulation. Assess and ascertain mental status changes and impact on safety judgement.
Tumor Lysis Syndrome	Symptoms may include nausea, vomiting, weakness, fatigue, lethargy, and arthralgia. Typical onset is during acute 6 to 72 hours post chemotherapy delivery.	Awareness of sudden changes in patient’s status including weakness, muscle cramping, dysrhythmias, dyspnea, central nervous system changes, irregular heart rhythms. In intensive care settings, early progressive mobility and rehabilitative interventions improve recovery and maintain functional status after discharge.
Hematologic Emergencies
Neutropenic Fever	Greatest risk is with ANC below 500 c/mm3 Trend of change in ANC count overtime is more important than absolute value. Presence of a fever > 101.3° F or > 100.4 ° F for more than 1 hour. Typical symptoms of infection such as redness, swelling and puss exudate from wounds are frequently absent.	Rehabilitation is not contraindicated. Considerations for protective wear including gowns, gloves, masks, and reducing risk of transmission of infectious agents by handwashing, keeping equipment clean, reducing exposure to raw foods and live plants.
Venothrombolic Events	DVT present with swelling in the extremity, redness and extreme tenderness. More commonly occur in the lower extremity but may also occur in the arms. Pulmonary emboli present with dyspnea, tachycardia, crackles, hemoptysis, chest pain, tachypnea, and anxiety. Diagnostic imaging includes Doppler ultrasound for suspected DVT and chest CT, ventilation perfusion scan and pulmonary angiography for suspected PE.	Support protocols for VTE prophylaxis including mechanical compression devices including compression hosiery and pneumatic applications. Ambulation is encouraged to reduce risk for VTE development in high risk populations. Awareness of pharmacologic interventions that alter platelet activity and clotting.

Conclusion

Rehabilitation is generally safe in oncology patients; however, there are numerous important considerations that are unique to this population. Moreover, oncology-directed therapies and protocols are constantly advancing and rehabilitation specialists need to keep up to date in order to ensure the safety of the patients they treat. Rehabilitation provides therapeutic interventions that may mitigate loss of function and disability in cancer survivors; however, the frailty of the patients, co-morbid conditions, advanced cancer, side-effects of oncology-directed therapies and a host of other factors contribute to making this one of the most medically complex populations that rehabilitation professionals treat. Assessing each patient through the lens of providing safe rehabilitation interventions in a medically supervised setting is required.