Over several decades, there has been a significant improvement in survival after cancer because of earlier detection and advances in surgery, chemotherapy, and radiation treatment. Thus, the number of cancer survivors has grown to approximately 14.5 million in 2014 with that number projected to be almost 19 million by 2024.1 Immediate and long-term toxicities of cancer treatment are increasingly an issue that affect cancer survivors’ physical function and quality of life.
Specific side effects of cancer treatment depend on the type of treatment, tumor characteristics, disease stage and severity, comorbidities and functional status, among other variables. In this article, three common complications of cancer surgery, chemotherapy, and radiation treatment will be reviewed, which include complications of breast cancer surgery, chemotherapy-induced peripheral neuropathy (CIPN), and radiation induced brachial plexopathy (RIBP).2
Epidemiology including risk factors and primary prevention
Complications after breast cancer surgery
Morbidity after breast or axillary procedures for breast cancer is reported to be as high as 68%, and can include impaired shoulder range of motion (ROM), pain, lymphedema, and brachial plexopathy.3 Advances in surgical techniques have decreased the incidence of postoperative sequelae, especially the transition from axillary lymph node dissection (66% morbidity) to sentinel lymph node biopsy (36% morbidity).3 Primary prevention may include early recognition and referral for rehabilitation interventions.
Chemotherapy-induced peripheral neuropathy (CIPN)
Incidence varies by chemotherapeutic agent and is typically dose-dependent. Neurotoxicity of platinum agents ranges from virtually 100% for cisplatin to around 50% for carboplatin and oxaliplatin, with severe CIPN in 10% of patients.4 Taxane-induced CIPN occurs more commonly with paclitaxel (57%-83% with up to 33% being severe) than docetaxel (11%-64% with only 14% being severe).2,4 Vincristine-induced CIPN occurs in virtually 100% of patients, as opposed to other vinca alkaloids, such as vinblastine (8%) and vinorelbine (20%).2,4 Risk factors include combination therapy with other neurotoxic agents, pre-existing peripheral neuropathy, low magnesium for platinum agents, and unrecognized hereditary peripheral neuropathy for vincristine.4 Several neuroprotective agents have been studied, including glutathione, vitamin E, and magnesium supplementation, but results have been inconclusive.4 Dose reduction is the only known primary prevention at this time. No gold standard screening tool exists for CIPN, however, the Common Terminology Criteria for Adverse Events Scale was developed by the Eastern Cooperative Oncology Group and the National Cancer Institute.
Radiation induced brachial plexopathy (RIBP)
RIBP is thought to be caused by fibrosis of connective tissue around peripheral nerves, ischemia from damage to surrounding capillaries, and changes to axons (both myelinated and unmyelinated). There seems to be a direct correlation with doses per fraction of radiation and total dose of radiation. Doses of 2.2-2.5 gray per fraction and total dose of 34-40 gray are associated with <1% risk of developing RIBP. The risk of RIBP increases to 73% with doses approaching 5 gray per fraction or total dose greater than 50 gray. Reducing dose per fraction and total dose of radiation is the only primary prevention.
Postoperative issues after breast cancer surgery
Impaired shoulder ROM may be a result of pain, surgical scarring, or axillary web syndrome (AWS), a series of cord-like structures palpable beneath the axillary skin because of the disruption of lymphatic vessel and veins. Pain is often the result of soft tissue damage, nerve injury (eg., intercostal-brachial nerve), and scarring of tissues to the chest wall. Lymphedema occurs after damage to the lymphatic system.
Mechanisms of chemotherapeutic agents on nervous tissue
Platinum agents bind to DNA, inducing neuronal apoptosis in the dorsal root ganglion (DRG).4 Taxanes disrupt microtubules of the mitotic spindle, interfere with axonal transport, and affect distal sensory axons and the DRG.4 Vinca-alkaloids also inhibit microtubules of the mitotic spindle, interefere with axonal transport, affecting motor and sensory axons.2,4
Mechanisms of radiation tissue damage
While not completely known, it is hypothesized that radiation causes tissue damage by free radical-mediated deoxyribonucleic acid damage and apoptosis, causing vascular endothelial damage, abnormal accumulation of thrombin, proliferative fibrin production, and subsequent sclerosis and progressive tissue fibrosis.5
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Progression of postoperative breast cancer morbidity
AWS often develops in the early weeks after surgery, and is generally a self-limiting condition.3 Timely treatment of acute postoperative pain may reduce the risk of developing chronic pain and shoulder impairment. Transient lymphedema can occur as a single episode lasting <3 months that resolves without treatment; lymphedema that lasts >3 months is considered chronic.3
Progression of CIPN
CIPN is dose-dependent and often develops during chemotherapy treatment. It may progress for 2-6 months after cessation of therapy (the “coasting effect”).4 Symptoms typically improve within the first 3-6 months after cessation of chemotherapy; however, recovery is often incomplete (20%-35%).4 Development of neuropathy outside of the time course expected for taxanes, platinum analogues and vinca alkaloids should warrant investigation into other causes of neuropathy.
RFS often appears as a late effect of treatment, occurring months to years later. It is typically slowly progressive and irreversible.5
Progression of RIBP: The effects of radiation can be acute (during treatment), early delayed (≤3 months after treatment), or late delayed (>3 months after treatment). RIBP is often a late complication of radiation therapy and is usually irreversible. The progression may lead to flail arm but the rate at which this happens varies.
2. ESSENTIALS OF ASSESSMENT
A comprehensive cancer-related history must include tumor type disease stage and previous or upcoming cancer treatments. Physiatrists should inquire about common cancer-related symptoms including fatigue, pain, and impaired ability to perform functional activities. Specific postoperative complications include cellulitis, wound infection or dehiscence, seroma, and nerve damage, and may increase the risk of morbidity. The number of lymph nodes removed, specific muscles sacrificed, and any reconstruction surgery should also be noted. Regarding CIPN, the type and dosing of the chemotherapeutic agent should be recorded, as well as the onset and characteristics of paresthesias, numbness, and weakness. It is important to understand the radiation field, because vessels, nerves, and soft tissues structures in that area will be affected by fibrotic change. Pre-existing neuromuscular and musculoskeletal conditions may also affect development of symptoms in the radiation field.2
A thorough musculoskeletal and neurologic exam will identify many complications of cancer treatment. Inspection of surgical scars or radiation burns, muscle atrophy, affected joint ROM, limb strength and sensation, and assessment of any swelling is essential to identifying postoperative and post-radiation changes. A neurologic exam, including strength, sensation, and reflexes should be performed, paying attention not only to loss of light touch and pinprick sensation, but importantly proprioception, because this may affect functional balance and gait.
The patient may self-report on impaired ability to perform self-care and mobility, or more standardized patient-reported outcome (PRO) measures (which will be subsequently discussed) may be used to assess function.
Laboratory tests may be used to rule out other common causes of neuropathy, including diabetes, vitamin deficiencies, endocrine abnormalities, or infection. Anemia may also be a contributor to fatigue and poor function.
Magnetic resonance imaging may be useful to identify contributing factors to shoulder morbidity after breast cancer surgery (eg., brachial plexopathy or rotator cuff pathology), exclude concurrent degenerative spine processes, as well as, rule out disease recurrence or metastases in late onset symptoms. Electromyography can identify characteristics of CIPN (motor or sensory involvement, axonal or demyelinating features) and diagnose RIBP and other lesions of the peripheral nervous system and musculature.
Early predictions of outcomes
Regarding surgery, early full ROM and excellent wound healing are predictors of good outcomes. For CIPN, an earlier resolution of symptoms can be predictive of a better overall recovery of sensation and pain, because severe symptoms may persist for longer.4 For radiation effects, early full ROM and minimal skin burning may have a better outcome.
Assuring early access to rehabilitation interventions will ultimately improve the patients’ quality of life. Ongoing surveillance of rehabilitation needs, excellent relationships with surgical and medical oncologists, and effective communication skills are important for physiatrists in this field.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines:
A core panel of cancer rehabilitation experts supported by the American Cancer Society (ACS) published clinical practice guidelines for breast cancer rehabilitation, including postoperative issues and CIPN.6 While specific to breast cancer, these guidelines can be used as framework for many cancer-related issues that span tumor type. The National Comprehensive Cancer Network has guidelines for clinical practice based on tumor type and common symptoms, such as pain and cancer-related fatigue.7
At different disease stages:
Immediately after surgery, exercise precautions may be necessary to allow for wound healing.3 However, early referral to a structured and progressive physical therapy (PT) program can improve ROM and shoulder dysfunction.3 Recent studies of supervised, progressive strengthening and aerobic exercise in breast cancer showed that exercise preserved aerobic capacity, improved self-esteem, and did not increase the incidence of lymphedema.8,9 There is increasing evidence that exercise is beneficial, even in the palliative stage of cancer.10
Pharmacologic treatment with anticonvulsants (gabapentin, pregabalin, carbamazepine) and antidepressants (tricyclics, venlafaxine, duloxetine) can reduce neuropathic pain associated with CIPN.2 A recent systematic review has suggested that there may be a role for natural products (i.e. vitamin E, glutamine, etc.) and complimentary therapies (i.e. acupuncture) to prevent and treat CIPN. PT can improve balance and gait mechanics, and may issue adaptive equipment to improve stability.
Rehabilitation should focus on adaptive and compensatory techniques that maximize the patient’s strength, reduce pain and preserve function. Although controversial, elective amputation is a consideration for chronic flail arm but may not reduce pain.
Coordination of care
Effective communication and ongoing relationships with the medical and surgical oncology team will ensure early access to rehabilitation interventions for cancer patients. The ACS, Institute of Medicine, and other organizations have recently highlighted the importance of providing cancer survivors with the necessary resources to regain function and quality of life after cancer treatment.11,12 Physiatrists must partner with the oncology community to monitor, preserve, and improve the functional health of cancer patients.
Patient & family education
Patient-oriented education must be provided regarding precautions for poor sensation as a result of CIPN and RIBP, maintaining mobility after surgery or radiation, and expected outcomes with treatment.
PRO measures have been developed for many cancer-specific issues. The Functional Assessment of Cancer Therapy is a questionnaire developed to assess physical, social, emotional, and functional well-being in cancer patients, and has additional subscales available for specific tumor types and cancer-related impairments including fatigue, lymphedema, and neurotoxicity. The Disabilities of Arm, Shoulder and Hand scale, the Simple Shoulder Test, and the Upper Extremity Functional Index are other tools specific to arm function. The BREAST-Q is a breast cancer surgery-specific tool used to assess chest, upper body, and trunk/abdomen dysfunction.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
A comprehensive cancer-related history, symptom inventory, functional assessment, and thorough musculoskeletal and neurologic exam will identify sequelae of cancer treatments, and should be performed in every cancer patient at multiple points along the disease trajectory.6 Regardless of subspecialty interest, all physiatrists need these skills as an increasing number of cancer survivors are seen throughout the scope of rehabilitation practice settings.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Significant advances are being made in hormonal and immunotherapy, with short-term effects including osteoporosis; however, long-term sequelae are unknown.
- American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2014-2015. Atlanta, GA: American Cancer Society; 2012.
- Stubblefield MD, O’Dell MW. Cancer Rehabilitation. New York, NY: Demos Medical Publishing; 2009.
- McNeely ML, Binkley JM, Pusic AL, Campbell KL, Gabram S, Soballe PW. A prospective model of care for breast cancer rehabilitation: postoperative and postreconstructive issues. Cancer. 2012;118(8 Supplement):2226-2236.
- Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Critical Reviews in Oncological Hematology. 2012;82:51-77.
- Stubblefied MD. Radiation fibrosis syndrome: neuromuscular and musculoskeletal complications in cancer survivors. PMR. 2011;3:1041-1054.
- Harris SR, Schmitz KH, Campbell KL, McNeely ML. Clinical practice guidelines for breast cancer rehabilitation. Cancer. 2012;118(8 Supplement):2312-2324.
- National Comprehensive Cancer Network. NCCN Guidelines. Available at: http://www.nccn.org/clinical.asp. Accessed August 1, 2016.
- Schmitz KH, Ahmed RL, Troxel AB, et al. Weight lifting for women at risk for breast cancer-related lymphedema: a randomized trial. JAMA. 2010;304:2699-2705.
- Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvent chemotherapy: a multicentered, randomized controlled trial. Journal of Clinical Oncology. 2007;25:4396-4404.
- Oldervoll LM, Loge JH, Paltiel H, et al. The effect of a physical exercise program in palliative care: a phase II study. Journal of Pain Symptom Management. 2006;31:421-430.
- Stubblefield MD, Levine A, Custodio CM, Fitzpatrick T. The role of botulinum toxin type A in the radiation fibrosis syndrome: a preliminary report. Arch Phys Med Rehabilitation. 2008;89:417-421.
- National Research Council. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC: The National Academies Press; 2005.
Bibliography [Further Reading]
Stubblefield MD, Keole N. Upper Body Pain and Functional Disorders in Patients With Breast Cancer. PMR. 2014 Feb;6(2):170-83
Brami C, Bao T, Deng G. Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: A systematic review. Critical Reviews in Oncological Hematology. 2016 Feb;98:325-34
Brewer JR, Morrison G, Dolan ME, Fleming GF. Chemotherapy-induced peripheral neuropathy: Current status and progress. Gynecological Oncology 2016 Jan;140(1):176-83
Cifu, D. X. (2016). Braddom’s Physical Medicine & Rehabilitation: Fifth edition
Curcio KR. Instruments for assessing chemotherapy-induced peripheral neuropathy: A review of the literature. Clinical Journal of Oncological Nursing. 2016 Apr 1;20(2):144-51. doi: 10.1188/16.CJON.20-01AP.
Solomon LR. Functional vitamin B12 deficiency in advanced malignancy: implications for the management of neuropathy and neuropathic pain. Support Care Cancer. 2016 Mar 22.
Boyette-Davis JA, Walters ET, Dougherty PM. Mechanisms involved in the development of chemotherapy-induced neuropathy. Pain Management. 2015;5(4):285-96.
De Boer AG, Taskila TK, Tamminga SJ, Feuerstein M, Frings-Dresen MH, Verbeek JH. Interventions to enhance return-to-work for cancer patients. Cochrane Database Syst Rev. 2015 Sep 25;9:CD007569.
Yang EJ, Kang E, Kim SW, and Lim JY. Discrepant Trajectories of Impairment, Activity, and Participation Related to Upper-Limb Function in Patients With Breast Cancer. Arch Phys Med Rehabil. 2015 Dec;96(12):2161-8.
Monleon S, Ferrer M, Tejero M, Pont A, Piqueras M, Belmonte R. Shoulder Strength Changes 1 Year After Axillary Lymph Node Dissection or Sentinel Lymph Node Biopsy in Patients With Breast Cancer. Arch Phys Med Rehabil. 2016 Jan 4. pii: S0003-9993(15)01567-1.
Original Version of the Topic:
Sarah M. Eickmeyer, MD, Gail L. Gamble, MD. Side effects of treatment (cancer surgery, chemotheraphy, radiation therapy). Publication Date: 2012/12/28.
Sarah M. Eickmeyer, MD
Nothing to Disclose
Michael Fediw, MD
Nothing to Disclose