Over several decades, there has been a significant improvement in survival after cancer due to earlier detection and advances in surgery, chemotherapy, and radiation treatment. Thus, the number of cancer survivors has grown to approximately 16.9 million as of January 2019 with that number projected to be almost 22.2 million by 2030.1 Immediate and long-term toxicities of cancer treatment are increasingly an issue that impact cancer survivors’ physical function and quality of life.
Specific side effects of cancer treatment depend on different cancer/treatment variables such as type and length of treatment, tumor characteristics, disease stage and severity. Patient variables such as age, co-morbidities, baseline health and functional status also may play a role. Cancer and cancer treatments can cause a variety of functionally impairing complications including neuropathies, myopathies, tendonopathies, biomechanical changes and metabolic/endocrine abnormalities. The complications can be many and vary based on location of tumor/treatment, however due to the scope of this article a few more common complications will be discussed. This includes 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, chest tightness and brachial plexopathy.3,61 Factors that influence the development of upper extremity morbidity after breast cancer surgery include baseline shoulder pathology, obesity, post-surgical complications and regional lymph node radiotherapy.60 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 were previously inconclusive.4 Dose reduction was the only known primary prevention. However more recently, lithium appears to prevent CIPN from taxanes, vinca alkaloids.5 Other compounds include a sigma-1 receptor and nicotinic acetylcholine antagonist in addition to cannabidiol are currently under investigation for treatment of CIPN5. Another approach to treating CIPN is to prevent it from occurring in the first place. Limb hypothermia or “Cooling therapy” has demonstrated potential benefit in limiting the peripheral neurotoxic effects of certain chemotherapeutic agents such as taxanes and platinum based therapies. While multiple studies have reported positive subjective and/or objective effects of cooling therapy on CIPN, factors such as significant heterogeneity in study design and low power make it difficult to draw definitive conclusions for this preventative treatment.
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. More modern techniques in radiation therapy have been developed over time to help decrease radiation exposure of surround tissues and limit collateral damage. Such techniques as intensity modulated radiation therapy (IMRT), gamma knife radiosurgery (GKRS) and Proton Therapy are some examples of this. An in depth discussion of radiation technique is outside the scope of this review. When conservative measures have failed, omentoplasty is an alternative treatment for RIBP.6
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. Decreased ROM in the shoulder can also be attributed to the length of pectoralis minor muscle7. Pain is often the result of soft tissue damage, nerve injury (e.g., intercostobrachial nerve), and scarring of tissues of 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, interfere 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.8
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. Up to 28% of patients have pain at three months post-surgery, and persistent pain is found more commonly in patients with higher pain scores 6 hours post-surgery as well as in those with preexisting chronic pain.9 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 certain chemotherapy treatments. It may progress for 2-6 months after cessation of therapy (the “coasting effect”) depending on the chemotherapeutic agent used.4 Symptoms typically improve within the first 3-6 months after cessation of chemotherapy; however, recovery is often incomplete (20%-35%).4 If used for prolonged periods at high therapeutic levels, the nervous system damage can be irreversible5. Development of neuropathy outside of the time course expected for taxanes, platinum analogues and vinca alkaloids should warrant investigation into other causes of neuropathy. Of note, Certain chemotherapeutic agents can cause presentation or worsening of symptoms shortly after cessation of treatment known as the “coasting” effect. This phenomenon is seen most commonly in platinum based agents, with cisplatin and oxaliplatin being the most common. Vinka alkaloids may also cause a coasting effect although this is less common.4
RFS often appears as a late effect of treatment, occurring months to years later. It is typically slowly progressive and irreversible.8
Progression of RIBP: Symptoms often start with paresthesia, followed by pain and then development of motor weakness.6 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.
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 paresthesia, 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. Dermatologic exam for evaluation of skin integrity is key when considering potential treatments (i.e., taping, splinting, compressive garments). HEENT exam to include assessment of temporomandibular range of motion, and associated muscle hypertonicity is key in the head and neck cancer population.
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.
Vitamin B12 deficiency, vitamin D deficiency, electrolyte imbalance, and anemia are potential causes of fatigue in the general population, and cancer patients can be at increased risk of these depending on their chemotherapeutic treatments. When considering CIPN, laboratory tests may be used to rule out other common causes of neuropathy, including diabetes, vitamin deficiencies, endocrine abnormalities, or infection. Neutropenia and/or thrombocytopenia are common with chemotherapy and are important to consider when planning interventions or establishing safety precautions.
Magnetic resonance imaging may be useful to identify contributing factors to shoulder morbidity after breast cancer surgery (e.g., 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. Regarding safety of EMG in setting of lymphedema, there is no published evidence of infection as a complication of EMG; however, lymphedema can be considered a relative contraindication to performing needle EMG.9
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 Abnormal SNAPs on NCS of radial and sural nerves mid-treatment have been shown to accurately predict severe oxaliplatin toxicity.10 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.
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 pain management, fatigue, individualized exercise program recommendations, bone health, weight management, and CIPN.11 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.12
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.13,14 There is increasing evidence that exercise is beneficial, even in the palliative stage of cancer.15 There is an increasing amount of research being done investigating prehabilitation as a way of improving post-surgical outcomes in cancer patients. Several therapeutic injections may be helpful for patients experiencing pain after breast surgery. Interventions such as intercostobrachial nerve block, serratus plane block, neuroma injection may be helpful for neuropathic pain in the chest wall or axilla. Peripheral joint or bursa injection (including scapulothoracic bursa injection) may be helpful for different shoulder pathologies. Chemodenervation for radiation induced spasm or myokymia of the chest wall or shoulder musculature may also be helpful.
Pharmacologic treatment with anticonvulsants (gabapentin, pregabalin, carbamazepine) and antidepressants (tricyclics, venlafaxine, duloxetine) can reduce neuropathic pain associated with CIPN.2 Duloxetine in particular has good evidence for improving patient reported pain scores when compared to placebo.16 There is mixed evidence on the role of natural products (i.e., vitamin E, glutamine, etc.) and complimentary therapies (i.e., acupuncture) to prevent and treat CIPN. Vitamin E in particular has had multiple RCTs, some of which have supported vitamin E as a treatment.17 TENS and acupuncture are both supported as generally safe by the National Comprehensive Cancer Guidelines.12 PT can improve balance and gait mechanics and may issue adaptive equipment to improve stability. One small study reported repetitive transcranial magnetic stimulation as potentially beneficial for improving pain and dysesthesias associated with CIPN.18
Rehabilitation should focus on adaptive and compensatory techniques that maximize the patient’s strength, reduce pain and preserve function. Bracing or splinting may be useful to prevent contracture or aid in function in patients demonstrating significant weakness. Surgical treatments such as omentoplasty and nerve grafting have been reported to improve pain or weakness from RIBP but there is not current surgical standard of care. 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 highlighted the importance of providing cancer survivors with the necessary resources to regain function and quality of life after cancer treatment.19,20 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, the importance of 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. The EORTC QLQ-C30 is used to assess quality of life in cancer patients.21 The PROMIS Cancer Function Brief 3D Profile was recently developed and validated in outpatient cancer rehab patients.22
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.11 Regardless of subspecialty interest, all physiatrists need to be educated on these skills as an increasing number of cancer survivors are seen throughout a variety of rehabilitation settings.
Cutting Edge/ Emerging and Unique Concepts and Practice
While controversial, there is limited evidence for medical marijuana for symptomatic control, particularly with CIPN, but it is still a topic that patients often ask about. State restrictions as well as employer policies are variable, further limiting a physiatrist’s ability to recommend various forms of cannabinoids (i.e. oral, sublingual, inhaled, topical) when patients do request such information. A recent review article details multiple placebo-controlled trials which yielded mostly beneficial results for pain relief and quality of sleep across various forms of THC/CBD products; however, there is still not sufficient evidence to fully establish risks and benefits of these treatments.23
Gaps in the Evidence-Based Knowledge
Significant advances are being made in oncologic treatment including hormonal and immunotherapies. A recent review noted side effects of recently developed cancer treatments can include pain and neurologic dysfunction with an increasing role for management by rehabilitation professionals.24 Further research needs to be conducted into the development of rehab protocols and interventions specific to different cancer populations.
- Cancer statistics. National Cancer Institute. https://www.cancer.gov/about-cancer/understanding/statistics. Published September 25, 2020. Accessed July 28, 2021.
- 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 post reconstructive issues. Cancer. 2012;118(8 Supplement):2226-223
- Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Critical Reviews in Oncological Hematology. 2012;82:51-77.
- Claudia Pellacani, Georgios Eleftheriou, Neurotoxicity of antineoplastic drugs: Mechanisms, susceptibility, and neuroprotective strategies, Advances in Medical Sciences, Volume 65, Issue 2, 2020, Pages 265-285, ISSN 1896-1126.
- De Oliveira AJM, Castro JPS, Foroni LH, Siqueira MG, Martins RS. Treatment of radiation-induced brachial plexopathy with omentoplasty. Autops Case Rep. 2020 Sep 2;10(3):e2020202. doi: 10.4322/acr.2020.202. PMID: 33344306; PMCID: PMC7703345.
- Lee, Chung Ho MDa; Chung, Seong Yun MDa; Kim, Woo Young MD, PhDb; Yang, Seung Nam MD, PhDa,∗ Effect of breast cancer surgery on chest tightness and upper limb dysfunction, Medicine: May 2019 – Volume 98 – Issue 19 – p e15524 doi: 10.1097/MD.0000000000015524
- Stubblefied MD. Radiation fibrosis syndrome: neuromuscular and musculoskeletal complications in cancer survivors. PMR. 2011;3:1041-1054.
- AANEM Position Statement. July 2014. risksinEDX.pdf (aahttps://www.aanem.org/getmedia/653e87b3-f930-4951-9bd8-dde95c291ce2/risksinEDX.pdfnem.org)
- Villa, G., Mandarano, R., Scirè-Calabrisotto, C. et al. Chronic pain after breast surgery: incidence, associated factors, and impact on quality of life, an observational prospective study. Perioper Med 10, 6 (2021).
- 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: https://www.nccn.org/guidelines/category_3
- 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.
- Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL; Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013 Apr 3;309(13):1359-67. doi: 10.1001/jama.2013.2813. PMID: 23549581; PMCID: PMC3912515.
- Chen J, Shan H, Yang W, Zhang J, Dai H, Ye Z. Vitamin E for the Prevention of Chemotherapy-Induced Peripheral Neuropathy: A meta-Analysis. Front Pharmacol. 2021 May 13;12:684550. doi: 10.3389/fphar.2021.684550. PMID: 34054560; PMCID: PMC8155355.
- Goto Y, Hosomi K, Shimokawa T, Shimizu T, Yoshino K, Kim SJ, Mano T, Kishima H, Saitoh Y. Pilot study of repetitive transcranial magnetic stimulation in patients with chemotherapy-induced peripheral neuropathy. J Clin Neurosci. 2020 Mar;73:101-107. doi: 10.1016/j.jocn.2020.01.020. Epub 2020 Feb 13. PMID: 32063448.
- 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.
- EORTC quality of Life WEBSITE: EORTC quality of Life group website. EORTC. https://qol.eortc.org/. Published May 29, 2019. Accessed July 28, 2021.
- Smith SR, Vargo M, Zucker D, Shahpar S, Gerber L, Henderson M, Jay G, Lee M, Cheville A. Psychometric Characteristics and Validity of the PROMIS Cancer Function Brief 3D Profile. Arch Phys Med Rehabil. 2021 Feb 4:S0003-9993(21)00133-7. doi: 10.1016/j.apmr.2020.12.027. Epub ahead of print. PMID: 33548209.
- Jensen B, Chen J, Furnish T, Wallace M. Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence. Curr Pain Headache Rep. 2015 Oct;19(10):50. doi: 10.1007/s11916-015-0524-x. PMID: 26325482
- Fediw, M., Lau, K. Novel Cancer Therapeutics and Implications for Rehabilitation. Curr Phys Med Rehabil Rep 9, 224–229 (2021). https://doi.org/10.1007/s40141-021-00323-6
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). 12/28/2012
Previous Revision(s) of the Topic:
Sarah M. Eickmeyer, MD, Michael Fediw, MD. Side effects of treatment (cancer surgery, chemotheraphy, radiation therapy). 9/15/2016
Kelsey Lau, DO
Nothing to Disclose
Jeffrey Barnett, DO
Nothing to Disclose
Michael Fediw, MD
Nothing to Disclose