The Orthopedic Burden of U.S. Cancer Care

As the longevity of people in the developed world increases, the incidence and prevalence of cancer continues to increase. In 2016, 1,685,210 new cancers were diagnosed in the United States, with an overall incidence of 454.8/100,000 individuals per year, and an estimated 50% of these patients may develop osseous metastatic disease [1,2]. As diagnostic and treatment strategies continue to evolve, the prevalence of cancer survivors is also increasing, with 5-year survivorship rates rising from 49% in 1975-77 to over 68% in 2003-2009 [2-4]. The number of individuals living beyond a cancer diagnosis will reach nearly 26.1 million individuals by 2024. It is estimated that roughly 39.6% of individuals will be diagnosed with some form of malignancy during their lifetime [3].


Introduction
As the longevity of people in the developed world increases, the incidence and prevalence of cancer continues to increase. In 2016, 1,685,210 new cancers were diagnosed in the United States, with an overall incidence of 454.8/100,000 individuals per year, and an estimated 50% of these patients may develop osseous metastatic disease [1,2]. As diagnostic and treatment strategies continue to evolve, the prevalence of cancer survivors is also increasing, with 5-year survivorship rates rising from 49% in 1975-77 to over 68% in [2003][2004][2005][2006][2007][2008][2009] [2][3][4]. The number of individuals living beyond a cancer diagnosis will reach nearly 26.1 million individuals by 2024. It is estimated that roughly 39.6% of individuals will be diagnosed with some form of malignancy during their lifetime [3].
A 2014 census of the membership of the American Academy of Orthopaedic Surgeons (AAOS) estimates that Orthopaedic Surgeons in the United States performed over 9.75 million orthopaedic procedures, and several million more patient encounters for nonoperative musculoskeletal conditions [4]. This suggests a statistical inevitability that every practicing orthopaedic surgeon will be involved in the care of cancer patients and cancer survivors at some point in their career. It is critical, therefore, for orthopaedists to have an understanding of the burden that cancer and the long-term complications associated with cancer treatment place on the orthopaedic profession, so as to identify specific interventions that can optimize patient outcomes.

Multiple myeloma
Technically considered a plasma cell dyscrasia, multiple myeloma is the most common primary malignancy of bone [7,8].
The presence of multiple osteolytic bone lesions is a defining trademark of the disease. As many as 30% of myeloma patients may present with a pathologic fracture, and up to two-thirds with bone pain alone as the initial symptom of disease [7]. In 2016 the incidence of multiple myeloma was close to 30,000 individuals. Survivorship has increased dramatically over the past decade, and over 50% of newly diagnosed cases are expected to live 5 years or more [8] (Table 1).

Primary soft tissue tumors
Nearly 9,000 soft tissue malignancies are diagnosed in the U.S. each year [9]. It is critical for the orthopedic practitioner to have a high degree of suspicion for soft tissue sarcoma, and to evaluate and refer appropriately. A mass that is firm, deep to fascia, rapidly growing, or larger than a table tennis ball should prompt further investigation. If a biopsy is warranted, referral to a musculoskeletal oncologist should be made to ensure that the biopsy does not adversely affect definitive surgical management in the future [10].

Metastatic disease
More than 50% of patients with terminal cancers are likely to develop a bone metastasis at some point. It is therefore a certainty that all orthopedic surgeons will see this problem in their career [11][12][13][14]. The practicing orthopaedist should expect to encounter metastatic disease to bone with some frequency. Breast, prostate, lung, thyroid, and renal carcinomas are the most common primary malignancies to spread to bone, with a recent increase in rates of malignant melanoma and gastrointestinal carcinomas as advancements in immunotherapy and other modalities improve survival rates in these patients [15,16]. Table 2 illustrates the overall number, survivorship, and rates of osseous metastasis of these common malignancies.

Electrolyte abnormalities
Malignancy is the second most common cause of undiagnosed hypercalcemia. Tumor production of PTHrp, 1, 25-dihydroxyvitamin D, and stimulation of osteoclast activation induce osteolysis [17]. The clinical presentation of hypercalcemia can range from mild to life threatening. Generalized bone pain, thirst, constipation and abdominal pains, biliary and renal stone formation, mental confusion, and eventually coma can manifest from elevated calcium level. Malignancies most commonly associated with increased PTHrp production include renal, breast, ovarian, and lung carcinomas, leukemia, and some lymphomas [17] (Table 3).
An estimated 20-30% of newly diagnosed cancer patients will demonstrate hypercalcemia, and this should be considered the most urgently life-threatening complication that should prompt immediate treatment. Treatment includes rehydration, loop diuretics and IV bisphonsonates or denosumab [18]. The orthopaedist called upon to evaluate a concerning bone lesion or pathologic fracture should have a high clinical suspicion for hypercalcemia, and initiate necessary treatments immediately.

Extremity pain and lytic bone lesions
Metastatic disease to bone should be considered in any patient with a history of cancer and new onset bone pain, lowenergy fractures, fractures unusual for the mechanism of injury, or when obvious lesions are identified on radiographic imaging. The orthopaedic surgeon must be able to decide whether or not to operate on a patient with metastatic disease without pathologic fracture. Several clinical scoring systems and imaging-based structural rigidity analyses have been developed to assist the orthopaedic practitioner predict the likelihood of fracture [19][20][21]. The wide range of surgical treatment options is beyond the scope of this conversation, but the goals of treatment should always focus on pain relief and functional optimization. The surgical intervention planned should provide a durable construct that is expected to provide indefinite stability until the patient's death.
Tumor-mediated osteolysis results from tumor stimulation of osteoclast precursor cells via the RANKL-RANK pathway [22]. Osteoclasts stimulate VEGF-A which directs angiogenesis and enables tumor survival, and osteolysis releases TGF-B which leads to production of PTHrp [22,23]. This self-destructive cycle of osteolysis perpetuates itself, and poses a risk for pathologic fracture that frequently necessitates orthopedic intervention. The orthopaedic surgeon is responsible for recognizing this and ensuring that patients with osseous metastases are initiated on antiresorptive therapy to block the RANK-RANKL pathway and reduce the risk of future skeletal events [24].

Spinal cord compression
Pain is the presenting complaint in 83-95% of patients with metastatic spine disease. Point tenderness, pain that occurs at rest, pain with movement due to instability, cord compression, or radicular pain should prompt investigation [25]. Degenerative thoracic pain is much less common than lumbar and cervical pain, so new onset pain in the thoracic region should raise suspicion for cancer [25]. A comprehensive neurologic exam is critical to identify neurological deficits so that early intervention can preserve function and mobility. The spine is the most common site of metastatic bone disease, observed in up to 40% of patients with bony involvement. Of these patients, 5-10% will demonstrate some degree of spinal cord compression [26].

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Ortho Res Online J Volume 1 -Issue -2 The Management of spinal metastases includes various surgical techniques, radiation therapy, and percutaneous ablation and augmentation. While life expectancy is a common part of the treatment algorithm, longevity may be difficult to predict [27]. Strong indications for surgical intervention include spinal instability, radio resistant tumors, significant kyphotic deformity, neurologic compromise, and lesions that have failed radiotherapy [28,29]. When comparing combined corticosteroid and radiotherapy versus surgical decompression and postoperative radiotherapy for patients with cord or nerve compression from metastatic disease, surgical decompression was associated with better preservation of ambulatory function and mobility [30,31].

Long term complications of cancer treatment
As cancer survivorship increases, and modalities for treatment continue to evolve, orthopedists will increasingly be tasked with caring for the long term consequences of cancer therapies. A thorough treatment history should be obtained in any patient with a history of cancer. Specific consequences that are highly relevant to orthopedic surgeons include bone density loss, degenerative joint disease, loss of function, and an increased risk for injuries and secondary malignancies.

Bone density loss
Cancer and cancer treatments cause bone loss via several different mechanisms. Aberrant hormonal regulation from chemotherapy agents can induce early menopause and premature ovarian failure. Luteinizing hormone (LH) agonists and antiestrogen and anti-androgen therapies used in the treatment of breast and prostate cancers affect bone density in profound ways [32][33][34]. Estrogen deficiency has a clear relationship to bone loss in women. Women with drug-induced ovarian failure or menopause have a faster rate of bone demineralization that begins at younger ages compared to matched controls [35]. Among long-term breast cancer survivors, 34.8% develop osteopenia and 11.3% develop osteoporosis within 6 years of diagnosis [36,37].
For breast cancer survivors treated with radiation, surgery, and anastrozole, an overall mineralization decline was observed within 12 months of treatment [36]. Ovarian failure rates may be as high as 85-100% when receiving combined chemotherapy regimens including cyclophosphamide and fluorouracil with either methotrexate or doxorubicin. For breast cancer survivors who sustained a fracture, aromatase inhibitors were the most common prior therapy [24]. Hip or femur fractures accounted for 29% of fragility fractures, followed by rib, vertebral and wrist fractures [36].
Decreased estrogen and bioavailable testosterone are prime suspects for osteoporosis and fragility fractures in men. Osteoporosis due to androgen deprivation therapy in men can be as high as 53% depending on the duration of treatment [38]. Given the expected increase in insufficiency fractures over the next several years, it becomes increasingly important to consider active bone density management in patients with a history of cancer.
Bone density loss is particularly important to address in survivors of pediatrics cancers, particularly females. Young women treated with radiation therapy below the diaphragm, and alkylating agents including those mentioned above, demonstrate an increased risk for early menopause at a rate nearly 4 times that of women treated with radiation alone [24,39].
The incidence of early menopause ranged from 2% of bone cancer survivors to 10% for survivors of either Hodgkin's disease or non-Hodgkin's lymphoma. Furthermore, the risk of menopause increase with increased age at diagnosis. Among all pediatric cancer survivors, there is a 25% rate of long-term osteopenia and/ or osteoporosis [39]. Lastly, bone density is also affected by the use of glucocorticoids [40]. Steroids are a component of several oncology regimens. Where ashormonal antagonists contribute to bone loss via the protective endocrine pathways, glucocorticoids inhibit osteoblast activity [41]. Daily doses of corticosteroid from 7.5mg to 11.5mg of prednisone equivalent can lead to osteopenia. The most rapid bone loss occurs in the first year of treatment, then an accelerated rate of loss persists thereafter. The effect of cotiscosteroids on bone density is directly related to the dose and duration of treatment [40].
Management strategies for bone density loss in cancer patients have yet to be perfected. Bisphosphonates slow the process of bone resorption that occurs with age and hormone-related bone density loss [42]. However, the side effects of treatment such as GERD, jaw necrosis, and atypical fractures preclude their long-term use. Denosumab, a monocolonal antibody against RANKL, has shown promising results with the benefit of improved tolerance compared to bisphosphonates, and greater safety for longer periods of treatment [43]. The orthopaedist must emphasize additional prevention measures including adequate calcium and vitamin D supplementation, and weight-bearing exercise [44].

Joint pain and degenerative joint disease
Long term cancer survivors will soon join the population of aging individuals seeking total joint arthroplasty. Avascular necrosis (AVN) and the subsequent need for TJA is elevated in recipients of bone marrow transplants [45,46]. The incidence of AVN after stem cell transplant is 2.9% with autologous donor, 5.4% with matched related donor and 15% after unrelated donor. In patients receiving corticosteroids for myeloma and other hematologic malignancies, AVN has been identified as a complication in roughly 9% of patients, correlated with cumulative dexamethasone dose, male sex and younger age at the time of therapy [47]. Roughly 80% of patients with femoral head AVN will require hip replacement within 5 years of diagnosis [48].
For survivors of pediatric leukemia and lymphoma, the overall incidence of AVN is 7.6%, diagnosed at an average of 17 months after treatment [49]. Younger patients with treatment-related avascular necrosis generally seek total joint arthroplasty within 20 years of diagnosis [48]. It is important to take a cancer patient's history into consideration when planning for any joint replacement,

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Ortho Res Online J Orthopedic Research Online Journal Volume 1 -Issue -2 as the risks for perioperative complications in cancer patients may be substantially different from that of the general population. Active malignancy is associated with an increased risk of infection and thromboembolism, as cancer patients are hyper coagulable at baseline [50]. In the elderly population, the presence of metastatic cancer is associated with an increased 90 day mortality in total hip arthroplasty. Therefore, patient selection and careful management is critical [51].

Loss of function
Loss of function and impaired mobility are common side effects from cancer and its related therapies. In 2013, it was reported that of 13.8 million cancer survivors, 20% of children and 53% of adults had difficulty with physical function, either from treatment or cancer itself [52]. In a large survey of cancer survivors, 31% of survivors reported some persistent adverse health affect, and younger patients most commonly reported arthritis and osteoporosis [53]. Upper extremity pain and dysfunction is increasingly common in breast cancer survivors. Up to one third of breast cancer survivors report extremity circulation problems [54]. Not including postsurgical pain, patients treated for breast cancer with mastectomy, axillary dissection and/or adjuvant radiotherapy often suffer from adhesive capsulitis, mononeuropathy, rotator cuff disease, lymphedema, radiation osteiitis, and axillary web syndrome [55]. When comparing range of motion and strength between women who had undergone mastectomy versus mastectomy and radiation, 40% of women reported impairment of shoulder function when radiated, 31% for surgery alone.
There was a significant reduction of range of motion in all planes in irradiated shoulders, and reduction in flexion only with surgery alone. Additionally, strength was found to be diminished on the operative side, worse when combined with radiation therapy [56,57]. In addition to upper extremity complications, postural effects commonly ensue, and postural failures are seen in 83% of breast cancer survivors as a result of treatment [58]. Surgery, chemotherapy, and radiation can all contribute to post-treament neuropathy. Chemotherapy-induced neuropathy is a common adverse effect of treatment, and reliable methods to prevent and treat neurotoxicity have not been identified [59]. Sensory alterations are the most common neuropathy.
More severe toxicity leads to pain, burning, and aching sensations that become limiting, this may cause ataxia and gait disturbance in the lower extremities, or clumsiness and diminished dexterity in the upper extremities. Treatment is largely symptomatic control with duloxetine, anticonvulsants, tricyclic antidepressants, and topical anesthetics, although the data is far from conclusive [59]. Radiation effects may be immediately apparent during the course of treatment, including burns or wounds, or may not become apparent for many years after treatment and evolve into fibrosis, joint contractures, and secondary malignancies. Radiation fibrosis is a major contributor to long term disability, and may mimic adhesive capsulitis, rotator cuff pathology, or brachial plexopathy [55,60]. Radiation-associated neuropathy is much less predictable than chemotherapy-induced neuropathy [61].
Brachial plexus neuropathy is increasingly common in breast cancer survivors, and the pathophysiology is thought to be due to microvascular damage combined with long term constrictive fibrosis. The development of radiation-induced neuropathy is directly related to dose delivered. A total dose between 34-40Gy is associated with a neuropathy risk less than 1%, but doses between 43.5-60Gy increase risk to 73%. High fractional doses further contribute to the risk of plexopathy [61]. For head and neck cancers treated with radiation, 14% of patients studied reported symptoms consistent with brachial plexus neuritis [62].
Lymphedema is a chronic condition characterized by retention of interstitial fluid due to impaired lymphatic drainage and venous return. It can contribute to increased limb weight, paresthesias, stiffness, diminished range of motion, and additional emotional difficulties. The overall incidence of lymphedema in the upper extremities of patients with breast cancer is as high as 65% [63,64]. The etiology of lymphedema is multi factorial, from any combination of surgical lymph node dissection and radiotherapy [64,65]. Although incurable, evolving modalities in physiotherapy and manual lymph drainage have been effective in symptom management, and early referral to lymphedema clinics is crucial for cancer survivors [65].

Conclusion
Cancer incidence and cancer survivorship numbers are growing in the United States and worldwide. In addition to the immediate orthopaedic complications of active malignancy, the orthopaedic practitioner should be aware of long-term complications that cancer survivors may manifest. A thorough inventory of the patient's prior diagnoses and treatments will enable the orthopaedic surgeon to properly assess the patient's risk of fragility fractures, joint degeneration, perioperative complications, and likelihood of success prior to surgery or other treatments.
The orthopaedic community must also take an active role in the management of bone density for cancer survivors who may present with complications of osteopenia/osteoporosis several years before routine densitometry is recommended by primary care providers. Any patient with a history of cancer who presents with new complaints of pain, swelling, or a mass should be evaluated more comprehensively. The burden that cancer care places on the orthopaedic community will increase sharply in the coming year, and the practicing orthopaedist must be equipped to handle the complexities of these patients.