Fig. 1 PET/CT scan of a 61-year-old female whose breast cancer has metastasized to her spine.
Courtesy of Margaret M. Baker, MD

AAOS Now

Published 1/1/2015
|
Margaret M. Baker, MD

Managing Sex-Based Metastatic Malignancies

Aside from skin cancer, breast cancer and prostate cancer are the most common malignancies among women and men, respectively, in the United States. New cases exceed primary bone and joint cancers by a 163:1 ratio. Although orthopaedic surgeons may see few primary bone cancers during their careers, they should expect to see metastatic disease frequently.

Lifetime personal probability for the development of invasive breast cancer in females is 1:8; for invasive prostate cancer in males it is 1:6. Metastatic disease spreading to bone frequently occurs with both breast and prostate cancers. Due to improvements in early diagnosis and treatment, patients with these cancers are living longer. However, sex-based malignancies and their associated treatments cause numerous deleterious effects on bone.

Orthopaedic surgeons, therefore, should be prepared to see more breast and prostate cancer survivors with musculoskeletal involvement. They also need to be familiar with the effects of current antihormone, chemotherapy, and radiation therapies on bone, and to understand the indications and techniques for surgical stabilization.

Presentation
Metastasis to bone develops in more than 50 percent of cancer patients by the end of life. Patients with bone metastasis generally see an orthopaedic surgeon due to pain. That’s because tumor erodes and weakens bone, impairing its ability to resist force. Overstrained, mechanically insufficient bone may translate as pain to the patient.

When structural failure occurs, a pathologic fracture ensues. For adults older than age 45, metastatic carcinoma is most probable with a destructive bone lesion. Work-up includes a history and physical, with special attention to identifying a primary tumor site. Laboratory work-up may be helpful, including such tumor markers as prostate specific antigen (PSA) for prostate cancer and CA 15-3, CA 27, and CA 29 for breast cancer.

Multiple breast cancer susceptibility genes have been identified including BRCA1 and BRCA2. Breast cancer is classified by subtype based on tumor expression of estrogen and progesterone receptors. Prostate cancer genetics and androgen receptor status research has produced less clear findings, although serum PSA is a widely available screening and diagnostic test.

Plain orthogonal radiographs of the entire involved bone are vital for planning and predicting pathologic fractures. A Technetium-99 whole-body bone scan to image the skeleton is very sensitive and may detect remote sites of metastatic disease. Chest, abdomen, and pelvic computed tomography (CT) with contrast are elements of the work-up for an unknown primary malignancy. CT-guided percutaneous biopsy can be diagnostic, with less morbidity compared to open biopsy. Positron emission tomography (PET)/CT highlights tumor metabolic activity (Fig. 1).

Surgical biopsy considerations
An accurate histologic diagnosis remains critically important in managing these patients. If the patient has a known primary and metastatic disease, then no new biopsy may be necessary. Importantly, lesions that are suspected to be a primary malignancy of bone should be referred to an orthopaedic oncologist for staging and biopsy.

The optimal approach is a coordinated presurgery strategy involving the orthopaedic surgeon, medical oncologist, radiation oncologist, pathologist, internist, radiologist, and other surgical specialists such as the urologist and general surgeon. If the patient has a pathologic fracture requiring stabilization, open biopsy may be performed just prior to fixation or reconstruction of the fracture.

Tumor effects on the skeleton
Primary malignant tumor cells proliferate at their site of origin and invade capillaries or lymphatics, before disseminating to distant sites including bone. Tumor cells destroy bone indirectly by producing cytokines to stimulate osteoclastic resorption. Osteoblasts normally secrete receptor activator of nuclear factor kappa-B ligand (RANKL), which in turn stimulates osteoclasts.

With tumor seeding, mechanical properties of bone may deteriorate leading to bone pain, decreased skeletal strength at physiologic loads, and ultimate structural failure (pathologic fracture). Breast cancer cells may also secrete other osteoclast stimulants (interleukin [IL]-6 and IL-8). Prostate cancer cells can secrete Endothelin-1, which stimulates osteoblasts to produce bone, resulting in the classic blastic appearance of prostate bony metastases.

Treatment-associated bone loss
Oncologic therapy for breast or prostate cancer patients commonly consists of chemotherapy and/or endocrine therapy, both of which increase the risk of bone loss and fracture. Sex hormone deprivation is a primary goal of breast and prostate cancer treatment because it targets hormone-sensitive tumors. Sex hormone deprivation may be achieved by surgical ablation, hormone synthesis inhibition, or receptor blockade.

Fig. 1 PET/CT scan of a 61-year-old female whose breast cancer has metastasized to her spine.
Courtesy of Margaret M. Baker, MD
Fig. 2 Serial radiographs of a 75-year-old male with breast cancer and symptomatic bony metastases. A lytic lesion (left) and progression to pathologic fracture (center). Postoperative image after surgical stabilization with an intramedullary rod (right).
Courtesy of Dieter Lindskog, MD

Estrogen or testosterone deficiency results in systemic bone loss with increased risk for osteoporosis and fragility fractures. Other cancer therapies—including methotrexate, prednisone, vincristine, cyclophosphamide, doxorubicin, ifosafamide, cisplatin, and radiation therapy—also have known deleterious effects on bone.

Systemic bone antiresorptive therapy works against osteoclast-mediated bone destruction and has become a mainstay of treatment for patients with metastatic breast and prostate cancer. The goals of antiresorptive treatment in prostate and breast cancer patients include the following:

  • prevent bone destruction
  • relieve metastasis-related bone pain
  • decrease the risk of hypercalcemia of malignancy
  • prevent pathologic fracture
  • improve short- and long-term quality of life

Antiresorptive agents consist of two classes of drugs: diphosphonates and biologics. The newest bone antiresorptive therapy is a biologic agent, the monoclonal antibody to RANKL (eg, denosumab). Antiresorptive therapy effectively mitigates decreases in both bone density and the rate of skeletal-related events for these patients.

Surgical interventions and complications
Before recommending surgical intervention to a patient with breast or prostate cancer and symptomatic bony metastases, the orthopaedic surgeon must confirm that the patient is an appropriate surgical candidate. Factors to take into consideration include life expectancy, medical fragility, relevant comorbidities (eg, hypercalcemia, coagulopathy, nutritional status, bone marrow suppression, cardiopulmonary function, and timing of radiation therapy), quality of life, and symptom severity.

The orthopaedic surgeon also needs to be able to identify lesions requiring prophylactic stabilization, to perform stabilization and/or reconstruction of pathologic fractures in long bones, and to decompress and stabilize the spinal column in the setting of instability and/or compression resulting from metastatic disease. The Mirels scoring system remains a commonly used tool to predict the risk of pathologic fracture in patients with metastatic bone disease.

Once surgical stabilization is indicated and the patient is medically optimized, the orthopaedic surgeon should choose an implant that enables rapid return of immediate weight bearing and optimization of function. An implant that protects the entire involved bone and that will exceed the patient’s life expectancy without fatigue failure generally achieves this goal. Typically long, locked intramedullary nails are chosen (Fig. 2). Open reduction internal fixation or megaprosthetic reconstruction may be required for peri-articular pathologic fractures. Augmentation of the surgical construct with polymethylmethacrylate cement may also be useful.

Orthopaedic surgeons should keep in mind that cancer patients, especially those with metastatic disease, are at higher risk for surgical complications. These include venous thromboembolism, wound complications, infection, nonunion, implant failure, and radiotherapy-related osteonecrosis.

Conclusion
Using a team approach to optimize the patient’s nutritional, hematologic, and medical status is key to improving outcomes. These challenging orthopaedic patients often understand that their remaining time with family and quality of life is precious. Thus the role of the orthopaedic surgeon is to improve and enhance the quality of life. The resultant experience with this special group of patients may be very rewarding to the orthopaedic surgeon.

Margaret M. Baker, MD, is a member-at-large of the AAOS Women’s Health Issues Advisory Board. She can be reached at drbaker@cbjs.org

Bottom Line

  • Breast and prostate cancers are common, and survivorship is increasing.
  • Oncologic treatment of sex-based malignancies can negatively affect bone.
  • Tumor cells destroy bone through an RANKL-mediated pathway.
  • Antiresorptive agents can decrease skeletal adverse events in patients with breast cancer who have CA tumor markers.
  • The Mirels score helps guide surgical decision making in patients with metastatic bone disease.
  • Treatment goals for patients with metastatic disease are relief of pain and rapid restoration of function.
  • Treatment should be multidisciplinary and tailored to the individual patient.

Putting sex in your orthopaedic practice
This quarterly column from the AAOS Women’s Health Issues Advisory Board and the Ruth Jackson Orthopaedic Society provides important information for your practice about issues related to sex (determined by our chromosomes) and gender (how we present ourselves as male or female, which can be influenced by environment, families and peers, and social institutions). It is our mission to promote the philosophy that male and female patients experience and react to musculoskeletal conditions differently; when it comes to patient care, surgeons should not have a one-size-fits-all mentality.

References:

  1. Cancer Facts & Figures 2013. American Cancer Society. Atlanta, ACS 2013.
  2. Clarke CA, Keegan TH, Yang J, Press DJ, Kurian AW, Patel AH, Lacey JV Jr: Age-specific incidence of breast cancer subtypes: Understanding the black-white crossover. J Natl Cancer Inst 2012;Jul 18;104(14):1094-1101. doi: 10.1093/jnci/djs264. Epub 2012;Jul 5. PMID: 22773826
  3. Brawley OW, Barnes S: The epidemiology of prostate cancer in the United States. Semin Oncol Nurs 2001;May;17(2):72-77.
  4. Office of Special Populations Research, National Cancer Institute/National Institute of Health, 6120 Executive Blvd, Executive Plaza South, Suite 320, Rockville, MD 20852, USA.
  5. Galasko CSB: Mechanisms of bone destruction in the development of skeletal metastases. Nature 1976; 263: 507-508.
  6. Mirels H: Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 2003, 415S: S4-S13.