Associate Professor (Surgical Oncology), Department of Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
Bone cancer pain is a distinct pain entity that has been studied most extensively in murine models. These bone cancer pain models have suggested that bone cancer pain causes sensitization of the peripheral and central nervous system and that the cause and modulation of this pain state is distinct from both neuropathic and inflammatory pain. The exact cause of bone cancer pain is not well understood and it appears to be multifactorial. Osteoclast-mediated osteolysis plays a major role in the development of bone cancer pain and osteoclast proliferation and hypertrophy is stimulated by the tumor. Osteoclasts contribute to bone cancer pain, both by the direct effects on the bone structure and by neurochemical effects. Bone destruction can lead to stimulation of mechanoreceptors and pain receptors in the periosteum and medullary cavity with mechanical stress, pathological fracture and microfracture, through direct compression of the sensory neurons that innervate the medullary canal, and through neurochemical effects. Osteoclasts and tumor cells create an acidic microenvironment that is permissive to bone resorption. Cell apoptosis from the tumor will contribute to this acidic pH. This stimulates acid-sensing channels in sensory neurons in bone. Osteolysis by osteoclasts also leads to release of growth factors from the bone that may directly activate pain fibers that innervate bone. Cancer cells and macrophages in the tumor also release prohyperalgesic factors which excite primary afferent neurons. As perceived by the patient, there are two types of pain that are felt. One is ongoing, background pain, which is a constant, dull, throbbing pain. The other is breakthrough pain, which is reported to be intense, severe pain that is often induced by movement or weight bearing on the affected area.
Because the causes of bone cancer pain are multifactorial, strategies to treat this pain in a palliative setting should be multimodal. Common strategies employed in the treatment of human bone cancer pain include analgesics, tumor ablation through radiation and chemotherapy, inhibition of osteolysis and mechanical support. With the exception of mechanical support, these strategies have also been adopted in the palliative management of bone cancer pain.
When assessing a veterinary patient with cancer, there are two pieces of information that must be obtained from the owner. The first is the owner's goals of therapy. It is important that the goals are realistic, given the diagnosis, concurrent disease and stage of disease, and that they are clearly stated. The owner must choose either a palliative or curative intent path of treatment. The second important piece of information in determining treatment options is to assess the owner's obstacles or limitations of certain treatment options. The obstacles can include financial limitations, time limitations, risk-averse clients, refusal of amputation for patient or client reasons, and clients averse to invasive treatments.
Reasons for palliative treatment of bone cancer in dogs usually include finances, inability to amputate, the presence of metastatic disease, and personal beliefs. Often the client perception that amputation is too much to "put their dog through" are unfounded and it is important to communicate to owners the paradox of this sentiment, as, in most dogs, amputation is a fast route towards the complete elimination of bone tumor pain, and is generally well-tolerated. There are also cases where palliation is not possible without surgery. This would be cases of pathological fracture or impending pathological fracture. In these cases, amputation is recommended, but surgical stabilization may be part of the palliative treatment protocol in cases where amputation is not accepted. For cases where a palliative course of treatment is selected, there are several options available. Management of bone cancer pain through more than one mechanism and modality is more likely to result in improved comfort compared to any one modality on its own.
Pain medication is the first line of treatment for bone cancer pain. If well-tolerated, NSAIDs should be the initial drug of choice for long-term management of bone cancer pain. Adjuvant analgesics, such as gabapentin, have been shown to help to mitigate the neuropathic component of bone cancer pain. Opioids are frequently used in the management of bone cancer pain in humans and animals. However, their use is somewhat controversial. In murine models comparing the dose of morphine required for the treatment of inflammatory pain and bone cancer pain, 3–10x more morphine was required to treat bone cancer pain. Again in murine models, there has been recent data to suggest that chronic morphine administration may also contribute to breakthrough pain and osteoclast-induced osteolysis. Translated into practice in human patients with metastatic cancer to bone, this means that extremely high doses of morphine are required to treat this pain, which results in severe opioid side effects that can affect quality of life. As well, morphine is thought to manage the ongoing pain component of bone cancer pain, but is not very effective at managing breakthrough pain. Current research in murine models of bone cancer pain are focused on determining the mechanism of this distinct pain entity to allow the development of analgesics that can treat bone cancer pain more effectively.
Palliative radiation is the second mainstay of the palliative treatment of appendicular osteosarcoma in dogs. Radiation is a common method for the palliation of bone cancer pain in human and animal cancer patients. It is a very effective method for treating bone cancer pain. The exact mechanism of pain relief is not known. However, it is probably a combination of a decrease tumor burden and a decrease in inflammatory cells. As in people, canine patients have a high reported response to palliative radiation (74–96%). Duration of pain relief in dogs varies from 1.8–4.3 months. The optimal protocol for palliative radiation in dogs is not known. Most published protocols for canine osteosarcoma use an 8 Gy dose given at weekly intervals for 2–4 treatments. The most common protocol is given at days 0, 7 ± 14 and 21. To date, there are no studies in canine patients to indicate which protocol is superior. In human patients, a recent study showed no difference in efficacy between single large doses of radiation versus more fractionated protocols. A further problem in our patients is that the response rate is generally measured by the owner. Further, duration of effect and/or survival times are based on when the owner elects to stop treatment. Although this will be a reflection of the patient's pain control, it is not an objective measure of pain relief and the placebo effect of radiation, coupled with the owner's desire not to euthanize their pet, may falsely increase reported response rates and survival times. These responses could therefore be an inaccurate reflection of our ability to control pain in our patients with radiation. There are currently few studies that use objective measures, such as force plate analysis to evaluate the efficacy of palliative radiation in dogs with appendicular osteosarcoma. Weinstein et al. have specifically evaluated this method to evaluate dogs that are treated with palliative radiation. Further studies with objective measures are necessary to determine both the efficacy of palliative radiation in general and the optimal protocol.
Bisphosphonates are a class of drugs that are osteoclast inhibitors. They are used in both human and veterinary medicine to treat bone cancer pain via inhibition of bone resorption and mechanical stabilization. Pamidronate was recently reported as the sole treatment in a clinical trial by Fan et al. for palliation in 43 dogs with osteosarcoma, with 12/43 (28%) having pain relief associated with this medication. A second study by Fan et al. that used force-plate analysis did not show a difference in efficacy in dogs with appendicular osteosarcoma treated with radiation and chemotherapy with and without pamidronate. In humans, there is a moderate pain relief seen in 50% of patients. However, newer generation bisphosphonates are used much more commonly in palliation of bone cancer pain in human cancer patients. The primary limitation in the use of new generation bisphosphonates, such as zoledronate, in our patients is cost. A recent retrospective study of canine patients with appendicular primary bone tumors treated with palliative radiation by Oblak and Boston showed that the addition of pamidronate to the protocol to be a significant and independent negative prognostic indicator. Although this finding is somewhat counterintuitive, it is possible that there is a negative interaction between radiation and bisphosphonate use. Other studies have shown a synergistic effect. It may be that the timing of bisphosphonate administration and palliative radiation therapy is important. Bisphosphonates require time to become incorporated into bone. One study in murine models has shown that a synergistic effect is only seen when pamidronate is given 3–6 days before palliative radiation and that this effect is not seen when they are given concurrently.
The addition of chemotherapy to palliative radiation protocols is controversial, with some studies reporting an increase in the response rate and duration of effect with chemotherapy and other studies reporting no effect. Direct killing of tumor cells by the chemotherapeutic agent has been reported to have an analgesic effect in people when preoperative neoadjuvant chemotherapy is administered for osteosarcoma. Systemic chemotherapy will be useful in cases of palliative radiation to suppress metastatic disease. This will be helpful in cases that have had a positive and durable response to local therapy.
Mechanical stabilization is employed regularly to treat people with impending pathological fracture due to metastatic bone cancer. This approach is not regularly employed in veterinary medicine, but has been reported as a case report by this author recently in a dog with a distal radial osteosarcoma. As well, a VSSO retrospective study has recently reported 16 dogs with pathological fracture with bone sarcoma that were treated with fracture stabilization. With the advent of MIPO (minimally invasive plate osteosynthesis), stabilization of appendicular fractures or primary bone tumors is an area that warrants further consideration and study.
An optimal palliative approach to bone cancer in dogs would treat the bone cancer pain by multiple modalities, while still aiming to suppress metastatic disease.
1. Bacci G, Picci P, Ferrari S, et al. Neoadjuvant chemotherapy for the treatment of osteosarcoma of the extremities: excellent response of the primary tumor to preoperative treatment with methotrexate, cisplatin, adriamycin, and ifosfamide. Preliminary results. Chir Organi Mov. 1995;80(1):1–10.
2. Boston SE, Bacon NJ, Culp WT, et al. Outcome after repair of a sarcoma-related pathological fracture in dogs: a Veterinary Society of Surgical Oncology Retrospective Study. Vet Surg. 2011;40(4):431–437.
3. Boston SE, Barry M, O'Sullivan LM. Transtumoral plating as a novel method for palliative limb spare and thromboembolism in a dog with distal radial primary bone tumor. Can Vet J. 2011;52:650–655.
4. Clohisy DR, Mantyh PW. Bone cancer pain. Cancer. 2003;(Suppl) 97;866–873.
5. Dernell WS, Ehrhart NP, Straw RC. Tumors of the skeletal system. In: Withrow SJ, Vail DM, eds. Small Animal Clinical Oncology. 4th ed. St. Louis, MO: Elsevier Health Sciences; 2007:540–582.
6. Fan TM, de Lorimer LP, O'Dell-Anderson K, et al. Single-agent pamidronate for palliative therapy of canine appendicular osteosarcoma bone pain. J Vet Intern Med. 2007;21:431–439.
7. Fan TM, Charney SC, de Lorimier LP, et al. Double-blind placebo-controlled trial of adjuvant pamidronate with palliative radiotherapy and intravenous doxorubicin for canine appendicular osteosarcoma bone pain. J Vet Intern Med. 2009;23(1):152–160.
8. Goblirsch MJ, Zwolack P, Clohisy DR. Biology of bone cancer pain. Clin Cancer Res. 2006;12:6231s–6235s.
9. Goblirsch MJ, Zwolack P, Clohisy DR. Advances in understanding bone cancer pain. J Cell Biochem. 2005;96:682–688.
10. Green EM, Adams WM, Forrest LJ. Four fraction palliative radiotherapy for osteosarcoma in 24 dogs. J Am Anim Hosp Assoc. 2002;38:445–451.
11. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short-versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97:798–804.
12. Honore P, Mantyh PW. Bone cancer pain: from mechanism to model to therapy. Pain Med. 2000;1:303–309.
13. King T, Vardanyan A, Majuta L, et al. Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer. Pain. 2007;132(1–2):154–168.
14. Luger NM, Mach, DB, Sevcik MA, et al. Bone cancer pain: from model to mechanism to therapy. J Pain Symptom Manage. 2005;29(5S).
15. Mayer MN, Grier CK. Palliative radiation therapy for canine osteosarcoma. Can Vet J. 2006;47:707–709.
16. McEntee MC, Page RL, Novotney CA, et al. Palliative radio-therapy for canine appendicular osteosarcoma. Vet Radiol Ultrasound. 1993;34:367–370.
17. Mueller F, Poirier V, Melzer K, et al. Palliative radiotherapy with electrons of appendicular osteosarcoma in 54 dogs. In Vivo. 2005;19:713–716.
18. Perez CA, Brady LW, Halperin EC, et al. Principles and Practice of Radiation Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.
19. Peters CM, Ghilardi JR, Keyser CP, et al. Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Exp Neurol. 2005;193:85–100.
20. Ramirez O III, Dodge RK, Page RL, et al. Palliative radiotherapy of appendicular osteosarcoma in 95 dogs. Vet Radiol Ultrasound. 1999;40:517–522.
21. Oblak M, Boston SE, Higginson G, et al. The impact of pamidronate and chemotherapy on survival times in dogs with appendicular primary bone tumors treated with palliative radiation therapy. Vet Surg. 2012;41(3):430–435.
22. Vassiliou V, Kardamakis D. The management of metastatic bone disease with the combination of bisphosphonates and radiotherapy: from theory to clinical practice. Anticancer Agents Med Chem. 2009;9:326–335.
23. Weinstein JI, Payne S, Poulson JM, et al. Use of force plate analysis to evaluate the efficacy of external beam radiation to alleviate osteosarcoma pain. Vet Radiol Ultrasound. 2009;50(6):673–678.