Transtumoral plating as a novel method for palliative limb spare and thromboembolism in a dog with a distal radial primary bone tumor

Abstract

A 7-year-old, spayed, female great Pyrenees with a primary tumor of the distal radius was treated with placement of a bone plate that spanned the tumor. The goals were palliation and prevention of pathologic fracture. This is an option for select patients with osteosarcoma.

Introduction

Osteosarcoma is the most common primary bone tumor in dogs with the distal radius frequently affected (1). Traditional treatment for osteosarcoma involves amputation followed by chemotherapy (1); however, some dogs are unable to tolerate amputation. For these dogs, a limb spare procedure can be performed. This procedure is cost-prohibitive for some owners and has a high rate of complication, with infection being most common, but local recurrence and implant failure are also reported (1).

Significant reduction in pain and improvement in function have been observed in human patients when impending or pathologic fractures are treated with stabilization (2,3). Furthermore, there is evidence in murine models that removal of the primary osteosarcoma tumor may allow angiogenesis that induces the progression of pulmonary metastatic disease. The angiogenesis was previously suppressed by the primary tumor (4–7). If, when treating osteosarcoma, the primary tumor can remain in place without causing pain to the patient, it may continue to suppress metastatic spread in certain cases. This may allow for prolonged success of treatment, even with a palliative protocol. Although surgical stabilization of bone tumors is not routinely performed in veterinary medicine, this approach may reduce pain by decreasing the forces that pass through the weakened bone, which may prevent pathologic fracture.

This report describes a novel surgical therapy for a distal radial primary bone tumor in a dog. The aim of the therapy was to control pain locally, preserve limb function, and prevent pathologic fracture. A secondary aim was to evaluate the theoretical concomitant tumor resistance that may occur when the primary tumor is left intact.

Case description

A 7-year-old spayed, female great Pyrenees was presented to the Ontario Veterinary College Teaching Hospital for assessment and treatment of a presumptive osteosarcoma of the left distal radius. The dog had a 3-month history of progressive left forelimb lameness. Radiographs taken by the referring veterinarian on initial examination showed a lytic lesion of the distal radius that was most consistent with a primary bone tumor. The dog was treated with Meloxicam (Metacam; Boehringer Ingelheim, Burlington, Ontario), 0.1 mg/kg body weight (BW), PO, q24h.

A general physical examination and an orthopedic examination revealed that abnormalities were limited to the left forelimb. The dog was minimally weight bearing on the left forelimb. There was a 4-cm diameter, firm swelling over the dorsal aspect of the left distal radius. A complete blood (cell) count (CBC) and serum biochemical profile indicated a mild normocytic, normochromic anemia (hematocrit = 0.37) consistent with chronic disease, and a mild increase in total solids (82 g/L) consistent with mild dehydration.

A 3-view radiographic study of the thorax showed no abnormal findings. Orthogonal views of the left antebrachium (Figures 1 and 2) showed moth-eaten to permeative bone lysis with cortical loss and interrupted irregular periosteal reaction. The zone of transition from normal to abnormal bone was moderate. There was a faint radiolucent line at the distolateral and craniodistal aspect of the radius, which appeared to extend into the antebrachiocarpal joint. The soft tissues overlying the region were moderately thick. The dog was diagnosed as having an aggressive bone lesion of the distal left radius with a probable pathologic fracture. The aggressive bone lesion was consistent with a presumptive diagnosis of an osteosarcoma. The radiolucent line, which extended into the subchondral bone, most likely represented a pathologic fracture.

Figure 1.

Antero-posterior (AP) projection radiograph of the limb at the time of presentation. Note the probable pathologic fracture.

Figure 2.

Lateral projection radiograph of the limb at the time of presentation. Note the probable pathologic fracture.

Whole body bone phase scintigraphy using technetium⁹⁹ indicated focal avid increased radiopharmaceutical uptake in the left distal radius, consistent with the previously diagnosed primary bone tumor. Focal increased activity was noted in the 4th digit of the left thoracic limb and was thought to be consistent with arthritis or metastatic disease. There was focal uptake around the maxillary canine teeth, thought to be consistent with periodontal disease. Radiographs of the left manus showed no evidence of neoplasia in the area corresponding to the increased uptake of radiopharmaceutical.

All options for the treatment of presumptive osteosarcoma were discussed with the owner. These included: amputation +/− chemotherapy, palliative radiation, limb spare surgery, pain control, and euthanasia. Because of the probable pathologic fracture radiographically, a standard limb spare procedure and palliation with pain medication and/or palliative radiation were considered less favorable options. Transtumoral plating of the fracture was discussed with the owner as a novel therapy for the treatment of osteosarcoma. The goal of the procedure was to prevent fracture or further fracture and to decrease the pain associated with force going through the tumoral bone. The owner elected to proceed with a palliative limb spare procedure.

The dog was premedicated with hydromorphone (Sandoz, Boucherville, Quebec), 0.1 mg/kg BW, IM. Anesthesia was induced using ketamine (Ketamine, Sandoz)/diazepam (Diazepam; Sandoz), intravenously. A 14-mm endotracheal tube was placed and anesthesia was maintained with isoflurane. A brachial plexus block was performed using bupivicaine (Marcaine HCl; Hospira, Saint-Laurent, Quebec), 2 mg/kg BW. Cefazolin (Ancef; Apotex, Toronto, Ontario), 25 mg/kg BW, IV was administered pre-operatively and every 90 min during the procedure. The patient was placed in right lateral recumbancy and the entire left forelimb was routinely prepared and draped to the level of the digits. A cranial approach was made to the left radius, carpus, and metacarpal through the skin, subcutaneous tissue, and antebrachial fascia. Extensor tendons were preserved, but were retracted laterally to allow exposure of the radius. A 3.5-mm, 18-hole LC-DCP was applied to the cranial surface of the radius and extended along the fourth metacarpal bone. No screws were placed in the gross confines of the mass (Figures 3 and 4). The bone plate was contoured around the tumor mass. A single core biopsy of the tumor was taken with a Jamshidi needle and submitted for histopathology. Unfortunately, the sample was consistent with reactive bone and a definitive diagnosis was not reached. The site was flushed with sterile physiologic saline and closed routinely in 3 layers. A soft, padded bandage was placed postoperatively.

Figure 3.

Intraoperative photograph showing the cranial approach to the radius and metacarpals and implant placement.

Figure 4.

Intraoperative photograph showing the cranial approach to the radius and metacarpals and implant placement.

Postoperative radiographs showed adequate implant placement and screw purchase in the proximal radius and fourth metacarpal bone (Figures 5 and 6). The patient was allowed to recover in the intensive care unit (ICU) for pain control and supportive care. Intravenous fluids were administered at 1.5 times maintenance rate overnight and then reduced to maintenance rate the following morning. Pain management was provided with fentanyl (Sublimaze; Sandoz) via a CRI of 2 to 6 μg/kg BW/h, meloxicam (Boehringer Ingelheim), 0.1 mg/kg BW, IV, or PO q24h, tramadol (Tramadol powder (Medisca, Saint-Laurent, Quebec), 2 mg/kg BW, PO, q8h, and gabapentin (Apo-Gabapentin; Apotex, Toronto, Ontario), 5 mg/kg BW, q24h after discharge. Cefazolin or cephalexin was administered at a dose of 25 mg/kg BW, q8h, IV or PO, respectively. The dog remained in the hospital for 48 h after surgery. A pamidronate infusion (Pamidronate Disodium Injection; Hospira, Saint-Laurent, Quebec), 1 mg/kg in 500 mL of NaCl was administered on the day of discharge. The patient was discharged with meloxicam and gabapentin, which were to be used for long-term pain control, and a 7-day course each of tramadol and cephalexin (25 mg/kg BW, PO, q8h).

Figure 5.

AP projection radiograph of the limb immediately after surgery.

Figure 6.

Lateral projection radiograph of the limb immediately after surgery.

Immediately after surgery and at the time of discharge, the dog was weight-bearing with moderate lameness. At the time of suture removal 14 d after the surgery, the dog was weight- bearing with mild lameness. The planned course of chemotherapy was alternating doxorubicin and carboplatin. The first dose of chemotherapy was initiated at suture removal and 375 mg of carboplatin (Carboplatin Injection; Hospira), 300 mg/m² was administered IV. The dog returned 25 d later for the second dose of chemotherapy. At this visit, the owner reported that the dog was panting more than usual and had collapsed the previous day. Other than these clinical signs, the owner reported the dog had been doing well at home with good limb use. On physical examination, the dog was quiet and her mucous membranes were pale grey. After resting for several minutes, her mucous membrane color improved to a pale pink.

Auscultation revealed a grade II/VI right mid-thoracic systolic heart murmur and fine pulmonary crackles over the right ventral lung field. Femoral pulses were weak bilaterally, and PCV was 40%. A cardiac ultrasound revealed mild right ventricular eccentric hypertrophy, marked dilation of the main pulmonary artery (PA), and right PA branch, an echogenic mass-like structure in the right PA, mild tricuspid regurgitation with moderately elevated velocity at 4.11 m/s (normal < 2.5 m/s), mild pulmonic insufficiency with elevated end-diastolic velocity at 2.36 m/s (normal < 1.5 m/s), normal pulmonic outflow velocity at 1.06 m/s (normal < 2 m/s), and small underperfused left ventricular cavity (Figures 7A, B, C). Findings were consistent with right pulmonary artery thrombosis causing moderately severe pulmonary arterial hypertension, with pulmonary artery pressure (PAP) estimate of at least 73/22 mmHg (normal < 25/10 mmHg) via the modified Bernoulli equation.

Figure 7.

Echocardiographic images from the initial diagnosis of pulmonary thromboembolism. A — Right parasternal short-axis view at the level of the pulmonary artery. The main pulmonary artery and right pulmonary artery branch are dilated. B — Right parasternal short-axis view at the level of the pulmonary artery. An echogenic mass-like structure is noted in the distal aspect of the right pulmonary artery branch. C — Left parasternal short-axis view at the level of the pulmonary artery. An echogenic mass-like structure is noted in the distal aspect of the right pulmonary artery branch. Ao — Aorta; MPA — main pulmonary artery; RPA — right pulmonary artery; RA — right atrium.

Three-view thoracic radiographs were taken. Findings included abrupt attenuation of the right caudal lobar pulmonary artery consistent with the ultrasound-diagnosed intraluminal mass, and a focal peripherally based alveolar pulmonary pattern in the cranial portion of the left caudal lung lobe consistent with infarction secondary to pulmonary thromboembolism (PTE), hemorrhage, pneumonia, or non-cardiogenic edema. There was no evidence of pulmonary metastatic disease. Further diagnostics and treatment options to assess the thrombus and treat it surgically or with thrombolysis were discussed with the owner. These were declined due to financial constraints and the level of invasiveness. The dog was placed on low-dose aspirin (40.5 mg, PO, q12h) as more aggressive antithrombotics and anticoagulants were also declined. The chemotherapeutic plan was suspended due to the development of the pulmonary arterial thromboembolism.

The dog returned in 8 d and was clinically improved. A repeat cardiac ultrasound was performed. At this time, the clot could not be visualized in the right pulmonary artery and the pulmonary arterial hypertension had improved (PAP estimate 44/13 mmHg). Limb use was good and the dog had mild left forelimb lameness. In light of these findings, the pamidronate and carboplatin were continued.

Despite recommendations, the owner did not return for further treatment or assessment for another 68 d (115 d post surgery). The owner had discontinued the low dose aspirin 1 wk prior to presentation. At that time, the dog was presented for collapse. A single lateral thoracic radiograph was performed. No other views were taken due to the patient’s status. Radiographs showed evidence of widening of the pulmonary arteries. There was no evidence of pulmonary metastasis. Findings from a cardiac ultrasound included moderate right atrial and right ventricular eccentric hypertrophy, flattening of the interventricular septum at end-systole indicating elevated right ventricular pressure, marked dilation of the main PA and right PA branch, absence of a visible pulmonary thrombus, a small underperfused left ventricle, and evidence of severe pulmonary arterial hypertension (PAP estimate 85/25 mmHg). Differential diagnoses at that time included a recurrence of pulmonary thromboembolism or progression of pulmonary arterial hypertension from the unresolved previous episode. Aspirin was reinstituted at the same dose. Sildenafil (Viagra; Pfizer, Kirkland, Quebec), 25 mg, PO, q12h was initiated for the treatment of pulmonary hypertension. Ongoing pain management included meloxicam and tramadol.

Despite recommendations, the dog was not reassessed again until 130 d after surgery when she was presented with a progressive left forelimb lameness of 2 wk duration. A recheck cardiac ultrasound revealed normal right and left-sided chamber sizes, normal PA size, and near resolution of pulmonary artery hypertension (PAP estimate 37/10 mmHg). Radiographs of the left antebrachium showed that the neoplastic lesion had progressed in size and was primarily lytic, with severe lysis involving the caudal radial cortex. The distal 3 screws had pulled out of the bone and the fourth most distal screw was broken. The fifth most distal screw was the only screw remaining engaged in the bone distal to the tumor (Figures 8 and 9). Amputation or euthanasia was recommended at this time. The owner declined these options. The dog was treated with a dose of palliative radiation to the site (single dose of 8 Gy using a Cobalt radiation unit) and another dose of intravenous pamidronate. The limb was splinted to improve comfort and prevent catastrophic fracture. The instructions to the owner were to return to our hospital or to the referring veterinarian for reassessment or splint changes every 7 d. The owner returned to our hospital at 137, 157, 173, and 179 d post surgery. The owner reported at those visits that the dog appeared comfortable on the limb and that she was eating, but had a decreased appetite. During these visits, the dog appeared to be comfortable and was using the limb in the splint. The dog’s weight decreased from 46.4 kg at first presentation to 38.4 kg at the last presentation. At 228 d post surgery, the referring veterinarian reported that the dog was not eating and was too weak to stand. The dog was euthanized 237 d post surgery. Unfortunately, a postmortem examination was not done.

Figure 8.

Lateral projection radiograph of the limb 130 d after surgery, at the time of implant failure.

Figure 9.

AP projection radiograph of the limb 130 d after surgery, at the time of implant failure.

Discussion

This case report represents both the first reported case of palliative limb spare in a dog with a distal radial primary bone tumor and a case of pulmonary arterial thromboembolism and pulmonary hypertension in a dog. Palliative limb spare is a novel method of managing canine osteosarcoma. The goals of this technique are to provide a cost-effective and accessible method of pain management for distal radial osteosarcoma and to decrease the risk of pathological fracture. A secondary goal of this therapy was to evaluate the theory that maintenance of the primary tumor may suppress the progression of metastatic disease in clinical cases of canine osteosarcoma. This process is termed concomitant resistance. Although the exact mechanism has not been elucidated, it is generally accepted that the primary tumor may suppress metastatic proliferation by the suppression of angiogenesis. There is experimental evidence of concomitant resistance in rat models of osteosarcoma and in human studies of osteosarcoma (4–7).

In this case, limb use and comfort were improved for 115 to 130 d after surgery. A pathologic fracture was suspected preoperatively. Although this time frame falls short of the expected pain relief and survival in dogs with osteosarcoma treated with standard therapy, the provision of 4 mo of limb use and pain relief is a success in the context of this case. Implant failure in this case resulted from screw pullout and screw breakage, which may have been avoided by the use of a locking plate and screws. Screws were not placed in the tumor bone because it seemed unlikely that they would provide significant holding power in the lytic tumor bone. This resulted in multiple open screw holes that could have been a potential site of stress concentration and failure. This may be avoided in the future by placing plugs in the holes of a locking plate or by developing a purpose-built locking plate that does not have screw holes over the distal radius.

This dog had no evidence of pulmonary metastasis at 115 d post surgery in a single lateral radiograph, and euthanasia and death occurred 237 d after surgery and 327 d after initial diagnosis. The exact cause of this patient’s demise is unknown. Differential diagnoses include: progressive pulmonary hypertension and thromboembolic disease, local pain causing inappetance and generalized weakness, or pulmonary and/or bone metastasis, or a combination of these conditions. A survival time of 237 d is within the realm of longevity for cases of osteosarcoma that are treated with standard therapy (1). Standard therapy for osteosarcoma would include limb amputation and full-course chemotherapy. This patient appeared to have had a good quality of life for 115 d post surgery (175 d from initial diagnosis). This is a reasonable expectation for a palliative procedure. Unfortunately, this owner was noncompliant and did not follow recommendations when the implant failed.

Human cancer patients have an increased risk of developing thromboembolic disease (8,9). Reported risk factors in human cancer patients include: immobilization, surgery, chemotherapy, radiation therapy, adjuvant hormone therapy, and central venous catheters (8). Cancer growth is associated with a hypercoagulable state. The mechanisms for this involve tumor specific clot-promoting mechanisms resulting from the prothrombotic properties expressed by tumor cells. Tumor cells produce procoagulant factors, proinflammatory and proangiogenic cytokines, and interact directly with endothelial cells and leukocytes (8,9). Although rare, pulmonary arterial embolic disease is a reported syndrome in adult and pediatric cases of osteosarcoma and sarcoma in humans (10–20). Reports from the human literature have cited both cases of tumor emboli in the pulmonary arterial system and thromboembolic events (10–20). Risk factors that have been identified in pediatric cases of sarcoma with thromboembolic disease include: malignancy, large tumor mass, large tumor burden (metastasis), indwelling venous access devices and dysfunction of these devices, intensive chemotherapy, surgery, limited mobility, tumor compression, pulmonary disease, older patients (adolescents versus children) and Ewing’s sarcoma compared with other sarcoma types (19,20). For the cases of documented tumor emboli in the pulmonary arterial system, no predisposing factors have been identified. In the cases reported in the human literature that were treated, the tumor embolism was successfully removed surgically using cardiopulmonary bypass in 3 cases (11–12). The syndrome caused fatality in 6 reported cases (13–16) and is considered a rare event in the human literature.

It is not known in this case if the mass that was visualized in the pulmonary artery was a tumor embolus or a true embolic event. However, the fact that it was not visualized on repeat ultrasound 8 d after diagnosis suggests that it was a true thromboembolus, rather than a tumor embolus. In cases of tumor emboli related to osteosarcoma in the human literature, the tumor embolus was either removed surgically or caused fatality (10–16). Resolution of the disease is more consistent with a clot compared with a tumor embolus. Although the incidence of embolic disease in this dog begs the question of whether or not the palliative limb-spare procedure increased the risk of pulmonary thromboembolism, there does not appear to be a direct cause and effect of the procedure and the development of thromboembolic disease. It is, however, possible, that the maintenance of the primary tumor intact may lead to a state of increased risk of embolic disease, either by a true hypercoagulable state, or by the development of tumor emboli within the pulmonary arterial vessels.

Thromboembolic disease in cancer patients is commonly managed with low molecular weight heparin (18). This had been recommended in this case, but due to financial constraints was declined. The dog was managed with low-dose aspirin and, after the second episode of collapse and pulmonary hypertension, with sildenafil (Viagra). Sildenafil has recently been reported to be beneficial in the management of PTE and pulmonary hypertension in human patients (21). Despite the severity of this dog’s clinical signs and the relatively nonaggressive treatment course for the pulmonary arterial thrombosis and pulmonary hypertension, this dog was managed successfully with this syndrome for 122 d. It is difficult to directly determine the impact that the prescribed medications had on the course of disease; however, it is worth noting that PAP was near normal at the last available echocardiographic examination.

Despite repeated discussions at the time of implant failure, this owner was unwilling to proceed with euthanasia or amputation of the limb. In this setting, splinting the limb and the addition of other palliative measures such as palliative radiation and pamidronate appeared to be the best way of helping this patient, but were far from ideal. Amputation at the onset of therapy would have obviated the need for the plating procedure. However, the owner was unwilling to proceed with amputation during initial and consequent discussions of treatment recommendations.

Palliative radiation was not part of the planned protocol for this case. This is primarily because this was considered a pilot case in an ongoing pilot study at the University of Guelph. The intent of the development of this procedure was to create a relatively low cost and easily accessible palliative treatment for dogs with distal radial osteosarcoma. The availability of radiation therapy is location dependent. This treatment modality was not included at the onset because the authors wanted to assess the effect of the surgical procedure without the addition of palliative radiation. It is not known if the concomitant tumor resistance effect of leaving the primary tumor intact has clinical application in dogs with osteosarcoma. Ideally, this effect could be established first before adding palliative radiation as an additional variable. There is, however, validity to combining multiple methods of palliation for a synergistic effect when treating bone tumor pain. A protocol that includes palliative limb spare, palliative radiation, full course chemotherapy, and systemic analgesics should be considered.

Unfortunately, a histologic diagnosis was not achieved from the surgical biopsy. As well, the owner declined a postmortem examination after euthanasia. Because of this, the primary bone tumor was not definitively diagnosed as an osteosarcoma. However, given the signalment, radiographic signs, and clinical picture, osteosarcoma was the presumptive diagnosis in this case.

Palliative limb spare is a novel method for the treatment of osteosarcoma in dogs that is currently being developed by the primary author for osteosarcoma of the distal radius. This technique shows promise as a palliative method of reducing bone tumor pain and preventing pathologic fracture. A secondary benefit of maintaining the primary bone tumor is that it may also suppress metastatic disease. The use of a locking plate or the development of a purpose-made locking plate without screw holes over the distal radius may help to improve success in future cases. Pulmonary thromboembolism and hypertension has not been previously reported in dogs with primary bone tumors; however, this syndrome is recognized in human osteosarcoma and sarcoma cases. The novel surgical technique does not appear to be a causative factor in the development of PTE. The maintenance of the primary tumor, however, may increase the risk of this rare complication. Further investigation into this novel technique is currently underway at the University of Guelph. CVJ