Veterinary Society of
Surgical Oncology

ETIOLOGY

  • OSA is occasionally associated with sites of bone pathology or treatment
  • bone pathology includes fractures, chronic osteomyelitis, bone infarcts, bone cysts, multiple cartilaginous exostosis, and OCD lesions
  • bone treatment includes internal fixation of fractures, total hip arthroplasty, and radiation therapy
  • OSA develops within the radiation field of 3.4% dogs treated with external beam radiation therapy for STS and 25% of dogs treated with intraoperative radiation therapy
  • factors involved with fracture-associated OSA include tissue damage from original injury, cellular activity associated with fracture healing, infection, implant corrosion, or electrolysis between dissimilar metals
  • cobalt, cadmium, nickel, and cobalt-chromium-molybdenum alloys induce tumors in animal models
  • polymethylmethacrylate and polyethylene have also been shown to induce tumors
  • development of foreign body sarcoma depends on size and physical and chemical properties of the foreign body
  • sarcomas predictably develop in rats when foreign body > 20 mm in length
  • smooth implant surfaces are more tumorogenic than rough surfaces
  • fracture-associated OSA present differently to spontaneous OSA:
  • 86% of fracture-associated OSA develop in the diaphysis v 5% of spontaneous OSA
  • 49% of fracture-associated OSA develop in the femur v 20% of spontaneous OSA

Radiation-Induced Sarcoma

  • radiation-induced OSA usually associated with high dose-fraction schemes (> 3.5-5.0 Gy/fraction)
  • criteria for radiation-induced OSA:
  • no radiographically detectable lesion prior to radiation therapy
  • OSA in the radiation-field
  • tumor type confirmed histologically
  • long asymptomatic period radiation therapy and tumor detection
  • tumor normally occurs with a low incidence at the site

Miscellaneous

  • viral as OSA has been diagnosed in littermates and induced experimentally when injected into the canine fetus
  • multiple physeal injury (large breed dogs with late closing physes are predisposed), however, microcrack density and length in the proximal humerus and distal radius is not significantly different to other metaphyseal areas and not influenced by either age or body weight, hence cyclic loading and fatigue-induced metaphyseal injury is unlikely to be a causative factor in dogs with OSA

BIOLOGIC BEHAVIOUR

Signalment

  • OSA is the most common primary bone tumor in dogs (85%-98%)
  • OSA is more common in large to giant dog, with dogs < 15 kg accounting for 5% of OSA cases
  • breed predisposition: Scottish Deerhound (genetic), Rottweilers (15% incidence), Irish Wolfhound, Saint Bernard, Great Dane, Doberman, GSD, and Golden Retriever
  • size, particularly height, is more important than breed
  • sex predisposition: male with a male-to-female ratio of 1.1-2.0:1
  • however, males are not over-represented for Saint Bernards, Great Danes, and Rottweilers with appendicular OSA, and dogs with non-rib or non-vertebral axial OSA
  • neutered dogs have 2-fold increase in the risk of OSA compared to sexually intact dogs
  • median age 9 years, but biphasic with 1st age peak at 1-2 years and 2nd peak at 8-10 years

Osteosarcoma Types

Endosteal Osteosarcoma

  • 3 basic types of OSA: endosteal (very common), periosteal, and parosteal
  • endosteal OSA arises from the medullary canal and periosteal and parosteal OSA arises from the periosteum
  • > 90% OSA are monostotic, with multiple (i.e., synchronous or metastatic) lesions reported in 7.8%-9.1% dogs
  • OSA rarely crosses cartilage into or across joints as cartilage provides a barrier due to collagenase inhibitors which may inhibit tumor cell invasion or neoangiogenesis
  • lack of joint involvement differentiates OSA from rheumatoid arthritis, septic arthritis, and synovial cell sarcoma
  • endosteal OSA is subclassified according to predominant mesenchymal component:
  • osteoblastic
  • chondroblastic
  • fibroblastic
  • telangiectatic
  • poorly differentiated
  • OSA subclassifications have no prognostic significance
  • OSA is histologically graded with 4% dogs with grade I OSA, 21% with grade II OSA, and 75% with grade III OSA
  • survival time is significantly decreased in dogs with grade III OSA

Parosteal and Periosteal Osteosarcoma

  • parosteal OSA are less aggressive in humans and associated with a better prognosis with a 10-year survival rate 90%
  • cortical lysis is minimal or inapparent and lesions are well-circumscribed
  • parosteal OSA contain well-differentiated cartilage, fibrous tissue, and bone with sparse sarcoma cells
  • periosteal OSA are less aggressive than endosteal OSA but more aggressive than parosteal OSA with a 70%-80% cure rate in humans

Appendicular Sites

  • OSA is usually located in metaphyseal regions of long bones, but diaphyseal OSA can occur (1.2%)
  • OSA involves thoracic limb sites 1.7-times more commonly than pelvic limb sites
  • thoracic limb sites are generally distant to the elbow:
  • distal radius is the most common site (23.1%)
  • proximal humerus is the 2nd most common site (18.5%)
  • ulna is uncommon (2.6%) with an equal distribution between metaphyseal and diaphyseal sites
  • distal humerus and proximal radius sites are rare (1%)
  • pelvic limb sites are generally towards the stifle, but this rule is less strict than the thoracic limb sites:
  • distal femur (8.5%)
  • distal tibia (8.2%)
  • proximal tibia (7.5%)
  • proximal femur (5.4%)
  • manus and pes OSA (i.e., distal to carpus or tarsus) is uncommon (1.8%)

Metastasis

  • appendicular OSA is a highly malignant tumor with < 15% dogs having clinically detectable metastasis at the time of initial diagnosis, but 75%-90% eventually developing metastatic disease
  • lung metastasis is initially more common, but bone metastasis is more prevalent following treatment with surgery and chemotherapy compared to surgery alone
  • amputation alone: 61% lungs, 5% bone, and 5% both lungs and bone
  • amputation or limb-spare followed by cisplatin: 26% lungs and 47% bone
  • other metastatic sites include regional and distant lymph nodes (6%-37%), kidneys, spleen, myocardium, diaphragm, mediastinum, spinal cord, small intestine, gingiva, and subcutaneous tissue
  • presurgical biopsy does not increase metastatic rate by dislodging tumor cells into the circulation

PALLIATIVE MANAGEMENT

Analgesia

  • marked pain due to extensive destruction of bone and surrounding soft tissue
  • MST 107 days
  • spontaneous regression has been reported in 4 dogs, but this is rare

External Beam Radiation Therapy

  • radiation therapy reduces local inflammation, minimizes pain, slows progression of metastatic lesions, and improves quality of life in dogs and humans with primary and metastatic lesions
  • radiation protocols: 3-4 fractions of 8-10 Gy on days 0, 7, and 21 (± day 14)
  • 50%-92% response rate with a median onset of response 11-14 days after initiation of radiation therapy
  • median duration of response 73-130 days
  • duration of response is significantly improved when < 42%-50% of the bone is involved and with OSA located in the proximal humerus
  • higher cumulative doses, higher intensity of treatment, and the addition of chemotherapy to palliative radiation protocols improves both the response rate and duration of response
  • MST for dogs treated with palliative radiation is 122-313 days

From: Liptak JM, et al: Canine appendicular osteosarcoma: diagnosis and palliative treatment. Compend Contin Educ Pract Vet, 26:172-183, 2004.

Radiopharmaceuticals

  • indications: palliation of bone pain associated with skeletal metastases and spinal lesions
  • advantages: minimal toxicity, cheaper, and local deposition at tumor site
  • samarium ( 153Sm-EDTMP) has best characteristics for bone lesions
  • response is better in primary bone tumors confined within the cortical margins, metastatic lesions < 2cm, and axial tumors
  • large lesions with minimal osteoblastic reaction have poor responses as chelators bind to bone matrix
  • complications include myelosuppression (due to proximity of bone marrow to lesion and sensitivity of proliferating marrow cells to ionizing radiation, peaks at one week and evident for 2-3 weeks), increased ALP activity without hepatocellular damage, increased bone pain after treatment (flare response due to radiation-induced endosseous edema = good prognostic sign), and cystitis

LIMB AMPUTATION

General Considerations

  • limb amputation is the gold standard for the local management of primary bone tumors
  • limb amputation can be performed alone for palliative management of tumor-related pain or pathologic fracture, or in combination with adjuvant chemotherapy for curative-intent treatment
  • absolute contraindication: neurologic disease
  • relative contraindications: osteoarthritis, obesity, and large breed dogs
  • thoracic limb OSA: forequarter amputation
  • pelvic limb OSA: coxofemoral disarticulation for distal pelvic limb lesions and en bloc acetabulectomy for proximal femoral lesions
  •    complications: hemorrhage, infection, and intraoperative air embolism

Functional Outcome

  • dogs with OSA adapt quickly following limb amputation with medium time to maximal adaption 4 weeks
  • speed of adjustment is significantly quicker with a positive reaction from the family
  • speed of adjustment is not associated with body weight, age, or thoracic or pelvic limb amputation
  • change in gait may lead to an increased incidence of orthopedic disease in the remaining limbs
  • thoracic limbs normally bear 60% of body weight and contribute more to the braking phase of the gait whereas the pelvic limbs normally bear 40% of body weight and contribute more to the propulsion phase of the gait
  • thoracic limb amputation results in:
  • remaining thoracic limb bearing 47% of body weight
  • decrease in total stance time in all limbs
  • significant changes in braking and propulsion times in the remaining thoracic limb so that the pelvic limbs do not compensate for the loss of braking force and impulse
  • pelvic limb amputation results in:
  • remaining pelvic limb bearing 26% of body weight
  • no difference in stance and braking times
  • decrease in propulsive forces in the thoracic limbs
  • decrease in the time taken to reach maximal breaking force in the remaining pelvic limb
  • increase in the time taken to reach maximal breaking force in the thoracic limbs
  • forces generated through the opposite limb are greater despite the shift in the centre of gravity
  • thoracic limb amputees have more difficulty in keeping balance in the early postoperative period as the ability to break decreases resulting in loss of coordination
  • pelvic limb amputees have more difficulty in gaining speed
  • behavioural changes occur in 32% dogs, including increased fear, aggression, anxiety, and reduced dominance

Oncologic Outcome

  • MST 101-175 days for amputation alone, with 1-year survival rate 11%-21% and 2-year survival rate 0%-4%
  • dogs treated with amputation alone have a significantly better survival time than palliative management with analgesic drugs or radiation therapy

LIMB-SPARING SURGERY

General Considerations

  • indications: OSA clinically and radiographically confined to the limb and primary OSA < 50% of bone
  • contraindication: pathologic fracture due to contamination of soft tissue, however, contamination can be reduced by neoadjuvant chemotherapy ± radiation therapy
  • degree of bone involvement can be determined by regional radiographs, bone scintigraphy, CT, and MRI
  • regional radiographs either underestimate or overestimate the degree of bone involvement depending on the study
  • lateromedial radiographs overestimate the degree of bone involvement by 17% and craniocaudal radiographs by 4%
  • nuclear scintigraphy overestimates the degree of bone involvement by 14%-30%
  • regional radiographs and nuclear scintigraphy are poorer predictors of bone tumor length as the bone tumor-to-total radius length increases (Leibman et al, Vet Surg, 2001)
  • CT is the most accurate technique when intramedullary fibrosis is taken into account
  • however, CT overestimates the degree of bone involvement by 27%
  • MRI overestimates the degree of bone involvement by 3%
  • non-contrast T1-weighted images provide the best detail of intramedullary tumor extent
  • distal radius is the most amenable site for limb-sparing surgery, and the following techniques have been described:
  • allograft
  • pasteurized and irradiated autografts
  • vascularized autograft
  • endoprosthesis
  • distraction osteogenesis

Cortical Allograft

Surgical Technique

  • fresh-frozen cortical allograft is thawed in a saline solution containing neomycin and penicillin
  • bone tumor is resected with 2-3 cm margins (including extensor muscles) based on preoperative imaging studies
  • proximal bone marrow is submitted for margin evaluation
  • radial carpal bone cartilage is removed to provide a flat surface to abut the cortical allograft
  • cortical allograft is cut to the appropriate size using an oscillating saw
  • cortical allograft is filled with methylmethacrylate
  • cortical allograft is plated to the proximal radius and 3rd or 4th metacarpal bone using a 3.5 mm broad DCP, 4.5 mm broad DCP, or 2.7-3.5 mm modified hybrid plate
  • 2 screws are inserted into the allograft to decrease the number of screw holes and increase strength of the allograft
  • autogenous cancellous bone graft can be used to fill defect between allograft and host bone

Bone Cement Filling

  • polymethylmethacrylate in the medullary canal of the allograft has the following effects:
  • increases maximal cortical screw pullout force and holding strength
  • reduces screw loosening
  • reduces allograft failure
  • polymethylmethacrylate may also augment allograft strength during revascularization and resorption
  • polymethylmethacrylate has the potential to act as a reservoir for antibiotics ± chemotherapy agents
  • however, bone cement may delay allograft healing at both the proximal and distal host-graft interfaces
  • Papineau technique (i.e., filling the allograft with cancellous bone graft) has not been successful in improving the rate of allograft incorporation

OPLA-Cisplatin

  • OPLA-Pt significantly decreases the rate of local tumor recurrence (10% v 25%-28%)
  • OPLA-Pt results in local wound concentration of cisplatin 50-times greater than after systemic administration
  • however, OPLA-Pt also causes local tissue toxicity is seen in up to 30% dogs with less bone formation, and greater degree of inflammation and loss of osteocytes in host bone

From: Liptak JM, et al: Canine appendicular osteosarcoma: curative-intent treatment. Compend Contin Educ Pract Vet, 26:186-197, 2004.

Pasteurized Autograft

  • pasteurized autografts have been described to reconstruct distal radial defects in 13 dogs with OSA
  • distal radius is pasteurized in a sterile saline solution preheated to and maintained at 65ºC for 40 minutes
  • median DFI 255 days
  • MST 324 days, with 12-month survival rate 50%, 18-month survival rate 44%, and 24-month survival rate 22%
  • complications include local tumor recurrence (15%), mild infection (31%), and implant failure (23%)
  • limb function ranges from fair in 8% (1 dog) to good in 92% (12 dogs)

Distraction Osteogenesis

  • regenerate bone is an excellent source of vascularized autogenous bone which rapidly remodels into lamellar bone through a process similar to intramembranous ossification
  • 83-147 days to complete transport of the intercalary segment
  • neoadjuvant radiation therapy significantly inhibits osteogenesis whereas cisplatin and methotrexate do not affect regenerate bone formation during intercalary transport
  • complications: owner compliance in distracting the apparatus 2-4 times per day, implant complications such as pin-tract drainage and loosening, maintenance of an external frame for > 70 days (depending on the size of the radial defect), difficulty in docking the intercalary bone on to the radial carpal bone, necrosis of regenerate bone, and local tumor recurrence (50%)

Microvascular Transfer

  • microvascular transfer of the mid-to-proximal ulna has been described based on the common interosseous vein and artery with a cuff of abductor pollicis longus and deep digital flexor muscles
  • proximal ulnar graft maintains both the nutrient artery and periosteal circulation, whereas distal ulnar grafts only preserve periosteal circulation
  • however, preservation of the nutrient artery and vein is not necessary for successful transfer
  • vascularized autogenous bone is resistant to infection and actively contributes to bone healing
  • other sites for autogenous cortical bone harvest include:
  • proximal ulna (based on common interosseous pedicle)
  • distal ulna (based on caudal interosseous pedicle)
  • medial tibia (based on medial saphenous pedicle)
  • trapezius myo-osseous flap (based on the prescapular branch of the superficial cervical vessels)

Roll-Over Technique

General Considerations

  • distal ulna is rolled into the radial defect based on the caudal interosseous artery and vein and muscular cuff consisting of the pronator quadratus and ulnar head of the deep digital flexor muscles
  • contraindications: ulnar involvement or involvement of the caudal muscles and area surrounding the host vessels

Surgical Technique

  • abductor pollicis longus and pronator quadratus attachments to the periosteum of the ulna are preserved during resection of the distal radius
  • ulna is osteotomized between the articular surface and metaphyseal area which allows the radius and styloid process to be resected en bloc
  • 2nd ulna osteotomy is performed 1-2 mm distal to radial osteotomy
  • preservation of the caudal interosseous artery and vein during radial dissection and ulna osteotomy is important
  • pronator quadratus remains intact proximally but resected distally
  • abductor pollicis longus is sectioned both proximally and distally
  • ulnar head of the deep digital flexor remains intact both proximally and distally
  • ulnar autograft is rolled 90º into the radial defect so that surface of bone exposed between attachments of abductor pollicis longus and ulnar head of the deep digital flexor is in the same plane as the cranial surface of the radius

Functional and Oncologic Outcome

  • caudal interosseous artery and vein can tolerate 90º rotation with minimal risk of disturbing vascular flow as caudal interosseous artery patency is preserved in 83% (10/12) of latex injected limbs and patent vessels are present in the medullary cavity of the ulna autograft in 100% (6/6) of barium sulfate injected limbs
  • limbs reconstructed with cortical allografts are biomechanically superior to ulnar transposition in axial loading, with:
  • 68% greater stiffness
  • 62% greater yield load
  • 60% greater maximum load
  • 30% greater maximum energy
  • 28% greater post-yield energy
  • however, mean yield loads are > 3 times peak vertical ground reaction forces for a normal dog at the trot
  • limbs reconstructed with an ulnar roll-over fail because of cranial plate bending
  • ulnar transposition results in limb shortening by 6%-10% in anatomic studies and 11%-24% in 3 clinical cases
  • limb function is good-to-excellent in 3 clinical cases, with survival times ranging from 84 days to > 241 days

Endoprosthesis

  • endoprosthesis is a surgical steel spacer which is commonly used in human limb-sparing surgery
  • limbs reconstructed with an endoprosthesis are biomechanically superior to cortical allograft-reconstructed limbs in axial loading, with (depending on whether the distal ulna is resected or preserved):
  • 47%-85% greater yield load
  • 41%-61% greater maximum load
  • 64%-133% greater yield energy
  • 26%-33% greater stiffness
  • clinically, there are no significant differences between cortical allografts and endoprostheses with an infection rate of 50%, construct failure rate of 40%, and good to excellent limb function in 80% dogs
  • local tumor recurrence rate was 10% and metastatic rate 60%
  • MST significantly improved by construct failure (685 days v 332 days) and infection (685 days v 289 days)

Limb-Sparing Surgery in Other Appendicular Sites

Humerus

  • limb-sparing of the proximal humerus has been described:
  • craniolateral approach
  • radial nerve and cephalic vein are preserved
  • shoulder joint disarticulated after transecting the transverse band of the intertubercular groove and retracting the biceps brachii muscle
  • tumor is resected with margin of normal deltoid, infraspinatus, teres minor, and brachialis muscles
  • shoulder arthrodesis is performed with an allograft 2 cm shorter than the resected bone to prevent a decrease in the range of motion of the elbow
  • 2nd plate at the distal allograft-host interface
  • pectoral muscles reattached to allograft with non-absorbable sutures
  • mechanical failure with spiral fracture of the distal humerus is a common postoperative complication due to the large lever arm and stress concentration caused by arthrodesis
  • double plating is recommended to reduce the risk of this complication
  • completeness of resection is prognostic for both local tumor recurrence and distant metastases
  • good-to-excellent outcome in only 12% of 17 dogs with proximal humeral OSA

Ulna

  • ulnectomy can be performed below the interosseous ligament without reconstruction and good functional results
  • styloid process can be resected without lateral instability as long as resection is performed close to the carpal bone
  • ulnectomy above the interosseous ligament causes radioulnar instability and elbow joint incongruity

Digit

  • digit amputation is a form of limb-sparing surgery and should include the metacarpal or metatarsal bone
  • proximal ostectomy or disarticulation is recommended to achieve adequate proximal margins
  • lameness can occur with ostectomy at the level of the mid-to-distal metacarpus or metatarsus

Postoperative Management

  • exercise limited for 3-4 weeks but encouraged to reduce foot swelling and flexural contracture of the digits

Complications

Infection

  • 39%-70% infection rate with limb-sparing procedures using cortical allografts
  • infection is more common after healing of the surgical wound, cessation of antibiotic therapy (usually 4 weeks after the chemotherapy course is finished), and in shorter allografts
  • 33% infections occur < 6 months and 67% occur ≥ 6 months after surgery
  • numerous bacterial organisms have been cultured with monomicrobial and polymicrobial infections occurring in approximately 50% dogs
  • cause of infection is unknown but may include:
  • immunosuppression caused by the tumor or treatment (i.e., anesthesia, surgery, and chemotherapy)
  • extensive soft tissue resection with vascular compromise to a poorly perfused site
  • limited soft tissue coverage
  • implantation of orthopedic implants
  • implantation of non-vascularized and possibly immunogenic cortical bone
  • administration of local and systemic chemotherapy
  • infection significantly increases survival time compared to dogs treated with limb amputation or non-infected limb-sparing surgery, probably due to activation of immune effector cells and response to cytokines (i.e., IL-1 and TNF)
  • treatment: antibiotics, antibiotic-impregnated polymethylmethacrylate beads, or limb amputation

Local Recurrence

  • 15%-28% local tumor recurrence rate in the distal radius without OPLA-Pt and 10% with OPLA-Pt
  • 21% local recurrence rate in the proximal humerus
  • local tumor recurrence can be caused by residual microscopic tumor burden in adjacent soft tissue (common) or incomplete resection (uncommon as tumor recurrence rarely occurs at allograft-host interface)
  • local tumor control following limb-sparing surgery is associated with percent tumor necrosis:
  • 91% tumor control with percent tumor necrosis > 90%
  • 78% tumor control with percent tumor necrosis between 80%-89%
  • 30% tumor control with percent tumor necrosis < 79%
  • neoadjuvant chemotherapy and radiation therapy is used in humans prior to limb-sparing surgery to reduce the risk of local tumor recurrence

Orthopedic Failure

  • 11%-60% dogs have implant failure
  • implant failure is often a sequela to infection, but other causes include screw loosening in the allograft during revascularization and resorption phases
  • prevention: polymethylmethacrylate inserted into the medullary canal of the allograft
  • limbs reconstructed with an ulnar roll-over fail because of cranial plate bending
  • limbs reconstructed with a cortical allograft fail because of either caudal plate bending (50%) or fracture of the 3rd metacarpal bone at the distal aspect of the plate (50%)
  • 54% of non-cemented and 60% cemented allografts fail distal to the antebrachiocarpal joint
  • metacarpal bone fracture was significantly more likely if the plate covered < 80% of the metacarpal bone

Other Complications

  • complications reported in humans with limb-sparing surgery include allograft resorption (30%), allograft fracture (19%-28%), and nonunion of the allograft-host bone interface (10%-17%)
  • nonunion occurs in 18% of dogs with limb-sparing surgery using cemented allografts

Prognosis

  • limb function is good-to-excellent in > 80% dogs with limb-sparing surgery of the distal radius
  • distal tibia associated with high rate of mechanical failure and infection due to poor soft-tissue coverage and arthrodesis of the glenohumeral, coxofemoral, stifle and tarsal joints has resulted in fair to poor function
  • MST 266 days, with 12-month survival rate 35% and 24-month survival rate 19%

CHEMOTHERAPY

General Considerations

  • adjuvant chemotherapy significantly improves survival time compared to surgery alone
  • chemotherapy timing is an important consideration in humans with OSA as neoadjuvant chemotherapy significantly increases survival time and provides an indication of tumor responsiveness to chemotherapy
  • however, survival times are not significantly different when chemotherapy is started preoperatively, intraoperatively, or up to 21 days postoperatively in dogs
  • grade 4 toxicities are significantly more likely when chemotherapy is started 2 days compared to 10 days after surgery (35% v 12%)
  • hematology ± urinalysis and renal profile should be performed prior to chemotherapy administration
  • chemotherapy is considered safe to administered when:
  • leukocytes > 3,000/μL
  • platelets > 100,000/μL
  • BUN and creatinine within the reference range
  • USG > 1.030 with no proteinuria or cast

Cisplatin

  • cisplatin is an alkylating agent which binds DNA and produces cross-linkage
  • dose: 50-70 mg/m 2 IV q 3-4 weeks for 2-6 treatments
  • higher cumulative doses and more than 3 treatments have better prognosis
  • aggressive isotonic saline diuresis is required to prevent nephrotoxicosis
  • amifostine reduces nephrotoxicity in humans and allows higher doses to be administered (up to 100 mg/m 2)
  • other adverse effects include nausea and myelosuppression
  • inappetance and decreased activity level is common in the 1st few days after administration

Carboplatin

  • 2nd generation platinum compound with less nephrotoxicity
  • dose: 300 mg/m 2 IV q 3 weeks for 4 treatments

Loboplatin

  • 3rd generation platinum compound
  • dose: 35 mg/m 2 IV q 3 weeks for 4 treatments

Doxorubicin

  • doxorubicin is an antibiotic that intercalates DNA and impairs DNA, RNA, and protein synthesis
  • dose: 30 mg/m 2 IV q 2-3 weeks
  • complications: extravasation causes severe tissue necrosis, myelosuppression, transient hemorrhagic colitis, and cardiac toxicity (cumulative dose > 150-240 mg/m 2 or in predisposed breeds i.e., Doberman, Great Dane, and Boxer)

Other Chemotherapy Protocols

Doxorubicin and Cisplatin

  • 15-30 mg/m 2 doxorubicin and 50-60 mg/m 2 cisplatin on consecutive days q 3 weeks for 4 treatments
  • mechanisms of action of doxorubicin and platinum drugs are different and hence can be used in combination
  • grade 4 toxicities are significantly more likely in dogs treated with doxorubicin at 25 mg/m 2v 12.5 mg/m 2 (67% v 25%)

Doxorubicin and Carboplatin

  • 15-30 mg/m 2 doxorubicin and 175-300 mg/m 2 carboplatin alternating q 3 weeks for 4-6 treatments

OPLA-Cisplatin

  • dose: 80 mg/m 2 implanted at amputation and 30 days postoperatively
  • median DFI 256 days
  • MST 278 days, with 12-month survival rate 41%
  • DFI and MST statistically similar to amputation and 2 intravenous doses of cisplatin

Metronomic Chemotherapy

  • metronomic chemotherapy is the delivery of cytotoxic drugs at low and constant doses to target tumor angiogenesis
  • aim: minimize the growth of primary and metastatic lesions, and prevent the development of new metastases
  • drugs with known antiangiogenic effects include cyclophosphamide, mitoxantrone, NSAID, tamoxifen, doxycycline, bisphosphonates, and paclitaxel
  • tetracycline antibiotics, such as doxycycline and minocycline, act as an MMP-1 inhibitor which inhibits the growth of OSA cells in a time- and dose-dependent manner
  • adverse effects commonly seen with these drugs are usually not encountered due to the low doses administered
  • efficacy of metronomic chemotherapy in dogs is unknown

PROGNOSIS

General Considerations

  • prognostic factors include:
  • body weight: dogs < 40 kg have significantly longer DFI and MST
  • age: dogs < 7 years and > 10 years
  • tumor site: proximal humerus OSA has significantly shorter DFI and MST due to larger tumor volume before diagnosis
  • tumor volume: large tumors have a poor prognosis
  • bone-specific and total ALP
  • percent tumor necrosis
  • histologic grade
  • infection in limb-sparing surgery

Alkaline Phosphatase

  • bone-specific and total ALP are prognostic in dogs with appendicular OSA:
  • preoperative total serum ALP > 110 U/L
  • median DFI 170 days v 366 days
  • MST 177 days v 495 days (or 5.5 months v 12.5 months)
  • preoperative bone-specific ALP > 23 U/L
  • median DFI 147 days v 431 days
  • MST 218 days v 546 days (or 9.5 months v 16.6 months)
  • preoperative increased ALP activity which does not return to reference range within 40 days
  • 100 U/L increase in either total or bone-specific ALP increases risk of tumor-related death by 25%
  • intratumoral ALP is highly predictive of the eventual development of pulmonary metastases
  • preoperative and postoperative bone-specific ALP is significantly associated with tumor recurrence in humans
  • bone-specific ALP may indicate metastatic disease ± response to chemotherapy in dogs

Tumor Necrosis

  • percent tumor necrosis in primary and metastatic lesions following neoadjuvant chemotherapy correlates with response to therapy, metastatic disease, and local tumor recurrence
  • > 90% tumor necrosis is associated with a better prognosis
  • chemotherapy protocol is changed if tumor necrosis is poor as indicates tumor is refractory to neoadjuvant chemotherapy protocol

Infection in Limb-Sparing Surgery

  • infection significantly improves both median MFI and MST, but mechanisms unknown
  • MST 289 days without infection and 685 days with infection

SURGICAL ONCOLOGY

Back to top