Treatment of Canine Appendicular Osteosarcoma Using Cobalt 60 Radiation and Intraarterial Cisplatin

Heidner, G. L., Page, R. L., McEntee, M. C., Dodge, R. K. and Thrall, D. E. (1991), Treatment of Canine Appendicular Osteosarcoma Using Cobalt 60 Radiation and Intraarterial Cisplatin. Journal of Veterinary Internal

                                                                                                             Medicine, 5: 313–316. 

                                                                                                             doi: 10.1111/j.1939-1676.1991.tb03143.x

Twelve dogs with appendicular osteosarcoma were treated with 24-40 Gy of cobalt 60 radiation and two doses of intraarterial cisplatin. Improvement in limb function occurred in four dogs, and three dogs, which had only mild initial lameness, had no worsening oftheir lameness post-treatment. In nine dogs in which local control was evaluable, eight had local failure, with the median (95%CI) duration of local control being 5.9 (4.6,6.7) months. Two dogs had metastatic disease before therapy, and an additional nine dogs had metastatic disease ata median time of6.4 months. Pathologic fracture was present in four dogs; two fractures occurred before treatment and two were documentedatthe time oftumor recurrence. Median (95%CI) survival time for all 12 dogs was 4.9 (3.4, 6.8) months. Excluding the two dogs with preexisting metastatic disease, median survival time was 6.7 months. Three dogs survived longer than 1 year. This mode of therapy was well tolerated and may be considered an alternative to amputation or limb-sparing surgical procedures in selected dogs with appendicular osteosarcoma. (Journal of Veterinary Internal Medicine 1991; 5313-316)

CANINE OSTEOSARCOMA is a malignancy affecting primarily the appendicular skeleton of large, middleaged to older Amputation is useful in alleviating pain associated with appendicular osteosarcoma,and resultinglocal tumor control is excellent. However, 90%of dogs treated with amputation have metastatic disease, generally in the lungs, within 1 year of ~urgery.',~Mean survival time after amputation alone is 3-6 months.'

Cisplatin has been found to be an effectiveadjuvant to amputation in dogs with appendicular osteosarcoma.6-8
In a nonrandomized study of dogs receivingamputation alone (n = 35) and dogs treated with amputation plus
cisplatin (n = 36), dogs receiving cisplatin lived longer than dogs treated by amputation alone.6 In another
study of 11 dogs receiving amputation followed by two to six courses ofintravenous cisplatin at a dose of40-50
mg/m2, median survival time was 10 months.

In a study that compared intraarterial versus intravenous cisplatin delivery on tumor necrosis, significantly
greater necrosis was achieved in resected osteosarcomas after intraarterial cisplatin administration.' Use ofradiotherapy in addition to intraarterial cisplatin further increased percent tumor necrosis. In addition, the extent
of tumor necrosis was found to be a statistically significant predictor of local tumor control.'

Amputation is not undertaken in some dogs with osteosarcoma because ofownerpreference or musculoskeletal disease in other limbs. Therefore, treatments directed at preserving the affected limb are needed. Radiotherapy as the sole treatment for osteosarcoma is generally unsuccessful.lo,' It provides palliation ofpain and reduces soft tissue swelling, but does not produce significant local control.

Limb-sparingsurgical procedures, employingremoval of the primary tumor and reconstruction of the tumor
sitewith graftingprocedures,have been used in dogs on a limited basis. 12-14 These limb-sparing procedures routinely involvetreatment ofthe primarytumor with radiation and/or chemotherapy before surgery in an attempt
to increase probability of local tumor control. Limbfunction after limb-sparing procedures is good to excellent. There are limited data regarding survival times after limb-sparing procedures in dogs. Initial data suggest median survival times in the range of 6 to 8 month.
Dogs with tumors involving more than 50% of the length of the affected bone are not good candidates for limb-sparing surgical procedures because of increased risk ofmechanical failure after surgery. Other dogs eligible for limb-sparing surgery may not receive treatment because of financial constraints. Therefore, effective treatments for dogs that have osteosarcoma who will not be subjected to limb-sparing surgical procedures or amputation are needed.

In this study, we evaluated 12 dogs with osteosarcoma treated with Cobalt-60 radiation and intraarterial cisplatin. Dogs were treated in this manner because either amputation was not desired by owners or dogs were ineligible for limb-sparing surgery.

Materials and Methods
Twelve dogs with appendicular osteosarcoma were treated with cobalt-60 radiation and intraarterial cisplatin. These patients were seen at North Carolina State University (NCSU) between September 1986 and September 1989.The median age ofdogs was 8 years (range: 4-1 1 yr). There were seven females and five males, and all were large or giant-breed dogs. The distribution of tumors by site was distal tibia (4),proximal humerus (2), distal radius (2), proximal tibia ( I ) , distal ulna ( I ) , distal femur ( l ) , and manus (3 bones, 1 dog). Radiographically, median percent bone length involved with tumor was 45% (range: 23-100%). Six dogs had marked soft tissue swelling. Neurologic impairment was present in one dog with humeral osteosarcoma.

Before starting therapy, all dogs had histologic confirmation of osteosarcoma. All dogs also underwent routine diagnostic testing before starting therapy. Significant problems that were identified included glomerulonephritis ( n = 2), pathologic fracture (n = 2), and metastatic disease (n = 2)-one to the lungs and one to the skin. Routine laboratory evaluation was repeated in most dogs before the second cisplatin treatment.

Radiographic characteristics of the primary tumor, such as percent ofbone involved, aggressiveness ofperiosteal reaction, and extent oflysis vs. sclerosiswere examined for prognostic significance using log-rank statistics.

Limb function was evaluated using the following scale of 0 to 4: 0 = weight bearing on affected limb 100%of time at walk and rest; I = weight bearing on affected limb 100%oftime at walk but not rest; 2 = weight bearing on affected limb > 50% of time at walk; 3 = weight bearing on affected limb < 50%of time at walk; 4 = no weight bearing on affected limb. Limb function scores for evaluable dogs were determined before treatment and at selected times after treatment.

Radiotherapy consisted of ten equally sized fractions of cobalt-60 photons, given via parallel opposed portals on a Monday, Wednesday, Friday schedule. Dogs were under isoflurane anesthesia for radiotherapy. The entire affected bone and a portion ofadjacent articular surfaces were included in the radiation field. A longitudinal strip of skin was excluded from the radiation fieldto maintain lymphatic drainage. One dog received 24 Gy, one dog received 32 Gy, eight dogs received 35 Gy, and 2 dogs received 40 Gy. Radiation dose varied because some dogs were part of a study in which dose was randomly
assigned. Overall, radiation doses are moderate and were believed to be in the range that would produce some
antitumor effect without also producing osteonecrosis.

Cisplatin (cis-diamminedichloroplatinum)* was administered intraarterially immediately before radiotherapy on the first and last treatment days. This was accomplished either by directly catheterizing an artery in the affected leg or by directing an angiographic catheter with fluoroscopic guidance into the desired location from a distant catheterization site. Water soluble, iodinated contrast medium was injected before cisplatin to ensure proper catheter placement. The cisplatin dose was 70
mg/m2except in one patient with glomerulonephritis in which the dose was reduced to 60 mg/m2. Cisplatin was
infused at a constant rate over 2 hours using a volumetric infusion pump.

Dogs were diuresed for approximately 16 hours before chemotherapy, using Lactated Ringers solution plus 20meq/L KCl, at a rate of 4.4 mL/kg/hr. After anesthesia was induced, the fluid type was changed to Lactated Ringers, and the rate was increased to 10 mL/kg/hr. Mannitol was administered at a dose of 0.5 gm/kg IV over a 20-minute period just before starting the cisplatin infusion.

After chemotherapy, diuresis was continued for approximately 12 hours using Lactated Ringers solution plus 20 meq/L KCl, at a rate of4.4 mL/kg/hr. The fluid rate was then reduced to 2.2 mL/kg/hr for an additional 8 hours. Antiemetics were neither given nor necessary.A closed urinary collection system was used during and after chemotherapy. The system was maintained until the IV fluids were discontinued.

When possible, dogs were re-evaluated at monthly intervals for the first 3 months, then every 3 months thereafter. Generally, a limb function assessment, bloodwork, and thoracic and limb radiographs were accomplishedat each recheck visit. Necropsies were done when possible.

All 12 dogs completed therapy without complications. Seven dogs returned to NCSU for all re-evaluations. Two dogs returned to NCSU for some re-evaluations, with the remainder done by the referring veterinarian. For three dogs, all re-evaluationswere done by the referring veterinarian.Sixdogs underwent necropsy examination.

Nine dogs were evaluable for post-treatment limb function assessment; the other three were not examined at NCSU. Limb function improved after therapy (Table 1). Improvement was noted at the 1- and 2-month rechecks. At 6 months, limb function had declinedin three dogs as a result oflocal recurrence.

Pathologicfractures occurred in four dogs.In two dogs (dog 6 and 1l), this was recognized initially. In one of these dogs (dog 1I), the pathologic fracture healed after treatment. In the other two dogs, (dogs 1and 2), multiple pathologicfractures occurred concurrently with local recurrence in one and in the other (dog2) a midshaft spiral fracture occurred proximal to the tumor 7 months after treatment.Thiswas repaired with a bone plate and intramedullary methylmethacrylate. Recovery after surgery was uneventful, and the dog regained excellent limb function.This dog lived an additional 10 months before
being euthanatized for metastatic disease.

Two dogs received additional chemotherapy. One dog received three doses of adriamycin and one additional dose ofcisplatin beginning 7 months post therapy when lung metastases were identified. Another dog received one dose ofcarboplatin, 10 months after treatment, and an additional 10 Gy of radiation 14 months after treatment. This was initiated to combat suspectedlocal recurrence, based on radiographic findings. Limb function remained excellent, and the dog was euthanatized for unrelated problems several months later.
The most common site ofdistant metastasis was lung (8 of 12 dogs), followed by bone (3 of 12 dogs). Less
common sites of metastasis were local lymphatics, skin,
and peritoneum (1 dog each). Three dogs had metastases
to more than one site, whereas one dog had no documented metastases. Two dogs had metastatic disease at initial presentation-one dog had metastatic disease in the lungs and one dog had metastatic disease to the skin. Both of these dogs were euthanatized less than 1 month after treatment. The median (95%CI)time to metastasis in all 12dogs was 4.6 (3.4,6.5) months. The median time to metastasis excluding the two dogs with pre-existing metastasiswas 6.4 months.

Local control was evaluable in nine dogs. Two dogs that did not return to NCSU after treatment were unevaluable. Another unevaluable dog had excellent limb function and radiographic local control at the time of euthanasia, 6 months after treatment, but an autopsy was not permitted. A tumor was determined to have recurred locallyifradiographicsigns oftumor progression, such as progressive bone destruction or formation of amorphus mineralization, were observed, or ifviableappearing tumor cells were found at the primary tumor site at necropsy.The median (95% CI) duration oflocal control in the nine evaluabledogs was 5.9 (4.6,6.7) months. Eight dogs had documented local failure, whereas one
dog had no evidence of tumor in the affected limb at necropsy.

Median (95%CI) survival time for all 12dogs was 4.9 (3.4,6.8)months. Ifthe 2 dogs with pre-existingmetastasis are excluded, median survival was 6.7 months.
There were no definitive radiographic findings that correlated with local tumor control, time to onset ofmetastasis, or overall survival time. It is possible that the small number ofdogs precluded finding a significantrelationship between these parameters.
In no dog did significant toxicosis develop as a result of therapy. All dogs completed treatment on schedule,
without reductions in either cisplatin or radiation dose. Dogs were usually returned to their ownersthe day after
the final treatment.

The results ofthis study suggest that megavoltage radiation and intraarterial cisplatin may be considered as an
alternative to amputation or limb-sparing surgical procedures for treatment ofosteosarcomaofthe appendicular skeleton in dogs. In this study, survivalwas comparable to other types oftreatment for osteosarcomaand 3 of 12 dogs survived longer than I year. This is noteworthy since tumors in this study were advanced, with the median length ofbone involvement by tumor being 45%.In addition, treatment was well tolerated by all dogs, and limb function improved.
Local recurrence and metastasis remained serious problems, with local recurrence documented in 8 of 9
evaluable dogs at a median time of 5.9 months and metastasis documented in 1 1 of 12dogs at a median time of

4.6 months. Therefore treatment asdescribed herein, although comparable to results from other treatment types, is considered palliative. However, these initial results are promisingand suggestthat radiation andintraarterial cisplatin for treatment of osteosarcoma should be investigated further.
Renal toxicosis was not observed, and myelosuppression was not severe or dose limiting. Emesis, usually encountered with cisplatin, was not seen in this series of patients.' Anesthesia may have acted in an antiemetic manner.
We were unable to conclusively determine the effect of cisplatin on local control or metastasis. Cisplatin was included in the treatment regimen because of its potential to exert a systemic antitumor effect and to impact positively on local tumor control. Clearly two courses of intraarterial cisplatin were not effectivein preventing development of metastasis in dogs in this study and additional courses of IV cisplatin may have lengthened survival. It would be inadvisable to substantially increase cisplatin dose per treatment, as the maximum tolerated dose of cisplatin in the dog appears to be 70 mg/m2,
when given IV (unpublished data). It is likely that cisplatin exerted a positive effect on local tumor control. This is based on previous data indicating: 1)the combination of radiation and intraarterial cisplatin is more effective than either radiation or cisplatin alone in producing necrosis in osteosarcoma, and 2) there is a direct relationship between tumor necrosis and local tumor control.

Radiation doses used in this preliminary study were well tolerated. Doses of 35-40 C ywith intraarterial cisplatin will result in greater than 90% tumor necrosis,' and this should be effective in delaying or preventing local tumor recurrence. It is not advisableto increasethe total dose more than 40-45 Gy using 10 fractions in a 3-per-week scheme because the large doses per fraction needed to do so would have a high probability ofproducing osteonecrosis. Ifadministration ofa higher total dose were to be assessed, this should be accomplished by use of a larger number of smaller dose fractions.
The cost of therapy as given in this study is high relative to amputation, but is less than limb-sparingsurgical procedures. Therefore, even though cost may be a factor, treatment as described herein may be a satisfactory alternative for dogs in which amputation or limb-sparingsurgical techniques are not feasible. In this group ofdogs, it offers the possibility of retaining the affected limb in an almost pain-free and functional state, and possibly with more aggressive chemotherapy, delaying the onset of metastatic disease.

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