Four Fraction Palliative Radiotherapy for Osteosarcoma in 24 Dogs
Twenty-four dogs underwent palliative radiotherapy consisting of four 8 gray (Gy) fractions of 60Co radiation on days 0, 7, 14, and 21 at 26 sites for axial (n=11) or appendicular (n=15) osteosarcoma. Response was noted in 92% of sites treated. Seventeen dogs were euthanized due to local or metastatic disease, one dog died of metastatic disease, five dogs died of unrelated causes, and one dog is alive. The four fraction protocol is effective for palliation of clinical signs associated with axial or appendicular osteosarcoma and may result in a higher response rate and longer survival time than three fraction palliative protocols.
Introduction
Radiotherapy is effective for the temporary relief of pain and dysfunction associated with primary and metastatic bony neoplasia in humans and dogs. Numerous palliative radiotherapy protocols have been described in the human literature.1–10 These range from a single large fraction (e.g., 15 gray [Gy]) to multiple daily fractions over 2 to 5 days. Total radiation doses reported ranged from 4 to 40 Gy. Little attention has been given to determining an optimal palliative protocol for veterinary patients. A three fraction palliative protocol (3 × 10 Gy at 0, 7, and 21 days)1112 has been described for appendicular osteosarcoma as has a similar protocol (3 × 8 Gy at 0, 7, and 21 days) for the palliation of pain associated with advanced cancers, including osteosarcoma.13 These schedules specify 2 weeks between the second and third treatments. This would presumably permit repopulation of the tumor and potentially compromise effectiveness of the radiotherapy. The protocol described in this paper was designed to eliminate the 2-week gap, with the intent of decreasing tumor repopulation during the course of therapy and therefore potentially increase duration of pain relief. The purposes of this retrospective study were to assess the effect of a four (0, 7, 14, and 21 days) 8 Gy per fraction radiotherapy protocol in palliating pain and dysfunction associated with canine osteosarcoma (either axial or appendicular) and to compare it with reported responses to other palliative protocols.
Materials and Methods
The radiotherapy database at the University of Wisconsin-Madison Veterinary Medical Teaching Hospital (UW-VMTH) was searched for all patients that completed a course of palliative radiotherapy for the treatment of osteosarcoma. This search revealed 24 dogs that presented between January 1994 and January 2001.
Palliative radiotherapy consisted of four 8 Gy fractions of 60Co radiation given on days 0, 7, 14, and 21 for a total of 32 Gy in 3 weeks. Most setups, whether axial or appendicular, consisted of two parallel-opposed, equally weighted fields. Two setups (nasal and maxilla) consisted of two equally weighted orthogonal beams (dorsal and lateral) with 30° wedges. All appendicular fields included a 3-cm margin beyond gross tumor and radiographically apparent bone involvement whenever possible and spared a proximal-to-distal strip of skin to minimize the potential for lymphatic obstruction. All axial fields included a 3-cm margin. Eyes, nasal planum, spinal cord, and urinary bladder were blocked when in the field.
Responses to radiotherapy at appendicular sites were defined as decreased or resolved lameness, increased partial or complete weight bearing, or increased activity using the affected limb, or a combination of the above. Oral or nasal tumor site response was defined as improved appetite, tumor regression, or both. Tumor size was recorded for axial sites and reevaluated at subsequent visits to determine response. Treatment responses were assessed by the owner and attending clinician. Time to onset of response was measured from the first day of radiotherapy to the first day of reported response. Duration of response was measured from the first day of reported improvement to the day of recurrence of signs (e.g., lameness, inappetence, etc.) due to disease progression. Survival time was measured from the first day of radiotherapy to the date of death, euthanasia, or affected limb amputation.
Comparisons of data sets were made using Kaplan-Meier analysis,a and differences between groups were evaluated using logrank tests. Data sets were censored to account for deaths due to other causes. Significance was assigned to values of P<0.05.
Results
The population included four intact males, eight castrated males, one intact female, and 11 spayed females. Fifteen breeds were represented, including four Labrador retrievers, three golden retrievers, three Doberman pinschers, two mastiffs, two Great Pyrenees, and one each of the following: Scottish deerhound, Siberian husky, cocker spaniel, Irish setter, borzoi, Old English sheepdog, boxer, leonberger, Saint Bernard, and Staffordshire bull terrier [see Table]. The median age was 10 years (range, 4 to 12 years), comparable to other reports.1214
All dogs had histopathological confirmation of osteosarcoma. Radiographs of the thorax and tumor site (whether axial or appendicular) were reviewed prior to radiotherapy. Metastasis was identified in six dogs prior to therapy (two pulmonary only; two pulmonary and bony; one bony only; one subcutaneous and removed prior to radiotherapy). Two of the three dogs with bony metastases had two sites treated concurrently (one appendicular and one axial). The other dog presented with bony metastasis following a limb amputation. Ten dogs developed metastatic disease after radiotherapy (seven pulmonary, two bony, one regional lymph node).
The percentage of bone length radiographically involved by tumor was evaluated for 14 of 15 appendicular sites [see Table]. This was performed to evaluate whether percentage of bone length involvement was related to response rate or duration of response, as has been reported previously.12 Radiographs for one dog were unavailable for review. Percentage of bone length involvement ranged from 20% to 78% (median, 42%; mean, 43.4%). All lesions were characterized as radiographically aggressive, with variable amounts of cortical lysis and bony proliferation, and were classified as T2 according to the World Health Organization staging system for primary bone tumors. The median duration of response for lesions with <42% bone length involvement was 220 days (mean, 234 days). The median duration of response for lesions with >42% bone length involvement was 52.5 days (mean, 89 days) [Figure 1]. No significant difference between these groups was found by Kaplan-Meier analysis and logrank test (P=0.49).
Twenty-six sites were treated with radiotherapy in 24 dogs. Case nos. 14 and 15 were treated at two sites concurrently (one axial, one appendicular); appendicular sites were thought to be the primary lesions in these two patients, as the locations (i.e., distal radial metaphysis and proximal humeral metaphysis) represent common predilection sites for primary osteosarcoma. Case nos. 11 and 24 were treated with additional radiotherapy, so only the time to response and duration of response for the initial treatment were included in analysis. Case no. 7 had a forelimb amputation shortly after the return of clinical signs. These three dogs were censored from survival data at the time they received additional radiotherapy or amputation. Eleven axial sites included pelvis (n=4), maxilla (n=3), intranasal (n=2), and mandible (n=2). Fifteen appendicular sites included distal radius (n=5), proximal humerus (n=4), scapula (n=2), distal femur (n=2), distal tibia (n=1), and distal ulna (n=1).
Dogs receiving radiotherapy to appendicular sites experienced no significant side effects. One dog experienced alopecia at the treatment site. Of the seven dogs that received radiotherapy to the maxilla (n=3), nasal cavity (n=2), or mandible (n=2), five experienced mucositis that resolved with conservative management (four judged mild, one severe). Case no. 23 (mandible) experienced side effects related to tumor necrosis (e.g., halitosis, oral discharge). One of three dogs that received radiotherapy to the pelvis experienced mild, moist desquamation. Two dogs with axial tumors (maxilla and sacrum) had no side effects. Case nos. 7 and 14 developed pathological fractures 408 and 90 days after the onset of radiotherapy, respectively. These were thought to be due to tumor progression.
Response to radiotherapy was noted in 24 (92%) of 26 sites. Case no. 15 (two sites) did not respond to radiotherapy at either site. Onset of response ranged from 6 to 30 days (median, 14 days; mean, 14 days) for appendicular sites and 6 to 42 days (median, 14 days; mean, 16.5 days) for axial sites. Duration of response ranged from 21 to 536 days (median, 94.5 days; mean, 163.2 days) and 9 to 341 days (median, 81.5 days; mean, 114.2 days) for appendicular and axial sites, respectively [Figure 2]. No significant difference in duration of response was found between appendicular and axial sites (P=0.42).
The survival time for dogs with tumors in appendicular sites ranged from 35 to 550 days (median, 313 days; mean, 243.8 days). The survival time for dogs with tumors in axial sites ranged from 51 to 391 days (median, 162 days; mean, 168.7 days) [Figure 3]. Kaplan-Meier analysis and logrank testing of these data sets showed no significant difference in survival time between appendicular and axial sites (P=0.056).
Six (25%) of the 24 dogs received systemic chemotherapy concurrent with the radiotherapy. Two of these six had pulmonary metastases at the onset of radiotherapy. Carboplatinb was administered at 240 to 300 mg/m2, intravenously q 3 weeks, for two to four treatments. The first two treatments were given at the time of the first and fourth radiotherapy fractions. Case no. 18 received two doses of cisplatinc (70 mg/m2) and was switched to carboplatin for further treatments. The median onset of response for these six dogs was 10.5 days (mean, 14.8 days); median duration of response was 65 days (mean, 103 days) compared to 14 days median onset of response (mean, 14.7 days) and 113.5 days median duration of response (mean, 178.5 days) for dogs that did not receive chemotherapy. Kaplan-Meier analysis and logrank testing found no significant difference in onset or duration of response between dogs receiving chemotherapy and those that did not (P=0.99 and P=0.21). Case no. 19 received immunotherapy after the completion of radiotherapy. Two dogs received experimental inhalational chemotherapy for pulmonary metastases (case no. 2 received it concurrent with radiotherapy, and case no. 3 received it at the time metastases were discovered [day 225]). Three of the nine dogs receiving chemotherapy, inhalant therapy, or immunotherapy were euthanized due to progressive disease at the irradiated site; two were euthanized due to metastatic disease; one died from metastatic disease; and three died from other causes. The median survival time for these nine dogs was 233.5 days (mean, 168.6 days). The median survival time for the 12 dogs (not including case nos. 8, 11, or 24) that did not receive adjunctive chemotherapy, inhalant therapy, or immunotherapy was 196 days (mean, 224.6 days). This difference in survival times was not significant (P=0.82).
Eighteen dogs were euthanized or died due to osteosarcoma; 10 were euthanized due to progressive local disease; seven were euthanized due to metastatic disease; and one died due to metastatic disease (survival time range, 51 to 461 days; median, 149.5 days; mean, 183.2 days). Five dogs died from causes unrelated to their osteosarcoma (survival time range, 35 to 550 days; median, 279 days; mean, 300 days). There was no significant difference in survival between those dogs that died or were euthanized due to osteosarcoma and those that died from other causes (P=0.08). When comparing the survival of the eight dogs that were euthanized or died from metastatic disease (median, 134 days) to the 10 that were euthanized due to local progressive disease (median, 153 days), no significant difference was found (P=0.81). One dog is alive but had a forelimb amputation shortly after a pathological fracture and the return of clinical signs (day 425).
Discussion
Palliative radiotherapy is a reasonable therapeutic option for canine osteosarcoma when definitive therapy is unavailable, unacceptable, or cost-prohibitive to the owner. The response rate (92%) in this study was higher than other reports of 74%, 80%, or 87%11–13 that used three fractions, including a 14-day gap between the second and third fractions (0-, 7-, 21-day protocol). The median onset of response (14 days for appendicular and axial sites) supports the perceived occurrence of an initial analgesic effect from a relatively low dose of radiation (16 Gy). The median duration of response for appendicular sites (94.5 days) in this report is longer than the 73 days recently reported using a three fraction protocol.12 Median survival time for dogs with tumors in appendicular sites in the present study (313 days) was over four times as long as recently reported12 and exceeded historical reports of 120 to 175 days following amputation surgery alone with intent to cure.1516 A recent report of canine axial osteosarcoma in large-breed dogs described a median survival time of 79 days for 12 dogs receiving either 20 or 30 Gy in two or three weekly treatments.17 In this study, the four fraction, 8 Gy protocol was effective for palliation of pain due to axial osteosarcoma and resulted in a median survival time of 162 days. These discrepancies in survival times could be artifacts of small sample sizes, but the possibility of increased therapeutic gain warrants further investigation.
Weekly fractions of 8 Gy were chosen for this protocol based on a recommended maximum fractional dose of 8.25 Gy in humans.18 Using 8 Gy per fractional dose, 71% (5/7) of at-risk patients in this study experienced mucositis. None of the at-risk patients in a report using the 0-, 7-, and 21-day protocol experienced mucositis.13 Calculation of the biological equivalent dose (BED) for this study’s protocol, using an α/βratio of 10 for acute effects and an α/βratio of 3 for late effects, yields 57.6 Gy10 and 117.3 Gy3, respectively. These values fall between those calculated for the protocol used in a recent report12 of 8 Gy per three fractions (43.2 Gy10 and 88 Gy3) and the 10 Gy per three fractions (60 Gy10 and 130 Gy3) described in the earlierreport.13 The BED formula uses the total dose and fraction size, along with a constant (α/βratio) to determine an effective dose for each protocol, allowing comparisons to be made between radiotherapy protocols. There were no patients at risk for mucositis in the recent report12 of appendicular sites. No serious late effects related to radiotherapy were reported with any of these three protocols. Fifteen percent of patients in the recent report developed pathological fractures at a median time of 154 days from the beginning of therapy.12 Similarly, 13% (2/15) of patients at risk in this study experienced pathological fractures (90 and 408 days).
Eighteen (75%) of the 24 dogs in this study were euthanized (n=17) or died (n=1) due to osteosarcoma. Ten of these dogs were euthanized due to progressive local disease (return of clinical signs [e.g., tumor progression, anorexia, lameness]). Six of these 10 dogs had an axial site, three had an appendicular site, and one dog (case no. 24) had both an axial and appendicular site at the time of euthanasia. Eight of the 18 dogs were euthanized because of metastatic disease, while their palliation sites remained under control. It is unknown what further duration of response and survival may have been achieved had these dogs not succumbed to metastatic disease. Of interest is the fact that the median survival time of those dogs that succumbed to local progressive disease was not different from the median survival time of those dogs that succumbed to metastases. Again, there may have been a difference if those dogs with local sites that remained under control were to have received effective systemic therapy. This emphasizes the importance of effective systemic therapy for control of metastases concurrent with palliative radiotherapy. This may be of greater importance for appendicular locations, as more dogs with axial sites were euthanized due to local progressive disease. Side effects of systemic therapy may contradict the purpose of palliative radiotherapy, however, if quality of life becomes compromised. It seems reasonable that systemic chemotherapy may extend the survival of dogs receiving palliative radiotherapy. This was not seen in the cases presented here. The number of dogs receiving chemotherapy in this study was small, and this population may reflect dogs perceived to have more extensive disease. Two of six dogs receiving chemotherapy had pulmonary metastases at the time of treatment. At the time these dogs were seen at the UW-VMTH, carboplatin was available free of charge and was given to patients at the discretion of the attending clinician. Platinum drugs are known to be radiosensitizers when given within an hour of radiation.19 The authors did not observe enhancement of local radiotherapy effects in dogs receiving cisplatin or carboplatin, but no attempt was made to temporally coordinate their administration with radiation fractions. Discrepancy between this finding and a recent report12 that described a greater likelihood of response and greater response duration when chemotherapy was combined with radiation may again be an artifact of the small sample size in this study or may relate to increased efficacy of the radiotherapy protocol presented here. The use of traditional chemotherapy agents for the treatment of bony metastases in humans is generally not effective in relieving bone pain.20
There was no relationship noted between the onset of response and the duration of response or survival. No significant difference was found between the onset of response for those dogs that had a duration of response or survival greater than the median and those that had a duration of response or survival less than the median using Student’s t-test.
Although most dogs received pain medications at some point before, during, or after radiotherapy, it was difficult to discern the dosage or frequency of administration from the medical records. It is unknown what effect their use had on the response to radiotherapy. This is an acknowledged shortcoming of this and previous retrospective studies.1112 The lack of understanding of the influence of concurrent pain medication use on the response to radiotherapy is recognized in the human literature as well.21 In the nine dogs that were euthanized due to progressive local disease, the concurrent use of pain medications could have prolonged their survival by delaying the decision to euthanize; but it is unknown whether this was the case.
Some difficulty arose in analyzing degree of pain experienced by the dogs. Often, several clinicians were involved in follow-up evaluations of a patient. Subjective impressions of the dog’s lameness and perceived discomfort by both the owner and clinician occasionally made comparisons difficult. The authors have since adopted the more objective performance and toxicity scoring system described by Bateman et al.13 for all radiotherapy patients to more easily assess response to therapy.
Case no. 7 serves to illustrate an important observation in this series. Although its onset of response to radiotherapy was rapid (7 days), the duration of pain response was only 28 days. Yet this dog is alive after having an amputation 425 days after the onset of radiotherapy. This dog represents the extreme case of those dogs that lived long after the return of clinical signs. It is possible that when clinical signs returned, they were less severe than initially or they were more easily managed with pain medications. It is also possible that some owners were more willing to tolerate the clinical signs after radiotherapy. In reviewing the medical records, it was often the case that these dogs were reported to be intermittently lame by their owners.
Intuitively, the percentage of bone length involved would be expected to relate directly to the duration of response to radiotherapy as recently reported.12 Although there was a trend toward this in the data of this report (median duration of response, 220 days for <42%; median duration of response, 52.5 days for >42%), it was not statistically significant. It is of interest, however, that even though the median percentage of bone length involvement was identical to the previous report,12 the median durations of responses of this report were longer (220 days versus 44 days for <42%, and 52.5 days versus 20 days for >42%). This could again be an artifact of small sample size or reflect an increase in this study’s protocol’s effectiveness.
The decision to include a 3-cm margin beyond gross and radiographically defined tumor within the treatment field is consistent with a previous veterinary report.12 Radiation fields used in the treatment of human osteosarcoma often include gross tumor and a generous margin of normal tissue, but rarely the entire length of bone.22 Another veterinary report11 describes including the entire length of bone in the treatment field. It is interesting, however, that only three of the 14 responding dogs with tumors in appendicular sites were euthanized due to local disease progression (uncontrolled pain). It was not documented if these dogs had radiographically progressive disease outside of the treatment field. If this were the case, then clearly a greater margin may need to be included in the treatment field; however, 11 dogs maintained a durable pain-free response without clinical evidence of out-of-field progression.
Survival data for case no. 11 was censored in analyses because the dog received additional 8 Gy doses on days 399 and 406. This dog experienced the second longest survival time (490 days) in this study and was euthanized because of a large abdominal mass (no histopathology was available). Similarly, survival data for case no. 24 was also censored in analyses as explained here. At day 178, the dog presented for tumor regrowth in his mandible and swelling of his distal radius. The distal radial site was determined to be a metastasis, and both it and the mandibular site were treated with 4 × 8 Gy (0, 7, 14, and 21 days). Both sites responded within 28 days with a duration of response of 50 days. No acute effects occurred after the second course of radiation to the mandible. The dog was euthanized due to progressive disease at 263 days after the onset of the first treatment. These two cases demonstrate the potential benefit of additional palliative radiotherapy to previously treated sites.
Retreatment is a reported option for palliation of bone pain in human medicine as well. Recent papers2324 suggest that a single 8 Gy fraction is as effective at palliation as 20, 24, or 30 Gy given in 5, 6, or 10 fractions. No difference in the duration of response or survival times was noted between groups. Patients that were treated with the single 8 Gy fraction did receive more retreatments than those that were treated with multiple fractions; however, it was not clear from the data that these retreatments were necessary, because pain scores between the single and multiple fraction groups were not significantly different. Retreatments did bring the cost of the 8 Gy fraction protocol to within 8% of the cost of the multiple fraction protocols. These results led the authors to suggest that single 8 Gy fractions are appropriate for the treatment of bone pain, are of greater convenience to the patient, and are more economical to radiotherapy departments.
The ideal palliative protocol in human medicine has yet to be decided. A recent report in the human literature comparing conventional fractionation (40 to 46 Gy in 20 to 23 fractions over 5 to 5.5 weeks), a short course (30 to 36 Gy in 10 to 12 fractions over 2 to 2.3 weeks), and a fast course (8 to 28 Gy per 1 to 4 daily fractions), concluded that total doses of ≥30 Gy were necessary to completely alleviate pain in ≥70% cases of bony metastasis.25
Conclusion
The 4 × 8 Gy (0, 7, 14, and 21 days) protocol provided timely palliation of bone pain due to axial or appendicular osteosarcoma with little risk of significant side effects. Ninety-two percent of dogs responded, and 50% of those achieved relief or improvement of clinical signs in 14 days. The median response was 2.7 to 3 months, and the median survival times were 5.4 and 10.4 months for axial and appendicular sites, respectively, with this palliative protocol. Concomitant effective systemic therapy to delay progression of metastasis as well as repeated radiotherapy doses are potential strategies to further improve quality of life and survival times in dogs with osteosarcoma.
GraphPad Prism; GraphPad Software, Inc., San Diego, CA
Paraplatin; Bristol Laboratories, Princeton, NJ
Plantinol-AQ; Bristol Laboratories, Princeton, NJ
Citation: Journal of the American Animal Hospital Association 38, 5; 10.5326/0380445
Citation: Journal of the American Animal Hospital Association 38, 5; 10.5326/0380445
Citation: Journal of the American Animal Hospital Association 38, 5; 10.5326/0380445
Response durations by percentage of bone length involvement. Radiographs were available for 14 of 15 dogs. Groups include only the 13 responders.
Response durations for appendicular and axial sites. Fourteen appendicular sites and 10 axial sites are represented.
Survival times for appendicular and axial sites. Data censored for deaths due to other causes or at the time of additional radiotherapy or amputation.
