Review Article
DOI: 10.1111/j.1476-5829.2008.00177.x
Radiation therapy for canine appendicular osteosarcoma A. Coomer1, J. Farese1, R. Milner1, J. Liptak2, N. Bacon1 and D. Lurie1 1
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA 2 Alta Vista Animal Hospital, Ottawa, ON, Canada
Abstract
Keywords oncology, radiation oncology, small animal, small animal internal medicine, surgical oncology
Radiation therapy (RT) for the management of canine appendicular osteosarcoma (OSA) can be described as either palliative- or curative intent. Palliative RT uses coarsely fractionated external beam RT or radiopharmaceuticals to provide relief of pain and lameness associated with OSA while resulting in minimal, if any, radiation-induced acute adverse effects. Limb amputation and chemotherapy are considered (together) the standard of care for curative-intent treatment of canine appendicular OSA. When limb amputation is not possible, RT can be used for limb sparing and is supplemented with chemotherapy for presumed micrometastatic disease. Fractionated tumour irradiation with curative intent appears to be ineffective and local disease control can more likely be achieved when stereotactic radiosurgery or intra-operative extracorporeal irradiation is combined with strict case selection and adjunctive chemotherapy. The availability of limb-sparing RT is limited by experience and availability of specialised equipment. When planned and administered appropriately, radiation-associated adverse effects are often mild and self-limiting.
Introduction
Correspondence address: J. Farese Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Florida 2015 SW 16th Avenue Gainesville FL 32610, USA e-mail:
[email protected]fl. edu
Osteosarcoma (OSA) accounts for up to 98% of all canine primary bone tumours and 5–6% of all canine malignancies.1–3 Appendicular OSA is also a highly malignant tumour with more than 90% of dogs having micrometastatic disease and 15% of dogs having clinically detectable metastasis at the time of initial diagnosis.4 Affected dogs typically present with progressive lameness, bony proliferation or swelling. Acute nonweight-bearing lameness is typically associated with the onset of pathologic fracture.1,2 Characteristic radiographic signs of appendicular OSA include bone lysis, periosteal proliferation, spiculated and sunburst bone formation, subperiosteal bone formation (Codman’s triangle) and soft tissue swelling, with calcification extending into surrounding soft tissues (amorphous new bone).1–3
The management of OSA encompasses palliativeor curative-intent strategies. Palliation can be achieved with combinations of radiation therapy (RT), radiopharmaceutical therapy, bisphosphonate treatment and/or analgesia.1 When analgesics are used as a sole treatment for appendicular OSA in dogs, median survival time (MST) is expected to be 1–3 months.1 Curative-intent strategies include amputation, limbsparing surgical techniques or RT, each combined with chemotherapy.1,5 Limb amputation remains the current standard of care for local management of primary bone tumours, and MST for dogs having limb amputation alone is 103–175 days.6–10 Importantly, MST for appendicular OSA treated with amputation doubles to 235–366 days when surgery is combined with chemotherapy.7–17 However, some dogs are not considered suitable candidates for amputation because of concurrent severe orthopaedic or neurologic conditions.4 Limb sparing can be
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd
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achieved with either surgical or radiation techniques or both.18–29 Limb-sparing techniques in the dog have been described for treating tumours involving the humerus, radius, ulna, femur and tibia.18–30 While allograft limb sparing of the distal radius is largely successful despite postoperative complications (infection rate approaching 50%), surgical techniques have been less successful at other locations because of implant failure and poor limb function.3,18,22,28–30 RT can be an effective method for the palliation of pain associated with appendicular OSA.28,31–35 Although no substantial evidence exists, when palliative radiation therapy (PTRT) is combined with chemotherapy, some degree of local tumour control can be achieved.28,31–35 An earlier review by McEntee of RT for canine OSA summarised much of the clinical recommendations still used today;31 however, recently published studies investigating both palliative- and curative-intent RT have prompted this updated review.3,21,27,28,31,36 The purpose of this report was to describe, compare and review the clinical applications of RT currently available for use in the management of canine OSA.
Types of radiation teletherapy The RT modality most commonly used in veterinary oncology is teletherapy. Teletherapy is external beam RT, where a photon or electron beam is produced from an orthovoltage or megavoltage (high energy) radiation unit. Megavoltage irradiation involves the use of photons or electrons with energy of greater than 1 MeV.37 The higher energy radiation beam penetrates further into tissue (than orthovoltage), allowing treatment of deeper seated tumours such as OSA.37 With megavoltage units, the maximum radiation dose is deposited some depth below the surface resulting in a skin-sparing effect.37
Palliative RT The goal of PTRT is to provide relief of specific clinical signs (decrease the pain and lameness associated with OSA) while resulting in minimal, if any, radiation-induced acute adverse effects.1,37 This can generally be achieved by delivering multiple large fractions (e.g. 8–10 Gy per fraction). Historically,
PTRT has been used most commonly for pain relief in dogs affected with appendicular OSA that are not surgical candidates for amputation (because of concurrent disease or stage III disease with skeletal metastasis) or if an owner has declined curativeintent therapy.32–44 Treatment of OSA in these patients with PTRT can result in local reduction in inflammation, pain relief, slowed progression of osseous metastatic lesions and improved quality of life.1,31 While the exact molecular and cellular mechanisms through which RT reduces bone pain are still unknown, it has been shown that some effect results from acute disruption of inflammatory cells, decreased progression of tumour-induced osteolysis and reduction in tumour size.38,39 The veterinary literature contains reports of PTRT for canine appendicular OSA delivering between 16 and 32 Gy in two, three or four fractions. The majority of these protocols achieve some level of analgesia within 7–14 days after the first dose of radiation, with clinical improvement lasting approximately 2–3 months.1,32–35 Unfortunately, the available literature is limited by variation in treatment protocols, including total radiation dose and fractionation, retrospective studies and sporadic reports of concurrent chemotherapy use. Recently, Boston et al. reported longer survival (MST 130 days) in dogs with metastatic (stage III) appendicular OSA treated with PTRT and chemotherapy, although no details of treatment course and clinical characteristics of treated patients were available36 (Table 1). The reports of PTRT for canine appendicular OSA are detailed below and are stratified based on fractionation protocol. Two-fraction protocols All reports of two-fraction protocols deliver 16 Gy total doses split equally on days 0 and 7. In 1999, Ramirez et al. compared a traditional 0, 7 and 21-day protocol of 10 Gy per fraction of 60Co photon to a day 0 and 7 protocol of 8 Gy per fraction.33 This latter abbreviated protocol was intended for retreatment following recurrence of clinical signs. Interestingly, no significant difference in the median time to onset of pain relief (11 days), rate of response (74%) or duration of response (73 days) was noted.33 Chemotherapy was administered to most dogs
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 7, 1, 15–27
30 Gy
0
0
0
Samarium
Samarium 37 MBq kg−
1
36–57 MBq kg−1
37 MBq kg−1
*OPLA-Pt, open cell polylactic acid containing 8% cisplatin.
0
0
Monday to Friday 48–57 Gy for 19 total fractions
20 Gy
70 Gy 70 Gy
0
0 0
24 Gy
0, 7, 14, 21
30 Gy
0, 7, 21 32 Gy
24 Gy
0, 7, 21
0, 7, 14, 21
30 Gy
0, 7, 21
Samarium
Full-course external beam RT Radiopharmaceuticals Samarium
SRS
Curative-intent protocols IORT
Four fraction
24 Gy
24–30 Gy
0, 7, 21
0, 7, 21
16 Gy
0, 1
Palliative protocols Two fraction
Three fraction
16 Gy
0, 7
Protocol
Total dose
Dose interval (days)
6*
5
35
15
9
10
6
5
13 4
54
15
58
–
15
54
–
37
Number of dogs
14
–
–
21
– –
–
14
11
–
15
–
21
–
11
Median onset of response (days)
53
70
53
95
73
209
–
105
274 –
–
130
–
73
100
63
40% no progression 100% no progression 50
77 –
83
93
74
50
80
83
83
–
74
Duration of response Response (days) rate (%)
93
150
209
–
363
298 586
–
313
122
–
125
–
–
–
122
Variable alternating chemotherapy Variable chemotherapy, frequent, severe complications; not recommended No chemotherapy; results for all 11 dogs in study Carboplatin day 0, then variable chemotherapy Variable radiosensitising: 8 of 10 OPLA-Pt, 1 of 10 cisplatin. Variable adjuvant chemotherapy
Variable chemotherapy, prolonged duration of response (P < 0.001) Carboplatin 240–300 mg m−2 day 0 (n = 2; P = 0.82) 33 of 54 dogs received carboplatin (day 0, no significant improvement)
–
33 of 54 dogs received carboplatin (day 0, no significant improvement) No chemotherapy
No chemotherapy
Variable chemotherapy, prolonged duration of response (P < 0.001)
MST (days) Chemotherapy
60
55
59
58
3
28
28
27
5
41
32
33
35
34
41
42
1,40
33
Reference
Table 1. Summary of palliative, curative-intent and radiopharmaceutical protocols including response, outcome and adjuvant chemotherapy for dogs with appendicular osteosarcoma treated with radiation therapy
RT for canine appendicular OSA 17
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 7, 1, 15–27
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receiving both RT protocols and appeared to increase both the probability and the duration of clinical response to PTRT.33 These findings must be interpreted with caution, however, because of the substantial bias and because of inconsistent chemotherapy schedules among cases. Liptak et al. and Mayer et al. both describe experience with twofraction protocols (8 Gy × 2 on days 0 and 1); however, no details of response or clinical characteristics of treated patients were available.1,40 Three-fraction protocols Three-fraction RT protocols are the most widely reported variation of PTRT for canine appendicular OSA. Reported protocols deliver 8–10 Gy fractions, typically on a 0-, 7- and 21-day schedule, for a total dose of 24–30 Gy.33,34,41,42 These protocols have achieved an 83% response rate, with median onset of response occurring 11–21 days after the first fraction, and median duration of response lasting 53–180 days.33,34,41,42 Variations of the 0-, 7- and 21-day protocol have been recently described where two consecutive daily fractions of 8 Gy are administered (days 0 and 1), followed by additional 8 Gy fractions on a monthly basis or as required.1,40 To date, however, no response rates or durations of response have been reported for these protocols.1,40 Four-fraction protocols Because most three-fraction protocols specify 2 weeks between the second and third treatments, Green et al. proposed that the possibility exists for repopulation of the tumour within this 2-week interval. In an effort to eliminate this 2-week gap, reduce the risk of tumour repopulation, and increase the duration of pain relief, Green et al. described a four-fraction (0, 7, 14 and 21 days) 60Co (gamma photons) radiotherapy protocol, delivering 8 Gy per fraction for a total dose of 32 Gy.32 Compared with three-fraction protocols, this technique resulted in a higher response rate (93%), similar onset of response (14 days) and a similar duration of response (95 days).32 A similar rate of pathologic fracture (13%) is reported, and while survival time with this four-fraction protocol appears considerably longer than other PTRT protocols (313 days),
limitations in retrospective analyses limit statistical comparison between studies.32 There was no apparent benefit of platinum derivatives (cisplatin or carboplatin), although the timing of administration of drugs was not consistent between cases.32 Interestingly, and unlike earlier protocols described by Ramirez et al., no significant difference in duration of response was noted for tumours that extended (radiographically) either 42% of bone length.32,33 More recently, Mueller et al. compared three fractions of 8 Gy (electrons; days 0, 7 and 21) and four fractions of 6 Gy (electrons; days 0, 7, 14 and 21) palliative protocols in 54 dogs, both with a total dose of 24 Gy.41 In this study, 45 dogs (83%) experienced pain relief during or following treatment. The median duration of effect was 53 days, with both protocols proving effective for palliation of clinical signs in dogs with appendicular OSA.41
Curative-intent RT Despite OSA previously being thought to be a radiation-resistant tumour,43 some reports detail significant tumour necrosis in OSA after RT.44–46 These reports have served as the basis for investigating RT for curative-intent purposes. Until recently, no curative-intent RT strategies existed for dogs with appendicular OSA. Since 2004, investigative curative-intent RT for canine OSA has been described with either curative-intent full-course fractionated external beam protocol (CI-F), single megadose RT as part of an intra-operative extracorporeal irradiation (IORT) limb-sparing procedure, and as part of a stereotactic radiosurgery (SRS) protocol.3,18,28 With any of these curative-intent strategies, RT is delivered for local tumour control, while chemotherapy (either platinum compounds or doxorubicin) must be given for metastatic disease.
Curative intent – fractionated external beam protocol CI-F RT delivers a lower dose per fraction on a daily basis and a higher total dose of radiation in an attempt to offer long-term local tumour control while minimising the late effects of radiation that occur more frequently with large fraction RT
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 7, 1, 15–27
RT for canine appendicular OSA 19
protocols. Fractionated RT is commonly used in veterinary medicine, but has only been reported twice for canine OSA, with limited success.3,47 Walter et al. report a response rate of 100%, with 50% of dogs (appendicular OSA) showing no progression of local disease based on radiographs and clinical signs before death or the end of the study.3 Median local control time was 196 days and MST was 209 days for dogs with appendicular OSA.3 These results were obtained from nine dogs treated on a Monday through Friday schedule, with the majority of dogs receiving a total radiation dose of 57 Gy (range 48–57 Gy), with most dogs receiving 3 Gy per fraction (range 3–5 Gy).3 These results did not show a substantial improvement over reported palliative protocols, and although treatments were well tolerated, no substantial local disease control or survival benefit was evident. However, limitations of the study including a small number of cases, variation in RT protocol and lack of consistent and definitive local outcome measures (necropsy and histopathology) may have affected these results. Interestingly, 66% of appendicular OSA evaluated with histopathology after RT showed no evidence of viable tumour cells.3 There is a similar paucity of published data involving the use of chemotherapeutic agents, such as cisplatin or carboplatin, which are often used in conjunction with definitive RT for proposed control of metastatic disease and chemical radiopotentiation.3,47,48 Walter et al. |report 4 of 10 cases of appendicular OSA being free of macroscopically visible metastasis at the time of death or euthanasia.3 The same limitations for interpretation of local disease control apply to metastatic disease also. The Comparative Oncology Lab at the University of Florida – College of Veterinary Medicine (UF-CVM) has recently confirmed moderate radioresistance of canine OSA cell lines in vitro with a relatively low alpha to beta ratio and high survival fraction at 2 Gy.49 Such findings may explain why OSAs may not respond well to conventional fractionated radiotherapy protocols and suggest that larger doses per fraction are needed to induce greater tumour cell kill. Thus, radiation treatment options that deliver large doses per fraction, while sparing normal surrounding tissue, may be more effective in achieving local tumour control.
Intra-operative extracorporeal radiation and radiation in situ Limb sparing with extracorporeal IORT has been investigated as a curative-intent, single-fraction protocol that involves isolation and exteriorisation of the bone tumour segment, so that a single fraction of 70 Gy can be safely delivered to it. Extraneous irradiated soft tissues are excised and the irradiated bone is reduced and stabilised with internal fixation18,27 (Figs 1–3). The biologic effect of a single dose of IORT is equivalent to two to four times the same dose of radiation delivered using fractionated external beam radiation protocols.50,51 Furthermore, 70 Gy IORT is tumouricidal to bone tumours and results in considerable necrosis of OSA lesions.18,27 Experimental studies using single-fraction, high-dose IORT have shown that peripheral nerves, muscle and skin are particularly radiation sensitive.52 In contrast, bone matrix, ligaments and articular cartilage are relatively resistant to high doses (50 Gy single dose) of radiation, which may allow preservation of normal joint and limb function.53 A principal advantage of extracorporeal IORT is that the radiation field can be focused on the target volume while sparing adjacent normal and radiosensitive soft tissue structures.18 The clinical benefits of limb-sparing protocols using extracorporeal IORT include the maintenance of autogenous bone scaffold with good anatomic fit, preservation of
Figure 1. Preparation of an OSA of the distal radius for IORT. An osteotomy of the radius has been made several centimetres proximal to the gross tumour margin. The soft tissues have been dissected off the tumour, and the distal radius is suspended for radiation treatment through a sterile cord.
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 7, 1, 15–27
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Figure 2. A gelatin radiation bolus is tied to the dissected tumour to allow delivery of a uniform radiation dose to the entire tumour. The proximal aspect of the isolated bone segment is spared from irradiation to maintain cell viability for osteotomy healing.
limb and joint function and, in some cases, good local tumour control.18 Specific surgical and RT techniques for extracorporeal IORT have been reported for appendicular OSA in the distal radius, proximal humerus, distal tibia and intercalary locations.18,27 Liptak et al. reported 10 of 13 dogs (77%) were improved clinically after IORT and assessed as having good to excellent limb function.18 Median local disease-free interval was 274 days and MST was 298 days when combined with chemotherapy.18 Adjunctive chemotherapeutic protocols were varied among individuals from both IORT studies, and metastatic disease was present in approximately
Figure 3. After tumour irradiation, the osteotomy is stabilised in compression with appropriately sized and numbered orthopaedic plates and screws.
50% of cases at the end of the study periods, which is comparable to Walter et al.3,18,27 While IORT appears to have comparable success to other definitive and PTRT strategies, a large number of dogs (69–100%) experienced postoperative complications, including deep infection, fracture of irradiated bone and implant failure, especially for distal lesions that have poor soft tissue coverage.18,27 Both Liptak et al. and Boston et al. stress the importance of strict case selection criteria to minimise complications; good soft tissue coverage allowing revasculatisation of irradiated bone by extra-osseous and periosteal vessels, therefore tumours in the diaphysis and upper extremity are preferred; minimal soft tissue involvement and no involvement of the ulna; selecting cases with
