Metronomic administration of lomustine following palliative radiation therapy for appendicular osteosarcoma in dogs

Abstract

The purpose of this study was to determine if metronomic administration of lomustine following palliative radiation therapy (RT) improved length of palliation and therefore survival in dogs with appendicular osteosarcoma compared to treatment with palliative radiation alone. A search of medical records identified dogs with appendicular osteosarcoma, treated with palliative RT (2 fractions of 8 Gray in a 24 hour time frame, day 0 and day 1; or day 0, 6 hours apart). Data collected included signalment, history, clinical signs, physical examination findings, clinicopathologic abnormalities, extent of disease, response, toxicity, other therapy, survival time, and whether dogs received metronomic lomustine (ML) or not. Of 86 patients, 43 received ML while 43 did not. Median survival time (MST) was not significantly different (P = 0.84), at 184 +/− 17 days for patients which received ML, and 154 +/− 20 days for those which did not. Metronomic lomustine administration was well-tolerated, but it did not improve survival in dogs with palliatively treated osteosarcoma.

Introduction

Standard treatment for canine appendicular osteosarcoma consists of amputation of the affected limb followed by adjuvant chemotherapy, yielding median survival times (MSTs) of 9 to 12 mo (1–10). However, amputation may not be an option for patients with severe orthopedic or neurologic disease, or gross metastatic disease at the time of diagnosis, or due to owner preference. Common palliative treatment strategies for dogs not undergoing amputation include radiation therapy (RT), bisphosphonate therapy, and oral analgesics.

Several protocols exist for hypofractionated or palliative-intent RT of primary appendicular bone tumors, typically involving 2 to 4 fractions of 6 to 10 Gray (11–18). The exact mechanism of pain relief by palliative RT is unknown, but may be related to the induction of apoptosis in malignant osteoblasts and absorbing osteoclasts (19). Multiple studies have demonstrated significant pain relief and increased limb use in 75% to 90% of treated dogs (11–18). Hyperfractionated or curative-intent RT has not been shown to confer a survival advantage over palliative RT (20). Stereotactic radiation therapy is an emerging local treatment strategy for appendicular osteosarcoma and can result in prolonged survivals in some patients, but this modality requires careful patient selection due to a strong concern for pathological fracture (21,22). Given that stereotactic treatment protocols also call for maximally tolerated dose (MTD) chemotherapy to be given afterward (21), a direct comparison between stereotactic and palliative radiation therapy protocols cannot be made. In terms of strictly palliative RT for the treatment of osteosarcoma, the optimal treatment protocol has not been determined for veterinary patients. At this institution, an expedited protocol of 2 fractions of 8 Gy radiation in a 24-hour time frame has been used (14). This protocol was designed to maximize client convenience without adversely impacting patient outcome, as MST for palliative RT alone is 4 to 6 mo regardless of protocol (11–18).

Multiple studies have demonstrated the survival benefit of anthracycline and/or platinum-based adjuvant chemotherapy in canine osteosarcoma patients (1–10). Platinum compounds, being radiosensitizers, are also potentially useful in combination with radiation therapy for patients which do not undergo amputation (23). Conflicting data exist relative to the use of MTD chemotherapy in patients which do not receive definitive local therapy, with some reports showing prolonged survival versus palliative radiation alone, and others finding no difference in MST (13,16–18).

Metronomic chemotherapy remains in the early stages of evaluation for dogs with osteosarcoma. In 1 report, metronomic administration of chlorambucil conferred modest survival times of 10 and 22 wk in 2 dogs with osteosarcoma (24). Other reports demonstrated that metronomic cyclophosphamide could be safely administered concurrently with or sequentially after MTD chemotherapy following amputation, though the addition of metronomic therapy did not confer a survival benefit in either situation (25,26).

Several reports exist regarding cytotoxic dosages of lomustine in humans and animals (27–36); however, metronomic administration of metronomic lomustine (ML) has undergone limited evaluation in veterinary medicine. Metronomic lomustine is an attractive drug for use in a metronomic setting due to its relatively low cost (in compounded form), oral formulation, and lipid solubility (37,38). Metronomic lomustine may also serve as a useful alternative for patients that develop sterile hemorrhagic cystitis secondary to cyclophosphamide administration, as well as for pet owners wishing to pursue some form of cancer treatment but minimize the potential for toxicity. A single study in a group of dogs with various advanced and treatment-refractory malignancies demonstrated that ML was tolerable, although some objective responses were noted (30). Among those patients were 6 dogs with osteosarcoma that received ML following palliative RT. The MST of these dogs was 8 mo, which was longer than anticipated based on previous reports at the same institution using the same palliative RT protocol (14,30). Because this finding occurred in a small population of patients, it was necessary to determine if survival benefit could be demonstrated in a larger patient cohort.

Osteosarcoma cells are known to have a low alpha/beta ratio, similar to that of late-responding non-neoplastic tissues (39). It would then follow that maximal tumor cell killing would result from a hypofractionated radiation protocol. We suspect that tumor control may be linked to degree and duration of pain palliation. In patients which are treated palliatively, and for which pain control is of paramount importance, it can be inferred that time to failure of palliation is closely associated with survival time. The goal of adjunct metronomic chemotherapy is to provide an additional mechanism of tumor control, and to therefore increase patient comfort and potentially improve survival. The aim of this study was to determine if administration of ML following palliative RT would improve survival in dogs with appendicular osteosarcoma compared to those treated with palliative RT alone.

Materials and methods

Criteria for case selection

A retrospective, non-randomized, observational study was performed. The radiation therapy database at the Washington State University Veterinary Teaching Hospital (WSU) was searched for dogs with appendicular osteosarcoma that were treated with palliative RT from December 12, 2008 to December 12, 2013, a time during which ML was consistently offered as follow-up therapy. This was first-line therapy for all included dogs. Patients with all stages of disease were eligible for inclusion. Dogs were included if a cytologic and/or histologic diagnosis of osteosarcoma was made and if a protocol of 2 fractions of 8 Gy radiation in a 24-hour time frame was administered (day 0 and day 1; or day 0, 6 h apart). Eligible tumor locations included the radius, ulna, humerus, scapula, tibia, and femur. Repeat RT was allowed if the owner perceived a reduction in the patient’s pain that lasted at least 2 mo before recurrence, as well as if there was radiographic confirmation that pain was not due to pathologic fracture. Pain relief was subjectively evaluated by owners and included observations such as increased mobility, increased exercise tolerance, increased comfort, improved quality of life, decrease in severity of lameness, and/or decreased need for oral analgesics. A standardized questionnaire was not used. A maximum of 3 treatment cycles consisting of the 2-fraction protocol (48 Gy total dose) was allowed per patient. All included cases demonstrated evidence that clients were offered ML to follow the first cycle of radiation therapy for their animals. All cases had a minimum of 2 mo of follow-up time. Cases were excluded if radiation therapy was administered before planned definitive therapy for the primary tumor (limb-sparing surgery, amputation, or stereotactic radiation).

Procedures

Medical and radiation therapy records were searched from December 1, 2008 to December 1, 2013. Data obtained from the records included signalment (age, breed, and gender), weight, tumor site, presence of lameness on presentation, duration of clinical signs, concurrent medications, clinicopathologic findings, diagnostic procedures and imaging findings (cytology, histopathology, radiography, ultrasonography, computed tomography), date of radiation therapy, lomustine information (dosage, start date and/or date prescribed, adverse events), follow-up physical examination, clinicopathologic evaluation, and/or repeat imaging, and date of death or euthanasia. Telephone contact was made with the referring veterinarian and/or the owner if any required information was missing or incomplete in the medical record.

Study design

Standard patient staging procedures included a complete blood (cell) count (CBC), serum biochemistry, thoracic imaging (3-view radiographs and/or computed tomography scan), limb radiographs, and sampling of the lesion via fine-needle aspirate and cytology with alkaline phosphatase (ALP) staining or biopsy with histopathology. Additional diagnostics such as nuclear scintigraphy were not carried out as this patient population was presented for palliative care and most clients sought a minimal amount of diagnostics and a simple treatment protocol. All staging procedures were performed at initial presentation for RT or within 30 d before admission. All radiation treatments were conducted at WSU with a linear accelerator (Elekta SL 15i Precise; Elekta AB, Stockholm, Sweden); before August 2010, an SL15 model was used. A standard 10 × 20 cm field using 6 MV photons was used for all cases, with the dose calculated via hand calculation to the center of the leg from external measurements, as described previously (14), with the exception that no strip of skin was spared in this protocol. This standard field size allowed for sufficient coverage of the tumor site as well as a significant margin of the affected limb in all cases. Patients were anesthetized for each treatment with a standard protocol involving mask induction with desflurane and 100% oxygen, intubation, and maintenance on the same drugs. Premedication with acepromazine (PromAce injectable; Boehringer Ingelheim Vetmedica, St. Joseph, Missouri, USA), 0.01 to 0.05 mg/kg body weight (BW), SC, was used if required.

All clients were offered the option of ML during the study period. The dose was set at 2.84 mg/m² per day as described previously (30). Each dose was administered once daily by mouth in a compounded capsule. All compounding was performed by the same pharmacy (Diamondback Drugs, Scottsdale, Arizona, USA), and the dose was prepared to the nearest 0.1 mg. Dogs were considered to have been administered ML if there was a record of WSU or the referring veterinarian prescribing the drug, and if there was communication from the owner that the dog was given the medication until death or the development of dose-limiting toxicity as determined by the attending clinician (minimum of 7 d), starting 14 to 28 d after RT. Similarly, dogs were considered to have not taken ML if there was no record of WSU or the referring veterinarian prescribing the drug, if there was documentation in the record that the drug was declined by the owner, or if there was communication from the owner that the dog did not take the drug. All patients were allowed to continue analgesics, supplements, or other medications as needed.

Recommended follow-up monitoring of patients taking ML consisted of a CBC and measurement of alanine aminotransferase (ALT) or serum biochemistry 1 mo after starting the medication, and every 2 mo thereafter. An absolute neutrophil count < 2500 cells/μL, platelet count of < 120 000 cells/μL, or elevation of ALT > 2 times the initial value were grounds for discontinuing the drug; determination of additional dose-limiting toxicities on an individual patient basis was made by the attending clinician.

Statistical analysis

All data were analyzed using SigmaStat 3.5 (Systat Software, Point Richmond, California, USA). Kaplan Meier analysis was used to evaluate survival, and LogRank analyses were used to evaluate significance except where noted. For all calculations, a P-value of < 0.05 was considered significant. Survival time was calculated from the date of initial RT to the date of death or euthanasia of the patient. In situations in which amputations were carried out due to failure of palliation, patients were censored at the date of amputation. Patients lost to follow-up were censored from the date of last contact.

Results

Eighty-six dogs with 89 primary tumors met inclusion criteria for the study (Table 1). Forty-nine dogs were male (5 intact, 44 castrated) and 37 dogs were female (1 intact, 36 spayed). Median age was 8.8 y (range: 1.8 to 14.6 y) and median weight was 42.0 kg (range: 16.8 to 88.6 kg). Breeds consisted of 23 mixed, 11 Labrador retriever, 10 Rottweiler, 7 great Pyrenees, 4 Anatolian shepherd, 4 Irish wolfhound, 3 golden retriever, 3 greyhound, 2 each of boxer, Chesapeake Bay retriever, German shepherd, great Dane, Leonberger, mastiff, Saint Bernard, and 1 each of Belgian sheepdog, borzoi, bullmastiff, English springer spaniel, kuvasz, pit bull terrier, and Siberian husky.

Table 1.

Comparison of selected characteristics of dogs which received ML and control dogs.

	ML	Control
Tumor locationa
Radius	24	16
Ulna	3	3
Humerus	8	6
Scapula	1	3
Femur	0	7
Tibia	9	9
Gender
Male intact	1	4
Male castrated	21	23
Female intact	0	1
Female spayed	21	15
Weightb
< 40 kg	15	22
> 40 kg	27	20
Age
< 9 years	20	25
≥ 9 years	23	18
Pulmonary metastasisc
Present	5	7
Absent	36	35
ALP level
Within reference	28	27
Elevated	15	16

^a43 dogs in the ML group had 45 tumors (1 had bilateral radial tumors, 1 had a tibial tumor and a radial tumor); 43 dogs in the control group had 44 tumors (1 had bilateral tibial tumors).

^bNo dog weighed exactly 40 kg. Weight was not recorded for 1 dog in each group.

^cResults of thoracic imaging were available for 41/43 dogs in the ML group and for 42/43 dogs in the control group.

The median duration of clinical signs before presentation was 30 d (range: 7 to 210 d). All dogs were lame at the time of presentation. Tumor locations included radius (n = 40), humerus (n = 14), tibia (n = 18), femur (n = 7), ulna (n = 6), and scapula (n = 4). Of 3 dogs with multiple tumors at the time of presentation 1 had bilateral tibial tumors, 1 had bilateral radial tumors, and 1 had both a radial tumor and a tibial tumor. Survey limb radiographs were available for review in 83/86 dogs. Osteosarcoma was diagnosed via cytology with ALP staining in 64/86 dogs, via histopathology in 15/86 dogs, and both methods were used in 7/86 dogs. Pulmonary metastatic disease was identified in 12/83 (14%; 7 non-ML and 5 ML) patients for which thoracic imaging results were available. No patients had overt bony metastases at the time of presentation other than the 3 dogs with what appeared to be 2 synchronous primary tumors, although comprehensive evaluation of the entire skeleton was not performed.

All patients received at least 1 cycle of the previously described RT protocol. Sixty-two dogs were treated 1 time only, 17 were treated twice, and 7 were treated 3 times. Forty-three dogs received ML following radiation, while 43 did not receive ML. Follow-up hematologic/biochemical evaluation was available at various time points for 29/43 dogs receiving ML, and 9 dogs experienced 12 adverse events of varying severity. Adverse event severity was graded in accordance with previously reported guidelines (40). Adverse events that were considered dose-limiting by the attending clinician were the development of azotemia, persistent grade I thrombocytopenia, and grade III increased ALT, each of which occurred in 1 dog. Adverse events that were not considered dose-limiting by the attending clinician included transient grade I diarrhea in 1 dog, transient grade I thrombocytopenia in 1 dog, increased ALP (1 grade I, 3 grade II, 1 grade III), and increased ALT (1 grade I; 1 grade II, which resolved following discontinuation of concurrent carprofen).

The MST for all dogs in the study was 167 d. The MST for the ML group was 184 +/− 17 d, while MST for the group not receiving ML was 154 +/− 20 d (Figure 1). The MST was not significantly different between the 2 groups (P = 0.84). Six dogs were censored from survival analysis. One was lost to follow-up at 132 d. Five dogs eventually had amputations performed due to failure of palliation of pain (4 dogs) or pathological fracture (1 dog); these dogs were censored from analysis at the time of amputation. There was no significant difference in survival based on gender (P = 0.34), age (< 9 y versus ≥ 9 y, P = 0.17), weight (over or under 40 kg, P = 0.14), or tumor location (radius, ulna, humerus, scapula, tibia, or femur, P = 0.48). Survival for patients which received 2 or 3 cycles of RT was increased compared to those receiving only 1 cycle of treatment (1 treatment, MST 145 +/− 11 d; 2 treatments, MST 197 d +/− 11 d; 3 treatments, MST 302 +/− 13 d), which was statistically significant (P = 0.01, Gehan-Breslow calculation). Specifically, survival time for patients which received 3 RT treatments versus 1 treatment was significantly different (P = 0.01, Holm-Sidak pairwise multiple comparison test). Median survival time for patients with radiographic evidence of pulmonary metastasis at presentation was significantly shorter (P = 0.01) than for those without overt evidence of metastasis [91 d +/− 5 d with metastasis, 184 d +/− 21 d without metastasis (Figure 2)]. When patients with pulmonary metastasis were removed from survival analysis, there remained no significant difference in survival between non-ML and ML dogs (non-ML, 156 +/− 29 d, ML 197 +/− 24 d, P = 0.97). Baseline ALP status was recorded for all patients. Of the non-ML dogs, 27/43 had ALP levels within reference interval, while 16 had elevations in ALP. Of the ML dogs, 28/43 had ALP levels within reference interval, while 15 had elevations in ALP. Survival times for patients with increased ALP were not significantly different from those with ALP values within reference interval (P = 0.13).

Figure 1.

Kaplan-Meier cumulative survival plot for dogs receiving palliative radiation with or without metronomic lomustine. The y-axis denotes survival as a percentage of the overall patient population still alive and the x-axis denotes survival time in days. The solid line denotes those that did not receive metronomic lomustine with 5 dogs censored; the dashed line denotes those that did receive metronomic lomustine with one dog censored. The solid circles denote censored dogs. There was no significant difference in survival, with median survival time for those receiving metronomic lomustine being 184 +/− 17 days and those that did not being 154 +/− 20 days. P = 0.84.

Figure 2.

Kaplan-Meier cumulative survival plot for dogs with or without evidence of pulmonary metastasis at the time of palliative radiation therapy (regardless of treatment group with or without metronomic lomustine). The solid line denotes dogs without pulmonary metastasis; the dashed line denotes dogs with evidence of pulmonary metastasis. The circles represent cases censored from analysis. There was a significant difference in survival, with median survival for those with metastasis being 91 +/− 5 days versus 184 +/− 21 days for those with no evidence of metastasis. P = 0.01.

When cause of death or reason for euthanasia was evaluated, 8 dogs died at home, 72 were euthanized, and 6 were censored from survival analysis. Of the dogs that died at home, no specific cause of death was reported. Of the 72 dogs which were euthanized, a reason for euthanasia was reported for 18 dogs — 5 due to pathologic fracture of the affected limb, 4 due to neurologic signs (paresis and/or paralysis), 3 due to pain and/or local tumor progression, 3 due to overall decreased quality of life, and 3 due to complications of pulmonary metastatic disease (e.g., pleural effusion, dyspnea).

Thirteen dogs received additional treatments (Table 2). In an attempt to control for inconsistency within the 2 treatment groups concerning other treatments administered, additional statistical calculations were performed. Because a few of the dogs in the non-ML group received other forms of chemotherapy, survival analysis was performed in which those patients were excluded, instead evaluating dogs which received ML compared to dogs which received no ML and no other form of chemotherapy (P = 0.55). An additional analysis was performed by further excluding dogs which received bisphosphonates, thus evaluating dogs which received ML (but no bisphosphonates) compared to dogs which received no ML, no form of chemotherapy, and no bisphosphonates (P = 0.88). Yet another analysis was performed by excluding the 9 dogs which did not receive NSAIDs; both of the aforementioned comparisons were repeated with this new criterion (P = 0.60 and P = 0.61). A final analysis was performed by evaluating dogs which received any form of metronomic chemotherapy (ML, cyclophosphamide, or chlorambucil) compared to dogs which received no ML and no other form of chemotherapy (metronomic or MTD, P = 0.95). There was no significant difference in survival between the compared populations for any of these groupings.

Table 2.

Comparison of additional treatments between dogs which received ML and control dogs.

	ML	Control
Bisphosphonates
Pamidronate	4	1
No Pamidronate	39	42
MTD Chemotherapy
Carboplatin	2	2
Cisplatin/toceranib/masitinib	0	1
No MTD chemotherapy	41	40
Metronomic chemotherapy
Chlorambucil	0	2
Cyclophosphamide	0	1
Lomustine	43	0
No metronomic chemotherapy	0	40
NSAID use
NSAID	40	37
no NSAID	3	6

Discussion

The results of this study demonstrate that metronomic administration of lomustine does not confer a survival advantage in dogs treated palliatively for appendicular osteosarcoma. While a previous study at this institution (30) noted a near doubling of survival time compared to the reported MST in a small number of dogs treated in this fashion, this retrospective study fails to confirm benefit across a larger patient population. However, the results of this study further validate the use of an expedited RT protocol to treat appendicular osteosarcoma, as patients in this study had similar MSTs to those of dogs with other reported RT protocols (11–18). Specifically, this RT protocol is simple and efficient to perform as well as convenient for clients. It should be noted that while no attempt was made to spare a strip of skin along the irradiated leg, no patient in the study population developed lymphedema. This may be due to overall short survival times of this patient population or may indicate that patients may not have had sufficiently long follow-up.

Lomustine was chosen for evaluation as a metronomically administered drug for several reasons. It is a relatively inexpensive bioavailable drug that is administered in oral form, allowing for relatively straightforward compounding of the drug into small doses for metronomic use. It was of particular interest based on previous results indicating prolonged patient survival even in the face of advanced disease (30). Lomustine, a chloroethyl derivative, is highly lipid soluble and can readily enter cells via passive diffusion that favors high biodistribution into body tissues including cells of the central nervous system (37). Lomustine and other nitrosoureas are also attractive for clinical use as they exhibit only partial cross resistance with other alkylating agents (38). This is clinically relevant given that commonly administered metronomic agents consist of other alkylators such as chlorambucil and cyclophosphamide, meaning that lomustine could still have activity against a given tumor that had previously failed therapy with the aforementioned agents.

The lomustine dose of 2.84 mg/m² per day was chosen in keeping with a previous report (30). It is possible that lomustine could have appreciable anti-tumor or anti-angiogenic activity at a different dose or dose interval. It is unknown if lomustine has activity against canine osteosarcoma at the MTD dose. However, cytotoxic activity in the MTD setting may not necessarily correlate with anti-angiogenic activity in the metronomic setting, as the target cell populations differ. Metronomic therapy targets endothelial cells and inhibits angiogenesis rather than asserting a direct cytotoxic effect on rapidly dividing cells (41–43). The ideal situation would involve pharmacokinetic evaluation of the drug in a cohort of dogs to determine optimal dosing and then evaluate drug activity. Circulating endothelial precursor cells, regulatory T-cells, and other biomarkers could also be evaluated in a future prospective study. Recently, concerns have been raised regarding the variability in content (potency) of compounded drugs, specifically lomustine (44,45). Given this information, the patients involved in this study may not have actually received their intended lomustine dosage. This could certainly account for perceived lack of activity as the labeled amount may have varied substantially from the actual contents of a given capsule.

The timing of lomustine administration relative to radiation therapy (14 to 28 d after RT) may not have been ideal. While lomustine, unlike carboplatin or cisplatin, is not known to be a radiosensitizer, it is possible that concurrent lomustine and radiation may have had an additive or synergistic effect, yielding an improved outcome. Lomustine is often separated from radiation at this institution due to anecdotal experience of more severe radiation side effects in patients receiving the 2 treatments concurrently. The typical turnaround time for the compounding pharmacy from the date the drug was prescribed to the date of drug receipt by the client was also generally 1 to 2 wk. However, this delay may also have been long enough for local and/or distant tumor progression to occur before ML was started, leading to no difference in outcome across patients which did or did not receive ML. Because concurrent administration of other medications was not discontinued or limited in study patients, and since several patients were taking multiple supplements with undefined ingredients, it is possible that a drug interaction occurred that may have changed the therapeutic activity of lomustine against the tumor in a given patient. Specifically, administration of a drug that induces cytochrome P450 activity could decrease or possibly abolish the activity of lomustine (46).

There are inherent limitations in this study, primarily due to its retrospective nature. Because this was a retrospective study and dogs were divided into ML versus control groups based on owner preference, it was impossible to match the 2 groups. Being a non-randomized and retrospective study, bias and the potential for type II error are always concerns. While a uniform monitoring protocol was recommended for all patients which received ML, most patients were managed by their referring veterinarians and may not have received recommended monitoring, and follow-up reporting was inconsistent. This means that subclinical adverse hematologic and biochemical events may have gone undetected. Repeat imaging occurred at varying times on an individual patient basis, and was not performed in every patient, making it impossible to document time to tumor progression or evaluate response to treatment other than via patient survival. This requires making the assumption that survival was a surrogate measure of time to failure of palliation.

Overall survival is also influenced by personal choices of pet owners regarding when and why to euthanize their pet, as most patients in this study were euthanized and only a few died naturally. As this protocol was intended for palliation of pain, the goal was to improve patient comfort and quality of life, which was assumed to translate to extended survival. We recognize that measuring survival time is not an accurate representation of patient quality of life or duration of pain palliation. Standardized quality of life assessments or evaluations were not performed in this study, but should be considered for future prospective evaluation. It can be inferred that quality of life influenced patient survival since most patients for which a reason for euthanasia was reported, euthanasia was secondary to clinical signs from the local tumor (pain, fracture) or occasionally due to systemic effects of the disease process.

Several dogs in this study received various other treatments beyond palliative RT with or without ML. As mentioned previously, the use of NSAIDs, carboplatin, pamidronate, or any chemotherapy drug (metronomic or otherwise), did not correlate with improved outcome. This finding suggests that at least for this specific population of patients, systemic therapy of any kind did not confer increased survival beyond that of RT alone. A definitive conclusion cannot be made considering that the groups of patients which did or did not receive these treatments were not balanced, numbers were small, and patients with more advanced disease may have been more likely to receive additional therapy, leading to selection bias.

In conclusion, metronomic administration of lomustine did not prolong survival in this retrospective observational study of dogs with appendicular osteosarcoma that underwent palliative radiation therapy in lieu of amputation. This chemotherapy protocol did not convey a survival benefit, though it is impossible to rule out a potential quality of life difference without further investigation. However, this study confirms the utility of radiation as a palliative pain management option, specifically in the setting of a previously described expedited protocol (14).