Ultrasonography of Osteosarcoma in Dogs
Sonography Atlas of Dogs

The 0-7-21 radiation therapy protocol was investigated as a palliative treatment in dogs with advanced malignancies. Twenty-four dogs with a variety of tumor types were irra- diated using 800 cGy fractions given on days 0, 7, and 21. Twenty-three dogs were evaluated. Palliative response was assessed using a quality of life instrument developed for veterinary use. This pain score was based on owner re- sponse to questions regarding analgesic requirement, ac- tivity level, appetite, and degree of lameness in the affected dogs. Seventeen (74%) of the 23 dogs experienced complete pain relief, and 3 (1 3%) obtained partial re- lief. Of the 17 dogs that achieved a complete response, pain recurred in 8 at a median time of 70 days. Six dogs were alive and free of pain up to 557 days after irradiation. The 0-7-21 protocol was well tolerated; pain relief oc- curred quickly, and acute radiation reactions were negligi- ble. J Vet Intern Med 1994;8:394-399. Copyright 0 1994 by the American College of Veterinary Internal Medicine.

When cancer patients present with advanced or disseminated disease, the goal of treatment be- comes palliative, rather than curative. Palliative ther- apy is directed at reducing pain and other clinical signs that detract from a patient’s quality of life. In many cancers, pain increases in frequency and sever- ity with disease progression.’’2 This is a major source of concern for pet owners. In humans, the incidence of pain is greatest in patients with primary bone tumors and cancers of the oral cavity.

In 1970, Gillette described radiation therapy as an effective means to alleviate pain and extend “mean- ingful” survival in domestic anirnal~.~ Despite this, the palliative qualities of radiation have received little attention in the veterinary literature. Radiation ther- apy has generally been approached with curative in- tent, although the result is often palliative.6 Dose and fractionation have not varied with the intended out- come. Without the possibility of cure, euthanasia has been considered a more humane option than a radical course of radiation therapy.’

In humans, close to 50% of radiation therapy is pre- scribed with palliative intent.’ Fractionation patterns have vaned widely and range from single 800 to 1,000 cGy fractions, to 2,000 cGy given over 5 days, to ex- tended courses of 5,000 cGy given over 5 weeks. The aim of palliative radiation is to achieve rapid, effective, and lasting symptomatic relief in as short a course as possible, provided the normal tissue reac- tions can be kept to a minimum.

The benefits of palliative therapy are difficult to as- sess. Traditional end points, such as survival and tu- mor control are not appropriate measurements of quality of life. Quality of life instruments have not been previously described for animal patients, but should be developed to evaluate palliative protocols.

The 0-7-21 radiation therapy protocol is a hypo- fractionated regime consisting of 800 cGy fractions given on days 0, 7, and 21. This protocol has shown promise in humans for the palliation of mucosal or metastatic melanoma.10-’2 The purposes of this study were to ( 1) determine if the 0-7-2 1 protocol resulted in palliation in a variety of spontaneous canine tu- mors; and (2) to evaluate the response to therapy us- ing a quality of life instrument.

Materials and Methods

From June 1989 to July 1991, 24 dogs presented to the Ontario Veterinary College with advanced malignancies re- ceived radiation therapy with palliative intent. Dogs were considered eligible if they had (I) advanced local disease not amenable to surgical resection; (2) a primary tumor with a high probability of metastatic dissemination; or (3) an oral melanoma. A further requirement of the study was owner agreement to complete satisfaction questionnaires. The me- dian age of the dogs was 1 1.5 years, with a range of 6 to 15 years. The 25th and 75th percentiles for age were 8.5 and 13 years, respectively. There were I I males and 13 females.

Distribution by histology and site is listed in Table 1. Length of illness (initial clinical signs to initiation of treatment) ranged from 13 to 135 days, with a median time of 44 days. The 25th percentile was 27 days, and the 75th percentile was 63 days. Seven dogs had recurrent disease after one or more surgical excisions.

All procedures performed on the dogs were in accordance with the guidelines set by the Canadian Council for Animal Care and were approved by the Animal Care Committee, University of Guelph. Pretreatment assessment included a history of analgesic use, physical examination, complete blood count, serum biochemical profile, 3 radiographic views of the thorax (right lateral, left lateral, ventrodorsal), and radiographs of the primary tumor, where applicable, to assess bone involvement. Fine needle aspirations of regional lymph nodes were obtained, for cytologic evaluation, when indicated. Histopathology slides of the primary tumors were reviewed by a pathologist at our institution. Dogs were staged according to the World Health Organization’s (TNM) system for dogs and cats.13 Treatments were given using a ceiling-mounted Cobalt 60 teletherapy unit. The source-to-surface distance was 80 cm. Radiation was deliv- ered via parallel-opposed fields in 12 dogs and by direct fields in 12 dogs with well-lateralized lesions. Tumor dose was prescribed at midplane to opposed fields and to D,,, for direct fields. Field sizes ranged from 24 to 323 cm2. Dogs received 2400 cGy in 3 fractions, delivered on day 0, day 7, and day 2 I. General anesthesia was administered for each treatment using thiopenthal and isoflurane. All dogs were treated on an outpatient basis.

Degree of pain relief was used as the main indicator of response. A pain scoring system was established for use in this trial (Table 2). Appetite, activity level, and degree of lameness (for dogs with limb tumors) were given a clinical score of 0 to 3, with 0 being normal. Scores were summed for a maximum possible pain score of 9. Clinical scores were based on observations by the owners of the dogs in their home environment. Dogs that were receiving analgesics at the time of presentation continued on these medications at the owners’ discretion. Pain scores were assigned, therefore, to some dogs while under analgesic effects.

Pain scores, analgesic requirement, weight of the dog, and objective tumor response were recorded before treatment, on each treatment day, and at 2 weeks, I, 2, 3, 6, and 12 months after therapy. Three levels of pain response were as- signed: complete response (complete disappearance of pain without analgesics), partial response (decrease in pain score by at least two levels without analgesics), and no response (no change or increase in pain score).

Four levels of objective tumor response were assigned: complete response (disappearance of all clinical evidence of tumor), partial response (greater than or equal to a 50% vol- ume reduction of tumor), stable disease (tumor reduction less than 50%), and no response (progressive tumor growth). Toxicity was scored using the Southwest Oncology Group (SWOG) Toxicity Criteria outlined in Table 3. This is a for- mal grading system developed for use in human trials by a large cooperative oncology group.14

Owner satisfaction questionnaires were introduced after dog 9 and were given prospectively to owners at 2 and 4 weeks after therapy and within 1 month of the animal’s death. Owners were questioned regarding their pets’ expres- sion of pain, degree and timing of pain relief after therapy, the treatment schedule, and the use of analgesics. On each occasion, owners were asked if they believed that radiation therapy had improved the quality of their pet’s life and if they would consider the same treatment on another animal. Refemng veterinarians completed a similar questionnaire after the death of a client’s dog.

Results

Initial pain scores on 24 dogs ranged from 1 to 8. The median score, 25th percentile, and 75th percentile were 2.5, 1, and 4, respectively. The highest pain scores were recorded in dogs with tonsillar squamous cell carcinoma (SCC) because of profound anorexia and lethargy, and in those with osteosarcomas of the extremities because of lameness. Thirty percent (7/ 24) of the dogs were receiving analgesic medications at the onset of radiation therapy. Six dogs (5 extremity osteosarcomas, 1 nasal carcinoma) were maintained on nonsteroidal anti-inflammatory drugs. These dogs had a median pain score of 4, with a range of 1 to 6. The 25th percentile was 4 and the 75th percentile was 5. One dog (tonsillar SCC) was receiving narcotics and had an initial pain score of 5.

Twenty-one dogs completed the treatment sched- ule as planned. Two dogs (extremity osteosarcoma, retrobulbar adenocarcinoma) were euthanized before the final fraction because of progressive deterioration. One dog (mandibular osteosarcoma) died of an unre- lated cause and was excluded from further analysis. Seventy-four percent (17/23) of the dogs experienced complete relief of pain, 13% (3/23) obtained partial relief, and 13% (3/23) had no response to treatment. The 3 dogs that achieved partial palliative responses had sarcomas involving the extremities (2 osteosarco- mas, 1 undifferentiated sarcoma). One dog (nasal car- cinoma) with extensive tumor involvement of the na- sal and frontal sinuses completed the treatment protocol but obtained no relief from radiation. Time to maximum response (lowest pain score achieved af- ter initiation of therapy) ranged from 1 to 7 weeks, with a median time of 3 weeks; the 25th percentile was 1 week and the 75th percentile was 3.5 weeks. Com- plete pain relief occurred in 75% (1 3/ 17) of the com- plete responders before the final radiation fraction. With the exception of the dog with nasal carcinoma, all dogs initially receiving analgesics were taken off these medications over the course of treatment.

Relapse occurred in 8 of the 17 dogs that achieved a complete palliative response. The duration of pain relief (pain score = 0) ranged from 2 1 to 143 days. The median duration was 70 days, and the 25th and 75th percentiles were 28 and 89 days, respectively. Pallia- tion was maintained until death in 1 dog (tonsillar SCC) that died of intercurrent disease 59 days after therapy, and in 2 dogs euthanized for metastatic mel- anoma 25 and 13 1 days after irradiation. Six dogs are currently alive and free of pain at 557 (melanoma), 39 1 (melanoma), 363 (lymphoma), 36 1 (osteosar- coma), 258 (melanoma), and 235 days (melanoma) after treatment.

Objective tumor response was assessed 4 weeks af- ter treatment in 13 of 24 dogs. Three dogs did not complete the treatment protocol and 2 (melanoma, nasal carcinoma) were euthanized before the 4-week follow-up appointment. Six remaining dogs in the os- teosarcoma group (5 extremity, 1 spinal) had radio- graphic lesions and biopsy confirmation but no clini- cally measurable tumor. The complete tumor response rate was 46% (6/ 13), and the partial tumor response rate was 45% (61 13). Although objective tu- mor response was not the primary end point in this study, it is interesting to note that in the oral tumors, pain relief was associated with a complete local re- sponse in 6 dogs (4 melanomas, 1 lymphoma, 1 un- differentiated sarcoma) and with a partial response in 3 (melanomas). Dogs with tonsillar squamous cell carcinoma all had partial responses but complete pal- liation of signs. Although objective response could not be determined in dogs with osteosarcoma, 4 of them experienced complete pain relief. In these cases, palli- ative response was not reflected in radiographic evi- dence of tumor shrinkage.

Treatment was well tolerated. All of the dogs that completed the course of radiation maintained their initial body weight (within 5%) or gained weight over the treatment and follow-up period. Acute radiation reactions were mild (Table 4). Nine dogs had mild skin desquamation, pigmentation, or partial alopecia (Southwest Oncology Group grade 1). One dog had a small patch of moist desquamation (grade 2) over a recent surgical scar. Alopecia was complete (grade 2) in 3 dogs. There were no cases of mucositis.

Late radiation damage, occurring 6 months or longer after treatment, has not been recorded to date. Mild complications occurred in 2 dogs with oral mel- anoma. One developed a tooth root abscess within the radiation field 5 months after treatment. A chronic, untreated sialocele included in the treatment volume in the 2nd dog abscessed 3 months after irradiation. Both complications healed with conservative man- agement. A pathological fracture led to the euthanasia of 1 dog with osteosarcoma 3 months after therapy.

Owner satisfaction questionnaires were a require- ment of the study for 15 dogs. Two of these dogs did not complete the treatment protocol and 1 was eu- thanized 3 weeks after irradiation. Thirteen owners completed questionnaires 2 weeks after therapy and 12 owners completed them 4 weeks after therapy. Seven clients were questioned after the death of their dogs. Owners felt their pets had expressed pain through decreased appetite (9/ 1 3), decreased activity ( 1 3/ 1 3), difficulty eating (6/ 13), lameness (5/ 1 3), ag- gression (0/ 13), and/or vocalization (6/ 13). None of the responders reported difficulty complying with the treatment schedule or felt that the therapy was detri- mental to their pet. Quality of life had improved after irradiation in all but 1 patient (nasal carcinoma). All owners replied that they would consider the same treatment for another pet.

Seven refemng veterinarians were questioned after the death of their clients’ dogs. All reported that radi- ation therapy had improved the quality of life in their patients. With the additional time afforded by the treatment, owners were better able to accept the out- come of the disease than at the time of diagnosis. Al- though all of the veterinarians replied that they would recommend palliative radiation therapy in the future, some felt that not all owners would benefit from this form of cancer treatment.

Discussion

Cancer pain places a significant restriction on a pet’s daily activity and is a constant reminder of the inevitable outcome of the disease to owners. Owners need to make decisions on how long they will support an animal with incurable cancer and at what level of comfort. Through properly administered palliative care programs, it is possible to prolong life and maintain or improve its quality.

Palliation can be achieved directly through the ad- ministration of analgesics or indirectly by reduction in the size of a tumor by chemotherapy, hormonal therapy, irradiation, or surgery.” There are 4 essential requirements for any palliative regimen: ( 1) treatment must preserve mental alertness and result in minimal functional impairment; (2) therapy must not produce side effects worse than the clinical signs being palli- ated; (3) palliation should occur quickly; (4) treat- ment time and hospitalization should be kept to a minimum. For animal patients, therapy should not be prohibitively expensive.

The success of a cancer therapy has traditionally been based on objective responses such as tumor regression and survival time. 16,17 These end points, however, inadequately assess the results of a palliative treatment because they do not directly measure the benefit to the patient. Recently, techniques have been developed to measure the impact of cancer and its treatment on a human patient’slife asa whole by eval- uating physical, psychological, and social components of quality of life.

Quality of life measurements for humans have made use of self-assessment scales because quality of life depends on how a patient perceives it. The mea- surement of pain and pain relief have been important components of quality of life instruments. Pain inten- sity scores have been developed using both linear analogue and categorical scale. Pain relief after therapy is evaluated in light of a patient’s analgesic requirement. Some pain scales use separate narcotic scores,21 but most include the use of analgesics within the scoring method.

Quality of life instruments are a recent develop- ment in human medicine and are still not well tested or widely used. Criteria, however, have been established for the selection and assessment of these measurements for use in clinical trials.17~18~24,25 Similar cri- teria should be applied to the development of a quality of life instrument for veterinary patients.

Quality of life in dogs is associated with physical comfort. Providing their environment or care has not changed, the quality of life in animal cancer patients is related to the degree of pain or discomfort associ- ated with disease progression or treatment. A quality of life measurement for dogs essentially needs to ad- dress pain and its interference with daily activity. A pain score was developed as a measure of response us- ing a categorical scale with 4 levels in each of 3 cate- gories, which assessed appetite, activity level, and de- gree of lameness. Appetite and activity level were chosen as general signs that could reflect pain for a variety of cancer sites. Lameness scores were included for tumors that involved the extremities.

In humans, both quality of life and pain scores de- pend on self-assessment. Similarly, measuring tech- niques for veterinary patients should rely on owner input. The owner can observe the animal in its own environment and make comparisons to how the pet behaved before the onset of cancer and its treatment. In this study, pain scores were assigned based on the observations of owners at the outset and during the interim period between examinations. Thus, the effects of therapy could be evaluated during and after the treatment period.

Although the number of dogs evaluated was small, the method developed for scoring pain in this study appeared to fulfill many of the criteria established for human quality of life instruments. The scoring tech- nique was easy to apply. Pain scores were based on alterations in clinical signs, which owners were able to recognize easily in the home setting. The scores ap- peared responsive to the effects of treatment. For the oral and tonsillar masses, they varied directly with tu- mor remission or progression. Based on experience with animal cancer patients, appetite and activity level were chosen as general signs that could reflect pain. Owners who completed questionnaires also be- lieved that their pets expressed pain by alterations in activity (100%) and appetite (69%).

Dogs entering this trial had a median pain score of 2.5. This is relatively low on a scale of 9 and may, in part, reflect patient selection. Owners of dogs in severe pain were more likely to elect euthanasia than pursue palliative therapy. A high proportion of dogs with oral tumors were represented in this study. In these dogs, signs of discomfort were vague and pain scores were often low. In the future, it may be beneficial to vary or weight components of the pain score according to tumor type and treatment. This may make the instru- ment more sensitive to subtle changes in these patients.

The palliative role of radiation therapy has been in- tensely studied in a variety of human tumors.Hypofractionation protocols were developed to decrease treatment time in patients with limited life expectan- cies while providing effective palliation with minimal toXicity.26.29.32-35

This study shows the potential palliative benefit of the 0-7-21 radiation therapy protocol in dogs. Seventy-four percent of the patients achieved complete pain relief. This response was obtained for a variety of tumor histologies and sites. Sustained relief of pain was most often obtained in dogs with oral melanoma and was associated with local tumor control. The greatest variability in response occurred in the dogs with osteosarcoma. Only 4 of 8 dogs finished the course of treatment and achieved a complete palliative response. Relapse of pain occurred in 3 of these dogs at 51, 56, and 70 days, respectively, but 1 dog remained free of pain 36 1 days after therapy. Inconsistency in the response of osteosarcoma to radiation has been reported both in the human and veterinary literature. Palliative radiation therapy, therefore, should be reserved for dogs in which amputation is not an option.

Only 30% of the dogs were receiving analgesics when radiation therapy was initiated, although all had positive pain scores. The majority were treated with nonsteroidal anti-inflammatory drugs. Owners tended to use these medications inconsistently, and most were reluctant to try narcotics. One dog (tonsil- lar SCC) obtained minimal pain relief from butorpha- no1 despite being moderately sedated on the drug. Ra- diation therapy appeared to provide a more reliable and consistent method of pain control in these dogs. Six of 7 dogs initially receiving analgesics were taken off these medications over the course of treatment.

Recurrence of pain occurred in the majority of pa- tients within 3 months of therapy. Despite the fact that palliation was often short-lived, owners were pleased with the results of therapy. All owners questioned expressed their willingness to attempt the same treatment on another animal, suggesting that an ex- tended life of good quality for a pet was important to them, even for a relatively short period of time. Prolongation of life in cancer patients allows owners a pe- riod of adjustment to the terminal nature of this disease.

0-7-2 1 radiation therapy fulfils the requirements of a palliative treatment. The protocol was well toler-ated; it allowed for the dogs to be treated as outpatients, and decreased the number of general anesthet- ics required by more conventional regimens. Acute radiation reactions were low-grade and limited to the skin, and the complication rate was acceptable. Palli- ative responses occurred quickly and were complete tumors within the time frame of treatment, in most cases. Total treatment costs, including initial workup and therapy, ranged from CDN $250 to $350. A radical course of radiation therapy would cost between $1,200 and $1,400 at this institution.

This paper introduces a method of measuring the subjective response to therapy. The development and use of quality of life instruments should be encouraged for use in veterinary cancer trials. Quality of life measurements are not only important in the assess- ment of palliative care, but they provide valuable information in the evaluation of curative regimes, par- ticularly where survival times are comparable.

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