Quality of life assessment in dogs and cats receiving chemotherapy a review of current methods

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1 Invited Review DOI: /vco Quality of life assessment in dogs and cats receiving chemotherapy a review of current methods Kåre K. Vøls 1,MartinA.Heden 1,AnnemarieT.Kristensen 2 and Peter Sandøe 1,3 1 Department of Large Animal Sciences, University of Copenhagen, Copenhagen, Denmark 2 Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark 3 Department of Food and Resource Economics, University of Copenhagen, Copenhagen, Denmark Keywords chemotherapy, comparative oncology, oncology, small animal, small animal internal medicine Abstract This study aimed to review currently reported methods of assessing the effects of chemotherapy on the quality of life (QoL) of canine and feline patients and to explore novel ways to assess QoL in such patients in the light of the experience to date in human pediatric oncology. A qualitative comparative analysis of published papers on the effects of chemotherapy on QoL in dogs and cats were conducted. This was supplemented with a comparison of the parameters and domains used in veterinary QoL-assessments with those used in the Pediatric Quality of Life Inventory (PedsQL ) questionnaire designed to assess QoL in toddlers. Each of the identified publications including QoL-assessment in dogs and cats receiving chemotherapy applied a different method of QoL-assessment. In addition, the veterinary QoL-assessments were mainly focused on physical clinical parameters, whereas the emotional (6/11), social (4/11) and role (4/11) domains were less represented. QoL-assessment of cats and dogs receiving chemotherapy is in its infancy. The most commonly reported method to assess QoL was questionnaire based and mostly included physical and clinical parameters. Standardizing and including a complete range of potentially relevant parameters in future QoL assessments may benefit owner decision making. Correspondence address: P. Sandøe Department of Large Animal Sciences University of Copenhagen Grønnegaardsvej Frederiksberg C Denmark pes@sund.ku.dk Introduction Today owners of canine and feline cancer patients are offered specialized diagnostics often followed by advanced medical or surgical treatment options for their pets. However, clients who seek veterinary care for pets with cancer are often concerned about the negative impact treatment, not least chemotherapy, could have on their animals quality of life (QoL). This concern, which may arise from the owner s experience of chemotherapy in human medicine, often causes owners to hesitate in proceeding with therapy. 1 A literature search on Web of Science with keywords: chemo(therapy) AND small animal, revealed that more than 2000 articles concerning These authors contributed equally to the paper. this subject have been published. These studies typically contain information on adverse effects on the physical health of the animal receiving treatment, whereas only a few of them included assessment basedonawidernotionofanimalqol. Toenableadverseeffectstobequantified,rating and reporting systems and consensus documents on terminology have been developed. The grading system currently used in veterinary oncology is VCOG-CTCAE* grading of adverse effects. This system was introduced in 2004 when the veterinary cooperative oncology group published a consensus document to promote and enhance standardized reporting of adverse events in clinical trials for comparative and veterinary use. 2 The recommended terminology for use with dogs and cats was updated in It involves broad classifications of adverse John Wiley & Sons Ltd

2 Canine and feline QoL assessments 685 events based on anatomy and/or pathophysiology 3 but currently not other aspects of QoL. However, health-related OoL-questionnaires designed broadly for canine and feline patients with cancer 4 (not specifically chemotherapy patients), pain secondary to cancer 5 and cardiac disease 6,7 have been developed, and QoL reporting as part of clinical studies is receiving increased focus in veterinary medicine. 8 Standardized systems allowing qualitative and quantitative assessments of the effects of chemotherapy treatment on QoL parameters not covered by the clinical, physical parameters could be invaluable in veterinary oncology practice, as they would support client and veterinarian decision-making. However, the literature on these other aspects of animal QoL is sparse. In human medicine, the way impacts of treatment on the cancer patient are assessed has developed over recent decades. Such assessments wereoncebasedonclinicalsigns,haematology and biochemical parameters. However, there hasforquitesometimenowbeenafocusona wider range of parameters relating to the patient s QoL, including physical, emotional, social and cognitive measures. 9 Comprehensive QoL measurements have been implemented in clinical trials among the endpoint criteria for measuring outcomes. 10,11 Even where health is taken as the starting point, a wider notion of QoL is now taken for granted; thus the Basic Documents of World Health Organization (WHO) define health as a state of complete physical, mental and social well-being, and not merely the absence of disease and infirmity. 12 QoL-assessment methods for use with infants are a special case, and when the clinician is making QoL-assessments of neonates and toddlers, or other patients who are unable to express themselves, proxy informants are usually the source of information. 10,13 Therefore in the case of humans, QoL-assessment are not limited to individuals who are able express themselves in words. An example of this is the Pediatric Quality of Life Inventory (PedsQL ) questionnaire which is a modular approach to measuring health-related quality of life (HRQoL) in healthy children and adolescents and those with acute and chronic health conditions. 14 It applies 23 parameters distributed across four domains.inthecaseof2 4-year-oldtoddlersthe domain physical functioning may for example be measured in terms of problems with walking or running, the domain emotional functioning in terms of problems with feeling sad or blue, the domain social functioning in terms of problems withkeepingupwhenplayingwithotherchildren and the domain role functioning in terms of problems with missing daycare. 14 Inlightofthissituation,thepurposeofthis study was to review published studies of the effects of chemotherapy on the QoL of canine and feline patients. More specifically it was aimed to assess currently reported methods of assessing QoL and to explore novel ways to assess QoL in dogs and cats receiving anti-cancer chemotherapy by comparison with a standard QoL tool used in human pediatric oncology. Materials and methods Search strategy for literature from the veterinary field Papers in the veterinary field were collected through searches of the following electronic databases: Web of Science, Medline, Google Scholar and CAB Abstracts. The keywords used were: quality of life, welfare, well being, well-being, QoL; cat(s), feline, felidae; dog(s), canine, canidae; chemotherapy, chemo(therapy); cancer, cancerous, neoplasia, neoplastic, tumour(s), oncology. Related articles were identified via referral sampling. The inclusion criteria for articles were as follows: 1. articles had to be in English, German or a Nordic language; 2. giventhelimitedliteratureonthissubject, studies covering both canine and feline patients and all established chemotherapy protocols for different types of cancer were included; 3. studies had to directly mention, or address, a wider range of QoL parameters than clinical parameters. Exclusion criteria: 1. Single animal case studies were excluded.

3 686 K. K. Vøls et al. Table 1. Placement of parameters in PedsQL domains Physical domain Emotional domain Social domain Role-functioning (Behaviour change) (Behaviour change) (Behaviour change) (Behaviour change) Happiness Relationship with owner Relationship with owner Appetite Depression Grooming Attitude General activity Quantity of good versus bad days Tiredness, lethargy, sedation Clinical parameters Choice of tool from the human field In the human field an explorative literature search was conducted on Medline, Google Scholar and Web of Science. The keywords used were: pediatric, child, children, kid, toddler; QoL, quality oflife,welfare,wellbeing,wellbeing,well-being; chemotherapy, chemo, cancer; tool, assessment, impact. Only reviews were included. In addition, a pediatric oncologist was consulted and gave expert advice on the suitability of different tools for QoL-assessments in young children. The explorative human field literature review showed that the above-mentioned PedsQL scale, which is a general QoL-assessment tool for chronic illness, is now widely used. The pediatric oncologist in human medicine consulted for this study confirmed that this was a state-of-the-art modality for QoL-assessment in infants. The PedsQL -parameters for infants applied as a baseline for comparing reported parameters in veterinary QoL-assessments Drawing on the PedsQL definition of the four domains: physical functioning, emotional functioning, social functioning and role functioning, the parameters from the reviewed veterinary studies were matched and tabulated under appropriate domains as shown in Table 1. Results Search results, veterinary medicine A total of 74 articles met the inclusion criteria and of these 11 also met the exclusion criteria: Bergmann et al., 15 Bowles et al., 16 Fox et al., 17 Kristiansen, 18 Lana et al., 19 Brønden et al., 20 Malik et al., 21 Mellanby et al., 22 Rivera et al., 23 Tzannes et al. 24 and Iliopoulou et al. 25 See a summary of the articles in Table 2. Qualitative analysis Descriptions of QoL parameters found in the papers arelistedintables3and4.becauseclinicalparameters form an integral part of QoL-assessments, the clinical parameters applied in the papers were included, alongside the wider measures of QoL. QoL-reportings Summaryofthearticles(Table2):In10of11studies the main method of assessing QoL was by questionnaire, and in 7 of 11 studies conclusions were drawn about QoL on the basis of parameters reported by owners. In the remaining studies, authors simply reported owners conclusions about their pets QoL. In6of11studiesQoLwasdefined. Clinical parameters (Table 3): Of 11 studies 10 reported mortality and treatment success. The two clinical parameters directly investigated or observed most frequently in the studies were vomiting (6/11) and diarrhoea (6/11). Iliopoulou et al. 25 did not ask specifically for any physical adverse effects, but asked owners about clinical signs of illness associated with cancer and if the animal showed fewer clinical signs of illness. Owner-reported QoL parameters (Table 4): The two owner-reported QoL parameters most frequently reported were loss of appetite (7/11), general activity level (5/11) and tiredness/lethargy/sedation (5/11). It was found that 5of11studieshadascaleformeasuringQoL. Two studies involved questions about the animal s relationship with the owner.

4 Canine and feline QoL assessments 687 Table 2. Summary of the articles (P = prospective, R = retrospective) Study design Species Number of animals Chemotherapy protocol Type of cancer Owner/author conclusions of QoL Way of determining QoL Definition of QoL Bergmann et al. 15 R Dog 123 Miscellaneous Malignant lymphoma Owner Postal questionnaire Undefined Bowleset al. 16 R Dog, cat 23 dogs, 5 Cats Carboplatin Miscellaneous Owner Postal questionnaire Undefined Bronden et al. 20 R Dog, cat 70 dogs, 10 CATS Miscellaneous Lymphoma, hemangiosarcoma Fox et al. 17 P, R Cat 18 Liposome-entrapped cis-bisneodecanoato-trans-r,r-1, 2-diaminocyclohexane platinum(ii) Oral squamous cell carcinoma Owner Questionnaire (hand out/postal) Author Performance status questionnaire Ilipoulou et al. 25 P, R Dog 29 Miscellaneous Miscellaneous Owner Questionnaire (handout/electronic) Undefined Functional behavior, attitude and weight loss Functional, psychological and social domains Kristiansen 18 R Dog, cat 55 dogs, 3 cats Miscellaneous Miscellaneous Owner Postal questionnaire Activity level, happiness, appetite/willingness to drink Lana et al. 19 P, R Dog 9 dogs/24 dogs LDC/DOX Stage II splenic hemangiosarcoma Malik et al. 21 P Cat 60 I-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate and prednisolone Author Questionnaire (hand out) Functional behavior, mental state, general activity level, QoL scale, quantity of good/bad days, pain, water intake, mobility, general health Lymphosarcoma Author/owner Postal questionnaire, physical examination Mellanby et al. 22 R Dog 25 Miscellaneous Multicentric lymphoma Owner Questionnaire telephone Undefined Rivera et al. 23 P Dog 29 Paclitaxel Grade II or III mast cell tumor Clinical signs (p) + owner satisfaction + owners perception of QoL Author Physical examination Loosely defined as a good performance score+ absence of adverse effects Tzannes et al. 24 R Cat 31 COP Lymphoma Owner Postal questionnaire Undefined QoL, quality of life.

5 688 K. K. Vøls et al. Table 3. Clinical parameters (adverse effects directly asked about in the studies or observed in the clinic, including treatment outcomes) Parameter Treatment outcome Adverse effects directly asked about in the study/observed in the clinic Papers Mortality Treatment success Vomiting Diarrhea Acute reaction Weight loss Pain Hair coat Urine abnormalities Fever Lumps Nasal discharge Lymphadenopathy Dyspnea Neurological symptoms Nausea Bergmann et al. 15 X X X X X X X X X Bowles et al. 16 X X X X Brønden et al. 20 X X X X X X X X X Fox et al. 17 X X X X Illopoulou et al. 25 X Kristiansen 18 X X X X X X X Lana et al. 19 X X X X X X Malik et al. 21 X X X X X X Mellanby et al. 22 X X X X X Rivera et al. 23 X X X X X Tzannes et al. 24 X X n/11 10/11 10/11 6/11 6/11 1/11 5/11 4/11 4/11 2/11 3/11 1/11 1/11 1/11 2/11 1/11 1/11 Table 4. Owner reported non-clinical QoL parameters Parameters Functional behaviors Mental state Direct QoL parameters Other Papers Loss of appetite Grooming Behavior change Relationship with owner General activity level Tiredness/ lethargy/ Sedation Happiness Depression Attitude/ anxiety Scale Good/ bad better/ worse Quantity of good/bad days Animal specific questions Owner happiness/ stress Bergmann et al. 15 X X Bowles et al. 16 X X X X Brønden et al. 20 X X X Fox et al. 17 X X X X Ilipoulou et al. 25 X X X X X X X X X X Kristiansen 18 X X X X Lana et al. 19 X X X X X X X X X X Malik et al. 21 X X Mellanby et al. 22 X X Rivera et al. 23 X X X Tzannes et al. 24 X X X n/11 7/11 2/11 3/11 2/11 5/11 5/11 3/11 2/11 3/11 5/11 5/11 2/11 2/11 1/11 QoL, quality of life.

6 Canine and feline QoL assessments 689 Table 5. PedsQL domains that are covered by the articles Domains Paper: Physical Emotional Social Role PedsQL X X X X Bergmann et al. 15 X Bowles et al. 16 X X X Brønden et al. 20 X (X) (X) (X) Fox et al. 17 X X Iliopoulou et al. 25 X X X X Kristiansen 18 X X Lana et al. 19 X X X X Malik et al. 21 X Mellanby et al. 22 X Rivera et al. 23 X Tzannes et al. 24 X X n/11 11/11 6/11 4/11 4/11 PedsQL, Pediatric Quality of Life Inventory. Comparison of PedsQL QoL domains as a model for veterinary QoL-assessments PedsQL domains(table5):fully11of11ofthe veterinary studies reviewed assessed QoL with reference to the physical domain. This compares with 6 of 11 studies addressing the emotional functioning domain, 4 of 11 addressing the social functioning domain and 4 of 11 the role functioning domain. Discussion QoL-assessments are mostly questionnaire based and going beyond clinical parameters is rare for dogs and cats receiving chemotherapy. Only studies met the criteria for this review. This contrasts strikingly with the abundance of QoL literature in human cancer research. However, a review of QoL measurements in prospective studies of cancer treatments in dogs and cats 26 reveals that QoL-measurements are more frequently reported in recently published studies compared with earlier studies. This indicates that QoL is increasingly recognized as an important endpoint of treatment, being especially true for treatments aiming at prolonging life, such as chemotherapy. 8 Also, in 2013 Iliopoulou et al. 25 validated a survey-tool to assess health-related QoL in small animal chemotherapy patients that completely addressed all four of the PedsQL domains, implying that a more holistic definition of QoL in veterinary chemotherapy patients is emerging. The use of divided domains found in the The PedsQL form enabled us to visualize different dimensions of QoL assessed in veterinary chemotherapy patients. The domains used in the PedsQL forms can readily be applied in the companion animal context. Physical functioning (e.g. can the animal walk, run and swim?), emotional functioning (has the animal s behaviour changed, and is it less happy, more frightened?), social functioning (has the animal s relationship with the owner/family changed?) and role functioning (e.g.ifitisahuntingdog,isitstillabletohunt?), are of relevance for companion animal veterinary medicine. The impact of chemotherapy on the mentioned domains can be usefully investigated in the future with questionnaires, although clearly in companion animals the role and social domains may merge as the main role of most dogs and cats is to be in a social relationship with the owner. This merger of the social and role domains in one new domain used exclusively in veterinary QoL-assessments could be termed relational QoL. Surprisingly, only two studies 16,27 asked about how chemotherapy affected the relationship between owners and their dogs or cats. Obviously, the owners of companion animals will have variousbeliefs,valuesandprioritiesandfactorsthat are important to some owners may be insignificant to others. However, in general the relationship is likely to play a central role for both owner and animal when it comes to companion animals. At present, there is clearly a potential to develop standardized QoL-assessment in veterinary oncology complementing the existing VCOG guidelines so that a more complete picture of the effects of chemotherapy on treated animals may emerge. So far there is only one example of such a tool available. 19 Amongitsmanyotherbenefits,asingle, comprehensive assessment protocol, which can be used by all veterinarians to assess QoL when chemotherapy is being considered, will also enable large-scale comparisons to be made. We suggest that in order to design a valid and standardized QoL-questionnaire, collaborations across professional and disciplinary boundaries involving veterinarians, ethologists, psychologists and social scientists are warranted to ensure that all

7 690 K. K. Vøls et al. relevantaspectsofanimalqolareincorporatedin theassessmenttool,andtoensurethattheweightings for the various domains and parameters afford themostaccuratepictureoftheanimal sqol,both within each domain and overall. The questionnaire should be addressed to the animal owner, as proxy ratings by significant others have been considered areliabletoolwithwhichtoassessqolofsmall children. 11,28 Conclusion QoL-assessment of cats and dogs receiving chemotherapyisinitsinfancy.themostcommonly reported method to assess QoL was questionnaire based and mostly included physical and clinical parameters. Standardizing and including other potentially relevant parameters in future QoL assessments may support owner decision making. The current review indicates that human QoL-assessment tools like the PedsQL developed for toddlers may be a source of ideas and inspiration for QoL tools for measuring the QoL in canine and feline patients receiving chemotherapy both for individual patients and clinical trials. Acknowledgements The authors want to thank Paul Robinson for indispensable help in improving the English and for givingusefuleditorialadviceandgeirtveitforhelping us to tidy up the references. Also we are most grateful to two anonymous referees who gave very useful comments to earlier versions of the paper. Finally we thank the Department of Food and Resource Economics for economic support. References 1. Slater MR, Barton CL, Rogers KS, Peterson JL, Harris CK and Wallace K. Factors affecting treatment decisions and satisfaction of owners of cats with cancer. Journal of the American Veterinary Medical Association 1996; 208: Veterinary Co-operative Oncology Group. Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Veterinary and Comparative Oncology 2004; 2: Veterinary Cooperative Oncology Group. Common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Veterinary and Comparative Oncology 2011; 5: Lynch S, Savary-Bataille K, Leeuw B and Argyle DJ. Development of a questionnaire assessing health-related QOL in dogs & cats w/cancer. Veterinary and Comparative Oncology 2010; 9: Yazbek KVB and Fantoni DT. Validity of a health-related quality-of-life scale for dogs with signs of pain secondary to cancer. Journal of the American Veterinary Medical Association 2005; 226: Freeman LM, Rush JE, Farabaugh AE and Must A. Development and evaluation of a questionnaire for assessing health-related quality of life in dogs with cardiac disease. Journal of the American Veterinary Medical Association 2005; 226: Freeman LM, Rush JE and Oyama MA. Development and evaluation of a questionnaire for assessment of health-related quality of life in cats with cardiac disease. Journal of the American Veterinary Medical Association 2012; 240: Yeates J and Main D. Assessment of companion animal quality of life in veterinary practice and research. Journal of Small Animal Practice 2009;50: Bottomley A. The Cancer Patient and Quality of Life. The Oncologist 2002; 7: Russell KMW, Hudson M, Long A and Phipps S. Assessment of health-related quality of life in children with cancer: consistency and agreement between parent and child reports. Cancer 2006; 106: Bernhard J, Cella DF, Coates AS, et al. Missing quality of life data in cancer clinical trials: serious problems and challenges. Statistics in Medicine 2006; 17: WHO. WHO definition of health McMillan FD. Maximizing quality of life in Ill animals. Journal of the American Animal Hospital Association 2003; 39: Bergmann M, Sauter-Louis C and Hirschberger J. Lebensqualität und Lebenserwartung am malignen Lymphom erkrankter Hunde unter Chemotherapie. Tierätctliche Prax Kleintiere 2011; 39: Bowles DB, Robson MC, Galloway PE and Walker L. Owner s perception of carboplatin in conjunction

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