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Olfactory Detection of Human Cancer by Dogs. A Review of Research and Results

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Olfactory Detection of Human Cancer by Dogs. A Review of Research and Results

  1. 1. Olfactory Detection of Human Cancer by Dogs: A Review of Research Studies and Results Naomi O’Donoghue BAAF2 Dundalk Institute of Technology
  2. 2. Contents Introduction .................................................................................................................................1 Methodology................................................................................................................................ 2 The Results ..................................................................................................................................2 Untrained pets detectives .......................................................................................................2 Pickel et al. (2004) ................................................................................................................ 3 Willis et al. (2004)................................................................................................................. 3 McCulloch et al. ( 2006) ........................................................................................................4 Horvath et al. (2008).............................................................................................................. 5 Gordon et al. (2008) .............................................................................................................. 5 Horvath et al. (2010a)............................................................................................................ 5 Cornu et al. (2011) ................................................................................................................ 6 Sonoda et al. (2011)............................................................................................................... 6 Elliker et al. (2014)................................................................................................................ 7 Discussion and Recommendations .................................................................................................7 References ...................................................................................................................................9 Bibliography .............................................................................................................................. 10 Webography............................................................................................................................... 10 Appendix 1 ................................................................................................................................ 11 Table 1: Methods of Canine Training Compared.............................................................. 11 Appendix 2 ................................................................................................................................ 12 Table 2: Results of Studies Compared............................................................................. 12
  3. 3. 1 Introduction Every year, across the world, billions of dollars are invested into curing and preventing cancer; the world’s leading cause of death. Advanced screening and detection methods are developed and new drugs and technologies are trialled to help fight the many forms of this disease. Yet still, the number of deaths caused by cancer continues to grow. Current figures show that approximately 8 million people die from cancer each year and the World Health Organisation predicts that this figure will increase 80% by 2030 (Centers for disease Contol and Prevention, 2014). Early detection may be man’s greatest from of defence. However, this is often difficult as screening techniques can be expensive and in some cases are not without their own health risks. In order to encourage people to seek regular care, less invasive, and simpler methods would be advantageous, especially if they can prove to be more sensitive and accurate in detecting early stages of cancer. This demand has led to many alternative methods and technologies being explored. The theory that dogs may be able to detect human cancer using their superior olfactory system is one such alternative that has been widely researched in recent years. A dog’s sense of smell is said to be anywhere from 1000 to 10,000 times more sensitive than humans. Research has already shown that a dog can sense when an epileptic person is going to have a seizure or when a diabetic’s blood glucose level drops. This is due to the dog’s ability to smell pheromones or chemical changes taking place in the body (Spake, 2008). Extensive training and tests have been carried out to discover if dogs can also be trained to identify and detect human cancers. Findings from these studies have prompted scientists to ask: what is it exactly that the dog can smell? Does cancer have a distinguishing odour signature made up of Volatile Organic Compounds (VOCs) which are emitted into the air? And if this chemical compound could be isolated and replicated then might it be possible to develop an electronic nose which could potentially mimic the dog’s olfactory sense? It is hoped to explore these ideas and attempt to answer the questions posed.
  4. 4. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 2 Methodology This review has been conducted to ascertain the validity of the hypothesis that dogs can smell and be trained to smell cancer with a degree of accuracy great enough for diagnostic purposes and worthy of an endeavour to replicate their skill electronically. Significant studies from the past decade were explored. Efforts were made to include those studies which tested the canine’s ability to identify a variety of cancers. Nine relevant studies were chosen under these criteria. The contrasting training techniques, sample tissues used, and testing conditions were examined and the results compared. The recorded accounts of untrained pet dogs who “sniffed out” cancer in their owners have been included for comparison as they acted as the catalyst for all future research into this topic. The Results Untrained pets detectives Several cases tell the story of how pet dogs alerted their owners to the existence of cancer. It began in 1989 with a letter to the British medical journal, the Lancet, which highlighted the story of a woman who had been assured that a blemish on her upper leg was just a mole. Her pet dog, showing an extraordinary interest in the mole, persisted in sniffing it for prolonged periods and eventually tried to bite it off. This motivated the women to seek a dermatologist’s opinion and a malignant melanoma was discovered. The authors were compelled to suggest that the melanoma must have given off a scent that the dog could detect (Williams & Pembroke, 1989). Many years later, a man who had eczema on his leg for over 18 years had it re-examined after his pet dog showed a bizarre interest in, and constantly sniffed at the lesion. Again it was discovered to be cancer (Church & Williams, 2001). In yet another example, a pet dog poked and nudged at its owners left breast until finally the women discovered a lump which a biopsy later revealed as cancerous. In this case the dog’s interest never waned despite mastectomy, chemotherapy and radiation, and the woman died a year later (Welsh, et al., 2005). What is important to note from these stories is that the dogs were not trained, there was no reward for correct identification and the cancers were of different varieties. This possibly suggests that the odour was so strong and at odds with what the dogs perceived as normal and healthy that it provoked such a reaction. The intriguing potential of these claims led to the
  5. 5. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 3 numerous research studies to discover if dogs can definitely sniff out cancer and if the odour emitted is from the cancer itself or manifested by the bodies attempt to fight against the disease. Pickel et al. (2004) This study tested the ability of dogs to detect melanoma in real patients. Dogs were first trained to recognise the scent of melanoma tissue cells and to associate this with praise from the handler. The several stages of training showed promising results and so testing commenced. (Please refer to Appendix 1 for a simple comparison of the training methods used in all nine studies examined). The final test stage involved seven real patients who were covered in a number of bandages, one of which concealed the suspicious target area of skin. Dog A found the correct target on six out of seven patients but failed to recognise any melanoma on the other. Dog B had a success rate of three out of four and similarly did not identify any melanoma on the same patient as Dog A. These results were deemed significant and the failure of both dogs on the same patient showed consistency in their scent detection (Pickel, et al., 2004). The test conditions displayed some flaws, however. It was not a double blind test and the patients or the person who placed the bandages could have given the dog hints or cues. It can also be argued that the numbers in the test group were too small. If healthy control patients had been added and the dogs had correctly identified no target area it would have given more validity to the results. One criticism is that the dogs’ response may not necessarily be to the actual cancer, as one must examine a dog’s treatment of cuts or sores on their own skin and how they often lick lesions on an owner. The changes in the skin itself may simply emit an odour that the dog finds unusual (Horvath, et al., 2008). Willis et al. (2004) A “proof of principle study” was carried out to establish if dogs could successfully be trained to locate bladder cancer with more accuracy than would be expected by “chance alone” (Willis, et al., 2004). Urine samples were used in testing and controls were taken from both healthy and diseased subjects. Efforts were made to attempt to match controls to cancer samples as close as was possible by age and sex. They also included control samples from patients who suffered with other urological disorders. This made for more accurate testing conditions as any difference in scent that the dog picked up would be most likely due to the cancer and not any other variable.
  6. 6. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 4 The dogs as a group had a success of 41% while mere chance was calculated at 14% (Willis, et al., 2004). Their hypothesis was proven as the success rate was well over the probability of it being just luck. (Please see Appendix 2 which compares the resulting data from all nine studies in tabular form). The study raises the issue of whether urine is the most appropriate sample to use in testing and the training methods and selection of the dogs are open to criticism. Results, none the less, showed positive findings that bladder cancer has an odour signature that dogs can identify. Of particular note, and pointed out in the commentary of Cole, (2004), was that all of the dogs indicated one control patient sample as positive for bladder cancer. This was of such interest to the physician that tests were carried out on the subject and kidney cancer was later discovered (Cole, 2004). McCulloch et al. ( 2006) This study proved that household dogs could be quickly trained to detect breast and lung cancer using breath samples; that these dogs could discriminate cancerous samples over those from control subjects; and that the dogs accuracy was unaffected by variables such as the stage the cancer was at or whether the subject was a smoker (McCulloch, et al., 2006). Sensitivity is the percentage of cancer targets that the dog correctly identifies, while specificity is the percentage of control subjects that the dog correctly ignores. For the lung cancer trials dogs scored 99% for both sensitivity and specificity. For breast cancer, results were 88% and 98% respectively. This was the one of the first tests that showed such successful and definitive results. One criticism was that the control samples used were all from healthy individuals. Had controls been obtained from subjects with other non-cancerous lung or breast conditions, sensitivity results may not have been so inflated (Moser & McCulloch, 2010). Or perhaps, the dogs performance would have remained as high and more credence could be attributed to their ability. For experimental purposes, three patients who were in remission were used as control samples. The dogs, however, indicated one of these controls as a cancerous target in 96% of tests. A year and a half after the study the dogs’ diagnosis was confirmed, as breast cancer was found to have recurred (McCulloch, et al., 2006).
  7. 7. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 5 Horvath et al. (2008) Cancers such as ovarian carcinoma have unfavourable survival rates, which is why it is so important to discover new techniques for early detection. Horvath et al. (2008) undertook this study to examine the detection rate of ovarian cancer by trained sniffer dogs in a bid to discover if the cancer has a specific signature. They argued that while results from previous studies were encouraging, there was no definitive proof that the dogs were in fact receiving a scent emitted directly from the cancer or if they were responding to other smells associated with the body’s fight against it. Moreover, they wanted to establish not only if the dogs could detect the cancer but if they could then distinguish it from other gynaecological cancers. The dog’s sensitivity level was an amazing 100%, detecting every target scent even when presented with other ovarian tissue as controls. Their findings also indicate that ovarian carcinoma has a distinct and significant odour which is different to other gynaecological cancers (Horvath, et al., 2008). Gordon et al. (2008) This study did not obtain the levels of success they had anticipated. Urine samples from patients of breast and prostate cancer were used but the dogs in the tests did not show significant detection rates. By their own admission, a more rigorous training discipline may have produced better results. Each dog was trained at the trainers own home which allowed for potential distractions and dogs were merely chosen on the basis of what breed the trainer owned (Gordon, et al., 2008). Trainers did not work together and no regular or regimented design was put in place which caused a lack of uniformity to occur. In a systematic review of these 5 initial studies, Moser and McCulloch (2010) suggested that the discrepancies in the training techniques adopted “may have made it nearly impossible for the dogs to perform well” (Moser & McCulloch, 2010, p. 151). Horvath et al. (2010a) Building on their success and what was learned from the 2008 study; new tests were carried out to include blood samples as well as tumour tissue samples. Again, they displayed an efficient and apparently effective dog training technique. They proved that dogs can differentiate between the blood from an ovarian cancer patient and the blood from a patient suffering from other related cancers, “such as endometrial, cervical and vulvar carcinoma” (Horvath, et al., 2010a). With these results the authors indicate that the distinguishing scent discharged from the carcinoma is also detectable in the blood.
  8. 8. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 6 In another study by the author they successfully showcased the performance of an electronic nose based on their 2008 findings that each cancer has a unique volatile organic compound. The objective was for the device to detect, as the dog had, the ovarian carcinoma tissue against healthy ovarian tissue based on the VOC that was being emitted. A sensitivity of 84.4% was achieved and a specificity of 86.8% (Horvath, et al., 2010b). Continuation studies such as these, which build on the successes of previous work, contribute some of the most significant data and results. Cornu et al. (2011) This study added to the now increasing list of cancers that dogs can be trained to detect. Successful results were obtained for canine detection of prostate cancer, with both significant sensitivity and specificity achieved (91% each). Theories established by previous studies that perhaps urine was not an effective sample for use in testing could be dismissed with the performance of the dog in this trial. The training period and methods were thorough and a wide range of urine samples were used. All 108 samples were given by men who has a biopsy of the prostate performed, the results from which distinguished the cancer targets from controls. Of the 33 tests performed the dog wrongly identified 3 control samples as targets. These were re-examined and 1 control patient was found to have prostate cancer (Cornu, et al., 2011). Sonoda et al. (2011) While this study set out to train the dog to detect colorectal cancer, in the course of training the dog learned to identify several cancer types. Initial training began with breath samples of oesophageal cancer. The dog was allowed to smell the breath sample from the oesophageal patient and then was instructed to find the cup which contained the same breath sample amongst 4 control samples. This was repeated over the following days using lung cancer and gastric cancer samples. In the next stage of training any 1 of those 3 cancer samples were used at random. This then advanced to a stage where the dog was allowed to smell the sample from 1 cancer and tasked to find another cancer type amongst the controls. Other cancer types were introduced over time and by the end of training the dog could identify 12 different forms of cancer (Sonoda, et al., 2011). For both sample types a specificity of 99% was achieved and a sensitivity of 91% and 97% respectively was achieved for breath and watery stool samples. Notably, results for colorectal
  9. 9. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 7 cancer in its early stage were also very precise. The excellent results and the advanced training techniques suggest that much had been learned from previous studies. Elliker et al. (2014) In this most recent study, ten dogs were trained to identify prostate cancer. Several stages of training took place followed by three test periods. While significant results were achieved in training, levels of success in the actual tests were extremely poor. Only two dogs were deemed good enough to progress to the test phase. Sensitivity and specificity ratings achieved in the test period by the first dog were 13% and 71% respectively, and 25% and 75% for the second dog. The researchers believed that the failure of the dogs to identify in tests what they could previously identify in training was down to the fact that the dogs were not familiar with the new samples presented during the test runs. 50 prostate cancer samples were used over the course of the training phase. They suggest that the dogs may have “memorised the odour of each individual donor’s urine during training” instead of learning the scent associated with the cancer in general (Elliker, et al., 2014). The study by Cornu et al. (2011) discredits this theory that the dog memorised targets samples, as 26 cancers were used during their training phase, and when the new, unfamiliar samples were introduced in the testing phase, the dogs still achieved sensitivity of 91%. In one stage of testing the dogs were rewarded whether they detected the target or not, as no one in the room knew where the sample target lay. This was rectified in the next stage but the author acknowledged that the dog’s decision making may have been confused by this error which could have contributed to the poor success rates. The only other study examined that displayed such poor results was Gordon et al. (2008) which similarly tested prostate cancer using urine and also used 10 dogs in training. It is widely acknowledged that the poor results were most probably due to the poor training structure, so this may also be the case in this study. The failure of so many of the dogs to even make it past the training stage could point to an ineffective training technique. Discussion and Recommendations Nine scientific studies and three anecdotal stories of dogs detecting human cancers have been reviewed throughout this report. The primary objective was to discover if dogs could be trained to detect human cancers and the overall combined findings reveal that they can. Some studies displayed far superior training techniques and their results reflected this effort
  10. 10. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 8 with much greater success rates. Most studies used the reward-based clicker method to train the dogs, which proved sufficient where it was adopted appropriately. The data does not reveal any one breed, sex or age profile of dogs that showed the best results. Indeed, it is difficult to compare the studies in this regard as successes or failures cannot solely be attributed to the dog in isolation, but the many other variables such as design of training, samples used and testing conditions must also be considered. It was hoped to establish if each cancer contains volatile organic compounds and a unique chemical signature. Several of the studies claimed evidence of this to be true. However, while we now know of their existence, research has still not been able to decipher what exactly this chemical make-up is. The establishment of a more concrete breakdown of chemical configurations and biomarkers was expected by this author due to the profound leaps forward in science and technology over the last twenty years. However, data found in this area was somewhat disappointing. Still, advances are being made which will undoubtedly lead to a break-through in the future. With regard to the sample types used, the exhaled breath and tumour tissue appears to give the highest success rates. This author would suggest that breath samples may be the most advantageous, non-invasive and cost effective means of cancer testing if the work that is being carried out on electronic noses continues to a prototype stage. Results from the Horvath et al. (2010b) study incite confidence that the dogs’ sense of smell will one day be fully replicated with substantial sensitivity. Perhaps in the future, blowing into a cancer breathalyser will be a routine procedure carried out at every G.P. visit and cancers will be caught at their early stages. These studies all stemmed from one occurrence where a dog potentially saved its owners life by sniffing out a skin cancer (Williams & Pembroke, 1989). A significant number of cases were found where volunteers who had simply given samples to be used as controls were discovered to have cancer. These people may be alive today due to the fact that this research is being carried out. So, while cancer sniffing dogs may not yet have advanced to the stages where they are being used in practical work conditions like other explosive and narcotic sniffer dogs, they have, none-the-less, already started their life saving work. One is left in no doubt that dogs really are man’s best friend!
  11. 11. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 9 References Centersfordisease Contol andPrevention,2014. CancerPrevention and Control. [Online] Available at:http://www.cdc.gov/cancer/dcpc/resources/features/worldcancerday/ [Accessed02 April 2014]. Church,J. & Williams,H.,2001. Anothersnifferdogforthe clinic?. Lancet, Volume 358,p. 930. Cole,T.,2004. Commentary:Teachingdogsnew tricks. BJM, Volume329, p.718. Cornu,J. etal.,2011. OlfactoryDetectionof Prostate CancerbyDogs SniffingUrine:A StepForward inEarly Diagnosis. European Association of Urology, 59(2),pp.197-201. Elliker,K.etal.,2014. Keyconsidertionsforthe experimentaltrainingandevaluationof cancer odourdetectiondogs:lessonslearntfromadouble-blind,controlledtrial of prostate cancer detection. BMCUrology, Volume14,p. 22. Gordon,R. et al.,2008. The Use of Caninesinthe Detectionof HumanCancers. The Journalof Alternativeand Complementary Medicine, 14(1),pp.61-67. Horvath,G., Andersson,H.& Paulsson,G.,2010a. Characteristicodourinthe bloodrevealsovarian carcinoma. BMC Cancer, Issue 10, p. 643. Horvath,G., Chilo,J.& Lindblad,T.,2010b. Differentvolatilesignalsemittedbyhumanovarian carcinomaand healthytissues. FutureOncology, 6(6),pp.1043-1049. Horvath,G., Jarverud,G.,Jarverud,S.& Horváth,I.,2008. Human OvarianCarcimonaDetectedby SpecificOdor. IntegrativeCancerTherapies, Issue 7,pp.76-80. McCulloch,M. et al.,2006. DiagnositcAccuracyof Canine ScentDetectioninEarly- andLate-Stage Lung and BreastCancers. IntegrativeCancerTherapies, 5(1),pp. 30-39. Moser,E. & McCulloch,M., 2010. Canine scentdetectionof human cancers:A review of methods and accuracy. Journalof Veterinary Behavior, Issue 5,pp.145-152. Pickel,D.etal.,2004. Evidence forcanine olfactorydetectionof melanoma. Applied Animal BehaviourScience, Volume 89,pp. 107-116. Sonoda,H. etal.,2011. Colorectal cancerscreeningwithodourmaterial bycanine scentdetection. Gut, 60(6), pp.814-819. Spake,A.,2008. Could a Dog SaveYourLife?. [Online] Available at:http://www.diabetesforecast.org/2008/mar/could-a-dog-save-your-life.html [Accessed 06 April 2014]. Welsh,J.,Barton,D. & Ahuja,H., 2005. A case of breastcancer detectedbya petdog. Community Oncology, Issue 2,pp.324-326. Williams,H.&Pembroke,A.,1989. Snifferdogsinthe melanomaclinic?. Lancet, Volume 1,p.734.
  12. 12. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 10 Willis,C. etal.,2004. Olfactorydetectionof humanbladdercancerbydogs:proof of principle study. BMJ, Volume 329, pp.712-718. Bibliography Balseiro,S.C.&Correia,H.R.,2006. Is olfactorydetectionof humancancerbydogsbasedon major histocompatibilitycomplex-dependentodourcomponents? –A possible cure anda precocious diagnosisof cancer. Medical Hypotheses, 66,pp.270-272. King,C.R.2006. Dogs May Be Able toDetectCancer. Oncology Nursing Forum, 33(1),pp.21-22. Lippi,G. 2011. Letterto the Editor. European Association of Urology, 60(4),p.29 Roine,A.etal.,2012. Detectionof smell printdifferencesbetweennonmalignant andmalignant prostate cellswithanelectronicnose. FutureOncology, 8(9),pp.1157-1165. Siegel,R.,Naishadham,D.andJemal,A.2013. Cancer statistics, 2013. CA: A CancerJournalfor Clinicians, 63(1), pp.11–30. Webography Cancer ResearchUK,2014. Transitionalcell cancer of the kidney (renalpelvis) or ureter and its treatment. [Online] Available at:http://www.cancerresearchuk.org/cancer-help/about-cancer/cancer- questions/transitional-cell-cancer-kidney-ureter-treatment [Accessed7April 2014]. Can Do Canines,2012. Diabetes AssistDogs. [Online] Available at:http://can-do-canines.org/how-dogs-help/diabetes-assist-dogs/ [Accessed05 April 2014]. Dog BreedInfoCentre,2014. Understanding a Dog'sSenses. [Online] Available at:http://www.dogbreedinfo.com/articles/dogsenses.htm [Accessed04 April 2014]. InSituFoundation,2013. Studies. [Online] Available at:http://www.dogsdetectcancer.org/category/info/studies [Accessed03 April 2014].
  13. 13. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 11 Appendix 1 Table 1: Methods of Canine Training Compared Breed of Dog(s) Age and Sex of dog Number of Dogs trained and used in testing Dog’s previous training history Method of dog training Length of training Picket et al. (2004) Standard Schnauzer Retriever Bitch 4 year old male 6 year old bitch 2 Certified bomb detection dog and Master Hunter Not indicated Several weeks and Less than several weeks Willis et al. (2004) Variety of breeds Not indicated 6 No previous search or scent training Clicker training 7 months McCulloch et al. (2006) 3 Labrador retrievers 2 Portuguese water dogs 7-18 months 3 dogs, 2 bitches 5 No previous training Food reward-based clicker training 2-3 weeks Horvath et al. (2008) Riesenschnauzer 4 years old 1 Not indicated Resembled sniffer dog training 12 months – twice per week Gordon et al (2008) Various Breeds 2-8 years old 10 Most had previous training Clicker training with food reward 12-14 months 2-7 times per week Horvath et. al. (2010) Black Giant Schnauzer 7 year old bitch 3 year old bitch 2 Previously trained to detect ovarian carcinoma No previous training Resembled sniffer dog training 9 months Cornu et. al. (2011) Belgian Malinois Shepherd Young Dog 1 No previous training Clicker Training with ball reward 24 months – 5 days per week Sonoda et. al. (2011) Labrador retriever 8 year old bitch 1 Trained in water rescue and then as a cancer detection dog Play reward-based approach Not indicated Elliker et. al (2014) 7 different breeds 1-11 years old 4 bitches and 6 dogs 10 and 2 No previous odour detection training Food reward-based clicker training 5-13 months
  14. 14. Naomi O’Donoghue Olfactory Detection of Human Cancer by Dogs BAAF2 12 Appendix 2 Table 2: Results of Studies Compared Cancer tested Sample type Structure of test Sensitivity / Specificity or Success rate Cancer : Control Picket et. al. (2004) Melanoma Melanoma tissue cells Single Blind 75-85.7% success 1:7-29 Willis et. al. (2004) Bladder Urine and dried urine Single Blind 41% success 1:6 McCulloch et. al. (2006) Lung and Breast Exhaled breath Double Blind 99/99% and 88/98% 1:4 Horvath et. al. (2008) Ovarian Tumour tissue Double Blind 100/97.5% 2:8 Gordon et. al (2008) Breast and Prostate Urine Blinded but unspecified 22/18% Sensitivity and 17% success 1:6 Horvath et. al. (2010) Ovarian Blood and tumour tissue Double Blind 100/98% and 100/95% 1:5 Cornu et. al. (2011) Prostate Urine Double Blind 91/91% 1:5 Sonoda et. al. (2011) Colorectal Exhaled breath and watery stool samples Double Blind 91/99% and 97/99% 1:4 Elliker et. al (2014) Prostate Urine Double Blind 13/1% and 25/75% 1:3

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