The Veterinary Journal 234 (2018) 126–129
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Short Communication
Treatment of solid tumors in dogs using veterinary high-intensity focused ultrasound: A retrospective clinical study M.-O. Ryu, S.-H. Lee, J.-O. Ahn, W.-J. Song, Q. Li, H.-Y. Youn* Department of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
A R T I C L E I N F O
Article history: Accepted 28 February 2018 Keywords: Cancer treatment Dog High-intensity focused ultrasound Solid tumor
A B S T R A C T
High-intensity focused ultrasound (HIFU) is a cancer treatment tool that focuses ultrasound energy on tumor tissues, which initiates necrosis via heat and mechanical effects. The efficacy of veterinary HIFU (vHIFU) was evaluated for the treatment of solid tumors in dogs. Data from 11 client-owned dogs with various solid tumors treated by vHIFU between 2013 and 2017 were retrospectively evaluated. Ten of the 11 dogs were followed up; clinical signs were alleviated in five. Four dogs exhibited a decrease in tumor size, and bleeding stopped in all four dogs with hemorrhagic tumors. Side effects included hyperthermia or erythema on the application site, enteritis, and skin ulcerations. These results suggest that vHIFU could be used as an alternative cancer treatment for dogs with solid tumors. © 2018 Published by Elsevier Ltd.
Cancer treatment in companion animals includes surgery, radiation therapy, chemotherapy, immunotherapy, and gene therapy (Ehrhart, 2005; Farese and Withrow, 2013). Despite the development of new anticancer drugs and new molecular therapies, cancer remains an exceedingly difficult disease to conquer. High-intensity focused ultrasound (HIFU) attacks cancer tissue via thermal and mechanical effects (Kennedy, 2005). Exposure to heat (56 C) for >1 s results in thermal damage to tissue and irreversible cellular damage due coagulative necrosis. Highintensity focused ultrasound focuses ultrasound energy to the target area to generate heat greater than 80 C, which results in cell death. The mechanical phenomenon begins with inertial cavitation. Acoustic fields create a gas cavity in the targeted tissue (inertial cavitation), and necrosis of surrounding tissue occurs as bubbles in the tissue are broken by ultrasonic waves. Subsequently, the necrotizing tissue gradually contracts to form fibrous scar tissue. In human medicine, HIFU is widely used to treat various tumors, including liver, breast, and prostate cancers (Kennedy, 2005). In addition, it is widely used for benign genital tumors, such as uterine fibroids, because of its noninvasive characteristics (Chapman and Ter Haar, 2007). Similarly, veterinary HIFU (vHIFU) can be used for the treatment of tumors, although the procedure has not been widely performed to date. In the present study, we
* Corresponding author. E-mail address:
[email protected] (H. -Y. Youn). https://doi.org/10.1016/j.tvjl.2018.02.019 1090-0233/© 2018 Published by Elsevier Ltd.
evaluated the effectiveness of veterinary HIFU (vHIFU) for the treatment of solid tumors in dogs. Data for all dogs with solid tumors treated with vHIFU at the Seoul National University Veterinary Medical Teaching Hospital (SNU-VMTH, Seoul, Republic of Korea) between 2013 and 2017 were retrospectively evaluated. The treatment was limited to dogs with solid tumors that could be penetrated by ultrasound (>10 mm in height, along the beam axis; and >5 mm in width, transverse). Dogs with tissues containing gas or metal-like objects, dogs that were unable to tolerate anesthesia, and dogs with calcified masses were excluded. All dogs were client-owned animals and owners’ consent was obtained before the entire procedure. This research was conducted in accordance with regulations dictated by the SNU-VMTH. A vHIFU device (VIFU2000, Alpinion Medical Systems) developed for animals was used in the present study (Fig. 1). All procedures were performed under general anesthesia to restrict movement. A transducer for a dry platform was used at a frequency of 1,500,000 Hz. The following default parameters were applied for each procedure: duty cycle, 50%; pulse-repetition frequency, 10 Hz; power, 100 W; time, 10 s; pulse width, 50; pulse repetition time, 100 ms; and number of radiofrequency cycles, 75,000. A total of three treatment sessions were planned for each dog; this number was adjusted according to the owner’s willingness to continue treatment and the dog’s condition. Therefore, the dogs underwent one to three HIFU procedures, with a 1-month interval between each procedure. All dogs were prescribed analgesics (tramadol, 4 mg/kg orally twice daily for 7 days; hydromorphone, 0.025 mg/kg intravenously on the procedure day) during the treatment period
M.-O. Ryu et al. / The Veterinary Journal 234 (2018) 126–129
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Fig. 1. A veterinary high-intensity focused ultrasound (HIFU) machine (A) and a dog being treated with vHIFU (B). C shows the main probe of vHIFU. The equipment enclosing the probe is filled with distilled water, and there is a membrane at the right angle of the probe. D: Side view of the probe. The membrane can be inflated by user control. E: A mass before vHIFU treatment. F: A mass following vHIFU treatment which resulted in a hyperechoic lesion within the targeted area.
to control procedure-related pain, which was evaluated by a pain scoring system for use in dogs.1 Recheck visits for all dogs were performed every 2 weeks until 1 month after the final procedure. At each follow-up visit, the dogs were evaluated for any improvements in clinical signs and the tumor size was measured. Moreover, a complete blood count and serum chemistry panel was performed, with additional urinalysis for dogs with urinary bladder tumors. The size of external masses was measured using a caliper, while masses in the body cavity were measured using ultrasound. In dogs with urinary bladder tumors, a fixed amount of sterile saline (depending on dog size, 10 to 35 mL) was injected after insertion of a urethral catheter. When the size was measured using ultrasound, the same operator performed all measurements for an individual dog. A total of 11 dogs received vHIFU therapy (Table 1). All dogs continued to receive the medication prescribed before the procedure; owners agreed to vHIFU because the previously prescribed treatments were ineffective. One (dog 5) was excluded because of wave reflection (a linear hyperechoic waveform that appeared on the entire ultrasound machine screen). Among the remaining 10 dogs, five experienced improvement in clinical signs after the first session. Alleviation of hematuria and dysuria after the procedure was observed for three dogs with transitional cell carcinoma of the urinary bladder. One dog (dog 4) experienced temporary resolution of sneezing, while another dog’s (dog 2) blood loss anemia markedly improved after cessation of oral bleeding (PCV (packed cell volume) before treatment: 22.2%; PCV at 1 week after treatment: 33.7%; reference interval: 37.3%–61.7%).
1 See: Colorado State University Veterinary Medical Center Canine Acute Pain Scale http://www.vasg.org/pdfs/CSU_Acute_Pain_Scale_Canine.pdf (Accessed 28 February, 2018).
Four of 10 dogs exhibited partial responses at 3 months after the first session as defined by RECIST (response evaluation criteria in solid tumors; Eisenhauer et al., 2009; Table 2). In one of the remaining six dogs (dog 11), the mass boundaries and hyperechoic region within the mass, as observed on ultrasound, appeared clearer and smaller after completion of vHIFU. Side effects immediately after the procedure included hyperthermia or erythema on the application area, enteritis, and skin ulceration (CTCAE, common terminology criteria for adverse events; grade 1; Veterinary cooperative oncology group, 2016). Hyperthermia, which was observed for most dogs immediately after the procedure, was temporary. One dog (dog 6) developed enteritis (abdominal pain, melena) likely due to shallow anesthesia and subsequent movement during the procedure which resolved after two days of symptomatic therapy. Skin ulceration affected the buccal region of a dog with an oral mass (dog 2) and the perianal area in a dog with apocrine gland anal sac adenocarcinoma (dog 10). None of the dogs exhibited hematological adverse effects. The distribution of pain scores after the procedure was as follows: 0 (n = 5); 1 (n = 4); and 2 (n = 1; dog 6). In the present study, we evaluated vHIFU therapy for dogs with solid tumors that could not be surgically resected and/or were refractory to conventional chemotherapy. Following vHIFU, the tumor size decreased in four of 10 dogs and two of the 10 dogs exhibited partial remission according to RECIST. Furthermore, all four dogs with bleeding from hemorrhagic tumors exhibited noticeably alleviated clinical signs. High-intensity focused ultrasound causes heat-induced coagulation of hemorrhagic regions; therefore, it has the potential to control local bleeding associated with hemorrhagic tumors. Previous studies investigated the hemostatic effects of HIFU and it was demonstrated that lacerated vessels could be occluded by heat, and thrombus formation,
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Table 1 Dog characteristics and response to therapy of n = 11 dogs with solid tumors treated with high-intensity focused ultrasound (HIFU). Dog
Sex
Age (years)
Bodyweight (kg)
Breed
Tumor location
Histopathological tumor type
HIFU applications
Improvement of clinical signs
Response (RECIST)
Side effects
1
MC
13
4.4
Maltese
UB
TCC
3
SD
None
Piroxicam
2
MC
10
4.43
Poodle
Oral cavity
SCC
3
PR
Skin ulcerations
Piroxicam, carboplatin
3
FS
8
3.28
Maltese
Ductal carcinoma
3
SD
4
MC
11
11.7
Cocker spaniel
Mammary gland Left orbit
Disappearance of hematuria Alleviation of dysuria Cessation of oral bleeding Alleviation of anemia None
Adenocarcinoma
1
Could not be evaluated
Sunitinib, carboplatin None
5
MC
10
10.39
Hip
MCT
1
–
–
None
6
MC
12
4.5
UB
TCC
1
None
SD
Enteritis
Piroxicam
7 8
MC MC
10 10
2.93 4.98
Cocker spaniel Yorkshire terrier Maltese Maltese
Temporary alleviation of sneezing –
Temporary erythema None
UB UB
TCC TCC
2 1
SD SD
None None
9
IF
13
2.25
UB
TCC
1
SD
None
Piroxicam Piroxicam, chlorambucil None
10
MC
10
5.57
Yorkshire terrier Dachshund
None Disappearance of hematuria None
AGASACA
2
None
PR
Skin ulcerations
Melphalan
11
IM
10
6.63
Shih-Tzu
Hip, abdominal cavitya UB
TCC
3
Disappearance of hematuria Alleviation of dysuria
SD
None
Piroxicam
Medication
FS, female spayed; IF, intact female; IM, intact male; MC, male castrated; UB, urinary bladder; TCC, transitional cell carcinoma; SCC, squamous cell carcinoma; MCT, mast cell tumor; AGASACA, apocrine gland anal sac adenocarcinoma; RECIST, response evaluation criteria in solid tumors. a The tumor located in the abdominal cavity of Dog 10 was a metastatic lymph node.
Table 2 Tumor size before and after veterinary high-intensity focused ultrasound (vHIFU) therapy. The tumor size was measured 3 months after initial vHIFU therapy and decreased in four of 10 dogs. Dog
Tumor type
Location of mass
Tumor size Before vHIFU
2
SCC
6 7 10
TCC TCC AGASACA
Left maxillary mass Right maxillary mass Urinary bladder Urinary bladder Abdominal massa Perianal mass
4.7 1.5 cm2 2.2 1.7 cm2 2.95 1.53 2.74 cm3 3.16 1.92 2.41 cm3 3.83 cm 1.98 1.41 cm2
After vHIFU Disappeared 1.66 1.54 cm2 2.58 1.37 2.38 cm3 3.34 1.11 1.82 cm3 3.55 cm Disappearedb
SCC, squamous cell carcinoma; TCC, transitional cell carcinoma; AGASACA, apocrine gland anal sac adenocarcinoma. a The size of the abdominal mass has been described as the maximal height of the mass. b The perianal mass disappeared in the acoustic window because of a decrease in size. The shrunken mass was probably located in the pelvic cavity.
vascular fibrosis, and granuloma formation also occurred (Martin et al., 1999; Hwang et al., 2003). It is noteworthy that HIFU can enhance drug delivery (Constatin and Ronald, 2008) and that synergism is expected to occur if it is used in combination with traditional chemotherapy. Moreover, thermosensitive or sonosensitive anticancer drugs such as liposomes have been developed (Fabienne et al., 2010). It would be interesting to investigate these anticancer drugs in combination with HIFU in veterinary clinical trials and whether it would have the potential to reduce systemic side effects of traditional chemotherapy while enhancing the local antitumor effect. To the best of our knowledge, this was the first study to investigate the clinical application of vHIFU therapy in dogs with naturally occurring solid tumors. In human medicine, many studies have described the clinical application of HIFU therapy in cancer dogs and demonstrated efficacy of this technique (Kennedy, 2005). We believe that HIFU can be an effective treatment for solid tumors
in dogs, similar to humans. Although it remains unclear whether the prolonged survival observed in the present study was a consequence of HIFU therapy, the treatment helped improving the quality of life by alleviating clinical signs. Conflict of interest statement None of the other authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. Acknowledgements This report was supported by the BK 21 Plus Program for Creative Veterinary Science Research and the Research Institute for Veterinary Science at the College of Veterinary Medicine, Seoul National University.
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