Post-surgical treatment of thyroid carcinoma in dogs with retinoic acid 9 cis improves patient outcome

Abstract

The objective of the present study was to compare the effects of isotretinoin 9-cis (RA9-cis) as a post-surgery treatment of thyroid carcinoma to a traditional treatment (doxorubicin) and no treatment. Owners who did not want their dogs to receive treatment were placed into the control group A (GA; n=10). The remaining dogs were randomly placed into either group B (GB; n=12) and received doxorubicin at a dose of 30 mg/m 2 every three weeks, for six complete cycles or group C (GC; n=15) and treated with RA9-cis at a dose of 2 mg/kg/day for 6 months. The time of the recurrence was significantly shorter in the GA and GB compared to GC (P=0.0007; P=0.0015 respectively), while we did not detect differences between GA and GB. The hazard ratio of recurrence between GA and GB compared to GC were 7.25 and 5.60 times shorter, respectively. We did not detect any differences between the other groups. The risk ratio of recurrence was 2.0 times higher in GA compared to GC and 2.1 times higher in GB compared to GC. The type of carcinoma had an effect on time of survival with follicular carcinomas having an increased mean survival time than follicular-compact carcinomas (P<0.0001) and follicular-compact carcinomas had a longer mean survival time than compact carcinomas. The interaction among treatment and type was significant, but survival time in follicular carcinomas did not differ between treatments. In follicular-compact carcinomas the survival time of GC was greater than GB (P<0.05), but we did not detect a difference between GA and GB. In conclusion, this study shows that the use of surgery in combination with RA9-cis treatment significantly increases survival rate and decreases the time to tumor recurrence when compared to doxorubicin treated or untreated dogs. The histological type of carcinoma interacted with treatment for time to recurrence and survival time, with more undifferentiated carcinomas having a worse prognosis than differentiated carcinomas.

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

“…However, endothelial cells of compact carcinomas showed higher expression of RARα than those of the other groups (healthy and follicular-compact carcinomas), and further studies are needed to help our understanding of the role of this receptor in carcinoma progression. Retinoic receptor expression in thyroid carcinoma is consistent with our recent study (Castillo et al, 2016) in which isotretinoin 9-cis (RA9-cis) treatment increased time of recurrence and survival time in dogs with follicular-compact and compact thyroid carcinoma when compared to doxorubicin after surgery. Miyajima et al (2006) showed that in canine masts cells, RARα expression was positively correlated with response to retinoic acid treatment.…”

“…These factors were expressed at an intermediate level in follicular-compact carcinomas, which is consistent with the degree of differentiation of this type of tumour compared with compact carcinoma. Indeed, we have recently shown (Castillo et al, 2016) that thyroid follicular compact carcinomas had a greater time to recurrence than compact carcinomas in dogs. In the present study, we showed that the pattern of expression of VEGF was similar to that of IGF-1/IGF-1R in the different groups, as demonstrated by the upregulation of VEGF expression in fibroblasts and endothelial cells of compact carcinoma.…”

“…Retinoids are natural or synthetic derivatives of vitamin A that modulate cell growth, differentiation and apoptosis (de Mello Souza et al, 2014). In dogs, retinoids are used to treat various types of cancer such as cutaneous lymphoma, mast cell tumours and corticotroph adenoma of the pituitary (White et al, 1993;Miyajima et al, 2006;Castillo et al, 2006;Castillo and Gallelli, 2010), and recently in thyroid carcinoma (Castillo et al, 2016). The action of retinoic acid is mediated by retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) (Kasimanickam et al, 2013).…”

Toceranib phosphate in the treatment of canine thyroid carcinoma: 42 cases (2009‐2018)

“…[22][23][24][58][59][60][61] There is also a small study reporting the administration of 9-cisretinoic acid, a first generation retinoid, for the treatment of canine thyroid tumour. 62 Overall, no studies have demonstrated improved measures of outcome. As the natural disease is acknowledged to be slowly progressive, SD is difficult to evaluate as representing CB.…”

“…Measurable tumour responses between 10 and 54% were reported, but significant improvements in PFIs and OSTs were not demonstrated 22–24,58–61 . There is also a small study reporting the administration of 9‐ cis ‐retinoic acid, a first generation retinoid, for the treatment of canine thyroid tumour 62 . Overall, no studies have demonstrated improved measures of outcome.…”