Abstract
Intranasal tumors in dogs are malignant solid tumors that are primarily treated with radiotherapy and often recur post-treatment. Combination therapy is pivotal in cancer therapy. Effective drugs include fluoropyrimidine 5-fluorouracil (5-FU) and toceranib phosphate. TS-1, an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil, is proven to be safe in dogs with solid tumors. While the oral drug toceranib phosphate (Palladia®) is safely administered, the combined toxicity with TS-1 is unknown. We aimed to determine the dosage of this combination in dogs. In the preclinical/clinical trials conducted here, we used a standard 3+3 cohort design with fixed doses of toceranib phosphate (2.4 mg/kg) administered thrice weekly. TS-1 administration was initiated at a dose of 0.5 mg/kg (upper limit 2.0 mg/kg) thrice weekly. Four cohorts were included to confirm the safety of TS-1 and toceranib phosphate. Each cohort was followed up for 1 month. The intranasal tumor types included in the clinical trial (n=13) were adenocarcinoma (n=7), squamous cell carcinoma (n=1), non-epithelial malignancy (n=2), undifferentiated carcinoma (n=1), and transitional carcinoma (n=2). The TS-1 dosage could be increased up to its dose limit in the preclinical/clinical trials. The TS-1 dose to combine with toceranib phosphate thrice weekly was 2.0 mg/kg. This regimen was well-tolerated in dogs. Thus, combined TS-1 and toceranib phosphate therapy is safe for dogs with intranasal tumors.
Keywords: dog, intranasal tumor, toceranib phosphate, TS-1
Most intranasal tumors in dogs are malignant solid tumors, with radiotherapy as the primary treatment. However, post-treatment recurrence is common [9]. Without treatment, the reported median survival time associated with nasal tumors is 3 months, extending to 8 to 19.7 months with radiation therapy [9]. Chemotherapy has also been cited for its palliative effect [9]. In human medicine, the fluoropyrimidine 5-fluorouracil (5-FU) is recognized for its antitumor properties [24]. However, in veterinary medicine, dose-dependent myelosuppression, gastrointestinal toxicity, and neurotoxicity have been observed in dogs following 5-FU administration, whereas severe central nervous system toxicity has been noted in cats [5]. Furthermore, using 5-FU is inconvenient as it requires weekly intravenous administration [5].
Combination therapy, a treatment modality that combines two or more therapeutic agents, is the cornerstone of cancer therapy [3]. The success of combination chemotherapy, compared with that of single-agent treatment, is attributed to the provision of maximal cell death within the range of tolerable host toxicity [5]. This approach potentially reduces drug resistance while simultaneously providing therapeutic anticancer benefits, such as reducing tumor growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis in cancer cells [3]. The treatment protocols for canine lymphoma best illustrate the success of combination therapy in veterinary oncology [5]. Drugs effective against solid tumors in veterinary medicine include carboplatin [4], doxorubicin [2], 5-FU [13], and toceranib phosphate [11]. However, combination chemotherapy is not frequently used in the treatment of solid tumors [5].
TS-1 is an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil [6, 8]. Tegafur is converted into 5-FU after absorption. Gimeracil is a dihydropyrimidine dehydrogenase inhibitor that prevents 5-FU degradation. Oteracil, an orotate phosphoribosyltransferase inhibitor, reduces 5-FU activity in the intestine and minimizes its toxicity to normal gastrointestinal mucosa. Toxicity studies have been conducted in dogs [6, 8], and the safety of TS-1, administered orally at a mean dose of 1.1 mg/kg twice daily on thrice-weekly (Monday, Wednesday, and Friday) every week, has been confirmed in dogs with solid tumors [14]. Antitumor effects of TS-1 have been confirmed in some cases [14].
Nasal tumor chemotherapy includes administration of toceranib phosphate (Palladia®, Zoetis Japan, Tokyo, Japan) [11], adriamycin, and carboplatin [10]. In this study, we focused on the combination of TS-1 with toceranib phosphate, as these were oral drug that were safe to administer, for monitoring the side effects upon adjusting dosage for palliative treatment. We hypothesized that the dose intensity could be increased by adding TS-1 to toceranib phosphate. We aimed to determine the dosage of the TS-1 and toceranib phosphate combination in normal dogs and to conduct a clinical trial demonstrating the safety of this combination in treating intranasal tumors in dogs.
MATERIALS AND METHODS
A 3+3 cohort study was performed for preclinical/clinical trials [22]. Three healthy intact female beagles aged 7 years, bred for research purposes, were used in the preclinical trial. TS-1 and toceranib phosphate were administered for 1 month followed by a 1-month washout. The dogs underwent physical examination as well as complete blood count (CBC) and blood chemistry tests before the preclinical trial. Physical examination was performed daily, whereas CBC and blood chemistry tests were performed at a 2-week interval. The dogs with intranasal tumors included in this prospective clinical trial had been brought to the Azabu University Veterinary Teaching Hospital between September 2022 and September 2023. Data regarding the breed, sex, age, body weight, diagnosis, treatment history, tumor-node-metastasis (TNM) classification at the time of the initiation of tegafur/gimeracil/oteracil therapy, toceranib phosphate dose, administration period, cause of discontinuation, tumor response to TS-1/ toceranib phosphate administration, and adverse events (AEs) were extracted from the medical records of the dogs. All the experimental and clinical procedures were approved and performed in accordance with the guidelines of Laboratory Animal Committee of Azabu University (No. 220404–3, 220526–2). This study was conducted in accordance with the best practice recommendations wherever possible [18]. Written informed consent was obtained from the animal owners. Dogs previously diagnosed with a solid tumor and receiving first-line treatment (i.e., RT) were included in the study. Dogs who were already receiving chemotherapeutic drugs other than toceranib phosphate and TS-1 and dogs who showed abnormal blood/chemistry test results were excluded. No chemotherapeutic agents (Toceranib phosphate and TS-1) were administered during the clinical study. When a cohort was completed, patients who had PD underwent re-irradiation before proceeding to the next cohort. Regarding the tumor response, the efficacy of TS-1 and toceranib phosphate was evaluated only in cases from 3 months post-irradiation, and a relatively high-dose of TS-1 (1.5 and 2.0 mg/kg) was administered.
Drug doses
Toceranib phosphate was effective against intranasal tumors [12]; therefore, it was administered at a dose of 2.4 mg/kg thrice weekly. TS-1 (S-1 Taiho, OKAYAMA TAIHO Pharmaceutical Co., Ltd., Bizen, Japan) was initially administered at a dose of 0.5 mg/kg thrice weekly and then increased to 1.0 and 1.5 mg/kg based on the Fibonacci sequence in both preclinical and clinical trials. Toceranib phosphate and TS-1 were not administered on the same day. Originally, when using the Fibonacci sequence, the next dose of 1.5 mg/kg would be 2.5 mg/kg. As the dosage was set at 2.0 mg/kg, which is the upper limit dose of TS-1 alone [14], 2.0 mg/kg was probably preferred instead of 2.5 mg/kg. Thus, the effects of all four doses (0.5, 1.0, 1.5, and 2.0 mg/kg) were examined. A 3+3 test was performed as described previously [19]. The TS-1 dose was increased if AEs related to these drugs were not observed in all the three dogs. The drug dose was determined to be the previous lower dose if AEs were observed in two dogs. All three dogs were tested again if AEs were observed in one dog. In clinical trial, dose escalation was performed only if antitumor efficacy was not achieved, or the ongoing cohort was completed.
Toxicity evaluation
AEs were classified using VCOG-CTCAE (2016) [23] during preclinical and clinical trials (Table 1). All laboratory findings from each cohort were considered, and the next cohort study was performed if the clinician determined that the AEs were unrelated to or due to an underlying disease and did not affect activities of daily living (ADL).
Table 1. List of adverse events in each cohort by grade based on Veterinary cooperative oncology group−Common terminology criteria for adverse events.
| AEs | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|---|
| Conjunctiva/Cornea | Symptomatic, intervention not indicated | Symptomatic, interfering with function but not ADL | Symptomatic, interfering with ADL | - | - |
| Anorexia | Coaxing or dietary change required to maintain appetite | Oral intake altered (≤3 days) without significant weight loss; oral nutritional supplements/appetite stimulants may be indicated | Of >3 days duration; associated with significant weight loss (≥10%) or malnutrition; IV fluids, tube feeding or force feeding indicated | Life-threatening consequences; TPN indicated; >5 days duration | Death |
| Vomiting | <3 episode in 24 hr, medical intervention not indicated | 3–10 episodes in 24 hr; <5 episodes/day for ≤48 hr; parenteral fluids (IV or SC) indicated ≤48 hr; medications indicated | Multiple episodes >48 hr and IV fluids or PPN/TPN indicated >48 hr | Life-threatening (e.g. hemodynamic collapse) | Death |
| Diarrhea | Increase of up to 2 stools per day over baseline; no increase in frequency, however, consistency decreased over baseline | Increase of 3–6 stools per day over baseline; medications indicated; parenteral (IV or SC) fluids indicated ≤48 hr; not interfering with ADL | Increase of >6 stools per day over baseline; incontinence >48 hr; IV fluids >48 hr; hospitalization; interfering with ADL | Life-threatening (e.g. hemodynamic collapse) | Death |
| Neutropenia | 1,500 μL–1 to <LLN | 1,000–1,499 μL–1 | 500–999 μL–1 | <500 μL–1 | Death |
| Elevated ALT | >ULN to 1.5 × ULN | >1.5–4.0 × ULN, transient (<2 weeks) | >4.0–10 × ULN | >10 × ULN | - |
| Elevated T-Bil | >ULN to 1.5 × ULN | >1.5−3.0 × ULN | >3.0–10 × ULN | >10 × ULN | - |
AEs: adverse events, ADL: activities of daily living, ALT: alanine transaminase, T-Bil: total bilirubin, LLN: lower limit of normal, ULN: upper limit of normal.
Response analysis
In clinical trial, tumor status prior to TS-1 administration and tumor response were evaluated using the WHO TNM classification [17] and cRECIST [15], respectively.
RESULTS
Preclinical trial
In this 3+3 cohort study, TS-1 in combination with toceranib phosphate was administered at four planned doses (0.5, 1.0, 1.5, and 2.0 mg/kg administered thrice weekly) for 1 month (Table 2). AEs were not observed during the physical examination, CBC, or chemical tests at any dose. Therefore, the optimal dose of TS-1 in combination with toceranib phosphate (2.4 mg/kg administered thrice weekly) that can be administered thrice weekly in normal Beagle dogs was determined to be 2.0 mg/kg.
Table 2. Dosing of TS-1 and toceranib phosphate in a preclinical trial.
| Dog | Age (years) |
Body weight (kg) |
Cohort (TS-1 dose) |
Toceranib phosphate doses (mg/kg) |
|||
|---|---|---|---|---|---|---|---|
| 0.5 mg/kg | 1.0 mg/kg | 1.5 mg/kg | 2.0 mg/kg | ||||
| A | 7 | 12.9 | 0.5 | 1.0 | 1.6 | 2.1 | 2.3 |
| B | 7 | 12.7 | 0.5 | 1.0 | 1.6 | 2.1 | 2.4 |
| C | 7 | 11.5 | 0.6 | 1.2 | 1.7 | 2.3 | 2.6 |
Clinical trial
The clinical trial included 8 dogs (total 13 enrolled) (Table 3). The breeds included Shiba (n=2, total 2 enrolled), Miniature Dachshund (n=1, total 1 enrolled), West Highland White Terrier (n=1, total 3 enrolled), White Shepherd (n=1, total 2 enrolled), Yorkshire Terrier (n=1, total 2 enrolled), and mixed breed (n=2, total 3 enrolled). Sex was five males (three castrated) and three females (three spayed). The median age of the patients was 11 years (range: 6–11 years). The median body weight was 7.6 kg (range: 4–30 kg). The diagnoses included adenocarcinoma (n=4), squamous cell carcinoma (n=1), non-epithelial malignancy (n=1), undifferentiated carcinoma (n=1), and transitional carcinoma (n=1). Regarding treatment history, all the dogs underwent radiotherapy. The median number of days of toceranib phosphate administration prior to TS-1 combination therapy was 43 (range: 28–180, n=5); then, TS-1 was administered additionally because these five cases did not respond to toceranib phosphate. The other three dogs were started receiving both toceranib phosphate and TS-1,simultaneously. Three of these eight dogs received one escalated doses of TS-1, and one of these eight dogs received two escalated doses of TS-1. Four of these escalated dogs were re-irradiated at the end of the cohort. The distribution of TNM classification at the time of initiating tegafur/gimeracil/oteracil therapy was stage 1 (n=5), stage 2 (n=1), stage 3 (n=3), and stage 4 (n=4). The median dose of toceranib phosphate was 2.5 mg/kg (range: 2.0–2.7 mg/kg). The median period of administration was 112 days (range: 77–251 days). The causes of discontinuation were PD (n=1), or death (n=4: tumor related [n=3], other [n=1]). Others were all moved to the next cohort for dose escalation (n=4). AEs were observed in the conjunctiva/cornea (n=2) and included gastrointestinal symptoms, such as diarrhea (n=1), anorexia (n=1), vomiting (n=1), neutropenia (n=1), elevated alanine transaminase (ALT) level (n=2), and elevated T-Bil level (n=1). The identified AEs did not impair the ADL and did not significantly impair the quality of life. In this study, it was possible to complete a 3+3 cohort study wherein TS-1 in combination with toceranib phosphate was administered at four planned doses (0.5, 1.0, 1.5, and 2.0 mg/kg thrice weekly) to dogs with tumors for 1 month (Table 4). The median treatment period for the relatively high doses of TS-1 (1.5 and 2.0 mg/kg) was 103 days (range, 99–140 days), and these dogs tolerated this combination well. Tumor response to high-dose TS-1/ toceranib phosphate administration was able to evaluate in one dog. The dog underwent irradiation and toceranib phosphate, followed by re-irradiation. However, since no antitumor effect was observed, a cohort administered with a TS-1 dose of 0.5 mg/kg was evaluated. Four months after re-irradiation, that was 6 months after starting TS-1 1.0 mg/kg (Fig. 1A), the tumor had grown; thus, the dose was increased to 2.0 mg/kg, and tumor shrinkage was observed 3 months after dose escalation of TS-1 (Fig. 1B). No serious AE was observed despite the concomitant use of radiotherapy.
Table 3. Demographic data and combination therapy in the clinical trial.
| No | Breed | Sex | Age | Body weight | Diagnosis | TNM classification | Stage | Treatment history before starting TS-1 administration |
Duration of Palladia administration alone (days) | Previous cohort doses of TS-1 (mg/kg) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First irradiation protocol (total dose [Gy]/fractions) | Second irradiation protocol (total dose [Gy]/fractions) | Total dose (Gy)/fractions | The number of course (s) | Cumulative absorbed dose to the cornea (Gy) |
|||||||||||
| OD | OS | ||||||||||||||
| 1 | White Shepherd | MC | 6 | 30 | Transitional carcinoma | T3 N0 M0 | 3 | 30/4 | - | 30/4 | 1 | 14.7 | 13.0 | 34 | - |
| 2 | West Highland White Terrier | FS | 9 | 7.6 | Adenocarcinoma | T1 N0 M0 | 1 | 30/4 | - | 30/4 | 1 | 0.0 | 0.1 | 43 | - |
| 3 | Shiba | MI | 14 | 11.2 | Adenocarcinoma | T1 N0 M0 | 1 | 30/4 | - | 30/4 | 1 | 13.8 | 18.2 | 28 | - |
| 4 | Mixed breed | MC | 13 | 4.6 | Squamous cell carcinoma | T4 N0 M0 | 4 | 30/4 | - | 56/8 | 1 | 13.8 | 14.6 | 180 | - |
| 5 | Yorkshire Terrier | MC | 11 | 4 | Adenocarcinoma | T4 N0 M0 | 4 | 30/4 | - | 30/4 | 1 | 26.0 | 12.7 | 90 | - |
| 6 | Mixed breed | FS | 15 | 7.5 | Non-epithelial malignancy | T1 N0 M0 | 1 | 30/4 | - | 30/4 | 1 | 0.3 | 0.2 | 0 | - |
| 2 | West Highland White Terrier | FS | 9 | 7.6 | Adenocarcinoma | T1 N0 M0 | 1 | 30/4 | 26/4 | 56/8 | 2 | 0.1 | 0.1 | - | 0.7 |
| 1 | White Shepherd | MC | 7 | 27 | Transitional carcinoma | T4 N0 M0 | 4 | 30/4 | 26/4 | 56/8 | 2 | 31.0 | 39.5 | - | 0.6 |
| 5 | Yorkshire Terrier | MC | 12 | 4 | Adenocarcinoma | T4 N0 M0 | 4 | 30/4 | 26/4 | 56/8 | 2 | 42.7 | 21.6 | - | 1.1 |
| 2 | West Highland White Terrier | FS | 9 | 8 | Adenocarcinoma | T1 N0 M0 | 1 | 30/4 | 26/4 | 56/8 | 2 | 0.1 | 0.1 | - | 1.1 |
| 6 | Mixed breed | FS | 15 | 8 | Non-epithelial malignancy | T1 N1b M0 | 2 | 30/4 | - | 30/4 | 1 | 0.3 | 0.2 | - | 1.3 |
| 7 | Shiba | MI | 11 | 10.5 | Adenocarcinoma | T3 N0 M0 | 3 | 30/4 | - | 30/4 | 1 | 16.6 | 25.4 | 0 | - |
| 8 | Miniature Dachshund | FS | 14 | 5 | Undifferentiated carcinoma | T3 N0 M0 | 3 | 30/4 | - | 30/4 | 1 | 25.2 | 25.2 | 0 | - |
FS: female spayed, MC: male castrated, MI: male intact, -: none.
Table 4. Adverse events and their grades in each case in the clinical trial.
| No. | TS-1 doses (mg/kg) | Cohort (TS-1 dose) |
Palladia doses (mg/kg) |
TS-1 administration period (days) | AEs classification |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.5 mg/kg |
1.0 mg/kg |
1.5 mg/kg |
2.0 mg/kg |
Conjunctiva/Cornea | Anorexia | Vomiting | Diarrhea | Neutropenia | Elevated ALT | Elevated T-Bil | ||||
| 1 | 0.6 | ● | 2.6 | 251 | 0 → 1 | 0 | 0 | 0 | 0 | 0 | 0 | |||
| 2 | 0.7 | ● | 2.0 | 77 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||
| 3 | 0.6 | ● | 2.5 | 178 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||
| 4 | 1.1 | ● | 2.2 | 46 | 0 → 1 | 0 → 1 | 0 → 1 | 0 | 0 | 2 → 3 | 0 | |||
| 5 | 1.1 | ● | 2.5 | 155 | 0 | 0 | 0 | 0 | 0 | 0 | 0 → 2 | |||
| 6 | 1.3 | ● | 2.7 | 115 | 0 | 0 | 0 | 0 → 1 | 0 → 1 | 0 | 0 | |||
| 2 | 1.3 | ○ | ● | 2.0 | 188 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| 1 | 1.5 | ○ | ● | 2.6 | 140 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| 5 | 1.6 | ○ | ● | 2.5 | 101 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| 2 | 2.1 | ○ | ○ | ● | 2.0 | 105 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| 6 | 2.0 | ○ | ● | 2.7 | 77 | 0 | 0 | 0 | 0 | 0 | 1 → 2 | 0 | ||
| 7 | 2.0 | ● | 2.3 | 99 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||
| 8 | 2.0 | ● | 2.5 | 112 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||
AE: adverse event, ALT: alanine transaminase,T-Bil: total bilirubin, ●: Assigned cohort dose of TS-1, ○: Previously assigned cohort doses of TS-1.
Fig. 1.
Computed tomography (CT) findings of case No. 2. TS-1 (1.3 mg/kg) and toceranib phosphate were administered thrice weekly; however, the tumor progressed (A left: axial, right: sagittal). The TS-1 dose was subsequently increased to 2.1 mg/kg thrice weekly, and the tumor showed a partial response (PR) on CT scan 3 month later after dose escalation of TS-1 (B left: axial, right: sagittal). Plain CT image, window level 50 HU, width 300 HU.
DISCUSSION
This study is important in three ways. First, the preclinical/clinical trials were conducted to determine the dosage of TS-1. The TS-1 dose that could be administered thrice weekly in combination with 2.4 mg/kg of toceranib phosphate for 1 month was determined to be 2.0 mg/kg. Second, AEs of the conjunctiva/cornea were concerning; however, no dose-limiting factor was observed in this study, even after radiotherapy. Third, this combination was effective against some tumors.
First, the preclinical/clinical trials were conducted to determine the dosage of TS-1. Toceranib phosphate acts on multiple receptor tyrosine kinases (RTKs) and inhibits tyrosine kinase activity associated with tumor growth, angiogenesis, and metastasis [11]. Suppression of the activity of these RTKs arrests the cell cycle of tumor cells, induces apoptosis, and exerts antitumor effects. Toceranib phosphate exerts antitumor effects in dogs with solid tumors [11]. Nonetheless, AEs such as myelosuppression, liver dysfunction, renal damage, and acute gastrointestinal disturbances have also been reported. TS-1 contains tegafur, a prodrug of 5-FU that exerts antitumor effects via metabolism in the liver. Consequently, the combination of TS-1 and toceranib phosphate is expected to increase the risk of liver dysfunction in patients undergoing treatment with TS-1 [6, 8]. However, hepatotoxicity was absent in both the preclinical and clinical trials. In addition, no abnormality was observed during other physical examinations or CBC and blood chemistry tests. The AEs associated with combination therapy of TS-1 and toceranib phosphate may be related to the method of administration. While TS-1 is administered twice daily to humans [16], it was not the case in this study. Bis in die (BID) (twice-daily) administration every other day yields similar results with fewer AEs [1, 20, 21]. Thus, in our previous study, we used BID administration three times a week [14]. However, AE-related discontinuation of TS-1 occurred after 5 months [14]. In this study, the median treatment period for the relatively high doses of TS-1 (1.5 and 2.0 mg/kg) was 103 days (range, 99–140 days), with dogs tolerating this combination well. However, even at 2.0 mg/kg, the risk of AEs would presumably increase if TS-1 was administered for a long duration. The findings of the present study suggest that toceranib phosphate and TS-1 combination therapy is safe for 1 month or more.
Second, AEs of the conjunctiva/cornea were concerning; however, no dose-limiting factor was observed in this study, even after radiotherapy. Ocular toxicity is a complication associated with long-term administration in beagles [6, 8], and conjunctival hyperemia requiring treatment (grade 2) has been observed in cases of administration for more than 3 months [14]. The instillation of artificial tears improves ocular AEs [7]. Conjunctival/corneal complications were not observed in this study, and the short duration of the trial and low dose were thought to play a role. However, ocular problems were rarely reported by the owner even in cases treated for a duration of more than 3 months, and the cases were asymptomatic grade 1 conjunctivitis/ocular surface diseases. The administration interval of TS-1 was changed in the present study, which could influence drug metabolism. Additionally, the clinical trial included a dog with previously irradiated eye(s) due to an intranasal tumor, leading to concerns about worsening conditions, such as corneal perforation. However, dose-related AEs were not suggested. The amount of drug transferred, attributed to decreased tear production, was minimal, suggesting no anticipated radiation-related complications.
Third, this combination was effective against some tumors. This combination is considered to have an effect on the epithelial system in humans [16]. Although only few cases of TS-1 use in animals have been reported, there have been cases wherein TS-1 alone was effective [14]. Even in recurrent cases, a response was observed upon increasing the TS-1 dose in this study, suggesting that TS-1 itself is effective.
This study has some limitations owing to the small sample size, the short duration of the preclinical and clinical trials (1 month), and its single-arm nature. It was a biased group of target animals, because the target cases in clinical trial were those in a veterinary referral hospital, previous treatments were not standardized, and the cases were limited to those with poor response to treatment. Increasing the TS-1 dose may be considered, as severe AEs were not observed following the administration of the TS-1 dose (2.0 mg/kg). The strategy of administering TS-1 as semel in die (SID) rather than a BID was to reduce the risk of exposure due to drug splitting by reducing the number of doses. Moreover, by ensuring similar dosing of TS-1 and toceranib phosphate, we wished to prevent confusion among the owners. However, the change in the method of administering TS-1 from divided BID to SID may affect the TS-1 dose. A dog that responded had an increased dose of TS-1, which may indicate the efficacy of TS-1 alone.
This study suggests that 2.0 mg/kg of TS-1 and 2.4 mg/kg of toceranib phosphate administered thrice weekly can be continued safely for 1 month or longer in dogs with intranasal tumors. It is necessary to confirm the long-term safety and efficacy of this dose in the future.
CONFLICT OF INTEREST
The authors have nothing to disclose.
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