Sage Journals: Discover world-class research

Abstract

Objectives

Mammary tumours in cats are biologically aggressive. The standard of care relies upon wide surgical resection. Chemotherapy has been described in the macroscopic disease setting; however, limited efficacy has been shown. The aim of this study was to assess the efficacy of toceranib phosphate in macroscopic feline mammary tumours (FMTs).

Methods

A total of 17 cats with cytologically or histopathologically confirmed mammary adenocarcinoma (gross disease) were prospectively enrolled. Toceranib phosphate was administered at a median dose of 2.77 mg/kg (range 2.3–3.2) PO q48 h. No corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) were administered. Toxicity was graded according to Veterinary Cooperative Oncology Group–Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 criteria. The response was assessed after 1 month, following Response Evaluation Criteria In Solid Tumours (RECIST) criteria.

Results

Toxicity was observed in eight cats, with most instances being grade 1 or 2, which were managed with supportive care. Only one cat experienced grade 3 toxicity (anorexia), which resolved after a dose reduction. Clinical benefit was seen in 12 (64.7%) cats and an objective response was seen in six (35.2%) cats. One cat experienced complete response, five had partial response, six had stable disease and five had progressive disease. One cat showed distant progression (malignant pleural effusion) despite continued partial remission of the primary tumour. The median progression-free survival and median overall survival time were 91 days (range 30–158) and 145 days (range 31–234), respectively.

Conclusions and relevance

Toceranib phosphate showed clinical benefit and a good safety profile in advanced or recurrent FMTs, offering a new alternative in the treatment of this disease; however, further prospective and randomised studies are required to further assess its efficacy. Interestingly, one cat developed distant metastases while the primary tumour showed partial response, suggesting that primary tumour and metastatic disease may not sustain the same sensitivity to toceranib.

Keywords

Toceranib phosphate feline cancer feline mammary tumour chemotherapy

Introduction

More than 80% of feline mammary tumours (FMTs) are malignant,¹ and tubular, tubulopapillary and solid carcinomas are most common.^2
–4 Malignant FMTs are biologically aggressive, with a high metastatic rate to the regional lymph nodes and lungs. Metastasis is a negative prognostic factor,^5
–9 as is tumour size, disease stage,^10,11 histological grade⁸ and surgical ‘dose’.^1,7,12

Surgical removal is the preferred first-line treatment for localised FMTs, either alone or in combination with chemotherapy. Bilateral mastectomy significantly increases both median progression-free survival (PFS) and overall survival time (OST) when compared with unilateral mastectomy, with survival extending to 917 days compared with 566 days.^7,12 Chemotherapy (doxorubicin alone or combined with cyclophosphamide) has been used in macroscopic disease,^13
–16 with objective responses in 50% of inoperable or stage IV tumours (those with distant metastases).13,14,17 Postoperative adjunctive chemotherapy has also been investigated and is often recommended by oncologists,¹⁵ despite the lack of clear survival benefit.10,16,18 –20

Toceranib phosphate (Palladia; Pfizer) is a multitarget tyrosine kinase inhibitor (TKI), similar to sunitinib, with activity against KIT receptor, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptors (PDGFR) and others. Toceranib can also decrease regulatory T cells.²¹ These tyrosine kinases are expressed in mast cell and other tumours in dogs and also in cats.^22–26 In cats, a clinical response has been demonstrated in squamous cell carcinomas^27,28 and mast cell tumours.^29,30 Clinical benefit has also been reported in carcinomas in diverse locations, including vertebral osteosarcoma, chemodectoma and cutaneous melanoma, when treated with toceranib, either as monotherapy or in conjunction with surgery,^31
–36 but not in injection site sarcomas.³⁷ Some case series include FMTs, but case numbers were low and specific FMT efficacy was not determined.^30,31 A recent study showed no difference in survival between patients with stage IV disease (those with measurable metastases) receiving traditional chemotherapy, metronomic chemotherapy and toceranib.³⁸

Toceranib is well tolerated in cats.³⁹ Reported side effects are mainly gastrointestinal, most often Veterinary Cooperative Oncology Group (VCOG) grades 1 and 2 (anorexia, vomiting and diarrhoea), similar to those described in dogs.^{27,28,30,31,37,39} Severe gastrointestinal side effects were uncommon and managed by temporarily discontinuing the drug or reducing the dose or frequency of administration. There may be a higher incidence of hepatotoxicity in cats compared with dogs.^30,39

The primary aim of this prospective study was to evaluate the effectiveness of oral toceranib in treating macroscopic FMTs. The secondary goal was to examine the safety of toceranib in this specific population.

Materials and methods

Cats presenting to the referral hospital Instituto Veterinario de Oncología Comparada (IVOC, Valencia, Spain) with a measurable, primary mammary adenocarcinoma confirmed histologically or cytologically, with or without metastasis, between December 2012 and 2015 were enrolled. Primary tumours were categorised as de novo (newly detected) or recurrent, and patients with metastatic disease were included. Cats were either not considered surgical candidates or the client declined surgery. Client consent was required for enrolment. This study did not require institutional ethical approval, as established internationally recognised ‘best practice’ was followed, and clinical decision-making and patient management were not altered by recruitment.

Histopathological classification (conducted in a single laboratory by non-board-certified pathologists) followed the Elston and Ellis grading system.^40,41 Cases diagnosed using cytology were classified as carcinoma if at least 30% of the cells showed more than three criteria of malignancy.^42
–44 Samples from lymph nodes were classified as metastatic if one or more clusters of epithelial cells with criteria of malignancy were detected.

The initial assessment of the patients (within 7 days before the start of therapy) included the following: physical examination; measurement of the maximum diameter of the primary lesion; full abdominal ultrasound; three-view thoracic radiography or thoracic CT; complete blood count (CBC); biochemistry (minimum alanine aminotransferase [ALT], alkaline phosphatase [ALP], creatinine, urea, glucose and total solids [TS]); and urine analysis (pH, density, glucose, ketone bodies, nitrites, leukocytes, bilirubin, protein). The urine protein:creatinine (UPC) ratio was measured if proteinuria was detected. Fine needle aspirates (FNAs) were taken from abnormal lymph nodes or suspected metastatic lesions detected on physical examination or imaging techniques. Cats were excluded for the following reasons: if they had received chemotherapy, corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) in the 2 weeks before enrolment; had haematological or biochemical abnormalities likely to impact survival or preclude administration of toceranib; or were systemically unwell or had non-mammary tumour related estimated life expectancy >2 months. Cats receiving other chemotherapy treatment or radiation therapy during toceranib treatment were excluded. However, supportive treatments (including antibiotics, anti-inflammatories and corticosteroids) were permitted as needed.

Toceranib phosphate was prescribed at a starting dose between 2.3 and 3.2 mg/kg q48h, at the discretion of the prescribing clinician, and compounding was allowed.

Information collected included signalment, weight, reproductive status (including spayed date), previous hormonal treatments, location and size of the tumour (maximum diameter, cm), previous tumour treatments, and histopathology and cytology reports. Best response was assessed as per modified Response Evaluation Criteria In Solid Tumours (RECIST)⁴⁵ (Table 1), and toceranib-related toxicity was assessed according to VCOG–Common Terminology Criteria for Adverse Events (VCOG-CTCAE) criteria⁴⁶ (Table 2). When cats presented with two tumours, the one with the longest diameter was considered for the RECIST response.⁴⁵ Dose reductions or delays, rescue treatment, dates of progression and death, and cause of death were also collected.

Table 1

Modified Response Evaluation Criteria In Solid Tumours (RECIST) criteria as applied to 17 cats with macroscopic mammary tumours⁴⁵

CR	Disappearance of all target lesions, or normalisation of lymph nodes
PR	At least 30% reduction in the longest diameter of target lesion
SD	Less than 30% reduction (or 20% increase) in the longest diameter of target lesion
PD	Either the appearance of one or more new lesions or at least a 20% increase in the diameter of target lesion

CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease

Table 2

Veterinary Cooperative Oncology Group–Common Terminology Criteria for Adverse Events for the most common in the study⁴⁶

Adverse event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Neutropenia (/μl)	1500 to <LLN	<1000–1499	500–999	<500	Death
ALT	>1.5 times upper limit	>1.5–4.0 times upper limit	>4.0–10 times upper limit	>10 times upper limit	Death
Vomiting	Lasting ⩽24 h that resolves with or without the use of medication and/or parenteral fluids	Lasting >24 h	Requires hospitalisation, interfering with activities of daily living (eating, drinking, sleeping, defecating and urinating)	Life-threatening (eg, haemodynamic collapse)	Death
Anorexia	Lasting <48 h	Lasting 2–3 days	Duration of 3–5 days; associated with significant weight loss (⩾10%) or malnutrition; IV fluids, tube feeding or force feeding indicated	Duration of >5 days; life-threatening consequences; total parenteral nutrition indicated	Death

ALT = alanine aminotransferase; IV = intravenous; LLN = lower limit of normal

Cats were reassessed (physical examination and CBC) 2 weeks after starting toceranib. The response was assessed after 1 month, repeating physical examination, measurement of the mass and imaging tests as performed on the initial assessment. At this visit, CBC, biochemistry and urine analysis were repeated to assess for toxicity. Cats that showed progressive disease (PD) were offered rescue treatments (alternative medical therapies, at the discretion of the clinician), while cats that responded or had stable disease (SD) continued on toceranib with a monthly assessment, including physical examination, CBC, biochemistry and urine analysis. Imaging tests were repeated every 3 months. Clinical benefit was complete response (CR), partial response (PR) or SD for at least 2 months.

Dose-limiting toxicities (DLTs) were those graded as 3 or 4, which were refractory to supportive treatment (maropitant or mirtazapine for gastrointestinal toxicity) or lasted >7 days. If cats experienced DLTs, toceranib treatment was temporarily suspended (usually for 5–7 days) and/or the dose (minimum 2.3 mg/kg) and/or the frequency of administration were reduced, at the clinician’s discretion.

Statistical analysis was performed using commercially available software (GraphPad Prism version 7.0; GraphPad Software).

The Kaplan–Meier product-limit method was used to determine median PFS (MPFS) and median OST (MOST). PFS was defined as the time from inclusion to the study (starting toceranib) to disease progression, while OST was defined as the time from inclusion in the study to death.

Results

A total of 23 cats were presented with macroscopic primary mammary adenocarcinoma (confirmed histologically or cytologically). Two were excluded: one due to stage IV chronic kidney disease (CKD); the other due to concurrent chemotherapy. Four eligible cats were not enrolled as their owners declined treatment. In total, 17 cats were included. A total of 16 owners declined surgery due to either financial constraints or previous negative experiences that made them unwilling to consider surgical procedures or anaesthesia. One cat was not considered a surgical candidate due to metastases to the suprasternal lymph node. Population characteristics and response data are summarised in Table 3.

Table 3

Clinical characteristics and response of 17 cats with macroscopic mammary carcinoma treated with toceranib

Case	Age (years)	Breed	Previous surgery	Presentation	Primary mass size (cm)	Histopathological grade	Ulceration	Metastasis at presentation	Previous chemotherapy	Dose toceranib (mg/kg)	Response (of primary lesion)
1	8	DSH	No	De novo	2.3	II	No	No	No	2.8	SD
2	12	Persian	No	De novo	3.7	II	Yes	No	Docetaxel	2.3	PR
3	11	DSH	Yes	Recurrence	4	N/A	No	No	No	3.0	PD
4	10	DSH	Yes*	De novo	1.8	III	No	No	No	2.6^†	SD
5	16	DSH	Yes	Recurrence	5.1	N/A	Yes	No	Doxorubicin	2.6^†	PR
6	9	Siamese	Yes	Recurrence	3.2	N/A	Yes	No	No	3.2	PD
7	10	DSH	No	De novo	4.1	II	No	No	Docetaxel	2.3	SD
8	12	DSH	Yes*	De novo	3.3	III	No	No	No	2.7	SD
9	8	DSH	Yes	Recurrence	2.1	III	Yes	No	No	3.1	PR
10	14	DSH	No	De novo	2.6	III	No	No	No	2.8	PD
11	8	Siamese	Yes*	De novo	1.5	N/A	No	No	No	2.6	CR
12	14	DSH	No	De novo	1.7	III (post morten)	No	No	No	2.5	SD
13	8	DSH	No	De novo	2.1	III	No	Axillary and sternal LN	No	3.0	PR
14	12	DSH	Yes*	De novo	2.8	II	No	No	No	2.9^†	SD
15	11	Siamese	Yes*	De novo	4.3	N/A	No	Axillary LN	Doxorubicin	3.1	PR
16	9	DSH	No	De novo	2.7	III	No	Inguinal LN	No	2.4	PD
17	10	DSH	Yes*	De novo	2.9	II	No	No	no	2.8	PD

*Previous surgery for a different mammary tumour

†

Cats for which toceranib phosphate was compounded

CR = complete response; DSH = domestic shorthair; LN = lymph node; N/A = not available; PD = progressive disease; PR = partial response; SD = stable disease

The median age of the cats was 10.6 years (range 8–16 years). All cats were female with 12 intact and five spayed cats (four had been spayed after 2 years of age; in the fifth cat, the date was unknown). In total, 13 cats were domestic shorthairs, three were Siamese and one was Persian. The median body weight was 3.8 kg (range 2.1–6.2). No cat had received hormonal treatments, including exogenous oestrogen, progesterone or combined treatments.

Four cats had recurrent primary tumours after surgery and six cats had de novo (newly detected) tumours after previous surgery for an FMT in another site (6/13, 46%). Four of the cats with de novo tumours had contralateral tumours after unilateral chain mastectomy, and two in the same chain after local mastectomies. The remaining sevn cats did not have a history of previous mammary tumours. Two cats presented with two tumours. In nine cats, the tumour was in the caudal mammary glands; in six cats, the tumour was in the cranial mammary glands; and in two cats, there were lesions in both. The median maximum tumour diameter was 2.95 cm (range 1.5–5.1). Four cats presented with ulcerated tumours, three of which were recurrent. Two of these cats were receiving cefovecin (Convenia; Zoetis), while the other two were treated with topical cleaning/disinfection.

A definitive diagnosis was achieved by punch biopsy in nine cats and wedge biopsy in two. There were no post-biopsy complications. Six cats were diagnosed with grade III adenocarcinoma, while five cats had grade II adenocarcinoma. Four cats had tubulopapillary adenocarcinomas and four had solid adenocarcinomas; in the remaining case, no subtype was assigned. In one case initially diagnosed by cytology, a grade III adenocarcinoma was confirmed at necropsy. Three cats presented with lymph node metastases, affecting the axillary and sternal nodes in one case, the axillary in the second and the inguinal in the third. No cats had pulmonary metastases at presentation: one cat had a thoracic CT that showed enlargement of the axillary lymph nodes. An abdominal ultrasound revealed no intra-abdominal metastasis in any of the cats.

CBC was performed in all 17 cats. Of them, four (23.5%) had mild anaemia (packed cell volume 25–35%, reference interval [RI] 30.3–52.3). White cell counts were in the range of 4.5–22.3 ×10³/μl (RI 5.1–17.2) with four cats having leukocytosis. One cat had a slight elevation of ALT (88 UI/l, RI 12–30), another had elevated urea (35 mg/dl, RI 5.7–12.9) and two cats had stage 2 CKD (International Renal Interest Society classification).

Four cats had previously received chemotherapy and received toceranib after disease progression: two cats had disease progression after treatment with doxorubicin (1 mg/kg IV every 3 weeks); and two cats had progression after docetaxel (2.25 mg/kg IV every 3 weeks). In all four cases, PD was recorded before the third planned chemotherapy treatment. The median administered dose of toceranib was 2.77 mg/kg PO q48h (range 2.3–3.2). In three cats, toceranib was compounded. No cats received corticosteroids or NSAIDs during toceranib treatment. The overall response rate was 35.2% (6/17), with a clinical benefit in 64.7% (12/17) of cases. One cat experienced CR, five PR), six SD for 2 months or more and five experienced PD. Three cats that experienced PR also experienced improvement in ulceration of primary masses. In one case (cat 15), the response was assessed by CT 30 days after starting toceranib, achieving PR for the primary tumour. Moreover, the assessment of the metastatic axillary lymph node was consistent with SD.

Eight cats (47%) had side effects, with only one cat showing DLTs (Table 3). Three cats had grade 1 neutropenia and two had grade 2 liver enzyme elevations during the first 3 months on toceranib. Both cases with liver toxicity were managed by decreasing the frequency of toceranib administration to twice per week. One cat experienced grade 2 vomiting, and two experienced grade 1 and grade 3 anorexia, respectively. These cats were given supportive care with a course of maropitant and mirtazapine, and clinical signs resolved.

The MPFS and MOST were 91 (range 30–158) and 145 days (range 31–234), respectively. PFS and OST for the cats with metastases at presentation were 125, 128 and 30 days and 234, 189 and 78 days, respectively. The Kaplan–Meier curves are shown in Figure 1.

Figure 1

Kaplan–Meier survival analysis for median (a) PFS and (b) OST for 17 cats with mammary adenocarcinoma treated with toceranib phosphate. The median PFS was 91 days and the median OST was 147 days. OST = overall survival time; PFS = progression-free survival

One cat developed acute respiratory distress secondary to pleural effusion, detected on day 43, despite maintaining PR in the primary tumour. The cytology of the pleural effusion was consistent with epithelial malignancy. Concurrent pulmonary metastases were not detected on radiographs, but the presence of the fluid limited interpretation. No pulmonary metastases had been detected at the initial staging.

Rescue treatments were offered to all cats when PD occurred. Four cats received docetaxel (2.25 mg/kg IV every 3 weeks) and one cat received doxorubicin (1 mg/kg IV every 3 weeks). One of the cats that received docetaxel had a PR, two cats achieved SD and one had PD. The cat treated with doxorubicin received a single dose without response.

All cats were included in the survival analysis: none were alive at 1 year and all died due to FMT progression. In seven cases, the cause of death was pulmonary metastases, and in two further cases malignant pleural effusion (cytologically confirmed). In five cases, the progression of local primary disease occurred with uncontrollable local inflammation, infection or bleeding, triggering euthanasia. Three cats were euthanased due to decreased quality of life (lethargy and anorexia). Overall, 14 cats were euthanased and three died naturally after being diagnosed with pulmonary metastasis.

Discussion

To the authors’ knowledge, this is the first prospective study assessing the response and toxicity profile of toceranib in macroscopic FMTs. Data on TKIs in FMTs are limited, but expression of VEGF and VEGFR has been reported,^47,48 supporting the use of toceranib. Toceranib has also been used in other non-mast cell tumours of various types, predominantly carcinomas.^{27,28,30–33}

The median age of the cats in this study was 10.6 years, similar to previous cohorts.^10,16,38 Most cats were intact or spayed when adults, again as described previously.^10,16 It is known that early neutering reduces the risk of developing mammary tumours.⁴⁹ No cats in this study received hormonal treatments such as exogenous progestins or oestrogen–progestin combinations, a practice that has largely ceased due to the relationship between the administration of these drugs and mammary cancer.^50,51

Overall, cats included in the study had advanced disease, with 4/17 (23.5%) cats presenting with local recurrences after previous surgeries and 3/17 (17%) cats having metastatic disease. Moreover, 4/17 (23.5%) cats had received chemotherapy previously. The advanced stage and previous treatments may have had a negative impact on the response to toceranib.

Of the 13 cats with de novo tumours, six (46%) had previously had mammary tumours in other mammary glands; this finding supports the recommendation for bilateral mastectomy in FMT, and may also reflect a reluctance to recommend this surgery in primary care practice. These de novo tumours were either truly independent tumours or metastases from previous tumours. The lymphatic drainage system of the mammary glands in cats is different from dogs, with connections between all the glands.⁵² Because of this, resection of at least one mammary chain (and ideally both) is recommended,¹ and bilateral chain mastectomy prolongs the disease-free interval.¹¹

True recurrence was also a common finding, supporting the recommendations of wide surgical margins (including at least 2 cm in the periphery and a deep fascial plane).^1,15

The distribution of tumours in this study was similar between the caudal and cranial mammary glands, and only two patients had multiple tumours at diagnosis. However, a higher incidence of mammary tumours arising from the caudal glands¹ and a high frequency of multiple tumours at initial diagnosis has been reported previously.^15,53

The size of the mammary tumours is a well-established prognostic factor, and the median size in our study was 2.95 cm, which is higher than in other studies,^10,11,16 in keeping with a population with advanced disease. Seven cats (41%) had a tumour exceeding 3 cm, a size clearly associated with a poor prognosis.^1,54,55 Ulceration has also been associated with poorer prognosis and four (23%) cats in the study showed ulceration, similar to the existing literature.⁵⁵

Similar to human breast cancer, where cytology is a reliable method to achieve a definitive diagnosis (77–99%), FNAs are reliable in cats, with good concordance between cytology and histopathology.⁵⁶ For this reason, cytology was accepted as a diagnostic method and published cytological criteria were applied.⁵⁶

Most tumours were histologically high-grade, as expected based on the literature.^42,57 None were diagnosed as inflammatory mammary carcinoma.

In three (17%) cats, metastatic lymph nodes were also diagnosed based on cytology at the time of diagnosis. Cats with metastatic lymph nodes have shorter free survival time,^7
–9,58 and approximately 25% of the cats with mammary tumours have lymph node metastasis,¹ affecting mainly the axillary and inguinal lymph nodes. Sternal lymph nodes may also be affected in up to 30% of cats.¹ In this study, lymph nodes were only aspirated if they were enlarged on physical examination or abnormal on imaging; therefore, the rate of metastasis may be underestimated. In addition, in up to 22% of metastatic carcinoma lymph nodes, cytology may not detect cancer cells that are obvious in histopathological studies.⁵⁹

Of the cats, 35.2% achieved an objective response, while 64.7% experienced clinical benefit, supporting the hypothesis that toceranib has a positive effect in the treatment of FMTs. Case numbers were too low to allow for meaningful statistical analysis, but there was no apparent correlation between tumour size, stage or grade with likelihood of response. The individual responses observed in this study may reflect the antiangiogenic or antitumour properties of the drug, or a combination of both effects.⁶⁰

These response rates are comparable with those described for traditional chemotherapy (in a gross disease setting), where reasonable objective response rates PR and CR of 45–64% have been reported in some studies.^13,14,17 However, others report lower response rates or only SD, with clinical benefit in 26–59.9% of cases.^33,61 Patient numbers are low in all studies, but overall the biological efficacy appears broadly similar to that of toceranib in advanced macroscopic canine mammary tumours.⁶² In addition, a recent study³⁸ of 10 cats with macroscopic mammary tumours treated with toceranib also suggested toceranib is a reasonable treatment option, though specific response was not evaluated. This response in the macroscopic setting suggests that toceranib might be effective as adjuvant therapy in microscopic disease; however, further prospective and randomised studies are required, as metastatic disease may not exhibit the same sensitivity as the primary tumour.

Sunitinib, a drug almost identical in its structure to toceranib, is used as monotherapy in ‘triple negative’ human breast cancer and has shown response rates in the range of 3–55%. However, first-line therapy does not improve outcomes compared with traditional chemotherapy.^63,64 In addition, the response to sunitinib is worse in patients who have previously received traditional chemotherapy rescue treatments.⁶³ In this study, four cats had previously received traditional chemotherapy, which may have altered the response to toceranib.

Three cats achieved a PR with the improvement of ulceration, likely to be of significant clinical benefit, and a similar response has been described in humans with sunitinib.⁶⁴

One cat (with PR of an ulcerated tumour) developed a malignant effusion before progression of the primary lesion. This development of metastatic disease alongside continued response of the primary tumour has been described in several human tumours.^65,66 Differences in response in primary and metastatic tumours may reflect a possible non-uniform distribution of TKIs in different organs, or different expression of proteins between primary tumours and metastases as described in human breast cancer.⁶⁷

In human medicine, when some antiangiogenic treatments, particularly sunitinib, are given after surgical removal of the primary tumour, progression of metastasis can accelerate.⁶⁸ This may reflect the selection and overgrowth of subpopulations of cancer cells resistant to the treatment simply by activating pathways of proangiogenic factors.⁶⁹ This may explain the differences in the response of primary and metastatic lesions in the current study.

Toceranib was well tolerated, with only one cat showing DLT (anorexia). Of the cats, 47% experienced mild adverse events; these were mainly haematological and gastrointestinal events, managed by decreasing the administration to twice per week. Toxicities were similar to those in previous publications;^{27,28,30,31,38,39} however, azotaemia was not reported in this study. As in other studies, the cats that experienced an increase in ALT did not show any clinical signs of hepatopathy.³⁰ Although routine monitoring of the blood pressure and UPC ratio was not performed, none of the cats showed proteinuria on urine analysis.

The MPFS of 91 days is very similar to that reported in a study assessing the response to docetaxel in macroscopic FMT (84 days).⁶¹ A study assessing different medical options, including toceranib, metronomic chemotherapy and traditional chemotherapy, reported a MPFS of only 50 days;³⁸ however, the MPFS was not calculated specifically for the group treated with toceranib.³⁸ Further, the MOST was only 63 days for the FMT group treated with toceranib, perhaps due to the patients all having stage IV disease. This is shorter than both the MPFS and MOST (145 days) in the current study.

The present study has some limitations. These include the small sample size, inconsistencies in patient enrolment criteria (with the inclusion of both treatment-naive and previously treated cats), and the variation in diagnostic and imaging techniques and for evaluating treatment response. In addition, the use of compounded toceranib represents a potential limitation, given the absence of studies on its efficacy and noted variability in the potency of compounded chemotherapy drugs,^70–72 which could affect the drug’s effectiveness. Future prospective studies could address these issues through a larger sample size, standardised enrolment and staging criteria, and monitoring and follow-up processes.

Conclusions

Toceranib is a reasonable therapeutic option in cats with advanced or recurrent mammary tumours, showing clinical benefit and a good toxicity profile. Further prospective and randomised studies are required to further assess its efficacy in this setting. Moreover, this cohort includes the first report of a cat showing a different response to toceranib in the primary tumour and metastatic disease suggesting that primary tumours and metastatic disease may not show the same sensitivity to toceranib.

Footnotes

Accepted: 27 April 2024

Author note

Preliminary data from this study was presented as a poster communication at the ESVONC Congress, Vienna, Austria, 2014.

Conflict of interest

For transparency, Laura Blackwood was a member of the Pfizer-funded Animal Cancer Experts (Europe) group from 2009 to 2012.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS. Although not required, where ethical approval was still obtained, it is stated in the manuscript.

Informed consent

Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.

ORCID iD

Isabel Del Portillo Miguel

Ignacio Pérez Roger

Enric Poch Jiménez

References

Morris

Mammary tumours in the cat: size matters, so early intervention saves lives. J Feline Med Surg 2013; 15: 391–400.

Rasotto

Caliari

Castagnaro

, et al. An immunohistochemical study of HER-2 expression in feline mammary tumours. J Comp Pathol 2011; 144: 170–179.

Zappulli

Caliari

Rasotto

, et al. Proposed classification of the feline ‘complex’ mammary tumors as ductal and intraductal papillary mammary tumors. Vet Pathol 2013; 50: 1070–1077.

Pérez-Alenza

Jiménez

Nieto

, et al. First description of feline inflammatory mammary carcinoma: clinicopathological and immunohistochemical characteristics of three cases. Breast Cancer Res 2004; 6: R300–R307.

De Campos

Damasceno

Gamba

, et al. Evaluation of prognostic factors and survival rates in malignant feline mammary gland neoplasms. J Feline Med Surg 2016; 18: 1003–1012.

Manoel

De Carvalho

PLT

Govoni

, et al. Immunoexpression and prognostic significance of multidrug resistance markers in feline mammary carcinomas. J Comp Pathol 2021; 183: 13–25.

Gemignani

Mayhew

Giuffrida

, et al. Association of surgical approach with complication rate, progression-free survival time and disease-specific survival time in cats with mammary adenocarcinoma: 107 cases (1991-2014). J Am Vet Med Assoc 2018; 252: 1393–1402.

Seixas

Palmeira

Pires

, et al. Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathological and survival analysis. Vet J 2011; 187: 65–71.

Weijer

Hart

AAM

. Prognostic factors in feline mammary carcinoma. J Natl Cancer Inst 1983; 70: 709–716.

10.

McNeill

Sorenmo

Shofer

, et al. Evaluation of adjuvant doxorubicin-based chemotherapy for the treatment of feline mammary carcinoma. J Vet Intern Med 2009; 23: 123–129.

11.

Novosad

Bergman

O’Brien

, et al. Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adenocarcinoma: 67 cases. J Am Anim Hosp Assoc 2006; 42: 110–120.

12.

Ito

Kadosawa

Mochizuki

, et al. Prognosis of malignant mammary tumor in 53 cats. J Vet Med Sci 1996; 58: 723–726.

13.

Jeglum

deGuzman

Young

KM.

Chemotherapy of advanced mammary adenocarcinoma in 14 cats.

J Am Vet Med Assoc 1985; 187: 157–160.

14.

Mauldin

Matus

Patnaik

, et al. Efficacy and toxicity of doxorubicin and cyclophosphamide used in the treatment of selected malignant tumors in 23 cats. J Vet Intern Med 1988; 2: 60–65.

15.

Sorenmo

Worley

Zapulli

. Tumors of mammary gland. In: Vail

Thamm

Liptak

(eds). Withrow & MacEwen’s small animal clinical oncology. 6th ed. St Louis, MO: Saunders Elsevier, 2020, pp 618–620.

16.

Borrego

Cartagena

Engel

Treatment of feline mammary tumours using chemotherapy, surgery and a COX-2 inhibitor drug (meloxicam): a retrospective study of 23 cases (2002–2007).

Vet Comp Oncol 2009; 7: 213–221.

17.

Stolwijk

Minke

Rutteman

, et al. Feline mammary carcinomas as a model for human breast cancer. II. Comparison of in vivo and in vitro adriamycin sensitivity. Anticancer Res 1989; 9: 1045–1048.

18.

Cunha

Corgozinho

Souza

, et al. Adjuvant chemotherapy with mitoxantrone for cats with mammary carcinomas treated with radical mastectomy. J Feline Med Surg 2015; 17: 1000–1004.

19.

Henry

Higginbotham

Rodriguez

, et al. Prospective evaluation of doxorubicin versus mitoxantrone for adjuvant therapy of feline mammary carcinoma. Proceedings of the 2006 Veterinary Cancer Society; 9–10 October 2006; Callaway Gardens, GA, p 54.

20.

De Campos

Nunes

Lavalle

, et al. Use of surgery and carboplatin in feline malignant mammary gland neoplasms with advanced clinical staging. In Vivo 2014; 28: 863–866.

21.

London

Hannah

Zadovoskaya

, et al. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res 2003; 9: 2755–2768.

22.

Lawrence

Saba

Gogal

, et al. Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells. Vet Comp Oncol 2012; 10: 143–154.

23.

Isotani

Yamada

Lachowicz

, et al. Mutations in the fifth immunoglobulin- like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours. Br J Haematol 2010; 148: 144–153.

24.

Bonkobara

Dysregulation of tyrosine kinases and use of imatinib in small animal practice.

Vet J 2015; 205: 180–188.

25.

Sabattini

Guadagni Frizzon

Gentilini

, et al. Prognostic significance of Kit receptor tyrosine kinase dysregulations in feline cutaneous mast cell tumors. Vet Pathol 2013; 50: 797–805.

26.

Bergkvist

Argyle

Pang

, et al. Studies on the inhibition of feline EGFR in squamous cell carcinoma: enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors. Cancer Biol Ther 2011; 11: 927–937.

27.

Wiles

Hohenhaus

Lamb

, et al. Retrospective evaluation of toceranib phosphate (Palladia) in cats with oral squamous cell carcinoma. J Feline Med Surg 2017; 19: 185–193.

28.

Olmsted

Farrelly

Post

, et al. Tolerability of toceranib phosphate (Palladia) when used in conjunction with other therapies in 35 cats with feline oral squamous cell carcinoma: 2009–2013. J Feline Med Surg 2017; 19: 568–575.

29.

Berger

Johannes

Post

, et al. Retrospective evaluation of toceranib phosphate (Palladia) use in cats with mast cell neoplasia. J Feline Med Surg 2018; 20: 95–102.

30.

Harper

Blackwood

Toxicity and response in cats with neoplasia treated with toceranib phosphate.

J Feline Med Surg 2017; 19: 619–623.

31.

Keepman

Pellin

MA.

Low dose meloxicam is safe and tolerable when combined with toceranib phosphate in cancer-bearing cats.

J Feline Med Surg 2021; 24: 1187–1194.

32.

Todd

Nguyen

SM.

Long-term survival in a cat with pancreatic adenocarcinoma treated with surgical resection and toceranib phosphate.

JFMS Open Rep 2020; 6. DOI: 10.1177/2055116920924911.

33.

Kopke

Gal

Piripi

, et al. Squamous cell carcinoma of the anal sac in two cats. J Small Anim Pract 2021; 62: 704–708.

34.

Martinez

Brockman

Purzycka

Caval chemodectoma in a cat.

JFMS Open Rep 2022; 8. DOI: 10.1177/20551169221106990.

35.

Giuliano

de Busscher

DDA

, et al. Successful treatment of vertebral osteosarcoma in a cat using marginal surgical excision and chemotherapy. Vet Sci 2022; 9. DOI: 10.3390/vetsci9070315.

36.

McGregor

Moore

Yeomans

Management of a feline gastric stromal cell tumour with toceranib phosphate: a case study.

Aust Vet J 2020; 98: 181–184.

37.

Holtermann

Kiupel

Hirschberger

The tyrosine kinase inhibitor toceranib in feline injection site sarcoma: efficacy and side effects.

Vet Comp Oncol 2017; 15: 632–640.

38.

Petrucci

Henriques

Gregório

, et al. Metastatic feline mammary cancer: prognostic factors, outcome and comparison of different treatment modalities – a retrospective multicentre study. J Feline Med Surg 2021; 23: 549–556.

39.

Merrick

Pierro

Schleis

, et al. Retrospective evaluation of toceranib phosphate (Palladia®) toxicity in cats. Vet Comp Oncol 2016; 15: 710–717.

40.

Castagnaro

Casalone

Bozzetta

, et al. Tumour grading and the one-year post-surgical prognosis in feline mammary carcinomas. J Comp Pathol 1998; 119: 263–275.

41.

Mills

Musil

Davies

, et al. Prognostic value of histologic grading for feline mammary carcinoma: a retrospective survival analysis. Vet Pathol 2015; 52: 238–249.

42.

Simon

Schoenrock

Nolte

, et al. Cytologic examination of fine-needle aspirates from mammary gland tumors in the dog: diagnostic accuracy with comparison to histopathology and association with postoperative outcome. Vet Clin Pathol 2009; 38: 521–528.

43.

Alleman

Bain

PJ.

Diagnosing neoplasia: the cytological criteria for malignancy.

Vet Med 2000; 95: 204–223.

44.

James

Meinkoth

RLC

. Recognition of basic cell types and criteria of malignancy. Vet Clin North Am Small Anim Pract 2002; 32: 1209–1235.

45.

Nguyen

Thamm

Vail

, et al. Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol 2015; 13: 176–183.

46.

Veterinary Cooperative Oncology Group–Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol 2016; 14: 417–446.

47.

Dagher

Dubreil

Chaumieau

, et al. C-kit prognostic value in feline invasive mammary carcinomas. Proceedings of the Annual Meeting of ESVONC; 20–22 October 2016; Nantes, France, p 164.

48.

Sorenmo

Rasotto

Zappulli

, et al. Development, anatomy, histology, lymphatic drainage, clinical features, and cell differentiation markers of canine mammary gland neoplasms. Vet Path 2011; 48: 85–97.

49.

Overley

Shofer

Goldschmidt

, et al. Association between ovariohysterectomy and feline mammary carcinoma. J Vet Intern Med 2005; 19: 560–563.

50.

Keskin

Yilmazbas

Yilmaz

, et al. Pathological abnormalities after long-term administration of medroxyprogresterone acetate in a queen. J Feline Med Surg 2009; 11: 518–521.

51.

Jacobs

Hoppe

Poehlman

, et al. Mammary adenocarcinomas in three male cats exposed to medroxyprogesterone acetate (1990–2006). J Feline Med Surg 2010; 12: 169–174.

52.

Papadopoulou

Patsikas

Charitanti

, et al. The lymph drainage pattern of the mammary glands in the cat: a lymphographic and computerized tomography lymphographic study. Anat Histol Embryol 2009; 38: 292–299.

53.

Hayes

Jr Milne

Mandell

CP.

Epidemiological features of feline mammary carcinoma.

Vet Rec 1981; 108: 476–479.

54.

Viste

Myers

Singh

, et al. Feline mammary adenocarcinoma: tumor size as a prognostic indicator. Can Vet J 2002; 43: 33–37.

55.

Zappulli

Rasotto

Caliari

, et al. Prognostic evaluation of feline mammary carcinomas: a review of the literature. Vet Pathol 2015; 52: 46–60.

56.

Amorim

Souza

HJM

Ferreira

AMR

, et al. Clinical, cytological and histopathological evaluation of mammary masses in cats from Rio de Janeiro, Brazil. J Feline Med Surg 2006; 8: 379–388.

57.

Hughes

Dobson

JM.

Prognostic histopathological and molecular markers in feline mammary neoplasia.

Vet J 2012; 194: 19–26.

58.

Skorupski

Overley

Shofer

, et al. Clinical characteristics of mammary carcinoma in male cats. J Vet Intern Med 2005; 19: 52–55.

59.

Kass

Christopher

MM.

Cytologic-histologic concordance in the diagnosis of neoplasia in canine and feline lymph nodes: a retrospective study of 367 cases.

Vet Comp Oncol 2017; 15: 1206–1217.

60.

Wang

Yang

, et al. Multitargeted antiangiogenic tyrosine kinase inhibitors combined to chemotherapy in metastatic breast cancer: a systematic review and meta-analysis. Eur J Clin Pharmacol 2014; 70: 531–538.

61.

Escriche

Borrego

Estudio prospectivo con docetaxel (taxotere®) en tumores mamarios felinos.

Proceedings congreso AMVAC, 3–5 March 2016; Madrid, Spain, p 59.

62.

Gattino

Buracco

De Maria

Response to toceranib in dogs with measurable, unresectable, recurrent or metastatic mammary carcinomas.

Proceedings Annu Meet ESVONC, 22–24 May 2014; Vienna, Austria, p 56.

63.

Bachelot

Garcia-Saenz

Verma

, et al. Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study. BMC Cancer 2014; 14. DOI: 10.1186/1471-2407-14-166.

64.

Sun

Zhao

Ding

, et al. Sunitinib as salvage treatment including potent anti-tumor activity in carcinomatous ulcers for patients with multidrug-resistant metastatic breast cancer. Oncotarget 2016; 7: 57894–57902.

65.

Mete

Singh

Kakkar

Sustained systemic response paralleled with ovarian metastasis progression by sunitinib in metastatic renal cell carcinoma: is this an anti-angiogenic potentiation of cancer?

Urol Ann 2015; 7: 387–390.

66.

Jafri

Porfiri

Differential response to sunitinib: sustained systemic response paralleled by intra-dural progression in the spine. Should standard response criteria be reviewed?

Clin Genitourin Cancer 2009; 7: E42–E44.

67.

Mellouli

Graja

Kridis

, et al. Discordance in receptor status between primary and metastatic breast cancer and overall survival: a single-center analysis. Ann Diagn Pathol 2022; 61: 152044. DOI: 10.1016/j.anndiagpath.2022.152044.

68.

Ebos

Mastri

Lee

, et al. Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy. EMBO Mol Med 2014; 6: 1561–1576.

69.

Vasudev

Reynolds

AR.

Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions.

Angiogenesis 2014; 17: 471–494.

70.

Burton

Knych

Stanley

, et al. Potency and stability of compounded formulations of chlorambucil, melphalan and cyclophosphamide. Vet Comp Oncol 2017; 15: 1558–1563.

71.

Burton

Stanley

Knych

, et al. Frequency and severity of neutropenia associated with Food and Drug Administration approved and compounded formulations of lomustine in dogs with cancer. J Vet Intern Med 2016; 30: 242–246.

72.

KuKanich

Slead

, et al. Evaluation of drug content (potency) for compounded and FDA-approved formulations of doxycycline on receipt and after 21 days of storage. J Am Vet Med Assoc 2017; 251: 835–842.

Evaluation of the efficacy and safety of toceranib phosphate in cats with macroscopic mammary adenocarcinoma

Abstract

Objectives

Methods

Results

Conclusions and relevance

Keywords

Introduction

Materials and methods

Results

Discussion

Conclusions

Footnotes

Author note

Conflict of interest

Funding

Ethical approval

Informed consent

ORCID iD

References