Abstract
Objectives
The purpose of this study was to investigate the disease-free interval, survival time and adverse events of a combined treatment approach in cats with mammary malignant tumors using radical mastectomy and adjuvant mitoxantrone.
Methods
All cats underwent surgery to remove the mammary chain containing the tumors. A 3 cm margin was obtained around removed tumors. For staging purposes, regional inguinal lymphadenectomy was performed in all cases. After histopathology, cats were staged according to the World Health Organization’s (WHO) staging system. Chemotherapy with mitoxantrone was started 15–30 days after surgery (6 mg/m2 IV every 21 days for four cycles) with the objective of delaying metastasis.
Results
Three cats were intact, one cat was early spayed, four cats were late spayed and four cats were spayed at an unknown age. Based on the WHO’s staging system, six cats were classified as stage I and six cats as stage III. The median disease-free interval and survival time were 360 and 480 days, respectively. Four (33%) cats received four doses of mitoxantrone, four (33%) cats received three doses and four (33%) cats received only one dose. The most frequent adverse effects of chemotherapy were azotemia, anorexia, leukopenia and vomiting.
Conclusions and relevance
Adjuvant mitoxantrone chemotherapy may be an option for feline mammary tumors. Further, sufficiently powered, randomized prospective trials are necessary to determine if mitoxantrone is superior, inferior or equivalent to doxorubicin in the adjuvant setting.
Introduction
Mammary tumors are usually malignant in cats, with a high metastatic rate.1–4 Surgery remains the main treatment for mammary tumors in cats. However, adjuvant chemotherapy has been suggested to increase survival time (ST) in cats.5–7
Cats subjected to radical surgery plus doxorubicin have a median ST and median disease-free interval (DFI) of 448 and 255 days, respectively. 5 Mitoxantrone is used for the treatment of neoplastic disease as an alternative in humans unable to tolerate the adverse events and toxicity of doxorubicin. In cats, the adverse events of doxorubicin chemotherapy, such as anorexia and nephrotoxicity, make studies of alternative agents necessary.8,9
The purpose of this study was to investigate, using radical mastectomy and adjuvant mitoxantrone, the DFI, ST and adverse events of a combined treatment approach in cats with mammary malignant tumors.
Materials and methods
Patient inclusion criteria
The medical records of cats with malignant mammary tumors examined at our veterinary hospital in Rio de Janeiro from 2009–2013 were reviewed. Criteria for entry included histologic confirmation of feline mammary carcinoma and surgical excision of the tumor followed by adjuvant mitoxantrone chemotherapy.
All cats underwent tumor staging before surgery, including complete history, physical examination, measurement of tumors, complete blood count (CBC), serum biochemistry profile, three-view thoracic radiographs (two laterals and a ventrodorsal view) and abdominal ultrasound. Cats with distant metastasis were excluded from analysis. Twelve cats meeting the eligibility criteria were included.
If preoperative examinations were suggestive of underlying renal disease (azotemia or ultrasonographic renal alterations), a urinalysis and urine culture were performed.
The reproductive status of the cats was classified as early spayed (ovariohysterectomy was performed at the age of <1 year), late spayed (aged >1 year) or intact. Oncologic examination included palpation of mammary nodules, gland localization, mass measurement and regional lymph node palpation. An aggressive treatment (chain unilateral mastectomy or chain bilateral mastectomies in steps) was performed in all cases, and no aspiration or biopsies of tumors were performed prior to surgery.
All cats underwent surgery to remove the mammary chain containing the tumors. If tumors were present at both chains, staged bilateral mastectomy was performed (the other mammary chain was removed 4–8 weeks after the first surgery). A 3 cm margin was obtained around tumors. For staging purposes, regional inguinal lymphadenectomy was performed in all cases. Axillary lymphadenectomy was performed in cases in which this lymph node was enlarged or visible during surgery. After histopathology, cats were classified according to the World Health Organization’s (WHO) Classification of Malignant Tumours staging system. 10
All cats received chemotherapy, which typically started at the time of suture removal (15–30 days after surgery). The chemotherapy regimen consisted of four doses of mitoxantrone (Evomixan 20 mg; Evolabis) administered at a dose of 6 mg/m2, as a slow intravenous (IV) injection, once every 3 weeks. Ondansetron (Vonau 8 mg; Biolab) was administered to all cats, at a dose of 0.5 mg/kg every 12 h orally in the first 7 days after mitoxantrone, in order to prevent nausea.
All cats underwent clinical examination and a CBC before and after 7 days of each administration of chemotherapy. Mitoxantrone-related toxicities, including anorexia and neutropenia, were recorded. Renal toxicity was monitored by evaluating serum renal values (blood urea nitrogen [BUN], creatinine) routinely during chemotherapy administration and every 3–5 months thereafter.
Local recurrence was defined as a tumor formation in the site of surgery (removed mammary chain), and new tumor was defined as tumor formation in the other mammary chain; these were determined by physical examination. Thoracic radiographs were performed every 3 months or when there was clinical evidence of metastasis (dyspnea and/or cough). Cats that developed local recurrence or new tumors after treatment were offered surgery and to restart mitoxantrone-based chemotherapy, and those in which distant metastasis were found were advised in favor of euthanasia when there was poor quality of life.
Collection of case data
Medical records were examined retrospectively. Data retrieved from the medical records included breed and age, and physical examination findings, such as number of tumors, tumor size and location. Staging data included the results of thoracic radiographs, lymph node histology and WHO stage. Treatment data included type of initial surgery, number of surgeries, histological margins and number of mitoxantrone treatments. Outcome information included local recurrence, formation of new tumors, development of distant metastasis, DFI and ST. Chemotherapy toxicity data were also collected, including history and laboratory analysis findings.
Statistical analysis
All cases that fulfilled the inclusion criteria were included in the statistical analysis. The DFI was defined as the time from surgery until the development of local recurrence or metastatic disease. Survival was defined as the time from the original surgery until death from any cause.
The median DFI and median ST were determined by the use of the Kaplan–Meier product-limit method. Results shown are median number of days with 95% confidence intervals. No censoring was performed. The effect on survival and DFI of tumor stage, regional metastasis and number of mitoxantrone treatments were examined using Kaplan–Meier survival analysis with log-rank and Wilcoxon tests.
Results
Twelve cats with a histologically confirmed mammary malignant tumor treated between August 2010 and December 2013 were reviewed. All cats were female and aged 7–15 years old (mean 11.9 years). Eight (67%) cats were mixed breed and four (33%) were Siamese. Mean weight was 4.24 kg. Three (25%) cats were intact, one (6%) was early spayed, four (33%) were late spayed and four (33%) were spayed at an unknown age.
Eight cats had a single tumor and four had multiple tumors. Nodules were located in the caudal glands in 10 cases, in the cranial glands in four cases and were poorly circumscribed in two cases. Four (33%) cats had histologically confirmed lymph node involvement at the time of surgery. Three (25%) cats were classified as stage I, three (25%) as stage II and six (50%) as stage III.
None of the cats had prior surgeries for mammary tumors. Ten (83%) cats underwent unilateral mastectomy and two (17%) cats underwent bilateral mastectomies performed in different surgeries. Ovariohysterectomy was performed in all intact cats at the time of surgery prior to tumor removal. Histopathological margins were considered complete in all cases.
Three cats had evidence of renal disease at the time of diagnosis based on sonographic abnormalities or evaluation of a urinalysis, but only one cat had azotemia. This cat received subcutaneous fluid therapy (150 ml three times a week) during tumor treatment (surgery and chemotherapy).
Four (33%) cats received four doses of mitoxantrone, four (33%) received three doses and four (33%) cats received only one dose. The majority of cats that did not complete five doses of mitoxantrone had treatment discontinued by the owners based on their inability to administer oral or subcutaneous medications, and declined hospitalization. The most frequent adverse events of chemotherapy were azotemia (n = 5), anorexia (n = 4), leukopenia (n = 3) and vomiting (n = 1). Anorexia and vomiting started 1–5 days after mitoxantrone administration and were resolved with supportive treatment. Leukopenia was mild in one case (neutrophils 1200/mm3) and severe in two cases (neutrophils <500/mm3). These cats were treated with filgrastin (Filgrastim 300 µg; Aché) at a dose of 5 µg/kg subcutaneously once daily for 3–5 days, and enrofloxacin (Baytril 15 mg; Bayer) at a dose of 5 mg/kg orally once daily for 7 days. Also, the mitoxantrone dose was decreased by 25% on subsequent chemotherapy. Azotemia occurred in the three cats with pre-existing or arising renal disease, but also in two healthy cats. In four cats, increased creatinine and BUN were detected after three or four mitoxantrone administrations, and only one cat was noted to have azotemia after a single dose. In all of them, azotemia persisted even after drug interruption.
Three (25%) cats had tumor recurrence in a median time of 270 days (range 210–360 days). Six cats had distant metastasis to the lungs in a median time of 270 days (range 150–700 days). One cat developed mesenteric lymph node enlargement 6 months after treatment, but biopsy was declined by the owners. Overall median DFI in this study was 360 days (range 150–700 days) and median ST was 480 days (range 150–730 days) (Table 1; Figure 1).
Age, breed, sex, tumor location, size, clinical staging, number of mitoxantrone doses, creatinine pre- and post-chemotherapy, outcome, survival time (ST) and disease-free interval (DFI) of 12 cats with mammary carcinomas treated with surgery and adjuvant mitoxantrone
Creatinine reference interval 0.5–1.9 mg/dl
LN met = lymph node metastasis; T = thoracic mammary gland; A = abdominal mammary gland; I = inguinal mammary gland
Kaplan–Meier graphs of cats treated with radical mastectomy and mitoxantrone chemotherapy. (A) Survival time plot. (B) Disease-free interval plot
Cats diagnosed with stage I/II disease had a median DFI and median ST of 270 and 450 days, respectively, while those with stage III had a median DFI and ST of 360 and 640 days, respectively. The log-rank and Wilcoxon tests compared the groups, and no significant difference was found between the groups.
No significant impact on DFI and ST was noted in cats with or without lymph node metastasis at the time of surgery. The median DFI and ST of cats without regional metastasis were 270 and 450 days, respectively, while they were 360 and 640 days, respectively, in cats with regional metastasis.
In a survival plot of the number of mitoxantrone treatments, a slightly sharper fall after 400 days was noticed in the group with only one session. The median ST and DFI for the one-chemotherapy session group were 450 and 270 days, respectively, and for those with two or more sessions, they were were 640 and 360 days, respectively. There was no significant difference found between groups.
Discussion
The mean age of cats in this study is similar to that reported in other studies. 5 Despite the small number of cats studied here, Siamese were frequently diagnosed with mammary tumors. This was also reported by previous studies. 3 Intact or late spayed cats were the majority of cases in this study, suggesting that early ovariohysterectomy reduces the risk of developing a mammary tumor in cats. 11
Cats with evidence of renal disease are not good candidates for doxorubicin chemotherapy because of its nephrotoxic properties.3,8 An alternative option for these cases is mitoxantrone.12,13 However, in this study, five cats had azotemia (three of them had previous kidney disease). In previous studies, the adverse effects of mitoxantrone were vomiting, anorexia, diarrhea, lethargy, myelosuppression and seizures;12,13 azotemia was not reported. Perhaps the azotemia observed in this study was pre-renal in nature as a result of anorexia and dehydration rather than renal azotemia secondary to mitoxantrone. Additional prospective studies will be necessary to determine the true significance of this finding and until these studies are performed renal function should be monitored closely in azotemic cats receiving mitoxantrone chemotherapy. The other adverse effects, including leukopenia, anorexia and vomiting, were similar to previous reports.12,13 However, these adverse events were considered important by owners, and lead to treatment interruption in many cases. Anorexia and vomiting are concerns for cat owners because force feeding and medication are required at home, which can be difficult, especially in fractious cats. Hospitalization/enteral feeding are seen negatively by owners as causing stress and ‘suffering’to their pets. Ideally, anorexia and vomiting should be avoided in feline chemotherapy because they can lead to withdrawal of treatment. Ondansetron was prescribed to all cats preventively, but it is possible that it was not correctly administered by owners at home, which allowed nausea to occur. The use of a broader spectrum antiemetic, such as maropitant, should be considered in these cases.
The median ST of cats with mammary tumors undergoing surgery alone is only 10–14 months, with the vast majority of cats dying of metastatic disease. 3 The median DFI in this study was 360 days and the median ST was 480 days. These values were longer than previous reports of surgery plus doxorubicin. Cats subjected to radical surgery plus doxorubicin had a median ST and a median DFI of 448 and 255 days, respectively, in one study, 5 and 269 and 460 days, respectively, when a cyclooxygenase-2 inhibitor was added. 6 However, further studies of mitoxantrone as adjuvant therapy for cats with mammary carcinomas are necessary, as most cats did not complete the chemotherapy protocol. Additionally, the small number of cases and lack of contemporary and randomized controls of this retrospective study does not allow a conclusion to be drawn about the efficacy and safety of mitoxantrone as adjuvant therapy for feline mammary carcinoma.
Conclusions
Adjuvant mitoxantrone chemotherapy can be a useful therapeutic option in cats with mammary tumors. Renal function should be monitored carefully during and after completion of chemotherapy, as several cats in this study that were treated with mitoxantrone developed azotemia. Anorexia and vomiting were also important adverse events and lead to treatment interruption in many cases. Further, sufficiently powered, randomized prospective trials are necessary to determine if mitoxantrone is superior, inferior or equivalent to doxorubicin in the adjuvant setting.
Footnotes
Conflict of interest
The authors do not have any potential conflicts of interest to declare.
Funding
The funding for this research was provided by FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).