1.1 Feline mammary gland tumor
Feline mammary gland tumor is a common neoplastic disease in feline and mostly occurs in female cats. Based on a previous investigation in California, the annual incidence rate in female cats was 25.4/100,000 [3], which is much lower than female dogs (198/100,000). Unlike dogs, approximate 90% of mammary gland masses are malignant [6]. Most malignant mammary gland tumors in cats are carcinomas; sarcomas are rare, which is also different from canine MGTs [38]. Most feline mammary carcinomas occur at the median age of 10 to 12 years, older neutered female cats or intact female cats are at higher risk [38]. Siamese cats appear overrepresented, but this breed cats are also high risk of developing other neoplasms [38].
1.1.1 Benign mammary gland masses
Benign mammary gland masses are rare. In one study, all cats diagnosed with benign mammary masses were all intact females and younger than 10 years old [12].
Fibroadenoma, other adenomas, duct papilloma, cyst, lobular hyperplasia, and fibroadenomatous hyperplasia were all benign lesions previously reported.
Ovariohysterectomy (OHE) is a curative treatment in cats with fibroadenomatous hyperplasia; as for other benign lesions, complete surgical removal can be also curative and is important to prevent those lesions transforming to malignant [6].
1.1.2 Feline mammary carcinoma (FMC)
The etiology of developing FMC remains uncertain. Since intact and older-neutered
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It is well established that OHE at early age can reduce the risk of developing FMC.
Ovariohysterectomy before age of 6 months, between 7 and 12 months, or 1 and 2 years can reduce the risk of developing FMC approximately 91%, 86%, and 11% respectively [33]. However, this protection effect was not seen in cats underwent OHE after 2 years old.
Feline mammary carcinomas can be further classified as adenocarcinoma, tubular carcinoma, cystic papillary carcinoma, cribriform carcinoma, micropapillary invasive carcinoma, comedocarcinoma, squamous cell carcinoma, mucinous carcinoma, and lipid-rich carcinoma [28]. Adenocarcinoma, tubular carcinoma, or a combination of tubular, papillary, and solid carcinoma are most common subtypes [38]. Feline mammary carcinomas are generally aggressive. They can grow rapidly and have ability to invade lymphatic and vascular vessels in order to metastasize. Regional lymph node, lung, pleura and liver are organs that commonly being metastasized [10].
Cats typically presented with palpable subcutaneous masses at mammary gland region; single, multiple or even bilateral mammary glands may be involved. Masses may be ulcerative and with discharge in some cases. For early stage patients, there are usually no other specific clinical signs. Affected lymph node can be in normal size when it contains few tumor cells, but it can become large and fixed in late stage. Edema of limbs may be found when lots tumor cells metastasize to regional lymph nodes or tumor emboli in vessels obstruct fluid return. Pain reaction can be observed in cats with ulcerative or inflamed tumors and cats with bone metastasis. Dyspnea, panting, paradoxical breathing, and pleural effusion are common in cats with pulmonary metastasis. Non-specific signs such as lethargy, poor appetite and weight loss are usually noted in advanced stage patients.
1.2 Treatment of mammary carcinoma
1.2.1 Surgery
Surgery is an important treatment in FMC. Aggressive and radical surgical procedure can provide favorable outcome for early stage patients. Unilateral chain mastectomy with removal of draining lymph nodes for cats presented with ipsilateral tumors and bilateral chain mastectomy with removal lymph nodes for cats presented with contralateral tumors are usually recommended [38]. Marginal excision of affected mammary glands or lumpectomy usually results in incomplete excision, and those procedures are therefore only recommended for advanced stage patients to relieve discomfort. In a retrospective study, 100 cats with FMC were reviewed [20], and the disease-free interval was significantly (P <0.01) longer for cats underwent radical surgery than cats with conservative surgery. The disease-free interval and overall survival time was 372 days and 1,406 days respectively for cats underwent surgery alone in another study [26].
1.2.2 Systemic therapy
Systemic treatment is usually recommended in FMC, especially for cats with high risk of local recurrence and metastasis. Tamoxifen, a selective estrogen receptor modulator, is commonly used as a first-line adjuvant therapy in human with hormone-receptor-positive breast cancer [29]. However, this agent used in feline is unlikely as effective as in human, because expression of estrogen receptors in FMC are relative low [38].
Chemotherapy is recommended in human with hormone-receptor-negative breast cancer, failure of endocrine therapy or presence of visceral metastasis [29].
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Anthracyclines and taxanes are their first choice, and other agents such as cisplatin, vinorelbine, alkylating agents and anti-metabolites were also documented to have activity against breast cancer in human. Similarly, doxorubicin-based chemotherapy is the most commonly used scheme in small animals. However, due to lack of a prospective, randomized controlled study in veterinary medicine, outcome of the cats treated with adjuvant chemotherapy varied in different retrospective studies. Fourteen cats with advanced stage mammary gland adenocarcinoma were treated with doxorubicin and cyclophosphamide [25]. Overall response rate was 50% and all responders experienced partial remission. The mean and median survival times of the 14 cats were 142 days and 90 days, respectively, and responders trended to have longer survival times (median survival time was 150 days and 75 days for responders and non-responders respectively), but there was no control group in the study. Another single-arm, multi-institutional retrospective study evaluated the outcome of 67 cats treated with doxorubicin alone [31].
The median disease-free interval was 255 days and the median survival time was 448 days in the study. A similar result was reported in another study; twenty-three cats treated with surgery, doxorubicin-based chemotherapy and meloxicam (a cyclooxygenase-2 inhibitor) and the median disease-free interval and median survival time was 269 days and 460 days respectively [1]. Unfortunately, those studies were all lack of control group to compare the efficacy of chemotherapy. In a non-randomized, retrospective study by McNeill et al [26], 73 cats were enrolled to compare the survival time between cats underwent surgery alone and cats underwent surgery and doxorubicin-based adjuvant chemotherapy. Although the rate of local recurrence and distant metastasis was slightly higher in surgery alone group, the difference was not significant. In addition, the median survival time between two groups was also non-significant (1,406 days for surgery alone group and 848 days for surgery combined chemotherapy group). Nevertheless, cats
received radical unilateral surgery and followed with chemotherapy had significant longer survival than cats underwent radical unilateral surgery alone in this study. A two-arm, retrospective study compared the efficacy of carboplatin in cats with advanced stage mammary carcinoma [2]. In that study, 9 cats underwent unilateral radical mastectomy and 7 cats received surgery and followed with 200 mg/m2 carboplatin every 3 weeks. The median survival time for cats treated with adjuvant chemotherapy was 428 days, longer than 387 days for cats treated with surgery alone, but the difference was not significant.
Although the benefit of adjuvant chemotherapy remains controversial in veterinary medicine due to lack of solid evidence from prospective randomized studies, it is still recommended to prescribe adjuvant chemotherapy for cats with larger tumors (diameter of tumor >3 cm), evidence of lymphatic/blood vessel invasion and lymph node metastasis.
1.3 Vinorelbine
Vinorelbine, a semi-synthetic vinca alkaloid, was first produced in 1979. Same as most vinca alkaloid, vinorelbine can cause cell death by inhibiting the polymerization of tubulin dimers into microtubules, and prevents cell division, mitotic arrest, and ultimately cell death [30]. Lipophilicity of vinorelbine is higher than other vinca alkaloids; hence, this drug distributed widely with high concentrations in all tissues, except brain. Besides, the concentration of this drug in lung tissue was 300-fold higher than in plasma [18].
Vinorelbine is metabolized by liver and eliminated mainly via biliary system and minor by renal. In human medicine, vinorelbine is mostly used in non-small cell lung cancer, and can be also used in non-Hodgkin lymphoma and breast cancer. In a phase II study in human [5], 157 chemotherapy-naïve patients with advanced or metastatic breast cancer were administer with a weekly 30 mg/m2 vinorelbine; the overall response rate was 41%
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(complete response, 7%; partial response, 34%) and 30% of patients had stable disease.
Neutropenia was the most common toxicity and few episodes of nausea or vomiting were observed in that study. Vinorelbine was found to be active as a single agent (overall response rate 25% to 45%), even in patients heavily pretreated with anthracyclines and taxanes [14], [35]. There were only few studies of vinorelbine in veterinary medicine. A dose-determining study by Poirier et al [35], a starting dosage of 15 mg/m2 for dogs was recommended and neutropenia was the dose-limiting toxicity; overall response rate was 12.5% in various and spontaneous tumor-bearing dogs. Another phase II study evaluated the efficacy of vinorelbine in dogs with cutaneous mast cell tumors [8]; overall response rate was 13% and a high prevalence of neutropenia was found in this study. Kaye et al used this drug as a rescue agent for dogs with primary urinary bladder carcinoma [15].
Although the overall response rate was 14%, fifty-seven percent of patients experienced stable disease and 78% of patients had subjective improvement in clinical signs. Adverse events were mild and tolerated in that study. There was one but only one study used vinorelbine in feline. In that phase I study for feline [34], a starting dosage of 11.5 mg/m2 was recommended. Similarly, neutropenia was the mostly observed adverse events for cats.
1.4 Doxorubicin
Doxorubicin is one of antitumor antibiotics which is widely used in both human and small animals. Doxorubicin can cause cell death by multimodal mechanism [9].
Doxorubicin can interact with deoxyribonucleic acid (DNA) by intercalation and alkylation. It also has the ability to inhibit the function of RNA and DNA polymerases and topoisomerase II. Generation of reactive oxygen, perturbation of cellular Ca2+
homeostasis, and inhibition of thioredoxin reductase were also reported to cause cellular toxicity. Doxorubicin is mainly metabolized by liver and eliminated via kidneys and biliary system. This drug is often used in lymphoma, soft tissue sarcoma and mammary gland tumors. Common dosing regimen in dogs is 30 mg/m2 intravenous infusion over 30 minutes, but 1 mg/kg or 20 mg/m2 is often substituted for 30 mg/m2 in dogs less than 15 kg and in all cats. This drug can only be delivered intravenously; if this drug is delivered external to the vein, it will lead to severe tissue damage. Gastrointestinal toxicity and myelosuppression are most common toxicities. Some dogs may experience hypersensitivity to this drug. It is well established that there is cumulative dose-related cardiotoxicity and nephrotoxicity in small animals [9], [32]. Comparison of basic characteristics of vinorelbine and doxorubicin was summarized in Table 1.
1.5 Prognostic factors
Several prognostic factors had been reported. However, most studies were retrospective and non-randomized; thus, some factors may be biased.
Tumor size is the most important prognostic factor. Cats with tumor smaller than 2 cm had an average 4.5 years of survival time, and in contrast, cats with tumor larger than 3 cm had a median survival time of only 6 months [20]. This correlation was also observed in many other reports [27], [31], [40]. Histopathological grade was also reported to have a strong correlation with survival time in many studies [27], [37], [40]. Median survival time for cats with grade 3 mammary carcinoma was only 5 to 8 months. In contrast, cats with grade 1 mammary carcinoma had a median survival about 27 to 36 months, and the median survival time was range 12 to 14 months for grade 2 tumors. Lymph node status is another factor that impacts survival. Median survival time was 9 months for cats with
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lymph node metastasis and 16 months for cats without lymph node metastasis [27]. The clinical stage is classified based on tumor size, lymph node status and whether presence of distant metastasis. Thus, it is not surprising that clinical stage at presentation also associated with survival. Median survival time was 29, 12.5, 9 and 1 months for cats with clinical stage of 1, 2, 3, 4, respectively [13]. Cats with clinical stage of 1, 2, 3 had median survival time of 18, 15, 10 months respectively, in another study [27].
Other possible prognostic factors included histopathological subtype, with or without lymphatic and vascular invasion, presence of ulcerative tumor and type of surgical procedure. Histopathological complex carcinoma presents with neoplastic epithelial and myoepithelial cells, and most of this type carcinomas were associated with grade 1 tumors [37]. Cats with cribriform carcinomas had significantly shorter survival time [27]. Presence of lymphatic and invasion was a negative prognostic factor in several studies [27], [31], [37]. Ulcerative tumors were reported to be associated with high histopathological grade [37]. Marginal excision often leads to incomplete margin and early recurrence. Cats underwent radical unilateral surgery had significantly longer disease-free interval [13], [20]. However, this result may be confounding with tumor size and clinical stage.