Chemotherapy in bovine oncology: Principles, applications and recent advances

Introduction

The contemporary use of pharmacological treatments for cancer started in the mid-1940s, when Alfred Gilman and Louis Goodman demonstrated the effectiveness of nitrogen mustard in mice with tumours, and these findings were promptly applied and confirmed in human patients (Vail et al., 2019) [1] . Chemotherapy is defined as the administration of pharmacological agents to eliminate or inhibit the proliferation of viruses and foreign cells, such as bacteria or fungi, within the body. Although cancer cells are derived from the host's own tissues, they are recognised as "foreign" in this context (Riviere and Papich, 2018). These foundational discoveries in cancer pharmacotherapy have directly shaped veterinary oncology practice. Building on these advances, chemotherapy modalities now serve as a cornerstone in the management of many cancers encountered in companion animals, livestock, and exotic species. While veterinary oncology employs many of the same chemotherapeutic agents used in human medicine, protocols, dosing, and objectives are carefully adapted to address the unique physiological needs and welfare considerations of animal patients. In order to provide a clear and systematic evaluation of chemotherapy in veterinary oncology, this discussion will begin by defining key technical terms related to chemotherapeutic agents, then will compare and contrast major therapeutic approaches, and finally, will explore specific clinical applications and outcomes in animal patients. When discussing chemotherapeutic agents, several technical terms are frequently encountered, and a brief comparative overview of these approaches clarifies their distinctions before examining the field in detail. 'Conventional chemotherapy' utilises cytotoxic drugs at the highest tolerated cycles to eliminate rapidly dividing cells, but its lack of selectivity can result in collateral effects on normal tissues. In contrast, 'metronomic chemotherapy' administers low doses frequently and continuously, focusing primarily on disrupting tumour angiogenesis and potentially reducing toxicity and resistance. 'Targeted chemotherapy using tyrosine kinase inhibitors (TKIs)' offers a more specific intervention by blocking tyrosine kinases essential for cancer cell growth and survival signaling. The choice among these strategies reflects a synthesis of therapeutic goals: maximizing tumour control, minimizing adverse effects, and aligning with the individual patient's clinical status and owner's resources.

Conventional chemotherapy

Conventional chemotherapy, often referred to as maximally tolerated dose (MTD) chemotherapy, involves administering chemotherapeutic agents at the highest recommended dosage, followed by a recovery phase for drug-sensitive cells, including those in the bone marrow and gastrointestinal tract. This approach aims to achieve the greatest possible reduction in tumour cells while typically carrying a lower risk of severe side effects. However, the intervals between treatment sessions can also permit tumour regrowth. Depending on the tumour type and disease stage, MTD chemotherapy may be used alone or as an adjunct to surgery or radiation therapy. In solid tumours, such as osteosarcoma, it is often used as adjuvant therapy after primary treatment to help prevent progression of occult micrometastatic disease (Biller et al., 2016) [2] . A micrometastasis is defined as a lymph node metastasis larger than 0.2 mm and/or containing more than 200 cells but not exceeding 2.0 mm in size. In contrast, isolated tumour cells or clusters measuring less than 0.2 mm are referred to as ITCs (Zhang et al., 2013) [3] . The primary objectives of conventional chemotherapy are to control tumour growth while maintaining or improving the patient's quality of life (Biller et al., 2016) [2] .

Metronomic chemotherapy

Metronomic chemotherapy is characterised by the continuous delivery of low doses of cytotoxic medications at regular and frequent intervals. Recent research suggests this approach may be as effective as traditional chemotherapy while causing lower toxicity and cost (Browder et al., 2000; Emmenegger et al., 2004) [4,5] . Unlike maximum tolerated dose (MTD) chemotherapy, which targets rapidly dividing cancer cells, metronomic chemotherapy primarily targets tumour angiogenesis. The endothelial cells recruited to facilitate tumour growth are particularly sensitive to low, uninterrupted doses of chemotherapy agents (Kerbel et al., 2004) [6] . Furthermore, the genetic stability of these endothelial cells makes them inherently less likely to develop drug resistance than cancer cells (Mancuso et al., 2006) [7] . Consequently, metronomic chemotherapy tends to produce fewer adverse effects on non-endothelial cells, such as epithelial cells and leukocytes. Unlike conventional chemotherapy, which typically aims for a reduction in tumour size, the objective of metronomic chemotherapy is often to stabilise the disease. Most veterinary oncologists consider metronomic chemotherapy for cases where conventional treatment has failed, or the pet owner has declined it (Biller et al., 2016) [2] .

Targeted chemotherapy using tyrosine kinase inhibitors

Tyrosine kinases are enzymes that activate proteins involved in signalling pathways that regulate normal cell growth and survival. Because many of these pathways are disrupted in cancer cells, tyrosine kinase inhibitors (TKIs) act as anti-cancer drugs that block signal transduction, thus preventing tumour growth (Biller et al., 2016) [2] . Mutations in the c-kit gene, an RTK associated with mast cell differentiation and proliferation, occur in approximately 25% of canine mast cell tumours (Barber & Burgess, 2023). Currently, two oral TKIs have been approved for use in dogs with cancer: toceranib phosphate and masitinib mesylate (conditionally approved in the United States). These TKIs are indicated for specific grades and stages of mast cell disease (Biller et al., 2016) [2] . Although these drugs target specific signalling pathways, they can also cause toxicity in rapidly dividing normal cells that rely on these pathways. Broader use of TKIs requires further investigation into critical questions, such as which tumour types are most likely to respond to TKIs and their optimal combination with conventional chemotherapy agents (Biller et al., 2016) [2] . The potential of harnessing the immune system to combat cancer presents significant opportunities for treating aggressive malignancies, particularly for the prevention and management of metastatic disease. One notable advancement is the development of the first U.S. Department of Agriculture-licensed immunotherapeutic agent for veterinary oncology: the canine melanoma vaccine. This DNA vaccine is specifically indicated for dogs diagnosed with stage II or III oral melanoma, where local disease control has already been established. It operates by leveraging the immune response to human tyrosinase, an enzyme crucial in melanin synthesis. The formulation contains a human tyrosinase gene integrated into a bacterial plasmid and is delivered transdermally. The immune reactions elicited by xenogeneic tyrosinase can cross-react with tyrosinase overexpressed on canine melanoma cells. Preliminary studies indicate that dogs with advanced-stage oral malignant melanoma that received radiation or surgical treatment for the primary tumour, followed by vaccination, experienced improved survival outcomes.

Term Definition

Cure

The complete eradication of all tumor cells from the body. This goal is often not achievable in most cases.

Palliation

The reduction of pain and improvement of a patient's function to enhance their quality of life, in situations where a cure is not possible. It's an increasingly recognized and acceptable therapeutic goal.

Therapeutic Index

The ratio of the toxic dose to the therapeutic dose of a drug. In the context of cytotoxic drugs for cancer, this is often considered an abstract concept.

Maximum Tolerated Dose (MTD)

The highest dose of a drug that can be given with a low chance of causing unacceptable or irreversible side effects. This value is determined through clinical experience and is the basis for most cancer drug dosing.

Biologically Effective Dose (BED)

A newer dosing concept for cancer drugs based on a measured biological response at a specific target. This is particularly relevant for molecularly targeted agents and signal transduction inhibitors but could also be applied to other drugs.

Dose Intensity (DI)

A measure of the drug dose given per unit of time. It's used to compare different dosing schedules to see if the total dose or the rate of administration affects the outcome or toxicity.

Therapeutic Gain

The improved tumor response achieved when combining two drugs or a drug with radiation, relative to any increase in toxicity to normal tissues. It is considered positive when the combined tumor effects are greater than the combined toxicity.

Primary Neoadjuvant Chemotherapy

The use of chemotherapy drugs before other treatments, most often surgery, to shrink the primary tumor, decrease its clinical stage (downstaging), and prevent the growth of micrometastases that may occur after surgery.

Adjuvant Chemotherapy

The use of chemotherapy drugs after the primary tumor has been surgically removed or controlled by radiation. Its purpose is to treat any remaining, hidden disease, such as residual tumor cells after incomplete excision or micrometastases.

Term

Definition

Consolidation Therapy

Reintensification of therapy (used most commonly with hematopoietic cancers) after remission is attained to further reduce the likelihood of relapse.

Maintenance Therapy

Low-intensity therapy given over a protracted period of time after remission is attained.

Rescue or Salvage Therapy

The use of chemotherapy after a tumor fails to respond to a previous therapy or after tumor recurrence

Radio-sensitization

The enhancement of cytotoxicity when irradiation and chemotherapeutic agents are combined such that a therapeutic gain is obtained Occult Disease Disease that is not clinically detectable but is present; often the target of adjuvant chemotherapy.

Palliative Chemotherapy

Delivered to decrease clinical signs in the case of unresectable or disseminated disease that is associated with functional disturbances or pain. The outcome is based more on quality of life issues..

Mitotic Index (MI)

The proportion of cells in the process of mitosis within a tumor. (Reported by a pathologist as MI or as the number of mitoses per high-power field).

Growth Fraction (GF)

The proportion of proliferating cells within a tumor. (Cannot be quantified in a patient).

Doubling Time (DT)

The time it takes for a tumor to double in size. (Calculated using sequential measurements of tumor vol-

] seen on imaging or determined by direct palpation).

Additionally, evidence from equine studies has shown either stabilisation or reduction in tumour size, alongside the emergence of anti-tyrosinase immunoreactivity. Furthermore, therapeutic autologous cancer vaccines utilise the patient's tumour to induce unique tumour-associated antigens. These vaccines are often administered alongside adjuvants to enhance the immune response and overcome tolerance to these antigens, aiming for immune-mediated destruction of cancer, especially in cases of microscopic metastatic disease (Barber & Burgess, 2023).

Basic principles of antineoplastic chemotherapy in animals

A combination of three or more drugs is commonly used to treat a given neoplasm. These chemotherapeutic agents are selected based on certain principles. Each drug should have a different mechanism of action, should have the desired action against the targeted tumour, and should not have overlapping toxicities. This helps to harness the antineoplastic effects of multiple drugs with maximum desired action and minimal side effects. It is conventional to name the designed protocol after the first letters of chemotherapeutic agents employed for treatment. Common examples of multi-agent protocols include CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone), which is frequently used for lymphoma in dogs, and COP (cyclophosphamide, vincristine [Oncovin], and prednisone), which is used as a less intensive alternative. For mast cell tumours, the VLP protocol (vinblastine, lomustine, prednisone) is sometimes chosen, while VAC (vincristine, actinomycin D, cyclophosphamide) may be used for osteosarcoma. Knowledge of these standard protocols aids selection based on tumour type and supports memorization. These multi-agent combinations delay or even prevent the development of drug-resistant clones, contributing to longer remissions and survival times than single-agent chemotherapeutic protocols. However, in certain cases, single-agent chemotherapeutic regimens are as effective as combination protocols; for example, in CTVT, vincristine, doxorubicin or carboplatin as single agents.

Another principle worth mentioning is that chemotherapy is more effective in a relatively smaller tumour than in a larger one, even if the inherent sensitivity to the drug is the same in both cases. This is because the smaller tumour has a higher mitotic index (MI) and growth fraction (GF), resulting in a shorter doubling time (DT). In other words, more cells are actively dividing at any given moment in the smaller tumour. This is clearer in Fig. . Chemotherapeutic drug dosing is based on body surface area and not on an animal's body weight. This is because physiological processes affecting drug activity correlate better with body surface area than with body weight. However, there is an exception to body surface area dosing: in very small patients (weighing less than 10 kg), BSAbased dosing leads to a comparatively higher dose and consequent adverse effects, so body weight-based dosing may be chosen. Weight can be converted to surface area using this formula:

K is a species constant with a value of 10.0 and 10.1 for cats and dogs, respectively (Riviere and Papich, 2018). For example, to calculate the body surface area of a 20 kg dog: First, convert weight to grams: 20 kg × 1000 = 20,000 grams Apply the formula using K = 10.1 (for dogs):

BSA = ( 10.1 × 20, 000 ) 2/3 10, 000

Calculate the value inside the parenthesis:

Now, raise to the 2/3 power:

Finally, divide by 10,000:

BSA ≈ 3, 457/10, 000 = 0.346 m 2

Therefore, the body surface area for this 20 kg dog is approximately 0.35 m 2 .

Administration guidelines

Chemotherapeutic intervention for different types of tumours in bovines

A study conducted between 2012 and 2014 examined 59 samples suspected of neoplasia in cattle (47 samples) and buffaloes (12 samples), confirming neoplasia in 57 of them. The study found a higher incidence of tumours in cattle (78.95%) compared to buffaloes (21.05%). The tumours with the highest incidence in bovines were papilloma (21.05% of cases). This was closely followed by squamous cell carcinoma and fibroma, both accounting for 17.54%. Lymphosarcoma was next at 14.04%, and adenoma represented 7.02% of cases. Furthermore, adenocarcinoma, melanoma, and myxosarcoma each occurred in two cases, collectively accounting for 3.51% of the total tumours.

Papilloma

Reported therapeutic approaches for bovine papillomatosis include conventional chemotherapeutic and immunomodulatory treatments.

Vincristine-based therapy combined with lithium antimony thiomalate, Thuja-30, and autohaemotherapy resulted in complete regression within 30-45 days. Homeopathic Thuja-30 and anthiomaline were also reported to produce substantial clinical improvement, whereas autogenous vaccination showed no cure and untreated animals showed no recovery. Ivermectin administered subcutaneously, with a repeat dose after two weeks, resulted in progressive regression of papillomas, with lesions beginning to disappear between 15 and 45 days and complete cure reported within 30-90 days. These findings indicate that several pharmacological and immunomodulatory approaches have been explored for the management of bovine papillomatosis, with variable therapeutic responses. Two additional chemotherapeutic modalities, aside from those previously mentioned, have been reported in the literature with ambiguous results. The first is intravenous infusions of magnesium chloride, often used when lesions are few; this treatment is frequently combined with Ivermectin (Lotfalizadeh et al., 2022) [9] . The second modality is a 25% magnesium sulfate solution administered intramuscularly at 0.005-0.05 g/kg (Mates, 2019).

Study

Treatment / Intervention Outcome / Findings

Squamous cell carcinoma

Podarala et al. (2020) [10] evaluated the therapeutic efficacy of intralesional Bacillus Calmette-Guérin (BCG) vaccine and surgical excision combined with topical Mitomycin C in bovine ocular squamous cell carcinoma. Animals treated with intralesional BCG vaccine administered at 0, 14, 35, and 56 days (2-4 mL depending on tumour size) showed progressive reduction in tumour size, along with drying and shrinkage, particularly evident after the fourth injection. This treatment protocol achieved 100% efficacy with no recurrence observed during a one-year follow-up period. Similarly, animals subjected to surgical excision followed by topical application of Mitomycin C (0.04%) on alternate weeks for two months demonstrated complete recovery in all cases, also with 100% efficacy and no recurrence over one year. These findings indicate that both immunotherapeutic and combined surgical-chemotherapeutic approaches are highly effective for managing ocular squamous cell carcinoma in bovines.

Group Treatment Protocol Outcome / Efficacy

Group I Intralesional BCG vaccine (0, 14, 35, 56 days; 2-4 mL depending on tumour size)

Reduction in size, drying, and shrinkage after the 4th injection. 100% efficacy with no recurrence for 1 year Group II Surgical excision + topical Mitomycin C (0.04%, applied on alternate weeks for 2 months)

Complete recovery in all animals. 100% efficacy with no recurrence for 1 year

The management of bovine squamous cell carcinoma (SCC) includes surgical, chemotherapeutic, immunotherapeutic and physical treatment approaches. Lakshmi et al. (2021) [11] compared surgical excision, intralesional Bacillus Calmette-Guérin (BCG), surgery combined with autogenous vaccination, and surgery followed by topical mitomycin C in bovine ocular SCC, emphasising that treatment selection should be based on the lesion's size, location, and extent. A multimodal approach was associated with favourable disease-free outcomes. As a chemotherapeutic approach, topical mitomycin C (0.04%) was administered following surgical excision. In contrast, cisplatin emulsified in sesame oil was evaluated as a locally administered adjunct after surgical removal of ocular and vulvar SCC. In the latter technique, the cisplatin dose was calculated according to the volume of the surgical bed at 1 mg/cm 3 , and the emulsion was infiltrated in parallel rows approximately 1 cm apart to ensure uniform distribution. Postoperative abscess formation was, however, reported in the majority of animals receiving cisplatin-sesame oil emulsion. Immunotherapeutic approaches have also been explored. Hoffmann et al. (1981) [12] treated bovine ocular SCC using a single intramuscular injection of phenol-saline extracts prepared from allogeneic carcinomas. Among 44 carcinomas, 33 (78%) responded, including complete regression in 15 cases, with better responses observed at doses of 200 mg or more of lyophilised extract. Halleran et al. (2021) [13] further investigated mycobacterial cell wall stimulants as an immunotherapeutic modality for SCC, supporting the potential role of local immunomodulation in tumour management. Physical tumour destruction using radiofrequency hyperthermia has also been investigated. This technique involved localised heating of tumour tissue to approximately 50 °C. Treatment duration varied according to tumour size and number, and repeated application was recommended for some larger lesions. Recurrence following apparent complete remission was mainly observed at tumour margins, highlighting the importance of adequate treatment coverage. Overall, the reviewed studies demonstrate that bovine SCC can be managed using a range of therapeutic modalities. While surgical excision remains central to treatment, adjunctive chemotherapy, immunotherapy and localised hyperthermia may improve local tumour control and provide alternative options depending on tumour characteristics and clinical feasibility.

Oral tumours

Oral tumours have been reported in buffaloes aged 3.5-10 years, with all 11 reported cases occurring in female animals. The lesions were predominantly located in the rostral mandible (n = 8), followed by the right mandibular gingiva (n = 2) and lower lip (n = 1). Histopathologically, ameloblastoma was the most frequently reported tumour (n = 4), followed by fibroma (n = 1), myxoma (n = 1), fibromyxoma (n = 1), papilloma (n = 1), ameloblastoma with fibroma (n = 1), fibromyxochondroma with actinomycotic granuloma (n = 1), and granulation tissue with hyperplastic epithelial cells (n = 1). Thus, the reported cases demonstrated considerable histopathological diversity, with a marked predominance of lesions involving the mandibular region (Kumar et al., 2022) [14] . The reported therapeutic approaches for oral tumours included surgical excision, vincristine, Anthiomaline®, and potassium iodide, either alone or in combination. A case of odontoma with secondary actinomycosis showed reduction in tumour size following Anthiomaline® and potassium iodide treatment without complications. In Murrah buffaloes with oral tumours, surgical excision combined with vincristine and Anthiomaline® was associated with recovery in most treated animals, although recurrence and mortality were also reported. Comparative treatment observations further indicated that vincristine was useful for smaller tumours, whereas combination therapy with Anthiomaline® was reported to provide better results; surgical debulking was suggested for larger tumours.

Study

Recent advances

Recent advances in cancer therapeutics have increasingly focused on molecularly targeted approaches, including RNA interference (RNAi)-based gene knockdown therapy. Mohan et al. (2017) [15] proposed using small interfering RNA (siRNA) and short hairpin RNA (shRNA) to target and suppress genes involved in tumour growth and angiogenesis in veterinary neoplasia. RNAi mediates sequence-specific degradation of target messenger RNA, thereby reducing the expression of selected genes associated with tumour progression. Synthetic siRNA produces transient gene silencing, whereas shRNAexpressing vectors may provide a more sustained inhibitory effect. The Sema4D-Plexin-B1 signalling pathway is a potential molecular target because it is involved in tumour-associated angiogenesis. The proposed strategy involves shRNA-mediated downregulation of Sema4D, which may inhibit tumour vascularisation and consequently restrict tumour growth. The authors suggested that Sema4D knockdown could complement conventional antiangiogenic therapies, particularly in tumours resistant to VEGF-targeted approaches. However, this approach remains largely experimental and prospective in veterinary oncology. Although RNAi-based knockdown therapies have shown potential in human cancer research, their clinical application in animals has not yet been established because of challenges related to delivery systems, cost, technical expertise, infrastructure and the need for further species-specific research. Recent case reports and pilot studies in companion animals have begun to explore safe delivery mechanisms and efficacy of RNAi therapeutics in selected tumour types, such as canine melanoma and feline fibrosarcoma, but largescale clinical trials remain limited. Some ongoing veterinary clinical trials are investigating nanoparticle-mediated delivery of siRNA to target tumour angiogenesis and growth in dogs, although published results are still pending. Thus, targeted gene silencing represents a promising future direction for developing more precise and personalised therapeutic strategies for animal neoplasia, including potentially SCC.

References

1. Vail DM, Thamm DH, Liptak JM. Withrow and MacEwen's small animal clinical oncology (6th ed., p. 192). Elsevier Health Sciences. 2019.
2. Biller B, Berg J, Garrett L, Ruslander D, Wearing R, Abbott B, Bryan C. 2016 AAHA oncology guidelines for dogs and cats. Journal of the American Animal Hospital Association. 2016;52(4):181-204.
3. Zhang ZY, Ge HY. Micrometastasis in gastric cancer. Cancer letters. 2013;336(1):34-45.
4. Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, Folkman J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer research. 2000;60(7):1878-1886.
5. Emmenegger U, Man S, Shaked Y, Francia G, Wong JW, Hicklin DJ, Kerbel RS. A comparative analysis of low-dose metronomic . 2004;64(11):3994-4000.
6. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer. 2004;4(6):423-436.
7. Mancuso P, Colleoni M, Calleri A, Orlando L, Maisonneuve P, Pruneri G, Bertolini F. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood. 2006;108(2):452-459.
8. Lotfalizadeh N, Gharib A, Hajjafari A, Borji H, Bayat Z. Anticancer Potential of Ivermectin: Mechanisms of Action and Therapeutic Implications. Journal of Lab Animal Research. 2022;1:52-59.
9. Podarala V, Prasanna Lakshmi M, Venkata SKR, Devalam RP. Efficacy of BCG vaccine and Mitomycin C for the treatment of ocular squamous cell carcinoma in bovines. Research in veterinary science. 2020;133:48-52.
10. Lakshmi MP, Veena P, Kumar RVS, Prameela DR, Reddy KJM. Efficacy of different treatment modalities for eye cancer in bovines. Indian Journal of Animal Research. 2021;55(9):11011104.
11. Hoffmann D, Jennings PA, Spradbrow PB. Immunotherapy of bovine ocular squamous cell carcinomas with phenol-saline extracts of allogeneic carcinomas. Australian Veterinary Journal. 1981.
12. Kumar S, Bisla RS, Singh P, Chaudhary RN, Jakhar KK. Diagnosis and therapeutic management of oral tumours in Murrah buffaloes. Buffalo Bulletin. 2022;41(1):5-11.
13. Mohan G, Kumar PS, Kumar S, Bhattacharya TK, Anandasekaran G, Karthiga S. Knockdown therapy for treatment of neoplasia in draught animals. International Journal of Current Microbiology and Applied Sciences. 2017;6(7):4372-4378.
14. Biller B. Metronomic chemotherapy in veterinary patients with cancer: rethinking the targets and strategies of chemotherapy. Veterinary Clinics: Small Animal Practice. 2014;44(5):817-829.
15. Fleming JM, Creevy KE, Promislow DE. Mortality in North American Dogs from 1984 to 2004: An investigation into age-, size-and breed-related causes of death. J Vet Intern Med. 2011;25(2):187-198.
16. De Ridder T, Ruppin M, Wheeless M, Williams S, Reddell P. Use of the intratumoural anticancer drug tigilanol tiglate in two horses. Frontiers in veterinary science. 2020;7:639.
17. Patel U, Karp CL, Dubovy SR. Update on the management of ocular surface squamous neoplasia. Curr Ophthalmol Rep. 2021;9:7-15.
18. Malalana F. Treatment of periocular tumours -what is the evidence? BEVA congress. 2015;66.
19. Clode AB, Miller C, McMullen RJ Jr, et al. A retrospective comparison of surgical removal and subsequent CO 2 laser ablation versus topical administration of mitomycin C as therapy for equine corneolimbal squamous cell carcinoma. Vet Ophthalmol. 2012;15:254-62.
20. Pucket JD, Gilmour MA. Intralesional 5-fluorouracil (5-FU) for the treatment of eyelid squamous cell carcinoma in 5 horses. Equine Veterinary Education. 2014;26(6):331-335.
21. Knottenbelt DC, Kelly DF. The diagnosis and treatment of periorbital sarcoid in the horse: 445 cases from 1974 to 1999. Veterinary Ophthalmology. 2000;3:169-191.
22. Knottenbelt DC, Watson AH, Hotchkiss JW, Chopra S, Higgins AJ. A pilot study on the use of ultra-deformable liposomes containing bleomycin in the treatment of equine sarcoid. Equine Veterinary Education. 2018;32:258-263.
23. Tamzali Y, Boidot M. Use of combination of tazarotene cream and imiquimod 5% cream in the treatment of equine sarcoids: a 20 case retrospective study. Journal of Veterinary Internal Medicine. 2014;28:709. 27. Pettersson CM, Brostrom H, Humblot P, Bergvall KE. Topical treatment of equine sarcoids with imiquimod 5% cream or Sanguinaria canadensis and zinc chloride -an open prospective study. Veterinary Dermatology. 2020;31:471-e126.
24. Mair TS, Krudewig C. Mast cell tumours (mastocytosis) in the horse: A review of the literature and report of 11 cases. Equine Veterinary Education. 2008;20(4):177-182.
25. Lamagna B, Greco A, Guardascione A, Navas L, Ragozzino M, Paciello O, Meomartino L. Canine lipomas treated with steroid injections: clinical findings. PloS one. 2012;7(11):e50234.
26. Kelly JM, Belding BA, Schaefer AK. Acanthomatous ameloblastoma in dogs treated with intralesional bleomycin. Veterinary and comparative oncology. 2010;8(2):81-86.
27. Cai S, Zhang T, Groer C, Forrest M, Aires D, Otte V, Barchman S, Faerber A, Forrest ML. Injectable Chemotherapy Downstaged Oral Squamous Cell Carcinoma from Nonresectable to Resectable in a Rescue Dog: Diagnosis, Treatment, and Outcome. Case reports in veterinary medicine. 2018;2018:9078537.
28. Dorbandt DM, Driskell EA, Hamor RE. Treatment of corneal squamous cell carcinoma using topical 1% 5-fluorouracil as monotherapy. Veterinary ophthalmology. 2016;19(3):256-261.
29. Kitchell BK, Orenberg EK, Brown DM, Hutson C, Ray K, Woods L, Luck E. Intralesional sustained-release chemotherapy with therapeutic implants for treatment of canine sun-induced squamous cell carcinoma. European journal of cancer (Oxford, England: 1990). 1995;31A(12):2093-2098.
30. Marconato L, Murgia D, Finotello R, Meier V, Morello EM, Pisoni L, Foglia A, Guerra D, Chalfon C, Aralla M, Mesto P, Annoni M, Albanese F, Bettini G, Sabattini S. Clinical Features and Outcome of 79 Dogs With Digital Squamous Cell Carcinoma Undergoing Treatment: A SIONCOV Observational Study. Frontiers in veterinary science. 2021;8:645982.
31. Szewczyk M, Lechowski R, Zabielska K. What do we know about canine osteosarcoma treatment? Review. Veterinary research communications. 2015;39(1):61-67.
32. Chu KT, Nekouei O, Giuliano A. Treatment outcomes of dogs with transitional cell carcinoma. Frontiers in veterinary science. 2025;12:1486786.
33. Masterson MA, Hull BL, Vollmer LA. Treatment of bovine lymphosarcoma with L-asparaginase. Journal of the American Veterinary Medical Association. 1988;192(9):1301-1302.
34. Onuma M, Yamamoto M, Yasutomi Y, Takahashi K, Kawakami Y, Azuma I. Regression of bovine lymphosarcoma by treatment with cell-wall skeleton of Nocardia rubra. Vaccine. 1989;7(2):121124.
35. Jhambh R, Yadav R, Sindhu N, Kumar T, Jangir BL, Kushwah M, Goel P. Management of lymphosarcoma in a Murrah buffalo with vincristine sulphate. 2014.
36. Kumar T, Yadav A, Kumar A, Sindhu N. Medicinal management of odontoma with secondary actinomycosis in buffalo: A case report. Pharma Innov J. 2021;10(5):523-524.
37. Kumar S, Chaudhary RN, Niwas R, Dinesh R. Update on oral tumours in bovine. Pharma Innov J. 2019;8(11):53-56.
38. Ankit Kumar AK, Anita Ganguly AG, Maharana BR, Devan Arora DA, Sandeep Potliya SP, Jangir BL, Bisla RS. Therapeutic management of papillomatosis in cattle. 2017.
39. Archana SN, Ambazamkandi P, Davis J, Seena TX. Bovine Papillomatosis and its Treatment under Farm Condition. International Journal of Current Microbiology and Applied Sciences. 2019;8:2880-2884.
40. Saied AA. Regression of bovine cutaneous papillomas via ivermectin-induced immunostimulant and oxidative stress. Journal of advanced veterinary and animal research. 2021;8(3):370-377.
41. Smith AN, Klahn S, Phillips B, et al. ACVIM small animal consensus statement on safe use of cytotoxic chemotherapeutics in veterinary practice. J Vet Intern Med. 2018;32:904-913.
42. International Journal of Advanced Biochemistry Research https://www.biochemjournal.com 26174707, 2026, 10(10), Downloaded from https://www.doi.org/10.33545/26174693.2026.v10.i10b.10308 by International Journal of Advanced Biochemistry Research on [03/10/2026]. See the Terms and Conditions (https://www.biochemjournal.com) for rules of use; OA articles are governed by the applicable Creative Commons License
43. Grier RL, Brewer WG Jr, Paul SR, Theilen GH. Treatment of bovine and equine ocular squamous cell carcinoma by radiofrequency hyperthermia. Journal of the American Veterinary Medical Association. 1980;177(1):55-61.