{"id":30747,"date":"2022-04-12T14:18:21","date_gmt":"2022-04-12T14:18:21","guid":{"rendered":"https:\/\/todaysveterinarypractice.com\/?p=30747"},"modified":"2024-07-02T17:11:52","modified_gmt":"2024-07-02T17:11:52","slug":"the-role-of-glucocorticoids-and-nsaids-in-cancer-treatment-for-dogs-and-cats","status":"publish","type":"post","link":"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/oncology\/the-role-of-glucocorticoids-and-nsaids-in-cancer-treatment-for-dogs-and-cats\/","title":{"rendered":"The Role of Glucocorticoids and NSAIDs in Cancer Treatment for Dogs and Cats"},"content":{"rendered":"

<\/h2>\n

Glucocorticoids In Cancer<\/h2>\n

Scientific Basis\u00a0<\/span><\/h3>\n

Natural and synthetic glucocorticoids (GCs) exert their functions within the body through the cytoplasmic glucocorticoid receptor, present on most cells.1,2<\/sup> Following binding, the GC\u2013receptor complex translocates to the nucleus of the cell, where binding to specific GC response elements or other transcription factors can activate or repress gene transcription.1,2<\/sup> Synthetic GCs (including prednisone\/prednisolone and dexamethasone) have been shown to cause apoptosis of malignant lymphocytes,1,3<\/sup> and thus are tenets of treatment for both human and veterinary hematopoietic tumors, including leukemias, lymphomas, and multiple myeloma.1,3-7<\/sup><\/span><\/p>\n

Is Prednisone or Dexamethasone Better?<\/h3>\n

In adult humans with acute lymphoblastic leukemia, the relative efficacy of prednisone or dexamethasone has been found to be dose dependent. Although dexamethasone may confer a moderately superior outcome, it causes significantly more side effects, leaving the decision of which GC to use up to the attending clinician based on individual patient needs.8<\/sup> However, this literature is mixed, with other clinical trials showing no advantage of one GC over another.9<\/sup> In the veterinary literature, it is unclear if prednisone or dexamethasone is superior for the treatment of cancer, or if the GC elected affects remission rates or outcomes. Thus, the decision to use prednisone or dexamethasone is typically at the discretion of the clinician or veterinarian, although most chemotherapy protocols use oral prednisone\/prednisolone.\u00a0<\/span><\/span><\/p>\n

The doses of GCs used in veterinary cancer chemotherapy protocols are typically those considered to be anti-inflammatory (0.5 to 1 mg\/kg\/day or 30 to 40\u00a0mg\/m2<\/sup>\/day)10<\/sup> rather than immunosuppressive (2 to 3\u00a0mg\/kg\/day or 50 to 60 mg\/m2<\/sup>\/day for dogs >25 kg), with the exception of very small patients (<10 kg), in which the anti-inflammatory doses mentioned here are immunosuppressive.11<\/sup> If given in conjunction with chemotherapy, GCs are also usually tapered quickly to avoid inducing adverse effects.<\/span><\/p>\n

Use in Treating Specific Cancers<\/h3>\n

Lymphoma\/Leukemia\u00a0<\/span><\/h4>\n

Standard therapy for canine and feline large cell lymphoblastic leukemia and lymphoma is CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone\/prednisolone), with some nuance based on location and specific type of malignancy.5,12<\/sup> When standard treatment is declined, GCs alone are often prescribed. A common misconception is that GCs provide palliative care only. However, as previously mentioned, GCs cause apoptosis and death of malignant lymphoid cells,1,3<\/sup> leading to decreased tumor burden and increased quality of life. However, this effect is transient and overall remission time is often short.5,13<\/sup>\u00a0<\/span><\/span><\/p>\n

A recent study examined the use of GCs alone in the treatment of na\u00efve peripheral nodal B-cell and T-cell canine lymphoma and found that the overall survival time was 50 days (95% confidence interval [CI], 41 to 59\u00a0days). Median survival time was significantly longer for dogs with substage a disease (not clinically ill) than for those with substage b disease (clinically ill), and for those with a higher quality of life score at diagnosis as assessed by the owner. Interestingly, dogs with T-cell disease had a longer survival time (90 days; 95% CI, 67\u00a0to 109 days) than those with B-cell disease (39 days; 95% CI, 28 to 49 days).5<\/sup> This is contrary to the typical finding of dogs with B-cell disease having a better outcome.14-16<\/sup> While this discrepancy could have been due to lack of statistical power, the authors postulated that perhaps dogs with T-cell lymphoma are more sensitive to the effects of GCs,5<\/sup> as it appears GCs cause a greater suppression of the blastogenic response of T\u00a0cells than of B cells.17<\/sup> A similar study in cats has not been completed. However, an overall response rate of 70% of cats to prednisolone alone with extranodal lymphoma has been reported, with only 30% of cats achieving a complete remission.13<\/sup> Median survival has been reported to be 60\u00a0days, compared with 138 days for cats receiving a variety of chemotherapy protocols.13<\/sup> Thus, although dogs and cats both initially respond to GCs, the response is transient.\u00a0<\/span><\/span><\/p>\n

In addition, eliminating prednisone from the CHOP chemotherapy protocol has not been shown to affect the complete remission rate, median progression-free survival, or overall survival time.18,19<\/sup> Although lack of prednisone was associated with an increased hazard for lymphoma progression and an increased hazard for death, neither result was statistically significant.18<\/sup><\/span><\/p>\n

Caution!<\/b><\/p>\n

Multiple studies have shown that GC use prior to CHOP chemotherapy for canine and feline leukemia and lymphoma creates chemotherapy resistance and\/or a reduced survival time even in patients that achieve a complete remission while on chemotherapy.13,14,20,21<\/sup> The mechanism of GC-induced chemotherapy resistance is unknown, although it does not appear to be due to early induction of P-glycoprotein expression, which is commonly associated with chemotherapy resistance.22<\/sup> Similarly, it is unknown when GC-induced resistance develops during treatment. It appears that the influence of GCs on remission times does not change if GCs are given for less than 2 weeks or for longer periods,23<\/sup> suggesting resistance has already developed 2 weeks into a course of treatment and possibly much earlier.\u00a0<\/span><\/span><\/p>\n

Due to the effects of GCs on lymphocytes, it is also possible that GC use may make a definitive diagnosis of lymphoma difficult if cytologic samples are hard to interpret because of lymphocyte fragility. Although this has not been definitively proven to occur in veterinary medicine, it appears to be a problem for some types of lymphomas in humans.24<\/sup>\u00a0<\/span><\/span><\/p>\n

Given these concerns, it is prudent to withhold GC treatment until a diagnosis of lymphoma is made and a treatment plan elected, except potentially in emergent cases (e.g., life-threatening hypercalcemia, tracheal obstruction due to lymph node enlargement).\u00a0<\/span><\/span><\/p>\n

Mast Cell Tumors\u00a0<\/span><\/h4>\n

A variety of treatment options exist for canine and feline mast cell tumors (MCTs). Typically, treatment involves surgical removal, if possible, followed by adjuvant radiation therapy or chemotherapy as dictated by the location and aggressiveness of the tumor. GCs are often part of the treatment plan, either neoadjuvantly to help shrink the tumor before surgery and control histamine release, or adjuvantly following surgical removal. The response rate of canine MCTs to systemic GCs alone ranges from 20% to 70%, supporting the use of GCs in treatment of MCTs.25-27<\/sup> This wide response rate is likely due to the expression levels of GC receptors on neoplastic mast cells, where lower GC receptor expression has been associated with a decreased response or resistance to GC treatment.28<\/sup> In addition, it has been shown that MCTs have some inherent drug resistance to GCs or develop GC resistance.29<\/sup> The impact of previous GC use on MCT response to chemotherapy has not been examined, although anecdotally, previous GC use does not seem to significantly affect outcome.\u00a0<\/span><\/span><\/p>\n

Intralesional administration of GCs, specifically triamcinolone, has been reported in dogs with cutaneous MCTs.30<\/sup> In one study, patients were treated with intralesional triamcinolone alone (n = 5); a combination of intralesional triamcinolone and systemic GCs (n = 6); or a combination of intralesional triamcinolone and cytotoxic chemotherapy, with or without systemic GCs and radiation therapy (n = 13). For those treated with triamcinolone only, 1 achieved a complete response, 3 had a partial response, and 1 had stable disease. Adverse events included local hemorrhage (n = 1) and suspected gastrointestinal (GI) ulceration (n = 2; one receiving oral GCs, one not). Thus, it was concluded that intralesional triamcinolone, with or without additional therapy, may be safe and effective for canine cutaneous MCTs.30<\/sup><\/span><\/p>\n

Caution!<\/b><\/p>\n

If GCs are used prior to MCT surgery, it is recommended that the fur over the mass be shaved, and the mass circled using a Sharpie pen. Due to the relatively high response rate of MCTs to GCs, it is possible that the mass may disappear entirely between starting GCs and the day of surgery. Having the location of the tumor marked will help facilitate appropriate removal of the tumor.\u00a0<\/span><\/span><\/p>\n

Multiple Myeloma\u00a0<\/span><\/h4>\n

Multiple myeloma is a rare hematopoietic tumor of malignant plasma cells that occurs in both dogs and cats. These malignant plasma cells, typically stemming from the bone marrow, produce an overabundance of a single type or portion of immunoglobulin (the M component), leading to hyperglobulinemia. The clinical signs of multiple myeloma are due to the high levels of circulating M component, neoplastic cell infiltration of bone or organs, or both. Clinical manifestations of multiple myeloma include discrete osteolytic lesions, hyperviscosity syndrome, renal disease, hypercalcemia, cytopenias, abnormal clotting times, and immunodeficiency. A diagnosis of multiple myeloma in dogs is based on the presence of neoplastic plasma cells in the bone marrow, lytic bone lesions, and serum or urine myeloma proteins.\u00a0<\/span><\/span><\/p>\n

In humans, GCs have been shown to have an antitumor effect in multiple myeloma and are an important part of single-agent and combination therapy.31<\/sup> This approach has been extrapolated to treatment protocols successfully utilized in dogs and cats with multiple myeloma.7,32<\/sup><\/span><\/p>\n

Caution!<\/b><\/p>\n

Hyperglobulinemia alone does not indicate a diagnosis of multiple myeloma. Lymphoma and tick-borne diseases also commonly present with hyperglobulinemia; therefore, it is important to complete a thorough workup to attain a correct diagnosis.\u00a0<\/span><\/span><\/p>\n

Nonhematologic Cancers<\/h4>\n

The treatment of nonhematologic cancers with GCs is more controversial. It appears that GCs, depending on the tumor type, may prevent tumor progression and metastasis, or may inhibit chemotherapy-induced cell apoptosis. These discrepant results are likely due to a multitude of factors, including different cell types of origin, varying GC receptor levels, the type of GC administered, and the dosage of GC administered.1<\/sup><\/span><\/p>\n

The Good<\/b><\/p>\n

In human medicine, GCs alone have been shown to produce favorable outcomes in thymoma, breast, and prostate cancer. In breast cancer, GCs increase the response rate to chemotherapy and endocrine therapy when given in combination but do not influence overall survival.33<\/sup> In vitro data suggest that GCs, through activation of the GC receptor, may reduce estrogen-induced cell proliferation in breast cancer and mitigate androgen receptor activation and expression in prostatic cancer, helping to suppress cancer cell growth in these 2 tumor types. For various types of GI cancer, GCs alone were not found to influence survival times compared with placebo. Studies evaluating the combination of GCs and chemotherapy for GI cancer are mixed, implying a likely neutral effect.33<\/sup><\/span><\/p>\n

Metastasis is responsible for 90% of cancer deaths, but adequate treatments for metastatic disease have not been thoroughly evaluated, including GCs.34<\/sup> In vitro evaluations suggest that GCs suppress cancer cell migration and invasion through induction of E-cadherin or downregulation of matrix metalloproteinases 2 and 9, RhoA (Ras homolog family member A), and interleukin (IL)-6.1<\/sup> Induction of microRNA, specifically miR-708, decreases cancer cell migration, adhesion, and abdominal metastasis through inhibition of Rap1B.35<\/sup> In addition, various studies have implied that GCs suppress angiogenesis through downregulation of proangiogenic factors (IL-8 and vascular endothelial growth factor [VEGF]), preventing additional blood and nutrients from reaching the growing tumor.<\/span><\/p>\n

The Bad<\/b><\/p>\n

Despite the positive effects seen in breast cancer patients in vivo, in vitro evidence suggests that GCs can induce resistance when combined with radiation or chemotherapy in culture or mouse xenograft models. Many epithelial cancers have been shown to have this propensity, such as breast, ovarian, cervical, prostatic, testicular, urothelial, and pancreatic.1<\/sup> This resistance is thought to be mediated through upregulation of mitogen-activated protein kinase phosphatase, serine\/threonine survival kinase 1, and negative regulator of nuclear factor kappa B (NF-<\/span>\u03ba<\/span>B), although this has not been supported in clinical patients.1<\/sup><\/span><\/p>\n

While studies in human medicine generally have shown GCs to have a positive effect, or at least a neutral one, on patient outcome, in some instances GCs lead to less favorable outcomes or deleterious secondary sequelae. The use of GCs for primary central nervous system cancers is typically supported due to their effects on tumor-induced edema and subsequent neurologic deficits.36<\/sup> However, there is evidence that GCs may exert only a neutral effect on the tumor and may cause significant adverse effects, including an increased risk of infection when combined with chemotherapy.33<\/sup> In lung cancer, it appears that GCs decrease overall survival when used as monotherapy or in combination with chemotherapy.33<\/sup> Given the information available, it has been recommended in human medicine to avoid high-dose continuous<\/i> GCs in patients with nonhematologic malignancies, as this dosage decreases survival.33<\/sup><\/span><\/p>\n

Veterinary Medicine<\/b><\/p>\n

The use of GCs for nonhematologic cancers in veterinary medicine has not been thoroughly studied, either in vitro or in vivo. It is generally accepted that patients with central nervous system tumors benefit from prednisone, likely due to the effect on peritumoral edema,37<\/sup> although the true impact and cellular changes induced by GCs in this and other nonhematologic malignancies are unknown.\u00a0<\/span><\/span><\/p>\n

Caution!<\/b><\/p>\n

Given the lack of evidence for GC use in veterinary nonhematologic malignancies and the potential detrimental effects as evidenced in human malignancies, judicious use of GCs is recommended in any nonhematologic malignancy.\u00a0<\/span><\/span><\/p>\n

Supportive Care\u00a0<\/span><\/h3>\n

Glucocorticoids are frequently used as an adjuvant to mitigate adverse events during chemotherapy and radiation therapy. In humans, GCs have been shown to increase appetite; decrease vomiting, nausea, and weight loss; reduce fatigue; decrease ureteric obstruction; and alleviate bone pain associated with metastasis.1<\/sup> Anecdotally, and based on human studies, GCs are also used in veterinary medicine for many of these same reasons, especially to reduce GI effects from chemotherapy.38<\/sup>\u00a0<\/span><\/span><\/p>\n

Despite the frequent use of GCs, the mechanisms through which they reduce nausea and vomiting have not been fully elucidated. In humans, several hypotheses exist: physiologically low levels of GCs have been linked to nausea and vomiting, which may be exacerbated during chemotherapy or radiation therapy treatment; anti-inflammatory effects may mitigate these GI signs, as other anti-inflammatory medications (e.g., cyclooxygenase [COX] inhibitors) appear to do; GCs have been shown to reduce serotonin production, blocking transmission of the vomiting response; and finally, GCs inhibit formation of other substances connected to the vomiting response, such as prostaglandin and substance\u00a0P.4<\/sup> The best use of GCs and their role in palliative treatment for dogs and cats with cancer have yet to be fully determined.<\/span><\/p>\n

Limitations\/Adverse Effects\u00a0<\/span><\/h3>\n

The use of GCs in veterinary oncologic care is stymied by the potential adverse effects and subsequent effect on quality of life for patient and owner. In dogs, the most frequent adverse effects of systemic GCs have been reported to be polydipsia, polyuria, vomiting, diarrhea, and polyphagia.39<\/sup> Less commonly reported adverse effects include panting, behavior changes, delayed wound healing,39<\/sup> and iatrogenic hyperadrenocorticism (Cushing\u2019s disease).40<\/sup> Research also suggests that anti-inflammatory doses of oral GCs can potentially affect cardiac function in dogs, but not cats, due to an increase in blood pressure and cardiac afterload.41,42<\/sup> Prednisolone-induced diabetes mellitus has been reported in about 10% of cats receiving high-dose prednisolone therapy (\u22651.9\u00a0mg\/kg\/day for >3\u00a0weeks)43<\/sup> but is rarely reported in dogs.44,45<\/sup> Given the many potential adverse effects of GCs, thorough consideration for each individual patient should be undertaken prior to prescribing GCs for any dog or cat.\u00a0<\/span><\/span><\/p>\n

Resistance\u00a0<\/span><\/h3>\n

While GC-induced resistance to chemotherapy or radiation therapy can be a concern, as discussed above, resistance to GCs can also develop, leading to reduction or loss of response. It appears the most common mechanism of GC resistance is misregulation of both pro-and anti-apoptotic factors, including BCL2 (B-cell lymphoma 2), BIM (BCL-2\u2013like protein 11), and MCL1 (myeloid cell leukemia 1).4<\/sup> Alternatively, general changes in transcription, repression of cell cycle genes, and alterations in GC receptor regulation may play a role in the development of resistance.4<\/sup> Unfortunately, it appears that mechanisms of GC resistance are specific to tumor type, preventing one broad-spectrum approach to decreasing GC resistance.\u00a0<\/span><\/span><\/p>\n

NSAIDs in Cancer<\/h2>\n

Scientific Basis \u00a0<\/span><\/h3>\n

Inflammation, particularly chronic inflammation, has been shown to initiate cancer development through increased angiogenesis, the development of fibrosis, infiltration of mononuclear immune cells, and tissue destruction.46<\/sup> Following initiation, inflammation has also been shown to influence progression and aggressiveness of certain cancers. Multiple malignancies have been shown to express phenotypes that mimic inflammatory cells as they grow and progress, driving cell migration, angiogenesis, and metastasis. Thus, reducing inflammation may provide an advantage in treating some malignancies.46<\/sup><\/span><\/p>\n

Potential therapeutic targets for anti-inflammatory drugs include a myriad of cytokines and chemokines, NF-<\/span>\u03ba<\/span>B, VEGF, fibroblast growth factor receptors, and most commonly, COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to increase apoptosis and decrease migration of tumor cells, as well as potentially increase tumor sensitivity to other treatments. In addition, blockade of COX-2 decreases the incidence of human colorectal, breast, lung, bladder, and esophageal cancers.46<\/sup><\/span><\/p>\n

Extrapolating from human medicine, many tumor types in veterinary medicine have been evaluated for the expression of COX-2 as a potential therapeutic target. It has been found that numerous cancers of epithelial origin express COX-2 (<\/span>BOX 1<\/span><\/strong>), and thus a COX-2 inhibitor may play a therapeutic role.47<\/sup> Interestingly, oral fibrosarcoma, histiocytic sarcoma, MCTs, and lymphoma in dogs, as well as cutaneous squamous cell carcinoma, pulmonary adenocarcinoma, intestinal carcinoma, lymphoma, and injection site sarcoma in cats, have not been shown to express COX-2.47<\/sup> \u00a0<\/span><\/span><\/p>\n

BOX 1 Tumors in Veterinary Medicine That Express Cyclooxygenase 247,48<\/sup><\/div>
Canine cancers <\/strong><\/p>\n