Elsevier

The Lancet Oncology

Volume 7, Issue 5, May 2006, Pages 425-430
The Lancet Oncology

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Glucocorticoid use in prostate cancer and other solid tumours: implications for effectiveness of cytotoxic treatment and metastases

https://doi.org/10.1016/S1470-2045(06)70694-5Get rights and content

Summary

Glucocorticoids have been used widely in conjunction with other treatment for patients with cancer because they have potent proapoptotic properties in lymphoid cells, can reduce nausea, and alleviate acute toxic effects in healthy tissue. However, glucocorticoids are used in a supportive-care role, even though to our knowledge no prospective clinical studies have assessed the effect of these steroids on the growth of solid tumours. Data from preclinical and, to some extent, clinical studies, suggest that glucocorticoids induce treatment resistance in solid tumours, including prostate cancer. Research has focussed on disseminated cells that have been shed by the tumour: the potential of glucocorticoids to render these cells resistant to apoptosis—and to downregulate the immune response—might contribute to tumour metastasis. Here, we review the benefits of glucocorticoids and their negative effects, such as induction of resistance in tumour cells and concomitant induction of apoptosis in immune cells, with particular emphasis on prostate cancer.

Introduction

For nearly 50 years, physicians have relied on glucocorticoids—hormones usually secreted by the body in response to stress—to treat several types of cancer (eg, prostate cancer; figure 1). Glucocorticoids can kill cancerous lymphoid cells, and are thus important for treatment of malignant diseases of the lymph-node tissue.1 Because glucocorticoids have several other beneficial effects, such as reduction of nausea and emesis, protection of healthy tissue from cytotoxic side-effects, and presumably a reduction of tissue reactions such as inflammation against invasive malignant growth, these steroid hormones are also used widely in combination with other treatment in advanced prostate cancer and other solid tumours.2, 3 However, glucocorticoids might induce a resistant phenotype in cells of solid tumours during proapoptotic activity in lymphoid tumour cells. Furthermore, at the high doses usually needed for combination treatment for cancer, glucocorticoids suppress the immune system, weakening the patient's ability to fight disease. Thus, although glucocorticoids have many benefits in cancer treatment, they might mediate fast growth and metastases of solid tumours.

In 2005, about 230 110 men in the USA were diagnosed with prostate cancer, and nearly 29 900 died from this disease. About one in five men will be diagnosed with prostate cancer during his lifetime, and one in 33 men will die of metastatic disease.4 As the population ages, these numbers are expected to increase. More than 60 years ago, Huggins and Hodges5 discovered that androgen deprivation could be used as a first-line treatment for metastatic prostate cancer. Hormone treatment leads to remissions that typically last 2–3 years, but in most men metastatic prostate cancer ultimately progresses to an androgen-independent state, resulting in death due to widespread metastases. Bone metastases are accompanied by an osteoblastic reaction the extent of which is unmatched by any other type of cancer. Postmortem studies show that metastases to other organs, such as the lymph nodes, lung, adrenal glands, and liver, are common.6

Glucocorticoids—eg, dexamethasone, prednisone, and hydrocortisone—have been used widely for a long time to treat patients with advanced androgen-independent prostate cancer (figure 2). As part of combination treatment, glucocorticoids increase appetite, decrease weight loss, reduce fatigue, relieve bone pain, diminish ureteric obstruction, and give temporary decompression of metastatic disease in epidural space that compresses the spinal cord.2 Moreover, glucocorticoids are commonly prescribed as: a pituitary suppressant to reduce the production of adrenal androgens in patients who do not respond to hormone treatment; as an antiemetic in patients receiving chemotherapy or radiotherapy, or both; and as a standard treatment in randomised studies.7, 8 Although common chemotherapy regimens that use mitoxantrone or taxane derivatives reduce time to progression in prostate cancer by about 6–8 months, evidence suggests they do not prevent further disease progression in most patients with hormone-refractory prostate cancer.6, 9, 10 However, glucocorticoids combined with chemotherapy are effective for palliation of advanced prostate cancer.2

Section snippets

Historical overview

The Italian anatomist Eustachi identified the suprarenal glands in the middle of the 16th century, but these glands were not shown to be necessary for survival until Addison defined a fatal syndrome associated with loss of adrenal function in 1855. In the first half of the 20th century, as biochemists prepared adrenal cortical extracts of increasing purity, research lent support to the idea that adrenal cortical hormones were crucial for the survival of animals under various systemic stresses

Unfavourable effects

Although glucocorticoids generally offer supportive treatment of tumour cells in lymphatic tissue, glucocorticoid-induced resistance has been identified in cells of solid tumours when used with various anticancer drugs and with radiotherapy. Such observations were made in established carcinoma cell lines cultured in vitro, in xenografts on nude mice, and in primary cells that had been isolated from fresh surgical samples of solid tumours (table).20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30

Disseminated tumour cells and metastasis of prostate cancer

Metastasis of tumour cells from the prostate to bone and other organs involves the dissemination of cancer cells via the bloodstream. This dissemination is a multistep process (figure 2), and includes escape from the primary tumour by loss of tumour-cell adhesion, induction of cell motility, and local invasion of tumour cells into the surrounding tissue.55 These steps are followed by either dissemination to regional lymph nodes, or circulation through the blood and homing to secondary organs

Glucocorticoid-induced apoptosis in immune cells

Glucocorticoids induce apoptosis of mononuclear cells, especially lymphocytes68 such as B cells and T cells, which are crucial for rejecting dormant disseminated tumour cells. Increased cellular apoptosis is the rationale for use of glucocorticoids in the treatment of many lymphoid diseases including lymphocytic cancers, and for prevention of rejection of solid-organ transplants. However, for solid-tumour cells such as prostate cancer, glucocorticoids might induce apoptosis resistance in cells

Conclusion

An increase in the frequency of metastases with glucocorticoid treatment has been recorded in patients with disseminated cancers of solid tumours (eg, of the breast). Glucocorticoid treatment might favour the growth of malignant solid tumours, and increase tumour spread to the blood and lymphatic system as a result of decreased adhesiveness between cancer cells and increased tissue permeability. Although protection of healthy tissue by glucocorticoids is of benefit, the protection of malignant

Search strategy and selection criteria

Relevant articles were identified by searches of MEDLINE, Current contents, PubMed, and the Cochrane library between 1950 and November, 2005. The search terms “corticosteroids”, “glucocorticoids”, “dexamethasone”, “prednisone”, “hydrocortisone”, “cortisone”, “steroid hormones”, “cancer”, “prostate cancer”, “solid tumour”, “carcinoma”, “chemotherapy”, “prevention”, “palliative”, “side-effects”, “nausea”, “emesis”, “antiemetic”, “apoptosis”, “resistance”, “protection”, and “metastases” were

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