Personal View
`
`Lancet Oncol 2006; 7: 425–30
`Department of Urology,
`University of Heidelberg,
`Heidelberg, Germany
`(Prof I Herr PhD,
`J Pfi tzenmaier MD); and
`Department of Molecular
`Uro-oncology, German Cancer
`Research Centre, Heidelberg,
`Germany (Prof I Herr)
`Correspondence to:
`Prof Ingrid Herr, German Cancer
`Research Centre, Molecular
`Uro-oncology–E095, Im
`Neuenheimer Feld 280, 69120
`Heidelberg, Germany
`i.herr@dkfz.de
`
`Glucocorticoid use in prostate cancer and other solid
`tumours: implications for eff ectiveness of cytotoxic
`treatment and metastases
`
`Ingrid Herr, Jesco Pfi tzenmaier
`
`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 eff ects in healthy
`tissue. However, glucocorticoids are used in a supportive-care role, even though to our knowledge no prospective
`clinical studies have assessed the eff ect 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 benefi ts of glucocorticoids and their negative eff ects, 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; fi gure 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
`benefi cial eff ects, such as reduction of nausea and
`emesis, protection of healthy tissue from cytotoxic side-
`eff ects, and presumably a reduction of tissue reactions
`such as infl ammation 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 fi ght disease. Thus, although
`glucocorticoids have many benefi ts 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 fi ve 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 fi rst-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 (fi gure 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
`
`Figure 1: Prostate cancer seen during apex preparation of gland
`Left arrow=urethra. Middle arrow=prostate gland. Right arrow=tumour.
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`Personal View
`
`A
`
`B
`
`C
`
`D
`
`Apoptosis resistance and spread of cells
`from solid tumours (eg, prostate cancer)
`
`Glucocorticoids
`
`Suppression of immune system
`
`Figure 2: Inhibition of apoptosis and suppression of immune system leads to spread and growth of tumours
`A=primary tumour. B=tumour cells escape from primary tumour by loss of cell adhesion and induction of cell
`motility. C=invasion of surrounding tissue and dissemination to lymph nodes or circulation through blood.
`D=homing to secondary organs and induction of bone metastases.
`
`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 eff ective for palliation of advanced
`prostate cancer.2
`
`Historical overview
`The Italian anatomist Eustachi identifi ed the suprarenal
`glands in the middle of the 16th century, but these glands
`were not shown to be necessary for survival until Addison
`defi ned a fatal syndrome associated with loss of adrenal
`function in 1855. In the fi rst 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 ranging from
`hypothermia to burns, and under psychological distress.
`In
`this context, adrenal cortical hormones were
`understood widely to stimulate the response to distress
`because in their absence animals seemed unable to
`mount a coordinated defensive response to almost any
`injury or
`infection. Therefore, physiologists were
`surprised by Hench and colleagues’11 fi nding that
`compound E (later known as cortisone) had potent anti-
`infl ammatory eff ects on disease symptoms in human
`beings. With the purifi cation of adrenal cortical hormones
`in the 1930s and 1940s, clinicians discovered the potent
`anti-infl ammatory actions of glucocorticoids. This
`unexpected fi nding dominated clinical and laboratory
`research on glucocorticoid function throughout the
`second half of the 20th century.12
`Cortisone was fi rst used clinically in 1948 for eff ective
`treatment of rheumatoid arthritis.13 Glucocorticoids have
`since been used in the treatment of asthma, dermatitis,
`and autoimmune diseases (eg, Crohn’s disease and tissue
`oedema). Moreover, they have antipyretic activity. In the
`early 1960s, glucocorticoids were fi rst used to induce
`remission of childhood
`leukaemia.14 The ability of
`
`glucocorticoids to kill lymphoid cells effi ciently has led to
`their
`inclusion
`in all chemotherapy regimens for
`malignant diseases of the lymphatic tissue.1 Glucocorticoids
`are used widely in combination with other treatment of
`solid tumours because of their eff ectiveness in treating
`oedema induced by the tumour or by cytotoxic treatment.
`They are also used to: treat infl ammation, pain, and
`electrolyte imbalance; to stimulate appetite; and to prevent
`nausea, emesis, and toxic eff ects caused by drugs.3
`Glucocorticoids are given before, during, and after
`chemotherapy at various doses to reduce acute toxic
`eff ects, particularly hyperemesis, and to protect healthy
`tissue against long-term eff ects of genotoxic drugs.3 For
`example, they protect bone-marrow progenitor cells15 and
`other healthy cells from damage by cytotoxic treatment.
`Furthermore, glucocorticoids might have a protective
`eff ect against damage induced by hypoxia or ischaemia in
`neurons16 and myocardial cells,17 and reduce apoptosis in
`injured spinal-cord tissue.18 Moreover, use of gluco-
`corticoids in cancer treatment relieves symptoms: ie, pain
`from osseous metastases; dyspnoea from pulmonary
`metastases; neurological manifestations from cerebral
`metastases; and discomfort from infl ammatory reactions
`and lymphoedema.19 This palliative eff ect is presumably
`due to a decrease in tissue reactions against invasive
`malignant growth.
`
`Unfavourable eff ects
`Although glucocorticoids generally off er supportive
`treatment of
`tumour cells
`in
`lymphatic
`tissue,
`glucocorticoid-induced resistance has been identifi ed 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).20–30 Tumours analysed were derived
`from bladder,31 bone (Herr I, unpublished data), brain,32–36
`breast,20,37–39 cervix,25,40,41 colon or rectum,27
`liver,27,42,43
`lung,25,44–46 kidney,31,28 nerve tissue,47 ovary,20,23 pancreas,29
`prostate,31,48 skin (Herr I, unpublished data), and testis.31
`In the presence of various anticancer agents, several
`glucocorticoid derivatives, in various doses, such as beta-
`met hasone, dexamethasone, corticosterone, fl uoci nolone,
`hydrocortisone, methylprednisolone, prednis olone, and
`prednisone substantially increased viability or inhibited
`apoptosis, or both, of most tumour cells of solid, but not
`of lymphoid, malignant diseases (Herr I, unpublished
`data). Glucocorticoids blocked the lethal signal delivered
`by cytotoxic drugs even if they were given several hours
`after induction of apoptosis by cytotoxic drugs. Moreover,
`resistance induced by a single treatment of established
`tumour cells with glucocorticoids lasted for up to 10 days
`before it started to decline, and resistance was noted at
`peak plasma concentrations and below
`(Herr I,
`unpublished data). Because low concentrations occur in
`patients after plasma concentrations of administered
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`
`glucocorticoids decline, the issue of whether normal
`concentrations of glucocorticoids in the body could
`interfere with cancer treatment is raised: several studies
`of xenografted human carcinomas of the breast,20 colon,27
`lung,25 ovary,20,23 pancreas,29 and prostate
`(Herr I,
`unpublished data), suggest that exogenous glucocorticoids
`stimulate the growth of tumours in vivo at concentrations
`substantially above those of endogenous glucocorticoids.
`An important underlying reason why glucocorticoids
`are given in combination with other cancer treatment is
`their obvious proapoptotic and antiproliferative eff ect in
`lymphoid cells.49 Although
`to our knowledge, no
`prospective studies have assessed
`the eff ect of
`glucocorticoids on the growth of solid tumours, these
`steroid hormones are commonly used in supportive care.
`However, data from retrospective clinical studies24,26,28
`suggest that glucocorticoids protect solid tumours,
`including prostate cancer, from cytotoxic treatment. In
`1981, Haid50 recommended that interpretation of fi ndings
`from cancers in lymphatic tissue to solid tumours might
`not be safe. The in-vitro and in-vivo animal studies
`reviewed here suggest that glucocorticoids could render
`solid tumours resistant to treatment, perhaps enhancing
`metastases.
`A retrospective study24 assessed records for 245 of
`763 patients with ovarian cancer, and found no adverse
`outcome with glucocorticoid treatment on survival
`(table). However, this study analysed survival only, and
`not tumour response, and therefore cannot answer the
`question of whether glucocorticoid treatment is safe for
`patients with ovarian cancer or other solid tumours;
`detailed reasons have been discussed previously.51 By
`contrast, a population-based cohort study30 showed an
`increased risk of skin cancer and lymphoma in users of
`systemic glucocorticoids.
`Although to our knowledge no prospective study has
`assessed no glucocorticoids versus glucocorticoids in a
`randomised setting, a retrospective study28 showed an
`association
`between
`increased
`serum
`cortisol
`concentrations and high tumour grade in 211 consecutive
`patients with renal-cell carcinoma before starting
`treatment. Concentration of serum cortisol was
`signifi cantly higher in patients with renal-cell carcinoma
`than
`in those with benign cysts. Serum cortisol
`concentration was associated with tumour diameter and
`grade, but not with disease stage. The outlook of patients
`with raised serum cortisol concentrations was worse than
`that of those with low concentrations. These fi ndings
`with endogenous cortisol concentrations lend support to
`the in-vitro and animal studies that showed cotreatment
`with glucocorticoids
`induced resistance
`to cancer.
`Furthermore, such fi ndings necessitate assessment of
`the hypothalamic–pituitary adrenal axis in patients with
`malignant disease, and its possible eff ect on outlook.
`Glucocorticoids suppress the immune system, and
`many studies have shown that immunosuppression can
`exacerbate the metastatic process and accelerate tumour
`
`growth in animals.52–54 Therefore, some researchers have
`associated development of metastases with steroid
`treatment,21 and have suggested that the reason for such
`association could be the immunosuppressive eff ect of
`these steroids. Sherlock and Hartmann21 analysed
`patterns of metastases in 204 patients with breast cancer,
`and found that those who were given glucocorticoids had
`a signifi cant increase in metastases to the lungs, liver,
`heart, brain, spleen, and gastrointestinal tract compared
`with patients who did not receive steroids. Further clinical
`research22 has confi rmed that glucocorticoids induce
`increased metastatic potential in patients with breast
`cancer. Furthermore, retrospective analysis26 showed that
`glucocorticoids had a negative eff ect on the effi cacy of
`teniposide. The
`investigators26 analysed
`the eff ect
`of teniposide on brain metastases from small-cell lung
`cancer in the presence or absence of a glucocorticoid. Of
`43 patients who received glucocorticoids, only nine
`responded, whereas 17 of 37 patients not treated with
`glucocorticoids had a response as assessed by neurological
`investigation and CT. Concomitant treatment with
`glucocorticoids and teniposide resulted in a subjective
`improvement in response—assessed by neurological
`function and number of brain metastases—for 18 of
`42 assessable patients, compared with 20 of 34 assessable
`patients given glucocorticoids alone. Thus, in-vitro,
`animal, and several clinical studies suggest
`that
`glucocorticoids induce resistance of carcinomas to
`chemotherapy and radiotherapy. However, before any
`conclusion from poorly controlled retrospective clinical
`
`Breast cancer
`Faster tumour growth of xenografts
`Increased metastasis to lungs, liver, heart, brain, spleen, and gastrointestinal tract
`in patients cotreated with glucocorticoids
`Ovarian cancer
`Faster tumour growth of xenografts
`No negative outcome on survival
`Lung cancer
`Faster tumour growth of xenografts
`Negative eff ect on effi cacy of teniposide in brain metastases
`Colon cancer
`Faster tumour growth of xenografts
`No clinical studies available
`Kidney cancer
`No xenograft studies available
`High serum concentrations of cortisol associated with renal-cell carcinoma
`Pancreatic cancer
`Faster tumour growth of xenografts
`No clinical studies available
`Skin cancer
`No xenograft studies available
`Enhanced risk of skin cancer and lymphomas
`Prostate cancer
`Faster tumour growth of xenografts
`No clinical studies available
`
`Table: Summary of glucocorticoid-induced protection of tumours
`
`Ref
`
`20
`21,22
`
`20,23
`24
`
`25
`26
`
`27
`
`28
`
`29
`
`30
`
`(Herr I, unpublished)
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`
`trials and laboratory studies can be drawn, well-designed
`clinical trials of glucocorticoids are necessary.
`
`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 (fi gure 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 where
`the cells undergo apoptosis, are cleared by the immune
`system, or might exist as viable cells in a dormant state.56
`Some of these cells eventually become precursors of
`metastases that can arise many years after curative
`resection of the primary tumour.57 Of the organs distant
`from the site of the tumour, the bone marrow is a common
`site of metastatic disease (eg, for disseminated prostate
`cancer cells). After entrance and survival
`in
`the
`bloodstream; extravasation; and infi ltration into the bone
`marrow, prostate-cancer cells interact with bone cells and
`matrix.58
`Why prostate-cancer cells survive in the bone marrow,
`and how they develop into clinically relevant metastases,
`is unclear. However, exogenous glucocorticoids or end-
`ogenously enhanced glucocorticoid concentrations might
`contribute to progression of metastasis by induction of
`apoptosis resistance in disseminated prostate-cancer
`cells, thus enabling survival and escape from the immune
`system. This idea is consistent with a clinical study22 that
`showed increased metastatic potential in patients with
`breast
`cancer
`in
`response
`to glucocorticoids.22
`Furthermore, studies in animals59–61 have shown that
`glucocorticoid treatment can increase the spread of some
`tumours, presumably because of decreased adhesiveness
`between malignant cells,62,63 increased permeability of
`connective tissue and blood vessels,64 lowered capacity of
`the reticuloendothelial system,65 and induced favourable
`conditions for tumour embolisms to establish these
`tumour cells in another organ.66,67
`
`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 of solid tumours and keep to a minimum the
`number of activated T cells necessary to attack remaining
`malignant cells after surgery and chemotherapy.
`
`in-vivo
`Furthermore, glucocorticoids might reduce
`expression of MHC antigens69 and inhibit activity of
`natural cytotoxic cells of patients when used as an
`antiemetic in chemotherapy.70 These results are confi rmed
`by a study71 that showed a role for natural cytotoxic cells
`in rejection of tumours in animals.71 Furthermore,
`human natural cytotoxic cells are more eff ective at lysing
`human tumour cells in vitro in the presence of cisplatin
`than in its absence,72 lending support to an additive eff ect
`by natural cytotoxic cells to chemotherapy. Thus,
`downregulation of the immune system’s attack on the
`tumour could be another negative eff ect of glucocorticoids
`in cancer treatment, and might contribute to the
`increased metastatic potential in patients with breast
`cancer who
`receive combination
`treatment with
`glucocorticoids and the increased risk of skin cancer and
`lymphoma in users of systemic glucocorticoids.21,22,30
`
`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 benefi t, the
`protection of malignant
`solid-tumour cells and
`downregulation of immune responses might keep to a
`minimum the eff ect of cytotoxic treatment and might
`support metastasis. However, fi ndings from retrospective
`clinical studies and animal experiments need controlled
`prospective clinical trials before conclusions regarding
`treatment can be made. Most
`likely, combination
`treatment with glucocorticoids will be given to patients
`with disseminated cancer because of the benefi cial
`subjective eff ects; however, our opinion is that these
`benefi ts are obtained at the expense of increased
`progression and spread of the cancer. Thus, at present,
`should patients with malignant disease be treated
`routinely with glucocorticoids?
`Confl icts of interest
`We declare no confl icts of interest.
`
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`Search strategy and selection criteria
`
`Relevant articles were identifi ed by searches of MEDLINE,
`Current contents, PubMed, and the Cochrane library between
`1950 and November, 2005. The search terms
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