Hormonal manipulation of prostatic cancer Too soon for total androgen blockade? Recently the hormonal management of prostatic cancer has provoked much controversy and commercial interest. New principles of treatment have emerged, entailing the use of luteinising hormone releasing hormone agonists and antiandrogens, but the role of these drugs is still unclear. About one in 10 men with metastatic prostatic cancer receiving palliative treatment with hormones will experience long term survival without progression of disease,' although well documented cases of hormonal "cure," supported by findings at necropsy, are very rare.2 If other causes of death do not supervene all prostatic cancers eventually become independent of the effects of hormonal manipulation. How this happens is unclear, but "clonal selection" and overgrowth of cell populations that are hormone independent occur. Despite extensive research our knowledge of which hormones have clinically important effects on prostatic cancer cells is incomplete. Undoubtedly, the most pronounced effect occurs after withdrawal of androgen. After castration plasma testosterone concentrations fall to one tenth of normal, but the amount of androgen detectable in prostatic cancer tissue may amount to 40-50% of normal.3 (Similar reductions in androgen concentration are achievable with depot preparations of luteinising hormone releasing hormone agonists, oestrogens and gestagens, and steroidal antiandrogens such as cyproterone acetate.) Is this sufficient to maintain or stimulate the growth of hormone dependent tumour cells? Studies in men soon after castration or with hypogonadotrophic hypogonadism and panhypopituitarism suggest not: the adrenal glands produce insufficient androgen to maintain proliferation and normal function of the prostate.4 Those who believe that the amount of androgen present in prostatic tissue after castration is sufficient to stimulate growth of cancer base their arguments on the results of in vitro studies of androgen sensitivity.5 One of the few transplantable human cancers of the prostate lines that is hormone dependent (PC 82) shows the arrest of growth when tissue concentrations of testosterone and dihydrotestosterone reach those found in castrated men. Regression of tumours occurs only if tissue concentrations are much lower.6 It is important to realise that even "hormone independent" tumours are sensitive to androgenic stimulation: patients with these tumours experience rapid progression and exacerbation of their disease if exposed to exogenous testosterone.7 Evidence of any clinically exploitable dependence of prostatic cancer on hormones other than androgens is scarce. Two studies have reported that treatment with oestrogen is superior to castration,89 but these results have not been confirmed. No randomised comparative studies of large doses of oestrogen have been performed. If one accepts that hormonal manipulation is never more than palliative then the benefits of palliation need to be considered alongside the adverse effects of treatment. Castration is effective but carries a large psychological burden. Oestrogens have life threatening cardiovascular complications. Although luteinising hormone releasing hormone agonists and antiandrogens have fewer side effects, their effects on libido and potency are the same as for other regimens that suppress androgens. Pure antiandrogens used as monotherapy may be an exception, although whether they are as effective as other forms of standard treatment is not known. Would "total androgen blockade" improve outcome? BMJ
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Labrie and coworkers, who coined the term, reported a 96% response rate in 29 patients suffering from metastatic prostatic cancer.'0 A large study by Crawford et al comparing monotherapy with luteinising hormone releasing hormone (leuprorelin) with total androgen blockade (leuprorelin and the antiandrogen flutamide) found significant advantages in terms of the median time to progression and median survival amounting to 2 6 months and 7 3 months, respectively, in the patients receiving both drugs." Doubts about these results make it too early to recommend the adoption of total androgen blockade as the standard management of metastatic prostatic cancer. The doubts relate to the choice of a luteinising hormone releasing hormone agonist given by daily injections as the control treatment; when castration is used as the control no extra benefit is found for total androgen blockade.'2 13 Used without an antiandrogen, luteinising hormone releasing hormone agonists lead to increased production of testosterone during the first week of treatment. This may be associated with "flare" (or exacerbation) of the disease,'4 15 which occurs in between one and three fifths of patients and is more frequent and severe with extensive disease. In a recent review of 765 patients who suffered disease flare, in nine different series, 15 died with the presence of acute symptoms of exacerbation. 16 In the study by Crawford et al flare may explain the difference between the two treatment groups: disease progressed more rapidly in patients treated with leuprorelin during the first three months, after which the survival curves ran parallel. To assess the effects of total androgen blockade, control treatments other than luteinising hormone releasing hormone agonists are therefore necessary. At least 10 such studies of patients with previously untreated metastatic disease have been carried out, and their results do not support the findings of Crawford et al. " These studies show, however, more pronounced early regression of tumour and symptomatic relief and that total androgen blockade may improve the quality of life, especially during early treatment. These findings hardly justify the routine use of (very costly) total androgen blockade, except perhaps for patients presenting with a large symptomatic metastatic tumour mass, who may benefit from the quicker and more pronounced relief of symptoms. Until further progress is reported, treatment that suppresses plasma and tissue androgens to the concentrations found in castrated men, with the fewest- possible side effects, should remain the standard. FRITZ H SCHRODER Professor of Biology, Department of Urology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands 1 Reiner WG, Scott WW, Eggleston JC, Walsh PC. Long-term survival after hormonal therapy for stage D prostatic cancer. J Urol 1979;122:183-4. 2 Johansson S, Ljunggren E. Prostatic carcinoma cured with hormonal treatment. Scand J Urol
Nephrol 1981;15:331-2. 3 Geller J, Albert JD, Nachtsheim DA, Loza D. Comparison of prostatic cancer tissue Dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol 1984;132:693-6. 4 Oesterling JE, Epstein JI, Walsh PC. The viability of adrenal androgens to stimulate the adult human prostate: an autopsy evaluation of men with gonadotropic hypogonadism and panhypopituitarism. J Urol 1986;136:1030-4. 5 Labrie F, Veilleux R, Fournier A. Low androgen levels induce the development of androgenhypersensitive cell clones in Shionogi mouse mammary carcinoma cells in culture. J Natl Cancer Inst 1988;80:1138-47. 6 van Weerden WM, van Steenbrugge GJ, van Kreuningen A, Moerings EPCM, de Jong FH,
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Schroder FH. Assessment of the critical level of androgen for growth response of transplantable human prostatic carcinoma (PC-82) in nude mice..7 Urol 1991;145:631-4. Fowler JE, Whitmore WF. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981;126:372-5. Haapiainen R, Ranniko S, Ruutu M, Ala-Opas M, Hansson E, Juusela H, et al. Orchiectomy versus oestrogen in the treatment of advanced prostatic cancer. BrJ Urol 1991;67:184-7. Johansson JE, Andersson SO, Holmberg L, Bergstrom R. Primary orchiectomy versus estrogen therapy in advanced prostatic cancer - a randomized study: results after 7 to 10 years of followup. j Urol 1991;145:519-22. Labrie F, Dupont A, Belanger A, Lacoursiere Y, Raynaud JP, Husson JM, et al. New approaches in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. The Prostate 1983;4:579-94. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N EnglJ Med 1989;321:419-24.
12 Iversen P, Suciu S, Sylvester R, Christensen I, Denis L. Zoladex and flutamide versus orchiectomy in the treatment of advanced prostatic cancer. Cancer 1990;66:1067-73. 13 Beland G, Elhilali M, Fradet Y, Laroche B, Ramsey EW, Trachtenberg J, et al. A controlled trial of castration with and without Nilutamide in metastatic prostatic carcinoma. Cancer 1990;66: 1074-9. 14 Waxman J, Man A, Hendry WF, Whitfield HN, Besser GM. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. BMJ 1985;291:1387-8. 15 Huben RP, Murphy GP, Investigators of the National Prostatic Cancer Project. A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylstilbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate. Cancer 1988;62: 1881-7. 16 Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing agonist therapy for carcinoma of the prostate. J Urol 1990;144:1479-80.
Tired all the time Most cases are managed in primary care-where the research needs to be done General practitioners often see a syndrome they call "tired all the time." How often doctors see it depends on how tiredness is defined and where it is measured. Morrell recorded fatigue as the most important reason for consultation in 24 per 2000 registered patients in one year'; Jerrett recorded fatigue as a presenting or supporting symptom in 150 per 2000 registered patients.2 Yet patients may not necessarily mention fatigue when they consult. A survey of patients waiting in one surgery found that a tenth reported "substantial fatigue" for a month or more3; 18-34% of respondents in a community survey reported always feeling tired in the past month4; and when young women patients were asked to record symptoms in diaries 400 episodes of fatigue were recorded for every one reported to the doctor.5 Clinicians may regard this iceberg as a puzzle, and a blessing. But how should they manage the cases that do present? Little has been published on tiredness in primary care, with only one prospective study from Britain2 and two retrospective ones from American family practice.67 The results suggest that psychosocial causes are paramount in 40-51% of cases and physical causes in 21-39%.267 The remaining cases are of mixed or undetermined cause. Fatigue presents three times more often in women of childbearing age,2 who often have a working day that is long and difficult to organise, with no boundary between home and work.8 The wise doctor steers between the extremes of trivialising and medicalising such "social" fatigue. If the cause is existential rather than medical counselling may help the patient consider various alternatives and make new choices. General practitioners are most likely to miss psychological distress when patients present with apparently physical symptoms,9 and the psychological symptoms then continue for longer than when the cause is correctly identified.' Although fatigue is a physical symptom, it is also a feature of depression, " so patients should be asked about change in appetite, weight, sleep, and ability to concentrate. Positive responses do not necessarily exclude organic or social causes. 12 If patients are convinced that symptoms are organic it is reasonable to examine and investigate while opening up a discussion of psychosocial causes. Patients will be relieved that their concerns are addressed, and sometimes they will piece together occult worries and mention them later. When the general practitioner does identify depression, antidepressants given in therapeutic doses help.'3 Particular physical causes depend on age and gender. In young women fatigue may be the presenting symptom of anaemia or pregnancy. In young people of both sexes it may be the presenting feature of glandular fever or some other infection.6 It is therefore worth inquiring about menorrhagia 1490
or a missed period and symptoms of infection. With young patients a blood count, monospot test, and pregnancy test are the investigations with the highest yield.6 Among older people fatigue is more commonly associated with circulatory disorders or, importantly, prescribed drugs, so all medications should be inquired about.2 Occasionally fatigue may be an early symptom of endocrine or malignant disease, but these medical firm "classics" are rare in primary care. Laboratory tests generally have a low yield and clinch the diagnosis in only 8% of patients.7 Less than 2% of patients with fatigue are referred to specialists,' so inferring from research done in secondary care about causal probabilities in general practice is inappropriate. When general practitioners record fatigue as a "diagnosis" at the end of the consultation patients consult on average only 1-4 times.'4 A few, however, complain of fatigue for much longer. This condition, sometimes called myalgic encephalitis (ME), is the subject of confusion and debate. Some definitions conflate ideas about cause when the cause is not yet known, and different definitions make it difficult to compare the results of research. A consensus group has proposed that severe fatigue lasting for more than six months in the absence of certain clinical conditions should simply be called the chronic fatigue syndrome.'5 So far. most of the suggested causes have not been confirmed, such as Coxsackie virus infection6 17 and peripheral nerve dysfunction. 18 '9 A few patients do have signs of immunological dysfunction after infectious mononucleosis,20 but Wessely and Powell found that 72% of patients referred over seven months at the National Hospital for Nervous Diseases with unexplained chronic fatigue had psychiatric disorders, particularly depression. 21 Doctors' uncertainties about the cause and prognosis of chronic fatigue may strain the doctor-patient relationship. General practitioners should acknowledge their uncertainty and keep an open mind; the patient's condition and scientific knowledge may change. Some patients will need long term support. Cognitive behaviour therapy has led to improvement in symptoms,22 and its potential benefit warrants assessment in a randomised trial. Whether it is subacute or chronic, the tired all the time syndrome is a clinical challenge in general practice, and it is clinicians in primary care who need to research the condition and apply the results. LEONE RIDSDALE Senior Lecturer, Department of General Practice, United Medical and Dental School, Guy's Hospital, London SEI 9RT
BMJ VOLUME 303
14 DECEMBER 1991
VOLUME 303
14 DECEMBER 1991
Labrie and coworkers, who coined the term, reported a 96% response rate in 29 patients suffering from metastatic prostatic cancer.'0 A large study by Crawford et al comparing monotherapy with luteinising hormone releasing hormone (leuprorelin) with total androgen blockade (leuprorelin and the antiandrogen flutamide) found significant advantages in terms of the median time to progression and median survival amounting to 2 6 months and 7 3 months, respectively, in the patients receiving both drugs." Doubts about these results make it too early to recommend the adoption of total androgen blockade as the standard management of metastatic prostatic cancer. The doubts relate to the choice of a luteinising hormone releasing hormone agonist given by daily injections as the control treatment; when castration is used as the control no extra benefit is found for total androgen blockade.'2 13 Used without an antiandrogen, luteinising hormone releasing hormone agonists lead to increased production of testosterone during the first week of treatment. This may be associated with "flare" (or exacerbation) of the disease,'4 15 which occurs in between one and three fifths of patients and is more frequent and severe with extensive disease. In a recent review of 765 patients who suffered disease flare, in nine different series, 15 died with the presence of acute symptoms of exacerbation. 16 In the study by Crawford et al flare may explain the difference between the two treatment groups: disease progressed more rapidly in patients treated with leuprorelin during the first three months, after which the survival curves ran parallel. To assess the effects of total androgen blockade, control treatments other than luteinising hormone releasing hormone agonists are therefore necessary. At least 10 such studies of patients with previously untreated metastatic disease have been carried out, and their results do not support the findings of Crawford et al. " These studies show, however, more pronounced early regression of tumour and symptomatic relief and that total androgen blockade may improve the quality of life, especially during early treatment. These findings hardly justify the routine use of (very costly) total androgen blockade, except perhaps for patients presenting with a large symptomatic metastatic tumour mass, who may benefit from the quicker and more pronounced relief of symptoms. Until further progress is reported, treatment that suppresses plasma and tissue androgens to the concentrations found in castrated men, with the fewest- possible side effects, should remain the standard. FRITZ H SCHRODER Professor of Biology, Department of Urology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands 1 Reiner WG, Scott WW, Eggleston JC, Walsh PC. Long-term survival after hormonal therapy for stage D prostatic cancer. J Urol 1979;122:183-4. 2 Johansson S, Ljunggren E. Prostatic carcinoma cured with hormonal treatment. Scand J Urol
Nephrol 1981;15:331-2. 3 Geller J, Albert JD, Nachtsheim DA, Loza D. Comparison of prostatic cancer tissue Dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol 1984;132:693-6. 4 Oesterling JE, Epstein JI, Walsh PC. The viability of adrenal androgens to stimulate the adult human prostate: an autopsy evaluation of men with gonadotropic hypogonadism and panhypopituitarism. J Urol 1986;136:1030-4. 5 Labrie F, Veilleux R, Fournier A. Low androgen levels induce the development of androgenhypersensitive cell clones in Shionogi mouse mammary carcinoma cells in culture. J Natl Cancer Inst 1988;80:1138-47. 6 van Weerden WM, van Steenbrugge GJ, van Kreuningen A, Moerings EPCM, de Jong FH,
1489
7
8 9
10 11
Schroder FH. Assessment of the critical level of androgen for growth response of transplantable human prostatic carcinoma (PC-82) in nude mice..7 Urol 1991;145:631-4. Fowler JE, Whitmore WF. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981;126:372-5. Haapiainen R, Ranniko S, Ruutu M, Ala-Opas M, Hansson E, Juusela H, et al. Orchiectomy versus oestrogen in the treatment of advanced prostatic cancer. BrJ Urol 1991;67:184-7. Johansson JE, Andersson SO, Holmberg L, Bergstrom R. Primary orchiectomy versus estrogen therapy in advanced prostatic cancer - a randomized study: results after 7 to 10 years of followup. j Urol 1991;145:519-22. Labrie F, Dupont A, Belanger A, Lacoursiere Y, Raynaud JP, Husson JM, et al. New approaches in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. The Prostate 1983;4:579-94. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N EnglJ Med 1989;321:419-24.
12 Iversen P, Suciu S, Sylvester R, Christensen I, Denis L. Zoladex and flutamide versus orchiectomy in the treatment of advanced prostatic cancer. Cancer 1990;66:1067-73. 13 Beland G, Elhilali M, Fradet Y, Laroche B, Ramsey EW, Trachtenberg J, et al. A controlled trial of castration with and without Nilutamide in metastatic prostatic carcinoma. Cancer 1990;66: 1074-9. 14 Waxman J, Man A, Hendry WF, Whitfield HN, Besser GM. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. BMJ 1985;291:1387-8. 15 Huben RP, Murphy GP, Investigators of the National Prostatic Cancer Project. A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylstilbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate. Cancer 1988;62: 1881-7. 16 Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing agonist therapy for carcinoma of the prostate. J Urol 1990;144:1479-80.
Tired all the time Most cases are managed in primary care-where the research needs to be done General practitioners often see a syndrome they call "tired all the time." How often doctors see it depends on how tiredness is defined and where it is measured. Morrell recorded fatigue as the most important reason for consultation in 24 per 2000 registered patients in one year'; Jerrett recorded fatigue as a presenting or supporting symptom in 150 per 2000 registered patients.2 Yet patients may not necessarily mention fatigue when they consult. A survey of patients waiting in one surgery found that a tenth reported "substantial fatigue" for a month or more3; 18-34% of respondents in a community survey reported always feeling tired in the past month4; and when young women patients were asked to record symptoms in diaries 400 episodes of fatigue were recorded for every one reported to the doctor.5 Clinicians may regard this iceberg as a puzzle, and a blessing. But how should they manage the cases that do present? Little has been published on tiredness in primary care, with only one prospective study from Britain2 and two retrospective ones from American family practice.67 The results suggest that psychosocial causes are paramount in 40-51% of cases and physical causes in 21-39%.267 The remaining cases are of mixed or undetermined cause. Fatigue presents three times more often in women of childbearing age,2 who often have a working day that is long and difficult to organise, with no boundary between home and work.8 The wise doctor steers between the extremes of trivialising and medicalising such "social" fatigue. If the cause is existential rather than medical counselling may help the patient consider various alternatives and make new choices. General practitioners are most likely to miss psychological distress when patients present with apparently physical symptoms,9 and the psychological symptoms then continue for longer than when the cause is correctly identified.' Although fatigue is a physical symptom, it is also a feature of depression, " so patients should be asked about change in appetite, weight, sleep, and ability to concentrate. Positive responses do not necessarily exclude organic or social causes. 12 If patients are convinced that symptoms are organic it is reasonable to examine and investigate while opening up a discussion of psychosocial causes. Patients will be relieved that their concerns are addressed, and sometimes they will piece together occult worries and mention them later. When the general practitioner does identify depression, antidepressants given in therapeutic doses help.'3 Particular physical causes depend on age and gender. In young women fatigue may be the presenting symptom of anaemia or pregnancy. In young people of both sexes it may be the presenting feature of glandular fever or some other infection.6 It is therefore worth inquiring about menorrhagia 1490
or a missed period and symptoms of infection. With young patients a blood count, monospot test, and pregnancy test are the investigations with the highest yield.6 Among older people fatigue is more commonly associated with circulatory disorders or, importantly, prescribed drugs, so all medications should be inquired about.2 Occasionally fatigue may be an early symptom of endocrine or malignant disease, but these medical firm "classics" are rare in primary care. Laboratory tests generally have a low yield and clinch the diagnosis in only 8% of patients.7 Less than 2% of patients with fatigue are referred to specialists,' so inferring from research done in secondary care about causal probabilities in general practice is inappropriate. When general practitioners record fatigue as a "diagnosis" at the end of the consultation patients consult on average only 1-4 times.'4 A few, however, complain of fatigue for much longer. This condition, sometimes called myalgic encephalitis (ME), is the subject of confusion and debate. Some definitions conflate ideas about cause when the cause is not yet known, and different definitions make it difficult to compare the results of research. A consensus group has proposed that severe fatigue lasting for more than six months in the absence of certain clinical conditions should simply be called the chronic fatigue syndrome.'5 So far. most of the suggested causes have not been confirmed, such as Coxsackie virus infection6 17 and peripheral nerve dysfunction. 18 '9 A few patients do have signs of immunological dysfunction after infectious mononucleosis,20 but Wessely and Powell found that 72% of patients referred over seven months at the National Hospital for Nervous Diseases with unexplained chronic fatigue had psychiatric disorders, particularly depression. 21 Doctors' uncertainties about the cause and prognosis of chronic fatigue may strain the doctor-patient relationship. General practitioners should acknowledge their uncertainty and keep an open mind; the patient's condition and scientific knowledge may change. Some patients will need long term support. Cognitive behaviour therapy has led to improvement in symptoms,22 and its potential benefit warrants assessment in a randomised trial. Whether it is subacute or chronic, the tired all the time syndrome is a clinical challenge in general practice, and it is clinicians in primary care who need to research the condition and apply the results. LEONE RIDSDALE Senior Lecturer, Department of General Practice, United Medical and Dental School, Guy's Hospital, London SEI 9RT
BMJ VOLUME 303
14 DECEMBER 1991
