EurJ Cancer, Vol. DA, Printed tn Great Bntntn
No. 12, ~0. 1937-1938.
0964~1947~92$5.00 + 0.00 Pergamon Press Ltd
1992
Comments and Critique A European Initiative for Prostatic Cancer
CANCER is becoming alarmingly common and, throughout the first and second worlds, has increased in incidence such that it is now the second most important cause of cancer deaths in men. Over the past 50 years, age-standardised mortality rates have also increased dramatically in the third world, in some areas by lo-fold. These changes are substantive and are not merely a function of the increasing age to which we live. Despite the significance of prostatic cancer as a cause of morbidity and mortality, and its pandemic scale, the experimental investigation of prostatic cancer is shamefully lacking. This is not easily understood and is in contrast to the situation for other common cancers. The lack of research into the molecular basis of prostatic cancer is such that the relevant observations can be easily summarised in one paragraph. Cytoplasmic oncogenes have been studied: the p21 protein product of the MSoncogene was expressed in 23 of 29 carcinomas but in none of 19 benign prostatic hypertrophy specimens. Positivity as assessed by immunohistochemistry correlated with differentiation [ 11. Mutations of the rus oncogene are unusual in prostatic cancer and have been reported in only 1 of 24 tumours [2]. Nuclear oncogenes have been investigated and c-myc RNA transcript levels are higher in tumours than in benign hypertrophy [3]. Androgens affect oncogene expression and in cell culture studies, c-fos mRNA levels dramatically decreased upon androgen withdrawal from the culture media [4]. Autocrine regulation may be a feature of prostatic cancer because human cell lines both secrete transforming growth factor alpha, epiderma1 growth factor, and gonadotropin-releasing hormone-like peptides and express receptors for these factors [5-81. There is differential expression of growth factor receptors in tumours compared with benign tissue. Epidermal growth factor receptors are reported in 68 % of prostatic tumours but in only 6 % of benign hypertrophy cases [7]. Epidermal growth factor receptor mRNA levels are higher in cancer than in benign tissue [8]. Tumour suppressor genes may be involved in the development of prostatic cancer. The retinoblastoma gene product was abnormally expressed in one of three cell lines examined and transfection of the normal gene into this cell line led to a decrease in its ability to form tumours in nude mice [9]. In contrast, there have been many changes in prostatic cancer treatment during the past decade. Treatment is now potentially humane and without major side-effects. The origins of endocrine treatment date back 100 years to the observation by White of the effects of orchiectomy on prostatic diseases [lo]. Endocrine treatments for prostatic cancer were introduced in the 1940s and an initial analysis of the effects of these therapies showed a survival advantage [ll]. This advantage has never been confirmed by subsequent studies, and the consensus view is that PROSTATIC
Correspondence to J. Waxman. Revised 23 Mar. 1992; accepted
8 Apr. 1992.
treatment acts only to palliate symptoms without prolonging life. As a result of this conclusion, the specific side-effects of treatment have been assessed in detail. The toxicity of oestrogen therapy includes indigestion, body shape change and cardiovascular morbidity and mortality [12]. Given the frequency of these toxicities and the availability of alternative therapies, we consider that prescription of oestrogens for the treatment of prostatic cancer, is no longer appropriate. Many clinicians, and even more patients, consider orchidectomy to be obsolete and so alternative medical treatments for prostatic cancer have been investigated. These include cyproterone acetate, flutamide, ketoconazole, casodex, and nilutamide but all of these, as single agents, are suboptimal because of lack of efficacy or side-effects [ 13-161. In contrast, the gonadotropin releasing hormone (GnRH) agonists provide a specific, rational treatment for prostatic cancer [17]. These peptides limit testicular androgen production. However, the testis is not the only source of androgenic steroids and in the medically castrate man, adrenal androgens may contribute up to 45% of prostatic androgen levels. Extra-testicular androgen production may be particularly relevant in a disease that is androgen sensitive, providing a means for the maintenance of continued growth of androgen responsive cells. The effects of adrenal androgens may be limited by the concurrent use of an anti-androgen, such as flutamide, casodex or nilutamide [18]; cyproterone acetate is precluded from use because of inherent androgenicity. The advantages of combination antiandrogen and GnRH agonist therapy were investigated in a randomised double-blind trial by the USA National Cancer Institute (NCI) [19]. In this meticulous study, an advantage in disease-free survival was found for combination therapies. This result has not been generally accepted and several other randomised studies have been instigated to investigate this hypothesis. At a recent congress, 10 such trials were reported involving 3447 patients. Many of these studies are not mature. However, in three of seven in which initial response is described, there was an advantage for combination therapy; in three of eight, an advantage in medium time to progression; but in only one of nine was survival prolonged [20-291. This trial was the NC1 study [19]. The issue remains contentious and no definite conclusion can be drawn about the advantage of combination endocrine therapy. Whatever the outcome is of this controversy, it should be noted that there is no gross disadvantage to the use of an antiandrogen in the treatment of patients with prostatic cancer with GnRH agonists, because of the antiandrogens value in the abrogation of tumour flare. However, there are some side-effects from the most frequently used antiandrogen, flutamide. Diarrhoea is reported in between 15 and 30% of patients and may be severe enough to warrant discontinuing therapy. Second-line therapies offer little hope in prostatic cancer, and
1937
J. Waxman and A. Gutierrez
1938
the most useful single agent is radiotherapy.
There has been interest in the effects of suramin, but most treatments have included steroid supplements [30]. Because steroids are effective treatments for prostatic cancer, any activity may be due to these agents. A major research initiative is required for prostatic cancer and needs to have two aims. The most important is the provision of an impetus for basic research. In view of the epidemic nature of the disease and its importance within Europe, a strong case could be argued for a European initiative. The second aim is for the continued investigation of new agents for the treatment of prostatic cancer. Because of the disease’s signi!icance, it is arguable whether this should be left to conventional market forces. Jonathan Waxman Senior Lecturer and Honorary Consultant Andres Gutierrez Research Fellow Department of Clinical Oncology Royal Postgraduate Medical School Hamrnersmith Hospital Du Cane Road London W12 ONN
12
13
14. 15. 16.
17. 18.
19.
20. 21.
22. 1. Viola MV. Fromowitz F, Oravez S, et al. Expression of ras oncogene p-21 in prostate cancer. A’EnglJMed 1986;314,133-137. _ 2. carter BS, Epstein JI, Isaacs WB. ras gene mutations in human nrostate cancer. CancerRes 1990,50,6830-6832. 3. ‘Fleming WH, Hamel A, MacDonald R, et al. Expression of the cnyc proto-oncogene in- human prostatic carcinoma and benign orostatic hvDerDlasia. Cancer Res 1986: 46: 1535-1538. 4. Rijinders KWM, Van der Korput JAGM, Van Steenbrugge GJ, Romiin JC, Trapman J. Expression of cellular oncogenes in human prostatic carcinoma cell lines. Biochem Siophys Res Comm 1985, 132,548-554. 5. MacDonald A, Chishohn GD, Habib FK. Production and response of a human prostatic cancer line to transforming growth factor-like molecules. Br 7 Cancer 1990,62,579-584. 6. Qayum A, Gullick W, Clayton RC, Sikora K, Waxman J. The effects of gonadotrophin releasing hormone analogues in prostate cancer are mediated through specific tumour receptors. BrJ Cancer 1990,62,96-99. 7. Fowler JE Jr, Lau JLT, Ghosh L, Mills SE, Mounzer A. Epidermal growth factor and prostatic carcinoma: an immunohistochemical study..7 Ural 1988,139,857-861. 8. Morris GL, Green Dodd J. Epidermal growth factor receptor mRNA levels in human nrostatic tumors and cell lines. 7 Ural 1990. 143,1272-1274. 9. Bookstein R, Shew JY, Chen PL, Scully P, Lee WH. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 1990,247,712-715. 10. White JW. The present position of the surgery of the hypertrophied prostate. AnnSurg 1893,18,152-188. 11. Nesbit RM, Baum WC. Endocrine control of prostatic carcinoma:
23.
24.
clinical and statistical survey of 1,818 cases. JAMA 1950, 143, 1317-1320. Veterans Administration Cooperative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gvnecol Obstet 1967,124,lOl l-1017. P&one-Macaluso M, de’voogt HJ, Viggiano G, et al. Comparison of diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: final analysis of a randomized phase III trial of the European Organization For Research on Treatment of Cancer Urological Group. 3 Ural 1986, 136,624-63 1. Sogani PC, Ray B, Whitmore WF Jr. Advanced prostatic carcinoma. Urology 1975, VI, 164166. Lunglmayr G. Casodex (ICI 176, 334), a new, non-steroidal antiandroaen. Earlv clinical results. Harm Res 1989.32.77-81. Beland G, Elhilali M, Fradet Y, et al. A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma. cancer 1990,66,1074-1079. Waxman J. Gonadotrophin hormone releasing analogues open new doors in cancer treatment. Br MedJ 1987,295,1084-1085. Labrie F, DuPont A, Giguere M, et al. Combination therapy with fluatmide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients.JSteroidBiochem 1987,27,525-532. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N EnglJMed 1989,321,419-424. Beland G, Elhilali M, Fradet Y, et al. Randomised study comparing orchiectomy versus orchiectomy and anandron in advanced prostate cancer. Gynecol Endocrirwll990,4,81. Mahler C, Pinto de Carvalho A, Smith PH et al. Randomized study of orchiectomy versus Zoladex and flutamide in metastatic prostatic cancer. Gynecol Endocrinoll990,4,8 1. Bertagna C. Treatment of metastatic prostate cancer with orchiectomy and anandro# (nilutamide): results of a double-blind study versus orchiectomy and placebo. Gynecol Endocrinoll990,4,82. De Vooet HI. Kliin TG. Studer U. et al. Comoarison of orchidectomy and buserelin combined with antiandrogens in the treatment of advanced prostatic cancer. (EORTC-trial30843). Gynecol Endocho1 1990,4,83. Boccardo F. Treatment of prostatic cancer with LH-RH analogues alone or in combination with pure antiandrogens. Gynecol Endocrinol 1990,4,84.
25. Crawford ED, Bertagna C, Smith JA, et al. R randomized, controlled clinical trial of leuprolide and anandron versus leuprolide and placebo for advanced prostate cancer. Gynecol EndocrinoZl990, 4,85.
26. Ferrari P, Castagnetti G, Pollastri C, Ferrari G, Tavoni F, Grassi D. LHRH analogue buserelin versus buserelin and fhnamide in the treatment of advanced metastatic prostatic carcinoma: Five Years Experience. Gynecol Endocrinoll990,4,87. 27. Haefliger JM. A multicentre randomised trial comparing the LHRH analogue ‘Zoladex’ vs ‘Zoladex’ in combination with flutamide in the treatment of advanced prostate cancer. Gynecol EndocrinoZl990, 4,88.
28. Iversen P and the Danish Prostatic Cancer Group. Daproca 86Zoladex and flutamide versus orchiectomy for advanced prostatic cancer. Gynecol Endocrinoll990,4,88. 29. Fourcade RO, Cariou G, Coloby P, et al. Total androgen blockade in advanced prostate carcinoma: interum report of a double blind study using Zoladex and flutamide. Gynecol Eticrinoll990,4,89. 30. Berns EMJ, Schuurmans ALG, Bolt J, Lamb DJ, Foekens JA, Mulder E. Antiproliferative effects of suramin on androgen responsive tumour cells. EurJ Cancer 1990,26,470-474.
No. 12, ~0. 1937-1938.
0964~1947~92$5.00 + 0.00 Pergamon Press Ltd
1992
Comments and Critique A European Initiative for Prostatic Cancer
CANCER is becoming alarmingly common and, throughout the first and second worlds, has increased in incidence such that it is now the second most important cause of cancer deaths in men. Over the past 50 years, age-standardised mortality rates have also increased dramatically in the third world, in some areas by lo-fold. These changes are substantive and are not merely a function of the increasing age to which we live. Despite the significance of prostatic cancer as a cause of morbidity and mortality, and its pandemic scale, the experimental investigation of prostatic cancer is shamefully lacking. This is not easily understood and is in contrast to the situation for other common cancers. The lack of research into the molecular basis of prostatic cancer is such that the relevant observations can be easily summarised in one paragraph. Cytoplasmic oncogenes have been studied: the p21 protein product of the MSoncogene was expressed in 23 of 29 carcinomas but in none of 19 benign prostatic hypertrophy specimens. Positivity as assessed by immunohistochemistry correlated with differentiation [ 11. Mutations of the rus oncogene are unusual in prostatic cancer and have been reported in only 1 of 24 tumours [2]. Nuclear oncogenes have been investigated and c-myc RNA transcript levels are higher in tumours than in benign hypertrophy [3]. Androgens affect oncogene expression and in cell culture studies, c-fos mRNA levels dramatically decreased upon androgen withdrawal from the culture media [4]. Autocrine regulation may be a feature of prostatic cancer because human cell lines both secrete transforming growth factor alpha, epiderma1 growth factor, and gonadotropin-releasing hormone-like peptides and express receptors for these factors [5-81. There is differential expression of growth factor receptors in tumours compared with benign tissue. Epidermal growth factor receptors are reported in 68 % of prostatic tumours but in only 6 % of benign hypertrophy cases [7]. Epidermal growth factor receptor mRNA levels are higher in cancer than in benign tissue [8]. Tumour suppressor genes may be involved in the development of prostatic cancer. The retinoblastoma gene product was abnormally expressed in one of three cell lines examined and transfection of the normal gene into this cell line led to a decrease in its ability to form tumours in nude mice [9]. In contrast, there have been many changes in prostatic cancer treatment during the past decade. Treatment is now potentially humane and without major side-effects. The origins of endocrine treatment date back 100 years to the observation by White of the effects of orchiectomy on prostatic diseases [lo]. Endocrine treatments for prostatic cancer were introduced in the 1940s and an initial analysis of the effects of these therapies showed a survival advantage [ll]. This advantage has never been confirmed by subsequent studies, and the consensus view is that PROSTATIC
Correspondence to J. Waxman. Revised 23 Mar. 1992; accepted
8 Apr. 1992.
treatment acts only to palliate symptoms without prolonging life. As a result of this conclusion, the specific side-effects of treatment have been assessed in detail. The toxicity of oestrogen therapy includes indigestion, body shape change and cardiovascular morbidity and mortality [12]. Given the frequency of these toxicities and the availability of alternative therapies, we consider that prescription of oestrogens for the treatment of prostatic cancer, is no longer appropriate. Many clinicians, and even more patients, consider orchidectomy to be obsolete and so alternative medical treatments for prostatic cancer have been investigated. These include cyproterone acetate, flutamide, ketoconazole, casodex, and nilutamide but all of these, as single agents, are suboptimal because of lack of efficacy or side-effects [ 13-161. In contrast, the gonadotropin releasing hormone (GnRH) agonists provide a specific, rational treatment for prostatic cancer [17]. These peptides limit testicular androgen production. However, the testis is not the only source of androgenic steroids and in the medically castrate man, adrenal androgens may contribute up to 45% of prostatic androgen levels. Extra-testicular androgen production may be particularly relevant in a disease that is androgen sensitive, providing a means for the maintenance of continued growth of androgen responsive cells. The effects of adrenal androgens may be limited by the concurrent use of an anti-androgen, such as flutamide, casodex or nilutamide [18]; cyproterone acetate is precluded from use because of inherent androgenicity. The advantages of combination antiandrogen and GnRH agonist therapy were investigated in a randomised double-blind trial by the USA National Cancer Institute (NCI) [19]. In this meticulous study, an advantage in disease-free survival was found for combination therapies. This result has not been generally accepted and several other randomised studies have been instigated to investigate this hypothesis. At a recent congress, 10 such trials were reported involving 3447 patients. Many of these studies are not mature. However, in three of seven in which initial response is described, there was an advantage for combination therapy; in three of eight, an advantage in medium time to progression; but in only one of nine was survival prolonged [20-291. This trial was the NC1 study [19]. The issue remains contentious and no definite conclusion can be drawn about the advantage of combination endocrine therapy. Whatever the outcome is of this controversy, it should be noted that there is no gross disadvantage to the use of an antiandrogen in the treatment of patients with prostatic cancer with GnRH agonists, because of the antiandrogens value in the abrogation of tumour flare. However, there are some side-effects from the most frequently used antiandrogen, flutamide. Diarrhoea is reported in between 15 and 30% of patients and may be severe enough to warrant discontinuing therapy. Second-line therapies offer little hope in prostatic cancer, and
1937
J. Waxman and A. Gutierrez
1938
the most useful single agent is radiotherapy.
There has been interest in the effects of suramin, but most treatments have included steroid supplements [30]. Because steroids are effective treatments for prostatic cancer, any activity may be due to these agents. A major research initiative is required for prostatic cancer and needs to have two aims. The most important is the provision of an impetus for basic research. In view of the epidemic nature of the disease and its importance within Europe, a strong case could be argued for a European initiative. The second aim is for the continued investigation of new agents for the treatment of prostatic cancer. Because of the disease’s signi!icance, it is arguable whether this should be left to conventional market forces. Jonathan Waxman Senior Lecturer and Honorary Consultant Andres Gutierrez Research Fellow Department of Clinical Oncology Royal Postgraduate Medical School Hamrnersmith Hospital Du Cane Road London W12 ONN
12
13
14. 15. 16.
17. 18.
19.
20. 21.
22. 1. Viola MV. Fromowitz F, Oravez S, et al. Expression of ras oncogene p-21 in prostate cancer. A’EnglJMed 1986;314,133-137. _ 2. carter BS, Epstein JI, Isaacs WB. ras gene mutations in human nrostate cancer. CancerRes 1990,50,6830-6832. 3. ‘Fleming WH, Hamel A, MacDonald R, et al. Expression of the cnyc proto-oncogene in- human prostatic carcinoma and benign orostatic hvDerDlasia. Cancer Res 1986: 46: 1535-1538. 4. Rijinders KWM, Van der Korput JAGM, Van Steenbrugge GJ, Romiin JC, Trapman J. Expression of cellular oncogenes in human prostatic carcinoma cell lines. Biochem Siophys Res Comm 1985, 132,548-554. 5. MacDonald A, Chishohn GD, Habib FK. Production and response of a human prostatic cancer line to transforming growth factor-like molecules. Br 7 Cancer 1990,62,579-584. 6. Qayum A, Gullick W, Clayton RC, Sikora K, Waxman J. The effects of gonadotrophin releasing hormone analogues in prostate cancer are mediated through specific tumour receptors. BrJ Cancer 1990,62,96-99. 7. Fowler JE Jr, Lau JLT, Ghosh L, Mills SE, Mounzer A. Epidermal growth factor and prostatic carcinoma: an immunohistochemical study..7 Ural 1988,139,857-861. 8. Morris GL, Green Dodd J. Epidermal growth factor receptor mRNA levels in human nrostatic tumors and cell lines. 7 Ural 1990. 143,1272-1274. 9. Bookstein R, Shew JY, Chen PL, Scully P, Lee WH. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 1990,247,712-715. 10. White JW. The present position of the surgery of the hypertrophied prostate. AnnSurg 1893,18,152-188. 11. Nesbit RM, Baum WC. Endocrine control of prostatic carcinoma:
23.
24.
clinical and statistical survey of 1,818 cases. JAMA 1950, 143, 1317-1320. Veterans Administration Cooperative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gvnecol Obstet 1967,124,lOl l-1017. P&one-Macaluso M, de’voogt HJ, Viggiano G, et al. Comparison of diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: final analysis of a randomized phase III trial of the European Organization For Research on Treatment of Cancer Urological Group. 3 Ural 1986, 136,624-63 1. Sogani PC, Ray B, Whitmore WF Jr. Advanced prostatic carcinoma. Urology 1975, VI, 164166. Lunglmayr G. Casodex (ICI 176, 334), a new, non-steroidal antiandroaen. Earlv clinical results. Harm Res 1989.32.77-81. Beland G, Elhilali M, Fradet Y, et al. A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma. cancer 1990,66,1074-1079. Waxman J. Gonadotrophin hormone releasing analogues open new doors in cancer treatment. Br MedJ 1987,295,1084-1085. Labrie F, DuPont A, Giguere M, et al. Combination therapy with fluatmide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients.JSteroidBiochem 1987,27,525-532. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N EnglJMed 1989,321,419-424. Beland G, Elhilali M, Fradet Y, et al. Randomised study comparing orchiectomy versus orchiectomy and anandron in advanced prostate cancer. Gynecol Endocrirwll990,4,81. Mahler C, Pinto de Carvalho A, Smith PH et al. Randomized study of orchiectomy versus Zoladex and flutamide in metastatic prostatic cancer. Gynecol Endocrinoll990,4,8 1. Bertagna C. Treatment of metastatic prostate cancer with orchiectomy and anandro# (nilutamide): results of a double-blind study versus orchiectomy and placebo. Gynecol Endocrinoll990,4,82. De Vooet HI. Kliin TG. Studer U. et al. Comoarison of orchidectomy and buserelin combined with antiandrogens in the treatment of advanced prostatic cancer. (EORTC-trial30843). Gynecol Endocho1 1990,4,83. Boccardo F. Treatment of prostatic cancer with LH-RH analogues alone or in combination with pure antiandrogens. Gynecol Endocrinol 1990,4,84.
25. Crawford ED, Bertagna C, Smith JA, et al. R randomized, controlled clinical trial of leuprolide and anandron versus leuprolide and placebo for advanced prostate cancer. Gynecol EndocrinoZl990, 4,85.
26. Ferrari P, Castagnetti G, Pollastri C, Ferrari G, Tavoni F, Grassi D. LHRH analogue buserelin versus buserelin and fhnamide in the treatment of advanced metastatic prostatic carcinoma: Five Years Experience. Gynecol Endocrinoll990,4,87. 27. Haefliger JM. A multicentre randomised trial comparing the LHRH analogue ‘Zoladex’ vs ‘Zoladex’ in combination with flutamide in the treatment of advanced prostate cancer. Gynecol EndocrinoZl990, 4,88.
28. Iversen P and the Danish Prostatic Cancer Group. Daproca 86Zoladex and flutamide versus orchiectomy for advanced prostatic cancer. Gynecol Endocrinoll990,4,88. 29. Fourcade RO, Cariou G, Coloby P, et al. Total androgen blockade in advanced prostate carcinoma: interum report of a double blind study using Zoladex and flutamide. Gynecol Eticrinoll990,4,89. 30. Berns EMJ, Schuurmans ALG, Bolt J, Lamb DJ, Foekens JA, Mulder E. Antiproliferative effects of suramin on androgen responsive tumour cells. EurJ Cancer 1990,26,470-474.
