- Email: [email protected]
Androgen suppression and irradiation for locally advanced prostate cancer
CORRESPONDENCE
disorders by modification of the function of brain circuits and the frequency and intensity of social contacts. Leo Sher Division of Neuroscience, Department of Psychiatry, Columbia University, 1051 Riverside Drive, Suite 2917, Box 42, New York, NY 10032, USA (e-mail: [email protected]) 1
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Hjern A, Lindblad F, Vinnerljung B. Suicide, psychiatric illness, and social maladjustment in intercountry adoptees in Sweden: a cohort study. Lancet 2002; 360: 443–48. Magnusson A, Axelsson J. The prevalence of seasonal affective disorder is low among descendants of Icelandic emigrants to Canada. Arch Gen Psychiatry 1993; 50: 947–51. Magnusson A. Acclimatization. In: Partonen T, Magnusson A, eds. Seasonal affective disorder: practice and research. Oxford: Oxford University Press, 2001: 47–53. Sher L. Relationships between seasonality and alcohol use: a genetic hypothesis. Med Hypotheses 2002; 59: 85–88. Preti A. The influence of climate on suicidal behavior in Italy. Psychiatry Res 1998; 78: 9–19.
Androgen suppression and irradiation for locally advanced prostate cancer Sir—Michel Bolla and colleagues (July 13, p 103)1 report the apparent survival advantage associated with a period of medical castration after external-beam irradiation in patients with locally advanced prostate cancer. We feel we must take issue with their conclusions. The authors fail to cite or raise in discussion the only existing three-arm randomised study comparing radiation, androgen deprivation, and the combination.2 In this UK Medical Research Council (MRC) study, although prematurely closed and underpowered to be definitively conclusive, androgen deprivation with or without radiation produced a significant delay in the detection of metastases. Our main concern, however, with respect to the author’s conclusion, is that the combination of androgen deprivation and radiotherapy had no significant advantage in local disease control or in overall survival. Thus radiation offered no obvious gain over androgen deprivation alone. Likewise, given increased recognition of the risks of long-term androgen suppression, there can be few clinicians who could presently recommend a continuous withdrawal of androgens— whether in the form of surgical or medical castration. There are, however, encouraging reports as to the potential
of intermittent androgen suppression in the management of such patients.3 These results seem to at least match the combination of radiation and androgen withdrawal with the additional advantage of an apparent delay in progression to the androgen-insensitive state. Long-term results from an open, non-randomised feasibility study4 of intermittent androgen suppression undertaken in our unit also tends to support these findings.5 Actuarial 5-year survival rates suggest that intermittent administration of androgen suppression is more effective than the continuous androgen deprivation plus radiotherapy described by Bolla and colleagues. The patients in our group are a select patient population, but whether or not they were irradiated was not a selection pressure. As a consequence, our results can at least be considered to provide justification for the establishment of a 2⫻2 trial comparing short-term with long-term androgen suppression, with each group being subrandomised to either immediate or deferred radiation.
I believe that this is an especially important point of view to test, since whether local therapy of any kind affects the survival of patients with localised prostate cancer withdrawal is unclear.2,3 Most of these men are, after all, destined to die with, not from, prostate cancer. Bolla and colleagues suggest that testing “higher doses [of irradiation] and the addition of chemotherapy” might be fruitful.4 This opinion does not seem logical to me. Since aggressive therapies for local disease do not provide clear survival advantage, perhaps less (temporary androgen withdrawal alone) is more. It is logical to me to test temporary androgen withdrawal alone against observation, especially in earlystage, low-grade prostate cancer. William J M Hrushesky University of South Carolina Schools of Medicine and Public Health, Columbia, SC 29209, USA (e-mail: [email protected]) 1
*Tim Lane, Wendy Ansell, Tim Oliver Department of Medical Oncology, St Bartholomews Hospital, London EC1M 6NQ, UK (e-mail: [email protected]) 1
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3
4
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Bolla M, Collette L, Blank L, et al. Longterm results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002 360: 103–08. Fellows G, Clark PB, Beynon LL, et al. Treatment of advanced prostate cancer by orchidectomy, radiotherapy or combined treatment: a Medical Research Council Study. Br J Urol 1993: 70: 304–09. Calais F, Bono A, Whelan P, et al. Phase III study of intermittent MAB versus continuous MAB international co-operative study. Eur Urol 2002 (Suppl): A531. Oliver RTD, Williams G, Badenoch D, et al. Intermittent androgen suppression after PSA-complete response as a strategy to reduce induction of hormone resistant prostate cancer. Urology 1997: 49: 79–82. Lane TM, Ansell W, Williams SG, et al. Long-term outcomes in patients managed with intermittent androgen suppression. Br J Urol 2002 (suppl 1): A82.
Sir—Michel Bolla and colleagues’ results1 suggests to me that radiation is not needed at all for the treatment of local prostate cancer. Had disease-free and overall survival been favourably affected by 3 years of androgen withdrawal alone, then the substantial toxic effects and costs of irradiation might be avoided. The ongoing Canadian study described in this paper in locally advanced disease is not relevant to most patients with early-stage prostate cancer whose cancers are discovered because of a symptomless increase in prostatespecific antigen.
THE LANCET • Vol 360 • December 14, 2002 • www.thelancet.com
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Bolla M, Collette L, Blank L, et al. Longterm results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–08. Chodak GW. Comparing treatments for localized prostate cancer: persisting uncertainty. JAMA 1998; 280: 1008–10. Wilt TJ. Prostate cancer: non-metastatic. Clin Evid 2001; 6: 682–92. Raghavan D. Prostate cancer management under scrutiny: one man’s meta-analysis is another man’s poisson. J Clin Oncol 1999; 17: 3371–73.
Author’s reply Sir—In the MRC trial1 mentioned by Tim Lane and colleagues, patients were randomly allocated radiotherapy (n=88), orchiectomy (90), or combined therapy (99). Planning of target volume, radiation technique, dose, number of fractions, and duration of treatment were not optimised. In the EORTC trial, we proposed an androgen suppression regimen with an analogue of luteinising-hormonereleasing hormone and did not choose a three-arm trial since we could not be sure that we would accrue 600 patients with a medical castration option. All radiation parameters were defined and quality assurance was mandatory with calibration of linear accelerators, individual case review, a dummy-run procedure to assess compliance, and correction of significant difference Such discrepancies accordingly.2 between trials can explain the absence of therapeutic gain from combined treatment in the MRC trial, since target volume and dose are of paramount importance. The standard of care with respect to
1987
For personal use. Only reproduce with permission from The Lancet Publishing Group.
disorders by modification of the function of brain circuits and the frequency and intensity of social contacts. Leo Sher Division of Neuroscience, Department of Psychiatry, Columbia University, 1051 Riverside Drive, Suite 2917, Box 42, New York, NY 10032, USA (e-mail: [email protected]) 1
2
3
4
5
Hjern A, Lindblad F, Vinnerljung B. Suicide, psychiatric illness, and social maladjustment in intercountry adoptees in Sweden: a cohort study. Lancet 2002; 360: 443–48. Magnusson A, Axelsson J. The prevalence of seasonal affective disorder is low among descendants of Icelandic emigrants to Canada. Arch Gen Psychiatry 1993; 50: 947–51. Magnusson A. Acclimatization. In: Partonen T, Magnusson A, eds. Seasonal affective disorder: practice and research. Oxford: Oxford University Press, 2001: 47–53. Sher L. Relationships between seasonality and alcohol use: a genetic hypothesis. Med Hypotheses 2002; 59: 85–88. Preti A. The influence of climate on suicidal behavior in Italy. Psychiatry Res 1998; 78: 9–19.
Androgen suppression and irradiation for locally advanced prostate cancer Sir—Michel Bolla and colleagues (July 13, p 103)1 report the apparent survival advantage associated with a period of medical castration after external-beam irradiation in patients with locally advanced prostate cancer. We feel we must take issue with their conclusions. The authors fail to cite or raise in discussion the only existing three-arm randomised study comparing radiation, androgen deprivation, and the combination.2 In this UK Medical Research Council (MRC) study, although prematurely closed and underpowered to be definitively conclusive, androgen deprivation with or without radiation produced a significant delay in the detection of metastases. Our main concern, however, with respect to the author’s conclusion, is that the combination of androgen deprivation and radiotherapy had no significant advantage in local disease control or in overall survival. Thus radiation offered no obvious gain over androgen deprivation alone. Likewise, given increased recognition of the risks of long-term androgen suppression, there can be few clinicians who could presently recommend a continuous withdrawal of androgens— whether in the form of surgical or medical castration. There are, however, encouraging reports as to the potential
of intermittent androgen suppression in the management of such patients.3 These results seem to at least match the combination of radiation and androgen withdrawal with the additional advantage of an apparent delay in progression to the androgen-insensitive state. Long-term results from an open, non-randomised feasibility study4 of intermittent androgen suppression undertaken in our unit also tends to support these findings.5 Actuarial 5-year survival rates suggest that intermittent administration of androgen suppression is more effective than the continuous androgen deprivation plus radiotherapy described by Bolla and colleagues. The patients in our group are a select patient population, but whether or not they were irradiated was not a selection pressure. As a consequence, our results can at least be considered to provide justification for the establishment of a 2⫻2 trial comparing short-term with long-term androgen suppression, with each group being subrandomised to either immediate or deferred radiation.
I believe that this is an especially important point of view to test, since whether local therapy of any kind affects the survival of patients with localised prostate cancer withdrawal is unclear.2,3 Most of these men are, after all, destined to die with, not from, prostate cancer. Bolla and colleagues suggest that testing “higher doses [of irradiation] and the addition of chemotherapy” might be fruitful.4 This opinion does not seem logical to me. Since aggressive therapies for local disease do not provide clear survival advantage, perhaps less (temporary androgen withdrawal alone) is more. It is logical to me to test temporary androgen withdrawal alone against observation, especially in earlystage, low-grade prostate cancer. William J M Hrushesky University of South Carolina Schools of Medicine and Public Health, Columbia, SC 29209, USA (e-mail: [email protected]) 1
*Tim Lane, Wendy Ansell, Tim Oliver Department of Medical Oncology, St Bartholomews Hospital, London EC1M 6NQ, UK (e-mail: [email protected]) 1
2
3
4
5
Bolla M, Collette L, Blank L, et al. Longterm results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002 360: 103–08. Fellows G, Clark PB, Beynon LL, et al. Treatment of advanced prostate cancer by orchidectomy, radiotherapy or combined treatment: a Medical Research Council Study. Br J Urol 1993: 70: 304–09. Calais F, Bono A, Whelan P, et al. Phase III study of intermittent MAB versus continuous MAB international co-operative study. Eur Urol 2002 (Suppl): A531. Oliver RTD, Williams G, Badenoch D, et al. Intermittent androgen suppression after PSA-complete response as a strategy to reduce induction of hormone resistant prostate cancer. Urology 1997: 49: 79–82. Lane TM, Ansell W, Williams SG, et al. Long-term outcomes in patients managed with intermittent androgen suppression. Br J Urol 2002 (suppl 1): A82.
Sir—Michel Bolla and colleagues’ results1 suggests to me that radiation is not needed at all for the treatment of local prostate cancer. Had disease-free and overall survival been favourably affected by 3 years of androgen withdrawal alone, then the substantial toxic effects and costs of irradiation might be avoided. The ongoing Canadian study described in this paper in locally advanced disease is not relevant to most patients with early-stage prostate cancer whose cancers are discovered because of a symptomless increase in prostatespecific antigen.
THE LANCET • Vol 360 • December 14, 2002 • www.thelancet.com
2
3 4
Bolla M, Collette L, Blank L, et al. Longterm results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–08. Chodak GW. Comparing treatments for localized prostate cancer: persisting uncertainty. JAMA 1998; 280: 1008–10. Wilt TJ. Prostate cancer: non-metastatic. Clin Evid 2001; 6: 682–92. Raghavan D. Prostate cancer management under scrutiny: one man’s meta-analysis is another man’s poisson. J Clin Oncol 1999; 17: 3371–73.
Author’s reply Sir—In the MRC trial1 mentioned by Tim Lane and colleagues, patients were randomly allocated radiotherapy (n=88), orchiectomy (90), or combined therapy (99). Planning of target volume, radiation technique, dose, number of fractions, and duration of treatment were not optimised. In the EORTC trial, we proposed an androgen suppression regimen with an analogue of luteinising-hormonereleasing hormone and did not choose a three-arm trial since we could not be sure that we would accrue 600 patients with a medical castration option. All radiation parameters were defined and quality assurance was mandatory with calibration of linear accelerators, individual case review, a dummy-run procedure to assess compliance, and correction of significant difference Such discrepancies accordingly.2 between trials can explain the absence of therapeutic gain from combined treatment in the MRC trial, since target volume and dose are of paramount importance. The standard of care with respect to
1987
For personal use. Only reproduce with permission from The Lancet Publishing Group.