- Email: [email protected]
Dutasteride and active surveillance of low-risk prostate cancer
Correspondence
5
Speer CP, Gefeller O, Groneck P, et al. Randomised clinical trial of two treatment regimes of natural surfactant preparations in neonatal respiratory distress syndrome. Arch Dis Child 1995; 72: F8–13.
Dutasteride and active surveillance of low-risk prostate cancer
Science Photo Library
We thank Chris Parker for his Comment (March 24, p 1078)1 on our REDEEM trial.2 We agree that most men with very low-risk prostate cancer do not require radical treatment and that a longer study would have been ideal. Nevertheless, we disagree with his recommendation against the use of 5α-reductase inhibitors (5ARIs) in this setting. Many men with low-risk cancers receive treatment, especially in the USA where more than 90% receive radical or even hormonal therapy.3 Furthermore, many men on active surveillance discontinue expectant therapy owing to anxiety over worsening biopsy results or increasing prostate-specific antigen (PSA) concentrations. Parker is correct in that we did not correct PSA as in other studies. This point was carefully considered and deemed to limit our ability to assess real-world benefits of these drugs. We disagree with Parker’s interpretation of the pathological progression data. The REDEEM study was not powered to assess pathological progression independently. Nonetheless, we found a trend towards a benefit on the basis of pathological progression only (p=0·079), and one cannot refute that, clinically and statistically significantly, more dutasteride-treated men had no cancer at final biopsy than did men on placebo.2 Whether 5ARIs increase rates of high-grade disease remains a matter of debate;4,5 however, in the active surveillance setting, patients are carefully monitored, which increases the likelihood of early identification of adverse changes. 1590
Finally, many men with low-risk tumours have enlarged prostates and significant lower urinary tract symptoms. There is credible level 1 evidence to support use of 5ARIs not only to alleviate such symptoms but to prevent urological catastrophe. We declare that we have no conflicts of interest other than those stated in the original paper.
Neil E Fleshner, on behalf of the REDEEM trial investigators neil.fl[email protected] Princess Margaret Hospital, University of Toronto, Toronto, ON M5G 2M9, Canada 1 2
3
4
5
Parker C. What (if anything) to do about low-risk prostate cancer. Lancet 2012; 378: 1078–80. Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet 2012; 378: 1103–11. Barocas DA, Cowan JE, Smith JA Jr, Carroll PR. What percentage of patients with newly diagnosed carcinoma of the prostate are candidates for surveillance? An analysis of the CaPSURE database. J Urol 2008; 180: 1330–34. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362: 1192–202. Thompson IM, Chi C, Ankerst DP, et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst 2006; 98: 1128–33.
When is grief a disease? The Lancet asks, “When should grief be classified as a mental illness?” (Feb 18, p 589).1 Our reply is, “never”. But some recently bereaved individuals are not simply grieving. They are also experiencing a full-blown major depressive episode. How can physicians help in such cases? That is the crux of the “bereavement exclusion” debate surrounding the forthcoming fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Bereavement-related grief does not immunise against a major depressive episode; indeed, bereavement can precipitate such episodes.2 But when a major depressive episode develops in the context of bereavement, it does not differ substantially from any other instance with respect to course, severity, or treatment response.3 Hence,
there is no clinical or scientific basis for singling out bereavement-related major depressive episodes for exclusion. Some who favour the bereavement exclusion focus on certain overlapping features of grief and major depressive episodes, such as intense sadness and withdrawal from customary activities. But grief and major depressive episodes also differ in important respects. Thus, in grief, painful feelings come in waves, often mixed with positive memories of the deceased; in major depressive episodes, mood and ideation are almost constantly negative. In grief, self-esteem is usually preserved; in major depressive episodes, feelings of worthlessness and self-loathing are common.4 As Thomas à Kempis noted,5 grief is one of the “proper sorrows of the soul” and must be allowed to run its course. But when a major depressive episode intercedes, professional attention is warranted. We must not medicalise grief—but neither can we afford to normalise major depressive episodes. Removing the bereavement exclusion helps prevent them from being overlooked, and facilitates the possibility of appropriate treatment. We declare that we have no conflicts of interest.
*Sidney Zisook, Ronald Pies, Emmanuelle Corruble [email protected] Department of Psychiatry, University of California— San Diego and San Diego VA Healthcare System, La Jolla, CA 92093, USA (SZ); Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA (RP); and Department of Psychiatry, INSERM U669, Bicêtre University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France (EC) 1 2
3
4
5
The Lancet. Living with grief. Lancet 2012; 379: 589. Kendler KS, Thornton LM, Gardner CO. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 2001; 158: 582–86. Zisook S, Kendler KS. Is bereavement-related depression different than non-bereavementrelated depression? Psychol Med 2007; 37: 779–94. Zisook S, Reynolds CF, III, Pies R, et al. Bereavement, complicated grief, and DSM—part 1: depression. J Clin Psychiatry 2010; 71: 955–56. à Kempis T. Counsels on the spiritual life. London: Penguin Books, 1995.
www.thelancet.com Vol 379 April 28, 2012
5
Speer CP, Gefeller O, Groneck P, et al. Randomised clinical trial of two treatment regimes of natural surfactant preparations in neonatal respiratory distress syndrome. Arch Dis Child 1995; 72: F8–13.
Dutasteride and active surveillance of low-risk prostate cancer
Science Photo Library
We thank Chris Parker for his Comment (March 24, p 1078)1 on our REDEEM trial.2 We agree that most men with very low-risk prostate cancer do not require radical treatment and that a longer study would have been ideal. Nevertheless, we disagree with his recommendation against the use of 5α-reductase inhibitors (5ARIs) in this setting. Many men with low-risk cancers receive treatment, especially in the USA where more than 90% receive radical or even hormonal therapy.3 Furthermore, many men on active surveillance discontinue expectant therapy owing to anxiety over worsening biopsy results or increasing prostate-specific antigen (PSA) concentrations. Parker is correct in that we did not correct PSA as in other studies. This point was carefully considered and deemed to limit our ability to assess real-world benefits of these drugs. We disagree with Parker’s interpretation of the pathological progression data. The REDEEM study was not powered to assess pathological progression independently. Nonetheless, we found a trend towards a benefit on the basis of pathological progression only (p=0·079), and one cannot refute that, clinically and statistically significantly, more dutasteride-treated men had no cancer at final biopsy than did men on placebo.2 Whether 5ARIs increase rates of high-grade disease remains a matter of debate;4,5 however, in the active surveillance setting, patients are carefully monitored, which increases the likelihood of early identification of adverse changes. 1590
Finally, many men with low-risk tumours have enlarged prostates and significant lower urinary tract symptoms. There is credible level 1 evidence to support use of 5ARIs not only to alleviate such symptoms but to prevent urological catastrophe. We declare that we have no conflicts of interest other than those stated in the original paper.
Neil E Fleshner, on behalf of the REDEEM trial investigators neil.fl[email protected] Princess Margaret Hospital, University of Toronto, Toronto, ON M5G 2M9, Canada 1 2
3
4
5
Parker C. What (if anything) to do about low-risk prostate cancer. Lancet 2012; 378: 1078–80. Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet 2012; 378: 1103–11. Barocas DA, Cowan JE, Smith JA Jr, Carroll PR. What percentage of patients with newly diagnosed carcinoma of the prostate are candidates for surveillance? An analysis of the CaPSURE database. J Urol 2008; 180: 1330–34. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362: 1192–202. Thompson IM, Chi C, Ankerst DP, et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst 2006; 98: 1128–33.
When is grief a disease? The Lancet asks, “When should grief be classified as a mental illness?” (Feb 18, p 589).1 Our reply is, “never”. But some recently bereaved individuals are not simply grieving. They are also experiencing a full-blown major depressive episode. How can physicians help in such cases? That is the crux of the “bereavement exclusion” debate surrounding the forthcoming fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Bereavement-related grief does not immunise against a major depressive episode; indeed, bereavement can precipitate such episodes.2 But when a major depressive episode develops in the context of bereavement, it does not differ substantially from any other instance with respect to course, severity, or treatment response.3 Hence,
there is no clinical or scientific basis for singling out bereavement-related major depressive episodes for exclusion. Some who favour the bereavement exclusion focus on certain overlapping features of grief and major depressive episodes, such as intense sadness and withdrawal from customary activities. But grief and major depressive episodes also differ in important respects. Thus, in grief, painful feelings come in waves, often mixed with positive memories of the deceased; in major depressive episodes, mood and ideation are almost constantly negative. In grief, self-esteem is usually preserved; in major depressive episodes, feelings of worthlessness and self-loathing are common.4 As Thomas à Kempis noted,5 grief is one of the “proper sorrows of the soul” and must be allowed to run its course. But when a major depressive episode intercedes, professional attention is warranted. We must not medicalise grief—but neither can we afford to normalise major depressive episodes. Removing the bereavement exclusion helps prevent them from being overlooked, and facilitates the possibility of appropriate treatment. We declare that we have no conflicts of interest.
*Sidney Zisook, Ronald Pies, Emmanuelle Corruble [email protected] Department of Psychiatry, University of California— San Diego and San Diego VA Healthcare System, La Jolla, CA 92093, USA (SZ); Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA (RP); and Department of Psychiatry, INSERM U669, Bicêtre University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France (EC) 1 2
3
4
5
The Lancet. Living with grief. Lancet 2012; 379: 589. Kendler KS, Thornton LM, Gardner CO. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 2001; 158: 582–86. Zisook S, Kendler KS. Is bereavement-related depression different than non-bereavementrelated depression? Psychol Med 2007; 37: 779–94. Zisook S, Reynolds CF, III, Pies R, et al. Bereavement, complicated grief, and DSM—part 1: depression. J Clin Psychiatry 2010; 71: 955–56. à Kempis T. Counsels on the spiritual life. London: Penguin Books, 1995.
www.thelancet.com Vol 379 April 28, 2012