Download Treatment or monitoring for early prostate cancer

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Edi t or i a l s
Treatment or Monitoring for Early Prostate Cancer
Anthony V. D’Amico, M.D., Ph.D.
The “best” initial approach to early (low-risk or
intermediate-risk)1 prostate cancer remains unknown. Specifically, does active monitoring with
the use of prostate-specific antigen (PSA) testing
as opposed to treatment lead to increased metastasis and death from prostate cancer? If yes, then
which treatment, radical prostatectomy or radiation with or without short-term (3 to 6 months)
androgen-suppression therapy, minimizes metastasis and death from prostate cancer?
Hamdy and colleagues now report in the Journal the results of a randomized comparison of
three of these four approaches after a median
follow-up of 10 years,2 and Donovan and colleagues present data on patient-reported healthrelated quality of life at 6 years of follow-up.3
Men were screened with PSA testing and presented at a median age of 62 years with favorable
clinical characteristics: 76% had stage T1c (PSAdetected) disease, 77% and 21% had tumors with
Gleason scores of 6 and 7, respectively (on a
scale from 6 to 10, with higher scores indicating
a worse prognosis), and the median PSA level
was 4.6 ng per milliliter. Although a median
follow-up of 10 years was too short to evaluate
the primary outcome of prostate-cancer mortality in this favorable cohort (death from prostate
cancer occurred in 8 of the 545 men assigned to
active monitoring, 5 of the 553 men assigned
to surgery, and 4 of the 545 men assigned to radiotherapy), it was adequate to evaluate the secondary outcome of the incidence of metastatic
disease, defined as bony, visceral, or lymph-node
metastasis on imaging or a PSA level above 100 ng
per milliliter.
Several important observations were made.
First, men assigned to active monitoring were
significantly more likely to have metastatic dis1482
ease than those assigned to treatment (P = 0.004
for the overall comparison), with an incidence
that was more than twice as high (6.3 per 1000
person-years vs. 2.4 to 3.0 per 1000 person-years).
There was also a trend toward decreased death
from prostate cancer among men assigned to
surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgendeprivation therapy (hazard ratio, 0.51; 95% CI,
0.15 to 1.69) versus active monitoring. Although
further follow-up will determine whether these
trends become significant, causality between an
increase in metastatic disease and the use of
active monitoring versus treatment was established. The clinical significance of this finding
is that with the use of active monitoring, more
men will have metastasis and the side effects of
salvage treatment (meaning at least lifelong intermittent androgen-deprivation therapy), which
are not inconsequential.4
Second, within the prerandomization stratum
of age, a near-significant interaction (P = 0.09 for
interaction) was observed given that men 65 years
of age or older were more likely to die from
prostate cancer if assigned to active monitoring
than if assigned to treatment. This finding probably reflects the fact that advancing age is associated with higher-grade disease than disease identified at an initial biopsy5 owing to sampling
error, resulting in undergrading, the risk of which
rises with the increasing prostate-gland volume6
that occurs with advancing age.7 Should the interaction between age and death from prostate
cancer among men assigned to treatment versus
monitoring become significant, it would support
recommending treatment as opposed to monitoring to otherwise healthy men 65 years of age
or older with early prostate cancer who today are
n engl j med 375;15 nejm.org October 13, 2016
The New England Journal of Medicine
Downloaded from nejm.org on March 11, 2017. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
Editorials
increasingly being placed on active surveillance,8
given that the reduction in death from prostate
cancer (hazard ratio, 0.63; 95% CI, 0.36 to 1.09)
in the Prostate Cancer Intervention versus Observation Trial (PIVOT) only trended toward
significance (P = 0.09).9 However, the increasing
use of surveillance is already of potential concern, considering that men enrolled in PIVOT had
a shorter life expectancy owing to coexisting
disease than men of similar age entered into
the Surveillance, Epidemiology, and End Results
database.10
Finally, a trend favoring radiation and shortcourse androgen-deprivation therapy over surgery
was observed. Specifically, the point estimate for
the hazard ratio for death from prostate cancer
when comparing these two treatments was 0.80
(95% CI, 0.22 to 2.99). If this trend becomes
significant, then one may consider radiation and
androgen-deprivation therapy as a preferred option for otherwise healthy men 65 years of age
or older with early prostate cancer for whom
treatment as compared with monitoring may be
more effective (P = 0.09 for interaction) in reducing death from prostate cancer.
For today, we can conclude on the basis of
level 1 evidence2 that PSA monitoring, as compared with treatment of early prostate cancer,
leads to increased metastasis. Therefore, if a
man wishes to avoid metastatic prostate cancer
and the side effects of its treatment,3 monitoring
should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up
of the current study.2 In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course
androgen-deprivation therapy, men with low-risk
or intermediate-risk1 prostate cancer should feel
free to select a treatment approach using the
data on health-related quality of life3 and without fear of possibly selecting a less effective cancer therapy.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Department of Radiation Oncology, Brigham and
Women’s Hospital and Dana–Farber Cancer Institute, Boston.
This editorial was published on September 14, 2016, at NEJM.org.
1. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate can-
cer, version 1.2016. J Natl Compr Canc Netw 2016;​14:​19-30.
2. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes
after monitoring, surgery, or radiotherapy for localized prostate
cancer. N Engl J Med 2016;​375:1415-24.
3. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate
cancer. N Engl J Med 2016;​375:1425-37.
4. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;​294:​238-44.
5. Anderson CB, Sternberg IA, Karen-Paz G, et al. Age is associated with upgrading at confirmatory biopsy among men with
prostate cancer treated with active surveillance. J Urol 2015;​194:​
1607-11.
6. Moussa AS, Kattan MW, Berglund R, Yu C, Fareed K, Jones
JS. A nomogram for predicting upgrading in patients with lowand intermediate-grade prostate cancer in the era of extended
prostate sampling. BJU Int 2010;​105:​352-8.
7. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development
of human benign prostatic hyperplasia with age. J Urol 1984;​
132:​474-9.
8. Cooperberg MR, Carroll PR. Trends in management for patients with localized prostate cancer, 1990-2013. JAMA 2015;​
314:​80-2.
9. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy
versus observation for localized prostate cancer. N Engl J Med
2012;​367:​203-13.
10. Aizer AA, Chen MH, Hattangadi J, D’Amico AV. Initial management of prostate-specific antigen-detected, low-risk prostate
cancer and the risk of death from prostate cancer. BJU Int 2014;​
113:​43-50.
DOI: 10.1056/NEJMe1610395
Copyright © 2016 Massachusetts Medical Society.
Solving the Problem of Overdiagnosis
Joann G. Elmore, M.D., M.P.H.
My patients’ fear of breast cancer is palpable.
I see them fret over whether or not to have a
mammogram, worry about false positive abnormalities, and struggle to pay for diagnostic evaluations for which they are not reimbursed. This
collateral damage of screening is obvious to
clinicians. However, increasing evidence now indicates a less obvious outcome of cancer screen-
ing — overdiagnosis of diseases that would
never cause symptoms or death. The presence and
effects of overdiagnosis are less tangible, buried in population statistics rather than patient
encounters.
Overdiagnosis of breast cancer has been suggested on the basis of multiple studies that used
different designs and approaches and is acknowl-
n engl j med 375;15 nejm.org October 13, 2016
The New England Journal of Medicine
Downloaded from nejm.org on March 11, 2017. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
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