Correspondence

matrix component of muscletendon regeneration

A Interval between Injury and Recovery
100 Early-therapy group is substantial and prolonged,4 which may con-
90
tribute to the difference in recovery time in our
80 study. Delay in rehabilitation can result in pro-
Delayed-therapy
longed pain and a delayed return to sports, a
Patient Recovery (%)

70 group
60 finding that emphasizes the importance of regu-
50 lar and controlled mechanical loading early after
40 trauma to large muscles.
30 MonikaL. Bayer, Ph.D.
20 S.Peter Magnusson, P.T., D.M.Sc.
10 Michael Kjaer, M.D., D.M.Sc.
0 Bispebjerg Hospital
0 30 50 60 90 120 150 233 Copenhagen, Denmark
Days since Injury monika.lucia.bayer@regionh.dk
for the Tendon Research Group Bispebjerg
B Median No. of Days until Recovery A complete list of members of the Tendon Research Group
150 P=0.01 Bispebjerg is provided in the Supplementary Appendix, available
No. of Days until Recovery

at NEJM.org.
Supported by Bispebjerg Hospital, Greater Region of Copen-
100 hagen Research Foundation, Danish Rheumatism Association,
Lundbeck Foundation, Danish Council for Independent Research,
Novo Nordisk Foundation, and Anti Doping Denmark.
Disclosure forms provided by the authors are available with
50
the full text of this letter at NEJM.org.

1. Reurink G, Goudswaard GJ, Moen MH, et al. Platelet-rich

0 plasma injections in acute muscle injury. N Engl J Med 2014;370:
Early-Therapy Group
Figure 1. Interval from Muscle-Strain Injury to Pain-free
Full Recovery, According to the Timing of Initiation of
Rehabilitation Therapy.
Panel A shows the number of days from injury to recovery
among the 50 patients who received early rehabilitation
(starting 2 days after injury) or delayed rehabilitation
(starting 9 days after injury). Panel B shows the median
number of days from injury to recovery; the I bars indicate
the interquartile range.
Delayed-Therapy Group 2546-7.
2. de Boer MD, Maganaris CN, Seynnes OR, Rennie MJ, Narici
MV. Time course of muscular, neural and tendinous adaptations
to 23 day unilateral lower-limb suspension in young men. J Physiol
2007;583:1079-91.
3. Bayer ML, Schjerling P, Herchenhan A, et al. Release of ten-
sile strain on engineered human tendon tissue disturbs cell ad-
hesions, changes matrix architecture, and induces an inflam-
matory phenotype. PLoS One 2014;9(1):e86078.
4. Mackey AL, Brandstetter S, Schjerling P, et al. Sequenced
response of extracellular matrix deadhesion and fibrotic regula-
tors after muscle damage is involved in protection against future
injury in human skeletal muscle. FASEB J 2011;25:1943-59.
DOI: 10.1056/NEJMc1708134

Prostatectomy versus Observation for Early Prostate Cancer

To the Editor: In reporting the results of the
Prostate Cancer Intervention versus Observation
Trial (PIVOT), Wilt et al. (July 13 issue)1 indicate
no significant decrease in all-cause or prostate-
cancer mortality among men assigned to sur-
gery, as compared with those assigned to ob-
servation (hazard ratio, 0.84; 95% confidence
interval, 0.70 to 1.01; P=0.06). These results al-
most certainly reflect a type II error from a lack
of power. The authors enrolled 731 men from a
targeted accrual of 2000 men. Doubling the trial
cohort to 1462 patients (still well short of the
targeted accrual) would have resulted in a 76%
probability of a significant effect.2
Furthermore, 74% of the cohort had low-grade
cancer. These men probably would not have died
from prostate cancer. Meaningful differences in
survival among men with prostate cancer were
likely to be seen only in the 26% of patients with
a score of 7 or higher on the Gleason scale (a
scale of 2 to 10, with higher scores indicating
a high-grade histologic subtype of prostate tu-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

mor), in whom the (nonsignificant) effect esti-
mate was 0.59. Finally, the PIVOT cohort com-
prised older, sicker patients than those who may
undergo radical prostatectomy today.3 The strident
statements in the lay press that surgery for
early-stage prostate cancer does not lead to lon-
ger lives4 are unwarranted. The PIVOT results are
consistent with a benefit of surgery in patients
with intermediate-risk and high-risk disease.
ChristopherJ.D. Wallis, M.D., Ph.D.
University of Toronto
Toronto, ON, Canada
wallis.cjd@gmail.com
Laurence Klotz, M.D.
Sunnybrook Health Sciences Centre
Toronto, ON, Canada
No potential conflict of interest relevant to this letter was re-
ported.
1. Wilt TJ, Jones KM, Barry MJ, et al. Follow-up of prostatec-
tomy versus observation for early prostate cancer. N Engl J Med
2017;377:132-42.
2. Wood J, Freemantle N, King M, Nazareth I. Trap of trends to
statistical significance: likelihood of near significant P value be-
coming more significant with extra data. BMJ 2014;348:g2215.
3. Barbosa PV, Thomas IC, Srinivas S, et al. Overall survival in The authors reply: Many of the comments
patients with localized prostate cancer in the US Veterans raised by the correspondents were addressed in
Health Administration: is PIVOT generalizable? Eur Urol 2016;
70:227-30.
4. Abed M. Surgery for early-stage prostate cancer does not Wallis and Klotz: recruitment was hampered be-
lead to longer lives, study finds. Los Angeles Times. July 12, 2017 cause of strong beliefs of patients and clinicians
(http://www.latimes.com/science/sciencenow/la-sci-sn-prostate
-cancer-surgery-20170712-story.html).
DOI: 10.1056/NEJMc1710384
To the Editor: The results of PIVOT highlight
the difficulty of conducting randomized trials
involving patients with localized prostate cancer.
As has previously been noted, the trial was under-
powered,1 included men with a high competing
risk of death,2 included a high proportion of U.S.
veterans,3 and showed 50% overall mortality
from any cause at 12 years in the observation
group despite the inclusion criteria of an esti-
mated life expectancy of at least 10 years. How-
ever, an underappreciated limitation of the current
trial is that 21.2% of the men in the radical-pros-
tatectomy group did not undergo a prostatectomy
and 20.4% of the men in the observation group
received definitive treatment; this dilutes the sig-
nificance of the results.
It is possible that men in the observation group
who chose definitive treatment were a higher-risk
cohort, whereas those in the prostatectomy group
who chose observation were a lower-risk cohort,
thereby diluting the observed benefit of radical
prostatectomy. Can the authors report the details
of the cancer in patients in each crossover group?
Finally, reanalyzing the data with either a treat-
ment-received or a modified intention-to-treat
analysis instead of a pure intention-to-treat analy-
sis may limit the effect of crossover on the trial
results.
Vidit Sharma, M.D.
R.Jeffrey Karnes, M.D.
Mayo Clinic
Rochester, MN
sharma.vidit@mayo.edu
No potential conflict of interest relevant to this letter was re-
ported.
1. Thompson IM Jr, Tangen CM. Prostate cancer uncertainty
and a way forward. N Engl J Med 2012;367:270-1.
2. Dalela D, Karabon P, Sammon J, et al. Generalizability of the
Prostate Cancer Intervention Versus Observation Trial (PIVOT)
results to contemporary North American men with prostate can-
cer. Eur Urol 2017;71:511-4.
3. Walsh PC. Re: Radical prostatectomy versus observation for
localized prostate cancer. J Urol 2012;188:2225-6.
DOI: 10.1056/NEJMc1710384
our article. With regard to the comments by
that surgery conveyed a large mortality benefit,
as compared with observation. Our sample size
provided a 91% power to detect a relative reduc-
tion of 25% and an absolute reduction of 10 per-
centage points in all-cause mortality, assuming a
median survival of 10 years. Extended follow-up
increased power. Statistical measures were not
adjusted for multiple comparisons; such adjust-
ments would have further reduced significance
levels. We encouraged readers to focus on abso-
lute effects and confidence intervals and to bal-
ance small and nonsignificant long-term reduc-
tions in mortality with larger, early, sustained,
and significant nonfatal harms of treatment.
We disagree that the PIVOT cohort comprised
older, sicker patients with a lower risk of disease
than those who are offered radical prostatectomy
today. Surgery remains the predominant treat-
ment even in older men with very-low-risk dis-
ease.1 Most enrollees reported excellent perfor-
mance status and did not have coexisting
conditions. One third were younger than 65 years
of age. Two thirds had intermediate-risk or high-
risk disease. Mortality did not vary according to
age, performance status, coexisting conditions,
or Gleason score. The difference between the

1302 n engl j med 377;13nejm.org September 28, 2017

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 Correspondence

groups with respect to mortality from cancer but increases harms among men with low-risk
was 1.1 percentage points when we used a higher- disease or those who are older than 65 years of
certainty cause-of-death definition. Results sug- age. We encourage physicians and guideline groups
gest modest reductions in all-cause mortality to recommend initial observation for these men.
among younger men and those with intermediate- For younger, healthy men with intermediate-risk
risk disease. or high-risk disease, treatment decisions should
In reply to Sharma and Karnes: adherence to include balancing benefits with harms.
radical treatment in PIVOT was similar to that in TimothyJ. Wilt, M.D., M.P.H.
other studies.2,3 Adherence to observation was Minneapolis Veterans Affairs Health Care System
superior to adherence to nonradical treatment in Minneapolis, MN
the Prostate Testing for Cancer and Treatment tim.wilt@va.gov
(ProtecT) trial.3 Although per-protocol analyses GeraldL. Andriole, M.D.
may slightly alter effect estimates, the results of Washington University School of Medicine
St. Louis, MO
previous nonrandomized trials led to the uncer-
tainty that gave rise to these randomized trials. MichaelK. Brawer, M.D.
Myriad Genetics Laboratories
Contemporary prostate-specific antigenSalt Lake City, UT
detected cancers have a better prognosis with Since publication of their article, the authors report no fur-
observation than the cancers in PIVOT.3 Refine- ther potential conflict of interest.
ments in surgery and radiation therapy cost more 1. Maurice MJ, Abouassaly R, Kim SP, Zhu H. Contemporary
and provide modest, if any, improvement in tu- nationwide patterns of active surveillance use for prostate cancer.
mor control or reduction in treatment harms JAMA Intern Med 2015;175:1569-71.
Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prosta-
than observation.4 In addition, new chemothera- 2. tectomy or watchful waiting in early prostate cancer. N Engl J
pies for disseminated prostate cancer yield larg- Med 2014;370:932-42.
er reductions in mortality than surgery for local- 3. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes
ized disease, and these agents are associated with after monitoring, surgery, or radiotherapy for localized prostate
cancer. N Engl J Med 2016;375:1415-24.
acceptable harms. Therefore, men who currently 4. Wilt TJ, Dahm P. Value of prostate cancer care: new informa-
5

undergo surgery or receive radiation therapy tion on new therapies suggest less is more. Eur Urol 2017 May 29
probably have smaller mortality benefits than (Epub ahead of print).
5. James ND, de Bono JS, Spears MR, et al. Abiraterone for
those in our trial and probably have similar prostate cancer not previously treated with hormone therapy.
harms. Multiple randomized trials now show N Engl J Med 2017;377:338-51.
that early treatment does not decrease mortality DOI: 10.1056/NEJMc1710384

Changes in Diet Quality and Total and Cause-Specific Mortality

To the Editor: Sotos-Prieto et al. (July 13 issue)1
report that improvement in diet quality during
the 12-year study period was consistently associ-
ated with a reduced risk of death. Their report
may be easily interpreted as suggesting that bene-
ficial effects of specific foods or a type of diet
(e.g., the Alternate Mediterranean Diet and Di-
etary Approaches to Stop Hypertension [DASH]
diet, as evaluated in the study) contributed to the
reduction in the risk of death.
However, in nutritional research, associations
derived from observational studies may not be
reliable indicators of causal effects, even with
the most rigorous study designs achievable.2
Since changing ones diet is a difficult task, a shinsw@kumc.or.kr
highly motivated and physically and psychologi-
cally healthy person could succeed in changing
and maintaining his or her diet.3 The reduced
risk of death could be because of a persons ini-
tial physical and psychological health, not from
the beneficial effect of a changed diet. Thus, the
association that was found in this study could be
due to attribution bias. Accordingly, we think
that the exact cause of the reduced risk of death
remains speculative.
SongJ. Lee, Ph.D.
Chungnam University
Daejeon, South Korea
SangW. Shin, M.D., Ph.D.
Korea University
Seoul, South Korea
No potential conflict of interest relevant to this letter was re-
ported.

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