Published Ahead of Print on January 7, 2013 as 10.1200/JCO.2012.41.7634
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.7634
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Prostate Cancer Diagnosis Among Men With Isolated
High-Grade Intraepithelial Neoplasia Enrolled Onto a
3-Year Prospective Phase III Clinical Trial of Oral Toremifene
Samir S. Taneja, Ronald Morton, Gary Barnette, Paul Sieber, Michael L. Hancock, and Mitchell Steiner
See accompanying editorial doi: 10.1200/JCO.2012.46.6151
Samir S. Taneja, New York University
Langone Medical Center, New York,
NY; Ronald Morton, Gary Barnette,
Michael L. Hancock, and Mitchell
Steiner, GTx, Memphis, TN; Paul
Sieber, Urological Associates of
Lancaster, Lancaster, PA.
Published online ahead of print at
www.jco.org on January 7, 2013
Supported by GTx, Memphis, TN.
Presented at the 2011 American
Urological Association Annual Meeting,
May 14-19, 2011, Washington, DC.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical trial information: NCT00106691.
Corresponding author: Samir S. Taneja,
MD, Division of Urologic Oncology, 150
East 32nd St, Ste 200, New York, NY
10016; e-mail: [email protected].
© 2013 by American Society of Clinical
Oncology
0732-183X/13/3099-1/$20.00
DOI: 10.1200/JCO.2012.41.7634
A
B
S
T
R
A
C
T
Purpose
Prostate cancer (PCa) prevention remains an appealing strategy for the reduction of overtreatment
and secondary adverse effects. We evaluated the efficacy of toremifene citrate 20 mg in PCa
prevention among men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN)
on biopsy.
Patients and Methods
One thousand five hundred ninety men with HGPIN, or HGPIN and atypia, and no PCa on prostate
biopsy were randomly assigned 1:1 to receive toremifene citrate 20 mg or placebo in a 3-year
phase III, double-blind, multicenter trial. Men underwent annual biopsy until cancer detection or
study end. Efficacy analysis was performed in 1,467 men who underwent at least one on-study
biopsy. Baseline risk factors were evaluated to determine influence on cancer detection.
Results
Cancer was detected in 34.7% and 32.3% of men in the placebo and treatment groups,
respectively, with no observed difference (P ⫽ .39, log-rank test) in PCa-free survival. The 3-year
Kaplan-Meier PCa-free survival estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo
group and 59.5% (99% CI, 48.1% to 70.9%) in the treatment group. Exploration of baseline risk
factors demonstrated no subset in which a risk reduction was observed. In the placebo group,
17.9%, 12.9%, and 13.6% of men at risk at the beginning of years 1, 2, and 3, respectively, were
diagnosed with PCa.
Conclusion
Although toremifene 20 mg did not lower the PCa detection rate, men with isolated HGPIN have
a high likelihood of eventual PCa diagnosis, demonstrating they are ideal candidates for inclusion
in chemoprevention trials and require surveillance by periodic prostate biopsy.
J Clin Oncol 30. © 2013 by American Society of Clinical Oncology
INTRODUCTION
Prostate cancer (PCa) is the most commonly diagnosed solid malignancy and the second-leading
cause of cancer death among American men.1 Treatment of PCa results in the potential for significant
long-term urinary and sexual dysfunction, making
prevention of PCa among men at increased risk
most desirable if it can be achieved with acceptable
toxicity and cost.2-4 Challenges in broad implementation of chemoprevention for PCa include both
selection of agent and defining an appropriate atrisk population.
High-grade prostatic intraepithelial neoplasia
(HGPIN) is a premalignant histologic entity.5-7 Its
presence on prostate biopsy has been implicated as a
surrogate measure of coexistent PCa, but with the
adaptation of lower prostate-specific antigen (PSA)
cutoffs for biopsy and increased biopsy core numbers at sampling, a lower likelihood of occult cancer
detection on immediate repeat biopsy has been
noted.8-11 The long-term risk of PCa among men
with isolated HGPIN on biopsy is not well defined,
and the optimal strategies for clinical management
of these men have been controversial.12-14 We hypothesized that the high rate of coexistent cancer
and the premalignant nature of HGPIN make these
men ideal candidates for testing chemoprevention strategies.
Estrogens play a significant role in prostate carcinogenesis and PCa proliferation in animal models.15,16 In a noncastrate environment, estrogen
receptor (ER) ␣ serves as mediator of growthstimulatory signal transduction through initiation
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Copyright 2013 by American Society of Clinical Oncology
1
Taneja et al
of stromal paracrine effect on PCa epithelium, whereas ER-␤ mediates
a direct antiproliferative effect on the epithelial compartment.17
Toremifene citrate is an oral selective ER modulator approved by the
US Food and Drug Administration for the treatment of advanced
breast cancer. At low concentrations, toremifene selectively inhibits
ER-␣.18,19 In both preclinical studies and a dose-finding phase IIb
clinical trial, toremifene reduced the progression of premalignant
HGPIN to PCa.20 On the basis of these studies, we undertook a
randomized phase III, double-blind, placebo-controlled clinical trial
of toremifene 20 mg for prevention of PCa in 1,590 men with isolated
HGPIN on biopsy treated for 3 years.
PATIENTS AND METHODS
Study Design
This was a 3-year, phase III, randomized, double-blind, placebocontrolled, multicenter clinical trial to evaluate the efficacy and safety of
toremifene for prevention of PCa in men with isolated HGPIN on prostate
biopsy. Men were randomly assigned 1:1 to receive toremifene 20 mg oral daily
or matching placebo. Isolated HGPIN was defined as men with HGPIN, with
or without coexistent atypical small acinar proliferation (ASAP), and no evidence of cancer on biopsy.
A sample size of 1,260 men was estimated to detect a difference in
PCa-free survival between treatment and placebo arms using a log-rank test,
based on 1-year PCa-free survival rates of 81% and 73% in treatment and
placebo arms, respectively, and a 3-year trial with no additional follow-up
(␣ ⫽ .01, power ⫽ 90%). Final sample size increased to 1,590 men on US Food
and Drug Administration request of additional patients for an ocular substudy
late in the trial.
The study was designed and conducted by the sponsor (GTx, Memphis,
TN) and the principal investigator (S.S.T.). Local institutional review board
approval was obtained at each of 140 sites (Appendix Table A1, online only),
and all men signed informed consent before enrollment. Health Decisions
(Raleigh, NC) provided data management, Bostwick Laboratories (Glen Allen,
VA) provided central anatomic pathology services, and CRL Medinet (Lenexa,
KS) provided central laboratory services. An independent data and safety
monitoring board met semiannually to oversee the study and monitor patient safety.
Participants
The study included men age ⱖ 30 years diagnosed with isolated HGPIN
on prostate biopsy confirmed by a central pathology reading. All men had
baseline serum PSA ⱕ 10 ng/mL; adequate bone marrow, liver, and renal
function; and a minimum 10-core negative prostate biopsy within 6 months of
random assignment or two minimum negative six-core biopsies within 12
months of random assignment. The study excluded men with exposure to
toremifene, finasteride within 30 days of random assignment, dutasteride
within 90 days of random assignment, or PC-SPES or saw palmetto within 2
years of random assignment or a history of thromboembolic disease, chronic
hepatitis, or cirrhosis.
End Points
The primary end point was PCa-free survival as determined by transrectal ultrasound– guided needle biopsy of the prostate. Secondary assessments
included the effects of toremifene on detection of HGPIN, lipid levels, gonadal
steroids, serum PSA, American Urological Association symptom score, and
Gleason grade.
Study Procedures
Transrectal ultrasound– guided biopsies of the prostate with a minimum
of 10 cores were obtained at months 12, 24, and 36 or until a diagnosis of PCa.
All pathologic specimens were analyzed by the central anatomic pathology lab.
Serum PSA levels were obtained at baseline, 3 months, and 6 months,
and every 6 months thereafter. Serum hormones (testosterone, dihydrotestos2
© 2013 by American Society of Clinical Oncology
terone, and estradiol) were obtained at baseline and every 6 months thereafter.
All labs were analyzed at a central laboratory.
Adverse events (AEs), recorded at baseline and at each interval monitoring visit, were assessed for duration, intensity, and necessary intervention.
Each AE was additionally determined to be related to the study drug, concurrent disease, reaction to concomitant medication, or progressive disease states,
when appropriate. Treatment compliance was calculated by applying the following formula: No. of pills dispensed – No. of pills returned or unused ⫻
100/No. of pills to be taken during the study.
Statistical Analyses
The probability of development of PCa was estimated using the KaplanMeier method, and SEs of the estimates were calculated with the Peto-Pike
formula.21,22 Time was calculated from the date of first dose of study drug until
the date of PCa diagnosis or date of last visit for censored patients. The
distributions of Gleason grades were compared between treatments using
Fisher’s exact test. Change in serum hormones (total testosterone, dihydrotestosterone, and estradiol) from baseline to end of study were compared between arms using analysis of variance with treatment arm as the single factor.
Presenting and demographic features of known or suspected prognostic significance for the development of PCa were explored using a Cox proportional
hazards model. Factors were examined first in univariate models, and those
factors significant at P ⬍ .20 were then included in a multivariate model. The
variables included in the final model were baseline age, baseline PSA value,
baseline ASAP status (present, absent), PSA velocity (last observation), and the
time-dependent covariates of digital rectal examination (DRE) result (normal,
abnormal) and prostate volume. P values are two-sided and unadjusted for
multiple comparisons, and P ⬍ .01 is considered significant.
RESULTS
Study Participants
Of 1,590 men who were randomly assigned, 787 and 803 men
were assigned to receive toremifene or placebo, respectively (Fig 1).
Median age of the men was 64 years (range, 41 to 87 years; Table 1).
Safety analyses included 1,589 randomly assigned men who received ⱖ one dose of study medication. Efficacy analyses included
1,426 men in the modified intent-to-treat (MITT) cohort with ⱖ one
on-study biopsy of the prostate. Biopsy compliance was 98%, 98%,
and 100% among 1,361, 1,003, and 780 at-risk participants eligible for
biopsy at years 1, 2, and 3, respectively. Among excluded patients, 85
patients in the placebo group and 77 patients in the toremifene group
did not undergo an on-study prostate biopsy, one patient was found to
have had PCa on baseline central pathology review, and one patient
was not dosed. Treatment compliance was 97.2% (⫾ 27.3%) and
98.12% (⫾ 40.7%) among participants receiving placebo and
toremifene, respectively.
PCa-Free Survival
The primary efficacy end point for the trial was PCa-free survival
in the MITT cohort. Two hundred forty-nine cancer events (34.7%)
occurred in the placebo group, and 229 cancer events (32.3%) occurred in the treatment group. The 3-year Kaplan-Meier cancer-free
survival estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo
group and 59.5% (99% CI, 48.1% to 70.9%) in the treatment group
(Fig 2). There was no observed difference (P ⫽ .39, log-rank test) in
PCa-free survival. Among men in the MITT population with a single
baseline core positive for HGPIN, the PCa progression-free survival
estimate at 3 years was 60.1% (99% CI, 50.2% to 70.0%) compared
with 51.4% (99% CI, 37.2% to 65.6%) for men with greater than one
core demonstrating HGPIN (P ⬍ .001, log-rank test).
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Prostate Cancer Detection Among Men With HGPIN
Assessed for eligibilty
(N = 3,004)
Excluded
Did not meet inclusion criteria
Declined to participate
Had other reasons
(n = 1,414)
(n = 1,176)
(n = 166)
(n = 72)
Randomly assigned
(n = 1,590)
Assigned to toremifene
(n = 787)
Assigned to placebo
(n = 803)
Did not receive drug
(n = 1)
Included in safety analyses
(n = 787)
Included in safety analyses
(n = 802)
Excluded from efficacy analyses
(n = 78)
Had screening biopsy only
(n = 77)
Had prostate cancer at screening (n = 1)
Excluded from efficacy analyses
Had screening biopsy only
(n = 85)
(n = 85)
Included in efficacy analyses
(n = 709)
Included in efficacy analyses
(n = 717)
Did not complete study
(n = 122)
Withdrew consent
(n = 51)
Adverse experience
(n = 32)
Investigator/sponsor decision
(n = 17)
Noncompliance
(n = 3)
Lost to follow-up
(n = 11)
Other protocol violation
(n = 5)
Other
(n = 3)
+ 49 of the above were found to have
prostate cancer on their end of study biopsy
Did not complete study
(n = 119)
Withdrew consent
(n = 54)
Adverse experience
(n = 25)
Investigator/sponsor decision
(n = 12)
Noncompliance
(n = 5)
Lost to follow-up
(n = 13)
Other protocol violation
(n = 2)
Other
(n = 8)
+ 51 of the above were found to have
prostate cancer on their end of study biopsy
Completed the 36-month study
Completed cancer free
Diagnosed with prostate cancer
Completed the 36-month study
Completed cancer free
Diagnosed with prostate cancer
(n = 587)
(n = 407)
(n = 180)
(n = 598)
(n = 400)
(n = 198)
Fig 1. CONSORT diagram showing patient enrollment, random assignment, and final analysis.
Gleason Grade
Among men diagnosed with PCa, 79.5% within the placebo
group and 82.4% in the toremifene group had a Gleason score of 6.
The next most commonly observed Gleason score was 7 (17.4% of the
placebo group and 15.6% of the toremifene group), whereas 3.1% and
2% of patients in the placebo and toremifene groups, respectively, had
Gleason scores of more than 7. The distributions of Gleason grades did
not differ (P ⫽ .84) between the two groups.
Exploratory Covariates
A number of exploratory covariates, specified before data analysis, were examined for influence on cancer detection within the MITT
population, including race, number of biopsy cores with HGPIN at
baseline, age, presence of ASAP at baseline, family history of PCa, time
www.jco.org
from HGPIN diagnosis until random assignment, prostate volume,
PSA velocity, and PSA. After accounting for all covariates, the hazard
ratio for cancer detection in the toremifene group was 1.0 (99% CI, 0.8
to 1.3), consistent with the overall observation that there was no
difference (P ⫽ .91) between the two groups. Among the covariates in
the multivariate model described earlier, baseline PSA, presence of
ASAP in the baseline biopsy, the last computed PSA velocity, and the
time-dependent covariates of prostate volume and DRE result each
were statistically significant (P ⬍ .001 for each) prognostic factors for
the development of PCa (Table 2).
PCa-Free Survival in Placebo Group
As previously mentioned, 34.7% of men in the placebo group
were diagnosed with PCa. Among men in the placebo group, the
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
3
Taneja et al
1.0
Table 1. Baseline Demographics and Clinical Characteristics of Men Enrolled
Onto the Trial and Randomly Assigned to Placebo or Toremifene
Demographic or
Clinical Characteristic
Age, years
Median
Range
Race
White
Black
Other
Ethnicity
Hispanic
Body mass index, kg/m2
Mean
SD
Relative with history of prostate cancer
Father
Sibling
ASAP present at screening
HGPIN diagnosed ⬎ 1 year before
random assignment
History of BPH
Abnormal digital rectal examination
Prostate volume, cm3
Mean
SD
PSA, ng/mL
Mean
SD
No. of cores
Median
Range
Mean
SD
Patients with single core with HGPIN
No. of
Patients
%
65
41-85
Placebo
(n ⫽ 802)
No. of
Patients
%
65
38-87
0.6
0.4
0.2
693
76
18
88.1
9.7
2.2
684
94
24
85.3
11.7
3.0
30
3.8
31
3.9
28.8
4.8
102
46
137
13.0
5.8
17.4
94
56
168
11.7
7.0
20.9
90
496
285
11.4
63.0
39.9
80
494
304
10.0
61.6
41.5
48.6
23.6
47.9
22.4
4.5
2.6
4.3
2.5
12
6-83
14.6
6.6
500
63.5
12
6-46
14.5
5.4
503
62.7
36-month PCa-free survival probability was 52.2% (99% CI, 37.1% to
67.3%) for men with a normal DRE at baseline compared with 59.3%
(99% CI, 40.9% to 77.7%) for men with an abnormal DRE. In the
MITT placebo group, 17.9%, 12.9%, and 13.6% of men at risk at the
beginning of years 1, 2, and 3, respectively, were diagnosed with PCa.
Serum Hormone Levels
In men treated with toremifene versus placebo, greater increases
in total testosterone (31.1% ⫾ 63.6% v 2.2% ⫾ 102.9%, respectively;
P ⬍ .001), dihydrotestosterone (46.4% ⫾ 60.2% v 17.7% ⫾ 48.3%,
respectively; P ⬍ .001), and estradiol levels (53.2% ⫾ 151.5% v
11.9% ⫾ 67.9%, respectively; P ⬍ .001) were noted at final assessment.
Adverse Events
The number of men who died, had a serious AE, had any AE, or
discontinued participation in the study because of an AE did not
significantly differ between study groups (Table 3). The most commonly reported AEs for both groups were hypertension, arthralgia,
© 2013 by American Society of Clinical Oncology
Placebo
Toremifene 20 mg
Log-rank P = .39
0
365
730
1,095 1,200
Time (days)
Fig 2. Kaplan-Meier analysis of cancer diagnosis among men treated with
toremifene citrate and placebo. The 3-year Kaplan-Meier cancer-free survival
estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo group and 59.5%
(99% CI, 48.1% to 70.9%) in the toremifene group.
28.7
4.6
Abbreviations: ASAP, atypical small acinar proliferation; BPH, benign prostatic
hyperplasia; HGPIN, high-grade prostatic intraepithelial neoplasia; PSA,
prostate-specific antigen; SD, standard deviation.
4
0.8
Probability
Toremifene
(n ⫽ 787)
urinary tract infection, upper respiratory tract infection, prostatitis,
and erectile dysfunction; rates for each of these AEs were similar for
men assigned to either group.
Venous thromboembolic events defined as pulmonary embolism or deep venous thrombosis were uncommon and balanced between groups. In the placebo group, there was one deep vein
thrombosis and two pulmonary embolisms (0.4%), whereas in the
toremifene group, there were three deep vein thromboses and one
pulmonary embolism (0.5%).
DISCUSSION
The current phase III clinical trial did not show an effect of toremifene
on the likelihood of PCa diagnosis in men with isolated HGPIN on
baseline biopsy. Exploration of multiple covariates, including the volume of HGPIN at baseline, did not reveal a therapeutic effect in any
subgroup. The likelihood of HGPIN on serial study biopsy was also
not reduced by treatment.
A randomized, phase IIb dose-finding clinical study of
toremifene in 514 men with isolated HGPIN demonstrated a 21.8%
(P ⫽ .048, Mantel-Cox analysis stratified by treatment site) cumulative relative risk reduction in PCa detected on follow-up biopsies
performed 6 months and 12 months after initiation of therapy with
toremifene citrate 20 mg.20 Distinctions between the current study
and the previously reported phase IIb clinical study include more
stringent baseline sampling criteria, longer treatment period (3 years v
1 year), and less frequent sampling (yearly v every 6 months). It was the
intent of these design modifications to provide a more pure population of men with isolated HGPIN who were less likely to harbor occult
malignancy, undiagnosed on inclusion biopsy, and, therefore, more
likely to benefit from prolonged exposure to the drug. It is notable that
the rate of cancer diagnosis on the year 1 scheduled biopsy in this trial
did not differ greatly from the 6-month biopsy in the phase IIb trial,
suggesting a significant rate of occult, coexistent cancer despite more
extensive baseline sampling.20
To our knowledge, this is the largest prospective evaluation of
men with isolated HGPIN reported to date. The study allows several
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Prostate Cancer Detection Among Men With HGPIN
Table 2. Univariate and Multivariate Analyses of Baseline and Clinical Features Potentially Predictive of Cancer Diagnosis
Univariate Analysesⴱ
Multivariable Analyses†
Factor
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
P
Age
PSA at baseline
Presence of ASAP at baseline
PSA velocity
Greater prostate volume (TRUS)
Normal DRE
1.02
1.05
1.81
1.05
1.00
0.87
1.00 to 1.03
1.02 to 1.08
1.48 to 2.21
1.04 to 1.06
0.99 to 1.00
0.71 to 1.06
.019
.003
⬍ .001
⬍ .001
.002
.17
1.02
1.09
1.91
1.05
0.989
0.89
1.00 to 1.03
1.06 to 1.13
1.54 to 2.36
1.04 to 1.07
0.985 to 0.994
0.72 to 1.10
.009
⬍ .001
⬍ .001
⬍ .001
⬍ .001
.28
NOTE. Variables were examined first in univariate models, and those reaching significance at P ⬍ .20 were evaluated by a Cox proportional hazards model. The
variables included in the final multivariate model were baseline age, baseline PSA value, baseline ASAP status (present, absent), PSA velocity (last observation), and
the time dependent covariates of DRE result (normal, abnormal) and prostate volume. P values are two sided and unadjusted for multiple comparisons, and P ⬍ .01
is considered significant.
Abbreviations: ASAP, atypical small acinar proliferation; DRE, digital rectal examination; PSA, prostate-specific antigen; TRUS, transrectal ultrasound.
ⴱ
Factor adjusted for treatment.
†Factor adjusted for treatment and all other factors listed.
observations regarding the 3-year risk of cancer in men with isolated
HGPIN, the influence of serial annual sampling on cancer detection,
and potential considerations for future clinical trial design in this
at-risk population. By Kaplan-Meier estimate, the 3-year freedom
from cancer rate in this trial was 52.2%, with 33.5% of men in the
group diagnosed with cancer during the course of the study. The
observed rate of detection on repeat biopsy in year 1 is higher than that
reported in several smaller, retrospective series of men with isolated
HGPIN.8,21,22 Whether the longitudinal rate of cancer detection re-
Table 3. Most Commonly Observed Adverse Events (⬎ 3% in overall
population) Among Men Treated With Placebo and Toremifene Citrate
Toremifene
20 mg
(n ⫽ 787)
Placebo
(n ⫽ 802)
Adverse Event
Hypertension
Arthralgia
Urinary tract
infection
Upper respiratory
tract infection
Prostatitis
Erectile dysfunction
Hematuria
Back pain
Dizziness
Nasopharyngitis
Benign prostatic
hyperplasia
Pain in extremity
Fatigue
Gastroesophageal
reflux disease
Pollakiuria
Cataract
Insomnia
Sinusitis
Urinary retention
Constipation
Headache
www.jco.org
Overall
(N ⫽ 1,589)
No. of
Patients
%
No. of
Patients
%
No. of
Patients
%
70
50
8.7
6.2
52
46
6.6
5.8
122
96
7.7
6.0
54
6.7
41
5.2
95
6.0
46
49
42
38
36
37
39
5.7
6.1
5.2
4.7
4.5
4.6
4.9
45
39
42
36
31
30
28
5.7
5.0
5.3
4.6
3.9
3.8
3.6
91
88
84
74
67
67
67
5.7
5.5
5.3
4.7
4.2
4.2
4.2
30
29
31
3.7
3.6
3.9
32
32
28
4.1
4.1
3.6
62
61
59
3.9
3.8
3.7
32
30
24
32
21
24
27
27
4.0
3.7
3.0
4.0
2.6
3.0
3.4
3.4
24
26
29
21
32
29
24
22
3.0
3.3
3.7
2.7
4.1
3.7
3.0
2.8
56
56
53
53
53
53
51
49
3.5
3.5
3.3
3.3
3.3
3.3
3.2
3.1
flects an increased risk of occult cancer or de novo cancer progression
among men with HGPIN or, in part, the frequency of sampling cannot
be determined in the absence of a control group of men without
isolated HGPIN who are serially biopsied on an annual basis. Nonetheless, the observed rate of cancer detection has substantial implications for the management of these men, particularly those who are
found to have HGPIN at a young age, in whom prolonged follow-up is
necessary. Many of these men would ultimately be biopsied in clinical
practice, diagnosed with cancer, and treated.
To date, the long-term natural history of HGPIN in men has only
been evaluated in small series. Lefkowitz et al12 demonstrated that
empiric repeat biopsy 3 years after the diagnosis of HGPIN on 12-core
biopsy resulted in a cancer detection of 25.8%, compared with 2.3%
when biopsied within 1 year of diagnosis. Recent follow-up from the
same group, using a surveillance strategy of serial biopsy every 2 to 3
years among men with stable PSA level, demonstrated that 22.3% and
23.4% of men were found to have cancer on repeat sampling at a mean
interval of 34.4 and 66.2 months, respectively.23 Overall, 32.1% of men
were found to have PCa at a median follow-up of 46.6 months, and 40
men had not yet undergone second repeat biopsy. Several other
groups have demonstrated a relatively high rate of cancer detection on
delayed repeat biopsy in men with HGPIN.13,14,24,25 Recently, in a
single-institution retrospective cohort, it was suggested that the greatest magnitude of risk for cancer detection at prolonged follow-up is in
men with multifocal HGPIN, whereas those with limited focality
disease had disease risk comparable to men with benign baseline
biopsies.13 We did observe a lower risk of cancer among men with a
single core positive for HGPIN at baseline compared with men with
two or more cores on univariate analysis, but this was not observed on
multivariate analysis.
At present, there is no consensus on the management of men
with HGPIN, and no pervasive standard of care exists in community
practice. Contemporary series have suggested that the risk of cancer
detection on immediate rebiopsy of men with isolated HGPIN is quite
low and may be no greater in men with HGPIN than those with benign
biopsies.21 As such, immediate repeat biopsy is generally not recommended for men with HGPIN, but there are limited data on the
long-term risk of cancer in these men. It is interesting to note that
among men in the placebo arm of this trial, cancer was detected in
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
5
Taneja et al
17.9%, 12.9%, and 13.2% of men biopsied in years 1, 2, and 3, respectively. This is distinct from screening cohorts in which a serial decline
in cancer detection rate is typically noted on sequential sampling of
men with elevated PSA and benign biopsy. In the European Randomized Study of Screening for Prostate Cancer, men underwent two
rounds of screening biopsies separated by 4 years.26 Among men with
negative baseline screening with follow-up PSA more than 4.0 ng/mL,
the rate of cancer detection on second biopsy was 8.3%. In this series,
baseline and repeat biopsies were sextant biopsies, suggesting that with
baseline extended core biopsy, the rate of cancer detection may have
been lower. Both the Prostate Cancer Prevention Trial (PCPT) and the
Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial
compared 5␣-reductase inhibitors with placebo as prevention agents
for PCa.27,28 In the REDUCE trial, repeat biopsies performed in the
placebo arm at 2 and 4 years demonstrated cancer in 17.2% and 11.9%
of men, respectively.28
No difference in Gleason score was observed between placebo
and treatment groups in this study; 20.5% of cancers identified in the
placebo arm of the study were Gleason score ⱖ 7, demonstrating the
potential for isolated HGPIN to coexist with high-grade disease and
suggesting that biopsy surveillance is warranted in these men. In the
REDUCE trial, 27.4% of men on placebo were found to have a Gleason score ⱖ 7 disease. When stratified by biopsy, only 21.4% of men
demonstrated high-grade disease at the 4-year biopsy, compared with
30.3% of men at the 2-year sampling. Our observed rate of Gleason
score 6 cancer may, in part, be a result of our frequent sampling
regimen because it is, perhaps, intuitive that repeat sampling would
result in a downward stage and grade migration. The fact that men
with small-volume, Gleason 6 cancers are most often subjected to
treatment, with potential for substantial adverse effects, supports the
assertion that men with HGPIN on biopsy may be ideally suited for
chemoprevention efforts.
Men with isolated HGPIN on prostate biopsy are at a relatively
high risk of cancer diagnosis in long-term follow-up by serial biopsy.
The high rate of cancer diagnosis on surveillance biopsy in short-term
REFERENCES
1. Jemal A, Siegel R, Xu J, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 2010
2. Lieberman R: Chemoprevention of prostate
cancer: Current status and future directions. Cancer
Metastasis Rev 21:297-309, 2002
3. Brewster AM, Patterson SL, Forman MR, et
al: Conference report: Eighth Annual AACR International Conference on Frontiers in Cancer Prevention
Research. Cancer Prev Res 3:1044-1048, 2010
4. Lippman SM, Lee JJ: Reducing the “risk” of
chemoprevention: Defining and targeting high risk—
2005 AACR Cancer Res and Prevention Foundation
Award Lecture. Cancer Res 66:2893-2903, 2006
5. Schlesinger C, Bostwick DG, Iczkowski KA:
High-grade prostatic intraepithelial neoplasia and
atypical small acinar proliferation: Predictive value
for cancer in current practice. Am J Surg Pathol
29:1201-1207, 2005
6. McNeal JE, Bostwick DG: Intraductal dysplasia: A premalignant lesion of the prostate. Hum
Pathol 17:64-71, 1986
7. Bostwick DG, Qian J: High-grade prostatic
intraepithelial neoplasia. Mod Pathol 17:360-379,
2004
6
© 2013 by American Society of Clinical Oncology
follow-up suggests a high rate of coexistent cancer and/or de novo
cancer progression among men with isolated HGPIN on biopsy.
Long-term management of men with HGPIN should include surveillance by periodic prostate biopsy while balancing the risk of oversampling through too frequent biopsy. Although toremifene citrate 20 mg
does not lower the risk of cancer in men with isolated HGPIN on
prostate biopsy, these men do seem to represent an ideal group for
consideration of prevention strategies.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U” are
those for which no compensation was received; those relationships marked
with a “C” were compensated. For a detailed description of the disclosure
categories, or for more information about ASCO’s conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Ronald Morton, GTx (C); Gary
Barnette, GTx (C); Michael L. Hancock, GTx (C); Mitchell Steiner, GTx
(C) Consultant or Advisory Role: Samir S. Taneja, GTx (C); Paul Sieber,
GTx (C) Stock Ownership: Ronald Morton, GTx; Gary Barnette, GTx;
Michael L. Hancock, GTx; Mitchell Steiner, GTx Honoraria: Paul Sieber,
GTx Research Funding: Samir S. Taneja, Gtx; Paul Sieber, GTx Expert
Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Samir S. Taneja, Gary Barnette, Mitchell Steiner
Collection and assembly of data: Samir S. Taneja, Gary Barnette
Data analysis and interpretation: Samir S. Taneja, Ronald Morton, Paul
Sieber, Michael L. Hancock
Manuscript writing: All authors
Final approval of manuscript: All authors
8. Lefkowitz GK, Sidhu GS, Torre P, et al: Is
repeat prostate biopsy for high-grade prostatic intraepithelial neoplasia necessary after routine 12-core
sampling? Urology 58:999-1003, 2001
9. Weinstein MH, Epstein JI: Significance of
high-grade prostatic intraepithelial neoplasia on needle biopsy. Hum Pathol 24:624-629, 1993
10. Herawi M, Kahane H, Cavallo C, et al: Risk of
prostate cancer on first re-biopsy within 1 year
following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores
sampled. J Urol 175:121-124, 2006
11. Kronz JD, Allan CH, Shaikh AA, et al: Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: Data
on men with more than one follow-up biopsy. Am J
Surg Pathol 25:1079-1085, 2001
12. Lefkowitz GK, Taneja SS, Brown J, et al:
Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia
is associated with high likelihood of prostate cancer,
independent of change in prostate specific antigen
levels. J Urol 168:1415-1418, 2002
13. Lee MC, Moussa AS, Yu C, et al: Multifocal
high grade prostatic intraepithelial neoplasia is a risk
factor for subsequent prostate cancer. J Urol 184:
1958-1962, 2010
14. Abdel-Khalek M, El-Baz M, Ibrahiem el-H: Predictors of prostate cancer on extended biopsy in
patients with high-grade prostatic intraepithelial neoplasia: A multivariate analysis model. BJU Int 94:
528-533, 2004
15. Risbridger GP, Bianco JJ, Ellem SJ, et al:
Oestrogens and prostate cancer. Endocr Relat Cancer 10:187-191, 2003
16. Ho SM: Estrogens and anti-estrogens: Key
mediators of prostate carcinogenesis and new therapeutic candidates. J Cell Biochem 91:491-503,
2004
17. Leav I, Lau KM, Adams JY, et al: Comparative
studies of the estrogen receptors beta and alpha
and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic
carcinoma. Am J Pathol 159:79-92, 2001
18. Taneja SS, Smith MR, Dalton JT, et al:
Toremifene: A promising therapy for the prevention
of prostate cancer and complications of androgen
deprivation therapy. Expert Opin Investig Drugs
15:293-305, 2006
19. Steiner MS, Raghow S: Antiestrogens and
selective estrogen receptor modulators reduce
prostate cancer risk. World J Urol 21:31-36, 2003
20. Price D, Stein B, Sieber P, et al: Toremifene
for the prevention of prostate cancer in men with
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Prostate Cancer Detection Among Men With HGPIN
high grade prostatic intraepithelial neoplasia: Results of a double-blind, placebo controlled, phase IIB
clinical trial. J Urol 176:965-970, 2006
21. Epstein JI, Herawi M: Prostate needle
biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma:
Implications for patient care. J Urol 175:820-834,
2006
22. Netto GJ, Epstein JI: Widespread high-grade
prostatic intraepithelial neoplasia on prostatic needle
biopsy: A significant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg Pathol 30:11841188, 2006
23. Godoy G, Huang GJ, Patel T, et al: Long-term
follow-up of men with isolated high-grade prostatic
intra-epithelial neoplasia followed by serial delayed
interval biopsy. Urology 77:669-674, 2011
24. Roscigno M, Scattoni V, Freschi M, et al:
Monofocal and plurifocal high-grade prostatic intraepithelial neoplasia on extended prostate biopsies:
Factors predicting cancer detection on extended
repeat biopsy. Urology 63:1105-1110, 2004
25. Akhavan A, Keith JD, Bastacky SI, et al: The
proportion of cores with high-grade prostatic intraepithelial neoplasia on extended-pattern needle biopsy is significantly associated with prostate cancer
on site-directed repeat biopsy. BJU Int 99:765-769,
2007
26. Roobol MJ, van der Cruijsen IW, Schröder FH:
No reason for immediate repeat sextant biopsy after
negative initial sextant biopsy in men with PSA level
of 4.0 ng/mL or greater (ERSPC, Rotterdam). Urology 63:892-897, 2004
27. Thompson IM, Goodman PJ, Tangen CM, et
al: The influence of finasteride on the development
of prostate cancer. N Engl J Med 349:215-224, 2003
28. Andriole GL, Bostwick DG, Brawley OW, et al:
Effect of dutasteride on the risk of prostate cancer.
N Engl J Med 362:1192-1202, 2010
■ ■ ■
www.jco.org
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
7
Taneja et al
Appendix
Table A1. Investigators and Investigation Sites
PI Last Name
Bailen
Belkoff
Bhayani
Cartwright
Chu
Colombo
Cowan
Efros
Eure
Fairchild
Feldman
Forrest
Gervasi
Gingrich
Gittelman
Lilly
Hackett
Palmer
Harrison
Hatcher
Hudnall
Castellanos
Immergut
Jablonski
Jacob
Jensen
Kahnoski
Kernen
Kotkin
Cantwell
Kriteman
Linder
McMurray
Hertzman
Murdock
Murphy
O’Leary
Oselinsky
Pearson
Pinto
Shore
Sieber
Snoy
Stallings
Stein
Stringer
Taneja
Teigland
White, Jr.
Zinner
Klimberg
Mazo
Peterson
Jones
Goldenberg
Cunningham
PI First Name
James L.
Laurence H.
Sam B.
Charles
Franklin
Giovanni
Barrett
Mitchell
Gregg
Thomas
Robert A.
John B.
Lawrence
Jeffrey
Marc
Joel D.
Kevin C.
Thomas E.
Emerson
Paul A.
Clayton H.
Ronald
Mark
David H.
David
James C.
Richard J.
Kenneth
Leonid
Anthony
Lewis S.
Earle S.
James G.
Bernard L.
Myron I.
Brian P.
Michael
David
Richard
Arthur
Neal D.
Paul
Frederick J.
J. Walt
Barry S.
Thomas
Samir
Chris
Charles F.
Norman
Ira W.
Richard
Andrew C.
William Terry
Samuel F.
David
Practice
City
State/Territory
Metropolitan Urology, PSC
Urologic Surgery, PC
Washington University Urologic Research Center
UroSearch - Dr Cartwright
San Bernardino Urological Associates
Specialty Care Research
Urology Associates, PC
AccuMed Research Associates
Devine-Tidewater Urology
Spokane Urology
Connecticut Clinical Research Center
Urology Specialists of Oklahoma
Southwest Urology
University of Pittsburgh
South Florida Medical Research
Seattle Urological Associates
The Urological Center, PA
Regional Urology, LLC
Georgia Urology, PA
Volunteer Research Group
Urology San Antonio Research, PA
Southwest Florida Urologic Associates
Mid Atlantic Clinical Research
Winter Park Urology Associates
DMI Research
Advanced Clinical Research
Michigan Medical, PC Urology
Michigan Institute of Urology (Research Department)
Boston Clinical Trials
Atlantic Urological Associates
North Fulton Urology, PC
Hamilton Urology PA
Medical Affiliated Research Center
Tri-State Urologic Services, PSC dba The Urology Group
Myron I. Murdock, MD, LLC
Urologic Associates of Allentown
Brigham and Women’s Hospital
State College Urologic Associates
The Conrad/Pearson Clinic, PC
Urological Associates of Bridgeport
Carolina Urologic Research Center
Urological Associates of Lancaster, Ltd
Urology Group of New Mexico
Arkansas Urology
University Urological Research Institute
UroSearch–Dr Stringer
New York University Urology Associates
McKay Urology
Coastal Clinical Research
Western Clinical Research
Florida Foundation for Healthcare Research
St Joseph’s/Candler Health System, Office of Research
Urology Services Madigan Army Medical Center
Urology of Indiana, LLC
Delaware Valley Urology, LLC
UroSearch–Dr Cunningham
Jeffersonville
Bala Cynwyd
St Louis
Ocala
San Bernardino
Peoria
Englewood
Garden City
Norfolk
Spokane
Middlebury
Tulsa
Middleburg Heights
Pittsburgh
Aventura
Seattle
Hagerstown
Shreveport
Atlanta
Knoxville
San Antonio
Fort Myers
Rockville
Orlando
Pinellas Park
Salt Lake City
Grand Rapids
Troy
Brighton
Daytona Beach
Roswell
Hamilton
Huntsville
Cincinnati
Greenbelt
Allentown
Boston
State College
Germantown
Trumbull
Myrtle Beach
Lancaster
Albuquerque
Little Rock
Providence
Ocala
New York
Charlotte
Mobile
Torrance
Ocala
Savannah
Tacoma
Greenwood
Marlton
Ocala
IN
PA
MO
FL
CA
IL
CO
NY
VA
WA
CT
OK
OH
PA
FL
WA
MD
LA
GA
TN
TX
FL
MD
FL
FL
UT
MI
MI
MA
FL
GA
NJ
AL
OH
MD
PA
MA
PA
TN
CT
SC
PA
NM
AR
RI
FL
NY
NC
AL
CA
FL
GA
WA
IN
NJ
FL
(continued on following page)
8
© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Prostate Cancer Detection Among Men With HGPIN
Table A1. Investigators and Investigation Sites (continued)
PI Last Name
PI First Name
Trochelman
Chopp
Tutrone, Jr.
Bennett
Lev
Freedman
Israeli
Kane
Naslund
Sharkey
Goldberg
Burzon
Ramos
Mehlhaff
Costa
Roper
Simon
Bilhartz
Barnswell
D’Esposito
Alabaster
Scott
Cohen
Hopkins
Lacy
Malkowicz
Krejci
Pomeroy
Nelson
Morgan
Rawl
Parkhurst
Fisher
Kim
Omarbasha
Lovinggood
Zachary
Asroff
Jayson
Kaufman
Boelter
Levine
Karsh
Spirnak
Goldberg
Singh
Kaminetsky
Chao
Patterson
Biber
Bilik
Tarantino
Grubman
Fleshner
R. Douglas
Richard T.
Ronald
James K.
Ronan
Sheldon J.
Ron S.
Richard
Michael
Jerrold
Kenneth
Daniel
Carlos E.
Bryan A.
Frank
Ronald P.
James
David
Carlton
Robert F.
A. Michael
John
Jeffrey K.
Scott Alan
Sushil
S. Bruce
Kent
Brandon
Roscoe Scott
William R.
John C.
Joseph
Hugh A.G.
Francis Y.
Bashar
Perry
James Mark
Scott W.
Maury A.
Joel Mark
Christopher W.
Michael A.
Lawrence I.
John Patrick
Gary
Errol O.
Jed
Roberto
Anthony
Robert J.
A. Joseph
Arthur
Jerold
Neil E.
Egerdie
Aaron
Barkin
Buckley
Casey
Flax
Blair
Lorne
Jack
Roger
Richard
Stan
Practice
Summa Health System, Cancer Research Office
The Urology Team PA
Chesapeake Urology Research Associates
Midtown Urology
St Louis Urological Surgeons
Sheldon J. Freedman, MD
Staten Island Urological Research, PC
Wake Urology Associates PA
Maryland Prostate Center
Advanced Research Institute
Research Across America
Coastal Urology Associates
Panama City Urological Center, PA
Oregon Urology Institute
The Urology Institute
Urology Enterprises
Columbus Urology Research, LLC
Urology Associates
Metropolitan Urologic Services, PC
Urological Surgeons of Long Island
Southeast Urology Network
Urologic Surgeons, Ltd
Triangle Urological Group
Salt Lake Research
Urology, PC
University of Pennsylvania/Division of Urology
Anne Arundel Urology, PA
Kansas City Urology Care, PA
Hope Research Institute, LLC
Med Atlantic (dba Virginia Urology)
Columbia Urological Associates, PA
Parkhurst Research Organization, LLC
The Urological Institute of Northeastern New York
Urologic Northwest Surgeons, PS
Central New York Urology, PC
Metropolitan Urological Specialists
Urology Consultants (c/o DMI Research)
Delaware Valley Urology, LLC
Demaur Clinical Research Center
Urology Research Options
Adult and Pediatric Urology, PLLP
Lake Success Urological Associates
The Urology Center of Colorado
Urology of Northern Ohio
Urology Associates, PC
Capital Urology
University Urology Associates
Asheboro Urology Clinic
University of Tennessee, Department of Urology
Midwest Urology and Radiation Oncology
Florida Urology Specialists
Connecticut Surgical Group, PC
Central Jersey Clinical Research
University Health Network–Princess Margaret Hospital
Prostate Centre
Urology Associates/Urologic Medical Research
Urology South Shore Research
The Male Health Centre
Roger Buckley, MD
The Fe/Male Health Centres
Stanley Flax Medical Professional Corp
City
State/Territory
Akron
Austin
Towson
Atlanta
Chesterfield
Las Vegas
Staten Island
Raleigh
Baltimore
New Port Richey
Dallas
Brick
Panama City
Springfield
Monroesville
Marietta
Columbus
Nashville
Elmont
Garden City
Memphis
Reno
Pittsburgh
Salt Lake City
Lincoln
Philadelphia
Annapolis
Overland Park
Phoenix
Richmond
Columbia
Bethany
Albany
Tacoma
Oneida
Florissant
Pinellas Park
Mt Laurel
Pembroke Pines
Aurora
Sartell
Lake Success
Denver
Elyria
Manhasset
Columbus
New York
Asheboro
Memphis
Independence
Sarasota
Hartford
Edison
Toronto
OH
TX
MD
GA
MO
NV
NY
NC
MD
FL
TX
NJ
FL
OR
PA
GA
OH
TN
NY
NY
TN
NV
PA
UT
NE
PA
MD
KS
AZ
VA
SC
OK
NY
WA
NY
MO
FL
NJ
FL
CO
MN
NY
CO
OH
NY
OH
NY
NC
TN
MO
FL
CT
NJ
ON
Kitchener
Greenfield Park
Toronto
Willowdale
Oakville
Toronto
ON
QC
ON
ON
ON
ON
(continued on following page)
www.jco.org
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
9
Taneja et al
Table A1. Investigators and Investigation Sites (continued)
PI Last Name
PI First Name
Jansz
Khonsari
Kinahan
Liquornik
Love
Mathur
Patrick
Woods
Steinhoff
Chetner
Rendon
Siemens
Donnelly
Eiley
Tanguay
Perrotte
Ken
Homa
Thomas J.
Morrie S.
William R.
Arun
Allan
Edward
Gary
Michael P.
Richardo A.
D. Robert
Bryan
David
Simon
Paul
Maillette
Izawa
Damia
Damia
Becher
Balbiani
Kobelinsky
Rossi
Alain
Johnathan
Omar
Oscar
Edgardo
Luis R.
Marcelo
Daniel
Practice
G. Kenneth Jansz Medicine Professional Corp
Male/Female Health and Research Centre
Southern Interior Medical Research
Mor Urology
Urology Resource Centre
Urotec
Allan B. Patrick, MD, Professional Corporation
The Health Institute for Men
Dr G. Steinhoff Clinical Research
Alberta Urology Institute Research Centre
Queen Elizabeth Health Sciences Centre
Centre for Advanced Urological Research
Prostate Cancer Institute
Ultra-Med
McGill Urology Associates
Les Urologues Associés du Centre Hospitalier de
l’Université de Montréal
Groupe de Recherche en Urologie de la Mauricie
London Health Sciences Centre
Hospital Pirovano
Hospital Italiano de Buenos Aires
Centro Urologico Buenos Aires
Sanatorio Municipal
Policlinico Bancario de Buenos Aires
SEDU (Servicio de Urología)
City
State/Territory
Burlington
Barrie
Kelowna
Newmarket
Burlington
Oshawa
Fredericton
Toronto
Victoria
Edmonton
Halifax
Kingston
Calgary
Pointe-Claire
Montreal
Montreal
ON
ON
BC
ON
ON
ON
NB
ON
BC
AB
NS
ON
AB
QC
QC
QC
Trois-Rivières
London
QC
ON
Abbreviations: AB, Alberta; BC, British Columbia; NS, Nova Scotia; ON, Ontario; PI, primary investigator; QC, Quebec.
10
© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.