Author's Accepted Manuscript Regular Transition Zone Biopsy during Active Surveillance for Prostate Cancer may Improve Detecting Pathological Progression Lih-Ming Wong, Ants Toi, Theodorus Van der Kwast, Greg Trottier, Shabbir M.H. Alibhai, Narhari Timilshina, Andrew Evans, Alexandre Zlotta, Neil Fleshner, Antonio Finelli PII: DOI: Reference:

S0022-5347(14)03336-9 10.1016/j.juro.2014.04.010 JURO 11388

To appear in: The Journal of Urology Accepted Date: 7 April 2014 Please cite this article as: Wong LM, Toi A, Van der Kwast T, Trottier G, Alibhai SMH, Timilshina N, Evans A, Zlotta A, Fleshner N, Finelli A, Regular Transition Zone Biopsy during Active Surveillance for Prostate Cancer may Improve Detecting Pathological Progression, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.04.010. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.

ACCEPTED MANUSCRIPT Regular Transition Zone Biopsy during Active Surveillance for Prostate Cancer may Improve Detecting Pathological Progression. Lih-Ming Wonga, Ants Toib, Theodorus Van der Kwastc, Greg Trottier, Shabbir M.H. Alibhaid, Narhari Timilshinad, Andrew Evansc, Alexandre Zlotta, Neil

RI PT

Fleshner, Antonio Finelli.

Cancer Center, University Health Network.

Department of Urology, St Vincent's Hospital and Austin Health, University of

M AN U

a

Melbourne, Australia. b

SC

Department of Uro-oncology, Division of Surgical Oncology, Princess Margaret

Department of radiology, Princess Margaret Hospital, University of Toronto,

Canada. c Department

of Pathology, Toronto General Hospital, University of Toronto,

of Medicine, University of Toronto, Canada.

EP

d Department

TE D

Canada.

Corresponding author:

AC C

Lih-Ming Wong

[email protected] +14169462851

Department of Surgical Oncology, Division of Urologic Oncology 3-130, Princess Margaret Cancer Centre 610 University Avenue Toronto, M5G 2M9, Canada

ACCEPTED MANUSCRIPT MeSH terms: prostate cancer, biopsy, active surveillance, transition zone, pathology, reclassification, grade progression

RI PT

Running head: Routine transition zone biopsy on Active Surveillance

-

Abstract: 250

-

Manuscript: 2495

SC

Word count:

M AN U

We disclose that an abstract from this manuscript was presented at the 2013 American Urological Association Annual meeting but has not been submitted or

AC C

EP

TE D

published anywhere else.

ACCEPTED MANUSCRIPT Abstract: Purpose We investigate the frequency of cancer and pathological progression found in

RI PT

transition zone (TZ) biopsies in men undergoing multiple re-biopsy while on AS.

Materials and Methods:

Our tertiary center AS prostate cancer database (1997-2012) has eligibility

SC

criteria: PSA ≤10, ≤cT2, no Gleason grade 4 or 5, ≤ 3 positive cores, no core >50% involved, age ≤ 75 years and having ≥1 biopsy after initial diagnostic biopsy. For

M AN U

analysis, men with total 24 months after B1, were excluded. Multiparametric magnetic resonance imaging was performed selectively to investigate incongruity between PSA and biopsy findings.

TE D

Pathological progression was defined as grade and/or volume (>50% core involved). TZ progression was subdivided into exclusive-TZ (only TZ) and

EP

combination TZ (both TZ and PZ). A multivariate Cox proportional hazards

AC C

model examined for predictors of TZ progression.

Results

392 men were considered, with a median follow-up of 45.5 months. At each biopsy during AS (B2-B5+), the frequency of TZ disease was: TZ positive cores (18.6-26.7%), all TZ-progression (5.9-11.1%) and exclusive TZ-progression (2.76.7%). Volume-related progression occurred more frequently than grade-related (n=24 versus 9). Predictors of exclusive-TZ progression were maximum % single

ACCEPTED MANUSCRIPT core (HR 1.99, C.I. 1.30-3.04, p=0.002), and MRI reporting cancer (HR 3.19, C.I. 1.23-8.27, p=0.02).

Conclusions

RI PT

Across multiple AS biopsies, 2.7-6.7% of men had TZ-exclusive progression. We recommend TZ biopsy be considered in all men at confirmatory biopsy.

Subsequently, positive MRI findings or high % core involvement may be useful to

AC C

EP

TE D

M AN U

SC

identify patients at risk.

ACCEPTED MANUSCRIPT Introduction The conventional biopsy template reported in active surveillance (AS) cohorts is the standard extended template (SET), which only samples the peripheral zone (PZ) (1-6). Prostate cancer is located in the PZ in 70-85% of cases with the

RI PT

remaining cancers located in the transition zone (TZ)(7). Review of established AS cohorts found only one recent series mentioning routine sampling of the TZ

using a Babaian-type template since 2001(9).

SC

(8). At our institution, the TZ has been routinely sampled during AS re-biopsy

M AN U

The TZ is easily accessible with standard transrectal ultrasound prostate biopsy (TRUSPB). However, the TZ is not routinely sampled because evidence from the diagnostic biopsies suggests that the yield for TZ cancer detection is low (10) and thus is best performed in the setting of prior negative TRUSPB(11). The

TE D

situation is different for men on AS. Having already been diagnosed with cancer, consideration of unsampled regions such as the TZ, which could potentially

EP

harbor significant cancer, necessitates a shift in the diagnostic focus of TRUSPB.

AC C

Information from radical prostatectomy series suggests the incidence of TZ tumors is 24-29%, of which 11.6-17.8% are the index (largest) tumor (7, 12). Multifocality with concomitant PZ tumors is common (65-85%). While TZ tumors are often associated with higher serum prostate specific antigen (PSA) and can be of large volume, they are often described to have lower Gleason scores, lower rates of extraprostatic extension and seminal vesicle invasion, and less risk of positive surgical margins when compared to PZ tumors of similar

ACCEPTED MANUSCRIPT volume. When present, positive surgical margins often involve the bladder neck and anterior fibromuscular zones (12).

In a cohort of men on AS having routine prostate re-biopsy, we investigated the

RI PT

impact of routine TZ biopsy by examining both amount of cancer and adverse

SC

pathology found in the TZ.

M AN U

Methods

Patients were identified from our tertiary referral centre AS database (19972012) at Princess Margaret Cancer Center (PMCC). Institutional ethics review board approval was obtained. Eligibility criteria included PSA 50% involved, age ≤ 75 years and ≥1 prostatic re-biopsy after diagnosis

EP

(n=622). Men who had < 10 cores in total (n=99) at diagnostic biopsy (B1), and/or a confirmatory (second biopsy) more than 24 months after B1 (n=131),

AC C

were excluded as these groups fall outside current acceptable standards for AS. Thus a total of 392 men were included for analysis.

TRUSPB were taken in a standard manner using an end-fire probe (C9-5 ICT, Philips, Bothwell, WA) under local anesthesia. A single operator (AT) performed most of the biopsies (75%). Biopsy cores collected were labeled by region sampled (e.g. left medial PZ). Cancer location was captured systematically together with other clinical pathological variables. For the baseline diagnostic

ACCEPTED MANUSCRIPT biopsy, a standard extended template (10-12 cores) was taken, sampling only the PZ. For subsequent re-biopsies, an AS protocol template (ASPT) modeled on Babaian et al, of 13-17 cores was taken(9). Whilst some diagnostic biopsies were performed outside our institution, all follow-up biopsies are performed in-house.

RI PT

The ASPT samples lateral and medial PZ, TZ and midline at the base of the

prostate (Fig. 1). TZ biopsies were directed at the thickest part of the prostate in the immediate paraurethral region. Operator discretion was used in deciding if 1

SC

or 2 TZ cores from each side were taken, for a total of 2-4 TZ cores. In addition to this systematic schema, extra cores of suspicious ultrasonographic areas may be

M AN U

taken.

Follow-up of patients on AS at our institution consists of PSA and digital rectal examination (DRE) 3 monthly for 2 years and then 6 monthly if stable. We do not

TE D

have a mandatory immediate confirmatory biopsy policy but it is recommended to patients within 12 months of initial biopsy, with re-biopsy every 1-3 years

EP

until the patient reaches 80 years of age or declines active treatment. “For cause” biopsy is allowed at the treating urologist’s discretion, often triggered by either

AC C

rising PSA or abnormal DRE. Multi-parametric MRI was utilized selectively to examine for anterior tumors, when PSA and biopsy findings differed (13).

By submission of biopsy cores from each location in a separate container labeled accordingly, men with TZ-cancer and TZ-pathological progression could be identified at each AS biopsy. Pathological progression for TZ cancers was defined as findings of GS≥7 (grade) and/or >50% single core involved (volume) on subsequent AS biopsy. Core involvement by cancer was visually estimated. For

ACCEPTED MANUSCRIPT cores with discontinuous cancer foci, core involvement was reported as percentage of total core length occupied by cancer. Benign prostate parenchyma between cancer foci was not included in the determination of the extent of core involvement. Number of positive cores (PCore >3) was not used as a measure

RI PT

for volume progression because it was felt that increasing total number of cores taken (by biopsying TZ) would increase the likelihood of finding cancer and thus

SC

affect over-estimate reporting of progression.

Men with disease progression in the TZ biopsies were sub-divided into 2 groups,

M AN U

“exclusive-TZ” and “combination-TZ” progression. “Combination-TZ” progression describes progression occurring in both TZ and PZ biopsies, and if no TZ biopsy was taken, the patient would have progressed on the basis of his PZ biopsy regardless. “Exclusive-TZ” progression only occurred in the TZ biopsies

TE D

and hence if the TZ had not been biopsied, these men would have been falsely reassured. The term grade-related progression was used to describe men with

EP

grade-only (GS≥7) and grade-and-volume progression (GS≥7 and >50% single core involvement). Volume-related progression described volume-only (>50%

AC C

single core involvement) and volume-and-grade progression.

Differences between groups were determined using the ANOVA or the Chisquared test. Important clinical and pathological variables were first analyzed using univariate analysis. Multivariate models were built using Cox proportional hazards with forward stepwise regression technique. Men were censored if they progressed, elected to have treatment without progression or were lost to follow-up. All statistical tests were two sided with p50% core involved) and location of progression (combination-TZ/PZ or exclusive-TZ). A total of 47 men had pathological progression in the TZ biopsies, of which 66.0% (n=31/47) occurred exclusively

RI PT

in the TZ. TZ grade-related progression occurred in 18 men, with 7 exclusively in the TZ. The GS breakdown for these 7 cases was 3+4 (n=6) and 4+3 (n=1)

respectively. For exclusive-TZ progression, volume-related progression occurred

SC

more frequently than grade (n=22 versus n=7 respectively, n=2 both volume and

M AN U

grade).

Multivariable analysis using Cox proportional hazards regression was performed to identify predictors of: TZ cancer, all-TZ progression and exclusive-TZ progression. Significant variables are summarized in Table 4, with the full

TE D

models included as supplementary tables. Maximum percentage of a single core involved was statistically significant in predicting exclusive-TZ progression (HR

EP

1.99, C.I. 1.30-3.04, p=0.002) and positive TZ biopsy cores (HR 1.88, C.I. 1.001.05, p=0.02). MRI diagnosing cancer was statistically significant in predicting

AC C

exclusive-TZ progression (HR 3.19, C.I. 1.23-8.27, p=0.02) and combination (TZ and PZ) progression (HR 1.76, C.I. 1.07-2.89, p=0.03). Total number of rebiopsies performed after B2 was associated with a lower risk of developing TZ cancer (HR 0.60, 0.47-0.77, p