Author's Accepted Manuscript Patterns of Local Failure Following Radiation Therapy for Prostate Cancer Mohamed Jalloh , Michael S. Leapman , Janet E. Cowan , Katsuto Shinohara , Kirsten L. Greene , Mack Roach , III, Albert J. Chang , June M. Chan , Jeffry P. Simko , Peter R. Carroll
PII: DOI: Reference:
S0022-5347(15)03944-0 10.1016/j.juro.2015.04.111 JURO 12607
To appear in: The Journal of Urology Accepted Date: 22 April 2015 Please cite this article as: Jalloh M, Leapman MS, Cowan JE, Shinohara K, Greene KL, Roach M III, Chang AJ, Chan JM, Simko JP, Carroll PR, Patterns of Local Failure Following Radiation Therapy for Prostate Cancer, The Journal of Urology® (2015), doi: 10.1016/j.juro.2015.04.111. 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.
Embargo Policy All article content is under 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. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT 1
Patterns of Local Failure Following Radiation Therapy for Prostate Cancer
2
Mohamed Jalloh MDa,e, Michael S. Leapman MDa,d, Janet E. Cowan MAa, Katsuto Shinohara
3
MDa,d, Kirsten L. Greene MD, MSa,d, Mack Roach III MDb,d, Albert J. Chang MD, PhDb,d,
4
June M. Chan ScDa,c, Jeffry P. Simko MD, PhDa,d, Peter R. Carroll MD, MPHa,d
5
Departments of a Urology, bRadiation Oncology, and cEpidemiology & Biostatistics, University of
6
California San Francisco (UCSF); dUCSF Helen Diller Family Comprehensive Cancer Center,
7
San Francisco, CA; eService d’Urologie-Andrologie, Hopital General de Grand Yoff, Dakar, Senegal
8
23
EP
Abstract word count: 241
TE D
Corresponding author: Peter R. Carroll, MD MPH 550 16th Street, Box 1695 San Francisco, CA 94143-1695 Telephone: 415-353-7098 Fax: 415-353-9932 E-mail:[email protected]
Text word count: 2,498
Keywords: prostate cancer, radiation, transrectal ultrasound, prostate biopsy
AC C
9 10 11 12 13 14 15 16 17 18 19 20 21 22
M AN U
SC
RI PT
1
ACCEPTED MANUSCRIPT 2
Abstract:
25
Introduction: Little is known about patterns of local failure following radiation therapy (RT) for
26
prostate cancer (PCa). We aimed to characterize post-radiation biopsy (PRB) findings, including
27
the presence of treatment effect, and the zonal distribution of recurrent disease after RT in men
28
experiencing biochemical recurrence (BCR).
29
Materials and Methods: We identified patients who received PRB in the setting of BCR
30
following primary radiation for localized disease. Histologic PRB results were categorized by
31
the absence of tumor, demonstration of radiation treatment effect, failure (recurrent cancer), or a
32
combination of treatment effect and failure. We describe patterns of histologic failure and
33
compared them to the diagnostic biopsy findings.
34
Results: 284 underwent mapped PRB for BCR. Mean age at initial diagnosis was 63 years,
35
median PSA was 8.2 ng/ml; 33% of men were classified as low, 32% intermediate, and 35%
36
high risk, based on clinical CAPRA categories. Median time to PRB was 61 months post-
37
treatment and findings were negative in 4%, treatment effect in 31%, failure in 45%, and a
38
combination in 20%. Failure rates were similar across sextants. Among 140 patients with
39
mapped pre-and post-treatment biopsies, 4% demonstrated cancer in a new location previously
40
identified as negative. Gleason upgrading occurred in 43%, with 85% upgraded ≥ 4+3.
41
Conclusions: Men with rising PSA after radiotherapy for PCa most often recur in dominant
42
tumor sites. Whether failure is due to inadequate targeting, dosing or intrinsic radiation
43
resistance remains unknown, and further study is warranted.
SC
M AN U
TE D
EP
AC C
44 45
RI PT
24
Introduction
ACCEPTED MANUSCRIPT 3
In the United States, prostate cancer is the most commonly diagnosed non-cutaneous
47
male cancer and the second-leading cancer related cause of death [1]. Widespread use of prostate
48
specific antigen (PSA) screening has resulted in dramatic stage migration favoring detection of
49
early stage disease [2]. The most common definitive treatment strategies include radical
50
prostatectomy (RP) and various forms of radiation therapy (RT). Following RT, the definition of
51
disease recurrence is controversial as reflected by the redefinition of biochemical recurrence on
52
several occasions: in 1996, the American Society of Therapeutic and Radiation Oncologists
53
(ASTRO) defined biochemical recurrence after RT for prostate cancer as three consecutive PSA
54
rises from the nadir backdated halfway between the nadir and first rise in PSA [3]. This
55
definition may be more relevant for patients who have undergone RT without hormonal
56
treatment (and therefore spared the PSA recovery rise that may be associated with testosterone
57
recovery) and is not a universal surrogate for clinical progression or survival [4]. Since 2005, the
58
Phoenix definition of biochemical recurrence, which identifies a PSA rise > 2 ng/mL from nadir
59
with or without hormonal therapy, has become widely accepted as a superior predictor of clinical
60
outcomes including systemic progression and cancer-specific mortality [5].
TE D
M AN U
SC
RI PT
46
Causes of local radiation failure—be they intrinsic tissue radio-resistance, inadequacy of
62
dosing and/or delivery—are yet unknown. These answers hold relevance for both selection of
63
primary treatment and for management of recurrence. Patients with biochemical failure often are
64
referred for prostate biopsy, where studies have demonstrated a wide range of histologic failure
65
rates and patterns of recurrence depending on the PSA threshold for prostate biopsy (PRB).
66
Though some insights have been offered by studies with protocoled biopsy in patients after RT
67
and via salvage surgery, little is known regarding the patterns of local failure, particularly in
68
relation to the initially perceived dominant tumor focus [6, 7]. Thus, we aimed to describe
AC C
EP
61
ACCEPTED MANUSCRIPT 4
69
biopsy findings at diagnosis and following biochemical recurrence (BCR), with respect to tumor
70
localization,
histologic
upgrade,
and
the
presence
of
radiation
treatment
effect.
71
73
Materials and Methods
RI PT
72
This study assessed men who underwent transrectal ultrasound (TRUS) guided biopsy between 2002 and 2012 in response to persistently rising PSA levels after primary RT for
75
prostate cancer. Study participants were patients biopsied by a single provider (KS) at University
76
of California San Francisco (UCSF). Patients received radiotherapy with brachytherapy and /or
77
external beam radiation treatment at UCSF or at referring external institutions. No patients
78
received androgen deprivation therapy (ADT) within six months of biopsy. Data were abstracted
79
and analyzed under institutional review board supervision. We described age at start of
80
treatment, race, and clinical characteristics at diagnosis (PSA, tumor stage, biopsy Gleason grade
81
and extent). Clinical risk at diagnosis was defined using Cancer of the Prostate Risk Assessment
82
(CAPRA) groupings for low (0-2), intermediate (3-5), or high (6-10) risk disease [8]. Primary
83
RT groups were brachytherapy alone (BT), external beam radiation (EBRT), or a combination
84
(BT+EBRT). Patients receiving BT monotherapy were treated with a prescription dose of 144
85
Gy2, while those receiving combination BT+EBRT received a primary implant dose of 90 or 108
86
Gy2 based on isotope. Patients treated with primary EBRT alone received a prescription dose of
87
72-74 Gy2 depending on treatment year. Treatment plans were available for 211 patients (74%).
M AN U
TE D
EP
AC C
88
SC
74
Prostate biopsy findings were mapped for bilateral apex, mid-gland, base, anterior, and
89
seminal vesicle locations using an extended sampling template of a minimum of 14 cores. We
90
described diagnostic biopsy findings as well as PRB results, defined as negative (absent tumor
91
architecture in all locations), treatment effect (adenocarcinoma with radiation effect; no Gleason
ACCEPTED MANUSCRIPT 5
score assigned), failure (viable carcinoma without any radiation effect; Gleason score assigned),
93
or a combination (areas with some mild degree of treatment effect and failure; Gleason score
94
assigned based on the area without treatment effect) (Figure 1). Secondary analyses compared
95
diagnostic and PRB findings, as well as rates of upgrade ≥ 3+4 and adjoining positive locations
96
compared to the diagnostic biopsy in a subset of patients with mapped results at both biopsies. Logistic regression models were used to evaluate the association between RT group (BT,
SC
97
RI PT
92
EBRT, BT+EBRT) and failure (i.e. positive finding without treatment effect) at follow-up
99
biopsy, adjusted for age, diagnostic PSA and Gleason grade, PSA at PRB, time from RT to PRB,
100
and radiation provider site (UCSF versus referring institutions). Model covariates were selected
101
a priori and some related variables were excluded due to poor distribution, missing data or
102
collinearity (clinical T-stage, prostate volume, percentage of positive biopsy cores, ADT
103
duration, year of RT). After 2005, BCR after primary RT was defined using the Phoenix
104
definition [5]. A p-value
PII: DOI: Reference:
S0022-5347(15)03944-0 10.1016/j.juro.2015.04.111 JURO 12607
To appear in: The Journal of Urology Accepted Date: 22 April 2015 Please cite this article as: Jalloh M, Leapman MS, Cowan JE, Shinohara K, Greene KL, Roach M III, Chang AJ, Chan JM, Simko JP, Carroll PR, Patterns of Local Failure Following Radiation Therapy for Prostate Cancer, The Journal of Urology® (2015), doi: 10.1016/j.juro.2015.04.111. 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.
Embargo Policy All article content is under 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. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT 1
Patterns of Local Failure Following Radiation Therapy for Prostate Cancer
2
Mohamed Jalloh MDa,e, Michael S. Leapman MDa,d, Janet E. Cowan MAa, Katsuto Shinohara
3
MDa,d, Kirsten L. Greene MD, MSa,d, Mack Roach III MDb,d, Albert J. Chang MD, PhDb,d,
4
June M. Chan ScDa,c, Jeffry P. Simko MD, PhDa,d, Peter R. Carroll MD, MPHa,d
5
Departments of a Urology, bRadiation Oncology, and cEpidemiology & Biostatistics, University of
6
California San Francisco (UCSF); dUCSF Helen Diller Family Comprehensive Cancer Center,
7
San Francisco, CA; eService d’Urologie-Andrologie, Hopital General de Grand Yoff, Dakar, Senegal
8
23
EP
Abstract word count: 241
TE D
Corresponding author: Peter R. Carroll, MD MPH 550 16th Street, Box 1695 San Francisco, CA 94143-1695 Telephone: 415-353-7098 Fax: 415-353-9932 E-mail:[email protected]
Text word count: 2,498
Keywords: prostate cancer, radiation, transrectal ultrasound, prostate biopsy
AC C
9 10 11 12 13 14 15 16 17 18 19 20 21 22
M AN U
SC
RI PT
1
ACCEPTED MANUSCRIPT 2
Abstract:
25
Introduction: Little is known about patterns of local failure following radiation therapy (RT) for
26
prostate cancer (PCa). We aimed to characterize post-radiation biopsy (PRB) findings, including
27
the presence of treatment effect, and the zonal distribution of recurrent disease after RT in men
28
experiencing biochemical recurrence (BCR).
29
Materials and Methods: We identified patients who received PRB in the setting of BCR
30
following primary radiation for localized disease. Histologic PRB results were categorized by
31
the absence of tumor, demonstration of radiation treatment effect, failure (recurrent cancer), or a
32
combination of treatment effect and failure. We describe patterns of histologic failure and
33
compared them to the diagnostic biopsy findings.
34
Results: 284 underwent mapped PRB for BCR. Mean age at initial diagnosis was 63 years,
35
median PSA was 8.2 ng/ml; 33% of men were classified as low, 32% intermediate, and 35%
36
high risk, based on clinical CAPRA categories. Median time to PRB was 61 months post-
37
treatment and findings were negative in 4%, treatment effect in 31%, failure in 45%, and a
38
combination in 20%. Failure rates were similar across sextants. Among 140 patients with
39
mapped pre-and post-treatment biopsies, 4% demonstrated cancer in a new location previously
40
identified as negative. Gleason upgrading occurred in 43%, with 85% upgraded ≥ 4+3.
41
Conclusions: Men with rising PSA after radiotherapy for PCa most often recur in dominant
42
tumor sites. Whether failure is due to inadequate targeting, dosing or intrinsic radiation
43
resistance remains unknown, and further study is warranted.
SC
M AN U
TE D
EP
AC C
44 45
RI PT
24
Introduction
ACCEPTED MANUSCRIPT 3
In the United States, prostate cancer is the most commonly diagnosed non-cutaneous
47
male cancer and the second-leading cancer related cause of death [1]. Widespread use of prostate
48
specific antigen (PSA) screening has resulted in dramatic stage migration favoring detection of
49
early stage disease [2]. The most common definitive treatment strategies include radical
50
prostatectomy (RP) and various forms of radiation therapy (RT). Following RT, the definition of
51
disease recurrence is controversial as reflected by the redefinition of biochemical recurrence on
52
several occasions: in 1996, the American Society of Therapeutic and Radiation Oncologists
53
(ASTRO) defined biochemical recurrence after RT for prostate cancer as three consecutive PSA
54
rises from the nadir backdated halfway between the nadir and first rise in PSA [3]. This
55
definition may be more relevant for patients who have undergone RT without hormonal
56
treatment (and therefore spared the PSA recovery rise that may be associated with testosterone
57
recovery) and is not a universal surrogate for clinical progression or survival [4]. Since 2005, the
58
Phoenix definition of biochemical recurrence, which identifies a PSA rise > 2 ng/mL from nadir
59
with or without hormonal therapy, has become widely accepted as a superior predictor of clinical
60
outcomes including systemic progression and cancer-specific mortality [5].
TE D
M AN U
SC
RI PT
46
Causes of local radiation failure—be they intrinsic tissue radio-resistance, inadequacy of
62
dosing and/or delivery—are yet unknown. These answers hold relevance for both selection of
63
primary treatment and for management of recurrence. Patients with biochemical failure often are
64
referred for prostate biopsy, where studies have demonstrated a wide range of histologic failure
65
rates and patterns of recurrence depending on the PSA threshold for prostate biopsy (PRB).
66
Though some insights have been offered by studies with protocoled biopsy in patients after RT
67
and via salvage surgery, little is known regarding the patterns of local failure, particularly in
68
relation to the initially perceived dominant tumor focus [6, 7]. Thus, we aimed to describe
AC C
EP
61
ACCEPTED MANUSCRIPT 4
69
biopsy findings at diagnosis and following biochemical recurrence (BCR), with respect to tumor
70
localization,
histologic
upgrade,
and
the
presence
of
radiation
treatment
effect.
71
73
Materials and Methods
RI PT
72
This study assessed men who underwent transrectal ultrasound (TRUS) guided biopsy between 2002 and 2012 in response to persistently rising PSA levels after primary RT for
75
prostate cancer. Study participants were patients biopsied by a single provider (KS) at University
76
of California San Francisco (UCSF). Patients received radiotherapy with brachytherapy and /or
77
external beam radiation treatment at UCSF or at referring external institutions. No patients
78
received androgen deprivation therapy (ADT) within six months of biopsy. Data were abstracted
79
and analyzed under institutional review board supervision. We described age at start of
80
treatment, race, and clinical characteristics at diagnosis (PSA, tumor stage, biopsy Gleason grade
81
and extent). Clinical risk at diagnosis was defined using Cancer of the Prostate Risk Assessment
82
(CAPRA) groupings for low (0-2), intermediate (3-5), or high (6-10) risk disease [8]. Primary
83
RT groups were brachytherapy alone (BT), external beam radiation (EBRT), or a combination
84
(BT+EBRT). Patients receiving BT monotherapy were treated with a prescription dose of 144
85
Gy2, while those receiving combination BT+EBRT received a primary implant dose of 90 or 108
86
Gy2 based on isotope. Patients treated with primary EBRT alone received a prescription dose of
87
72-74 Gy2 depending on treatment year. Treatment plans were available for 211 patients (74%).
M AN U
TE D
EP
AC C
88
SC
74
Prostate biopsy findings were mapped for bilateral apex, mid-gland, base, anterior, and
89
seminal vesicle locations using an extended sampling template of a minimum of 14 cores. We
90
described diagnostic biopsy findings as well as PRB results, defined as negative (absent tumor
91
architecture in all locations), treatment effect (adenocarcinoma with radiation effect; no Gleason
ACCEPTED MANUSCRIPT 5
score assigned), failure (viable carcinoma without any radiation effect; Gleason score assigned),
93
or a combination (areas with some mild degree of treatment effect and failure; Gleason score
94
assigned based on the area without treatment effect) (Figure 1). Secondary analyses compared
95
diagnostic and PRB findings, as well as rates of upgrade ≥ 3+4 and adjoining positive locations
96
compared to the diagnostic biopsy in a subset of patients with mapped results at both biopsies. Logistic regression models were used to evaluate the association between RT group (BT,
SC
97
RI PT
92
EBRT, BT+EBRT) and failure (i.e. positive finding without treatment effect) at follow-up
99
biopsy, adjusted for age, diagnostic PSA and Gleason grade, PSA at PRB, time from RT to PRB,
100
and radiation provider site (UCSF versus referring institutions). Model covariates were selected
101
a priori and some related variables were excluded due to poor distribution, missing data or
102
collinearity (clinical T-stage, prostate volume, percentage of positive biopsy cores, ADT
103
duration, year of RT). After 2005, BCR after primary RT was defined using the Phoenix
104
definition [5]. A p-value
