Radical prostatectomy or external beam radiation therapy versus no local therapy for survival benefit in metastatic prostate cancer: a SEER-Medicare analysis

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1

Radical Prostatectomy or External Beam Radiation
Therapy versus No Local Therapy for Survival Benefit in
Metastatic Prostate Cancer - A SEER-Medicare Analysis

by

Raj Satkunasivam

A thesis submitted in conformity with the requirements for the degree of Masters of
Science in Clinical, Biomedical and Translational Investigations
Department of Preventive Medicine, University of Southern California
Degree Conferral: August 2015

© Copyright by Raj Satkunasivam, 2015

2

Table of Contents
Acknowledgements
.....................................................................................................................................................
3

List of Abbreviations
..................................................................................................................................................
4

Abstract
...........................................................................................................................................................................
5

Introduction
....................................................................................................................................................................
6

Materials and Methods
...............................................................................................................................................
7

Study Subjects
..........................................................................................................................................................
7

Outcome Measures, Treatment Categories and Covariates
......................................................................
7

Propensity Score Adjustment
..............................................................................................................................
9

Statistical Analysis
...............................................................................................................................................
10

Results
...........................................................................................................................................................................
11

Discussion
....................................................................................................................................................................
13

Conclusions
.................................................................................................................................................................
16

Tables
............................................................................................................................................................................
17

Figures
..........................................................................................................................................................................
28

References
...................................................................................................................................................................
32

3

Acknowledgements

I would like to firstly thank my wife, Nadia, for her unwavering support and
patience during my graduate work. I drew much strength from her and our two children,
Aidan and Laila.
The application of the statistical methods used in this project could not have been
achieved without the persistent support of Andre E. Kim, whom I have had the privilege
to be a co-graduate student with. The support and guidance of many others was necessary
for the successful completion of this Thesis. Firstly, my supervisors Drs. Inderbir S. Gill
and Mariana C. Stern provided much needed guidance, and the necessary leadership.
Lastly, the critical thinking and contributions of others, including Drs. Mike M. Nguyen,
Mihir M. Desai, Ann S. Hamilton, Juan Pablo Lewinger, Monish Aron, David I. Quinn,
and Leslie Ballas were of tremendous help for this project.
I would also like to acknowledge the efforts of the Applied Research Program,
NCI; the Office of Research, Development and Information, CMS; Information
Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results
(SEER) Program tumour registries in the creation of the SEER-Medicare database and for
their generous assistance in individually auditing cases for this study.

4

List of Abbreviations

MPCa – Metastatic Prostate Cancer
RP – Radical Prostatectomy
IMRT – Intensity Modulated Radiation Therapy
CRT – Conformal Radiation Therapy
NLT – No Local Therapy
CCI – Charlson Comorbidity Index
ADT – Androgen Deprivation Therapy
ACM – All Cause Mortality
PCSM – Prostate Cancer Specific Mortality
SEER - Surveillance Epidemiology and End Results
HR – Hazard Ratio
SHR – Sub Hazard Ratio

5

Abstract

Purpose: To assess survival following radical prostatectomy (RP), intensity modulated
radiation therapy (IMRT) or conformal radiation therapy (CRT) versus no local therapy
(NLT) for metastatic prostate cancer (MPCa), adjusting for patient comorbidity, androgen
deprivation therapy (ADT) and other factors.
Materials and Methods: Men ≥66 with MPCa undergoing treatment by RP, IMRT, CRT
or NLT identified from SEER-Medicare linked database (2004–2009). Multivariable Cox
proportional hazards models, before and after inverse propensity score weighting, were
used to assess all cause and PCa specific mortality. Competing risk regression analysis
was used to assess PCa specific mortality.
Results: Among 4069 men with MPCa, RP (n=47), IMRT (n=88), CRT (n=107) were
selected as local therapy versus NLT (n=3827). RP was associated with a 52% (HR: 0.48,
95% CI: 0.27-0.85) reduction in the risk of PCa specific mortality, after adjusting for
socio-demographic, primary tumour characteristics, comorbidity, ADT and bone
radiation within 6 months of diagnosis. IMRT was associated with a 62% (HR: 0.38, 95%
CI: 0.24-0.61) reduction in the risk of PCa specific mortality, respectively. CRT was not
associated with improved survival compared to NLT. Propensity score weighting yielded
comparable results. Competing risk analysis revealed a 42% (SHR: 0.58, 95% CI: 0.35-
0.95) and 57% (SHR: 0.43, 95% CI: 0.27-0.68) reduction in the risk of PCa specific
mortality for RP and IMRT.
Conclusions: Local therapy with RP and IMRT, but not CRT, was associated with a
survival benefit in MPC and warrants prospective evaluation in clinical trials.

6

Introduction

The standard of care for metastatic prostate cancer (MPCa) is continuous
androgen deprivation therapy (ADT) (Hussain et al., 2013; Loblaw et al., 2007). A
secondary analysis of SWOG 8894 suggesting radical prostatectomy (RP) prior to MPCa
was associated with a decreased risk of death implicated a potential role for local
therapy(Thompson, Tangen, Basler, & Crawford, 2002). Recent population based studies
utilizing the Surveillance Epidemiology and End Results (SEER) database have
demonstrated a potential survival benefit to RP in MPCa(Antwi & Everson, 2014; Culp,
Schellhammer, & Williams, 2014; Fossati et al., 2014).
Population-based studies have not assessed the role of intensity modulated
radiation therapy (IMRT) or conformal radiation therapy (CRT) for local treatment in
MPCa. Further, these studies have not investigated the differential utilization of androgen
deprivation therapy (ADT) and patient comorbidity, which can dictate treatment selection
and confound the relationship between treatment type and survival. To disentangle the
relationship between these factors and survival we utilized the SEER-Medicare linked
database to assess survival outcomes of RP, IMRT, CRT and no local treatment (NLT)
for MPCa.

7

Materials and Methods

Study Subjects
The SEER registry captures 28% of the US population and contains information
on patient demographics, tumour characteristics and choice of primary treatment
modality(Hankey, Ries, & Edwards, 1999). Linkage to Medicare, which provides
benefits to 97% of Americans aged ≥65 years, offers additional treatment data, including
therapies administered in the outpatient setting such as ADT (Fleming et al., 2012;
Warren, Klabunde, Schrag, Bach, & Riley, 2002).
We identified a source population (N= 240,663) based on the International
Classification of Diseases for Oncology (third edition, code 8140) of the prostate (site
code 61.9) diagnosed between 2004-2009. Figure 1 details the exclusion process to
optimize data reliability. MPCa was defined by radiographic and/or pathologic
confirmation of metastatic cancer (SEER-collaborative stage) as per the American Joint
Committee on Cancer (AJCC) Cancer Staging Manual 6
th
.

Outcome Measures, Treatment Categories and Covariates
The outcomes of interest were all cause mortality (ACM) and PCa specific
mortality (PCSM). Survival time was determined from registry vital statistics from the
date of diagnosis to the date of death, last known to be alive or last follow-up (December
2010), whichever occurred first. Patients receiving intensity-modulated radiotherapy
(IMRT) or conformal radiotherapy (CRT) were identified from Medicare inpatient,
outpatient, and carrier component files based on Current Procedural Terminology, Fourth
Edition (CPT-4) codes as previously described using prostate diagnosis codes for

8

treatment claims(Goldin et al., 2013). Patients with ≤15 treatment claims were excluded
as this likely represented palliative radiation (e.g. bone) or treatment for local symptom
control(Cameron, Kersten, Guren, Fosså, & Vistad, 2014). The practice pattern for
palliative radiation varies, however, we selected a cut-off of 15, which represents the
largest number of fractions reported from published randomized trials on palliative
regimes(Ellsworth et al., 2014; Wu et al., 2003). We also identified patients who
received EBRT to bone within 6 months of diagnosis as a marker of advanced disease.
RP was defined using SEER surgery site codes 50 or 70(Culp et al., 2014). In order to
assess possible discrepancies between SEER and Medicare data on treatment
assignment(Noone et al., 2014), we also identified patients that underwent RP using
Medicare billing codes(Hu et al., 2009). Accuracy of staging and treatment for each
individual RP patient (n=47) was re-confirmed by directly contacting SEER registry
directors for repeat patient-to-patient data reconfirmation. On review of 228 cases
identified from SEER (2004-2010) as having metastatic PCa and receiving RP, 65% were
confirmed as correct after registry audits, with individual registries varying from 45-
100% with respect to accuracy of classification (Figure 2). Patients receiving NLT for
PCa never received RP, EBRT, brachytherapy(Goldin et al., 2013), or prostate
cryotherapy (CPT-4 code 55873)(Roberts et al., 2011).
Covariates of interest included age at diagnosis (years, continuous), race (African
American, Hispanic, Non-Hispanic White, Asian and Other/Unknown), marital status
(single, married, unknown or other), year of diagnosis (categorical 2004-2009), pre-
treatment PSA (highest recorded, continuous and categorical), Gleason score and clinical
AJCC staging from registry data. Approximately 15% of patients had unknown PSA

9

values. In order to ensure that missing PSA was non-informative, PSA was assessed as a
categorical variable with an unknown category. PSA was also assessed as continuous
variable after excluding unknown values, however, a sensitivity analysis showed
comparable effect estimates (data not shown). Specifically, for Gleason score, we used
the SEER Collaborative Stage Site-Specific Factor 6 grade variable, categorized as well
(≤ 4) or moderately differentiated (5–6), intermediate (7) and poor (≥ 8) differentiated. A
validated algorithm was used to derive the Charlson comorbidity index (CCI) from
claims one year prior to the diagnosis of MPCa(Klabunde, Potosky, Legler, & Warren,
2000). Lastly, androgen deprivation therapy (ADT) exposure was determined as
previously reported(Shahinian, Kuo, Freeman, & Goodwin, 2005). Specifically, ADT
exposure in this study included administration of GnRH agonists 3 months before to 12
months after diagnosis, or bilateral orchiectomy within 3 months of diagnosis.

Propensity Score Adjustment
In observational studies there can be significant bias introduced by inherent
differences between patients based on treatment selection. In order to decrease the risk of
biased estimates of treatment effect, we computed propensity scores by multinomial
logistic regression with a four-level outcome variable (RP, IMRT, CRT or NLT) with
predictor variables age at diagnosis, year of diagnosis, race, marital status, pre-treatment
PSA (categorical), clinical tumour stage and grade, CCI, ADT use and bone radiation
within 6 months of diagnosis. Propensity scores were then utilized for inverse propensity
score weighted adjustment in the final cox proportional hazards models (Austin, 2011).

10

Statistical Analysis
Differences between the distributions of socio-demographic and primary tumour
factors according to RP, IMRT, CRT and NLT were examined using the Chi-square test.
The hazard function of overall survival and PCa specific survival by treatment type was
described using the Kaplan–Meier method. Cox proportional hazard models were fitted to
assess the crude and adjusted hazard ratios (HRs) comparing RP, IMRT and CRT to NLT
for ACM and PCSM. Covariates that were a priori deemed clinically important were
mutually adjusted in multivariable models; the final adjusted model included registry, age
at diagnosis, year of diagnosis, race, marital status, PSA, Gleason grade, AJCC T, N and
M staging, CCI, and bone radiation within 6 months.
We hypothesized that ADT might modify the effect of treatment modality on
survival, however, interaction (likelihood ratio test) was not significant (p=0.1) and ADT
was included as a covariate in the final model. The proportional hazards assumption was
satisfied in all variables except for ADT, where there was statistically significant
interaction with time. Modeling ADT as a time-varying covariate did not significantly
change the effect estimates (data not shown).
Given the possibility that Cox proportional hazard regression estimates of disease
specific survival can overestimate risk, we also performed competing risk regression
analysis to compute sub hazard ratios (SHR) as described by Fine and Gray(Berry, Ngo,
Samelson, & Kiel, 2010; Fine & Gray, 1999). All statistical analyses were performed
using SAS version 9.4 (SAS Inc, Cary, NC, USA) and Stata S/E 12.1 (Stata Corporation,
College Station, TX). A p-value < 0.05 was considered statistically significant.

11

Results

A total of 4069 cases with MPCa were identified as receiving RP (n = 47), IMRT
(n=88), CRT (n=107) or NLT (n=3827). Total treatments by claim number for CRT
(median: 23 [IQR: 19-30]) was less than for IMRT (median: 38 [IQR: 28-42], p<0.001).
RP and IMRT groups were younger, had lower pre-treatment PSA, lower Gleason score,
lower stage AJCC T and N stage compared to CRT and NLT (Table 1). The metastatic
AJCC stage distribution between the treatment groups was relatively comparable.
Additionally, RP and IMRT groups were less likely to receive ADT or bone radiation
within 6 months of diagnosis (Table 1). The overall median follow up was 20 months
(IQR: 10-36) with a total of 2872 total deaths (71%), of which 2058 (72%) deaths were
attributable to PCa.
RP and IMRT when compared to NLT were associated with 57% (HR: 0.43, 95%
CI: 0.26-0.70) and 55% (HR: 0.45, 95% CI: 0.31-0.65) lower risk of ACM respectively,
after adjusting for socio-demographic, primary tumour characteristics, CCI, ADT and
bone radiation within 6 months of diagnosis (Table 2). The adjusted PCa specific
mortality was 52% (HR: 0.48, 95% CI: 0.27-0.85) and 62% (HR: 0.38, 95% CI: 0.24-
0.61) lower in patients undergoing RP and IMRT respectively, compared to NLT (Table
2). In contrast, CRT compared to NLT, was not associated with lower risk of death from
prostate cancer (HR: 0.85, 95% CI: 0.64-1.14). IMRT and CRT as a combined category
was associated with a decreased risk of PCSM (HR: 0.64, 95% CI: 0.50-0.82. Older age,
higher PSA, more aggressive primary tumour pathology (AJCC Stage), increasing CCI
and bone radiation within 6 months of diagnosis were independently associated with
increase risk of PCSM. The 3-year overall survival rate was 73% for RP, 72% for IMRT,

12

37% for CRT, and 34% for NLT (Figure 3A). The 3-year disease specific survival rate
was 79% for RP, 82% for IMRT, 49% for CRT, and 46% for NLT (Figure 3B).
Using Medicare billing codes, we identified 39 patients with MPCa as receiving
RP. RP and IMRT when compared to NLT were associated with 66% (HR: 0.34, 95% CI:
0.15-0.76) and 62% (HR: 0.38, 95% CI: 0.24-0.61) adjusted lower risk of death from
prostate cancer, respectively (data not shown).
Competing risk regression analysis showed that RP (SHR: 0.58, 95% CI: 0.35-
0.95) and IMRT (SHR: 0.43, 95% CI: 0.27-0.68) were associated with decreased risk of
PCSM compared to NLT (Table 3). Increasing age, PSA, Gleason score, more advanced
primary tumour pathology (AJCC Stage), and bone radiation within 6 months of
diagnosis were associated with PCSM.
After propensity score adjustment, RP compared to NLT was associated with a
45% lower risk of PCSM (HR: 0.55, 95% CI: 0.30-1.02), although not statistically
significant (Table 4). IMRT was associated with a 53% decreased risk of PCSM (HR:
0.47, 95% CI: 0.31-0.72). There was no statistically significant evidence of interaction
between local treatment type and CCI, PSA, metastatic stage, ADT exposure, age and
bone radiation within 6-months with respect to ACM and PCSM. As these variables are
of clinical interest, exploratory analyses were undertaken by relevant subsets, although
limited in sample size in several groups. RP was associated with improved PCSM (HR:
0.07, 95% CI: 0.02-0.23) in the subset of patients with PSA ≤ 20, whereas the same
protective association was not observed in those with PSA > 20. A consistent pattern was
not observed after subsets by age, Charlson comorbidity index, metastatic stage and by
ADT exposure.

13

Discussion

To our knowledge, this is the first population-based study examining the
outcomes of RP in comparison to two modalities of external beam radiation therapy
(IMRT and CRT) or no local treatment in MPCa. Additionally, in contrast to past studies
(Antwi & Everson, 2014; Culp et al., 2014), we adjusted for important confounders of
survival in the metastatic setting by using billing derived patient comorbidity, receipt of
ADT and early (<6 month) bone radiation as a marker of advanced disease. After
accounting for these and conventional risk factors, RP and IMRT were associated with a
52% and 62% reduction in the risk of PCa specific mortality, respectively. Similar results
were seen after propensity score adjustment and competing risk analysis.
Our results remain consistent with earlier SEER based analyses, which also
suggested a benefit to RP and brachytherapy (Antwi & Everson, 2014; Culp et al., 2014).
The observation that IMRT but not CRT was associated with improved ACM and PSCM
may be indicative that patients receiving CRT have more advanced tumour burden, worse
tumour biology and higher comorbidity that are inadequately measured and controlled for
by the variables we have utilized in this retrospective study. In contemporary practice,
CRT may be viewed as non-definitive therapy, used in the setting of MPCa for local
symptom control, wherein lower doses and treatments are delivered(Cameron et al.,
2014). Consistent with this, we observed a nearly two-fold lower number of treatment
claims for CRT compared to IMRT.
The SEER-Medicare database provides important claims derived patient
variables, however, there are important limitations. This cohort consists of men > 65

14

years of age and hence these results may not be broadly generalizable. Further, errors in
coding can occur in large databases like SEER and can be more problematic in studies
involving small study samples(Nguyen & Gill, 2010). However, in this study, men
undergoing RP were all individually confirmed to have the correct staging and treatment
by registry audits. Nonetheless, while the same protective effect of RP was observed
when treatment was classified by Medicare billing codes, the discrepancy between SEER
and Medicare highlights the need for prospective evaluation and caution related to
accuracy of stage and treatment classification. Other limitation of the data include
uncertainty regarding radiation doses and whether radiation was indeed delivered to the
prostate and not elsewhere (e.g. bone). Further, critical variables including imaging
results (e.g bone scan), lab values (e.g. PSA response to ADT) and baseline pain scores,
which are necessary to define the metastatic burden, were not available. Moreover, the
receipt of docetaxel based chemotherapy, immunotherapy or novel androgen receptor
pathway targeted agents after the development of castrate-resistant PCa is unknown and
can differentially impact survival if one group receives aggressive treatment. Taken
together, selection bias may be driving the conclusions about RP and IMRT, reflecting
residual confounding due to the lack critical variables that can be measured, but also
concerns about the reliability and quality of measurements, such as comorbidity from
claims based data(Stattin & Loeb, 2014). Despite accounting for the receipt of early bone
radiation as a marker of advanced disease, the most important selection bias that remains
is metastatic burden. It remains possible that the survival benefit observed for RP and
IMRT is purely on the basis of having less or slowly progressing metastatic deposits than
patients whom underwent no local therapy. Despite these limitations, the consistency in

15

findings for ACM and PCSM using traditional multivariable, propensity-weighted and
competing risk analyses warrants further investigation.
Adoption of local treatment in MPCa must be judicious as the treatments
themselves increase the risk of surgical morbidity and can be detrimental to health related
quality of life. Recent data for RP in the setting of MPCa supports its feasibility with
acceptable functional outcomes as well as decreased need for percutaneous or surgical
interventions for local tumour growth(Heidenreich, Pfister, & Porres, 2014). The
mechanism and underlying tumour biology that explains a potential oncologic benefit
remains unknown, however, there are several hypotheses. First, eradication of the
primary tumour eliminates the source of cytokine signalling that prepares niches for
eventual sites of metastases and promotes their growth(Psaila & Lyden, 2009). Second,
the primary tumour may remain a source of circulating tumour cells that are capable of
“self-seeding” the primary organ (Kim et al., 2009). Lastly, local therapy may eradicate
self-renewing progenitor cells persisting after ADT which have been shown to have a
immature luminal, androgen receptor low phenotype and are capable of propagating
adenocarcinoma(Stoyanova et al., 2013). Moving forward, at the very least, tissue
banking RP specimens after ADT may facilitate studies of tumour and progenitor cell
biology(Tzelepi et al., 2011) including the use of high throughput genomic and
transcriptome analyses to improve patient prognosis and eventually develop targeted
therapy.

16

Conclusions

Local therapy with RP or IMRT but not CRT compared to no local treatment was
associated with decreased risk of all cause and prostate cancer specific mortality, after
accounting for patient comorbidity, ADT exposure and receipt of early palliative bone
radiation. These results should be viewed as hypothesis generating as the lack of
information on metastatic disease burden is a critical caveat in this analysis. Future
prospective trials are crucial and must aim to access health related quality of life as well
as oncological benefits to local therapy.

17

Tables

Table 1. Socio-demographics, tumour characteristics, comorbidity, ADT use and receipt
of bone radiation within 6 months among men with metastatic prostate cancer (N=4069)
that received radical prostatectomy (RP), intensity modulated radiation therapy (IMRT),
conformal radiation therapy (CRT), or No Local Treatment (NLT). Percentages are
shown in parenthesis. One-way ANOVA (PSA and log-transformed age) and two-tailed
chi-square tests were used to test the hypothesis that at least one of the
proportions/distribution of covariates is different by treatment type. Note that 595
patients (~15%) have unknown PSA values and are not included in continuous
description of PSA.

18

RP IMRT CRT NLT p-value
47 88 107 3827

Year of Diagnosis – N (%)

2004 6 (13) 12 (14) 21 (20) 709 (19) 0.2
2005 5 (11) 9 (10) 26 (24) 692 (18)

2006 7 (15) 14 (16) 21 (20) 667 (17)

2007 11 (23) 21 (24) 16 (15) 619 (16)

2008 10 (21) 18 (20) 14 (13) 580 (15)

2009 8 (17) 14 (16) 9 (8) 560 (15)

Age at Diagnosis

Mean (SD) 73.0 (6.0) 74.2 (6.1) 76.4 (6.3) 78.2 (7.2) < 0.001
Race – N (%)

NHW 38 (81) 75 (85) 81 (76) 2925 (76) 0.5
AA 7 (15) 9 (10) 13 (12) 608 (16)

Hisp 0 (0) 2 (2) 3 (3) 95 (2)

Asian 2 (4) 1 (1) 6 (6) 103 (3)

Other/Unknown 0 (0) 1 (1) 4 (4) 96 (3)

Marital Status – N (%)

Single 2 (4) 10 (11) 6 (6) 408 (11) 0.1
Married 35 (74) 60 (68) 68 (64) 2248 (59)

Separated/divorced/widowed/do
mestic partners
9 (19) 12 (14) 27 (25) 933 (24)

Unknown 1 (2) 6 (7) 6 (6) 238 (6)

PSA – N (%)

< 10 ng/ml 25 (53) 35 (40) 9 (8) 401 (10) < 0.001
10-19 ng/ml 6 (13) 16 (18) 20 (19) 449 (12)

20-29 ng/ml 3 (6) 10 (11) 9 (8) 286 (7)

≥ 30 ng/ml 6 (13) 17 (19) 55 (51) 2127 (56)

Unknown 7 (15) 10 (11) 14 (13) 564 (15)

PSA (Continuous)

Mean (SD) 181 (263) 282 (338) 531 (369) 590 (380) < 0.001

Gleason Score – N (%)

≤6 5 (11) 10 (11) 8 (7) 167 (4) < 0.001
7 22 (47) 24 (27) 22 (21) 569 (15)

≥8 19 (40) 43 (49) 59 (55) 2042 (53)

Unknown 1 (2) 11 (13) 18 (17) 1049 (27)

T Stage – N (%)

T1 0 (0) 27 (31) 31 (29) 839 (22) < 0.001

19

T2 21 (45) 36 (41) 28 (26) 1282 (33)

T3 19 (40) 10 (11) 9 (8) 298 (8)

T4 6 (13) 9 (10) 17 (16) 461 (12)

Unknown 1 (2) 6 (7) 22 (21) 947 (25)

N Stage – N (%)

N0 34 (72) 59 (67) 63 (59) 1930 (50) < 0.001
N1 10 (21) 11 (13) 15 (14) 577 (15)

NX 3 (6) 18 (20) 29 (27) 1320 (34)

M Stage – N (%)

M1a 3 (6) 4 (5) 4 (4) 190 (5) 0.2
M1b 26 (55) 65 (74) 72 (67) 2570 (67)

M1c 17 (36) 16 (18) 31 (29) 922 (24)

M1 NOS 1 (2) 3 (3) 0 (0) 145 (4)

Charlson Comorbidity Index – N
(%)
0 32 (68) 60 (68) 67 (63) 2462 (64) 0.9
1 9 (19) 19 (22) 25 (23) 757 (20)

2 4 (9) 4 (5) 10 (9) 331 (9)

≥3 2 (4) 5 (6) 5 (5) 277 (7)

Androgen Deprivation Therapy –
N (%)
None 27 (57) 30 (34) 13 (12) 1132 (30) < 0.001
Orchiectomy 3 (6) 0 (0) 5 (5) 331 (9)

GnRH Agonist 16 (34) 56 (64) 88 (82) 2330 (61)

Both 1 (2) 2 (2) 1 (1) 34 (1)

Bone Radiation Within 6 mo of
Diagnosis – N (%)

No 47 (100) 86 (98) 99 (93) 3420 (89) 0.005
Yes 0 (0) 2 (2) 8 (7) 407 (11)

20

Table 2. Crude and adjusted probability of all cause and prostate cancer specific
mortality after local treatment for metastatic prostate cancer. Hazard Ratios (HR) are
adjusted for treatment group (NLT, CRT, IMRT and RP), age, year of diagnosis, race,
marital status, PSA, Gleason score, AJCC staging (TNM), Charlson Comorbidity Index,
androgen deprivation therapy, receipt of bone radiation within 6 months of diagnosis and
registry. The model for prostate cancer specific mortality treats non-prostate cancer
deaths as censored observations.

Table 2.
Characteristic N All-Cause Mortality P value
Prostate Cancer
Specific Mortality
P
value

Adjusted HR (95%
CI)

Adjusted HR (95% CI)

Treatment

NLT 3827 1.0 (Ref)

1.0 (Ref)

CRT 107 0.90 (0.70-1.14) 0.4 0.85 (0.64-1.14) 0.3
IMRT 88 0.45 (0.31-0.65) < 0.001 0.38 (0.24-0.61) < 0.001
RP 47 0.43 (0.26-0.72) 0.001 0.48 (0.27-0.85) 0.01
Age

5 yr. increment 4069 1.17 (1.14-1.20) < 0.001 1.12 (1.09-1.16) < 0.001
Year of Diagnosis

2004
748 1.0 (Ref)

1.0 (Ref)

2005
732 1.05 (0.93-1.18)
0.4
1.07 (0.93-1.22)
0.4
2006
709 0.98 (0.87-1.11)
0.8
1.05 (0.91-1.20)
0.5
2007
667 0.95 (0.84-1.08)
0.4
0.90 (0.78-1.05)
0.2
2008
622 0.98 (0.85-1.12)
0.7
1.03 (0.88-1.21)
0.7
2009
591 0.88 (0.75-1.04)
0.1
0.87 (0.72-1.06)
0.2
Race

NHW
3,119 1.0 (Ref)

1.0 (Ref)

AA
637 0.97 (0.86-1.08)
0.6
0.94 (0.83-1.08)
0.4
Hispanic
100 1.11 (0.87-1.43)
0.4
1.08 (0.80-1.47)
0.6
Asian
112 0.79 (0.61-1.02)
0.1
0.78 (0.57-1.06)
0.1
Other/Unknown
101 0.89 (0.68-1.16)
0.4
0.75 (0.54-1.05)
0.1
Marital Status

21

Single 426 1.0 (Ref) 1.0 (Ref)
Married 2411 0.72 (0.64-0.82) < 0.001 0.77 (0.66-0.89) < 0.001
Separated/Divorced/Wid
owed
981 0.80 (0.70-0.91) 0.001 0.82 (0.70-0.96) 0.01
Unknown 251 0.70 (0.57-0.84) < 0.001 0.69 (0.55-0.88) 0.002
PSA

< 10 ng/ml 470 1.0 (Ref) 1.0 (Ref)
10-19 ng/ml 491 1.08 (0.92-1.28) 0.3 1.03 (0.84-1.25) 0.8
20-29 ng/ml 308 1.04 (0.87-1.25) 0.7 1.04 (0.84-1.30) 0.7
30+ ng/ml 2205 1.25 (1.09-1.42) 0.001 1.29 (1.10-1.51) 0.002
Unknown 595 1.16 (0.99-1.35) 0.07 1.10 (0.91-1.32) 0.3
Gleason Score

≤6 190 1.0 (Ref) 1.0 (Ref)
7 637 0.99 (0.81-1.22) 0.9 1.12 (0.86-1.47) 0.4
≥8 2163 1.39 (1.15-1.68) 0.001 1.72 (1.35-2.21) < 0.001
Unknown 1079 1.59 (1.30-1.94) < 0.001 1.92 (1.48-2.49) < 0.001
T Stage

T1 897 1.0 (Ref) 1.0 (Ref)
T2 1367 1.09 (0.98-1.21) 0.1 1.15 (1.01-1.31) 0.03
T3 336 1.10 (0.94-1.30) 0.2 1.05 (0.87-1.28) 0.6
T4 493 1.30 (1.13-1.48) < 0.001 1.35 (1.15-1.58) < 0.001
Unknown 976 1.35 (1.19-1.54) < 0.001 1.34 (1.14-1.57) < 0.001
N Stage

N0 2086 1.0 (Ref) 1.0 (Ref)
N1 613 1.15 (1.03-1.29) 0.02 1.15 (1.01-1.32) 0.04
NX 1370 1.07 (0.97-1.17) 0.17 1.09 (0.98-1.21) 0.13
M Stage

M1a 201 1.0 (Ref) 1.0 (Ref)
M1b 2733 1.59 (1.29-1.94) < 0.001 1.86 (1.44-2.40) < 0.001
M1c 986 1.93 (1.57-2.39) < 0.001 2.25 (1.72-2.93) < 0.001
M1 NOS 149 1.69 (1.28-2.23) < 0.001 1.97 (1.40-2.77) < 0.001
Charlson Comorbidity
Index

0 2621 1.0 (Ref) 1.0 (Ref)
1 810 1.09 (0.99-1.20) 0.09 1.04 (0.93-1.16) 0.5
2 349 1.41 (1.24-1.61) < 0.001 1.21 (1.03-1.43) 0.02
≥3 289 1.85 (1.61-2.12) < 0.001 1.51 (1.27-1.79) < 0.001
Androgen Deprivation
Therapy

None 1202 1.0 (Ref) 1.0 (Ref)
Orchiectomy 339 0.82 (0.71-0.94) 0.006 0.87 (0.74-1.02) 0.09
GnRH Agonist 2490 0.68 (0.62-0.74) < 0.001 0.72 (0.65-0.80) < 0.001
Both 38 0.59 (0.40-0.87) 0.007 0.67 (0.44-1.04) 0.07
Bone Radiation Within 6
mos. of Diagnosis

No 3652 1.0 (Ref) 1.0 (Ref)

Yes 417 1.36 (1.21-1.53) < 0.001 1.53 (1.34-1.75) < 0.001

22

Table 3. Multivariable competing risk regression analysis by Fine and Gray method of
patients receiving local therapy for metastatic prostate cancer. Sub Hazard Ratios (SHR)
are reported after adjustment for treatment group (NLT, CRT, IMRT and RP), age, year
of diagnosis, race, marital status, PSA, Gleason score, AJCC staging (TNM), Charlson
Comorbidity Index, androgen deprivation therapy, receipt of bone radiation within 6
months of diagnosis and registry.

23

Table 3.

Characteristic N

Adjusted SHR (95%
CI)
P value

Treatment

NLT 3827

1.0 (Ref)

CRT
107

0.87 (0.65-1.18)
0.4
IMRT 88

0.43 (0.27-0.68) < 0.001
RP 47

0.58 (0.35-0.95)
0.03
Age Group

5 yr. increment
4069

1.05 (1.02-1.08)
0.003
Year of Diagnosis

2004
748 1.0 (Ref)

2005
732 1.06 (0.92-1.21)
0.4
2006
709 1.04 (0.91-1.19)
0.5
2007
667 0.83 (0.72-0.97)
0.02
2008
622 0.94 (0.81-1.10)
0.5
2009
591 0.73 (0.60-0.88)
0.001
Race

NHW
3,119 1.0 (Ref)

AA
637 0.97 (0.85-1.11)
0.7
Hispanic
100 0.96 (0.71-1.29)
0.8
Asian
112 0.82 (0.59-1.15)
0.3
Other/Unknown
101 0.71 (0.50-1.03)
0.07
Marital Status

Single 426

1.0 (Ref)

Married 2411

0.88 (0.76-1.02) 0.1
Separated/divorced/widowe
d
981

0.88 (0.75-1.04)
0.1
Unknown 251

0.77 (0.61-0.98)
0.04
PSA

< 10 ng/ml 470

1.0 (Ref)
10-19 ng/ml 491

1.01 (0.83-1.23)
0.9
20-29 ng/ml 308

1.06 (0.86-1.31) 0.6
30+ ng/ml 2205

1.26 (1.08-1.48)
0.003
Unknown 595

1.07 (0.89-1.29) 0.5
Gleason Score

≤6 190

1.0 (Ref)

7 637

1.14 (0.88-1.47)
0.3
≥8 2163

1.66 (1.32-2.10)
< 0.001
Unknown 1079

1.73 (1.35-2.22)
< 0.001
T Stage

24

T1 897

1.0 (Ref)

T2 1367

1.16 (1.02-1.31)
0.02
T3
336

0.97 (0.80-1.16)
0.7
T4 493

1.25 (1.07-1.46)
0.005
Unknown 976

1.23 (1.05-1.44)
0.009
N Stage

N0
2086

1.0 (Ref)

N1 613

1.13 (0.98-1.29) 0.08
NX
1370

1.07 (0.96-1.19)
0.2
M Stage

M1a 201

1.0 (Ref)

M1b 2733

1.76 (1.37-2.25)
< 0.001
M1c 986

1.93 (1.49-2.51)
< 0.001
M1 NOS
149

1.82 (1.29-2.56)
0.001
Charlson Comorbidity
Index

0
2621

1.0 (Ref)

1
810

1 (0.89-1.12)
> 0.9
2
349

1.01 (0.85-1.19)
> 0.9
≥3
289

1.06 (0.89-1.27)
0.5
Androgen Deprivation
Therapy

None
1202

1.0 (Ref)

Orchiectomy 339

1.01 (0.85-1.19) > 0.9
GnRH Agonist
2490

0.87 (0.78-0.97)
0.01
Both 38

0.91 (0.59-1.40) 0.7
Bone Radiation Within 6
mo of Diagnosis

No
3652

1.0 (Ref)

Yes
417

1.54 (1.34-1.77)
< 0.001

25

Table 4. Inverse propensity score weight adjusted probability of all cause mortality and
prostate cancer specific mortality in patients with metastatic prostate cancer at diagnosis.
Results are shown for full study cohort and after stratification by age, Charlson
Comorbidity Index, PSA level, metastatic stage and androgen deprivation therapy
exposure. Patients with unknown PSA levels or metastatic stage were excluded for
stratified analysis.

26

All-Cause Mortality P value

Prostate Cancer
Specific Mortality

Treatment Type N
Adjusted HR (95%
CI)

Adjusted HR (95%
CI)
P
value
Non-Stratified
NLT
3827
1.0 (Ref)

1.0 (Ref)

CRT 107 1.01 (0.73-1.39) 0.9 0.97 (0.66-1.43) 0.9
IMRT 88 0.57 (0.41-0.79) 0.001 0.47 (0.31-0.72) 0.001
RP 47 0.42 (0.18-0.96) 0.04 0.55 (0.30-1.02) 0.057

Stratified
Analyses

AGE

≤ 75
NLT 1400 1.0 (Ref) 1.0 (Ref)
CRT 49 1.15 (0.72-1.86) 0.6 1.26 (0.72-2.20) 0.4
IMRT 54 0.57 (0.37-0.88) 0.01 0.44 (0.25-0.76) 0.004
RP 35 0.76 (0.36-1.61) 0.5 1.12 (0.56-2.22) 0.8

> 75
NLT 2427 1.0 (Ref) 1.0 (Ref)
CRT 58 1.41 (0.96-2.08) 0.08 1.25 (0.80-1.97) 0.3
IMRT 34 0.54 (0.33-0.89) 0.02 0.41 (0.22-0.78) 0.006
RP 12 0.36 (0.11-1.20) 0.10 0.38 (0.16-0.89) 0.03

Charlson Comorbidity Index

< 2
NLT 3219 1.0 (Ref) 1.0 (Ref)
CRT 92 0.99 (0.72-1.36) > 0.9 0.98 (0.66-1.44) > 0.9
IMRT 79 0.41 (0.24-0.70) 0.001 0.34 (0.17-0.66) 0.002
RP 41 0.61 (0.26-1.46) 0.3 0.60 (0.28-1.29) 0.19

≥ 2
NLT 608 1.0 (Ref) 1.0 (Ref)
CRT 15 1.34 (0.35-5.13) 0.7 0.82 (0.25-2.63) 0.7
IMRT 9 0.61 (0.26-1.39) 0.2 0.62 (0.15-2.63) 0.5
RP 6 0.37 (0.16-0.83) 0.02 0.36 (0.15-0.88) 0.03

PSA

≤ 20
NLT 850 1.0 (Ref) 1.0 (Ref)
CRT 29 0.85 (0.47-1.55) 0.6 1.14 (0.56-2.31) 0.7
IMRT 51 0.61 (0.32-1.17) 0.1 0.40 (0.15-1.09) 0.07
RP 31 0.07 (0.02-0.24) < 0.001 0.07 (0.02-0.23) < 0.001

> 20
NLT 2413 1.0 (Ref) 1.0 (Ref)
CRT 64 1.50 (1.03-2.18) 0.03 1.29 (0.81-2.06) 0.3
IMRT 27 0.55 (0.35-0.86) 0.009 0.44 (0.27-0.74) 0.002
RP 9 0.69 (0.22-2.14) 0.5 0.62 (0.29-1.30) 0.2

27

Metastatic
Stage

M1a + M1b
NLT 2760 1.0 (Ref) 1.0 (Ref)
CRT 76 1.43 (0.97-2.12) 0.07 1.56 (1.03-2.35) 0.04
IMRT 69 0.69 (0.47-1.00) 0.051 0.60 (0.37-0.98) 0.04
RP 29 0.73 (0.27-1.93) 0.5 0.64 (0.32-1.30) 0.2

M1c
NLT 922 1.0 (Ref) 1.0 (Ref)
CRT 31 0.90 (0.57-1.44) 0.7 0.75 (0.40-1.41) 0.4
IMRT 16 0.48 (0.22-1.01) 0.054 0.37 (0.16-0.85) 0.02
RP 17 0.33 (0.13-0.82) 0.017 0.34 (0.12-0.95) 0.04

Androgen Deprivation Therapy

No
NLT 1132 1.0 (Ref) 1.0 (Ref)
CRT 13 1.14 (0.62-2.11) 0.7 1.34 (0.67-2.66) 0.4
IMRT 30 0.60 (0.34-1.08) 0.09 0.54 (0.23-1.27) 0.2
RP 27 0.78 (0.30-2.04) 0.6 0.83 (0.31-2.27) 0.7

Yes
NLT 2695 1.0 (Ref) 1.0 (Ref)
CRT 94 1.21 (0.86-1.71) 0.3 1.10 (0.75-1.61) 0.6
IMRT 58 0.55 (0.37-0.82) 0.003 0.43 (0.25-0.72) 0.002
RP 20 0.47 (0.24-0.92) 0.03 0.82 (0.45-1.50) 0.5

28

Figures

Figure 1. Exclusion criteria utilized to derive the final study cohort from the SEER-
Medicare linked database (2004-2009).

!
Patients( Reason(for(Exclusion(
( (
62,398! Age!at!diagnosis!younger!than!65!years!
8,990! Pathology!not!consistent!with!adenocarcinoma!
5,108! Not!first!and!only!malignancy!
1,068! Invalid!diagnosis!month!
1,550! Louisiana!registry!in!2005!
294!
Diagnosis!obtained!from!death!certificate,!autopsy,!or!
nursing/convalescent!home/hospice!
! !
! !
! !
154,584! NonH metastatic!disease!
1,631! With!HMO!coverage!1!year!prior!diagnosis!
819! Without!Part!A/B!Medicare!coverage!1!year!prior!diagnosis!
12! Prostate!Cryotherapy!
49! Prostate!Brachytherapy!
5! CRT!+!IMRT!
86! Censored!at!study!entry!
Prostate!Cancer!(61.9)!
17!SEER!Registries,!2004H
2009:!
!
240,663!patients!
Prostate!cancer,!age!≥!
65!years!
!
161,255!patients!
Final!study!population!
!
4,069!patients!
Radical!Prostatectomy!(RP)!
n!=!47!
Intensity!Modulated!Radiation!
Therapy!(IMRT)!!
n!=!88!
Conformal!Radiotherapy!(CRT)!!
n!=!107!
No!Local!Treatment!(NLT)!
n!=!3,827!

29

Figure 2. Distribution of patients correctly coded with respect to metastatic stage and
receipt of radical prostatectomy sorted by individual SEER registry (SEER 2004-2010
Dataset).

30

Figure 3. Kaplan-Meier survival curve of all cause mortality (A) and prostate-cancer
specific mortality (B) in patients with metastatic prostate cancer treated by RP, IMRT,
CRT or NLT. Curves have been adjusted for treatment group (NLT, CRT, IMRT and
RP), age, year of diagnosis, marital status, PSA, Gleason score, AJCC staging (TNM),
Charlson Comorbidity Index, androgen deprivation therapy, receipt of bone radiation
within 6 months of diagnosis and registry.

31

32

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Asset Metadata

Creator Satkunasivam, Raj (author)

Core Title Radical prostatectomy or external beam radiation therapy versus no local therapy for survival benefit in metastatic prostate cancer: a SEER-Medicare analysis

Contributor Electronically uploaded by the author (provenance)

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 07/16/2015

Defense Date 06/20/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag intensity-modulated,mortality,OAI-PMH Harvest,Prostatectomy,prostatic neoplasms,Radiotherapy,SEER program

Format application/pdf (imt)

Language English

Advisor Lewinger, Juan Pablo (committee chair), Stern, Mariana C. (committee chair), Aron, Monish (committee member), Gill, Inderbir (committee member)

Creator Email raj.satkunasivam@gmail.com,rsatkuna@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-595743

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Abstract (if available)

Abstract Purpose: To assess survival following radical prostatectomy (RP), intensity modulated radiation therapy (IMRT) or conformal radiation therapy (CRT) versus no local therapy (NLT) for metastatic prostate cancer (MPCa), adjusting for patient comorbidity, androgen deprivation therapy (ADT) and other factors. ❧ Materials and Methods: Men ≥66 with MPCa undergoing treatment by RP, IMRT, CRT or NLT identified from SEER-Medicare linked database (2004–2009). Multivariable Cox proportional hazards models, before and after inverse propensity score weighting, were used to assess all cause and PCa specific mortality. Competing risk regression analysis was used to assess PCa specific mortality. ❧ Results: Among 4069 men with MPCa, RP (n=47), IMRT (n=88), CRT (n=107) were selected as local therapy versus NLT (n=3827). RP was associated with a 52% (HR: 0.48, 95% CI: 0.27-0.85) reduction in the risk of PCa specific mortality, after adjusting for socio-demographic, primary tumour characteristics, comorbidity, ADT and bone radiation within 6 months of diagnosis. IMRT was associated with a 62% (HR: 0.38, 95% CI: 0.24-0.61) reduction in the risk of PCa specific mortality, respectively. CRT was not associated with improved survival compared to NLT. Propensity score weighting yielded comparable results. Competing risk analysis revealed a 42% (SHR: 0.58, 95% CI: 0.35-0.95) and 57% (SHR: 0.43, 95% CI: 0.27-0.68) reduction in the risk of PCa specific mortality for RP and IMRT. ❧ Conclusions: Local therapy with RP and IMRT, but not CRT, was associated with a survival benefit in MPC and warrants prospective evaluation in clinical trials.