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Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer
Brachytherapy
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(2016)
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Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer Yu-Wei Chen1, Vinayak Muralidhar2, Brandon A. Mahal3, Michelle D. Nezolosky1, Clair J. Beard1, Toni K. Choueiri4, Karen E. Hoffman5, Neil E. Martin1, Peter F. Orio1, Christopher J. Sweeney4, Felix Y. Feng6,7,8, Quoc-Dien Trinh9, Paul L. Nguyen1,* 1
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA 2 Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 3 Department of Medicine, Brigham and Women’s Hospital, Boston, MA 4 Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA 5 Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX 6 Department of Radiation Oncology, University of California, San Francisco, CA 7 Department of Urology, University of California, San Francisco, CA 8 Department of Medicine, University of California, San Francisco, CA 9 Department of Surgery, Division of Urology, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston, MA
ABSTRACT
PURPOSE: Androgen deprivation therapy (ADT) has been shown to improve survival for men with unfavorable-risk prostate cancer (PCa). We investigated the utilization and factors associated with the omission of ADT in radiation-managed high-risk PCa. METHODS AND MATERIALS: We used the National Cancer Database to identify men with National Comprehensive Cancer Network high-risk PCa treated with external beam radiation therapy (EBRT) with or without brachytherapy boost from 2004 to 2012. Multivariable logistic regression adjusting for clinical and sociodemographic factors was used to identify independent predictors for ADT use. RESULTS: A total of 57,968 radiation-treated high-risk PCa men were included in our analysis. There were 49,363 patients (85.2%) treated with EBRT alone and 8605 patients (14.8%) treated with EBRT plus brachytherapy boost. Overall, 77% of men received ADT. In multivariable regression analysis, the use of brachytherapy boost was associated with a significantly lower utilization of ADT (70% vs. 78%; adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62e0.69; p-Value !0.0001), as was treatment at an academic vs. nonacademic center (AOR: 0.90; 95% CI: 0.86e0.95; p-Value !0.0001) and treatment in 2010e2012 compared to 2004e2006 (AOR: 0.85; 95% CI: 0.81e 0.90; p-Value !0.0001). Conversely, greater ADT use was seen with higher Gleason scores, PSA, and T-category (all p-Values !0.001). CONCLUSIONS: Approximately one in four men with radiation-managed high-risk PCa do not receive ADT, which may reflect concerns about its toxicity profile despite known improvements in overall survival. Practice patterns suggest that some providers believe dose escalation through brachytherapy boost may obviate the need for ADT in some high-risk patients, but this hypothesis requires further testing. Ó 2016 Published by Elsevier Inc. on behalf of American Brachytherapy Society.
Keywords:
Brachytherapy boost; Androgen deprivation therapy; High-risk prostate cancer; Prostate neoplasm
Received 14 June 2016; received in revised form 3 July 2016; accepted 8 July 2016. Conflict of interest: PLN consulted for Medivation, Ferring, Genome DX, and Nanobiotix. FYF has consulted for Medivation, Astellas, Celgene, and GenomeDx Biosciences. Financial disclosure: This work is supported by Prostate Cancer Foundation, Fitz’s Cancer Warriors, David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, the Scott Forbes and Gina Ventre Fund, Jeffrey Campbell in Honor of Joan Campbell, and a grant from an anonymous family foundation. Author contributions: All authors participated in some way to the conception and design of this study. All authors also participated in the drafting and critical revision of this manuscript. All authors also contributed to some aspect of the technical, administrative, or material support of this manuscript. Y-WC and PLN had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. * Corresponding author. 75 Francis St., Boston, MA 02115. Tel.: þ1-617-732-7936; fax: þ1-617-975-0912. E-mail address: [email protected] (P.L. Nguyen). 1538-4721/$ - see front matter Ó 2016 Published by Elsevier Inc. on behalf of American Brachytherapy Society. http://dx.doi.org/10.1016/j.brachy.2016.07.001
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Introduction Although not in all, androgen deprivation therapy (ADT) in combination with external beam radiation therapy (EBRT) has been shown to improve overall survival for men with high-risk prostate cancer (PCa) in several studies (1e3). However, the potential adverse effects (4) of ADT are considerable and might deter clinicians from prescribing ADT and patients from receiving it (5). In this study, we aim to investigate the trends of ADT use in radiation-treated high-risk PCa in the contemporary US population using the US National Cancer Database (NCDB) (6). We also aim to identify the factors associated with the omission of ADT.
Methods and materials Data source and study population We used the NCDB, a joint program of the Commission on Cancer and the American Cancer Society, to select our study population. NCDB is the largest cancer registry worldwide (6), and it captures 70% of the newly diagnosed cases in the United States. Men diagnosed with National Comprehensive Cancer Network’s nonmetastatic high-risk (7) PCa (PSA O20 ng/mL or Gleason $ 8 or clinical tumor stage $ T3) in 2004e2012 were identified, and men who received EBRT with or without brachytherapy boost as the definitive treatment were included in our study. Of note, we restricted our study population to patients with only PCa diagnosis and excluded patients with multiple cancers. We also excluded patients with unavailable prostate-specific antigen (PSA), Gleason score, or tumor stage to ensure precisely defined National Comprehensive Cancer Network’s high-risk disease. Figure 1 summarized the study cohort selection process.
Fig. 1. Study population selection process. NCCN 5 National Comprehensive Cancer Network; NCDB 5 National Cancer Database; PSA 5 prostate-specific antigen.
United States Department of Agriculture Economic Research Service. Statistical analysis Descriptive statistics were used to present the baseline characteristics. Categorical variables were compared with c2 test, and continuous variables were compared by Wilcoxon rank-sum test. ManteleHaenszel c2 analysis for trend was used to examine ADT use over the study period. A multivariable logistic regression model was used to identify independent predictors for omission of ADT. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). We used a two-sided p-Value !0.05 in all analyses as criteria for statistical significance.
Primary end point and determinants The primary end point was to identify factors associated with the omission of ADT. Clinical factors in this study included PSA (!10, 10e20, O20 ng/mL), Gleason score (#6, 7, 8e10), tumor stage, and Charlson comorbidity score (0, 1, $2). Consistent with a recent prior publication, ‘‘favorable high-risk disease’’ (8) was defined as stage T1c with Gleason score 4 þ 4 5 8 and PSA !10 ng/mL or stage T1c with Gleason 6 and PSA O20 ng/mL. Sociodemographic factors included age (!65, $65 years), race (non-Hispanic White, Hispanic white, Black, others, unknown), year of diagnosis (2004e2006, 2007e2009, 2010e2012), insurance status (none, private, Medicaid, Medicare, other), residence type (rural, urban, metropolitan), household income, and the percent of education level less than high school for each patient’s area of residence. As provided by the NCDB, the patients’ household income (9) and education level (10) were quartiles among all US zip codes based on the 2012 American Community Survey and the residence type (11) was determined with the 2003
Results Patient baseline characteristics Our study population consisted of 57,968 radiationtreated men with high-risk PCa. There were 49,363 (85.2%) treated with EBRT alone and 8605 (14.8%) treated with EBRT with brachytherapy boost. Men who received brachytherapy boost were younger (median age: 68 vs. 71 years for men who received EBRT alone, p-Value ! 0.0001). There were 18,096 (31.2%) men treated in academic centers, and 39,872 (68.8%) were treated at nonacademic centers. Table 1 summarizes the patient baseline characteristics. Utilization and independent predictors of omission of ADT In total, 44,461 (77%) men received ADT and 13,507 (23%) men did not. Overall, a lower rate of ADT use was
Y.-W. Chen et al. / Brachytherapy Table 1 Patient baseline characteristics
Variables Radiation modality EBRT alone EBRT þ Brachytherapy Facility type Academic Nonacademic Age !65 $65 Race Non-Hispanic white Black Hispanic white Other Unknown PSA !10 10e20 O20 Gleason score #6 7 8e10 Tumor stage T1 T2 T3 T4 Risk subcategories Favorable high risk Other higher risk Charlson comorbidity score 0 1 2þ Year of diagnosis 2004e2006 2007e2009 2010e2012 Insurance status None Private Medicaid Medicare Other Unknown Income !$38,000 $38,000e47,999 $48,000e62,999 $63,000 Unknown Education ! high school $21% 13e20.9% 7e12.9% !7% Unknown
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Table 1 (continued )
No ADT (N 5 13,507, 23.3%)
Received ADT (N 5 44,461, 76.7%)
p-Value !0.0001
10,962 (22.2) 2545 (29.6)
38,401 (77.8) 6060 (70.4)
4289 (23.7) 9218 (23.1)
13,807 (76.3) 30,654 (76.9)
3646 (23.6) 9861 (23.2)
11,794 (76.4) 32,667 (76.8)
9927 2478 507 393 202
32,721 7641 1844 1649 606
0.12
0.29
!0.0001 (23.3) (24.5) (21.6) (19.3) (25)
(76.7) (75.5) (78.4) (80.8) (75) !0.0001
4966 (21.1) 1753 (17.0) 6788 (28.1)
18,533 (78.9) 8552 (83.0) 17,376 (71.9)
3118 (53.5) 3333 (27.1) 7056 (17.7)
2716 (46.6) 8969 (72.9) 32,776 (82.3)
7871 4352 1226 58
18,517 17,739 7650 555
!0.0001
!0.0001 (29.8) (19.7) (13.8) (9.5)
(70.2) (80.3) (86.2) (90.5) !0.0001
3740 (40.1) 9767 (20.1)
5587 (59.9) 38,874 (79.9) 0.44
11,820 (23.4) 1419 (23.1) 268 (21.8)
38,784 (76.6) 4718 (76.9) 959 (78.2)
4327 (22.9) 4714 (24.4) 4466 (22.6)
14,542 (77.1) 14,607 (75.6) 15,312 (77.4)
255 4089 379 8131 383 270
(22.3) (24.0) (21.1) (22.9) (25) (27)
888 12,965 1421 27,307 1150 730
(77.7) (76.0) (78.9) (77.1) (75) (73)
2629 3252 3441 3939 246
(24.4) (23.8) (23.2) (22.1) (28.7)
8144 10,391 11,390 13,924 612
(75.6) (76.2) (76.8) (78.0) (71.3)
2478 3598 4150 3042 239
(24.4) (24.0) (22.6) (22.3) (29.2)
7677 11,389 14,237 10,578 580
(75.6) (76.0) (77.4) (77.7) (70.8)
0.38
Variables
No ADT (N 5 13,507, 23.3%)
Received ADT (N 5 44,461, 76.7%)
Residence Metropolitan Urban Rural Unknown
10,749 2030 242 486
34,797 7328 1080 1256
p-Value !0.0001
(23.6) (21.7) (18.3) (27.9)
(76.4) (78.3) (81.7) (72.1)
PSA 5 prostate-specific antigen; ADT 5 Androgen deprivation therapy; EBRT 5 external beam radiation therapy.
observed in men treated with EBRT with brachytherapy boost than EBRT alone (70.4% vs. 77.8%; p-Value ! 0.0001). The rate of ADT use was consistently lower in men treated with EBRT with brachytherapy boost, but the rate increased from 67% to 77% from 2004 to 2012 (Fig. 2) ( p-Value for trend: 0.004). Men with higher Gleason score and tumor stage had a higher rate of ADT use, and men with ‘‘favorable high-risk disease’’ had a lower rate of ADT use (Fig. 3) than other men with high risk disease (60% vs. 80%; p-Value !0.0001). In multivariable logistic regression analysis, men who received EBRT plus brachytherapy boost were significantly less likely to receive ADT compared with men who received EBRT alone (adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62e0.69; p-Value !0.0001); academic centers were associated with a lower likelihood of giving ADT than nonacademic centers (AOR: 0.90; 95% CI: 0.86e0.95; p-Value: !0.0001); men treated in a more recent era (2010e2012 or 2007e2009 vs. 2004e2006) were less likely to receive ADT (AOR: 0.85; 95% CI: 0.81e0.90; AOR:0.82; 95% CI: 0.78e0.86, respectively). Being white, age O65 years, and living in metropolitan areas were associated with higher likelihood of omission of ADT, whereas there was no observed difference in ADT use for men with higher vs. lower Charlson comorbidity score (Table 2).
0.0004
Discussion
!0.0001
!0.0001
(Continued)
In this largest US contemporary population cancer database, our study revealed that approximately one in four men with radiation-treated high-risk PCa did not receive ADT. One of the critical factors for omission of ADT was the radiation modality: Omission of ADT was more common in men treated with EBRT plus brachytherapy boost compared with men treated with EBRT alone. This finding remained statistically significant after robust regression adjustment for baseline clinical and sociodemographic characteristics. The implication of this finding is that although previous clinical trials have shown that ADT improves outcomes, including overall survival (1e3), a significant proportion of men with high-risk Pca are not receiving it and therefore may be at risk of poorer survival. The strongest driving
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Fig. 2. Trend of androgen deprivation therapy use. ADT 5 Androgen deprivation therapy.
factor for whether ADT was omitted was a brachytherapy boost, suggesting some clinicians feel that increasing the radiation dose can substitute for ADT in high-risk disease. Whether high dose radiation can substitute for ADT remains controversial, and one major argument against this is that ADT has been proven to improve overall survival in clinical trials (1e3), but dose-escalation trials have thus
far generally shown improvements only in biochemical failure-free survival or recurrence-free survival but not in overall survival (12e15). The RTOG 08e15 trial (16) is testing this concept for intermediate risk disease, but whether more dose can substitute for ADT for high risk disease remains unknown and untested at this time. It should be noted that even if the RTOG 08e15 trial does not show
Fig. 3. Percentage of androgen deprivation therapy use by Gleason score, tumor stage, PSA level, and disease group. 1. Favorable high-risk disease was defined as stage T1c with Gleason score 4 þ 4 5 8 and PSA !10 ng/mL or stage T1c with Gleason six and PSA O20 ng/mL. PSA 5 prostate-specific antigen; ADT 5 Androgen deprivation therapy.
Y.-W. Chen et al. / Brachytherapy Table 2 Multivariable logistic analysis for omission of ADT Variables Treatment modality EBRT only EBRT þ Brachytherapy Hospital type Nonacademic Academic Age !65 $65 Race Non-Hispanic white Black Hispanic white Other PSA !10 10e20 O20 Gleason score #6 7 8e10 Tumor stage T1 T2 T3 T4 Charlson comorbidity score 0 1 2þ Year of diagnosis 2004e2006 2007e2009 2010e2012 Insurance status Private None Medicaid Medicare Other Income !$38,000 $38,000e47,999 $48,000e62,999 $63,000 Education ! high school $21% 13e20.9% 7e12.9% !7% Residence Metropolitan Urban Rural
AOR (95% CI)
p-Value
Ref 0.65 (0.62e0.69)
!0.0001
Ref 0.90 (0.86e0.95)
!0.0001
Ref 0.92 (0.87e0.98)
0.0093
Ref 1.16 (1.10e1.24) 1.21 (1.08e1.35) 1.34 (1.19e1.51)
!0.0001 0.001 !0.0001
Ref 1.27 (1.20e1.36) 1.63 (1.53e1.74)
!0.0001 !0.0001
Ref 2.86 (2.67e3.06) 7.64 (7.07e8.25)
!0.0001 !0.0001
Ref 1.50 (1.43e1.57) 3.45 (3.20e3.73) 3.51 (2.63e4.68)
!0.0001 !0.0001 !0.0001
Ref 0.98 (0.92e1.05) 1.07 (0.92e1.24)
0.54 0.37
Ref 0.82 (0.78e0.86) 0.85 (0.81e0.90)
!0.0001 !0.0001
Ref 0.99 1.23 1.06 0.94
(0.85e1.16) (1.08e1.40) (0.99e1.12) (0.83e1.07)
0.98 0.002 0.048 0.40
Ref 0.99 (0.93e1.07) 1.04 (0.97e1.12) 1.15 (1.06e1.25)
0.99 0.37 0.002
Ref 1.04 (0.97e1.11) 1.09 (1.01e1.17) 1.07 (0.98e1.17)
0.26 0.022 0.11
Ref 1.21 (1.14e1.29) 1.41 (1.21e1.64)
!0.0001 !0.0001
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micrometastases is much higher, and therefore, the rationale for combining with ADT is much stronger. The fact that white and metropolitanearea patients were receiving less rather than more ADT suggests that ADT omission was not related to the lower quality care often received by minority (17e20) or rural patients (21, 22). Rather, one of the major reasons for not using ADT may be related to its side effect profile and the desire of clinicians to avoid the potential bone loss, possible cardiac toxicity, metabolic changes, and sexual dysfunction (4). Of note, the most recent update of the D’Amico/Dana-Farber trial of radiation with or without 6 months of ADT (23) that initially showed the value of ADT for intermediateand high-risk patients with 5 and 8 years of followup no longer showed a statistically significant benefit after 16 years of followup with a p-Value of 0.22, suggesting that some of the PCa-specific gains may be counterbalanced by long-term harms from ADT. Also, there have been new toxicities emerging including the possibility of cognitive dysfunction (24), Alzheimer’s (25) disease, and depression (26). The lower use of ADT in academic centers and less use of ADT in more recent years suggests that clinicians are becoming more wary about the potential harms of ADT. Of note, men with increased comorbidities did not receive less ADT, suggesting that clinicians do not seem to be particularly moved by the suggestion that those with higher comorbidity may be at increased risk of harm from ADT (1, 27). Recent studies have revealed several biomarker candidates (28e30) which could further guide clinicians to personalize the use of ADT based on disease aggressiveness and to balance the benefit and harms of ADT in future practice. Certain potential limitations should be considered. First, the NCDB does not provide the duration of ADT, which impedes further analysis of ADT prescription pattern in this high-risk disease cohort. Second, the Charlson comorbidity score is a summary score for comorbidity profile, and thus, we were not able to do a more granular analysis to determine whether certain specific comorbidities were associated with ADT omission.
Conclusions
PSA 5 prostate-specific antigen; ADT 5 Androgen deprivation therapy; EBRT 5 external beam radiation therapy; CI 5 confidence interval; AOR 5 adjusted odds ratio.
Overall, we found that one in four men with high-risk PCa are not receiving ADT in this contemporary cohort of US men treated with radiation. This may reflect increasing concerns about the side effects of ADT. Some clinicians are substituting higher dose radiation for ADT, but it remains unknown if this will result in equivalent survival. Randomized trials of this strategy are needed. References
a benefit to ADT with dose escalation for intermediate risk disease, this will not necessarily answer the question for high-risk patients, in whom the risk of harboring
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Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer Yu-Wei Chen1, Vinayak Muralidhar2, Brandon A. Mahal3, Michelle D. Nezolosky1, Clair J. Beard1, Toni K. Choueiri4, Karen E. Hoffman5, Neil E. Martin1, Peter F. Orio1, Christopher J. Sweeney4, Felix Y. Feng6,7,8, Quoc-Dien Trinh9, Paul L. Nguyen1,* 1
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA 2 Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 3 Department of Medicine, Brigham and Women’s Hospital, Boston, MA 4 Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA 5 Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX 6 Department of Radiation Oncology, University of California, San Francisco, CA 7 Department of Urology, University of California, San Francisco, CA 8 Department of Medicine, University of California, San Francisco, CA 9 Department of Surgery, Division of Urology, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston, MA
ABSTRACT
PURPOSE: Androgen deprivation therapy (ADT) has been shown to improve survival for men with unfavorable-risk prostate cancer (PCa). We investigated the utilization and factors associated with the omission of ADT in radiation-managed high-risk PCa. METHODS AND MATERIALS: We used the National Cancer Database to identify men with National Comprehensive Cancer Network high-risk PCa treated with external beam radiation therapy (EBRT) with or without brachytherapy boost from 2004 to 2012. Multivariable logistic regression adjusting for clinical and sociodemographic factors was used to identify independent predictors for ADT use. RESULTS: A total of 57,968 radiation-treated high-risk PCa men were included in our analysis. There were 49,363 patients (85.2%) treated with EBRT alone and 8605 patients (14.8%) treated with EBRT plus brachytherapy boost. Overall, 77% of men received ADT. In multivariable regression analysis, the use of brachytherapy boost was associated with a significantly lower utilization of ADT (70% vs. 78%; adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62e0.69; p-Value !0.0001), as was treatment at an academic vs. nonacademic center (AOR: 0.90; 95% CI: 0.86e0.95; p-Value !0.0001) and treatment in 2010e2012 compared to 2004e2006 (AOR: 0.85; 95% CI: 0.81e 0.90; p-Value !0.0001). Conversely, greater ADT use was seen with higher Gleason scores, PSA, and T-category (all p-Values !0.001). CONCLUSIONS: Approximately one in four men with radiation-managed high-risk PCa do not receive ADT, which may reflect concerns about its toxicity profile despite known improvements in overall survival. Practice patterns suggest that some providers believe dose escalation through brachytherapy boost may obviate the need for ADT in some high-risk patients, but this hypothesis requires further testing. Ó 2016 Published by Elsevier Inc. on behalf of American Brachytherapy Society.
Keywords:
Brachytherapy boost; Androgen deprivation therapy; High-risk prostate cancer; Prostate neoplasm
Received 14 June 2016; received in revised form 3 July 2016; accepted 8 July 2016. Conflict of interest: PLN consulted for Medivation, Ferring, Genome DX, and Nanobiotix. FYF has consulted for Medivation, Astellas, Celgene, and GenomeDx Biosciences. Financial disclosure: This work is supported by Prostate Cancer Foundation, Fitz’s Cancer Warriors, David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, the Scott Forbes and Gina Ventre Fund, Jeffrey Campbell in Honor of Joan Campbell, and a grant from an anonymous family foundation. Author contributions: All authors participated in some way to the conception and design of this study. All authors also participated in the drafting and critical revision of this manuscript. All authors also contributed to some aspect of the technical, administrative, or material support of this manuscript. Y-WC and PLN had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. * Corresponding author. 75 Francis St., Boston, MA 02115. Tel.: þ1-617-732-7936; fax: þ1-617-975-0912. E-mail address: [email protected] (P.L. Nguyen). 1538-4721/$ - see front matter Ó 2016 Published by Elsevier Inc. on behalf of American Brachytherapy Society. http://dx.doi.org/10.1016/j.brachy.2016.07.001
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Introduction Although not in all, androgen deprivation therapy (ADT) in combination with external beam radiation therapy (EBRT) has been shown to improve overall survival for men with high-risk prostate cancer (PCa) in several studies (1e3). However, the potential adverse effects (4) of ADT are considerable and might deter clinicians from prescribing ADT and patients from receiving it (5). In this study, we aim to investigate the trends of ADT use in radiation-treated high-risk PCa in the contemporary US population using the US National Cancer Database (NCDB) (6). We also aim to identify the factors associated with the omission of ADT.
Methods and materials Data source and study population We used the NCDB, a joint program of the Commission on Cancer and the American Cancer Society, to select our study population. NCDB is the largest cancer registry worldwide (6), and it captures 70% of the newly diagnosed cases in the United States. Men diagnosed with National Comprehensive Cancer Network’s nonmetastatic high-risk (7) PCa (PSA O20 ng/mL or Gleason $ 8 or clinical tumor stage $ T3) in 2004e2012 were identified, and men who received EBRT with or without brachytherapy boost as the definitive treatment were included in our study. Of note, we restricted our study population to patients with only PCa diagnosis and excluded patients with multiple cancers. We also excluded patients with unavailable prostate-specific antigen (PSA), Gleason score, or tumor stage to ensure precisely defined National Comprehensive Cancer Network’s high-risk disease. Figure 1 summarized the study cohort selection process.
Fig. 1. Study population selection process. NCCN 5 National Comprehensive Cancer Network; NCDB 5 National Cancer Database; PSA 5 prostate-specific antigen.
United States Department of Agriculture Economic Research Service. Statistical analysis Descriptive statistics were used to present the baseline characteristics. Categorical variables were compared with c2 test, and continuous variables were compared by Wilcoxon rank-sum test. ManteleHaenszel c2 analysis for trend was used to examine ADT use over the study period. A multivariable logistic regression model was used to identify independent predictors for omission of ADT. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). We used a two-sided p-Value !0.05 in all analyses as criteria for statistical significance.
Primary end point and determinants The primary end point was to identify factors associated with the omission of ADT. Clinical factors in this study included PSA (!10, 10e20, O20 ng/mL), Gleason score (#6, 7, 8e10), tumor stage, and Charlson comorbidity score (0, 1, $2). Consistent with a recent prior publication, ‘‘favorable high-risk disease’’ (8) was defined as stage T1c with Gleason score 4 þ 4 5 8 and PSA !10 ng/mL or stage T1c with Gleason 6 and PSA O20 ng/mL. Sociodemographic factors included age (!65, $65 years), race (non-Hispanic White, Hispanic white, Black, others, unknown), year of diagnosis (2004e2006, 2007e2009, 2010e2012), insurance status (none, private, Medicaid, Medicare, other), residence type (rural, urban, metropolitan), household income, and the percent of education level less than high school for each patient’s area of residence. As provided by the NCDB, the patients’ household income (9) and education level (10) were quartiles among all US zip codes based on the 2012 American Community Survey and the residence type (11) was determined with the 2003
Results Patient baseline characteristics Our study population consisted of 57,968 radiationtreated men with high-risk PCa. There were 49,363 (85.2%) treated with EBRT alone and 8605 (14.8%) treated with EBRT with brachytherapy boost. Men who received brachytherapy boost were younger (median age: 68 vs. 71 years for men who received EBRT alone, p-Value ! 0.0001). There were 18,096 (31.2%) men treated in academic centers, and 39,872 (68.8%) were treated at nonacademic centers. Table 1 summarizes the patient baseline characteristics. Utilization and independent predictors of omission of ADT In total, 44,461 (77%) men received ADT and 13,507 (23%) men did not. Overall, a lower rate of ADT use was
Y.-W. Chen et al. / Brachytherapy Table 1 Patient baseline characteristics
Variables Radiation modality EBRT alone EBRT þ Brachytherapy Facility type Academic Nonacademic Age !65 $65 Race Non-Hispanic white Black Hispanic white Other Unknown PSA !10 10e20 O20 Gleason score #6 7 8e10 Tumor stage T1 T2 T3 T4 Risk subcategories Favorable high risk Other higher risk Charlson comorbidity score 0 1 2þ Year of diagnosis 2004e2006 2007e2009 2010e2012 Insurance status None Private Medicaid Medicare Other Unknown Income !$38,000 $38,000e47,999 $48,000e62,999 $63,000 Unknown Education ! high school $21% 13e20.9% 7e12.9% !7% Unknown
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Table 1 (continued )
No ADT (N 5 13,507, 23.3%)
Received ADT (N 5 44,461, 76.7%)
p-Value !0.0001
10,962 (22.2) 2545 (29.6)
38,401 (77.8) 6060 (70.4)
4289 (23.7) 9218 (23.1)
13,807 (76.3) 30,654 (76.9)
3646 (23.6) 9861 (23.2)
11,794 (76.4) 32,667 (76.8)
9927 2478 507 393 202
32,721 7641 1844 1649 606
0.12
0.29
!0.0001 (23.3) (24.5) (21.6) (19.3) (25)
(76.7) (75.5) (78.4) (80.8) (75) !0.0001
4966 (21.1) 1753 (17.0) 6788 (28.1)
18,533 (78.9) 8552 (83.0) 17,376 (71.9)
3118 (53.5) 3333 (27.1) 7056 (17.7)
2716 (46.6) 8969 (72.9) 32,776 (82.3)
7871 4352 1226 58
18,517 17,739 7650 555
!0.0001
!0.0001 (29.8) (19.7) (13.8) (9.5)
(70.2) (80.3) (86.2) (90.5) !0.0001
3740 (40.1) 9767 (20.1)
5587 (59.9) 38,874 (79.9) 0.44
11,820 (23.4) 1419 (23.1) 268 (21.8)
38,784 (76.6) 4718 (76.9) 959 (78.2)
4327 (22.9) 4714 (24.4) 4466 (22.6)
14,542 (77.1) 14,607 (75.6) 15,312 (77.4)
255 4089 379 8131 383 270
(22.3) (24.0) (21.1) (22.9) (25) (27)
888 12,965 1421 27,307 1150 730
(77.7) (76.0) (78.9) (77.1) (75) (73)
2629 3252 3441 3939 246
(24.4) (23.8) (23.2) (22.1) (28.7)
8144 10,391 11,390 13,924 612
(75.6) (76.2) (76.8) (78.0) (71.3)
2478 3598 4150 3042 239
(24.4) (24.0) (22.6) (22.3) (29.2)
7677 11,389 14,237 10,578 580
(75.6) (76.0) (77.4) (77.7) (70.8)
0.38
Variables
No ADT (N 5 13,507, 23.3%)
Received ADT (N 5 44,461, 76.7%)
Residence Metropolitan Urban Rural Unknown
10,749 2030 242 486
34,797 7328 1080 1256
p-Value !0.0001
(23.6) (21.7) (18.3) (27.9)
(76.4) (78.3) (81.7) (72.1)
PSA 5 prostate-specific antigen; ADT 5 Androgen deprivation therapy; EBRT 5 external beam radiation therapy.
observed in men treated with EBRT with brachytherapy boost than EBRT alone (70.4% vs. 77.8%; p-Value ! 0.0001). The rate of ADT use was consistently lower in men treated with EBRT with brachytherapy boost, but the rate increased from 67% to 77% from 2004 to 2012 (Fig. 2) ( p-Value for trend: 0.004). Men with higher Gleason score and tumor stage had a higher rate of ADT use, and men with ‘‘favorable high-risk disease’’ had a lower rate of ADT use (Fig. 3) than other men with high risk disease (60% vs. 80%; p-Value !0.0001). In multivariable logistic regression analysis, men who received EBRT plus brachytherapy boost were significantly less likely to receive ADT compared with men who received EBRT alone (adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62e0.69; p-Value !0.0001); academic centers were associated with a lower likelihood of giving ADT than nonacademic centers (AOR: 0.90; 95% CI: 0.86e0.95; p-Value: !0.0001); men treated in a more recent era (2010e2012 or 2007e2009 vs. 2004e2006) were less likely to receive ADT (AOR: 0.85; 95% CI: 0.81e0.90; AOR:0.82; 95% CI: 0.78e0.86, respectively). Being white, age O65 years, and living in metropolitan areas were associated with higher likelihood of omission of ADT, whereas there was no observed difference in ADT use for men with higher vs. lower Charlson comorbidity score (Table 2).
0.0004
Discussion
!0.0001
!0.0001
(Continued)
In this largest US contemporary population cancer database, our study revealed that approximately one in four men with radiation-treated high-risk PCa did not receive ADT. One of the critical factors for omission of ADT was the radiation modality: Omission of ADT was more common in men treated with EBRT plus brachytherapy boost compared with men treated with EBRT alone. This finding remained statistically significant after robust regression adjustment for baseline clinical and sociodemographic characteristics. The implication of this finding is that although previous clinical trials have shown that ADT improves outcomes, including overall survival (1e3), a significant proportion of men with high-risk Pca are not receiving it and therefore may be at risk of poorer survival. The strongest driving
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Fig. 2. Trend of androgen deprivation therapy use. ADT 5 Androgen deprivation therapy.
factor for whether ADT was omitted was a brachytherapy boost, suggesting some clinicians feel that increasing the radiation dose can substitute for ADT in high-risk disease. Whether high dose radiation can substitute for ADT remains controversial, and one major argument against this is that ADT has been proven to improve overall survival in clinical trials (1e3), but dose-escalation trials have thus
far generally shown improvements only in biochemical failure-free survival or recurrence-free survival but not in overall survival (12e15). The RTOG 08e15 trial (16) is testing this concept for intermediate risk disease, but whether more dose can substitute for ADT for high risk disease remains unknown and untested at this time. It should be noted that even if the RTOG 08e15 trial does not show
Fig. 3. Percentage of androgen deprivation therapy use by Gleason score, tumor stage, PSA level, and disease group. 1. Favorable high-risk disease was defined as stage T1c with Gleason score 4 þ 4 5 8 and PSA !10 ng/mL or stage T1c with Gleason six and PSA O20 ng/mL. PSA 5 prostate-specific antigen; ADT 5 Androgen deprivation therapy.
Y.-W. Chen et al. / Brachytherapy Table 2 Multivariable logistic analysis for omission of ADT Variables Treatment modality EBRT only EBRT þ Brachytherapy Hospital type Nonacademic Academic Age !65 $65 Race Non-Hispanic white Black Hispanic white Other PSA !10 10e20 O20 Gleason score #6 7 8e10 Tumor stage T1 T2 T3 T4 Charlson comorbidity score 0 1 2þ Year of diagnosis 2004e2006 2007e2009 2010e2012 Insurance status Private None Medicaid Medicare Other Income !$38,000 $38,000e47,999 $48,000e62,999 $63,000 Education ! high school $21% 13e20.9% 7e12.9% !7% Residence Metropolitan Urban Rural
AOR (95% CI)
p-Value
Ref 0.65 (0.62e0.69)
!0.0001
Ref 0.90 (0.86e0.95)
!0.0001
Ref 0.92 (0.87e0.98)
0.0093
Ref 1.16 (1.10e1.24) 1.21 (1.08e1.35) 1.34 (1.19e1.51)
!0.0001 0.001 !0.0001
Ref 1.27 (1.20e1.36) 1.63 (1.53e1.74)
!0.0001 !0.0001
Ref 2.86 (2.67e3.06) 7.64 (7.07e8.25)
!0.0001 !0.0001
Ref 1.50 (1.43e1.57) 3.45 (3.20e3.73) 3.51 (2.63e4.68)
!0.0001 !0.0001 !0.0001
Ref 0.98 (0.92e1.05) 1.07 (0.92e1.24)
0.54 0.37
Ref 0.82 (0.78e0.86) 0.85 (0.81e0.90)
!0.0001 !0.0001
Ref 0.99 1.23 1.06 0.94
(0.85e1.16) (1.08e1.40) (0.99e1.12) (0.83e1.07)
0.98 0.002 0.048 0.40
Ref 0.99 (0.93e1.07) 1.04 (0.97e1.12) 1.15 (1.06e1.25)
0.99 0.37 0.002
Ref 1.04 (0.97e1.11) 1.09 (1.01e1.17) 1.07 (0.98e1.17)
0.26 0.022 0.11
Ref 1.21 (1.14e1.29) 1.41 (1.21e1.64)
!0.0001 !0.0001
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micrometastases is much higher, and therefore, the rationale for combining with ADT is much stronger. The fact that white and metropolitanearea patients were receiving less rather than more ADT suggests that ADT omission was not related to the lower quality care often received by minority (17e20) or rural patients (21, 22). Rather, one of the major reasons for not using ADT may be related to its side effect profile and the desire of clinicians to avoid the potential bone loss, possible cardiac toxicity, metabolic changes, and sexual dysfunction (4). Of note, the most recent update of the D’Amico/Dana-Farber trial of radiation with or without 6 months of ADT (23) that initially showed the value of ADT for intermediateand high-risk patients with 5 and 8 years of followup no longer showed a statistically significant benefit after 16 years of followup with a p-Value of 0.22, suggesting that some of the PCa-specific gains may be counterbalanced by long-term harms from ADT. Also, there have been new toxicities emerging including the possibility of cognitive dysfunction (24), Alzheimer’s (25) disease, and depression (26). The lower use of ADT in academic centers and less use of ADT in more recent years suggests that clinicians are becoming more wary about the potential harms of ADT. Of note, men with increased comorbidities did not receive less ADT, suggesting that clinicians do not seem to be particularly moved by the suggestion that those with higher comorbidity may be at increased risk of harm from ADT (1, 27). Recent studies have revealed several biomarker candidates (28e30) which could further guide clinicians to personalize the use of ADT based on disease aggressiveness and to balance the benefit and harms of ADT in future practice. Certain potential limitations should be considered. First, the NCDB does not provide the duration of ADT, which impedes further analysis of ADT prescription pattern in this high-risk disease cohort. Second, the Charlson comorbidity score is a summary score for comorbidity profile, and thus, we were not able to do a more granular analysis to determine whether certain specific comorbidities were associated with ADT omission.
Conclusions
PSA 5 prostate-specific antigen; ADT 5 Androgen deprivation therapy; EBRT 5 external beam radiation therapy; CI 5 confidence interval; AOR 5 adjusted odds ratio.
Overall, we found that one in four men with high-risk PCa are not receiving ADT in this contemporary cohort of US men treated with radiation. This may reflect increasing concerns about the side effects of ADT. Some clinicians are substituting higher dose radiation for ADT, but it remains unknown if this will result in equivalent survival. Randomized trials of this strategy are needed. References
a benefit to ADT with dose escalation for intermediate risk disease, this will not necessarily answer the question for high-risk patients, in whom the risk of harboring
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