Hallo,
Ich habe eine Studie gefunden zur Lebenserwartung bei verzögertem Anfang von Androgentherapie.
Mein Englisch ist nicht so gut, ist die Lebenserwartung tatsächlich so lange, wenn erst beim Auftauchen von Metastasen die Androgentherapie beginnt ?
Open AccessJournal of UrologyAdult Urology1 Sep 2021Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent Prostate Cancer in the Context of Novel Therapies
Catherine Handy Marshall
, Yongmei Chen
, Claire Kuo
, Jennifer Cullen
, Jiji Jiang
, Inger Rosner
, Mark Markowski
, David G. McLeod
, Bruce J. Trock
, and Mario A. Eisenberger
View All Author Informationhttps://doi.org/10.1097/JU.0000000000001797
Abstract
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Abstract
Purpose:
There were 3 recent U.S. Food and Drug Administration approvals for drugs to be used in nonmetastatic castration resistant prostate cancer, a state that arises from the unproven start of continuous androgen deprivation therapy (ADT) for biochemical recurrent prostate cancer (BCR), before metastatic disease is evident. This report examines the outcome of men with BCR who defer ADT until time of metastasis.
Materials and Methods:
Retrospective review of men diagnosed with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins Hospital and Walter Reed National Military Medical Center and developed BCR with a prostate specific antigen doubling time of not more than 10 months (806 patients). The primary end points were metastasis-free survival and overall survival from time of local treatment among men who delayed ADT until time of metastasis.
Results:
The median metastasis-free survival of men with BCR and a prostate specific antigen doubling time <6 months and 10 months who delay ADT until metastasis is 144 months (95% CI 48–not reached) and 192 months (95% CI 72–not reached), respectively, with a median overall survival of 168 months (95% CI 96–276 months) and 204 months (95% CI 120–276), respectively.
Conclusions:
Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population.
Abbreviations and Acronyms
The practice of early initiation of continuous androgen deprivation therapy (ADT) in men with biochemical recurrent prostate cancer (BCR), an unproven treatment paradigm with significant long-term toxicities, resulted in a new paradigm: nonmetastatic castration resistant prostate cancer (nmCRPC; see figure). NmCRPC is defined as prostate cancer progression with only a rising serum prostate specific antigen (PSA) and castrate levels of testosterone.1 There is a lack of high level evidence supporting the use of continuous ADT alone in the setting of PSA relapse. A large randomized study comparing continuous to intermittent ADT done by Crook et al demonstrated that intermittent ADT was non-inferior to continuous ADT in terms of overall survival (OS) but does not address whether or not ADT should be deferred entirely.2 Subsequent randomized placebo controlled studies have been done in men with nmCRPC and indicate that the addition of novel androgen receptor antagonists (NARA) result in robust improvements in the time to development of metastatic disease and overall survival.3–8 In these trials, baseline characteristics prior to ADT and criteria for implementation of initial ADT were not described. This limits our ability to assess the benefits of NARAs to patients with BCR. Because these patients typically survive for many years and have virtually no symptoms until metastasis, quality of life issues are particularly important since ADT is associated with significant side effects and major costs.
To provide information that may help inform risk-benefit decisions about appropriate management of men with BCR, we estimated overall and metastasis-free survival (MFS) in a large, prospectively collected cohort of men with BCR who did not receive systemic treatment prior to the development of metastases (see figure). Our goal is to illustrate the length of survival in the absence of early ADT, as illustrated by the conceptual framework in the figure—not to develop a prognostic model to risk stratify patients after BCR.
Methods
This was a retrospective review of 2 prospective clinical cohorts of men with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins University (JHU) and Walter Reed National Military Medical Center (WRNMMC; IRB No. NA_00087593).9,10 All men who had a radical prostatectomy from 1983 to 2014 and developed BCR with a PSA doubling time of <10 months were included, consistent with the eligibility criteria of the nmCRPC trials. Those who were started on ADT prior to metastatic disease were excluded which includes patients who received adjuvant or salvage radiotherapy with ADT.
Baseline characteristics, at the time of radical prostatectomy, are reported with the mean and standard deviation. The primary outcome was OS and the secondary end point was MFS. Kaplan-Meier estimates of survival were defined from time of radical prostatectomy to time of event or last followup.
Subset analyses were done by PSA doubling time (PSADT). PSADT was calculated using the natural log of 2 (p=0.693) divided by the slope of the linear regression of the natural log of PSA vs time.11 It is reported in months and uses at least 2 PSA values prior to the development of metastatic disease. If the slope was negative (declining PSA after initial rise) or 0 (stable PSA), the PSADT was arbitrarily set to 100 months. Multivariable Cox proportional hazard models were used to identify factors predictive of MFS and OS. SAS version 9.4 (SAS Institute, Cary, North Carolina) was used for all analyses.
For comparison to the nmCRPC trials, the median OS and MFS were obtained from published results. We measured OS as time from initial treatment to event (death or metastasis) or censoring.
Results
In the database of all men who underwent prostatectomy, 806 men fulfilled the full eligibility criteria. Baseline characteristics are presented in table 1. The median age of the cohort was 61 years (IQR 56–65). In all, 79% of the cohort was Caucasian and 16% African American; 38% had positive surgical margins, 17% had Gleason ≤6, 54% had Gleason 7 and 29% had Gleason 8–10 disease. The median PSADT following BCR was 5.6 months (IQR 3.6–7.7) and the median followup was 9 years (IQR 5–14).
The median time to metastatic disease measured from the time of local treatment in patients with PSADT of ≤6 months was 144 months (IQR 48– not reached; table 2). In multivariable analysis, risk of metastasis was higher at JHU vs WRNMMC (HR 5.3, 95% CI 4.1–6.8) and African American race was associated with a lower risk of metastasis compared to Caucasians (HR 0.5, 95% CI 0.4–0.7; table 3). Time from RP to BCR correlated with the risk for development of metastatic disease (HR 0.8, 95% CI 0.8–0.9). Additionally, PSADT <6 months was associated with higher risk of developing metastatic disease compared to those with doubling time 6–10 months (HR 3.2, 95% CI 2.6–3.9).
NR, not reached
The median OS for men with BCR and a PSADT ≤6 months was 168 months (IQR 96–276 months). Older age, higher pathologic T stage, higher Gleason sum and faster PSADT were all associated with higher likelihood of death in multivariable models (table 3).
Discussion
While it is now widely recognized that in men with nmCRPC the addition of NARAs result in clinically meaningful improvements on MFS and OS, it should be emphasized that the nmCRPC clinical state results from a controversial practice of initiation of early ADT which remains unsubstantiated by level 1 evidence. Several reports on the natural history of patients with BCR illustrate that this represents a widely heterogeneous group of patients in terms of natural progression of metastasis and survival.1,11 While it is recognized that knowledge of baseline clinical and pathological information would not resolve the therapeutic dilemma around the timing of ADT implementation, it cannot be assumed that the nmCRPC studies included men that would necessarily benefit from early ADT. This is especially significant since the survival of these patients is measured by several years, often exceeding 1 decade.
To estimate how long men with BCR survive in the absence of salvage ADT, we evaluated a large prospectively collected cohort of men who did not receive systemic treatment prior to metastasis. In our study, we found that the median MFS of men with BCR and a PSADT <10 months who delay ADT until metastasis is approximately 192 months, with a median OS of 204 months. In the population with PSADT of ≤6 months the median MFS was 144 months and the median overall survival 168 months. MFS from local treatment was136 months estimated from the apalutamide arm and 110 months in the placebo arm of the SPARTAN trial,3 and 126.6 months in the darolutamide arm and 102.6 months in the placebo arm of the ARAMIS trial (table 2).4 Information on time of local treatment to study entry was not reported on the PROSPER trial.5 The estimated overall survival, from time of initial diagnosis or treatment, from the apalutamide arm was 169 months and 154 months on the placebo arm of the SPARTAN study (table 2).7 There was insufficient data from the PROSPER trial to estimate OS,6 and median OS was not reached in the ARAMIS trial.8 Our results are in line with the estimated OS in the SPARTAN and ARAMIS trials.3,4,7,12
There are limitations to our study. First, our population includes patients who relapsed after surgery usually applied with curative intent, which differs from the nmCRPC studies where patients were treated with surgery, radiation or primary ADT alone. Despite these considerations, our data illustrate the similarities in the OS compared with the same outcome reported in the pivotal nmCRPC studies. Another limitation of this approach is measuring from time of diagnosis rather than time of biochemical relapse; however, in order to illustrate the similarities to current trials, we have maintained the survival from diagnosis. Finally, our study was done at only 2 centers in the United States, where additional unmeasured confounders may have contributed to a difference in MFS between the sites. The nmCRPC studies were global multi-institutional studies and there may be additional unmeasured confounders that are contributing to these similarities.
NARAs have also improved outcomes in patients with metastatic hormone sensitive and metastatic castration resistant prostate cancer.13 The therapeutic benefits of these compounds are substantial but primarily limited to the first-line setting. Extensive data now demonstrate that after progression on the first line androgen receptor targeted agent, subsequent responses to alternate compounds have only modest effects because of the development of irreversible androgen receptor based and other mechanisms of resistance.14 Early treatment with these agents therefore, will undoubtedly affect subsequent treatment decisions and efficacy.
Conclusions
Men with biochemically recurrent prostate cancer, who defer hormone therapy until metastasis have overall survival that is quite long and the early initiation of continuous androgen deprivation therapy for biochemical relapse, may not meaningfully improve overall survival. Adequately designed prospectively randomized studies in patients with BCR testing the role of early vs deferred ADT remain critical to inform treatment decisions in this population and enhance patients’ and physicians’ understanding of the clinical significance of the nmCRPC pivotal studies.
Funding: This work was partly supported by National Institutes of Health Cancer Center Support Grants P30 CA006973.
USU-DoD-HJF Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.
Editor's Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 791 and 792.
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
Work of the United States Government
Ich habe eine Studie gefunden zur Lebenserwartung bei verzögertem Anfang von Androgentherapie.
Mein Englisch ist nicht so gut, ist die Lebenserwartung tatsächlich so lange, wenn erst beim Auftauchen von Metastasen die Androgentherapie beginnt ?
Open AccessJournal of UrologyAdult Urology1 Sep 2021Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent Prostate Cancer in the Context of Novel Therapies
- This article is commented on by the following:
Catherine Handy Marshall
, Yongmei Chen
, Claire Kuo
, Jennifer Cullen
, Jiji Jiang
, Inger Rosner
, Mark Markowski
, David G. McLeod
, Bruce J. Trock
, and Mario A. Eisenberger
View All Author Informationhttps://doi.org/10.1097/JU.0000000000001797
Abstract
Tools
Share
Abstract
Purpose:
There were 3 recent U.S. Food and Drug Administration approvals for drugs to be used in nonmetastatic castration resistant prostate cancer, a state that arises from the unproven start of continuous androgen deprivation therapy (ADT) for biochemical recurrent prostate cancer (BCR), before metastatic disease is evident. This report examines the outcome of men with BCR who defer ADT until time of metastasis.
Materials and Methods:
Retrospective review of men diagnosed with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins Hospital and Walter Reed National Military Medical Center and developed BCR with a prostate specific antigen doubling time of not more than 10 months (806 patients). The primary end points were metastasis-free survival and overall survival from time of local treatment among men who delayed ADT until time of metastasis.
Results:
The median metastasis-free survival of men with BCR and a prostate specific antigen doubling time <6 months and 10 months who delay ADT until metastasis is 144 months (95% CI 48–not reached) and 192 months (95% CI 72–not reached), respectively, with a median overall survival of 168 months (95% CI 96–276 months) and 204 months (95% CI 120–276), respectively.
Conclusions:
Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population.
Abbreviations and Acronyms
ADT | androgen deprivation therapy |
BCR | biochemical recurrent prostate cancer |
CPDR | Center for Prostate Disease Research |
JHU | Johns Hopkins University |
MFS | metastasis-free survival |
NARA | novel androgen receptor antagonists |
nmCRPC | nonmetastatic castration-resistant prostate cancer |
OS | overall survival |
PSA | prostate specific antigen |
PSADT | prostate specific antigen doubling time |
To provide information that may help inform risk-benefit decisions about appropriate management of men with BCR, we estimated overall and metastasis-free survival (MFS) in a large, prospectively collected cohort of men with BCR who did not receive systemic treatment prior to the development of metastases (see figure). Our goal is to illustrate the length of survival in the absence of early ADT, as illustrated by the conceptual framework in the figure—not to develop a prognostic model to risk stratify patients after BCR.
Methods
This was a retrospective review of 2 prospective clinical cohorts of men with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins University (JHU) and Walter Reed National Military Medical Center (WRNMMC; IRB No. NA_00087593).9,10 All men who had a radical prostatectomy from 1983 to 2014 and developed BCR with a PSA doubling time of <10 months were included, consistent with the eligibility criteria of the nmCRPC trials. Those who were started on ADT prior to metastatic disease were excluded which includes patients who received adjuvant or salvage radiotherapy with ADT.
Baseline characteristics, at the time of radical prostatectomy, are reported with the mean and standard deviation. The primary outcome was OS and the secondary end point was MFS. Kaplan-Meier estimates of survival were defined from time of radical prostatectomy to time of event or last followup.
Subset analyses were done by PSA doubling time (PSADT). PSADT was calculated using the natural log of 2 (p=0.693) divided by the slope of the linear regression of the natural log of PSA vs time.11 It is reported in months and uses at least 2 PSA values prior to the development of metastatic disease. If the slope was negative (declining PSA after initial rise) or 0 (stable PSA), the PSADT was arbitrarily set to 100 months. Multivariable Cox proportional hazard models were used to identify factors predictive of MFS and OS. SAS version 9.4 (SAS Institute, Cary, North Carolina) was used for all analyses.
For comparison to the nmCRPC trials, the median OS and MFS were obtained from published results. We measured OS as time from initial treatment to event (death or metastasis) or censoring.
Results
In the database of all men who underwent prostatectomy, 806 men fulfilled the full eligibility criteria. Baseline characteristics are presented in table 1. The median age of the cohort was 61 years (IQR 56–65). In all, 79% of the cohort was Caucasian and 16% African American; 38% had positive surgical margins, 17% had Gleason ≤6, 54% had Gleason 7 and 29% had Gleason 8–10 disease. The median PSADT following BCR was 5.6 months (IQR 3.6–7.7) and the median followup was 9 years (IQR 5–14).
Overall | CPDR | JHU | |
No. pts | 806 | 340 | 466 |
Yrs age at surgery: | |||
Mean (SD) | 61 (6.7) | 62 (6.9) | 59 (6.3) |
Median (IQR) | 61 (56, 65) | 63 (58, 67) | 60 (55, 64) |
No. race (%): | |||
African American | 132 (16) | 81 (23.8) | 51 (10.9) |
Caucasian | 639 (79) | 232 (68.2) | 407 (87.3) |
Other/unknown | 35 (4) | 27 (7.9) | 8 (1.7) |
No. pathological T stage (%): | |||
T2 | 247 (31) | 145 (44) | 102 (22) |
T3-T4 | 539 (66) | 182 (56) | 357 (78) |
No. pathological Gleason sum (%): | |||
<6 | 124 (17) | 73 (26) | 51 (11) |
7 | 403 (54) | 145 (52) | 258 (56) |
8–10 | 219 (29) | 63 (22) | 156 (34) |
No. surgical margin (%): | |||
Neg | 495 (62) | 183 (54) | 312 (68) |
Pos | 304 (38) | 157 (46) | 147 (32) |
Mos PSADT: | |||
Mean (SD) | 5.6 (2.5) | 6.0 (2.5) | 5.3 (2.5) |
Median (IQR) | 5.6 (3.6, 7.7) | 6.3 (4.0, 8.0) | 5.1 (3.2, 7.3) |
No. death (%) | 304 (38) | 108 (32) | 196 (42) |
Median yrs followup time (IQR) | 9.0 (5.0, 14.0) | 9.5 (6.1, 14) | 9.0 (5.0, 14) |
Study | ||||||||
JHU/CPDR | SPARTAN2,6 | PROSPER4,5 | ARAMIS3,7 | |||||
PSADT <6 Mos | PSADT <10 Mos | Apalutamide | Placebo | Enzalutamide | Placebo | Darolutamide | Placebo | |
% Local treatment | 100 | 100 | 77 | 77 | Not reported | Not reported | ||
Median mos time from local treatment to study entry | 95 | 94 | Not reported | 86 | 84 | |||
Median mos MFS, from study entry (95% CI) | 41 | 16 | 37 (33–NR) | 15 (14–15) | 40 (34–NR) | 18 (16–22) | ||
Median mos OS, from study entry (95% CI) | 74 | 60 | 67 (64–NR) | 56 (54–63) | NR | |||
Estimated mos MFS, from time of local treatment (IQR) | 144 (48–NR) | 192 (72–NR) | 136 | 110 | Unable to estimate | 127 | 103 | |
Estimated mos OS, from time of local treatment (IQR) | 168 (96–276) | 204 (120–276) | 169 | 154 | Unable to estimate |
Parameter | MFS | OS | ||
HR (95% CI) | p Value | HR (95% CI) | p Value | |
Site JHU (466 pts) vs CPDR (340 pts) | 5.49 (4.24, 7.11) | <0.001 | 1.37 (1.13, 1.67) | 0.002 |
Age at surgery (continuous) | 1.00 (0.99, 1.02) | 0.708 | 1.05 (1.04, 1.07) | <0.001 |
Race: | 0.004 | 0.266 | ||
African American (132 pts) vs Caucasian (639 pts) | 0.56 (0.40, 0.79) | 1.01 (0.79, 1.30) | ||
Other/unknown (35 pts) vs Caucasian | 0.83 (0.46, 1.48) | 0.58 (0.30, 1.12) | ||
Pathological stage T3-T4 (539 pts) vs T2 (247 pts) | 1.29 (1.02, 1.64) | 0.035 | 1.35 (1.09, 1.67) | 0.006 |
Gleason sum: | <0.001 | <0.001 | ||
7 (403 pts) vs ≤6 (124 pts) | 2.22 (1.64, 3.00) | 0.97 (0.79, 1.19) | ||
8–10 (219 pts) vs ≤6 (124 pts) | 5.97 (4.34, 8.21) | 1.86 (1.48, 2.33) | ||
Pos (304 pts) vs neg (495 pts) surgical margin | 0.87 (0.72, 1.05) | 0.148 | 0.96 (0.81, 1.14) | 0.662 |
Time from RP to BCR (yrs, continuous) | 0.81 (0.79, 0.84) | <0.001 | 0.88 (0.86, 0.90) | <0.001 |
PSADT ≤6 (436 pts) vs >6 (2,494 pts) | 3.21 (2.65, 3.90) | <0.001 | 2.01 (1.67, 2.43) | <0.001 |
Year of surgery (continuous) | 0.98 (0.97, 0.99) | 0.001 | 0.98 (0.96, 0.99) | 0.004 |
Discussion
While it is now widely recognized that in men with nmCRPC the addition of NARAs result in clinically meaningful improvements on MFS and OS, it should be emphasized that the nmCRPC clinical state results from a controversial practice of initiation of early ADT which remains unsubstantiated by level 1 evidence. Several reports on the natural history of patients with BCR illustrate that this represents a widely heterogeneous group of patients in terms of natural progression of metastasis and survival.1,11 While it is recognized that knowledge of baseline clinical and pathological information would not resolve the therapeutic dilemma around the timing of ADT implementation, it cannot be assumed that the nmCRPC studies included men that would necessarily benefit from early ADT. This is especially significant since the survival of these patients is measured by several years, often exceeding 1 decade.
To estimate how long men with BCR survive in the absence of salvage ADT, we evaluated a large prospectively collected cohort of men who did not receive systemic treatment prior to metastasis. In our study, we found that the median MFS of men with BCR and a PSADT <10 months who delay ADT until metastasis is approximately 192 months, with a median OS of 204 months. In the population with PSADT of ≤6 months the median MFS was 144 months and the median overall survival 168 months. MFS from local treatment was136 months estimated from the apalutamide arm and 110 months in the placebo arm of the SPARTAN trial,3 and 126.6 months in the darolutamide arm and 102.6 months in the placebo arm of the ARAMIS trial (table 2).4 Information on time of local treatment to study entry was not reported on the PROSPER trial.5 The estimated overall survival, from time of initial diagnosis or treatment, from the apalutamide arm was 169 months and 154 months on the placebo arm of the SPARTAN study (table 2).7 There was insufficient data from the PROSPER trial to estimate OS,6 and median OS was not reached in the ARAMIS trial.8 Our results are in line with the estimated OS in the SPARTAN and ARAMIS trials.3,4,7,12
There are limitations to our study. First, our population includes patients who relapsed after surgery usually applied with curative intent, which differs from the nmCRPC studies where patients were treated with surgery, radiation or primary ADT alone. Despite these considerations, our data illustrate the similarities in the OS compared with the same outcome reported in the pivotal nmCRPC studies. Another limitation of this approach is measuring from time of diagnosis rather than time of biochemical relapse; however, in order to illustrate the similarities to current trials, we have maintained the survival from diagnosis. Finally, our study was done at only 2 centers in the United States, where additional unmeasured confounders may have contributed to a difference in MFS between the sites. The nmCRPC studies were global multi-institutional studies and there may be additional unmeasured confounders that are contributing to these similarities.
NARAs have also improved outcomes in patients with metastatic hormone sensitive and metastatic castration resistant prostate cancer.13 The therapeutic benefits of these compounds are substantial but primarily limited to the first-line setting. Extensive data now demonstrate that after progression on the first line androgen receptor targeted agent, subsequent responses to alternate compounds have only modest effects because of the development of irreversible androgen receptor based and other mechanisms of resistance.14 Early treatment with these agents therefore, will undoubtedly affect subsequent treatment decisions and efficacy.
Conclusions
Men with biochemically recurrent prostate cancer, who defer hormone therapy until metastasis have overall survival that is quite long and the early initiation of continuous androgen deprivation therapy for biochemical relapse, may not meaningfully improve overall survival. Adequately designed prospectively randomized studies in patients with BCR testing the role of early vs deferred ADT remain critical to inform treatment decisions in this population and enhance patients’ and physicians’ understanding of the clinical significance of the nmCRPC pivotal studies.
Funding: This work was partly supported by National Institutes of Health Cancer Center Support Grants P30 CA006973.
USU-DoD-HJF Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.
Editor's Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 791 and 792.
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
Work of the United States Government
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