Optimal timing of early versus delayed adjuvant radiotherapy following radical prostatectomy for locally advanced prostate cancer

doi:10.1016/j.urolonc.2013.09.004

Urologic Oncology: Seminars and Original Investigations

Volume 32, Issue 3, April 2014, Pages 303-308

https://doi.org/10.1016/j.urolonc.2013.09.004 Get rights and content

Abstract

Objectives

Although post–radical prostatectomy (RP) adjuvant radiation therapy (ART) benefits disease that is staged as pT3 or higher, the optimal ART timing remains unknown. Our objective is to characterize the outcomes and optimal timing of early vs. delayed ART.

Materials and methods

From the Surveillance, Epidemiology and End Results-Medicare data from 1995 to 2007, we identified 963 men with pT3N0 disease receiving early (<4 mo after RP, n = 419) vs. delayed (4–12 mo after RP, n = 544) ART after RP. Utilizing propensity score methods, we compared overall mortality, prostate cancer–specific mortality (PCSM), bone-related events (BRE), salvage hormonal therapy utilization, and intervention for urethral stricture. We then used the maximal statistic approach to determine at what time post-RP ART had the most significant effect on outcomes of interest in men with pT3N0 disease.

Results

When compared with delayed ART in men with pT3 disease, early ART was associated with improved PCSM (0.47 vs. 1.02 events per 100 person-years; P = 0.038) and less salvage hormonal therapy (2.88 vs. 4.59 events per 100 person-years; P = 0.001). Delaying ART beyond 5 months is associated with worse PCSM (hazard ratio [HR] 2.3; P = 0.020), beyond 3 months is associated with more BRE (HR 1.6; P = 0.025), and beyond 4 months is associated higher rates of salvage hormonal therapy (HR 1.6; P = 0.002). ART performed after 9 months was associated with fewer urethral strictures (HR 0.6; P = 0.042).

Conclusion

Initiating ART less than 5 months after RP for pT3 is associated with improved PCSM. Early ART is also associated with fewer BRE and less use of salvage hormonal therapy if administered earlier than 3 and 4 months after RP, respectively. However, ART administered later than 9 months after RP is associated with fewer urethral strictures. Our population-based findings complement randomized trials designed with fixed ART timing.

Introduction

Prostate cancer is the most commonly diagnosed solid malignancy in men and the second leading cause of deaths due to cancer in men in the United States [1]. Radical prostatectomy (RP) remains the most common treatment for clinically localized prostate cancer [2] with proven long-term cancer control compared with other treatment options [3]. However, despite recent stage migration secondary to prostate specific antigen (PSA) screening, up to one-third of men undergoing RP have locally advanced disease [4].

Although adverse tumor characteristics such as extraprostatic extension, seminal vesicle invasion, and positive surgical margins increase the risk of biochemical recurrence [5], level 1 evidence demonstrates that adjuvant radiation therapy (ART) lowers the risk of biochemical recurrence and [6], [7] distant metastases [8], and improves overall survival [8] compared with observation. Although the Southwest Oncology Group (SWOG) 8794 trial randomized subjects to ART within 4 months of surgery vs. observation [8], the European Organisation for Research and Treatment of Cancer [6] and ARO 96-02/AUO AP 09/95 [7] trials randomized the subjects to radiation therapy (RT) within 90 and 81 days of surgery, respectively; these cut points were inherent to the study design, and the optimal timing for ART for maximal benefit remains unknown. In contrast, ART may interfere with postprostatectomy recovery and is associated with urethral stricture and decline in urinary and sexual function [9], [10], [11]. Extending the interval between RP and ART may attenuate the risk of long-term functional sequelae. Using a population-based approach, we examined the outcomes of early vs. delayed ART following RP for locally advanced prostate cancer. Additionally, we sought to determine the optimal timing for ART within 1 year of RP.

Section snippets

Data source

Our study was approved by the Brigham and Women's Institutional Review Board; patient data were deidentified and the requirement for consent was waived. We analyzed the Surveillance, Epidemiology and End Results (SEER)-Medicare data that comprised a linkage of population-based cancer registries from 20 SEER areas covering approximately 28% of the U.S. population with Medicare administrative data [12]. Medicare provides health care benefits to most Americans who are 65 years or older.

Results

The sociodemographic characteristics are demonstrated in Table 1. Before propensity weighting, men were more likely to receive early ART between 1995 and 2004, whereas delayed ART was more common after 2005 (P = 0.012). Although pathologic stage and grade were similar, late vs. early ART was more frequently associated with elevated preoperative PSA levels (P = 0.030). Finally, concurrent ADT utilization along with ART was more common in men receiving delayed ART vs. early ART (41.1% vs. 29.3%; P

Comment

The optimal timing of ART for locally advanced prostate cancer following RP remains elusive. Initial findings from RCTs comparing immediate ART vs. observation revealed improved biochemical recurrence-free survival without overall survival differences [7], [21], [22]. An update of the SWOG 8794 trial in 2009 demonstrated fewer distant metastases and an 11% improvement in overall survival with ART with median follow-up of 12.6 years [8]. RCT study designs are limited in their ability to assess

Conclusions

Initiating ART earlier than 5 months after RP for pT3 prostate cancer is associated with improved PCSM. Early ART is also associated with fewer bone-related events and less use of salvage hormonal therapy if administered within 3 and 4 months after RP, respectively. However, fewer urethral strictures are noted when ART is administered 9 months after RP. Our population-based findings complement level 1 evidence and provide cut points for the optimal timing of ART to improve cancer control while

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Cited by (20)

Observation with or without late radiotherapy is equivalent to early radiotherapy in high-risk prostate cancer after radical prostatectomy: A SEER-Medicare analysis on trends, survival outcomes, and complications
2021, Prostate International
Citation Excerpt :
Currently, American Urologic Association/American Society of Radiation Oncology (AUA/ASTRO) guidelines, backed by randomized clinical trial data, support offering adjuvant RT to high-risk patients.1,4 Despite the oncologic benefits of adjuvant RT, it may lead to potential overtreatment and unnecessarily expose patients to radiation toxicities.2,5,6 Salvage RT given to post-RP patients with a prostate-specific antigen (PSA) relapse represents an effort to reduce overtreatment while maintaining the oncologic benefits of RT.7 However, some critics argue that salvage RT compromises the efficacy of RT, fearing that in waiting for PSA elevation, high-risk patients miss a narrow treatment window and that the disease becomes no longer ‘salvageable’.8
We aimed to illustrate national trends of post-radical prostatectomy (RP) radiotherapy (RT) and compare outcomes and toxicities in patients receiving eRT versus observation with or without late radiotherapy (lRT).
Utilizing the Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2001 to 2011, we identified 7557 patients with high-risk pathologic features after RP (≥pT3N0 and/or positive surgical margins). Our study cohort consisted of patients receiving RT within 6 months of surgery (eRT), those receiving RT after 6 months (lRT), and those never receiving RT (observation). Another subcohort, delayed RT (dRT), encompassed both lRT and observation. Trends of post-RP RT were compared using the Cochran–Armitage trend test. Cox regression models identified factors predictive of worse survival outcomes. Kaplan–Meier analyses compared the eRT and the dRT groups.
Among those with pathologically confirmed high-risk prostate cancer (PCa) after RP, 12.7% (n = 959), 13.2% (n = 1710), and 74.1% (n = 4888) underwent eRT, lRT, and observation without RT, respectively. Of these strategies, the proportion of men on observation without RT increased significantly over time (p = 0.004). The multivariable Cox regression model demonstrated similar outcomes between the eRT and the dRT groups. At a median follow-up of 5.9 years, five-year overall and cancer-specific survival outcomes were more favorable in the dRT group, when compared to the eRT group.
A blanket adoption of the eRT in high-risk PCa based on clinical trials with limited follow-up may result in overtreatment of a significant number of men and expose them to unnecessary radiation toxicity.
Identifying skeletal-related events for prostate cancer patients in routinely collected hospital data
2019, Cancer Epidemiology
Citation Excerpt :
Based on earlier studies, a comprehensive a priori list of diagnosis codes related to SREs was generated. This list was informed by previous publications [15] and expert input from the co-authors who had a range of clinical backgrounds (MGP, AS, PC, HP, NC, AA). This step is termed ‘forward coding’.
Non-osteoporotic skeletal-related events (SREs) are clinically important markers of disease progression in prostate cancer. We developed and validated an approach to identify SREs in men with prostate cancer using routinely-collected data.
Patients diagnosed with prostate cancer between January 2010 and December 2013 were identified in the National Prostate Cancer Audit, based on English cancer registry data. A coding framework was developed based on diagnostic and procedure codes in linked national administrative hospital and routinely-collected radiotherapy data to identify SREs occurring before December 2015. Two coding definitions of SREs were assessed based on whether the SRE codes were paired with a bone metastasis code (‘specific definition’) or used in isolation (‘sensitive definition’). We explored the validity of both definitions by comparing the cumulative incidence of SREs from time of diagnosis according to prostate cancer stage at diagnosis with death as a competing risk.
We identified 40,063, 25,234 and 13,968 patients diagnosed with localised, locally advanced and metastatic disease, respectively. Using the specific definition, we found that the 5-year cumulative incidence of SREs was 1.0 % in patients with localised disease, 6.0 % in patients with locally advanced disease, and 42.3 % in patients with metastatic disease. Using the sensitive definition, the corresponding cumulative incidence figures were 9.0 %, 14.9 %, and 44.4 %, respectively.
The comparison of the cumulative incidence of SREs identified in routinely collected hospital data, based on a specific coding definition in patients diagnosed with different prostate cancer stage, supports their validity as a clinically important marker of cancer progression.
Assessment of performance indicators of a radiotherapy department using an electronic medical record system
2017, Reports of Practical Oncology and Radiotherapy
Citation Excerpt :
Among GU cancers, prostate carcinoma is the most common and known to be a slowly growing tumor, therefore, not too sensitive to eventual delays of radiotherapy. Research showed that treatment delays of 2.5, 4 and 5 months can result in a 5-year estimates of PSA failure-free survival of 55%, increased use of salvage hormonal therapy, and increased prostate cancer-specific mortality, respectively.37,38 The waiting times reported to adversely affect the outcome in prostate radiotherapy are outstanding and unlikely to be reached in our practice.
To retrospectively assess the performance indicators of our radiotherapy department and their temporal trends, using a commercially available electronic-medical-record (EMR) system.
A recent trend in healthcare quality is to define and evaluate performance indicators of the service provided.
Patient and external-beam-radiotherapy-treatments data were retrieved using the Mosaiq EMR system from 1-January-2012 till 31-December-2015.
Annual performance indicators were evaluated as: productivity (number of new cases/year and diagnosis distribution); complexity (ratio of Volumetric-Modulated-Arc-Therapy (VMAT) courses, average number of imaging procedures/patient); and quality (average, median and 90th percentile waiting times from admission to first treatment).
The temporal trends of all performance indicators were assessed by linear regression.
Productivity: the number of new cases/year increased with an average rate of 4%. Diagnosis distribution showed that breast is the main pathology treated, followed by gastro-intestinal and head-and-neck.
Complexity: the ratio of VMAT courses increased from 13% to 35%, with an average rate of 7% per year. The average number of imaging procedures/patient increased from 8 to 11.
Quality: the waiting times from admission to treatment remained stable over time (R² ≤ 0.1), with average, median and 90th percentile values around 20, 15, and 31 days, respectively.
An EMR system can be used to: monitor the performance indicators of a radiotherapy department, identify workflow processes needing attention and improvement, estimate future demands of resources.
Temporal analysis of our data showed an increasing trend in productivity and complexity paired with constant waiting times.
Cost-effectiveness of the Decipher Genomic Classifier to Guide Individualized Decisions for Early Radiation Therapy After Prostatectomy for Prostate Cancer
2017, Clinical Genitourinary Cancer
Controversy exists regarding the effectiveness of early adjuvant versus salvage radiation therapy after prostatectomy for prostate cancer. Estimates of prostate cancer progression from the Decipher genomic classifier (GC) could guide informed decision-making and improve the outcomes for patients.
We developed a Markov model to compare the costs and quality-adjusted life years (QALYs) associated with GC-based treatment decisions regarding adjuvant therapy after prostatectomy with those of 2 control strategies: usual care (determined from patterns of care studies) and the alternative of 100% adjuvant radiation therapy. Using the bootstrapping method of sampling with replacement, the cases of 10,000 patients were simulated during a 10-year time horizon, with each subject having individual estimates for cancer progression (according to GC findings) and noncancer mortality (according to age).
GC-based care was more effective and less costly than 100% adjuvant radiation therapy and resulted in cost savings up to an assay cost of $11,402. Compared with usual care, GC-based care resulted in more QALYs. Assuming a $4000 assay cost, the incremental cost-effectiveness ratio was $90,833 per QALY, assuming a 7% usage rate of adjuvant radiation therapy. GC-based care was also associated with a 16% reduction in the percentage of patients with distant metastasis at 5 years compared with usual care.
The Decipher GC could be a cost-effective approach for genomics-driven cancer treatment decisions after prostatectomy, with improvements in estimated clinical outcomes compared with usual care. The individualized decision analytic framework applied in the present study offers a flexible approach to estimate the potential utility of genomic assays for personalized cancer medicine.
Benefits and concerns of early adjuvant radiotherapy for prostate cancer with pathological adverse tumor characteristics
2015, Urological Science
Results of early or delayed adjuvant radiotherapy for prostate cancer with adverse pathological tumor characteristics: A single-institute experience
2015, Urological Science
Citation Excerpt :
Immediate ART < 5 months after RP for pT3 is associated with improved PCSM and fewer BREs, and less use of salvage hormonal therapy. However, delayed ART is associated with fewer urethral strictures.9 In our study, we considered the strategy of the combination with advanced robotic surgery and more aggressive monitor postoperation PSA.
Despite an earlier detection of prostate cancer (Pca) is promising, pathologically advanced disease still exists in 40–52% of cases. We present a retrospective study of adjuvant radiotherapy (ART) in adverse pathological tumor characteristics of PCa, and analyze the optimal time for ART.
From 2004 to 2012, we identified 53 men with adverse pathological characteristics of PCa receiving early [< 3 months after radical prostatectomy (RP), n = 42] or delayed (3–12 months after RP, n = 11) ART after RP. The adverse pathological characteristics of PCa were defined as positive surgical margins, extracapsular extension, seminal-vesicle invasion, or detectable prostate-specific antigen after RP. The primary-outcome collection includes 5-year biochemical-free survival (BCFS), PCa-specific mortality, bone-related events, salvage-hormonal-therapy utilization, and intervention for urethral stricture.
There was no PCa-specific mortality in the 5-year follow-up. When compared with the delayed ART in men with adverse pathological characteristics of PCa, early ART was associated with the trend to improve the 5-year BCFS (89% vs. 73%; p = 0.1) and less salvage hormonal therapy (45% vs. 54%; p = 0.29). The delayed ART is associated with the trend of fewer urethral strictures (9% vs. 14 %; p = 0.32). But, there was no significant difference between both groups.
Compared with the delayed ART, early ART for adverse pathological tumor characteristics of PCa seems to have the trend in improvement in the 5-year BCFS and metastasis-free survival. Because of our limited case number, a prospective study with more cases to confirm the effect of ART is needed.

View all citing articles on Scopus

¹: Funding: This work was supported by a Department of Defense Prostate Cancer Physician Training Award (W81XWH-08-1-0283) presented to Dr. Hu.

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Original articleOptimal timing of early versus delayed adjuvant radiotherapy following radical prostatectomy for locally advanced prostate cancer1

Abstract

Objectives

Materials and methods

Results

Conclusion

Introduction

Section snippets

Data source

Results

Comment

Conclusions

J Urol

J Urol

J Urol

J Urol

J Clin Epidemiol

J Urol

Lancet

Ann Oncol

J Urol

Eur Urol

Cancer statistics, 2010

CA Cancer J Clin

The changing face of low-risk prostate cancer: trends in clinical presentation and primary management

J Clin Oncol

Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer

J Am Med Assoc

Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911

J Clin Oncol

Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95

J Clin Oncol

Original article
Optimal timing of early versus delayed adjuvant radiotherapy following radical prostatectomy for locally advanced prostate cancer¹