The Impact of Brachytherapy on Prostate Cancer–Specific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis

doi:10.1016/j.ijrobp.2011.09.055

International Journal of Radiation OncologyBiologyPhysics

Volume 83, Issue 4, 15 July 2012, Pages 1154-1159

https://doi.org/10.1016/j.ijrobp.2011.09.055 Get rights and content

Purpose

This population-based analysis compared prostate cancer–specific mortality (PCSM) in a cohort of patients with high-risk prostate cancer after nonsurgical treatment with external beam radiation therapy (EBRT), brachytherapy (BT), or combination (BT + EBRT).

Methods and Materials

We identified from the Surveillance, Epidemiology and End Results database patients diagnosed from 1988 through 2002 with T1–T3N0M0 prostate adenocarcinoma of poorly differentiated grade and treated with BT, EBRT, or BT + EBRT. During this time frame, the database defined high grade as prostate cancers with Gleason score 8–10, or Gleason grade 4–5 if the score was not recorded. This corresponds to a cohort primarily with high-risk prostate cancer, although some cases where only Gleason grade was recorded may have included intermediate-risk cancer. We used multivariate models to examine patient and tumor characteristics associated with the likelihood of treatment with each radiation modality and the effect of radiation modality on PCSM.

Results

There were 12,745 patients treated with EBRT (73.5%), BT (7.1%), or BT + EBRT (19.4%) included in the analysis. The median follow-up time for all patients was 6.4 years. The use of BT or BT + EBRT increased from 5.1% in 1988–1992 to 31.4% in 1998–2002. Significant predictors of use of BT or BT + EBRT were younger age, later year of diagnosis, urban residence, and earlier T-stage. On multivariate analysis, treatment with either BT (hazard ratio, 0.66; 95% confidence interval, 0.49–0.86) or BT + EBRT (hazard ratio, 0.77; 95% confidence ratio, 0.66–0.90) was associated with significant reduction in PCSM compared with EBRT alone.

Conclusion

In patients with high-grade prostate cancer, treatment with brachytherapy is associated with reduced PCSM compared with EBRT alone. Our results suggest that brachytherapy should be investigated as a component of definitive treatment strategies for patients with high-risk prostate cancer.

Introduction

In 2010, the American Cancer Society estimated that there were approximately 210,000 men diagnosed with prostate cancer (1). In the era of prostate-specific antigen (PSA) screening, approximately 15% of prostate cancer patients present with localized, high-risk prostate cancer (2). Although no absolute consensus exists for the definition of “high risk,” the commonly used D’Amico risk classification defines high-risk tumors as follows: Gleason score ≥8, stage ≥T2c, or PSA >20 ng/mL (3). Outcomes from randomized clinical trials have reported 10-year PCSM rates of 10.3%–16% 4, 5, 6, 7 in patients with high-risk prostate cancer. These results are suboptimal, and management strategies continue to be refined.

Local therapy options for the definitive treatment of prostate cancer include radical prostatectomy (RP), EBRT, and BT with or without supplemental EBRT. Although BT achieves tumor control rates equivalent to other options for low-risk and selected intermediate-risk prostate cancers, its use in high-risk prostate cancer is controversial (3). Early retrospective reports found that prostate seed implantation was associated with inferior biochemical control rates among patients with high-risk prostate cancer (3). However, subsequent single and multi-institution investigators have reported 10- to 15-year biochemical control rates of 68.6%–92.6% in patients treated with brachytherapy monotherapy or combination therapy 8, 9, 10, 11, 12. These results compare favorably with historical outcomes with EBRT and androgen deprivation therapy (ADT) for high-risk prostate cancer where biochemical failures occurred in up to 50% of patients at 10 years 4, 5, 6, 7.

We hypothesized that BT-containing treatment for patients with high-risk prostate cancer may achieve survival rates higher than EBRT alone when evaluated in a large observational cohort of U.S. males. To test this hypothesis, we undertook a population-based study using the SEER database to compare PCSM in patients with high-risk prostate cancer treated with BT, BT + EBRT, or EBRT alone.

Section snippets

Methods and Materials

Patient data were identified from the National Cancer Institute’s SEER database. We selected patients who were diagnosed January 1, 1988, through December 31, 2002, with T1–T3N0M0 prostate adenocarcinoma and who received nonsurgical treatment with radiation therapy: EBRT, BT, or combination (BT + EBRT). Data regarding ADT use are not available in the SEER database. We excluded patients who underwent any surgery other than biopsy. To define a high-risk population, we limited our search to

Patient demographics

We identified 12,745 patients who were diagnosed with localized, high-grade prostate adenocarcinoma from 1988 through 2002 and treated with radiation therapy. Of these, 9,369 (73.5%) were treated with EBRT alone, 910 (7.1%) with prostate BT alone, and 2,466 (19.4%) with combination BT + EBRT. Patients treated with BT and BT + EBRT were younger (p < 0.01) and lived in census tracts with higher median household income (p = 0.01). The EBRT alone group included fewer T1 and more T3 tumors than the

Discussion

The use of BT for localized, high-grade prostate adenocarcinomas increased in the study population from 1988 to 2002, and a wide geographic variation in BT utilization was observed. Predictors of the use of BT, with or without EBRT, included later year of diagnosis, younger age, urban residence, non-Hispanic ethnicity, and lower T-stage. Our results suggest that geographic disparities exist in the use of BT in the treatment of high-risk, localized prostate cancer. We found an association

Conclusion

In conclusion, we report that in a large population-based study of men with high-risk prostate cancer treated during 1988–2002, the utilization of BT as a component of treatment increased during the study period and was associated with a reduced rate of PCSM. These data could be considered hypothesis-generating regarding the role of BT in the multimodality management of high-risk prostate cancer. Future clinical trials should be conducted to evaluate prospectively the influence of BT on

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Cited by (32)

Dosimetric evaluation in brachytherapy and teletherapy for prostate cancer using Monte Carlo simulation and anatomically realistic virtual anthropomorphic phantom
2023, Radiation Physics and Chemistry
The benefits that radiotherapy provides to the patient are unquestionable. However, there is growing concern about the increased risk of radiation-induced secondary cancer and the late damage to organs and tissues associated with the treatment. In this sense, the main objective of this study was to determine the radiation doses in the organs and tissues of the prostate cancer patient for two radiotherapy options, using the Monte Carlo code MCNP×2.7.0. The patient was represented by the ICRP 110 reference virtual anthropomorphic phantom and underwent brachytherapy with a¹⁹²Ir source, Nucletron Microselectron V2 model, and alternatively, conventional 3D-CRT radiotherapy with an 18 MV X-ray beam from a Varian 2100c medical linear accelerator with 4-field planning (anteroposterior, 0°; posteroanterior, 180°; left lateral, 90°; and right lateral, 270°). A set of conversion factors (CF) for equivalent and effective dose were determined. The obtained results showed that in the more distant organs related to the prostate, such as the lung, brain, and salivary glands, the contribution of scattered radiation decreases, especially when brachytherapy is used. Comparing the two treatment modalities, the CF for effective dose per therapeutic dose was 42% lower when ¹⁹²Ir was chosen as the main form of treatment. The CF values for photon equivalent doses calculated in 3D-CRT 4-fields are among one and two orders of magnitude higher than ¹⁹²Ir therapy. These differences are even higher when the neutron equivalent dose in 3D-CRT is considered. In this way, the tools and methodology presented significantly improve the previously used to accurately estimate the equivalent doses in organs and tissues, which is the best quantity to assess the risk of inducing secondary cancer of healthy organs and tissues of patients undergoing treatment with radiotherapy.
Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review[Formula presented]
2020, European Urology
Citation Excerpt :
The categories were EBRT versus EBRT + BT, EBRT/BT dose/fractionation/field size comparisons, and the addition of chemotherapy to RT as multimodality therapy. There were 17 studies comparing EBRT with BT (monotherapy or as boost to EBRT; ±ADT) [20–22,70–72,74,76,77,82–87,92,100]. Of these, there was one RCT [20–22], two prospective comparative studies [70,84], and 14 NRSs.
The optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown.
To perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported.
Medline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4–5 [Gleason score {GS} 8–10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3–4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed.
Overall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems.
Based on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment.
We reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.
ASCENDE-RT: An Analysis of Health-Related Quality of Life for a Randomized Trial Comparing Low-Dose-Rate Brachytherapy Boost With Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer
2017, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Focusing on radiation therapy, randomized trials have shown that dose-escalated, external beam radiation therapy (EBRT) improves biochemical-progression-free survival (b-PFS), although adverse effects are usually more common in the dose-escalated arms (1-8). Because only a small (if any) overall survival advantage is likely with dose escalation (9, 10), it is crucial to develop a deeper understanding of the impact of dose escalation on HR-QoL to assist physicians and patients in making informed decisions with respect to treatment options. The present study is a multicenter, randomized, controlled trail comparing b-PFS using the American Society for Radiation Oncology consensus definition, as well as other survival endpoints, treatment-related morbidity, and HR-QoL outcomes, between dose escalation with an EBRT boost (DE-EBRT) versus dose escalation using a low-dose-rate prostate brachytherapy (LDR-PB) boost.
To report the patient-reported health-related quality of life (HR-QoL) outcomes for a multicenter randomized trial evaluating the safety and efficacy of 2 different techniques for dose escalation.
A total of 357 men with intermediate- and high-risk prostate cancer were stratified by risk group and randomized (1:1) to either a dose-escalated external beam (DE-EBRT) boost (n=177) or a low-dose-rate prostate brachytherapy (LDR-PB) boost (n=180) as part of combined modality therapy. The HR-QoL was assessed using the SF36v2 questionnaire, with additional scales for urinary, bowel, and sexual function. Date of starting androgen deprivation therapy was considered time zero, the median follow-up of 6 years. Scales were scored from 0 to 100; a decline in a mean score ≥10 compared with baseline was considered a clinically significant decline. This was an intent-to-treat analysis.
Mean domain scores at baseline were well balanced between the 2 treatment arms. A clinically significant decline in mean scores in both the arms compared with baseline was noted for role physical (DE-EBRT [−11.4] and LDR-PB [−15.3]) and sexual function scale (DE-EBRT [−15.1] and LDR-PB [−19.2]). There was a significantly larger drop in mean scores in the LDR-PB group compared with the DE-EBRT group for physical function (−15.3 vs −6.9; P=.03), urinary function (−3.6 vs −0.5; P=.04).
At 6 years' follow up, there were no significant differences in mean scores in 9 of 11 scales compared with baseline in both arms. A clinically significant decline in mean scores was noted in both arms for role physical and sexual function scales. There was a statistically significant decline in physical function and urinary function scales in the LDR-PB arm compared with the DE-EBRT arm.
American Brachytherapy Society Task Group Report: Use of androgen deprivation therapy with prostate brachytherapy—A systematic literature review
2017, Brachytherapy
Citation Excerpt :
Recent publications using large national databases indicate an increase in CSS (35) and OS (36) in PCa patients treated with any form of brachytherapy. Brachytherapy results in superior disease outcomes, particularly bPFS (22–24, 35, 36), higher complete prostate metabolic atrophy, and lower nadir PSA (21). For these reasons, addition of ADT to either brachytherapy monotherapy or a boost may have less impact on outcomes than when ADT is combined with EBRT.
Prostate brachytherapy (PB) has well-documented excellent long-term outcomes in all risk groups. There are significant uncertainties regarding the role of androgen deprivation therapy (ADT) with brachytherapy. The purpose of this report was to review systemically the published literature and summarize present knowledge regarding the impact of ADT on biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS).
A literature search was conducted in Medline and Embase covering the years 1996–2016. Selected were articles with >100 patients, minimum followup 3 years, defined risk stratification, and directly examining the role and impact of ADT on bPFS, CSS, and OS. The studies were grouped to reflect disease risk stratification. We also reviewed the impact of ADT on OS, cardiovascular morbidity, mortality, and on-going brachytherapy randomized controlled trials (RCTs).
Fifty-two selected studies (43,303 patients) were included in this review; 7 high-dose rate and 45 low-dose rate; 25 studies were multi-institutional and 27 single institution (retrospective review or prospective data collection) and 2 were RCTs. The studies were heterogeneous in patient population, risk categories, risk factors, followup time, and treatment administered, including ADT administration and duration (median, 3–12 months);71% of the studies reported a lack of benefit, whereas 28% showed improvement in bPFS with addition of ADT to PB. The lack of benefit was seen in low-risk and favorable intermediate-risk (IR) disease and most high–dose rate studies. A bPFS benefit of up to 15% was seen with ADT use in patients with suboptimal dosimetry, those with multiple adverse risk factors (unfavorable IR [uIR]), and most high-risk (HR) studies. Four studies reported very small benefit to CSS (2%). None of the studies showed OS advantage; however, three studies reported an absolute 5–20% OS detriment with ADT. Literature suggests that OS detriment is more likely in older patients or those with pre-existing cardiovascular disease. Four RCTs with an adequate number of patients and well-defined risk stratification are in progress. One RCT will answer the question regarding the role of ADT with PB in favorable IR patients and the other three RCTs will focus on optimal duration of ADT in the uIR and favorable HR population.
Patients treated with brachytherapy have excellent long-term disease outcomes. Existing evidence shows no benefit of adding ADT to PB in low-risk and favorable IR patients. UIR and HR patients and those with suboptimal dosimetry may have up to 15% improvement in bPFS with addition of 3–12 months of ADT, with uncertain impact on CSS and a potential detriment on OS. To minimize morbidity, one should exercise caution in prescribing ADT together with PB, in particular to older men and those with existing cardiovascular disease. Due to the retrospective nature of this evidence, significant selection, and treatment bias, no definitive conclusions are possible. RCT is urgently needed to define the potential role and optimal duration of ADT in uIR and favorable HR disease.
Survival outcomes of dose-escalated external beam radiotherapy versus combined brachytherapy for intermediate and high risk prostate cancer using the national cancer data base
2016, Journal of Urology
Citation Excerpt :
Of the patients 82% did not receive ADT. A population based analysis using the SEER (Surveillance, Epidemiology and End Results) database reviewed patients with prostate cancer at high risk and found that adding brachytherapy decreased prostate cancer specific mortality.16 However this study was limited as it could not account for the EBRT dose received or for receipt of ADT.
We evaluated survival outcomes between dose-escalated EBRT (external beam radiotherapy) vs EBRT plus brachytherapy for intermediate and high risk prostate cancer using NCDB (National Cancer Data Base).
Patients with cN0M0 prostate cancer treated from 2004 to 2006 were divided into radiotherapy comparison groups, including EBRT alone (75.6 to 81 Gy) and EBRT (40 to 50.4 Gy) plus brachytherapy with EBRT delivered at 1.8 to 2.0 Gy per fraction. Brachytherapy data were limited to yes/no with no information on modality, dose or schedule. Eligible patients were known to have received androgen deprivation therapy. Overall survival was evaluated using multivariate Cox regression and propensity score matched analyses.
Of the 20,279 study patients with prostate cancer, including 12,617 at intermediate risk and 7,662 at high risk, 71.3% received EBRT alone and 28.7% received EBRT plus brachytherapy. Median followup was 82 months (range 3 to 120) and median age was 70 years (range 36 to 90). On multivariate analysis compared to EBRT alone (75.6 to 81 Gy) EBRT plus brachytherapy was associated with improved survival (HR 0.75, p <0.001). This significance remained consistent for intermediate and high risk when analyzed separately (HR 0.73 and 0.76, respectively, each p <0.001). However on subset analysis compared to very high dose EBRT alone (79.2 to 81 Gy) in all patients combined EBRT plus brachytherapy was not associated with improved survival (HR 0.91, p = 0.083).
Compared to EBRT (75.6 to 81 Gy) we observed an association of EBRT plus brachytherapy with a decreased risk of death in men with intermediate and high risk prostate cancer. However this association was no longer significant when EBRT doses of 79.2 to 81 Gy were used.
Prostate cancer
2016, Medicina Clinica
El equipo multidisciplinario de cáncer de próstata (CP) del Hospital Universitario Vall d’Hebron revisa los avances recientes en el tratamiento de esta neoplasia. Estudios de cribado y largo seguimiento ponen de manifiesto una reducción de la mortalidad, mientras la vigilancia activa emerge como una actitud terapéutica frente al diagnóstico de cánceres no agresivos. Nuevos marcadores incrementan la especificidad del PSA y, además, permiten focalizar la sospecha de cánceres con comportamiento agresivo. La resonancia magnética multiparamétrica (RMm) se ha posicionado como el método más eficaz en la selección de pacientes para biopsia y también para estadificar el tumor a nivel local. El paradigma de biopsia aleatoria ecodirigida está cambiando, y a través de la fusión de imágenes entre RMm y ecografía se está convirtiendo en una biopsia guiada a zonas sospechosas. La prostatectomía radical (PR) y la radioterapia (RT) son los tratamientos curativos del CP localizado y en ambas se han experimentado mejorías tecnológicas notables. La PR es altamente eficaz y la incorporación de la cirugía robótica está reduciendo su morbilidad. La moderna RT permite administrar mayores dosis en el tumor y mínimas dosis adyacentes, reduciéndose significativamente su toxicidad.
La supresión androgénica con análogos de la LHRH sigue siendo el tratamiento de elección del CP avanzado, pero debe limitarse a esta indicación. La pérdida de masa ósea y los efectos metabólicos adversos incrementan la frecuencia de fracturas y morbimortalidad cardiovascular. En la fase de resistencia a la castración con diseminación metastásica nuevos fármacos de base hormonal han demostrado eficacia incluso después de resistencia a quimioterapia.
The Vall d’Hebron multidisciplinary prostate cancer (PC) team reviews recent advances in the management of this neoplasm. Screening studies with long follow-up show a reduction in mortality, whereas active surveillance is emerging as a therapeutic approach of non-aggressive cancers. New markers increase the specificity of PSA and also allow targeting suspected aggressive cancers. Multiparametric magnetic resonance (mMRI) has emerged as the most effective method in the selection of patients for biopsy and also for local tumor staging. The paradigm of random prostatic biopsy is changing through the fusion techniques that allow guiding ultrasonography-driven biopsy of suspicious areas detected in mMRI. Radical prostatectomy (RP) and radiotherapy (RT) are curative treatments of localized PC and both have experienced significant technological improvements. RP is highly effective and the incorporation of robotic surgery is reducing morbidity. Modern RT allows the possibility of high tumor dose with minimal adjacent dose reducing its toxicity.
Androgen deprivation therapy with LHRH analogues remains the treatment of choice for advanced PC, but should be limited to this indication. The loss of bone mass and adverse metabolic effects increases the frequency of fractures and cardiovascular morbimortality. After castration resistance in metastatic disease, new hormone-based drugs have demonstrated efficacy even after chemotherapy resistance.

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: This research was supported in part by National Cancer Institute Cancer Center Support (Grant No. P30 CA56036).

: Conflict of interest: none.

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Clinical InvestigationThe Impact of Brachytherapy on Prostate Cancer–Specific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Methods and Materials

Patient demographics

Discussion

Conclusion

Lancet Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Brachytherapy

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
The Impact of Brachytherapy on Prostate Cancer–Specific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis