Biologically effective dose values for prostate brachytherapy: Effects on PSA failure and posttreatment biopsy results

doi:10.1016/j.ijrobp.2005.07.981

International Journal of Radiation OncologyBiologyPhysics

Volume 64, Issue 2, 1 February 2006, Pages 527-533

https://doi.org/10.1016/j.ijrobp.2005.07.981 Get rights and content

Purpose: To analyze the effect of biologically effective dose (BED) values on prostate-specific antigen (PSA) failure and posttreatment biopsy.

Methods and Materials: From 1990 to 2003, 1,377 patients had prostate brachytherapy alone (I-125 or Pd-103) (571), hormonal and brachytherapy (371), and trimodality therapy (hormonal, implant, and external beam) (435). Dose was defined as the D90 (dose delivered to 90% of the gland from the dose–volume histogram).

Results: Freedom from PSA failure (FFPF) at 10 years was 87%. The 10-year FFPF for BED <100, >100–120, >120–140, >140–160, <160–180, >180–200, and >200 were 46%, 68%, 81%, 85.5%, 90%, 90%, and 92%, respectively (p < 0.0001). BED and Gleason score had the greatest effect, with p values of p < 0.0001 in multivariate analysis. Posttreatment positive biopsy rate was 7% (31/446). The positive biopsy rates for BED ≤100, >100–120, >120–140, >140–160, >160–180, >180–200, and >200 were 24% (8/33), 15% (3/20), 6% (2/33), 6% (3/52), 7% (6/82), 1% (1/72), and 3% (4/131), respectively (p < 0.0001). BED was the most significant predictor of biopsy outcome in multivariate analysis (p = 0.006).

Conclusions: Biologically effective dose equations provide a method of comparing different isotopes and combined therapies in the brachytherapy management of prostate cancer. The effects of BED on FFPF and posttreatment biopsy demonstrate a strong dose–response relationship.

Introduction

Recent advances in the radiotherapeutic management of prostate cancer have focused on the relationship of radiation dose and tumor control. Although new technology such as three-dimensional conformal and intensity-modulated external beam radiation therapy (EBRT) has brought attention to this relationship, it is not a new area of study. Hanks et al., through the patterns of care studies, helped demonstrate that increasing dose in the external beam management of prostate cancer could translate into improved local control (1). Fuks et al. explored the relationship between implant quality and local control in a cohort of patients treated with retropubic I-125 prostate implants and found a similar improvement in outcome with higher dose distributions (2). These early studies used the digital rectal examination to assess local control and as an endpoint for the dose–response analysis. In recent years, investigators have shifted the emphasis toward examining the relationship between dose and biochemical control. Retrospective studies have demonstrated that increasing dose over the standard 70 Gy of EBRT has resulted in improved biochemical control rates. These findings were confirmed in a randomized trial reported by Pollack et al. (3). In 1998, our institution established the first dose–response relationship for ultrasound-guided I-125 implants (4). Subsequent studies confirmed these findings with longer follow-up and greater numbers of patients (5, 6). In addition, brachytherapy dose–response relationships were found using posttreatment biopsy as an endpoint (6, 7). A dose–response for prostate permanent seed implantation has also been supported using other data sets (8, 9). These reports sought to explore these relationships by comparing isotope and treatment regimens. This was accomplished by looking at the implant dose derived from the postimplant dosimetric analysis as a percentage of the prescription dose. This method is problematic because prescription doses have been empirically chosen and the same percentage of a prescription dose for one isotope or treatment does not necessarily equate biologically to another.

To overcome these problems, we analyzed the dose–response relationship by developing biologically effective dose (BED) values for all brachytherapy treatments. In this way, different isotopes and treatment regimens (i.e., combined implant and EBRT) could be compared on a valid basis to test a dose–response relationship. In addition, the connection between local control and biochemical control was explored by testing the effect of BED on both prostate-specific antigen (PSA) failure and posttreatment biopsy results.

Section snippets

Methods and materials

A total of 1377 patients with T1 to T3 prostate cancer were treated with brachytherapy at Mount Sinai Hospital in New York from June 1990 to January 2003. No patient had radiologic or pathologic evidence of metastatic disease. All patients were staged using the 1992 American Joint Committee on Cancer staging system (10). The clinical stage, presenting Gleason score, and presenting PSA for all patients can be found in Table 1.

Seminal vesicle biopsy was performed in 609 patients (44%).

Biochemical control

The overall freedom from PSA failure (FFPF) for the whole cohort at 10 years was 87% (Fig. 1). Patient age had a significant effect on PSA failure. Ten-year FFPF rates for patients <60 (305), >60–70 (659), and >70 (413) were 91%, 87%, and 85%, respectively (p = 0.03). The FFPF rates broken out by presenting disease characteristics can be found in Table 2. All of the disease characteristics significantly affected FFPF in univariate analysis. The choice of treatment did not significantly affect

Discussion

In 1998, we published our first report on the effect of implant dose on biochemical outcome using I-125 implants (4). The decision made at that time was to perform the dose–response analysis only on one isotope to avoid having to compare doses between two isotopes with different half-lives and dose rates. In addition, patients treated with combined implant and EBRT were also excluded for similar reasons. In 2000, we analyzed the effect of dose on posttreatment biopsy outcomes. Because of our

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This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer.
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Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P = .65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P = .62) and 1.2 versus 0.6% (P = .62), respectively.
Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.
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We evaluated the treatment outcomes of different prostate volumes (PVs), <15 cc, 15–20 cc, and > 20 cc, in patients with prostate cancer who underwent permanent seed implantation (PI) ± external beam radiation therapy ± hormone therapy in a national Japanese prospective cohort study (J-POPS).
Of the 6721 patients in J-POPS from 2005 to 2011, 6652 were included in the analysis population. We categorized the patients into the following three PV groups: <15 cc, 15–20 cc, and > 20 cc. We evaluated the effect of PV on biochemical freedom from failure (bFFF), prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM) using the Phoenix definition and Cox proportional hazard models.
The median follow-up period was 60.0 months. Patients in each PV group was 491 (7.4%), 1118 (16.8%), and 5043 (75.8%), respectively. No difference was observed in bFFF (94.7%, 96.2%, and 95.7%, p = 0.407), PCSM (99.8%, 99.7%, and 99.8%, p = 0.682), and ACM (98.2%, 96.7%, and 97.2%, p = 0.119) at 5 years for each PV group. In univariate and multivariate analyses, PV was not associated with bFFF, PCSM, ACM, or grade 2 toxicity. The percentage of positive biopsies was the single most significant predictor for all treatment outcomes.
Our results obtained by analyzing a very large Japanese prospective database showed no difference in treatment outcomes according to PV (<15 cc, 15–20 cc, and ˃20 cc). Our study confirmed that PI in small prostates (even < 15 cc) remains an effective treatment option.
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We evaluated the effect of age, <60 and ≥60 years, on biochemical outcomes and toxicities in patients with prostate cancer who underwent permanent seed implantation (PI) ± external beam radiation therapy ± hormone therapy in a national Japanese prospective cohort study (J-POPS).
The safety and efficacy analyses included 6721 and 6662 patients, respectively. We categorized patients into two age groups: <60 (n = 716) and ≥60 (n = 6,005) years. We used propensity score matching (PSM) to estimate the marginal effect of age on biochemical freedom from failure (bFFF) using a Phoenix definition and Cox proportional hazard models.
The median followup period was 60.0 months. Without PSM, men <60 years demonstrated similar 5-year bFFF (96.3%) compared with men ≥60 years (95.6%; p = 0.576); percent positive biopsies, biologically effective dose, Gleason score, risk classification, and supplemental external beam radiation therapy (p <0.001, <0.001, <0.001, 0.008, and <0.001) were significantly associated with bFFF while age was not (p = 0.576). With PSM, bFFF was not significantly different between age groups (p = 0.664); however, men <60 years showed a significantly lower incidence of declining erectile function, grade ≥2 all urinary toxicities, urinary frequency/urgency, and rectal bleeding (p <0.001, 0.024, 0.031, and 0.010) than men ≥60 years.
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Integrating external beam and prostate seed implant dosimetry for intermediate and high-risk prostate cancer using biologically effective dose: Impact of image registration technique
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Combining external beam radiation therapy (EBRT) and prostate seed implant (PSI) is efficacious in treating intermediate- and high-risk prostate cancer at the cost of increased genitourinary toxicity. Accurate combined dosimetry remains elusive due to lack of registration between treatment plans and different biological effect. The current work proposes a method to convert physical dose to biological effective dose (BED) and spatially register the dose distributions for more accurate combined dosimetry.
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Clinical investigationProstateBiologically effective dose values for prostate brachytherapy: Effects on PSA failure and posttreatment biopsy results

Introduction

Section snippets

Methods and materials

Biochemical control

Discussion

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

J Urol

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

Int J Radiat Oncol Boil 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

Clinical investigation
Prostate
Biologically effective dose values for prostate brachytherapy: Effects on PSA failure and posttreatment biopsy results