prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer - related deaths amongst men in the united states .
brachytherapy is an effective treatment modality that can be utilized either alone or in combination with external beam radiation therapy ( ebrt ) for patients with localized prostate cancer of all risk groups [ 25 ] .
the combination of ebrt with brachytherapy can improve prostate cancer outcomes by allowing meaningful dose escalation while minimizing dose to organs at risk .
predictors of psa progression free survival following prostate brachytherapy have been extensively evaluated , whereas fewer studies have characterized predictors of distant metastases [ 2 , 7 ] .
the bulk of the data on predictors of distant metastasis are from external beam radiation therapy and low dose rate brachytherapy [ 2 , 79 ] .
data with respect to predictors of distant metastasis outcomes following high - dose - rate brachytherapy are more limited .
higher gleason score has been a significant predictor of distant metastasis in most series , whereas total dose has not always been [ 1113 ] .
determining predictors of metastatic disease following combination therapy is important , because it identifies men who could benefit from additional treatment .
we reviewed the clinical outcomes on our single institution experience treating localized prostate cancer with high - dose - rate brachytherapy boost ( hdr - b ) , and ebrt to identify predictors of distant metastases .
an institutional review board approved retrospective study that was performed on men with clinically localized biopsy - proven prostate cancer who were treated between 1991 and 2002 at a single center with hdr - b , and ebrt with at least one year of follow - up .
pretreatment evaluation included history and physical examination , digital rectal examination ( dre ) , transrectal ultrasonography ( trus ) , prostate biopsies with gleason score , and psa determination .
staging procedures , such as bone scan and ct of the abdomen and pelvis were performed for intermediate and higher risk patients .
hdr - b and ebrt were administered with a 2 week interval in between ( most commonly hdr first followed by ebrt ) .
two implants were performed 1 week apart with each implant used to deliver 2 hdr fractions ( i.e. total of 4 fractions ) . the procedure consisted of transperineal interstitial implantation of 17 - 18 flexiguides directed by trus , cystoscopy , and fluoroscopy .
simulation radiography , during the period of study , was based on plain film simulation , and dosimetry was computed using nucletron , versions 10 through 11.4 ( nucletron , an elekta company , elekta ab , stockholm , sweden ) .
the 100% isodose was normalized to a 5 - 6 mm margin anterior and lateral to the prostatic capsule to include microscopic disease extension , but the margin was limited to approximately 2 - 3 mm posteriorly to prevent rectal injury .
the urethral dose limits were 120% , except for cases of prior transuretheral resection of the prostate , where the maximum urethral dose constraint was reduced to 105% .
fluoroscopic verification of the brachytherapy catheter position was performed prior to the second treatment delivery .
dosimetric quality was determined by evaluation of dose volume histograms , analysis of clinical target volume coverage ( d90  dose to 90% prostate , v100  prostate volume receiving 100% prescription dose , and v150  prostate volume receiving 150% of the prescription dose ) and normal tissue dose constraints .
pelvic ebrt was delivered using 3d conformal treatment planning , and was delivered in 1.8 - 2.0 gy per fraction initially to 36 gy and later to 39.6 gy . when adt was utilized , it consisted of a luteinizing hormone releasing agonist usually with an antiandrogen .
it was typically initiated 3 months before ebrt and consisted of a short course (  6 months ) .
indications for adt were quite variable over the course of the study . in the early years , it was widely administered by referring physicians regardless of risk group . over time , the use of adt was less commonly prescribed for favorable disease . in some cases , it was used , without regard to risk group , to reduce the prostate volume prior to brachytherapy .
follow up consisted of office visits with digital rectal examination , psa testing and search of patient medical records for evidence of distant metastasis .
psa measurements were done for 3-month intervals for the first 2 years following completion of treatment , every 6 months for years 2 - 5 , and then yearly thereafter .
a cox proportional hazards model was employed to examine the risk of developing dm by several patient disease and treatment parameters , including age at diagnosis , t stage , gleason score , use of adt , and bed ( an / ratio of 1.2 gy was assumed ) .
beds were also converted to an equivalent 2 gy dose ( eqd2 ) for ease of interpretation , and are presented in the discussion section [ 14 , 15 ] . a two - sided p value < 0.05 was considered significant for all tests .
we identified 768 men with localized prostate cancer who were treated at our institution with hdr - b and ebrt ( table 1a ) . according to nccn risk stratification criteria , the distribution of patients was 26% low , 50% intermediate , and 24% high risk .
adt was administered to 380 patients ( 49% ) for a median duration of 4.5 months ( maximum 6 months ) .
the mean pre - treatment psa  standard deviation was 10.2  7 ng / ml .
the mean ebrt dose was 37.5 gy ( range : 30.6 - 45 gy ) and hdr - b dose 22 gy for 15% , and 24 gy for 85% of patients .
the median bed for hdr - b plus ebrt was 234 gy ( range : 212 - 249 gy ) . 
 
sd  standard deviation , bed  biologically equivalent dose , ebrt  external 
 beam radiation therapy , hdr
 high dose rate the median follow - up time for the entire patient population was 4.2 years ( range : 1.0 - 11.2 years ) .
the median follow - up for patients with low , intermediate , and high risk disease was 3.9 , 3.6 , and 3.8 years .
three percent ( 22/768 ) of patients developed distant metastases with a median time to a diagnosis of metastatic disease of 4.1 years ( range : 1.0 - 7.2 years ) .
all but one patient who developed metastatic disease had high ( n = 17 ) or intermediate ( n = 4 ) risk disease .
all distant metastasis , except for one , occurred in patients who received bed  234 gy ( table 1b ) .
actuarial curves for freedom from distant metastasis for low , intermediate , and high risk prostate cancer patients are shown in figure 1 . 
 
kaplan meier actuarial survival curve for psa progression free probability stratified by risk groups patient characteristics grouped by distant metastasis dm  distant metastases , bed  biologically equivalent dose psa failure ( phoenix definition ) developed in 7% of men with a median time to failure of 3.8 years ( range : 1.0 - 9.8 years ) . by nccn risk group psa failure developed in 3% , 5% , and 14% of men with low , intermediate , and high risk disease ( table 2 ) .
actuarial curves for psa progression free survival for low , intermediate , and high risk patients are shown in figure 2 . local tumor control ( i.e. failure to manifest clinical disease progression in the prostate )
kaplan meier actuarial survival curve for distant metastasis free probability stratified by risk groups patient characteristics grouped by psa failure bed 
biologically equivalent dose on univariate analysis , t stage , gs , and use of adt were significantly associated with developing dm ( table 3 ) .
multivariate analysis showed increasing gs was associated with an increased risk of developing distant metastasis ( p < 0.05 ) ( table 3 ) .
multivariate analysis also showed an increased risk of developing distant metastasis with the use of adt .
this lead us to compare the makeup of patients treated with adt to those without adt to determine if patient selection bias could explain this finding .
we found that patients selected for adt had significantly higher gs , t stage , and pre - treatment psa ( all p < 0.0001 ) compared to those who did not receive adt ( table 4 ) . 
 
univariate and multivariate analysis for predictors of psa failure ( phoenix definition ) and distant metastasis bf  biochemical failure ,
dm  distant metastasis patient characteristics based on androgen deprivation therapy ( adt ) bf  biochemical failure , dm  distant metastasis
most clinical reports following definitive treatment of prostate cancer use psa control as a primary endpoint , but it is clear from longitudinal studies that biochemical failure does not always lead to other evidence of disease progression . such an observation was made in a series of 1997 men with clinically localized prostate cancer treated with radical prostatectomy , of whom 15% ( n = 315 ) developed psa progression .
after a median follow - up of eight years only , 30% of men of those with psa failure went on to developed metastasis .
this discordance between psa failure and the development of distant metastases underscores the need to identify factors that predict for a higher likelihood of developing clinically meaningful events such as the occurrence of distant metastasis which can impact quality of life and survival .
one of the largest series looking at predictors of distant metastasis was performed on 8669 men with clinically localized or locally advanced non - metastatic prostate cancer , treated with either ebrt alone or surgery .
they found that a post - treatment psa doubling time of less than 3 months predicted a 20-fold increase in the risk of dying from prostate cancer .
combining gleason score with psa doubling time further improves predicting prostate cancer - specific mortality .
other studies in patients treated definitively with ebrt have identified t stage , gleason score , pretreatment psa , adt use , and higher radiation dose as other significant predictors of distant metastasis free survival . while some information is known regarding predictors of distant metastasis following ebrt , less is known following brachytherapy . in two of the largest low dose rate ( ldr ) brachytherapy series forsythe et al . showed gleason score and psa doubling time as significant predictors , whereas taira et al . found that metastasis free survival was most closely related to gleason score and year of treatment .
hdr is significantly different from ldr with respect to dose rate , and technique suggesting there may be differences in predictors of outcomes between the two modalities . in terms of hdr ,
the largest published study of predictors of distant metastasis following hdr and ebrt comes from the experience at william beaumont hospital ( wbh ) by martinez et al . , who reported on 472 men with intermediate and high risk disease .
they performed a dose escalation investigation starting with hdr doses of 5.5 gy x 3 and ending with 11.5 gy x 2 for the hdr component of treatment .
they found that when the bed ( / ratio 1.2 ) was  268 gy ( which corresponded to 9.5 gy x 2 ) there was less biochemical failure , better local control , and fewer cases of distant metastasis .
they also observed that gleason score predicted biochemical and overall clinical control , but did not independently correlate with freedom from distant metastasis . in another series from memorial sloan kettering cancer center ( mskcc ) , kotecha et al .
reported on the outcomes of 229 patients with clinically localized prostate cancer treated with a hdr brachytherapy boost ( 5.5 gy x 3 to 7.5 gy x 3 ) followed by ebrt ( most patients were treated to 50.4 gy ) . amongst high risk patients a higher bed ( > 190 gy , / ratio of 2 ) resulted in improved biochemical control and distant metastases free survival . in a final large series from prada et al . that included outcomes of 313 patients with localized prostate cancer with 46 gy of ebrt , and hdr brachytherapy boost of 11.5 gy x 2 , gleason score was the only factor significantly associated with developing distant metastasis .
our data is consistent with the published literature demonstrating the importance of gs in predicting the risk of developing distant metastasis , however we did not find that bed was significant on multivariate analysis . our early standard treatment consisted of 36 gy ebrt plus 6 gy x 4 fractions of hdr .
in 1999 we increased the ebrt dose from 36 gy to 39.6 gy without changing the hdr program . if we convert the doses used in this series ( ebrt 39.6 gy + 6 gy x 4 hdr ) , the wbh series over which they saw improved outcomes ( ebrt 46 gy + 9.5 gy x 2 hdr ) , the mskcc series over which they saw improved outcomes in high risk patients ( ebrt 50.4 gy + 7.5 gy x 3 hdr ) , and the prada series ( ebrt 46 gy + 11.5 gy x 2 ) to a bed assuming an / ratio of 1.2 gy we get 243 gy , 292 gy , 289 gy , and 366 gy . converting these beds to eqd2s we
get 203 , 243 , 241 , and 305 gy . while there is variation in the total bed ; the bed from the hdr component of treatment for the four series are similar at 144 gy , 169 gy , and 163 gy .
it is speculative whether this suggests the hdr component of treatment is more critical to treatment outcomes than the ebrt dose .
differences in dosimetry policies between institutions may also affect the actual biologically significant dose delivered that is not manifest in the hdr prescription alone .
for example , the dose was prescribed to the prostate plus a several millimeter margin beyond the prostate ( except where it was immediately adjacent to the bladder and rectum ) .
the bed dose to the prostate was then ebrt 39.6 + hdr 6.6 gy x 4 ( bed 99 + 172 = 271 ) .
ultimately one explanation for why we did not find a significant relationship in our cohort of 768 patients between developing distant metastasis and bed could be because the total ebrt plus brachytherapy dose , and range of total dose delivered was lower than the thresholds seen for improved outcomes in the wbh series .
patients who received adt had significantly higher risk features such as gleason score , t stage , and pre - treatment psa that we believe explains the higher incidence of distant metastases as opposed to a negative interaction between hdr - b and adt .
in addition , the median duration of hormone therapy was 4.5 months which is much shorter than is now commonly recommended for high risk patients , and as a result some men may have been undertreated .
this analysis has shortcomings that include its retrospective design and a short median follow - up . despite these issues ,
our overall clinical results are consistent with other published studies reporting outcomes of hdr brachytherapy in combination with external beam radiation therapy [ 13 , 1923 ] .
this report on a very large group of patients strengthens the evidence regarding the importance of gs in predicting outcomes even after delivering high doses of local radiation .
in men treated with hdr - b and ebrt , gs is a significant factor on multivariate analysis for developing distant metastasis .
 purposeto determine predictors of distant metastases ( dm ) in prostate cancer patients treated with high dose rate brachytherapy boost ( hdr - b ) and external beam radiation therapy ( ebrt).material and methodsfrom 1991 to 2002 , 768 men with localized prostate cancer were treated with hdr - b and ebrt . 
 the mean ebrt dose was 37.5 gy ( range : 30.6 - 45 gy ) , and the hdr - b was 22 or 24 gy delivered in 4 fractions . 
 univariate and multivariate analyses using a cox proportional hazards model including age at diagnosis , t stage , gleason score ( gs ) , pretreatment psa , biologically equivalent dose ( bed ) , and use of androgen deprivation therapy ( adt ) was used to determine predictors of developing distant metastases.resultsthe median follow - up time for the entire patient population was 4.2 years ( range : 1 - 11.2 years ) . 
 distant metastases were identified in 22/768 ( 3% ) of patients at a median of 4.1 years . 
 psa failure according to the phoenix definition developed in 3% , 5% , and 14% of men with low , intermediate , and high risk disease with a median time to failure of 3.8 years . 
 prostate cancer specific mortality was observed in 2% of cases . 
 t stage , gs , and use of adt were significantly associated with developing dm on univariate analysis . 
 gs , and use of adt were the only factors significantly associated with developing dm on multivariate analysis ( p < 0.01 ) . 
 patients who received adt had significantly higher risk features suggesting patient selection bias for higher dm in this group of patients rather than a negative interaction between hdr - b and ebrt.conclusionsin men treated with hdr - b and ebrt , gs is a significant factor on multivariate analysis for developing distant metastasis . 