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The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy
Brachytherapy 10 (2011) 442e448
The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy Christopher Herbert1,*, W. James Morris1, Jeremy Hamm2, Vincent Lapointe1, Michael McKenzie1, Tom Pickles1, Ingrid Spadinger1, Mira Keyes1 1
Department of Radiation Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada 2 Surveillance and Outcomes Unit, BC Cancer Agency, Vancouver, British Columbia, Canada
ABSTRACT
PURPOSE: The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort. METHODS AND MATERIALS: Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) O0.4 ng/mL at $48 months postimplant. Actuarial estimates were calculated by the KaplaneMeier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model. RESULTS: There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6e96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8e96.2) for patients treated with RS according to Phoenix definition ( p 5 0.846). Using the PSA O0.4 ng/mL definition, estimated rates were 91.3% (95% CI, 88.0e94.6) and 91.9% (95% CI, 89.7e94.1) for loose and stranded seeds, respectively ( p 5 0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED. CONCLUSION: This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA O0.4 ng/mL definitions of biochemical failure. Crown Copyright Ó 2011 Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Brachytherapy; Loose seeds; Stranded seeds; Biochemical relapse
Introduction Ultrasound-guided transperineal lowedose rate prostate brachytherapy is a standard treatment option for men with localized adenocarcinoma of the prostate. Implants can be performed using either loose seeds or stranded seeds, such Received 6 December 2010; received in revised form 17 January 2011; accepted 18 January 2011. Conflict of interest statement: The authors declare no conflict of interest. * Corresponding author. Department of Radiation Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. Tel.: þ1-604-8776000, local 2697; fax: þ1-604-8770505. E-mail address: [email protected] (C. Herbert).
as RAPIDStrand (RS; Oncura Inc., Plymouth Meeting, PA), where multiple sources with intervening spacers are linked together. A recent study by Hinnen et al. (1) has assessed the difference between loose and stranded seeds in terms of biochemical control rates in 896 patients, using the Phoenix definition of biochemical relapse. Although no significant differences were found between the groups on univariate analysis, when adjusted for confounding factors in a multivariate analysis, it was shown that seed type was significantly associated with the risk of biochemical failure with a 43% risk reduction for patients treated with loose seeds compared with stranded seeds.
1538-4721/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.brachy.2011.01.011
C. Herbert et al. / Brachytherapy 10 (2011) 442e448
The British Columbia Cancer Agency (BCCA) has been performing iodine-125 (125I) prostate brachytherapy implants since July 20, 1998. Overall survival and biochemical outcomes for the first 1006 patients have been reported elsewhere (2). To date, more than 3000 implants have been performed. Initially, all implants were performed using loose seeds. The first RS implant was performed in March 1999 and RS was used intermittently until November 2000, when all subsequent implants were carried out using stranded seeds (RS). The routine use of RS was implemented to reduce the incidence of seed embolization (3) and permit the reliable use of extraprostatic seed placement. Furthermore, initial study demonstrated that implant dosimetry did not seem to be inferior to that of loose seed implants (3). The aim of this study was to investigate whether the risk of biochemical relapse after 125I brachytherapy was different in patients treated with loose seeds compared with stranded seeds, among a population-based cohort of the first 1500 patients treated by the BCCA Provincial Prostate Brachytherapy Program.
Methods and materials Between July 20, 1998 and February 7, 2006, 1500 consecutive patients were treated at the BCCA using a preplan technique (4). The cutoff date was selected to allow a minimum of 4-year followup. All patients were Stage #T2c, N0/X, M0/X with the exception of 1 patient who was Stage T3a. Intermediate-risk patients and patients with prostate volumes $50 cm3 received 3 months of neoadjuvant and 3 months of adjuvant androgen suppression therapy using gonadotropin-releasing hormone (luteinizingreleasing hormone) agonist therapy combined with 1 month of an oral antiandrogen. The study was approved by the institutional ethics committee. Treatment parameters The planning and implant procedure performed at BCCA has previously been described (5, 6). A transrectal ultrasound (TRUS) was performed in the treatment position between 4 and 10 weeks before implantation. All implants were performed by one of 10 radiation oncologists trained in the procedure. TRUS images were imported to a VariSeed planning system (Varian Medical Systems Inc., Palo Alto, CA), and the prostate was contoured by a radiation oncologist. The prostate was expanded to a planning target volume (PTV) by adding the following margins: 3e5 mm margin laterally, 0 mm posteriorly, 3e5 mm anteriorly, 0e5 mm inferiorly, and 5e10 mm superiorly. With respect to the superior margin, 10 mm was sometimes used in the posterior aspect, deliberately implanting sources in the proximal seminal vesicles and perivesicle soft tissues; smaller margins were used in the anterior base, and the bladder lumen was specifically excluded form the PTV.
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Use of this conformal superior margin predates both the use of RS and reports of RS-associated caudal shift. The manual planning algorithm used featured symmetric source and needle positions with respect to the midsagittal plane and greater source densities in the posterioreperipheral region of the PTV. A minimum peripheral dose of 144 Gy was prescribed to cover at least 98% of the PTV. Relative sparing of the periurethral region was used with dose limited to !150% of the minimum peripheral dose. To ensure adequate coverage of the PTV, sources were planned for placement in the soft tissues adjacent to the posterior bladder neck, base of the seminal vesicles, and the periprostatic tissue near the apex. Implantation was performed using a real-time TRUSguided technique, as previously described by the Seattle group (4). All implants used the same source strength (0.33 mCi; 0.424 U [National Institute of Standards and Technology 99] 125I sources [model 6711; Oncura Inc., Arlington Heights, IL]). Before November 2000, loose sources were used for all but a few patients. Subsequently, all implants were performed using stranded sources (RS). Loose seeds (typically between 0 and 20 seeds) were used only in centrally located special load needles for the purpose of urethral sparing, or as up to five unplanned sources at the end of a procedure to boost areas of known disease, or to correct suspected areas of dose deficiency. A CT scan was performed 28 days after implantation and used for dosimetric evaluation unless the patient was from a remote location, when the scan was undertaken at Day 0. CT images were imported into VariSeed planning system, and the prostate and rectum were contoured by a radiation oncologist. A medical physicist identified the source coordinates by using a combination of manual selection and automated redundancy checks available in VariSeed planning system. Dosimetric values calculated included postoperative minimum dose covering 90% of the postimplant CT prostate volume (D90) and the percentage of postimplant CT prostate volume covered by 200%, 150%, 100%, 90%, and 80% of the prescription dose, respectively (V200, V150, V100, V90, and V80, respectively). Followup The date of brachytherapy implant was considered Day 0 for followup. Patients were assessed in clinic at 6 weeks postimplant, then every 6 months for 2e3 years, and then annually. Prostate-specific antigen (PSA) and testosterone were measured every 6 months. Physical examination, toxicity, as well as PSA and testosterone levels were recorded and entered prospectively into a database. End points Biochemical relapse was defined and analyzed using two alternative definitions. The conventional means of reporting biochemical failure for patients treated with radiotherapy
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has been the Phoenix definition (an increase in PSA level by 2 ng/mL or greater than nadir) (7). This has been criticized as it does not allow fair comparison to surgical series that use much stricter definitions of biochemical failure. Other authors have suggested using an absolute threshold of PSA O0.4 ng/mL (8, 9). Therefore, we also defined biochemical recurrence as PSA O0.4 ng/mL at $48 months postimplant. The $48-month cutoff was used because of the phenomenon of ‘‘PSA bounce’’ seen within the first 4 years postimplant, whereby 20e40% of implanted patients experience benign and transitory increases in PSA, which subsequently settle without intervention (10e15). Statistical analysis Actuarial estimates for overall survival and biochemical no evidence of disease (bNED) according to both Phoenix and the PSA O0.4 ng/mL threshold were calculated by the KaplaneMeier method (16). The same analysis was repeated with the first 100 loose and stranded seed implants excluded as a surrogate means of assessing whether there was a ‘‘learning curve’’ effect associated with the introduction of a new technique. Log-rank (ManteleCox) test was used to evaluate differences between survival curves. Variables were screened in univariate models, and those showing some association with bNED were included with seed type in a Cox regression multivariate model. Statistical analyses were undertaken using the Statistical Package of Social Sciences, version 14.0 (SPSS Inc., Chicago, IL).
bNED was 93.5% (95% CI, 90.6e96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8e96.2) for patients treated with stranded seeds according to the Phoenix definition ( p 5 0.846). Using the PSA O0.4 ng/mL definition, actuarial estimated rates of bNED at 7 years were 91.3% (95% CI, 88.0e94.6) and 91.9% (95% CI, 89.7e94.1) for loose seeds and stranded seeds, respectively ( p 5 0.871). KaplaneMeier plots are shown in Figs. 1 and 2. Exclusion of the first 100 loose and stranded implants from the analysis also revealed no difference in bNED according to seed type. Actuarial bNED estimates at 7 years using the Phoenix definition were 95.1% (95% CI, 92.0e98.2) and 93.3% (95% CI, 90.8e95.8) for loose seeds vs. stranded seeds ( p 5 0.311). Using the PSA O0.4 ng/mL definition of biochemical relapse, bNED estimates at 9 years were 92.2% (95% CI, 88.3e96.1) and 91.3% (95% CI, 88.9e93.7) for loose and stranded seeds, respectively ( p 5 0.647). Multivariate Cox regression analysis was performed to adjust for potential confounding factors. Terms included in the analysis were seed type, log initial PSA, use of androgen deprivation therapy (ADT), Gleason score $7, and implant order. There was no statistically significant difference between loose and stranded seeds in terms of bNED using either the Phoenix (hazard ratio [HR], 0.77; 95% CI, 0.43e1.37; p 5 0.3740) or the PSA O0.4 ng/mL definitions (HR, 0.81; 95% CI, 0.51e1.30; p 5 0.3873). The results of the Cox regression analysis are shown in Table 4.
Results Three hundred twenty-seven patients1 (21.8%) were treated with loose seeds and 1173 (78.2%) with RS. The median age was 66 years (range, 45e82). Median followup was 72.7 months (range, 0.7e141.4) for patients treated with loose seeds and 56.8 months (range, 0.8e127.9) for patients treated with stranded seeds. Postimplant dosimetric data were available for 1467 patients (97.8%). Baseline clinical and dosimetric characteristics of the patients are shown in Table 1. Patient outcomes are shown in Table 2. Actuarial overall survival (death from all causes) for all patients at 7 years was 89.8% (95% confidence interval [CI], 87.8e91.8). Of the 9 patients who have died with or from disease, 7 patients developed metastases and died of their disease, whereas 2 patients developed biochemical relapses and died of other causes. Biochemical recurrence occurred in 61 patients according to the Phoenix definition and 98 patients according to the PSA O0.4 ng/mL definition of biochemical failure. Univariate analysis demonstrated no difference between loose and stranded seeds (see Table 3). Estimated rate of 1 Note: Our previous publication comparing postimplant dosimetry (3) stated that 334 loose seed implants had been performed at BCCA. This has been amended to 327.
Discussion The results from this large population-based cohort of consecutive patients treated with 125I prostate brachytherapy showed no evidence of any difference between loose and stranded seeds in terms of biochemical control rates using either the Phoenix definition or the alternative PSA O0.4 ng/mL definition of biochemical failure. The study had power to detect a 5% difference in biochemical control rates between the two groups. Of note, there were significantly more patients with Gleason score O6 ( p! 0.0001), bilaterally palpable tumors ( p !0.0001), and a larger proportion with $50% of cores positive ( p! 0.0001) in the group treated with RS. In addition, significantly fewer RS patients received ADT ( p !0.0001). Only pretreatment PSA values were greater in the group treated with loose seeds ( p 5 0.03). In our earlier article where outcomes in terms of biochemical control for the first 1006 patients treated by the BCCA Provincial Prostate Brachytherapy Program were presented, ADT was shown on multivariate analysis to be associated with a decreased risk of biochemical failure (HR, 0.47; p 5 0.044), whereas higher pretreatment PSA correlated with increased risk of relapse (HR, 7.86 per log10 increase in PSA; p 5 0.031) (2). Despite these generally less favorable characteristics
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Table 1 Clinical and dosimetric characteristics of patients treated with prostate brachytherapy Loose (n 5 327)
Variable
Stranded (n 5 1173)
p-Value
Total (n 5 1500)
0.79 0.01
66 (45e82) 6.3 (0.3e40)
Clinical characteristics Age (y) Pretreatment PSA (ng/mL) Gleason score #6 $7 Clinical stage T1 T2 T2a unilateral T2b bilateral T3a NCCN risk group Low Intermediate High ADT % positive cores !50 $50 Missing
66 (49e80) 6.6 (0.3e16)
66 (45e82) 6.2 (0.3e40)
278 (85.0%) 49 (15.0%)
781 (66.6%) 392 (33.4%)
!0.0001
138 189 131 58
572 600 478 122
!0.0001
(42.2%) (57.8%) (40.1%) (17.7%)
0
(48.8%) (51.2%) (40.8%) (10.4%)
1 185 (56.6%) 142 (43.4%)
710 789 609 180
(47.3%) (52.6%) (40.6%) (12%)
828 668 4 958
(55.2%) (44.5%) (0.3%) (63.9%)
1
238 (72.8%)
643 526 4 720
167 (51.1%) 88 (26.9%) 72 (22.0%)
802 (68.4%) 344 (29.3%) 27 (2.3%)
0
1059 (70.6%) 441 (29.4%)
(54.8%) (44.8%) (0.3%) (61.4%)
0.47
0.0001 !0.0001
969 (64.6%) 432 (28.8%) 99 (6.6%)
Dosimetric characteristics Variable
Loose (n 5 321)
D90 (%) V100 (%) V150 (%) V200 (%)
102.5 91.3 52.6 22.3
Stranded (n 5 1146)
(102.2 13.8) (89.2 8.0) (51.3 14.1) (23.0 9.2)
106.5 93 57.2 24.9
(106.7 12.1) (92.2 4.9) (57.0 11.2) (25.2 8.9)
p-Value
Total (n 5 1467)
!0.0001 !0.0001 !0.0001 0.0004
105.6 92.6 56.3 24.3
(105.7 12.7) (91.5 5.9) (55.7 12.1) (24.7 9.0)
PSA 5 prostate-specific antigen; NCCN risk group 5 National Comprehensive Cancer Network risk group (17); ADT 5 androgen deprivation therapy; D90 5 minimum dose covering 90% of the postimplant CT prostate volume; Vx 5 postimplantation CT prostate volume covered by x%. Values expressed as median (range), number (percent), or median (mean standard deviation). Pearson c2 statistic was used to display the probability of type of seed having a relationship with the variable of interest. Median values were compared for continuous variables using the Wilcoxon rank sum test.
among the RS patients, however, we did not detect a difference between the two groups in terms of bNED. Because the BCCA Provincial Prostate Brachytherapy Program first performed implants using loose seeds and later switched to stranded seeds for all cases, one possible factor that might influence biochemical outcome is the ‘‘learning curve’’ that may be experienced with the introduction of a new technique. Our group has previously shown that a learning curve effect was seen when we analyzed dosimetry between seed types in a smaller sample from this patient Table 2 Patient outcomes Outcome Relapsed Alive (n 5 1369) ANED AWD Dead (n 5 131) DNED DO/WD
Phoenix
PSA O0.4 ng/mL
61 (4.1%)
98 (6.5%)
1317 (87.8%) 52 (3.5%)
1280 (85.3%) 89 (5.9%)
122 (8.1%) 9 (0.6%)
122 (8.1%) 9 (0.6%)
PSA 5 prostate-specific antigen; ANED 5 alive with no evidence of disease; AWD 5 alive with disease; DNED 5 dead with no evidence of disease; DO/WD 5 dead of or with disease.
cohort (3). However, excluding the first 100 patients implanted with both loose and stranded seeds from the analysis also failed to demonstrate a statistically significant difference between loose and stranded seeds. It is important to note that the first 100 loose seed implants represented both the BCCA Provincial Prostate Brachytherapy Program and individual learning curves, whereas the first 100 RS implants simply represented the learning curve associated with the change in seed type. This is reflected in postimplant dosimetry, with a mean D90 of 139.2 Gy (standard deviation [SD] 20.5 Gy) for the first 100 loose seed implants compared with a mean D90 of 146.7 Gy (SD 21.9 Gy) for the first 100 RS implants. Similarly, mean V100 for the first 100 loose implants was 85.8% (SD 9.8%) and 89.8% (SD 6.1%) for the first 100 stranded implants. Our findings are in contrast to those of Hinnen et al. (1), the only other article to have reported biochemical outcomes to date. They examined outcome in terms of bNED, using the Phoenix definition, in 538 patients implanted with stranded seeds, either RS or Intersource (IBt Bebig, Belgium), and 358 patients treated with loose seeds. When adjusted for confounding factors in a multivariate analysis, they found that seed type was significantly
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Table 3 Univariate analysis (Cox regression) of effect of seed type on biochemical no evidence of disease Variable
HR
95% CI
p-Value
Phoenix definition Age at the time of implant Log iPSA % positive cores Gleason score Implant order NCCN risk group Androgen deprivation T stage D90 V100
0.95 0.98 0.91 0.86 0.66 0.95 0.93 0.96 0.99 0.98
0.54e1.66 0.56e1.71 0.50e1.66 0.48e1.52 0.34e1.28 0.54e1.66 0.53e1.63 0.55e1.63 0.56e1.75 0.55e1.76
0.85 0.93 0.77 0.60 0.22 0.85 0.80 0.90 0.96 0.95
PSA O0.4 ng/mL Age at the time of implant Log iPSA % positive cores Gleason score Implant order NCCN risk group Androgen deprivation T stage D90 V100
0.97 0.99 0.98 0.92 0.70 0.97 0.93 0.98 1.0 1.1
0.61e1.53 0.63e1.57 0.60e1.63 0.57e1.47 0.41e1.22 0.61e1.53 0.58e1.47 0.62e1.55 0.65e1.67 0.66e1.72
0.88 0.98 0.95 0.72 0.21 0.88 0.75 0.93 0.85 0.79
HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostatespecific antigen; NCCN risk group 5 National Comprehensive Cancer Network risk group (17); PSA 5 prostate-specific antigen; D90 5 minimum dose covering 90% of the postimplant CT prostate volume; V100 5 postimplantation CT prostate volume covered by 100%.
associated with the risk of biochemical failure with a 43% risk reduction for loose seeds vs. stranded seeds. They speculate that possible reasons for this difference between seed types include retraction of stranded seeds during implantation, the loading pattern of stranded seeds with spacers
between each active source, and the fact that stranded seeds (unlike loose seeds) cannot track with the expanding edematous prostate gland postimplantation. An earlier study by this group looking at postimplant dosimetry found a decline in D90 for all seed types from time of implant to assessment at 4 weeks postimplant. There was, however, a significantly larger decline in D90 for stranded seeds compared with loose seeds (18). It was hypothesized that this may be because of strand retraction either during or after implantation. One explanation for our findings might be that RS implants achieve superior postimplant dosimetry compared with loose seed implants. Within our patient cohort, we observed statistically significant differences in D90% ( p ! 0.001), V100% ( p! 0.001), V150% ( p !0.001), and V200% ( p 5 0.001) favoring RS implants. These findings are supported by most of other studies in the literature that have assessed differences between postimplant dosimetry according to seed type (3, 19e23). Fagundes et al. (19) assessed dosimetry in 473 patients (337 treated with loose seeds) and demonstrated higher mean D90 and V100 for the patients treated with stranded seeds. This finding was supported by the study from Heysek et al. (20) where 272 patients were assessed and D90 was found to be higher in those treated with stranded seeds, although this difference was not clinically significant. Three smaller studies (21e23) also suggested that stranded seeds gave an improved dosimetry. Our own earlier comparison of loose and RS dosimetry where 54 loose seed and 81 RS patients from our database were analyzed showed statistically significant differences with significantly higher V150, V200, and contiguous V200 in the RS implants when assessing the whole prostate. These differences were, however, very small and may not be clinically significant. In addition,
Fig. 1. Biochemical no evidence of disease (Phoenix) according to seed type.
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Fig. 2. Biochemical no evidence of disease (prostate-specific antigen O0.4 ng/mL) according to seed type.
these differences may be attributable to factors other than seed type (such as maturity of our program, leading to a gradual increase in mean dosimetry in the much larger and mature RS cohort). It is important to note that no statistically significant difference was observed, however, between seed types in terms of D90 and V100 (3). On the other hand, other studies support better dosimetry in loose seed implants compared with stranded seeds. The findings by Moerland et al. (18) are summarized above. Reed et al. (24), in a randomized prospective study of 62 patients, found improved dosimetry for loose seeds, although the difference between the two groups was not statistically significant. Saibishkumar et al. (25) reported that loose seeds had better dosimetry at Day 0, but that there was no difference at Day 30 between the two seed types. Table 4 Multivariate analysis (Cox regression) of effect of seed type on biochemical no evidence of disease
Conclusions In this population-based study of 1500 consecutive patients treated with ultrasound-guided transperineal prostate brachytherapy, we found no evidence of a difference between loose and stranded seeds in terms of bNED, using either the Phoenix or PSA O0.4 ng/mL definitions of biochemical failure. Exclusion of the first 100 loose and RS implants from the analysis as a surrogate measure of assessing the learning curve effect made no significant difference to our analysis. Given the divided evidence in the literature, the logical conclusion is that either seed format can provide excellent results. However, this is not to say that the two formats are interchangeable for a single operator because of subtle differences in planning and technique may lead to noticeably different outcomes with loose vs. stranded seeds.
References
Variable
HR
95% CI
p-Value
Phoenix definition Loose vs. stranded seeds Log iPSA Androgen deprivation Gleason score $7
0.77 2.58 0.38 2.55
0.43e1.37 1.42e4.70 0.20e0.73 1.39e4.68
0.3740 0.0019 0.0033 0.0025
PSA O0.4 ng/mL Loose vs. stranded seeds Log iPSA Androgen deprivation Gleason score $7
0.81 2.53 0.38 1.82
0.51e1.30 1.60e4.02 0.23e0.62 1.12e2.97
0.3873 !0.0001 0.0001 0.0163
HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostatespecific antigen; PSA 5 prostate-specific antigen.
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The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy Christopher Herbert1,*, W. James Morris1, Jeremy Hamm2, Vincent Lapointe1, Michael McKenzie1, Tom Pickles1, Ingrid Spadinger1, Mira Keyes1 1
Department of Radiation Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada 2 Surveillance and Outcomes Unit, BC Cancer Agency, Vancouver, British Columbia, Canada
ABSTRACT
PURPOSE: The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort. METHODS AND MATERIALS: Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) O0.4 ng/mL at $48 months postimplant. Actuarial estimates were calculated by the KaplaneMeier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model. RESULTS: There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6e96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8e96.2) for patients treated with RS according to Phoenix definition ( p 5 0.846). Using the PSA O0.4 ng/mL definition, estimated rates were 91.3% (95% CI, 88.0e94.6) and 91.9% (95% CI, 89.7e94.1) for loose and stranded seeds, respectively ( p 5 0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED. CONCLUSION: This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA O0.4 ng/mL definitions of biochemical failure. Crown Copyright Ó 2011 Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Brachytherapy; Loose seeds; Stranded seeds; Biochemical relapse
Introduction Ultrasound-guided transperineal lowedose rate prostate brachytherapy is a standard treatment option for men with localized adenocarcinoma of the prostate. Implants can be performed using either loose seeds or stranded seeds, such Received 6 December 2010; received in revised form 17 January 2011; accepted 18 January 2011. Conflict of interest statement: The authors declare no conflict of interest. * Corresponding author. Department of Radiation Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. Tel.: þ1-604-8776000, local 2697; fax: þ1-604-8770505. E-mail address: [email protected] (C. Herbert).
as RAPIDStrand (RS; Oncura Inc., Plymouth Meeting, PA), where multiple sources with intervening spacers are linked together. A recent study by Hinnen et al. (1) has assessed the difference between loose and stranded seeds in terms of biochemical control rates in 896 patients, using the Phoenix definition of biochemical relapse. Although no significant differences were found between the groups on univariate analysis, when adjusted for confounding factors in a multivariate analysis, it was shown that seed type was significantly associated with the risk of biochemical failure with a 43% risk reduction for patients treated with loose seeds compared with stranded seeds.
1538-4721/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.brachy.2011.01.011
C. Herbert et al. / Brachytherapy 10 (2011) 442e448
The British Columbia Cancer Agency (BCCA) has been performing iodine-125 (125I) prostate brachytherapy implants since July 20, 1998. Overall survival and biochemical outcomes for the first 1006 patients have been reported elsewhere (2). To date, more than 3000 implants have been performed. Initially, all implants were performed using loose seeds. The first RS implant was performed in March 1999 and RS was used intermittently until November 2000, when all subsequent implants were carried out using stranded seeds (RS). The routine use of RS was implemented to reduce the incidence of seed embolization (3) and permit the reliable use of extraprostatic seed placement. Furthermore, initial study demonstrated that implant dosimetry did not seem to be inferior to that of loose seed implants (3). The aim of this study was to investigate whether the risk of biochemical relapse after 125I brachytherapy was different in patients treated with loose seeds compared with stranded seeds, among a population-based cohort of the first 1500 patients treated by the BCCA Provincial Prostate Brachytherapy Program.
Methods and materials Between July 20, 1998 and February 7, 2006, 1500 consecutive patients were treated at the BCCA using a preplan technique (4). The cutoff date was selected to allow a minimum of 4-year followup. All patients were Stage #T2c, N0/X, M0/X with the exception of 1 patient who was Stage T3a. Intermediate-risk patients and patients with prostate volumes $50 cm3 received 3 months of neoadjuvant and 3 months of adjuvant androgen suppression therapy using gonadotropin-releasing hormone (luteinizingreleasing hormone) agonist therapy combined with 1 month of an oral antiandrogen. The study was approved by the institutional ethics committee. Treatment parameters The planning and implant procedure performed at BCCA has previously been described (5, 6). A transrectal ultrasound (TRUS) was performed in the treatment position between 4 and 10 weeks before implantation. All implants were performed by one of 10 radiation oncologists trained in the procedure. TRUS images were imported to a VariSeed planning system (Varian Medical Systems Inc., Palo Alto, CA), and the prostate was contoured by a radiation oncologist. The prostate was expanded to a planning target volume (PTV) by adding the following margins: 3e5 mm margin laterally, 0 mm posteriorly, 3e5 mm anteriorly, 0e5 mm inferiorly, and 5e10 mm superiorly. With respect to the superior margin, 10 mm was sometimes used in the posterior aspect, deliberately implanting sources in the proximal seminal vesicles and perivesicle soft tissues; smaller margins were used in the anterior base, and the bladder lumen was specifically excluded form the PTV.
443
Use of this conformal superior margin predates both the use of RS and reports of RS-associated caudal shift. The manual planning algorithm used featured symmetric source and needle positions with respect to the midsagittal plane and greater source densities in the posterioreperipheral region of the PTV. A minimum peripheral dose of 144 Gy was prescribed to cover at least 98% of the PTV. Relative sparing of the periurethral region was used with dose limited to !150% of the minimum peripheral dose. To ensure adequate coverage of the PTV, sources were planned for placement in the soft tissues adjacent to the posterior bladder neck, base of the seminal vesicles, and the periprostatic tissue near the apex. Implantation was performed using a real-time TRUSguided technique, as previously described by the Seattle group (4). All implants used the same source strength (0.33 mCi; 0.424 U [National Institute of Standards and Technology 99] 125I sources [model 6711; Oncura Inc., Arlington Heights, IL]). Before November 2000, loose sources were used for all but a few patients. Subsequently, all implants were performed using stranded sources (RS). Loose seeds (typically between 0 and 20 seeds) were used only in centrally located special load needles for the purpose of urethral sparing, or as up to five unplanned sources at the end of a procedure to boost areas of known disease, or to correct suspected areas of dose deficiency. A CT scan was performed 28 days after implantation and used for dosimetric evaluation unless the patient was from a remote location, when the scan was undertaken at Day 0. CT images were imported into VariSeed planning system, and the prostate and rectum were contoured by a radiation oncologist. A medical physicist identified the source coordinates by using a combination of manual selection and automated redundancy checks available in VariSeed planning system. Dosimetric values calculated included postoperative minimum dose covering 90% of the postimplant CT prostate volume (D90) and the percentage of postimplant CT prostate volume covered by 200%, 150%, 100%, 90%, and 80% of the prescription dose, respectively (V200, V150, V100, V90, and V80, respectively). Followup The date of brachytherapy implant was considered Day 0 for followup. Patients were assessed in clinic at 6 weeks postimplant, then every 6 months for 2e3 years, and then annually. Prostate-specific antigen (PSA) and testosterone were measured every 6 months. Physical examination, toxicity, as well as PSA and testosterone levels were recorded and entered prospectively into a database. End points Biochemical relapse was defined and analyzed using two alternative definitions. The conventional means of reporting biochemical failure for patients treated with radiotherapy
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has been the Phoenix definition (an increase in PSA level by 2 ng/mL or greater than nadir) (7). This has been criticized as it does not allow fair comparison to surgical series that use much stricter definitions of biochemical failure. Other authors have suggested using an absolute threshold of PSA O0.4 ng/mL (8, 9). Therefore, we also defined biochemical recurrence as PSA O0.4 ng/mL at $48 months postimplant. The $48-month cutoff was used because of the phenomenon of ‘‘PSA bounce’’ seen within the first 4 years postimplant, whereby 20e40% of implanted patients experience benign and transitory increases in PSA, which subsequently settle without intervention (10e15). Statistical analysis Actuarial estimates for overall survival and biochemical no evidence of disease (bNED) according to both Phoenix and the PSA O0.4 ng/mL threshold were calculated by the KaplaneMeier method (16). The same analysis was repeated with the first 100 loose and stranded seed implants excluded as a surrogate means of assessing whether there was a ‘‘learning curve’’ effect associated with the introduction of a new technique. Log-rank (ManteleCox) test was used to evaluate differences between survival curves. Variables were screened in univariate models, and those showing some association with bNED were included with seed type in a Cox regression multivariate model. Statistical analyses were undertaken using the Statistical Package of Social Sciences, version 14.0 (SPSS Inc., Chicago, IL).
bNED was 93.5% (95% CI, 90.6e96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8e96.2) for patients treated with stranded seeds according to the Phoenix definition ( p 5 0.846). Using the PSA O0.4 ng/mL definition, actuarial estimated rates of bNED at 7 years were 91.3% (95% CI, 88.0e94.6) and 91.9% (95% CI, 89.7e94.1) for loose seeds and stranded seeds, respectively ( p 5 0.871). KaplaneMeier plots are shown in Figs. 1 and 2. Exclusion of the first 100 loose and stranded implants from the analysis also revealed no difference in bNED according to seed type. Actuarial bNED estimates at 7 years using the Phoenix definition were 95.1% (95% CI, 92.0e98.2) and 93.3% (95% CI, 90.8e95.8) for loose seeds vs. stranded seeds ( p 5 0.311). Using the PSA O0.4 ng/mL definition of biochemical relapse, bNED estimates at 9 years were 92.2% (95% CI, 88.3e96.1) and 91.3% (95% CI, 88.9e93.7) for loose and stranded seeds, respectively ( p 5 0.647). Multivariate Cox regression analysis was performed to adjust for potential confounding factors. Terms included in the analysis were seed type, log initial PSA, use of androgen deprivation therapy (ADT), Gleason score $7, and implant order. There was no statistically significant difference between loose and stranded seeds in terms of bNED using either the Phoenix (hazard ratio [HR], 0.77; 95% CI, 0.43e1.37; p 5 0.3740) or the PSA O0.4 ng/mL definitions (HR, 0.81; 95% CI, 0.51e1.30; p 5 0.3873). The results of the Cox regression analysis are shown in Table 4.
Results Three hundred twenty-seven patients1 (21.8%) were treated with loose seeds and 1173 (78.2%) with RS. The median age was 66 years (range, 45e82). Median followup was 72.7 months (range, 0.7e141.4) for patients treated with loose seeds and 56.8 months (range, 0.8e127.9) for patients treated with stranded seeds. Postimplant dosimetric data were available for 1467 patients (97.8%). Baseline clinical and dosimetric characteristics of the patients are shown in Table 1. Patient outcomes are shown in Table 2. Actuarial overall survival (death from all causes) for all patients at 7 years was 89.8% (95% confidence interval [CI], 87.8e91.8). Of the 9 patients who have died with or from disease, 7 patients developed metastases and died of their disease, whereas 2 patients developed biochemical relapses and died of other causes. Biochemical recurrence occurred in 61 patients according to the Phoenix definition and 98 patients according to the PSA O0.4 ng/mL definition of biochemical failure. Univariate analysis demonstrated no difference between loose and stranded seeds (see Table 3). Estimated rate of 1 Note: Our previous publication comparing postimplant dosimetry (3) stated that 334 loose seed implants had been performed at BCCA. This has been amended to 327.
Discussion The results from this large population-based cohort of consecutive patients treated with 125I prostate brachytherapy showed no evidence of any difference between loose and stranded seeds in terms of biochemical control rates using either the Phoenix definition or the alternative PSA O0.4 ng/mL definition of biochemical failure. The study had power to detect a 5% difference in biochemical control rates between the two groups. Of note, there were significantly more patients with Gleason score O6 ( p! 0.0001), bilaterally palpable tumors ( p !0.0001), and a larger proportion with $50% of cores positive ( p! 0.0001) in the group treated with RS. In addition, significantly fewer RS patients received ADT ( p !0.0001). Only pretreatment PSA values were greater in the group treated with loose seeds ( p 5 0.03). In our earlier article where outcomes in terms of biochemical control for the first 1006 patients treated by the BCCA Provincial Prostate Brachytherapy Program were presented, ADT was shown on multivariate analysis to be associated with a decreased risk of biochemical failure (HR, 0.47; p 5 0.044), whereas higher pretreatment PSA correlated with increased risk of relapse (HR, 7.86 per log10 increase in PSA; p 5 0.031) (2). Despite these generally less favorable characteristics
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Table 1 Clinical and dosimetric characteristics of patients treated with prostate brachytherapy Loose (n 5 327)
Variable
Stranded (n 5 1173)
p-Value
Total (n 5 1500)
0.79 0.01
66 (45e82) 6.3 (0.3e40)
Clinical characteristics Age (y) Pretreatment PSA (ng/mL) Gleason score #6 $7 Clinical stage T1 T2 T2a unilateral T2b bilateral T3a NCCN risk group Low Intermediate High ADT % positive cores !50 $50 Missing
66 (49e80) 6.6 (0.3e16)
66 (45e82) 6.2 (0.3e40)
278 (85.0%) 49 (15.0%)
781 (66.6%) 392 (33.4%)
!0.0001
138 189 131 58
572 600 478 122
!0.0001
(42.2%) (57.8%) (40.1%) (17.7%)
0
(48.8%) (51.2%) (40.8%) (10.4%)
1 185 (56.6%) 142 (43.4%)
710 789 609 180
(47.3%) (52.6%) (40.6%) (12%)
828 668 4 958
(55.2%) (44.5%) (0.3%) (63.9%)
1
238 (72.8%)
643 526 4 720
167 (51.1%) 88 (26.9%) 72 (22.0%)
802 (68.4%) 344 (29.3%) 27 (2.3%)
0
1059 (70.6%) 441 (29.4%)
(54.8%) (44.8%) (0.3%) (61.4%)
0.47
0.0001 !0.0001
969 (64.6%) 432 (28.8%) 99 (6.6%)
Dosimetric characteristics Variable
Loose (n 5 321)
D90 (%) V100 (%) V150 (%) V200 (%)
102.5 91.3 52.6 22.3
Stranded (n 5 1146)
(102.2 13.8) (89.2 8.0) (51.3 14.1) (23.0 9.2)
106.5 93 57.2 24.9
(106.7 12.1) (92.2 4.9) (57.0 11.2) (25.2 8.9)
p-Value
Total (n 5 1467)
!0.0001 !0.0001 !0.0001 0.0004
105.6 92.6 56.3 24.3
(105.7 12.7) (91.5 5.9) (55.7 12.1) (24.7 9.0)
PSA 5 prostate-specific antigen; NCCN risk group 5 National Comprehensive Cancer Network risk group (17); ADT 5 androgen deprivation therapy; D90 5 minimum dose covering 90% of the postimplant CT prostate volume; Vx 5 postimplantation CT prostate volume covered by x%. Values expressed as median (range), number (percent), or median (mean standard deviation). Pearson c2 statistic was used to display the probability of type of seed having a relationship with the variable of interest. Median values were compared for continuous variables using the Wilcoxon rank sum test.
among the RS patients, however, we did not detect a difference between the two groups in terms of bNED. Because the BCCA Provincial Prostate Brachytherapy Program first performed implants using loose seeds and later switched to stranded seeds for all cases, one possible factor that might influence biochemical outcome is the ‘‘learning curve’’ that may be experienced with the introduction of a new technique. Our group has previously shown that a learning curve effect was seen when we analyzed dosimetry between seed types in a smaller sample from this patient Table 2 Patient outcomes Outcome Relapsed Alive (n 5 1369) ANED AWD Dead (n 5 131) DNED DO/WD
Phoenix
PSA O0.4 ng/mL
61 (4.1%)
98 (6.5%)
1317 (87.8%) 52 (3.5%)
1280 (85.3%) 89 (5.9%)
122 (8.1%) 9 (0.6%)
122 (8.1%) 9 (0.6%)
PSA 5 prostate-specific antigen; ANED 5 alive with no evidence of disease; AWD 5 alive with disease; DNED 5 dead with no evidence of disease; DO/WD 5 dead of or with disease.
cohort (3). However, excluding the first 100 patients implanted with both loose and stranded seeds from the analysis also failed to demonstrate a statistically significant difference between loose and stranded seeds. It is important to note that the first 100 loose seed implants represented both the BCCA Provincial Prostate Brachytherapy Program and individual learning curves, whereas the first 100 RS implants simply represented the learning curve associated with the change in seed type. This is reflected in postimplant dosimetry, with a mean D90 of 139.2 Gy (standard deviation [SD] 20.5 Gy) for the first 100 loose seed implants compared with a mean D90 of 146.7 Gy (SD 21.9 Gy) for the first 100 RS implants. Similarly, mean V100 for the first 100 loose implants was 85.8% (SD 9.8%) and 89.8% (SD 6.1%) for the first 100 stranded implants. Our findings are in contrast to those of Hinnen et al. (1), the only other article to have reported biochemical outcomes to date. They examined outcome in terms of bNED, using the Phoenix definition, in 538 patients implanted with stranded seeds, either RS or Intersource (IBt Bebig, Belgium), and 358 patients treated with loose seeds. When adjusted for confounding factors in a multivariate analysis, they found that seed type was significantly
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Table 3 Univariate analysis (Cox regression) of effect of seed type on biochemical no evidence of disease Variable
HR
95% CI
p-Value
Phoenix definition Age at the time of implant Log iPSA % positive cores Gleason score Implant order NCCN risk group Androgen deprivation T stage D90 V100
0.95 0.98 0.91 0.86 0.66 0.95 0.93 0.96 0.99 0.98
0.54e1.66 0.56e1.71 0.50e1.66 0.48e1.52 0.34e1.28 0.54e1.66 0.53e1.63 0.55e1.63 0.56e1.75 0.55e1.76
0.85 0.93 0.77 0.60 0.22 0.85 0.80 0.90 0.96 0.95
PSA O0.4 ng/mL Age at the time of implant Log iPSA % positive cores Gleason score Implant order NCCN risk group Androgen deprivation T stage D90 V100
0.97 0.99 0.98 0.92 0.70 0.97 0.93 0.98 1.0 1.1
0.61e1.53 0.63e1.57 0.60e1.63 0.57e1.47 0.41e1.22 0.61e1.53 0.58e1.47 0.62e1.55 0.65e1.67 0.66e1.72
0.88 0.98 0.95 0.72 0.21 0.88 0.75 0.93 0.85 0.79
HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostatespecific antigen; NCCN risk group 5 National Comprehensive Cancer Network risk group (17); PSA 5 prostate-specific antigen; D90 5 minimum dose covering 90% of the postimplant CT prostate volume; V100 5 postimplantation CT prostate volume covered by 100%.
associated with the risk of biochemical failure with a 43% risk reduction for loose seeds vs. stranded seeds. They speculate that possible reasons for this difference between seed types include retraction of stranded seeds during implantation, the loading pattern of stranded seeds with spacers
between each active source, and the fact that stranded seeds (unlike loose seeds) cannot track with the expanding edematous prostate gland postimplantation. An earlier study by this group looking at postimplant dosimetry found a decline in D90 for all seed types from time of implant to assessment at 4 weeks postimplant. There was, however, a significantly larger decline in D90 for stranded seeds compared with loose seeds (18). It was hypothesized that this may be because of strand retraction either during or after implantation. One explanation for our findings might be that RS implants achieve superior postimplant dosimetry compared with loose seed implants. Within our patient cohort, we observed statistically significant differences in D90% ( p ! 0.001), V100% ( p! 0.001), V150% ( p !0.001), and V200% ( p 5 0.001) favoring RS implants. These findings are supported by most of other studies in the literature that have assessed differences between postimplant dosimetry according to seed type (3, 19e23). Fagundes et al. (19) assessed dosimetry in 473 patients (337 treated with loose seeds) and demonstrated higher mean D90 and V100 for the patients treated with stranded seeds. This finding was supported by the study from Heysek et al. (20) where 272 patients were assessed and D90 was found to be higher in those treated with stranded seeds, although this difference was not clinically significant. Three smaller studies (21e23) also suggested that stranded seeds gave an improved dosimetry. Our own earlier comparison of loose and RS dosimetry where 54 loose seed and 81 RS patients from our database were analyzed showed statistically significant differences with significantly higher V150, V200, and contiguous V200 in the RS implants when assessing the whole prostate. These differences were, however, very small and may not be clinically significant. In addition,
Fig. 1. Biochemical no evidence of disease (Phoenix) according to seed type.
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Fig. 2. Biochemical no evidence of disease (prostate-specific antigen O0.4 ng/mL) according to seed type.
these differences may be attributable to factors other than seed type (such as maturity of our program, leading to a gradual increase in mean dosimetry in the much larger and mature RS cohort). It is important to note that no statistically significant difference was observed, however, between seed types in terms of D90 and V100 (3). On the other hand, other studies support better dosimetry in loose seed implants compared with stranded seeds. The findings by Moerland et al. (18) are summarized above. Reed et al. (24), in a randomized prospective study of 62 patients, found improved dosimetry for loose seeds, although the difference between the two groups was not statistically significant. Saibishkumar et al. (25) reported that loose seeds had better dosimetry at Day 0, but that there was no difference at Day 30 between the two seed types. Table 4 Multivariate analysis (Cox regression) of effect of seed type on biochemical no evidence of disease
Conclusions In this population-based study of 1500 consecutive patients treated with ultrasound-guided transperineal prostate brachytherapy, we found no evidence of a difference between loose and stranded seeds in terms of bNED, using either the Phoenix or PSA O0.4 ng/mL definitions of biochemical failure. Exclusion of the first 100 loose and RS implants from the analysis as a surrogate measure of assessing the learning curve effect made no significant difference to our analysis. Given the divided evidence in the literature, the logical conclusion is that either seed format can provide excellent results. However, this is not to say that the two formats are interchangeable for a single operator because of subtle differences in planning and technique may lead to noticeably different outcomes with loose vs. stranded seeds.
References
Variable
HR
95% CI
p-Value
Phoenix definition Loose vs. stranded seeds Log iPSA Androgen deprivation Gleason score $7
0.77 2.58 0.38 2.55
0.43e1.37 1.42e4.70 0.20e0.73 1.39e4.68
0.3740 0.0019 0.0033 0.0025
PSA O0.4 ng/mL Loose vs. stranded seeds Log iPSA Androgen deprivation Gleason score $7
0.81 2.53 0.38 1.82
0.51e1.30 1.60e4.02 0.23e0.62 1.12e2.97
0.3873 !0.0001 0.0001 0.0163
HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostatespecific antigen; PSA 5 prostate-specific antigen.
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