Variability of prostate brachytherapy preimplant dosimetry: A multi ...

Brachytherapy 4 (2005) 241–251

Variability of prostate brachytherapy preimplant dosimetry: A multi-institutional analysis Gregory S. Merrick1,*, Wayne M. Butler1, Kent E. Wallner2, John C. Blasko3, Jeff Michalski4, Jesse Aronowitz5, Peter Grimm3, Brian J. Moran6, Patrick W. McLaughlin7, Jacqueline Usher1, Jonathan H. Lief1, Zachariah A. Allen1 1 Schiffler Cancer Center and Wheeling Jesuit University, Wheeling, WV Puget Sound Healthcare Corporation, University of Washington, Seattle, WA 3 Seattle Prostate Institute, Seattle, WA 4 Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 5 Department of Radiation Oncology, University of Massachusetts Memorial Hospital, Worcester, MA 6 Chicago Prostate Cancer Center, Chicago, IL 7 Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 2

ABSTRACT

PURPOSE: To conduct a multi-institutional comparison of prostate brachytherapy preimplant dosimetry of Pd-103 and I-125. METHODS AND MATERIALS: Eight experienced brachytherapists submitted Pd-103 and I-125 monotherapeutic and boost preimplant dosimetry plans for central review. All 32 plans were calculated using the same transrectal ultrasound volumetric study. Seeds of any strength were acceptable, but were restricted to Theraseed Model 200 (Theragenics Inc., Buford, GA) and Oncura Oncoseed Model 6711 (Oncura, Plymouth Meeting, PA). The dosimetric analysis included evaluation of target volume, target to prostate ratio, target length, number of needles, seed activity, number of seeds, total activity, total activity divided by treatment planning volume, the use of extracapsular seeds, and average treatment margins (defined as the perpendicular distance between the prostate capsule and the 100% isodose line). Prostate coverage was defined in terms of V100/V150/V200/V300 and D100/D90/D50, whereas urethral dosimetry consisted of UV100/UV150/UV200 and UD90/UD50. RESULTS: The mean planning target volume to prostate volume ratio varied dramatically (mean 1.29, range 0.99–1.76) with the target length ranging from 3.5 to 4.5 cm. Although the prostate V100 wasO95% in all cases, the V150 ranged from 29.9% to 92.1% and the V200 from 6.72% to 52.5%. The urethral V100 was 100% in all cases with six of the eight brachytherapists limiting the UV150 to!3%. However, the median urethral dose varied by up to 50%. Treatment margins also varied significantly (average 3.98 mm, range 0.32–7.68 mm). All brachytherapists used extracapsular seeds with five implanting O25% of the seeds in extracapsular locations (range 6.4–58.2%). In addition, significant variability existed in the number of needles, number of seeds, and seed strength. CONCLUSIONS: This study highlights the substantial variability that exists regarding target volume, seed strength, dose homogeneity, treatment margins, and extracapsular seed placement, although prostate brachytherapy prescription doses are uniform. The standardization of preimplant dosimetry is essential for meaningful multi-institutional comparisons of biochemical outcomes and morbidity. Ó 2005 American Brachytherapy Society. All rights reserved.

Keywords:

Prostate; Brachytherapy; Dosimetry; Pd-103; I-125

Introduction Received 14 March 2005; received in revised form 27 April 2005; accepted 2 May 2005. * Corresponding author. Schiffler Cancer Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV 26003-6300. Tel.: 11-304-243-3490; fax: 11-304-243-5047. E-mail address: [email protected] (G.S. Merrick).

Despite the widespread acceptance of prostate brachytherapy as a curative treatment for clinically localized prostate cancer, a paucity of evidence-based data has accumulated regarding the relationships between planning parameters, biochemical control rates, and morbidity

1538-4721/05/$ – see front matter Ó 2005 American Brachytherapy Society. All rights reserved. doi:10.1016/j.brachy.2005.05.002

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G.S. Merrick et al. / Brachytherapy 4 (2005) 241–251

profiles. Although multiple permanent prostate brachytherapy seed planning philosophies are currently used, definitive recommendations for preimplant dosimetry have not been formulated. The absence of broad-based guidelines has made multi-institutional comparison of biochemical and quality of life outcomes questionable. Quality is easy to conceptualize, but difficult to quantitate. It is universally accepted that an adequate implant should encompass the target volume, but there is no consensus as to what represents the target volume. In addition, substantial variability exists regarding seed strength, choice of isotope, seed distribution, dose homogeneity, treatment margins, and normal tissue tolerances (1, 2). These planning differences along with the imprecision of intraoperative execution may account for some of the reported institutional differences in biochemical control rates and morbidity (3–6). To compare prostate brachytherapy preimplant dosimetry, eight experienced prostate brachytherapists submitted Pd-103 and I-125 plans for an identical ultrasound volumetric study for central review. Methods and materials Eight prostate brachytherapists with extensive experience with Pd-103 and I-125 monotherapy were invited to participate in the study. All brachytherapists received the same transrectal ultrasound volumetric study with the prostate contoured on each 5 mm slice (Siemens Medical Systems, Issaquah, WA) and instructions to generate four plans (Pd-103 monotherapy, prescription dose 125 Gy ABS-2000; I-125 monotherapy, prescription dose 145 Gy TG-43; Pd-103 boost, prescription dose 90 Gy ABS-2000; I-125 boost, prescription dose 110 Gy TG-43). The prostate volume was 30.1 cm3 with a prostate length of 3.50 cm. A urethral catheter was in place at the time of ultrasonography for urethral identification. For the monotherapeutic plans, the clinical history consisted of a patient with clinical Stage T1c, prostatespecific antigen (PSA) 6.0 ng/mL, Gleason score 6 (3 1 3), and two of eight biopsies positive for malignancy without evidence of perineural invasion. For the boost plans, the patient profile included clinical Stage T1c, PSA 12.0 ng/ mL, Gleason score 7 (4 1 3), and two of eight biopsies positive with evidence of perineural invasion. The brachytherapy planning instructions were as follows: ‘‘If your planning approach utilizes a defined target volume (prostate plus margin) that you normally draw on the ultrasound, please do. If you normally do not define such a volume, do not change your approach. Please generate each of the four requested plans as if this were a patient in your clinic. Regardless of whether or not you normally report urethral doses, please do so. For this study, the only acceptable seeds are Theraseed Model 200 (Theragenics Inc., Buford, GA) and Oncura Oncoseed Model 6711 (Oncura, Plymouth Meeting, PA).’’

Seven of the eight investigators generated plans using Variseed (Varian Medical Systems, Palo Alto, CA), whereas the other brachytherapist used Rosses Medical Systems (Carmichaels, PA). The plans generated on the Rosses system had their seed coordinates and planning target volumes (PTV) redigitized into Variseed. The calculation algorithms and seed parameters used in planning were recommended by the American Association of Physicists in Medicine Task Group No. 43 (7). Central dosimetric review included evaluation of target volume, target to prostate ratio, target length, number of needles, seed activity, number of seeds, total activity, total activity divided by target planning volume, number of extracapsular seeds including seminal vesicle and infraapical seeds (defined as seeds planned inferior to the apex of the prostate gland), and average treatment margins (defined as the perpendicular distance between the ultrasound-determined prostate capsule and the 100% isodose line). The dosimetric treatment margins were determined by a software package under development by Variseed. Margins were determined at eight angles (every 45 ) on every transverse prostate ultrasound slice. The software was not designed to measure superior or inferior margins. Cumulative dose–volume histograms (DVHs) and natural DVHs were determined for each plan (8). The prostate dosimetric evaluation was defined by the volume of the gland receiving 100%, 150%, 200%, and 300% of the prescription dose (V100/V150/V200/V300) and the minimum dose received by 100%, 90%, and 50% of the prostate gland (D100/D90/D50). Urethral dosimetry was defined in terms of the volume of the urethra receiving 100%, 150%, and 200% of the prescribed dose (UV100/UV150/UV200) and the minimum dose received by 90% and 50% of the urethra (UD90/UD150). Robustness of the plans to random seed perturbations was tested by applying a standard deviation of 2 mm in the lateral and anterior–posterior directions (x, y) and a standard deviation of 3 mm in the superior–inferior direction (z) (9). Prostate and urethral quality parameters (Vxx and Dyy) were recorded for each perturbation as were dosimetric margins at selected angles on each of the eight prostate slices. Pearson correlation coefficients and their statistical significance between dosimetric margins and other implant parameters were determined using SPSS 12.0 (SPSS Inc., Chicago, IL). Changes in the mean values of all dosimetric and marginal parameters after the 100 perturbation cycles were also tested for significance and correlation with all the initial dosimetric and marginal parameters. Comparisons between brachytherapists and modalities used a linear mixed model analysis where the data may exhibit correlated and nonconstant variability. Of the numerous models tested, a first-order autoregressive covariate structure provided the best fit to the data for most clinical and dosimetric parameters and therefore was used throughout.


Results Table 1 summarizes the volumetric planning parameters for Pd-103 and I-125 monotherapy and boost plans. An explicit PTV was drawn by six of eight investigators. The mean PTV to prostate ratio was 1.37 among those six with a ratio of 1.29 for the entire group. The drawn PTV to prostate volume ratio varied dramatically from brachytherapist to brachytherapist, ranging from 0.99 to 1.76. The target length was taken to be the distance from the most superior seed slice to the most inferior seed slice and was the same as the transverse ultrasound prostate length (3.5 cm) in the plans of three investigators. Two investigators added seeds both superior and inferior to the ultrasound (US) prostate, and the rest added seed planes either superiorly or inferiorly so that the target length also varied from 3.5 to 4.5 cm. The number of needles, needle loading characteristics, seeds, and seed strength showed considerable variation as detailed in Table 2. Within each institution, planning dosimetric quality parameter trends were consistent for monotherapy and boost plans and as such, subsequent tables summarize data only for monotherapy. Although there was a wide range in the number of needles within each approach (a high-to-low ratio of 2.1), the mean number of needles across the four modalities differed by less than one. Specially loaded needles are those multiseed needles that differ in any way from the regular 1 cm centerto-center seed spacing. The designation characterized either extra spacing between seeds or the presence of back-toback seeds. Although only two brachytherapists used single seed needles, all brachytherapists used specially loaded needles ranging from less than 10% of the total number of needles to nearly 90%. The seed strength for boost therapy was typically about 20% lower than that for monotherapy, although one brachytherapist (D) used the same strength for monotherapy and boost so that the range of seed strengths (high/low) for a given modality was as large as 2.9 for I-125 boost. Total seed strength was about 25% less for boost therapy compared to monotherapy with a range within each Table 1 Brachytherapy parameters applied by each investigator for all treatment modalities

Investigator

Ultrasound prostate volume (cm3)

A (JM) B (BM) C (PG) D (KW) E (GM) F (JB) G (JM) H (JA) Mean

PTV (cm3)

PTV/ prostate ratio

PTV length (cm)

30.1 30.1 30.1 30.1 30.1 30.1 30.1 30.1

48.2 29.9 35.1 30.1 52.9 47.3 36.4 30.1

1.60 0.99 1.17 1.00 1.76 1.57 1.21 1.00

4.5 4.0 4.0 3.5 4.5 4.0 3.5 3.5

30.1

38.73

1.29

3.94

243

modality (high/low) of 1.6 in I-125 and Pd-103 boost to 1.8 in Pd-103 monotherapy. One investigator (E) used the same number of needles and seeds for all four plans by maintaining a constant seed strength to prescription dose ratio. For the entire group, on average two to three fewer seeds were used in boost plans compared to those used in monotherapy. The total activity per cm3 of planned target volume also displayed significant high/low variation (as high as 1.9–2.1). Table 2 delineates large variations in the use of extracapsular seeds. Striking differences were discerned in both absolute number and percent of planned total extracapsular seeds along with marked differences in the extracapsular seed placement. Six of the eight brachytherapists planned more than 25% of the seeds in extracapsular locations. However, only four of the eight brachytherapists planned seminal vesicle seeds with only three using infraapical seeds. Of note, no seed was placed greater than 5 mm beyond the prostate capsule. The DVHs for Pd-103 and I-125 monotherapy plans are shown in Fig. 1. All the curves depart from the 100% volume coverage at different dose levels and then diverge further because of differing slopes. Higher slopes expressed as %volume/%prescription dose at the D50 level indicate greater dose homogeneity. For Pd-103, the slopes range from 0.54 (investigator D) to 1.63 (A) and for I-125 from 0.83 (D) to 2.86 (E). In all cases, urethral DVHs completely encompassed the urethra with the prescription dose. The DVHs for monotherapy plans are plotted in Fig. 2. The slopes of the urethral DVHs at the D50 level of the Pd-103 plans were quite steep, and the variation of dose at D50 level was small (108–141% of prescription dose). The slopes at D50 for I125 were even steeper, but the spread of doses at D50 level was somewhat greater (108–153% of prescription dose). Prostate and urethral monotherapeutic dosimetric parameters are summarized in Table 3. A natural dose ratio (the natural prescription dose to the prescribed prescription dose) of 1.00 represents the most efficient use of dose, whereas higher and lower values reflect overdosing and underdosing of the prostate gland, respectively. The mean ratios were nearly ideal, whereas individual plans ranged from 1.15 for Pd-103 boost therapy to 0.82 for Pd-103 monotherapy. Coverage of the prostate in terms of V100 was greater than 95% for all investigators, and urethral coverage in terms of UV100 was 100% in all cases (Table 3). The similarities, however, end at that point. Significant variations in V150 with values as high as 86.0% and as low as 29.9% of prescription dose were noted in Pd-103 plans and from 92.1% to 31.7% of prescription dose in I125 plans. A similarly large variation was seen in V200 values, which ranged from as low as 6.7% to as high as 52.5%. Because of the relative seed strength and fall-off differences between Pd-103 and I-125, the average V150, V200, and V300, are notably higher for Pd-103 plans than

244

Table 2 Variable brachytherapy planning parameters stratified by investigator and monotherapy treatment modality Single seed needles

Back-toback seed pairs

Seed strength (U )

Total strength (U )

Total U/PTV (U/cm3)

A B C D E F G H

20 14 23 18 22 24 29 24

3 6 2 16 9 4 3 15

0 0 0 2 0 0 6 0

0 6 0 52 4 0 4 4a

2.33 2.47 2.00 2.95 3.05 1.81 2.59 2.20

86 62 91 78 91 100 74 78

200.4 153.1 182.0 230.1 277.6 181.0 191.7 171.6

4.16 5.13 5.19 7.65 5.25 3.83 5.25 5.70

Pd mono

21.8

198.4

5.27

A B C D E F G H

19 14 23 22 22 24 21 25

I mono a

21.3

7.2 2 6 2 10 10 4 2 16 6.5

1.0

8.8

2.43

82.5

0 0 0 6 0 0 6 0

0 8 0 8 4 0 0 4a

0.495 0.460 0.414 0.889 0.560 0.414 0.761 0.419

75 64 87 54 91 92 52 80

37.13 29.44 36.02 48.01 50.96 38.09 39.57 33.52

0.77 0.99 1.03 1.60 0.96 0.81 1.09 1.11

1.5

3.0

0.552

74.4

39.09

1.04

Investigator H had nine additional pairs of seeds separated by less than 5 mm.

Extracapsular seeds (% total) 41 17 34 24 50 41 8 5

(47.7) (27.4) (37.4) (30.8) (54.9) (41.0) (10.8) (6.4)

27.5 (32.1) 33 17 31 23 53 42 10 8

(44.0) (26.6) (35.6) (42.6) (58.2) (45.6) (19.2) (10.0)

27.1 (35.2)

Sem. ves. (SV) seeds

Infra-apical (IA) seeds

Total seeds 2 SV 2 IA

6 10 0 0 10 8 0 0

2 0 12 0 7 0 0 0

78 52 79 78 74 92 74 78

4.25 6 10 0 0 10 8 0 0 4.3

2.63 0 0 12 0 7 0 0 0 2.4

75.6 69 54 75 54 74 84 52 72 66.8


Specially loaded needles

Number of seeds

Investigator

Number of needles


245

100

% Prostate Volume

80 D H G

60

E F C

40

A B

20

a 0

75

100

125

150

175

200

225

250

% Prescription Dose

% Prostate Volume

100

80

D H

60

G

40

E

C F A B

20

b 0

75

100

125

150

175

200

225

250

% Prescription Dose Fig. 1. Prostate monotherapy DVHs for (a) Pd-103 and (b) I-125 stratified by brachytherapist from highest to lowest D60 dose.

I-125 plans. The boost therapy values of those three parameters were each slightly higher than those of their monotherapy counterparts due to the use of a higher seed strength to prescription dose ratio in boost plans compared to that in monotherapy plans. In terms of D100, only one Pd-103 plan and three I-125 plans had minimum prostate dose coverage that equaled or exceeded the prescribed dose for both monotherapy and boost with D100 coverage as low as 67% of prescription dose (Table 3). D90 values demonstrated somewhat less variability with all institutions delivering at least 112% of prescription dose with a maximum of 151%. D50 values represent the median dose to the gland. Consistent with significant inconsistencies in dose homogeneity (V150), the high/low D50s varied by as much as 1.50. In terms of urethral dosimetry, all institutions delivered 100% of the prescribed dose to the urethra with six of eight Pd-103 plans demonstrating a urethral V150 less than 3% for Pd-103 and I-125 (Table 3). Consistent with the prostate D90, the urethral D90 revealed somewhat less variability, whereas the D50 (representing the median urethral dose)

varied significantly from investigator to investigator with differences approaching 50%. Selected slices from a composite isodose plan incorporating all seeds from all brachytherapists for Pd-103 monotherapy are shown in Fig. 3. The 660 seeds placed by individual investigators resulted in 376 unique seed positions, and the maximum redundancy at any position was five seeds in four instances. One investigator used transverse needle, and longitudinal seed offsets were adjusted for purposes of the composite plan so that seeds appeared on the nearest regular grid coordinate. Investigators with the two highest number of unique seed locations were C and A with 58 and 56 positions, respectively. Investigators whose plans resulted in the fewest number of unduplicated positions were H and F with 5 and 9 positions, respectively. There were 118 duplicated positions with the most common pairings between investigators E and F (17 positions), G and H (16 positions), and A and D (14 positions). Of the 57 triplicate positions, the combination of investigators B, E, and F accounted for 32 occurrences. These three brachytherapists used regular

246

G.S. Merrick et al. / Brachytherapy 4 (2005) 241–251 100

% Urethra Volume

80 D A E

60

C G F

40

H B

20

a 0 100

110

120

130

140

150

160

% Prescription Dose 100

% Urethra Volume

80 D C E

60

H G A

40

B F

20

b 0 100

110

120

130

140

150

160

% Prescription Dose Fig. 2. Prostate monotherapy urethral DVHs for (a) Pd-103 and (b) I-125 stratified by brachytherapist from highest to lowest D60 dose.

1 cm spacing between seeds in most needles and began many of their source trains 5 mm superior to the base (Table 2). Monotherapy dosimetric treatment margins (defined as the perpendicular distance from the prostate capsule to the 100% isodose line) measured at eight angles on each of the eight slices are listed in Table 4. The overall mean margin was 3.98 G 2.64 mm. The more rapid dose fall-off with distance for Pd-103 compared with that of I-125 resulted in a trend for smaller margins in Pd-103. In boost plans, a trend for larger margins was noted because of a larger relative seed strength. As expected, the differences between brachytherapists were pronounced. For example, in Pd-103 monotherapy, the mean treatment margin was 3.81 mm with a range of 1.13–7.68 mm. For I-125, the range of treatment margins was similarly pronounced with a mean of 4.11 mm (range 0.32–7.49 mm).

Table 5 lists coefficients of variation (CV) as the standard deviation/mean (as a percentage) for both investigators and treatment approaches. These coefficients indicate the degree of consistency of a given parameter across modalities for each investigator and across investigators for each modality. Negative values in the dosimetric margin parameters arose whenever a mean margin was negative. Parameters with the lowest CV are those that the brachytherapists tended to consider more important to maintain within a tightly constrained individual range. These crucial parameters include prostate V100 and D90 and urethral UD50 and UD10. Dosimetric margins were not well controlled either by intent or because of difficulties in maintaining a standard. Except for a few cases, the consistency of the individual brachytherapist was greater across modalities than across investigators for each modality.


247

Table 3 Dosimetric parameters stratified by investigator Investigator

Nat Rx dose/Rx dose

V100

V150

V100

V300

D100

D90

D50

UV150

UD50

UD10

A B C D E F G H

1.10 0.92 0.82 1.02 1.13 0.90 0.99 0.86

98.8 97.6 99.9 100.0 100.0 99.8 99.9 100.0

43.1 48.1 50.4 86.0 58.1 53.0 67.4 68.5

15.1 20.2 14.5 52.5 16.2 13.3 37.9 35.0

6.5 6.9 4.4 18.7 4.5 3.8 14.7 10.0

81.5 68.3 98.8 99.2 111.7 96.5 94.5 95.1

124.5 111.5 117.3 144.5 130.7 120.5 128.2 123.7

145.1 147.8 150.4 204.8 155.7 152.6 172.9 176.1

23.4 1.3 1.4 33.2 2.9 1.3 0.0 0.3

134.8 108.7 127.9 141.1 129.9 123.3 124.9 111.8

159.0 133.6 140.1 161.9 140.4 137.1 134.7 137.3

Pd mono

0.97

99.5

59.3

25.6

8.7

93.2

125.1

163.2

8.0

125.3

143.0

A B C D E F G H

1.05 1.01 1.01 1.09 1.07 0.92 1.01 1.03

99.4 95.7 100.0 100.0 100.0 99.8 100.0 100.0

35.8 32.0 41.9 92.1 35.3 39.6 56.5 61.8

10.5 10.2 8.9 46.9 6.7 8.6 17.9 17.9

4.7 3.2 2.7 9.7 1.9 2.4 5.0 4.3

91.1 67.0 102.5 114.9 117.3 94.3 98.4 99.8

120.1 111.8 122.9 151.2 129.0 114.4 127.3 129.3

140.1 134.4 144.7 194.6 143.9 140.5 155.3 159.1

0.0 2.8 0.7 67.3 1.8 0.0 0.0 0.5

119.6 117.7 134.1 155.0 133.4 109.4 125.8 125.8

124.2 136.7 143.6 206.0 141.1 122.3 129.4 137.2

I mono

1.02

99.4

49.4

15.9

4.3

98.2

125.8

151.6

9.1

127.6

142.6

p*

0.223

0.659

0.010

0.002

0.001

0.139

0.622

0.001

0.966

0.825

0.959

Vxx and UVxx are percent prostate and urethral volume covered by xx percent of the prescription dose, respectively. Dyy and UDyy are the minimum doses, as percentage of the prescription dose, covering yy percent of the volume. *Significance was determined across all four modalities using a linear mixed model repeated measures analysis. Significant differences are in bold.

The robustness of plans to random perturbations in seed position was tested by applying a 2 mm standard deviation to transverse seed coordinates and 3 mm SD to longitudinal coordinates. The mean percentage changes in dosimetric and marginal parameters after 100 perturbations are listed in Table 6 for monotherapy Pd-103. All plans were quite stable to perturbations, and the calculated changes are likely to be of no clinical consequence. Of the mean dosimetric and marginal parameters, only UV150 and the posterior margin changed by more than 5%. In both cases, the initial unperturbed values for the overall mean and the individual brachytherapists were less than 0.02 cm3 for UV150 and less than 1 mm for the posterior margin (Table 4) so that even inconsequential changes seem large as a percentage. Bivariate correlations between isodose margins and various treatment planning parameters were calculated to determine which factors have a significant effect on treatment margins (Table 7). Significant positive correlations were found between treatment margins and PTV, extraprostatic seeds and needles, and V90, D10 and UD90, UD50. Pearson correlation coefficients and significance values were also calculated between the original planning parameters and changes in dosimetric and marginal parameters after 100 seed perturbations. Table 8 shows only the original parameters and perturbed variables that had at least one significant bivariate correlation. What is most notable about Table 8 is that there were only 14 significant correlations out of a vast array of unperturbed– perturbed bivariate tests. It is not surprising that larger V150,

D100, D90, and D50 are associated with larger changes in V100, but it is surprising that parameters such as the number of seeds or extraprostatic seeds or the PTV/US volume ratio had no significant correlation. Discussion In general, four seed loading philosophies (uniform loading, peripheral loading, modified uniform loading, and modified peripheral loading) have been used in prostate brachytherapy with 75% of brachytherapists using a modified peripheral loading approach (10, 11). Although it is universally accepted that an adequate implant should encompass the target volume, currently there is little consensus as to what represents the optimal target volume as illustrated in Table 1. Sophisticated postimplant dosimetric analyses have demonstrated that biochemical disease-free survival and morbidity after prostate brachytherapy are related to specific source placement patterns and the dose gradients produced (4, 12–15). Unfortunately, definitive recommendations for preimplant dosimetry that would maximize optimal postimplant dose distributions have not been formulated. Although no definitive far-reaching recommendations have been proposed for preimplant dosimetry, American Association of Physicists in Medicine Task Group No. 56 concluded that treatment plans be ‘‘designed to place seeds peripherally to improve dose homogeneity and to avoid unnecessary radiation damage to the urethra’’ (16). Consistent with this statement, the ABS suggested

248


a

Base – 5 mm

b

Prostate base

c

Midgland

d

Prostate apex

Fig. 3. Composite Pd-103 monotherapy isodose plan incorporated all seeds from each brachytherapist weighted by 1/8, which resulted in 375 unique seed positions and a maximum redundancy of five seeds on one coordinate. The isodose lines from outermost to innermost are 100%, 150%, and 200% of prescription dose. (a) Superior to the base by 5 mm, (b) prostate base, (c) midgland, and (d) prostate apex. Diagonal lines on the midgland image show the eight rays along which the dosimetric margins were measured on every slice. Table 4 Dosimetric margins (in mm) from the prostate to the 100% isodose line at 45 angle increments stratified by investigator and treatment modality Investigator

Ant.

45

Lt lat.

135

Post.

225

Rt lat.

315

Mean

GSD

A B C D E F G H

6.61 20.17 1.92 8.10 9.02 0.46 3.43 0.29

7.02 0.66 4.14 9.20 8.68 4.94 5.88 3.47

4.30 2.15 5.96 5.42 8.59 6.09 3.65 2.91

21.83 1.20 1.73 2.14 6.60 2.53 1.77 3.78

0.08 0.56 20.65 2.24 4.61 0.13 0.19 0.14

20.46 2.09 3.40 2.78 7.28 3.51 2.37 4.30

4.51 2.12 5.93 5.18 8.37 6.11 3.43 2.90

6.85 0.45 3.92 8.91 8.66 4.75 5.56 3.36

3.39 1.13 3.29 5.50 7.68 3.56 3.28 2.65

3.90 2.99 2.73 3.03 2.44 3.09 2.05 1.87

3.71

5.50

4.89

2.24

0.91

3.16

4.82

5.31

3.81

2.76

7.13 20.69 2.46 8.95 8.49 2.30 3.25 0.25

5.99 0.27 4.52 9.98 8.64 5.57 7.78 3.21

6.79 1.37 4.93 6.59 8.37 6.59 3.96 2.73

20.71 20.39 3.16 3.02 6.10 3.44 2.83 3.32

20.86 0.23 1.85 3.34 4.68 2.06 0.78 0.72

0.46 0.41 4.00 3.58 6.80 4.31 2.30 3.86

6.70 1.35 4.83 6.31 8.22 6.54 3.31 2.73

5.77 0.04 4.27 9.65 8.66 5.33 7.25 3.07

3.91 0.32 3.75 6.43 7.49 4.52 3.93 2.49

3.69 2.44 1.90 3.11 2.34 3.02 2.60 1.57

I-125 mono

4.02

5.74

5.17

2.60

1.60

3.22

5.00

5.50

4.11

2.58

Overall meana

3.77

5.43

5.16

2.49

1.34

3.29

5.13

5.23

3.98

2.64

Pd-103 mono A B C D E F G H

a

The overall mean includes data from Pd-103 and I-125 boost therapy implants as well as the monotherapy data listed.


249

Table 5 Percentage CV (CV 5 standard deviation/mean) indicating degree of consistency for various dosimetric and marginal parameters across the four modalities for each investigator or across each modality Prostate dosimetry

Urethral dosimetry

Dosimetric margins

Investigator or modality

Seeds

V100

V150

V200

D90

UV150

UD50

UD10

Anterior

Lt lat.

135

Posterior

A B C D E F G H Invest. mean

11.09 7.11 3.35 27.55 0.00 6.32 19.34 1.46 9.53

0.39 1.43 0.10 0.00 0.00 0.21 0.10 0.25 0.31

16.19 21.11 8.75 3.46 28.53 14.68 12.85 13.61 14.90

18.19 35.66 24.14 4.94 48.05 21.28 43.73 45.43 30.18

4.61 1.99 2.68 2.30 0.93 2.38 0.67 3.85 2.43

169.45 47.39 48.82 31.80 33.11 130.20 200.00 172.97 104.22

7.13 5.74 5.06 6.38 1.35 5.64 1.85 5.03 4.77

13.30 2.49 3.89 16.01 0.22 6.29 4.06 7.17 6.68

16.25 275.96 66.96 6.18 3.23 93.30 7.54 3294.26 426.47

39.74 62.40 33.66 8.90 1.52 7.82 12.09 12.79 22.36

2334.20 103.58 32.08 35.61 4.09 25.15 48.27 29.00 27.05

294.11 40.09 178.33 21.08 1.65 145.88 69.80 63.07 53.22

Pd mono Pd boost I mono I boost

14.46 22.21 21.57 25.60

0.87 0.44 1.50 0.49

23.59 34.24 40.98 40.48

56.55 66.08 82.69 88.67

7.92 7.98 9.68 8.98

161.06 206.52 257.43 252.85

8.69 9.99 10.79 12.63

7.72 8.95 18.77 22.24

100.13 110.17 92.34 90.53

42.30 41.95 45.58 32.81

106.19 75.30 84.78 76.22

187.19 192.66 111.21 85.98

Modal. mean

20.96

0.83

34.82

73.50

8.64

219.46

10.52

14.42

98.29

40.66

85.62

144.26

Total %CVa

20.65

0.89

34.12

71.36

8.26

218.20

10.18

15.00

93.20

38.98

81.31

127.49

a

The total percent CV was determined from the mean and standard deviation of all 32 cases.

that modified peripheral loading techniques be used to minimize the length of the urethra receiving 200% of prescription dose (17). In contemporary prostate brachytherapy series, these specific recommendations are of little use. Even in this study, which demonstrated widely divergent urethral doses, doses O200% of prescription

dose were not delivered to any segment of the urethra by any investigator. In this study, although prescription doses were uniform, substantial variability existed regarding the definition of target volume, seed strength, seed distribution, dose homogeneity, treatment margins, and the use of extracapsular

Table 6 Robustness of monotherapy Pd-103 implant quality parameters to 100 random perturbations in seed position using a 2 mm standard deviation transversely and a 3 mm SD longitudinally Investigator

D V100

D V150

D D100

D D90

D D50

D UV150

D UD100

D UD50

D UD10

A B C D E F G H

20.038 20.047 20.038 20.001 0.000 20.031 20.013 20.012

0.052 0.280 20.448 0.037 0.635 20.210 0.221 20.266

20.230 20.104 21.422 20.140 20.100 20.143 20.388 21.385

20.432 20.161 20.178 0.002 20.150 20.114 20.120 20.162

20.009 0.096 20.020 20.003 0.116 0.046 20.063 20.057

2.611 4.908 37.167 20.890 8.188 90.750 0.000 0.000

0.155 20.121 0.019 0.125 20.018 20.042 20.540 20.371

0.548 0.099 0.007 0.174 0.133 0.051 20.219 20.047

0.131 0.257 20.068 0.319 0.357 0.235 0.159 0.015

Average

20.023

0.038

20.489

20.164

0.013

17.842

20.099

0.093

0.176

Anterior, 0

Lt lat., 90

Posterior, 180

Rt lat., 270

Investigator margins

D mm

D%

D mm

D%

D mm

D%

D mm

D%

A B C D E F G H

0.06 0.19 20.01 0.07 0.08 0.29 0.12 0.16

0.93 106.55 20.52 0.88 0.91 63.85 3.61 54.92

0.24 0.22 0.00 0.11 0.18 0.24 0.17 0.20

5.59 10.13 20.04 2.02 2.10 3.90 4.73 6.81

0.12 0.33 20.07 0.11 0.18 0.55 0.21 0.21

141.44 58.38 210.24 5.10 4.06 429.31 113.48 149.95

0.24 0.20 0.00 0.12 0.15 0.22 0.14 0.18

5.40 9.57 20.06 2.37 1.73 3.67 4.20 6.32

0.12

3.26

0.17

3.45

0.21

19.30

0.16

3.25

Average

Dosimetric quality parameters are expressed as the percentage difference between the mean of 100 perturbed plans and the initial unperturbed plan. Dosimetric margins from the prostate to the 100% isodose line are expressed as the difference between the mean of the 100 perturbed plans and the unperturbed plan in both mm and percentages.

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Table 7 Correlation coefficients (r) and significance values ( p) between selected mean dosimetric 100% isodose margins Anterior

135

Left lateral

Posterior

Mean margin

Parameter

r

p

r

p

r

p

r

p

r

p

PTV Target length Slices with seeds Needles Seeds Seed strength Total strength Extrapros. seeds Infra-apical seeds Extrapros. needles V90 V100 V150 V200 V300 D100 D90 D50 D10 UV100 UV150 UV200 UD90 UD50 UD10

0.496 0.349 20.015 20.028 20.091 0.172 0.158 0.429 0.105 0.688 0.354 0.396 0.234 0.235 0.260 0.637 0.638 0.301 0.208 0.262 0.496 0.324 0.578 0.660 0.468

0.004 0.050 0.941 0.879 0.619 0.345 0.387 0.014 0.566 0.000 0.047 0.025 0.198 0.195 0.150 0.000 0.000 0.095 0.254 0.148 0.004 0.070 0.001 0.000 0.007

0.646 0.477 0.229 0.021 0.247 20.010 0.064 0.688 0.235 0.762 0.462 0.436 20.062 20.138 20.145 0.650 0.190 20.070 20.191 0.244 0.120 0.098 0.284 0.234 0.073

0.000 0.006 0.261 0.909 0.174 0.958 0.728 0.000 0.195 0.000 0.008 0.013 0.737 0.452 0.430 0.000 0.299 0.703 0.296 0.178 0.512 0.592 0.116 0.198 0.693

0.255 0.035 20.631 0.387 0.241 0.008 0.079 0.340 0.354 0.325 0.379 0.515 0.231 0.045 20.076 0.778 0.362 0.183 20.033 0.046 0.060 0.176 0.239 0.218 0.142

0.159 0.851 0.001 0.029 0.184 0.963 0.667 0.057 0.047 0.070 0.033 0.003 0.203 0.805 0.679 0.000 0.042 0.317 0.856 0.803 0.746 0.336 0.188 0.231 0.437

0.234 0.107 20.481 0.037 20.032 20.007 20.023 0.333 0.255 0.456 0.200 0.315 0.273 0.148 0.067 0.691 0.534 0.247 0.071 0.013 0.395 0.338 0.507 0.484 0.379

0.198 0.561 0.013 0.840 0.862 0.970 0.902 0.062 0.160 0.009 0.272 0.079 0.131 0.418 0.716 0.000 0.002 0.173 0.699 0.942 0.025 0.058 0.003 0.005 0.033

0.567 0.291 20.233 0.184 0.108 0.086 0.129 0.554 0.227 0.694 0.514 0.585 0.233 0.128 0.083 0.859 0.582 0.244 0.065 0.198 0.343 0.279 0.511 0.543 0.348

0.001 0.106 0.252 0.313 0.558 0.641 0.482 0.001 0.212 0.000 0.003 0.000 0.199 0.485 0.650 0.000 0.000 0.178 0.723 0.277 0.054 0.122 0.003 0.001 0.051

Correlations with a p value!0.01 are in bold.

that 61% of brachytherapists added periprostatic margins with 5 mm being most common (range 1–10 mm). In this study, the PTV to prostate ratio and the extent of periprostatic treatment margins represented two of the most striking differences in implant philosophies (Tables 1 and 4). Five of the eight brachytherapists used a target volume greater than the actual ultrasound volume with an overall planning target volume to prostate volume ratio of 1.29 (range 0.99–1.76). Monotherapy treatment margins ranged from 1.13 to 7.68 mm for Pd-103 and 0.32 to 7.49 mm for I-125. Generous periprostatic margins may necessitate the placement of periprostatic seeds. An ABS survey noted that

seeds (Tables 1 and 2). Substantial variations in treatment margins could potentially impact cure and/or brachytherapyrelated morbidity (1, 2, 5, 6). Despite these differences, all plans were highly resilient to seed misplacement (Table 6). The rationale for periprostatic margins is based on pathologic measures of the probability of microscopic extracapsular disease and estimates that seed placement uncertainty is approximately 5 and 3 mm in the longitudinal and transverse directions, respectively (9, 18). Previous detailed pathologic evaluations of radical prostatectomy series demonstrated that extracapsular extension is limited to within 5 mm of the prostate capsule in 99% of cases (19, 20). In a previous ABS survey, Prete et al. (11) reported

Table 8 Correlation coefficients (r) and significance values ( p) between preimplant parameters and changes in dosimetric and marginal parameters after the mean of 100 perturbations in seed position using a 2 mm standard deviation transversely and a 3 mm SD longitudinally D V100

D Rt lat. margin

D Anterior margin

Parameter

r

p

r

D V150 p

r

D D90 p

r

p

r

p

Seed strength Total seed strength Slices with seeds V90 V100 V150 D100 D90 D50

0.665 0.723 20.820 0.632 0.721 0.806 0.757 0.840 0.734

0.072 0.043 0.024 0.093 0.043 0.016 0.030 0.009 0.038

0.800 0.587 20.029 20.288 20.247 0.026 0.031 0.248 20.036

0.017 0.126 0.951 0.488 0.555 0.951 0.942 0.554 0.932

0.280 0.143 20.812 0.211 0.405 0.745 0.402 0.406 0.675

0.502 0.735 0.027 0.615 0.320 0.034 0.323 0.319 0.066

20.079 20.578 0.108 20.778 20.771 20.221 20.830 20.436 20.175

0.852 0.133 0.817 0.023 0.025 0.599 0.011 0.280 0.678

20.351 0.165 20.213 0.863 0.805 0.266 0.639 0.314 0.237

0.393 0.696 0.646 0.006 0.016 0.524 0.088 0.449 0.572

Only parameters with at least one correlation with a p value < 0.05 are listed and the significant correlations are in bold.


63% of brachytherapists implanted seeds in periprostatic locations (11). In our series, all brachytherapists used extracapsular seeds with five of the eight brachytherapists implanting greater than 25% of seeds in extracapsular locations. However, only four of the eight brachytherapists used seminal vesicle seeds and three used infra-apical seeds. Of note, no investigator placed seeds greater than 5 mm beyond the prostate capsule. Although there was considerable controversy regarding target volume (i.e., the use of explicitly drawn planning treatment margins) and dose homogeneity, all brachytherapists generated a plan that resulted in a prostate V100 O95%. Significant variation, however, was noted in dose homogeneity (V150 ranged from 29.9% to 92.1% and V200 from 6.7% to 52.5%; Table 3). Unfortunately, to date commonly accepted recommendations for dose homogeneity have not been formulated. The D90 revealed somewhat less variability, however, the median dose (D50) varied by as much as 50%. Identification of the urethra on the plan ensures the ability to use urethral sparing doses (100–150% of prescription dose) (1, 2, 21). In an ABS survey, it was reported that two-third of the brachytherapists identified the urethra on the plan (11). Volume parameters, such as UV125 and UV150, and the dosimetric parameters, UD10 and UD25, should be kept as small as possible (1, 2). In the current study, all brachytherapists delivered O100% of prescription to the urethra with six brachytherapists limiting the UV150 to !3%. However, the median urethral dose (D50) varied significantly with differences approaching 50%. Although this study implies significant independent evolution of implant strategies, the explanation for these variations is beyond the scope of this study. However, it is likely that planning variations may be minimized with the inclusion of critical details regarding intraoperative execution (i.e., the accuracy of seed placement) and postimplant evaluation.

Conclusions This study highlights that although prostate brachytherapy prescription doses are uniform, substantial variability exists regarding target volume, seed strength, dose homogeneity, treatment margins, and extracapsular seed placement. Standardization of preimplant dosimetry for the design of multi-institutional prospective randomized trials should facilitate multi-institutional comparison of biochemical and quality of life outcomes. Standardization of preimplant dosimetry should also help to ensure the reproducibility of published favorable outcomes.

Acknowledgments The authors are grateful to Vrinda Narayana, PhD, Michael Sitter, RT(T), Zuofeng Li, PhD, Devi Naidoo, BS,

251

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