Inter-institutional variation of implant activity for permanent prostate brachytherapy

Brachytherapy 7 (2008) 297e300

Inter-institutional variation of implant activity for permanent prostate brachytherapy Jesse N. Aronowitz1,*, Juanita M. Crook2,3, Jeff M. Michalski4, John E. Sylvester5, Gregory S. Merrick6, Christie Mawson3, David Pratt4, Devi Naidoo5, Wayne M. Butler6, Kathryn Karolczuk7 1 Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada 3 Department of Radiation Medicine, Princess Margaret Hospital, Toronto, ON, Canada 4 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 5 Seattle Prostate Institute, Seattle, WA 6 Schiffler Cancer Center, Wheeling Jesuit University, Wheeling, WV 7 Quality Assurance Review Center, Providence, RI

2

ABSTRACT

PURPOSE: Despite the existence of guidelines for permanent prostate brachytherapy, it is unclear whether there is interinstitutional consensus concerning the parameters of an ideal implant. METHODS AND MATERIAL: Three institutions with extensive prostate brachytherapy expertise submitted information regarding their implant philosophy and dosimetric constraints, as well as data on up to 50 radioiodine implants. Regression analyses were performed to reflect each institution’s utilization of seeds and implanted activity. RESULTS: Despite almost identical implant philosophy, target volume, and dosimetric constraints, there were statistically significant interinstitutional differences in the number of seeds and total implant activity across the range of prostate volumes. For larger volumes, the variation in implanted activity was 25%; for smaller glands, it exceeded 40%. CONCLUSIONS: There remain wide variations in implanted activity between institutions espousing seemingly identical implant strategies, prescription, and dosimetry constraints. Brachytherapists should therefore be wary of using nomograms generated at other institutions. Ó 2008 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords:

Prostate neoplasms; Brachytherapy; Nomograms; Dosimetry

Introduction Despite the widespread acceptance and application of transperineal interstitial permanent prostate brachytherapy, the procedure is relatively new, barely 25 years old. The past decade has seen the accumulation and analysis of outcome data, resulting in guidelines formulated by expert panels to facilitate optimal implants (1e3). It is not clear, however, that there is consensus concerning the parameters of an ideal implant. Received 12 February 2008; received in revised form 29 June 2008; accepted 18 July 2008. * Corresponding author. Department of Radiation Oncology, University of Massachusetts Medical School, Levine Cancer Center, 33 Kendall Street, Worcester, MA 01605. Tel.: þ1-508-334-6550; fax: þ1-508-3345624. E-mail address: [email protected] (J.N. Aronowitz).

We reviewed recent implants performed at three centers of brachytherapy excellence to evaluate conformity in the qualitative and quantitative parameters of permanent prostate brachytherapy.

Methods and materials Three institutions with extensive prostate brachytherapy expertise and mature technique consented to share data on 50 previously performed I-125 implants. Information regarding each institution’s implant philosophy and dosimetric constraints was obtained by questionnaire. There were five stipulations for submitted cases: 1. A wide array of prostate volumes (from !20 mL to O50 mL) were to be represented.

1538-4721/08/$ e see front matter Ó 2008 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.brachy.2008.07.002

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2. The implants were intended to be the sole radiotherapy to be delivered (without adjuvant beam therapy). 3. The implants’ quality had been deemed ‘‘satisfactory’’ by the brachytherapist, based on seed distribution and postimplant dosimetry. 4. Implant data were to include planning ultrasound prostate volume, seed activity, the number of seeds implanted, and implant D90 derived from a postimplant CT scan. 5. No information that would allow patient identification was to be submitted. Information regarding the use of androgen deprivation, seed model/manufacturer, and seed stranding was not obtained. Individual cases that did not meet inclusion criteria (e.g., implants intended to be combined with beam therapy) were excluded. The study was approved by the analyzing institution’s review board, and participating brachytherapists were encouraged to obtain similar approval. Based on the supplied data, regression analyses were performed using JMP v7.0 software (SAS Institute, Cary, NC) and power equations Number of seeds 5 aðvolumeÞ

b

Total activity 5 aðvolumeÞb (where a and b are regression fitting coefficients) were generated for each institution. Power equations were used because they are the most frequent type of equations cited in the literature for describing the relationship between prostate volume and seed requirements. Analysis of variance (ANOVA) was used to determine if there were significant differences between the institutions, in regard to the number of implanted seeds, or the total implanted activity, as related to preimplant prostate volume. For purposes of illustration, the generated equations were used to calculate hypothetical seed and activity utilization for each institution, for small (20 mL), medium (40 mL), and large (60 mL) prostate volumes. Graphing was performed using CricketGraph III (Cricket Software, Philadelphia, PA).

6. Utilization of preplanning (not intraoperative planning) 7. Variseed software for preplan and postimplant dosimetry Table 1 contains information regarding each institution’s target volume, prescription parameters, dosing constraints, and timing of postimplant imaging. Although data on 152 implants were submitted, 16 implants were clearly intended to be combined with adjuvant beam therapy, and were excluded from analysis. Table 2 summarizes seed usage and postimplant dosimetry. The item ‘‘prostate volume D’’ refers to the change in prostate volume between preimplant transrectal ultrasound (TRUS) and postimplant CT (Institution A’s postimplant dosimetry was based on fused CT and MRI images). Based on submitted data, power equations reflecting seed usage were generated for each institution: Institution A No. of seeds 5 16.3 (volume)0.525 Implant activity (mCi) 5 4.22 (volume)0.588 Institution B No. of seeds 5 14.8 (volume)0.516 Implant activity (mCi) 5 4.87 (volume)0.513

Response to a questionnaire indicated that the participating institutions nominally share a similar implant philosophy, prescription, and dosimetry parameters: 1. Prescription dose of 145 Gy 2. Target volume consisting of the prostate with a margin 3. Modified peripheral distribution of seeds 4. Use of ‘‘low-strength’’ seeds (!0.43 mCi, !0.54 unit of kerma strength [U]) 5. Ten percent to 30% of seeds intentionally placed outside the gland

R2 5 0.86 R2 5 0.89

Institution C No. of seeds 5 23.9 (volume)0.408 Implant activity (mCi) 5 9.13 (volume)0.415

R2 5 0.90 R2 5 0.90

Figure 1 graphs the power curves generated from these equations. ANOVA indicated that there was a statistically significant interaction between institution and volume in regard to the number of implanted seeds ( p !0.05) and a highly significant interaction between institution and volume in regard to implanted activity ( p !0.001). Table 1 Summary of target volumes and dosimetry constraints Institution A

Results

R2 5 0.96 R2 5 0.96

Extracapsular coverage (mm) Anterior Lateral Longitudinal Posterior 0, at Prescription parameters D90 (Gy) V100 (%)

5 3 5 except 3 base

165e175 O99.5

Constrains V150 (%) Rectal V100 (mL) Urethra, any (Gy) Timing of postimplant CT *No specific constraints.

55e59 !1 !180 1 month

B

C

‘‘Few’’ 5e8 5 0, except ‘‘few’’ at base

3 3 5 0

160e175 O90

O140 O90

45e50 !1 !195

!50 * !217

Same day

3e4 weeks

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Table 2 Summary of implant data Institution A No. of implants 48 Prostate volume (mL) Mean 37.1 Range 16e70 No. of seeds implanted Mean 107.2 Range 66e152 Seed activity, mCi (U) Median 0.32 (0.41) Range 0.29e0.38 (0.37e0.48) Implant activity, mCi (U) Mean 34.8 (44.2) Range 21.3e55.5 (27.1e70.5) Prostate volume D* (%) Mean þ3 Range 29 to þ 63 Postimplant D90 (Gy) Mean 169 Range 142e196

B

C

42

46

38.1 15e63

32.0 10e62

96.4 66e140

96.7 55e131

0.33 (0.42) 0.28e0.35 (0.36e0.44)

0.39 (0.50) 0.36e0.40 (0.46e0.51)

31.3 (39.8) 21.8e41.6 (27.7e52.8)

37.8 (48.0) 20.4e55.0 (25.9e69.9)

þ11 11 to þ 37

þ28 14 to þ 76

155 130e183

167 132e206

*Change in volume from preimplant TRUS to postimplant CT.

Table 3 shows the estimated seed usage and implant activity (calculated from the power equations) for each institution, for hypothetical prostates of small, medium, and large volume. SmPD, the idealized minimal implant strength that would deliver at least 145 Gy to the periphery of the gland by optimal seed placement, is listed for reference (1, 4). Discussion ‘‘Different institutions are treating the same disease differently,’’ concluded Bice et al., in reporting a similar investigation 10 years ago (5). They had invited five institutions to submit data on their 10 most recent consecutive implants and found that ‘‘a large difference in total activity for a given size gland existed between institutions.’’ But the experience of the participating institutions varied widely (the least experienced brachytherapist had performed only 30 procedures), and the use of consecutive implants may have included some of poor quality, skewing the results; indeed, the correlation coefficients for the generated equations varied from 0.73 to 0.93 (median, 0.84), probably reflecting uneven implant quality secondary to the relative inexperience of some of the participating institutions. There were no data regarding each institution’s implant philosophy, target volume, dosimetric goals, or constraining parameters (beyond the statement that ‘‘each institution used an ultrasound-guided technique patterned after that described by Blasko’’). The authors did not attempt to explain the variance in implanted activity (calculated to be 39% for a 30 mL gland) beyond noting the differences in intended extracapsular coverage, postimplant CT timing,

Fig. 1. Regression analyses of the 3 institutions’ (a) number of implanted seeds and (b) total implant activity.

and point on the ‘‘learning curve’’ of the participating institutions. More recently, Merrick et al. studied interinstitutional variability in treatment planning (6). Eight experienced brachytherapists were asked to plan an implant for a submitted 30 mL prostate. Although the prescription dose was specified, the authors noted a wide variation in target volume (range, 30e53 mL), number of seeds (range, 64e92), individual seed strength (range, 0.414e0.889 U), total implant strength (range, 29.4e51.0 U), and seed distribution (the percentage of extracapsular seeds ranged from 10% to 58%). Not surprisingly, resultant D100 (range, 67e117%) and V150 reflected the wide variation in target specification and seed distribution. Although the implant philosophy for each center was not identified, it is clear that the brachytherapists had very different visions as to what constituted an optimal implant.

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Table 3 Estimated seed usage and implant activity for hypothetical small, medium, and large prostates Institution Prostate volume

A

B

C

SmPD

20 mL No. of seeds Implant activity, mCi (U)

79 24.3 (30.9)

68 22.2 (28.2)

82 31.7 (40.3)

19.4 (24.6)

40 mL No. of seeds Implant activity, mCi (U)

113 36.9 (46.7)

99 32.3 (41.0)

108 42.3 (53.7)

31.1 (39.4)

60 mL No. of seeds Implant activity, mCi (U)

140 40.7 (59.7)

124 40.1 (50.9)

127 50.1 (63.6)

41.0 (52.1)

One might expect that, with accrued experience and mature outcome data, a consensus of vision might have been achieved. To investigate if this is currently the case, we reviewed a relatively large number of recent implants (covering a wide range of prostate volumes) performed at recognized ‘‘centers of excellence,’’ whose published data are among the benchmarks for the procedure. Despite sharing a common implant philosophy (modified peripheral loading), technique (heavy reliance on extracapsular seed placement), and dosimetry goals, these institutions have very different implant activities. For a large (60 mL) gland, the difference in implanted activity was as high as 25%; for a small (20 mL) gland, the difference exceeded 40%. Why is there so much variability in implant activity? A possible explanation is the difference in the definition of the target volume. Although Table 1 suggests that these differences are subtle, even the addition of 2 mm in circumferential margin to a target volume with an average dimension of 5 cm would result in a volumetric increase of 26%. Although the magnitude of the difference could account for most of the activity variance, it should be noted that the institution implanting the greatest activity across the entire range of volumes (C) reported the narrowest margins, whereas the institution that reported the widest margins (B) typically implanted the least activity. Intuitively, a larger number of implanted seeds should result in a more homogeneous dose distribution, resulting in the need for a lower total activity. But Institution B, which generally implanted the fewest seeds, typically implanted the lowest activity. It is apparent from Fig. 1 that the variation in number of implanted seeds was smaller than the variation in total activity. The variation in implant activity may simply reflect the tendency of certain institutions to perform ‘‘warmer’’ implants. Institution A’s planning parameters (D90 5 165e175 Gy, V100 O99.5%, V150 5 55e59%) suggest that it favors ‘‘warmer’’ implants and its postimplant D90 (at 169 Gy, the highest mean D90 of the three institutions) seems to reflect

it. But Institution A’s postimplant dosimetry is based on relatively late (one month) imaging, when implant-induced edema is all but resolved. Institution B’s relatively low postimplant D90 is probably a reflection of early (Day 1) imaging. One significant limitation of this study is that there has been no central review of either preimplant or postimplant contouring. As noted above, subtle variations in target definition can result in large alterations in volume. It was beyond the resources of this study, however, to analyze contouring on so many plans. Another limitation of the study is that we did not factor in the potential impact of androgen deprivation, which can shrink the gland between planning TRUS and actual implant, perhaps leading to higher D90. We have demonstrated large interinstitutional variation in implant activity for a given volume, but haven’t elucidated the cause. Perhaps only large cooperative studies with central review and outcome correlation can generate guidelines that can result in optimal implants for the largest number of patients. Until then, brachytherapists should be aware of this phenomenon before adopting nomograms generated at other institutions.

Conclusions Despite the accumulation of more than a decade of data, and the recommendations of expert panels of physicists and radiation oncologists, there remain wide variations in implant strength for a given prostate volume, even among brachytherapists espousing seemingly identical implant strategies, prescription, and dosimetry constraints. Perhaps large multi-institutional studies of process and outcome, with central review and analysis, will result in guidelines that will facilitate uniformly optimal implants. Until interinstitutional conformity is achieved, brachytherapists should be wary of using nomograms generated at other institutions. References [1] Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64. Med Phys 1999;26:2054e2076. [2] Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46: 221e230. [3] Salembier C, Lavignini P, Nickers P, et al. Tumour and target volumes in permanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTC recommendations on prostate brachytherapy. Radiother Oncol 2007;83:3e10. [4] Yu Y, Waterman FM, Suntharalingham N, et al. Limitations of the minimum peripheral dose as a parameter for dose specification in permanent I-125 prostate implants. Int J Radiat Oncol Biol Phys 1996;34: 717e725. [5] Bice WS, Prestidge BR, Grimm PD, et al. Centralized multiinstitutional postimplant analysis for interstitial prostate brachytherapy. Int J Radiat Oncology Biol Phys 1998;41:921e927. [6] Merrick GS, Butler WM, Wallner KE, et al. Variability of prostate brachytherapy preimplant dosimetry: a multi-institutional analysis. Brachytherapy 2004;4:241e251.