A comprehensive review of prostate cancer brachytherapy: defining an optimal technique

Int. J. Radiation Oncology Biol. Phys., Vol. 44, No. 3, pp. 483– 491, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter

PII S0360-3016(99)00047-4

CRITICAL REVIEW

A COMPREHENSIVE REVIEW OF PROSTATE CANCER BRACHYTHERAPY: DEFINING AN OPTIMAL TECHNIQUE FRANK A. VICINI, M.D., VIJAY R. KINI, M.D., GREGORY EDMUNDSON, B.S., GARY S. GUSTAFSON, M.D., JANNIFER STROMBERG, M.D., AND ALVARO MARTINEZ, M.D. Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI Purpose: A comprehensive review of prostate cancer brachytherapy literature was performed to determine if an optimal method of implantation could be identified, and to compare and contrast techniques currently in use. Methods and Materials: A MEDLINE search was conducted to obtain all articles in the English language on prostate cancer brachytherapy from 1985 through 1998. Articles were reviewed and grouped to determine the primary technique of implantation, the method or philosophy of source placement and/or dose specification, the technique to evaluate implant quality, overall treatment results (based upon pretreatment prostate specific antigen, (PSA), and biochemical control) and clinical, pathological or biochemical outcome based upon implant quality. Results: A total of 178 articles were identified in the MEDLINE database. Of these, 53 studies discussed evaluable techniques of implantation and were used for this analysis. Of these studies, 52% used preoperative ultrasound to determine the target volume to be implanted, 16% used preoperative computerized tomography (CT) scans, and 18% placed seeds with an open surgical technique. An additional 11% of studies placed seeds or needles under ultrasound guidance using interactive real-time dosimetry. The number and distribution of radioactive sources to be implanted or the method used to prescribe dose was determined using nomograms in 27% of studies, a least squares optimization technique in 11%, or not stated in 35%. In the remaining 26%, sources were described as either uniformly, differentially, or peripherally placed in the gland. To evaluate implant quality, 28% of studies calculated some type of dose–volume histogram, 21% calculated the matched peripheral dose, 19% the minimum peripheral dose, 14% used some type of CT-based qualitative review and, in 18% of studies, no implant quality evaluation was mentioned. Six studies correlated outcome with implant dose. One study showed an association of implant dose with the achievement of a PSA nadir < 0.5. Two studies showed an improvement in biochemical control with a D90 (dose to 90% of the prostate volume) of 120 to 140 Gy or higher, and 2 additional studies found an association of clinical outcome with implant dose. One study correlated implant quality with biopsy results. Of the articles, 33 discussed evaluable treatment results, but only 16 reported findings based upon pretreatment PSA and biochemical control. Three- to 5-year biochemical control rates ranged from 48% to 100% for pretreatment PSAs < 4, 55% to 90% for PSAs between 4 and 10, 30% to 89% for PSAs > 10, < 20 and < 10% to 100% for PSAs > 20. Due to substantial differences in patient selection criteria (e.g., median Gleason score, clinical stage, pretreatment PSA), number of patients treated, median follow-up, definitions of biochemical control, and time points for analysis, no single technique consistently produced superior results. Conclusions: Our comprehensive review of prostate cancer brachytherapy literature failed to identify an optimal treatment approach when studies were analyzed for treatment outcome based upon pretreatment PSA and biochemical control. Although several well-designed studies showed an improvement in outcome with total dose or implant quality, the numerous techniques for implantation and the varied and inconsistent methods to specify dose or evaluate implant quality suggest that standardized protocols should be developed to objectively evaluate this treatment approach. These protocols have recently been suggested and, when implemented, should significantly improve the reporting of treatment data and, ultimately, the efficacy of prostate brachytherapy. © 1999 Elsevier Science Inc. Prostatic neoplasms, Brachytherapy, Interstitial brachytherapy.

The optimal management of clinically localized prostate cancer has not yet been defined. Current options for treatment include observation, surgery, cryotherapy, irradiation, or hormonal manipulation (1–3). Despite reports suggesting that one particular treatment approach may be more advantageous than another, recent studies indicate that objective

comparisons of treatment alternatives cannot be made until standardized methods for staging patients and reporting outcome are adopted (3–5). Interstitial brachytherapy is one treatment approach that has generated renewed interest due to the development of ultrasound guidance technology for more accurate source positioning, new and improved radioisotopes for dose delivery, sophisticated treatment planning soft-

Reprint requests to: Frank A. Vicini, M.D., Department of Radiation Oncology, William Beaumont Hospital, 3601 West

Thirteen Mile Road, Royal Oak, MI 48073. Accepted for publication 4 February 1999.

INTRODUCTION

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ware for dosimetric calculations, and inexpensive and less morbid methods of implantation (6 –16). As a result, the number of prostate implants performed in the USA is expected to increase significantly over the next several years. Despite the fact that preliminary results have been extremely promising, the efficacy of prostate cancer brachytherapy has not been thoroughly evaluated, and several different methods of implantation, dose specification, and treatment analysis currently exist. Recently, a significant effort has been directed towards investigating if centralized, multi-institutional postimplant analyses can be performed (17). If practical, these efforts may provide a framework to develop multi-institutional trials designed to study the efficacy of the numerous brachytherapy procedures in use. Because results from these efforts will not be available for some time, we reviewed all available prostate cancer brachytherapy literature to determine if an optimal method of implantation can be identified, and to compare and contrast the numerous techniques currently in use.

METHODS AND MATERIALS A MEDLINE search was conducted to obtain all articles in the English language on prostate cancer treatment using brachytherapy from January 1, 1985 to August 1, 1998. Medical subject headings (MeSH) used to search the MEDLINE database were prostatic neoplasms, prostatic neoplasms brachytherapy, prostatic neoplasms interstitial brachytherapy, and 1985 to 1998. Studies were reviewed and coded, by two of the authors, to be analyzed for the following parameters: 1. overall treatment results based upon pretreatment PSA and biochemical control, 2. the primary technique used for implantation, 3. the method or philosophy of dose specification and/or source placement, 4. the technique used to evaluate implant quality, and 5. clinical, biochemical or pathological results based upon implant quality. A total of 178 citations were initially identified by the MEDLINE database. Several articles represented literature reviews and were not included in this analysis. Additional studies discussed technical aspects of brachytherapy, but did not present treatment data. A total of 53 studies presented treatment results from multiple institutions and constitute the articles evaluated in this analysis (several studies presented updates of previous experiences). It should be noted that not all evaluable articles were reported in this analysis due to space limitations. As a result, only the most recent studies with the largest group of patients treated (or the most comprehensive methods and materials section) were included in this analysis. A total of 33 studies presented evaluable treatment results. However, only 16 of these studies presented treatment data based upon pretreatment PSA and biochemical control.

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Statistical analyses To be analyzed for the evaluation of treatment results, studies had to stratify patients by pretreatment PSA and evaluate outcome using biochemical control as an endpoint. Due to substantial differences in the reporting and distribution of critical pretreatment prognostic factors (e.g., Gleason score, PSA, stage), the variability in minimum and median follow-up from series to series, and the inconsistent definitions of biochemical control used in most studies, no statistical analyses could be performed to compare treatment results from the institutions identified. RESULTS Implant technique A total of 3 major subheadings were identified, including 1. permanent seed implants alone, 2. permanent seed implants combined with external beam radiotherapy, and 3. temporary interstitial implants combined with external beam radiotherapy. Table 1 lists the 27 major series identified using permanent seeds alone (8, 18 – 45). Table 2 lists the 23 major studies using combined modality therapy (10, 22–24, 44 – 65). The most common isotope used for permanent implants alone was 125iodine (125I) (76%), followed by 103 palladium (103Pd) (8%), and 125I or 103Pd (16%). For combined modality treatment, 125I seeds were more frequently used (53%), followed by 192iridium (192Ir) (26%), 198 gold (198Au) (11%), 103Pd (5%) and both 125I and 103Pd in another 5%. Of these, 9 studies used loose seeds and 10 studies used seeds held together by strings. Among the studies, 15 used preloaded needles and 14 used afterloading needles (not all studies provided this information). Target volume delineation The target volume to be implanted was determined preoperatively using ultrasound imaging in approximately 52% of studies, CT imaging in 16% (ultrasound and fluoroscopy were also used in some of these studies), and in 18% of studies an open surgical technique was used. An additional 11% of studies placed seeds or needles under ultrasound guidance using interactive realtime dosimetry. One study did not state how the target volume was delineated. Dose prescription The primary method or philosophy used to calculate the optimal source distribution and/or to specify dose (e.g., calculate the activity to be implanted or the dose covering the entire gland) was difficult to determine in many studies. However, 27% of studies appeared to use nomograms (implying that the distribution of seeds was relatively uniform) (66, 67). An additional 11% of studies used a least squares optimization technique and in 35% of studies, dose-specification criteria were not stated. In the remaining studies (26%), sources appeared to be placed in a uniform/homogenous pattern in 11%, differentially positioned in the gland in 9%, or peripherally biased in 6%. Again, due to limited

Prostate cancer brachytherapy

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Table 1. Studies using permanent seeds alone No. of Total dose Dose Method of patients Isotope (Gy) Needles Seeds specification seed placement

Study

Stone et al. (35) 58 125I/103Pd 125 Ragde et al. (29, 30, 45) 126 I 125 Blasko et al. (19) 197 I 125 Wallner et al. (37) 20 I 125 Zelefsky et al. (41) 1078 I Stock et al. (31, 32, 43) 134 125I/103Pd 125 Kaye et al. (22–24) 45 I 125 Beyer et al. (18) 499 I 125 Stokes et al. (33, 34) 142 I Brosman et al. (20) 41(?) 103Pd 125 Kumar et al. (25) 85* I 125 van’T Reit et al. (36) 23 I 103 Nag et al. (26) 32 Pd 125 Holm et al. (21) NS I 125 103 Prestidge et al. (27) 402 I/ Pd 125 Priestley et al. (28) 133 I 103 Sharkey (42) 434 Pd 125 Stock (43) 134 I 103 D’Amico (44) 66 Pd 125 Ragde (45) 98 I 125 Wallner et al. (8, 38, 39, 40) 92 I

NS 160 160 160–180 140 160 160 160 160 170 160–200 160 120 NS 115–144 160 115 160 115 160 140–160

Afterloaded Preloaded Preloaded Afterloaded Afterloaded Afterloaded Preloaded Afterloaded Preloaded Afterloaded Afterloaded Preloaded Afterloaded Preloaded Preloaded Afterloaded Afterloaded Afterloaded Afterloaded Preloaded Afterloaded

L L NS NS L L NS NS NS L S L L L L/S NS L L NS L NS

Implant quality evaluation

NOM/PL US/RT DVH UL US CT-based qualitative review UL US CT-based qualitative review LSO/DF US/CT Orthogonal films/MPD NOM Open retropubic MPD PL/NOM US/RT DVH NS US/F Radiographs/MPD NS US Orthogonal films/CT PL US Orthogonal films NS US Radiograph (MiPD) NS CT/F MiPD UL/NOM US NVDH NOM CT/US MiPD/CT NS US NS UL/MiPD US NS NS US Orthogonal films PL US/RT NS PL/NOM US/RT DVH MiPD NS Orthogonal films/CT UL US CT-based qualitative review LSO/DF CT/US Orthogonal films/MPD/DVH

NS 5 Not stated; L 5 Loose; S 5 Strands; NOM 5 Nomogram-based; PL 5 Peripheral loading; DF 5 Differential loading; UL 5 Uniform loading; F 5 Fluoroscopy; RT 5 Real time; NVDH 5 Natural volume-dose histogram; DVH 5 Dose-volume histograms; MPD 5 Matched peripheral dose; CT 5 Computed tomography MiPD 5 Minimum peripheral dose; LSO 5 Least squares optimization technique; * 9 patients received EBRT as well.

descriptions of technical details in many studies, the accuracy and/or completeness of the above data may be limited. In addition, several of the above studies appeared to use

more than one method to determine the activity to be implanted, the source distribution, and/or the method to specify dose.

Table 2. Studies using permanent seeds or a temporary implant combined with external-beam irradiation Dose (Gy) Study Iverson et al. (57) Blasko et al. (10) Blasko et al. (10) Donnelly et al. (54) Vijverberg et al. (58) Dattoli et al. (53) Critz et al. (49) D’Addessi et al. (52) Goad et al. (55) Carey et al. (48) Gottesman et al. (56) Stromberg et al. (59, 60) Borghede et al. (46, 47) Kaye et al. (23, 24) Critz et al. (49–51) Zeitlin et al. (61) Eastham et al. (63) Ragde et al. (45) Mate et al. (65)

No. of patients Isotope 33 160 160 170 52 73 239 63 68 72 41 58 54 31 536 212 136 54 104

125

External beam

Implant

I 47.4 160 I 45 120 103 Pd 45 90 192 Ir 45 35 125 I 40 160 103 Pd 41 80 125 I 45 80 125 I 45 (1LN) 132 198 Au 40–50 35 198 Au 40 30–35 125 I 35–40* 150 192 Ir 45.6 5.5–6.5 3 3 192 Ir 50 10 3 2 125 I 45 120 125 I 45 80 125 103 I/ Pd 45 90/120 198 Au 50 25–30 125 I 45 120 192 Ir 50.4 3.0–4.0 3 4 125

Needles Preloaded Preloaded Preloaded Afterloaded Preloaded Afterloaded NS NS NS NS NS Afterloaded Afterloaded Preloaded NS Afterloaded NS Preloaded Afterloaded

Seeds

Dose specification

L NOM/UL S UL S UL NA NS L NOM/UL NS PL NS NOM/DF/CT NS NOM L NS NS NS (MiPD) NS NS NA US/RT NA DF (Optimized) NS NS NS NOM/CT/DF L UL NS NS L UL NA Optimized

Method of seed placement

Implant quality evaluation

US US US Open US US Open Open NS Open Open US US US/F Open US Open US US

Radiographs/MiPD CT-based qualitative review CT-based qualitative review NS Radiographs/MiPD NS NS/MiPD NS NS CT-based qualitative review MPD Modified DVH DVH Radiographs/MPD NS/MiPD CT-based qualitative review NS CT-based qualitative review CT-based qualitative review

US 5 Ultrasound; CT 5 Computed tomography; MiPD 5 Minimum peripheral dose, NOM 5 Nomogram; RT 5 Real time; L 5 Loose; S 5 Strands; NA 5 Not applicable; LN 5 Lymph nodes; DF 5 Differential loading; NS 5 Not stated; MPD 5 Matched peripheral dose; UL 5 Uniform loading; F 5 Fluoroscopy; DVH 5 Dose-volume histograms; * Supplemental radiation given if MPD , 150 Gy.

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Table 3. Treatment parameters for permanent seed implant alone series Institution

Dates

26 30 35 18 18 36

NS #7 5–6 5–6 7 2–4

125

1/88–12/92

45 142 489 83 14 197

1/88–12/94 1/87–6/88 1/89–10/97 12/91–7/96

96 98 66 434

36 119 41 28

5–7 5–6 5–6 5–6

125

Kaye et al. (23, 24) 5/88–8/93 Stokes et al. (33, 34) 10/88–12/92 Beyer et al. (18) 12/88–12/93 Stock et al. (32) 1/90–12/94 Blasko et al. (19) Wallner et al. (39) Ragde et al. (45) D’Amico et al. (44) Sharkey et al. (42)

n Median F/U Median Gleason Implant dose PSA Patients (months) score Isotope (Gy) Definition of biochemical failure I I 125 I 125 I 103 Pd 125 I

. 4 ng/ml NS . 4 ng/ml 2 PSA increases after nadir

160 160 160 121 67 160

125

I I 103 Pd 103 Pd

2 consecutive PSA rises or any posttx. PSA . 4 ng/ml . 1 ng/ml at follow-up . 0.5 ng/ml 3 consecutive PSA rises 3 consecutive PSA rises

140–160 160 115 115

125

NS 5 Not stated.

Implant quality evaluation To evaluate implant quality, 28% of studies calculated some type of dose–volume histogram (DVH), 21% calculated the matched peripheral dose (MPD), 19% the minimum peripheral dose (MiPD), 14% used some type of CT-based qualitative review of individual images and, in 18% of studies, no implant-quality evaluation was mentioned. Again, it should be noted that it was not always possible to accurately determine the method of implantquality evaluation. In some of the above studies, more than one technique appeared to be used and/or a modification of a previously described method was utilized. Implant quality vs. outcome Of the 33 studies identified that presented evaluable treatment results, only 6 correlated outcome with implant quality. One study showed an association of implant dose with the achievement of a PSA nadir # 0.5 (50). Two studies showed an improvement in biochemical control with a D90 (the dose received by 90% of the gland) of 120–140 Gy or higher (32, 43), and two additional studies found an association of clinical outcome with implant dose (41, 68). One study correlated results of follow-up biopsies with implant quality (58). Although none of the studies directly correlated the implant technique with the development of complications, 4 studies did report increasing complications with a past history of a trans-

urethral resection of the prostate (TURP) (41). In addition, one study attempted to correlate the rate of rectal ulceration with the MPD (no relationship was found) (69). The same study did, however, show an increase in urinary morbidity with the maximum urethral dose and an increase in rectal morbidity with doses . 100 Gy to the rectal wall surface.

Biochemical control Tables 3 and 4 list all 10 studies that calculated treatment outcome based upon pretreatment PSA and biochemical control. Table 3 lists permanent seed-alone studies that met the selection criteria. Table 4 lists studies that combined external-beam irradiation with either a permanent seed implant or temporary interstitial brachytherapy. Treatment results were quite variable and are summarized in Table 5. Three- to 5-year biochemical control rates ranged from 48% to 100% for pretreatment PSAs # 4, 55% to 90% for PSAs between 4 and 10, 30% to 89% for PSAs . 10 # 20, and , 10% to 100% for PSAs . 20. Due to substantial differences in the reporting and distribution of pretreatment prognostic factors, substantial differences in minimum and median follow-up, and the variable methods of defining outcome, no inferential methodologies could be applied to these data to determine an optimal implant technique.

Table 4. Treatment parameters for studies combining external-beam irradiation with permanent seeds or temporary implants

Institution

Dates

n of Median F/U Median Gleason Implant dose External beam Patients (months) score Isotope (Gy) dose (Gy)

Goad et al. (55)

1987–1991

76

27

NS

198

Critz et al. (51)

1/84–9/95

363

60

NS

125

1991–1994 11/91–11/95 1/87–6/88 1/91–11/96 10/89–8/95

73 58 45 212 104

24 43 119 33 45

4–9 7 6–7 5–6 NS

103

Dattoli et al. (53) Stromberg et al. (59, 60) Ragde et al. (45) Zeitlin et al. (61) Mate et al. (65)

Au I

35 80–160

Pd 80 Ir 5.5–6.5 3 3 125 I 120 125 103 I/ Pd 90–120 192 Ir 3.0–4.0 3 4 192

50 45 41 45.6 45 45 50.4

PSA Definition of biochemical failure 2 consecutive PSA rises or single rise . 2 ng/ml Nadir . 0.5 ng/ml or a rise . 0.5 ng/ml PSA . 1 ng/ml at follow-up PSA . 1.5 ng/ml and 2 rises . 0.5 ng/ml . 0.5 ng/ml 3 consecutive PSA rises

84% 50%

, 10%

30%

85%

70% 60%

10 yrs 5 yrs 5 yrs

100% 45% 80% 38%

F/u* 5 Time-point for analysis; ‡ D90 $ 140 Gy.

38% 33% 42%

47% 79%

18%

82%

83% 70% 86%

55%

58%

100%‡

45%

79%

89%

90%

72%

87%

90% 70%

89%

85%

83%

50%

76%

95% 72%

5 yrs 4 yrs 90% 3 yrs 2.5 yrs 5 yrs 93% 5 yrs 98% 4 yrs 100% 4 yrs 2 yrs 5 yrs 94% 5 yrs 100% 92%

2.5 yrs 100%

3 yrs 48%

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DISCUSSION

F/u* ,4 .4 4–10 # 10 . 10 , 15 . 15 10–20 , 20 . 20 20–30 . 30

Sharkey et al. (42) Stromberg et al. (59–60) Dattoli et al. (53) Critz et al. (49–51) Blasko et al. (19) Wallner et al. (39) Stock et al. (43) Stock et al. (32) Goad et al. (55) Beyer et al. (18) Stokes et al. (33–34) Kaye et al. (23–24) PSA (ng/ml)

Table 5. Rates of biochemical control stratified by pretreatment PSA for brachytherapy series

Zeitlin et al. (61)

Mate et al. (65)

D’Amico et al. (44)

Ragde et al. (45)

Prostate cancer brachytherapy

In the current analysis, we reviewed all the available prostate cancer brachytherapy literature to determine if an optimal method of implantation could be identified, and to compare and contrast the numerous techniques currently in use. Due to the inconsistent reporting of pretreatment prognostic factors, the unequal distribution of critical prognostic variables from series to series, the significant differences in the length of follow-up in most studies, and substantially different ways of reporting treatment outcome, no optimal brachytherapy technique could be identified. Despite several well-designed studies showing improved clinical local or biochemical control with implant dose and/or quality, no consistent or reproducible method of stratifying pretreatment prognostic factors or evaluating implant quality was identified so that an ideal technique of implantation (i.e., source positioning or dose specification) could be ascertained. These findings suggest that, until standard methods of reporting pretreatment prognostic factors, treatment techniques, or outcome are adopted, no valid conclusions can be reached on the optimal method of implantation or the efficacy of the many treatment approaches currently in use. Prostate cancer brachytherapy has enjoyed a renewed interest due to the development of several technological factors that have improved the accuracy, reproducibility, and morbidity of this treatment technique (6, 7, 9). However, multiple methods of implantation currently exist and no consistent measures detailing all the technical aspects of prostate implantation have yet been developed. For example, there are currently 3 or more distinct techniques in use to preplan and perform permanent seed implants (ultrasound, CT scan-, or open retropubic-based systems). In addition, there are several philosophically different methods for planning optimal source positions or for specifying dose [e.g., nomogram-based (1, 2), least squares optimization technique, differential loading, uniform loading, or peripheral loading]. Although the prescribed dose at the periphery of the prostate may be roughly equivalent with all of the above techniques, the characteristics of the dose distribution within the gland and in adjacent tissues can vary dramatically, depending upon the strength of the individual seeds, the total activity implanted, the pattern of seed distribution, and the method of analysis (10 –13, 15, 16, 39). For example, some of the authors in Tables 1 and 2 recommend low-activity seeds placed in a uniform pattern across the gland with minimal (, 15%) activity in the periphery. Proponents of this approach argue that this results in a more homogenous dose distribution that is less likely to be disrupted by the imprecise alignment of seeds that inevitably occurs (see below). Conversely, as much as 70% of the activity can be implanted in the periphery of the gland using higher activity sources. Advocates of this approach cite lower central urethral doses, but acknowledge that this technique may be more dependent upon accurate source positioning because minor deviations in seed alignment can theoretically create significant areas of overdosage

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Table 6. Implant quality/dose vs. outcome Dose (Gy) Study

Isotope

Implant EBRT

Vijverberg et al. (58)

125

160

40

Stock et al. (32)

125

160

–

Zelefsky et al. (41)

125

140

–

Critz et al. (49–51)

125

80

45

Stock et al. (43)

125

160

–

I I or 103Pd I I I

Parameter Implant

Outcome

Correlation

Implant quality based on Follow-up biopsy Negative biopsies increased with “percent underdosage” better quality D90 of 120 Gy Biochemical (PSA) control Improved control with D90 of 120 Gy or higher Matched peripheral dose DRE/biopsy/bladder outlet Improved local control with obstruction MPD $ 140 Gy Implant dose PSA nadir # 0.5 ng/ml Probability of achieving nadir increased with dose . 80 Gy D90 $ 140 Gy Biochemical control Improved control with D90 $ 140 Gy

DRE 5 Digital rectal examination; D90 5 Dose to 90% of the prostate volume; MPD 5 Matched peripheral dose.

or underdosage of the gland or rectum (10, 11). Unfortunately, no consistent or reproducible method to evaluate implant quality has been developed to allow an accurate assessment of the individual and unique aspects of each implant preplanning technique or source/dose specification philosophy (70). As a result, all of the above philosophies are currently in use (71). Additionally, significant limitations in accurate source positioning (regardless of implant technique) have also been identified. Recent studies indicate that substantial deviations in source placement (related to seed-spacing changes, seed splaying, gland compression and retraction, gland edema, and needle deviations) can occur, leading to significant under- or overdosage of the gland (72–80). In addition, the magnitude of the effect of postimplant edema on the volume of the gland and seed positions can be so significant (73–75) that, depending upon when implant quality is judged, incorrect conclusions may be reached on the efficacy of a particular treatment technique (81–85). It is also not certain if computed tomography (CT scanning) is capable of accurately delineating the true extent of the prostate gland to adequately judge implant quality (86–89), or if seed positions can be adequately defined threedimensionally for implant quality measurements (77, 83, 90– 93). Fortunately, certain techniques of implantation using continuously updated isodose-distribution calculations superimposed on real-time images of an immobilized gland during radiation delivery (high-dose rate brachytherapy combined with external-beam irradiation) have been developed that may eliminate some of the problems identified above (59, 60, 94). Until similar reproducible techniques for radiation delivery with permanent seed implants are developed, it is extremely difficult to objectively compare implant quality vs. outcome in these patients, or to identify an optimal technical approach in the planning, placement, and evaluation of seed distributions (95). Several recent reports of prostate cancer brachytherapy indicate superb treatment outcome in patients treated with a particular technique or protocol. However, the substantial differences in pretreatment prognostic factors in many of these studies does not allow a meaningful comparison of results to be performed. We have recently shown that several of these

reports have significant numbers of patients with more favorable tumors (low Gleason scores), possibly accounting for much of the improved results obtained (4, 5). In addition, the liberal and inconsistent use of the definition of biochemical cure in some of these reports can, in and of itself, significantly misrepresent treatment results (5). Though the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel recently developed a standardized definition of biochemical failure, the consistent reporting of all critical pretreatment prognostic factors must be undertaken to evaluate the effectiveness of any therapy (96). For example, certain combined-modality therapy studies (external-beam irradiation plus either a permanent or temporary interstitial implant) report numerically better results in patients with pretreatment PSAs above 10–20 (see Table 5). However, the median Gleason score in some studies is dramatically higher than in others (59, 60), or simply was not stated. Without taking all critical pretreatment prognostic factors into account, the true efficacy of many of these techniques is unknown because treatment results may be incorrectly attributed to implant technique, rather than selection bias. The issue of implant quality and total dose vs. outcome has only minimally been investigated. Though 6 studies showed improved results with either increasing dose or implant quality, the technical limitation in accurately determining dosimetric coverage of the gland (and the uncertainties of edema resolution over time) make interpretation of results extremely difficult (Table 6). As we have shown in this report, there are numerous and substantially different ways of evaluating implant quality (e.g., MiPD-, MPD-, DVH- or CT-based), which can give misleading and contradictory assessments of outcome (83). In effect, the relationship between prescribed dose, achieved dose, and cancer eradication with each implant technique remains uncertain. Similarly, there are few consistent data correlating radiation dose and volume to urethral and rectal complications (39, 40, 69). Fortunately, there has been a recent effort at performing centralized multi-institutional postimplant analyses for interstitial permanent seed implants (17, 97). If practical, these efforts should provide a framework with which to develop multi-institutional trials designed to study the effi-

Prostate cancer brachytherapy

cacy of the numerous brachytherapy procedures in use. Without these efforts, single-institution treatment programs (rather than prospective randomized trials) will persist in dictating what treatment is given to a patient with certain pretreatment prognostic factors. The results of this review serve only to emphasize the necessity of standardizing treatment techniques and outcome analyses so that inappropriate or incorrect conclusions on the efficacy of a particular technique are not drawn. Already, several studies may have generated questionable conclusions on the value of prostate brachytherapy due to nonstandardized methods of reporting data or inadequate dosimetric analyses (44). Such invalid conclusions not only confuse patients and clinicians as to the most optimal means of treating prostate cancer, but also set back the significant progress made in improving brachytherapy techniques over the past 10 years.

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CONCLUSIONS When all available literature on prostate cancer brachytherapy was objectively reviewed, no optimal technique or protocol was identified. These data suggest that the true efficacy of the numerous and varied techniques currently available for implantation can only be compared if 1. consistent reporting of pretreatment prognostic variables is performed, 2. a common definition of biochemical cure (e.g., ASTRO Consensus Panel Recommendation) is uniformly applied, and 3. standardized methods to technically evaluate implant quality are developed. Considering the potential for truly conformal dose escalation with less morbidity (and potentially less cost) that prostate brachytherapy can offer, these issues need to be thoroughly addressed so that the optimal method or methods of implantation can be identified (17, 97).

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