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Comparison of day 0 and day 14 dosimetry for permanent prostate implants using stranded seeds
Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 1, pp. 144 –150, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter
doi:10.1016/j.ijrobp.2005.06.044
CLINICAL INVESTIGATION
Prostate
COMPARISON OF DAY 0 AND DAY 14 DOSIMETRY FOR PERMANENT PROSTATE IMPLANTS USING STRANDED SEEDS PATRICK MCLAUGHLIN, M.D.*† VRINDA NARAYANA, PH.D.,*† CHARLIE PAN, M.D.,* SALLY BERRI, M.S.,* SARA TROYER, B.S.,* JOSEPH HERMAN, M.D.,* VICKI EVANS,* AND PETER ROBERSON, PH.D.* *Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI; †Department of Radiation Oncology, Providence Cancer Center, Southfield, MI Purpose: To determine, using MRI-based dosimetry (Day 0 and Day 14), whether clinically significant changes in the dose to the prostate and critical adjacent structures occur between Day 0 and 14, and to determine to what degree any changes in dosimetry are due to swelling or its resolution. Methods and Materials: A total of 28 patients with a permanent prostate implant using 125I rapid strands were evaluated at Days 0 and 14 by CT/MRI fusion. The minimal dose received by 90% of the target volume (prostate D90), percentage of volume receiving 100% of prescribed minimal peripheral dose (prostate V100), external sphincter D90, and 4-cm3 rectal volume dose were calculated. An acceptable prostate D90 was defined as D90 >90% of prescription dose. Prostate volume changes were calculated and correlated with any dosimetry change. A paradoxic dosimetric result was defined as an improvement in D90, despite increased swelling; a decrease in D90, despite decreased swelling; or a large change in D90 (>30 Gy) in the absence of swelling. Results: The D90 changed in 27 of 28 patients between Days 0 and 14. No relationship was found between a change in prostate volume and the change in D90 (R2 ⴝ 0.01). A paradoxic dosimetric result was noted in 11 of 28 patients. The rectal dose increased in 23 of 28 patients, with a >30-Gy change in 6. The external sphincter D90 increased in 19 of 28, with a >50-Gy increase in 6. Conclusion: The dose to the prostate changed between Days 0 and 14 in most patients, resulting in a change in clinical status (acceptable or unacceptable) in 12 of 28 patients. Profound increases in normal tissue doses may make dose and toxicity correlations using Day 0 dosimetry difficult. No relationship was found between the prostate volume change and D90 change, and, in 11 patients, a paradoxic dosimetric result was noted. A differential z-axis shift of stranded seeds vs. prostate had a greater impact on final dosimetry and dose to critical adjacent tissues than did prostate swelling. These findings challenge the model that swelling is the principal cause of dosimetric changes after implantation. Stranded seeds may have contributed to this outcome. On the basis of these findings, a change in technique to avoid placement of stranded seeds inferior to the prostate apex has been adopted. These results may not apply to implants using single seeds within the prostate. © 2006 Elsevier Inc. Prostate brachytherapy, Postimplant dosimetry, Prostate swelling.
INTRODUCTION The success of permanent prostate implant therapy is directly related to implant quality (1, 2). Implant quality is traditionally defined by coverage (minimal dose received by 90% of the target volume [D90] and percentage of volume receiving 100% of prescribed minimal peripheral dose [V100]) of the prostate on CT obtained either immediately after implant (Day 0) or weeks after the implant (3). A confounding variable in dosimetric evaluation is prostate swelling after implantation, which is highly variable in extent and in the time course of onset and resolution (4 – 8). Poor dosimetric coverage may result from swelling beyond
the ultrasound expansion for swelling, and may improve with resolution of the swelling. Because of this confounding effect, the optimal timing of postimplant dosimetric evaluation remains controversial. Day 0 dosimetry allows for immediate feedback and implant correction, and Day 30 dosimetry is less obscured by swelling, but is arguably beyond an ideal point for correction. Our practice has been the compromise timing of Day 14 CT scans for postimplant dosimetry. Studies directly comparing Day 0 with later dosimetry evaluation have suggested that Day 0 dosimetry bears some relationship to the final dosimetry (9, 10), especially if models that simulate swelling are included (11).
Reprint requests to: Patrick McLaughlin, M.D., Department of Radiation Oncology, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0010. Tel: (248) 849-3321; Fax: (248) 849-8448; E-mail: mclaughb@med. umich.edu
Presented at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 3–7, 2004, Atlanta, GA. Received April 13, 2005, and in revised form June 15, 2005. Accepted for publication June 22, 2005. 144
Day 0, Day 14 dosimetry
A second limitation of postimplant evaluation is the poor prostate definition seen on the CT scan because of swelling, seed artifact, and variations in prostate contouring (12, 13). Although training and practice allow for interobserver consensus in prostate contouring and, therefore, consensus in prostate coverage (14), MRI may be necessary to overcome fully the distortions seen on the CT scan (15–18). The assumption that the CT-defined prostate is an overestimation and, therefore, that coverage of the CT-defined prostate proves coverage of the actual prostate, has not been supported by direct comparison of MRI- and CT-based dosimetry (19). False inflation of dosimetric endpoints on CT has been due to an overestimation of the prostate inferior to the apex resulting from “circling the seeds,” and an underestimation of the base resulting from poor definition of the base and the tendency to stop contouring when the seeds are no longer visible. MRI after implantation provides precise definition of the prostate and improves the accuracy of the postimplant dosimetry. Because acceptable dosimetry is based on clinical correlation with CT dosimetry, the cutpoint for acceptable vs. unacceptable MRI postimplant dosimetry has not been established. Despite the lack of an acceptable standard, MRI-based dosimetry remains useful in quality assessment and the testing of planning strategies and is especially useful in defining subtle differences in dosimetry. In the current study, MRI-based dosimetry was used to evaluate changes in D90 and V100 at two differing points (Days 0 and 14) after implantation to evaluate whether clinically significant changes in dose to the prostate and critical adjacent structures occur between Days 0 and 14 and to what degree the changes in dosimetry are due to swelling or resolution of swelling.
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arbitrarily at 85% (no clinical correlation of V100 and clinical outcomes has been established). The external sphincter and rectal wall were contoured on the MRI data set, and dose–volume histograms of these structures were calculated. To assess base coverage, the area of the prescription isodose was measured at the superior base contour. Of the 28 patients, 17 had preimplant CT and MRI studies 2 weeks before the implant procedure. The coronal MRI data sets from the preprocedure, Day 0, and Day 14 studies were used to measure the distance of the prostatic apex from a line across the superior edge of the ischial bones. The distance from the same bony reference point to the isodose volume was also measured for the Day 0 and Day 14 scans. The relative shift in the isodose and prostate volumes was then determined.
RESULTS Change in D90 and V100 between Days 0 and 14 The average MRI D90 on Days 0 and 14 was 1.01 (⫾0.21) and 0.97 (⫾0.23) of the prescription dose, respectively. The average MRI V100 on Days 0 and 14 was 89.3% (⫾7.8%) and 87.1% (⫾7.3%), respectively. Acceptable average values in such a data set are deceptive because of the balancing effect of high- and low-dose implants, reflected in the standard deviation. In Figs. 1 and 2, the change in MRI D90 and V100, respectively, for the study patients is shown. Of the 28 patients, 27 (96%) had a change in D90 between Days 0 and 14, with a decrease in 16 (57%). Of the 28 patients, 24 (85%) had a change in V100. The significance of the changes was determined by a scoring system of acceptable if the D90 was ⱖ90% of the intended prescription dose and acceptable if the V100 was ⱖ85% of the intended prescription dose. In reference to D90, 8 (40%) of 20 patients with acceptable implants on Day 0 had unacceptable ones on Day 14. Of 7 patients with unacceptable results on Day 0, 4 (57%)
METHODS AND MATERIALS A total of 28 patients with a permanent prostate implant using I rapid strands were dosimetrically evaluated at the University of Michigan using imaging studies obtained at two points (Days 0 and 14). CT and MRI studies were performed immediately after the implant procedure (Day 0) and 14 days later (Day 14). CT scans were obtained with a slice thickness of 2 mm. Axial, coronal, and sagittal T2-weighted MRI scans were obtained with a slice thickness of 3 mm. The prostate volume was contoured on the MRI data sets, and a composite prostate volume was obtained using the information from all three MRI scans. The prostate length was defined as the length of the composite prostate along the superior– inferior direction. Seed positions were determined from the CT data set using UMPLAN, the University of Michigan treatment planning system. The CT and MRI studies were registered using mutual information and seed-to-seed techniques. D90 and V100 parameters were calculated for the Day 0 and Day 14 studies. The prescription isodose volume was determined, and the prescription isodose length (PIL) was defined as the length of the prescription isodose along the superior–inferior direction. The D90 was coded as acceptable if the D90 was ⱖ90% of the intended prescription dose and unacceptable if the D90 was ⬍90% of the prescription dose (2). The V100 cutpoint for acceptable vs. unacceptable was set 125
Fig. 1. Change in minimal dose received by 90% of the target volume (D90) between Days (D) 0 and 14. Clinical impact coded as acceptable D0/acceptable D14 (white), acceptable D0/unacceptable D14 (dark gray), unacceptable D0/acceptable D14 (light gray), and unacceptable D0/unacceptable D14 (black). Acceptable defined as MRI D90 ⬎90% planned prescription dose.
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Fig. 2. Change in percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) between Days (D) 0 and 14. Clinical impact coded as acceptable D0/acceptable D14 (white), acceptable D0/unacceptable D14 (dark gray), unacceptable D0/acceptable D14 (light gray), and unacceptable D0/unacceptable D14 (black). Acceptable defined as V100 ⬎85%.
had acceptable ones on Day 14. In reference to V100, 8 (38%) of 21 patients with an acceptable implant on Day 0 had unacceptable ones on Day 14, and 3 (42%) of 7 patients with unacceptable implants on Day 0 had acceptable ones on Day 14.
Change in D90 relative to change in prostate volume Figure 3 shows a plot of the change in D90 relative to the change in prostate volume. No relationship was found between swelling or resolution of swelling and the change in D90 (R2 ⫽ 0.01). A paradoxic dosimetric result was defined as an improvement in D90 despite swelling, a decrease in D90 despite resolution of swelling, or a large change in D90 without a change in prostate volume. A paradoxic dosimetric result was noted in 11 (40%) of 28 patients. Patients with a paradoxical dosimetric result are represented with white in Fig. 3. Of 8 patients with a decrease in volume, 4 (50%) had a decrease in D90, and 5 (31%) of 16 patients with an increase in volume had an increase in D90. Two patients with no swelling had profound (⬎30 Gy) changes in D90.
Fig. 3. Relationship between change in minimal dose received by 90% of the target volume (D90) to change in prostate volume between Days (D) 0 and 14. White triangles signify paradoxic dosimetric result.
Fig. 4. Relationship between change in minimal dose received by 90% of the target volume (D90) and change in (a) prostate length and (b) prescription isodose length (PIL).
Change in D90 relative to changes in prostate length and PIL Figure 4 shows a plot of the change in D90 relative to the changes in prostate length and PIL. The prostate length changed in 25 (90%) of 28 patients (Fig. 4a). In 11 (44%) of 25 patients, it increased. No relationship was detected between the change in prostate length and the change in D90 (R2 ⫽ 0.25). Of the 28 patients, 23 (82%) had a change in PIL between Days 0 and 14 (Fig. 4b). The most common change was a decrease in the isodose length (compression). No relationship was detected between the change in PIL and the change in D90 (R2 ⫽ 0.0). Change in rectal dose, base dose, and external sphincter dose on Day 0 vs. Day 14 Figure 5 shows a graph of the change in normal tissue dose between Days 0 and 14. In Fig. 5a, the dose to the 4-cm3 rectal wall volume is presented. In 23 (82%) of 28 patients, an increase occurred in dose to the rectum on Day 14 relative to Day 0; profound (⬎30 Gy) changes were noted in 6 patients. Figure 5b shows a graph of the change in the external sphincter dose between Days 0 and 14. In 19 (68%) of 28 patients, the D90 of the external sphincter increased between Days 0 and 14; in 6 patients, the D90 increased ⬎50 Gy and in 1 patient, the D90 increased ⬎150 Gy. Figure 5c shows a graph of the change in the base dose between Days 0 and 14. The area of the prescription isodose
Day 0, Day 14 dosimetry
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line at the superior base cut was used as a surrogate for the base dose. In 18 (62%) of 28 patients, the base dose decreased on Day 14 relative to Day 0. Shift in isodose line and prostate position in z axis between Days 0 and 14 In 17 (60%) of 28 patients, pre, Day 0, and Day 14 CT and MRI data sets were available. The z-axis shift of the prostate and isodose line (IDL) were determined by measuring the relative position of the prostate apex and base to a line across the ischial bones on coronal MRI. The superior and inferior extent of the prescription IDL was also determined relative to the same reference. The most common patterns of shift are presented in Fig. 6a. At Day 0, the prostate apex shifted superiorly owing to genitourinary diaphragm (GUD) bleeding and edema. The prescription IDL is in an ideal position relative to the prostate. By Day 14, the
Fig. 6. Relative z-axis shift of prostate and seeds at Days 0 and 14. (a) Common pattern of inferior prescription isodose length (PIL) shift relative to prostate shift and (b) less common superior PIL shift relative to prostate shift.
GUD distortion has resolved, and the prostate has moved inferiorly relative to Day 0 but not to baseline. The prescription IDL shifts inferiorly more than the prostate and more inferiorly within the GUD, resulting in an increase in the external sphincter dose, an increase in the rectal dose, and a decrease in the base dose. Alternatively (Fig. 6b), the prostate and prescription IDL are out of phase on Day 0, with a greater superior shift of the prostate than the prescription IDL. By Day 14, the prescription IDL may shift superiorly as the prostate moves inferiorly, resulting in improved dosimetry. These figures represent extremes and individual variations in x-axis shift in combination with prostate swelling and resolution contributed to the final dosimetric outcome. DISCUSSION
Fig. 5. Change in dose to critical adjacent normal structures and prostate base between Days 0 and 14. (a) Change in dose to 4-cm3 rectal volume, (b) external sphincter, and (c) area of prescription isodose line (IDL) at superior base.
Our findings confirmed the challenge of defining optimal timing for postimplant dosimetry. At two points (Days 0 and 14), clinically significant changes in dosimetry were noted in most patients. The finding that presents the greatest challenge to current theory is the lack of a detected relationship between the dosimetric change and prostate volume change. The widely accepted model purports that swelling is the major postimplant factor responsible for postoperating room dosimetry change. In this model, swelling after implantation causes a worsening of dosimetric endpoints, and resolution of swelling improves such endpoints. In the current study, several patients had a dosimetric outcome contradictory to what the model predicted. We termed this the paradoxic dosimetric result. Such patients had worsening dosimetry despite decreased swelling, improved dosimetry despite increased swelling, or a large change in dosimetry in the absence of swelling. Differential z-axis shifting of stranded seeds may have contributed to these findings and may not apply to implants using loose seeds within the
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prostate. These findings have profound implications for treatment planning and postimplant dosimetry. One clinical implication is that interpretation of a single D90 or V100 is made more difficult. For example, if a patient has profound swelling at Day 0, and marginal dosimetry, the assumption in the past has been that the dosimetry would improve with resolution of the swelling (11). Models to correct Day 0 dosimetry for swelling assume a uniform resolution of swelling and improvement in dosimetry proportional to the resolution of swelling. This assumption is not supported by the findings of the current study. Several patients with swelling and excellent dosimetry actually had unacceptable dosimetry by Day 14, despite swelling resolution. Others with unacceptable dosimetry on Day 0 had acceptable dosimetry on Day 14, despite an increase in prostate swelling. A second implication is that correlation of dose and toxicity may be difficult using Day 0 results. Most patients had a profound increase in the rectal and external sphincter dose on Day 14. This would likely cause rectal and urethral toxicity, but correlating such symptoms with Day 0 dosimetry is problematic owing to the low dose to the rectum and sphincter at dosimetry. In the current study, a subset of patients had an extreme increase in rectal dose by Day 14 owing to a superior prostate shift and downward IDL shift. In the surgical literature, the body of work on techniques to repair rectal– urethral fistulas is growing, which implies that such complications may be underreported (20 –23). The data in the current article suggest that such a rare, but devastating, complication may not be technical failure in the operating room but due to an independent postoperative change. The mechanism responsible for the changes in dosimetry could not be fully defined in the current study. The single most common contributing factor was a disparity in the z-axis shift of the prostate and seeds. In patients with a similar and parallel shift of prostate and seeds, the prostate volume change did contribute to the dosimetric outcome, but this was a rare pattern. The most common pattern was a shift of the prostate superiorly relative to the seeds, resulting in decreased prostate coverage, independent of the change in prostate swelling. This may have been due to swelling and bleeding in the GUD after implantation, which is visible on MRI. As the GUD changes resolve, the prostate shifts inferiorly. The seeds shift inferiorly as well and appeared in some patients to be pulled inferior to their intended position within the GUD. This common pattern of shift explains the most common pattern of dosimetric change. With a greater inferior shift of seeds, the external sphincter and rectal dose increase, and the base dose decreases. A second pattern was an inferior prostate shift with a minimal or superior seed shift, resulting in improved prostate coverage, independent of prostate volume changes. However, this was a less common pattern. An unexpected finding was the tendency for seed compression, with a decrease in the z-axis length of the prescription IDL in 23 (82%) of 28 patients on Day 14 vs. Day
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0. Such a change could influence dosimetry positively or negatively. We hypothesized that if the IDL compression occurred in the setting of a parallel decrease in prostate length, no change, or an improvement, in dosimetry would result. However, we could not establish any such relationship. Some patients with an IDL z-axis decrease and prostate length increase had improved dosimetry, dependent on the relative z-axis shift more than on the relative change in length. The mechanism of seed compression independent of prostate volume change was not established. One factor that may explain both z-axis compression and the tendency toward an inferior shift is the use of stranded seeds, especially when such strands extend inferior to the prostate within the GUD. The levator ani is responsible for voluntary control of continence, and its action is presented in Fig. 7. As the levator ani contracts, it compresses the GUD and lifts the prostate an average of 5 cm (24). After implantation, this function may be compromised, resulting in exaggerated bladder muscle contraction. If this contraction anchors the seeds as the prostate shifts superiorly, this would explain the failure of the seeds to track with the prostate and explain the common pattern of base underdose. The increase in dose to the external sphincter implies an actual inferior shift of seeds within the GUD (the external sphincter extends the entire length of the GUD). Because the seeds are connected, shifts within the GUD would influence prostate dosimetry. The mechanism for actual inferior displacement within the GUD was not explained but may also be a function of complex genitourinary physiology. The potential impact of stranded seeds reported here must be reviewed in the context of the growing literature comparing loose seeds and stranded seeds, and Day 0 vs. postimplant dosimetry. Fagundes et al. (25) compared free seed vs. stranded seed postimplant dosimetry in a retrospective study of 473 patients and concluded that both V100 and D90 were superior in the stranded seed patients. In a randomized study of 8 patients in whom one-half of the prostate was implanted with loose seeds and one-half with strands, no difference in postimplant dosimetry was noted
Fig. 7. Levator ani function. (Left) Relaxed levator ani. (Right) Levator ani contracted and compressing external sphincter to override involuntary relaxation of external sphincter. Prostate has moved superiorly and anteriorly by levator ani contraction. Stranded seeds may be held in place by contraction as prostate moves superiorly, resulting in underdosing at base.
Day 0, Day 14 dosimetry
(26). Stranded seeds resulted in less seed migration to the lung in a study of 60 patients (27). No comparisons of Day 0 and operating room dosimetry vs. postimplant dosimetry that directly compared seeds vs. strands have been reported. In a careful study of operating room dosimetry vs. postimplant dosimetry using loose seeds, Potters et al. (9) reported no significant difference in D90, V100, or V150. Operating room seed position was compared with the postimplant position, and seeds had shifted a root mean square of 4.6 mm. The greatest deviation occurred in the z axis, despite loose seeds placed within the prostate. The seed shift correlated with edema. In a similar study by Stone et al. (10), the needle position in the prostate was used to approximate dosimetry, and the approximation was correlated with postimplant dosimetry. This group also used loose seeds, but a direct seed-to-seed shift was not measured. Both studies of operating room dosimetry, which used loose seeds and CT-based dosimetry, suggested a correlation between operating room and postimplant dosimetry. However, CT-based dosimetry may not be as sensitive to subtle changes in V100 or D90. In a study by Crook et al. (28), MRI-based dosimetry was used, and an improvement in postimplant dosimetry was demonstrated after switching from stranded seeds to loose seeds. They postulated that loose seeds track with prostate edema and stranded seeds cannot expand (28). On the basis of the current study, we have changed our planning strategy and do not place strands below the prostate and within the GUD. This adjustment has improved our postimplant dosimetry to the extent that the “low-dose base, high-dose GUD, and external sphincter” pattern is uncommon, but a formal repeat of the Day 0 and Day 14 comparison may be necessary to prove that the adjustments in technique have solved the differential z-axis shift. The strength of the current study was the use of MRIbased dosimetry, which allows extremely accurate dose calculations after implantation. The findings of this study have clearly demonstrated a substantial change in seed position relative to the prostate and independent of prostate volume changes. A limitation of the study was the lack of
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clinical correlation of MRI-based dosimetry and clinical outcomes. The CT-defined prostate tends to be an overestimation of the prostate below the apex, but tends to be an underestimation at the base. Even without seeds present, the apex and base are poorly defined on CT (16). With the additional obscuration by seeds, the natural tendency is to use the seeds as a surrogate for the prostate. “Circling the seeds” accounts for both CT contouring tendencies (apex overestimation and base underestimation), both of which falsely inflate the D90. MRI-based dosimetry prevents overand underestimation, resulting in a lower D90. It may be logical to assume that an MRI-based D90 of 80% prescription dose may be equivalent to a CT-based D90 of 90% prescription dose. However, clinical correlative studies are necessary to allow quantification of the clinical affect of the changes reported in this article. The findings were definitive enough to raise questions about implant planning strategies and have resulted in significant changes in our planning strategy. CONCLUSION These findings challenge the importance of swelling in postimplant dosimetry and suggest that caution must be applied in interpreting a single D90 result. Differential z-axis shift of prostate vs. seeds may be a more important factor than swelling in the final dosimetric outcome. Such a z-axis shift of seeds may be influenced by the use of stranded seed technology, and the results presented may not apply to groups using single seeds. We have avoided placement of seeds inferior to the prostate apex to prevent fixation of strands in the GUD and to allow a parallel shift of seeds and prostate. We have also increased the ratio of single seeds to strands, and cut strands of more than three seeds to prevent displacement of an entire strand along the z-axis. We have been able to integrate these changes in the context of real-time planning. Studies are underway to determine whether this adjustment will improve prostate coverage and decrease the differential z-axis shift of prostate and seeds.
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CLINICAL INVESTIGATION
Prostate
COMPARISON OF DAY 0 AND DAY 14 DOSIMETRY FOR PERMANENT PROSTATE IMPLANTS USING STRANDED SEEDS PATRICK MCLAUGHLIN, M.D.*† VRINDA NARAYANA, PH.D.,*† CHARLIE PAN, M.D.,* SALLY BERRI, M.S.,* SARA TROYER, B.S.,* JOSEPH HERMAN, M.D.,* VICKI EVANS,* AND PETER ROBERSON, PH.D.* *Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI; †Department of Radiation Oncology, Providence Cancer Center, Southfield, MI Purpose: To determine, using MRI-based dosimetry (Day 0 and Day 14), whether clinically significant changes in the dose to the prostate and critical adjacent structures occur between Day 0 and 14, and to determine to what degree any changes in dosimetry are due to swelling or its resolution. Methods and Materials: A total of 28 patients with a permanent prostate implant using 125I rapid strands were evaluated at Days 0 and 14 by CT/MRI fusion. The minimal dose received by 90% of the target volume (prostate D90), percentage of volume receiving 100% of prescribed minimal peripheral dose (prostate V100), external sphincter D90, and 4-cm3 rectal volume dose were calculated. An acceptable prostate D90 was defined as D90 >90% of prescription dose. Prostate volume changes were calculated and correlated with any dosimetry change. A paradoxic dosimetric result was defined as an improvement in D90, despite increased swelling; a decrease in D90, despite decreased swelling; or a large change in D90 (>30 Gy) in the absence of swelling. Results: The D90 changed in 27 of 28 patients between Days 0 and 14. No relationship was found between a change in prostate volume and the change in D90 (R2 ⴝ 0.01). A paradoxic dosimetric result was noted in 11 of 28 patients. The rectal dose increased in 23 of 28 patients, with a >30-Gy change in 6. The external sphincter D90 increased in 19 of 28, with a >50-Gy increase in 6. Conclusion: The dose to the prostate changed between Days 0 and 14 in most patients, resulting in a change in clinical status (acceptable or unacceptable) in 12 of 28 patients. Profound increases in normal tissue doses may make dose and toxicity correlations using Day 0 dosimetry difficult. No relationship was found between the prostate volume change and D90 change, and, in 11 patients, a paradoxic dosimetric result was noted. A differential z-axis shift of stranded seeds vs. prostate had a greater impact on final dosimetry and dose to critical adjacent tissues than did prostate swelling. These findings challenge the model that swelling is the principal cause of dosimetric changes after implantation. Stranded seeds may have contributed to this outcome. On the basis of these findings, a change in technique to avoid placement of stranded seeds inferior to the prostate apex has been adopted. These results may not apply to implants using single seeds within the prostate. © 2006 Elsevier Inc. Prostate brachytherapy, Postimplant dosimetry, Prostate swelling.
INTRODUCTION The success of permanent prostate implant therapy is directly related to implant quality (1, 2). Implant quality is traditionally defined by coverage (minimal dose received by 90% of the target volume [D90] and percentage of volume receiving 100% of prescribed minimal peripheral dose [V100]) of the prostate on CT obtained either immediately after implant (Day 0) or weeks after the implant (3). A confounding variable in dosimetric evaluation is prostate swelling after implantation, which is highly variable in extent and in the time course of onset and resolution (4 – 8). Poor dosimetric coverage may result from swelling beyond
the ultrasound expansion for swelling, and may improve with resolution of the swelling. Because of this confounding effect, the optimal timing of postimplant dosimetric evaluation remains controversial. Day 0 dosimetry allows for immediate feedback and implant correction, and Day 30 dosimetry is less obscured by swelling, but is arguably beyond an ideal point for correction. Our practice has been the compromise timing of Day 14 CT scans for postimplant dosimetry. Studies directly comparing Day 0 with later dosimetry evaluation have suggested that Day 0 dosimetry bears some relationship to the final dosimetry (9, 10), especially if models that simulate swelling are included (11).
Reprint requests to: Patrick McLaughlin, M.D., Department of Radiation Oncology, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0010. Tel: (248) 849-3321; Fax: (248) 849-8448; E-mail: mclaughb@med. umich.edu
Presented at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 3–7, 2004, Atlanta, GA. Received April 13, 2005, and in revised form June 15, 2005. Accepted for publication June 22, 2005. 144
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A second limitation of postimplant evaluation is the poor prostate definition seen on the CT scan because of swelling, seed artifact, and variations in prostate contouring (12, 13). Although training and practice allow for interobserver consensus in prostate contouring and, therefore, consensus in prostate coverage (14), MRI may be necessary to overcome fully the distortions seen on the CT scan (15–18). The assumption that the CT-defined prostate is an overestimation and, therefore, that coverage of the CT-defined prostate proves coverage of the actual prostate, has not been supported by direct comparison of MRI- and CT-based dosimetry (19). False inflation of dosimetric endpoints on CT has been due to an overestimation of the prostate inferior to the apex resulting from “circling the seeds,” and an underestimation of the base resulting from poor definition of the base and the tendency to stop contouring when the seeds are no longer visible. MRI after implantation provides precise definition of the prostate and improves the accuracy of the postimplant dosimetry. Because acceptable dosimetry is based on clinical correlation with CT dosimetry, the cutpoint for acceptable vs. unacceptable MRI postimplant dosimetry has not been established. Despite the lack of an acceptable standard, MRI-based dosimetry remains useful in quality assessment and the testing of planning strategies and is especially useful in defining subtle differences in dosimetry. In the current study, MRI-based dosimetry was used to evaluate changes in D90 and V100 at two differing points (Days 0 and 14) after implantation to evaluate whether clinically significant changes in dose to the prostate and critical adjacent structures occur between Days 0 and 14 and to what degree the changes in dosimetry are due to swelling or resolution of swelling.
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arbitrarily at 85% (no clinical correlation of V100 and clinical outcomes has been established). The external sphincter and rectal wall were contoured on the MRI data set, and dose–volume histograms of these structures were calculated. To assess base coverage, the area of the prescription isodose was measured at the superior base contour. Of the 28 patients, 17 had preimplant CT and MRI studies 2 weeks before the implant procedure. The coronal MRI data sets from the preprocedure, Day 0, and Day 14 studies were used to measure the distance of the prostatic apex from a line across the superior edge of the ischial bones. The distance from the same bony reference point to the isodose volume was also measured for the Day 0 and Day 14 scans. The relative shift in the isodose and prostate volumes was then determined.
RESULTS Change in D90 and V100 between Days 0 and 14 The average MRI D90 on Days 0 and 14 was 1.01 (⫾0.21) and 0.97 (⫾0.23) of the prescription dose, respectively. The average MRI V100 on Days 0 and 14 was 89.3% (⫾7.8%) and 87.1% (⫾7.3%), respectively. Acceptable average values in such a data set are deceptive because of the balancing effect of high- and low-dose implants, reflected in the standard deviation. In Figs. 1 and 2, the change in MRI D90 and V100, respectively, for the study patients is shown. Of the 28 patients, 27 (96%) had a change in D90 between Days 0 and 14, with a decrease in 16 (57%). Of the 28 patients, 24 (85%) had a change in V100. The significance of the changes was determined by a scoring system of acceptable if the D90 was ⱖ90% of the intended prescription dose and acceptable if the V100 was ⱖ85% of the intended prescription dose. In reference to D90, 8 (40%) of 20 patients with acceptable implants on Day 0 had unacceptable ones on Day 14. Of 7 patients with unacceptable results on Day 0, 4 (57%)
METHODS AND MATERIALS A total of 28 patients with a permanent prostate implant using I rapid strands were dosimetrically evaluated at the University of Michigan using imaging studies obtained at two points (Days 0 and 14). CT and MRI studies were performed immediately after the implant procedure (Day 0) and 14 days later (Day 14). CT scans were obtained with a slice thickness of 2 mm. Axial, coronal, and sagittal T2-weighted MRI scans were obtained with a slice thickness of 3 mm. The prostate volume was contoured on the MRI data sets, and a composite prostate volume was obtained using the information from all three MRI scans. The prostate length was defined as the length of the composite prostate along the superior– inferior direction. Seed positions were determined from the CT data set using UMPLAN, the University of Michigan treatment planning system. The CT and MRI studies were registered using mutual information and seed-to-seed techniques. D90 and V100 parameters were calculated for the Day 0 and Day 14 studies. The prescription isodose volume was determined, and the prescription isodose length (PIL) was defined as the length of the prescription isodose along the superior–inferior direction. The D90 was coded as acceptable if the D90 was ⱖ90% of the intended prescription dose and unacceptable if the D90 was ⬍90% of the prescription dose (2). The V100 cutpoint for acceptable vs. unacceptable was set 125
Fig. 1. Change in minimal dose received by 90% of the target volume (D90) between Days (D) 0 and 14. Clinical impact coded as acceptable D0/acceptable D14 (white), acceptable D0/unacceptable D14 (dark gray), unacceptable D0/acceptable D14 (light gray), and unacceptable D0/unacceptable D14 (black). Acceptable defined as MRI D90 ⬎90% planned prescription dose.
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Fig. 2. Change in percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) between Days (D) 0 and 14. Clinical impact coded as acceptable D0/acceptable D14 (white), acceptable D0/unacceptable D14 (dark gray), unacceptable D0/acceptable D14 (light gray), and unacceptable D0/unacceptable D14 (black). Acceptable defined as V100 ⬎85%.
had acceptable ones on Day 14. In reference to V100, 8 (38%) of 21 patients with an acceptable implant on Day 0 had unacceptable ones on Day 14, and 3 (42%) of 7 patients with unacceptable implants on Day 0 had acceptable ones on Day 14.
Change in D90 relative to change in prostate volume Figure 3 shows a plot of the change in D90 relative to the change in prostate volume. No relationship was found between swelling or resolution of swelling and the change in D90 (R2 ⫽ 0.01). A paradoxic dosimetric result was defined as an improvement in D90 despite swelling, a decrease in D90 despite resolution of swelling, or a large change in D90 without a change in prostate volume. A paradoxic dosimetric result was noted in 11 (40%) of 28 patients. Patients with a paradoxical dosimetric result are represented with white in Fig. 3. Of 8 patients with a decrease in volume, 4 (50%) had a decrease in D90, and 5 (31%) of 16 patients with an increase in volume had an increase in D90. Two patients with no swelling had profound (⬎30 Gy) changes in D90.
Fig. 3. Relationship between change in minimal dose received by 90% of the target volume (D90) to change in prostate volume between Days (D) 0 and 14. White triangles signify paradoxic dosimetric result.
Fig. 4. Relationship between change in minimal dose received by 90% of the target volume (D90) and change in (a) prostate length and (b) prescription isodose length (PIL).
Change in D90 relative to changes in prostate length and PIL Figure 4 shows a plot of the change in D90 relative to the changes in prostate length and PIL. The prostate length changed in 25 (90%) of 28 patients (Fig. 4a). In 11 (44%) of 25 patients, it increased. No relationship was detected between the change in prostate length and the change in D90 (R2 ⫽ 0.25). Of the 28 patients, 23 (82%) had a change in PIL between Days 0 and 14 (Fig. 4b). The most common change was a decrease in the isodose length (compression). No relationship was detected between the change in PIL and the change in D90 (R2 ⫽ 0.0). Change in rectal dose, base dose, and external sphincter dose on Day 0 vs. Day 14 Figure 5 shows a graph of the change in normal tissue dose between Days 0 and 14. In Fig. 5a, the dose to the 4-cm3 rectal wall volume is presented. In 23 (82%) of 28 patients, an increase occurred in dose to the rectum on Day 14 relative to Day 0; profound (⬎30 Gy) changes were noted in 6 patients. Figure 5b shows a graph of the change in the external sphincter dose between Days 0 and 14. In 19 (68%) of 28 patients, the D90 of the external sphincter increased between Days 0 and 14; in 6 patients, the D90 increased ⬎50 Gy and in 1 patient, the D90 increased ⬎150 Gy. Figure 5c shows a graph of the change in the base dose between Days 0 and 14. The area of the prescription isodose
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line at the superior base cut was used as a surrogate for the base dose. In 18 (62%) of 28 patients, the base dose decreased on Day 14 relative to Day 0. Shift in isodose line and prostate position in z axis between Days 0 and 14 In 17 (60%) of 28 patients, pre, Day 0, and Day 14 CT and MRI data sets were available. The z-axis shift of the prostate and isodose line (IDL) were determined by measuring the relative position of the prostate apex and base to a line across the ischial bones on coronal MRI. The superior and inferior extent of the prescription IDL was also determined relative to the same reference. The most common patterns of shift are presented in Fig. 6a. At Day 0, the prostate apex shifted superiorly owing to genitourinary diaphragm (GUD) bleeding and edema. The prescription IDL is in an ideal position relative to the prostate. By Day 14, the
Fig. 6. Relative z-axis shift of prostate and seeds at Days 0 and 14. (a) Common pattern of inferior prescription isodose length (PIL) shift relative to prostate shift and (b) less common superior PIL shift relative to prostate shift.
GUD distortion has resolved, and the prostate has moved inferiorly relative to Day 0 but not to baseline. The prescription IDL shifts inferiorly more than the prostate and more inferiorly within the GUD, resulting in an increase in the external sphincter dose, an increase in the rectal dose, and a decrease in the base dose. Alternatively (Fig. 6b), the prostate and prescription IDL are out of phase on Day 0, with a greater superior shift of the prostate than the prescription IDL. By Day 14, the prescription IDL may shift superiorly as the prostate moves inferiorly, resulting in improved dosimetry. These figures represent extremes and individual variations in x-axis shift in combination with prostate swelling and resolution contributed to the final dosimetric outcome. DISCUSSION
Fig. 5. Change in dose to critical adjacent normal structures and prostate base between Days 0 and 14. (a) Change in dose to 4-cm3 rectal volume, (b) external sphincter, and (c) area of prescription isodose line (IDL) at superior base.
Our findings confirmed the challenge of defining optimal timing for postimplant dosimetry. At two points (Days 0 and 14), clinically significant changes in dosimetry were noted in most patients. The finding that presents the greatest challenge to current theory is the lack of a detected relationship between the dosimetric change and prostate volume change. The widely accepted model purports that swelling is the major postimplant factor responsible for postoperating room dosimetry change. In this model, swelling after implantation causes a worsening of dosimetric endpoints, and resolution of swelling improves such endpoints. In the current study, several patients had a dosimetric outcome contradictory to what the model predicted. We termed this the paradoxic dosimetric result. Such patients had worsening dosimetry despite decreased swelling, improved dosimetry despite increased swelling, or a large change in dosimetry in the absence of swelling. Differential z-axis shifting of stranded seeds may have contributed to these findings and may not apply to implants using loose seeds within the
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prostate. These findings have profound implications for treatment planning and postimplant dosimetry. One clinical implication is that interpretation of a single D90 or V100 is made more difficult. For example, if a patient has profound swelling at Day 0, and marginal dosimetry, the assumption in the past has been that the dosimetry would improve with resolution of the swelling (11). Models to correct Day 0 dosimetry for swelling assume a uniform resolution of swelling and improvement in dosimetry proportional to the resolution of swelling. This assumption is not supported by the findings of the current study. Several patients with swelling and excellent dosimetry actually had unacceptable dosimetry by Day 14, despite swelling resolution. Others with unacceptable dosimetry on Day 0 had acceptable dosimetry on Day 14, despite an increase in prostate swelling. A second implication is that correlation of dose and toxicity may be difficult using Day 0 results. Most patients had a profound increase in the rectal and external sphincter dose on Day 14. This would likely cause rectal and urethral toxicity, but correlating such symptoms with Day 0 dosimetry is problematic owing to the low dose to the rectum and sphincter at dosimetry. In the current study, a subset of patients had an extreme increase in rectal dose by Day 14 owing to a superior prostate shift and downward IDL shift. In the surgical literature, the body of work on techniques to repair rectal– urethral fistulas is growing, which implies that such complications may be underreported (20 –23). The data in the current article suggest that such a rare, but devastating, complication may not be technical failure in the operating room but due to an independent postoperative change. The mechanism responsible for the changes in dosimetry could not be fully defined in the current study. The single most common contributing factor was a disparity in the z-axis shift of the prostate and seeds. In patients with a similar and parallel shift of prostate and seeds, the prostate volume change did contribute to the dosimetric outcome, but this was a rare pattern. The most common pattern was a shift of the prostate superiorly relative to the seeds, resulting in decreased prostate coverage, independent of the change in prostate swelling. This may have been due to swelling and bleeding in the GUD after implantation, which is visible on MRI. As the GUD changes resolve, the prostate shifts inferiorly. The seeds shift inferiorly as well and appeared in some patients to be pulled inferior to their intended position within the GUD. This common pattern of shift explains the most common pattern of dosimetric change. With a greater inferior shift of seeds, the external sphincter and rectal dose increase, and the base dose decreases. A second pattern was an inferior prostate shift with a minimal or superior seed shift, resulting in improved prostate coverage, independent of prostate volume changes. However, this was a less common pattern. An unexpected finding was the tendency for seed compression, with a decrease in the z-axis length of the prescription IDL in 23 (82%) of 28 patients on Day 14 vs. Day
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0. Such a change could influence dosimetry positively or negatively. We hypothesized that if the IDL compression occurred in the setting of a parallel decrease in prostate length, no change, or an improvement, in dosimetry would result. However, we could not establish any such relationship. Some patients with an IDL z-axis decrease and prostate length increase had improved dosimetry, dependent on the relative z-axis shift more than on the relative change in length. The mechanism of seed compression independent of prostate volume change was not established. One factor that may explain both z-axis compression and the tendency toward an inferior shift is the use of stranded seeds, especially when such strands extend inferior to the prostate within the GUD. The levator ani is responsible for voluntary control of continence, and its action is presented in Fig. 7. As the levator ani contracts, it compresses the GUD and lifts the prostate an average of 5 cm (24). After implantation, this function may be compromised, resulting in exaggerated bladder muscle contraction. If this contraction anchors the seeds as the prostate shifts superiorly, this would explain the failure of the seeds to track with the prostate and explain the common pattern of base underdose. The increase in dose to the external sphincter implies an actual inferior shift of seeds within the GUD (the external sphincter extends the entire length of the GUD). Because the seeds are connected, shifts within the GUD would influence prostate dosimetry. The mechanism for actual inferior displacement within the GUD was not explained but may also be a function of complex genitourinary physiology. The potential impact of stranded seeds reported here must be reviewed in the context of the growing literature comparing loose seeds and stranded seeds, and Day 0 vs. postimplant dosimetry. Fagundes et al. (25) compared free seed vs. stranded seed postimplant dosimetry in a retrospective study of 473 patients and concluded that both V100 and D90 were superior in the stranded seed patients. In a randomized study of 8 patients in whom one-half of the prostate was implanted with loose seeds and one-half with strands, no difference in postimplant dosimetry was noted
Fig. 7. Levator ani function. (Left) Relaxed levator ani. (Right) Levator ani contracted and compressing external sphincter to override involuntary relaxation of external sphincter. Prostate has moved superiorly and anteriorly by levator ani contraction. Stranded seeds may be held in place by contraction as prostate moves superiorly, resulting in underdosing at base.
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(26). Stranded seeds resulted in less seed migration to the lung in a study of 60 patients (27). No comparisons of Day 0 and operating room dosimetry vs. postimplant dosimetry that directly compared seeds vs. strands have been reported. In a careful study of operating room dosimetry vs. postimplant dosimetry using loose seeds, Potters et al. (9) reported no significant difference in D90, V100, or V150. Operating room seed position was compared with the postimplant position, and seeds had shifted a root mean square of 4.6 mm. The greatest deviation occurred in the z axis, despite loose seeds placed within the prostate. The seed shift correlated with edema. In a similar study by Stone et al. (10), the needle position in the prostate was used to approximate dosimetry, and the approximation was correlated with postimplant dosimetry. This group also used loose seeds, but a direct seed-to-seed shift was not measured. Both studies of operating room dosimetry, which used loose seeds and CT-based dosimetry, suggested a correlation between operating room and postimplant dosimetry. However, CT-based dosimetry may not be as sensitive to subtle changes in V100 or D90. In a study by Crook et al. (28), MRI-based dosimetry was used, and an improvement in postimplant dosimetry was demonstrated after switching from stranded seeds to loose seeds. They postulated that loose seeds track with prostate edema and stranded seeds cannot expand (28). On the basis of the current study, we have changed our planning strategy and do not place strands below the prostate and within the GUD. This adjustment has improved our postimplant dosimetry to the extent that the “low-dose base, high-dose GUD, and external sphincter” pattern is uncommon, but a formal repeat of the Day 0 and Day 14 comparison may be necessary to prove that the adjustments in technique have solved the differential z-axis shift. The strength of the current study was the use of MRIbased dosimetry, which allows extremely accurate dose calculations after implantation. The findings of this study have clearly demonstrated a substantial change in seed position relative to the prostate and independent of prostate volume changes. A limitation of the study was the lack of
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clinical correlation of MRI-based dosimetry and clinical outcomes. The CT-defined prostate tends to be an overestimation of the prostate below the apex, but tends to be an underestimation at the base. Even without seeds present, the apex and base are poorly defined on CT (16). With the additional obscuration by seeds, the natural tendency is to use the seeds as a surrogate for the prostate. “Circling the seeds” accounts for both CT contouring tendencies (apex overestimation and base underestimation), both of which falsely inflate the D90. MRI-based dosimetry prevents overand underestimation, resulting in a lower D90. It may be logical to assume that an MRI-based D90 of 80% prescription dose may be equivalent to a CT-based D90 of 90% prescription dose. However, clinical correlative studies are necessary to allow quantification of the clinical affect of the changes reported in this article. The findings were definitive enough to raise questions about implant planning strategies and have resulted in significant changes in our planning strategy. CONCLUSION These findings challenge the importance of swelling in postimplant dosimetry and suggest that caution must be applied in interpreting a single D90 result. Differential z-axis shift of prostate vs. seeds may be a more important factor than swelling in the final dosimetric outcome. Such a z-axis shift of seeds may be influenced by the use of stranded seed technology, and the results presented may not apply to groups using single seeds. We have avoided placement of seeds inferior to the prostate apex to prevent fixation of strands in the GUD and to allow a parallel shift of seeds and prostate. We have also increased the ratio of single seeds to strands, and cut strands of more than three seeds to prevent displacement of an entire strand along the z-axis. We have been able to integrate these changes in the context of real-time planning. Studies are underway to determine whether this adjustment will improve prostate coverage and decrease the differential z-axis shift of prostate and seeds.
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