- Email: [email protected]
Prostate gland edema after single-fraction high-dose rate brachytherapy before external beam radiation therapy
Brachytherapy 9 (2010) 208e212
Prostate gland edema after single-fraction high-dose rate brachytherapy before external beam radiation therapy Fabio L. Cury1,*, Marie Duclos1, Armen Aprikian2, Horacio Patrocinio3, Luis Souhami1 1
Division of Radiation Oncology, Department of Oncology, McGill University Health Centre, Montreal, Quebec, Canada 2 Division of Urology, Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada 3 Department of Medical Physics, McGill University Health Centre, Montreal, Quebec, Canada
ABSTRACT
PURPOSE: Highedose rate brachytherapy (HDRB) is frequently used as a boost to external beam radiation therapy (EBRT) in prostate cancer patients. With the increasing use of small planning target volume margins in EBRT, prostatic edema induced by HDRB can be a contributing factor to geometric miss when HDRB is performed before or during EBRT. We assessed prostate gland volumetric change after single-fraction HDRB and its impact on definition of treatment volume for EBRT. METHODS AND MATERIALS: Thirty-one consecutive patients with intermediate-risk prostate cancer treated with single-fraction HDRB (10 Gy) combined with hypofractionated EBRT were analyzed. A second CT scan was performed 7 days after HDRB, and images were coregistered with the planning CT scan that contained the original clinical target volume (CTV). The post-HDRB prostate CTV volume was compared with the original CTV by a single observer. RESULTS: All patients presented volumetric variation. In most cases (68%), the prostate increased in volume, whereas it decreased in 32%. The mean prostatic volume was 42.2 cc before HDRB and 43.6 cc after HDRB, representing a mean volume difference of 3.4%, ranging from 14.2% to 23.8% ( p 5 0.756). This difference is the result of mean changes of 0.6 mm (6.1 to 6.6) in the anterioreposterior, 0.5 mm (5.5 to 3.0) in the lateral, and 0.2 mm (5.0 to 5.0) in the superioreinferior axes. CONCLUSIONS: Although a nonsignificant volumetric change occurs after single-fraction HDRB, individual variations on specific axis could lead to important uncertainties during EBRT. Ó 2010 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Edema; High dose rate brachytherapy; Hypofractionation
Introduction Important technologic advances in the last decades have changed the practice of prostate radiotherapy. Better definition of the target volumes has been achieved by enhanced radiologic techniques, and important developments in computer-assisted dose calculations have substantially improved the conformality of dose distributions around the clinical target volume (CTV) and organs at risk. Given the trend in prostate cancer (PCa) treatment toward dose
Received 18 June 2009; received in revised form 24 August 2009; accepted 24 September 2009. * Corresponding author. Montreal General Hospital, 1650 Cedar Avenue, Room D5-400, Montreal, Quebec H3G 1A4, Canada. Tel.: þ1514-934-8040; fax: þ1-514-934-8220. E-mail address: [email protected] (F.L. Cury).
escalation, in order to reduce treatment-related toxicity, smaller margins have been used in the determination of planning target volume (PTV) for external beam radiation therapy (EBRT). The use of smaller margins generated a genuine concern regarding organ motion and geometric uncertainties, and the use of image-guided radiation therapy has become a crucial element of daily practice. In an attempt to improve the therapeutic ratio, the use of highedose rate brachytherapy (HDRB) has been introduced as a complement to EBRT in patients with PCa. This change in practice is thought to be a better approach for several major reasons: first, escalating radiation doses have been proven to be associated with a higher rate of disease control, as demonstrated by a better biochemical failurefree survival in several randomized trials (1e4); second, HDRB constitutes a highly conformal treatment modality with the potential to lead to reduced treatment-related side
1538-4721/$ - see front matter Ó 2010 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.brachy.2009.09.003
F.L. Cury et al. / Brachytherapy 9 (2010) 208e212
effects (5, 6); and finally, the recent evidence for a low alpha to beta ratio for PCa (7, 8) has generated a renewed interest on hypofractionated radiation therapy for the treatment of localized PCa. The optimal timing for HDRB is not known and it has been performed before (6, 9e12), after (13e15), or concomitantly (16, 17) to the course of EBRT. Considering that smaller PTV margins are a trend in modern radiation therapy, prostatic edema induced by HDRB (18) may be another source of geometrical miss during EBRT when HDRB is delivered before or during the course of EBRT. The potential prostatic edema after lowedose rate brachytherapy and its impact on dose distribution have been extensively studied (19e22). Unfortunately, similar data for HDRB are so far limited (18, 23). The aim of the present study was to investigate the magnitude of prostate gland edema induced by a single highedose fraction of HDRB performed before EBRT and to correlate the potential impact this volumetric change could have on PTV margin definition for EBRT.
Methods and materials Patient population and preparation In May 2001, we started a program of single-fraction HDRB combined with hypofractionated EBRT for hormone-naive patients with intermediate-risk PCa (24). All patients had histologic confirmation of PCa and were staged with abdominal or pelvic CT scan and bone scan. For logistic reasons, because of the short interval between HDRB and the start of EBRT, we performed CT scans for EBRT planning before the brachytherapy procedure, so that EBRT could start within the scheduled time. Patients were treated exclusively with radiation therapy, which consisted of one HDRB fraction followed 7e10 days later by hypofractionated EBRT. To verify possible volumetric prostate changes and the potential need of changes in the original treatment PTV, a second CT scan was performed 1 week after the brachytherapy procedure and before the start of EBRT for the first 31 patients enrolled in our program.
209
skin. Patients were then transferred to the CT simulator where a CT scan was performed for brachytherapy planning, using 5-mm slice thickness. Treatment planning was carried out using Plato Planning System (Nucletron B.V.). A total dose of 10 Gy was prescribed to be delivered to the prostate surface in a single fraction. The urethral volume receiving more than 125% of the prescribed dose was constrained to be lower than 1 cc (V125 urethra ! 1 cc). The brachytherapy catheters were removed immediately after treatment. The Foley catheter was usually removed on the same day, after urologic assessment, and the patient was discharged home several hours after the implant. Patients presenting bleeding or obstructive urinary symptoms were kept in observation for one night and discharged the next morning. All patients were medicated postimplant with ciprofloxacin for 1 week, celecoxib for 1 month, and alfuzosin for 3 months. Hypofractionated EBRT Treatment planning was carried out before the brachytherapy procedure. Using CT scan images with 5-mm slice thickness and urethrogram to assist on prostate apex localization, the prostate gland was defined as the CTV. Organs at risk were also delineated on AcQSim CT-Sim software (Phillips Medical Systems, Andover, MA). The PTV was defined as a 10-mm margin around the CTV in all directions. Treatment planning was done at CadPlan (Varian Medical Systems, Palo Alto, CA), and patients were treated with three-dimensional conformal radiation therapy, typically with a 5-field technique using 18-MV photons. A total of 50 Gy was delivered to the isocenter in 20 daily fractions of 2.5 Gy/fraction. The treatment was delivered with the patient in the supine position, with a comfortably full bladder and free of immobilization. A styrofoam device was placed daily between both ankles and aligned with the frontal room laser, maintaining a constant separation between both legs. Image-guided radiation therapy was performed using the BAT System (North American Scientific, Chatsworth, CA) for daily prostate localization and interfraction correction of organ motion (25). Assessment of volumetric changes after HDRB
High dose rate brachytherapy Under spinal anesthesia and in dorsal lithotomy position, patients underwent a transrectal ultrasound (TRUS) for prostate gland visualization in the axial and sagittal planes. A Foley catheter was inserted, and the balloon was inflated with saline solution. Using the CET Prostate Applicator Set (Nucletron B.V., Veenendaal, the Netherlands), typically 17 brachytherapy catheters were placed under TRUS guidance using axial and sagittal views. A cystoscopy was performed immediately after completion of the implant for assessment of catheter positioning in relationship to the bladder wall. The template was pressed and anchored against the perineal
One week after the HDRB implant and treatment, a second CT scan was obtained on the first 31 consecutive patients entered in our program. The prostate gland was contoured on both pre- and post-HDRB CT scan sets of blind images by the same observer (FC). A total of 62 sets of images were contoured. Images were then coregistered using a rigid coregistration system (AcQSim; Philips Medical Systems), and data concerning prostate gland dimensions and volume provided by the planning system were recorded and analyzed. The data collected are presented by descriptive statistics, as mean standard deviations unless otherwise specified.
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Two-sided paired t tests were used to ascertain the difference between pre- and post-HDRB prostate volumes. A p !0.05 was considered statistically significant. Statistical analyses were performed using Graph Pad Prism version 4.0 for Macintosh (GraphPad Software, San Diego, CA).
Results All 31 patients presented prostate gland volumetric variation after single-fraction HDRB. In 21 patients (68%), the prostatic volume post-HDRB was larger than the baseline values, whereas a reduction in the gland volume was noticed in the remaining 32%. Figure 1 shows that 6 patients (19.3%) presented an enlargement greater than 10% of the prostate initial volume, and only 1 patient presented a volumetric reduction greater than 10%. The baseline prostate volume was 42.2 cm3 (16.8) compared with 43 6 cm3 (17.8) 1 week after HDRB (Fig. 2), representing a mean difference of 3.4%, ranging from 14.2 to 23.8% ( p 5 0.756). When assessed separately, patients with prostate volume enlargement presented a pre-HDRB mean prostate volume of 40.86 cm3 (17.54) and mean post-HDRB volume of 43.95 cm3 (19.01), corresponding to a mean difference of 7.5%. On the other hand, patients with decreased volume were found to have a pre-HDRB mean volume of 45.16 cm3 (15.73) and mean post-HDRB volume of 43.99 cm3 (15.93), which represents a mean difference of 2.6%. Initial prostate gland volume or tumor stage did not correlate with the amount of variation. The analysis of independent unidimensional variations revealed that the volumetric changes observed were
Fig. 1. Distribution of prostate gland volumetric changes noticed between pre- and post-highedose rate brachytherapy for each patient.
Fig. 2. Prostate gland volumes before and after highedose rate brachytherapy ( p 5 0.756).
consequent to mean changes of 0.6 mm (6.1 to 6.6) in the anterioreposterior (AP), 0.5 mm (5.5 to 3.0) in the lateral (LL), and 0.2 mm (5.0 to 5.0) in the superiore inferior (SI) prostatic dimensions (Fig. 3). Assessment of SI dimension changes was unsatisfactory because of the CT scan slice thickness used. Enlargement superior than 3 mm in a single dimension was observed in the AP dimension of 3 patients (4.9, 5.0, and 5.6 mm), in the SI dimension of 3 patients (5 mm each), and no changes larger than 3 mm were noticed in the LL dimension. Reduction of more than 3 mm was noticed in the AP dimension of 4 patients (5.4, 6.1, 6.1, and 6.6 mm), in the SI dimension of 2 patients (5 mm each), and in the LL dimension of 1 patient (5.5 mm). Discussion Adequate margin definition around the prostate gland for PTV determination has become a critical step during treatment planning in modern radiation therapy. Treatment margins must be wide enough to ensure adequate target coverage, taking into consideration possible geometric uncertainties, and, at the same time, must have limited extension to avoid excessive doses of radiation to normal tissues. Typically, HDRB has been delivered before (6, 9e12) and during (16, 17) EBRT, and only few centers have done it after (13e15) EBRT. Our decision to give HDRB before EBRT was not based on any established radiobiologic advantage, but simply to facilitate, in our opinion, the logistics of performing upfront HDRB, as patients would be devoid of any possible acute toxicity related to the delivery of previous EBRT. Little information on prostatic edema after HDRB is available. Martinez et al. (18) published a Phase II study on HDRB monotherapy for PCa, documenting volumetric variations experienced by the prostate gland, measured by TRUS, after four fractions of 9.5 Gy. He reported that the mean prostate volume changed from 30.7 cm3 (21.5e41.6 cm3) at baseline, to 37.0 cm3 (25.0e43.9 cm3)
F.L. Cury et al. / Brachytherapy 9 (2010) 208e212
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Fig. 3. Independent variations in the anterioreposterior (AP) (a), lateralelateral (b), (LL) and superioreinferior (SI) (c) dimensions, for each individual patient. Assessment of SI dimension changes was unsatisfactory because of CT scan slice thickness used (5 mm).
immediately after implant, and to 38.2 cm3 3 (25.7e47.8 cm ) after the fourth fraction. Interestingly, the most significant volumetric changes occurred between the baseline TRUS and the immediate postimplant sets of images, suggesting that volumetric changes are mainly related to the traumatic stress induced during the procedure, with little changes occurring because of the radiation delivery. It should be noted that most reported programs of HDRB preceding EBRT differ substantially from our own. Typically, a fractionated HDRB regimen is used, with some treatments given weekly apart, and EBRT usually starts 2e3 weeks post implant (6, 9e12). To our knowledge, none of the other programs have reported CT scan volumetric studies attempting to define the magnitude of the prostate gland edema post HDRB. We found that prostate gland volumetric changes measured 1 week after 10 Gy single-fraction HDRB are
small. However, significant variation on individual dimensions was identified, which could lead to geometrical uncertainties if smaller PTV margins were used. Volumetric changes were not related to initial prostate volume or tumor stage, therefore, difficult to be predicted clinically. It is important to emphasize that our volumetric measurements were done 1 week after the HDRB implant, with patients routinely receiving a potent anti-inflammatory, and whether larger variations in volume could be identified should the CT scan be done 24e48 h after the implant remains to be established. Our study has two potential limitations. One is the use of CT scan to assess volumetric changes. CT scan imaging has its own resolution limitations, and we acknowledge that the precise contouring of the prostate is difficult to recognize exactly by CT image. Although other imaging modalities have a better capability to delineate the prostate gland
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and, therefore, allow for a more accurate volume determination, CT scan is still the most commonly used modality in PCa planning, and we believe that our data are still representative of the common practice. Another limitation of our study is the relatively larger CT scan slice thickness employed that can be a contributor to volume uncertainty. The use of smaller slice thicknesses may lead to a better degree of accuracy, particularly in assessing size changes in the SI directions.
[11]
[12]
[13]
Conclusions With increasing number of centers using brachytherapy as a boost before or during EBRT and the current trend on using small PTV margins, it is fundamental to ensure adequate assessment of potential volumetric changes after HDRB, particularly when small margins are used and EBRT is delivered early after the implant.
[14]
[15]
[16]
References [1] Dearnaley DP, Hall E, Lawrence D, et al. Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects. Br J Cancer 2005;92:488e498. [2] Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:67e74. [3] Sathya JR, Davis IR, Julian JA, et al. Randomized trial comparing iridium implant plus external-beam radiation therapy with externalbeam radiation therapy alone in node-negative locally advanced cancer of the prostate. J Clin Oncol 2005;23:1192e1199. [4] Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 2005;294:1233e1239. [5] Chin YS, Bullard J, Bryant L, et al. High dose rate iridium-192 brachytherapy as a component of radical radiotherapy for the treatment of localised prostate cancer. Clin Oncol (R Coll Radiol) 2006;18:474e479. [6] Demanes DJ, Rodriguez RR, Schour L, et al. High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy’s 10-year results. Int J Radiat Oncol Biol Phys 2005;61:1306e1316. [7] Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6e13. [8] Wang JZ, Li XA, Yu CX, et al. The low alpha/beta ratio for prostate cancer: What does the clinical outcome of HDR brachytherapy tell us? Int J Radiat Oncol Biol Phys 2003;57:1101e1108. [9] Shigehara K, Mizokami A, Komatsu K, et al. Four year clinical statistics of iridium-192 high dose rate brachytherapy. Int J Urol 2006;13:116e121. [10] Pinkawa M, Fischedick K, Treusacher P, et al. Dose-volume impact in high-dose-rate iridium-192 brachytherapy as a boost to external
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beam radiotherapy for localized prostate cancerdA phase II study. Radiother Oncol 2006;78:41e46. Deger S, Boehmer D, Roigas J, et al. High dose rate (HDR) brachytherapy with conformal radiation therapy for localized prostate cancer. Eur Urol 2005;47:441e448. Yamada Y, Bhatia S, Zaider M, et al. Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer. Brachytherapy 2006;5:157e164. Akimoto T, Katoh H, Noda SE, et al. Acute genitourinary toxicity after high dose rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: Second analysis to determine the correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity. Int J Radiat Oncol Biol Phys 2005;63: 472e478. Hsu IC, Cabrera AR, Weinberg V, et al. Combined modality treatment with high-dose-rate brachytherapy boost for locally advanced prostate cancer. Brachytherapy 2005;4:202e206. Pellizzon AC, Nadalin W, Salvajoli JV, et al. Results of high dose rate afterloading brachytherapy boost to conventional external beam radiation therapy for initial and locally advanced prostate cancer. Radiother Oncol 2003;66:167e172. Astrom L, Pedersen D, Mercke C, et al. Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer. Radiother Oncol 2005;74:157e161. Martinez AA, Demanes DJ, Galalae R, et al. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime. Int J Radiat Oncol Biol Phys 2005;62:1322e1331. Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61e69. Villeneuve M, Leclerc G, Lessard E, et al. Relationship between isotope half-life and prostatic edema for optimal prostate dose coverage in permanent seed implants. Med Phys 2008;35: 1970e1977. Taussky D, Austen L, Toi A, et al. Sequential evaluation of prostate edema after permanent seed prostate brachytherapy using CT-MRI fusion. Int J Radiat Oncol Biol Phys 2005;62:974e980. Yamada Y, Potters L, Zaider M, et al. Impact of intraoperative edema during transperineal permanent prostate brachytherapy on computeroptimized and preimplant planning techniques. Am J Clin Oncol 2003;26:e130ee135. Dogan N, Mohideen N, Glasgow GP, et al. Effect of prostatic edema on CT-based postimplant dosimetry. Int J Radiat Oncol Biol Phys 2002;53:483e489. Kiffer JD, Schumer WA, Mantle CA, et al. Impact of oedema on implant geometry and dosimetry for temporary high dose rate brachytherapy of the prostate. Australas Radiol 2003;47:172e176. Lukka H, Warde P, Pickles T, et al. Controversies in prostate cancer radiotherapy: Consensus development. Can J Urol 2001;8: 1314e1322. Poli ME, Parker W, Patrocinio H, et al. An assessment of PTV margin definitions for patients undergoing conformal 3D external beam radiation therapy for prostate cancer based on an analysis of 10,327 pretreatment daily ultrasound localizations. Int J Radiat Oncol Biol Phys 2007;67:1430e1437.
Prostate gland edema after single-fraction high-dose rate brachytherapy before external beam radiation therapy Fabio L. Cury1,*, Marie Duclos1, Armen Aprikian2, Horacio Patrocinio3, Luis Souhami1 1
Division of Radiation Oncology, Department of Oncology, McGill University Health Centre, Montreal, Quebec, Canada 2 Division of Urology, Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada 3 Department of Medical Physics, McGill University Health Centre, Montreal, Quebec, Canada
ABSTRACT
PURPOSE: Highedose rate brachytherapy (HDRB) is frequently used as a boost to external beam radiation therapy (EBRT) in prostate cancer patients. With the increasing use of small planning target volume margins in EBRT, prostatic edema induced by HDRB can be a contributing factor to geometric miss when HDRB is performed before or during EBRT. We assessed prostate gland volumetric change after single-fraction HDRB and its impact on definition of treatment volume for EBRT. METHODS AND MATERIALS: Thirty-one consecutive patients with intermediate-risk prostate cancer treated with single-fraction HDRB (10 Gy) combined with hypofractionated EBRT were analyzed. A second CT scan was performed 7 days after HDRB, and images were coregistered with the planning CT scan that contained the original clinical target volume (CTV). The post-HDRB prostate CTV volume was compared with the original CTV by a single observer. RESULTS: All patients presented volumetric variation. In most cases (68%), the prostate increased in volume, whereas it decreased in 32%. The mean prostatic volume was 42.2 cc before HDRB and 43.6 cc after HDRB, representing a mean volume difference of 3.4%, ranging from 14.2% to 23.8% ( p 5 0.756). This difference is the result of mean changes of 0.6 mm (6.1 to 6.6) in the anterioreposterior, 0.5 mm (5.5 to 3.0) in the lateral, and 0.2 mm (5.0 to 5.0) in the superioreinferior axes. CONCLUSIONS: Although a nonsignificant volumetric change occurs after single-fraction HDRB, individual variations on specific axis could lead to important uncertainties during EBRT. Ó 2010 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Edema; High dose rate brachytherapy; Hypofractionation
Introduction Important technologic advances in the last decades have changed the practice of prostate radiotherapy. Better definition of the target volumes has been achieved by enhanced radiologic techniques, and important developments in computer-assisted dose calculations have substantially improved the conformality of dose distributions around the clinical target volume (CTV) and organs at risk. Given the trend in prostate cancer (PCa) treatment toward dose
Received 18 June 2009; received in revised form 24 August 2009; accepted 24 September 2009. * Corresponding author. Montreal General Hospital, 1650 Cedar Avenue, Room D5-400, Montreal, Quebec H3G 1A4, Canada. Tel.: þ1514-934-8040; fax: þ1-514-934-8220. E-mail address: [email protected] (F.L. Cury).
escalation, in order to reduce treatment-related toxicity, smaller margins have been used in the determination of planning target volume (PTV) for external beam radiation therapy (EBRT). The use of smaller margins generated a genuine concern regarding organ motion and geometric uncertainties, and the use of image-guided radiation therapy has become a crucial element of daily practice. In an attempt to improve the therapeutic ratio, the use of highedose rate brachytherapy (HDRB) has been introduced as a complement to EBRT in patients with PCa. This change in practice is thought to be a better approach for several major reasons: first, escalating radiation doses have been proven to be associated with a higher rate of disease control, as demonstrated by a better biochemical failurefree survival in several randomized trials (1e4); second, HDRB constitutes a highly conformal treatment modality with the potential to lead to reduced treatment-related side
1538-4721/$ - see front matter Ó 2010 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.brachy.2009.09.003
F.L. Cury et al. / Brachytherapy 9 (2010) 208e212
effects (5, 6); and finally, the recent evidence for a low alpha to beta ratio for PCa (7, 8) has generated a renewed interest on hypofractionated radiation therapy for the treatment of localized PCa. The optimal timing for HDRB is not known and it has been performed before (6, 9e12), after (13e15), or concomitantly (16, 17) to the course of EBRT. Considering that smaller PTV margins are a trend in modern radiation therapy, prostatic edema induced by HDRB (18) may be another source of geometrical miss during EBRT when HDRB is delivered before or during the course of EBRT. The potential prostatic edema after lowedose rate brachytherapy and its impact on dose distribution have been extensively studied (19e22). Unfortunately, similar data for HDRB are so far limited (18, 23). The aim of the present study was to investigate the magnitude of prostate gland edema induced by a single highedose fraction of HDRB performed before EBRT and to correlate the potential impact this volumetric change could have on PTV margin definition for EBRT.
Methods and materials Patient population and preparation In May 2001, we started a program of single-fraction HDRB combined with hypofractionated EBRT for hormone-naive patients with intermediate-risk PCa (24). All patients had histologic confirmation of PCa and were staged with abdominal or pelvic CT scan and bone scan. For logistic reasons, because of the short interval between HDRB and the start of EBRT, we performed CT scans for EBRT planning before the brachytherapy procedure, so that EBRT could start within the scheduled time. Patients were treated exclusively with radiation therapy, which consisted of one HDRB fraction followed 7e10 days later by hypofractionated EBRT. To verify possible volumetric prostate changes and the potential need of changes in the original treatment PTV, a second CT scan was performed 1 week after the brachytherapy procedure and before the start of EBRT for the first 31 patients enrolled in our program.
209
skin. Patients were then transferred to the CT simulator where a CT scan was performed for brachytherapy planning, using 5-mm slice thickness. Treatment planning was carried out using Plato Planning System (Nucletron B.V.). A total dose of 10 Gy was prescribed to be delivered to the prostate surface in a single fraction. The urethral volume receiving more than 125% of the prescribed dose was constrained to be lower than 1 cc (V125 urethra ! 1 cc). The brachytherapy catheters were removed immediately after treatment. The Foley catheter was usually removed on the same day, after urologic assessment, and the patient was discharged home several hours after the implant. Patients presenting bleeding or obstructive urinary symptoms were kept in observation for one night and discharged the next morning. All patients were medicated postimplant with ciprofloxacin for 1 week, celecoxib for 1 month, and alfuzosin for 3 months. Hypofractionated EBRT Treatment planning was carried out before the brachytherapy procedure. Using CT scan images with 5-mm slice thickness and urethrogram to assist on prostate apex localization, the prostate gland was defined as the CTV. Organs at risk were also delineated on AcQSim CT-Sim software (Phillips Medical Systems, Andover, MA). The PTV was defined as a 10-mm margin around the CTV in all directions. Treatment planning was done at CadPlan (Varian Medical Systems, Palo Alto, CA), and patients were treated with three-dimensional conformal radiation therapy, typically with a 5-field technique using 18-MV photons. A total of 50 Gy was delivered to the isocenter in 20 daily fractions of 2.5 Gy/fraction. The treatment was delivered with the patient in the supine position, with a comfortably full bladder and free of immobilization. A styrofoam device was placed daily between both ankles and aligned with the frontal room laser, maintaining a constant separation between both legs. Image-guided radiation therapy was performed using the BAT System (North American Scientific, Chatsworth, CA) for daily prostate localization and interfraction correction of organ motion (25). Assessment of volumetric changes after HDRB
High dose rate brachytherapy Under spinal anesthesia and in dorsal lithotomy position, patients underwent a transrectal ultrasound (TRUS) for prostate gland visualization in the axial and sagittal planes. A Foley catheter was inserted, and the balloon was inflated with saline solution. Using the CET Prostate Applicator Set (Nucletron B.V., Veenendaal, the Netherlands), typically 17 brachytherapy catheters were placed under TRUS guidance using axial and sagittal views. A cystoscopy was performed immediately after completion of the implant for assessment of catheter positioning in relationship to the bladder wall. The template was pressed and anchored against the perineal
One week after the HDRB implant and treatment, a second CT scan was obtained on the first 31 consecutive patients entered in our program. The prostate gland was contoured on both pre- and post-HDRB CT scan sets of blind images by the same observer (FC). A total of 62 sets of images were contoured. Images were then coregistered using a rigid coregistration system (AcQSim; Philips Medical Systems), and data concerning prostate gland dimensions and volume provided by the planning system were recorded and analyzed. The data collected are presented by descriptive statistics, as mean standard deviations unless otherwise specified.
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F.L. Cury et al. / Brachytherapy 9 (2010) 208e212
Two-sided paired t tests were used to ascertain the difference between pre- and post-HDRB prostate volumes. A p !0.05 was considered statistically significant. Statistical analyses were performed using Graph Pad Prism version 4.0 for Macintosh (GraphPad Software, San Diego, CA).
Results All 31 patients presented prostate gland volumetric variation after single-fraction HDRB. In 21 patients (68%), the prostatic volume post-HDRB was larger than the baseline values, whereas a reduction in the gland volume was noticed in the remaining 32%. Figure 1 shows that 6 patients (19.3%) presented an enlargement greater than 10% of the prostate initial volume, and only 1 patient presented a volumetric reduction greater than 10%. The baseline prostate volume was 42.2 cm3 (16.8) compared with 43 6 cm3 (17.8) 1 week after HDRB (Fig. 2), representing a mean difference of 3.4%, ranging from 14.2 to 23.8% ( p 5 0.756). When assessed separately, patients with prostate volume enlargement presented a pre-HDRB mean prostate volume of 40.86 cm3 (17.54) and mean post-HDRB volume of 43.95 cm3 (19.01), corresponding to a mean difference of 7.5%. On the other hand, patients with decreased volume were found to have a pre-HDRB mean volume of 45.16 cm3 (15.73) and mean post-HDRB volume of 43.99 cm3 (15.93), which represents a mean difference of 2.6%. Initial prostate gland volume or tumor stage did not correlate with the amount of variation. The analysis of independent unidimensional variations revealed that the volumetric changes observed were
Fig. 1. Distribution of prostate gland volumetric changes noticed between pre- and post-highedose rate brachytherapy for each patient.
Fig. 2. Prostate gland volumes before and after highedose rate brachytherapy ( p 5 0.756).
consequent to mean changes of 0.6 mm (6.1 to 6.6) in the anterioreposterior (AP), 0.5 mm (5.5 to 3.0) in the lateral (LL), and 0.2 mm (5.0 to 5.0) in the superiore inferior (SI) prostatic dimensions (Fig. 3). Assessment of SI dimension changes was unsatisfactory because of the CT scan slice thickness used. Enlargement superior than 3 mm in a single dimension was observed in the AP dimension of 3 patients (4.9, 5.0, and 5.6 mm), in the SI dimension of 3 patients (5 mm each), and no changes larger than 3 mm were noticed in the LL dimension. Reduction of more than 3 mm was noticed in the AP dimension of 4 patients (5.4, 6.1, 6.1, and 6.6 mm), in the SI dimension of 2 patients (5 mm each), and in the LL dimension of 1 patient (5.5 mm). Discussion Adequate margin definition around the prostate gland for PTV determination has become a critical step during treatment planning in modern radiation therapy. Treatment margins must be wide enough to ensure adequate target coverage, taking into consideration possible geometric uncertainties, and, at the same time, must have limited extension to avoid excessive doses of radiation to normal tissues. Typically, HDRB has been delivered before (6, 9e12) and during (16, 17) EBRT, and only few centers have done it after (13e15) EBRT. Our decision to give HDRB before EBRT was not based on any established radiobiologic advantage, but simply to facilitate, in our opinion, the logistics of performing upfront HDRB, as patients would be devoid of any possible acute toxicity related to the delivery of previous EBRT. Little information on prostatic edema after HDRB is available. Martinez et al. (18) published a Phase II study on HDRB monotherapy for PCa, documenting volumetric variations experienced by the prostate gland, measured by TRUS, after four fractions of 9.5 Gy. He reported that the mean prostate volume changed from 30.7 cm3 (21.5e41.6 cm3) at baseline, to 37.0 cm3 (25.0e43.9 cm3)
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Fig. 3. Independent variations in the anterioreposterior (AP) (a), lateralelateral (b), (LL) and superioreinferior (SI) (c) dimensions, for each individual patient. Assessment of SI dimension changes was unsatisfactory because of CT scan slice thickness used (5 mm).
immediately after implant, and to 38.2 cm3 3 (25.7e47.8 cm ) after the fourth fraction. Interestingly, the most significant volumetric changes occurred between the baseline TRUS and the immediate postimplant sets of images, suggesting that volumetric changes are mainly related to the traumatic stress induced during the procedure, with little changes occurring because of the radiation delivery. It should be noted that most reported programs of HDRB preceding EBRT differ substantially from our own. Typically, a fractionated HDRB regimen is used, with some treatments given weekly apart, and EBRT usually starts 2e3 weeks post implant (6, 9e12). To our knowledge, none of the other programs have reported CT scan volumetric studies attempting to define the magnitude of the prostate gland edema post HDRB. We found that prostate gland volumetric changes measured 1 week after 10 Gy single-fraction HDRB are
small. However, significant variation on individual dimensions was identified, which could lead to geometrical uncertainties if smaller PTV margins were used. Volumetric changes were not related to initial prostate volume or tumor stage, therefore, difficult to be predicted clinically. It is important to emphasize that our volumetric measurements were done 1 week after the HDRB implant, with patients routinely receiving a potent anti-inflammatory, and whether larger variations in volume could be identified should the CT scan be done 24e48 h after the implant remains to be established. Our study has two potential limitations. One is the use of CT scan to assess volumetric changes. CT scan imaging has its own resolution limitations, and we acknowledge that the precise contouring of the prostate is difficult to recognize exactly by CT image. Although other imaging modalities have a better capability to delineate the prostate gland
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and, therefore, allow for a more accurate volume determination, CT scan is still the most commonly used modality in PCa planning, and we believe that our data are still representative of the common practice. Another limitation of our study is the relatively larger CT scan slice thickness employed that can be a contributor to volume uncertainty. The use of smaller slice thicknesses may lead to a better degree of accuracy, particularly in assessing size changes in the SI directions.
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[12]
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Conclusions With increasing number of centers using brachytherapy as a boost before or during EBRT and the current trend on using small PTV margins, it is fundamental to ensure adequate assessment of potential volumetric changes after HDRB, particularly when small margins are used and EBRT is delivered early after the implant.
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