Radiotherapy and Oncology 113 (2014) 121–125
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Prostate brachytherapy
Optimal source distribution for focal boosts using high dose rate (HDR) brachytherapy alone in prostate cancer Pittaya Dankulchai a,b,⇑, Roberto Alonzi a, Gerry J. Lowe a, James Burnley a, Anwar R. Padhani c, Peter J. Hoskin a a Mount Vernon Cancer Centre, Northwood, United Kingdom; b Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; c Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, United Kingdom
a r t i c l e
i n f o
Article history: Received 7 October 2013 Received in revised form 16 July 2014 Accepted 6 September 2014 Available online 25 September 2014 Keywords: Focal monotherapy HDR brachytherapy Prostate cancer Dominant lesion Multi-parametric MRI
a b s t r a c t Purpose: To investigate the optimal distribution of sources using high dose rate brachytherapy to deliver a focal boost to a dominant lesion within the whole prostate gland based on multi-parametric magnetic resonance imaging (mpMRI). Methods: Sixteen patients with prostate cancer underwent mpMRI each of which demonstrated a dominant lesion. There were single lesions in 6 patients, two lesions in 4 and 3 lesions in 6 patients. Two dosimetric models and parameters were compared in each case. The first model used 10 mm intervals between needles, and the second model used additional needles at 5 mm intervals between each needle in the boost area. Results: Three of thirty-two plans did not achieve the plan objectives. These three plans were in the first model. A higher median urethral volume was seen in the ‘unsuccessful’ group (2.7 cc, and 1.9 cc, respectively, p-value = 0.12). Conformity indices of the second model were also better than the first model (COIN index; 0.716 and 0.643, respectively). Conclusions: Focal monotherapy based on mpMRI achieves optimal dosimetry by individualizing the needle positions using 5 mm spacing rather than 10 mm spacing within the boost volume. A larger urethral volume may have an adverse effect on this distribution. Formal clinical evaluation of this approach is currently underway. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 113 (2014) 121–125
In recent years, there has been increasing interest in different techniques for the local treatment of prostate cancer using surgery and radiation therapy. Both low dose rate (LDR) permanent seed brachytherapy and temporary high dose rate brachytherapy (HDR BT) have become established as highly effective treatments for early localized and locally advanced prostate cancer. Treatment development has mainly focused on dose escalation strategies to achieve higher dose to the target organ while reducing the dose to the surrounding normal tissues. HDR brachytherapy delivers a highly conformal dose to the prostate with little dose to normal organs. Excellent biochemical disease-free survival rates are reported after HDR monotherapy in prostate cancer, typically 85– 100% in low-, 75–95% in intermediate-, and 79–93% in high-risk groups [1–8]. Current practice is underpinned by recent published guidelines from both GEC/ESTRO and the American Brachytherapy Society (ABS) [9,10]. ⇑ Corresponding author at: Mount Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, United Kingdom. E-mail address: [email protected] (P. Dankulchai). http://dx.doi.org/10.1016/j.radonc.2014.09.001 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Multiparametric MR imaging (mpMRI), which includes diffusion weighted imaging (DWI), dynamic contrast-enhanced (DCE), and magnetic resonance spectroscopy (MRS), can identify significant prostate cancer, defined as Gleason score P7 and a volume >0.5 ml, as distinct from benign and low grade disease with high sensitivity and specificity [11]. Thus biological subvolumes comprising ‘significant’ prostate cancer can be delineated within the whole gland clinical target volume (CTV1) based on the functional MRI using DWI and DCE in the peripheral zone [12]. A number of studies have established that a dose–response relationship exists for prostate cancer with survival advantages for high dose strategies [13,14]. In addition, HDR BT using high doses per fraction has a theoretical biological advantage for tumours which have a low alpha beta ratio, such as prostate cancer. This is the basis of integrating a focal boost volume (CTV2) within the planning process for HDR prostate brachytherapy with the assumption that such dominant lesions will benefit from higher doses. HDR BT using multiple afterloading catheters within which variable dwell times can be used to vary dose delivery along the length is an ideal modality for focal therapy [15–17]. The use of HDR BT to boost the
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peripheral zone to a higher dose than other regions of the gland without the use of mpMRI has been previously described [18]. The aim of this study was to investigate the feasibility of achieving a 10% dose escalation to the dominant focal lesion while delivering a standard HDR monotherapy dose to the whole gland.
intensity on T2-weighted MR within the prostate gland and where difficult to define was assumed to be at the central prostate at the border of peripheral and central zone extrapolating from the position of the urethra at slices above and below. Planning model
Materials and methods Case selection and imaging Sixteen patients with prostate cancer, who were to receive HDR prostate brachytherapy, also underwent mpMRI as part of their initial staging using a GE 3.0 Tesla scanner. The MRI sequences consisted of T2 weighted, DWI, DCE, and MRS. The scans were assessed by a radiologist with a specialist interest in prostate MRI (AP).
Contouring The diagnostic MR images were imported into the Eclipse treatment planning system (Eclipse v. 10.0, Varian Medical System, Inc., Palo Alto, CA, USA). The entire prostate gland was outlined to define the clinical target volume of the prostate (CTV1), and the dominant lesion(s) based on the functional MRI was contoured as CTV of boost area (CTV2) by one experienced oncologist (DP). These were then expanded with a 3 mm margin excluding the rectum to form the planning target volume (PTV) from the respective CTV [10]. In addition a ‘PTV3’ was created from PTV1 excluding the PTV2. This concept of CTV outlining is shown in Fig. 1A–C. For the organs at risk, the outer wall of the rectum and urethra were outlined. The urethra was contoured by the visible white signal
Two models of needle distribution were designed to encompass the target volume. The first model (Model A) simulated needles with a regular 1 cm interval between each needle for the whole prostate and boost volume (Fig. 1D), while the second model (Model B) simulated needles as in Model A but with additional needles at 0.5 cm intervals for the boost volume (Fig. 1E). The prescription was defined for the two separate volumes, PTV2 and PTV3. PTV2 was prescribed to 21 Gy in a single dose with the aim that 95% of the prescription volume received this dose. PTV3 was prescribed to 19 Gy with the aim that a minimum of 65% and a maximum of 75% of the prescription volume received this. A lower dose objective of 15 Gy to 95% of the PTV3 volume was also defined in order to ensure adequate low dose cover of the non-boost area. Optimization was used to achieve the plan objectives (Table 1). The aim of planning was to cover the PTV3 and PTV2 to the 15 and 21 Gy isodose levels respectively adjusting any dwells within the PTV3 in order to maintain 19 Gy to approximately 70% of the volume but obeying constraints for the adjacent urethra and rectum whose position varied with respect to the boost volume. Statistics The dose parameters were also evaluated. The achievement of plan objectives in each plan for 16 patients was defined as either
Fig. 1. The drawing of contouring is shown as (A). The example of contouring based on apparent diffusion coefficient (ADC) is shown as (B); the light blue line is CTV1, the dark blue line is PTV1, the red lines are CTV2, the orange lines are PTV2, the pink line is the urethra, and the green line is the rectum. PTV3 (cyan colourwash) is shown as (C). The example of the dose distribution with 1 cm interval (Model A) and 0.5 cm interval between each needle for boost area (Model B) is shown as (D), and (E), respectively. The coverage dose to PTV2 and the dose to rectum in Model B are shown slightly better than in Model A. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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P. Dankulchai et al. / Radiotherapy and Oncology 113 (2014) 121–125 Table 1 The plan objectives.
Table 2 Patient characteristics.
Structures
Plan objectives
Characteristics
Number
Percentage (%)
PTV2 (Boost area)
V100% is more than 95% of volume D95% is more than 21 Gy
PTV3 (Non boost area)
V19 Gy is less than 75% of volume V19 Gy is more than 65% of volume V15 Gy is more than 95% of volume
Number of lesions One lesion Two lesions Three lesions
6 4 6
37.5% 25% 37.5%
Urethra
D30% is less than 20.8 Gy D10% is less than 22 Gy V150% is less than 0.01 cc
Area of lesions Peripheral zone Transitional zone Both
33 1 2
91.7% 2.8% 5.5%
Rectum
V19 Gy is less than 0.01 cc D2 cc is less than 15 Gy
59.3 cc 91.8 cc 1.6 cc 7.45 cc 83.35 cc
23.3–97.4 cc 43.1–139.9 cc 0.1–6.1 cc 1.4–18.6 cc 40.3–125 cc
Median size of target volume
‘successful’ group (Group 1) when all constraint objectives were achieved; in contrast, when the objectives were not achieved the designation ‘unsuccessful’ (Group 2) was used. All clinical target volumes and the organs at risk volumes of both groups were described as median and range. The Mann–Whitney test was used to compare the factors between both groups; a p-value less than 0.05 was defined as statistically significant. Statistical analysis was carried out using SPSS version 18.0.
CTV1 PTV1 CTV2 PTV2 PTV3
Range
Median volume of organs at risk Rectum Urethra
Range 34.95 cc 1.9 cc
Median number of needles 1 cm spacing for boost area (Model A) 0.5 cm spacing for boost area (Model B)
18.2–51.3 cc 1.3–3.3 cc Range
21.5 25
15–28 19–34
Dose conformity Based on the dose volume histograms, a conformity index (CI), a healthy tissue conformity index (HTCI), a conformation number (CN), and a conformal index (COIN) have been defined in evaluating treatment plan conformality to PTV2 [19]. The CI was defined as
Conformity index ¼
TVRI TV
ð1Þ
where TVRI was the volume of the target covered by the reference isodose line of 21 Gy and TV was the target volume. The modified Healthy Tissue Conformity Index (mHTCI) was defined as
modified Healthy Tissue Conformity Index ¼
TVRI VRI VRI;PTV3
ð2Þ
where VRI was the volume of the reference isodose and VRI,PTV3 was the planning target volume of the non-boost area covered by the reference isodose (excluding the urethral volume). The Conformation Number (CN) was defined as:
Conformation Number ¼ CI mHTCI
ð3Þ
The COIN presented the quality of the implant was defined as
VCOref;i CO COIN ¼ CN PNi¼1 1 VCO;i
ð4Þ
where NCO was number of critical organs, VCOref;i was critical organ volume receiving at least the constraint dose, and VCO;i was critical organ volume. There were two critical organs in this study, including the urethra and rectum. These indices ranged from 0 to 1, and a higher index represents a plan that is more optimal. Results Patient characteristics are shown in Table 2. Six patients had one lesion, four patients had two lesions and six patients had three lesions in the prostate gland. There were 33 of 36 lesions in the peripheral zone. The median volumes of prostate gland and boost area were 59.3 cc and 1.6 cc, respectively; while the median of organ at risk volumes (rectum and urethra) were 34.95 cc and 1.9 cc, respectively. In addition, the median number of needles for the two plans was 21.5 (15–28) for Model A, and 25 (19–34) for Model B.
There were 32 plans for the 16 patients. Three plans failed to achieve the plan objectives, particularly in the criteria for PTV2, which was prescribed to 21 Gy with the aim that 95% of the prescription volume received this dose (V100% of PTV2 > 95%), and the criteria for less than 0.01 cc of the rectal volume to receive the constraint of 19 Gy (V19 Gy < 0.01 cc). All three of these plans were in the group planned using Model A. One plan failed to achieve both plan objectives, including V100% of PTV2 > 95% (87.68%), and V19 Gy < 0.01 cc of rectum (0.04 cc). While one plan failed to reach the plan objectives of V100% of PTV2 > 95% (94.65%), and another plan could not achieve the plan objectives of V19 Gy < 0.01 cc of rectum (0.12 cc). An example of the dose distribution using Model A and Model B is shown in Fig. 1D and E. A comparison of the factors between the ‘successful’ (Group 1) and ‘unsuccessful’ (Group 2) is shown in Table 3. Three plans, which were all in the group 2, included two cases of a single dominant lesion and one case of three dominant lesions. There was no statistically significant difference between the parameters of the median target volume for both groups. The median urethral volume in the group 2 was larger than in the group 1 (2.7 cc, and 1.9 cc, respectively) although this did not reach statistical significance. The median rectal volume in the group 2 was slightly smaller than in the group 1 (30.6 cc, and 36.5 cc, respectively). The treatment plan evaluation of both models using CI, mHTCI, CN, and COIN is shown in Table 4. The CI, mHTCI, CN, and COIN indices of model B (0.5 cm) were overall better than those of model A (1 cm) with a COIN index for model B of 0.716, compared to 0.643 for model A. Discussion This study is the first to explore the optimum dosimetric model for a focal monotherapy boost using HDR brachytherapy in localized prostate cancer based on multi-parametric MR. One study has evaluated the feasibility of HDR brachytherapy for the dominant intra-prostatic tumor region defined with functional images, including endorectal MRI or PET-CT imaging in 20 cases using hemi-gland HDR brachytherapy boost [13]. External beam radiotherapy delivering 64 Gy was followed by an HDR brachytherapy boost with two fractions of 6, 7, or 8 Gy. The 5-year biochemical disease free survival and overall survival rates were 79.7% and
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Table 3 Comparison of factors between fulfilled criteria for the planning group and non-fulfilled criteria for planning in Model A. Factors
Group 1 (Successful) Median (Range)
Group 2 (Unsuccessful) Median (Range)
Number of patients
13
3
Number of lesions One lesion Two lesions Three lesions
4 4 5
2 0 1
Median target volume (cc) CTV1 PTV1 CTV2 PTV2 PTV3
59.3 (33.7–97.4) 91.5 (56.4–139.9) 1.6 (0.1–6.1) 7.7 (1.4–18.6) 82.1 (48.2–125)
60.6 (23.3–69.2) 92.2 (43.1–105.4) 1.3 (0.4–4) 5.2 (2.5–15.2) 86.7 (40.3–89.7)
0.74 0.74 0.54 0.46 0.64
Median organ at risk volume (cc) Rectum Urethra
36.5 (18.2–51.3) 1.9 (1.3–2.4)
30.6 (23.6–34.1) 2.7 (1.7–3.3)
0.16 0.12
Table 4 Treatment plan evaluation by the conformity index (CI), modified Healthy Tissue Conformity Index (mHTCI), Conformation Number (CN), and conformal index (COIN). Index
The planning target volume of boost area (21 Gy) CI mHTCI CN (CI HTCI) COIN
Model A (1 cm) Median
Model B (0.5 cm) Median
0.960 0.808 0.771 0.643
0.963 0.850 0.819 0.716
81%, respectively and 5-year grade P2 late rectal and genito-urinary toxicity free survival rates were 84.4% and 70%, respectively. Cosset et al. [20] studied 21 patients with a focal seed implantation brachytherapy based on two series of prostate biopsies and a highresolution MRI and their results showed that this modality was feasible with acceptable acute toxicity. Gaudet et al. [21] investigated 120 patients with an intraprostatic boost compared to 70 patients with standard planning for permanent prostate I-125 seed implantation. Their results showed that there were no differences between the groups in terms of acute and late morbidity. Definition of the dominant lesion remains controversial and while radiological guidelines are clear there are a number of potential confounding factors which should be considered. In particular it is well recognized that significant physiological changes are seen in the prostate gland after only a short period of exposure to androgen deprivation [22] and that this may well modify some of the MR characteristics. A more rigorous approach is to combine the imaging information from mpMRI with those of choline PET although substantive evidence for the latter as a means of staging prostate cancer is lacking. Multiple template based biopsy mapping is perhaps the gold standard and in our clinical protocol we include this to confirm the areas to be given a focal boost. The results from our study show that it is feasible to plan a focal boost using HDR brachytherapy in this case achieving a 10% dose increment to the boost volume delivering 21 Gy to the dominant lesion and 15–19 Gy to the reminder of the PTV but that this needs to be predicted and preplanned using 0.5 cm intervals between each needle for the boost areas. When this strategy was used all plans achieved the plan objectives, whereas when a standard regular 1 cm spacing was used three plans (19%) failed to achieve the plan objectives, although in one of these the failure was borderline (94.65%).
p value
There is a suggestion that the urethral volume in the three plans in the unsuccessful group may have been larger than in the other groups, which might have contributed to the outcome in these three patients. A dominant lesion close to a larger urethral volume will be more difficult to cover within urethral constraints. This suggests that patients who have had a recent transurethral resection (TURP) and have a residual cavity should not be considered for this approach as stipulated in the GEC/ESTRO guidelines and the ABS recommendations [9,10]. One limitation of this study was the difficulty in identification of the urethra on MRI without urethral catheterization. The dosimetry of the urethra may therefore not be equal to that which would be achieved at implantation. Ultimately however, the optimal dose coverage depends on the size of the prostate, and the organs at risk, and the individual anatomy of the patient. The size of the prostate gland may be a factor that predicts satisfactory dosimetry in focal brachytherapy. There are several publications that have reported the influence of prostate volume on dosimetry during brachytherapy. In LDR seed brachytherapy some authors have suggested that small glands have poorer coverage [23,24] although others have not found that gland size was a factor [25,26]. With HDR brachytherapy in a series of patients with a median volume of 60ml no difference in dosimetry was seen between those below and those above the median [27]. However when considering focal boosts to a small sub-volume then it may be more difficult to achieve selective dose to the boost volume within a small gland and still achieve the organs at risk constraints, although the data presented do not show an independent effect of prostate volume. The conformity index (CI) represents the dose coverage of the target volume of PTV2. In this study, the HTCI index, computed for PTV2, has been modified because the reference isodose of the urethra and PTV3 is within the PTV1 entirely. Therefore, the volume of PTV3 is excluded from the HTCI calculation. These indices showed that the conformity index of the strategy of model B (0.5 cm spacing of needles in the boost area) is overall better than that of model A (1 cm spacing). It shows that the dose coverage of the target volume, the protection of healthy tissue, and the quality of dosimetry of model B is better than that of model A. The COIN index of both models was shown in this study which reflects the good quality of dose distribution. Needle spacing less than 1 cm in the boost area is clearly required to achieve optimal focal dose distributions; whether 5 mm is optimal or an even closer spacing of 2 or 3 mm will improve conformality further needs to be tested although there is likely to be a point at which small improvements do not justify the additional impact of additional catheter/needle placement.
P. Dankulchai et al. / Radiotherapy and Oncology 113 (2014) 121–125
Conclusion Focal boosts using HDR brachytherapy in prostate cancer can successfully achieve a 10% dose escalation to the boost volume while maintaining a lower dose to the remaining gland. Optimal dosimetry is achieved by individualizing the needle positions using 5 mm spacing rather than 10 mm spacing within the boost volume. Good differential dosimetry is more difficult to achieve in smaller glands and those with a larger urethra. Clinical evaluation of this approach is currently underway.
Conflicts of interest No potential conflict of interests. Acknowledgements P. Dankulchai at Mount Vernon Cancer Centre (the United Kingdom) was supported by a grant of the Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. References [1] Demanes DJ, Martinez AA, Ghilezan M, et al. High-dose-rate monotherapy: safe and effective brachytherapy for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2011;81:1286–92. [2] Yoshioka Y, Konishi K, Sumida I, et al. Monotherapeutic high-dose-rate brachytherapy for prostate cancer: five-year results of an extreme hypofractionation regimen with 54 Gy in nine fractions. Int J Radiat Oncol Biol Phys 2011;80:469–75. [3] Hoskin P, Rojas A, Lowe G, et al. High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence. Int J Radiat Oncol Biol Phys 2012;82:1376–84. [4] Barkati M, Williams SG, Foroudi F, et al. High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: a Phase II trial. Int J Radiat Oncol Biol Phys 2012;82:1889–96. [5] Prada PJ, Jimenez I, Gonzalez-Suarez H, Fernandez J, Cuervo-Arango C, Mendez L. High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: treatment description and preliminary results. Brachytherapy 2012;11:105–10. [6] Rogers CL, Alder SC, Rogers RL, et al. High dose brachytherapy as monotherapy for intermediate risk prostate cancer. J Urol 2012;187:109–16. [7] Shah C, Lanni Jr TB, Ghilezan MI, et al. Brachytherapy provides comparable outcomes and improved cost-effectiveness in the treatment of low/ intermediate prostate cancer. Brachytherapy 2012;11:441–5. [8] Zamboglou N, Tselis N, Baltas D, et al. High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results. Int J Radiat Oncol Biol Phys 2013;85:672–8.
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[9] Yamada Y, Rogers L, Demanes DJ, et al. American Brachytherapy Society consensus guidelines for high-dose-rate prostate brachytherapy. Brachytherapy 2012;11:20–32. [10] Hoskin PJ, Colombo A, Henry A, et al. GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer: an update. Radiother Oncol 2013;107:325–32. [11] Dickinson L, Ahmed HU, Allen C, et al. Magnetic resonance imaging for the detection, localisation, and characterisation of prostate cancer: recommendations from a European consensus meeting. Eur Urol 2011;59:477–94. [12] Groenendaal G, Borren A, Moman MR, et al. Pathologic validation of a model based on diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging for tumor delineation in the prostate peripheral zone. Int J Radiat Oncol Biol Phys 2012;82:537–44. [13] Prada PJ, Gonzalez H, Fernandez J, Bilbao P. High-dose-rate intensity modulated brachytherapy with external-beam radiotherapy improves local and biochemical control in patients with high-risk prostate cancer. Clin Trans Oncol 2008;10:415–21. [14] Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009;74:1405–18. [15] Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MDCRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47:551–60. [16] Schick U, Popowski Y, Nouet P, et al. High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer. Prostate 2011;71:1309–16. [17] Vogelius IR, Bentzen SM. Meta-analysis of the alpha/beta ratio for prostate cancer in the presence of an overall time factor: bad news, good news, or no news? Int J Radiat Oncol Biol Phys 2013;85:89–94. [18] Kovacs G, Potter R, Loch T, et al. GEC/ESTRO-EAU recommendations on temporary brachytherapy using stepping sources for localised prostate cancer. Radiother Oncol 2005;74:137–48. [19] Feuvret L, Noel G, Mazeron JJ, Bey P. Conformity index: a review. Int J Radiat Oncol Biol Phys 2006;64:333–42. [20] Cosset JM, Cathelineau X, Wakil G, et al. Focal brachytherapy for selected lowrisk prostate cancers: a pilot study. Brachytherapy 2013;12:331–7. [21] Gaudet M, Vigneault E, Aubin S, et al. Dose escalation to the dominant intraprostatic lesion defined by sextant biopsy in a permanent prostate I-125 implant: a prospective comparative toxicity analysis. Int J Radiat Oncol Biol Phys 2010;77:153–9. [22] Alonzi R, Padhani AR, Taylor NJ, et al. Antivascular effects of neoadjuvant androgen deprivation for prostate cancer: an in vivo human study using susceptibility and relaxivity dynamic MRI. Int J Radiat Oncol Biol Phys 2011;80:721–7. [23] Badiozamani KR, Wallner K, Sutlief S, Ellis W, Blasko J, Russell K. Anticipating prostatic volume changes due to prostate brachytherapy. Radiat Oncol Invest 1999;7:360–4. [24] McNeely LK, Stone NN, Presser J, Chircus JH, Stock RG. Influence of prostate volume on dosimetry results in real-time 125I seed implantation. Int J Radiat Oncol Biol Phys 2004;58:292–9. [25] Merrick GS, Butler WM, Dorsey AT, Lief JH. Effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation. Techniques in urology 2001;7:233–40. [26] Mayadev J, Merrick GS, Reed JR, et al. Permanent prostate brachytherapy in prostate glands
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Prostate brachytherapy
Optimal source distribution for focal boosts using high dose rate (HDR) brachytherapy alone in prostate cancer Pittaya Dankulchai a,b,⇑, Roberto Alonzi a, Gerry J. Lowe a, James Burnley a, Anwar R. Padhani c, Peter J. Hoskin a a Mount Vernon Cancer Centre, Northwood, United Kingdom; b Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; c Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, United Kingdom
a r t i c l e
i n f o
Article history: Received 7 October 2013 Received in revised form 16 July 2014 Accepted 6 September 2014 Available online 25 September 2014 Keywords: Focal monotherapy HDR brachytherapy Prostate cancer Dominant lesion Multi-parametric MRI
a b s t r a c t Purpose: To investigate the optimal distribution of sources using high dose rate brachytherapy to deliver a focal boost to a dominant lesion within the whole prostate gland based on multi-parametric magnetic resonance imaging (mpMRI). Methods: Sixteen patients with prostate cancer underwent mpMRI each of which demonstrated a dominant lesion. There were single lesions in 6 patients, two lesions in 4 and 3 lesions in 6 patients. Two dosimetric models and parameters were compared in each case. The first model used 10 mm intervals between needles, and the second model used additional needles at 5 mm intervals between each needle in the boost area. Results: Three of thirty-two plans did not achieve the plan objectives. These three plans were in the first model. A higher median urethral volume was seen in the ‘unsuccessful’ group (2.7 cc, and 1.9 cc, respectively, p-value = 0.12). Conformity indices of the second model were also better than the first model (COIN index; 0.716 and 0.643, respectively). Conclusions: Focal monotherapy based on mpMRI achieves optimal dosimetry by individualizing the needle positions using 5 mm spacing rather than 10 mm spacing within the boost volume. A larger urethral volume may have an adverse effect on this distribution. Formal clinical evaluation of this approach is currently underway. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 113 (2014) 121–125
In recent years, there has been increasing interest in different techniques for the local treatment of prostate cancer using surgery and radiation therapy. Both low dose rate (LDR) permanent seed brachytherapy and temporary high dose rate brachytherapy (HDR BT) have become established as highly effective treatments for early localized and locally advanced prostate cancer. Treatment development has mainly focused on dose escalation strategies to achieve higher dose to the target organ while reducing the dose to the surrounding normal tissues. HDR brachytherapy delivers a highly conformal dose to the prostate with little dose to normal organs. Excellent biochemical disease-free survival rates are reported after HDR monotherapy in prostate cancer, typically 85– 100% in low-, 75–95% in intermediate-, and 79–93% in high-risk groups [1–8]. Current practice is underpinned by recent published guidelines from both GEC/ESTRO and the American Brachytherapy Society (ABS) [9,10]. ⇑ Corresponding author at: Mount Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, United Kingdom. E-mail address: [email protected] (P. Dankulchai). http://dx.doi.org/10.1016/j.radonc.2014.09.001 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Multiparametric MR imaging (mpMRI), which includes diffusion weighted imaging (DWI), dynamic contrast-enhanced (DCE), and magnetic resonance spectroscopy (MRS), can identify significant prostate cancer, defined as Gleason score P7 and a volume >0.5 ml, as distinct from benign and low grade disease with high sensitivity and specificity [11]. Thus biological subvolumes comprising ‘significant’ prostate cancer can be delineated within the whole gland clinical target volume (CTV1) based on the functional MRI using DWI and DCE in the peripheral zone [12]. A number of studies have established that a dose–response relationship exists for prostate cancer with survival advantages for high dose strategies [13,14]. In addition, HDR BT using high doses per fraction has a theoretical biological advantage for tumours which have a low alpha beta ratio, such as prostate cancer. This is the basis of integrating a focal boost volume (CTV2) within the planning process for HDR prostate brachytherapy with the assumption that such dominant lesions will benefit from higher doses. HDR BT using multiple afterloading catheters within which variable dwell times can be used to vary dose delivery along the length is an ideal modality for focal therapy [15–17]. The use of HDR BT to boost the
122
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peripheral zone to a higher dose than other regions of the gland without the use of mpMRI has been previously described [18]. The aim of this study was to investigate the feasibility of achieving a 10% dose escalation to the dominant focal lesion while delivering a standard HDR monotherapy dose to the whole gland.
intensity on T2-weighted MR within the prostate gland and where difficult to define was assumed to be at the central prostate at the border of peripheral and central zone extrapolating from the position of the urethra at slices above and below. Planning model
Materials and methods Case selection and imaging Sixteen patients with prostate cancer, who were to receive HDR prostate brachytherapy, also underwent mpMRI as part of their initial staging using a GE 3.0 Tesla scanner. The MRI sequences consisted of T2 weighted, DWI, DCE, and MRS. The scans were assessed by a radiologist with a specialist interest in prostate MRI (AP).
Contouring The diagnostic MR images were imported into the Eclipse treatment planning system (Eclipse v. 10.0, Varian Medical System, Inc., Palo Alto, CA, USA). The entire prostate gland was outlined to define the clinical target volume of the prostate (CTV1), and the dominant lesion(s) based on the functional MRI was contoured as CTV of boost area (CTV2) by one experienced oncologist (DP). These were then expanded with a 3 mm margin excluding the rectum to form the planning target volume (PTV) from the respective CTV [10]. In addition a ‘PTV3’ was created from PTV1 excluding the PTV2. This concept of CTV outlining is shown in Fig. 1A–C. For the organs at risk, the outer wall of the rectum and urethra were outlined. The urethra was contoured by the visible white signal
Two models of needle distribution were designed to encompass the target volume. The first model (Model A) simulated needles with a regular 1 cm interval between each needle for the whole prostate and boost volume (Fig. 1D), while the second model (Model B) simulated needles as in Model A but with additional needles at 0.5 cm intervals for the boost volume (Fig. 1E). The prescription was defined for the two separate volumes, PTV2 and PTV3. PTV2 was prescribed to 21 Gy in a single dose with the aim that 95% of the prescription volume received this dose. PTV3 was prescribed to 19 Gy with the aim that a minimum of 65% and a maximum of 75% of the prescription volume received this. A lower dose objective of 15 Gy to 95% of the PTV3 volume was also defined in order to ensure adequate low dose cover of the non-boost area. Optimization was used to achieve the plan objectives (Table 1). The aim of planning was to cover the PTV3 and PTV2 to the 15 and 21 Gy isodose levels respectively adjusting any dwells within the PTV3 in order to maintain 19 Gy to approximately 70% of the volume but obeying constraints for the adjacent urethra and rectum whose position varied with respect to the boost volume. Statistics The dose parameters were also evaluated. The achievement of plan objectives in each plan for 16 patients was defined as either
Fig. 1. The drawing of contouring is shown as (A). The example of contouring based on apparent diffusion coefficient (ADC) is shown as (B); the light blue line is CTV1, the dark blue line is PTV1, the red lines are CTV2, the orange lines are PTV2, the pink line is the urethra, and the green line is the rectum. PTV3 (cyan colourwash) is shown as (C). The example of the dose distribution with 1 cm interval (Model A) and 0.5 cm interval between each needle for boost area (Model B) is shown as (D), and (E), respectively. The coverage dose to PTV2 and the dose to rectum in Model B are shown slightly better than in Model A. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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P. Dankulchai et al. / Radiotherapy and Oncology 113 (2014) 121–125 Table 1 The plan objectives.
Table 2 Patient characteristics.
Structures
Plan objectives
Characteristics
Number
Percentage (%)
PTV2 (Boost area)
V100% is more than 95% of volume D95% is more than 21 Gy
PTV3 (Non boost area)
V19 Gy is less than 75% of volume V19 Gy is more than 65% of volume V15 Gy is more than 95% of volume
Number of lesions One lesion Two lesions Three lesions
6 4 6
37.5% 25% 37.5%
Urethra
D30% is less than 20.8 Gy D10% is less than 22 Gy V150% is less than 0.01 cc
Area of lesions Peripheral zone Transitional zone Both
33 1 2
91.7% 2.8% 5.5%
Rectum
V19 Gy is less than 0.01 cc D2 cc is less than 15 Gy
59.3 cc 91.8 cc 1.6 cc 7.45 cc 83.35 cc
23.3–97.4 cc 43.1–139.9 cc 0.1–6.1 cc 1.4–18.6 cc 40.3–125 cc
Median size of target volume
‘successful’ group (Group 1) when all constraint objectives were achieved; in contrast, when the objectives were not achieved the designation ‘unsuccessful’ (Group 2) was used. All clinical target volumes and the organs at risk volumes of both groups were described as median and range. The Mann–Whitney test was used to compare the factors between both groups; a p-value less than 0.05 was defined as statistically significant. Statistical analysis was carried out using SPSS version 18.0.
CTV1 PTV1 CTV2 PTV2 PTV3
Range
Median volume of organs at risk Rectum Urethra
Range 34.95 cc 1.9 cc
Median number of needles 1 cm spacing for boost area (Model A) 0.5 cm spacing for boost area (Model B)
18.2–51.3 cc 1.3–3.3 cc Range
21.5 25
15–28 19–34
Dose conformity Based on the dose volume histograms, a conformity index (CI), a healthy tissue conformity index (HTCI), a conformation number (CN), and a conformal index (COIN) have been defined in evaluating treatment plan conformality to PTV2 [19]. The CI was defined as
Conformity index ¼
TVRI TV
ð1Þ
where TVRI was the volume of the target covered by the reference isodose line of 21 Gy and TV was the target volume. The modified Healthy Tissue Conformity Index (mHTCI) was defined as
modified Healthy Tissue Conformity Index ¼
TVRI VRI VRI;PTV3
ð2Þ
where VRI was the volume of the reference isodose and VRI,PTV3 was the planning target volume of the non-boost area covered by the reference isodose (excluding the urethral volume). The Conformation Number (CN) was defined as:
Conformation Number ¼ CI mHTCI
ð3Þ
The COIN presented the quality of the implant was defined as
VCOref;i CO COIN ¼ CN PNi¼1 1 VCO;i
ð4Þ
where NCO was number of critical organs, VCOref;i was critical organ volume receiving at least the constraint dose, and VCO;i was critical organ volume. There were two critical organs in this study, including the urethra and rectum. These indices ranged from 0 to 1, and a higher index represents a plan that is more optimal. Results Patient characteristics are shown in Table 2. Six patients had one lesion, four patients had two lesions and six patients had three lesions in the prostate gland. There were 33 of 36 lesions in the peripheral zone. The median volumes of prostate gland and boost area were 59.3 cc and 1.6 cc, respectively; while the median of organ at risk volumes (rectum and urethra) were 34.95 cc and 1.9 cc, respectively. In addition, the median number of needles for the two plans was 21.5 (15–28) for Model A, and 25 (19–34) for Model B.
There were 32 plans for the 16 patients. Three plans failed to achieve the plan objectives, particularly in the criteria for PTV2, which was prescribed to 21 Gy with the aim that 95% of the prescription volume received this dose (V100% of PTV2 > 95%), and the criteria for less than 0.01 cc of the rectal volume to receive the constraint of 19 Gy (V19 Gy < 0.01 cc). All three of these plans were in the group planned using Model A. One plan failed to achieve both plan objectives, including V100% of PTV2 > 95% (87.68%), and V19 Gy < 0.01 cc of rectum (0.04 cc). While one plan failed to reach the plan objectives of V100% of PTV2 > 95% (94.65%), and another plan could not achieve the plan objectives of V19 Gy < 0.01 cc of rectum (0.12 cc). An example of the dose distribution using Model A and Model B is shown in Fig. 1D and E. A comparison of the factors between the ‘successful’ (Group 1) and ‘unsuccessful’ (Group 2) is shown in Table 3. Three plans, which were all in the group 2, included two cases of a single dominant lesion and one case of three dominant lesions. There was no statistically significant difference between the parameters of the median target volume for both groups. The median urethral volume in the group 2 was larger than in the group 1 (2.7 cc, and 1.9 cc, respectively) although this did not reach statistical significance. The median rectal volume in the group 2 was slightly smaller than in the group 1 (30.6 cc, and 36.5 cc, respectively). The treatment plan evaluation of both models using CI, mHTCI, CN, and COIN is shown in Table 4. The CI, mHTCI, CN, and COIN indices of model B (0.5 cm) were overall better than those of model A (1 cm) with a COIN index for model B of 0.716, compared to 0.643 for model A. Discussion This study is the first to explore the optimum dosimetric model for a focal monotherapy boost using HDR brachytherapy in localized prostate cancer based on multi-parametric MR. One study has evaluated the feasibility of HDR brachytherapy for the dominant intra-prostatic tumor region defined with functional images, including endorectal MRI or PET-CT imaging in 20 cases using hemi-gland HDR brachytherapy boost [13]. External beam radiotherapy delivering 64 Gy was followed by an HDR brachytherapy boost with two fractions of 6, 7, or 8 Gy. The 5-year biochemical disease free survival and overall survival rates were 79.7% and
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Focal monotherapy HDR brachytherapy in prostate cancer
Table 3 Comparison of factors between fulfilled criteria for the planning group and non-fulfilled criteria for planning in Model A. Factors
Group 1 (Successful) Median (Range)
Group 2 (Unsuccessful) Median (Range)
Number of patients
13
3
Number of lesions One lesion Two lesions Three lesions
4 4 5
2 0 1
Median target volume (cc) CTV1 PTV1 CTV2 PTV2 PTV3
59.3 (33.7–97.4) 91.5 (56.4–139.9) 1.6 (0.1–6.1) 7.7 (1.4–18.6) 82.1 (48.2–125)
60.6 (23.3–69.2) 92.2 (43.1–105.4) 1.3 (0.4–4) 5.2 (2.5–15.2) 86.7 (40.3–89.7)
0.74 0.74 0.54 0.46 0.64
Median organ at risk volume (cc) Rectum Urethra
36.5 (18.2–51.3) 1.9 (1.3–2.4)
30.6 (23.6–34.1) 2.7 (1.7–3.3)
0.16 0.12
Table 4 Treatment plan evaluation by the conformity index (CI), modified Healthy Tissue Conformity Index (mHTCI), Conformation Number (CN), and conformal index (COIN). Index
The planning target volume of boost area (21 Gy) CI mHTCI CN (CI HTCI) COIN
Model A (1 cm) Median
Model B (0.5 cm) Median
0.960 0.808 0.771 0.643
0.963 0.850 0.819 0.716
81%, respectively and 5-year grade P2 late rectal and genito-urinary toxicity free survival rates were 84.4% and 70%, respectively. Cosset et al. [20] studied 21 patients with a focal seed implantation brachytherapy based on two series of prostate biopsies and a highresolution MRI and their results showed that this modality was feasible with acceptable acute toxicity. Gaudet et al. [21] investigated 120 patients with an intraprostatic boost compared to 70 patients with standard planning for permanent prostate I-125 seed implantation. Their results showed that there were no differences between the groups in terms of acute and late morbidity. Definition of the dominant lesion remains controversial and while radiological guidelines are clear there are a number of potential confounding factors which should be considered. In particular it is well recognized that significant physiological changes are seen in the prostate gland after only a short period of exposure to androgen deprivation [22] and that this may well modify some of the MR characteristics. A more rigorous approach is to combine the imaging information from mpMRI with those of choline PET although substantive evidence for the latter as a means of staging prostate cancer is lacking. Multiple template based biopsy mapping is perhaps the gold standard and in our clinical protocol we include this to confirm the areas to be given a focal boost. The results from our study show that it is feasible to plan a focal boost using HDR brachytherapy in this case achieving a 10% dose increment to the boost volume delivering 21 Gy to the dominant lesion and 15–19 Gy to the reminder of the PTV but that this needs to be predicted and preplanned using 0.5 cm intervals between each needle for the boost areas. When this strategy was used all plans achieved the plan objectives, whereas when a standard regular 1 cm spacing was used three plans (19%) failed to achieve the plan objectives, although in one of these the failure was borderline (94.65%).
p value
There is a suggestion that the urethral volume in the three plans in the unsuccessful group may have been larger than in the other groups, which might have contributed to the outcome in these three patients. A dominant lesion close to a larger urethral volume will be more difficult to cover within urethral constraints. This suggests that patients who have had a recent transurethral resection (TURP) and have a residual cavity should not be considered for this approach as stipulated in the GEC/ESTRO guidelines and the ABS recommendations [9,10]. One limitation of this study was the difficulty in identification of the urethra on MRI without urethral catheterization. The dosimetry of the urethra may therefore not be equal to that which would be achieved at implantation. Ultimately however, the optimal dose coverage depends on the size of the prostate, and the organs at risk, and the individual anatomy of the patient. The size of the prostate gland may be a factor that predicts satisfactory dosimetry in focal brachytherapy. There are several publications that have reported the influence of prostate volume on dosimetry during brachytherapy. In LDR seed brachytherapy some authors have suggested that small glands have poorer coverage [23,24] although others have not found that gland size was a factor [25,26]. With HDR brachytherapy in a series of patients with a median volume of 60ml no difference in dosimetry was seen between those below and those above the median [27]. However when considering focal boosts to a small sub-volume then it may be more difficult to achieve selective dose to the boost volume within a small gland and still achieve the organs at risk constraints, although the data presented do not show an independent effect of prostate volume. The conformity index (CI) represents the dose coverage of the target volume of PTV2. In this study, the HTCI index, computed for PTV2, has been modified because the reference isodose of the urethra and PTV3 is within the PTV1 entirely. Therefore, the volume of PTV3 is excluded from the HTCI calculation. These indices showed that the conformity index of the strategy of model B (0.5 cm spacing of needles in the boost area) is overall better than that of model A (1 cm spacing). It shows that the dose coverage of the target volume, the protection of healthy tissue, and the quality of dosimetry of model B is better than that of model A. The COIN index of both models was shown in this study which reflects the good quality of dose distribution. Needle spacing less than 1 cm in the boost area is clearly required to achieve optimal focal dose distributions; whether 5 mm is optimal or an even closer spacing of 2 or 3 mm will improve conformality further needs to be tested although there is likely to be a point at which small improvements do not justify the additional impact of additional catheter/needle placement.
P. Dankulchai et al. / Radiotherapy and Oncology 113 (2014) 121–125
Conclusion Focal boosts using HDR brachytherapy in prostate cancer can successfully achieve a 10% dose escalation to the boost volume while maintaining a lower dose to the remaining gland. Optimal dosimetry is achieved by individualizing the needle positions using 5 mm spacing rather than 10 mm spacing within the boost volume. Good differential dosimetry is more difficult to achieve in smaller glands and those with a larger urethra. Clinical evaluation of this approach is currently underway.
Conflicts of interest No potential conflict of interests. Acknowledgements P. Dankulchai at Mount Vernon Cancer Centre (the United Kingdom) was supported by a grant of the Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. References [1] Demanes DJ, Martinez AA, Ghilezan M, et al. High-dose-rate monotherapy: safe and effective brachytherapy for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2011;81:1286–92. [2] Yoshioka Y, Konishi K, Sumida I, et al. Monotherapeutic high-dose-rate brachytherapy for prostate cancer: five-year results of an extreme hypofractionation regimen with 54 Gy in nine fractions. Int J Radiat Oncol Biol Phys 2011;80:469–75. [3] Hoskin P, Rojas A, Lowe G, et al. High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence. Int J Radiat Oncol Biol Phys 2012;82:1376–84. [4] Barkati M, Williams SG, Foroudi F, et al. High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: a Phase II trial. Int J Radiat Oncol Biol Phys 2012;82:1889–96. [5] Prada PJ, Jimenez I, Gonzalez-Suarez H, Fernandez J, Cuervo-Arango C, Mendez L. High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: treatment description and preliminary results. Brachytherapy 2012;11:105–10. [6] Rogers CL, Alder SC, Rogers RL, et al. High dose brachytherapy as monotherapy for intermediate risk prostate cancer. J Urol 2012;187:109–16. [7] Shah C, Lanni Jr TB, Ghilezan MI, et al. Brachytherapy provides comparable outcomes and improved cost-effectiveness in the treatment of low/ intermediate prostate cancer. Brachytherapy 2012;11:441–5. [8] Zamboglou N, Tselis N, Baltas D, et al. High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results. Int J Radiat Oncol Biol Phys 2013;85:672–8.
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