Since August 2015 a prospective single-centre register study (ProRegPros) evaluating proton therapy for patients with localised prostate cancer has been carried out at the West German Proton Therapy Centreer and since March 2016 we have begun to offer hypofractionated/dose escalated SIB-IMPT as an option to patients with intermediate- and high-risk prostate cancer. Pretreatment staging included prostate-specific antigen (PSA), histologic diagnosis, magnetic resonance imaging (MRI), CT, bone scan, surgical lymphadenectomy for lymph node assessment, or radiologic assessment with MRI, and if applicable PSMA-PET/CT. SIB-IMPT with or without androgen deprivation therapy (ADT) was implemented in 23 patients with cT2b-4 histologically proven prostate adenocarcinoma treated consecutively between March 2016 and June 2018. In 15 patients, a transperineal injection of hydrogel spacer was carried out successfully one week before acquisition of the planning CT to increase distance between prostate and rectum (spacer group). Seven patients refused spacer injection, and one patient had improper implantation of the spacer (non-spacer group). Characteristics are listed in Table 1.
Table 1
Patients’ characteristics
Variable | 23 Patients No (%) |
Age at diagnosis (years) Range (Mean ± SD) | 52- 79 (66.65 ± 7.36) |
Prostate volume (cc) | 25.73 – 109.35 (60.67 ± 21.18) |
PSA at diagnosis (ng/ml) Range (Mean ± SD) < 10 10-20 >20 | 5.03 – 34.78 (13.1 ± 8.5) 11 (47.8%) 7 (30.4%) 5 (21.7%) |
Gleason Score 3+4 4+3 ≥ 4+4 | 10 (43.5%) 5 (21.7%) 8 (34.8%) |
T Stage cT2b cT2c cT3a cT3b cT4 | 4 (17.4%) 14 (60.9%) 2 (8.7%) 1 (4.3%) 2 (8.7%) |
N Stage N0 N+ | 23 (100%) 0 |
ADT Yes No | 10 (43.5%) 13 (56.5%) |
Hydrogel Spacer Yes No | 15 (65.2%) 8 (34.8%) |
Table 2
Dose–volume histogram results for PTV2RU
| Range | Mean±SD |
Volume (cc) | 113.2-329.25 | 194.58±63.04 |
Dmax (Gy) | 73.2-76.5 | 74.39±0.856 |
D2% (Gy) | 72.7-74.0 | 73.22-0.31 |
Dmean (Gy) | 71.54-72.06 | 71.78±0.11 |
Dmedian (Gy) | 71.82-72.14 | 71.94±0.1 |
D95% (Gy) | 68.85-71.03 | 69.92±0.59 |
D98% (Gy) | 66.68-70.16 | 69.0±0.92 |
PTV95%IDL (%) | 96.16-99.95 | 98.84±1.21 |
CI | 1.02-1.21 | 1.12±0.057 |
HI | 1.00- 1.06 | 1.04±0.014 |
Abbreviations; RU= range uncertainty, CI= conformity index== VRI/Volume of PTV;, HI= dose homogeneity index= D5%/D95% |
All patients underwent non-contrasted planning computed tomography (CT) scans with 1 mm axial slice thickness in the supine position and were immobilised with an individualised vacuum cushion and an individualised body thermoplastic cast fixed to the couch. Because of the steep drop in dose beyond the spread-out Bragg peak (SOBP) with subsequent high sensitivity of the dose distribution to the intra-fraction motion of the prostate, we aimed at minimising the prostate motion. A fixed bladder filling protocol (to drink 350 ml on empty bladder 30 minutes prior to treatment) applied to all patients. For further fixation of the prostate, to increase the distance between prostate and the dorsal rectal wall, and in order to gain a fixed reproducible rectal volume, the planning and treatment were implemented with a 120 ml fluid-filled endorectal balloon customised daily for each patient. For daily pretreatment prostate localisation, three fiducial markers (VisicoilTM 0.5m x 0.5 cm) were implanted for each patient at the same setting of hydrogel spacer injection using a transperineal approach with transrectal ultrasound guidance. For better target volumes/OARs delineation, each patient underwent a planning-MRI, T1-weighted / T2-weighted images, with and without contrast media. Target volumes were defined on co-registered CT and MRI scans as follow; the gross tumor volume (GTV) was the prostate, and the clinical target volume for low risk volume (CTV1) was defined as the GTV + 5 mm peri-prostatic tissue + 2 cm of the seminal vesicles. In case of extracapsular extension or a cT4 situation, the CTV1 was laterally extended to the pelvic sidewall. The CTV for high risk volume (CTV2) was defined as the GTV + 1 cm of the seminal vesicles. Two planning volumes, PTV1 and PTV2 were generated by adding 5-mm margins in all directions (except for 7 mm expansions at the seminal vesicle region) around CTV1 and CTV2, respectively. PTV1 and PTV2 were treated simultaneously in 30 fractions with 2 dose levels; a dose of 60 Gy (2 Gy/fraction) and 72 Gy (2.4 Gy/fraction) was delivered to the PTV1, and PTV2, respectively. The dose to PTV2 is biologically equivalent to 80.2 Gy in 2Gy/fx, assuming an α/β ratio of 1.5 for prostate cancer. The rectum was contoured as a solid organ extending from just above the anal verge up to the sigmoid flexure.
IMPT planning and optimisation were performed using the RaySearch’s treatment planning system version 5 (RaySearch Laboratories, Stockholm, Sweden) with pencil beam algorithm (24). Two lateral-opposed IMPT beams were implemented taking into consideration the range uncertainty, by applying additional distal margin of 3.5% in the proton beam range + 2-mm to the PTV, with subsequent generation of corresponding PTV1RU and PTV2RU.
Optimisation for each plan was done until fulfilment of the dose distribution requirements and OARs constraints; Dpres(GTV,CTV) = 100%, D95%,(PTV) ≥95%, D2%,(PTV2) ≤107%; RV73Gy<2%, RV68.4Gy<12%, RV66Gy<20%, RV62Gy<25%, RV60Gy<35%, RV50Gy<50%, RV40Gy<70%, BV73Gy< 12%, BV68Gy<20%, BV66Gy<30%, BV64Gy<45%, BV50Gy <60%; femoral head Dmax<40 Gy, penile bulb Dmean< 50 Gy.
The following dosimetric parameters were analysed for PTV2 and PTV2RU; Dmax, D2%, Dmean, Dmedian, D98%, D5%, D95%, and PTV95%IDL (volume of PTV covered by 95% of the prescribed dose=68.4 Gy).
For further plan evaluation, the conformality index (CI) and the dose homogeneity index (HI) were collected for PTV2 and PTV2RU;
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The conformality index (CI) was defined as a ratio between reference isodose volume (VRI= volume received 95% of the prescribed dose=68.4 Gy) and target volume= VRI/Volume of PTV
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The HI was defined as a ratio between the dose reached in 5% of the PTV volume and the dose reached in 95% of the PTV volume= D5%/D95%
For OARs the following parameters were analysed; for rectum; Dmax, Dmean, Dmedian, RV73Gy (percent of rectal volume received 73 Gy), RV72Gy ,RV70Gy, RV68.2Gy (percent of rectal volume received 95% of the prescribed dose), RV766Gy, RV65Gy, RV62G, RV60Gy, RV55Gy, RV50Gy, RV40Gy, RV30Gy, RV20Gy, and RV10Gy; For bladder; Dmax, Dmean, Dmedian, BV73Gy (percent of bladder volume received 73 Gy), BV72Gy, BV70Gy, BV68.2Gy (percent of bladder volume received 95% of the prescribed dose), BV65Gy, BV60Gy, BV55Gy, BV50Gy, BV40Gy, BV30Gy, BV20Gy and BV10Gy; for right and left femoral heads; Dmax, and Dmean; and for penile bulb; Dmean.
Further analysis was performed for the rectum as a solid organ, distinguishing between the spacer group (15 patients) and the non-spacer group (8 patients). For the NTCP calculation, different biological models were used for the rectum; the Poisson-LQ model for necrosis/stenosis with D50 = 80 Gy, γ = 2.2, S=1, and α/β = 3 (25) ; the Layman Kutcher Burman (LKB) model for late rectal bleeding ≥ 2 with D50 =81.8Gy, γ = 3, m = 0.22, n = 0.29, and α/β = 3 (26) ; and LKB model for late effects grade ≥ 3 with D50 =80Gy, m = 0.15, n = 0.06, and α/β = 3.9 (27).
All results were described as range and mean ± standard deviation (± SD). The Wilcoxon-Mann-Whitney-Test was used to compare continuous data between the spacer group and the non-spacer group non-parametrically. All statistical analysis was done using the IBM SPSS Statistics programme V22.