- Email: [email protected]
Learning curve of MRI-based planning for high-dose-rate brachytherapy for prostate cancer
Brachytherapy
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(2016)
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Learning curve of MRI-based planning for high-dose-rate brachytherapy for prostate cancer Simon Buus1,*, Susanne Rylander1, Steffen Hokland1, Christian Skou Søndergaard1, Erik Morre Pedersen2, Kari Tanderup1,3, Lise Bentzen1 1
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Department of Radiology, Aarhus University Hospital, Aarhus, Denmark 3 Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark 2
ABSTRACT
PURPOSE: To evaluate introduction of MRI-based high-dose-rate brachytherapy (HDRBT), including procedure times, dose-volume parameters, and perioperative morbidity. METHODS AND MATERIALS: Study included 42 high-risk prostate cancer patients enrolled in a clinical protocol, offering external beam radiotherapy þ two HDRBT 8.5 Gy boosts. Time was recorded for initiation of anesthesia (A), fixation of needle implant (B), end of MR imaging (C), plan approval (D), and end of HDRBT delivery (E). We defined time AeE as total procedure time, AeB as operating room time, BeC as MRI procedure time, CeD as treatment planning time, and D to E as treatment delivery time. Dose-volume parameters were retrieved from the dose planning system. Results from the first 21 patients were compared with the last 21 patients. RESULTS: Total procedure time, operating room time, MRI procedure time, and treatment planning time decreased significantly from average 7.6 to 5.3 hours ( p ! 0.01), 3.6 to 2.4 hours ( p ! 0.01), 1.6 to 0.8 hours ( p ! 0.01), and 2.0 to 1.3 hours ( p ! 0.01), respectively. HDRBT delivery time remained unchanged at 0.5 hours. Clinical target volume prostateþ3mm D90 fulfilled planning aim in 92% of procedures and increased significantly from average 8.3 to 9.0 Gy ( p ! 0.01). Urethral D0.1 cm3 and rectal D2 cm3 fulfilled planning aim in 78% and 95% of procedures, respectively, and did not change significantly. Hematuria occurred in (95%), hematoma (80%), moderate to strong pain (35%), and urinary retention (5%) of procedures. CONCLUSIONS: After introduction of MRI-based HDRBT, procedure times were significantly reduced. D90 Clinical target volumeprostateþ3mm fulfilled constraints in most patients and improved over time, but not at expense of an increased urethral or rectal dose. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
HDR; Workflow; Morbidity; MRI; Prostate cancer; Learning curve
Introduction Brachytherapy (BT) either alone or in combination with external beam radiotherapy (EBRT) for localized prostate cancer has demonstrated a favorable relapse-free survival (1e3). BT, and high-dose-rate brachytherapy (HDRBT) in particular, has superior physical abilities for sparing the rectal and bladder wall in comparison with modern external
Received 27 January 2016; received in revised form 13 March 2016; accepted 23 March 2016. * Corresponding author. Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, Building 5, DK-8000 Aarhus, Denmark. Tel.: þ4560935413; fax: þ4578462530. E-mail address: [email protected] (S. Buus).
beam techniques (4). BT for prostate cancer is an established treatment modality that has been used increasingly over the past decade (5, 6). Transrectal ultrasoundebased BT has been the mainstay of prostate cancer BT since the pioneer work of Holm et al. (7). This may be changing as MRI-based HDRBT seems superior to US-based HDRBT with regard to target definition, needle reconstruction, and delineation of organs at risk (OAR). MRI can more accurately define the prostate gland especially at the apex and base, and it is useful for identifying the dominant intraprostatic lesion as well as extracapsular cancer extensions (8). MRI enables detailed definition of organs as risk such as the neurovascular bundles, external urinary sphincter, bladder neck, and intraprostatic ejaculatory ducts (9, 10). Arguments against MRI-based HDRBT is extra
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.03.011
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procedure time, a more complex workflow, and unavailability of MRI. In 2012, HDRBT was introduced in our department as a new treatment modality for prostate cancer patients. HDRBT was performed in a newly built facility, housing contemporary imaging modalities including an MRI scanner dedicated for radiotherapy planning. The purpose of this study was to evaluate the introduction of MRI-based HDRBT, including procedure times, perioperative morbidity, and dose-volume parameters.
Methods and materials
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ileostomia, colostomia, prior pelvic radiotherapy, and comorbidity interfering with anesthesia. External beam radiotherapy Before HDRBT, patients received EBRT 46 Gy in 23 fractions, 5 weekly fractions. EBRT was delivered to the prostate gland and seminal vesicles using volumetric arc therapy technique based on planning CT and MRI. Clinical target volume (CTV)prostate was defined on planning MRI as prostate gland plus extracapsular extension. Planning target volume was generated from the CTVprostate þ CTVvesicles added a margin of 7 mm axially and 9 mm craniocaudally. No elective lymph node irradiation was performed.
Facility Facility includes a patient room, operating room (OR), stepper system (Oncoselect tablemount stepper þ ECRM endocavity rotation mover), MR compatible template (TPS 061 1.5 mm), ultrasound system (Prosius Integrated Ultrasound System þ US transformer Logiscan 128 Model INT-2ZKit þ BiopSee biplanar transrectal ultrasound probe), remote afterloader (Flexitron, Elekta þ Flexisource Ir 191, 370 Bq), treatment planning system (OncentraProstate version 4.2.21, Nucletron), MRI scanner (Ingenia 1.5 T, Philips Healthcare, The Netherlands), PET/CT scanner (Philips Gemini TF Big Bore., The Netherlands), and a treatment delivery room. The patient-related procedures involved four different rooms located in the same building and on the same floor. Training A team of radiotherapists, physicists, radiologists, and nurses was trained to perform MRI-based HDRBT. Training included site visits to two departments with significant experience in MRI and US-guided prostate BT, respectively. The HDRBT procedure was simulated several times using a prostate phantom (CIRS 053A). During the first patient procedures, an HDRBT experienced technician and an urologist were present. Patient selection The study included 42 consecutive D’Amico high-risk prostate cancer patients (11) enrolled in a prospective clinical protocol in which patients were offered combined EBRT þ HDRBT. In December 2014, we changed our procedure to include repeated MRI to assess the stability of the needle implant, and patients from this time on are not included in the study. Inclusion criteria beyond GEC ESTRO guidelines (12, 13) were biopsy-proven prostate adenocarcinoma, Stage T1eT3a, no lymph node metastases on lymph node dissection, negative bone scan, and planned 3 years of luteinizing hormoneereleasing hormone agonist treatment initiated 3 months before radiotherapy. Exclusion criteria were maximal urinary flow !15 mL/s (later changed to !10 mL/s), inflammatory bowel disease,
Patient preparation Patients were instructed to discontinue anticoagulants 3e5 days before the first HDRBT procedure. Blood samples were taken 2e3 days before each HDRBT procedure for analysis of coagulation parameters, hematological parameters, pretransfusion compatibility, and electrolytes. Patients were fasting for at least 6 hours and received bisacodyl 10 mg 2 orally and 2 mg rectally for bowel emptying. Venous thromboembolism prophylaxis included the use of antiembolism stockings during the HDRBT procedure, and subcutaneous dalteparin 5000 IU was administered two times postoperatively with a 12-hour interval. For microbial prophylaxis, a urine sample was examined with a urine test stick 2e3 days before each HDRBT for excluding urinary infection. Patients were advised to shave the perineum and scrotum, and 500-mg ciprofloxacin and 500-mg metronidazole were administered orally 3 hours before the HDRBT procedure. Anesthesia General anesthesia was used for the first 28 patients, but the procedure was changed to spinal anesthesia for subsequent patients. In patient number 31, general anesthesia was used for the second HDRBT due to a severe anaphylactic reaction during the first HDRBT. If general anesthesia was performed, patients received infiltration analgesia of the perineum with 10e12 cm3 of bupivacaine 2.5 mg/cm3. For postoperative pain and nausea, patients received 1-g paracetamol, 20-mg morphinesulphate, and 8-mg ondansetron 3e4 hours before HDRBT. High-dose-rate brachytherapy HDRBT was delivered twice with each procedure separated by 1 week after EBRT. Plastic needles were inserted US guided, but HDRBT dose plans were based on MRI reconstructed needles and MRI defined volumes (CTVprostate, urethra, rectum, and bladder) (Table 1). The tip of each needle was resolved by the resulting signal loss artifact on MRI, and the first available dwell position was defined as
S. Buus et al. / Brachytherapy Table 1 Mean volume (SD) of prostate, urethra, rectum, and bladder (cm3) Volume
EBRT
CTVprostate CTVprostateþ3mm Urethra Rectum Bladder
35.2 d 1.6 67.5 81.3
11.5 0.7 19.0 41.1
1st HDRBT 40.4 59.9 2.4 42.8 109.6
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reduce risk of needle migration. Details of the workflow are provided in Table 3.
2nd HDRBT
13 16.4 0.5 12.1 63.4
44.5 64.0 2.4 45.4 121.9
12.6 16.0 0.5 13.0 61.8
SD 5 standard deviation; EBRT 5 external beam radiotherapy; HDRBT 5 high-dose-rate brachytherapy; CTV 5 clinical target volume.
6 mm below the needle tip. CTVprostateþ3mm was generated by adding an isotropic 3-mm margin to CTVprostate, avoiding bladder and rectum. Dose optimization was performed using the hybrid inverse planning optimization algorithm (OncentraProstate version 4.1.6, Nucletron, ELEKTA Brachytherapy, Veenendaal, The Netherlands) followed by manual corrections of the loading pattern. The initial planning aim for CTVprostateþ3mm D90 was 8.1 Gy, which in 2014 was changed to 8.5 Gy. Planning aims for combined EBRT þ2 HDRBT boosts were calculated in biological equivalent doses (EQD2) assuming an a/b 5 3. Further details are provided in Table 2. Magnetic resonance imaging After needle implant, a transversal T2-weighted turbo spin echo MRI sequence (slice thickness of 2 mm, acquired resolution 1.4 mm 1.76 mm, echo time 5 80 ms, repetition time 5 11,366 ms) was performed. Total scan time amounted to approximately 12 minutes. No endorectal coil was used for the MRI procedure.
Recovery After HDRBT, guide tubes were disconnected, and the plastic needles were removed. After removal, the bladder was irrigated with isotonic saline and the perineum was compressed for 4e5 minutes. The patient was then observed in the ward for median 20.5 hours (range, 15.2e45.8). The bladder catheter was to be removed the day after HDRBT, and the patient could be discharged from the ward after two micturations. Evaluation Time points for initiation of the main parts in the HDRBT were recorded, and the duration for each main step was calculated. Furthermore, the total procedure time was calculated from initiation of anesthesia to end of HDRBT delivery. Dose-volume parameters were retrieved from the dose planning system (Oncentra Prostate, Nucletron). Information of perioperative morbidity was collected from the patient record. COIN was calculated for CTVprostateþ3mm for assessing the conformity of the dose plans (14). Procedure times for the main steps in the workflow and dose-volume parameters from the first 21 patients were compared with last 21 patients using independent samples t-test (SPSS 20). Chi-square test was performed for comparison of pain records for patients receiving general anesthesia and spinal anesthesia.
Workflow
Results
The workflow was divided into four main steps: OR time, MRI procedure time, treatment planning time, and HDRBT delivery time. The patient stayed on the MRI couch after MR imaging and until end of treatment to
Patients were median 68 years of age (range, 52e76), cT1cecT3a, median Gleason score 7 (range, 6e10), and median PSA 20.5 (range, 4.7e63.8). Urinary flow measurements before RT showed a maximal flow of
Table 2 Planning aims and prescribed dose of target and OAR (median, range) HDRBT
EBRT (Gy)
Total course (Gy EQD2)
Volume
Planned
Prescribed
Planned
Prescribed
Planned
Prescribed
CTVprostateþ3mm CTVprostateþ3mm
D90% $ 8.5 Gy D90% $ 8.1 Gy (8.5 Gya) V150% ! 45% V200% ! 20% COIN D2 cm3 ! 75% V100% 5 0% D0.1 cm3 ! 10 Gy D10% ! 115% D30% ! 110% D0.1 cm3 D2 cm3
9.4 Gy (6.4e10) 8.8 Gy (5.6e9.4) 32.4% (20.3e43.3) 11.3% (6.8e19.1) 0.80 (0.39e0.89) 66% (49e76) 0% 9.8 Gy (9.1e11.1) 114% (104e128) 112% (99e128) 9.6 Gy (4.4e16.4) 6.7 Gy (3.5e8.9)
46 Gy 46 Gy d d
46 Gy (46e62) 46 Gy (46e62) d d
$85.1 Gy $81.8 Gy d d
92.4 Gy (80.2e96.6) 87.5 Gy (73.8e91.2) d d
!46 Gy d !46 Gy d d d !46 Gy
45.7 Gy (43.9e61.9) d 45.7 Gy (44.9e61.8) d d d 45.8 Gy (45.5e61.9)
!69.9 Gy d !98 Gy d d d d
65 Gy (58.5e73.9) d 96.8 Gy (85.7e101.5) d d 96.6 (85.5e101.2) 72 (60.1e81.9)
Rectum Urethra
Bladder
OAR 5 organs at risk; EQD2 5 equivalent dose in 2 Gy per fraction; EBRT 5 external beam radiotherapy; HDRBT 5 high-dose-rate brachytherapy; CTV 5 clinical target volume; COIN 5 conformal index. a Planning aim increased to 8.5 Gy in 2014.
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Table 3 HDRBT workflow main and detailed steps I. OR time
II. MRI procedure
III. Treatment planning
IV. HDRBT delivery
1. Anesthesia 2. Patient positioning 3. Disinfection of pelvic region 4. Placement of bladder catheter 5. Surgical drape 6. Placement of rectal tube 7. Stepper system on operating table 8. Insertion of rectal US probe 9. Template on stepper system 10. Two anchor needles in prostate gland 11. 3D US acquisition scan 12. Contouring of CTVprostate, CTVprostateþ3mm, urethra, and rectum 13. Preplanning 14. Plastic needle insertion 15. Label plastic needles with numbers 16. Removal of US probe from rectum 17. Fixation of template to perineum with sutures
18. Transferral of patient from operating table to MR couch on trolley 19. Waiting time 20. Transport of patient to MR scanner 21. MR scana
22. Import of MR images into dose planning system 23. Delineation of CTVprostate, CTVprostateþ3mm, urethra, bladder, and rectum 24. Needle reconstruction on MRI 25. Dose planning 26. Approval of HDRBT dose plan.
27. Export of dose plan to remote afterloading system. 28. Transport of patient into treatment room 29. Connection of guide tubes to needles 30. Treatment delivery.
HDRBT 5 high-dose-rate brachytherapy; OR 5 operating room; US = ultrasound. a During the first 23 HDRBT procedures, patients received a CT scan to support the reconstruction of the tip of the plastic needles. This meant that patients were transferred from the operating table to a bed, transported to the CT couch, and finally to the MRI couch. CT imaging was later abandoned as definition of the needle tip was done satisfactory using MRI.
median 14.5 cm3/s (range, 8.7e38.4), voided volume median 252 cm3 (range, 60e537), and residual urine was median 60 cm3 (range, 0e529). All patients received luteinizing hormoneereleasing hormone agonist, which was initiated median 94 days (range, 60e124 days) before the start of EBRT. Prostate volume estimated from EBRT planning images was median 35 cm3 (range, 16e65). Patient number 11 did not receive the second HDRBT due to a decubitus ulcer developed during the first HDRBT procedure. Instead, the patient received an additional EBRT course of 16 Gy in eight fractions. Workflow Figure 1 shows the mean duration of each main step in the MRI-based HDRBT workflow for the first 21 patients and for the last 21 patients. Total procedure time decreased significantly from average 7.6 1.70 (standard deviation) to 5.3 0.84 hours ( p ! 0.01). OR time decreased significant from average 3.6 0.82 to 2.4 0.33 hours ( p ! 0.01), the MRI procedure time decreased significantly from average 1.6 0.55 to 0.8 0.28 hours ( p ! 0.01), treatment planning time decreased significantly from average 2.0 0.74 to 1.5 0.1 hours ( p ! 0.01), and HDRBT delivery time did not change with average 0.4 0.2 vs. 0.5 0.38 hours ( p 5 0.07). Figure 2 shows in more details the total procedure time, OR time, MRI procedure time, and treatment planning
time. In procedure 33, treatment planning time (Fig. 2d) was calculated to take 0.3 hours and MRI procedure time 2.0 hours, which may be a consequence of an error in the time recording of the MRI. Needles The number of needles per procedure was median 18 (range, 13e24). The number of needles per procedure increased from average 17.5 to 18.5 from the first 21 patients to the last 21 patients ( p 5 0.04). CTVprostateþ3mm per needle was median 3.4 cm3 (range, 1.5e5.5), and it increased from average 3.1 0.6 to 3.7 0.7 cm3 per needle from the first 21 patients to the last 21 patients ( p ! 0.01). CTVprostateþ3mm was median 63.3 cm3 (range, 25.6e98.9), and it increased First 21 paƟents
Last 21 paƟents
0
2
Operating room time MRI procedure time Treatment planning time HDR BT delivery time 4
6
8
Time (hours)
Fig. 1. Bars show the mean duration of each main step in workflow. Top bar shows results for the first 21 patients and bottom bar the last 21 patients. HDRBT 5 high-dose-rate brachytherapy.
S. Buus et al. / Brachytherapy
a
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5
8 6 4 st
1 HDRBT 2nd HDRBT
2
OR Ɵme
10
DuraƟon (hours)
DuraƟon (hours)
(2016)
b Total procedure Ɵme
10
1st HDRBT 2nd HDRBT
8 6 4 2
0
0 0
c
20 40 60 Number of procedures
d
6 4 2
20 40 60 Number of procedures
10
Treatment planning Ɵme
8
1st HDRBT 2nd HDRBT
DuraƟon (hours)
1st HDRBT 2nd HDRBT
8
0
80
MRI procedure Ɵme
10
DuraƟon (hours)
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80
6 4 2
0
0 0
20 40 60 Number of procedures
80
0
20 40 60 Number of procedures
80
Fig. 2. Panels show the number of each procedure plotted against the total procedure time (a), operation room time (b), MRI procedure time (c), and treatment planning time (d). Filled circles represent the first HDRBT and open circles the second HDRBT.
from average 53.6 13.7 to 69.3 15.7 cm3 from the first 21 to the last 21 patients ( p ! 0.01). Target dose CTVprostateþ3mm D90 fulfilled planning aim in 76 of 83 procedures (Fig. 3). Postimplant US and MRI were examined for the seven procedures that did not fulfill our planning aim. Insufficient coverage was caused by suboptimal catheter implant in five procedures and catheter migration in two procedures. CTVprostateþ3mm D90 coverage increased significantly from average 8.3 0.71 to 9.0 0.24 Gy from the first 21 to the last 21 patients ( p ! 0.01) and tended to increase from first to the second HDRBT. CTVprostate D90 fulfilled planning aim in 78 of 83 procedures and increased significantly ( p ! 0.01) from the first 21 to the last 21 patients. Conformity of the dose plans evaluated by COIN was median 0.80 (0.39e0.89) for CTVprostateþ3mm and increased significantly from average 0.76 0.07 to 0.81 0.04 from the first 21 to the last 21 patients ( p ! 0.01). Heterogeneity of the dose plans evaluated by
V150% and V200% was median 32.4% (range, 20.3e43.3) and 11.3% (range, 6.8e19.1), respectively. V150% remained unchanged from the first to last 21 patients with an average of 32.4 4.64 vs. 32.2 4.28%, whereas V200% decreased significantly ( p 5 0.04) from average 11.8 0.38 to 10.8 0.27%. For the whole RT course including EBRT þ2 HDRBT, the planning aim for CTVprostate D90 (85.1 Gy EQD2) was fulfilled in 39 of 42 patients, and the planning aim for CTVprostateþ3mm D90 (81.7 Gy EQD2) was fulfilled in 36 of 42 patients. Overall treatment time was median 42 days (range, 40e52 days).
Normal tissue Urethral D0.1 cm3 fulfilled planning aim (#10 Gy) in 65 of 83 procedures, and it did not change significantly ( p 5 0.92) from the first to last 21 patients. Rectal dose D2 cm3 fulfilled planning aim (!6.4 Gy) in 79 of 83 procedures, and it did not change significantly ( p 5 0.12) from the first to last 21 patients (Fig. 4).
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anesthesia chi-square, p 5 0.82. Other reported side effects were constipation (nine procedures), urge incontinence (six procedures), syncope (three procedures), suspected urethral lesion (two procedures), Quincke’s odema (one procedure), and decubitus ulcer (one procedure). For the latter patient, OR time and total procedure time were 5.4 and 9.1 hours, respectively.
10
CTV-P + 3mm D90 (Gy)
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9 8 7 6
Discussion
5 4 0
20
40
60
80
Number of procedures Fig. 3. Prescribed D90 for CTVprostateþ3mm for each HDRBT plotted against the number of HDRBT procedures performed. Closed circles represent the first HDRBT and open circles the second HDRBT. Dotted line represents our initial planning aim of 8.1 Gy and the dashed line our current planning aim of 8.5 Gy. CTV 5 clinical target volume; HDRBT 5 highdose-rate brachytherapy.
Perioperative morbidity
11
7
10
6
Rectal D2cc (Gy)
Urethral D0.1cc (Gy)
Hematuria was observed after 79 procedures. Blood clotting was observed in urine in 49 of 83 procedures, and blood clotting resulted in urinary retention in six procedures. Hematoma of perineum/scrotum was observed in 63 of 79 procedures (data missing in four procedures). Decrease of hemoglobin levels after the first HDRBT procedure was median 0.3 mmol/L (0.3, 1.7 mmol/L). The patient, who experienced a decrease of 1.7 mmol/L, received a blood transfusion. No infections were observed within 2 weeks after the last HDRBT. Minor or no pain was reported in 53 of 82 procedures (data missing in one procedure) and moderate-to-strong pain in 29 of 82 procedures. No difference in frequency of pain was found between patients receiving either general or spinal
In the present study, we demonstrated that an MRIbased HDRBT procedure can be successfully introduced into a radiotherapy department, which did not have experience with prostate BT. Proper training was initiated before the first patient treatment, and specific equipment was acquired with the criteria of full MRI compatibility. Significant improvements in terms of target coverage and reduced procedure times were seen from the first 21 to the last 21 patients, suggesting that about 40 HDRBT procedures are needed for performing an optimal HDRBT. OR time and total procedure time were significantly reduced during the observed period, indicating that more experience and small changes in the workflow can significantly reduce the procedure time. Menard et al. (15) found a similar reduction in the procedure time, when they initiated an MRI-guided technique for needle insertion. Changing the standard anesthetic procedure to spinal anesthesia from patient 29 and onward did not seem to influence procedure times or dosimetric parameters, as these had reached a steady level before the change. OR time is similar to the time spent in the OR, and with 2.4 hours in the OR, it is possible to perform two HDRBT procedures within a normal working day with a single OR. Further reductions in the OR time may be possible, as Tselis et al. (16) reported using in average 100 minutes for patient positioning, preplanning, and needle insertion. MRI procedure time was
9
8
7
5
4
3 0
20
40
60
Number of procedures
80
0
20
40
60
80
Number of procedures
Fig. 4. Prescribed urethral D0.1 cm3 (left panel) and rectal D2 cm3 (right pannel) for each HDRBT plotted against the number of the procedure. Closed circles represent the first HDRBT and open circles the second HDRBT. Dashed lines represent constraints for urethral and rectal dose. HDRBT 5 high-dose-rate brachytherapy.
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Fig. 5. Postimplant images of the prostate gland for patient number 42, second HDRBT. Top panels are at the midaxial and bottom panels at the midsagittal plane of the prostate. Left panels show the TRUS images and right panels T2-weighted MRI. HDRBT 5 high-dose-rate brachytherapy; TRUS 5 transrectal ultrasound.
in average 1.1 hours, which may seem much, but besides the actual scan time, it includes transferral of patient from operating table to MRI couch on trolley, waiting time, and transport of patient to MRI scanner. Time used for MRI may be compensated for by improved delineation of targets, OAR, and needles (Fig. 5). Initially, we focused at reducing the OR time and the total procedure time to minimize patient discomfort. Now focus has changed toward reducing time from MRI to treatment delivery, due to the risk of needle migration, which may adversely impact an otherwise optimal HDRBT (17). The average number of needles used for each HDRBT procedure increased from 17.5 to 18.5 from the first 21 to the last 21 patients, which is surprising. However, CTVprostateþ3mm and CTVprostateþ3mm per needle also increased, indicating that needles over time were placed more optimally. Fewer needles per implant may be achievable as other groups with more experience in prostate cancer HDRBT report using a median of 16 needles (17, 18). In the present study, all patients received $80.2 Gy EQD2 to the CTVprostate. This is significantly higher than
the commonly used EBRT schedule of 78 Gy in 39 fractions where a typical planning aim is D100 of 74.1 Gy (95% of 78 Gy) to CTVprostate. In fact, 39 of 42 patients received a biologically equivalent dose $85.1 Gy to CTVprostate, and 36 of 42 patients received a biologically equivalent dose $81.7 Gy to CTVprostateþ3mm. Previous studies have demonstrated the importance of a high CTVprostate D90 in prostate cancer BT to minimize the risk of biochemical relapse (19, 20). Experience plays a significant role for achieving an optimal target coverage in prostate BT (20), but technology advances like improved imaging techniques (Fig. 5) may be helpful for a successful introduction of prostate BT (21). A strategy of two separate HDRBT procedures in combination with EBRT seems robust when initiating HDRBT, which may be preferable to a strategy with single fraction BT monotherapy. A suboptimal needle implant in one HDRBT procedure may be compensated for in the following procedure reducing the risk of a patient receiving an inferior radiotherapy course. Urethral D 0.1 cm3 constraint !10 Gy was violated in 18 of 83 procedures and median D 0.1 cm3 of 9.8 Gy close to the
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urethra constraint, which indicates difficulties in keeping a low urethral dose, while reaching the CTV planning aim. Rectal dose constraint !6.4 Gy was violated in only in five procedures, and the median D2 cm3 was 5.6 Gyda difference of 0.8 Gy indicates that a lower and more ambitious rectal dose constraint could be considered to further minimize rectal dose. One of the major advantages of HDRBT is the low frequency of gastrointestinal toxicity (22, 23). The rectal sparing ability of HDRBT is superior to other treatment modalities due to the steep BT dose gradient (4). MRIbased HDRBT may further improve this with a more accurate delineation of OARs. Furthermore, treating the patient after removal of the rectal ultrasound probe may also result in less rectal toxicity due to a larger distance between the rectum and prostate (24). Hematuria occurred after most our HDRBT procedures, which may be more frequent from that experienced by other groups working with prostate BT (15, 25). This may be explained by our procedure, where the needle tip was placed in the bladder 15e20 mm cranially prostate base to stabilize the implant. Repositioning the patient from lithotomy to supine position before MRI may cause significant needle migration. Other groups treating the patient in lithotomy position place the needle tip just below the bladder (15, 26). No infections and no thromboembolic events were observed indicating a good antimicrobial and venous thromboembolism prophylaxis. Pain was a frequent complication, which seemed to decrease with the change from general anesthesia to spinal anesthesia. However, the difference was not apparent when comparing pain records for patients receiving either spinal or general anesthesia. Transrectal ultrasoundebased HDRBT has shown excellent long-term outcomes (27, 28) questioning the relevance of an MRI-based HDRBT procedure. Further improvements in outcome may be achieved by escalating the dose to the prostate gland as indicated by recent results from the ASCENDE-RT trial that demonstrated a significant benefit in relapse-free survival from escalating the dose with a low-dose-rate boost in intermediate- and high-risk prostate cancer (29). However, dose escalation resulted in a substantial increase in the risk of Grade 3 genitourinary toxicity. These results emphasize the need for state of the art imaging for improved definition of target, OAR, and needles in HDRBT, which may be provided by MRI.
Conclusion After introduction of MRI-based HDRBT, total procedure time (5.3 hours), OR time (2.4 hours), MRI procedure time (0.8 hours), and treatment planning time (1.3 hours) were significantly reduced. CTVprostateþ3mm fulfilled institutional constraints in most patients and improved over time, but not at the expense of an increased urethral or rectal dose.
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References [1] Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109:22e29. [2] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103:217e222. [3] Deutsch I, Zelefsky MJ, Zhang Z, et al. Comparison of PSA relapsefree survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT. Brachytherapy 2010; 9:313e318. [4] Georg D, Hopfgartner J, Gora J, et al. Dosimetric considerations to determine the optimal technique for localized prostate cancer among external photon, proton, or carbon-ion therapy and high-dose-rate or low-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2014;88: 715e722. [5] Poortmans PM, Aarts MJ, Jobsen JJ, et al. A population-based study on the utilisation rate of primary radiotherapy for prostate cancer in 4 regions in the Netherlands, 1997-2008. Radiother Oncol 2011;99: 207e213. [6] Guedea F, Torrecilla JL, Londres B, et al. Patterns of care for brachytherapy in Europe: updated results for Spain. Clin Transl Oncol 2012; 14:36e42. [7] Holm HH, Juul N, Pedersen JF, et al. Transperineal 125iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130:183e286. [8] Bloch BN, Furman-Haran E, Helbich TH, et al. Prostate cancer: accurate determination of extracapsular extension with high-spatialresolution dynamic contrast-enhanced and T2-weighted MR imagingeinitial results. Radiology 2007;245:176e185. [9] Tanderup K, Viswanathan AN, Kirisits C, et al. Magnetic resonance image guided brachytherapy. Semin Radiat Oncol 2014;24:181e191. [10] Albert JM, Swanson DA, Pugh TJ, et al. Magnetic resonance imaging-based treatment planning for prostate brachytherapy. Brachytherapy 2013;12:30e37. [11] D’Amico a V, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969e974. [12] Kovacs G, P€otter R, Loch T, et al. GEC/ESTRO-EAU recommendations on temporary brachytherapy using stepping sources for localised prostate cancer. Radiother Oncol 2005;74:137e148. [13] 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;107:325e332. [14] Baltas D, Kolotas C, Geramani K, et al. A conformal index (COIN) to evaluate implant quality and dose specification in brachytherapy. Int J Radiat Oncol Biol Phys 1998;40:515e524. [15] Menard C, Susil RC, Choyke P, et al. MRI-guided HDR prostate brachytherapy in standard 1.5T scanner. Int J Radiat Oncol Biol Phys 2004;59:1414e1423. [16] Tselis N, Maurer U, Popp W, et al. Evaluation of time, attendance of medical staff, and resources during interstitial brachytherapy for prostate cancer: DEGRO-QUIRO trial. Strahlenther Onkol 2014; 190:358e363. [17] Hoskin PJ, Bownes PJ, Ostler P, et al. High dose rate afterloading brachytherapy for prostate cancer: catheter and gland movement between fractions. Radiother Oncol 2003;68:285e288. [18] Batchelar D, Gazta M, Schmid M, et al. Validation study of ultrasound-based high-dose-rate prostate brachytherapy planning compared with CT-based planning. Brachytherapy 2014;13:75e79. [19] Hoskin PJ, Rojas AM, Ostler PJ, et al. Dosimetric predictors of biochemical control of prostate cancer in patients randomised to
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[20]
[21]
[22]
[23]
[24]
external beam radiotherapy with a boost of high dose rate brachytherapy. Radiother Oncol 2014;110:110e113. Henry AM, Al-Qaisieh B, Gould K, et al. Outcomes following iodine-125 monotherapy for localized prostate cancer: the results of leeds 10-year single-center brachytherapy experience. Int J Radiat Oncol Biol Phys 2010;76:50e56. Beaulieu L, Evans DA, Aubin S, et al. Bypassing the learning curve in permanent seed implants using state-of-the-art technology. Int J Radiat Oncol Biol Phys 2007;67:71e77. 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: 1376e1384. Ghadjar P, Oesch SL, Rentsch CA, et al. Late toxicity and five year outcomes after high-dose-rate brachytherapy as a monotherapy for localized prostate cancer. Radiat Oncol 2014; 9:122. Rylander S, Buus S, Bentzen L, et al. The influence of a rectal ultrasound probe on the separation between prostate and rectum in highdose-rate brachytherapy. Brachytherapy 2015;14:711e717.
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[25] Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial. Int J Radiat Oncol Biol Phys 2000;48:675e681. [26] Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading 192Iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998;41:525e533. [27] 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. [28] Sylvester JE, Grimm PD, Wong J, et al. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011; 81:376e381. [29] Morris WJ, Tyldesley S, Pai H, et al. Low-dose-rate brachytherapy is superior to dose-escalated EBRT for unfavourable risk prostate cancer: the results of the ASCENDE-RT* Randomized control trial. Brachytherapy 2015;14:S12.
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Learning curve of MRI-based planning for high-dose-rate brachytherapy for prostate cancer Simon Buus1,*, Susanne Rylander1, Steffen Hokland1, Christian Skou Søndergaard1, Erik Morre Pedersen2, Kari Tanderup1,3, Lise Bentzen1 1
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Department of Radiology, Aarhus University Hospital, Aarhus, Denmark 3 Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark 2
ABSTRACT
PURPOSE: To evaluate introduction of MRI-based high-dose-rate brachytherapy (HDRBT), including procedure times, dose-volume parameters, and perioperative morbidity. METHODS AND MATERIALS: Study included 42 high-risk prostate cancer patients enrolled in a clinical protocol, offering external beam radiotherapy þ two HDRBT 8.5 Gy boosts. Time was recorded for initiation of anesthesia (A), fixation of needle implant (B), end of MR imaging (C), plan approval (D), and end of HDRBT delivery (E). We defined time AeE as total procedure time, AeB as operating room time, BeC as MRI procedure time, CeD as treatment planning time, and D to E as treatment delivery time. Dose-volume parameters were retrieved from the dose planning system. Results from the first 21 patients were compared with the last 21 patients. RESULTS: Total procedure time, operating room time, MRI procedure time, and treatment planning time decreased significantly from average 7.6 to 5.3 hours ( p ! 0.01), 3.6 to 2.4 hours ( p ! 0.01), 1.6 to 0.8 hours ( p ! 0.01), and 2.0 to 1.3 hours ( p ! 0.01), respectively. HDRBT delivery time remained unchanged at 0.5 hours. Clinical target volume prostateþ3mm D90 fulfilled planning aim in 92% of procedures and increased significantly from average 8.3 to 9.0 Gy ( p ! 0.01). Urethral D0.1 cm3 and rectal D2 cm3 fulfilled planning aim in 78% and 95% of procedures, respectively, and did not change significantly. Hematuria occurred in (95%), hematoma (80%), moderate to strong pain (35%), and urinary retention (5%) of procedures. CONCLUSIONS: After introduction of MRI-based HDRBT, procedure times were significantly reduced. D90 Clinical target volumeprostateþ3mm fulfilled constraints in most patients and improved over time, but not at expense of an increased urethral or rectal dose. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
HDR; Workflow; Morbidity; MRI; Prostate cancer; Learning curve
Introduction Brachytherapy (BT) either alone or in combination with external beam radiotherapy (EBRT) for localized prostate cancer has demonstrated a favorable relapse-free survival (1e3). BT, and high-dose-rate brachytherapy (HDRBT) in particular, has superior physical abilities for sparing the rectal and bladder wall in comparison with modern external
Received 27 January 2016; received in revised form 13 March 2016; accepted 23 March 2016. * Corresponding author. Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, Building 5, DK-8000 Aarhus, Denmark. Tel.: þ4560935413; fax: þ4578462530. E-mail address: [email protected] (S. Buus).
beam techniques (4). BT for prostate cancer is an established treatment modality that has been used increasingly over the past decade (5, 6). Transrectal ultrasoundebased BT has been the mainstay of prostate cancer BT since the pioneer work of Holm et al. (7). This may be changing as MRI-based HDRBT seems superior to US-based HDRBT with regard to target definition, needle reconstruction, and delineation of organs at risk (OAR). MRI can more accurately define the prostate gland especially at the apex and base, and it is useful for identifying the dominant intraprostatic lesion as well as extracapsular cancer extensions (8). MRI enables detailed definition of organs as risk such as the neurovascular bundles, external urinary sphincter, bladder neck, and intraprostatic ejaculatory ducts (9, 10). Arguments against MRI-based HDRBT is extra
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.03.011
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procedure time, a more complex workflow, and unavailability of MRI. In 2012, HDRBT was introduced in our department as a new treatment modality for prostate cancer patients. HDRBT was performed in a newly built facility, housing contemporary imaging modalities including an MRI scanner dedicated for radiotherapy planning. The purpose of this study was to evaluate the introduction of MRI-based HDRBT, including procedure times, perioperative morbidity, and dose-volume parameters.
Methods and materials
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ileostomia, colostomia, prior pelvic radiotherapy, and comorbidity interfering with anesthesia. External beam radiotherapy Before HDRBT, patients received EBRT 46 Gy in 23 fractions, 5 weekly fractions. EBRT was delivered to the prostate gland and seminal vesicles using volumetric arc therapy technique based on planning CT and MRI. Clinical target volume (CTV)prostate was defined on planning MRI as prostate gland plus extracapsular extension. Planning target volume was generated from the CTVprostate þ CTVvesicles added a margin of 7 mm axially and 9 mm craniocaudally. No elective lymph node irradiation was performed.
Facility Facility includes a patient room, operating room (OR), stepper system (Oncoselect tablemount stepper þ ECRM endocavity rotation mover), MR compatible template (TPS 061 1.5 mm), ultrasound system (Prosius Integrated Ultrasound System þ US transformer Logiscan 128 Model INT-2ZKit þ BiopSee biplanar transrectal ultrasound probe), remote afterloader (Flexitron, Elekta þ Flexisource Ir 191, 370 Bq), treatment planning system (OncentraProstate version 4.2.21, Nucletron), MRI scanner (Ingenia 1.5 T, Philips Healthcare, The Netherlands), PET/CT scanner (Philips Gemini TF Big Bore., The Netherlands), and a treatment delivery room. The patient-related procedures involved four different rooms located in the same building and on the same floor. Training A team of radiotherapists, physicists, radiologists, and nurses was trained to perform MRI-based HDRBT. Training included site visits to two departments with significant experience in MRI and US-guided prostate BT, respectively. The HDRBT procedure was simulated several times using a prostate phantom (CIRS 053A). During the first patient procedures, an HDRBT experienced technician and an urologist were present. Patient selection The study included 42 consecutive D’Amico high-risk prostate cancer patients (11) enrolled in a prospective clinical protocol in which patients were offered combined EBRT þ HDRBT. In December 2014, we changed our procedure to include repeated MRI to assess the stability of the needle implant, and patients from this time on are not included in the study. Inclusion criteria beyond GEC ESTRO guidelines (12, 13) were biopsy-proven prostate adenocarcinoma, Stage T1eT3a, no lymph node metastases on lymph node dissection, negative bone scan, and planned 3 years of luteinizing hormoneereleasing hormone agonist treatment initiated 3 months before radiotherapy. Exclusion criteria were maximal urinary flow !15 mL/s (later changed to !10 mL/s), inflammatory bowel disease,
Patient preparation Patients were instructed to discontinue anticoagulants 3e5 days before the first HDRBT procedure. Blood samples were taken 2e3 days before each HDRBT procedure for analysis of coagulation parameters, hematological parameters, pretransfusion compatibility, and electrolytes. Patients were fasting for at least 6 hours and received bisacodyl 10 mg 2 orally and 2 mg rectally for bowel emptying. Venous thromboembolism prophylaxis included the use of antiembolism stockings during the HDRBT procedure, and subcutaneous dalteparin 5000 IU was administered two times postoperatively with a 12-hour interval. For microbial prophylaxis, a urine sample was examined with a urine test stick 2e3 days before each HDRBT for excluding urinary infection. Patients were advised to shave the perineum and scrotum, and 500-mg ciprofloxacin and 500-mg metronidazole were administered orally 3 hours before the HDRBT procedure. Anesthesia General anesthesia was used for the first 28 patients, but the procedure was changed to spinal anesthesia for subsequent patients. In patient number 31, general anesthesia was used for the second HDRBT due to a severe anaphylactic reaction during the first HDRBT. If general anesthesia was performed, patients received infiltration analgesia of the perineum with 10e12 cm3 of bupivacaine 2.5 mg/cm3. For postoperative pain and nausea, patients received 1-g paracetamol, 20-mg morphinesulphate, and 8-mg ondansetron 3e4 hours before HDRBT. High-dose-rate brachytherapy HDRBT was delivered twice with each procedure separated by 1 week after EBRT. Plastic needles were inserted US guided, but HDRBT dose plans were based on MRI reconstructed needles and MRI defined volumes (CTVprostate, urethra, rectum, and bladder) (Table 1). The tip of each needle was resolved by the resulting signal loss artifact on MRI, and the first available dwell position was defined as
S. Buus et al. / Brachytherapy Table 1 Mean volume (SD) of prostate, urethra, rectum, and bladder (cm3) Volume
EBRT
CTVprostate CTVprostateþ3mm Urethra Rectum Bladder
35.2 d 1.6 67.5 81.3
11.5 0.7 19.0 41.1
1st HDRBT 40.4 59.9 2.4 42.8 109.6
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reduce risk of needle migration. Details of the workflow are provided in Table 3.
2nd HDRBT
13 16.4 0.5 12.1 63.4
44.5 64.0 2.4 45.4 121.9
12.6 16.0 0.5 13.0 61.8
SD 5 standard deviation; EBRT 5 external beam radiotherapy; HDRBT 5 high-dose-rate brachytherapy; CTV 5 clinical target volume.
6 mm below the needle tip. CTVprostateþ3mm was generated by adding an isotropic 3-mm margin to CTVprostate, avoiding bladder and rectum. Dose optimization was performed using the hybrid inverse planning optimization algorithm (OncentraProstate version 4.1.6, Nucletron, ELEKTA Brachytherapy, Veenendaal, The Netherlands) followed by manual corrections of the loading pattern. The initial planning aim for CTVprostateþ3mm D90 was 8.1 Gy, which in 2014 was changed to 8.5 Gy. Planning aims for combined EBRT þ2 HDRBT boosts were calculated in biological equivalent doses (EQD2) assuming an a/b 5 3. Further details are provided in Table 2. Magnetic resonance imaging After needle implant, a transversal T2-weighted turbo spin echo MRI sequence (slice thickness of 2 mm, acquired resolution 1.4 mm 1.76 mm, echo time 5 80 ms, repetition time 5 11,366 ms) was performed. Total scan time amounted to approximately 12 minutes. No endorectal coil was used for the MRI procedure.
Recovery After HDRBT, guide tubes were disconnected, and the plastic needles were removed. After removal, the bladder was irrigated with isotonic saline and the perineum was compressed for 4e5 minutes. The patient was then observed in the ward for median 20.5 hours (range, 15.2e45.8). The bladder catheter was to be removed the day after HDRBT, and the patient could be discharged from the ward after two micturations. Evaluation Time points for initiation of the main parts in the HDRBT were recorded, and the duration for each main step was calculated. Furthermore, the total procedure time was calculated from initiation of anesthesia to end of HDRBT delivery. Dose-volume parameters were retrieved from the dose planning system (Oncentra Prostate, Nucletron). Information of perioperative morbidity was collected from the patient record. COIN was calculated for CTVprostateþ3mm for assessing the conformity of the dose plans (14). Procedure times for the main steps in the workflow and dose-volume parameters from the first 21 patients were compared with last 21 patients using independent samples t-test (SPSS 20). Chi-square test was performed for comparison of pain records for patients receiving general anesthesia and spinal anesthesia.
Workflow
Results
The workflow was divided into four main steps: OR time, MRI procedure time, treatment planning time, and HDRBT delivery time. The patient stayed on the MRI couch after MR imaging and until end of treatment to
Patients were median 68 years of age (range, 52e76), cT1cecT3a, median Gleason score 7 (range, 6e10), and median PSA 20.5 (range, 4.7e63.8). Urinary flow measurements before RT showed a maximal flow of
Table 2 Planning aims and prescribed dose of target and OAR (median, range) HDRBT
EBRT (Gy)
Total course (Gy EQD2)
Volume
Planned
Prescribed
Planned
Prescribed
Planned
Prescribed
CTVprostateþ3mm CTVprostateþ3mm
D90% $ 8.5 Gy D90% $ 8.1 Gy (8.5 Gya) V150% ! 45% V200% ! 20% COIN D2 cm3 ! 75% V100% 5 0% D0.1 cm3 ! 10 Gy D10% ! 115% D30% ! 110% D0.1 cm3 D2 cm3
9.4 Gy (6.4e10) 8.8 Gy (5.6e9.4) 32.4% (20.3e43.3) 11.3% (6.8e19.1) 0.80 (0.39e0.89) 66% (49e76) 0% 9.8 Gy (9.1e11.1) 114% (104e128) 112% (99e128) 9.6 Gy (4.4e16.4) 6.7 Gy (3.5e8.9)
46 Gy 46 Gy d d
46 Gy (46e62) 46 Gy (46e62) d d
$85.1 Gy $81.8 Gy d d
92.4 Gy (80.2e96.6) 87.5 Gy (73.8e91.2) d d
!46 Gy d !46 Gy d d d !46 Gy
45.7 Gy (43.9e61.9) d 45.7 Gy (44.9e61.8) d d d 45.8 Gy (45.5e61.9)
!69.9 Gy d !98 Gy d d d d
65 Gy (58.5e73.9) d 96.8 Gy (85.7e101.5) d d 96.6 (85.5e101.2) 72 (60.1e81.9)
Rectum Urethra
Bladder
OAR 5 organs at risk; EQD2 5 equivalent dose in 2 Gy per fraction; EBRT 5 external beam radiotherapy; HDRBT 5 high-dose-rate brachytherapy; CTV 5 clinical target volume; COIN 5 conformal index. a Planning aim increased to 8.5 Gy in 2014.
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Table 3 HDRBT workflow main and detailed steps I. OR time
II. MRI procedure
III. Treatment planning
IV. HDRBT delivery
1. Anesthesia 2. Patient positioning 3. Disinfection of pelvic region 4. Placement of bladder catheter 5. Surgical drape 6. Placement of rectal tube 7. Stepper system on operating table 8. Insertion of rectal US probe 9. Template on stepper system 10. Two anchor needles in prostate gland 11. 3D US acquisition scan 12. Contouring of CTVprostate, CTVprostateþ3mm, urethra, and rectum 13. Preplanning 14. Plastic needle insertion 15. Label plastic needles with numbers 16. Removal of US probe from rectum 17. Fixation of template to perineum with sutures
18. Transferral of patient from operating table to MR couch on trolley 19. Waiting time 20. Transport of patient to MR scanner 21. MR scana
22. Import of MR images into dose planning system 23. Delineation of CTVprostate, CTVprostateþ3mm, urethra, bladder, and rectum 24. Needle reconstruction on MRI 25. Dose planning 26. Approval of HDRBT dose plan.
27. Export of dose plan to remote afterloading system. 28. Transport of patient into treatment room 29. Connection of guide tubes to needles 30. Treatment delivery.
HDRBT 5 high-dose-rate brachytherapy; OR 5 operating room; US = ultrasound. a During the first 23 HDRBT procedures, patients received a CT scan to support the reconstruction of the tip of the plastic needles. This meant that patients were transferred from the operating table to a bed, transported to the CT couch, and finally to the MRI couch. CT imaging was later abandoned as definition of the needle tip was done satisfactory using MRI.
median 14.5 cm3/s (range, 8.7e38.4), voided volume median 252 cm3 (range, 60e537), and residual urine was median 60 cm3 (range, 0e529). All patients received luteinizing hormoneereleasing hormone agonist, which was initiated median 94 days (range, 60e124 days) before the start of EBRT. Prostate volume estimated from EBRT planning images was median 35 cm3 (range, 16e65). Patient number 11 did not receive the second HDRBT due to a decubitus ulcer developed during the first HDRBT procedure. Instead, the patient received an additional EBRT course of 16 Gy in eight fractions. Workflow Figure 1 shows the mean duration of each main step in the MRI-based HDRBT workflow for the first 21 patients and for the last 21 patients. Total procedure time decreased significantly from average 7.6 1.70 (standard deviation) to 5.3 0.84 hours ( p ! 0.01). OR time decreased significant from average 3.6 0.82 to 2.4 0.33 hours ( p ! 0.01), the MRI procedure time decreased significantly from average 1.6 0.55 to 0.8 0.28 hours ( p ! 0.01), treatment planning time decreased significantly from average 2.0 0.74 to 1.5 0.1 hours ( p ! 0.01), and HDRBT delivery time did not change with average 0.4 0.2 vs. 0.5 0.38 hours ( p 5 0.07). Figure 2 shows in more details the total procedure time, OR time, MRI procedure time, and treatment planning
time. In procedure 33, treatment planning time (Fig. 2d) was calculated to take 0.3 hours and MRI procedure time 2.0 hours, which may be a consequence of an error in the time recording of the MRI. Needles The number of needles per procedure was median 18 (range, 13e24). The number of needles per procedure increased from average 17.5 to 18.5 from the first 21 patients to the last 21 patients ( p 5 0.04). CTVprostateþ3mm per needle was median 3.4 cm3 (range, 1.5e5.5), and it increased from average 3.1 0.6 to 3.7 0.7 cm3 per needle from the first 21 patients to the last 21 patients ( p ! 0.01). CTVprostateþ3mm was median 63.3 cm3 (range, 25.6e98.9), and it increased First 21 paƟents
Last 21 paƟents
0
2
Operating room time MRI procedure time Treatment planning time HDR BT delivery time 4
6
8
Time (hours)
Fig. 1. Bars show the mean duration of each main step in workflow. Top bar shows results for the first 21 patients and bottom bar the last 21 patients. HDRBT 5 high-dose-rate brachytherapy.
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8 6 4 st
1 HDRBT 2nd HDRBT
2
OR Ɵme
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DuraƟon (hours)
DuraƟon (hours)
(2016)
b Total procedure Ɵme
10
1st HDRBT 2nd HDRBT
8 6 4 2
0
0 0
c
20 40 60 Number of procedures
d
6 4 2
20 40 60 Number of procedures
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Treatment planning Ɵme
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1st HDRBT 2nd HDRBT
DuraƟon (hours)
1st HDRBT 2nd HDRBT
8
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MRI procedure Ɵme
10
DuraƟon (hours)
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80
6 4 2
0
0 0
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0
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Fig. 2. Panels show the number of each procedure plotted against the total procedure time (a), operation room time (b), MRI procedure time (c), and treatment planning time (d). Filled circles represent the first HDRBT and open circles the second HDRBT.
from average 53.6 13.7 to 69.3 15.7 cm3 from the first 21 to the last 21 patients ( p ! 0.01). Target dose CTVprostateþ3mm D90 fulfilled planning aim in 76 of 83 procedures (Fig. 3). Postimplant US and MRI were examined for the seven procedures that did not fulfill our planning aim. Insufficient coverage was caused by suboptimal catheter implant in five procedures and catheter migration in two procedures. CTVprostateþ3mm D90 coverage increased significantly from average 8.3 0.71 to 9.0 0.24 Gy from the first 21 to the last 21 patients ( p ! 0.01) and tended to increase from first to the second HDRBT. CTVprostate D90 fulfilled planning aim in 78 of 83 procedures and increased significantly ( p ! 0.01) from the first 21 to the last 21 patients. Conformity of the dose plans evaluated by COIN was median 0.80 (0.39e0.89) for CTVprostateþ3mm and increased significantly from average 0.76 0.07 to 0.81 0.04 from the first 21 to the last 21 patients ( p ! 0.01). Heterogeneity of the dose plans evaluated by
V150% and V200% was median 32.4% (range, 20.3e43.3) and 11.3% (range, 6.8e19.1), respectively. V150% remained unchanged from the first to last 21 patients with an average of 32.4 4.64 vs. 32.2 4.28%, whereas V200% decreased significantly ( p 5 0.04) from average 11.8 0.38 to 10.8 0.27%. For the whole RT course including EBRT þ2 HDRBT, the planning aim for CTVprostate D90 (85.1 Gy EQD2) was fulfilled in 39 of 42 patients, and the planning aim for CTVprostateþ3mm D90 (81.7 Gy EQD2) was fulfilled in 36 of 42 patients. Overall treatment time was median 42 days (range, 40e52 days).
Normal tissue Urethral D0.1 cm3 fulfilled planning aim (#10 Gy) in 65 of 83 procedures, and it did not change significantly ( p 5 0.92) from the first to last 21 patients. Rectal dose D2 cm3 fulfilled planning aim (!6.4 Gy) in 79 of 83 procedures, and it did not change significantly ( p 5 0.12) from the first to last 21 patients (Fig. 4).
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anesthesia chi-square, p 5 0.82. Other reported side effects were constipation (nine procedures), urge incontinence (six procedures), syncope (three procedures), suspected urethral lesion (two procedures), Quincke’s odema (one procedure), and decubitus ulcer (one procedure). For the latter patient, OR time and total procedure time were 5.4 and 9.1 hours, respectively.
10
CTV-P + 3mm D90 (Gy)
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Discussion
5 4 0
20
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Number of procedures Fig. 3. Prescribed D90 for CTVprostateþ3mm for each HDRBT plotted against the number of HDRBT procedures performed. Closed circles represent the first HDRBT and open circles the second HDRBT. Dotted line represents our initial planning aim of 8.1 Gy and the dashed line our current planning aim of 8.5 Gy. CTV 5 clinical target volume; HDRBT 5 highdose-rate brachytherapy.
Perioperative morbidity
11
7
10
6
Rectal D2cc (Gy)
Urethral D0.1cc (Gy)
Hematuria was observed after 79 procedures. Blood clotting was observed in urine in 49 of 83 procedures, and blood clotting resulted in urinary retention in six procedures. Hematoma of perineum/scrotum was observed in 63 of 79 procedures (data missing in four procedures). Decrease of hemoglobin levels after the first HDRBT procedure was median 0.3 mmol/L (0.3, 1.7 mmol/L). The patient, who experienced a decrease of 1.7 mmol/L, received a blood transfusion. No infections were observed within 2 weeks after the last HDRBT. Minor or no pain was reported in 53 of 82 procedures (data missing in one procedure) and moderate-to-strong pain in 29 of 82 procedures. No difference in frequency of pain was found between patients receiving either general or spinal
In the present study, we demonstrated that an MRIbased HDRBT procedure can be successfully introduced into a radiotherapy department, which did not have experience with prostate BT. Proper training was initiated before the first patient treatment, and specific equipment was acquired with the criteria of full MRI compatibility. Significant improvements in terms of target coverage and reduced procedure times were seen from the first 21 to the last 21 patients, suggesting that about 40 HDRBT procedures are needed for performing an optimal HDRBT. OR time and total procedure time were significantly reduced during the observed period, indicating that more experience and small changes in the workflow can significantly reduce the procedure time. Menard et al. (15) found a similar reduction in the procedure time, when they initiated an MRI-guided technique for needle insertion. Changing the standard anesthetic procedure to spinal anesthesia from patient 29 and onward did not seem to influence procedure times or dosimetric parameters, as these had reached a steady level before the change. OR time is similar to the time spent in the OR, and with 2.4 hours in the OR, it is possible to perform two HDRBT procedures within a normal working day with a single OR. Further reductions in the OR time may be possible, as Tselis et al. (16) reported using in average 100 minutes for patient positioning, preplanning, and needle insertion. MRI procedure time was
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80
Number of procedures
Fig. 4. Prescribed urethral D0.1 cm3 (left panel) and rectal D2 cm3 (right pannel) for each HDRBT plotted against the number of the procedure. Closed circles represent the first HDRBT and open circles the second HDRBT. Dashed lines represent constraints for urethral and rectal dose. HDRBT 5 high-dose-rate brachytherapy.
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Fig. 5. Postimplant images of the prostate gland for patient number 42, second HDRBT. Top panels are at the midaxial and bottom panels at the midsagittal plane of the prostate. Left panels show the TRUS images and right panels T2-weighted MRI. HDRBT 5 high-dose-rate brachytherapy; TRUS 5 transrectal ultrasound.
in average 1.1 hours, which may seem much, but besides the actual scan time, it includes transferral of patient from operating table to MRI couch on trolley, waiting time, and transport of patient to MRI scanner. Time used for MRI may be compensated for by improved delineation of targets, OAR, and needles (Fig. 5). Initially, we focused at reducing the OR time and the total procedure time to minimize patient discomfort. Now focus has changed toward reducing time from MRI to treatment delivery, due to the risk of needle migration, which may adversely impact an otherwise optimal HDRBT (17). The average number of needles used for each HDRBT procedure increased from 17.5 to 18.5 from the first 21 to the last 21 patients, which is surprising. However, CTVprostateþ3mm and CTVprostateþ3mm per needle also increased, indicating that needles over time were placed more optimally. Fewer needles per implant may be achievable as other groups with more experience in prostate cancer HDRBT report using a median of 16 needles (17, 18). In the present study, all patients received $80.2 Gy EQD2 to the CTVprostate. This is significantly higher than
the commonly used EBRT schedule of 78 Gy in 39 fractions where a typical planning aim is D100 of 74.1 Gy (95% of 78 Gy) to CTVprostate. In fact, 39 of 42 patients received a biologically equivalent dose $85.1 Gy to CTVprostate, and 36 of 42 patients received a biologically equivalent dose $81.7 Gy to CTVprostateþ3mm. Previous studies have demonstrated the importance of a high CTVprostate D90 in prostate cancer BT to minimize the risk of biochemical relapse (19, 20). Experience plays a significant role for achieving an optimal target coverage in prostate BT (20), but technology advances like improved imaging techniques (Fig. 5) may be helpful for a successful introduction of prostate BT (21). A strategy of two separate HDRBT procedures in combination with EBRT seems robust when initiating HDRBT, which may be preferable to a strategy with single fraction BT monotherapy. A suboptimal needle implant in one HDRBT procedure may be compensated for in the following procedure reducing the risk of a patient receiving an inferior radiotherapy course. Urethral D 0.1 cm3 constraint !10 Gy was violated in 18 of 83 procedures and median D 0.1 cm3 of 9.8 Gy close to the
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urethra constraint, which indicates difficulties in keeping a low urethral dose, while reaching the CTV planning aim. Rectal dose constraint !6.4 Gy was violated in only in five procedures, and the median D2 cm3 was 5.6 Gyda difference of 0.8 Gy indicates that a lower and more ambitious rectal dose constraint could be considered to further minimize rectal dose. One of the major advantages of HDRBT is the low frequency of gastrointestinal toxicity (22, 23). The rectal sparing ability of HDRBT is superior to other treatment modalities due to the steep BT dose gradient (4). MRIbased HDRBT may further improve this with a more accurate delineation of OARs. Furthermore, treating the patient after removal of the rectal ultrasound probe may also result in less rectal toxicity due to a larger distance between the rectum and prostate (24). Hematuria occurred after most our HDRBT procedures, which may be more frequent from that experienced by other groups working with prostate BT (15, 25). This may be explained by our procedure, where the needle tip was placed in the bladder 15e20 mm cranially prostate base to stabilize the implant. Repositioning the patient from lithotomy to supine position before MRI may cause significant needle migration. Other groups treating the patient in lithotomy position place the needle tip just below the bladder (15, 26). No infections and no thromboembolic events were observed indicating a good antimicrobial and venous thromboembolism prophylaxis. Pain was a frequent complication, which seemed to decrease with the change from general anesthesia to spinal anesthesia. However, the difference was not apparent when comparing pain records for patients receiving either spinal or general anesthesia. Transrectal ultrasoundebased HDRBT has shown excellent long-term outcomes (27, 28) questioning the relevance of an MRI-based HDRBT procedure. Further improvements in outcome may be achieved by escalating the dose to the prostate gland as indicated by recent results from the ASCENDE-RT trial that demonstrated a significant benefit in relapse-free survival from escalating the dose with a low-dose-rate boost in intermediate- and high-risk prostate cancer (29). However, dose escalation resulted in a substantial increase in the risk of Grade 3 genitourinary toxicity. These results emphasize the need for state of the art imaging for improved definition of target, OAR, and needles in HDRBT, which may be provided by MRI.
Conclusion After introduction of MRI-based HDRBT, total procedure time (5.3 hours), OR time (2.4 hours), MRI procedure time (0.8 hours), and treatment planning time (1.3 hours) were significantly reduced. CTVprostateþ3mm fulfilled institutional constraints in most patients and improved over time, but not at the expense of an increased urethral or rectal dose.
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References [1] Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109:22e29. [2] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103:217e222. [3] Deutsch I, Zelefsky MJ, Zhang Z, et al. Comparison of PSA relapsefree survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT. Brachytherapy 2010; 9:313e318. [4] Georg D, Hopfgartner J, Gora J, et al. Dosimetric considerations to determine the optimal technique for localized prostate cancer among external photon, proton, or carbon-ion therapy and high-dose-rate or low-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2014;88: 715e722. [5] Poortmans PM, Aarts MJ, Jobsen JJ, et al. A population-based study on the utilisation rate of primary radiotherapy for prostate cancer in 4 regions in the Netherlands, 1997-2008. Radiother Oncol 2011;99: 207e213. [6] Guedea F, Torrecilla JL, Londres B, et al. Patterns of care for brachytherapy in Europe: updated results for Spain. Clin Transl Oncol 2012; 14:36e42. [7] Holm HH, Juul N, Pedersen JF, et al. Transperineal 125iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130:183e286. [8] Bloch BN, Furman-Haran E, Helbich TH, et al. Prostate cancer: accurate determination of extracapsular extension with high-spatialresolution dynamic contrast-enhanced and T2-weighted MR imagingeinitial results. Radiology 2007;245:176e185. [9] Tanderup K, Viswanathan AN, Kirisits C, et al. Magnetic resonance image guided brachytherapy. Semin Radiat Oncol 2014;24:181e191. [10] Albert JM, Swanson DA, Pugh TJ, et al. Magnetic resonance imaging-based treatment planning for prostate brachytherapy. Brachytherapy 2013;12:30e37. [11] D’Amico a V, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969e974. [12] Kovacs G, P€otter R, Loch T, et al. GEC/ESTRO-EAU recommendations on temporary brachytherapy using stepping sources for localised prostate cancer. Radiother Oncol 2005;74:137e148. [13] 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;107:325e332. [14] Baltas D, Kolotas C, Geramani K, et al. A conformal index (COIN) to evaluate implant quality and dose specification in brachytherapy. Int J Radiat Oncol Biol Phys 1998;40:515e524. [15] Menard C, Susil RC, Choyke P, et al. MRI-guided HDR prostate brachytherapy in standard 1.5T scanner. Int J Radiat Oncol Biol Phys 2004;59:1414e1423. [16] Tselis N, Maurer U, Popp W, et al. Evaluation of time, attendance of medical staff, and resources during interstitial brachytherapy for prostate cancer: DEGRO-QUIRO trial. Strahlenther Onkol 2014; 190:358e363. [17] Hoskin PJ, Bownes PJ, Ostler P, et al. High dose rate afterloading brachytherapy for prostate cancer: catheter and gland movement between fractions. Radiother Oncol 2003;68:285e288. [18] Batchelar D, Gazta M, Schmid M, et al. Validation study of ultrasound-based high-dose-rate prostate brachytherapy planning compared with CT-based planning. Brachytherapy 2014;13:75e79. [19] Hoskin PJ, Rojas AM, Ostler PJ, et al. Dosimetric predictors of biochemical control of prostate cancer in patients randomised to
S. Buus et al. / Brachytherapy
[20]
[21]
[22]
[23]
[24]
external beam radiotherapy with a boost of high dose rate brachytherapy. Radiother Oncol 2014;110:110e113. Henry AM, Al-Qaisieh B, Gould K, et al. Outcomes following iodine-125 monotherapy for localized prostate cancer: the results of leeds 10-year single-center brachytherapy experience. Int J Radiat Oncol Biol Phys 2010;76:50e56. Beaulieu L, Evans DA, Aubin S, et al. Bypassing the learning curve in permanent seed implants using state-of-the-art technology. Int J Radiat Oncol Biol Phys 2007;67:71e77. 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: 1376e1384. Ghadjar P, Oesch SL, Rentsch CA, et al. Late toxicity and five year outcomes after high-dose-rate brachytherapy as a monotherapy for localized prostate cancer. Radiat Oncol 2014; 9:122. Rylander S, Buus S, Bentzen L, et al. The influence of a rectal ultrasound probe on the separation between prostate and rectum in highdose-rate brachytherapy. Brachytherapy 2015;14:711e717.
-
(2016)
-
9
[25] Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial. Int J Radiat Oncol Biol Phys 2000;48:675e681. [26] Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading 192Iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998;41:525e533. [27] 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. [28] Sylvester JE, Grimm PD, Wong J, et al. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011; 81:376e381. [29] Morris WJ, Tyldesley S, Pai H, et al. Low-dose-rate brachytherapy is superior to dose-escalated EBRT for unfavourable risk prostate cancer: the results of the ASCENDE-RT* Randomized control trial. Brachytherapy 2015;14:S12.