- Email: [email protected]
Performance of a palladium-103 line source for prostate brachytherapy implants: A Phase I trial
Brachytherapy
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(2017)
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Performance of a palladium-103 line source for prostate brachytherapy implants: A Phase I trial Richard Stock1,*, David Beyer2, Jed Kaminetsky3, William Ge4 2
1 Radiation Oncology, Mount Sinai Hospital, New York City, NY Radiation Oncology, Cancer Centers of Northern Arizona Healthcare, Sedona, AZ 3 Manhattan Medical Research, New York City, NY 4 Ascenture MPTR, PLLC, New York City, NY
ABSTRACT
PURPOSE: To evaluate the use of a polymer-encapsulated palladium-103 (103 Pd) source with a unique linear radioactive distribution in prostate brachytherapy. This feasibility study assessed dosimetry, ease and efficiency of use, and side effects. The number of needles required for adequate coverage was the primary end point. METHODS AND MATERIALS: CivaString 103 Pd Model CS10 implants were preplanned for 25 patients. CivaStrings were custom manufactured according to plan. CivaStrings were implanted with 18 gauge needles. Post-implant dosimetry was performed at 3-6 weeks. RESULTS: Monotherapy (125 Gy) was prescribed for 11 implants. External beam radiation with CivaString boost (100 Gy) was prescribed for 14 implants. The mean time to implant the sources was 23.5 min. The number of planned needles and prostate sizes ranged from 14 to 25 and 21-101 cm3, respectively. 70% of implants in prostates less than 50 cm3 required #17 needles. Planned source strength ranged from 2.8 U/cm to 3.9 U/cm. Total source strength averaged 216 U (130323 U) for monotherapy and 154 U (92.4-245 U) for boost. Nomograms were generated at both prescription dose levels. CONCLUSIONS: The linear 103Pd source provides good dose coverage to the prostate. Prostate volume changes were minimal suggesting minimal swelling using the CivaString device. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
CivaString;
103
Pd; Brachytherapy; Prostate; LDR; Dosimetry
Introduction Interstitial brachytherapy (BT) has been established as a reliable treatment for early-stage prostate cancer (1). The long-term data demonstrate that BT is an effective treatment option with an acceptable side effect profile. Urinary incontinence, retention, proctitis, and erectile dysfunction are the most problematic complications for radiation treatments. The CivaString was designed to
Received 14 December 2016; received in revised form 19 May 2017; accepted 19 May 2017. Conflict of interest: Drs. Kaminetsky and Beyer received compensation from CivaTech Oncology for the administration and enrollment of patients in this trial. Dr. Stock and Dr. Ge have received consulting fees from CivaTech Oncology. * Corresponding author. Radiation Oncology, Mount Sinai Hospital, 1184 5th Avenue, New York, NY 10029. Tel.: 212 241 7503; fax: 212 410 7194. E-mail address: [email protected] (R. Stock).
reduce the side effects caused by traditional radioactive seeds by providing a more uniform dose distribution (Figs. 1 and 2) and using fewer strands (2). In addition, the goal of using the CivaString was to minimize the number of needles and hence the trauma that can lead to swelling and bleeding. The current paradigm in low-dose-rate (LDR) BT relies on loose or stranded isotope seeds whose dosimetry is characterized as point sources. These seeds have nonuniformities in the dose distribution at their ends. The CivaString, a palladium-103 (103Pd) source encapsulated in polymer, was developed as a refinement of the present seed technology (Fig. 1). The CivaString, Model CS10, is a line source with the 103Pd distributed along the length of the source. These line sources do not have nonuniformities at the end because they are polymer encapsulated. Each source is 1.0 cm long and 0.8 mm thick. In the middle of each segment, a gold marker provides enhanced visibility on imaging and landmarks for distal needle placement.
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.05.008
2
R. Stock et al. / Brachytherapy
Fig. 1. The CivaString 103Pd Model CS10. Each source is 1.0 cm long and 0.8 mm thick. In the middle of each segment, a gold marker provides enhanced visibility on imaging. 103Pd 5 palladium-103.
CivaStrings can be ordered in lengths from 1 to 6 cm with or without 1 cm polymer spacer units. The CivaStrings can easily be identified postimplant on CT imaging due to the gold markers. Preclinical experience suggests that these attributes provide for more accurate dosimetry planning, reduce procedure time, and result in less trauma (3). To evaluate a polymer-encapsulated 103Pd source with a unique linear radioactive distribution, a Phase I trial was initiated. The purpose of this study was to use CivaString in the BT management of low- and intermediate-risk prostate cancer and to collect data on the actual number of needles, the stability of the implant, and the homogeneity of the dose delivered. The results of the study were also compared with other LDR BT products and their published outcomes.
Methods and materials Twenty-eight patients with low- and intermediate-risk prostate cancer were screened at two centers with institutional review board approval. Patients were consented with institutional review boardeapproved informed consent form. The study was designed as a Phase I trial. Exclusion criteria were as follows: prostate-specific antigen O20 ng/ mL or Gleason score O7, severe urinary irritative/obstructive symptomatology (at discretion of treating physician), extensive transurethral resection of prostate defect (at discretion of treating physician), substantial median lobe
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hyperplasia (at discretion of treating physician), prostate dimensions that were larger than the implant grid, severe pubic arch interference, gross seminal vesicle involvement on staging workup, prior pelvic radiation therapy, inflammatory bowel disease, pelvic lymph node involvement, distant metastases, or life expectancy ! 5 years. Implantation was performed in 25 subjects using 18 gauge needles preloaded with the custom-ordered 103Pd CivaStrings. An independent organization, Tab Clinical (Cary, NC), collected the data and monitored the sites. Investigators and teams were experienced in LDR BT implants. Preimplant data collection included subject characteristics, medical history, biopsy results, laboratory, and subjectadministered quality of life questionnaires. Subjects were not excluded from the study based on preimplant urinary, rectal, or erectile function scores. Subjects underwent standard initial planning imaging (MRI, CT, or transrectal ultrasound). Implants were preplanned using the CivaString 103Pd Model CS10 and VariSeed or BrachyVision treatment planning software. The planned prescription dose was 125 Gy for monotherapy and 100 Gy for boost when combined with external beam radiation therapy. In combination therapy, the implant was done first, and the external beam was delivered 6 weeks postimplant to a dose of 45 Gy in 25 fractions. External beam was given to the prostate and seminal vesicles using intensity modulated radiation therapy and image guided radiation therapy with cone beam imaging. The CivaStrings were delivered with ultrasound and template guidance in the same manner as stranded BT seeds currently on the market. The first implanted subject at each site had an additional CT scan immediately after the implant. The preimplant plan including the number of strands, total source strength, and isodose distribution was reported by the investigators. Postimplant dosimetry was performed based on CT images obtained at 3e6 weeks. Copies of these plans were also submitted for analysis. Movement of the CivaStrings, dose homogeneity of the plan, and postimplant prostate size was reported in addition to the standard dosimetry parameters.
Results Subject and prostate cancer characteristics
Fig. 2. Isodose distribution (at 100%, 150%, and 200% of prescription) is shown for two adjacent line sources compared with identically spaced seeds. Source strength is held constant with 4 U/cm for line sources and 2 U/seed with sources placed end to end. Note that due to differences in anisotropy, the dose between line sources is higher and thus greater spacing could be used without compromising the prescription isodose.
The average age of the study population was 68 years (range, 48e88). A broad range of prostate sizes from 20 cm3 to 100 cm3 were implanted, with mean and median values of 43.5 cm3 and 40.4 cm3. The mean and median initial prostate-specific antigens were 6.07 ng/mL and 5.5 ng/mL (range, 1.6e14.3 ng/mL). The tumor characteristics are detailed in Table 1. In 4 cases, the subject had a transurethral resection of prostate before enrollment.
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R. Stock et al. / Brachytherapy Table 1 Tumor characteristics n
%
18 6 1
73 23 4
18 7
73 27
8 14 3
35 54 12
Preplanning was performed for all subjects. A median of 17 needles (range, 14e25) were preplanned to be used to achieve appropriate distribution of the linear sources in the prostate (Fig. 3a). Thirteen of 25 cases required 17 or fewer needles. All planned sources were implanted in all subjects. Of the 25 total subjects, 11 were prescribed monotherapy with a dose of 125 Gy, and 14 were prescribed boost CivaString implants with a dose of 100 Gy followed by external beam radiation therapy. All subjects completed radiation therapy. As expected, the total source strength implanted scaled linearly with prostate size, and monotherapy implants involved greater implanted source strength per size than boost implants (Fig. 3b). The source strength per centimeter of source was nominally 3.8 U/cm for monotherapy and 3.2 U/cm for boost (Fig. 3c). The number of sources and total source strength increased with increasing prostate size. From
Time to plan and implant CivaString The overall time needed to preplan the implants ranged from 14 to 120 min (mean, 54.5 [SD, 38]). The actual time needed to perform the implant, from insertion of the first needle to completion of implant, ranged from 14 to 45 min (mean, 23.5 [SD, 8.35]). The time needed to
350
b
24
Total Source Strength (U)
Number of Needles Planned (#)
3
Planning and dosimetry
PSA 5 prostate-specific antigen.
22 20 18 16 14 12
300 y = 4.07x + 17.21 250 y = 3.26x + 13.76
200 150 100 50 0
10 0
20
40
60
80
Prostate Size (cm3)
0
100 120 125 Gy 100 Gy
Percent Change in Prostate Volume (%)
3.9 3.7 3.5 3.3 3.1 2.9 2.7 2.5 0
20
40
60
80
Prostate Size (cm3)
100
120
20
40
60
80
100
120
Prostate Size (cm3)
d
c Source Strength per source (U/cm)
-
complete the postimplant CT dosimetry ranged from 45 to 90 min (mean, 46.7 [SD, 8.83]).
T stage T1ceT2a T2beT2c T3a Gleason score 6 7 Initial PSA (ng/mL) 0e5 5e10 10e20
a
(2017)
40% 30% 20% 10% 0% -10% -20% 0
20
40
60
80
100
120
Prostate Volume Prior to Implant (cm3)
Fig. 3. (a) The number of planned needles and prostate sizes ranged from 14 to 25 and 21 to 101 cm3, respectively. (b) For monotherapy (black), the total source strength ranged from 129.5 to 261.8 U; for boost (gray), source strength ranged from 92.4 to 244.8 U. The lines of fit represent the curves derived for the nomogram for monotherapy (black) and boost (gray). (c) For monotherapy (black), the air kerma strength per cm ranged from 3.4 to 3.85 U/cm; for boost (gray), air kerma strength per cm ranged from 2.8 to 3.4 U/cm (d) The percent change in prostate volume calculation (postimplant/preplan) for all patients.
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R. Stock et al. / Brachytherapy
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(2017)
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Table 2 Planning and postoperative dosimetric parameter median (range) values for subject-prescribed 125 Gy monotherapy and 100 Gy combined therapy 125 Gy (n 5 11)
100 Gy (n 5 14)
Parameter
Preoperative
Postoperative
Preoperative
Postoperative
Prostate size (cm3) D90% D100% V150% V100% Urethral V150%a (cm3) Urethral D30%a Rectal V100% (cm3) Bladder V100% (cm3)
39.7 125.0% 65.0% 69.4% 98.4%
36.9 103.2% 46.6% 67.1% 90.9% 0.09 143.4% 0.06 0.01
44.8 127.9% 63.0% 77.8% 97.9%
43.5 103.9% 43.8% 73.5% 91.3% 0.12 167.3% 0.02 0.03
a
(22.43e100.6) (117.9e133.7) (40.1e86.5) (61.8e81.2) (95.5e99.8)
(22.35e82.94) (81.0e120.5) (34.0e67.9) (37.5e72.4) (74.2e97.0) (0e0.16) (121.9e160.5) (01e0.47) (0e0.64)
(20.6e71.9) (115.6e131.4) (44.3e73.4) (72.2e80.5) (95.0e99.4)
(20.8e68.5) (93.8e128.7) (30.0e74.2) (56.9e84.1) (87.8e97.3) (0e0.52) (122.4e273.7) (0e1.34) (0e0.39)
Data only available for 5 of 11 subjects.
this information, a nomogram was developed to facilitate future patient planning. The nomogram can be summarized by the following equations. Monotherapy 5 4:07 volume cm3 þ 17:21 Boost 5 3:26 volume cm3 þ 13:76 Postimplant dosimetry was performed based on CT images obtained at 3e6 weeks postimplant. The results are reported in percentages to account for differences between monotherapy and boost prescription doses (Table 2). Planning was consistent between centers with mean D90 and V150 values of 125% and 67% (Site 1) and 126% and 77% (Site 2). For a dose of 125 Gy, the postimplant D90 ranged from 81% to 121% (average, 104%). For a dose of 100 Gy, the postimplant D90 ranged from 94% to 129% (average 107%). An example of a typical isodose distribution for the CivaString implant can be found in
Fig. 4. The ratio of postimplant/preplan prostate volume ranged from 0.82 to 1.37 (average 0.97) (Fig. 3d). Fixity In 2 patients, CT scans were taken on the day of the procedure as well at 1 month postimplant. In those patients, there was no evidence of string movement between the Day 0 and Day 30 scans. Figure 5 demonstrates the fixity of the CivaString in one of the patients. At 3e6 weeks postimplant, movement was reported in one subject. One subject (4%) required cystoscopy to retrieve a string from the bladder. The confirmed movement was identified a week after implant, the string was safely removed with a routine cystoscopy, and no additional clinical sequela was reported at the closure of the study. Implant procedure side effects There was one complaint of mild perineal bruising which resolved without any intervention in 4 weeks. There
Fig. 4. 200% (blue), 150% (green), and 100% (magenta) isodose lines for selected subject. The dose is distributed homogeneously through the prostate (aqua). CivaString sources have been placed to provide appropriate dose sparing to the urethra while maintaining excellent dose coverage to the surrounding prostate. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
R. Stock et al. / Brachytherapy
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(2017)
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5
Fig. 5. Comparison of the location of the sources on day of implant (left column) to 30 days postimplant (right column). Sources appear as white spots in the prostate gland. Note the location of the sources with respect to the bony anatomy does not change between the day of implant and 30 days postimplant.
were no reports of persistent hematuria, hematoma, scrotal hematoma or swelling, or postprocedure discomfort. Discussion The CivaString implants were practical in terms of time needed for preplanning, execution, and postplanning. The mean time to perform the implant was 23.5 minu, which compares favorably to other techniques. The median number of needles planned and implanted was 17 compared with the 20e23 needles reported in studies with similar population using a preplanning technique (4, 5). In prostates !50 cm3, 70% of the cases required 17 or fewer needles. The CivaString study data reveal a 4% dislodgement rate which demonstrates superior device stability compared with loose and stranded seed BT. In the prospective randomized trial reported by Reed et al. (6), dosimetric parameters and seed loss were compared between stranded and loose iodine-125 seeds. Based on 0 and 30-day imaging (X-ray, CT, and MRI), 47% of subjects with loose seeds and 23% of subjects with stranded seeds experienced seed loss. In another report by Nag et al. (7), a small population of 32 subjects was implanted with loose 103Pd seeds. Seed migration to the lung was reported in 20% of subjects, and 9% experienced voiding of seeds. The linear source design of the CivaString has a higher fixity rate than loose seeds based on these reports. There was only one complaint of mild bruising which resolved without any intervention in 4 weeks. The lack of bleeding, hematoma, swelling, and postprocedure discomfort reported compares favorably to other BT studies in the literature (8, 9).
The small changes in the prostate size as seen in Fig. 3d reflect the relative lack of prostate swelling because of the procedure. Prostate volume changes from preimplant to postimplant dosimetry have a demonstrated effect on dosimetry (10, 11). The small changes measured in these patients contribute to the excellent dosimetry. In addition, the reported movement of the CivaString is lower than with other sources. BT source fixity is highly associated with good dosimetric outcomes (11e15). This, in turn, reflects the relative ease of insertion of the product, the low number of needles placed, and the expertise of the brachytherapists involved.
Conclusions Excellent quality implants across a range of gland sizes were accomplished. Prostate volume changes were minimal suggesting minimal swelling using the CivaString needles and strands. The product is robust with minimal movement (4%) evidenced by CT. Good dosimetry is achieved with both the preplans and the postplans. Using a line source, the number of needles required to deliver the radiation therapy is less than that reported with standard preloaded or stranded BT products. This study demonstrates that the CivaString product can be safely and effectively integrated into the LDR BT management of prostate cancers.
Acknowledgment This trial was funded by a grant from CivaTech Oncology.
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R. Stock et al. / Brachytherapy
References [1] Davis BJ, Horwitz EM, Lee WR, et al. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 2012;11:6e19. [2] Rivard MJ, Reed JL, DeWerd LA. 103Pd Strings: Monte Carlo assessment of a new approach to brachytherapy source design. Med Phys 2014;41:011716. [3] Reed JL, Rivard MJ, Micka JA, et al. Experimental and Monte Carlo dosimetric characterization of a 1 cm 103Pd brachytherapy source. Brachytherapy 2014;13:657e667. [4] Merrick GS, Butler WM, Wallner KE, et al. Variability of prostate brachytherapy preimplant dosimetry: A multi-institutional analysis. Brachytherapy 2005;4:241e251. [5] Birckhead BJ, Fossum CC, Deufel CL, et al. Stranded seed displacement, migration, and loss after permanent prostate brachytherapy as estimated by Day 0 fluoroscopy and 4-month postimplant pelvic xray. Brachytherapy 2016;3:714e721. [6] Reed DR, Wallner KE, Merrick GS, et al. A prospective randomized comparison of stranded vs. loose I-125 seeds for prostate brachytherapy. Brachytherapy 2007;6:129e134. [7] Nag S, Scaperoth DD, Badalament R, et al. Transperineal palladium 103 prostate brachytherapy: Analysis of morbidity and seed migration. Urology 1995;45:87e92. [8] Stock R, Stone N. Complications following prostate brachytherapy. Eur Urol 2002;41:427e433.
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[9] Sylvester J, Grimm P, Naidoo D, et al. First report on the use of a thinner 125I radioactive seed within 20-gauge needles for permanent radioactive seed prostate brachytherapy: Evaluation of postimplant dosimetry and acute toxicity. Brachytherapy 2013;12:375e381. [10] Crook J, McLean M, Yeung I, et al. MRI-CT fusion to assess post brachytherapy prostate volume and the effects of prolonged edema on dosimetry following transperineal interstitial permanent prostate brachytherapy. Brachytherapy 2004;3:55e60. [11] Pinkawa M, Asadpour B, Gagel B, et al. Evaluation of source displacement and dose-volume change after permanent prostate brachytherapy with stranded seeds. Radiother Oncol 2007;84:190e 196. [12] Moerland MA, van Deursen MJ, Elias SG, et al. Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: Comparison between loose and stranded seed plants. Radiother Oncol 2009;91:202e206. [13] Sugawara A, Nakashima J, Kunieda E, et al. Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose I-125 seeds. Radiat Oncol 2011; 6:1. [14] Fuller DB, Koziol JA, Feng AC. Prostate brachytherapy seed migration and dosimetry: Analysis of stranded sources and other potential predictive factors. Brachytherapy 2004;3:10e19. [15] Wang Y, Nasser NJ, Borg J, et al. Evaluation of the dosimetric impact of loss and displacement of seeds in prostate low-dose-rate brachytherapy. J Contemp Brachytherapy 2015;7:203e210.
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Performance of a palladium-103 line source for prostate brachytherapy implants: A Phase I trial Richard Stock1,*, David Beyer2, Jed Kaminetsky3, William Ge4 2
1 Radiation Oncology, Mount Sinai Hospital, New York City, NY Radiation Oncology, Cancer Centers of Northern Arizona Healthcare, Sedona, AZ 3 Manhattan Medical Research, New York City, NY 4 Ascenture MPTR, PLLC, New York City, NY
ABSTRACT
PURPOSE: To evaluate the use of a polymer-encapsulated palladium-103 (103 Pd) source with a unique linear radioactive distribution in prostate brachytherapy. This feasibility study assessed dosimetry, ease and efficiency of use, and side effects. The number of needles required for adequate coverage was the primary end point. METHODS AND MATERIALS: CivaString 103 Pd Model CS10 implants were preplanned for 25 patients. CivaStrings were custom manufactured according to plan. CivaStrings were implanted with 18 gauge needles. Post-implant dosimetry was performed at 3-6 weeks. RESULTS: Monotherapy (125 Gy) was prescribed for 11 implants. External beam radiation with CivaString boost (100 Gy) was prescribed for 14 implants. The mean time to implant the sources was 23.5 min. The number of planned needles and prostate sizes ranged from 14 to 25 and 21-101 cm3, respectively. 70% of implants in prostates less than 50 cm3 required #17 needles. Planned source strength ranged from 2.8 U/cm to 3.9 U/cm. Total source strength averaged 216 U (130323 U) for monotherapy and 154 U (92.4-245 U) for boost. Nomograms were generated at both prescription dose levels. CONCLUSIONS: The linear 103Pd source provides good dose coverage to the prostate. Prostate volume changes were minimal suggesting minimal swelling using the CivaString device. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
CivaString;
103
Pd; Brachytherapy; Prostate; LDR; Dosimetry
Introduction Interstitial brachytherapy (BT) has been established as a reliable treatment for early-stage prostate cancer (1). The long-term data demonstrate that BT is an effective treatment option with an acceptable side effect profile. Urinary incontinence, retention, proctitis, and erectile dysfunction are the most problematic complications for radiation treatments. The CivaString was designed to
Received 14 December 2016; received in revised form 19 May 2017; accepted 19 May 2017. Conflict of interest: Drs. Kaminetsky and Beyer received compensation from CivaTech Oncology for the administration and enrollment of patients in this trial. Dr. Stock and Dr. Ge have received consulting fees from CivaTech Oncology. * Corresponding author. Radiation Oncology, Mount Sinai Hospital, 1184 5th Avenue, New York, NY 10029. Tel.: 212 241 7503; fax: 212 410 7194. E-mail address: [email protected] (R. Stock).
reduce the side effects caused by traditional radioactive seeds by providing a more uniform dose distribution (Figs. 1 and 2) and using fewer strands (2). In addition, the goal of using the CivaString was to minimize the number of needles and hence the trauma that can lead to swelling and bleeding. The current paradigm in low-dose-rate (LDR) BT relies on loose or stranded isotope seeds whose dosimetry is characterized as point sources. These seeds have nonuniformities in the dose distribution at their ends. The CivaString, a palladium-103 (103Pd) source encapsulated in polymer, was developed as a refinement of the present seed technology (Fig. 1). The CivaString, Model CS10, is a line source with the 103Pd distributed along the length of the source. These line sources do not have nonuniformities at the end because they are polymer encapsulated. Each source is 1.0 cm long and 0.8 mm thick. In the middle of each segment, a gold marker provides enhanced visibility on imaging and landmarks for distal needle placement.
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.05.008
2
R. Stock et al. / Brachytherapy
Fig. 1. The CivaString 103Pd Model CS10. Each source is 1.0 cm long and 0.8 mm thick. In the middle of each segment, a gold marker provides enhanced visibility on imaging. 103Pd 5 palladium-103.
CivaStrings can be ordered in lengths from 1 to 6 cm with or without 1 cm polymer spacer units. The CivaStrings can easily be identified postimplant on CT imaging due to the gold markers. Preclinical experience suggests that these attributes provide for more accurate dosimetry planning, reduce procedure time, and result in less trauma (3). To evaluate a polymer-encapsulated 103Pd source with a unique linear radioactive distribution, a Phase I trial was initiated. The purpose of this study was to use CivaString in the BT management of low- and intermediate-risk prostate cancer and to collect data on the actual number of needles, the stability of the implant, and the homogeneity of the dose delivered. The results of the study were also compared with other LDR BT products and their published outcomes.
Methods and materials Twenty-eight patients with low- and intermediate-risk prostate cancer were screened at two centers with institutional review board approval. Patients were consented with institutional review boardeapproved informed consent form. The study was designed as a Phase I trial. Exclusion criteria were as follows: prostate-specific antigen O20 ng/ mL or Gleason score O7, severe urinary irritative/obstructive symptomatology (at discretion of treating physician), extensive transurethral resection of prostate defect (at discretion of treating physician), substantial median lobe
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(2017)
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hyperplasia (at discretion of treating physician), prostate dimensions that were larger than the implant grid, severe pubic arch interference, gross seminal vesicle involvement on staging workup, prior pelvic radiation therapy, inflammatory bowel disease, pelvic lymph node involvement, distant metastases, or life expectancy ! 5 years. Implantation was performed in 25 subjects using 18 gauge needles preloaded with the custom-ordered 103Pd CivaStrings. An independent organization, Tab Clinical (Cary, NC), collected the data and monitored the sites. Investigators and teams were experienced in LDR BT implants. Preimplant data collection included subject characteristics, medical history, biopsy results, laboratory, and subjectadministered quality of life questionnaires. Subjects were not excluded from the study based on preimplant urinary, rectal, or erectile function scores. Subjects underwent standard initial planning imaging (MRI, CT, or transrectal ultrasound). Implants were preplanned using the CivaString 103Pd Model CS10 and VariSeed or BrachyVision treatment planning software. The planned prescription dose was 125 Gy for monotherapy and 100 Gy for boost when combined with external beam radiation therapy. In combination therapy, the implant was done first, and the external beam was delivered 6 weeks postimplant to a dose of 45 Gy in 25 fractions. External beam was given to the prostate and seminal vesicles using intensity modulated radiation therapy and image guided radiation therapy with cone beam imaging. The CivaStrings were delivered with ultrasound and template guidance in the same manner as stranded BT seeds currently on the market. The first implanted subject at each site had an additional CT scan immediately after the implant. The preimplant plan including the number of strands, total source strength, and isodose distribution was reported by the investigators. Postimplant dosimetry was performed based on CT images obtained at 3e6 weeks. Copies of these plans were also submitted for analysis. Movement of the CivaStrings, dose homogeneity of the plan, and postimplant prostate size was reported in addition to the standard dosimetry parameters.
Results Subject and prostate cancer characteristics
Fig. 2. Isodose distribution (at 100%, 150%, and 200% of prescription) is shown for two adjacent line sources compared with identically spaced seeds. Source strength is held constant with 4 U/cm for line sources and 2 U/seed with sources placed end to end. Note that due to differences in anisotropy, the dose between line sources is higher and thus greater spacing could be used without compromising the prescription isodose.
The average age of the study population was 68 years (range, 48e88). A broad range of prostate sizes from 20 cm3 to 100 cm3 were implanted, with mean and median values of 43.5 cm3 and 40.4 cm3. The mean and median initial prostate-specific antigens were 6.07 ng/mL and 5.5 ng/mL (range, 1.6e14.3 ng/mL). The tumor characteristics are detailed in Table 1. In 4 cases, the subject had a transurethral resection of prostate before enrollment.
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R. Stock et al. / Brachytherapy Table 1 Tumor characteristics n
%
18 6 1
73 23 4
18 7
73 27
8 14 3
35 54 12
Preplanning was performed for all subjects. A median of 17 needles (range, 14e25) were preplanned to be used to achieve appropriate distribution of the linear sources in the prostate (Fig. 3a). Thirteen of 25 cases required 17 or fewer needles. All planned sources were implanted in all subjects. Of the 25 total subjects, 11 were prescribed monotherapy with a dose of 125 Gy, and 14 were prescribed boost CivaString implants with a dose of 100 Gy followed by external beam radiation therapy. All subjects completed radiation therapy. As expected, the total source strength implanted scaled linearly with prostate size, and monotherapy implants involved greater implanted source strength per size than boost implants (Fig. 3b). The source strength per centimeter of source was nominally 3.8 U/cm for monotherapy and 3.2 U/cm for boost (Fig. 3c). The number of sources and total source strength increased with increasing prostate size. From
Time to plan and implant CivaString The overall time needed to preplan the implants ranged from 14 to 120 min (mean, 54.5 [SD, 38]). The actual time needed to perform the implant, from insertion of the first needle to completion of implant, ranged from 14 to 45 min (mean, 23.5 [SD, 8.35]). The time needed to
350
b
24
Total Source Strength (U)
Number of Needles Planned (#)
3
Planning and dosimetry
PSA 5 prostate-specific antigen.
22 20 18 16 14 12
300 y = 4.07x + 17.21 250 y = 3.26x + 13.76
200 150 100 50 0
10 0
20
40
60
80
Prostate Size (cm3)
0
100 120 125 Gy 100 Gy
Percent Change in Prostate Volume (%)
3.9 3.7 3.5 3.3 3.1 2.9 2.7 2.5 0
20
40
60
80
Prostate Size (cm3)
100
120
20
40
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80
100
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Prostate Size (cm3)
d
c Source Strength per source (U/cm)
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complete the postimplant CT dosimetry ranged from 45 to 90 min (mean, 46.7 [SD, 8.83]).
T stage T1ceT2a T2beT2c T3a Gleason score 6 7 Initial PSA (ng/mL) 0e5 5e10 10e20
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40% 30% 20% 10% 0% -10% -20% 0
20
40
60
80
100
120
Prostate Volume Prior to Implant (cm3)
Fig. 3. (a) The number of planned needles and prostate sizes ranged from 14 to 25 and 21 to 101 cm3, respectively. (b) For monotherapy (black), the total source strength ranged from 129.5 to 261.8 U; for boost (gray), source strength ranged from 92.4 to 244.8 U. The lines of fit represent the curves derived for the nomogram for monotherapy (black) and boost (gray). (c) For monotherapy (black), the air kerma strength per cm ranged from 3.4 to 3.85 U/cm; for boost (gray), air kerma strength per cm ranged from 2.8 to 3.4 U/cm (d) The percent change in prostate volume calculation (postimplant/preplan) for all patients.
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Table 2 Planning and postoperative dosimetric parameter median (range) values for subject-prescribed 125 Gy monotherapy and 100 Gy combined therapy 125 Gy (n 5 11)
100 Gy (n 5 14)
Parameter
Preoperative
Postoperative
Preoperative
Postoperative
Prostate size (cm3) D90% D100% V150% V100% Urethral V150%a (cm3) Urethral D30%a Rectal V100% (cm3) Bladder V100% (cm3)
39.7 125.0% 65.0% 69.4% 98.4%
36.9 103.2% 46.6% 67.1% 90.9% 0.09 143.4% 0.06 0.01
44.8 127.9% 63.0% 77.8% 97.9%
43.5 103.9% 43.8% 73.5% 91.3% 0.12 167.3% 0.02 0.03
a
(22.43e100.6) (117.9e133.7) (40.1e86.5) (61.8e81.2) (95.5e99.8)
(22.35e82.94) (81.0e120.5) (34.0e67.9) (37.5e72.4) (74.2e97.0) (0e0.16) (121.9e160.5) (01e0.47) (0e0.64)
(20.6e71.9) (115.6e131.4) (44.3e73.4) (72.2e80.5) (95.0e99.4)
(20.8e68.5) (93.8e128.7) (30.0e74.2) (56.9e84.1) (87.8e97.3) (0e0.52) (122.4e273.7) (0e1.34) (0e0.39)
Data only available for 5 of 11 subjects.
this information, a nomogram was developed to facilitate future patient planning. The nomogram can be summarized by the following equations. Monotherapy 5 4:07 volume cm3 þ 17:21 Boost 5 3:26 volume cm3 þ 13:76 Postimplant dosimetry was performed based on CT images obtained at 3e6 weeks postimplant. The results are reported in percentages to account for differences between monotherapy and boost prescription doses (Table 2). Planning was consistent between centers with mean D90 and V150 values of 125% and 67% (Site 1) and 126% and 77% (Site 2). For a dose of 125 Gy, the postimplant D90 ranged from 81% to 121% (average, 104%). For a dose of 100 Gy, the postimplant D90 ranged from 94% to 129% (average 107%). An example of a typical isodose distribution for the CivaString implant can be found in
Fig. 4. The ratio of postimplant/preplan prostate volume ranged from 0.82 to 1.37 (average 0.97) (Fig. 3d). Fixity In 2 patients, CT scans were taken on the day of the procedure as well at 1 month postimplant. In those patients, there was no evidence of string movement between the Day 0 and Day 30 scans. Figure 5 demonstrates the fixity of the CivaString in one of the patients. At 3e6 weeks postimplant, movement was reported in one subject. One subject (4%) required cystoscopy to retrieve a string from the bladder. The confirmed movement was identified a week after implant, the string was safely removed with a routine cystoscopy, and no additional clinical sequela was reported at the closure of the study. Implant procedure side effects There was one complaint of mild perineal bruising which resolved without any intervention in 4 weeks. There
Fig. 4. 200% (blue), 150% (green), and 100% (magenta) isodose lines for selected subject. The dose is distributed homogeneously through the prostate (aqua). CivaString sources have been placed to provide appropriate dose sparing to the urethra while maintaining excellent dose coverage to the surrounding prostate. (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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Fig. 5. Comparison of the location of the sources on day of implant (left column) to 30 days postimplant (right column). Sources appear as white spots in the prostate gland. Note the location of the sources with respect to the bony anatomy does not change between the day of implant and 30 days postimplant.
were no reports of persistent hematuria, hematoma, scrotal hematoma or swelling, or postprocedure discomfort. Discussion The CivaString implants were practical in terms of time needed for preplanning, execution, and postplanning. The mean time to perform the implant was 23.5 minu, which compares favorably to other techniques. The median number of needles planned and implanted was 17 compared with the 20e23 needles reported in studies with similar population using a preplanning technique (4, 5). In prostates !50 cm3, 70% of the cases required 17 or fewer needles. The CivaString study data reveal a 4% dislodgement rate which demonstrates superior device stability compared with loose and stranded seed BT. In the prospective randomized trial reported by Reed et al. (6), dosimetric parameters and seed loss were compared between stranded and loose iodine-125 seeds. Based on 0 and 30-day imaging (X-ray, CT, and MRI), 47% of subjects with loose seeds and 23% of subjects with stranded seeds experienced seed loss. In another report by Nag et al. (7), a small population of 32 subjects was implanted with loose 103Pd seeds. Seed migration to the lung was reported in 20% of subjects, and 9% experienced voiding of seeds. The linear source design of the CivaString has a higher fixity rate than loose seeds based on these reports. There was only one complaint of mild bruising which resolved without any intervention in 4 weeks. The lack of bleeding, hematoma, swelling, and postprocedure discomfort reported compares favorably to other BT studies in the literature (8, 9).
The small changes in the prostate size as seen in Fig. 3d reflect the relative lack of prostate swelling because of the procedure. Prostate volume changes from preimplant to postimplant dosimetry have a demonstrated effect on dosimetry (10, 11). The small changes measured in these patients contribute to the excellent dosimetry. In addition, the reported movement of the CivaString is lower than with other sources. BT source fixity is highly associated with good dosimetric outcomes (11e15). This, in turn, reflects the relative ease of insertion of the product, the low number of needles placed, and the expertise of the brachytherapists involved.
Conclusions Excellent quality implants across a range of gland sizes were accomplished. Prostate volume changes were minimal suggesting minimal swelling using the CivaString needles and strands. The product is robust with minimal movement (4%) evidenced by CT. Good dosimetry is achieved with both the preplans and the postplans. Using a line source, the number of needles required to deliver the radiation therapy is less than that reported with standard preloaded or stranded BT products. This study demonstrates that the CivaString product can be safely and effectively integrated into the LDR BT management of prostate cancers.
Acknowledgment This trial was funded by a grant from CivaTech Oncology.
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References [1] Davis BJ, Horwitz EM, Lee WR, et al. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 2012;11:6e19. [2] Rivard MJ, Reed JL, DeWerd LA. 103Pd Strings: Monte Carlo assessment of a new approach to brachytherapy source design. Med Phys 2014;41:011716. [3] Reed JL, Rivard MJ, Micka JA, et al. Experimental and Monte Carlo dosimetric characterization of a 1 cm 103Pd brachytherapy source. Brachytherapy 2014;13:657e667. [4] Merrick GS, Butler WM, Wallner KE, et al. Variability of prostate brachytherapy preimplant dosimetry: A multi-institutional analysis. Brachytherapy 2005;4:241e251. [5] Birckhead BJ, Fossum CC, Deufel CL, et al. Stranded seed displacement, migration, and loss after permanent prostate brachytherapy as estimated by Day 0 fluoroscopy and 4-month postimplant pelvic xray. Brachytherapy 2016;3:714e721. [6] Reed DR, Wallner KE, Merrick GS, et al. A prospective randomized comparison of stranded vs. loose I-125 seeds for prostate brachytherapy. Brachytherapy 2007;6:129e134. [7] Nag S, Scaperoth DD, Badalament R, et al. Transperineal palladium 103 prostate brachytherapy: Analysis of morbidity and seed migration. Urology 1995;45:87e92. [8] Stock R, Stone N. Complications following prostate brachytherapy. Eur Urol 2002;41:427e433.
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[9] Sylvester J, Grimm P, Naidoo D, et al. First report on the use of a thinner 125I radioactive seed within 20-gauge needles for permanent radioactive seed prostate brachytherapy: Evaluation of postimplant dosimetry and acute toxicity. Brachytherapy 2013;12:375e381. [10] Crook J, McLean M, Yeung I, et al. MRI-CT fusion to assess post brachytherapy prostate volume and the effects of prolonged edema on dosimetry following transperineal interstitial permanent prostate brachytherapy. Brachytherapy 2004;3:55e60. [11] Pinkawa M, Asadpour B, Gagel B, et al. Evaluation of source displacement and dose-volume change after permanent prostate brachytherapy with stranded seeds. Radiother Oncol 2007;84:190e 196. [12] Moerland MA, van Deursen MJ, Elias SG, et al. Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: Comparison between loose and stranded seed plants. Radiother Oncol 2009;91:202e206. [13] Sugawara A, Nakashima J, Kunieda E, et al. Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose I-125 seeds. Radiat Oncol 2011; 6:1. [14] Fuller DB, Koziol JA, Feng AC. Prostate brachytherapy seed migration and dosimetry: Analysis of stranded sources and other potential predictive factors. Brachytherapy 2004;3:10e19. [15] Wang Y, Nasser NJ, Borg J, et al. Evaluation of the dosimetric impact of loss and displacement of seeds in prostate low-dose-rate brachytherapy. J Contemp Brachytherapy 2015;7:203e210.