Strahlenther Onkol DOI 10.1007/s00066-014-0769-z
C a s e R e p o rt
Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer Michael Pinkawa · Carolin Schubert · Nuria Escobar-Corral · Richard Holy · Michael J. Eble
Received: 18 June 2014 / Accepted: 3 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Background In contrast to primary radiotherapy, no reports are available for a hydrogel spacer application in postoperative salvage radiotherapy for prostate cancer. Case report A 77-year-old patient presented 20 years after radical prostatectomy with a digitally palpable local recurrence at the urethrovesical anastomosis (PSA 5.5 ng/ml). The hydrogel spacer (10 ml, SpaceOARTM) was injected between the local recurrence and rectal wall under transrectal ultrasound guidance. Treatment planning was performed with an intensity-modulated technique up to a total dose of 76 Gy in 2-Gy fractions. The same planning was performed based on computed tomography before spacer injection for comparison. Results The local recurrence, initially directly on the rectal wall, could be displaced more than 1 cm from the rectal wall after hydrogel injection. With a mean total dose of 76 Gy to the planning target volume, rectal wall volumes included in the 70 Gy, 60 Gy, 50 Gy isodoses were 0 cm3, 0 cm3, and 0.4 cm3 with a spacer and 2.9 cm3, 4.5 cm3, and 6.2 cm3 without a spacer, respectively. The patient reported rectal urgency during radiotherapy, completely resolving after the end of treatment. The PSA level was 5.4 ng/ml a week before the end of radiotherapy and dropped to 0.9 ng/ ml 5 months after radiotherapy. Conclusion A hydrogel spacer was successfully applied for dose-escalated radiotherapy in a patient with macroscopic local prostate cancer recurrence at the urethrovesical anas-
Prof. Dr. med. M. Pinkawa () · C. Schubert · N. Escobar-Corral · R. Holy · M. J. Eble Department of Radiation Oncology, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany e-mail: [email protected]
tomosis to decrease the dose at the rectal wall. This option can be considered in specifically selected patients. Keywords Prostate neoplasm · Postoperative radiotherapy · Intensity-modulated radiotherapy · Treatment planning · Spacer gel Einsatz eines Hydrogel-Abstandhalters bei der postoperativen Salvage-Radiotherapie des Prostatakarzinoms Zusammenfassung Hintergrund Im Gegensatz zum Einsatz bei der primären Radiotherapie gibt es bisher keine Berichte zum Einsatz eines Hydrogel-Abstandhalters bei der postoperativen Salvage-Radiotherapie des Prostatakarzinoms. Fallbericht Ein 77-jähriger Patient stellte sich 20 Jahre nach radikaler Prostatektomie mit einem digital palpablem Lokalrezidiv im Bereich der urethrovesikalen Anastomose vor (PSA 5,5 ng/ml). Es erfolgte eine durch einen transrektalen Ultraschall gesteuerte Injektion eines Hydrogel-Abstandhalters (10 ml, SpaceOARTM) zwischen Lokalrezidiv und Rektumwand. Die Bestrahlungsplanung erfolgte in intensitätsmodulierter Technik mit einer Verschreibungsdosis von 76 Gy und Einzeldosen von 2 Gy. Zum Vergleich wurde die gleiche Planung basierend auf einer Computertomographie vor Injektion des Abstandhalters durchgeführt. Ergebnisse Das ursprünglich unmittelbar an der Rektumwand gelegene Lokalrezidiv konnte nach der Hydrogelinjektion um > 1 cm von der Rektumwand distanziert werden. Bei einer mittleren Dosis von 76 Gy im Planungszielvolumen wurde innerhalb der 70-Gy-, 60-Gy-, 50-Gy-Isodose ein Rektumwandvolumen von 0 cm3, 0 cm3 und 0,4 cm3 mit Abstandhalter und 2,9 cm3, 4,5 cm3 und 6,2 cm3 bei der ent-
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sprechenden Planung ohne Abstandhalter eingeschlossen. Der Patient berichtete über vermehrten Stuhldrang während der Radiotherapie, der nach Ende der Behandlung vollständig rückläufig war. Der PSA lag bei 5,4 ng/ml eine Woche vor Ende der Radiotherapie und fiel 5 Monate nach Ende der Radiotherapie auf 0,9 ng/ml ab. Schlussfolgerung Ein Hydrogel-Abstandhalter wurde zur Dosiseskalation bei einem makroskopischen Lokalrezidiv eines Prostatakarzinoms im Bereich der urethrovesikalen Anastomose erfolgreich zur Entlastung der Dosis an der Rektumwand eingesetzt. Diese Option kann in Einzelfällen in Betracht gezogen werden. Schlüsselwörter Prostataneoplasien · Postoperative Radiotherapie · Intensitätsmodulierte Radiotherapie · Bestrahlungsplanung · Platzhaltergel Radiotherapy is an established treatment for primary or postoperative prostate cancer patients [6, 18, 21]. Several randomized studies have demonstrated improved biochemical control with higher total doses of 76–78 Gy using conventional fractionation. These studies found significantly higher grade 2 or higher rectal toxicity rates [24]. Technical advances in recent years, such as intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), have led to improved dose conformity and the possibility to reduce safety margins around the clinical target volume(CTV), thereby reducing the toxicity risk associated with higher doses [11]. Total doses of 60–64 Gy have been used in prospective adjuvant postprostatectomy radiotherapy studies in the past [1, 20, 26]. Retrospective studies suggest a benefit for dose escalation particularly in salvage radiotherapy [2, 9]. Minimum doses of 64–66 Gy are recommended in the German Prostate Cancer Guidelines and ASTRO (American Society for Radiation Oncology)/AUA (American Urological Association) guidelines for salvage radiotherapy [23, 25]. As prostate-specific antigen (PSA) is routinely included in the follow-up and the benefit of early radiotherapy has been clearly shown, most patients receive salvage treatment at the time of biochemical recurrence without evidence of a tumor on digital palpation or imaging [9]. Taking into account the benefit of dose escalation in primary prostate cancer radiotherapy and postoperative salvage radiotherapy, a dose-escalated treatment concept for a patient with a macroscopic local recurrence many years after radical prostatectomy is presented in this report. Apart from using IMRT and IGRT, the feasibility of applying a hydrogel spacer to protect the anterior rectal wall was evaluated in this case. An increasing number of studies have been published on spacer application for primary prostate cancer radiotherapy [4, 7, 10, 12]. However, no reports are available for spacer application in postoperative salvage radiotherapy.
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Case report A 77-year-old patient presented 20 years after radical prostatectomy with a digitally palpable local recurrence at the urethrovesical anastomosis (PSA 5.5 ng/ml). After a PSA increase to 1 ng/ml in 2005, the patient received treatment with finasteride (5-α-reductase inhibitor with some antiandrogen properties, usually for the treatment of benign prostatic hyperplasia), leading to a temporary decrease of the PSA level followed by a consecutive steep increase. An inflatable artificial sphincter cuff was implanted 2 years after radical prostatectomy to treat urinary incontinence. Urinary function had deteriorated in the last few years, so that urinary incontinence was still a problem for the patient. He suffered from recurrent urinary infections, necessitating antibiotic treatments several times a year. A local recurrence with a maximum diameter of 2.5 cm was diagnosed on 18F-choline-positron emission tomography/computed tomography imaging (PET/CT; Philips, Amsterdam, The Netherlands) and magnetic resonance imaging (MRI; Philips, Amsterdam, The Netherlands). Local lymph node or distant metastases were not detected in these imaging studies. The hydrogel spacer (10 ml, SpaceOARTM System, Augmenix Inc., Waltham, Mass.) was injected between the local recurrence and rectal wall with transrectal ultrasound guidance with the patient under local anesthesia after prior hydrodissection with 20 ml of a saline/lidocaine solution. During digital rectal examination, transrectal ultrasound, and hydrodissection, the tumor was not found to be adherent to the rectal wall. Hydrodissection would not have been impossible in the case of rectal wall infiltration, thus being a prerequisite for hydrogel injection. The time needed for the procedure (patient on the table) was only about 15 min. The sagittal view on transrectal ultrasound before and after injection, demonstrating the position of the local recurrence and distancing of the rectum as a consequence of the hydrogel, is shown in Fig. 1. T2-weighted magnetic resonance imaging showed the same anatomy with a wider field of view (Fig. 2). Treatment planning CT was performed 3 days after injection, MRI 5 days after injection. The patient was asked to have a full bladder for the planning CT scans and every treatment fraction. A cone-beam CT was used for IGRT during the first five fractions and once to twice weekly in the following weeks. Matching was performed on the CTV. Treatment planning was performed using a five-field intensity-modulated technique up to a total mean dose of 76 Gy in 2-Gy fractions with 15-MeV photons in the Pinnacle treatment planning system (Philips, Fitchburg, Wis.). The same planning was performed based on CT before spacer injection for comparison. Local recurrence was defined as a CTV of 7 cm3.
Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer
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A safety margin of 8 mm in the anterior, posterior, and lateral directions, and 5 mm in the cranial and caudal directions, was added for the PTV (planning target volume, 35 cm3). The bladder and rectum were delineated by identifying the external contours. The rectum enclosed the region from the anal canal to the rectosigmoid flexure. Additionally, the rectal wall was defined as a 3-mm outer rim within the initially defined rectum volume (including filling). Results Fig. 1 Sagittal view on transrectal ultrasound before (left) and after (right) hydrogel spacer injection
Fig. 2 Sagittal view on T2-weighted magnetic resonance imaging (hydrogel hyperintense)
The distance between the rectal wall and local recurrence could be increased from the immediate vicinity to more than 1 cm after hydrogel injection, so that the PTV and rectum volume did not overlap. With a mean total dose of 76 Gy to the PTV, rectal wall volumes included in the 76-Gy, 70-Gy, 60-Gy, and 50-Gy isodoses were 0 cm3, 0 cm3, 0 cm3, and 0.4 cm3 with a spacer and 1.5 cm3, 2.9 cm3, 4.5 cm3, and 6.2 cm3without a spacer, respectively. The corresponding rectum (including filling) volumes within the 76-Gy, 70-Gy, 60-Gy, and 50-Gy isodoses were 0 cm3, 0 cm3, 0 cm3, and 0.4 cm3 with a spacer and 2.7 cm3, 7.2 cm3, 12.4 cm3, and 17.7 cm3without a spacer, respectively. The anatomy before and after hydrogel injection on an axial CT slice is demonstrated in Fig. 3 with the corresponding isodose distribution. PSA was measured 1 week before the end of treatment, indicating a PSA level of 5.4 ng/ml – thus, there was no change in comparison to the baseline level of 5.5 ng/ml before treatment. Two, 5, and 8 months after the end of radiotherapy, the PSA level decreased considerably to 1.3 ng/ml, 0.9 ng/ml, and 0.9 ng/ml, respectively. The patient reported an increased frequency of bowel movements and rectal discomfort, persisting for a few days after hydrogel injection. The patient was free of rectal complaints at the beginning of radiotherapy. After 4 weeks of treatment, the patient reported urinary urgency, which was treated with a spasmolytic anticholinergic agent and an anti-
Fig. 3 Isodose distribution in treatment planning computed tomography before (left) and after (right) hydrogel injection
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biotic as a urinary tract infection was diagnosed in urinary culture – grade 2 toxicity according to RTOG/EORTC criteria (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer). During the last 2 weeks of treatment, the patient had soft stools about once or twice a day with occasional rectal urgency (medication not needed), corresponding to grade 1 rectal toxicity according to RTOG/EORTC criteria. Apart from the urinary incontinence and another urinary tract infection a few weeks after the end of treatment, the patient reported no complaints in the elapsed 8 months of follow-up. CT was performed 6 months after the end of treatment, showing complete hydrogel absorption without pathologic findings (Fig. 4). Local recurrence was no longer digitally palpable. Discussion Currently available data indicate improved tumor control with dose escalation for salvage radiotherapy [2, 9]. Higher doses are needed for comparable tumor control in the case of higher pretreatment PSA levels. However, rectal toxicity rates also increase. Severe grade ≥ 3 gastrointestinal toxicity rates range from 0 to 9 % after salvage postprostatectomy radiotherapy [9]. In a systematic review of 25 articles, Ohri et al. [9] found that a rise in pretreatment PSA from 0.4 to 1.0 ng/ml increases the dose required to achieve a 50 % 5-year biochemical progression-free survival rate from 60 to 70 Gy. This could increase the rate of severe late toxicity by approximately 10 % (severe grade ≥ 3 gastrointestinal toxicity increased by 1.2 % per Gy). An ongoing randomized trial is comparing the dose levels of 64 Gy and 70 Gy for salvage radiotherapy [5]. The patient in this report presented with a PSA level of > 5 ng/ml and a palpable local recurrence, suggesting the need for dose escalation to > 70 Gy, comparable to primary prostate cancer radiotherapy, so as to reach satisfactory long-term tumor control. As these dose levels are associated with a considerable risk of severe late toxicity, a hydrogel spacer was injected to increase the distance to the rectal wall. The hydrogel injection proved to be feasible, as a distance of > 1 cm could be created and only minor toxicity Fig. 4 Computed tomography before hydrogel injection (a), after (b) hydrogel injection, and 6 months after treatment (c)
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occurred shortly after and during radiotherapy treatment. An effect was seen on the PSA level and the local tumor within a short follow-up period. A stable PSA level at the end of radiotherapy was shown to have no value in predicting the subsequent response to treatment in this case. Experience with spacer application is increasing with a growing number of studies published in the last few years [4, 7, 10, 12, 19]. Well-tolerated injection techniques and low rectal treatment-related toxicity have been demonstrated in prospective studies for primary prostate cancer treatment, respecting toxicity, proctoscopy results, spacer stability, and quality of life [12, 13, 15, 22]. Spacers have been used before external beam radiotherapy and/or brachytherapy for primary prostate cancer treatment [8, 14, 17]. Spacer application for adjuvant or salvage radiotherapy in the case of biochemical recurrence is not useful. The entire prostatic fossa, ranging from the pubic bone to the rectal wall in the anterior–posterior direction, includes potential microscopic tumor spread and needs to be included in the CTV [16]. Local recurrences after radical prostatectomy are known to occur in the vicinity of the vesicourethral anastomosis in the majority of cases [16]. In view of the long period of many years between prostatectomy and diagnosis of the recurrence and the well-defined tumor volume, we decided to include only the recurrence in the CTV and not the complete prostatic fossa, as in standard postoperative radiotherapy. The analysis of patients after radical prostatectomy suggests that the subset of patients with well-differentiated tumors of Gleason score 6 can relapse locally, but is very unlikely that they develop lymph node or distant metastases [3]. The prerequisites for the applied strategy are the presence of a single, macroscopically visible tumor recurrence located in the vicinity of the rectal wall and a very high level of safety that the lesion is the only site of recurrence. Standard treatment for a biochemical or macroscopic local recurrence is the treatment of the prostatic fossa. The benefit of a hydrogel injection and distancing the rectum from the target must be balanced against the risk of potential tumor cell displacement during the injection and potentially remaining cells at the rectal wall. An alternative concept with hydrogel application might be to include the complete prostatic fossa and hydrogel within the CTV up to a standard dose (e.g.,
Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer
66 Gy) and to focus a higher dose (> 70 Gy) on the macroscopically identified and displaced recurrence. Conclusion A hydrogel spacer was successfully applied for dose-escalated radiotherapy in a patient with macroscopic local prostate cancer recurrence at the urethrovesical anastomosis to decrease the dose at the rectal wall. This option can be considered in specifically selected patients. Compliance with ethical guidelines Conflict of interest M. Pinkawa, C. Schubert, N. Escobar-Corral, R. Holy, and M.J. Eble state that there are no conflicts of interest.
References 1. Bolla M, Van PH, Tombal B et al (2012) Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: longterm results of a randomised controlled trial (EORTC trial 22911). Lancet 380:2018–2027 2. Cozzarini C, Montorsi F, Fiorino C et al (2009) Need for high radiation dose ( >or = 70 gy) in early postoperative irradiation after radical prostatectomy: a single-institution analysis of 334 high-risk, node-negative patients. Int J Radiat Oncol Biol Phys 75:966–974 3. Donin NM, Laze J, Zhou M et al (2013) Gleason 6 prostate tumors diagnosed in the PSA era do not demonstrate the capacity for metastatic spread at the time of radical prostatectomy. Urology 82:148–153 4. Eckert F, Alloussi S, Paulsen F et al (2013) Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer. BMC Cancer 13:27 5. Ghadjar P, Zwahlen D, Aebersold DM et al (2012) Postoperative radiotherapy after radical prostatectomy: indications and open questions. Prostate Cancer 2012:963417 6. Lohm G, Lutcke J, Jamil B et al. (2014) Salvage radiotherapy in patients with prostate cancer and biochemical relapse after radical prostatectomy: long-term follow-up of a single-center survey. Strahlenther Onkol 190:727-731 7. Melchert C, Gez E, Bohlen G et al. (2013) Interstitial biodegradable balloon for reduced rectal dose during prostate radiotherapy: results of a virtual planning investigation based on the pre- and post-implant imaging data of an international multicenter study. Radiother Oncol 106:210–214 8. Nguyen PL, Devlin PM, Beard CJ et al (2013) High-dose-rate brachytherapy for prostate cancer in a previously radiated patient with polyethylene glycol hydrogel spacing to reduce rectal dose: case report and review of the literature. Brachytherapy 12:77–83 9. Ohri N, Dicker AP, Trabulsi EJ et al (2012) Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer 48:837–844 10. Pinkawa M, Corral NE, Caffaro M et al (2011) Application of a spacer gel to optimize three-dimensional conformal and intensity modulated radiotherapy for prostate cancer. Radiother Oncol 100:436–441
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11. Pinkawa M, Piroth MD, Holy R et al (2011) Combination of dose escalation with technological advances (intensity-modulated and image-guided radiotherapy) is not associated with increased morbidity for patients with prostate cancer. Strahlenther Onkol 187:479–484 12. Pinkawa M, Piroth MD, Holy R et al (2012) Quality of life after intensity-modulated radiotherapy for prostate cancer with a hydrogel spacer. Matched-pair analysis. Strahlenther Onkol 188:917–925 13. Pinkawa M, Piroth MD, Holy R et al (2013) Spacer stability and prostate position variability during radiotherapy for prostate cancer applying a hydrogel to protect the rectal wall. Radiother Oncol 106:220–224 14. Pinkawa M, Bornemann C, Escobar-Corral N et al (2013) Treatment planning shortly after injection of a hydrogel spacer to protect the rectal wall during radiotherapy of prostate cancer. Strahlenther Onkol 189:796–800 15. Pinkawa M, Klotz J, Djukic V et al (2013) Learning curve in the application of a hydrogel spacer to protect the rectal wall during radiotherapy of localized prostate cancer. Urology 82:963–968 16. Poortmans P, Bossi A, Vandeputte K et al (2007) Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the eortc radiation oncology group. Radiother Oncol 84:121–127 17. Prada PJ, Jimenez I, Gonzalez-Suarez H et al (2012) High-doserate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: treatment description and preliminary results. Brachytherapy 11:105–110 18. Sanpaolo P, Barbieri V, Genovesi D (2014) Biologically effective dose and definitive radiation treatment for localized prostate cancer: treatment gaps do affect the risk of biochemical failure. Strahlenther Onkol 190:732-738 19. Susil RC, McNutt TR, DeWeese TL et al (2010) Effects of prostate-rectum separation on rectal dose from external beam radiotherapy. Int J Radiat Oncol Biol Phys 76:1251–1258 20. Thompson IM, Tangen CM, Paradelo J et al (2009) Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 181:956–962 21. Tselis N, Maurer U, Popp W et al (2014) Evaluation of time, attendance of medical staff, and resources during interstitial brachytherapy for prostate cancer: DEGRO-QUIRO trial. Strahlenther Onkol 190:358–363 22. Uhl M, Herfarth K, Eble MJ et al (2014) Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 months toxicity and proctoscopy results of a prospective multicenter phase II trial. Radiat Oncol 9:96 23. Valicenti RK, Thompson I Jr, Albertsen P et al (2013) Adjuvant and salvage radiation therapy after prostatectomy: American Society for Radiation Oncology/American Urological Association guidelines. Int J Radiat Oncol Biol Phys 86:822–828 24. Viani GA, Stefano EJ, Alfonso SL (2009) Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 74:1405–1418 25. Wenz F, Martin T, Bohmer D et al (2010) The German S3 guideline prostate cancer: aspects for the radiation oncologist. Strahlenther Onkol 186:531–534 26. Wiegel T, Bottke D, Steiner U et al (2009) Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95. J Clin Oncol 27:2924–2930
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Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer Michael Pinkawa · Carolin Schubert · Nuria Escobar-Corral · Richard Holy · Michael J. Eble
Received: 18 June 2014 / Accepted: 3 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Background In contrast to primary radiotherapy, no reports are available for a hydrogel spacer application in postoperative salvage radiotherapy for prostate cancer. Case report A 77-year-old patient presented 20 years after radical prostatectomy with a digitally palpable local recurrence at the urethrovesical anastomosis (PSA 5.5 ng/ml). The hydrogel spacer (10 ml, SpaceOARTM) was injected between the local recurrence and rectal wall under transrectal ultrasound guidance. Treatment planning was performed with an intensity-modulated technique up to a total dose of 76 Gy in 2-Gy fractions. The same planning was performed based on computed tomography before spacer injection for comparison. Results The local recurrence, initially directly on the rectal wall, could be displaced more than 1 cm from the rectal wall after hydrogel injection. With a mean total dose of 76 Gy to the planning target volume, rectal wall volumes included in the 70 Gy, 60 Gy, 50 Gy isodoses were 0 cm3, 0 cm3, and 0.4 cm3 with a spacer and 2.9 cm3, 4.5 cm3, and 6.2 cm3 without a spacer, respectively. The patient reported rectal urgency during radiotherapy, completely resolving after the end of treatment. The PSA level was 5.4 ng/ml a week before the end of radiotherapy and dropped to 0.9 ng/ ml 5 months after radiotherapy. Conclusion A hydrogel spacer was successfully applied for dose-escalated radiotherapy in a patient with macroscopic local prostate cancer recurrence at the urethrovesical anas-
Prof. Dr. med. M. Pinkawa () · C. Schubert · N. Escobar-Corral · R. Holy · M. J. Eble Department of Radiation Oncology, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany e-mail: [email protected]
tomosis to decrease the dose at the rectal wall. This option can be considered in specifically selected patients. Keywords Prostate neoplasm · Postoperative radiotherapy · Intensity-modulated radiotherapy · Treatment planning · Spacer gel Einsatz eines Hydrogel-Abstandhalters bei der postoperativen Salvage-Radiotherapie des Prostatakarzinoms Zusammenfassung Hintergrund Im Gegensatz zum Einsatz bei der primären Radiotherapie gibt es bisher keine Berichte zum Einsatz eines Hydrogel-Abstandhalters bei der postoperativen Salvage-Radiotherapie des Prostatakarzinoms. Fallbericht Ein 77-jähriger Patient stellte sich 20 Jahre nach radikaler Prostatektomie mit einem digital palpablem Lokalrezidiv im Bereich der urethrovesikalen Anastomose vor (PSA 5,5 ng/ml). Es erfolgte eine durch einen transrektalen Ultraschall gesteuerte Injektion eines Hydrogel-Abstandhalters (10 ml, SpaceOARTM) zwischen Lokalrezidiv und Rektumwand. Die Bestrahlungsplanung erfolgte in intensitätsmodulierter Technik mit einer Verschreibungsdosis von 76 Gy und Einzeldosen von 2 Gy. Zum Vergleich wurde die gleiche Planung basierend auf einer Computertomographie vor Injektion des Abstandhalters durchgeführt. Ergebnisse Das ursprünglich unmittelbar an der Rektumwand gelegene Lokalrezidiv konnte nach der Hydrogelinjektion um > 1 cm von der Rektumwand distanziert werden. Bei einer mittleren Dosis von 76 Gy im Planungszielvolumen wurde innerhalb der 70-Gy-, 60-Gy-, 50-Gy-Isodose ein Rektumwandvolumen von 0 cm3, 0 cm3 und 0,4 cm3 mit Abstandhalter und 2,9 cm3, 4,5 cm3 und 6,2 cm3 bei der ent-
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sprechenden Planung ohne Abstandhalter eingeschlossen. Der Patient berichtete über vermehrten Stuhldrang während der Radiotherapie, der nach Ende der Behandlung vollständig rückläufig war. Der PSA lag bei 5,4 ng/ml eine Woche vor Ende der Radiotherapie und fiel 5 Monate nach Ende der Radiotherapie auf 0,9 ng/ml ab. Schlussfolgerung Ein Hydrogel-Abstandhalter wurde zur Dosiseskalation bei einem makroskopischen Lokalrezidiv eines Prostatakarzinoms im Bereich der urethrovesikalen Anastomose erfolgreich zur Entlastung der Dosis an der Rektumwand eingesetzt. Diese Option kann in Einzelfällen in Betracht gezogen werden. Schlüsselwörter Prostataneoplasien · Postoperative Radiotherapie · Intensitätsmodulierte Radiotherapie · Bestrahlungsplanung · Platzhaltergel Radiotherapy is an established treatment for primary or postoperative prostate cancer patients [6, 18, 21]. Several randomized studies have demonstrated improved biochemical control with higher total doses of 76–78 Gy using conventional fractionation. These studies found significantly higher grade 2 or higher rectal toxicity rates [24]. Technical advances in recent years, such as intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), have led to improved dose conformity and the possibility to reduce safety margins around the clinical target volume(CTV), thereby reducing the toxicity risk associated with higher doses [11]. Total doses of 60–64 Gy have been used in prospective adjuvant postprostatectomy radiotherapy studies in the past [1, 20, 26]. Retrospective studies suggest a benefit for dose escalation particularly in salvage radiotherapy [2, 9]. Minimum doses of 64–66 Gy are recommended in the German Prostate Cancer Guidelines and ASTRO (American Society for Radiation Oncology)/AUA (American Urological Association) guidelines for salvage radiotherapy [23, 25]. As prostate-specific antigen (PSA) is routinely included in the follow-up and the benefit of early radiotherapy has been clearly shown, most patients receive salvage treatment at the time of biochemical recurrence without evidence of a tumor on digital palpation or imaging [9]. Taking into account the benefit of dose escalation in primary prostate cancer radiotherapy and postoperative salvage radiotherapy, a dose-escalated treatment concept for a patient with a macroscopic local recurrence many years after radical prostatectomy is presented in this report. Apart from using IMRT and IGRT, the feasibility of applying a hydrogel spacer to protect the anterior rectal wall was evaluated in this case. An increasing number of studies have been published on spacer application for primary prostate cancer radiotherapy [4, 7, 10, 12]. However, no reports are available for spacer application in postoperative salvage radiotherapy.
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Case report A 77-year-old patient presented 20 years after radical prostatectomy with a digitally palpable local recurrence at the urethrovesical anastomosis (PSA 5.5 ng/ml). After a PSA increase to 1 ng/ml in 2005, the patient received treatment with finasteride (5-α-reductase inhibitor with some antiandrogen properties, usually for the treatment of benign prostatic hyperplasia), leading to a temporary decrease of the PSA level followed by a consecutive steep increase. An inflatable artificial sphincter cuff was implanted 2 years after radical prostatectomy to treat urinary incontinence. Urinary function had deteriorated in the last few years, so that urinary incontinence was still a problem for the patient. He suffered from recurrent urinary infections, necessitating antibiotic treatments several times a year. A local recurrence with a maximum diameter of 2.5 cm was diagnosed on 18F-choline-positron emission tomography/computed tomography imaging (PET/CT; Philips, Amsterdam, The Netherlands) and magnetic resonance imaging (MRI; Philips, Amsterdam, The Netherlands). Local lymph node or distant metastases were not detected in these imaging studies. The hydrogel spacer (10 ml, SpaceOARTM System, Augmenix Inc., Waltham, Mass.) was injected between the local recurrence and rectal wall with transrectal ultrasound guidance with the patient under local anesthesia after prior hydrodissection with 20 ml of a saline/lidocaine solution. During digital rectal examination, transrectal ultrasound, and hydrodissection, the tumor was not found to be adherent to the rectal wall. Hydrodissection would not have been impossible in the case of rectal wall infiltration, thus being a prerequisite for hydrogel injection. The time needed for the procedure (patient on the table) was only about 15 min. The sagittal view on transrectal ultrasound before and after injection, demonstrating the position of the local recurrence and distancing of the rectum as a consequence of the hydrogel, is shown in Fig. 1. T2-weighted magnetic resonance imaging showed the same anatomy with a wider field of view (Fig. 2). Treatment planning CT was performed 3 days after injection, MRI 5 days after injection. The patient was asked to have a full bladder for the planning CT scans and every treatment fraction. A cone-beam CT was used for IGRT during the first five fractions and once to twice weekly in the following weeks. Matching was performed on the CTV. Treatment planning was performed using a five-field intensity-modulated technique up to a total mean dose of 76 Gy in 2-Gy fractions with 15-MeV photons in the Pinnacle treatment planning system (Philips, Fitchburg, Wis.). The same planning was performed based on CT before spacer injection for comparison. Local recurrence was defined as a CTV of 7 cm3.
Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer
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A safety margin of 8 mm in the anterior, posterior, and lateral directions, and 5 mm in the cranial and caudal directions, was added for the PTV (planning target volume, 35 cm3). The bladder and rectum were delineated by identifying the external contours. The rectum enclosed the region from the anal canal to the rectosigmoid flexure. Additionally, the rectal wall was defined as a 3-mm outer rim within the initially defined rectum volume (including filling). Results Fig. 1 Sagittal view on transrectal ultrasound before (left) and after (right) hydrogel spacer injection
Fig. 2 Sagittal view on T2-weighted magnetic resonance imaging (hydrogel hyperintense)
The distance between the rectal wall and local recurrence could be increased from the immediate vicinity to more than 1 cm after hydrogel injection, so that the PTV and rectum volume did not overlap. With a mean total dose of 76 Gy to the PTV, rectal wall volumes included in the 76-Gy, 70-Gy, 60-Gy, and 50-Gy isodoses were 0 cm3, 0 cm3, 0 cm3, and 0.4 cm3 with a spacer and 1.5 cm3, 2.9 cm3, 4.5 cm3, and 6.2 cm3without a spacer, respectively. The corresponding rectum (including filling) volumes within the 76-Gy, 70-Gy, 60-Gy, and 50-Gy isodoses were 0 cm3, 0 cm3, 0 cm3, and 0.4 cm3 with a spacer and 2.7 cm3, 7.2 cm3, 12.4 cm3, and 17.7 cm3without a spacer, respectively. The anatomy before and after hydrogel injection on an axial CT slice is demonstrated in Fig. 3 with the corresponding isodose distribution. PSA was measured 1 week before the end of treatment, indicating a PSA level of 5.4 ng/ml – thus, there was no change in comparison to the baseline level of 5.5 ng/ml before treatment. Two, 5, and 8 months after the end of radiotherapy, the PSA level decreased considerably to 1.3 ng/ml, 0.9 ng/ml, and 0.9 ng/ml, respectively. The patient reported an increased frequency of bowel movements and rectal discomfort, persisting for a few days after hydrogel injection. The patient was free of rectal complaints at the beginning of radiotherapy. After 4 weeks of treatment, the patient reported urinary urgency, which was treated with a spasmolytic anticholinergic agent and an anti-
Fig. 3 Isodose distribution in treatment planning computed tomography before (left) and after (right) hydrogel injection
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biotic as a urinary tract infection was diagnosed in urinary culture – grade 2 toxicity according to RTOG/EORTC criteria (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer). During the last 2 weeks of treatment, the patient had soft stools about once or twice a day with occasional rectal urgency (medication not needed), corresponding to grade 1 rectal toxicity according to RTOG/EORTC criteria. Apart from the urinary incontinence and another urinary tract infection a few weeks after the end of treatment, the patient reported no complaints in the elapsed 8 months of follow-up. CT was performed 6 months after the end of treatment, showing complete hydrogel absorption without pathologic findings (Fig. 4). Local recurrence was no longer digitally palpable. Discussion Currently available data indicate improved tumor control with dose escalation for salvage radiotherapy [2, 9]. Higher doses are needed for comparable tumor control in the case of higher pretreatment PSA levels. However, rectal toxicity rates also increase. Severe grade ≥ 3 gastrointestinal toxicity rates range from 0 to 9 % after salvage postprostatectomy radiotherapy [9]. In a systematic review of 25 articles, Ohri et al. [9] found that a rise in pretreatment PSA from 0.4 to 1.0 ng/ml increases the dose required to achieve a 50 % 5-year biochemical progression-free survival rate from 60 to 70 Gy. This could increase the rate of severe late toxicity by approximately 10 % (severe grade ≥ 3 gastrointestinal toxicity increased by 1.2 % per Gy). An ongoing randomized trial is comparing the dose levels of 64 Gy and 70 Gy for salvage radiotherapy [5]. The patient in this report presented with a PSA level of > 5 ng/ml and a palpable local recurrence, suggesting the need for dose escalation to > 70 Gy, comparable to primary prostate cancer radiotherapy, so as to reach satisfactory long-term tumor control. As these dose levels are associated with a considerable risk of severe late toxicity, a hydrogel spacer was injected to increase the distance to the rectal wall. The hydrogel injection proved to be feasible, as a distance of > 1 cm could be created and only minor toxicity Fig. 4 Computed tomography before hydrogel injection (a), after (b) hydrogel injection, and 6 months after treatment (c)
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occurred shortly after and during radiotherapy treatment. An effect was seen on the PSA level and the local tumor within a short follow-up period. A stable PSA level at the end of radiotherapy was shown to have no value in predicting the subsequent response to treatment in this case. Experience with spacer application is increasing with a growing number of studies published in the last few years [4, 7, 10, 12, 19]. Well-tolerated injection techniques and low rectal treatment-related toxicity have been demonstrated in prospective studies for primary prostate cancer treatment, respecting toxicity, proctoscopy results, spacer stability, and quality of life [12, 13, 15, 22]. Spacers have been used before external beam radiotherapy and/or brachytherapy for primary prostate cancer treatment [8, 14, 17]. Spacer application for adjuvant or salvage radiotherapy in the case of biochemical recurrence is not useful. The entire prostatic fossa, ranging from the pubic bone to the rectal wall in the anterior–posterior direction, includes potential microscopic tumor spread and needs to be included in the CTV [16]. Local recurrences after radical prostatectomy are known to occur in the vicinity of the vesicourethral anastomosis in the majority of cases [16]. In view of the long period of many years between prostatectomy and diagnosis of the recurrence and the well-defined tumor volume, we decided to include only the recurrence in the CTV and not the complete prostatic fossa, as in standard postoperative radiotherapy. The analysis of patients after radical prostatectomy suggests that the subset of patients with well-differentiated tumors of Gleason score 6 can relapse locally, but is very unlikely that they develop lymph node or distant metastases [3]. The prerequisites for the applied strategy are the presence of a single, macroscopically visible tumor recurrence located in the vicinity of the rectal wall and a very high level of safety that the lesion is the only site of recurrence. Standard treatment for a biochemical or macroscopic local recurrence is the treatment of the prostatic fossa. The benefit of a hydrogel injection and distancing the rectum from the target must be balanced against the risk of potential tumor cell displacement during the injection and potentially remaining cells at the rectal wall. An alternative concept with hydrogel application might be to include the complete prostatic fossa and hydrogel within the CTV up to a standard dose (e.g.,
Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer
66 Gy) and to focus a higher dose (> 70 Gy) on the macroscopically identified and displaced recurrence. Conclusion A hydrogel spacer was successfully applied for dose-escalated radiotherapy in a patient with macroscopic local prostate cancer recurrence at the urethrovesical anastomosis to decrease the dose at the rectal wall. This option can be considered in specifically selected patients. Compliance with ethical guidelines Conflict of interest M. Pinkawa, C. Schubert, N. Escobar-Corral, R. Holy, and M.J. Eble state that there are no conflicts of interest.
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