Prostate Cancer and Prostatic Disease (2015) 18, 96–103 © 2015 Macmillan Publishers Limited All rights reserved 1365-7852/15 www.nature.com/pcan REVIEW A review of rectal toxicity following permanent low dose-rate prostate brachytherapy and the potential value of biodegradable rectal spacers ME Schutzer1, PF Orio2, MC Biagioli3, DA Asher4, H Lomas1 and D Moghanaki1,5 Permanent radioactive seed implantation provides highly effective treatment for prostate cancer that typically includes multidisciplinary collaboration between urologists and radiation oncologists. Low dose-rate (LDR) prostate brachytherapy offers excellent tumor control rates and has equivalent rates of rectal toxicity when compared with external beam radiotherapy. Owing to its proximity to the anterior rectal wall, a small portion of the rectum is often exposed to high doses of ionizing radiation from this procedure. Although rare, some patients develop transfusion-dependent rectal bleeding, ulcers or fistulas. These complications occasionally require permanent colostomy and thus can significantly impact a patient’s quality of life. Aside from proper technique, a promising strategy has emerged that can help avoid these complications. By injecting biodegradable materials behind Denonviller’s fascia, brachytherpists can increase the distance between the rectum and the radioactive sources to significantly decrease the rectal dose. This review summarizes the progress in this area and its applicability for use in combination with permanent LDR brachytherapy. Prostate Cancer and Prostatic Disease (2015) 18, 96–103; doi:10.1038/pcan.2015.4; published online 17 February 2015 A BRIEF HISTORY OF LOW DOSE-RATE PROSTATE demonstrated an 82% 8-year bPFS for 1444 patients treated with BRACHYTHERAPY radioactive seed implant for low-risk disease;4 (2) a series by Originally described in 1917, low dose-rate (LDR) prostate Taira et al. that reported a 12-year bPFS of 97.4% for 319 low-risk brachytherapy represents the earliest form of radiotherapy for patients and of 96.4% for 144 intermediate-risk patients following prostate cancer.1 During the early years, seed placement through brachytherapy as the sole definitive treatment;5 and (3) a report an open abdominal incision was technically challenging and by Merrick et al. that reported a bPFS of 89% for 284 high- imprecise. This technique was largely abandoned until the risk patients treated with brachytherapy, 90.5% of whom development of the current transrectal ultrasound-guided closed received EBRT and 63% of whom received androgen deprivation perineal technique, first described in 1983, which remarkably therapy. improved the accuracy of seed placement via image guidance, Despite excellent reported outcomes, improved patient con- and ushered in the era of modern prostate brachytherapy.2 The venience and well-established cost effectiveness, the use of subsequent development of software to evaluate the radioactive brachytherapy has declined since the early twenty-first century. dose coverage in three dimensions ultimately established In an analysis of data from the national cancer database, brachytherapy as a standard treatment for prostate cancer, which Martin et al. analyzed rates of brachytherapy utilization for 41.5 is now widely used as either a sole modality or in combination million patients with localized prostate cancer between 1998 and with external beam radiotherapy (EBRT). 2010. Utilization of prostate brachytherapy peaked in 2002 with In an analysis of over 52 000 prostate cancer patients treated 16.7% of patients treated with this modality, but it showed a for low-, intermediate- and high-risk prostate cancer, Grimm et al.3 steady downward trend to 8% of patients in 2010.6 Reimburse- summarized an extensive body of literature published for various ment for prostate brachytherapy decreased during this time primary treatment modalities. Among patients with both low- and interval,7 whereas highly reimbursed competing modalities of intermediate-risk disease, higher rates of biochemical progression- treatment emerged, which included intensity modulated radiation – free survival (bPFS) were reported for brachytherapy when therapy and robotically assisted radical prostatectomy.8 10 Despite compared with EBRT or radical prostatectomy. For patients the promise of higher biochemical control rates with dose- with high-risk disease, superior outcomes were achieved in escalated external beam therapies and highly magnified surgeries, those treated with a combination of EBRT with a brachytherapy the biochemical control rates continue to be as good if not boost plus or minus androgen deprivation therapy. Several superior with high-quality brachytherapy-based treatment reports are highlighted, and those include the following: (1) a regiments.11–13 Brachytherapy is perfectly situated for a renais- multi-institutional retrospective study by Zelefsky et al. that sance if national trends appropriately focus on the cost and 1Department of Radiation Oncology, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA; 2Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA, USA; 3Department of Radiation Oncology, Florida Hospital Cancer Institute, Orlando, FL, USA; 4Virginia Commonwealth University School of Medicine, Richmond, VA, USA and 5Department of Radiation Oncology Service, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, USA. Correspondence: Dr ME Schutzer, Department of Radiation Oncology, Virginia Commonwealth University Medical Center, 401 College Street, PO Box 980058, Richmond, VA 23298-0058, USA. E-mail: [email protected] Received 14 October 2014; revised 2 December 2014; accepted 10 December 2014; published online 17 February 2015 Injectable spacers in prostate brachytherapy ME Schutzer et al 97 effectiveness of treatments and direct payments accordingly. The MANAGEMENT OF RECTAL INJURY cost of biochemical failure is high not only in terms of monetary Although asymptomatic grade 2 rectal bleeding is not rare, it is 14,15 cost but also in decreased patient quality of life when salvage almost always self-limited. Interventions, when indicated, may treatments are offered in hopes of equalizing overall survival. include noninvasive medications, hyperbaric oxygen therapy and endoscopic cautery. 53–55 RATES OF RECTAL INJURY AFTER BRACHYTHERAPY Medical therapy may consist of 5-Aminosalicylic acid, sucralfate56,57 or short-chain fatty acids.58 The use of steroid When interpreting the rates of rectal toxicity, it is critical suppositories or enemas is often considered, although some to consider the duration of follow-up as radiation injury radiation oncologists have concerns about the impact of local can occur many years after treatment. Although the majority immunosuppression of a contaminated area and about further – 16–19 of complications occur within 2 3 years after implantation, atrophic changes to the rectal mucosa from chronic corticosteroid – fi 4 20 late prostate rectal stula can occur 10 years after treatment. exposure. An alternative strategy entails a prolonged course of Fortunately, the rates of grade ⩾ 2 rectal injury after LDR brachy- fi 16,19,21–38 pentoxy lene (800 mg per day) and vitamin E (1000 U per day) therapy are low and range from 2.2 to 26% (Table 1). with the rationale that the former can improve red blood cell Across studies, this corresponds to a weighted average of 7.9%. perfusion through ischemic tissue, while vitamin E facilitates fi Rectal stula formation occurs even less frequently, with reported wound healing.59 Numerous studies suggest a benefit from – 24,39,40 rates of 0.4 3.3%. These rates may or may not necessarily all of the aforementioned medical interventions, but a lack of be different when comparing reports between LDR and high dose randomized evidence makes it difficult to understand the efficacy rate (HDR). For example, with a median follow-up of 7.25 years, of these drugs, particularly for low-grade toxicity, which often ⩾ Demanes et al. demonstrated no grade 3 late rectal toxicity in resolves spontaneously. 209 patients treated with EBRT and HDR brachytherapy boost 41 When the above strategies fail to resolve rectal bleeding, and reported late grade 1 or 2 toxicity rates of only 2%, each. A some may consider hyperbaric oxygen therapy, which has separate report of 36 patients treated with a combination of EBRT been shown in multiple single-arm studies60,61 to result in ⩾ and HDR brachytherapy showed a grade 2 toxicity rate of clinical improvement in radiation proctitis. In addition, a double- 11% with a median follow-up of 78 months compared with no blinded randomized phase III crossover trial demonstrated a 32% 42 grade ⩾ 3. In a prospective assessment of 173 patients treated absolute risk reduction for refractory chronic proctitis.62 However, 43 with two fractions of 13.5 Gy each, Ghilezan et al. demonstrated the availability, duration of the treatment, and expense of this no grade ⩾ 2 acute toxicity even though a single patient had strategy that may exceed $150 000 per course often limits its chronic grade 3 rectal bleeding. As summarized in Table 1, addi- utilization. tional HDR monotherapy and combined modality studies report When minor rectal bleeding evolves into hematochezia, 42–50 grade ⩾ 2 rectal toxicity rates ranging from o1 to 14.1%, patients are often referred for endoscopic procedures. Manage- corresponding to a weighted average of 6.3%. ment options include topical therapy, bipolar