With today’s IMRT techniques, rectal toxicities are relatively low and, thus, adding tissue spacers to IMRT may have little additional reduction of rectal toxicity. However, these tissue spacers may be more beneficial in men receiving higher doses per fraction such as those on SBRT protocols. SBRT typically involves doses >5 Gy per fraction. Multiple phase I and II trials with small numbers of patients have been reported that examined the role of SBRT in prostate cancer.73–78 In these studies, the Grade ≥2 GI toxicity rates ranged from 0 to 12%. However, in a phase I dose-escalation trial,79 grades 3–4 rectal toxicity was observed in 6.6% of patients enrolled in the highest dose level – 50 Gy in 5 fractions. The risk of toxicity increased when the rectal volume receiving 50 Gy exceeded 3 cc and when >35% of the rectal wall received 39 Gy. Despite this need to reduce rectal dose during SBRT delivery, few studies have been published examining the role of tissue spacers with SBRT. Alongi et al69 performed a phase I–II trial of SBRT in 40 patients. Within this cohort of patients, 8 patients underwent SpaceOAR injection prior to SBRT. No Grade ≥3 toxicities were reported in the SpaceOAR patients; however, the median follow-up was only 11 months.
Fortunately, we now have a recently published phase III randomized trial that examined the role of SpaceOAR with median follow-up of three years in patients receiving conventionally fractionated RT. Hamstra et al80 enrolled 222 men that were randomized 2:1 to the spacer or control group. All patients received 79.2 Gy in 1.8-Gy fractions to the prostate and SVs, if indicated. The patients were blinded to the treatment allocation. The primary endpoint is the proportion of subjects with >25% reduction in rectal V70, relative to the control group, together with the incidence of clinical rectal toxicity as a secondary endpoint. With a three-year follow-up, those with the hydrogel had a smaller volume of rectum treated to all volumes from V50 to V80 (P < 0.0001). Grade ≥1 rectal toxicity decreased by 75% in the spacer arm (P < 0.03; HR 0.24, 95% CI 0.06–0.97), and no Grade ≥2 rectal toxicity was observed in the spacer arm (control: 6%, vs spacer: 0%; P < 0.015). With regard to bowel QOL, the investigators found that the spacer-arm bowel QOL score was near, or greater than, the baseline score but had declined significantly in the control arm, indicating worsening QOL without the spacer.
Continue Reading
Systemic agents
The molecular and cellular events leading to late toxicity after RT begin virtually immediately after the first exposure to ionizing radiation. Vascular damage is important in the phenotype of RT-induced rectal injury, where telangiectatic vessels are often responsible for the bleeding characteristic of this condition. The cholesterol-lowering agents – HMG-CoA reductase inhibitors (statins) – have been demonstrated to reduce the risk of myocardial infarction, in part, through their vascular protective effects. In vitro, statins have been shown to protect human endothelial cells from ionizing radiation.81–83 Multiple mechanisms appear to be involved, including attenuation of extracellular stress responses,84,85 downregulation of chemokines and chemokine receptors,86 and exerting anti-inflammatory and antithrombotic effects81,87–89 on these cells.
Wedlake et al90 performed a retrospective analysis of 308 patients treated for various pelvic malignancies, including prostate cancer. They found that the use of statins alone or in combination with angiotensin-converting enzyme inhibitors during radiotherapy was associated with reduced GI toxicities, both acutely and at 1 year after radiotherapy. The authors suggested a stronger protective effect from the nonlipophilic statin, pravastatin, as this class of statins is not cleared as readily by the liver in contrast to the lipophilic statins, and concentrates more readily in peripheral tissues.
Palumbo et al91 enrolled 195 patients into a prospective trial in which patients received 74.25 Gy in 33 fractions to the prostate and, if involved, to the SVs with IMRT. They assessed for acute rectal side effects weekly during RT and at 1 and 3 months after treatment. Late rectal side effects and disease status were monitored every 4–6 months for the first 5 years, and then annually. The authors observed which patients had been on antihypertensives, statins, or both during their course of RT. They found that the majority of patients (137/195; 70.26%) were taking antihypertensive drugs; 42 patients (27.69%) were on calcium channel blockers; and 55 patients (28.21%) were on statins. Univariate analysis showed that statins and calcium channel blockers significantly reduced the rate of acute rectal toxicity, while multivariate analysis confirmed that only statins were an independent protective factor. Although these results are intriguing, the statins were not given in a randomized prospective manner; thus, additional studies are needed to confirm this benefit.
Anscher et al92 performed a prospective phase II trial evaluating the ability of statins to protect against the development of late rectal injury in a group of patients receiving high-dose RT for prostate cancer. Lovastatin was the HMG-CoA reductase inhibitor used in this study and was administered concurrently for 1 year. Fifty-three patients were enrolled and evaluable at the end of the study. Patients could receive EBRT, BT, or a combination of both. EBRT was given with both 3DCRT and IMRT. Patients receiving adjuvant or salvage RT after prostatectomy were also enrolled. To be eligible for the study, a portion of the rectum had to receive at least 60 Gy. The authors looked at all late rectal toxicities and found that 20/53 (38%) patients developed Grade ≥2 late rectal toxicity during the 2-year follow-up period after RT. This incidence was not lower than the anticipated incidence of 30% based on the literature available at the time of study implementation. The authors concluded that lovastatin was not effective as an agent to reduce the frequency and severity of late RT-induced rectal injury. However, based on preclinical data, other more potent members of the HMG-CoA reductase inhibitor class deserve further study as radiation protectors, especially with the implementation of IMRT.
CONCLUSION
Many technological advances have occurred over the past two decades that have allowed radiation oncologists to safely escalate the doses needed for prostate cancer while sparing acute and late rectal toxicities. We now have published dose–volume constraints that can prevent rectal injury and the use of IMRT, in combination with IGRT, which has led to significant reductions in these toxicities. Endorectal balloons have been studied in patients receiving both 3DCRT and IMRT. However, the recommendation for their use remains controversial, with some studies showing successful reduction of rectal toxicities but with others revealing no difference when compared to patients without balloons. Tissue spacers involve injecting a biodegradable material into the rectoprostatic fascia to physically move the prostate away from the rectal wall. The use of these spacers is promising as they show significant reduction in acute and late toxicities. However, longer follow-up is needed, as there is currently only one published phase III trial with a 3-year follow-up. Last, systemic agents such as statins and antihypertensives have been studied as radioprotectors of late rectal injury. The retrospective studies on this topic are promising, but additional prospective data is needed before this can be recommended to all patients undergoing RT for prostate cancer.
Disclosure
The authors report no conflicts of interest in this work.
Nicholas A. Serrano,1 Noah S. Kalman,1 Mitchell S. Ancher2
1Department of Radiation Oncology, Virginia Commonwealth University – Massey Cancer Center, Richmond, VA, 2Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
References
1. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–122.
2. Hauer-Jensen M, Wang J, Denham JW. Bowel injury: current and evolving management strategies. Semin Radiat Oncol. 2003;13(3):357–371.
3. Buchi K. Radiation proctitis: therapy and prognosis. JAMA. 1991; 265(9):1180.
4. Hasleton PS, Carr N, Schofield PF. Vascular changes in radiation bowel disease. Histopathology. 1985;9(5):517–534.
5. Fajardo LF. The pathology of ionizing radiation as defined by morphologic patterns. Acta Oncol. 2005;44(1):13–22.
6. Zelefsky MJ, Fuks Z, Happersett L, et al. Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol. 2000;55(3):241–249.
7. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294(10):1233–1239.
8. Merrick GS, Wallner KE, Butler WM, Blasko JC. Permanent prostate brachytherapy: is supplemental external-beam radiation therapy necessary? Oncology (Williston Park). 2006;20(5):514–522; discussion 522–525.
9. Morris WJ, Tyldesley S, Rodda S, et al. Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT Trial): an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017;98(2):275–285.
10. Giordano SH, Lee A, Kuo YF, Freeman J, Goodwin JS. Late gastrointestinal toxicity after radiation for prostate cancer. Cancer. 2006;107(2):423–432.
11. Al-Mamgani A, van Putten WL, Heemsbergen WD, et al. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;72(4):980–988.
12. Dearnaley DP, Sydes MR, Graham JD, et al; RT01 collaborators. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol. 2007;8(6):475–487.
13. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70(1):67–74.
14. Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70(4):1124–1129.
15. Alicikus ZA, Yamada Y, Zhang Z, et al. Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer. Cancer. 2011;117(7):1429–1437.
16. Peeters ST, Heemsbergen WD, van Putten WL, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys. 2005;61(4):1019–1034.
17. Boyer AL, Antonuk L, Fenster A, et al. A review of electronic portal imaging devices (EPIDs). Med Phys. 1992;19(1):1–16.
18. Kessler ML, McShan DL, Fraass BA. A computer-controlled conformal radiotherapy system. III: graphical simulation and monitoring of treatment delivery. Int J Radiat Oncol Biol Phys. 1995;33(5):1173–1180.
19. Jaffray DA, Siewerdsen JH, Wong JW, Martinez AA. Flat-panel cone-beam computed tomography for image-guided radiation therapy. Int J Radiat Oncol Biol Phys. 2002;53(5):1337–1349.
20. Lu W, Olivera GH, Chen Q, et al. Deformable registration of the planning image (kVCT) and the daily images (MVCT) for adaptive radiation therapy. Phys Med Biol. 2006;51(17):4357–4374.
21. Shirato H, Harada T, Harabayashi T, et al. Feasibility of insertion/implantation of 2.0-mm-diameter gold internal fiducial markers for precise setup and real-time tumor tracking in radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56(1):240–247.
22. Balter JM, Wright JN, Newell LJ, et al. Accuracy of a wireless localization system for radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61(3):933–937.
23. Rajendran RR, Plastaras JP, Mick R, McMichael Kohler D, Kassaee A, Vapiwala N. Daily isocenter correction with electromagnetic-based localization improves target coverage and rectal sparing during prostate radiotherapy. Int J Radiat Oncol Biol Phys. 2010;76(4):1092–1099.
24. Chung HT, Xia P, Chan LW, Park-Somers E, Roach M 3rd. Does image-guided radiotherapy improve toxicity profile in whole pelvic-treated high-risk prostate cancer? Comparison between IG-IMRT and IMRT. Int J Radiat Oncol Biol Phys. 2009;73(1):53–60.
25. Fiorino C, Valdagni R, Rancati T, Sanguineti G. Dose-volume effects for normal tissues in external radiotherapy: pelvis. Radiother Oncol. 2009;93(2):153–167.
26. Jackson A, Skwarchuk MW, Zelefsky MJ, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys. 2001;49(3):685–698.
27. Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions. Radiother Oncol. 2002;64(1):1–12.
28. Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys. 2003;57(4):953–962.
29. Rancati T, Fiorino C, Gagliardi G, et al. Fitting late rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101). Radiother Oncol. 2004;73(1):21–32.
30. Vargas C, Martinez A, Kestin LL, et al. Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62(5):1297–1308.
31. Söhn M, Yan D, Liang J, Meldolesi E, Vargas C, Alber M. Incidence of late rectal bleeding in high-dose conformal radiotherapy of prostate cancer using equivalent uniform dose-based and dose-volume-based normal tissue complication probability models. Int J Radiat Oncol Biol Phys. 2007;67(4):1066–1073.
32. Fiorino C, Fellin G, Rancati T, et al. Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: preliminary results of a multicenter prospective study. Int J Radiat Oncol Biol Phys. 2008;70(4):1130–1137.
33. Storey MR, Pollack A, Zagars G, Smith L, Antolak J, Rosen I. Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys. 2000;48(3):635–642.
34. Huang EH, Pollack A, Levy L, et al. Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2002;54(5):1314–1321.
35. van der Laan HP, van den Bergh A, Schilstra C, Vlasman R, Meertens H, Langendijk JA. Grading-system-dependent volume effects for late radiation-induced rectal toxicity after curative radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70(4):1138–1145.
36. Peeters ST, Hoogeman MS, Heemsbergen WD, Hart AA, Koper PC, Lebesque JV. Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling. Int J Radiat Oncol Biol Phys. 2006;66(1):11–19.
37. Michalski JM, Winter K, Purdy JA, et al. Toxicity after three-dimensional radiotherapy for prostate cancer with RTOG 9406 dose level IV. Int J Radiat Oncol Biol Phys. 2004;58(3):735–742.
38. Peeters ST, Hoogeman MS, Heemsbergen WD, et al. Volume and hormonal effects for acute side effects of rectum and bladder during conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2005;63(4):1142–1152.
39. Schaake W, van der Schaaf A, van Dijk LV, Bongaerts AH, van den Bergh AC, Langendijk JA. Normal tissue complication probability (NTCP) models for late rectal bleeding, stool frequency and fecal incontinence after radiotherapy in prostate cancer patients. Radiother Oncol. 2016;119(3):381–387.
40. Mirjolet C, Walker PM, Gauthier M, et al. Absolute volume of the rectum and AUC from rectal DVH between 25Gy and 50Gy predict acute gastrointestinal toxicity with IG-IMRT in prostate cancer. Radiat Oncol. 2016;11(1):145.
41. Dréan G, Acosta O, Ospina JD, et al. Identification of a rectal subregion highly predictive of rectal bleeding in prostate cancer IMRT. Radiother Oncol. 2016;119(3):388–397.
42. Brenner DJ, Martinez AA, Edmundson GK, Mitchell C, Thames HD, Armour EP. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys. 2002;52(1):6–13.
43. Miralbell R, Roberts SA, Zubizarreta E, Hendry JH. Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: α/β = 1.4 (0.9–2.2) Gy. Int J Radiat Oncol Biol Phys. 2012;82(1):e17–e24.
44. Thames HD, Bentzen SM, Turesson I, Overgaard M, Van den Bogaert W. Time-dose factors in radiotherapy: a review of the human data. Radiother Oncol. 1990;19(3):219–235.
45. Dearnaley D, Syndikus I, Mossop H, et al; CHHiP Investigators. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047–1060.
46. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III oninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34(20):2325–2332.
47. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol. 2017;35(17):1884–1890.
48. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1061–1069.
49. Benjamin LC, Tree AC, Dearnaley DP. The role of hypofractionated radiotherapy in prostate cancer. Curr Oncol Rep. 2017;19(4):30.
50. D’Amico AV, Manola J, Loffredo M, et al. A practical method to achieve prostate gland immobilization and target verification for daily treatment. Int J Radiat Oncol Biol Phys. 2001;51(5):1431–1436.
51. McGary JE, Teh BS, Butler EB, Grant W 3rd. Prostate immobilization using a rectal balloon. J Appl Clin Med Phys. 2002;3(1):6–11.
52. Teh BS, Woo SY, Mai WY, et al. Clinical experience with intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of rectal balloon for prostate immobilization. Med Dosim. 2002;27(2):105–113.
53. van Lin EN, van der Vight LP, Witjes JA, Huisman HJ, Leer JW, Visser AG. The effect of an endorectal balloon and off-line correction on the interfraction systematic and random prostate position variations: a comparative study. Int J Radiat Oncol Biol Phys. 2005;61(1):278–288.
54. El-Bassiouni M, Davis JB, El-Attar I, Studer GM, Lütolf UM, Ciernik IF. Target motion variability and on-line positioning accuracy during external-beam radiation therapy of prostate cancer with an endorectal balloon device. Strahlenther Onkol. 2006;182(9):531–536.
55. Wachter S, Gerstner N, Dorner D, et al. The influence of a rectal balloon tube as internal immobilization device on variations of volumes and dose-volume histograms during treatment course of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2002;52(1):91–100.
56. Hille A, Schmidberger H, Töws N, Weiss E, Vorwerk H, Hess CF. The impact of varying volumes in rectal balloons on rectal dose sparing in conformal radiation therapy of prostate cancer. A prospective three-dimensional analysis. Strahlenther Onkol. 2005;181(11):709–716.
57. Elsayed H, Bölling T, Moustakis C, et al. Organ movements and dose exposures in teletherapy of prostate cancer using a rectal balloon. Strahlenther Onkol. 2007;183(11):617–624.
58. Patel RR, Orton N, Tome WA, Chappell R, Ritter MA. Rectal dose sparing with a balloon catheter and ultrasound localization in conformal radiation therapy for prostate cancer. Radiother Oncol. 2003; 67(3):285–294.
59. van Lin EN, Hoffmann AL, van Kollenburg P, Leer JW, Visser AG. Rectal wall sparing effect of three different endorectal balloons in 3D conformal and IMRT prostate radiotherapy. Int J Radiat Oncol Biol Phys. 2005;63(2):565–576.
60. van Lin EN, Kristinsson J, Philippens ME, et al. Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy. Int J Radiat Oncol Biol Phys. 2007;67(3):799–811.
61. Schutzer ME, Orio PF, Biagioli MC, Asher DA, Lomas H, Moghanaki D. A review of rectal toxicity following permanent low dose-rate prostate brachytherapy and the potential value of biodegradable rectal spacers. Prostate Cancer Prostatic Dis. 2015;18(2):96–103.
62. Prada PJ, Gonzalez H, Menéndez C, et al. Transperineal injection of hyaluronic acid in the anterior perirectal fat to decrease rectal toxicity from radiation delivered with low-dose-rate brachytherapy for prostate cancer patients. Brachytherapy. 2009;8(2):210–217.
63. Noyes WR, Hosford CC, Schultz SE. Human collagen injections to reduce rectal dose during radiotherapy. Int J Radiat Oncol Biol Phys. 2012;82(5):1918–1922.
64. Melchert C, Gez E, Bohlen G, et al. 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. 2013;106(2):210–214.
65. Susil RC, McNutt TR, DeWeese TL, Song D. Effects of prostate-rectum separation on rectal dose from external beam radiotherapy. Int J Radiat Oncol Biol Phys. 2010;76(4):1251–1258.
66. Strom TJ, Wilder RB, Fernandez DC, et al. A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy±intensity modulated radiation therapy. Radiother Oncol. 2014;111(1):126–131.
67. Beydoun N, Bucci JA, Chin YS, Malouf D, Enari E, Painter SD. First report of transperineal polyethylene glycol hydrogel spacer use to curtail rectal radiation dose after permanent iodine-125 prostate brachytherapy. Brachytherapy. 2013;12(4):368–374.
68. Mahal BA, Ziehr DR, Hyatt AS, et al. Use of a rectal spacer with low-dose-rate brachytherapy for treatment of prostate cancer in previously irradiated patients: initial experience and short-term results. Brachytherapy. 2014;13(5):442–449.
69. Alongi F, Cozzi L, Arcangeli S, et al. Linac based SBRT for prostate cancer in 5 fractions with VMAT and flattening filter free beams: preliminary report of a phase II study. Radiat Oncol. 2013;8:171.
70. Uhl M, van Triest B, Eble MJ, Weber DC, Herfarth K, De Weese TL. Low rectal toxicity after dose escalated IMRT treatment of prostate cancer using an absorbable hydrogel for increasing and maintaining space between the rectum and prostate: results of a multi-institutional phase II trial. Radiother Oncol. 2013;106(2):215–219.
71. Eckert F, Alloussi S, Paulsen F, et al. Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer. BMC Cancer. 2013;13:27.
72. Pinkawa M, Piroth MD, Holy R, et al. Quality of life after intensity-modulated radiotherapy for prostate cancer with a hydrogel spacer. Matched-pair analysis. Strahlenther Onkol. 2012;188(10):917–925.
73. Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys. 2007;67(4):1099–1105.
74. McBride SM, Wong DS, Dombrowski JJ, et al. Hypofractionated stereotactic body radiotherapy in low-risk prostate adenocarcinoma: preliminary results of a multi-institutional phase 1 feasibility trial. Cancer. 2012;118(15):3681–3690.
75. Katz A, Kang J. Stereotactic body radiotherapy with or without external beam radiation as treatment for organ confined high-risk prostate carcinoma: a six year study. Radiat Oncol. 2014;9:1.
76. Loblaw A, Cheung P, D’Alimonte L, et al. Prostate stereotactic ablative body radiotherapy using a standard linear accelerator: toxicity, biochemical, and pathological outcomes. Radiother Oncol. 2013;107(2):153–158.
77. Kang JK, Cho CK, Choi CW, et al. Image-guided stereotactic body radiation therapy for localized prostate cancer. Tumori. 2011;97(1):43–48.
78. Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiat Oncol. 2011;6:3.
79. Kim DW, Cho LC, Straka C, et al. Predictors of rectal tolerance observed in a dose-escalated phase 1-2 trial of stereotactic body radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014;89(3):509–517.
80. Hamstra DA, Mariados N, Sylvester J, et al. Continued benefit to rectal separation for prostate radiation therapy: final results of a phase III trial. Int J Radiat Oncol Biol Phys. 2017;97(5):976–985.
81. Boerma M, Burton GR, Wang J, Fink LM, McGehee RE Jr, Hauer-Jensen M. Comparative expression profiling in primary and immortalized endothelial cells: changes in gene expression in response to hydroxy methylglutaryl-coenzyme A reductase inhibition. Blood Coagul Fibrinolysis. 2006;17(3):173–180.
82. Gaugler MH, Vereycken-Holler V, Squiban C, Vandamme M, Vozenin-Brotons MC, Benderitter M. Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses. Radiat Res. 2005;163(5):479–487.
83. Nübel T, Damrot J, Roos WP, Kaina B, Fritz G. Lovastatin protects human endothelial cells from killing by ionizing radiation without impairing induction and repair of DNA double-strand breaks. Clin Cancer Res. 2006;12(3 Pt 1):933–939.
84. Rikitake Y, Kawashima S, Takeshita S, et al. Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 2001;154(1):87–96.
85. Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb. 2002;9(4):178–183.
86. Waehre T, Damås JK, Gullestad L, et al. Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease. J Am Coll Cardiol. 2003;41(9):1460–1467.
87. Undas A, Brozek J, Musial J. Anti-inflammatory and antithrombotic effects of statins in the management of coronary artery disease. Clin Lab. 2002;48(5–6):287–296.
88. Shi J, Wang J, Zheng H, et al. Statins increase thrombomodulin expression and function in human endothelial cells by a nitric oxide-dependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulation. Blood Coagul Fibrinolysis. 2003;14(6):575–585.
89. Pérez-Guerrero C, Alvarez de Sotomayor M, Jimenez L, Herrera MD, Marhuenda E. Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME. J Cardiovasc Pharmacol. 2003;42(2):204–210.
90. Wedlake LJ, Silia F, Benton B, et al. Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies. Eur J Cancer. 2012;48(14):2117–2124.
91. Palumbo I, Matrone F, Montesi G, et al. Statins protect against acute RT-related rectal toxicity in patients with prostate cancer: an observational prospective study. Anticancer Res. 2017;37(3):1453–1457.
92. Anscher MS, Chang MG, Moghanaki D, et al. A phase II study to prevent radiation-induced rectal injury with lovastatin. Am J Clin Oncol. Epub 2016 July 19.
93. Sarosdy MF. Urinary and rectal complications of contemporary permanent transperineal brachytherapy for prostate carcinoma with or without external beam radiation therapy. Cancer. 2004;101(4):754–760.
94. Akimoto T, Muramatsu H, Takahashi M, et al. Rectal bleeding after hypofractionated radiotherapy for prostate cancer: correlation between clinical and dosimetric parameters and the incidence of grade 2 or worse rectal bleeding. Int J Radiat Oncol Biol Phys. 2004;60(4):1033–1039.
95. Lee CM, Lee RJ, Handrahan DL, Sause WT. Comparison of late rectal toxicity from conventional versus three-dimensional conformal radiotherapy for prostate cancer: analysis of clinical and dosimetric factors. Urology. 2005;65(1):114–119.
96. Sherertz T, Wallner K, Merrick G, et al. Factors predictive of rectal bleeding after 103Pd and supplemental beam radiation for prostate cancer. Brachytherapy. 2004;3(3):130–135.
97. Tucker SL, Dong L, Cheung R, et al. Comparison of rectal dose-wall histogram versus dose-volume histogram for modeling the incidence of late rectal bleeding after radiotherapy. Int J Radiat Oncol Biol Phys. 2004;60(5):1589–1601.
98. Waterman FM, Dicker AP. Probability of late rectal morbidity in 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2003;55(2):342–353.
99. Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate brachytherapy as monotherapy for localized prostate cancer: a retrospective analysis with special focus on tolerance and chronic toxicity. Int J Radiat Oncol Biol Phys. 2003;56(1):213–220.
100. Albert M, Tempany CM, Schultz D, et al. Late genitourinary and gastrointestinal toxicity after magnetic resonance image-guided prostate brachytherapy with or without neoadjuvant external beam radiation therapy. Cancer. 2003;98(5):949–954.
101. Ryu JK, Winter K, Michalski JM, et al. Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy). Int J Radiat Oncol Biol Phys. 2002;54(4):1036–1046.
102. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys. 2000;47(1):103–113.
103. Hoffman KE, Skinner H, Pugh TJ, et al. Patient-reported urinary, bowel, and sexual function after hypofractionated intensity-modulated radiation therapy for prostate cancer: results from a randomized trial. Am J Clin Oncol. Epub 2016 Sep 15.
104. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31(31):3860–3868.
105. Katz AJ, Kang J. Quality of life and toxicity after SBRT for organ-confined prostate cancer, a 7-year study. Front Oncol. 2014;4:301.
106. Chen LN, Suy S, Uhm S, et al. Stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer: the Georgetown University experience. Radiat Oncol. 2013;8:58.
107. King CR, Brooks JD, Gill H, Presti JC Jr. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82(2):877–882.
108. World Endoscopy Organization [homepage on the Internet]. Radiation proctitis; 2012 [cited December 25, 2012]. Available from: http://www.endoatlas.org/index.php?page=results_jquery&mstcat=3. Accessed July 14, 2017.
109. Lang S, Riesterer O. Progress in Physics: Modern Techniques in Radiation Oncology. SPG Mitteilungen. 2013;41(36):19–22.
110. Augmenix, Inc. [homepage on the internet]. Bedford, MA, USA: SpaceOAR® system – spacing organs at risk. Available from: http://review.augmenix.com/products/spaceoar/. Accessed April 5, 2017.
Source: Cancer Management and Research
Originally published July 28, 2017.
