Stereotactic Radiation Potential Emerges in Prostate Cancer

Oncology Live®Vol. 17/No. 19
Volume 17
Issue 19

Stereotactic ablative radiosurgery, which is administered in far fewer but larger doses than conventional radiotherapy, has the potential to benefit a substantial proportion of patients with low-, intermediate-, and potentially even high-risk prostate cancers.

Michael Folkert, MD, PhD

Assistant Professor

Radiation Oncology

UT Southwestern Medical Center

Dallas, TX

With widespread use of prostate-specific antigen (PSA) screening, a majority of newly diagnosed prostate cancers are confined to the organ and are typically treated with radical prostatectomy or radiotherapy.

An emerging radiotherapy option is stereotactic ablative radiosurgery (SABR), also called stereotactic body radiation therapy (SBRT), in which multiple- focused radiation beams deliver a large ablative or destructive dose of radiation to a tumor target.

SABR, which is administered in far fewer but larger doses than conventional radiotherapy, has the potential to benefit a substantial proportion of patients with low-, intermediate-, and potentially even high-risk prostate cancers. While all patients are potentially eligible for radiation treatmenfigut, these shortened courses may be the treatment of choice for those who, due to comorbidities, are not candidates for surgery, or those who have difficulty meeting scheduling demands of traditional, longer-term radiotherapy.

Clinical trials over the past decade have revealed therapeutic advantages of various short-course, or hypofractionated, approaches in prostate cancer, including SABR. Investigations also are underway to address a specific challenge associated with SABR to the prostate: the potential for rectal injury.

Evidence has indicated that dose escalation of conventionally fractionated external-beam radiation improves prostate cancer control and can provide a survival advantage for patients with intermediate- or high-risk disease.1,2,3 With this approach, 3-dimensional conformal or intensity-modulated radiation therapy (IMRT) approaches can limit toxicity—although many fractions are required, typically 5 days a week for a period of 8 or 9 weeks.

Given prostate cancer’s damage-repair characteristics, which indicate that the disease might be better eradicated with fewer, more powerful radiation doses than with longer, lower-dose courses of treatment,4,5 modest hypofractionated regimens (with fraction sizes ranging from ~2-3 Gy) have been proposed to improve treatment efficacy as well as patient convenience. Recent clinical trials using regimens that are more hypofractionated than conventional treatment schedules have shown that efficacious therapy can be delivered more efficiently, and with manageable toxicity, using equivalent effective doses with hypofractionation.6-10 Subsequently, a handful of studies have demonstrated excellent therapeutic outcomes, along with acceptable safety profiles, using even more hypofractionated approaches (6.5-10 Gy per fraction). Among them:

  • In a phase I/II trial, 40 men with low-risk prostate cancer (Gleason score ≤6, PSA <10 ng/mL and clinical stage ≤T2a) received 5 fractions, 6.7 Gy per fraction, for a total dose of 33.5 Gy targeting the prostate plus a 4 to 5 mm margin. Four-year actuarial freedom from biochemical recurrence was 90% under the Phoenix failure definition (nadir + 2 ng/mL).11
  • A phase II trial involving 67 patients with low-to-intermediate risk (Gleason score 3+3 or 3+4, PSA ≤10 ng/mL, and clinical stage ≤T2b) tested 5 fractions of 7.25 Gy, a total dose of 36.25 Gy, delivered to the prostate with a margin of 3 to 5 mm. PSA relapse-free survival was 94% at 4 years.12
  • In a trial testing SABR in 304 low-, intermediateand high-risk patients with prostate cancer, the majority of whom were low risk, 50 patients were administered 5 fractions of 7 Gy (total dose 35 Gy); the rest received 5 fractions of 7.25 Gy (36.25 Gy total). With median follow-up of 30 months for the lower-dose patients and 17 months for the higher-dose group, actuarial 5-year biochemical recurrence-free survival was 97% for the patients with low-risk cancers, almost 91% for intermediate- risk patients, and 74% for high-risk patients.13 In a phase I/II study led by the UT Southwestern Medical Center at Dallas and 4 other sites,14,15 investigators have tested SABR in low- and intermediate-risk patients using substantially higher doses, starting in 15 patients at 45 Gy in 5 fractions—similar to those used in hypofractionated high-dose-rate brachytherapy.16 The 5-fraction total doses were escalated to 47.5 Gy and finally to 50 Gy. No grade 3-5 toxicities occurred within 90 days after treatment. Overall, grade ≥2 GI toxicities occurred in 18% of patients, and grade ≥3 in 2%, while grade ≥2 GU toxicities were experienced by 31% of patients, with grade ≥3 occurring in 4%. In the subsequent phase II expansion, 46 additional patients were enrolled and treated at the 50-Gy dose level. At median follow-up of 54 months, actuarial freedom from biochemical failure was 98.6% at 5 years.17 However, 6 patients developed high-grade rectal toxicity, primarily ulceration to the anterior rectal wall, that ultimately required 5 patients to undergo a diverting colostomy—highlighting a crucial limitation to dose escalation in prostate cancer radiotherapy.18 Aiming to reduce the radiation dose to the rectal wall while retaining the therapeutic benefit of highdose treatment, the UT Southwestern team has been investigating the use of a minimally invasive, biodegradable spacer to increase the distance between the prostate and the rectum in patients with low- and intermediate-risk prostate cancer treated with SABR in a prospective clinical trial (NCT02353832). The spacer is an FDA-approved polyethylene glycol (PEG)-based gel that can be placed via transperineal injection at the same time radio-opaque markers are implanted to help target the prostate during radiation therapy (Figure). The spacer dissolves after 12 weeks. Courtesy of Augmenix This approach already has proved successful in conventional and IMRT, with no evidence of ulceration, stricture, or necrosis to rectal tissue after a year.19-21 The trial accrual is nearly complete, and results should be available within a year. Additionally, a trial investigating treatment of both the prostate and pelvis with SABR in 5 fractions in conjunction with androgen deprivation therapy for patients with high-risk prostate cancer has opened and is currently accruing at UT Southwestern (NCT02353819). References Kalbasi A, Li J, Berman A, et al. Dose-escalated irradiation and overall survival in men with nonmetastatic prostate cancer. JAMA Oncol. 2015;1(7):897-906. doi: 10.1001/jamaoncol.2015.2316. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol. 2010;28(7):1106-1111. doi: 10.1200/JCO.2009.25.8475. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the MD Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:67-74. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43:1095-1101. Williams SG, Taylor JM, Liu N, et al. Use of individual fraction size data from 3756 patients to directly determine the alpha/beta ratio of prostate cancer. Int J Radiat Oncol Biol Phys. 2007;68:24-33. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31:3860-3868. doi: 10.1200/JCO.2013.51.1972. Arcangeli G, Saracino B, Gomellini S, et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78(1):11-18. doi: 10.1016/j.ijrobp.2009.07.1691. Kuban DA, Nogueras-Gonzalez GM, Hamblin L, et al. Preliminary report of a randomized dose-escalation trial for prostate cancer using hypofractionation. Int J Radiat Oncol Biol Phys. 2010;78:S58-S9. Kupelian PA, Willoughby TR, Reddy CA, Klein EA, Mahadevan A. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys. 2007;68:1424-1430. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34(20):2325-2332. doi: 10.1200/JCO.2016.67.0448. 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;67:1099-1105. 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;82:877-882. doi: 10.1016/j.ijrobp.2010.11.054. Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years. Radiat Oncol 2013;8:118. doi: 10.1186/1748-717X-8-118. Kim DW, Straka C, Cho LC, Timmerman RD. Stereotactic body radiation therapy for prostate cancer: Review of experience of a multicenter phase I/II dose-escalation study. Frontiers in Oncol. 2014;4:319. doi: 10.3389/fonc.2014.00319. Hannan R, Tumati V, Xie XJ, Cho LC, Kavanagh BD, Brindle J, Raben D, Nanda A, Cooley S, Kim DW, Pistenmaa D, Lotan Y, Timmerman R. Stereotactic body radiation therapy for low- and intermediate-risk prostate cancer: Results from a multi-institutional clinical trial. Eur J Cancer. 2016;59:142-151. doi: 10.1016/j.ejca.2016.02.014. Duchesne GM, Peters LJ. What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 1999;44(4):747-748. Hannan R, Tumati V, Xie XJ, et al. Stereotactic body radiation therapy for low and intermediate risk prostate cancer-Results from a multi-institutional clinical trial. Eur J Cancer. 2016;59:142-151. doi: 10.1016/j.ejca.2016.02.014. Kim DW, Cho LC, Straka C, et al. Predictors of rectal tolerance observed in a dose-escalated phase I/II trial of stereotactic body radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014;89(3):509-517. doi: 10.1016/j.ijrobp.2014.03.012. Mariados N, Sylvester J, Shah D, et al. Hydrogel Spacer Prospective Multicenter Randomized Controlled Pivotal Trial: Dosimetric and clinical effects of perirectal spacer application in men undergoing prostate image-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2015;92(5):971-977. doi: 10.1016/j.ijrobp.2015.04.030. Uhl M, Herfarth K, Eble MJ, et al. Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial. Radiat Oncol. 2014;9:96. doi: 10.1186/1748-717X-9-96. Song DY, Herfarth KK, Uhl M, et al. A multi-institutional clinical trial of rectal dose reduction via injected polyethylene-glycol hydrogel during intensity modulated radiation therapy for prostate cancer: Analysis of dosimetric outcomes. Int J Radiat Oncol Biol Phys. 2013;87(1):81-87. doi: 10.1016/j.ijrobp.2012.12.019.
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