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.
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.
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.
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
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Source: Cancer Management and Research
Originally published July 28, 2017.