Acute side effects after definitive stereotactic body radiation therapy (SBRT) for patients with clinically localized or locally advanced prostate cancer: a single institution prospective study

Prostate cancer is the most common malignancy among men of European western countries.1 In the male population, the incidence of prostate cancer ranks third in Hungary.2 Based on the available evidence, treatment options for organ-confined prostate cancer include radical prostatectomy, external beam radiation therapy, brachytherapy, and active follow-up.3, 4, 5 In a three-arm, phase III, randomized trial (ProtecT), active monitoring, radical prostatectomy and external beam radiation therapy (EBRT) were compared in patients with non-metastatic, lymph node negative prostate cancer.6, 7

After a median follow-up of 10 years there was no significant difference in prostate cancer specific mortality and overall survival. Significant differences were recognized only in the late side effects regarding bowel-, urinary- and sexual function. Therefore, the toxicity after any curative treatment, and the length and burden of the treatment itself are of great importance. Since Brenner and Hall8 suggested a low α/β ratio (1.5) for prostate adenocarcinoma, two treatment options have been investigated for external beam irradiation therapy of prostate cancer patients: moderate hypofractionation (2.2–4Gy/fraction)9 and extreme hypofractionation (3.5–15Gy/fraction).10 Three non-inferiority, phase III randomized trials compared conventional fractionation (CF) with moderate hypofractionation (MH), enrolling more than 5500 patients with prostate cancer.11,12,13 At 5-year follow-up these two modalities were shown to be equivalent in terms of tumor control and late side effects, supporting MH as a standard-of-care. In addition to MH, another method of hypofractionation can be used in the radiation treatment of prostate cancer mainly for patients with low- and intermediate-risk. The extreme hypofractionation (stereotactic body radiation therapy, SBRT) can be performed with either a conventional linear accelerator14, 15 or a robotic arm (CyberKnife, Accuray Incorporated, Sunnyvale, CA) linear accelerator.16 Currently, more and more results are reported on the effectiveness and tolerability of SBRT, predominantly from retrospective and prospective, non-randomized trials. The advantage of SBRT lies in the use of high and precise ablative doses. In addition, overall treatment-time is relatively short (1–2 weeks) compared to conventional or moderately hypofractionated EBRT, and in contrast to surgery or brachytherapy the treatment is non-invasive.

At our institution we have been performing robotic-arm stereotactic radiation treatments since February 2018. The aim of our prospective study was to implement extreme hypofractionated, robotic-arm based SBRT for the treatment of low-, intermediate- and high-risk, lymph node negative prostate cancer patients and to investigate the acute radiotherapy-related side effects.

Our prospective study was initiated in February 2018 after approval by our institutional Ethics Committee. Histologically confirmed, low-, intermediate- and high-risk prostate cancer patients were enrolled. Before radiation therapy staging was required (CT scan or pelvic MRI and bone scan). Lymph node or distant metastasis and previous pelvic irradiation were exclusion criteria. Gold fiducial markers were implanted into the prostate of each patient for image-guided radiotherapy (IGRT). The method is described in details in our previous studies.17, 18 Briefly, patients received 100 mg tramadol and 5 mg metoclopramide intramuscularly half an hour prior to the procedure. Subsequently, patients were laid down in lithotomy position and 4 gold markers were transperineally inserted into the prostate under rectal ultrasound (US) guidance. In the same plane, two markers were placed near the prostate base, two in the apex. For treatment planning, 14–20 days after marker implantation a topometric CT (TOP CT) was performed in supine position using knee fixation support system for immobilization of the legs. Axial images were obtained with 1.25 mm slice thickness from L1 vertebra to about 3 cm below the ischial tuberosities. A Metal Artefact Reduction (MAR) corrected CT scan was also acquired to reduce the artefact effects of implanted gold markers. Prior to TOP CT, patients were instructed to have moderately, comfortably filled bladder by drinking 0.5 litre of water (after having it emptied) half an hour prior to CT and an empty rectum. In case of habitual constipation light laxative was recommended. In our study, patients were treated according to D’Amico’s classification in 3 risk groups.19 In low-risk patients the clinical target volume for ptostate (CTVpros) was the prostate gland. For intermediate-risk two clinical target volumes were created. CTVpros was the same as above. The prostate and seminal vesicles CTV (CTVpsv) was generated by 5 mm expansion of CTVpros in all directions except posteriorly at the prostate-rectum interface + proximal 1 cm of the seminal vesicles. For high-risk patients CTVpros was the same as above. CTVpsv was defined by 5 mm expansion of CTVpros in all directions except posteriorly + proximal 2 cm of seminal vesicles (in case of cT3b the entire seminal vesicles were included).

Planning target volumes (PTVpros, PTVpsv) were formed from CTVs with 3mm extensions in each direction. Depending on the performance status and age of the patients for low-risk patients 7.5–8 Gy fraction dose was applied to PTVpros. In case of intermediate- and high-risk disease 7.5–8 Gy fraction dose to PTVpros and a 6–6.5 Gy fraction dose to PTVpsv, with a simultaneous integrated boost (SIB) technique was given. A total of 5 fractions (total dose for prostate 37.5–40 Gy) were administered every other day. The dose constraints for the organs at risk are detailed in Table 1.

The treatment plans were prepared using the Accuray Precision 1.1.1.1 planning system. The dose was prescribed to the 80–85% isodose curve. Dose-coverage requirement for target volumes (PTVpros, PTVpsv) was V100% > 95%. Irradiation from non-coplanar fields was performed using a multileaf collimator with a CyberKnife M6 (Accuray, Sunyvale, CA) robotic accelerator. Based on planning CT digitally reconstructed X-ray images (DRRs) from 45 and 315 degrees were generated and served as reference images for patient alignment. At the start of the treatment, x-rays of the same directions were taken showing the position of gold markers in the prostate. Subsequently, the images were matched by a software and the inaccuracy of the alignment was determined based on the position of the markers in three directions (lateral, longitudinal, vertical) and rotation (roll, pitch, rotation). If the inaccuracy of the set-up was greater than 10 mm or 3 degrees, we automatically corrected the deviation by moving the treatment couch. In case of a smaller set-up inaccuracy, the corrections were applied by the robotic arm during operation. This verification course was repeated every 20–60 seconds during the treatments, depending on the intra-fractional prostate movements. Patients were followed-up during radiation treatment, after the second and last fractions, then every 3 months. In the present study, maximal acute toxicity data were reported up to the last day of radiotherapy and 3 months after treatment. Acute genitourinary (GU) and gastrointestinal (GI) side effects were classified according to the Radiation Therapy Oncology Group (RTOG) scoring system (Table 2.).20 In Statistica software (StatSoft, Inc., USA) Spearman rank order tests were used to evaluate the correlations between risk groups, total dose (37.5 Gy vs. 40 Gy), age of patients, hormonal therapy, volume of CTVpros, PTVpros, CTVpsv, PTVpsv, dosimetric parameters of rectum (D0.04ccm, D20ccm), bladder (V26Gy, D0.04ccm), pre-treatment transurethral resection of prostate (TURP) and acute GI, GU side effects. Statistical significance was set at p < 0.05.

Between February 2018 and August 2019, 205 patients with prostate cancer were treated definitively with SBRT. Median follow-up was 8 months. The mean age of the patients was 71 years (range: 58–78 years). The patient, tumor and treatment characteristics are summarized in Table 3. No peri-and postoperative complications were observed after implantation of the gold markers. 179 patients (87.3%) received a total dose of 40 Gy (8 Gy/ fraction[fx]) and 26 patients (12.7%) 37.5 Gy (7.5 Gy/fx). Dose volumes parameters of the rectum and bladder, volumes and dose coverage of the prostate and seminal vesicles clinical- and planning target volumes (CTVpros, CTVpsv, PTVpros, PTVpsv) of patients are summarized in Tables 4 and 5. The duration of radiation treatment was 1 week and 3 days (3 fractions per week). The delivery of a fraction took 25–45 minutes, depending on the complexity of the treatment plan and the frequency of verification X-rays. The frequency of control imaging was related to intra-fractional prostate movements. During control imaging, all the implanted gold markers were clearly visible with a sufficient distance from each other. No marker migration was detected.

In our patients, acute grade 3 side effects were rare, most of acute toxicity resolved spontaneously or with the administration of medications. 202 patients (98.5%) completed radiation therapy at the planned dose and did not require a therapeutic interruption due to radiotherapy-related adverse events. Three patients (1.5%) had to have an urethral catheter inserted due to a complete retention of urine. One of them underwent transurethral resection of prostate (TURP) two months after treatment. After that the radiation therapy was completed with conventional fractionation. The second one refused to complete the radiation treatment, he is currently receiving hormone therapy. The third patient had a urethral catheter only for one week, after that urinary complaints resolved by using α-blockers and the treatment was completed with the planned dose. Acute grade 2 and 3 GU toxicity was reported in 104 (50.7%) and 3 (1.5%) cases, respectively. Acute grade 2 and 3 GI adverse events occurred in 12 (5.9%) and 0 (0%) patients, respectively. None of the patients developed ≥ grade 4 acute side effect. At 3 months after the treatment the incidence of grade 2 and 3 GI toxicity was 0.5% (n = 1) and 0% (n = 0), while grade 2 and 3 GU side effects occurred in 9.7% (n = 20) and 1% (n = 2) of the patients, respectively. Frequency of radiotherapy-related toxicities according to the RTOG grading system during radiation therapy and 3 months after treatment are detailed in Table 6. Acute side effects at the end of radiotherapy according to the risk groups are shown in Table 7.

No statistical correlation was detected between risk groups, age of patients, hormone therapy, pretreatment TURP and acute GI, GU side effects.

Significant correlation was observed between acute ≤ 2 GU toxicities and pre-treatment TURP, delivered dose, volumes of CTVpros, CTVpsv, PTVpros, PTVpsv, bladder V26Gy, D0.04ccm (p < 0.05). No other parameters had a significant correlation with toxicity.

Organ confined prostate cancer is usually treated with EBRT. Data from phase III, randomized studies support MH to be non-inferior to CF. Recently a great interest is shown in SBRT. According to surveys, the biggest disadvantage of CF is the long treatment time.21 Due to the low fraction number, on our opinion SBRT may have the potential to increases patient satisfaction with treatment. This is supported by the fact that it is a non-invasive treatment option.22 Compared with conventional EBRT stereotactic irradiation treatment of prostate cancer seems to be the most cost-effective management option.23 Also taking into account the radiobiological benefit of hypofractionation, the acceptance of extreme hypofractionation with SBRT is increasing in medical communities.

Recently, Brand et al.24 first reported acute toxicity from a randomized, non-inferiority, phase III study (PACE-B). A total of 847 low- and intermediate risk patients were randomly assigned to CF/ MH (78 Gy in 39 fractions/62 Gy in 20 fractions) or SBRT (36.25 Gy in 5 fractions). The frequency of acute grade 1, 2, 3 and 4 GU toxicity in the CF/MH arm versus the SBRT arm was 59%, 26%, 1% and < 1%, versus 57%, 21%, 2% and < 1%, respectively. Acute grade 1,2,3 and 4 GI side effects occurred in CF/MH arm in 61%, 11%, 1% and 0% versus in the SBRT arm in 53%, 10%, <1% and 0%, respectively. These results suggest that shortened treatment time (SBRT) does not increase neither acute GI nor GU toxicity.

Immediately after that, the second phase III, non-inferiority, randomized trial (HYPO-RT-PC) was published comparing CF radiotherapy with SBRT in intermediate- and high-risk prostate cancer patients.25 In contrast with PACE-B trial in HYPO-RT-PC patients were treated mostly with 3D conformal technique. In the SBRT arm acute grade 1–2 and 3 GU toxicity was recorded in 48% and 5% of the patients. Acute grade 1–2 and 3 GI side effects occurrence was 51% and 1%. Acute GU toxicity was significantly worse in the SBRT arm, but no significant difference was recorded in acute GI or late GU/GI toxicities and failure free survival (84% vs. 84%) at 5-year median follow up, conforming the non-inferiority of SBRT to CF radiotherapy.

In the last 10–15 years several prospective and retrospective studies reported low rates of severe acute toxicity with the use of SBRT for extreme hypofractionation applying commonly a total of 5 fractions with 7–8 Gy fraction doses.^15,26-37 The frequency of acute ≥ grade 3 GU and GI side effects was 0–5% and 0–3%, respectively (Table 8).

In our phase II prospective study, we reported acute toxicity after extremely hypofractionated, intensity-modulated radiotherapy with SBRT technique for prostate cancer patients. Patients with low- (n = 23), intermediate- (n = 120) and high-risk (n = 62) prostate cancer patients were treated with SBRT, in every second working day and 7.5–8 Gy to the prostate and 6–6.5 Gy to the seminal vesicles was delivered with SIB technique, in a total of 5 fractions (total dose 37.5–40 Gy). Of the 205 patients treated, grade 1–2 GU and GI side effects occurred in 81% and 38%. Three months after treatment, these side effects were present only in 24% and 5%, respectively. The frequency of grade 3 GU toxicity was 1.5%. In the case of extreme hypofractionation, due to pelvic anatomy and radiation sensitivity, the most critical organ at risk is the rectum. In our study, no grade 3 GI acute side effect was observed, and at 3 months after irradiation 95% of patients had no gastrointestinal complaints (GI Gr.0). Our results regarding acute toxicity are similar to those of reported in the literature using similar total doses and fractionation schemes (Table 8).

Because of the lack of prospective data and paucity of the literature, the effect of pre-treatment TURP on side effects after SBRT currently needs to be investigated. One of the most important data on this issue was reported by Murthy et al.38 Fifty prostate cancer patients with pre-treatment TURP were propensity score matched to a similar non-TURP cohort. No significant difference was recorded regarding acute ≥ grade 2 GU side effects (8% vs. 6%, P = 0.45). Wang et al.39 concluded that a pre-treatment TURP increases the incidence of urinary incontinence and worsens urinary quality of life. In our patient cohort 22 patients (10.7%) underwent prior TURP. There was no difference between TURP and non-TURP patients with respect to acute GU toxicity. However, the impact of prior TURP on GU toxicity after SBRT is still controversial.

Based on our statistical analyses, a significant correlation was shown between the volume of the prostate gland (CTVpros), CTVpsv, PTVpros, PTVpsv and acute GU toxicities. These findings draw our attention to the fact that a large volume of prostate or a large safety margin can affect GU side effects. According several studies, patients with a large prostate volume before SBRT experienced worse GU side effects.40,41,42 Katz et al.41 reported in 336 patients that the rate of late grade 2 and 3 GU toxicity was 15% versus 8% in patients with prostate volume greater than versus less than 60 cm³, respectively.

Three large randomized trials are ongoing to establish SBRT as the preferred standard option for localized disease. The NRG GU-005 trial (NCT03367702) compares SBRT (36.25 Gy in 5 fractions) with moderately hypofractionated radiation therapy (70 Gy in 28 fractions) and is designed to confirm the superiority of SBRT. The PACE series trials (A–C) aim to assess whether SBRT (36.25 Gy in 5 fractions) offers a therapeutic benefit over prostatectomy or conventional radiation therapy (78 Gy in 39 fractions) for patients with localized disease (NCT01584258). The MIRAGE trial is randomized phase III trial comparing MRI-guided SBRT (40 Gy in five fractions) with CT-guided SBRT for organ-confined prostate cancer. The purpose of this study is to demonstrate the benefit of using MRI-guided SBRT in terms of acute grade ≥ 2 GU side effects when compared to CT-guided SBRT (NCT04384770).

One limitation of our single arm phase II prospective study is that SBRT was not compared with CF or MH in a randomized manner. Another factor slightly reducing the value of this study is that the side effects were graded by the physician, which increases the subjectivity of the assessment and may differ in the proportion and severity of the patient-reported toxicities. Further follow-up is needed to validate late side effects and tumor control.

At our institute, treatment with CF (2 Gy/day) or MH (2.5 Gy/day) takes 39 or 28 working days. During SBRT, radiation treatment can be delivered in less than 2 weeks, thus reducing the total radiation treatment time by up to 6 weeks. Routine application of SBRT can reduce waiting time and total treatment time. Shorter treatment times are also beneficial for patients.

The treatment of clinically localized prostate cancer patients using SBRT with 7.5–8 Gy fractions delivered every other working day, with a total dose of 37.5–40 Gy, appears to be a safe treatment and can be introduced into daily routine. Acute GI and GU side effects were moderate, with rare grade 3 GU side effects and no acute grade 3–4 GI side effects. In the majority of cases, toxicities resolved spontaneously by 3 months after treatment. The total treatment time with SBRT is more than 6 weeks shorter compared to EBRT with conventional fractionation.