Abstract
Background: The present study aimed to evaluate the toxicity and efficacy of stereotactic body radiotherapy (SBRT) for localized prostate cancer. Patients and Methods: We investigated 25 patients treated with SBRT of 35 Gy per five fractions from May 2014 to March 2015. Results: The median age of patients was 70 years, four (16%) patients were low risk and 21 (84%) were intermediate risk. Seven (28%) patients received neoadjuvant androgen-deprivation therapy. The median follow-up time was 53 months. Grade 2 acute and late genitourinary toxicities were observed in five (20%) and two (8%) patients and there were no Grade 2 gastrointestinal toxicities. There were no Grade 3 or higher acute or late toxicities at 2 years follow-up. The biochemical relapse-free survival rate at 2 years was 100%. Conclusion: SBRT of 35 Gy per five fractions is a promising treatment method in the short term for prostate cancer.
Prostate cancer is one of the most common cancers in the world. In Japan, nearly 74,000 patients are newly diagnosed with prostate cancer and more than 12,000 patients died from prostate cancer in 2017 (1). Radical treatment methods of prostate cancer are surgery, or external beam or interstitial radiation therapy (RT). There is almost no difference between treatment outcomes of surgery and RT. Therefore, RT, especially external beam RT, has an important role as a non-invasive treatment modality in the aging society.
When external beam RT is performed, conventional (1.8-2 Gy/fraction) or moderate hypofractionated (2.4-3 Gy/fraction) intensity modulated radiation therapy is widely used (2). However, this therapy takes a long time, which is a burden on patients and medical Institutions. Additionally, the long treatment time has a negative effect on treatment outcome in many types of cancers (3). Therefore, a novel RT modality which achieves a drastic reduction in the total radiation time needs to be developed.
Our group has previously reported a good outcome of high-dose-rate brachytherapy (HDR-BT) (4). HDR-BT enables delivery of a highly conformal dose of RT to the prostate within the relatively short treatment period (about one week), whereas the radiation dose distributed to the surrounding tissues is reduced. In recent years, the technology of ultra-hypofractionated stereotactic body radiotherapy (SBRT) has advanced. SBRT enables “HDR-BT like” high accuracy of treatment with favourable dose concentration, which is brought by development of radiation physics and computer technology. Additionally, fiducial gold marker-based SBRT, which enables precise RT for moving organs, has been available. This technique has become the focus of attention as one of the most promising treatment modalities for prostate cancer.
SBRT can reduce the total treatment time and is expected to overcome the weaknesses of traditional RT. However, the therapeutic effect and toxicity of SBRT have not been yet determined and the optimal dose for SBRT is debatable. We conducted a dose-escalation clinical trial in which we investigated the feasibility, efficacy, and optimal dose of SBRT for prostate cancer. We report the initial outcome of this study in which patients underwent SBRT with 35 Gy per five fractions.
Patients and Methods
Overview of clinical trial. This study is a part of a single-institution, prospective, phase I/II dose escalation study (UMIN000014328). We assessed the safety and efficacy of fiducial-based SBRT using CyberKnife (Accuray Inc., Sunnyvale, CA, USA) for localized low- or intermediate-risk prostate cancer. The study protocol was approved by the Human Ethics Review Committee of the Osaka University and a signed informed consent form was obtained from each patient.
Endpoints. The primary endpoint was the occurrence rates of Grate 2 or higher late gastrointestinal (GI) and genitourinary (GU) adverse events at 2 years. The secondary endpoint was the 2-year biochemical relapse-free survival (bRFS) rate. Adverse effects were evaluated by the Common Terminology Criteria for Adverse Events ver.4.0 (5). Biochemical relapse was defined by the Phoenix definition [prostate specific antigen (PSA) levels >2 ng/ml from the nadir] (6).
Patient eligibility. The eligibility criteria for this study were as follows: (i) histologically confirmed prostatic adenocarcinoma by biopsy, (ii) no lymph node metastasis and distant metastasis diagnosed by computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy (CT could be omitted if pelvic lymph nodes were evaluated by MRI), (iii) clinical T1c to T2c and N0 and M0 according to UICC 2009 TNM classification(7), (iv) Gleason's score was ≤7 (including 4+3) (v) the pre-treatment PSA level was ≤20 ng/ml [in patients who underwent neoadjuvant androgen deprivation therapy (ADT), the level before starting ADT was used], (vi) retaining sufficient major organ function (white blood cell count ≥3,000/μl, haemoglobin levels ≥10.0 g/dl, platelet count ≥10×104/μl, creatinine levels ≤2.0 mg/dl, glutamic-oxaloacetic transaminase levels ≤100 U/l, glutamic pyruvic transaminase levels ≤100 U/l, and no haemostatic dysfunction), (vii) at least 20 years old and <80 years old at enrolment and (viii) written informed consent was obtained.
Exclusion criteria included the following: (i) active double cancer, (ii) uncontrolled diabetes, (iii) use of anticoagulant or antiplatelet drugs, that could not be stopped, (iv) severe cranial nerve disease, (v) collagen vascular disease, (vi) prior pelvic surgery or RT, (vii) history of transurethral resection of the prostate, (viii) prostatic enlargement (prostate volume ≥50 ml) and lower urinary tract symptoms (International Prostate Symptom Score ≥15), (ix) no consent or medically impossible to insert gold markers, (x) ADT was continued for >1 year before starting radiation, (xi) castration-resistant prostate cancer (disease progression or PSA levels were increased >2ng/ml from the nadir during ADT, with serum testosterone levels <50 ng/dl).
Androgen deprivation therapy. Neoadjuvant ADT for 6 months was applied for intermediate-risk patients with 2 or more of the following factors: (i) cT2c, (ii) initial PSA levels >10 ng/ml, and (iii) Gleason's score was 3+4 or 4+3. No patients underwent adjuvant ADT.
Radiation therapy. Because the prostate has non-negligible organ movement due to changes in the volume and shape of the rectum and bladder that are adjacent organs (8), three or four gold markers were placed in the prostate for tracking. CT was then performed 1-2 weeks later. During planning of CT, a urinary catheter was inserted to visualize the urethra. After urinating just before a CT scan, 100 ml of saline were injected into the bladder and the urinary catheter was clamped.
The clinical target volume (CTV) was set around the prostate (a 1-mm margin to dorsal side and a 3-mm margin in the other directions) and the proximal region of the seminal vesicles (approximately 1 cm from the prostate). The planning target volume (PTV) was the CTV with a 2-mm margin in all directions. The defined organs at risk (OAR) were the rectum (delineated in CT slices in the range of 1 cm from the cranial and caudal ends of the PTV), whole bladder, urethra, and femoral heads. The prescribed dose of RT was 35 Gy per five fractions to the lowest dose distributed to 95% volume of the PTV. The dose constraints for the PTV and OAR are shown in Table I.
The study dose constraints.
We confirmed that there was no relative displacement between the gold marker and prostate or urethra by CT scanning before each treatment. The urinary catheter was placed continuously throughout the treatment period or inserted before each treatment. Urination was performed from the urinary catheter immediately before CT scanning, and then 100 ml of saline were injected into the bladder and the urinary catheter was clamped. Irradiation was performed on five consecutive weekdays, with a total treatment period of 5-8 days.
Follow-up and evaluation. All patients were followed-up 1 month after treatment with a medical examination and blood and urine tests. The medical examination and evaluation of PSA levels were performed at 3, 6, 9, 12, 15, 18, 21, and 24 months. The blood and urine tests were performed at 12, and 24 months after treatment.
Statistical analysis. The time to occurrence of toxicity or biochemical relapse was defined as the number of months from the initial day of SBRT to the day of the events. Occurrence rates of toxicity and bRFS were calculated using the Kaplan–Meier method. All statistical analyses were performed with JMP Pro (version 13; SAS Inc., Cary, NC, USA).
Results
From May 2014 to March 2015, we treated consecutive 25 patients with localized prostate cancer of low or intermediate risk according to the National Comprehensive Cancer Network guidelines (9). The patients' characteristics are shown in Table II. The median age was 70 years, four (16%) patients were low risk and 21 (84%) were intermediate risk. Seven (28%) patients received neoadjuvant ADT.
Patient characteristics.
The median follow-up time was 53 months (range=24-60 months). Grade 2 acute GU toxicity were observed in five (20%) patients and Grade 2 late GU toxicity were observed in two (8%) patients. Overall, there were no Grade 3 or higher GU adverse effects or no Grade 2 or higher GI adverse effects observed. A summary of the acute and late toxicities is shown in Table III.
The bRFS rate at 2 years was 100%. In one patient, the PSA level exceeded 2 ng/ml from the nadir within 2 years. He was diagnosed with prostatitis and PSA levels gradually fell after medication for prostatitis without any cancer treatment. Therefore, we did not consider this transition in PSA levels as biochemical relapse. There were no other increases in PSA levels, including PSA bounce (transient elevation of PSA) in two years, while there was one patient with biochemical relapse at 42 months within all follow-up time.
Discussion
There are various modalities for RT, such as external-beam RT, brachytherapy, and particle beam therapy, all of which are effective for low- or intermediate-risk prostate cancer. When choosing a treatment modality, there is concern about not only efficacy, but also safety, because prostate cancer is generally not life-threatening and patients have good prognosis.
Summary of grade 2 or higher toxicities.
In terms of efficacy, our results are satisfactory. No patient had local recurrence in two years and the dose of 35 Gy per five fractions appeared to be sufficient for controlling the tumour at least in the short term. Clinical reports of SBRT for prostate cancer began to be published in approximately 2010, many of which were from the United States. According to a report from Stanford University, 67 patients have been treated with SBRT since 2003 with sufficient biochemical control rates and acceptable adverse events (10). Since then, many authors have reported results of SBRT, including a multicentre, prospective study and pooled analysis of 1,100 patients (11), all of whom achieved good treatment outcomes. Our results are comparable with these studies, while longer follow-up is certainly required.
In our study, there was no Grade 3 or higher acute or late toxicity observed, and the occurrence rates of Grade 2 acute GU and GI toxicity were 20% and 0%, respectively. These findings are consistent with previous studies. The 2-year occurrence rates of late GU and GI toxicity were 8% and 0%, respectively, and all GI toxicities were Grade 1. The 2-year adverse event rates of SBRT are reportedly lower than those of conventional fractionated RT (12-17) (Table IV). Furthermore, the results of our study, in which we used relatively lower radiation doses, seemed to be safe compared to previous SBRT studies (12-15), and SBRT with 35 Gy per five fractions is promising treatment method.
The efficacy and feasibility of SBRT for prostate cancer are attributable to its biological features. The α/β ratio, which affects the relative sensitivity to hypofractionated RT of prostate cancer, is approximately 1.5 (18). This ratio is lower than those in other cancers, and is even more than those in normal tissues, thus hypofractionated RT enables to lead cancer cell death efficiently while avoiding toxicities to OAR. Based on the linear-quadratic model, the EQD2 (equivalent dose in 2 Gy fractions) of 35 Gy per five fractions is approximately 85 Gy for prostate cancer and 70 Gy for OAR (of which the α/β ratio is approximately 3). This dose is relatively higher for prostate cancer and lower for OAR than the dose used in conventional fractionated RT. Our results of lower incidence of GU and GI toxicity and favourable bRFS rate support the biological basis of SBRT.
Comparison of SBRT and conventional fractionated RT.
A limitation of our study is the short follow-up time. The GU or GI toxicity rate of RT gradually increases until 10 years (19). Our follow-up was short for assessing late toxicity. Although some researchers reported the risk factors of late toxicity after RT using other modalities (20, 21) and those are also helpful in treatment planning of SBRT, unexpected events may occur after the treatment using the new modality. Therefore, a longer follow-up time is required to observe the presence and extent of late toxicity, which occurs after 2 years. From the perspective of efficacy, a 2-year follow-up is short because relapse of prostate cancer becomes obvious even after 5 years of latency. The EQD2 of SBRT is higher than that of a conventional RT dose and is expected to conduce favourable treatment outcome. However, some investigators have reported that a higher dose may be required because a small amount of relapses occur with SBRT of 35 Gy (15). Therefore, a careful and long-term survey is required in the future to determine the presence or absence of relapse.
Our results showed that SBRT of 35 Gy per five fractions is a promising treatment method for low- or intermediate-risk prostate cancer to achieve favourable therapeutic effect and safety under a small burden on patients, while its long-time outcome has not been yet established. SBRT for eligible patients should be considered with polite provision of information on current status of its development.
Conclusion
SBRT of 35 Gy per five fractions for low- or intermediate-risk prostate cancer is a promising treatment in the short term. We are continuing our clinical trial to assess longer efficacy and safety of SBRT and determine the results of SBRT using a higher dose (37.5 Gy or 40 Gy per five fractions). An adequate method of SBRT for prostate cancer will hopefully be determined on the basis of subsequent results of our study.
Footnotes
Authors' Contributions
Conceptualization: Ryosuke Nakamura, Osamu Suzuki, Keisuke Otani and Yasuo Yoshioka. Funding acquisition: Kazuhiko Ogawa. Data curation: Ryosuke Nakamura, Takero Hirata, Naoki Kai and Osamu Suzuki. Formal analysis: Ryosuke Nakamura. Investigation: Ryosuke Nakamura, Takero Hirata, Osamu Suzuki and Kazunori Tanaka. Supervision: Osamu Suzuki, Keisuke Otani, Koji Hatano, Kazutoshi Fujita, Motohide Uemura, Ryoichi Imamura, Yasuo Yoshioka, Norio Nonomura and Kazuhiko Ogawa. Writing: Ryosuke Nakamura and Takero Hirata.
Conflicts of Interest
The Authors declare that there are no conflicts of interest.
- Received February 12, 2020.
- Revision received February 23, 2020.
- Accepted February 26, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
