|Ahead of print
Stereotactic body radiotherapy as a boost after external beam radiotherapy for high-risk prostate cancer patients
Menekse Turna, Halil Akboru, Ekin Ermis, Sedenay Oskeroglu, Selvi Dincer, Suleyman Altin
Radiation Oncology Department, Okmeydani Research and Education Hospital, Sisli, Istanbul, Turkey
|Date of Submission||29-Apr-2019|
|Date of Decision||19-Jul-2019|
|Date of Acceptance||24-Jul-2019|
|Date of Web Publication||02-Nov-2020|
Radiation Oncology Department, Okmeydani Research and Education Hospital, Sisli, Istanbul
Source of Support: None, Conflict of Interest: None
Background: The effect of high-dose-rate (HDR) brachytherapy after external radiation in high-risk prostate cancer patients has been proven. Stereotactic body radiotherapy as a less invasive method has similar dosimetric results with HDR brachytherapy. This study aims to evaluate the prostate-specific antigen (PSA) response, acute side effects, and quality of life of patients who underwent stereotactic body radiotherapy (SBRT) as a boost after pelvic radiotherapy (RT).
Methods: A total of 34 patients diagnosed with high-risk prostate cancer treated with SBRT boost (21 Gy in three fractions) combined with whole pelvic RT (50 Gy in 25 fractions) were evaluated. Biochemical control has been evaluated with PSA before, and after treatment, acute adverse events were evaluated with radiation therapy oncology group (RTOG) grading scale and quality of life with the Expanded Prostate Cancer Index Composite (EPIC) scoring system.
Results: The mean follow-up of 34 patients was 41.2 months (range 7-52). The mean initial PSA level was 22.4 ng/mL. None of the patients had experienced a biochemical or clinical relapse of the disease. Grade 2 and higher acute gastrointestinal (GI) was observed in 14%, and genitourinary (GU) toxicity was observed in 29%. None of the patients had grade 3-4 late toxicity.
Conclusions: SBRT boost treatment after pelvic irradiation has been used with a good biochemical control and acceptable toxicity in high-risk prostate cancer patients. More extensive randomized trial results are needed on the subject.
Keywords: Intensity modulated radiation therapy, prostate cancer, quality of life, stereotactic body radiotherapy, toxicity
Key Message Dose escalation with SBRT boost may have a role in high-risk prostate cancer patients with good biochemical control and acceptable toxicity.
|How to cite this URL:|
Turna M, Akboru H, Ermis E, Oskeroglu S, Dincer S, Altin S. Stereotactic body radiotherapy as a boost after external beam radiotherapy for high-risk prostate cancer patients. Indian J Cancer [Epub ahead of print] [cited 2021 Feb 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=299720
| » Introduction|| |
Prostate cancer is one of the most common cancers in men and often does not threaten life. Despite these high rates of incidence, mortality due to prostate cancer is low.
Radiotherapy (RT) is one of the main treatment options for the disease. Hypofractionation in prostate RT is now standard in definitive treatment with the accumulated data.,,,,, Prostate brachytherapy has shown efficacy and safe toxicity profile as both monotherapy and boost after external RT. Stereotactic body radiotherapy (SBRT) as a less invasive procedure can be an alternative to brachytherapy with similar dosimetric results.
| » Subjects and Methods|| |
We evaluated 34 patients with high-risk prostate cancer and treated them with curative intent external beam RT (EBRT) followed by SBRT boost radiotherapy at Okmeydani Training and Research Hospital Radiation Oncology Clinic between February 2014 and February 2015. The patients who were diagnosed with high-risk prostate cancer (>7 Gleason score or >20 ng/mL prostate specific antigen (PSA) value or ≥2c T stage) and treated with SBRT boost in our department were included in the study. Patients with intermediate or low-risk prostate cancer were excluded. Ethical clearance was obtained from the Institutional Review Board (IRB date 12.15.2015 and no: 380). Informed consent of all patients was obtained before treatment.
In the pretreatment evaluation, detailed history was obtained. Digital rectal examination, performance status evaluation, laboratory tests including complete blood count, and PSA values were obtained. Abdomino-pelvic magnetic resonance (MR) imaging was used to evaluate the local-regional spread of the disease, and bone scan was obtained to identify distant metastases.
Total androgen blockade with bicalutamide and luteinizing hormone-releasing hormone (LHRH) agonists were administered to 30 patients and LHRH monotherapy with 10 days bicalutamide for flair phenomenon was administered to four patients. Patients received neoadjuvant hormonal therapy (HT) for 3 months. HT continued during the RT and terminated after 3 years.
Five fiducial implants were placed in urology clinic with the guidance of ultrasonography after prescribing bowel preparation and antibiotic prophylaxis. Two of the implants were placed in the prostate apex, two in the base and one in the central zone. Computed tomography (CT) simulation was performed 1 week after the implantation considering that there may be a fiducial migration. A fiber-rich diet and laxatives were given before the CT simulation. In order to fill the bladder, all the patients drank half a liter of water and waited for 30 minutes. Vacuum bag was used for immobilization. Planning CTs were performed in supine position starting from the superior border of iliac bone to the perineal region with 1 mm cross-sectional images.
The rectum, bladder, intestines, and penile bulb were contoured in the Eclipse program as stated in the male Radiation Therapy Oncology Group (RTOG) normal pelvis atlas.
The target volumes were planned in two phases. In phase 1, seminal prostate vesicles and iliac lymph nodes; in phase 2, prostate and proximal vesicles were treated.
The gross tumor volume (GTV), the clinical target volume (CTV), and the planned target volume (PTV) were contoured as described in International Commission on Radiation Units and Measurements (ICRU) 50/62 [Table 1] and [Figure 1], [Figure 2].
Phase 1 was planned with a total of 50 Gy in 25 fractions and phase 2 was planned with 21 Gy in three fractions with six MV photon energy in the Eclipse treatment planning system with two arc method [Figure 3] and [Figure 4].
In phase 1, the dose was normalized as 95% of the PTV was receiving the prescription dose. The maximum high dose within the PTV was 110% of the prescribed dose. The entire bladder and rectum doses were kept below 30 Gy, and the maximum doses did not exceed 55 Gy at any point within bladder and rectum. Maximum dose of femur heads was kept below 45 Gy.
In phase 2 treatment planning, the maximum doses for rectum and bladder did not exceed 30 Gy. V20.4 Gy of the rectum was lower than 20 mL, and V15 Gy of the bladder was below 15 mL.
Treatment was applied on consecutive days in the first phase and on alternate days in the second phase. 3D volumetric cone beam CTs and fiducial markers were used for interfractional positioning correction.
The patients have been followed-up at the end of the first month, at the end of treatment, and then every 3 months. Patients were assessed for toxicity according to the common terminology criteria for adverse events in each control. Expanded Prostate Cancer Index Composite (EPIC) test was administered four times; before the start of HT and RT treatment, at the first month after treatment and at the end of 1 year. Biochemical recurrence was defined as PSA nadir value + 2 ng/mL.
| » Results|| |
A total of 34 high-risk prostate cancer patients treated between February 2014 and February 2015 were included in the study. Median follow-up was 41.2 months (range 7-52). The median patient age was 70.4 years (range 57-84). The median PSA level was 22.4 ng/mL. The most common comorbidities were diabetes mellitus (n: 9), hypertension (n: 8), and chronic obstructive pulmonary disease (COPD) (n: 5). A total of 11 patients had at least two comorbidities. Other tumor characteristics are summarized in [Table 2].
The mean prostate volume was 39.5 mL (range 21.6-78 mL). Mean PTV1 dose was 52.1 Gy, mean PTV1 maximum dose was 54.9. For phase 1, the mean doses for bladder, rectum, and penile bulb were 36.3 Gy, 32.8 Gy, and 27.1 Gy, respectively. The mean dose for PTV2 was 22 Gy, and the average maximum dose was 23.2 Gy. The mean values of D2, D20, and Dmax for the rectum were 21.3 Gy, 13.7 Gy, and 21.8 Gy, respectively. D2, D15, and Dmax mean values for bladder were 21.6 Gy, 17.6 Gy, and 22.7 Gy. Conformity index was found 1.06 on average.
No clinical or biochemical failure was seen in any of the patients with a median follow-up of 41.2 months. In two patients, noncancer-related death occurred at 6 and 18 months after treatment. The median PSA nadir level was 0.019 ng/mL (range from 0.33 to 0.003) and the median time to PSA nadir was 13.4 months (range 6-49).
Most of the acute toxicities observed in patients were grade 1. [Table 3] and [Table 4] summarize the acute side effects. Grade 3 genitourinary (GU) side effect was developed in only one patient 1 week after the end of RT with transfusion requiring hematuria, and the patient was on enoxaparin sodium treatment due to coronary artery disease in this period. The patient's anticoagulant therapy was reorganized after the hematuria.
Patients with grade 2 and above gastrointestinal (GI) side effects had an average prostate volume of 38.7 mL. There was no difference in the mean prostate volume between the patients having grade two to three side effects (41.7 mL) and the entire group (39.5 mL) (P > 0.05).
None of the patients had grade 3-4 late side effect during follow-up [Table 5]. Grade 2 bleeding was observed in five patients at an average of 8.5 months. Bleeding control was achieved with argon plasma coagulation in four patients. Intermittent minor bleeding was continued after 1 year in two patients after the radiotherapy.
Grade 2 late GU side effects were controlled with alpha blockers. All three patients with grade 2 genitourinary side effects had at least one comorbid disease (two had diabetes mellitus and COPD, and one had a peripheral vascular disease).
A total of 13 patients were followed up without any complaints. At least one side effect was observed in 60% of patients in the long term.
Quality of life
Patients completed the EPIC tests before HT, beginning of RT, after 1 month and 1 year after RT. The urinary, intestinal, sexual, and hormonal quality of life scores of the patients are shown in [Figure 5]. All patients completed the pre-HT and pre-RT tests, 88% completed the first month, and 83% completed the first year tests. When compared with the first month after RT scores, the mean urinary and intestinal scores before RT decreased 0.5% and 10.2%, respectively. Compared with the first year after RT, the scores decreased by 20% and 16.2%. This downtrend continued with the effect of RT in the following months. In the first year after treatment, all patients (except the patient who died at the sixth month) were still under HT, and their hormonal scores decreased by an average of 36% compared to the baseline level.
| » Discussion|| |
Prostate cancer has a low alpha/beta ratio as opposed to other tumor types with a long doubling time of 15-70 days. Studies suggest that the alpha/beta ratio for prostate cancer is between 1-2., This low alpha/beta ratio of prostate cancer is also below the alpha/beta ratio of late rectal side effects. This radiobiological characteristic has led to hypofractionated schemes in which higher therapeutic doses can be applied for prostate cancer while keeping late reactions at the same rate. Current data support the moderate and extreme hypofractionation in localized prostate cancer patients with non-inferior efficacy and similar toxicity profile with conventionally fractionation.,,,,,
One of the primary uses of hypofractionation in the treatment of prostate cancer was high-dose-rate (HDR) brachytherapy boost. Several studies evaluated the efficacy of the combination of brachytherapy with EBRT.,,, According to Pieters et al. meta-analysis, the combination of EBRT and HDR brachytherapy provides better biochemical control and overall survival than other RT modalities. Despite these good outcomes of HDR brachytherapy, it is an invasive procedure and also needs hospitalization, anesthesia, and technical experience for planning, resource, and time. These requirements are obstacles to its widespread use.
Fuller et al. reported that SBRT could achieve similar dosimetric results with HDR brachytherapy. Theoretically, the use of SBRT will have the radiobiological advantage of the hypofractionation, eliminates the disadvantages of the invasive procedure as well as the financial burden of HDR brachytherapy. Today SBRT is used especially in patients with low and intermediate risk prostate cancer.,,,,,,,,,,
Acute side effects were reported in many studies on SBRT boost after EBRT.,,, No Grade 3-4 acute GI side effects was observed in any of the studies. In this study, there was no grade 3 GI side effect except hematuria in a patient who received anticoagulant treatment due to coronary artery disease. Grade 2 GU side effect was observed in 26% of patients, which was consistent with the results of similar published studies (6.8-42%). Acute urinary retention is a frequent problem in patients undergoing brachytherapy. In the study by Keyes, acute side effect rate was reported as 37% in patients who underwent iodine-125 interstitial brachytherapy (BT).
The effect of neoadjuvant HT on urinary toxicity in patients receiving RT is also controversial. According to many studies, HT, especially in neoadjuvant setting itself, can adversely affect urinal toxicity., In this study, it is difficult to distinguish clearly whether the cause of urinary toxicity is RT or HT.
In similar studies, acute grade 2 GI toxicity was observed between 4% and 14.8%.,,, As reported by Michalski et al., elder age, androgen suppression therapy, and diabetes mellitus are clinical factors that are associated with the risk of complication development. The mean age of the patients who developed grade 2 rectal bleeding was 69.1 (range 57-76) years, which was higher than other similar studies. These patients also had at least two comorbid diseases, including diabetes mellitus, hypertension, cerebrovascular disease, coronary artery disease, and COPD.
According to the results of similar studies,,,, grade 2 side effects were between 4.1-25%. Grade 3 GU toxicity was observed between 1.4% and 5%, and none of the patients developed grade 4 side effects. In the interstitial brachytherapy series performed by Keyes et al., grade 3 late GU toxicities were reported as 2% in the first year after the implantation. In this study, no grade 3-4 late GU side effects were observed during the mean follow-up period, which was 41 months. Grade 2 GU side effect rate was 8%, and these results were interpreted in favor of acceptable toxicity.
In an analysis reported by Kuban et al., increasing the dose from 70 Gy to 78 Gy increased the grade 2-3 late toxicity from 12% to 26%. In the same analysis, it has been shown that the complication rate can be reduced by reducing the rectal volume of the received dose to 70 Gy. Hoskin et al. compared brachytherapy boost and EBRT in terms of toxicity and reported 5 years GU and GI toxicity rates as 26% and 7%, respectively, for brachytherapy boost arm. Although EBRT doses were relatively low, the toxicity was similar in both groups. Low Dose Rate (LDR) brachytherapy boost increased the risk of needing temporary catheterization and/or requiring incontinence pads in Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial). At 5 years, the cumulative incidence of grade 3 GU events was 18.4% for brachytherapy arm and 5.2% for EBRT arm (P < 0.001). In this study, 2 Gy biologically equivalent (EQD2) of phase 2 treatment is 51 Gy, and when added to phase 1 treatment, total EQD2 is 101 Gy for 1.5 alpha/beta ratio. This total dose is slightly higher than the toxicity reporting series. The mean dose of the rectum in phase 1, the maximum dose of rectum, D2 and D20 in phase 2 were evaluated. These doses did not make a statistically significant difference between the patients with and without grade 2 and higher toxicity. In this study, no significant correlation was found between the doses applied to the rectum and toxicity.
Zelefsky et al. reported that the late side effects were much higher in patients with acute side effects (42% vs. 9%). Acute side effects were observed in 76.4% of patients who had late side effects in this study.
In general, the bladder volume receiving high-dose is associated with high complication risk. There is no absolute dose limit to predict bladder toxicity contrary to the rectum toxicity. Zelefsky et al. reported the late GU toxicity rate as 20% in patients who received 81 Gy dose and 12% for lesser doses. In this study, bladder doses were not statistically significant when the patients with grade 2 and above side effects were compared with the others (P > 0.05). This situation may be related to the relatively small sample size of the current study.
The evaluation of sexual functions after radiotherapy is complicated and difficult because of subjectivity. The impotence typically begins 1 or 2 years after RT and is similar to the natural aging process. Patients may also develop impotence due to accompanying diabetes, atherosclerosis, or drugs used. Periprostatic neurovascular bundle and penile bulb are structures that may be associated with erectile dysfunction. According to Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC), average penile bulb dose above 50 Gy is associated with the risk of erectile dysfunction. In this study, most of the patients had impotence before treatment. Almost all of the patients developed sexual dysfunction with start of HT. It would be more objective to assess the effect of penile bulb doses on sexual dysfunction in non-HT patients.
Sanda et al. reported that the quality of life of all patients was affected who underwent surgery, EBRT, or brachytherapy. Adjuvant HT increased the side effects in patients receiving EBRT and brachytherapy. Obesity, older age, large prostate volume, and high PSA levels before treatment were also associated with poor quality of life. In this study, the deterioration in the quality of life was evaluated according to the patient, tumor, and treatment characteristics, and no direct relationship was found. The reliability of the response to EPIC testing is controversial, especially for patients with poor intellectual level. By correlating the results of different quality of life tests, more accurate results can be obtained. More objective testing and measurements are needed in order to assess the quality of life.
| » Conclusion|| |
SBRT boost treatment after the whole pelvic irradiation in high-risk prostate cancer patients is safe and feasible. Good biochemical control was achieved and the toxicity was tolerable. Larger randomized trial must be conducted.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]