Abstract
Objective:
To determine morphological and biological control as well as toxicity and quality of life (QoL) of men with localized prostate cancer (PCa) treated with MRI-guided focal boost radiotherapy.
Material and Methods:
30 patients with PCa and a visible dominant intraprostatic lesion (DIL) identified on mpMRI were included in a prospective Phase II trial. Matching point registration of planning CT and T2W, diffusion-weighted and a gradient-recalled echo (GRE) MRI images made in treatment position was used for prostate and tumour delineation. Treatment consisted on 35 daily fractions of 2.17 Gy with a concomitant focal boost to the DIL of 2.43 Gy using volumetric modulated arc therapy (VMAT) and image-guided radiation therapy (IGRT) with intraprostatic fiducial markers. Biochemical failure was analysed using PSA nadir +2 ng/mL criteria and local control using mpMRI evaluation at 6–9 months following RT. Acute and late toxicity were defined according to CTCAE v.4.0 and RTOG/EORTC scales and QoL was assessed using IPSS, EPIC short-form and UCLA-PCI questionnaires.
Results:
The median radiation dose to the prostate was 77.6 Gy (IQR 77.3–78.1), and to the DIL was 85.5 Gy (IQR 85.0–86.0). With a median follow up of 30.0 months (IQR 25.5–40.27), all patients remain free of biochemical relapse. An mpMRI complete response was observed in 25 patients during the first post-treatment evaluation at 6 months. The remaining five patients achieved a complete disappearance of the DIL both on T2 and DWI on the second mpMRI performed at 9 months following treatment. Six out of 30 (20%) patients presented acute Grade 2 urinary toxicity with no Grade 3 acute complications. Acute rectal toxicity was only found in 2 (6.6%) patients (both Grade 1). Only late Grade 1 urinary and rectal complications were observed in 3/30 patients, respectively, with no Grade 2 or more late toxicity. The urinary, bowel and sexual bother EPIC scores were slightly and insignificantly increased in the first 3 months post-treatment, returning to normal afterwards.
Conclusions:
mpMRI-guided focal boost using VMAT hypofractionated technique is associated with an excellent morphological and functional response control and a safe toxicity profile.
Advances in knowledge:
In the present trial, we examined the potential role of mpMRI for radiological assessment (functional and morphological) of treatment response in high-risk prostate cancer patients treated with MRI-guided focal radiotherapy dose intensification to dominant Intraprostatic lesion.
Introduction
External beam radiotherapy is a recommended treatment for patients with localized prostate cancer. There is mounting proof that a dose intensification greater than 80 Gy (EQD2Gy>80 Gy) results in a biochemical significant improvement and this benefit is more evident in patients with intermediate or high-risk features. Recent evidence from pathology studies of patterns of failure following radiotherapy suggest the existence of a dominant cancer focus or intraprostatic lesion within the gland that may be the nucleus of the tumour-aggressiveness and post-treatment recurrence. 1–3 Strategies to identify and intensify treatment to this DIL, including the advances in multiparametric magnetic resonance imaging (mpMRI) or positron emission tomography (PET) imaging together with highly modulated and accurate image-guided radiation therapy (IGRT) techniques are warranted and under active research.
Several studies have reported early encouraging results with highly selected focal radiation dose intensification. 4–8 Based on these findings and our own experience, in 2016, we implemented a Phase II trial of focal dose intensification with a MRI-guided tumour-targeted approach using volumetric modulated arc therapy (VMAT) with IGRT in patients with localized prostate cancer. The aim of this study was to determine the PSA (prostate specific antigen) and mpMRI response, toxicity and quality of life (QoL) of males with localized prostate cancer treated with MRI-guided focal boost. Here, we report early results on morphological and biological control as well as urinary and rectal toxicity and quality of life (QOL) assessment.
Material and methods
Study design and patients’ selection
This is a single institution prospective Phase II study approved by the IRB and Ethics committee of our centre (approval number: 2892) and is registered on ClinicalTrials.gov database (NCT03030625). The inclusion criteria were patients with histologic diagnostic of prostate adenocarcinoma, clinical stage cT2a‐T3a N0 M0 (AJCC seventh edition) PSA <100 ng ml−1, Gleason score 6‐10 and a life expectancy >5 years. All patients had unilateral disease confirmed by the presence of a dominant intraprostatic lesion (DIL) visible in a 1.5 T mpMRI with T2W and DWI at diagnosis. Patients were excluded if they had prior transurethral resection of the prostate or prostate surgery, pelvic radiotherapy, urethral stenosis with or without prior dilations and an IPSS score >18. Before patient registration, a written informed consent was obtained from all patients according to ICH/ GCP and national/local regulations.
Treatment protocol
All patients in the study underwent staging 1.5 T mpMRI of the prostate consisting of T2 in axial, coronal and sagittal planes, axial T1 non-contrast of the pelvis, DWI, and T1 dynamic contrast-enhanced sequences (DCE), using a body-phased array coil. The acquisition and imaging protocol was consistent with the ESUR (European Society of Urogenital Radiology) recommendations. 9 A prostate imaging reporting and data system (PI-RADS version 2.0) score of at least 3 was required for the lesion to be considered suitable for focal intensification. In all cases, a minimum of three gold fiducial seeds were implanted in the prostate through ultrasound-guided trans-perineal pre-loaded needles. Two weeks after fiducial implantation, a computed tomography (CT, slice thickness of 2 mm) and a new mpMRI study of the prostate that included axial T2W images, DWI and a T2* gradient recalled echo (GRE) images were performed in radiotherapy supine position (flat table top with knee and ankle immobilization device) for treatment planning. A matching point registration of planning CT and the MRI was used for prostate and tumour delineation. To minimize variation in the anatomy of the patient, the MRI study was acquired within 3 days immediately after the acquisition of the CT. Patients followed a low fibre dietary protocol to reduce intestinal activity and were imaged following a comfortably full bladder and an empty rectum protocol. In those patients treated with neoadjuvant hormonotherapy, we also used a second diagnostic mpMRI registration to add prostate and tumour delineation.
The clinical target volume (CTV) included the prostate and one-third of seminal vesicles for favourable intermediate risk and two-third of seminal vesicles for unfavourable intermediate and high-risk patients. A margin of 5–7 mm posteriorly and 7–9 mm in all the other directions was added to create the planning target volume for the prostate (PTV-P) and 3 mm in all directions except posteriorly (2 mm) for the mpMRI visible tumour (PTV-DIL). Since 2018, we followed the ESTRO ACROP consensus guideline for CT-MRI target volume delineation. 10 Radiation treatment consisted on 35 daily fractions of 2.17 Gy to the whole prostate gland and the seminal vesicles with a concomitant focal boost of 2.43 Gy to the mpMRI visible intraprostatic nodule. We selected this dose schedule to further escalate dose to the tumour lesion to an EQD2Gy (equivalent dose in 2 Gy fractions) of 95.4 Gy (alfa/β 1.5), while maintaining an EQD2Gy of 79.7 Gy to the whole prostate. PTVs had to be covered at least by 95% of the prescription dose (D95% ≥ 98% for PTV-P and D95% ≥ 98% for PTV-DIL); maximum dose (up to 110%). Mandatory organ-at-risk (OAR) constraints were rectum V72 <21%, V58 <40%, Dmean < 46 Gy, Dmax <79 Gy; bladder V67 <40%; Dmax <80 Gy; sigma Dmax <58 Gy; bulbar urethra Dmax <50 Gy and femoral heads V50 <5%. Radiation treatment was delivered using VMAT and an IGRT protocol with daily cone beam CT (CBCT) and intraprostatic fiducial markers.
Short- (6 months) or long-term (18–28 months) androgen derivation therapy (ADT) was allowed for unfavourable intermediate and high-risk tumours, respectively, in agreement with clinical guidelines.
Clinical and toxicity assessment and follow-up
Clinical assessment was planned at baseline, weekly during radiation treatment, at 3, 6, 9 and 12 months follow-up and every 6 months thereafter until 5 years. PSA values, serum testosterone level and a complete blood count were obtained at each visit. An mpMRI study was mandatory at six months following radiation treatment and was repeated 3 months later in cases in which a non-complete response was achieved.
Acute and late toxicity were assessed using the radiation morbidity scoring criteria of the EORTC/RTOG, the Common Terminology Criteria for Adverse Events (CTCAEs) v.4.0 scoring scheme and QoL questionnaires. Side-effects occurring within 90 days from the start of therapy were considered acute radiation morbidity, and those appearing or persisting for 90 days after treatment start were considered late side effects. All patients completed the International Prostate Symptom Score (IPSS) at baseline, and the Expanded Prostate Cancer Index Composite (EPIC) and de UCLA-PCI (University California, LA, prostate cancer Index) questionnaires at enrollment, before treatment and during follow-up (at 3 and 6 months following treatment and every 6 months afterwards).
Definitions and statistics
The primary endpoints were the biochemical-disease-free survival, the mpMRI- defined local control and acute toxicity. Biochemical failure was defined according to the Phoenix definition (PSA >2 ng/mL above the currently observed PSA nadir). An image complete response was defined as disappearance of all morphological and functional lesions in mpMRI 6 to 9 months after radiotherapy. No confirmatory biopsy was performed. Urinary and rectal toxicity were calculated using the maximal recorded toxicity per patient. Secondary endpoints included late toxicity and QoL assessment.
Descriptive statistics were used to describe the frequency of events. Analysis was performed using the SPSS statistical software program, and the statistical significance between groups was determined using standard measures. The chi2 or Fisher exact test was used to evaluate differences in patient and treatment characteristics for categorical variables. The t-test, analysis of variance, or Mann-Whitney test was used, depending on the type and distribution of the variables, to evaluate differences in patient and treatment characteristics for continuous data. The three domains of EPIC and UCLA scores and subscores (urinary [function/bother], bowel [function/bother] and sexual [function/bother]) were analysed to estimate differences in QoL score change from baseline, adjusting by baseline score. A decreased of >0.5 standard deviation (SD) of baseline values for each domain score was considered clinically relevant (mild change). A change >1 (SD) of baseline values was considered moderately relevant (moderate change) and a change of >2 SD was considered a severe change.
Results
From March 2017 to January 2020, 30 patients with localized prostate cancer who fulfilled the inclusion criteria were eligible for the study; five further patients were initially enrolled but then excluded mainly due to elevated IPSS score, prior adenomectomy or high prostate volume (>80 cc). Fifteen (50%) and 11 (37%) of patients were classified as having NCCN (National Comprehensive Cancer Network) intermediate and high-risk disease, respectively. The characteristics of the patients and treatment are summarized in Table 1. Dose intensification was feasible in the 30 patients. Twenty-three patients had an MRI T2a disease and 7 patients had a T3 disease (16 and 3, respectively, with tumours localized in the apex). The median radiation dose to the prostate was 77.6 Gy (IQR 77.3–78.1), to the PTV-DIL was 85.2 Gy (IQR 85.0–85.4) and to the GTV (gross tumour volume: DIL without margin) was 85.5 Gy (IQR 85.0–86.0). Long-term and short-term ADT was administered to 11 and 4 patients, respectively.
Table 1.
Patients’ and treatment characteristics
| TOTAL N = 30 | |
|---|---|
| Median follow-up, months (IQR) | 30.0 (25.5–40.27) |
| Median age, years (IQR: interquartiles) | 72.0 (67.7–76.0) |
| Clinical T stage (mpMRI-assisted) | |
| T2a | 23 (76.7%) |
| T3a | 7 (23.3%) |
| Gleason group (ISUP 2014/WHO 2016) | |
| 1 | 6 (20.0%) |
| 2 | 13 (43.3%) |
| 3 | 7 (23.3%) |
| 4 | 2 (6.7%) |
| 5 | 2 (6.7%) |
| Pre-treatment PSA, ng/mL | |
| Median | 8.5 (5.5–14.5) |
| <10 | 18 (60.0%) |
| 0–20 | 8 (26.7%) |
| >20 | 4 (13.3%) |
| Median baseline IPSS score (IQR) | 7.0 (6.0–9.0) |
| NCCN Risk Groups | |
| Low | 4 |
| Intermediate | 15 |
| High | 11 |
| Hormone therapy | |
| None | 15 (50.0%) |
| STAD | 3 (10.0%) |
| LTAD | 12 (40.%) |
| Median PTV-prostate dose (Gy) (IQR) | 77.6 (77.3–78.1) |
| Median PTV-DIL dose (Gy) | 85.2 (85.0–85.4) |
| Median GTV-DIL dose (Gy) | 85.5 (85.0–86.0) |
DIL, dominant intraprostatic lesion; GTV, Gross tumour volume; IQR: Interquartile range; ISUP: International Society of Urological Pathology;LTAD, Long-term androgen deprivation; NCCN, National Comprehensive Cancer Network; PSA: Prostate-specific antigen;PTV, Planning target volume; STAD, Short-term androgen deprivation; WHO: World Health Organization.
Biochemical and local outcomes
With a median follow-up of 30.0 months (IQR 25.5–40.27), all 30 patients remain free of biochemical relapse. An mpMRI morphological and functional complete response was observed in the 30 patients included in the analysis. Twenty-five patients presented a disappearance of the dominant index lesions both on DWI and in the T2W images during the first post-treatment evaluation performed at six moths. The remaining five patients presented a reduction in the size of the dominant nodules on T2 images without diffusion restriction in the first mpMRI performed at 6 months, and achieved a complete disappearance of the dominant nodule both on T2 and DWI on the second mpMRI performed at 9 months following treatment.
Toxicity and patient reported outcomes
Six out of 30 (20%) patients presented acute Grade 2 urinary toxicity (frequency and dysuria) with no Grade 3 acute complications. Acute rectal toxicity was only found in 2 (6.6%) patients (both Grade 1). Only late Grade 1 urinary and rectal complications were observed in 3/30 patients, respectively, with no Grade 2 or more late toxicity (Table 2).
Table 2.
Cumulative worst acute (<=3 months) and late (>3 months) rectal and urinary toxicity for all eligible patients
| CTCAE toxicity | N = 30 patients |
|---|---|
| Acute rectal toxicity | |
| Grade 0 | 28 |
| Grade 1 | 2 |
| Grade >=2 | 0 |
| Acute urinary toxicity | |
| Grade 0 | 11 |
| Grade 1 | 13 |
| Grade 2 (frequency and dysuria) | 6 |
| Late rectal toxicity | |
| Grade 0 | 27 |
| Grade 1 | 3 |
| Grade >=2 | 0 |
| Late urinary toxicity | |
| Grade 0 | 27 |
| Grade 1 | 3 |
| Grade >=2 | 0 |
CTCAE, Common Terminology Criteria for Adverse Events.
Adequate baseline and follow-up QoL data were available for the all patients. The mean changes in the EPIC QoL score over time for each domain are shown in Figure 1. There was no substantial change in mean EPIC values for urinary incontinence. The average of EPIC irritative or obstructive symptoms was increased from 2.06 before the treatment to 3.89 at the end of radiotherapy returning to baseline (2.05) by month 3. Bowel symptoms were more pronounced after radiotherapy (baseline 0.63, end of treatment 2.20) but they returned to baseline scores by month 6 (0.84. The sexual function analysed in patients not receiving ADT (N = 15) declined from 3.94 at the baseline to 6.32 by 12 months. Finally, the urinary, bowel and sexual bother scores were slightly and insignificantly increased in the first 3 months post-treatment, returning to normal afterwards. The total UCLA-PCI scores showed similar pattern scores that EPIC for all but bowel domain where no significant deterioration was observed (data not shown).
Figure 1.
EPIC QoL changes (mean ± standard deviation) from baseline in the urinary (a), bowel (b), sexual (c) and health state (d) domains.
Discussion
The preliminary analysis of this prospective Phase II trial showed that MRI-guided focal boost to the DIL using VMAT/IGRT was technically feasible and well tolerated, did not lead to a significant change in QoL at 2 years and resulted in an excellent morphological and functional MRI local control. We did not observe grade ≥2 late urinary or rectal complications by 2 years. Although a direct comparison of the toxicity data of the different trials is unfeasible because of differences in treatment protocols, the results of the present trial are more favourable than our previous series of 733 patients treated with whole prostate 80 Gy dose escalation without DIL boost 11 and are in line with those of contemporary studies of focal boost. 12–16 In these trials, the average estimated incidence of grade ≥3 gastrointestinal and genitourinary late toxicity was, respectively, 2.5 and 3.1% for IMRT (intensity modulated radiation therapy) boost, 10 and 6% for SBRT (stereotactic body radiation therapy), 6 and 2% for LDR BT (low dose-rate brachytherapy), and 4 and 4.3% for HDR BT (high dose-rate BT). 17 Also, in agreement with other modern series, we observed that acute urinary toxicity was more frequent and relevant than rectal toxicity. 18 This change in the pattern of toxicity, despite the higher radiation dose, is probably related to an increase in radiotherapy delivery accuracy with strict protocols of IGRT with daily CBCT and fiducial markers that allow the reduction of the margins posteriorly and to a strict observance of normal tissues constrains. 11,19
The FLAME Phase III randomized trial 20 is probably the largest published study of focal dose escalation with external beam radiotherapy. This trial assessed the benefit of boosting the DIL to 95 Gy in 35 fractions of 2.7 Gy compared to a no-boost technique (77 Gy in 35 fractions). With a median follow-up of 72 months, the results showed that dose escalation with focal boost improved the biochemical disease-free survival (hazard ratio 0.45) for patients with localized intermediate and high-risk prostate cancer without impacting toxicity and QoL. Although the reported evidence indicates that doses in excess of 95 Gy EQD2 will be required, the optimal boost dose and schedule remains unknown. The preliminary results of our study showed excellent results in terms of biochemical and local control besides a modest focal dose intensification (the median GTV radiation dose in our study was 85.5 Gy compared to 91.9 Gy in the FLAME trial).
With several ongoing trials of extreme hypofractionated radiotherapy suggesting equivalent or similar 3 to 5 years biochemical control with acceptable toxicity profile results, 21–24 it seems obvious to integrate focal boost techniques with SBRT. A few studies have investigated this approach with encouraging results. Alayed et al 25 reported toxicity and QoL outcomes of two Phase 2 trials of prostate and pelvic SBRT, with or without a simultaneous DIL boost. There were notsignificant differences in acute Grade 2 toxicity, late toxicity, and QoL between both treatments. Other authors have also showed no significant increase in toxicity with the addition of focal boost in SBRT treatments with promising biochemical control. 5,26,27 Randomized trials are needed to confirm the impact of SBRT focal dose escalation on clinical outcome and QoL.
The use of mpMRI has proved to be a highly valuable tool in the diagnosis, staging and localization of prostate cancer, providing the opportunity for focal treatment approach. However, MRI is infrequently used to evaluate treatment response or predict the efficacy of radiation therapy. In the present trial, we examined the potential role of mpMRI in the assessment of treatment response. All patients in the study experienced a complete response defined as the complete disappearance of the suspicious lesions in all morphological and functional sequences on the mpMRI performed at 6–9 months after radiotherapy. Other authors have also reported mpMRI response following RT. Song et al 28 reported changes of apparent diffusion coefficient (ADC) values in prostate cancers after radiotherapy. Iturriaga et al 14 described a complete morphological and functional response rate at 12 months of 86.7% in a series of 15 patients treated with focal dose escalation using HDR combined with external beam radiation therapy. Recent series of mpMRI validated by transperineal systematic template prostate mapping have shown a good performance for detection of radio-recurrent prostate cancer with an area under the curve of 0.84. 29 In a prior retrospective analysis of 232 patients with localized prostate cancer who underwent a prostate re-biopsy 24–36 months after high-dose radiotherapy, we observed a significant association between local control determined by post-radiotherapy biopsy and metastasis free survival. 30 Since prostate re-biopsy is an invasive procedure not recommended in routine clinical practice, the validation of mpMRI in the assessment of tumour response after radiotherapy deserves further research.
Recent advances with hybrid machines for MRI-guided SBRT have shown very promising results in terms of tolerability and preliminary clinical outcomes, although the currently available devices are still in the early stages of their potential clinical application in this field. The integration of new algorithm tools in the near future will certainly increase its clinical use in daily adapted treatments. 31
Radiomics has attracted increasing interest in recent years as a potential new prognostic and predictive tool following radiotherapy and neoadjuvant systemic therapy in localized prostate cancer, although most radiomic studies have been performed in lung and colorectal cancer and the reported experience in prostate cancer is still scant and mostly directed to improve characterization and diagnosis. 32,33 However, the results of studies that have evaluated the relationship between pretreatment mpMRI radiomics features and biochemical and pathologic response are promising. 34–36 Our group is now exploring to broaden the mpMRI analysis incorporating radiomic features that could correlate with prognosis and treatment response following focal dose escalation and SBRT.
The present study was subject to several limitations including the limited number of patients, the lack of a comparison cohort, the short follow-up and the lack of post-treatment histological confirmation. Furthermore, since the population was mainly intermediate and high-risk patients, 50% of them received hormone therapy which can interfere in the interpretation of the findings. Nevertheless, we cannot obviate the strengths of this report. First, the use of a matching point registration of the planning TC with a second mpMRI (T 2-weighted, DWI and a T2* GRE images) to improve prostate and tumour delineation. Second, the inclusion of a 2–3 mm margin around DIL to account for uncertainties in delineation and treatment planning and delivery. Finally, we also incorporated the mpMRI for radiological assessment of treatment response. Interestingly, our study included 11 (37%) patients with high-risk disease (seven with T3), a subgroup of patients that should benefit from treatment intensification, and the preliminary data showed a 100% rate of morphological and functional control defined by mpMRI. A further analysis with longer follow-up will be performed to analyse the pattern of relapse adjusted by hormone therapy treatment.
Conclusion
In this prospective study, we have confirmed that MRI-guided focal boost using VMAT is feasible to escalate the dose to the tumour lesion up to an EQD2Gy of 95.4 Gy (alfa/β 1.5) while maintaining an EQD2Gy of 79.7 Gy to the whole prostate, without increasing the risk of urinary or rectal toxicity and with encouraging results in term of mpMRI morphological and functional response. Future work will focus on the exploration of a predictive radiomic pattern in patients treated with prostate SBRT with integrated focal boost.
Footnotes
Acknowledgment: The authors wish to thank Elena Pintos, Marta de los Ríos and Gina Mejías for their review and management of the clinical data.
Contributor Information
Almudena Zapatero, Email: almudena.zapatero@salud.madrid.org.
Maria Roch, Email: maria.roch@salud.madrid.org.
Pablo Castro Tejero, Email: pablo.castro@salud.madrid.org.
David Büchser, Email: david.buchser@salud.madrid.org.
Carmen Martin de Vidales, Email: carmen.martinvidales@salud.madrid.org.
Saturnino González, Email: saturgonza@gmail.com.
Luis Alberto San Jose, Email: lsanjoseman@hotmail.com.
Guillermo Celada, Email: guillermo.celada@salud.madrid.org.
Maria Teresa Murillo, Email: mariateresa.murillo@salud.madrid.org.
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