Cancer Investigation, Early Online:1–6, 2014 ISSN: 0735-7907 print / 1532-4192 online C 2014 Informa Healthcare USA, Inc. Copyright DOI: 10.3109/07357907.2014.988343
Three-Dimensional Ultrasound-Based Image-Guided Hypofractionated Radiotherapy for Intermediate-Risk Prostate Cancer: Results of a Consecutive Case Series Umberto Ricardi,1 Pierfrancesco Franco,1 Fernando Munoz,2 Mario Levis,1 Christian Fiandra,1 Alessia Guarneri,2 Francesco Moretto,2 Sara Bartoncini,1 Francesca Arcadipane,1 Serena Badellino,1 Cristina Piva,1 Elisabetta Trino,1 Andrea Ruggieri,1 Andrea Riccardo Filippi,1 and Riccardo Ragona1
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Department of Oncology, Radiation Oncology, University of Torino, Turin, Italy,1 Radiotherapy Department, AOU Citt`a della Salute e della Scienza, Turin, Italy2 Consistent clinical data emerged in the last decades in all risk categories as monotherapy or in combination with androgen deprivation therapy (ADT) (2). Conventionally fractionated and “dose escalated” EBRT has proven to provide favorable biochemical control with an acceptable toxicity profile (3). Nevertheless, given the lower α/β ratio of prostate cancer compared to surrounding normal tissues, hypofractionated schedules were proposed as a suitable approach (4). Prospective phase III trials investigating hypofractionation in prostate cancer showed isoeffectiveness with conventional fractionation, even though results of early trials are not considered conclusive given the suboptimal biological equivalent dose (BED) usually delivered (5,6). However, most recent trials were designed to employ biologically equivalent schedules, resulting in comparable outcome and toxicity providing robust reliability for hypofractionation in this context (7). Recent technological advances allowed for a safe delivery of high dose hypofractionated EBRT (8). In recent years, new radiation delivery techniques provided conformality and homogeneity in target coverage and new possibilities in organs at risk avoidance. Image-guided radiotherapy (IGRT) improved ballistic precision, minimizing geometric uncertainties and further diminishing unintended normal tissue irradiation (9,10). Moreover, it has been demonstrated to potentially be able to reduce biochemical relapse rate allowing to tackle target volumes variation in position and shape eventually responsible for geographical “tumor miss” (11). Several solutions are commercially available to performIGRT in prostate cancer: electronic portal images devices (EPIDs), cone-beam computed tomography (CBCT) with both KvCT and MvCT, CT-on-rails, room-mounted X-ray imaging systems, implanted fiducial markers (tracked with both EPID/other X-ray imaging and CBCT), electromagnetic beacons and ultrasounds (10). The Clarity platform (Clarity System, Elekta, Stockholm, Sweden) allows for the acquisition of three-dimensional ultrasound scans (3D-US)
External beam radiotherapy (EBRT) is a standard of care in the treatment of prostate cancer. Hypofractionation is a valid option either radiobiologically and logistically in this context. Image-guidance procedures are strongly needed to provide ballistic precision to radiation delivery. The Clarity platform allows for the acquisition of three-dimensional ultrasound scans (3D-US) to perform image-guided radiotherapy. We treated a consecutive series of intermediate-risk prostate cancer patients (according to NCCN stratification) with a hypofractionated schedule (70.2 Gy/26 fractions at 2.7 Gy/daily to the prostate gland excluding the seminal vesicles at 62.1 Gy) under 3D-US guidance with the Clarity platform. The 3-year biochemical-relapse-free survival, distant-metastases-free, cancer-specific and overall survival were 98.6% (CI: 91.1–99.6%), 98.6% (CI: 91.1–99.6%), 97.5% (CI: 94.5–99.1%), and 94.3% (CI: 90.4–96.7%), respectively. Maximum detected acute GU toxicity was G0 in 22 patients (29.7%), G1 in 30 (22.7%), G2 in 19 (25.6%), G3 in 3 (4%). Maximum detected acute GI toxicity at the end of EBRT was G0 in 42 patients (56.8%), G1 in 22 (29.7%), G2 in 9 (12.1%), G3 in 1 (1.4%). The 3-year actuarial rates of ≥ G2 late toxicities were 6.1% for genito-urinary and 8.9% for gastrointestinal. The whole image-guidance workflow resulted in being robust and reliable. EBRT delivered employing a hypofractionated schedule under 3D-US-based image guidance proved to be a safe and effective treatment approach with consistent biochemical control and a mild toxicity profile. Hence, it has been transferred into daily clinical practice in our Department. Keywords: Hypofractionation, IGRT, 3D Ultrasounds, Clarity, Prostate cancer Radiotherapy, Radiation
INTRODUCTION External beam radiation therapy (EBRT) is a mainstay therapeutic option for patients affected with prostate cancer (1).
Correspondence to: Pierfrancesco Franco, MD. Department of Oncology, Radiation Oncology, University of Turin School of Medicine, Via Genova 3, 10126, Turin, Italy. email:
[email protected] Received 4 August 2014; revised xx xxxx; accepted 2 November 2014.
U. Ricardi et al.
of the pelvic region, using a two-dimensional (2D) transabdominal probe equipped with positional sensors, which should be swept across patient’s sovrapubic region. The system employs an infrared camera to track sensors’ positional changes, thus deriving spatial information of each 2D image acquisition subsequently used to reconstruct a 3D dataset. 3D images are then utilized for target verification and patient alignment. We herein present clinical results of a prospective case series of intermediate risk prostate cancer patients treated with US-based image-guided radiotherapy employing an hypofractionated schedule, reporting on clinical outcomes and treatment-related toxicities.
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MATERIAL AND METHODS Inclusion criteria Patients affected with organ-confined prostate cancer were included if classified as “intermediate risk” according to the National Comprehensive Cancer Network (NCCN) stratification: clinical stage cT2b-cT2c, GS = 7 and PSA between 10 and 20 ng/mL (12). All patients underwent histological confirmation using trans-rectal ultrasound (TRUS)-guided biopsies and pre-treatment evaluation (complete medical history, physical examination including digital rectal examination, blood test with PSA level, multi-parametric pelvic magnetic resonance imaging). ADT was allowed given neoadjuvantly, concomitantly and adjuvantly to EBRT for a total of 4–6 months. Synchronous inflammatory bowel disease and severe comorbid conditions were considered as exclusion criteria. All patients should have a reliable ultrasound visualization of the prostate gland within the Clarity platform. The Ethical Review Board of our Institution approved the present study. Written informed consent was obtained from all patients. Set up, target volumes, and organs at risk definition Each patient underwent a pelvic CT scan for planning purposes in supine position with an indexed-shaped knee rest and ankle support (CIVCO Medical Solutions, Kalona, IA, USA) to prevent hip rotation. Three millimeters axial-images were acquired from the top of L5 vertebral body to the bottom of ischial tuberosities. An isocenter was found during CT virtual simulation and its projection was subsequently marked on the patient’s skin under laser guidance. To allow for daily reproducibility of bladder and rectal filling, all patients were instructed to introduce 500 mL of water 1 hour before planning CT (as in every treatment fraction) and to perform a daily enema and to follow a low-residue diet starting 3 days prior to simulation. Clinical target volumes (CTVs) included prostate gland (from the apex to the proximal portion of seminal vesicles) and the proximal portion of the seminal vesicles. A 10 mm margin expansion was required from CTVs to planning target volumes (PTVs) except for prostate and seminal vesicles in the posterior direction (7 mm) to generate corresponding PTVs. Organs at risk outlined for the optimization process were bladder and rectum (from the anal canal to the recto-sigmoid flexure) defined as solid organs, bilateral
femoral heads, penile bulb and peritoneal cavity, including small bowel. Dose prescription, planning, and delivery All patients received 62.1 Gy/23 fractions (2.7 Gy daily) to the prostate gland and seminal vesicles; a subsequent boost of 8.1 Gy in three fractions was delivered sequentially to the prostate gland up to a total dose of 70.2 Gy/26 fractions. The dose was prescribed at the International Commission of Radiation Units (ICRU) point. Dose distribution was optimized so that 95% of all PTVs received at least 95% of the prescription dose, minimizing hot spots occurrence (D max < 105% of prescribed dose). Dose constraints for OARs were set to V50 < 35%, V60 < 25%, V65 < 15%, and V68 < 5% (rectum), V60 < 35% and V40 < 50% (bladder), D mean < 50 Gy (penile bulb), D50 < 40 Gy, D10 < 50 Gy and D5 < 60 Gy (peritoneal cavity), D max < 50 Gy (femural heads). Radiation was delivered employing a 3D conformal technique with a five field beam arrangement or a static-field intensity-modulated approach using 10 MV photons. 3D-US based IGRT workflow The Clarity 3D-US system is made of two separate platforms, located in the CT and treatment room, respectively, a special dedicated work-station for image co-registration and storage. An optical tracking system (OTS) is used to determine the position and orientation of the 3D-US probe, being registered to the external laser system in both rooms, were the paired US data are referenced within the same spatial coordinates. This “mutual referencing” effectively links the simulation and treatment room coordinate systems. After planning CT scan, a free-hand axial sweep is acquired, reconstructed and used to generate 3D-US images. This is due to the detection performed by the OTS of an array of infrared reflectors connected to the probe handle. The acquisition of US images in the CT-room coordinate system, defined by the laser coordinates, allows for the automatic (but manually modifiable) registration between the different acquisitions at the Clarity Workstation. A guidance structure is defined and named Positioning Reference Volume (PRV) in the Clarity workstation and then used as a reference in the treatment room. During each treatment session, a free-hand axial sweep is acquired to be then segmented into axial and sagittal planes. Subsequently, the treatment PRV is at first automatically aligned with the reference PRV using an optimization algorithm based on gray values and thereafter manually by the operator. Whenever the alignment is considered ideal, the system automatically takes into account for final target displacements with a couch translation alongside anterior-posterior, cranio-caudal and latero-lateral directions (13). The whole procedure takes only a few minutes in an appropriately trained environment, with comparable timeframes to CBCT-based approaches. Tumor control and toxicity assessment All patients underwent a weekly clinical examination during EBRT course. As preventive medication, milk enzymes were given during treatment. Follow-up evaluation, Cancer Investigation
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Hypofractionation and Image-Guidance for Prostate Cancer Radiotherapy consisting of clinical examination and PSA level assessment, was performed at 3 and 6 months and every 6 months thereafter. Follow up discontinuation was planned at 5 years. Biochemical failure (BF) was defined as a 2 ng/mL PSA level rise after Nadir has been reached, according to the Phoenix Criteria (14). Distant metastases (DM) were defined as radiological evidence of macroscopic disease in sites other than prostate gland. Death of disease was defined as death due to disease and considered for cancer-specific survival (CSS). Death of any cause was considered for overall survival (OS). Gastrointestinal (GI) and genitor-urinary (GU) acute and late toxicities were prospectively evaluated according to the Radiation Therapy Oncology Group (RTOG) criteria (15). Late toxicities were defined whenever occurring after 3 months from the end of EBRT. Generally, as Grade 1 toxicities, we scored those with the occurrence of new symptoms not requiring medications or those with an increase in the magnitude of symptoms compared to baseline. Grade 2 toxicities were defined whenever new medications (e.g. antidiarrheal drugs) or an increase in previous medications were needed or in case of a single surgical intervention performed (i.e. single laser coagulation for bleeding). Grade 3 toxicities were defined as those requiring surgery (i.e. TURP or permanent catheter or multiple laser coagulation for bleeding occurrence) (15). Statistical analysis All statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, USA). Clinical variable tested with respect to bRFS were: tumor stage (T1 vs. T2), Gleason Score (GS 7 vs. GS < 7) as dichotomic variables and age, zenith PSA and PSA nadir as continuous variables. Dosimetric parameters included D30 for both bladder and rectum and were tested with respect to ≥ G3 GU and GI toxicity. Univariate logistic analysis was performed using Student’s T-test for continuous variables; categorical variables were analyzed by Pearson’s chi-square test or Fisher’s exact test, as appropriate. Statistical significance was established at p < 0.05. Multivariate analysis was performed using Cox proportional hazard method with backward exclusion of nonsignificant variables and related to bRFS. Survival curves and actuarial rates of relapse were generated using Kaplan–Meier method, RESULTS A total of 74 patients were treated between January 2009 and May 2012. Median follow up was 38 months (range 24–61). Patients had a mean age of 71.7 years (Table 1 for details); those ≥ 70 years were 69% and were mainly affected with cT2b-cT2c tumors (40.6%), with a Gleason Score of 7 (78.4%) and a PSA level at diagnosis < 10 ng/mL (52.7%). Androgen deprivation therapy (ADT) was given in 93.2% of patients. Four patients experienced biochemical failure. Among them, two patients also went into distant spread with bone lesions. Only one patient died of disease, while other five died of other causes. The 3-year biochemical-relapse freesurvival (bRFS), DM free survival (DMFS), CSS, and OS were 98.6% (CI: 91.1–99.6%), 98.6% (CI: 91.1–99.6%), 97.5% (CI: C 2014 Informa Healthcare USA, Inc. Copyright
Table 1. Patients’ characteristics Pts characteristics Age
