Abstract
Aim: To retrospectively investigate outcomes, and acute and late complications following postoperative hypofractionated 3D conformal radiotherapy. Patients and Methods: Sixty-nine consecutive patients underwent radical prostatectomy. Radiotherapy was delivered to the prostatic fossa by means of a7-fieldLINACwith 6-15 MV to a total dose of 62.5 Gy in 25 fractions (2.5 Gy per fraction) in five consecutive weeks. Results: Median follow-up was 54.7 months (range=38-76 months). Five-year overall survival, metastasis-free survival and biochemical relapse-free survival were 91.1%, 84.6% and 66.7%, respectively. Grade 2 or more genitourinary and gastrointestinal acute toxicity was reported in 12% and 5% of patients, respectively. Urinary incontinence grade 2 or more was recorded in 19%. Conclusion: Postoperative radiotherapy either in the adjuvant or salvage setting resulted in acceptable rates of acute and late toxicity with good tumor control while reducing overall treatment time. Confirmatory results from an ongoing prospective trial are awaited.
The American Urology Association (AUA) and the American Society for Radiation Oncology (ASTRO) (1) recently developed joined guidelines for adjuvant radiotherapy (RT) after prostatectomy which have also been endorsed, with some clarification, by the American Society of Clinical Oncology (ASCO) (2). These guidelines pointed out that adjuvant RT improves biochemical control in patients with adverse pathological features of prostate cancer as extra-prostatic extension, seminal vesicle involvement and positive surgical margins compared to observation alone. The pertinent data were provided by three prospective (SWOG 8794, EORTC 22911, and ARO/AUO 96-02)(3-5) with over a 10-year follow-up time. As a matter of fact, the current applicability of adjuvant RT suffers from the inclusion of patients with detectable or unknown post-surgical Prostate-Specific Antigen (PSA) level, use of old-fashioned RT techniques, comparison with observation instead of salvage RT, as well as different results deriving from more demanding endpoints (6). As a consequence, three randomized trials (TROG RAVES 0803 clinicaltrials.gov, number NCT 00423475; GETUG-17 NCT00667069 and RADICALS ClinicalTrials.gov Identifier: NCT00541047) (7-9) are currently ongoing to clarify the benefit of adjuvant RT or salvage radiotherapy RT.
Regardless of these settings, external beam RT for prostate cancer is usually a protracted course, since a total dose of 66 to 70Gy is needed in order to be effective. At the typical rate of 1.8 to 2.0 Gy per treatment, it takes approximately 35 treatments over the course of 7 weeks to complete, which is very costly and extremely time consuming. The α/β ratio for prostate cancer is estimated to be as low as 1.5 Gy (10-12), significantly lower than the 3 Gy value estimated to produce late complications (13). Therefore, the delivery of the same equivalent total dose at 2 Gy per fraction (normalized total dose) to the prostate using a hypofractionation regimen, aside from the practical benefits of reducing the treatment cost and number of sessions for patients at radiotherapy departments, should have a sparing effect on early responding normal tissues through the reduction of the total dose delivered, as well as a reduction in the incidence of late complications. Trials investigating clinical and toxicity outcomes of moderate hypofractionation schedules in the curative setting have reached sufficient follow-up to show them to have similar efficacy and toxicity to conventionally fractionated regimens (14-17). Many clinicians are, however, reluctant to adopt a hypofractionated approach postoperatively because of the risk of tissue injury following the delivery of too high a radiation dose to the anastomosis (where most recurrences occur). These concerns need to be counterbalanced by the greater need for a lower total dose to address microscopic disease than in the curative setting, aiming to maintain the same local control (isoeffective) while potentially reducing the risk of treatment-related toxicities. The present study retrospectively evaluated outcomes, and acute and late complications following postoperative hypofractionated 3Dconformal radiotherapy (HCRT) in patients with adverse pathological features or early biochemical failure.
Patients and Methods
Between February 2011 and January 2014, 69 consecutive patients who previously underwent radical prostatectomy were treated with postoperative HCRT to the prostatic fossa because of adverse pathological features (80%) or early biochemical failure (20%). The median time between surgery and the start of RT was 5 (range=2-121) months. A total of 14 (20%) patients were also offered androgen deprivation therapy (ADT) before or during radiotherapy, 12 of whom in the form of a short course (≤6 months). An Institutional Review Board-approved retrospective analysis was performed (Ethics Committee ASL Brindisi number: 13298). Patients and tumours characteristics are shown in Table I.
Treatment planning and radiation delivery. All patients were placed in supine position with a leg fixation device, an empty rectum and a comfortably full bladder. Planning computed tomographic scan of the pelvis was obtained at 5-mm intervals from the mid-abdomen to 3 cm below the ischial tuberosities. Postoperative hypofractionated radiotherapy was delivered with a three-dimensional conformal technique in seven coplanar fields using 15-MV photons from a Varian 2100 LINAC, equipped with 80-leaf collimators. The clinical target volume (CTV) included only the prostatic fossa, as per the Radiation Therapy Oncology Group (RTOG) Consensus Guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer (18). A 1 cm expansion was added to the CTV to create the planning target volume (PTV), except posteriorly at the rectal interface, where 5 mm was used. The prescription dose at the isocenter was 62.5 Gy in 25 consecutive fractions (5 weeks), and was intended to cover 95% of the CTV. This regimen was hypothesized to be equivalent to a conventional total dose of 70 Gy or more assuming an a/b value of 1.5 Gy for tumor control. Dose constraints for the rectum and bladder were the following: rectal volume receiving 39.8 Gy (rV39.8 Gy) <50%; rV56.6 Gy<30%; bladder volume receiving 39.8 Gy (bV39.8 Gy) <70%; bV56.6 Gy<50%. Set-up accuracy was monitored daily by verifying the isocenter position with respect to that from digitally reconstructed radiography through orthogonal portal images. Treatment characteristics are summarized in Table II.
Outcome and toxicity assessment. Survival endpoint: 5-Year overall survival (OS), metastasis-free survival (MFS) and biochemical recurrence free survival (bRFS). Biochemical relapse post-RT was defined as a PSA level greater than 0.2 ng/ml (19). When postoperative PSA nadir was not <0.2 ng/ml and post-RT PSA nadir was less than 0.2 ng/ml once, then the last date of RT was defined as the date of PSA failure. The interval to biochemical failure was defined as the time from the beginning of RT to the cutoff point.
Patient and tumor characteristics.
Treatment characteristics.
All patients were clinically evaluated for urinary and rectal complications according to RTOG acute effects and RTOG/European Organization for Research and Treatment of Cancer late effects score (20) and Common Terminology Criteria for Adverse Events (Version 4.0) (21).
Patients were monitored weekly during and until 1 month after the end of radiotherapy, then at 3-month interval for 3 years and twice per year thereafter. At each follow-up visit, PSA determination and treatment-related morbidity were evaluated. In cases of increased PSA or suspected clinical local (new or progressive palpable prostate nodule) or distant failure (bone pain, low extremity edema, unjustified dyspnea, etc.), patients underwent standard diagnostic imaging procedures to detect disease progression.
Statistics. Survival was estimated using the Kaplan–Meier method, and univariate and multivariate analyses of survival were performed using the Cox proportional hazards model. All statistical analyses were performed using SPSS® v. 21 (IBM Corp., New York, NY, USA). A two-sided p-value of less than 0.05 was considered statistically significant in all tests. The following parameters were evaluated as potential predictive factors for OS, MFS and bRFS: age (≥65 years vs. <65 years), preoperative PSA (≥10 ng/ml vs. <10 ng/ml), pathologic stage (pT2 vs. pT3) and Gleason score (≥8 vs. <8), extraprostatic extension (yes vs. no), seminal vesicles and apex involvement (yes vs. no), perineural infiltration (yes vs. no).
Disease status at end of follow-up. Two patients were lost to follow-up.
Results
The median age was 69 (range=51-77) years. The median follow-up was 54.7 (range=38-76) months. Two patients were lost to follow up. Five-year OS, MFS and bRFS were 91.1%, 84.6% and 66.7%, respectively. No local recurrences were detected. A total of three (4.5%) deaths occurred, two of which were non-cancer-related. Disease status is summarized in Table III.
With regard to treatment-related toxicity, grade 4 late GU toxicity (urinary fistula) occurred in one patient, while grade 3 late GU toxicity (urethral stricture) was detected in three (4.5%) patients. No grade 4 late GI side-effects were found, while grade 2 or more late GI toxicity (rectal bleeding) developed in three (4.5%) patients. No grade 3 or more GU or GI acute side-effects were observed. Acute grade 2 GU and GI toxicityoccurred in three (4.5%) and one (1.5%) patients, respectively. Postoperatively, the incidence of urinary incontinence (any grade) was 42%, and reached 52.5% post-HCRT, although only 12% of the patients experienced a worsening of symptoms. Treatment related toxicity is summarized in Table IV.
Discussion
Hypofractionated radiotherapy has been extensively investigated in the non-surgical setting and was found to be non-inferior to conventional radiotherapy (15,16). While it is less clear whether such radiobiological advantages apply postoperatively – where microscopic rather than macroscopic cancer would be expected– a hypofractionated approach in this setting still clearly offers advantages in terms of cost and convenience to the patient. A number of studies have evaluated the toxicity outcome of postoperative radiotherapy with a hypofractionated scheme, in the adjuvant or salvage setting (19-21). Ippolito et al. performed an Intensity-modulated radiotherapy-based dose-finding trial with four increasing simultaneous integrated boosts (56.8 Gy/2.27 Gy; 59.7 Gy/2.39 Gy; 61.25 Gy/2.45 Gy and 62.5 Gy/2.5 Gy) to the prostate bed while irradiating the pelvic lymph nodes (45 Gy/1.8 Gy). No dose-limiting toxicity was seen at a median follow-up time of 19 months and therefore the recommended dose was 62.5 Gy in 2.5-Gy fractions (22). Macchia et al. treated 124 patients (108 in the adjuvant and 16 in the salvage setting) in a phase I/II study with simultaneous integrated boost IMRT to a total dose of 62.5 Gy to the prostatic bed and 45 Gy to the pelvic nodes in 25 fractions. After a median follow-up of 30 months, only one (0.8%) case of grade 4 GU toxicity was observed, and the 5-year rates of grade 2 or more GI and GU toxicity were 1.1% and 7.3%, respectively, with 5-year bRFS of 86.5% (23). Unlike these favorable findings, Cozzarini et al., with a more mature follow-up of 68 months, detected an unexpected high rate of severe late urinary toxicity (16.5% grade 3 or more) in 247 patients who underwent a hypofractionated adjuvant RT using helical tomotherapy, with doses per fraction ranging from 2.35 Gy to 2.9 Gy, in 28 and 20 fractions, respectively. Interestingly, the fraction size has been shown to be an independent prognostic factor for severe late urinary toxicity in univariate and multivariate Cox analyses. Thus, the authors recommended particular caution when using a hypofractionated schedule in the post-prostatectomy setting due to the risk of severe late urinary toxicity (24). Compared to this latter study with a similar follow-up, in our series, the incidence of major late toxicity was lower despite the use of 3D conformal RT. It is likely that targeting the prostatic fossa only instead of the whole pelvis – a factor that potentially reduces the dose received by the bladder and thus the risk of urinary toxicity – might have accounted for the relatively better toxicity profile in our study. In the salvage setting, Kruser et al. published their experience of hypofractionated RT (65.0 Gy/2.5 Gy in 26 fractions) for 108 patients with a median PSA elevation of 0.44 ng/ml after prostatectomy. The therapeutic results were encouraging: there was only moderate toxicity with only one acute grade 3 GU and no acute grade 3 GI toxicity, and no late grade 3 GU or GI toxicities. Furthermore, freedom from biochemical relapse was 66.7%±5.3% at 5 years (25). Our findings show similar biochemical control, but higher rates of late GI and GU toxicities, likely due to the use of now obsolete 3D conformal RT. We also sought potential predictive factors for each type of survival (OS, MFS and b-RFS), but none was found to be significantly associated at univariate analysis, likely due to the paucity of events. These data largely paralleled our previous experience with high-dose 3Dconformal RT where a cohort of patients received equivalent doses to the prostatic fossa (70 Gy): after a similar median follow-up (59.2 months), the cause-specific survival was 97% and major (grade 3 or more) GU and GI toxicities were observed in 10.6% and 1%, respectively (26).
Acute and late toxicities experienced by patients after 3D conformal hypofractionated radiotherapy following radical prostatectomy for prostate cancer.
For the time being, the use of image-guided intensity-modulated radiotherapy instead of 3DconformalRT might dramatically increase the therapeutic ratio, giving strength to the use of moderate hypofractionation in the postoperative setting.
The main limitations of this study are its retrospective nature and the heterogeneity that exists with regard to treatment parameters and pathological factors in the patient cohort (use of hormone ablation, inclusion of patients with bulky recurrence and markedly high PSA). In summary, postoperative HCRT reduced the length of treatment by 3 weeks, with obvious benefits to patients and the healthcare services. The acceptable toxicity and encouraging biochemical control rates herein observed warrant future investigation in prospective clinical trials. Currently, there is only one study that is addressing the role of hypofractionated RT in the postoperative setting: the University of Virginia (NCT01868386) is running a trial of moderate hypofractionation schedules ranging from 2.5 Gy in each of 26 treatments to 4.26 Gy in each of 10 treatments.
Conclusion
Our findings show that moderately hypofractionated RT either in the adjuvant or salvage setting resulted in acceptable rates of acute and late toxicity with good tumor control while reducing overall treatment time. Confirmatory results form ongoing prospective trials are awaited.
- Received February 22, 2018.
- Revision received March 19, 2018.
- Accepted March 30, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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