Abstract
Aim: We report the long-term tumor control and toxicity outcomes of patients undergoing hypofractionated (2.2 Gy) image-guided intensity-modulated radiotherapy (IG-IMRT) using tomotherapy for clinically localized prostate cancer. Patients and Methods: We examined the cases of 138 consecutive patients with stage T1-T3 prostate cancer that were treated with IG-IMRT from June 2007 to July 2009. The median follow-up time was 79 months (range=31-96 months). The planning target volume received a dose of 72.6-74.8 Gy in 33-34 fractions (2.2 Gy/fraction). Megavoltage computed tomographic (CT) scans were performed before each treatment and corrected to the registered positions on the planning CT scans using prostate soft-tissue matching. Results: The 5-year biochemical and clinical relapse-free survival rates were 95% for the low-risk group, 92% for the intermediate-risk group, and 77% for the high-risk group. The 5-year incidence rates of grade 2 and 3 late gastrointestinal toxicities were 6.3% and 3.1%, respectively, and those of grade 2 and 3 late genitourinary toxicities were 7.9% and 0%, respectively. Multivariate analysis indicated that T-stage is a prognostic factor for biochemical relapse-free survival rates. Conclusion: This report involved the longest followed-up cohort of patients to have received hypofractionated (2.2 Gy) soft tissue-matched IG-IMRT using tomotherapy. The findings of this study indicate that hypofractionated IMRT is well tolerated and is associated with good long-term tumor-control outcomes in patients with localized prostate cancer.
Randomized clinical trials showed that dose-escalated radiotherapy improves control of localized prostate cancer (1-7). Intensity-modulated radiotherapy (IMRT) is an advanced form of 3-dimentional, conformal radiation therapy which delivers non-uniform beam intensities to an irregularly shaped target to create a highly sculpted dose distribution, with concurrent dose reductions to adjacent tissues (8, 9). Image-guided (IG) radiotherapy is also-promising technique for achieving a more precise dose delivery; helical tomotherapy (HT) allows delivery of both techniques using megavoltage CT (MVCT) (10).
The TomoTherapy (TomoTherapy, Accuray, Madison, WI, USA) system has been developed exclusively for IMRT and its use has spread in the past 10 years. It provides rotational delivery of radiation along helical planes using thousands of beamlets, which can result in better dose conformity to the target. TomoTherapy also incorporates MVCT and reduces daily set-up error. However, the appropriate dose constraints required for a reduction in the rate of complications associated with rectal bleeding still remain to be investigated in this system.
TomoTherapy is a unique form of IMRT that may offer improvement in the treatment plan. Shah et al. investigated the treatment advantage of TomoTherapy over static-field IMRT. They found that TomoTherapy achieved reduced dose exposure in the bladder and rectum and an improvement in target homogeneity (11). Wolff et al. compared volumetric arc therapy with TomoTherapy, step-and-shoot IMRT and 3D-conformal radiation therapy (CRT) for prostate cancer. All intensity-modulated techniques significantly improved treatment quality when compared to 3D-CRT. They found that TomoTherapy provided the best rectal dose sparing (12). Tsai et al. also investigated the planning advantages among these intensity-modulated strategies and found that TomoTherapy achieved better dose conformity of the target and rectal sparing (13).
On the other hand, hypofractionated prostate radiotherapy delivers a high biologically effective dose over a shorter time when compared with conventional fractionation. The α/β ratio for prostate cancer has been suggested to be low, indicating that prostate cancer treatments may benefit from hypofractionation, although some publications have suggested higher α/β values, especially for high-risk patients.
At our institution, an HT approach was implemented in 2006 and we began hypofractionated (2.2 Gy/fraction) IG-IMRT for treatment of localized prostate cancer. Although we previously reported relatively high incidence of late rectal bleeding (14), we report the 5-year update on tumor control and toxicity results for 138 patients.
Patients and Methods
Patients. We examined the cases of 138 consecutive patients with stage T1-T3 prostate cancer that were treated with IG-IMRT from June 2007 to July 2009. All patients had biopsy-proven adenocarcinoma. Patients were staged according to the 2002 Union for International Cancer Control (International Union Against Cancer; UICC version 6) staging classification system (15). The clinical characteristics of patients are shown in Table I.
The median follow-up time was 79 months (range=31-96 months). Patients were followed up on a 3- to 6-monthly basis to assess long-term toxicity and outcome, measured by biochemical relapse-free survival (bRFS), cause-specific survival and overall survival. Prostate-specific antigen (PSA) failure was defined using the Phoenix definition (nadir +2 ng/ml) (16). Toxicity was classified and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (17).
Hormonal therapy. Overall, 81 patients (61%) received androgen deprivation therapy (ADT). ADT was added at the discretion of the treating urologist. Androgen deprivation primarily consisted of an oral anti-androgen or gonadotropin-releasing hormone agonist. Indications for ADT were cytoreduction or higher risk features. Patients usually received 3-6 months of neoadjuvant ADT and continued it during the course of treatment. Patients had treatment modification in the sense of a decrease or an increase in the duration of the prescription, according to the decision of their urologist.
Treatment methods. HT treatments were described in our previous study (14). In brief, the clinical target volume (CTV) consisted of the prostate and seminal vesicles, and the planning target volume (PTV) consisted of the CTV plus 5 mm in all directions, not avoiding the rectum. Ninety-five percent of the PTV (D95) received at least the prescribed dose of 74.8 Gy in 34 fractions (2.2 Gy/fraction), unless the tumor was of low risk (stage T1c, Gleason score (GS) <7, PSA<10 ng/ml), in which case a dose of 72.6 Gy in 33 fractions was used.
In this study, we assumed an α/β value of 1.5 Gy for prostate cancer. The biologically effective dose (BED) reached 179.08-184.51 Gy. This dose regimen is equivalent to a conventional fractionation regimen of 76-78 Gy in 38-39 fractions, at 2 Gy per fraction.
We defined the bladder and rectum as organs at risk. The rectum volumes were contoured on axial slices 10 mm above and below the PTV. Planning constraints were set for the rectum and bladder: 35% of the rectal volume received <40 Gy; 18% of the rectal volume received <60 Gy; 35% of the bladder volume received <40 Gy; and 25% of the bladder volume received <65 Gy. MVCT scan was performed before each treatment to confirm the PTV location and verify that the rectum and bladder conditions were met. Late rectal toxicity was defined as any toxicity experienced 3 months after the completion of radiotherapy.
Patient characteristics.
Statistical analysis. StatView 5.0 statistical software (SAS Institute Inc. Cary, NC, USA) was used for statistical analyses. Kaplan–Meier method was used to analyze PSA control. The 5-year actuarial cause-specific survival and overall survival rates were also evaluated by Kaplan–Meier method. Univariate and multivariate analyses were performed to determine the related PSA relapse-free survival predictors (risk stratification, age, GS, ADT use, T-stage, initial PSA). Multivariate analysis was perfomed using a Cox regression model.
For all analyses, values of p<0.05 was considered statistically significance.
Results
All patients completed radiotherapy without interruption. The 5-year bRFS rates were 90.8% for the whole patient group, 95% for the low-risk group, 92% for the intermediate-risk group, and 77% for the high-risk group (Figure 1).
The risk group and T-stage in univariate analysis, and T-stage in multivariate analysis was related to bRFS (Table II).
The 5-year biochemical and clinical relapse-free survival rates for all risk groups combined (a) and for the low-, intermediate-, and high-risk groups (b).
The 5-year cancer-specific survival rate for the whole patient group was 98.5%, and for the low-, intermediate- and high-risk patients were 100, 100 and 97%, respectively (Figure 2).
The 5-year overall survival rate for the whole patient group was 90.8%, and for the low-, intermediate- and high-risk patients were 87.1, 97.5 and 87.1%, respectively (Figure 3).
Table III shows the incidence of late rectal and urinary toxicities.
The 5-year incidence rates of grade 2 and 3 late gastrointestinal (GI) toxicities were 6.3% and 3.1%, respectively (Figure 4a). Rectal hemorrhage as a grade 3 GI toxicity occurred in four patients who were treated with several transfusions and a laser cauterization procedure. No grade 4 or greater GI complications were observed.
The 5-year cancer-specific survival rates for all risk groups combined (a) and for the low-, intermediate-, and high-risk groups (b).
The 5-year incidence rates of grade 2 and 3 late genitourinary (GU) toxicities were 6.4% and 0%, respectively (Figure 4b). No grade 4 or greater GU complications were observed.
Discussion
Here we report an update of the 5-year outcome of patients treated with moderate hypofractionated IG-IMRT for prostate cancer. The results of our study have shown that moderately hypofractionated IG-IMRT using tomotherapy is safe and well-tolerated with acceptable rates of late toxicity, and is highly effective. Although we previously reported a relatively high incidence of GI toxicity probably due to the use of hypofractionation, GI toxicity of our current findings is acceptable compared to other hypofractionated or conventional fractionation studies with IMRT. Our overall rates of grade 2 or more late GI and GU toxicity at 5 years was 9.4% and 6.4%, respectively, comparable with the toxicity reported in recent studies with the use of high-dose IMRT including tomotherapy (8, 9, 18-20). In IMRT studies, incidence of late grade 2 or more GI and GU toxicity ranged from 1.7-4.2% and from 12-15.5%, respectively (8, 9, 16). In IG-IMRT studies, grade 2 or more GI and GU toxicity ranged from 3-9.7% and from 10.7-16%, respectively (18, 20).
Cox regression model for biochemical relapse-free survival.
Incidence of late rectal and urinary toxicities.
In hypofraction studies with IMRT or 3D-CRT, incidence of late grade 2 or more GI and GU toxicity ranged from 4-22.5% and from 4-44.9%, respectively (21-25) (Table IV). Koontz et al. reported in a systematic review that prospective studies support the safety and similar biochemical control of moderate hypofractionation, while extreme fractionation may have greater toxicity (26). Lieng et al. reported long-term radiation toxicity and biochemical control of two moderately hypofractionated radiotherapy regimens (60 Gy or 66 Gy in 3 Gy) using IG-IMRT. They also reported that in the 66 Gy cohort, the rate of grade 2 or more GI toxicity was significantly worse (25).
The 5-year overall survival rates for all risk groups combined (a) and for the low-, intermediate-, and high-risk groups (b).
Studies with moderate hypofraction.
Studies with moderate hypofraction using tomotherapy.
In studies using HT with conventional fractionation, incidence of late grade 2 or more GI and GU toxicity ranged from 6.1-9.7% and from 1.2-10.7%, respectively (20, 27, 28), and bRFS rates at 3-5 years were almost ≥90% (20, 28). Tomita et al. reported outcomes of HT at a median dose of 78 Gy in 2 Gy fractions for prostate cancer. The 5-year bRFS rates for low-, intermediate-, high- and very-high-risk groups were 100, 98.2, 97.7 and 87.9%, respectively. The rate of grade 2 or more GI and GU toxicities were 9.7 and 10.7% (20).
In hypofractionated HT studies, incidence of grade 2 or more GI and GU toxicity ranged from 8.8-23.3% and from 8.8-26.1%, respectively (29, 30) (Tables V and VI). Di Muzio et al. reported relatively worse toxicity rate and that major predictors of grade 3 or more GU and GI late toxicity were GU acute toxicity grade 2 or more and previous surgery (30). The overall 5-year bRFS was 93.7% (low-94.6%, intermediate-95%, high-risk: 91.1%), and overall survival was 88.6% (low-90.5%, intermediate-87.4%, high-risk: 87%). Consequetly, in hypofractionated HT studies, GI and GU toxicities may be relatively worse compared with conventional fraction HT studies, while bRFS was similar to that with conventional fractionation HT.
Studies with moderate hypofraction using tomotherapy.
The Kaplan–Meier curve of grade 2 or more late gastrointestinal toxicity (a) and grade 2 or more late genitourinary toxicity (b).
In our study, rectal hemorrhage as a grade 3 GI toxicity occurred in four patients who were treated with several transfusions and a laser cauterization procedure. We previously reported that a dose &volume analysis did not reveal any significant correlation between V10-70 and rectal or bladder toxicities in our population. To our knowledge, only one study has investigated dosimetric risk factors for late rectal toxicity after IMRT (31). In that report, freedom from GI toxicity of grade 2 or higher at 4 years was 100% with rectal V70 ≤10%, V65 ≤20%, and V40 ≤40% using IMRT. Our data satisfied their requirement and the more strict constrains of the rectum might be needed for IG-IMRT using tomotherapy. We also proposed in our previous report that the margin status needs to considered. Other reports using tomotherapy apply a PTV margin for 4-6mm in the posterior direction. Iwama et al. analyzed intrafractional organ motion during HT in patients with prostate cancer and reported that a PTV margin of 3-5 mm is sufficient (32).
The limitations of our study are its moderately small sample size and moderately short follow-up time. Longer follow-up and data accumulation are needed to evaluate the long-term treatment outcomes.
In conclusion, we demonstrated the 5-year tumor control and toxicity outcomes of patients undergoing hypofractionated IG-IMRT using tomotherapy for clinically-localized prostate cancer. The current data show that this therapy is well-tolerated and provides valuable biochemical tumor control.
- Received July 27, 2017.
- Revision received August 16, 2017.
- Accepted August 22, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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