Acute toxicity profile in prostate cancer with conventional and hypofractionated treatment
© Viani et al.; licensee BioMed Central Ltd. 2013
Received: 9 January 2012
Accepted: 17 April 2013
Published: 21 April 2013
To compare the acute toxicities in radical treatment of prostate cancer between conventional schedule (C-ARM) with 78 Gy/39 fractions and hypofractionation conformal treatment (H-ARM) with 69 Gy/23 fractions.
Methods and material
This prospective double arm study consisted of 217 patients with prostate cancer, 112 in H-ARM and 105 in C-ARM arm. C-ARM received conventional six- field conformal radiotherapy with 78 Gy in 39 fractions while H-ARM received hypofractionation with 69 Gy in 23 fractions. Weekly assessment of acute reactions was done during treatment and with one, and 3 months using RTOG scale. Univariated analysis was performed to evaluate differences between the incidences of acute reaction in the treatment arms. Variables with p value less than 0.1 were included in the multivariated logistic regression.
There was no difference between H-ARM versus C-ARM for severity and incidence in genitourinary (GU) and gastrointestinal (GI) acute toxicity. During the treatment comparing H-ARM with C-ARM no differences was observed for GI toxicity (grade 0–3; H-ARM = 45.5%, 34%, 18.7% and 1.8% versus C-ARM = 47.6%, 35.2%, 17.2% and 0). For acute GU toxicity no difference was detected between H-ARM (grade 0–3; 22.3%, 54.5%, 18.7% and 4.5%) and C-ARM (grade 0–3; 25.8%, 53.3%, 17.1% and 3.8%).
At the 3- months follow-up, persistent Grade > =2 acute GU and GI toxicity were 2.5% and 1.8% in H-ARM versus 5.7% and 3% in C-ARM (p > 0.05). In univariated and multivariated analyses, there was not any dosimetric predictor for GI and GU toxicity.
Our data demonstrate that hypofractionated radiotherapy achieving high biological effective dose using conformal radiotherapy is feasible for prostate cancer, being well tolerated with minimal severe acute toxicity.
In the last decades, it has been shown that exists a dose–response relation between the prostate cancer biochemical control and the total dose of radiotherapy delivered . Evidences have also been growing from experimental and clinical studies that the α/β ratio of the linear-quadratic formulation for prostate cancer might be between 1.5 and 1.85 Gy [2–4]. This low α/β ratio suggests that prostate cancer has high sensitivity to dose per fraction, which suggests that a hypofractionation, with a large radiation dose delivered in a smaller number of fractions, might be more advantageous when compared to other type of cancer cells. On the other hand, the α/β ratio of the rectum is as important as that of prostate cancer for exploring which hypofractionation regimens will be most beneficial. Although α/β ratio for the rectal wall is not known precisely, animal studies suggest α/β ratio for the rectum of 4–6 G  . If the α/β ratio for rectum is higher than that for prostate, theoretically, larger hypofractionated doses could be given with larger clinical gains within the same or lower complication rates .
Although the hypofractionation schedule for prostate cancer appears more attractive than conventional fractionation, the experience of using hypofractionation with total equivalent doses of 78–80 Gy has been limited.
These limited data are from a randomized Phase III trial comparing a conventional fractionation regimen of 80 Gy given in 2-Gy fractions with a hypofractionation regimen of 62 Gy given in 20 fractions of 3.1 Gy/d , a nonrandomized study of hypofractionation vs. conventional fractionation delivered using 3D conformal radiotherapy technique , and a few other Phase I-II reports using image guide radiotherapy (IGRT) or intensity-modulated radiotherapy (IMRT) [9–11].
In order to compare two-fractionation regimens of radiotherapy in prostate cancer patients, we compared a high dose hypofractionation schedule (69 Gy/ 23 fractions) with conventional fractionation (78 Gy/39 fractions). This report summarizes the acute genitourinary and gastrointestinal side effects for all patients included in our prospective nonrandomized study, comparing conventional or hypofractionated RT.
Material and methods
It is a prospective study conducted after the approval of the institutional review board. The study population consisted of 217 patients with localized prostate cancer, who were treated between November 2009 and January 2011, with patients selected into two arms. Patients in C-Arm received conventional radiotherapy and those in H-Arm received hypofractionated radiotherapy, both treatments with conformal technique.
The pretreatment evaluation consisted of a full history, with special emphasis on pretreatment urinary and rectal symptoms, and a physical examination. The prognostic groups were defined as follows: low risk, Stage T1-T2a, Gleason score <7, and initial prostate-specific antigen (iPSA) level <10 ng/mL; intermediate risk, Stage T1-T2b, Gleason score <7, and iPSA level of 10–19.9 ng/mL or Stage T1-T2b, Gleason score 7, and iPSA <20 ng/mL; and high risk, Stage T3, Gleason score 8–10, or iPSA >20 ng/mL. Patients with metastases were excluded this trial.
Selection for treatment arms
Patients were selected for treatment arms according to their convenience. This bias was permitted, because the most patients came from long distances to treat. The groups were balance to achieve similar distribution between the treatment arms. If a patient was chosen to be treated in the H- Arm, the next patient automatically was allocated in C-arm.
95% of PTV78 to receive 78 Gy
95% of PTV69 to receive 69Gy
V60 Gy < = 50%
V50Gy < = 50%
V65 Gy < = 35%
V54Gy < = 35%
V70Gy < = 25%
V58Gy < =25%
V75Gy < = 15%
V62Gy < = 15%
V65Gy < = 50%
V54Gy < = 50%
V70Gy < = 35%
V58Gy < = 35%
V75Gy < = 25%
V62Gy < = 25%
V80Gy < = 15%
V67Gy < = 15%
Maximal dose < = 55 Gy
Maximal dose < = 46 Gy
The primary study outcome was acute treatment reactions from the beginning of treatment to 3 months after the end of treatment. Patients were seen weekly, or as required, during treatment by a radiation oncologist. Pre-existent urinary or rectal disorders, such as dysuria, pollakiuria, stress incontinence, hemorrhoids, and so forth, were assigned a grade complication if RT had exacerbated the baseline dysfunction. Acute gastrointestinal (GI) (retite, diarrhea, tenesmus and fecal incontinence) and genitourinary (GU) toxicity (dysuria, urinary frequency, retention, hematuria and urinary incontinence) were prospectively assessed and graded according to the Radiation Therapy Oncology Group scoring system for the rectum and bladder.
The association between the two groups was determined through bivariate analysis using Pearson’s chi square test or Fisher test, when necessary. To compare continuous variable the student T test was used. Two sided p value was calculated and any difference with a p value < 0.05 was considered significant. The dosimetric parameters such as; rectal, PTV and bladder volume were extracted from the treatment plan as well as age and ADT. These variables were tested whether they were related to the probability of having > = Grade 2 RTOG toxicity. Univariated analysis and multivariated logistic regression were performed to evaluate differences between the incidences of acute reaction in the treatment arms. All statistical analysis was performed using SPSS (Statistical Analysis Systems software), version 19.
Baseline Gleason score
Initial PSA level (ng/mL)
0.59 – 62.8
Mean rectal volume (cm3)
60.8 + −2.9
59.7 + −2.7
Mean bladder volume (cm3)
262.0 + −16.5
258.9 + − 17.7
PTV Mean total volume (cm3)
167.5 + − 30.5
162.8 + − 31.2
Incidence of maximum acute RTOG toxicity during the treatment
Maximum acute RTOG toxicity at 3 months of follow up
Maximum acute toxicity during follow up and clinical parameters
Grade > =2 Acute GI toxicity
PTV volume > =165
PTV volume < 165
Rectal volume > = 60
Rectal volume < 60
Age > = 70
Age < 70
Grade > = 2 acute GU toxicity
PTV volume > = 165
PTV volume < 165
Bladder volume > = 260
Bladder volume < 260
Age > =70
Age < 70
The multivariate analysis (logistic regression) evaluating the gastrointestinal or the genitourinary toxicity > = grade 2
0.45 - 15.56
0.27 - 15.72
Age > = 70 years
0.68 - 13.42
PTV volume > = 165
0.72 - 11.14
Rectal volume > = 60
0.38 - 7.55
0.52 – 15.65
Age > = 70 years
0.59 – 14.01
PTV volume > = 165
0.76 – 10.92
Bladder volume > = 260
0.18 – 6.92
The present trial is the first nonrandomized study to compare a high-dose hypofractionated with conventionally fractionated schedule using conformal radiotherapy for prostate cancer. This study was designed to test the hypothesis that a high- dose hypofractionation regimen is equivalent to a conventional fractionation scheme in terms of acute GI and GU toxicity. This hypothesis was determined from the assumption that the α/β ratio would be 1.5–2 Gy for prostate cancer [3, 4] and 10 and 3 Gy for early and slowly proliferating normal tissue, respectively. With the delivery of the same equivalent total dose to prostate tumors using a hypofractionation regimen, the corresponding equivalent doses to normal tissue would be lower. Therefore, with a slight prolongation of the shorter overall treatment time (from 4.5 weeks), both acute and late toxicity would be reduced compared with that occurring after conventional fractionation.
Overview of published clinical data on hypofractionation in prostate cancer
NTD2 for α/β
α/β = 1.5
Livsey et al. 
Kupelian et al. 
Soete et al. 
Madsen et al. 
Pollack et al. 
Martin et al. 
FAMEMA trial (present study)
Moreover, the hypofractination schedule was quite well tolerated with more than 45% of patients presenting no acute GI toxicity during the treatment and at 3 months of follow up, only 2% of patients had residual grade > = 2 toxicity. This data are comparable to other hypofractionation cohorts with residual Grade > =2 GI toxicity rates of 4–5%. The incidence of Grade 2 or greater acute reactions reported in the present report for our standard fractionation was not greater (rectal 17.2%, urinary 20.9%), than other trials of dose escalation. Acute toxicity has been addressed in several randomized clinical trials of dose escalation using standard fractionation. In a French trial , 30% of patients presented with acute rectal reactions of Grade 2 or greater and 37% with urinary reactions of Grade 2 or greater in the arm treated to a mean dose of 78.5 Gy. In another study from The Netherlands , gastrointestinal complications of Grade 2 or greater were experienced by 51% of patients in the 78-Gy arm and urinary complications of Grade 2 or greater in 55%. Therefore, the use of five fractions weekly, instead of three or four, with an overall treatment time of 38 days for our hypofractionation regimen, have not increased the acute toxicity.
Another point that deserves attention is our margin given to the planning target volume (PTV). Despite the use of a larger posterior margin (7mm) given to the PTV in our cohort, the rates of acute GI toxicity were similar to Soete et al.  delivering 56 Gy in 16 fractions of 3.5 Gy with 3 mm of margin. In their study was reported 5% of Grade 2 acute GI toxicity with no Grade 3 toxicity. For us, this satisfactory level of acute toxicity observed in our study can be result of an accurate treatment planning and set up verification, associated with a close attention to the dose–volume constraints for the organs at risk (Table 1). Although, does not exist a consensus on the optimal dosimetric parameters to be used in clinical practice. Rectal and bladder constraints are used to reduce the incidence of bladder and rectal toxicity. So, we speculate that although the dose–volume histograms based on the initial planning CT may not reflect the real dose received by the rectum because of displacement of the prostate and rectum during and between treatments, the use of restrictive DVH can help to maintain the acute toxicity rates in a satisfactory level.
In our univariated and multivariated analysis comparing dosimetric and clinical variables (e.g., risk group designation, PTV volume, SV irradiation, or hormonal therapy) between the two groups, no significant relationship with acute GI or GU effects was observed. This can be probably related to the large variability of bladder and rectum volumes during and between the treatments. This founds are in agreement with those of Pollack et al. , who also did not observe a target volume or normal tissue dose–volume dosimetric relationship with either acute GI or GU toxicity, nor with group designation or use of hormonal therapy.
We present here our early outcomes for a high dose hypofractionated conformal radiotherapy regime for the treatment of prostate cancer. This study suggests that hypofractionated dose-escalated radiotherapy using conformal radiotherapy in prostate cancer is feasible and produces acceptable toxicity with the dose constraints used. No difference in incidence or severity of acute gastrointestinal and genitourinary toxicity was observed when compared to conventional fractionation. Moreover, the acute toxicity rates were comparable to those of other dose escalation trials using standard or hypofractionated schedules, being transient, with only 2 patients having persistent Grade 2 or higher GI toxicity by 3 months follow up.
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