Conventional fractionation for prostate cancer involves delivering daily fractions of 1.8–2 Gy per day over 7–9 weeks. Recent advances in radiation therapy technologies have renewed interest in hypofractionation – defined as delivery of daily fractions of 2.5–10 Gy. Moderate hypofractionation (MH) has been defined as <4 Gy per fraction and, recently, has been tested in prospective trials against conventional fractionation. The linear quadratic model describes the association of the total isoeffective dose and fraction size. The model uses two constants: α and β, and the ratio α/β is inversely related to the effect of changes in fraction size on normal and malignant tissues. Most cancers and acute normal tissue reactions are believed to have high α/β ratios of 10 Gy. However, prostate cancer has been suggested to have an α/β of 1.5 Gy.42,43 This is lower than the 3 Gy reported for the late reactions of most normal tissues, including the rectum.44 MH also has advantages of increased convenience for the patient and a lower cost burden for the health-care system.
Recently, four large randomized trials have been published that compared standard fractionation (SF) to MH. The trials were CHHiP,45 RTOG 0415,46 PROFIT,47 and HYPRO.48 The first three trials were non-inferiority trials and the doses in the MH arms ranged from 57 to 70 Gy administered in 2.5–3.4 Gy per fraction. The HYPRO48 study was a superiority trial and the patients in the MH arm received 64.6 Gy in 3.4 Gy per fraction. Overall, these studies demonstrated that the safety and efficacy of MH was similar to that of SF. However, the MH arm in the HYPRO study was not superior to conventional radiotherapy with respect to 5-year relapse-free survival.
The CHHiP trial45 was the largest non-inferiority randomized study of MH and randomized 3,216 patients to 74 Gy/37 fractions/7.4 weeks, 60 Gy/20 fractions/4 weeks, or 57 Gy/19 fractions/3.8 weeks, with treatment delivery using IMRT. After a median follow-up of 62.4 months, acute RTOG GI toxicity had become similar in each arm by 18 weeks, it peaked earlier in the hypofractionated arm (4–5 weeks) compared to the control arm (7–8 weeks). Early Grade ≥2 GI toxicity was significantly higher in the hypofractionated arms; it was 25% in the 74-Gy arm, 38% in the 60-Gy arm (P < 0.0001), and 38% in the 57-Gy arm (P < 0.0001). The 5-year clinician and patient-reported side effects were not significantly different. RTOG Grade ≥2 GI toxicity was reported at 13.7, 11.9, and 11.5% in the 74-, 60-, and 57-Gy arms respectively. Comparison of the 60- and 57-Gy arms revealed a slightly higher rate of cumulative LENT-SOM Grade ≥2 GI toxicity [hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.14–1.70; P = 0.001].
The PROFIT trial47 enrolled 1,206 men and randomized them to 60 Gy/20 fractions/4 weeks versus 78 Gy/39 fractions/7.8 weeks. The median follow-up was 6 years. The proportion of patients with acute Grade ≥3 toxicity was low in both arms. Late Grade ≥3 toxicity was not significantly different between groups; interestingly, there was a trend toward higher levels in the standard arm (P = 0.10). There was a significant increase in acute Grade ≥2 toxicity in the MH arm (P = 0.003). However, the late Grade ≥2 toxicity was significantly increased in the standard arm (P = 0.006). The RTOG 0415 study46 randomized 1,092 patients with low-risk disease to 73.8 Gy/41 fractions/8.2 weeks or 70 Gy/28 fractions/5.6 weeks. The median follow-up was 5.8 years. The acute side effects did not differ significantly in the two arms of the study. Late grades 2 and 3 GI adverse events were approximately 60% more likely in men who were assigned to treatment with MH (RR, 1.55–1.59).
In contrast to RTOG 0415,46 CHHiP45 reported no difference in late toxicity, whereas PROFIT47 reports a lower rate of late toxicity in the MH arm. These differences may be due to the biologically effective dose (BED) in the MH and control arms of each individual study as explained by Benjamin et al.49 Assuming an α/β of 3.0 Gy for bladder/rectum, the BED in the MH arm is higher than in the control arm in RTOG 041546 (128 Gy vs 118 Gy), similar to the control arm in CHHiP45 (120 Gy vs 123 Gy), and lower than the control arm in PROFIT47 (120 Gy vs 130 Gy).
The HYPRO study48 is the largest of the MH superiority studies. HYPRO randomized 804 patients with intermediate- or high-risk disease to 64.6 Gy/19 fractions/3 fractions per week/6.5 weeks or 78 Gy/39 fractions/5 fractions per week/7.8 weeks, respectively. The cumulative incidence for acute Grade ≥2 GI toxicity was significantly higher (OR 1.6; P = 0.0015) in the MH arm (42%, 95% CI 37.2%–46.9%) compared to control (31.2%, 95% CI 26.6%–35.8%). There were no statistically significant differences in cumulative Grade ≥3 late GI toxicity between the two arms (2.6% vs 3.3%).
Endorectal balloons are silicon or latex devices that are filled with either air or water and are inserted into the rectum just prior to an RT treatment. These balloons have been utilized during radiation therapy as prostate immobilizers to reduce interfraction and intrafraction variations in prostate position, thus facilitating treatment with tighter margins. D’Amico et al50 evaluated intrafraction prostate motion by obtaining CT-images at 1-minute time intervals, both with and without an air-filled (60 cc) endorectal balloon in place. The mean displacement of the prostate gland with the endorectal balloon present versus that when absent was 1.3 mm (range 0–2.2 mm) versus 1.8 mm (range 0–9.1 mm) at 2 minutes, respectively, and both were statistically significant (P = 0.03). The maximum displacement in any direction (anterior–posterior, superior–inferior, or right–left) when the endorectal balloon was inflated versus absent was reduced to ≤1 mm from 4 mm.
Other investigators looked at larger endorectal balloons (100 cc) and studied the interfraction motion throughout a prostate RT course. Two groups of investigators using 100 cc balloon51,52 found small interfraction displacements when the device was inserted. The largest mean displacement was in the superior–inferior direction and measured 0.92 mm. Additionally, no organ displacement was seen during normal breathing with the balloon inserted. Given this limited prostate motion, smaller treatment margins were advised when using the balloon.
van Lin et al53 investigated the effect of an endorectal balloon on the day-to-day interfraction prostate gland motion. They compared prostate displacements daily in three orthogonal directions with portal images in patients with the balloon, compared to measurements made without the balloon. They found that prostate displacements were essentially the same for both groups: 1.3–1.8 mm. The mean 3D displacement was reduced to 2.8 and 2.4 mm for the balloon and no-balloon groups, respectively. The random interfraction displacements, relative to the treatment isocenter, were not reduced by the endorectal balloon and remained nearly unchanged in all three directions: 3.1 mm left–right, 2.6 mm superior–inferior, and 4.7 mm anterior–posterior. They concluded that off-line corrections using fiducial markers were effective at reducing the systematic prostate displacements and that endorectal balloons did not further reduce interfraction prostate motion. A similar conclusion was made by a separate group of investigators that prospectively analyzed weekly portal images of 15 patients undergoing external-beam radiotherapy with endorectal balloons.54 Thus, there are conflicting reports on the utility of these balloons.