Discussion

In this retrospective dosimetric study comparing doses to OARs, we demonstrated that CHHiP treatment protocol delivers less dose to the bladder, rectum, and penile bulb. The results of this study favor the use of CHHiP protocol over the PROFIT protocol when treating patients with localized, low- to intermediate-risk prostate cancer with moderate hypofractionated external beam radiation therapy.

The radiobiological rationale for using hypofractionation in the treatment of prostate cancer is the low α/β value, which indicates that higher doses per fraction can have a therapeutic advantage while minimizing long-term adverse effects on the surrounding normal tissues.³ Safely decreasing the number of fractions also has logistic and socioeconomic advantages to patients and radiation centers. There have been several trials comparing different dose fractionations to the standard regimens, which use 1.8-2 Gy per fraction. Among these trials are CHHiP and PROFIT.

CHHiP is the largest of these randomized trials that enrolled more than 3000 patients across Europe and New Zealand, and it demonstrated noninferiority of the hypofractionated 60 Gy arm compared with the standard fractionated 74 Gy arm in terms of biochemical and clinical failure-free survival at 5 years (> 90%)⁶ and at 8 years (>80%).¹⁴ The hypofractionated regimen had an acceptable toxicity profile as per the Radiation Therapy Oncology Group (RTOG) scale: the cumulative incidence of grade > 2 bladder and bowel toxicity at 5 years was estimated at 11.7% and 11.9%, respectively.⁶

PROFIT was also a randomized trial comparing standard and hypofractionated radiation therapy, by enrolling more than 1200 patients from Canada, Australia, and France. It showed a 5-year biochemical/clinical failure disease-free survival of 85% in both arms with no difference in overall RTOG grade > 3 bladder and bowel toxicity. Although gastrointestinal (GI) adverse events grade ≥ 2 were higher in the hypofractionated arm in the acute setting (first 14 weeks), this was reversed in the long term (6 months onward), with late GI toxicity in the hypofractionated arm being lower than in the standard arm (7.4% vs 11%, P value = .006).⁸

We decided to compare the CHHiP and PROFIT regimens due to identical dose and fractionation in the 2 studies as well as their popularity. PROFIT is more user friendly for both the radiation oncologist and the dosimetrist because there is a single target volume that is treated to a dose of 60 Gy in 20 fractions contrary to the CHHiP protocol where 3 different target volumes exist, requiring a simultaneous integrated boost technique. It may be argued that a comparison between CHHiP and PROFIT cannot be done due to the differential dose distribution in either regimen (ie, CHHiP delivers 60 Gy to PTV1, 57.6 Gy to PTV2, and 48 Gy to PTV3, whereas PROFIT delivers the entire 60 Gy to a single PTV). Both protocols were compared in phase 3 randomized trials to standard fractionation and were shown to be equivalent in terms of oncological outcomes. The question of which shall be preferred in terms of radiation toxicity cannot be answered unless they are compared head-to-head without delineation and dose prescription modifications. To the best of our knowledge, our dosimetric study is the first to compare the two.

Despite moderate hypofractionation becoming standard of care for localized prostate cancer, significant variety exists in target volume definitions in the literature. The American College of Radiology Appropriateness Criteria mentions 2 CTVs in case the risk of seminal vesicle involvement is high (ie, >15%). The first CTV involves both prostate and seminal vesicles, while the second covers the prostate only.¹⁵ The French Genito-urinary Group (GETUG) recommendations mention a single CTV, which may include the first centimeter of the seminal vesicles if the tumor is deemed to be high-intermediate risk for SVI.¹⁶ Given the different guidelines and recommendations among treatment groups, our comparison is relevant to the current practice of radiation oncology in prostate cancer.

When CHHiP and PROFIT were initiated, image-guided radiation therapy (IGRT) was not yet widespread. When image guidance became more available, the CHHiP trialists started a substudy, where patients either received no IGRT, or IGRT with the original margins, or IGRT with reduced margins: 6 mm/6 mm/3 mm and posteriorly 6 mm/3 mm/0 mm.¹⁷ The reduced margins significantly spared the bladder and rectum to a greater degree, as illustrated in lower dose volume and surface percentages ( P value < .0001). Even though radiation oncologists are now inclined to reduce the margins, significant variability still exists in clinical practice. For example, GETUG recommends a margin of 7-10 mm (5-7 mm posteriorly),¹⁶ whereas physicians at the Memorial Sloan Kettering Cancer Center suggest margins to be reduced as much as 5 mm (3 mm posteriorly) in a recently published treatment planning guide.¹⁸ Similarly, the moderately hypofractionated plans in the PACE-B trial used 5-9 mm margins (3-7 mm posteriorly),¹⁹ while those in POP-RT had them at 7 mm (5 mm posteriorly).²⁰ Some protocols require the insertion of fiducial markers, which may not be available in all centers, or the availability of daily cone beam CT imaging, which may be problematic in busy radiation therapy centers with limited resources. As such, in our comparison, we decided to rely on the PTV margins as originally described in the trial protocols.

Our study illustrated that the CHHiP treatment protocol delivered less dose to the bladder, rectum, and penile bulb compared with the PROFIT protocol. While the 2 regimens have not been compared head-to-head in terms of toxicity, we expect this dosimetric benefit to translate into clinical benefit as per dose-toxicity relationships.

In terms of GI toxicity, several reports have correlated the dose received by the rectum in prostate radiation therapy to the incidence of late rectal bleeding. The quantitative analysis of normal tissue effects in the clinic (QUANTEC) review suggested dose constraints in order to decrease the risk of late rectal toxicity of grade ≥ 2 and of grade ≥ 3 to less than 15% and 10%, respectively.²¹ Accordingly, it was recommended that the rectal volumes receiving 75 Gy, 70 Gy, 65 Gy, 60 Gy, and 50 Gy not exceed 15%, 20%, 25%, 35%, and 50%, respectively. In its recommendations, the QUANTEC review relied on studies where three-dimensional conformal radiation therapy was applied and where radiation was given in standard fractionation. More recently, Wilkins et al presented a dose-volume study that is more applicable to prostate cancer care nowadays.²² Relying on the CHHiP trial, they were the first to derive anorectal dose constraints for hypofractionated IMRT: the volumes receiving 60 Gy, 50 Gy, 40 Gy, 30 Gy, and 20 Gy should be kept below 0.01%, 22%, 38%, 57%, and 85%, respectively. The constraints on the higher doses (40-60 Gy), much tighter than those of QUANTEC, were particularly significant in minimizing rectal bleeding.²² In our comparison, both CHHiP and PROFIT plans met the tighter V50 and V40 constraints suggested by Wilkins et al, but neither satisfied that of V60. That said, V60 in the CHHiP plans was on average 0.5%, which was 9 times less than the average V60 in PROFIT (4.5%). We infer that the CHHiP protocol potentially decreases GI toxicity as opposed to PROFIT, even with the original margins used. We also acknowledge that the plans can be further optimized by using IGRT and reducing the margins, so that all constraints by Wilkins et al may be met and that GI toxicity may be minimized.

Urinary toxicity is also a significant consideration for the quality of life of patients after radiation therapy for prostate cancer, with long-term symptoms including hematuria, dysuria, and increased frequency. However, the QUANTEC review reported that there were no comprehensive data to extract generalizable dose constraints for the bladder.²³ With that, it recommended the reliance on the constraints as per the conventional fractionation arm in the noninferiority RTOG 0415 trial, which limited the bladder volume receiving 80 Gy, 75 Gy, 70 Gy, and 65 Gy from exceeding 15%, 25%, 35%, and 50%, respectively.⁷ Interestingly, for that same trial, a later dose-toxicity analysis found no correlation between the dose received by the bladder and the incidence of genitourinary (GU) toxicity in patients assigned to the hypofractionated arm.²⁴ In our comparison, both CHHiP and PROFIT plans satisfy V48 and V40, but only CHHiP satisfies V60 (1.9% vs 7.7% in PROFIT). While more evidence is surely required to better understand dose and GU toxicity relationships, it is prudent to reduce the dose to the bladder if possible, providing one more reason to favor CHHiP.

The penile bulb is considered a surrogate for neurovascular structures necessary for erectile function, and doses to the penile bulb have been implicated in sexual toxicity. In 2010, the QUANTEC review based on standard fractionated regimens suggested 50 Gy as a threshold mean dose to the penile bulb so as not to increase the risk of impotence post radiation therapy.²⁵ More recently, studies based on hypofractionated regimens have recommended stricter thresholds. In the CHHiP IGRT substudy, researchers found a correlation between the mean and maximum dose to the penile bulb and the incidence of erectile dysfunction.²⁶ With a Royal Marsden Hospital (RMH) grade 2 erectile potency at 2 years as an endpoint, the derived mean dose constraint was 22 Gy, delivered in 3 Gy per fraction, in such a way that the odds of an RMH grade 2 erectile potency were 2.6 times higher in patients whose plans met the constraint than in those whose plans did not. Similar cutoff values have been suggested by a dose-response study from the HYPO-RT-PC trial²⁷ and by another smaller trial from the University of Alabama at Birmingham,²⁸ both of which delivered hypofractionated radiation therapy. In our study, CHHiP plans, which averaged a mean dose of 21.9 Gy, performed significantly better in respecting the stricter threshold (ie, 22 Gy) than the PROFIT plans, which averaged 30.5 Gy. Given the impact of erectile dysfunction on patients’ quality of life, our results once again favor CHHiP.

This study provides the first head-to-head dosimetric comparison between these 2 popular treatment protocols. However, it has several limitations. The IMRT plans generated were step and shoot IMRT and not volumetric-modulated arc therapy. The study was conducted retrospectively in a single tertiary care center on a homogeneous patient population and did not have long-term clinical follow-up to assess for toxicity profiles. It is important to note that these differences in doses delivered to the OARs may not directly correlate to clinical toxicity, especially when the constraints are met. Also, our study is limited to patients with localized low-intermediate-risk disease, and conclusions cannot be extrapolated to other patient populations or to other dose fractionations. Our conclusions may also not apply in case different PTV margins are defined. In other words, our results apply within the scope of the comparison herein, and further studies are needed to corroborate our findings: CHHiP offers superior sparing of the bladder, rectum, and penile bulb compared with PROFIT.