At the very least, we can conclude that hypofractionated radiotherapy is noninferior to conventionally fractionated radiotherapy but not necessarily better. These results allow us to be confident we are not losing efficacy when using hypofractionation, but its impact on late effects still needs to be further clarified.

— Talha Shaikh, MD (left), and Eric M. Horwitz, MD

Tweet this quote

For at least the past quarter of a century, radiobiologists and radiation oncologists have debated the role of hypofractionation (fewer total fractions with a higher dose per fraction) for prostate cancer. The debate stems from the unique radiobiology of prostate cancer and the best means to exploit the difference to improve outcomes.

The inherent radiosensitivity of a tumor can be described using the linear-quadratic formula that models the cells killed according to the radiation dose used. The alpha/beta ratio is a critical component of the model and characterizes the sensitivity of a cell type. Cells with a higher alpha/beta ratio are less sensitive to dose per fraction vs low alpha/beta cells. Although most tumors are thought to have a high alpha/beta (> 10 Gy) ratio, radiobiologic experiments have suggested that prostate cancer tissue has an alpha/beta ratio of 1.5 Gy—lower than even the surrounding normal tissue. In theory, increasing the dose per fraction using hypofractionation may more effectively treat prostate cancer than delivering smaller conventionally fractionated doses (1.8–2.0 Gy/fraction).

Largest Hypofractionation Trials Conducted

Multiple previous randomized trials have attempted to identify the role of hypofractionation in patients with prostate cancer. These trials have had conflicting reports due to different study endpoints and a lack of power to detect meaningful differences. The HYPRO and CHHiP trials^1,2—reviewed in this issue of The ASCO Post—are two large multicenter randomized phase III trials attempting to clarify the role of hypofractionation in patients with prostate adenocarcinoma. These studies are the largest hypofractionation trials conducted; they have the strengths of utilizing modern treatment technique at multiple centers and thus are applicable to commonly used radiotherapy practices.

The CHHiP trial² was a multicenter noninferiority trial conducted in the United Kingdom. It enrolled 3,216 patients and compared conventionally fractionated radiotherapy of 74 Gy in 37 fractions with 2 moderately hypofractionated radiotherapy schedules of 60 Gy in 20 fractions and 57 Gy in 19 fractions in patients with clinically localized prostate cancer. The trial included mostly patients with intermediate-risk disease, and the majority of patients received androgen-deprivation therapy.

After a median follow-up of approximately 5 years, the biochemical or clinical failure–free rates were 88.3% (95% confidence interval [CI] = 86.0%–90.2%), 90.6% (95% CI = 88.5%–92.3%), and 85.9% (83.4%–88.0%) in the 74-Gy, 60-Gy, and 57-Gy groups, respectively. The study confirmed that 60 Gy was noninferior to 74 Gy, with a hazard ratio of 0.84 (90% CI = 0.68–1.03) but was unable to confirm noninferiority in the 57-Gy arm, with a hazard ratio of 1.20 (95% CI = 0.99–1.46). The researchers concluded that the regimen of 60 Gy in 20 fractions is noninferior to conventionally fractionated radiotherapy and should be the new standard of care for external-beam radiotherapy.

The HYPRO trial¹ was a multicenter superiority trial conducted in the Netherlands. It enrolled 820 patients who were randomized to receive either conventionally fractionated radiotherapy consisting of 78 Gy in 39 fractions or hypofractionated radiotherapy consisting of 64.6 Gy in 19 fractions. The HYPRO trial was powered to demonstrate an absolute increase in relapse-free survival of 10% at 3 years with hypofractionation. Unlike the CHHiP trial, the HYPRO trial included mostly patients with high-risk disease.

At 5 years, the relapse-free rate was 80.5% (95% CI = 75.7%–84.4%) vs 77.1% (95% CI = 71.9%–81.5%) in the hypofractionation vs conventionally fractionated arm, with an adjusted hazard ratio of 0.86 (95% CI = 0.63%–1.16%). The researchers concluded that hypofractionated radiotherapy was not superior to conventionally fractionated radiotherapy and cannot be considered the new standard of care.

Different Endpoints, Different Conclusions

Although the CHHiP and HYPRO trials have many similarities, their diverging conclusions stem from the endpoints utilized for each clinical trial. The CHHiP trial was powered to establish whether hypofractionated radiotherapy was noninferior to conventionally fractionated radiotherapy using biochemical or clinical failure as the primary endpoint; that means the hypofractionated arms are no worse than the standard conventionally fractionated arm for clinically localized prostate cancer. Meanwhile, the HYPRO trial was a superiority trial that was powered to detect a 10% increase in relapse-free survival at 3 years with hypofractionation. That means hypofractionation is better than conventionally fractionated radiotherapy.

While the CHHiP trial confirmed noninferiority, HYPRO was unable to demonstrate superiority. Neither of these results is surprising, and both are consistent with previous similar analyses. The Regina Elena (Italy), Fox Chase Cancer Center (United States), and MD Anderson Cancer Center (United States) studies were powered for superiority similar to the HYPRO trial and were unable to confirm the superiority of hypofractionation vs conventionally fractionated radiotherapy.^3–5 Similar to the CHHiP trial, RTOG (Radiation Therapy Oncology Group) 0415 is the only other noninferiority trial reported and has also confirmed noninferiority of hypofractionated radiotherapy vs conventionally fractionated radiotherapy.⁶

Impact on Late Toxicity

Another critical component regarding the utilization of hypofractionated radiotherapy is the impact on late toxicity. Due to the low alpha/beta of the surrounding normal tissue, there has long been concern that hypofractionation may increase the risk for late treatment-related toxicity.

Previous data have demonstrated an increased risk of late side effects in patients undergoing hypofractionated radiotherapy. In the CHHiP trial, there was no significant difference in late genitourinary, gastrointestinal, or sexual side effects when comparing the hypofractionated and conventionally fractionated arms. Meanwhile, the HYPRO trial was not able to demonstrate noninferiority of hypofractionation to conventionally fractionated radiotherapy, with hazard ratios of 1.16 (90% CI = 0.98–1.38) and 1.19 (90% CI = 0.93–1.52) for late grade 2+ genitourinary and gastrointestinal toxicities, respectively.⁷ Further long-term data are needed to identify the impact of hypofractionation on long-term outcomes.

What Constitutes a New Standard of Care?

So what does it take to become a new standard of care? Is demonstrating noninferiority sufficient or must a treatment show superior outcomes to overtake a standard treatment?

At the very least, we can conclude that hypofractionated radiotherapy is noninferior to conventionally fractionated radiotherapy but not necessarily better. These results allow us to be confident we are not losing efficacy when using hypofractionation, but its impact on late effects still needs to be further clarified. Although the results of these trials demonstrate similar overall late toxicity, patients may experience late effects at 10 to 15 years following treatment. Given the results of the CHHiP and HYPRO trials, as well as previously reported analyses, we believe moderate hypofractionated radiotherapy can be considered an acceptable treatment option for men with clinically localized prostate cancer; however, patients should be informed of the potential risk for late effects and the limited long-term data.

The CHHiP and HYPRO trials add to the growing body of evidence suggesting that moderate hypofractionation may be an appropriate treatment for appropriately selected patients with clinically localized prostate cancer. Although hypofractionation may not necessarily offer a therapeutic advantage, it does provide the benefits of patient convenience and reduced treatment cost. Future long-term reports of these analysis as well as trials examining extreme hypofractionation (ie, stereotactic body radiotherapy) will further define the new standard of care in the next era. In the interim, both conventionally fractionated and hypofractionated radiotherapy appear to be reasonable treatment options for patients with clinically localized prostate cancer. ■

Disclosure: Drs. Shaikh and Horwitz reported no potential conflicts of interest.

References

1. Incrocci L, Wortel RC, Alemayehu WG, et al: Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): Final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. June 20, 2016 (early release online).

2. Dearnaley D, Syndikus I, Mossop H, et al: Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. June 20, 2016 (early release online).

3. Arcangeli G, Saracino B, Gomellini S, et al: A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys 78:11-18, 2010.

4. Pollack A, Walker G, Horwitz EM, et al: Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol 31:3860-3868, 2013.

5. Kuban DA, Nogueras-Gonzalez GM, Hamblin L, et al: Preliminary report of a randomized dose escalation trial for prostate cancer using hypofractionation. Int J Radiat Oncol Biol Phys 78:S58-S59, 2010.

6. Lee WR, Dignam JJ, Amin MB, et al: Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol 34:2325-2332, 2016.

7. Aluwini S, Pos F, Schimmel E, et al: Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): Late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol 17:464-474, 2016.