Definitive radiotherapy has long been considered one of the preferred treatment options for patients with clinically localized prostate cancer. The current standard definitive radiotherapy regimen consists of conventionally fractionated (1.8-2 Gy per fraction) intensity modulated radiation therapy (IMRT) for approximately 8-9 weeks (76-80 Gray [Gy]). Although this has been demonstrated to be efficacious, the long treatment time can result in increased healthcare costs and is inconvenient for patients.
Over the past several decades, radiobiologists and radiation oncologists have debated whether delivering conventionally fractionated radiotherapy (1.8-2 Gy per fraction) is the optimal treatment schedule for localized 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 radio sensitivity 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 forms the basis for the radiobiologic response of normal and cancerous tissue. Cells with a low alpha/beta are capable of sublethal damage repair and have a greater sparing effect with small fraction sizes versus cells with higher alpha/beta. When treating a tumor with a lower alpha/beta than surrounding tissue, decreasing dose per fraction actually has a sparing effect on the tissue. In theory, increasing the dose per fraction may more effectively treat prostate cancer versus delivering smaller conventionally fractionated doses (1.8-2 Gy per fraction).
Hypofractionated radiotherapy (delivering a larger dose of radiation per fraction) has been increasingly adopted in disease sites such as breast and early-stage lung cancer, but remains controversial for patients with localized prostate cancer. While theoretically, hypofractionated radiotherapy can improve treatment outcomes and also reduce the cost of care, long-term efficacy and toxicity data is limited for localized prostate cancer.
Over the past several years, several randomized studies have examined the role of moderate hypofractionation (2.5-4 Gy per fraction) for clinically localized prostate cancer.
Two of the most recently published trials examining hypofractionation, the CHHiP and the HYPRO trials, yielded similar results but different conclusions (Lancet Oncol 2016;17:1061-9, Lancet Oncol 2016;17:1047-6). The CHHiP trial was a multi-center non-inferiority trial conducted in the United Kingdom that enrolled 3,216 patients and compared conventionally fractionated radiotherapy of 74 Gy in 37 fractions to two moderately hypofractionated radiotherapy schedules 60 Gy in 20 fractions and 57 Gy in 19 fractions in patients with clinically localized prostate cancer. After a median follow-up of approximately 5 years, the biochemical or clinical failure-free rates were 88.3 percent, 90.6 percent, and 85.9 percent in the 74 Gy, 60 Gy, and 57 Gy groups, respectively. The study confirmed that 60 Gy was non-inferior to 74 Gy, but they were unable to confirm non-inferiority in the 57 Gy arm.
The HYPRO trial was a multi-center superiority trial conducted in the Netherlands that enrolled 820 patients who were randomized to 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 percent at 3 years with hypofractionation. At 5 years, the relapse rate was 80.5 percent versus 77.1 percent in the hypofractionation versus conventionally fractionated arm with an adjusted hazard ratio of 0.86 (95% CI 0.63-1.16). The trial was unable to demonstrate superiority of hypofractionation to conventionally fractionated radiotherapy.
The results of the CHHiP and HYPRO trials are consistent with previous non-inferiority and superiority studies. Previous series were powered for superiority similar to the CHHiP trial and were unable to confirm the superiority of hypofractionation versus conventionally fractionated radiotherapy.
RTOG 0415 is the only other modern non-inferiority trial reported and has also confirmed non-inferiority of hypofractionated radiotherapy versus conventionally fractionated radiotherapy similar to the HYPRO trial (J Clin Oncol 2016;34:2325-32). There are multiple trials currently ongoing and will add to the growing body of evidence regarding the role of moderate hypofractionation in clinically localized prostate cancer.
While there is growing evidence demonstrating efficacy for moderate hypofractionation, there is still limited data for extreme hypofractionation (5-10 Gy per fraction) also known as stereotactic body radiotherapy in patients with clinically localized prostate cancer.
In extreme fractionation, patients are treated with doses >5 Gy per fraction and it has the theoretical advantage of further reducing treatment time and cost. Although extreme hypofractionation has many benefits, delivering such high doses per fraction also has the potential of increased toxicity.
There is currently no randomized phase III data examining extreme hypofractionation for prostate cancer although multiple trials are ongoing. The largest series conducted treated 515 patients with 35-36.25 Gy in 5 fractions. Researchers found freedom from biochemical control rates of 97 percent, 92 percent, and 70 percent at 6 years for low-risk, intermediate-risk, and high-risk patients, respectively. Another series reported the outcome of 84 patients with low-risk prostate cancer. In this series, they also found high rates of biochemical control (98%) at 5 years. There are other multiple small series that have been reported examining extreme hypofractionation for prostate cancer with biochemical control rates of 95-98 percent although these studies suffer from a lack of long term follow-up.
While there is a growing body of evidence demonstrating the effectiveness of moderate and extreme hypofractionation for prostate cancer, there is relatively limited long-term data regarding late toxicity in patients receiving this treatment.
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 has demonstrated mixed results in regards to late side effects in patients undergoing hypofractionated radiotherapy.
Patients receiving moderate hypofractionated radiotherapy have an approximately 15-20 percent risk of late grade 2+ GU toxicity and 10 percent risk of late grade 2+ GI toxicity, which is similar to patients receiving standard treatment. Long-term results from the Fox Chase hypofractionation trial also demonstrated similar quality-of-life outcomes in both treatment arms (Int J Radiat Oncol Biol Phys 2015;93:S34-S35).
When examining extreme hypofractionation, there is data suggesting higher rates of late toxicity compared to typical standard treatment although level 1 evidence is limited. In one study, more than 30 percent of patients experienced grade 2+ GU toxicity.
Future of Radiotherapy
Hypofractionated radiotherapy for prostate cancer offers the potential ability to deliver an efficacious treatment while minimizing treatment time and cost.
Current data suggest that moderate hypofractionated radiotherapy is at least as effective as standard therapy with relatively similar long-term toxicity. There is still limited data on extreme hypofractionation in this setting although early results suggest that outcomes may be similar to conventionally fractionated radiotherapy. Long-term toxicity data is still needed to identify whether late effects are compromised when using these treatment methods.
Data from recently completed randomized trials will further define the future of radiotherapy for localized prostate cancer.
TALHA SHAIKH, MD, is a Radiation Oncology Resident at Fox Chase Cancer Center, Philadelphia. ERIC M. HORWITZ, MD, is Chair, Radiation Oncology, Fox Chase Cancer Center.
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