Time to light the FLAME: Focal boosting in external beam radiotherapy for localized prostate cancer

Abstract

Multiparametric Magnetic Resonance Imaging (mpMRI) is playing an increasingly significant role in the diagnosis of prostate cancer, as well as in radiotherapy for the prostate. Increasing the radiation dose to the entire prostate leads to improved biochemical recurrence-free survival. However, this also increases the risk of side effects due to a higher radiation dose to surrounding organs. Local recurrences after external beam radiotherapy of the prostate are often found at the location of the primary tumor, suggesting that the dose to the primary tumor was not high enough. These local recurrences can eventually lead to distant metastases, resulting in an increased risk of prostate cancer related death. A higher dose specifically to the visible tumor in the prostate, could potentially improve local tumor control (and subsequently metastasis-free survival), without increasing the risk of toxicity or deteriorating quality of life. In 2009, the multicenter phase III randomized Focal Lesion Ablative Microboost in prostatE cancer (FLAME) trial was initiated, which compared a conventional radiation schedule of 77 Gy in 35 fractions to the entire prostate with or without a focal boost to the visible tumor up to 95 Gy in patients with intermediate- and high-risk localized prostate cancer. The primary endpoint of the FLAME trial was five-year biochemical recurrence-free survival. Secondary endpoints were treatment-related toxicity scored by the treating physician, and quality of life scored by the patient. The five-year biochemical recurrence-free survival in the focal boost arm was 92%, which was significantly better compared to 85% in the standard arm. The FLAME trial has thereby demonstrated that the concept of a focal boost is effective. The focal boost in the FLAME trial did not result in a significant increase in toxicity and did not affect the quality of life. The development of radiation-related toxicity is dependent on many factors. Dose-response relationships for gastrointestinal and genitourinary toxicity show that an increase in dose to the surrounding organs will lead to an increase in toxicity. The dose to the urethra, in particular, has a strong influence on genitourinary toxicity. It is therefore important to consider the urethra as a risk organ when planning a radiotherapy schedule, and to avoid high doses to the urethra. The introduction of MRI in radiotherapy planning makes it possible to delineate the urethra. In the FLAME trial, more genitourinary toxicity was observed than gastrointestinal toxicity. Analysis of the number of local recurrences, regional, and distant metastases, shows that adding a focal boost reduces the number of local recurrences by half and also decreases the combined number of regional and distant metastases. No difference was found in distant metastases, overall survival, or prostate cancer specific survival between the two study arms. While there was no difference in distant metastases between the two study arms, a dose-response relationship was observed between the focal boost dose and the risk of distant metastases. A longer follow-up period will determine whether this has an impact on the risk of distant metastases and prostate cancer-specific survival in the focal boost arm.