Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities

Abstract

Objectives: Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities.

Materials and methods: We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed.

Results: Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P<0.05); but not with improvement of OS, DM, or CSM at either time point. BED escalation was not correlated with increased acute toxicities; it was correlated with increased late gastrointestinal toxicities in patients treated with 3D-CRT (1.5% increase over BED range, P<0.01). IMRT patients had significantly fewer late toxicities, despite being treated at higher BED.

Conclusions: RT BED escalation has resulted in significantly improved PCa FFBF at up to 10 years; but not with improvement in OS, DM, or CSM. Thus, FFBF is a poor surrogate of overall patient outcomes for trials of RT. Late toxicities were less frequent with IMRT than with 3D-CRT, even at higher BED.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram literature selection process.

Figure 2.. Plots of outcomes vs. BED_1.5 of trials included in this analysis.

Radiotherapy BED escalation has resulted in improved FFBF of low-, intermediate-, and high-risk patients at 5 and 10 years (top left, lower left). However, BED escalation has correlated with improved patient outcomes of OS, DM, or CSM at 5 and 10 years (top right, lower right).

Figure 3.. Plots of toxicities vs. BED₁₀ and BED_3.0 of trials included in this analysis.

The advent of IMRT in the early 2000s coincided with radiotherapy BED escalation using CFRT and HFRT; thus trials using 3D-CRT and IMRT were analyzed separately. Radiotherapy BED escalation was not correlated with increased acute GU or GI toxicities in patients treated with 3D-CRT or IMRT. Radiotherapy BED escalation was correlated with increased late GU and GI toxicities in patients treated with 3D-CRT. All patients treated with IMRT had significantly less late GU and GI toxicity, despite being treated at higher BEDs. Trend lines are plotted, and the corresponding slopes are listed in Table 2.