Brief RT for Early Prostate Cancer Gets High Marks in Preliminary Trial

prostate cancer

Himanshu Lukka, MD

Ultra-hypofractionated radiation therapy for low-risk prostate cancer led to significantly lower rates of bowel and urinary dysfunction compared with patients treated with conventional radiotherapy regimens, according to a randomized trial data of two ultra-hypofractionated protocols, reported at the American Society for Radiation Oncology meeting in San Antonio, TX.

Patients treated with 5- or 12-fraction protocols had a significantly lower incidence of bowel (P<.0001), urinary (P<.001), and sexual (P<.001) dysfunction compared with contemporary data from a recently completed trial of conventional radiotherapy. Additionally, fewer than 2% of patients in either group had acute or late grade 3 gastrointestinal/genitourinary (GI/GU) toxicity, and one patient had grade 4 or 5 GI/GU toxicity. Data on rates of biochemical failure with the two protocols remain immature for analysis and comparison with standard radiotherapy protocols.

&ldquo;Both the 5- and 12-fraction ultra-hypofractionation regimens are well tolerated, with respect to bowel, urinary, and sexual patient-reported outcomes,&rdquo; said Himanshu Lukka, MD, a radiation oncologist at McMaster University and the Juravinski Cancer Center in Hamilton, Ontario. &ldquo;Acute and late toxicity data showed good tolerability, as well. &ldquo;There is a real need for a randomized study comparing one or both of these ultra-hypofractionated regimens with standard radiotherapy.&rdquo;

Benjamin Movsas, MD, chair of radiation oncology at Henry Ford Health System in Detroit, MI, asked whether or not the results effectively eliminated the 12-fraction regimen from consideration, given the increased patient convenience and similar patient-reported outcomes with the 5-fraction arm. Lukka answered that additional follow-up is needed to see whether or not the shorter regimen is associated with late effects and also to assess the frequency of biochemical relapse.

The rationale for hypofractionation began as an argument in favor of improved patient convenience and health economics. Shorter radiotherapy protocols would reduce patients&rsquo; time commitments to treatment and increase the number of patients who could be treated with available radiation therapy resources, according to Lukka.

More recently, the alpha/beta argument has entered into the discussion. A lower alpha/beta ratio (predicted tissue response relative to radiation dose delivered) for prostate cancer offers a potential for better outcomes. The potential remains to be demonstrated, maintained Lukka.

If hypofractionation leads to similar efficacy and toxicity, patient-reported outcomes assume a more prominent role in evaluation of hypofractionated protocols, he continued. A substantial proportion of men with early prostate cancer develop bowel, urinary, and sexual dysfunction following conventional radiation therapy, although symptoms resolve in many cases within a year.

Nonetheless, the unresolved issues regarding hypofractionation and patient-reported outcomes provided additional justification for a randomized trial, according to Lukka.

&ldquo;We hypothesized that short hypofractionation regimens of 5 and 12 fractions will show similar quality of life and toxicity scores when compared to standard fractional radiotherapy schedules in the treatment of low-risk prostatic carcinoma,&rdquo; said Lukka.

Investigators enrolled 255 patients with newly diagnosed, low-risk prostate cancer (Gleason score 2-6, T1-2a, PSA <10 ng/mL), of whom 240 were included in the data analysis. Patients were randomized to receive 36.25 Gy administered in 5 fractions over 2 weeks or 51.6 Gy in 12 fractions over 2.5 weeks.

The trial had two primary endpoints:

• Percentage of patients who had >5-point reduction in the EPIC Bowel Quality of Life (QOL) measurement at 1 year compared with baseline.
• Proportion of patients with >2-point reduction in the EPIC Urinary QOL measurement at 1 year.

Investigators also determined the proportion of patients who had &ge;2-point improvement in sexual function.

Statistical parameters for the trial were derived from the recently completed RTOG 0415 trial, which also compared hypofractionated radiotherapy with conventional radiotherapy in men with low-risk prostate cancer. Among men assigned to the control (conventional radiotherapy) arm of RTOG 0415, 35% had >5-point worsening in EPIC bowel score at 1 year, and 39% had >2-point worsening in the urinary score.

On the basis of the RTOG 0415 results, investigators defined <35% incidence of bowel dysfunction (>5-point change) and <40% incidence of urinary dysfunction (>2-point change) as acceptable. A bowel dysfunction rate 55% and urinary dysfunction in 60% of men was considered unacceptable.

The results showed that 23.5% of patients assigned to 5-fraction radiotherapy had >5-point change in EPIC bowel score, as did 23.1% of men in the 12-fraction arm (P<.0001 versus prespecified cutoffs for acceptability). The proportion of men with >2-point change in urinary score was 35.3% in the 5-fraction group and 34.7% in the 12-fraction group (P<.001).

Rates of sexual dysfunction at 1 year were 24.4% and 23.1% in the 5-fraction and 12-fraction arms, respectively, Lukka reported.

Two patients in each group (1.7%) had acute (within 30 days) grade 3 GI/GU adverse events (AEs), and one patient in the 12-fraction arm. Lukka mentioned that the investigation of the grade 4 AEs is ongoing. The incidence of late grade 3+ AEs was 0.8% with 5 fractions and 1.7% with 12 fractions, and all were grade 3 in severity.

A multivariate analysis that included specific types of radiation therapy employed in the study (cyberknife, IMRT, Linac) showed no independent predictors of increased or decreased risk of bowel, urinary, or sexual dysfunction in either the 5- or 12-fraction treatment groups.

Lukka H. Patient reported outcomes in NRG Oncology/RTOG 0938, a randomised phase II study evaluating two ultrahypofractionated regimens (UHR) for prostate cancer. Presented at the American Society for Radiation Oncology meeting in San Antonio, TX: October 18, 2015. Abstract LBA3.