Five-session prostate radiotherapy eased bowel side effects, but relapse on blood tests was more common

Radiotherapy for prostate cancer used to mean a hospital visit every weekday for two months. It now usually means four to six weeks, and a newer technique compresses the whole course into five sessions. A trial of nearly 700 men, published in JAMA in August, set the five-session course against the standard ones to see whether shorter was also better.

It was better for the bowel and no worse for the bladder. On the outcome that matters most over the long run, control of the cancer, the result leaned the other way. Signs of relapse on blood tests were more common after the short course. The trial has run for only about three years, and whether that early signal matters is not yet known.

Why prostate radiotherapy is getting shorter

Radiation is given in daily doses called fractions. Over the past two decades trials have tested whether fewer, larger fractions can do the same job, on the theory that prostate tumors are unusually sensitive to the size of each dose.

The first step was from about 37 sessions to 20. A British trial of 3,216 men found that 60 Gy was non-inferior to 74 Gy, which is to say that a 20-session course controlled the cancer no worse than a 37-session one. Gy stands for gray, the unit of radiation dose.

The next step was more radical. A Scandinavian trial of 1,200 men compared seven sessions with 39. The estimated failure-free survival at 5 years was 84% in both groups.

The five-session approach is called stereotactic body radiotherapy, or SBRT. It uses tightly focused beams and image guidance to give very large doses to a small target. A British-led trial called PACE-B tested it in 874 men. In that trial the 5-year incidence of freedom from biochemical or clinical failure was 95.8% with five sessions and 94.6% with longer courses, a result which indicated the noninferiority of SBRT. Biochemical failure means a rise in a blood marker that signals the cancer is returning. The short course came at a price: the cumulative rate of moderate or worse late genitourinary toxic effects was 26.9%, against 18.3%, genitourinary meaning the urinary and genital organs.

The new trial asked a harder question. Its aim was to show that five sessions are better, not merely as good.

How the five-session trial compared the two courses

The authors open with the reason for the study. The treatment of prostate cancer with radiotherapy is evolving, they write, and the question is how quickly radiotherapy can be delivered, and what is gained and lost by doing so.

The trial, called NRG-GU005, was run by an American research network, NRG Oncology. It was large and international. There were 136 centers in Asia, Canada, Europe, and the United States that accrued patients to the study. The men had cancer confined to the prostate and classed as intermediate risk, judged by how the tumor looked under the microscope and by a prostate-specific antigen (PSA) level less than 20 ng/mL. PSA is a protein measured in the blood that rises with prostate cancer.

A total of 698 patients were randomized. Median age was 68 years; 3% were Asian, 13% Black, and 80% White.

Half were assigned to stereotactic body radiotherapy (SBRT), given as 36.25 Gy in 5 fractions. The other half had the kind of radiotherapy now standard for this cancer, a course of 70 Gy in 28 fractions or 60 Gy in 20 fractions.

The trial had two main tests, and both had to succeed. The first was quality of life at two years, measured by a questionnaire on which men rate their bowel and urinary symptoms. For each man the question was whether his score had fallen by enough to matter. The second was disease-free survival, meaning being alive with no sign of the cancer. NRG Oncology explained the rule: both co-endpoints needed to be met for the trial to be positive. An endpoint is the outcome a trial is designed to test.

Patients and doctors knew which course was being given. Median follow-up was 3.2 years.

Bowel, bladder and sexual side effects after radiotherapy

Outcome (cancer control is discussed in the next section)	Five sessions	20 or 28 sessions
Meaningful bowel decline at 2 years	34.9%	43.8%
Meaningful decline in urinary irritation or blockage at 2 years	35.4%	33.7%
Serious urinary or genital side effects	0.6%	2.5%
Alive and free of disease at 3 years	88.6%	92.1%
Rising PSA by 3 years	7.8%	4.2%

On the bowel, the short course was ahead. A decline large enough to matter was reported by 34.9% of men after five sessions and 43.8% after the longer courses. That is about nine fewer men in every hundred.

On urinary irritation and blockage, the difference, 35.4% against 33.7%, was within the range of chance.

Other measures leaned toward the short course. Urinary incontinence at 1 and 2 years after treatment and sexual function at 1 year after treatment favored SBRT. Serious side effects in the urinary and genital organs, the kind graded 3 or 4 on a scale of severity, were uncommon in both groups and rarer with five sessions, 0.6% against 2.5%.

One technical detail helped in both groups. A spacer placed between the prostate and the rectum before treatment was linked to better results: in both cohorts, rectal spacing was associated with improved patient-reported bowel function.

The authors summarize the favorable half of the result this way. Stereotactic body radiotherapy using a modest dose prescription improved multiple quality-of-life domains.

Relapse on blood tests was more common after five sessions

The other half was a disappointment for the short course. At three years, 88.6% of men who had five sessions were alive and free of disease, with a plausible range of 85.2% to 92.1%. For the longer courses the figure was 92.1%, with a range of 88.9% to 95.2%. The two ranges overlap, so on this combined measure the trial shows that the short course was not better; it does not show that it was clearly worse.

The trial had been designed to show five sessions superior on this measure, and an interim analysis concluded early that it would not. NRG Oncology gave the reason. The Disease-Free Survival (DFS) co-primary endpoint was reported early because of futility of superiority related solely to higher biochemical failure, determined by PSA, in the SBRT arm. In plain terms, the result was released ahead of schedule because the short course was clearly not going to prove better, and the reason was more PSA rises in that group.

Urology Times, reporting the paper, gives the numbers. PSA failure had occurred in the two groups with rates of 7.8% vs 4.2%, respectively, at 3 years, the higher figure after five sessions. That is about four more men in every hundred whose blood tests suggested the cancer was coming back, a difference just beyond what chance alone would be expected to produce.

A rising PSA is an early warning. It is not a symptom, and it does not by itself mean the cancer will cause harm. It can lead to more scans and, for some men, more treatment.

Because both main tests had to succeed, and the short course came out ahead on the bowel measure alone, the trial is formally negative. NRG Oncology described it that way while pointing to the gains in quality of life.

How the trial fits with earlier radiotherapy trials

The obvious comparison is with PACE-B, which found five sessions as good as longer courses for cancer control. The two trials differ in an important respect. The British-led trial, a trade report notes, allowed a higher-dose regimen as permitted by the trial protocol. It also recorded more urinary side effects with five sessions, where the new trial recorded fewer.

Read together, and with the caution that the two trials differ in more than dose, the results suggest a trade. A higher dose in five sessions appears to control the cancer as well as longer courses and irritates the bladder more. A more modest dose is easier on the bowel, causes fewer serious urinary problems, and may give up some control.

Rodney Ellis of the University of South Florida, the lead author, described the PSA result in correspondence with Urology Times. “An increase in PSA failure was noted prior to the planned 5-year end point for reporting,” Ellis said. On the likely explanation, Ellis added that more work is needed to learn whether the dose to the whole gland has to match the earlier trial, or whether an extra dose aimed at the highest-risk part of the prostate would be enough.

The investigators see the result as usable now. In the paper’s words, “This study has immediate impact on patients and physicians considering a shorter course of radiotherapy for localized prostate cancer.”

Mitchell Machtay, chief scientific officer of NRG Oncology, expects it to shape practice. “It will influence radiation oncology practice and future research for years to come,” Machtay said.

What is not yet known about five-session radiotherapy

Whether the PSA difference matters. A rise in PSA at three years does not show that more men will develop symptoms or die of prostate cancer. Prostate cancer of this kind progresses slowly, and the answer needs much longer follow-up. NRG Oncology says so: further follow-up is warranted to assess the longer-term results.

Which dose is right. The trial tested one prescription. The authors conclude that future research should explore differences in SBRT techniques for prostate cancer.

Blinding. Men knew which course they had received when they filled in the questionnaires. Someone who finished treatment in a week or two may judge his symptoms differently from someone who attended for five weeks.

Who it applies to. The men had what one report calls favorable intermediate-risk prostate cancer. The results do not cover higher-risk disease.

The research was publicly funded, with grants from the National Cancer Institute (NCI), part of National Institutes of Health.

The choice between a five-session course and a longer one depends on the cancer, the equipment available and what a man most wants to avoid, which is assessed by their doctor.

Radiotherapy given in five sessions led to fewer reports of bowel decline than courses of 20 or 28 sessions, 34.9% against 43.8%, in a trial of 698 men with intermediate-risk prostate cancer, but was followed by more relapses on PSA testing, 7.8% against 4.2% at three years, a difference whose long-term importance the trial is still too young to show.