'Risky': Prostate Radiation, Second Cancers Linked

Nick Mulcahy

March 02, 2016

External-beam radiation for prostate cancer appears to be tied to the development of secondary cancers.

Compared with other prostate cancer treatment types, the use of radiotherapy was associated with an increased risk for additional cancers in the lower half of the torso, according to a meta-analysis of 21 studies.

Specifically, there was an increased risk for cancers of the bladder (adjusted hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.55 - 1.80), colorectum (three studies) (HR, 1.79; 95% CI, 1.34 - 2.38), and rectum (HR, 1.79; 95% CI, 1.34 - 2.38).

However, there was no increased risk for hematologic or lung cancers, say the authors, led by Paul Nam, MD, a urologist at the University of Toronto.

Notably, the odds of a secondary cancer were greater for bladder and rectal cancers over a longer time span (the researchers analyzed 5- and 10-year "lag" periods between treatment and the development of a secondary cancer).

But there was an overall increased risk for all three additional cancers in the analysis.

The results indicate a "possible association" between radiotherapy and secondary cancers, the authors note, adding that confirmatory evidence is needed.

However, Dr Nam and his colleagues emphasize that the absolute risks were "low."

Table. Range of Absolute Rates for Secondary Cancers in Case–Control Studies

Cancer Lowest Rate, % Highest Rate, %
Bladder 0.1 3.8
Colorectal 0.3 4.2
Rectal 0.3 1.2


Only external-beam radiotherapy was consistently associated with increased risk. Brachytherapy was not.

Intensity-modulated radiotherapy (IMRT) was not part of the meta-analysis. However, results would likely be the same with IMRT and external-beam radiotherapy, Dr Nam told Medscape Medical News.

He hesitated to give brachytherapy a blanket endorsement. "Brachytherapy alone shows lower survival rates than surgery," he said. "And often for aggressive cancer, hormone therapy is required or it is paired with additional external-beam boost."

The study, which was published online today in BMJ, is the strongest of its type to date. There is only one other meta-analysis on this subject, but it involved only four studies.

The relative risks of the extra cancers are "impressive," Christine Eyler, MD, and Anthony Zeitman, MD, a pair of radiation oncologists at the Massachusetts General Hospital Cancer Center in Boston, write in a linked editorial.

But they insist on placing these academic findings into a practical context.

"A pragmatist," they write, "might ask, what are the real world implications for individual patients?"

The absolute risk remains small.

"The absolute risk remains small," the pair states.

The age and health of the patient is the key to treatment decision-making, they explain.

"Young patients with few comorbidities might be more likely to factor this risk into their decision-making, whereas older patients or those with competing health risks might not and indeed should not," they write.

This meta-analysis reveals a relatively "risky business," Drs Eyler and Zeitman state, suggesting that circumstance dictates the degree of risk.

In fact, "concern about second malignancies should not...stand in the way of an effective and well-studied treatment being given to men with higher grade, lethal prostate cancer for whom the potential benefit simply dwarfs the risk," they explain.

But, "perhaps most important," the pair believes that second malignancy should be added to the "already long list of avoidable hazards" that is associated with the treatment of men with low-risk prostate cancer — who really should be on active surveillance.

They also suggest that the study results are dated.

"Many studies included in this analysis were performed at a time when older poorly targeted radiation techniques were used, and large volumes of normal pelvic tissue were irradiated during treatment," Dr Eyler and Dr Zeitman write.

There is a "well-recognized" association between exposure to radiation and carcinogenesis, they state, but prostate cancer has not been implicated to date for a variety of reasons, including the relatively older age of the patients.

Smaller, Tighter Treatment Volumes

Most of the 21 studies were large multi-institutional reports, and the most common type of radiotherapy was external beam. In 13 of the studies, the control subjects were patients treated with surgery; in eight of the studies, the control subjects were patients who did not undergo radiotherapy.

As noted above, there were no studies of IMRT in the meta-analysis. To date, only a single study has independently examined the effect of IMRT on secondary cancers, and no increased risk was found (BJU Int. 2012;110:1696-1701).

There are lessons to be learned from the study by Dr Nam's team, according to Drs Eyler and Zeitman.

Most notably, the meta-analysis revealed that brachytherapy (a high radiation dose to a small volume of tissue) is not associated with a detectable increase in risk.

The current move with all types of radiotherapy for prostate cancer — toward "smaller, tighter" treatment volumes — "might well shift the contemporary risk back," they write.

Dr Nam, the study authors, Dr Eyler, and Dr Zeitman have disclosed no relevant financial relationships.

BMJ. 2016;352:i851. Abstract, Editorial


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