The real risk of secondary malignancies due to prostate radiation

Some of the media (see this Medscape article) have already pounced on a meta-analysis published by a group of researchers from the University of Toronto. The media misguidedly focus on relative risk rather than absolute risk. We examined this very complex subject last year (see this link). Wallis et al. looked at 21 studies in which secondary cancers were reported. They found that men who had external beam prostate radiation also had a higher rate of bladder and colorectal cancers, but not lung cancer or hematological malignancies. This shows association, but not causation.

Incidence of secondary cancers ranges in men who had each therapy were:

• ·      External beam radiation (EBRT): 0.2-2.3%
• ·      Brachytherapy (BT): 0.1-2.1%
• ·      External beam plus brachytherapy boost: 0.2- 1.7%
• ·      No radiation: 0.3-2.3%

The absolute difference in secondary bladder cancers per 1000 men treated for prostate cancer were:

• ·      EBRT vs no radiation: +2 (range: -2 to +6)
• ·      BT vs. no radiation: 0 (range: -4 to +4)

The absolute difference in secondary colorectal cancers per 1000 men treated for prostate cancer were:

• ·      EBRT vs no radiation: +7 (range: +3 to +10)
• ·      BT vs. no radiation: 3 (range: -5 to +11)

Risk of secondary bladder cancers was the subject of 9 studies.

• ·      7 of the 9 did not find significantly increased risk
• ·      The average increase was 39%
• ·      Of the 3 studies that allowed for a 5 year lag time for secondary cancers to develop after radiation exposure,:

o   2 of the 3 did not find significantly increased risk

o   The average increase was 30%

• ·      Of the 2 studies that allowed for a 10 year lag time for secondary cancers to develop after radiation exposure,:

o   1 of the 2 did not find significantly increased risk

o   The average increase was 89%

• ·      Of the 4 studies that included a multivariate analysis that included age:

o   2 of the 4 did not find significantly increased risk

o   The average increase was 67%

Risk of secondary colorectal cancers was the subject of 10 studies.

• ·      5 of the 10 did not find significantly increased risk
• ·      The average increase was 68%
• ·      Of the 4 studies that allowed for a 5 year lag time for secondary cancers to develop after radiation exposure,:

o   2 of the 4 did not find significantly increased risk

o   The average increase was 94%

• ·      Of the 2 studies that allowed for a 10 year lag time for secondary cancers to develop after radiation exposure,:

o   1 of the 2 did not find significantly increased risk

o   The average increase was 56%

• ·      Of the 3 studies that included a multivariate analysis that included age:

o   1 of the 3 did not find significantly increased risk

o   The average increase was 79%

While the media focus on the increase in incidence when expressed as a percent, the actual incidence and the absolute increases are really very small.  This was the subject of an accompanying editorial by Eyler and Zietman. They also point out that many of the studies included in the meta-analysis included men treated with older forms of external beam radiation that lack the accuracy of today’s technology. We expect to report soon on an analysis of IMRT only.

Many of the studies lacked data on age and other risk factors that contribute to bladder and colorectal cancers. Patients who received EBRT are an average of 10 years older than patients receiving surgery and about 5 years older than patients receiving BT. It is established that bladder and colorectal cancer incidence increase with age, so it is difficult to separate the competing risk factors. The problem is compounded by the lag time necessary to observe secondary cancers. Other risk factors confounding any such analysis include smoking and ethnicity. Because we are increasingly vigilant after a first cancer diagnosis, we are more likely to detect other cancers. This also confounds our analyses.

All of these studies really only tell us about association but not causation. For that, we require randomized clinical trials with very long tracking. While such trials are a long way off, we can take comfort in the fact that the risk is really very small.  While any risk should be acknowledged, and may be a decision factor for choosing active surveillance in low-risk men, this should not be a reason for anyone to avoid needed and curative radiation therapy.