Risk of Second Cancer Diagnosis Following Various Radiation Therapy Modalities

August 5, 2020

A recent study compared the risk of a second cancer diagnosis after primary cancer treatment following the use of either intensity-modulated radiotherapy, 3-dimensional conformal radiotherapy, or proton beam radiotherapy.

The risk of a second cancer diagnosis after primary cancer treatment was similar after intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3DCRT), while proton beam radiotherapy (PBRT) was correlated with a lower risk of second cancer diagnosis, according to findings published in Cancer.

“Our current results, although hypothesis-generating, are consistent with the conjectured reduction in second cancers with PBRT, although the absolute benefit may be small in an unselected population because of the rarity of second cancers,” the authors wrote. “Furthermore, we did not find evidence that the use of IMRT gives rise to more second cancers compared with 3DCRT, although additional follow-up is required.”

Using the National Cancer Database, researchers identified pediatric and adult patients with a first diagnosis of cancer between 2004 and 2015 who received 3DCRT, IMRT, or PBRT treatment for a number of tumor types, including head and neck, gastrointestinal, gynecologic, lymphoma, lung, prostate, breast, bone/soft tissue, or brain/central nervous system. The total study cohort identified 450,373 individuals, including 33.5% who received 3DCRT, 65.2% who received IMRT, and 1.3% who received PBRT.

The median follow-up after completion of radiotherapy was 5.1 years (range, 2-13.8 years) overall and 7.4 years among patients who had >5 years of follow-up. The cumulative follow-up period was 2.54 million person-years. The crude absolute incidence of second cancer per 100 patient-years was 1.55 overall (95% CI, 1.53-1.57), 1.60 after 3DCRT (95% CI, 1.57-1.62), 1.55 after IMRT (95% CI, 1.53-1.57), and 0.44 after PBRT (95% CI, 0.37-0.52).

In a comparison between IMRT versus 3DCRT, there was no overall difference observed in the risk of second cancer (OR, 1.00; 95% CI, 0.97-1.02; P= 0.75). The sole exception to this was head and neck cancer, which saw a modest decrease in second cancer risk with IMRT (OR, 0.85; 95% CI, 0.77-0.94; P= 0.001).

“Conversely, we did not identify a difference between IMRT and 3DCRT. It is unclear whether they are truly equivalent or whether our study simply did not have sufficient time in follow-up to detect a difference,” the authors wrote. “It remains possible that the second cancer risks for IMRT versus 3DCRT could diverge with longer follow-up, as more second cancers occur.”

However, by comparison, PBRT had an overall lower risk of second cancer versus IMRT (OR, 0.31; 95% CI, 0.26-0.36; P< 0.0001). Interestingly, lung cancer was the only tumor type that did not have an adjusted OR favoring PBRT, which researchers suggest could be due to the high prevalence of smoking in this population dominating second cancer development relative to the radiotherapy modality.

“In our study, the point estimates for second cancer risk favored PBRT across all age subgroups, including younger patients,” the authors wrote. “Although the 95% CI crossed 1 among those aged <40 years, this may reflect a limitation in sample size, because only 4.3% of patients in the IMRT/PBRT cohorts were aged <40 years. Nonetheless, there was no significant interaction of PBRT with patient age.”

Notably, the results observed within each tumor type were generally consistent in the pooled analyses and were also maintained in propensity score-matched analyses.

Importantly, the investigators indicated that these study results should be interpreted in the context of several limitations, including the lack of data regarding known cancer risk factors, such as smoking and obesity, which can be correlated with certain tumor types. Given that these results are only hypothesis-generating, the researchers highlighted the need for future studies to continue this research.

“Future work is warranted to determine the cost-effectiveness of PBRT and to identify the patients best suited for this treatment,” the authors concluded.


Xiang M, Chang DT, Pollom EL. Second Cancer Risk After Primary Cancer Treatment With Three-Dimensional Conformal, Intensity-Modulated, or Proton Beam Radiation Therapy. Cancer. doi: 10.1002/cncr.32938.