Neoadjuvant radiotherapy increases risk of second gynaecological malignant neoplasms

March 2021 Prevention Tobias Rawson

Neoadjuvant radiotherapy for rectal cancer is known to improve locoregional control, but is not associated with increased long-term survival. Furthermore, radiotherapy is associated with the development of secondary primary cancers. Specifically, these secondary malignancies occur in organs immediately surrounding the rectum. For women undergoing pelvic radiation for rectal cancer, the risk of second gynaecological malignant neoplasms (SGMN) is uncertain. Recently, a large cohort study has investigated the risk radiotherapy poses on the development of individual SGMNs, and patient’s subsequent survival outcomes.

Between 1973 and 2015, 20,142 women with primary rectal cancer were identified from 9 registries of the SEER database and included in this study. Patients were split into two groups; those who had received neoadjuvant radiotherapy followed by surgery, and those who were treated with surgery alone. The primary outcome of this study was the development of an SGMN. Follow-up began 5 years after rectal cancer diagnosis and ended at the time of diagnosis of an SGMN, all-cause death, or after 30 years follow-up, which ever occurred first.

Higher cumulative risk with neoadjuvant radiotherapy

Of the 20,142 women included in this study, 34.3% (N= 5310) received neoadjuvant radiotherapy and the median age of all patients within this study was 65. At a median-follow up of 140 months, the cumulative incidence of combined SGMNs was 4.53% in patients who received neoadjuvant radiotherapy, and 1.53% in patients who did not receive radiotherapy (HR: 2.99, 95%-CI: 2.23-4.02, p< 0.001). In an organ-specific analysis, the cumulative incidences of cancer of the uterine corpus, ovarian cancer and other SGMNs were significantly increased in patients exposed to radiotherapy, compared to those were not (Uterine corpus: 1.00% vs. 2.80%; p< 0.001. Ovarian cancer: 0.29% vs. 0.98%; p= 0.007. Other SGMNs: 0.20% vs. 0.62%; p= 0.007). Interestingly, there was no difference observed in rates of cervical cancer between the two groups. 

These results were further supported by the finding that undergoing radiotherapy was associated with an increased risk of developing cancer in the uterine corpus (HR: 3.06, 95%-CI: 2.14-4.37, p< 0.001) and ovarian cancer (HR 2.08, 95%-CI:1.22-3.56, p= 0.007). Furthermore, the risk of cancer in the uterine corpus with radiotherapy significantly increased with age (aged 20-49 years: adjusted RR: 0.79, 95%-CI: 0.35-1.79, p = 0.57; aged 50-69 years: adjusted RR: 3.74, 95%-CI: 2.63-5.32, p< 0.001; aged ≥70 years: adjusted RR: 5.13, 95%-CI: 2.64-9.97, p< 0.001). Conversely, this risk decreased with an increase in latency since the diagnosis of rectal cancer (60-119 months: adjusted RR: 3.22, 95%-CI: 2.12-4.87, p< 0.001; 120-239 months: adjusted RR: 2.72, 95%-CI: 1.75-4.24, p< 0.001; 240-360 months: adjusted RR: 1.95, 95%-CI: 0.67-5.66, p= 0.22). Interestingly, the opposite was true for ovarian cancer. The risk of ovarian cancer from radiotherapy increased with latency (60-119 months: adjusted RR: 0.70, 95%-CI: 0.26-1.89, p = 0.48, 120-239 months: adjusted RR: 2.26, 95%-CI: 1.09-4.70, p = 0.03; 240-360 months: adjusted RR: 11.84, 95%-CI: 2.18-64.33, p = 0.004). Finally, the 10-year overall survival of patients with radiotherapy-associated cancer of the uterine corpus was significantly lower than those with a primary cancer of the uterine corpus (21.5% vs. 33.6%; p= 0.01).


This is the first large cohort study to study the risk dynamics and prognoses of individual types of radiotherapy-associated SGMNs, in rectal cancer patients who received neoadjuvant radiotherapy. In these patients, this study demonstrated an increased risk of developing cancer of the uterine corpus and ovarian cancer. Furthermore, these risks increased with age for both cancer types, but relative risk for each differed with increased latency. Ultimately, this evidence provides a meaningful reference for individualised management and follow-up plans.


Guan X et al., Association of Radiotherapy for Rectal Cancer and Second Gynecological Malignant Neoplasms. JAMA network. 2021; 4(1): e2031661.