Risk of Second Malignancies After Adjuvant Radiotherapy for Breast Cancer: A Large-Scale, Single-Institution Review

Kirova. IJROBP 2007;68:359

Purpose: The aim of this study was to estimate the risk of second malignancies (SM) after radiation therapy (RT) for breast cancer (BC) in a large, institutional, homogeneous cohort of patients.

Methods and Materials: We retrospectively studied 16,705 patients with nonmetastatic BC treated at the Institut Curie in Paris between 1981 and 1997. Adjuvant RT was given to 13,472 of these patients, and no RT was given to 3,233. The SM included all first nonBCs occurring during follow-up. Cumulative risks for each group were calculated using Kaplan-Meier estimates, censoring for contralateral cancer or death.

Results: Median patient age at diagnosis of BC was 55 years for the whole population, and 53 and 60 years for patients who had and had not undergone irradiation, respectively. At the 10.5-year median follow-up, 709 patients were diagnosed with SM (113 in the non-RT and 596 in the RT group). There was a significant increase in the rate of sarcomas and lung cancers in the RT group compared with non-RT group (p 0.02). Treatment with RT was not found to increase the risk of other types of cancers such as thyroid cancer, malignant melanoma, gastrointestinal or genitourinary, and hematologic SM.

Conclusions: This study suggests that adjuvant RT increased the rate of sarcomas and lung cancers, whereas it did not increase the rate of other malignancies.

Adjuvant RT plays a significant role in preventing local failure in women treated for early-stage breast cancer (BC). Many randomized studies over the past 30 years have studied the importance of RT in local control. A recently updated meta-analysis showed that the RT regimens produced moderate but definite reductions not only in 15-year BC mortality but also in 15-year overall mortality.

Sarcomas are a rare but recognized complication of radiation therapy (RT) for BC, also some other cancers such as lung carcinomas, mostly in smokers. Recently increased risk of esophageal cancer after adjuvant RT for primary BC has been reported. The role of adjuvant RT for BC in causing secondary cancers is debatable.

Discussion

This large-scale, single-institution, retrospective study of 16,705 patients treated for nonmetastatic BC suggests that RT did not increase the incidence of second primary cancers other than sarcomas and lung cancer. To our knowledge, this is the largest series from a single institution.

Our results could be discussed in the context of the existing literature, especially recently published results of meta-analyses (Table 3). The weakness of some large epidemiologic studies, despite very large populations studied and long follow-up periods, is the lack of individual information concerning the patientsí treatment, especially information concerning irradiation fields. Other single-institution series are limited by small numbers of patients, but they have confirmed the relationship between RT and arising of sarcomas

This study showed the increased risk of sarcomas and lung cancers. The risk of radiation-induced sarcomas is well known, and our experience is previously described. It is already shown that approximately 9 cases of radiation-induced lung cancer per year could be expected to occur among 10,000 women who received an average lung dose of 10 Gy and survived for at least 10 years. Another problem, as confirmed by present study, is that lung cancer is greater among cigarette smokers and it is extremely difficult to analyze the risk in this patient population. Our study confirms also the findings of Galper , who reported increased risk of lung cancers and sarcomas. In some cases, lung cancers such as SM may be sporadic and/or related to environmental factors, and in others it may be related to BC treatment such as RT. Another diagnostic problem is to distinguish a new lung primary from a lung metastasis from BC, especially in cases of adenocarcinoma. As previously reported, some of our patients with lung cancer had been treated in another hospital. The histologic confirmation of their lung cancer, all simulation films and radiologic charters of the BC treatment were available but in more than 60% of the cases the precise localization of new lung primary was not found. We were thus unable to determine the precise relationship between the lung SM and irradiation fields and doses. At the other hand, Obedian did not find an increased risk in lung cancers among patients who have undergone irradiation compared with matched control subjects treated with mastectomy without RT. Based on analysis of the study findings and previously published data  it is concluded that patients who undergo RT and who are smokers present with an increased risk of lung cancer. This population of patients may need to undergo follow-up using computed tomography as screening for early detection of lung cancer.

Some recently published studies showed increased incidence of esophageal cancers after RT. The recently published study  in the SEER series showed that postmastectomy RT moderately increases the risk of squamous cell esophageal carcinoma starting 5 years after exposure and persisting after 10 years, with no increase in the risk of adenocarcinoma. Other investigators  did not find any difference in the incidence of GI malignancies in patients who had and had not undergone RT, as in the present series.

In this study there was no significant difference between the populations of patients who had and had not undergone RT for contralateral BC (Table 2). This finding shows that, in our population, there were no radiation-induced contralateral cancers. The use of adequate, individually adapted technique is an important part of breast-conserving treatment.

As recommended, longer and careful follow-up of these patients is required to confirm the validity and stability of these results. Despite the importance of studied population and the follow-up period (nearly 11 years), this may still not have been long enough to detect a difference in the incidence of SM between the patients who had and had not undergone RT, because the long latency of radiation-induced tumors

Conclusion

In conclusion, second malignancies occur in a minority of patients undergoing RT for BC. Adjuvant RT increased the rate of sarcomas and lung cancers, whereas it did not increase the rate of other malignancies. Long-term follow-up is needed for this patient population to exclude other late complications.