VIENNA — The risk of developing a primary lung cancer after radiotherapy for breast cancer increases in a dose-response manner, with these odds jumping 17-fold in smokers, according to new research from a cohort of more than 23,000 irradiated patients from the Danish Breast Cancer Cooperative Group.
"Overall, these findings indicate that any reduction of the radiotherapy dose would result in a decreased risk of second lung cancer," researcher Trine Grantzau, MD, from Aarhus University Hospital, Denmark, told Medscape Medical News.
The findings were presented here at the European Society for Radiotherapy and Oncology (ESTRO) 33.
When approached for comment, Lindsay Morton, PhD, from the National Cancer Institute in Bethesda, Maryland, said these data, combined with several other studies of radiation and lung cancer, also "emphasize the need to better understand the potential synergy between cigarette smoking and chest radiotherapy on risk of subsequent lung cancer."
Dr. Grantzau added that "with increasing breast cancer survival rates, a growing number of patients will live long enough to experience long-term, potentially life-threatening side effects of radiotherapy. This highlights the need for clinicians to have an increased awareness towards radiation-induced second cancers, consider these risks in regard to the indications for radiotherapy, continuously improve treatment techniques to minimize the dose to normal tissue without compromising the target, and, finally, consider more advanced treatment techniques that spare the normal tissue."
The study is the first work by Dr. Grantzau's group showing a dose-response relationship between breast cancer radiotherapy and second cancers. The findings are similar to those from Dr. Morton's group ( Ann Oncol. 2012;23:3081-91) of a dose-related risk for esophageal cancer with 35 Gy or more of breast cancer radiotherapy (odds ratio [OR], 8.3; P < .001) and a dose-response relationship showing a 9% increased risk per Gy of exposure. Dr. Morton's group also showed that supraclavicular and internal mammary treatments were the largest contributors to esophageal radiation exposure.
Dr. Grantzau and colleagues previously published evidence ( Radiother Oncol. 2013;106:42-9) showing an overall increased risk for a variety of cancers described as "radiotherapy-associated" after breast cancer irradiation, with a hazard ratio (HR) reaching 1.79 at 15 years or longer after radiotherapy, and translating to the equivalent of 1 cancer for every 200 women treated with breast cancer radiotherapy.
The current study is based on the same DBCG cohort of 23,627 irradiated breast cancer patients, among whom a total of 151 were identified who developed lung cancer.
Control patients who did not develop a second cancer (n = 443) were identified from the same irradiated cohort and matched to the lung cancer patients on the basis of age of breast cancer diagnosis, year of breast cancer treatment, and length of cancer-free survival.
Case patients and control patients were well balanced according to systemic and adjuvant treatment and breast cancer surgery; however, there were significantly more ever-smokers among case patients than control patients (91% vs 40%, P < .001).
The mean age of all patients at breast cancer diagnosis was 54 years, and the mean age of second lung cancer diagnosis in the case patients was 68 years.
Using patient-specific dose reconstructions based on radiotherapy records, the radiation dose to the area around the lung cancer patients' tumors was estimated and found to be significantly greater than the dose to the equivalent anatomic area in control patients (8.7 Gy vs 5.6 Gy; P = .01).
After adjusting for smoking status and adjuvant systemic treatment, the ORs for lung cancer were calculated according to radiation dose and time from breast cancer treatment.
Compared with nonirradiated patients, patients exposed to 15-24 Gy had a significantly increased risk for lung cancer at both 5 or more years and 10 or more years after treatment, with ORs of 3.83 and 3.84, respectively (P = .016), whereas for exposures of more than 25 Gy, the 5- and 10-year ORs were 3.45 and 6.27, respectively (P = .014), reported Dr. Grantzau.
The analysis also showed that the risk for second lung cancer increased linearly by 8.5% for every 1 Gy of exposure (P < .001).
Compared with nonsmokers, ever-smokers had a 17.3% increased risk (P < .005).
Risk for All Secodary Cancers
In another session at the meeting, Dr. Grantzau presented a meta-analysis of the risk for a variety of second cancers, including breast, lung, esophagus, sarcoma, and thyroid, at 5, 10, and 15 or more years since radiotherapy for breast cancer.
The analysis included 14 studies, with 762,468 breast cancer patients, of whom 42% were irradiated and 58% were not. Treatment took place between 1954 and 2007 and included either mastectomy or breast conserving surgery, with a mean radiation exposure of between 36 and 60 Gy. The mean age of the patients at breast cancer diagnosis was 59 years, and the mean duration of follow-up after breast cancer treatment was 8 years.
For the overall endpoint of second nonbreast cancers, 7 studies included 299,883 breast cancer patients and a follow-up of up to 37 years. Overall, the analysis showed a significantly increased relative risk (RR) of 1.22, which remained elevated (1.12) at 5 or more years after treatment, she said.
Studies that looked at the risk for esophageal cancer showed no significantly increased risk at 5 or more years postradiotherapy (HR, 1.17), but at 10 or more years, the HR was 1.56 and reached a maximum of 3.7 at 15 or more years after radiotherapy.
For sarcomas, there was a significantly increased risk overall (RR, 2.41), as well as at 5 years postradiotherapy (RR, 2.53).
For second lung cancers, there was an increased risk overall (RR, 1.23), as well as at 5 or more years and 10 or more years postradiotherapy (1.39 and 1.59, respectively), to reach a maximum RR of 1.66 at 15 years or more postradiotherapy.
For thyroid cancer, there was no increased risk.
"Although the absolute risk of second cancers is small, a small risk multiplied by millions does add up to a public health problem that should be integrated in a balanced perspective of risks and benefits associated with radiotherapy," concluded Dr. Grantzau.
"Improved understanding of late treatment effects provides important information for clinicians and patients as they weigh different treatment options," commented Dr. Morton. "These analyses help provide valuable data on second cancer risks after radiotherapy for breast cancer overall. However, risks for an individual patient will vary based on specific treatment attributes, such as which radiotherapy fields she received. The case-control study of lung cancer took just this type of information into account and thus provides the detailed data that are needed to quantify the lung cancer risks after specific treatment exposures."
Commenting on the study, the president of ESTRO, Professor Vincenzo Valentini, a radiation oncologist at the Policlinico Universitario A. Gemelli, Rome, Italy, said in a written statement: "This research shows the importance of monitoring the safety of radiotherapy procedures so that we can use the information gained to achieve a good balance between the risks and benefits of a particular treatment. Reducing the radiation dose to normal tissue is always beneficial, and knowing the exact target and the best radiation dose will help to reduce any long-term side-effects of a therapy that research has long shown to be instrumental in helping to save the lives of women with breast cancer. Dr. Grantzau's research suggests there is a small increased risk of lung cancer in the years after radiotherapy for breast cancer, particularly in women who smoke. This underlines the importance to women of not smoking, as this increases the risk of a range of diseases. We, as radiation oncologists, will continue to work to monitor and improve the safety and efficacy of our therapies."
Dr. Grantzau, Dr. Morton, and Dr. Valentini have disclosed no relevant financial relationships.
European Society for Radiotherapy and Oncology (ESTRO) 33: Abstracts OC-0489 and SP-0630. Presented April 7 and 9, 2014.
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Cite this: Lung Cancer: A Dose-Dependent Risk After Breast Cancer RT - Medscape - Apr 14, 2014.