The overall survival of early stage breast cancer is good so that there are increasing numbers oflong-term breast cancer survivors that need to be followed for the occurrence of secondary malignancies.
It is well established that patients treated for one breast cancer have a higher risk of subsequent contralateral breast cancer (CBC).168-172 The risk for CBC averages between 1.1% and 1.5% per year. On the basis of the evidence from both randomized trials and population-based studies, it does not appear that breast radiation to one breast increases this risk for subsequent CBC. In the randomized trials evaluating breast conserving therapy, the rate of subsequent CBC was similar in either the mastectomy or radiation treatment arms. The Milan I trial that randomized 701 breast cancer patients to either radical mastectomy or quadrantectomy and radiation demonstrated 28 CBC in the mastectomy arm and 22 in the radiation group at up to 19 years follow-up.170 Ten-year follow-up of the NCI randomized trial demonstrated 10 CBC in the 116 mastectomy patients and 7 in the 121 who underwent lumpectomy and radiation.169 At 15-year follow-up of the Institut Gustave, Roussy, 13 CBC occurred in the 91 patients treated with mastectomy and 10 in the 88 patients who had radiation following tumorectomy.168
Multiple population-based studies have evaluated whether the incidence of CBC could be linked to radiotherapy for the first breast cancer. A study from the Connecticut Tumor Registry of41,109 breast cancer patients treated between 1935 and 1982 revealed 655 CBC that were matched with 1189 controls did not demonstrate an overall increase in CBC after radiation treatment.171 A non-significant trend for increase in CBC was seen in a subset of 45 women who were <45 years old at diagnosis and who were 10 years post-radiation treatments. A population-based study from Denmark looking at 529 breast cancer patients with CBC and 529 matched controls did not demonstrate an increased risk of CBC after radiation for a first breast cancer.172 A 4.2% incidence of CBC was documented for 134,501 breast cancer cases treated between 1973 and 1996 in the SEER database.173 In this study, a cox proportional hazards regression model demonstrated that radiation treatment for the first cancer was associated with an increased risk of CBC after 5 years of follow-up (RR = 1.14, 95% CI 1.03-1.26, P = 0.001). This study was limited by the unavailability of confounding information, such as tamoxifen use, that could affect the incidence of CBC. In conclusion, there has been no consistent evidence that the use of radiation for one breast cancer causes a second CBC. However, adherence to radiation techniques that reduce the contralateral breast dose is advised, especially in younger patients.
There is increasingly compelling evidence that breast cancer patients are at higher risk of subsequently developing lung cancer following radiation; especially for those who smoke. Data from SEER were used to assess the subsequent risk of lung cancer in breast cancer patients that were irradiated. A total of 122 lung cancers developed in 13,750 women who received radiation and 473 in the 41,196 who were not radiated (0.88% vs. 0.11%).174 This risk was confined to the ipsilateral lung. A population-based study from the Danish Cancer Registry has also demonstrated a slightly elevated lung cancer risk after 10 years in radiated breast cancer patients.176 A study from the Connecticut Tumor Registry with an analysis for smoking history demonstrated that the increased risk of subsequent lung cancer in the ipsilateral lung following radiation for breast cancer was much greater for smokers than non-smokers.175 The relative risk for a subsequent ipsilateral lung cancer was 6.7 (95% CI 0.6—79.4) for non-smokers and 76.6 (95% CI 8.1—724) in smokers. No information was available in this study regarding radiation technique, volume of lung radiated, or extent of smoking history. This relationship between radiation for breast cancer, smoking, and secondary lung cancers was further evaluated in a study from MD Anderson Cancer Center using 280 lung cancer cases with a prior diagnosis of breast cancer matched to a group of300 randomly selected breast cancer cases who did not develop lung cancer.177 Smoking increased the odds of lung carcinoma in breast cancer patients who were not irradiated (OR 6.0, 95% CI 3.6—10.1). Irradiation did not increase the odds for developing lung cancer in non-smokers (OR 0.5, 95% CI 0.3—1.1). The odds ratio for both smoking and irradiation was 9.0 (95% CI 5.1—15.9). The volume of lung-irradiated during breast cancer treatment may be an important determinant for risk of secondary lung cancer. This was demonstrated in a study from the NSABP that found an increased risk of subsequent ipsilateral lung cancer in patients who underwent chest wall and regional nodal irradiation following mastectomy but non-breast irradiation alone after lumpectomy.178 In summary, breast cancer patients who smoke should be strongly encouraged to quit. We find in our clinic that breast cancer patients are very receptive to and successful with smoking cessation interventions. The amount of lung irradiated in all patients should be minimized, but particular attention should be paid to smokers with low-risk breast cancer.
Second primary sarcomas occur in or near the treatment field in approximately 0.1— 0.2% of patients at 10 years. At the Institut Gustave, Roussy, France, 6919 patients treated for breast cancer, 11 developed secondary soft tissue sarcoma at a mean latency time of 9.5 years.179 Similarly, 19 soft tissue sarcomas were noted in a population of 13,490 women treated for breast cancer in Sweden between 1960 and 1980.180 A higher incidence of angiosarcoma, in particular, was demonstrated after irradiation for breast cancer in 194,798 cases in the SEER database.181 A total of 20 cases developed in 48,975 irradiated patients versus 7 in the 146,303 non-irradiated cohort. This emphasizes the importance of long-term follow-up for breast cancer patients who have been irradiated so that early diagnosis and intervention of this rare complication can be done.
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