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Second solid cancers after radiotherapy for breast cancer in SEER cancer registries
extensive cell killing at high doses. When data were adjusted for radiation dose and age at irradiation, differences by type of first cancer were not statistically significant. As such, the dose-response model applies for all types of first cancers. When data were separated for women whose treatment for the initial cancer included a sterilizing dose to the ovaries ($5 Gy), the data still followed a linear dose-response curve, but the slope decreased to 0.06 per Gy. This information translates into the tangible finding that women who received breast doses of 40 Gy had an overall 11-fold higher risk for developing second breast cancers as compared to nonirradiated patients. However, women whose treatment for the initial cancer included 5 Gy or more to the ovaries had a lower risk of developing a second breast cancer, showing only a 3.4-fold higher risk relative to nonirradiated patients. Chemotherapy for the initial cancer was not found to significantly affect
breast cancer risk when analyses were adjusted for radiation dose to the breast and ovaries. A notable strength of this study is that it has substantial information regarding the patients as well as their radiation and chemotherapy treatments. Data on surgical procedures and all chemotherapeutic agents, including cumulative doses and routes of administration, were obtained from the medical record of each study participant. Furthermore, the radiation therapy records were abstracted to identify the dates of therapy, beam energy, field size, field location, number of treatment fractions, and total dose to each field. This information was then used to reconstruct the dose distributions for each case-control set to the most specific breast tumor location possible. The dosimetric reconstructions also considered the stage of breast development by changing the size of the breast for dose calculations on the basis of stage of development.
The dose reconstructions were also used to determine the dose to the ovaries for each case-control set. An additional strength of this study is that statistical power was maximized by using individually matched controls, with a control-to-case ratio of 4:1. This study by Inskip and colleagues is by far one of the best studies to date that addresses second breast cancers. Its main strengths include the large number of patients in the study as well as patient-specific information, most notably the excellent patient-specific dosimetry. The overarching implications of this work are the demonstration of a linear dose-response model and the associated inference that every effort should be made to minimize the dose to healthy breast tissue during radiation therapy for patients under 20 years of age.
Second solid cancers after radiotherapy for breast cancer in SEER cancer registries
year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCISEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. Results.—By the end of 2005 (median follow-up ¼ 13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence
interval (CI) ¼ 1.33–1.58) for highdose second cancer sites (1 + Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04–1.15) for contralateral breast cancer (z1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5–0.99 Gy, RR ¼ 0.89 (0.74–1.06)) or low doses (<0.5 Gy, RR ¼ 1.01 (0.95–1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI ¼ 69– 284) contralateral breast cancers or 5% (2–8%) of the total in all 1 + year survivors, and 292 (222–362) other solid cancers or 6% (4–7%) of the total.
Berrington de Gonzalez A, Curtis RE, Gilbert E, et al (Natl Cancer Inst, Bethesda, MD; et al) Br J Cancer 102:220-226, 2010
Background.—Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. Methods.—We evaluated long-term second cancer risks among 182 057 5-
R. M. Howell, PhD S. F. Kry, PhD
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 3 2010
271
Conclusions.—Most second solid cancers in breast cancer survivors are not related to radiotherapy. It is well known that cancer survivors are at an elevated risk of developing a second cancer; as Berrington de Gonzalez and colleagues report, breast cancer survivors have an 18% higher risk of developing a second cancer than the general public (based on Surveillance, Epidemiology, and End Results [SEER] data). However, the etiology of these malignancies remains unknown. While genetic and environmental factors clearly play a role, treatment agents such as radiation are also well known to be carcinogenic. The relative significance of these risk factors is important when considering the longterm health of the patient. This work evaluated this question for breast cancer survivors, separating the number of second cancers observed into those not associated with radiation (based on a ‘‘surgery alone’’ population) and those attributable to radiation. Berrington de Gonzalez and colleagues found that of all the second cancers, only approximately 5% to 10% were due to radiation and the vast majority of second cancers were related to other risk factors. It is important to recognize, however, that 5% to 10% of second cancers may still be a sizeable absolute number for the population of breast cancer survivors; this cohort alone had in excess of 15 000 second cancers. The authors further examined the relationship between radiation and
272
the risk of second cancers by determining the second cancer risk for a comprehensive list of possible solid second cancer sites. They found that radiation was associated with an elevated risk of second cancers only in organs that had received a ‘‘high’’ dose. It must be pointed out, though, that the authors classified high-dose organs as those whose mean dose was greater than 1 Gy, which included organs as far as approximately 10 cm from the edge of the treatment field. Nevertheless, there was clearly a dosimetric relationship, confirming that radiation is indeed a risk factor for second cancers. The findings reported in this article reinforce some other known trends for second cancer predilection in addition to the dose response. In particular, the risk of radiationinduced second cancers is greatest for younger women and for women with the longest survival. This sort of information should factor into clinical care decisions; while long-term radiation effects for older women with comorbidities are almost certainly irrelevant, effort should be spent on minimizing non-target radiation doses to younger, healthier women. This effort could include avoiding the use of physical wedges, using delivery techniques that reduce the total number of monitor units, or using radiation techniques to minimize the volume of irradiated tissue. A potentially reassuring finding for the oncology community was that the RR of second cancers decreased with treatment era—the risk is lower for women treated with radiation after
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 3 2010
1993 than for those treated before 1993. This is at least partially the result of refined radiotherapy and surgical techniques and equipment that have led to less radiation being delivered to healthy tissue. However, the finding is also confounded by the shorter follow-up time for these patients, and the long-term result is unclear. The patient population in this study consisted of women whose diagnoses were reported to the registries of the SEER Program, the use of which is a double-edged sword for epidemiologic studies. This large database allowed for the staggering cohort size of 182 057 individuals; it is designed to represent the entire US population. The drawback of this database is that it lacks details regarding individual patients and treatments. Consequently, generalized dosimetry was conducted based on an assumed typical breast treatment. Although breast therapy is relatively standardized in the modern clinic, variations are certainly seen, particularly in more historical treatments, which could create substantial dosimetric uncertainty. Nevertheless, this study by Berrington de Gonzalez and colleagues offers a valuable and comprehensive evaluation of the sites of second cancer induction following breast therapy and of the relative importance of radiation to that risk. S. F. Kry, PhD R. M. Howell, PhD
breast cancer risk when analyses were adjusted for radiation dose to the breast and ovaries. A notable strength of this study is that it has substantial information regarding the patients as well as their radiation and chemotherapy treatments. Data on surgical procedures and all chemotherapeutic agents, including cumulative doses and routes of administration, were obtained from the medical record of each study participant. Furthermore, the radiation therapy records were abstracted to identify the dates of therapy, beam energy, field size, field location, number of treatment fractions, and total dose to each field. This information was then used to reconstruct the dose distributions for each case-control set to the most specific breast tumor location possible. The dosimetric reconstructions also considered the stage of breast development by changing the size of the breast for dose calculations on the basis of stage of development.
The dose reconstructions were also used to determine the dose to the ovaries for each case-control set. An additional strength of this study is that statistical power was maximized by using individually matched controls, with a control-to-case ratio of 4:1. This study by Inskip and colleagues is by far one of the best studies to date that addresses second breast cancers. Its main strengths include the large number of patients in the study as well as patient-specific information, most notably the excellent patient-specific dosimetry. The overarching implications of this work are the demonstration of a linear dose-response model and the associated inference that every effort should be made to minimize the dose to healthy breast tissue during radiation therapy for patients under 20 years of age.
Second solid cancers after radiotherapy for breast cancer in SEER cancer registries
year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCISEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. Results.—By the end of 2005 (median follow-up ¼ 13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence
interval (CI) ¼ 1.33–1.58) for highdose second cancer sites (1 + Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04–1.15) for contralateral breast cancer (z1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5–0.99 Gy, RR ¼ 0.89 (0.74–1.06)) or low doses (<0.5 Gy, RR ¼ 1.01 (0.95–1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI ¼ 69– 284) contralateral breast cancers or 5% (2–8%) of the total in all 1 + year survivors, and 292 (222–362) other solid cancers or 6% (4–7%) of the total.
Berrington de Gonzalez A, Curtis RE, Gilbert E, et al (Natl Cancer Inst, Bethesda, MD; et al) Br J Cancer 102:220-226, 2010
Background.—Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. Methods.—We evaluated long-term second cancer risks among 182 057 5-
R. M. Howell, PhD S. F. Kry, PhD
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 3 2010
271
Conclusions.—Most second solid cancers in breast cancer survivors are not related to radiotherapy. It is well known that cancer survivors are at an elevated risk of developing a second cancer; as Berrington de Gonzalez and colleagues report, breast cancer survivors have an 18% higher risk of developing a second cancer than the general public (based on Surveillance, Epidemiology, and End Results [SEER] data). However, the etiology of these malignancies remains unknown. While genetic and environmental factors clearly play a role, treatment agents such as radiation are also well known to be carcinogenic. The relative significance of these risk factors is important when considering the longterm health of the patient. This work evaluated this question for breast cancer survivors, separating the number of second cancers observed into those not associated with radiation (based on a ‘‘surgery alone’’ population) and those attributable to radiation. Berrington de Gonzalez and colleagues found that of all the second cancers, only approximately 5% to 10% were due to radiation and the vast majority of second cancers were related to other risk factors. It is important to recognize, however, that 5% to 10% of second cancers may still be a sizeable absolute number for the population of breast cancer survivors; this cohort alone had in excess of 15 000 second cancers. The authors further examined the relationship between radiation and
272
the risk of second cancers by determining the second cancer risk for a comprehensive list of possible solid second cancer sites. They found that radiation was associated with an elevated risk of second cancers only in organs that had received a ‘‘high’’ dose. It must be pointed out, though, that the authors classified high-dose organs as those whose mean dose was greater than 1 Gy, which included organs as far as approximately 10 cm from the edge of the treatment field. Nevertheless, there was clearly a dosimetric relationship, confirming that radiation is indeed a risk factor for second cancers. The findings reported in this article reinforce some other known trends for second cancer predilection in addition to the dose response. In particular, the risk of radiationinduced second cancers is greatest for younger women and for women with the longest survival. This sort of information should factor into clinical care decisions; while long-term radiation effects for older women with comorbidities are almost certainly irrelevant, effort should be spent on minimizing non-target radiation doses to younger, healthier women. This effort could include avoiding the use of physical wedges, using delivery techniques that reduce the total number of monitor units, or using radiation techniques to minimize the volume of irradiated tissue. A potentially reassuring finding for the oncology community was that the RR of second cancers decreased with treatment era—the risk is lower for women treated with radiation after
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 3 2010
1993 than for those treated before 1993. This is at least partially the result of refined radiotherapy and surgical techniques and equipment that have led to less radiation being delivered to healthy tissue. However, the finding is also confounded by the shorter follow-up time for these patients, and the long-term result is unclear. The patient population in this study consisted of women whose diagnoses were reported to the registries of the SEER Program, the use of which is a double-edged sword for epidemiologic studies. This large database allowed for the staggering cohort size of 182 057 individuals; it is designed to represent the entire US population. The drawback of this database is that it lacks details regarding individual patients and treatments. Consequently, generalized dosimetry was conducted based on an assumed typical breast treatment. Although breast therapy is relatively standardized in the modern clinic, variations are certainly seen, particularly in more historical treatments, which could create substantial dosimetric uncertainty. Nevertheless, this study by Berrington de Gonzalez and colleagues offers a valuable and comprehensive evaluation of the sites of second cancer induction following breast therapy and of the relative importance of radiation to that risk. S. F. Kry, PhD R. M. Howell, PhD