Radiotherapy and Oncology 115 (2015) 432–433
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Letter to the Editor Second cancers after radiotherapy for early breast cancer
To the Editor It has been argued by Mallick et al. [1] that our meta-analysis on second cancers after radiotherapy for breast cancer [2] would send an unclear message to clinicians concerning the beneficial effect of postoperative radiotherapy. We would like to stress the following: Radiotherapy continues to play an essential role in the treatment of early breast cancer. The beneficial effect of radiation therapy with both reduced recurrence and mortality rates among women with node-positive disease has been demonstrated by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) [3,4]. However, among women with node-negative disease treated with a mastectomy, radiotherapy had no effect. Conversely, radiotherapy increased the overall mortality rate; with a 20 year loss of 6% [3]. This excess mortality was primarily attributable to cardiac toxicity and second malignancies, which both are long-term side effects of radiation therapy. In the meta-analysis, including over 700,000 women treated for early breast cancer, we demonstrated that radiation therapy is significantly associated with an excess risk of second cancers in organs with fairly close proximity to the former treatment fields [2]. These results are in line with the results of the 2005 EBCTCG overview of clinical trials covering approximately the same treatment period [5]. We further demonstrated, that the risk of second cancer increased over time, up to 15 or more years after treatment – a latency pattern consistent with the suggested biology of radiation induced second cancers [6]. Our meta-analysis included all available non-overlapping cohort studies, but as it consisted of summary results it also inherited several limitations. 1. Patient specific radiotherapy techniques are typically not available in cohort studies, thus the risk according to the different regimes and radiation fields cannot be calculated. 2. The specific anatomical location of the second tumors is rarely provided, therefore risk estimates were limited to the specific organs. 3. Also unavailable is information on smoking and alcohol consumption. However, these confounders would only introduce bias, if unevenly distributed between irradiated and unirradiated patients. This however seems unlikely, as radiotherapy is not allocated on the basis of the smoking or drinking habits of the individual patients. 4. Studies included in the analysis were all dominated by women treated in the 1980s and 90s, where radiation regimes were slightly different from current techniques. The treatment fields were possibly somewhat larger than today and the majority of http://dx.doi.org/10.1016/j.radonc.2015.06.002 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
the patients were treated before the area of CT-guided radiotherapy planning. Overall, this could result in slightly higher normal tissue doses compared to today. However, due to the nature of radiation induced second cancers with a minimum latency period of 5–9 years, studies on second cancers will inevitably be based on techniques that are somewhat dated. Although there is some uncertainty as to the risk of radiation induced second cancers associated with current techniques, in that the risk could be slightly lower, it has also been shown that the dose–response correlation of tumor induction in the lung and the esophagus after breast cancer irradiation appear linear [7–9]. This suggests that any dose reduction to the normal tissue would result in a beneficial second cancer risk reduction. In the meta-analysis we demonstrated what has been known for years; that some patients pay the price for radiation therapy through an increased risk of second cancers. It is evident though; that the benefit of radiation therapy in regard to local tumor control and consequently improved survival rates by far outweigh the absolute risk of developing subsequent cancers 10–20 years after treatment in the majority of patients. But with continuously improving survival rates, it is important to note that the majority of breast cancer patients today will be cured for the disease to become long-term survivors. The current clinical challenge in radiation therapy is therefore to incrementally improve the treatment techniques we use, in order to reduce the radiation dose to the normal tissue. This has been done successfully for the heart in breast cancer patients. Secondly, to identify an additional group of lowrisk patients, where radiotherapy can safely be omitted. With declining local recurrence rates, it is becoming increasing important to identify those patients where the risks of side-effects after radiation therapy are outweighed by the benefits. Disclosures The authors have nothing to disclose. Conflict of interest The authors declare that they have no conflict of interest. References [1] Mallick S, Giridhar P, Prasad VB. In regard to ‘‘Risk of second non-breast cancer after radiotherapy for breast cancer: A systematic review and meta-analysis of 762,468 patients’’. Radiother Oncol 2015 [Epub ahead of print]. [2] Grantzau T, Overgaard J. Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients. Radiother Oncol 2014;114:56–65. [3] EBCTCG Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence
Letter to the Editor / Radiotherapy and Oncology 115 (2015) 432–433
[4]
[5]
[6]
[7]
[8]
and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014;383:2127–35. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707–16. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. IARC. Ionizing Radiation, Part 1: X- and Gamma (g)-radiation, and neutrons. IARC monographs on the evaluation of carcinogenic risks to humans, vol. 75. Lyon: World Health Organization International Agency for Research on Cancer; 2000. Grantzau T, Thomsen MS, Vaeth M, Overgaard J. Risk of second primary lung cancer in women after radiotherapy for breast cancer. Radiat Oncol 2014;111:366–73. Berrington de GA, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose–response relationship. Int J Radiat Oncol Biol Phys 2013;86:224–33.
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[9] Morton LM, Gilbert ES, Hall P, et al. Risk of treatment-related esophageal cancer among breast cancer survivors. Ann Oncol 2012;23:3081–91.
Trine Grantzau Jens Overgaard Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark E-mail address: [email protected] (T. Grantzau) Received 3 June 2015 Received in revised form 4 June 2015 Accepted 4 June 2015 Available online 13 June 2015
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Letter to the Editor Second cancers after radiotherapy for early breast cancer
To the Editor It has been argued by Mallick et al. [1] that our meta-analysis on second cancers after radiotherapy for breast cancer [2] would send an unclear message to clinicians concerning the beneficial effect of postoperative radiotherapy. We would like to stress the following: Radiotherapy continues to play an essential role in the treatment of early breast cancer. The beneficial effect of radiation therapy with both reduced recurrence and mortality rates among women with node-positive disease has been demonstrated by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) [3,4]. However, among women with node-negative disease treated with a mastectomy, radiotherapy had no effect. Conversely, radiotherapy increased the overall mortality rate; with a 20 year loss of 6% [3]. This excess mortality was primarily attributable to cardiac toxicity and second malignancies, which both are long-term side effects of radiation therapy. In the meta-analysis, including over 700,000 women treated for early breast cancer, we demonstrated that radiation therapy is significantly associated with an excess risk of second cancers in organs with fairly close proximity to the former treatment fields [2]. These results are in line with the results of the 2005 EBCTCG overview of clinical trials covering approximately the same treatment period [5]. We further demonstrated, that the risk of second cancer increased over time, up to 15 or more years after treatment – a latency pattern consistent with the suggested biology of radiation induced second cancers [6]. Our meta-analysis included all available non-overlapping cohort studies, but as it consisted of summary results it also inherited several limitations. 1. Patient specific radiotherapy techniques are typically not available in cohort studies, thus the risk according to the different regimes and radiation fields cannot be calculated. 2. The specific anatomical location of the second tumors is rarely provided, therefore risk estimates were limited to the specific organs. 3. Also unavailable is information on smoking and alcohol consumption. However, these confounders would only introduce bias, if unevenly distributed between irradiated and unirradiated patients. This however seems unlikely, as radiotherapy is not allocated on the basis of the smoking or drinking habits of the individual patients. 4. Studies included in the analysis were all dominated by women treated in the 1980s and 90s, where radiation regimes were slightly different from current techniques. The treatment fields were possibly somewhat larger than today and the majority of http://dx.doi.org/10.1016/j.radonc.2015.06.002 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
the patients were treated before the area of CT-guided radiotherapy planning. Overall, this could result in slightly higher normal tissue doses compared to today. However, due to the nature of radiation induced second cancers with a minimum latency period of 5–9 years, studies on second cancers will inevitably be based on techniques that are somewhat dated. Although there is some uncertainty as to the risk of radiation induced second cancers associated with current techniques, in that the risk could be slightly lower, it has also been shown that the dose–response correlation of tumor induction in the lung and the esophagus after breast cancer irradiation appear linear [7–9]. This suggests that any dose reduction to the normal tissue would result in a beneficial second cancer risk reduction. In the meta-analysis we demonstrated what has been known for years; that some patients pay the price for radiation therapy through an increased risk of second cancers. It is evident though; that the benefit of radiation therapy in regard to local tumor control and consequently improved survival rates by far outweigh the absolute risk of developing subsequent cancers 10–20 years after treatment in the majority of patients. But with continuously improving survival rates, it is important to note that the majority of breast cancer patients today will be cured for the disease to become long-term survivors. The current clinical challenge in radiation therapy is therefore to incrementally improve the treatment techniques we use, in order to reduce the radiation dose to the normal tissue. This has been done successfully for the heart in breast cancer patients. Secondly, to identify an additional group of lowrisk patients, where radiotherapy can safely be omitted. With declining local recurrence rates, it is becoming increasing important to identify those patients where the risks of side-effects after radiation therapy are outweighed by the benefits. Disclosures The authors have nothing to disclose. Conflict of interest The authors declare that they have no conflict of interest. References [1] Mallick S, Giridhar P, Prasad VB. In regard to ‘‘Risk of second non-breast cancer after radiotherapy for breast cancer: A systematic review and meta-analysis of 762,468 patients’’. Radiother Oncol 2015 [Epub ahead of print]. [2] Grantzau T, Overgaard J. Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients. Radiother Oncol 2014;114:56–65. [3] EBCTCG Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence
Letter to the Editor / Radiotherapy and Oncology 115 (2015) 432–433
[4]
[5]
[6]
[7]
[8]
and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014;383:2127–35. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707–16. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. IARC. Ionizing Radiation, Part 1: X- and Gamma (g)-radiation, and neutrons. IARC monographs on the evaluation of carcinogenic risks to humans, vol. 75. Lyon: World Health Organization International Agency for Research on Cancer; 2000. Grantzau T, Thomsen MS, Vaeth M, Overgaard J. Risk of second primary lung cancer in women after radiotherapy for breast cancer. Radiat Oncol 2014;111:366–73. Berrington de GA, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose–response relationship. Int J Radiat Oncol Biol Phys 2013;86:224–33.
433
[9] Morton LM, Gilbert ES, Hall P, et al. Risk of treatment-related esophageal cancer among breast cancer survivors. Ann Oncol 2012;23:3081–91.
Trine Grantzau Jens Overgaard Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark E-mail address: [email protected] (T. Grantzau) Received 3 June 2015 Received in revised form 4 June 2015 Accepted 4 June 2015 Available online 13 June 2015
