- Email: [email protected]
In Reply to Gyenes and Butler
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Comments In Regard to Mast et al
References
To the Editor: Mast et al suggest that patients with breast cancer might be at higher risk for coronary artery disease (CAD) as shown by their higher coronary artery calcium (CAC) scores (1). Their findings, however, may be due to chance. We would also be interested in the authors’ opinion of what might be the mechanism behind their finding. The use of CAC scores for cardiovascular screening is controversial in women in particular (2). Patients’ vascular risks should primarily be assessed by the calculation of a global risk score such as the Framingham or the Reynolds score. These scores incorporate multiple, appropriately-weighted cardiac risk factors. Authors listed some of these (eg, age, diabetes, smoking); therefore, it might be possible to calculate such a score in their cohorts. The higher CAC scores found in the study may well be due to higher overall cardiovascular risks in their patients and therefore, the data should be adjusted to their global risks. Calcium scores in the general population have been found to be most helpful in the reclassification of patients with moderately high Framingham risk scores. Otherwise CAC screening increases the chance of having further unnecessary tests without the potential of improving outcomes (3). Elevated high-sensitivity C-reactive protein (hs-CRP) levels have also been shown to improve cardiovascular risk classification (4). As well, in the JUPITER Study elevated hs-CRP levels appeared to identify an apparently healthy population who would benefit from statin therapy (5). Therefore, if the connection between breast cancer and increased cardiovascular risks was found to be true in untreated patients, then hs-CRP levels could potentially provide the link to prevention. However, this hypothesis would need to be tested in an appropriately sized cohort. As the authors pointed out, there is consensus in the literature that left-sided radiation therapy may increase the risk of heart disease. We agree that a systematic, evidence-based approach to estimate preradiation cardiovascular risks as well as an attempt to reduce the long-term complications in a large number of patients with early breast cancer would be prudent.
1. Mast ME, Heijenbrok MW, Petoukhova AL, Scholten AN, Schreur JHM, Struikmans H. Preradiotherapy calcium scores of the coronary arteries in a cohort of women with early-stage breast cancer: a comparison with a cohort of healthy women. Int J Radiat Oncol Biol Phys 2012;83:853-858. 2. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in womend2011 update: a guideline from the American Heart Association. Circulation 2011; 123:1243-1262. 3. Bonow RO. Should coronary calcium screening be used in cardiovascular prevention strategies? N Engl J Med 2009;361:990-997. 4. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843. 5. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
Gabor T. Gyenes, MD, PhD Craig R. Butler, MD, FRCP(C) Mazankowski Alberta Heart Institute (Division of Cardiology) Department of Medicine University of Alberta, Edmonton Alberta, Canada http://dx.doi.org/10.1016/j.ijrobp.2012.06.027
Int J Radiation Oncol Biol Phys, Vol. 85, No. 3, pp. 579e582, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
In Reply to Gyenes and Butler To the Editor: We thank Gyenes and Butler for their interest in our recent publication, and we thank them for confirming the importance of an evidence-based approach to estimate pre-radiation cardiovascular risks and to attempt to reduce the long-term complications of patients who received radiation therapy for breast cancer (1, 2). They raise the question as to which mechanism could be pointed out with respect to the observed higher risk for coronary artery disease in breast cancer. In the literature, a high body mass index (BMI) and a low level of physical activity were defined for the risk of developing breast cancer as well as for the risk of developing coronary artery disease (and heart disease) (3, 4). With regard to a higher BMI, this was found in our cohort as well (1). As Gyenes and Butler point out, the Framingham risk score (FRS) represents a commonly used instrument to predict coronary artery disease. In a recent paper by Kavousi et al, it appeared that the addition of the Coronary Artery Calcium (CAC) scores improved even further the prediction of coronary heart disease based on FRS. This was the case for white women 55 years or older (5). In our Coronary Artery Calcium (CAC) study, we analyzed a group of women with similar characteristics (1). It also appeared that high-sensitivity C-reactive protein (hs-CRP) levels, as studied by Kavousi et al, are a risk marker significantly associated with incidental coronary heart disease after adjustment for traditional risk factors (5). These hs-CRP levels are a marker for inflammation. Stewart et al, in their preclinical study, proposed
580
International Journal of Radiation Oncology Biology Physics
Comments
that irradiation accelerates the development of inflammatory atherosclerotic lesions prone to intraplaque hemorrhage (6). Therefore, we thank Gyenes and Butler for their suggestions, and we will consider incorporating the FRS and the hs-CRP levels in our ongoing studies. M.E. Mast, MSc H. Struikmans, MD, PhD Radiotherapy Centre West The Hague, the Netherlands J.H.M. Schreur, MD, PhD Department of Cardiology Medical Center Haaglanden The Hague, the Netherlands H. Struikmans, MD, PhD Department of Clinical Oncology Leiden University Medical Centre Leiden, the Netherlands http://dx.doi.org/10.1016/j.ijrobp.2012.06.036
authors discussed potential explanations (of note, this was a retrospective study, and unknown confounders might have influenced the results), but several important and different hypotheses not included in the article should also be considered. Many patients with prostate cancer have comorbidities and use different types of prescription drugs. It has been suggested that use of various anticoagulants (2), aspirin (3), and statins (35) might improve biochemical outcomes after radiation therapy. If such drugs also reduce acute toxicity, their use might explain the findings described by Vesprini et al. In fact, these types of effects have already been reported for statins and angiotensinconverting enzyme inhibitors (6, 7). Smoking pattern could provide another potential explanation. As discussed by Pickles et al (8), smoking seems to compromise the outcome after prostate cancer radiation therapy. Moreover, smoking was associated with higher risk of bowel- and anal sphincter-related longterm toxicity (9). Given the fact that a link between acute and late toxicity risks repeatedly has been found, smoking might well result in increased acute and late toxicity and reduced BFFR. Taken together, these intriguing findings offer exciting research opportunities directed at better understanding of the relationship between toxicity and BFFR and ultimately broadening of the therapeutic window.
References 1. Mast ME, Heijenbrok MW, Petoukhova AL, Scholten AN, Schreur JHM, Struikmans H. Preradiotherapy calcium scores of the coronary arteries in a cohort of women with early-stage breast cancer: a comparison with a cohort of healthy women. Int J Radiat Oncol Biol Phys 2012;83:853-858. 2. Gyenes GT, Butler CR. In Regard to Mast et al. Int J Radiat Oncol Biol Phys 2013;85:579. 3. Gast GCM, Frenke FJM, van Leest LATM, et al. Intra-national variation in trends in overweight and leisure time physical activities in the Netherlands since 1980: stratification according to sex, age and urbanisation degree. Int J Obes 2007;31:515-520. 4. McPherson K, Steel CM, Dixon JM. ABC of breast diseases. Breast cancerdepidemiology, risk factors, and genetics. BMJ 2000;321: 624-628. 5. Kavousi M, Elias-Smale S, Rutten JHW, et al. Evaluation of newer risk markers for coronary heart disease risk classification. A cohort study. Ann Intern Med 2012;156:438-444. 6. Stewart FA, Heeneman S, Te Poele J, et al. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am J Pathol 2006;168:649-658.
In Regard to Vesprini et al To the Editor: Vesprini et al (1) recently analyzed biochemical failure-free rate (BFFR; American Society for Radiation Oncology definition) and acute toxicity in 362 patients with localized prostate cancer treated with image guided radiation therapy. At 5 years, 76% of patients who reported acute toxicity scores <2 were failure free. In contrast, only 53% of those who reported worse acute toxicity (defined as “sensitive” by the authors) were failure free. Comparable findings were reported when using the Phoenix definition of BFFR. Maybe we should borrow the term “double trouble” to describe this inverse relationship? The difference remained significant when controlled for radiation dose, prognostic stratification, and prostate volume. The
Carsten Nieder, MD Department of Oncology and Palliative Medicine Nordland Hospital Trust Bodø, Norway http://dx.doi.org/10.1016/j.ijrobp.2012.08.009
References 1. Vesprini D, Catton C, Jacks L, et al. Inverse relationship between biochemical outcome and acute toxicity after image-guided radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2012; 83:608-616. 2. Choe KS, Correa D, Jani AB, et al. The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy. Cancer 2010;116:1820-1826. 3. Zaorsky NG, Buyyounouski MK, Li T, et al. Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys 2012;84:e13-e17. 4. Kollmeier MA, Katz MS, Mak K, et al. Improved biochemical outcomes with statin use in patients with high-risk localized prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2011;79:713-718. 5. Gutt R, Tonlaar N, Kunnavakkam R, et al. Statin use and risk of prostate cancer recurrence in men treated with radiation therapy. J Clin Oncol 2010;28:2653-2659. 6. Ostrau C, Hu¨lsenbeck J, Herzog M, et al. Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo. Radiother Oncol 2009; 92:492-499. 7. Wedlake LJ, Silia F, Benton B, et al. Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies. Eur J Cancer 2012;48: 2117-2124. 8. Pickles T, Liu M, Berthelet E, et al. The effect of smoking on outcome following external radiation for localized prostate cancer. J Urol 2004; 171:1543-1546. 9. Alsadius D, Hedelin M, Johansson KA, et al. Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer. Radiother Oncol 2011;101: 495-501.
Radiation Oncology biology
physics
www.redjournal.org
Comments In Regard to Mast et al
References
To the Editor: Mast et al suggest that patients with breast cancer might be at higher risk for coronary artery disease (CAD) as shown by their higher coronary artery calcium (CAC) scores (1). Their findings, however, may be due to chance. We would also be interested in the authors’ opinion of what might be the mechanism behind their finding. The use of CAC scores for cardiovascular screening is controversial in women in particular (2). Patients’ vascular risks should primarily be assessed by the calculation of a global risk score such as the Framingham or the Reynolds score. These scores incorporate multiple, appropriately-weighted cardiac risk factors. Authors listed some of these (eg, age, diabetes, smoking); therefore, it might be possible to calculate such a score in their cohorts. The higher CAC scores found in the study may well be due to higher overall cardiovascular risks in their patients and therefore, the data should be adjusted to their global risks. Calcium scores in the general population have been found to be most helpful in the reclassification of patients with moderately high Framingham risk scores. Otherwise CAC screening increases the chance of having further unnecessary tests without the potential of improving outcomes (3). Elevated high-sensitivity C-reactive protein (hs-CRP) levels have also been shown to improve cardiovascular risk classification (4). As well, in the JUPITER Study elevated hs-CRP levels appeared to identify an apparently healthy population who would benefit from statin therapy (5). Therefore, if the connection between breast cancer and increased cardiovascular risks was found to be true in untreated patients, then hs-CRP levels could potentially provide the link to prevention. However, this hypothesis would need to be tested in an appropriately sized cohort. As the authors pointed out, there is consensus in the literature that left-sided radiation therapy may increase the risk of heart disease. We agree that a systematic, evidence-based approach to estimate preradiation cardiovascular risks as well as an attempt to reduce the long-term complications in a large number of patients with early breast cancer would be prudent.
1. Mast ME, Heijenbrok MW, Petoukhova AL, Scholten AN, Schreur JHM, Struikmans H. Preradiotherapy calcium scores of the coronary arteries in a cohort of women with early-stage breast cancer: a comparison with a cohort of healthy women. Int J Radiat Oncol Biol Phys 2012;83:853-858. 2. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in womend2011 update: a guideline from the American Heart Association. Circulation 2011; 123:1243-1262. 3. Bonow RO. Should coronary calcium screening be used in cardiovascular prevention strategies? N Engl J Med 2009;361:990-997. 4. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843. 5. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
Gabor T. Gyenes, MD, PhD Craig R. Butler, MD, FRCP(C) Mazankowski Alberta Heart Institute (Division of Cardiology) Department of Medicine University of Alberta, Edmonton Alberta, Canada http://dx.doi.org/10.1016/j.ijrobp.2012.06.027
Int J Radiation Oncol Biol Phys, Vol. 85, No. 3, pp. 579e582, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
In Reply to Gyenes and Butler To the Editor: We thank Gyenes and Butler for their interest in our recent publication, and we thank them for confirming the importance of an evidence-based approach to estimate pre-radiation cardiovascular risks and to attempt to reduce the long-term complications of patients who received radiation therapy for breast cancer (1, 2). They raise the question as to which mechanism could be pointed out with respect to the observed higher risk for coronary artery disease in breast cancer. In the literature, a high body mass index (BMI) and a low level of physical activity were defined for the risk of developing breast cancer as well as for the risk of developing coronary artery disease (and heart disease) (3, 4). With regard to a higher BMI, this was found in our cohort as well (1). As Gyenes and Butler point out, the Framingham risk score (FRS) represents a commonly used instrument to predict coronary artery disease. In a recent paper by Kavousi et al, it appeared that the addition of the Coronary Artery Calcium (CAC) scores improved even further the prediction of coronary heart disease based on FRS. This was the case for white women 55 years or older (5). In our Coronary Artery Calcium (CAC) study, we analyzed a group of women with similar characteristics (1). It also appeared that high-sensitivity C-reactive protein (hs-CRP) levels, as studied by Kavousi et al, are a risk marker significantly associated with incidental coronary heart disease after adjustment for traditional risk factors (5). These hs-CRP levels are a marker for inflammation. Stewart et al, in their preclinical study, proposed
580
International Journal of Radiation Oncology Biology Physics
Comments
that irradiation accelerates the development of inflammatory atherosclerotic lesions prone to intraplaque hemorrhage (6). Therefore, we thank Gyenes and Butler for their suggestions, and we will consider incorporating the FRS and the hs-CRP levels in our ongoing studies. M.E. Mast, MSc H. Struikmans, MD, PhD Radiotherapy Centre West The Hague, the Netherlands J.H.M. Schreur, MD, PhD Department of Cardiology Medical Center Haaglanden The Hague, the Netherlands H. Struikmans, MD, PhD Department of Clinical Oncology Leiden University Medical Centre Leiden, the Netherlands http://dx.doi.org/10.1016/j.ijrobp.2012.06.036
authors discussed potential explanations (of note, this was a retrospective study, and unknown confounders might have influenced the results), but several important and different hypotheses not included in the article should also be considered. Many patients with prostate cancer have comorbidities and use different types of prescription drugs. It has been suggested that use of various anticoagulants (2), aspirin (3), and statins (35) might improve biochemical outcomes after radiation therapy. If such drugs also reduce acute toxicity, their use might explain the findings described by Vesprini et al. In fact, these types of effects have already been reported for statins and angiotensinconverting enzyme inhibitors (6, 7). Smoking pattern could provide another potential explanation. As discussed by Pickles et al (8), smoking seems to compromise the outcome after prostate cancer radiation therapy. Moreover, smoking was associated with higher risk of bowel- and anal sphincter-related longterm toxicity (9). Given the fact that a link between acute and late toxicity risks repeatedly has been found, smoking might well result in increased acute and late toxicity and reduced BFFR. Taken together, these intriguing findings offer exciting research opportunities directed at better understanding of the relationship between toxicity and BFFR and ultimately broadening of the therapeutic window.
References 1. Mast ME, Heijenbrok MW, Petoukhova AL, Scholten AN, Schreur JHM, Struikmans H. Preradiotherapy calcium scores of the coronary arteries in a cohort of women with early-stage breast cancer: a comparison with a cohort of healthy women. Int J Radiat Oncol Biol Phys 2012;83:853-858. 2. Gyenes GT, Butler CR. In Regard to Mast et al. Int J Radiat Oncol Biol Phys 2013;85:579. 3. Gast GCM, Frenke FJM, van Leest LATM, et al. Intra-national variation in trends in overweight and leisure time physical activities in the Netherlands since 1980: stratification according to sex, age and urbanisation degree. Int J Obes 2007;31:515-520. 4. McPherson K, Steel CM, Dixon JM. ABC of breast diseases. Breast cancerdepidemiology, risk factors, and genetics. BMJ 2000;321: 624-628. 5. Kavousi M, Elias-Smale S, Rutten JHW, et al. Evaluation of newer risk markers for coronary heart disease risk classification. A cohort study. Ann Intern Med 2012;156:438-444. 6. Stewart FA, Heeneman S, Te Poele J, et al. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am J Pathol 2006;168:649-658.
In Regard to Vesprini et al To the Editor: Vesprini et al (1) recently analyzed biochemical failure-free rate (BFFR; American Society for Radiation Oncology definition) and acute toxicity in 362 patients with localized prostate cancer treated with image guided radiation therapy. At 5 years, 76% of patients who reported acute toxicity scores <2 were failure free. In contrast, only 53% of those who reported worse acute toxicity (defined as “sensitive” by the authors) were failure free. Comparable findings were reported when using the Phoenix definition of BFFR. Maybe we should borrow the term “double trouble” to describe this inverse relationship? The difference remained significant when controlled for radiation dose, prognostic stratification, and prostate volume. The
Carsten Nieder, MD Department of Oncology and Palliative Medicine Nordland Hospital Trust Bodø, Norway http://dx.doi.org/10.1016/j.ijrobp.2012.08.009
References 1. Vesprini D, Catton C, Jacks L, et al. Inverse relationship between biochemical outcome and acute toxicity after image-guided radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2012; 83:608-616. 2. Choe KS, Correa D, Jani AB, et al. The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy. Cancer 2010;116:1820-1826. 3. Zaorsky NG, Buyyounouski MK, Li T, et al. Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys 2012;84:e13-e17. 4. Kollmeier MA, Katz MS, Mak K, et al. Improved biochemical outcomes with statin use in patients with high-risk localized prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2011;79:713-718. 5. Gutt R, Tonlaar N, Kunnavakkam R, et al. Statin use and risk of prostate cancer recurrence in men treated with radiation therapy. J Clin Oncol 2010;28:2653-2659. 6. Ostrau C, Hu¨lsenbeck J, Herzog M, et al. Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo. Radiother Oncol 2009; 92:492-499. 7. Wedlake LJ, Silia F, Benton B, et al. Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies. Eur J Cancer 2012;48: 2117-2124. 8. Pickles T, Liu M, Berthelet E, et al. The effect of smoking on outcome following external radiation for localized prostate cancer. J Urol 2004; 171:1543-1546. 9. Alsadius D, Hedelin M, Johansson KA, et al. Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer. Radiother Oncol 2011;101: 495-501.