Letters
opacities (ICD-9-CM code 366.0) as distinct from senile cataract (ICD-9-CM code 366.1) without providing an anatomical definition. Furthermore, ophthalmic diagnosis of cataract may vary by the technique of examination as well as the observer’s threshold for calling lens changes a cataract. One man’s cataract is another’s minor opacity. All of this is to say that cataract as a single generic outcome is not uniformly described, and finding specific and consistently identified risk or protective factors when there is such phenotypic heterogeneity is likely to be difficult. Another issue with outcome definition that is often overlooked is the timing of the cataract after risk exposure and the appropriate duration of follow-up. Many studies ignore the timing aspect because it is quite difficult to assess, especially for observational studies with outcomes that often do not have a clear-cut incidence. However, keeping some aspect of timing in mind is important when comparing results across studies. It is important to consider the latency period from the risk exposure to observation of the outcome. Some studies follow up with patients for 5 years, while others follow up with patients for 20 years. Is 5 years following an exposure enough time to follow up with a patient before cataract development can be attributed to the exposure and not just be a result of the other lifestyle factors or comorbidities that existed prior to statin exposure? Changes in outcome following exposure may be better, but these are very difficult to measure in observational studies, especially those using database mining. Much more needs to be understood about cataract development, the timing of exposure, and whether the exposure interacts with age. These difficult questions can best be addressed by clinical trials. Acknowledging how the different studies address the timing may help to evaluate why studies give inconsistent results. The characteristics of the population and the adjustment approaches are other considerations when comparing results among different studies. Leuschen and colleagues used data from a military population. It is unclear how this population may differ from a general clinic-based or population-based study that could affect the statin association, but more important is the approach used for adjustment of confounders. Matching the propensity score may exclude an important portion of the population; the matched set is then not representative of the whole population. In any study, inclusion of factors that influence exposure and outcome is important. Drawing again from the article by Leuschen and colleagues, it is very difficult, if not impossible, to separate the impact of long-term high levels of serum total cholesterol exposure from the potential effects of statin use for the development of cataract. The attenuation of the odds ratio in that article for the effect of statin use on all cataract when low-density lipoprotein cholesterol level was included in the model may be related to a beneficial effect of statins. It seems likely that the odds ratio for nonsecondary cataract, likely the group of greatest interest, was not significant and therefore not reported. While the study by Leuschen and colleagues suggests risks for age-related cataracts due to statin use, we must evaluate this study along with the other evidence from the many different studies using varying analytic techniques and defini-
tions of this potential relationship. We should encourage welldefined and uniform diagnostic criteria for outcomes and relevant exposures with appropriate and adequate quality control before suggesting that common outcome is causally related to a common exposure. Understanding the nature and strength of the association between statin use and cataract is of interest to eye care providers and primary care providers as well as researchers.2 In view of the benefits of statins for those at high risk for cardiovascular disease, such risk must be balanced against potential effects on lens opacities, which are not life threatening and can be successfully treated. An objective assessment of the true effects of statins on the lens could be incorporated into a clinical trial designed to evaluate the many potential benefits and risks of statins (including cataract types) as suggested by Ioannidis.3 We support this. Barbara E. K. Klein, MD, MPH Kristine E. Lee, MS Ronald Klein, MD, MPH Author Affiliations: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin–Madison, Madison. Corresponding Author: Barbara E. K. Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin–Madison, 610 N Walnut St, Fourth Floor, WARF, Madison, WI 53726 ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grant EY06594 from the National Institutes of Health (Drs B. E. K. Klein and R. Klein) and an unrestricted grant from Research to Prevent Blindness. Role of the Sponsor: The funders had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Disclaimer: The content of this commentary is solely the responsibility of the authors and does not necessarily reflect the official views of the National Eye Institute or the National Institutes of Health. REFERENCES 1. Leuschen J, Mortensen EM, Frei CR, Mansi EA, Panday V, Mansi I. Association of statin use with cataracts: a propensity score-matched analysis. JAMA Ophthalmol. 2013;131(11):1427-1434. 2. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. 3. Ioannidis JPA. More than a billion people taking statins? potential implications of the new cardiovascular guidelines [published online December 2, 2013]. JAMA. doi:10.1001/jama.2013.284657.
Regarding Stereotactic Radiosurgery for Uveal Melanoma To the Editor It was with great interest that we read the article by Suesskind et al titled “Retrospective Evaluation of Patients With Uveal Melanoma Treated by Stereotactic Radiosurgery With and Without Tumor Resection.”1 The authors describe their institutional experience of treating uveal melanoma with linear accelerator–based single-dose stereotactic radiotherapy (SDRT). There is suggestion in the article that theirs is the first report of using SDRT for the treatment of uveal melanoma. While their results are encouraging and certainly additive to the paucity of existing literature regarding linear accelerator–based SDRT, the first report in this specific area was actually by Furdova et al in an article titled “One-Day Session
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Letters
LINAC-Based Stereotactic Radiosurgery of Posterior Uveal Melanoma.”2 It is worth recognizing the original contribution by Furdova and colleagues and reviewing their article to further explore the role of SDRT for uveal melanoma. Joshua T. McKenzie, MD Michelle L. Mierzwa, MD Author Affiliations: Department of Radiation Oncology, Barrett Cancer Center, University of Cincinnati, Cincinnati, Ohio. Corresponding Author: Joshua T. McKenzie, MD, Department of Radiation Oncology, Barrett Cancer Center, University of Cincinnati, 234 Goodman St, ML 0757, Cincinnati, OH 45267 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Suesskind D, Scheiderbauer J, Buchgeister M, et al. Retrospective evaluation of patients with uveal melanoma treated by stereotactic radiosurgery with and without tumor resection. JAMA Ophthalmol. 2013;131(5):630-637. 2. Furdova A, Strmen P, Waczulikova I, Chorvath M, Sramka M, Slezak P. One-day session LINAC-based stereotactic radiosurgery of posterior uveal melanoma. Eur J Ophthalmol. 2012;22(2):226-235.
In Reply We thank McKenzie and Mierzwa for pointing to the article by Furdova et al,1 who also evaluated linear accelerator–based stereotactic radiosurgery (SRS) of uveal melanoma (UM). We had not seen their March-April 2012 issue when our manuscript was submitted in April 2012. Furdova et al treated 39 patients between 2001 and 2008 and our study included 78 patients between 2003 and 2008, indicating that experiences with SRS were collected during a comparable treatment period.1,2 Our treatment approach was not based on the experiences of Furdova et al, and we compared SRS as monotherapy vs planned combined SRS and tumor resection. Nonetheless, we apologize for the failure of not considering their results and certainly would like to comment on their work on SRS of UM. The authors followed a different treatment approach using 35 Gy as the tumor-surrounding dose and a mechanical fixation of the eye to the stereotactic frame to immobilize the patient’s eye. The decision parameter for the various second treatment modalities in their article is not described, so it is not clear whether combined treatment is performed as the primary approach (as in our group 2) or as salvage therapy. Additionally, juxtapapillary tumors were excluded,1 but they were a key aspect in our collective data. Furdova et al primarily looked at
368
the visual results, which were not the main outcome in our study. Nevertheless, both articles noted a significant decline in visual acuity. Only 1 of 39 patients treated by Furdova et al had a posttreatment visual acuity of 20/40 or better,1 which was similar to the 4 patients in our study group.2 Tumor regression was seen in 75% of small UMs and 27% of UMs up to 8 mm in height, and large UMs did not show tumor regression.1 The number of recurrences was not addressed. Enucleation was performed in 20% of eyes after SRS as a single treatment without mentioning the reason for eye loss.1 A comparable percentage of enucleations in our group 1 (SDRT monotherapy) was found.2 In 50% of patients treated by Furdova et al with SRS plus endoresection or cyclectomy and transpupillary thermotherapy or brachytherapy after endoresection, enucleation was necessary because of secondary neovascular glaucoma or tumor relapse.1 Only 17% of eyes were enucleated in our group 2 (combined therapy).2 A compilation of the radiation complications was not provided by Furdova et al. Salvage as a reason for the second treatment modality might explain their higher enucleation rate. As different UM characteristics are included and given that our analysis was based on the primary treatment plan, the subgroup results do not seem comparable. For a better comparison of both studies, detailed information of the proportion of tumor resections and the timing would be necessary. We can conclude that using 25 Gy as the tumor-surrounding dose and a functional immobilization device for SDRT seems to achieve results similar to those reported by Furdova et al. Daniela Suesskind, MD Frank Paulsen, MD Author Affiliations: Center for Ophthalmology, Eberhard Karls University Tuebingen, Tuebingen, Germany (Suesskind); Department of Radiation Oncology, Eberhard Karls University Tuebingen, Tuebingen, Germany (Paulsen). Corresponding Author: Daniela Suesskind, MD, Center for Ophthalmology, Schleichstrasse 12-16, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany ([email protected]). Conflict of Interest Disclosures: None reported. 1. Furdova A, Strmen P, Waczulikova I, Chorvath M, Sramka M, Slezak P. One-day session LINAC-based stereotactic radiosurgery of posterior uveal melanoma. Eur J Ophthalmol. 2012;22(2):226-235. 2. Suesskind D, Scheiderbauer J, Buchgeister M, et al. Retrospective evaluation of patients with uveal melanoma treated by stereotactic radiosurgery with and without tumor resection. JAMA Ophthalmol. 2013;131(5):630-637.
JAMA Ophthalmology March 2014 Volume 132, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 06/01/2015
jamaophthalmology.com
opacities (ICD-9-CM code 366.0) as distinct from senile cataract (ICD-9-CM code 366.1) without providing an anatomical definition. Furthermore, ophthalmic diagnosis of cataract may vary by the technique of examination as well as the observer’s threshold for calling lens changes a cataract. One man’s cataract is another’s minor opacity. All of this is to say that cataract as a single generic outcome is not uniformly described, and finding specific and consistently identified risk or protective factors when there is such phenotypic heterogeneity is likely to be difficult. Another issue with outcome definition that is often overlooked is the timing of the cataract after risk exposure and the appropriate duration of follow-up. Many studies ignore the timing aspect because it is quite difficult to assess, especially for observational studies with outcomes that often do not have a clear-cut incidence. However, keeping some aspect of timing in mind is important when comparing results across studies. It is important to consider the latency period from the risk exposure to observation of the outcome. Some studies follow up with patients for 5 years, while others follow up with patients for 20 years. Is 5 years following an exposure enough time to follow up with a patient before cataract development can be attributed to the exposure and not just be a result of the other lifestyle factors or comorbidities that existed prior to statin exposure? Changes in outcome following exposure may be better, but these are very difficult to measure in observational studies, especially those using database mining. Much more needs to be understood about cataract development, the timing of exposure, and whether the exposure interacts with age. These difficult questions can best be addressed by clinical trials. Acknowledging how the different studies address the timing may help to evaluate why studies give inconsistent results. The characteristics of the population and the adjustment approaches are other considerations when comparing results among different studies. Leuschen and colleagues used data from a military population. It is unclear how this population may differ from a general clinic-based or population-based study that could affect the statin association, but more important is the approach used for adjustment of confounders. Matching the propensity score may exclude an important portion of the population; the matched set is then not representative of the whole population. In any study, inclusion of factors that influence exposure and outcome is important. Drawing again from the article by Leuschen and colleagues, it is very difficult, if not impossible, to separate the impact of long-term high levels of serum total cholesterol exposure from the potential effects of statin use for the development of cataract. The attenuation of the odds ratio in that article for the effect of statin use on all cataract when low-density lipoprotein cholesterol level was included in the model may be related to a beneficial effect of statins. It seems likely that the odds ratio for nonsecondary cataract, likely the group of greatest interest, was not significant and therefore not reported. While the study by Leuschen and colleagues suggests risks for age-related cataracts due to statin use, we must evaluate this study along with the other evidence from the many different studies using varying analytic techniques and defini-
tions of this potential relationship. We should encourage welldefined and uniform diagnostic criteria for outcomes and relevant exposures with appropriate and adequate quality control before suggesting that common outcome is causally related to a common exposure. Understanding the nature and strength of the association between statin use and cataract is of interest to eye care providers and primary care providers as well as researchers.2 In view of the benefits of statins for those at high risk for cardiovascular disease, such risk must be balanced against potential effects on lens opacities, which are not life threatening and can be successfully treated. An objective assessment of the true effects of statins on the lens could be incorporated into a clinical trial designed to evaluate the many potential benefits and risks of statins (including cataract types) as suggested by Ioannidis.3 We support this. Barbara E. K. Klein, MD, MPH Kristine E. Lee, MS Ronald Klein, MD, MPH Author Affiliations: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin–Madison, Madison. Corresponding Author: Barbara E. K. Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin–Madison, 610 N Walnut St, Fourth Floor, WARF, Madison, WI 53726 ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grant EY06594 from the National Institutes of Health (Drs B. E. K. Klein and R. Klein) and an unrestricted grant from Research to Prevent Blindness. Role of the Sponsor: The funders had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Disclaimer: The content of this commentary is solely the responsibility of the authors and does not necessarily reflect the official views of the National Eye Institute or the National Institutes of Health. REFERENCES 1. Leuschen J, Mortensen EM, Frei CR, Mansi EA, Panday V, Mansi I. Association of statin use with cataracts: a propensity score-matched analysis. JAMA Ophthalmol. 2013;131(11):1427-1434. 2. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. 3. Ioannidis JPA. More than a billion people taking statins? potential implications of the new cardiovascular guidelines [published online December 2, 2013]. JAMA. doi:10.1001/jama.2013.284657.
Regarding Stereotactic Radiosurgery for Uveal Melanoma To the Editor It was with great interest that we read the article by Suesskind et al titled “Retrospective Evaluation of Patients With Uveal Melanoma Treated by Stereotactic Radiosurgery With and Without Tumor Resection.”1 The authors describe their institutional experience of treating uveal melanoma with linear accelerator–based single-dose stereotactic radiotherapy (SDRT). There is suggestion in the article that theirs is the first report of using SDRT for the treatment of uveal melanoma. While their results are encouraging and certainly additive to the paucity of existing literature regarding linear accelerator–based SDRT, the first report in this specific area was actually by Furdova et al in an article titled “One-Day Session
jamaophthalmology.com
JAMA Ophthalmology March 2014 Volume 132, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 06/01/2015
367
Letters
LINAC-Based Stereotactic Radiosurgery of Posterior Uveal Melanoma.”2 It is worth recognizing the original contribution by Furdova and colleagues and reviewing their article to further explore the role of SDRT for uveal melanoma. Joshua T. McKenzie, MD Michelle L. Mierzwa, MD Author Affiliations: Department of Radiation Oncology, Barrett Cancer Center, University of Cincinnati, Cincinnati, Ohio. Corresponding Author: Joshua T. McKenzie, MD, Department of Radiation Oncology, Barrett Cancer Center, University of Cincinnati, 234 Goodman St, ML 0757, Cincinnati, OH 45267 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Suesskind D, Scheiderbauer J, Buchgeister M, et al. Retrospective evaluation of patients with uveal melanoma treated by stereotactic radiosurgery with and without tumor resection. JAMA Ophthalmol. 2013;131(5):630-637. 2. Furdova A, Strmen P, Waczulikova I, Chorvath M, Sramka M, Slezak P. One-day session LINAC-based stereotactic radiosurgery of posterior uveal melanoma. Eur J Ophthalmol. 2012;22(2):226-235.
In Reply We thank McKenzie and Mierzwa for pointing to the article by Furdova et al,1 who also evaluated linear accelerator–based stereotactic radiosurgery (SRS) of uveal melanoma (UM). We had not seen their March-April 2012 issue when our manuscript was submitted in April 2012. Furdova et al treated 39 patients between 2001 and 2008 and our study included 78 patients between 2003 and 2008, indicating that experiences with SRS were collected during a comparable treatment period.1,2 Our treatment approach was not based on the experiences of Furdova et al, and we compared SRS as monotherapy vs planned combined SRS and tumor resection. Nonetheless, we apologize for the failure of not considering their results and certainly would like to comment on their work on SRS of UM. The authors followed a different treatment approach using 35 Gy as the tumor-surrounding dose and a mechanical fixation of the eye to the stereotactic frame to immobilize the patient’s eye. The decision parameter for the various second treatment modalities in their article is not described, so it is not clear whether combined treatment is performed as the primary approach (as in our group 2) or as salvage therapy. Additionally, juxtapapillary tumors were excluded,1 but they were a key aspect in our collective data. Furdova et al primarily looked at
368
the visual results, which were not the main outcome in our study. Nevertheless, both articles noted a significant decline in visual acuity. Only 1 of 39 patients treated by Furdova et al had a posttreatment visual acuity of 20/40 or better,1 which was similar to the 4 patients in our study group.2 Tumor regression was seen in 75% of small UMs and 27% of UMs up to 8 mm in height, and large UMs did not show tumor regression.1 The number of recurrences was not addressed. Enucleation was performed in 20% of eyes after SRS as a single treatment without mentioning the reason for eye loss.1 A comparable percentage of enucleations in our group 1 (SDRT monotherapy) was found.2 In 50% of patients treated by Furdova et al with SRS plus endoresection or cyclectomy and transpupillary thermotherapy or brachytherapy after endoresection, enucleation was necessary because of secondary neovascular glaucoma or tumor relapse.1 Only 17% of eyes were enucleated in our group 2 (combined therapy).2 A compilation of the radiation complications was not provided by Furdova et al. Salvage as a reason for the second treatment modality might explain their higher enucleation rate. As different UM characteristics are included and given that our analysis was based on the primary treatment plan, the subgroup results do not seem comparable. For a better comparison of both studies, detailed information of the proportion of tumor resections and the timing would be necessary. We can conclude that using 25 Gy as the tumor-surrounding dose and a functional immobilization device for SDRT seems to achieve results similar to those reported by Furdova et al. Daniela Suesskind, MD Frank Paulsen, MD Author Affiliations: Center for Ophthalmology, Eberhard Karls University Tuebingen, Tuebingen, Germany (Suesskind); Department of Radiation Oncology, Eberhard Karls University Tuebingen, Tuebingen, Germany (Paulsen). Corresponding Author: Daniela Suesskind, MD, Center for Ophthalmology, Schleichstrasse 12-16, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany ([email protected]). Conflict of Interest Disclosures: None reported. 1. Furdova A, Strmen P, Waczulikova I, Chorvath M, Sramka M, Slezak P. One-day session LINAC-based stereotactic radiosurgery of posterior uveal melanoma. Eur J Ophthalmol. 2012;22(2):226-235. 2. Suesskind D, Scheiderbauer J, Buchgeister M, et al. Retrospective evaluation of patients with uveal melanoma treated by stereotactic radiosurgery with and without tumor resection. JAMA Ophthalmol. 2013;131(5):630-637.
JAMA Ophthalmology March 2014 Volume 132, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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