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Top Ten Clinical Research Downloads of 2011
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Top Ten Clinical Research Downloads of 2011 By Anthony Zietman, MD, Editor in Chief In medicine, when we wish to assess the importance of a specific paper we have traditionally done so by solemnly counting literature citations over the subsequent years. This method tends toward a rather academic bias with a dry and unemotional approach, often taking a long time to yield its opinions. If we want to take a more immediate check on what speaks to the hearts and minds of our readers, we can do no better than look at which articles they are downloading. Most physicians these days speedily download articles that interest them to read and reference later. Even if they never read them, the act of downloading is a measure of interest. An analysis of download numbers for individual papers is like taking the specialty’s pulse. You can see what makes it race and what leaves it unmoved. Earlier this year, I described the top 10 downloaded articles of 2011 (1). Many of these were practice guidelines which illustrated the desire of the field to practice within a defined, evidence-based framework. Several others were anatomic atlases revealing the thirst to learn the radiology that underlies image guided therapy. But, excluding these, which were the most downloaded original clinical research manuscripts? What novel work excited radiation oncologists beyond the desire to simply practice safely? These are the subject of this article and they tell a different story. The top 10 clinical research papers unsurprisingly reflect the practice of a contemporary radiation oncologist who treats prostate, breast, lung, head and neck, and central nervous system tumors. They describe new technologies, better cancer control, and the management of morbidity. They also utilize the best techniques of modern clinical investigation and most are welldesigned prospective studies, several of which are randomized. It seems that readers have a nose for the quality studies that will shape future practice. In the realm of prostate cancer, 2 randomized trials of dose escalation rose to the top. The first is the initial report of a French study by Beckendorf et al that compared 80 Gy with 70 Gy, both delivered by 3-dimensional (3D) conformal therapy (2). At 5 years, a biochemical control advantage was reported, confirming what had been described in other studies. The second was an update of the University of Texas MD Anderson Cancer Center (MDACC) randomized trial comparing 78 Gy with 70 Gy (3). This trial now has a median of 8.7 years of follow-up and the biochemical advantage seen
at 5 years is starting to “progress” into an advantage in terms of freedom from clinical events. Survival gains have yet to be seen. The MDACC trial was actually printed in the Red Journal in 2008, yet it continues to be one of the top downloaded papers 3 years later, a testament to its enduring importance. The desire to deliver high-dose radiation to the prostate by safer or more convenient means is demonstrated by the other 3 “top 10” prostate articles. Martinez described a large mature series of intermediate- and high-risk patients treated with pelvic external beam radiation therapy, followed by 1 of 2 dose levels of hypofractionated high-dose-rate (HDR) brachytherapy (4). Again, higher doses produced lower rates of biochemical relapse at 10 years and thus, presumably, a lower need for additional treatments. Barney et al systematically compared the 2 most common techniques for image guidance of high-dose prostate radiation: fiducial markers and cone beam computed tomography (CT) (5). Their data suggested that kV imaging of fiducial markers carries less uncertainty than low-resolution cone beam CT. Most provocatively, there was considerable interest in the report by King et al of the efficacy of stereotactic body radiation therapy (SBRT) in low-risk prostate cancer (6). Here the technical advances of image guidance are combined with the inferences drawn from the use of hypofractionated HDR and the new models of prostate radiobiology. King’s meticulously followed cohort, at this early stage, appears to have acceptable morbidity and gratifying PSA declines. Randomized trials are now underway to definitively test this hypothesis. SBRT remains a hot treatment in lung cancer and the small but mature series of stage I non-small cell lung cancer (NSCLC) reported by Onishi et al drew much interest (7). The eye-catching 5year local control rates for T1 disease of 92% are difficult to ignore and practice is changing rapidly across the world. I expect similar papers, especially those that sharpen the clinical indications and the technical demands of this technique, to be heavily downloaded through 2012. Breast cancer was represented by the work of Chan et al’s University of California, San Francisco team that followed 55 women who had close margins after a mastectomy for ductal carcinoma in situ (DCIS) without receiving chest wall radiation (8). The risk of chest wall recurrence in this series of patients is 1.7% for all patients and 3.3% for high grade DCIS.
Int J Radiation Oncol Biol Phys, Vol. 84, No. 4, pp. 869e870, 2012 0360-3016/$ - see front matter Ó 2012 . Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/S0360-3016(12)03630-9
870
Oncology Scan
International Journal of Radiation Oncology Biology Physics
Top 10 Clinical Downloads of 2011 Rank 1 2 3 4 5 6 7 8 9 10
Article title Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System. Concurrent Cisplatin and Radiation Versus Cetuximab and Radiation for Locally Advanced Head-and-Neck Cancer. Image-Guided Radiotherapy (IGRT) for rostate Cancer Comparing kV Imaging of Fiducial Markers With Cone Beam Computed Tomography. Long-Term Results of the M.D. Anderson Randomized Dose-Escalation Trial for Prostate Cancer. 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial. Stereotactic Body Radiotherapy (SBRT) for Operable Stage I Non-Small-Cell Lung Cancer: Can SBRT Be Comparable to Surgery? Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins? Dose Escalation Improves Cancer-Related Events at 10 Years for Intermediate- and High-Risk Prostate Cancer Patients Treated With Hypofractionated High-Dose-Rate Boost and External Beam Radiotherapy. Long-Term Outcomes from a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer. A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.
This risk of a chest wall recurrence appeared insufficient to warrant a recommendation for post-mastectomy radiation therapy for those with margins of less than 5 mm. This is an important and practice-defining study. Radiation oncologists want to know not only when they should irradiate but also when they should not. The interest in combining radiation with molecular-targeted agents continues to grow. Koutcher et al reported a study of locally advanced head-and-neck cancer patients in which some had received platinum with their radiation while others received C225 (9). Those receiving radiation achieved better loco-regional control, failure-free survival, and overall survival. This study, though retrospective in nature, reminds us that not every new agent is “a winner” and that conventional, well-understood agents should not be neglected. Another time-honored and not to be neglected modulation of radiation therapy comes through altered fractionation. The report of RTOG 9003 by Fu et al was published in the Red Journal in 2000 and still, in 2011, it is among the top 10 clinical downloads (10). The recognition that accelerated fractionation, and particularly concomitant boost, is more efficacious than conventional fractionation continues to reverberate over a decade later. It is finding new importance as we struggle to combine radiation with systemic agents in a way that synergizes anticancer activity but does not exceed acute tolerance. The final member of the elite class of 2011 was, perhaps, the smallest yet the most positive randomized trial I have ever seen. Patients with radiographic- or biopsy-proven central nervous system necrosis and neurologic symptoms were randomized to receive either intravenous saline or bevacizumab in a trial with a crossover design (11). After just 14 patients, the outcome was clear. All bevacizumab-treated patients, and none of the placebotreated patients, showed improvement in neurologic symptoms or signs coupled with radiographic improvement. Statistics were simply unnecessary. It remains unclear what the impact will be on practice because bevacizumab is such a costly drug. This study illuminates the tension between clinical benefit and healthcare economics of which much will be written in the years ahead.
References 1. Zietman AL. The Red Journal’s Top 10 Most Downloaded Articles of 2011. Int J Radiat Oncol Biol Phys. 2012;83(4):1073-1074. 2. Beckendorf V, Guerif S, Le Prise´ E, et al. 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial. Int J Radiat Oncol Biol Phys. 2011;80(4):1056-1063. 3. Kuban DA, Tucker SL, Dong L, et al. Long-Term Results of the M.D. Anderson Randomized Dose-Escalation Trial for Prostate Cancer. Int J Radiat Oncol Biol Phys. 2008;70(1):67-74. 4. Martinez AA, Gonzalez J, Ye H, et al. Dose Escalation Improves Cancer-Related Events at 10 Years for Intermediate- and High-Risk Prostate Cancer Patients Treated With Hypofractionated High-DoseRate Boost and External Beam Radiotherapy. Int J Radiat Oncol Biol Phys. 2011;79(2):363-370. 5. Barney BM, Lee RJ, Handrahan D, et al. Image-Guided Radiotherapy (IGRT) for Prostate Cancer Comparing kV Imaging of Fiducial Markers With Cone Beam Computed Tomography. Int J Radiat Oncol Biol Phys. 2011;80(1):301-305. 6. King CR, Brooks JD, Gill H, et al. Long-Term Outcomes from a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2012;82(2):877-882. 7. Onishi H, Shirato H, Nagata Y, et al. Stereotactic Body Radiotherapy (SBRT) for Operable Stage I Non-Small-Cell Lung Cancer: Can SBRT Be Comparable to Surgery? Int J Radiat Oncol Biol Phys. 2011;81(5): 1352-1358. 8. Chan LW, Rabban J, Hwang ES, et al. Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins? Int J Radiat Oncol Biol Phys. 2011;80(1):25-30. 9. Koutcher L, Sherman E, Fury M, et al. Concurrent Cisplatin and Radiation Versus Cetuximab and Radiation for Locally Advanced Head-and-Neck Cancer. Int J Radiat Oncol Biol Phys. 2011;81(4): 915-922. 10. Fu KK, Pajak TF, Trotti A, et al. A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48(1):7-16. 11. Levin VA, Bidaut L, Hou P, et al. Randomized Double-Blind PlaceboControlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System. Int J Radiat Oncol Biol Phys. 2011; 79(5):1487-1495.
Radiation Oncology biology
physics
www.redjournal.org
Top Ten Clinical Research Downloads of 2011 By Anthony Zietman, MD, Editor in Chief In medicine, when we wish to assess the importance of a specific paper we have traditionally done so by solemnly counting literature citations over the subsequent years. This method tends toward a rather academic bias with a dry and unemotional approach, often taking a long time to yield its opinions. If we want to take a more immediate check on what speaks to the hearts and minds of our readers, we can do no better than look at which articles they are downloading. Most physicians these days speedily download articles that interest them to read and reference later. Even if they never read them, the act of downloading is a measure of interest. An analysis of download numbers for individual papers is like taking the specialty’s pulse. You can see what makes it race and what leaves it unmoved. Earlier this year, I described the top 10 downloaded articles of 2011 (1). Many of these were practice guidelines which illustrated the desire of the field to practice within a defined, evidence-based framework. Several others were anatomic atlases revealing the thirst to learn the radiology that underlies image guided therapy. But, excluding these, which were the most downloaded original clinical research manuscripts? What novel work excited radiation oncologists beyond the desire to simply practice safely? These are the subject of this article and they tell a different story. The top 10 clinical research papers unsurprisingly reflect the practice of a contemporary radiation oncologist who treats prostate, breast, lung, head and neck, and central nervous system tumors. They describe new technologies, better cancer control, and the management of morbidity. They also utilize the best techniques of modern clinical investigation and most are welldesigned prospective studies, several of which are randomized. It seems that readers have a nose for the quality studies that will shape future practice. In the realm of prostate cancer, 2 randomized trials of dose escalation rose to the top. The first is the initial report of a French study by Beckendorf et al that compared 80 Gy with 70 Gy, both delivered by 3-dimensional (3D) conformal therapy (2). At 5 years, a biochemical control advantage was reported, confirming what had been described in other studies. The second was an update of the University of Texas MD Anderson Cancer Center (MDACC) randomized trial comparing 78 Gy with 70 Gy (3). This trial now has a median of 8.7 years of follow-up and the biochemical advantage seen
at 5 years is starting to “progress” into an advantage in terms of freedom from clinical events. Survival gains have yet to be seen. The MDACC trial was actually printed in the Red Journal in 2008, yet it continues to be one of the top downloaded papers 3 years later, a testament to its enduring importance. The desire to deliver high-dose radiation to the prostate by safer or more convenient means is demonstrated by the other 3 “top 10” prostate articles. Martinez described a large mature series of intermediate- and high-risk patients treated with pelvic external beam radiation therapy, followed by 1 of 2 dose levels of hypofractionated high-dose-rate (HDR) brachytherapy (4). Again, higher doses produced lower rates of biochemical relapse at 10 years and thus, presumably, a lower need for additional treatments. Barney et al systematically compared the 2 most common techniques for image guidance of high-dose prostate radiation: fiducial markers and cone beam computed tomography (CT) (5). Their data suggested that kV imaging of fiducial markers carries less uncertainty than low-resolution cone beam CT. Most provocatively, there was considerable interest in the report by King et al of the efficacy of stereotactic body radiation therapy (SBRT) in low-risk prostate cancer (6). Here the technical advances of image guidance are combined with the inferences drawn from the use of hypofractionated HDR and the new models of prostate radiobiology. King’s meticulously followed cohort, at this early stage, appears to have acceptable morbidity and gratifying PSA declines. Randomized trials are now underway to definitively test this hypothesis. SBRT remains a hot treatment in lung cancer and the small but mature series of stage I non-small cell lung cancer (NSCLC) reported by Onishi et al drew much interest (7). The eye-catching 5year local control rates for T1 disease of 92% are difficult to ignore and practice is changing rapidly across the world. I expect similar papers, especially those that sharpen the clinical indications and the technical demands of this technique, to be heavily downloaded through 2012. Breast cancer was represented by the work of Chan et al’s University of California, San Francisco team that followed 55 women who had close margins after a mastectomy for ductal carcinoma in situ (DCIS) without receiving chest wall radiation (8). The risk of chest wall recurrence in this series of patients is 1.7% for all patients and 3.3% for high grade DCIS.
Int J Radiation Oncol Biol Phys, Vol. 84, No. 4, pp. 869e870, 2012 0360-3016/$ - see front matter Ó 2012 . Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/S0360-3016(12)03630-9
870
Oncology Scan
International Journal of Radiation Oncology Biology Physics
Top 10 Clinical Downloads of 2011 Rank 1 2 3 4 5 6 7 8 9 10
Article title Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System. Concurrent Cisplatin and Radiation Versus Cetuximab and Radiation for Locally Advanced Head-and-Neck Cancer. Image-Guided Radiotherapy (IGRT) for rostate Cancer Comparing kV Imaging of Fiducial Markers With Cone Beam Computed Tomography. Long-Term Results of the M.D. Anderson Randomized Dose-Escalation Trial for Prostate Cancer. 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial. Stereotactic Body Radiotherapy (SBRT) for Operable Stage I Non-Small-Cell Lung Cancer: Can SBRT Be Comparable to Surgery? Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins? Dose Escalation Improves Cancer-Related Events at 10 Years for Intermediate- and High-Risk Prostate Cancer Patients Treated With Hypofractionated High-Dose-Rate Boost and External Beam Radiotherapy. Long-Term Outcomes from a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer. A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.
This risk of a chest wall recurrence appeared insufficient to warrant a recommendation for post-mastectomy radiation therapy for those with margins of less than 5 mm. This is an important and practice-defining study. Radiation oncologists want to know not only when they should irradiate but also when they should not. The interest in combining radiation with molecular-targeted agents continues to grow. Koutcher et al reported a study of locally advanced head-and-neck cancer patients in which some had received platinum with their radiation while others received C225 (9). Those receiving radiation achieved better loco-regional control, failure-free survival, and overall survival. This study, though retrospective in nature, reminds us that not every new agent is “a winner” and that conventional, well-understood agents should not be neglected. Another time-honored and not to be neglected modulation of radiation therapy comes through altered fractionation. The report of RTOG 9003 by Fu et al was published in the Red Journal in 2000 and still, in 2011, it is among the top 10 clinical downloads (10). The recognition that accelerated fractionation, and particularly concomitant boost, is more efficacious than conventional fractionation continues to reverberate over a decade later. It is finding new importance as we struggle to combine radiation with systemic agents in a way that synergizes anticancer activity but does not exceed acute tolerance. The final member of the elite class of 2011 was, perhaps, the smallest yet the most positive randomized trial I have ever seen. Patients with radiographic- or biopsy-proven central nervous system necrosis and neurologic symptoms were randomized to receive either intravenous saline or bevacizumab in a trial with a crossover design (11). After just 14 patients, the outcome was clear. All bevacizumab-treated patients, and none of the placebotreated patients, showed improvement in neurologic symptoms or signs coupled with radiographic improvement. Statistics were simply unnecessary. It remains unclear what the impact will be on practice because bevacizumab is such a costly drug. This study illuminates the tension between clinical benefit and healthcare economics of which much will be written in the years ahead.
References 1. Zietman AL. The Red Journal’s Top 10 Most Downloaded Articles of 2011. Int J Radiat Oncol Biol Phys. 2012;83(4):1073-1074. 2. Beckendorf V, Guerif S, Le Prise´ E, et al. 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial. Int J Radiat Oncol Biol Phys. 2011;80(4):1056-1063. 3. Kuban DA, Tucker SL, Dong L, et al. Long-Term Results of the M.D. Anderson Randomized Dose-Escalation Trial for Prostate Cancer. Int J Radiat Oncol Biol Phys. 2008;70(1):67-74. 4. Martinez AA, Gonzalez J, Ye H, et al. Dose Escalation Improves Cancer-Related Events at 10 Years for Intermediate- and High-Risk Prostate Cancer Patients Treated With Hypofractionated High-DoseRate Boost and External Beam Radiotherapy. Int J Radiat Oncol Biol Phys. 2011;79(2):363-370. 5. Barney BM, Lee RJ, Handrahan D, et al. Image-Guided Radiotherapy (IGRT) for Prostate Cancer Comparing kV Imaging of Fiducial Markers With Cone Beam Computed Tomography. Int J Radiat Oncol Biol Phys. 2011;80(1):301-305. 6. King CR, Brooks JD, Gill H, et al. Long-Term Outcomes from a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2012;82(2):877-882. 7. Onishi H, Shirato H, Nagata Y, et al. Stereotactic Body Radiotherapy (SBRT) for Operable Stage I Non-Small-Cell Lung Cancer: Can SBRT Be Comparable to Surgery? Int J Radiat Oncol Biol Phys. 2011;81(5): 1352-1358. 8. Chan LW, Rabban J, Hwang ES, et al. Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins? Int J Radiat Oncol Biol Phys. 2011;80(1):25-30. 9. Koutcher L, Sherman E, Fury M, et al. Concurrent Cisplatin and Radiation Versus Cetuximab and Radiation for Locally Advanced Head-and-Neck Cancer. Int J Radiat Oncol Biol Phys. 2011;81(4): 915-922. 10. Fu KK, Pajak TF, Trotti A, et al. A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48(1):7-16. 11. Levin VA, Bidaut L, Hou P, et al. Randomized Double-Blind PlaceboControlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System. Int J Radiat Oncol Biol Phys. 2011; 79(5):1487-1495.