VOLUME 31 䡠 NUMBER 36 䡠 DECEMBER 20 2013
JOURNAL OF CLINICAL ONCOLOGY
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Improved Cosmesis in Early Breast Cancer Using Conformal Radiotherapy Brian D. Kavanagh and Rachel Rabinovitch, University of Colorado School of Medicine, Aurora, CO Najeeb Mohideen, Northwest Community Hospital, Arlington Heights, IL See accompanying article on page 4488
In the article that accompanies this editorial, Mukesh et al1 from Cambridge University report a randomized study comparing two external-beam radiotherapy techniques for early-stage breast cancer. The central conclusion is that cosmetic outcome is improved by adding a layer of technologic sophistication to the most basic technique for whole-breast radiotherapy. The authors are to be congratulated for successfully executing the study; however, like most good research, the article raises at least as many questions as it answers. Before we can discuss the clinical results of the study, we first need to acknowledge that there are differences in the terminology used to describe the same treatment procedures in different countries. This nomenclature issue is particularly important in the United States, where there can be substantial financial implications. Mukesh et al1 correctly note that the term intensity-modulated radiotherapy (IMRT) has been applied loosely at times to cover a wide range of techniques. These range from simple modifications that slant the cross-sectional profile of the generally flat beam coming out of the linear accelerator to yield a uniform gradient of internal dose to highly complex configurations of rotating gantries with shape-shifting multileaf collimators and variable photon fluence rates that texturize the beam to paint an undulating internal dose distribution. The latter complex approach allows coverage, for example, of a base-of-tongue primary cancer and regional draining lymph nodes with a high dose, while sparing sensitive normal structures such as the parotid gland and spinal cord. In one of its Choosing Wisely campaign recommendations, the American Society for Radiation Oncology (ASTRO) advises, “Don’t routinely use intensity modulated radiotherapy (IMRT) to deliver whole breast radiotherapy as part of breast conservation therapy.”2 At first glance this statement seems to conflict with the results of the Cambridge study, but on closer analysis the disconnect is reconciled by considering differences in IMRT definitions. What Mukesh et al1 label as “simple IMRT” is not properly considered IMRT in the United States, at least not in the sense of being billable according to the Common Procedural Terminology (CPT) code for IMRT. Instead, what is described in the article, in CPT-speak, is a method of threedimensional (3D) conformal radiation therapy, here accomplished using an open tangential beam augmented by several additional fieldin-field segments. That we are here wallowing in the murky morass of CPT billing semantics is not a criticism of Mukesh et al1 as much as a concession Journal of Clinical Oncology, Vol 31, No 36 (December 20), 2013: pp 4483-4484
that the CPT definition of IMRT is ambiguous and often misunderstood. For the record, in other studies in which investigators have compared so-called IMRT with a simpler technique of breast radiotherapy, the same terminology confusion has occurred. For example, Pignol et al3 similarly referred to a field-in-field 3D conformal RT technique as IMRT in a study published several years ago in Journal of Clinical Oncology. The problem with mistakenly referring to a form of 3D conformal RT as IMRT is that some might misinterpret the study to mean that it is appropriate to bill for IMRT in this setting, which would substantially escalate costs.4 Fortunately, parsing help is on the way through proposed revisions of the definitions of IMRT and certain other billing codes that should help to avoid this confusion.5 To nonradiation oncologists, it might be expected that the type of trial executed by the Cambridge group should be commonplace. How hard can it be to compare older technology with newer technology? It is important to realize that it was around 1990 that software capable of integrating computed tomography scan– based anatomic information with the choice of linear accelerator beam direction and aperture design appeared—in effect, it was the dawn of the era of 3D treatment planning and delivery. Since that epochal advance, innumerable individual software and hardware inventions have expedited stepwise evolution toward highly refined methods of depositing ionizing radiation therapy inside a patient, all geared toward maximizing the therapeutic ratio, a semiquantitative index conceived as the chance of providing benefit (eg, tumor control) divided by the chance of causing harm (ie, adverse effects), although rarely if ever explicitly calculated. The myriad component contributions that have enabled progress include the development of multileaf collimators, computerized dose calculation algorithms accounting for tissue electron density, and image guidance software and hardware that facilitate target relocalization at the time of treatment. And these are just a few of the thousand small steps in a journey of many miles that cannot all be tested separately as to whether they are the best choice in the quest for excellence. In most cases they have to be accepted at face value as intrinsically better on a res ipsa loquitur basis, because there are not enough resources available to perform a randomized study at each point along the way. Nevertheless, we must periodically pause to gauge where we are and where we should go, as the Cambridge group has done. At the very least, it can be reassuring when what is supposed to matter actually does matter. Here, an adjustment in the treatment plan that avoided © 2013 by American Society of Clinical Oncology
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excess dose to the skin and subcutaneous tissues proved useful for reducing toxicity to the skin and subcutaneous tissues, positively affecting patient-reported cosmesis. Alternatively, it can be an eye-opening surprise and cause for introspection when things do not play out as anticipated. Because more radiation dose is almost always better for aggressive cancers, many expected that the results of the Radiation Therapy Oncology Group (RTOG) 0617 trial, a randomized study comparing 74 Gy against 60 Gy for non–small-cell lung cancer that incorporated modern treatment delivery technology, would be a slam-dunk, bet-thefarm-on-it, foregone conclusion: surely, the higher dose should prove better than the lower dose. Except that it did not.6 A similar quandary relates to proton therapy for prostate cancer—maybe the path length uncertainty issue or some other technical shortcoming is a bigger problem than some have foreseen, because concerns have been raised about whether protons are actually any better than other forms of radiation therapy for prostate cancer.7 Hopefully, the ongoing randomized study comparing protons versus IMRT will shed more light on that issue.8 Refocusing on the Cambridge study, it is relevant to ask what happened to the patients whose initial radiotherapy plan did not reveal a level of dose heterogeneity that was sufficient to trigger random assignment. How did their cosmetic outcome compare with that of the group randomly assigned to IMRT? If the nonrandomly assigned group had equal cosmesis with the IMRT group, then the explanation is easy: dose homogeneity is paramount. Conversely, if the nonrandomly assigned patients had either better or worse cosmetic outcomes than the IMRT group, then further evaluation would be needed to understand the results. Additionally, although we are unable to comment on other countries, we think it is unlikely that the results of the study will be practice changing in the United States. In the American College of Radiology appropriateness criteria published in 2008, computed tomography– based multiplane or 3D treatment planning with dose homogeneity compensation was recommended as the most appropriate technique.9 Thus, we believe that most US radiation oncologists are presently aware of the need to be mindful of avoiding dose hotspots. Having said that, in the 2011 ASTRO guideline concerning the use for breast cancer of shortened, or hypofractionated, radiotherapy schedules of the type used by the Cambridge group, the strategy was endorsed for certain patient subgroups with the caveat that there needs to be dose homogeneity within ⫾7% along the central axis of the beam10—a rather simplistic two-dimensional guideline to which the current Cambridge study adds 3D nuance.
In summary, we emphasize that all jargon discrepancies aside, whether they call it IMRT or we call it 3D conformal RT, the Cambridge group has provided specific volumetric descriptors of what constitutes a properly homogeneous dose distribution within a breast, defining and validating a useful and practical dosimetric quality indicator. Furthermore, the overall excellent tumor control and cosmetic outcomes that were achieved with their hypofractionated schedule add to the compendium of literature that supports another of ASTRO’s Choosing Wisely goals, “Don’t initiate whole breast radiotherapy as a part of breast conservation therapy in women age ⱖ 50 [years] with early stage invasive breast cancer without considering shorter treatment schedules.”2 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Mukesh MB, Barnett GC, Wilkinson JS, et al: Randomized controlled trial of intensity-modulated radiotherapy for early breast cancer: 5-year results confirm superior overall cosmesis. J Clin Oncol 31:4488-4495, 2013 2. American Society for Radiation Oncology Choosing Wisely Campaign: Five things physicians and patients should question. http://www.choosingwisely.org/ wp-content/uploads/2013/09/ASTRO-5things-List_092013.pdf 3. Pignol JP, Olivotto I, Rakovitch E, et al: A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 26:2085-2092, 2008 4. Smith BD, Pan IW, Shih YC, et al: Adoption of intensity-modulated radiation therapy for breast cancer in the United States. J Natl Cancer Inst 103:798-809, 2011 5. Butcher L: ASTRO developing payment reform plan. Oncol Times 35:1819, 2013 6. Bradley JD, Paulus R, Komaki R, et al: A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617. J Clin Oncol 31:458s, 2013 (suppl; abstr 7501) 7. Sheets NC, Goldin GH, Meyer AM, et al: Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307:1611-1620, 2012 8. Clinicaltrials.gov: Proton therapy vs. IMRT for low or intermediate risk prostate cancer (PARTIQoL). http://clinicaltrials.gov/show/NCT01617161 9. White JR, Halberg FE, Rabinovitch R, et al: American College of Radiology appropriateness criteria on conservative surgery and radiation: Stages I and II breast carcinoma. J Am Coll Radiol 5:701-713, 2008 10. Smith BD, Bentzen SM, Correa CR, et al: Fractionation for whole breast irradiation: An American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys 81:59-68, 2011
DOI: 10.1200/JCO.2013.52.6442; published online ahead of print at www.jco.org on November 18, 2013
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© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
JOURNAL OF CLINICAL ONCOLOGY
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Improved Cosmesis in Early Breast Cancer Using Conformal Radiotherapy Brian D. Kavanagh and Rachel Rabinovitch, University of Colorado School of Medicine, Aurora, CO Najeeb Mohideen, Northwest Community Hospital, Arlington Heights, IL See accompanying article on page 4488
In the article that accompanies this editorial, Mukesh et al1 from Cambridge University report a randomized study comparing two external-beam radiotherapy techniques for early-stage breast cancer. The central conclusion is that cosmetic outcome is improved by adding a layer of technologic sophistication to the most basic technique for whole-breast radiotherapy. The authors are to be congratulated for successfully executing the study; however, like most good research, the article raises at least as many questions as it answers. Before we can discuss the clinical results of the study, we first need to acknowledge that there are differences in the terminology used to describe the same treatment procedures in different countries. This nomenclature issue is particularly important in the United States, where there can be substantial financial implications. Mukesh et al1 correctly note that the term intensity-modulated radiotherapy (IMRT) has been applied loosely at times to cover a wide range of techniques. These range from simple modifications that slant the cross-sectional profile of the generally flat beam coming out of the linear accelerator to yield a uniform gradient of internal dose to highly complex configurations of rotating gantries with shape-shifting multileaf collimators and variable photon fluence rates that texturize the beam to paint an undulating internal dose distribution. The latter complex approach allows coverage, for example, of a base-of-tongue primary cancer and regional draining lymph nodes with a high dose, while sparing sensitive normal structures such as the parotid gland and spinal cord. In one of its Choosing Wisely campaign recommendations, the American Society for Radiation Oncology (ASTRO) advises, “Don’t routinely use intensity modulated radiotherapy (IMRT) to deliver whole breast radiotherapy as part of breast conservation therapy.”2 At first glance this statement seems to conflict with the results of the Cambridge study, but on closer analysis the disconnect is reconciled by considering differences in IMRT definitions. What Mukesh et al1 label as “simple IMRT” is not properly considered IMRT in the United States, at least not in the sense of being billable according to the Common Procedural Terminology (CPT) code for IMRT. Instead, what is described in the article, in CPT-speak, is a method of threedimensional (3D) conformal radiation therapy, here accomplished using an open tangential beam augmented by several additional fieldin-field segments. That we are here wallowing in the murky morass of CPT billing semantics is not a criticism of Mukesh et al1 as much as a concession Journal of Clinical Oncology, Vol 31, No 36 (December 20), 2013: pp 4483-4484
that the CPT definition of IMRT is ambiguous and often misunderstood. For the record, in other studies in which investigators have compared so-called IMRT with a simpler technique of breast radiotherapy, the same terminology confusion has occurred. For example, Pignol et al3 similarly referred to a field-in-field 3D conformal RT technique as IMRT in a study published several years ago in Journal of Clinical Oncology. The problem with mistakenly referring to a form of 3D conformal RT as IMRT is that some might misinterpret the study to mean that it is appropriate to bill for IMRT in this setting, which would substantially escalate costs.4 Fortunately, parsing help is on the way through proposed revisions of the definitions of IMRT and certain other billing codes that should help to avoid this confusion.5 To nonradiation oncologists, it might be expected that the type of trial executed by the Cambridge group should be commonplace. How hard can it be to compare older technology with newer technology? It is important to realize that it was around 1990 that software capable of integrating computed tomography scan– based anatomic information with the choice of linear accelerator beam direction and aperture design appeared—in effect, it was the dawn of the era of 3D treatment planning and delivery. Since that epochal advance, innumerable individual software and hardware inventions have expedited stepwise evolution toward highly refined methods of depositing ionizing radiation therapy inside a patient, all geared toward maximizing the therapeutic ratio, a semiquantitative index conceived as the chance of providing benefit (eg, tumor control) divided by the chance of causing harm (ie, adverse effects), although rarely if ever explicitly calculated. The myriad component contributions that have enabled progress include the development of multileaf collimators, computerized dose calculation algorithms accounting for tissue electron density, and image guidance software and hardware that facilitate target relocalization at the time of treatment. And these are just a few of the thousand small steps in a journey of many miles that cannot all be tested separately as to whether they are the best choice in the quest for excellence. In most cases they have to be accepted at face value as intrinsically better on a res ipsa loquitur basis, because there are not enough resources available to perform a randomized study at each point along the way. Nevertheless, we must periodically pause to gauge where we are and where we should go, as the Cambridge group has done. At the very least, it can be reassuring when what is supposed to matter actually does matter. Here, an adjustment in the treatment plan that avoided © 2013 by American Society of Clinical Oncology
4483
Editorial
excess dose to the skin and subcutaneous tissues proved useful for reducing toxicity to the skin and subcutaneous tissues, positively affecting patient-reported cosmesis. Alternatively, it can be an eye-opening surprise and cause for introspection when things do not play out as anticipated. Because more radiation dose is almost always better for aggressive cancers, many expected that the results of the Radiation Therapy Oncology Group (RTOG) 0617 trial, a randomized study comparing 74 Gy against 60 Gy for non–small-cell lung cancer that incorporated modern treatment delivery technology, would be a slam-dunk, bet-thefarm-on-it, foregone conclusion: surely, the higher dose should prove better than the lower dose. Except that it did not.6 A similar quandary relates to proton therapy for prostate cancer—maybe the path length uncertainty issue or some other technical shortcoming is a bigger problem than some have foreseen, because concerns have been raised about whether protons are actually any better than other forms of radiation therapy for prostate cancer.7 Hopefully, the ongoing randomized study comparing protons versus IMRT will shed more light on that issue.8 Refocusing on the Cambridge study, it is relevant to ask what happened to the patients whose initial radiotherapy plan did not reveal a level of dose heterogeneity that was sufficient to trigger random assignment. How did their cosmetic outcome compare with that of the group randomly assigned to IMRT? If the nonrandomly assigned group had equal cosmesis with the IMRT group, then the explanation is easy: dose homogeneity is paramount. Conversely, if the nonrandomly assigned patients had either better or worse cosmetic outcomes than the IMRT group, then further evaluation would be needed to understand the results. Additionally, although we are unable to comment on other countries, we think it is unlikely that the results of the study will be practice changing in the United States. In the American College of Radiology appropriateness criteria published in 2008, computed tomography– based multiplane or 3D treatment planning with dose homogeneity compensation was recommended as the most appropriate technique.9 Thus, we believe that most US radiation oncologists are presently aware of the need to be mindful of avoiding dose hotspots. Having said that, in the 2011 ASTRO guideline concerning the use for breast cancer of shortened, or hypofractionated, radiotherapy schedules of the type used by the Cambridge group, the strategy was endorsed for certain patient subgroups with the caveat that there needs to be dose homogeneity within ⫾7% along the central axis of the beam10—a rather simplistic two-dimensional guideline to which the current Cambridge study adds 3D nuance.
In summary, we emphasize that all jargon discrepancies aside, whether they call it IMRT or we call it 3D conformal RT, the Cambridge group has provided specific volumetric descriptors of what constitutes a properly homogeneous dose distribution within a breast, defining and validating a useful and practical dosimetric quality indicator. Furthermore, the overall excellent tumor control and cosmetic outcomes that were achieved with their hypofractionated schedule add to the compendium of literature that supports another of ASTRO’s Choosing Wisely goals, “Don’t initiate whole breast radiotherapy as a part of breast conservation therapy in women age ⱖ 50 [years] with early stage invasive breast cancer without considering shorter treatment schedules.”2 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Mukesh MB, Barnett GC, Wilkinson JS, et al: Randomized controlled trial of intensity-modulated radiotherapy for early breast cancer: 5-year results confirm superior overall cosmesis. J Clin Oncol 31:4488-4495, 2013 2. American Society for Radiation Oncology Choosing Wisely Campaign: Five things physicians and patients should question. http://www.choosingwisely.org/ wp-content/uploads/2013/09/ASTRO-5things-List_092013.pdf 3. Pignol JP, Olivotto I, Rakovitch E, et al: A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 26:2085-2092, 2008 4. Smith BD, Pan IW, Shih YC, et al: Adoption of intensity-modulated radiation therapy for breast cancer in the United States. J Natl Cancer Inst 103:798-809, 2011 5. Butcher L: ASTRO developing payment reform plan. Oncol Times 35:1819, 2013 6. Bradley JD, Paulus R, Komaki R, et al: A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617. J Clin Oncol 31:458s, 2013 (suppl; abstr 7501) 7. Sheets NC, Goldin GH, Meyer AM, et al: Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307:1611-1620, 2012 8. Clinicaltrials.gov: Proton therapy vs. IMRT for low or intermediate risk prostate cancer (PARTIQoL). http://clinicaltrials.gov/show/NCT01617161 9. White JR, Halberg FE, Rabinovitch R, et al: American College of Radiology appropriateness criteria on conservative surgery and radiation: Stages I and II breast carcinoma. J Am Coll Radiol 5:701-713, 2008 10. Smith BD, Bentzen SM, Correa CR, et al: Fractionation for whole breast irradiation: An American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys 81:59-68, 2011
DOI: 10.1200/JCO.2013.52.6442; published online ahead of print at www.jco.org on November 18, 2013
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© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
