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Originally published as JCO Early Release 10.1200/JCO.2007.15.9442 on February 19 2008 © 2008 American Society of Clinical Oncology.
Should Intensity-Modulated Radiation Therapy Be the Standard of Care in the Conservatively Managed Breast Cancer Patient?
Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Cancer Institute of New Jersey, New Brunswick, NJ
M.D. Anderson Cancer Center, Houston, TX
Memorial Sloan-Kettering Cancer Center, New York, NY In this issue of the Journal of Clinical Oncology, Pignol et al1 report the results of a randomized clinical trial that found that intensity-modulated radiation therapy (IMRT) delivery of breast radiation reduces acute skin toxicity associated with treatment compared with conventional methods of radiation treatment delivery. This article may have a significant impact on the practice of breast radiation. To understand the implications of this study, some background, particularly for the nonradiation oncology readership, is in order. Radiation therapy, delivered daily to the whole breast in 1.8 to 2.0 Gy/d fractions over a course of 5 to 7 weeks after lumpectomy, remains the most widely used and acceptable standard of care in the local-regional management of early-stage invasive breast cancer and ductal carcinoma in situ.2 Radiation therapy is typically delivered by two opposing tangential fields directed to the breast at an angle approximately parallel to the chest wall. The target of the radiation fields is the entire involved breast, with the field borders extending superiorly from the level of the clavicular head, inferiorly to the inframammary fold, medially to the mid sternum, and laterally to the midaxillary line. This simple tangential technique spares most of the underlying normal structures and encompasses all breast tissue. This treatment has been demonstrated to be safe and effective, with the majority of patients experiencing good to excellent cosmetic outcomes, excellent local control, and long-term disease-free and overall survival equivalent to patients treated with mastectomy.3,4 When radiation is delivered with two opposing open fields (without tissue compensation) the distribution of radiation dose throughout the breast can be quite inhomogeneous due to variations in the breast contour. Specifically, due to the shape of the breast, the radiation must traverse through more tissue along the chest wall than it traverses in the subareolar/nipple region, resulting in significantly higher doses (hot spots) in the subareolar/nipple region. To compensate for the changing contour of the breast, a common practice is to use physical wedges, which are essentially wedge-shaped beam attenuators placed in the radiation beam that gradually attenuate the beam from a minimum attenuation along the chest wall to a maximum attenuation in the subareolar region. This compensates for the decreasing tissue volume from the chest wall to the apex of the breast by differentially decreasing the intensity of the beam from the chest wall to the nipple areolar region, and creates a more homogenous radiation dose distribution in the breast. In a sense, this is the simplest form of IMRT, and has been commonly used for the last 30 years in the conservative management of breast cancer. The major issue with the simple wedge is that it is designed to adjust for dose heterogeneity in a two-dimensional (2D) plane, usually optimized in the central axial slice of the breast at the level of the nipple. This provides the same compensation arrangement from the most superior to the most inferior aspect of the breast. As the breast contour changes significantly superiorly to inferiorly, although a simple wedge can result in excellent dose homogeneity along the central axis of the breast, results are less optimal in the superior and/or inferior portions of the breast. Accordingly, 2D wedge compensation can result in substantial hot spots in areas of the breast away from the central axis, where the shape and volume of the breast substantially differs from the central axis. During the last decade, there have been significant improvements in computerized treatment planning systems and modifications to linear accelerators, which can allow for three-dimensional (3D) dose compensation. Treatment planning systems currently have developed accurate 3D dose calculation algorithms and accelerators now are routinely equipped with multileaf collimators. This can allow for rapid differential and segmental blocking of the radiation beam throughout the entire treatment field. This advance in technology allows for attenuation of the radiation beam differentially in multiple planes, resulting in improved homogeneity throughout the breast tissue, essentially moving from 2D treatment planning and dose compensation (as has been used for years with the simple wedges described in the previous paragraph), to 3D planning. The effect is a more homogeneous dose distribution not only in the central breast, but equal improvement in homogeneity at the most superior and inferior aspects of the breast, resulting in a reduction in hot spots throughout the breast tissue, with potential improvements in normal tissue reactions and cosmetic outcome.5 This is demonstrated nicely in Figure 2 in the article by Pignol et al, with improvement in the sagittal dose gradient from approximately 10% to 1%.1 In the study presented by Pignol et al, as expected, the dose distribution within the breast was significantly improved with the IMRT technique, with a reduction in the clinically significant maximum from 110% with standard wedges to 105% with IMRT, and a reduction in the relative volume of breast receiving more than 105% of the prescribed dose from 16.9% with standard wedges to 7.7% with IMRT. This improvement in dosimetric performance translated into a significant clinical gain, with reduction in moist desquamation in a portion of the skin overlying the breast tissue from 47.8% to 31.2%. Although there was no statistically significant improvement in quality of life between the two arms, there was improvement in quality of life and pain scores when assessed at the time of moist desquamation. The validity and strength of the study is strengthened by its randomized design and stratification, the fact that patients and clinical research assistants were blinded to the treatment arm, and the skin assessment was performed in a separate clinic to ensure consistency and minimize bias. This study has several potential practical clinical implications. First, although the study clearly demonstrated a significant improvement in acute skin reactions, with longer follow-up the improved dose homogeneity and improved skin reactions could potentially translate into decreased chronic skin changes, decreased fibrosis, and improved cosmetic outcomes. This can only be realized through longer follow-up from this randomized clinical trial. A similar phase III trial comparing 2D wedges to 3D IMRT from the United Kingdom did demonstrate a statistically significant improvement in the breast appearance at 5 years, as would be predicted in the study by Pignol et al.6 The improved homogeneity achieved through IMRT techniques can also have implications regarding more widespread acceptance of accelerated whole breast irradiation, and evaluation of other novel accelerated fractionation schemes. One of the concerns regarding more accelerated whole breast irradiation is increased fibrosis and decreased cosmetic outcomes with the larger fraction sizes.7 Hot spots inherent in 2D treatment plans are magnified with the larger daily doses. The improved homogeneity achieved with IMRT may lessen the potential impact of larger fraction sizes on fibrosis and cosmesis with accelerated whole breast irradiation techniques. IMRT techniques can also be used to deliver radiation to the whole breast, while simultaneously delivering the boost to the tumor bed (so-called concomitant boost). This can also accelerate the treatment course with potentially acceptable acute and long-term outcomes.8 Another potential clinical implication of this technology relates to the use of concurrent chemotherapy with whole breast irradiation. Concurrent chemotherapy and radiation in the conservative management of breast cancer has fallen out of favor due to the increased acute and potential long-term toxicity using standard techniques. However, there is both randomized and retrospective evidence that concurrent chemoradiotherapy may be beneficial with respect to local control in selected patients.9,10 The improved dose homogeneity associated with IMRT allows for a revisiting of this issue. All of these potential applications of IMRT, however, should ideally be evaluated in the context of prospective trials under controlled conditions, with clear hypothesis and well-established end points, in an effort to fully realize the potential benefits of this advance in technology. It is important to recognize that IMRT does not have a universally accepted definition within the field of radiation oncology. As indicated above, the primary goal of IMRT in the intact breast is to improve the dose distribution within the treatment field. In other disease sites where IMRT has become standard of care, such as prostate cancer and head and neck cancer, the major benefit of IMRT over conventional techniques is in improving the conformality of radiation dose to the targeted area.11,12 In these areas, however, the IMRT is much more complex, requiring multiple, conformally shaped, intensity-modulated beams directed at the target from a variety of angles. For example, in head and neck cancer, IMRT can use computer technologies to shape the high-dose regions around the targeted tissues while significantly sparing dose to the normal parotid glands, spinal cord, and other key organs. But this requires many hours (on the part of both the physician and the planner) to identify structures to target and to protect before the treatment planning computers are able to do this through complex iterative processes. In prostate cancer, the more conformal radiation fields has allowed for significant sparing of the surrounding normal pelvic structures and substantial dose escalation to the prostate target, which has significantly improved local control and biochemical disease-free survival rates. There is significant additional complexity and time put into the treatment planning processes and the daily treatment for this form of IMRT, and compensation levels related to the technical delivery of radiation are appropriately higher. For breast cancer, multileaf 3D dose compensation planning is generally much less complex than IMRT planning for these other sites, and the treatment time daily is similar to a standard 2D tangent field. At present, disparity exists throughout the United States about whether this improvement in treatment planning for breast cancer is reimbursed at IMRT levels or at levels closer to the historical standards; in some practices, the radiation oncologist must revert back to a 2D wedge plan for patients when the superior IMRT plan is not covered by insurance. Given that breast cancer is a common disease, there is a need for an appropriately defined standard, particularly in light of the favorable trial results reported by Pignol et al and Donovan et al.1,6 In addition to continued efforts in evaluation of IMRT in the clinical and physics arena, there are significant economic issues that need to be addressed. The technical charges for IMRT treatment planning and delivery are approximately three times the charges for conventional non-IMRT treatment. Although these charges may be appropriate for the complex IMRT in sites such as prostate and head and neck cancer, IMRT for breast treatment is typically less complex and less time consuming. It is beyond the scope of this editorial to discuss the issues surrounding what constitutes an appropriate definition of IMRT from a charge coding perspective. Currently, however, there is only one standard charge for IMRT treatment delivery, regardless of the complexity. This has resulted in widespread confusion and disagreement between health care providers and health care payors regarding the appropriate use and charging of IMRT codes for breast IMRT. This has lead to well-founded misunderstandings regarding how to compensate IMRT in breast cancer treatment fairly and appropriately. The current charge coding system for technical delivery of IMRT, which uses only one fixed charge, should be modified to more appropriately reflect the complexity for the treatment delivered, with perhaps two or three separate levels, with more clearly defined guidelines for coding. The concept of less complex degrees of IMRT is not new; so-called simple IMRT was first described for breast cancer in 2002.13 Unfortunately, this concept has not as yet been embraced by the medical reimbursement system and third party payors. Should IMRT be the standard of care for delivery of radiation to the whole breast after lumpectomy? It is clear from the phase III trials by Pignol et al1 and Donovan et al6 that there are both dosimetric and clinical advantages to improved homogeneity achieved with IMRT to the whole breast as employed here. Most facilities that have the necessary planning equipment and technology available should strive for optimal homogeneity, which can be readily achieved with the techniques described. It is hoped that the economic issues related to delivery of IMRT can be resolved in the near future, so that clinical applications of this exciting technology can continue to move forward. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Bruce G. Haffty, Thomas A. Buchholz, Beryl McCormick Final approval of manuscript: Bruce G. Haffty, Thomas A. Buchholz, Beryl McCormick NOTES published online ahead of print at www.jco.org on February 19, 2008. REFERENCES
1. Pignol J: A multicentre randomized trial of breast IMRT to reduce acute radiation dermatitis. J Clin Oncol 26:2085-2092, 2008 2. Eifel P, Axelson JA, Costa J, et al: National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93:979-989, 2001 3. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002 4. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1232, 2002 5. Vicini FA, Sharpe M, Kestin L, et al: Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 54:1336-1344, 2002[CrossRef][Medline] 6. Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 82:254-264, 2007[CrossRef][Medline] 7. Whelan T, MacKenzie R, Julian J, et al: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 94:1143-1150, 2002 8. Formenti SC, Gidea-Addeo D, Goldberg JD, et al: Phase I-II trial of prone accelerated intensity modulated radiation therapy to the breast to optimally spare normal tissue. J Clin Oncol 25:2236-2242, 2007 9. Arcangeli G, Pinnaro P, Rambone R, et al: A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer. Int J Radiat Oncol Biol Phys 64:161-167, 2006[CrossRef][Medline] 10. Toledano A, Garaud P, Serin D, et al: Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conservative surgery enhances late toxicities: Long-term results of the ARCOSEIN multicenter randomized study. Int J Radiat Oncol Biol Phys 65:324-332, 2006[CrossRef][Medline] 11. Eisbruch A: Intensity-modulated radiation therapy in the treatment of head and neck cancer. Nat Clin Pract Oncol 2:34-39, 2005[CrossRef][Medline] 12. Cahlon O, Hunt M, Zelefsky MJ: Intensity-modulated radiation therapy: Supportive data for prostate cancer. Semin Radiat Oncol 18:48-57, 2008[CrossRef][Medline] 13. Chui CS, Hong L, Hunt M, et al: A simplified intensity modulated radiation therapy technique for the breast. Med Phys 29:522-529, 2002[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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