- Email: [email protected]
Advances in Radiation Treatments of Breast Cancer
comprehensive
review
Advances in Radiation Treatments of Breast Cancer Steven J. Frank,1 Marsha D. McNeese,1 Eric A. Strom,1 George Perkins,1 Mohammad Salehpour,2 Naomi Schechter,1 Thomas A. Buchholz1 Abstract During the past decade, improvements in treatment-planning tools, computer and imaging technologies, and new therapeutic modalities have allowed radiation to be delivered in a conformal fashion while minimizing treatment toxicity. It is important that physicians involved in breast cancer treatment recognize the numerous advances that have occurred in the delivery of radiation therapy. Changes in 3 specific areas in treatment planning and delivery have revolutionized the way we approach breast cancer treatment: the design of radiation fields using computed tomography (CT) data sets, the development of 3-dimensional dose-calculation algorithms, and the development of new methods to modulate the delivery of radiation dose. With the advent of CT simulators, individual patient anatomy and pathology can be readily visualized and reconstructed in axial, coronal, and sagittal views. With an improved anatomic delineation between the target volumes and critical organ structures, the treatment fields can be designed to be more congruous to the areas at highest risk. In the past few years, new 3-dimensional dose-calculation algorithms have been generated that more accurately calculate dose distributions throughout the treatment-planning volume. Finally, modern linear accelerators allow for modulation of the dose intensity of the radiation beam, which may lead to improved aesthetics and decreased side effects while ensuring that the volumes at high risk receive the prescribed dose. Radiation therapy can be delivered safely and effectively to patients with breast cancer. Clinical Breast Cancer, Vol. 4, No. 6, 401-406, 2004 Key words: Computed tomography, Dose-calculation algorithms, Dose intensity, Linear acceleration, Radiation beam, Target volume
Introduction Radiation therapy is a critically important component of treatment for the majority of patients diagnosed with breast cancer. For patients with ductal carcinoma in situ or early-stage breast cancer, phase III randomized trials have conclusively demonstrated that radiation use reduces the probability of breast cancer recurrence.1,2 Radiation use after mastectomy is also considered to be the standard of
1Department of Radiation Oncology 2Department of Radiation Physics
The University of Texas M. D. Anderson Cancer Center, Houston Submitted: May 29, 2003; Revised: Jul 28, 2003; Accepted: Jul 30, 2003 Address for correspondence: Thomas A. Buchholz, MD, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcolmbe Blvd, Unit 97, Houston, TX 77030 Fax: 713-563-2366; e-mail: [email protected]
care for patients with advanced disease and for patients with stage II breast cancer with ≥ 4 positive lymph nodes.3-5 Despite clinical trials and studies clearly showing the benefits of radiation therapy in early-stage breast cancer, it remains underused in the United States.6,7 This underuse of radiation therapy may in part reflect a decision by the referring physician and/or the patient to forgo appropriate care because of concern over the toxicity of radiation treatment.8 Therefore, it is crucial that physicians recognize the numerous advances that have occurred in the delivery of radiation therapy and the resulting decrease in morbidity associated with treatment. Particularly during the past decade, improvements in treatment-planning tools, computer technologies, imaging technologies, and new therapeutic modalities allow radiation to be delivered in a much more conformal fashion. It is predicted that these technologic improvements will further minimize the risk of long-
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Breast Cancer February 2004 • 401
Radiation Advances in Breast Cancer Figure 1 Designing Radiation Field Using Computed Tomography
Computed tomography treatment planning permits the visualization of the highrisk areas of recurrence and regional lymphatics, which are identified in this supraclavicular treatment field. The visualization of the axillary lymph nodes and the internal mammary chain nodes permit optimal radiation treatment planning and delivery.
term treatment-associated morbidity. These recent advances have been revolutionary and have made the past decade one of the most intellectually and clinically exciting in the century-long history of radiation oncology. Unfortunately, radiation oncology is a relatively small field within the medical profession and these advances have been underappreciated by most physicians and patients with breast cancer. For radiation to kill breast tumor cells and avoid normal tissue injury, there must be a therapeutic ratio that allows for a selective killing of residual disease while normal tissue structure is preserved. For radiation treatments, biology and physics determine this therapeutic ratio. For example, normal tissue and tumors have different abilities to repair sublethal radiation damage. With fractionated therapy, this repair difference can be exploited and can lead to accumulation of damage selectively within tumors to the threshold of lethality.9 The biologic considerations of fractionated radiation treatment delivery have not significantly changed in the past decade. A number of the very early historical breast cancer clinical trials used fractionation schemes in excess of 2 Gy for treatment delivery, which are no longer considered standard. In the United States, the delivery of a daily dose of 1.8-2.0 Gy for 5-6 weeks has been standard for some time. Most of the recent advances in radiation treatments for breast cancer have been physics-based. Whereas the biology of fractionated therapy attempts to spare normal tissue within the treatment field, a primary goal of radiation physics is to determine the optimal delivery of radiation dose. Meticulous treatment planning is required to deliver the appropriate radiation dose selectively to the areas recognized to be at risk for cancer recurrence. The planning of radiation therapy requires an in-depth knowledge of clinical
402 • Clinical Breast Cancer February 2004
and radiographic anatomy, and must be individualized by taking into account the patient’s anatomy, volumes of tissue at risk, and critical organ structures. In this article, we review selected important technologic advances in radiation treatment for breast cancer. Three specific changes in treatment planning and delivery have revolutionized the way we approach breast cancer treatment. These changes include the design of radiation fields using computed tomography (CT) data sets, the development of 3-dimensional (3D) dose-calculation algorithms in treatment planning, and improved radiation treatment delivery by modulating the intensity of radiation therapy. Other breast treatment advances, including partial-breast irradiation with brachytherapy, external-beam radiation therapy, and respiratory gating, are under current investigation and will not be discussed in this article. The purposes of this article are to characterize recent technologic advances and to provide an overview of the consequences of these changes.
Designing Radiation Fields Using Computed Tomography Data Sets One of the most critical recent advances in the field of radiation oncology has been in the design of treatment fields. The goal of all radiation treatments is to include the region at risk of recurrence completely within the irradiated volume while minimizing the volume of normal tissue that receives coincidental treatment. Historically, the delineation of radiation fields for breast cancer was done based on an empiric understanding of anatomy and visualization of anatomic structures using fluoroscopy. Currently, at our institution, the construction of radiation fields is performed with use of a 3D rendering of the virtual anatomy obtained with treatment-planning CT. Many radiation oncology departments currently have dedicated CT scanners that are specifically designed for the purpose of radiation treatment planning. These CT scanners differ from diagnostic units in that they are equipped with lasers to provide orientation to 3D points in space that are used to verify the day-to-day patient alignment. They precisely correspond to similar laser-localized points associated with the linear accelerators that are used to deliver the radiation treatments. In addition, large-bore treatment-planning CT scanners are available to allow for accommodation of various bodies sizes, treatment positions, and immobilization devices. These devices are important to assure that patients are scanned in the exact position in which they will receive their radiation therapy. Each treatment field is individualized according to the patient’s anatomy, sites believed to be at risk of recurrence, and areas believed necessary to avoid complications. The use of CT in designing these fields is an exciting development for a number of reasons. First, the goal of radiation therapy in most patients with breast cancer is to kill the residual microscopic tumor cells present after surgery. Based on data documenting the recurrence patterns in early- and advanced-stage breast cancer, radiation therapy is used most
Steven J. Frank et al often in the adjuvant setting to facilitate local control of disease in the breast, chest wall, and selective regional lymphatics. Attempts to include the axilla and/or internal mammary lymph nodes were historically done based on an empiric understanding of lymphatic anatomy referenced to bony landmarks. Two-dimensional (2D) fluoroscopic simulations do not allow direct visualization of lymph nodes in the axilla, infraclavicular and supraclavicular fossa, or internal mammary chain. Conversely, with 3D CT simulation, the individual patient’s anatomy, including the lymphatics, muscles, vasculature, and nerves, may be visualized and reconstructed in axial, coronal, and sagittal views. Multiple iterations of treatment fields can be virtually generated on CT data sets to optimize the radiation fields. Although CT simulation provides imaging that is superior to traditional 2D simulations, its value for tangential field design during breast-conservation therapy has come into question secondary to the clinical significance and cost of treatment planning.10-12 To assist in the demarcation of targeted regions such as the postoperative surgical bed and lymph node basins, the anatomic areas at risk can be digitized on sequential axial CT slices. Subsequently, a 3D volume of each structure can be generated, and the relationship of this volume to the radiation field is more easily visualized.13 Therefore, the probability of an at-risk area falling outside the treatment field should be dramatically reduced with 3D CT simulations. An example of the type of reconstructed anatomic rendering is shown in Figure 1, illustrating the extent of an axillary dissection that can be easily visualized and included in a radiation field. Additionally, a digitized reconstruction of the upper internal mammary lymph nodes was obtained by outlining the anatomic region on sequential axial CT slices. These images significantly aid in the design of an optimal treatment plan. Ultimately, by minimizing the risk of a marginal miss, CT treatment planning may improve the efficacy of treatment and decrease dose to normal tissues.14 In addition to providing important information regarding the anatomic location of high-risk regions, another important result of CT simulation planning is the reduction in the dose to normal tissues. Data has shown that the design of radiation fields used for breast cancer treatment may increase the risk of cardiovascular deaths.15 Presumably, these deaths were secondary to treatment effects on the heart and coronary vasculature. When treating the left breast or left chest wall, care must be taken to avoid irradiation of the heart and coronary vessels because postirradiation perfusion defects have been observed.16,17 The apex of the heart is often difficult to visualize and precisely localize on tangential fluoroscopic images. Unlike fluoroscopic imaging, CT imaging provides better visualization of these critical organ structures and consequently can help to design fields that minimize dose to these critical organ structures.18 For example, the left anterior descending artery typically lies in close proximity to the deep border of tangential fields used to treat the breast or chest wall. Computed tomographic planning may permit the visualization
Figure 2 Dosimetric Planning of Breast-Conservation Therapy
The standard medial and lateral tangents for a patient receiving breast-conservation therapy illustrates the dosimetric challenge that includes increased "hot spots" at the apex of the breast. The shorter separation distance at the apex along the plane of the beam may increase normal breast tissue toxicity because of the higher dose of delivered radiation.
of the left anterior descending artery and provide the radiation oncologist with the opportunity to modify the design of the treatment fields to optimize for the individual patient.19 Additionally, the internal mammary vessels can be visualized on noncontrast CT, and the distance to these vessels is used to calculate the appropriate electron beam energy to treat this nodal region. Such precision is difficult with a fluoroscopic simulator, and there is a risk of missing part of the targeted volume and including more normal tissue than is actually necessary.
Three-Dimensional Dose-Calculation Algorithms in Treatment Planning Three-dimensional treatment planning includes the target volume delineation, beam geometry selection, and dose calculation. When the geometric design of the treatment fields is optimized to insure inclusion of therapeutic targets while minimizing normal tissue structures within the target volume, dosimetric planning occurs. The dose varies according to the physical properties of the radiation beam and tissue being treated. For example, in general, the dose of radiation decreases as the beam travels deeper into tissue. To accommodate for this, 2 opposed fields are often used and the dose falloff from each beam must be matched to provide a relatively uniform dose throughout the treatment volume. The technique of opposing fields is the standard for treatment of the breast, which is typically performed with a matched pair of medial and lateral tangent beams. However, the separation distance at the apex of the breast along the plane of the beam is much shorter than that at the base, so the corresponding
Clinical Breast Cancer February 2004 • 403
Radiation Advances in Breast Cancer Figure 3 Isodose Distribution Curves
thermore, other areas in the upper or lower portion of the field that would not be recognized and corrected with traditional 2D planning would commonly receive in excess of 110% of the prescribed dose.23 Although multiple axial levels may be visualized with 2D treatment planning, an advantage to 3D treatment planning is that the dose can be calculated and observed simultaneously in the axial, coronal, and sagittal planes to insure adequate coverage.
Modulating the Intensity of Radiation Therapy
This sagittal view of a patient receiving breast-conservation therapy illustrates the isodose distribution (percentage of prescribed dose) that is generated by medial and lateral tangential radiation treatment fields.
dose in the apex is higher than that at the base (Figure 2). To correct for these differences in dose across the volume, dosimetry planning is performed. Dosimetry planning optimizes dose uniformity, ensures that the target volume receives the prescribed dose, and verifies that the critical organ structures are spared unnecessary amounts of radiation. There are many approaches to treatment planning that may vary depending on the institution. Historically, at our institution, treatment planning consisted of optimizing the dose distribution in a single 2D axial plane in the center of the field. An external contour of the breast or chest wall in the center of the field was obtained by transposing a plaster cast or a wire during simulation. This external cast was transferred onto treatment-planning graph paper. Dosimetrists then calculated the resulting dose distributions on this central axial slice. The dose distribution could then be optimized through preferential weighting of the 2 fields and through introduction of beam-modification devices called wedges, which could decrease the dose at the apex relative to the base. In the past few years, new 3D dose-calculation algorithms have been generated that more accurately calculate dose throughout the entire 3D volume included in the field.20,21 In addition to permitting dose visualization in areas outside of the central plane, these new treatment-planning systems more accurately calculate dose because they account for differences in the density of the tissue within the fields (determined according to CT Hounsfield units). This improvement is clinically important in many ways, including improvement in coverage of the axilla.22 For example, we have demonstrated that 2D plans can fail to recognize a significant underdosage in the axillary lymph nodes (eg, 77% of nominal dose). Fur-
404 • Clinical Breast Cancer February 2004
One of the more recent and exciting advances in the radiation treatment of breast cancer lies in the ability to selectively modify the intensity of the radiation dose in the treatment volume. Pioneering work has advanced the ability to modulate the intensity of radiation therapy within the target volume.24 Numerous fields may be created to achieve a more uniform dose distribution, as opposed to the 2-field arrangements that have been conventionally designed. With the recent advent of the multileaf collimator, which resides inside the treatment head of modern linear accelerators, static intensity-modulated radiation beams can reduce the “hot spots” (regions where the dose is excessively higher than prescribed) in the treatment volume and optimize the homogeneity of dose delivered in the treatment volume.25 This dose modulation is achieved by selectively designing additional fields that block out the hot spots of radiation dose in the treatment volume while increasing the dose in the cool regions, a technique commonly known as field-in-field. The multileaf collimators allow computer-controlled segments to be move into or out of the treatment field. The resulting plan is then reviewed and approved or modified by the radiation oncologist. Modification of the dose within the treatment volume to achieve a homogeneous dose distribution traditionally used external fixed wedges. These fixed wedges provided the physician with a limited number of solutions for excessive hot spots and “cold spots” (regions where the dose is excessively lower than prescribed) that arose within the treatment volume. In large-breasted women, one clinical consequence of hot spots within the normal tissue and treatment volume is damage to breast tissue that can contribute to a poor aesthetic outcome.26,27 The potential consequences of cold spots include underdosing the target volume, which may increase the risk of local recurrence. With the new generation of treatment-planning software and multileaf collimators, an infinite number of solutions may be created to optimize dose distribution within the treatment volume. Therefore, no matter how different one patient’s anatomy is from another, hot spots and cold spots can be minimized, thereby providing each individual patient with an optimal solution. At our institution, we use the field-in-field technique for dose modulation to minimize the high dose volume in tangential breast irradiation and potentially decrease the longterm side effects.28,29 The field-in-field technique is a form of intensity-modulated radiation therapy (IMRT) that varies
Steven J. Frank et al from the classic IMRT in that fields are created in a stepwise fashion to generate the optimal solution. In classic IMRT treatment, the physician defines planning goals and restrictions and the treatment planning software defines the optimal solution.30 The inverse planning usually results in the use of many beams and often delivers a low dose to a larger volume of normal tissues. Because of the potential carcinogenic risk of low dose delivery to the lungs and contralateral breast we have chosen not to use the inverse planning method.31 Additionally, dose heterogeneity has been shown to increase with respiratory motion with use of IMRT,32 and techniques that limit the intrafraction motion, such as respiratory gating, are currently being investigated. After CT simulation of the patient is performed, the radiation oncologist defines target volumes and designs treatment fields as discussed earlier, and then selects the dose and fractionation schedule that best achieve the therapeutic ratio. A medical dosimetrist then enters the data sets into a treatment-planning software system and generates an initial optimized open-beam treatment solution. The dose distribution in the target volume is defined with isodose curves, which display the volume of breast tissue treated with various doses (Figure 3). At our institution, isodose line increments of 5% greater than the prescribed dose are sequentially evaluated and eliminated to achieve greater homogeneity within the target volume to minimize the amount of radiation received by normal tissue and decrease potential adverse reactions. For example, after an initial optimized open-beam treatment solution is generated, there is often a 110%-isodose hot spot in the apex of the breast. An isodose cloud, which represents in 3D the portion of the treatment volume that has 10% greater dose than was prescribed by the physician, is then created. The medical dosimetrist creates a new field with the original treatment field that specifically blocks out the dose cloud (Figure 4). The dose and weighting of each treatment field is then modified so that the 110% dose cloud disappears. In practical terms, adjusting the multileaf collimator in the linear accelerator while treating the patient will generate this new field. Sequential dose clouds are then generated and additional field reductions are performed. The dose is modified as stated earlier, and this process undergoes multiple iterations until the ideal treatment planning solution is achieved.33 The treatment planning system not only increases dose uniformity by permitting selective reduction in high dose areas but also facilitates increased planning efficiency and shorter treatment delivery time.
Figure 4 Dosimetric Fields to Block Out Dose Cloud
A
B
C
Conclusion Exciting recent advances in radiation treatment planning for breast cancer have occurred during the past decade. Although these advances have increased treatment-planning time and cost, data on improved clinical outcomes with conformal therapy in prostate and head and neck cancer warrant further investigation in conformal breast cancer treatment.34 With the advent of CT simulators, there is an im-
A. A beam's-eye view of a 110% "hot spot" dose cloud in the apex of the right breast. B. Static intensity-modulated radiation beams (ie, field-in-field) can reduce the hot spots in the treatment volume and optimize the homogeneity of dose delivered in the treatment volume. C. Field-in-field selectively blocks out the hot spots of radiation dose in the treatment volume while maintaining the prescribed dose to the target volume.
Clinical Breast Cancer February 2004 • 405
Radiation Advances in Breast Cancer proved anatomic delineation between the target volumes and critical organ structures. Therefore, treatment fields can be designed that are more congruous to the tissue volumes at highest risk of recurrence. Future studies must critically evaluate whether this dosimetric benefit correlates with improved clinical outcomes.35 Through the development of 3D treatment-planning computer systems and improved dosimetric calculation algorithms, we are better able to calculate and visualize dose distributions throughout the treatment planning volume. Finally, modern accelerators allow for modulation of the dose intensity of the radiation beam, which may lead to improved skin aesthetics and decreased pulmonary and cardiac toxicity without compromising the prescribed dose to the target volume.
Acknowledgements The authors acknowledge financial support from grants CA16672 and T32CA77050 from the National Cancer Institute and from Department of Defense Breast Cancer Research Program Career Development Award BC980154.
References 1.
2. 3. 4. 5. 6. 7.
8. 9. 10. 11.
12.
Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985; 312:665-673. Veronesi U, Banfu A, Salvadori B, et al. Breast conservation is the treatment of choice in small breast cancer: long-term results of a randomized trial. Eur J Cancer 1990; 26:668-670. Buchholz TA, Strom EA, Perkins GH, et al. Controversies regarding the use of radiation after mastectomy in breast cancer. Oncologist 2002; 7:539-546. Arriagada R, Rutqvist LE, Le MG, et al. Postmastectomy radiotherapy: randomized trials. Semin Radiat Oncol 1999; 9:275-286. Katz A, Strom EA, Buchholz TA, et al. The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy. Int J Radiat Oncol Biol Phys 2001; 50:735-742. Patton ML, Moss, BE, Kraut JD, et al. Underutilization of breastconservation surgery with radiation therapy for women with stage Tis, I or II breast cancer. Int Surg 1996; 81:423-427. Hokanson P, Seshadri R, Miller KD, et al. Underutilization of breast-conserving therapy in a predominantly rural population: need for improved surgeon and public education. Clin Breast Cancer 2000; 1:72-76. Neugut AI, Weinberg MD, Ashan H, et al. Carcinogenic effects of radiotherapy for breast cancer. Oncology (Huntingt) 1999; 13:1245-1256. Hall EJ, Astor M, Bedford J, et al. Basic radiobiology. Am J Clin Oncol 1988; 11:220-252. Meeks SL, Buatti JM, Bova FJ, et al. Potentiol clinical efficacy of intensity-modulated conformal therapy. Int J Radiat Oncol Biol Phys 1998; 40:483-495. Kong FM, Klein EE, Bradly JD, et al. The impact of central lung distance, maximal heart distance, and radiation technique on the volumetric dose of the lung and heart for intact breast radiation. Int J Radiat Oncol Biol Phys 2002; 54:963-971. Leonardi MC, Brambilla MG, Zurrida S, et al. Analysis of irradiated lung and heart volumes using virtual simulation in postoperative treatment of stage I breast carcinoma. Tumori 2003; 89:60-67.
406 • Clinical Breast Cancer February 2004
13. 14.
15. 16.
17. 18. 19. 20. 21. 22. 23. 24.
25. 26.
27. 28. 29. 30. 31. 32. 33. 34. 35.
Regine WF, Ayyangar KM, Komarnicky LT, et al. Computer-CT planning of the electron boost in fefinitive breast irradiation. Int J Radiat Oncol Biol Phys 1991; 20:121-125. Muren LP, Maurstad G, Halslund G, et al. Cardiac and pulmonary doses and complication probaabilites in standard and conformal tangential irradiation in conservative management of breast cancer. Radiother Oncol 2002; 173-183. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. Early Breast Cancer Trialists’ Collaborative Group. N Engl J Med 1995; 333:1444-1455. Lind PA, Pagnanelli R, Marks LB, et al. Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution. Int J Radiat Oncol Biol Phys 2003; 55:914-920. Seddon B, Cook A, Gothard L, et al. Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy. Radiother Oncol 2002; 64:53-63. Das IJ, Chen EC, Freedman G, et al. Lung and heart dose volume analyses with CT simulator in radiation treatment of breast cancer. Int J Radiat Oncol Biol Phys 1998; 42:11-19. Storey MR, Munden R, Strom EA, et al. Coronary artery dosimetry in intact left breast irradiation. Cancer J 2001; 7:492-497. Herrick JS, Newman FD. Verification of a photon beam algorithm in a 3-D radiation therapy treatment planning system. Med Dosim 1999; 24:179-182. Davis JB, Pfafflin A, Cozzi AF, et al. Accuracy of two- and three-dimensional photon dose calculation for tangential irradiation of the breast. Radiother Oncol 1997; 42:245-248. Smitt MC, Goffinet DR. Utility of three-dimensional planning for axillary node coverage with breast-conserving radiation therapy: early experience. Radiology 1999; 210:221-226. Buchholz TA, Gurgoze E, Bice WS, et al. Dosimetric analysis of intact breast irradiation in off-axis planes. Int J Radiat Oncol Biol Phys 1997; 39:261-267. Rosenman JG, Chaney EL, Cullip TJ, et al. VISTAnet: interactive real-time calculation amd display of 3-dimensional radiation dose: an application of gigabit networking. Int J Radiat Oncol Biol Phys 1993; 25:123-129. Lo YC, Yasuda G, Fitzgerald TJ, et al. Intensity modulation for breast treatment using static multi-leaf collimators. Int J Radiat Oncol Biol Phys 2000; 46:187-194. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992; 10:356-363. Gray JR, McCormick B, Cox L, et al. Primary breast irradiation in large-breasted or heavy women: analysis of cosmetic outcome. Int J Radiat Oncol Biol Phys 1991; 21:347-354. Evans PM, Donavan EM, Partridge M, et al. The delivery of intensity modulated radiotherapy to the breast using multiple static fields. Radiother Oncol 2000; 57:79-89. Gagliardi G, Lax I, Soderstrom S, et al. Prediction of excess risk of long-term cardiac mortality after radiotherapy of stage I breast cancer. Radiother Oncol 1998; 46:63-71. Leibel SA, Fuks Z, Zelefsky MJ, et al. Intensity-modulated radiotherapy. Cancer J 2002; 8:164-176. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003; 56:83-88. George R, Keall PJ, Kini PR, et al. uantifying the effect of intrafraction motion during breast IMRT planning and dose delivery. Med Phys 2003; 30:552-562. Buchholz TA, Strom E, McNeese MD. The breast. In: Cox JD, Ang KK, eds. Radiation Oncology: Rationale, Techniques, Results, 8th ed. St. Louis, MO: Mosby, 2003:333-385. Tubiana M, Eschwege F. Conformal radiotherapy and intensity-modulated radiotherapy—clinical data. Acta Oncol 2000; 39:555-567. Hong L, Hunt M, Chui C, et al. Intensity-modulated tangential beam irradiation of the intact breast. Int J Radiat Oncol Biol Phys 1999; 44:1155-1564.
review
Advances in Radiation Treatments of Breast Cancer Steven J. Frank,1 Marsha D. McNeese,1 Eric A. Strom,1 George Perkins,1 Mohammad Salehpour,2 Naomi Schechter,1 Thomas A. Buchholz1 Abstract During the past decade, improvements in treatment-planning tools, computer and imaging technologies, and new therapeutic modalities have allowed radiation to be delivered in a conformal fashion while minimizing treatment toxicity. It is important that physicians involved in breast cancer treatment recognize the numerous advances that have occurred in the delivery of radiation therapy. Changes in 3 specific areas in treatment planning and delivery have revolutionized the way we approach breast cancer treatment: the design of radiation fields using computed tomography (CT) data sets, the development of 3-dimensional dose-calculation algorithms, and the development of new methods to modulate the delivery of radiation dose. With the advent of CT simulators, individual patient anatomy and pathology can be readily visualized and reconstructed in axial, coronal, and sagittal views. With an improved anatomic delineation between the target volumes and critical organ structures, the treatment fields can be designed to be more congruous to the areas at highest risk. In the past few years, new 3-dimensional dose-calculation algorithms have been generated that more accurately calculate dose distributions throughout the treatment-planning volume. Finally, modern linear accelerators allow for modulation of the dose intensity of the radiation beam, which may lead to improved aesthetics and decreased side effects while ensuring that the volumes at high risk receive the prescribed dose. Radiation therapy can be delivered safely and effectively to patients with breast cancer. Clinical Breast Cancer, Vol. 4, No. 6, 401-406, 2004 Key words: Computed tomography, Dose-calculation algorithms, Dose intensity, Linear acceleration, Radiation beam, Target volume
Introduction Radiation therapy is a critically important component of treatment for the majority of patients diagnosed with breast cancer. For patients with ductal carcinoma in situ or early-stage breast cancer, phase III randomized trials have conclusively demonstrated that radiation use reduces the probability of breast cancer recurrence.1,2 Radiation use after mastectomy is also considered to be the standard of
1Department of Radiation Oncology 2Department of Radiation Physics
The University of Texas M. D. Anderson Cancer Center, Houston Submitted: May 29, 2003; Revised: Jul 28, 2003; Accepted: Jul 30, 2003 Address for correspondence: Thomas A. Buchholz, MD, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcolmbe Blvd, Unit 97, Houston, TX 77030 Fax: 713-563-2366; e-mail: [email protected]
care for patients with advanced disease and for patients with stage II breast cancer with ≥ 4 positive lymph nodes.3-5 Despite clinical trials and studies clearly showing the benefits of radiation therapy in early-stage breast cancer, it remains underused in the United States.6,7 This underuse of radiation therapy may in part reflect a decision by the referring physician and/or the patient to forgo appropriate care because of concern over the toxicity of radiation treatment.8 Therefore, it is crucial that physicians recognize the numerous advances that have occurred in the delivery of radiation therapy and the resulting decrease in morbidity associated with treatment. Particularly during the past decade, improvements in treatment-planning tools, computer technologies, imaging technologies, and new therapeutic modalities allow radiation to be delivered in a much more conformal fashion. It is predicted that these technologic improvements will further minimize the risk of long-
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Breast Cancer February 2004 • 401
Radiation Advances in Breast Cancer Figure 1 Designing Radiation Field Using Computed Tomography
Computed tomography treatment planning permits the visualization of the highrisk areas of recurrence and regional lymphatics, which are identified in this supraclavicular treatment field. The visualization of the axillary lymph nodes and the internal mammary chain nodes permit optimal radiation treatment planning and delivery.
term treatment-associated morbidity. These recent advances have been revolutionary and have made the past decade one of the most intellectually and clinically exciting in the century-long history of radiation oncology. Unfortunately, radiation oncology is a relatively small field within the medical profession and these advances have been underappreciated by most physicians and patients with breast cancer. For radiation to kill breast tumor cells and avoid normal tissue injury, there must be a therapeutic ratio that allows for a selective killing of residual disease while normal tissue structure is preserved. For radiation treatments, biology and physics determine this therapeutic ratio. For example, normal tissue and tumors have different abilities to repair sublethal radiation damage. With fractionated therapy, this repair difference can be exploited and can lead to accumulation of damage selectively within tumors to the threshold of lethality.9 The biologic considerations of fractionated radiation treatment delivery have not significantly changed in the past decade. A number of the very early historical breast cancer clinical trials used fractionation schemes in excess of 2 Gy for treatment delivery, which are no longer considered standard. In the United States, the delivery of a daily dose of 1.8-2.0 Gy for 5-6 weeks has been standard for some time. Most of the recent advances in radiation treatments for breast cancer have been physics-based. Whereas the biology of fractionated therapy attempts to spare normal tissue within the treatment field, a primary goal of radiation physics is to determine the optimal delivery of radiation dose. Meticulous treatment planning is required to deliver the appropriate radiation dose selectively to the areas recognized to be at risk for cancer recurrence. The planning of radiation therapy requires an in-depth knowledge of clinical
402 • Clinical Breast Cancer February 2004
and radiographic anatomy, and must be individualized by taking into account the patient’s anatomy, volumes of tissue at risk, and critical organ structures. In this article, we review selected important technologic advances in radiation treatment for breast cancer. Three specific changes in treatment planning and delivery have revolutionized the way we approach breast cancer treatment. These changes include the design of radiation fields using computed tomography (CT) data sets, the development of 3-dimensional (3D) dose-calculation algorithms in treatment planning, and improved radiation treatment delivery by modulating the intensity of radiation therapy. Other breast treatment advances, including partial-breast irradiation with brachytherapy, external-beam radiation therapy, and respiratory gating, are under current investigation and will not be discussed in this article. The purposes of this article are to characterize recent technologic advances and to provide an overview of the consequences of these changes.
Designing Radiation Fields Using Computed Tomography Data Sets One of the most critical recent advances in the field of radiation oncology has been in the design of treatment fields. The goal of all radiation treatments is to include the region at risk of recurrence completely within the irradiated volume while minimizing the volume of normal tissue that receives coincidental treatment. Historically, the delineation of radiation fields for breast cancer was done based on an empiric understanding of anatomy and visualization of anatomic structures using fluoroscopy. Currently, at our institution, the construction of radiation fields is performed with use of a 3D rendering of the virtual anatomy obtained with treatment-planning CT. Many radiation oncology departments currently have dedicated CT scanners that are specifically designed for the purpose of radiation treatment planning. These CT scanners differ from diagnostic units in that they are equipped with lasers to provide orientation to 3D points in space that are used to verify the day-to-day patient alignment. They precisely correspond to similar laser-localized points associated with the linear accelerators that are used to deliver the radiation treatments. In addition, large-bore treatment-planning CT scanners are available to allow for accommodation of various bodies sizes, treatment positions, and immobilization devices. These devices are important to assure that patients are scanned in the exact position in which they will receive their radiation therapy. Each treatment field is individualized according to the patient’s anatomy, sites believed to be at risk of recurrence, and areas believed necessary to avoid complications. The use of CT in designing these fields is an exciting development for a number of reasons. First, the goal of radiation therapy in most patients with breast cancer is to kill the residual microscopic tumor cells present after surgery. Based on data documenting the recurrence patterns in early- and advanced-stage breast cancer, radiation therapy is used most
Steven J. Frank et al often in the adjuvant setting to facilitate local control of disease in the breast, chest wall, and selective regional lymphatics. Attempts to include the axilla and/or internal mammary lymph nodes were historically done based on an empiric understanding of lymphatic anatomy referenced to bony landmarks. Two-dimensional (2D) fluoroscopic simulations do not allow direct visualization of lymph nodes in the axilla, infraclavicular and supraclavicular fossa, or internal mammary chain. Conversely, with 3D CT simulation, the individual patient’s anatomy, including the lymphatics, muscles, vasculature, and nerves, may be visualized and reconstructed in axial, coronal, and sagittal views. Multiple iterations of treatment fields can be virtually generated on CT data sets to optimize the radiation fields. Although CT simulation provides imaging that is superior to traditional 2D simulations, its value for tangential field design during breast-conservation therapy has come into question secondary to the clinical significance and cost of treatment planning.10-12 To assist in the demarcation of targeted regions such as the postoperative surgical bed and lymph node basins, the anatomic areas at risk can be digitized on sequential axial CT slices. Subsequently, a 3D volume of each structure can be generated, and the relationship of this volume to the radiation field is more easily visualized.13 Therefore, the probability of an at-risk area falling outside the treatment field should be dramatically reduced with 3D CT simulations. An example of the type of reconstructed anatomic rendering is shown in Figure 1, illustrating the extent of an axillary dissection that can be easily visualized and included in a radiation field. Additionally, a digitized reconstruction of the upper internal mammary lymph nodes was obtained by outlining the anatomic region on sequential axial CT slices. These images significantly aid in the design of an optimal treatment plan. Ultimately, by minimizing the risk of a marginal miss, CT treatment planning may improve the efficacy of treatment and decrease dose to normal tissues.14 In addition to providing important information regarding the anatomic location of high-risk regions, another important result of CT simulation planning is the reduction in the dose to normal tissues. Data has shown that the design of radiation fields used for breast cancer treatment may increase the risk of cardiovascular deaths.15 Presumably, these deaths were secondary to treatment effects on the heart and coronary vasculature. When treating the left breast or left chest wall, care must be taken to avoid irradiation of the heart and coronary vessels because postirradiation perfusion defects have been observed.16,17 The apex of the heart is often difficult to visualize and precisely localize on tangential fluoroscopic images. Unlike fluoroscopic imaging, CT imaging provides better visualization of these critical organ structures and consequently can help to design fields that minimize dose to these critical organ structures.18 For example, the left anterior descending artery typically lies in close proximity to the deep border of tangential fields used to treat the breast or chest wall. Computed tomographic planning may permit the visualization
Figure 2 Dosimetric Planning of Breast-Conservation Therapy
The standard medial and lateral tangents for a patient receiving breast-conservation therapy illustrates the dosimetric challenge that includes increased "hot spots" at the apex of the breast. The shorter separation distance at the apex along the plane of the beam may increase normal breast tissue toxicity because of the higher dose of delivered radiation.
of the left anterior descending artery and provide the radiation oncologist with the opportunity to modify the design of the treatment fields to optimize for the individual patient.19 Additionally, the internal mammary vessels can be visualized on noncontrast CT, and the distance to these vessels is used to calculate the appropriate electron beam energy to treat this nodal region. Such precision is difficult with a fluoroscopic simulator, and there is a risk of missing part of the targeted volume and including more normal tissue than is actually necessary.
Three-Dimensional Dose-Calculation Algorithms in Treatment Planning Three-dimensional treatment planning includes the target volume delineation, beam geometry selection, and dose calculation. When the geometric design of the treatment fields is optimized to insure inclusion of therapeutic targets while minimizing normal tissue structures within the target volume, dosimetric planning occurs. The dose varies according to the physical properties of the radiation beam and tissue being treated. For example, in general, the dose of radiation decreases as the beam travels deeper into tissue. To accommodate for this, 2 opposed fields are often used and the dose falloff from each beam must be matched to provide a relatively uniform dose throughout the treatment volume. The technique of opposing fields is the standard for treatment of the breast, which is typically performed with a matched pair of medial and lateral tangent beams. However, the separation distance at the apex of the breast along the plane of the beam is much shorter than that at the base, so the corresponding
Clinical Breast Cancer February 2004 • 403
Radiation Advances in Breast Cancer Figure 3 Isodose Distribution Curves
thermore, other areas in the upper or lower portion of the field that would not be recognized and corrected with traditional 2D planning would commonly receive in excess of 110% of the prescribed dose.23 Although multiple axial levels may be visualized with 2D treatment planning, an advantage to 3D treatment planning is that the dose can be calculated and observed simultaneously in the axial, coronal, and sagittal planes to insure adequate coverage.
Modulating the Intensity of Radiation Therapy
This sagittal view of a patient receiving breast-conservation therapy illustrates the isodose distribution (percentage of prescribed dose) that is generated by medial and lateral tangential radiation treatment fields.
dose in the apex is higher than that at the base (Figure 2). To correct for these differences in dose across the volume, dosimetry planning is performed. Dosimetry planning optimizes dose uniformity, ensures that the target volume receives the prescribed dose, and verifies that the critical organ structures are spared unnecessary amounts of radiation. There are many approaches to treatment planning that may vary depending on the institution. Historically, at our institution, treatment planning consisted of optimizing the dose distribution in a single 2D axial plane in the center of the field. An external contour of the breast or chest wall in the center of the field was obtained by transposing a plaster cast or a wire during simulation. This external cast was transferred onto treatment-planning graph paper. Dosimetrists then calculated the resulting dose distributions on this central axial slice. The dose distribution could then be optimized through preferential weighting of the 2 fields and through introduction of beam-modification devices called wedges, which could decrease the dose at the apex relative to the base. In the past few years, new 3D dose-calculation algorithms have been generated that more accurately calculate dose throughout the entire 3D volume included in the field.20,21 In addition to permitting dose visualization in areas outside of the central plane, these new treatment-planning systems more accurately calculate dose because they account for differences in the density of the tissue within the fields (determined according to CT Hounsfield units). This improvement is clinically important in many ways, including improvement in coverage of the axilla.22 For example, we have demonstrated that 2D plans can fail to recognize a significant underdosage in the axillary lymph nodes (eg, 77% of nominal dose). Fur-
404 • Clinical Breast Cancer February 2004
One of the more recent and exciting advances in the radiation treatment of breast cancer lies in the ability to selectively modify the intensity of the radiation dose in the treatment volume. Pioneering work has advanced the ability to modulate the intensity of radiation therapy within the target volume.24 Numerous fields may be created to achieve a more uniform dose distribution, as opposed to the 2-field arrangements that have been conventionally designed. With the recent advent of the multileaf collimator, which resides inside the treatment head of modern linear accelerators, static intensity-modulated radiation beams can reduce the “hot spots” (regions where the dose is excessively higher than prescribed) in the treatment volume and optimize the homogeneity of dose delivered in the treatment volume.25 This dose modulation is achieved by selectively designing additional fields that block out the hot spots of radiation dose in the treatment volume while increasing the dose in the cool regions, a technique commonly known as field-in-field. The multileaf collimators allow computer-controlled segments to be move into or out of the treatment field. The resulting plan is then reviewed and approved or modified by the radiation oncologist. Modification of the dose within the treatment volume to achieve a homogeneous dose distribution traditionally used external fixed wedges. These fixed wedges provided the physician with a limited number of solutions for excessive hot spots and “cold spots” (regions where the dose is excessively lower than prescribed) that arose within the treatment volume. In large-breasted women, one clinical consequence of hot spots within the normal tissue and treatment volume is damage to breast tissue that can contribute to a poor aesthetic outcome.26,27 The potential consequences of cold spots include underdosing the target volume, which may increase the risk of local recurrence. With the new generation of treatment-planning software and multileaf collimators, an infinite number of solutions may be created to optimize dose distribution within the treatment volume. Therefore, no matter how different one patient’s anatomy is from another, hot spots and cold spots can be minimized, thereby providing each individual patient with an optimal solution. At our institution, we use the field-in-field technique for dose modulation to minimize the high dose volume in tangential breast irradiation and potentially decrease the longterm side effects.28,29 The field-in-field technique is a form of intensity-modulated radiation therapy (IMRT) that varies
Steven J. Frank et al from the classic IMRT in that fields are created in a stepwise fashion to generate the optimal solution. In classic IMRT treatment, the physician defines planning goals and restrictions and the treatment planning software defines the optimal solution.30 The inverse planning usually results in the use of many beams and often delivers a low dose to a larger volume of normal tissues. Because of the potential carcinogenic risk of low dose delivery to the lungs and contralateral breast we have chosen not to use the inverse planning method.31 Additionally, dose heterogeneity has been shown to increase with respiratory motion with use of IMRT,32 and techniques that limit the intrafraction motion, such as respiratory gating, are currently being investigated. After CT simulation of the patient is performed, the radiation oncologist defines target volumes and designs treatment fields as discussed earlier, and then selects the dose and fractionation schedule that best achieve the therapeutic ratio. A medical dosimetrist then enters the data sets into a treatment-planning software system and generates an initial optimized open-beam treatment solution. The dose distribution in the target volume is defined with isodose curves, which display the volume of breast tissue treated with various doses (Figure 3). At our institution, isodose line increments of 5% greater than the prescribed dose are sequentially evaluated and eliminated to achieve greater homogeneity within the target volume to minimize the amount of radiation received by normal tissue and decrease potential adverse reactions. For example, after an initial optimized open-beam treatment solution is generated, there is often a 110%-isodose hot spot in the apex of the breast. An isodose cloud, which represents in 3D the portion of the treatment volume that has 10% greater dose than was prescribed by the physician, is then created. The medical dosimetrist creates a new field with the original treatment field that specifically blocks out the dose cloud (Figure 4). The dose and weighting of each treatment field is then modified so that the 110% dose cloud disappears. In practical terms, adjusting the multileaf collimator in the linear accelerator while treating the patient will generate this new field. Sequential dose clouds are then generated and additional field reductions are performed. The dose is modified as stated earlier, and this process undergoes multiple iterations until the ideal treatment planning solution is achieved.33 The treatment planning system not only increases dose uniformity by permitting selective reduction in high dose areas but also facilitates increased planning efficiency and shorter treatment delivery time.
Figure 4 Dosimetric Fields to Block Out Dose Cloud
A
B
C
Conclusion Exciting recent advances in radiation treatment planning for breast cancer have occurred during the past decade. Although these advances have increased treatment-planning time and cost, data on improved clinical outcomes with conformal therapy in prostate and head and neck cancer warrant further investigation in conformal breast cancer treatment.34 With the advent of CT simulators, there is an im-
A. A beam's-eye view of a 110% "hot spot" dose cloud in the apex of the right breast. B. Static intensity-modulated radiation beams (ie, field-in-field) can reduce the hot spots in the treatment volume and optimize the homogeneity of dose delivered in the treatment volume. C. Field-in-field selectively blocks out the hot spots of radiation dose in the treatment volume while maintaining the prescribed dose to the target volume.
Clinical Breast Cancer February 2004 • 405
Radiation Advances in Breast Cancer proved anatomic delineation between the target volumes and critical organ structures. Therefore, treatment fields can be designed that are more congruous to the tissue volumes at highest risk of recurrence. Future studies must critically evaluate whether this dosimetric benefit correlates with improved clinical outcomes.35 Through the development of 3D treatment-planning computer systems and improved dosimetric calculation algorithms, we are better able to calculate and visualize dose distributions throughout the treatment planning volume. Finally, modern accelerators allow for modulation of the dose intensity of the radiation beam, which may lead to improved skin aesthetics and decreased pulmonary and cardiac toxicity without compromising the prescribed dose to the target volume.
Acknowledgements The authors acknowledge financial support from grants CA16672 and T32CA77050 from the National Cancer Institute and from Department of Defense Breast Cancer Research Program Career Development Award BC980154.
References 1.
2. 3. 4. 5. 6. 7.
8. 9. 10. 11.
12.
Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985; 312:665-673. Veronesi U, Banfu A, Salvadori B, et al. Breast conservation is the treatment of choice in small breast cancer: long-term results of a randomized trial. Eur J Cancer 1990; 26:668-670. Buchholz TA, Strom EA, Perkins GH, et al. Controversies regarding the use of radiation after mastectomy in breast cancer. Oncologist 2002; 7:539-546. Arriagada R, Rutqvist LE, Le MG, et al. Postmastectomy radiotherapy: randomized trials. Semin Radiat Oncol 1999; 9:275-286. Katz A, Strom EA, Buchholz TA, et al. The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy. Int J Radiat Oncol Biol Phys 2001; 50:735-742. Patton ML, Moss, BE, Kraut JD, et al. Underutilization of breastconservation surgery with radiation therapy for women with stage Tis, I or II breast cancer. Int Surg 1996; 81:423-427. Hokanson P, Seshadri R, Miller KD, et al. Underutilization of breast-conserving therapy in a predominantly rural population: need for improved surgeon and public education. Clin Breast Cancer 2000; 1:72-76. Neugut AI, Weinberg MD, Ashan H, et al. Carcinogenic effects of radiotherapy for breast cancer. Oncology (Huntingt) 1999; 13:1245-1256. Hall EJ, Astor M, Bedford J, et al. Basic radiobiology. Am J Clin Oncol 1988; 11:220-252. Meeks SL, Buatti JM, Bova FJ, et al. Potentiol clinical efficacy of intensity-modulated conformal therapy. Int J Radiat Oncol Biol Phys 1998; 40:483-495. Kong FM, Klein EE, Bradly JD, et al. The impact of central lung distance, maximal heart distance, and radiation technique on the volumetric dose of the lung and heart for intact breast radiation. Int J Radiat Oncol Biol Phys 2002; 54:963-971. Leonardi MC, Brambilla MG, Zurrida S, et al. Analysis of irradiated lung and heart volumes using virtual simulation in postoperative treatment of stage I breast carcinoma. Tumori 2003; 89:60-67.
406 • Clinical Breast Cancer February 2004
13. 14.
15. 16.
17. 18. 19. 20. 21. 22. 23. 24.
25. 26.
27. 28. 29. 30. 31. 32. 33. 34. 35.
Regine WF, Ayyangar KM, Komarnicky LT, et al. Computer-CT planning of the electron boost in fefinitive breast irradiation. Int J Radiat Oncol Biol Phys 1991; 20:121-125. Muren LP, Maurstad G, Halslund G, et al. Cardiac and pulmonary doses and complication probaabilites in standard and conformal tangential irradiation in conservative management of breast cancer. Radiother Oncol 2002; 173-183. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. Early Breast Cancer Trialists’ Collaborative Group. N Engl J Med 1995; 333:1444-1455. Lind PA, Pagnanelli R, Marks LB, et al. Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution. Int J Radiat Oncol Biol Phys 2003; 55:914-920. Seddon B, Cook A, Gothard L, et al. Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy. Radiother Oncol 2002; 64:53-63. Das IJ, Chen EC, Freedman G, et al. Lung and heart dose volume analyses with CT simulator in radiation treatment of breast cancer. Int J Radiat Oncol Biol Phys 1998; 42:11-19. Storey MR, Munden R, Strom EA, et al. Coronary artery dosimetry in intact left breast irradiation. Cancer J 2001; 7:492-497. Herrick JS, Newman FD. Verification of a photon beam algorithm in a 3-D radiation therapy treatment planning system. Med Dosim 1999; 24:179-182. Davis JB, Pfafflin A, Cozzi AF, et al. Accuracy of two- and three-dimensional photon dose calculation for tangential irradiation of the breast. Radiother Oncol 1997; 42:245-248. Smitt MC, Goffinet DR. Utility of three-dimensional planning for axillary node coverage with breast-conserving radiation therapy: early experience. Radiology 1999; 210:221-226. Buchholz TA, Gurgoze E, Bice WS, et al. Dosimetric analysis of intact breast irradiation in off-axis planes. Int J Radiat Oncol Biol Phys 1997; 39:261-267. Rosenman JG, Chaney EL, Cullip TJ, et al. VISTAnet: interactive real-time calculation amd display of 3-dimensional radiation dose: an application of gigabit networking. Int J Radiat Oncol Biol Phys 1993; 25:123-129. Lo YC, Yasuda G, Fitzgerald TJ, et al. Intensity modulation for breast treatment using static multi-leaf collimators. Int J Radiat Oncol Biol Phys 2000; 46:187-194. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992; 10:356-363. Gray JR, McCormick B, Cox L, et al. Primary breast irradiation in large-breasted or heavy women: analysis of cosmetic outcome. Int J Radiat Oncol Biol Phys 1991; 21:347-354. Evans PM, Donavan EM, Partridge M, et al. The delivery of intensity modulated radiotherapy to the breast using multiple static fields. Radiother Oncol 2000; 57:79-89. Gagliardi G, Lax I, Soderstrom S, et al. Prediction of excess risk of long-term cardiac mortality after radiotherapy of stage I breast cancer. Radiother Oncol 1998; 46:63-71. Leibel SA, Fuks Z, Zelefsky MJ, et al. Intensity-modulated radiotherapy. Cancer J 2002; 8:164-176. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003; 56:83-88. George R, Keall PJ, Kini PR, et al. uantifying the effect of intrafraction motion during breast IMRT planning and dose delivery. Med Phys 2003; 30:552-562. Buchholz TA, Strom E, McNeese MD. The breast. In: Cox JD, Ang KK, eds. Radiation Oncology: Rationale, Techniques, Results, 8th ed. St. Louis, MO: Mosby, 2003:333-385. Tubiana M, Eschwege F. Conformal radiotherapy and intensity-modulated radiotherapy—clinical data. Acta Oncol 2000; 39:555-567. Hong L, Hunt M, Chui C, et al. Intensity-modulated tangential beam irradiation of the intact breast. Int J Radiat Oncol Biol Phys 1999; 44:1155-1564.