Breast Cancer: New Radiation Treatment Options

Transcription

1 Review Article [1] November 01, 2004 By Douglas W. Arthur, MD [2], Monica M. Morris, MD [3], and Frank A. Vicini, MD [4] Conventional radiotherapeutic treatment for early and advanced breast cancer has been based on broad-field radiation treatment principles that date back several decades. Although these strategies have been successful, newer techniques now offer the ability to incorporate improved target imaging, dosimetric planning, and treatment delivery into the treatment design. These newer techniques include accelerated partial-breast irradiation and hypofractionated whole-breast irradiation for early-stage breast cancer, and intensity-modulated radiotherapy (IMRT) for both early and advanced breast cancer. Accelerated partial- breast irradiation and hypofractionated whole-breast radiotherapy are treatment approaches that promise both reduced overall treatment times and the potential for increased use of breast-conservation therapy. IMRT offers unparalleled dose homogeneity and conformality that enables dose reduction to normal structures with the potential to reduce treatment toxicity and improve cosmesis. Based on the published literature, an increasing number of treatment facilities are offering treatment with these techniques. However, further clinical study remains important to thoroughly define the appropriate clinical setting, patient selection criteria, and limitations for each of these innovative treatment approaches. Radiotherapy has long since established itself as integral in the treatment of breast cancer. From early-stage to locally advanced disease, radiotherapy has been incorporated into the treatment plan for patients with breast cancer, based upon the known reduction in the risk of locoregional failure and evidence suggesting an improvement in overall survival.[ 1-4] The extent of the areas targeted for treatment has been historically based on previously established surgical principles, pathologic findings, and failure patterns. This has resulted in broad-field irradiation, encompassing the whole breast and/or chest wall with or without regional nodes. These original broad fields were simplistic in design and limited by the planning and treatment delivery systems available. However, because of their simplicity, success in reducing disease recurrence, and ease of implementation, these treatment techniques quickly became widely adopted. In fact, the majority of treatment centers continue to use these same general disease management principles and treatment approaches originally designed and practiced in the 1970s and 1980s. Although upgraded field-matching techniques and com puted tomography (CT)-based treatment planning have been incorporated, only minimal modifications have been made until recently. Whole-breast radiotherapy has routinely provided acceptable local control rates and cosmetic outcomes.[ 1,2,5] However, despite the excellent results, a surprising number of women-more than half-alternatively undergo a mastectomy or breastconserving surgery without the recommended adjuvant radiotherapy.[ 6,7] Although patient preference may account for some of these choices, many appear to take this course due to the time and travel difficulties presented by the standard 6 weeks of daily radiotherapy. Others balk at the recommended radiotherapy out of fear of toxicity. Improving Radiation Treatment Designs Recent investigations into the radiation treatment of breast cancer allow the incorporation of improved target imaging, dosimetric planning, and treatment delivery into the treatment design. With early positive evidence, this treatment technology is now beginning to disseminate and become more commonly practiced in the United States. New treatment techniques that utilize this technology offer the reduction of overall treatment time, optimized homogeneity of dose delivery, and improved dose conformality to the target. New radiation treatment approaches include accelerated partial-breast irradiation and hypofractionated whole-breast irradiation for early-stage breast cancer, and intensity-modulated radiotherapy (IMRT) for both early and advanced breast cancer. Determining the Treatment Target The combination of radiographic imaging and radiation treatment planning continue to advance the specialty of radiation oncology, providing the ability to create highly conformal dosimetric plans. To maximize the effectiveness of this process, the treatment target must be well imaged and clearly defined. In breast-conservation therapy, the convention is to treat the whole breast. However, whether measured by physical exam or CT evaluation, the extent of breast tissue is difficult to delineate.[8] With con- continued study, it has become obvious that the whole-breast target volume is frequently not completely encompassed within the bounds of standard tangential fields. Despite this, local control rates approach 95% in contemporary studies. On the other hand, knowing that not Page 1 of 10

2 all patients with early-stage breast cancer benefit from postlumpectomy radiotherapy (approximately 60%), many studies have searched for a reliably identifiable subgroup of breast cancer patients who might be safely excused from postlumpectomy radiation.[ 9,10] This subgroup has not yet been identified, and therefore, it is recommended that all patients should complete radiation therapy following breast-conserving therapy. This logic leads us to the conclusion that the size of the target requiring treatment following lumpectomy is greater than the lumpectomy cavity itself but less than the whole breast. Development of Partial-Breast Irradiation In the early 1990s, the problem of physician and patient compliance with recommended postlumpectomy radiotherapy was confronted with a proposal suggesting that if the target to be treated following lumpectomy is not the whole breast, but rather, a reduced volume of breast tissue delineated by a margin of tissue around the lumpectomy cavity, then the treatment time could possibly be reduced to 5 days, ie, accelerated partial-breast irradiation. Clinical data have documented that the overwhelming majority of in-breast failures following breast-conservation therapy are in the immediate vicinity of the lumpectomy cavity (referred to as true recurrences). Although the frequency of these true recurrences is greatly reduced with postlumpectomy radiotherapy, the location of the majority of in-breast failures remains at the site of lumpectomy.[2,11,12] Interestingly, the pattern of "elsewhere failures" (in-breast failures remote from the site of lumpectomy) remains infrequent (< 5%) and unaltered with the addition of externalbeam radiotherapy. These data support the concept that the impact of whole wholebreast radiotherapy is exclusively at the site of the original primary lesion and that it does not have the ability to prevent new primary disease from arising elsewhere in the breast at a later date.[13] The clinical failure pattern data suggest that accelerated partial-breast irradiation should be successful and equivalent to standard whole-breast radiotherapy. However, delineation of the target requiring treatment is not yet clearly defined. Shortcomings of Pathologic Studies There has been considerable speculation on how far microscopic disease might extend from the cavity edge. The most logical place to look for guidance in defining the target would be the pathologic literature, but little contemporary guidance is available. The classic pathologic studies examining mastectomy specimens are now over 20 years old. It would be inappropriate to extrapolate the findings from these studies to patients treated in the modern era, where advanced mammographic technology allows earlier detection, and modern surgical and pathologic techniques enable the removal of malignant lesions with microscopically negative margins. Unfortunately, there is a paucity of contemporary pathologic studies that address this question. To date, three published studies have focused on the distance of microscopic disease extension from the primary lesion.[14-16] These studies suggest that the microscopic extension of disease beyond the primary lesion is no greater than 1 cm in a population of patients more than 45 to 50 years old. The maximal disease extension in younger patients was documented to be beyond 1 cm. Limitations of these studies include low patient numbers, measurement of the extension of ductal carcinoma in situ only, and difficulty in extrapolating the measured distance from the edge of the primary lesion to a case where the surgeon obtained a negative microscopic margin. Although these pathologic studies can be criticized as to their relevance, they support the concept of limitedfield radiotherapy following lumpec- tomy for early-stage breast cancer. Relevant pathologic studies refuting the concept of accelerated partialbreast irradiation and supporting the need for whole-breast radiotherapy have not been identified. Accelerated Partial-Breast Irradiation For accelerated partial-breast irradiation to be accepted into the common practice of radiation oncology, treatment techniques that are safe and reproducible need to be available, and data demonstrating equivalence to standard breast-conservation therapy must be reported. Presently, reports in the literature begin to support both of these requirements. Brachytherapy, three-dimensional (3D) externalbeam, and intraoperative radiotherapy have been the three accelerated partial- breast irradiation treatment approaches investigated. Brachytherapy In the United States, a fractionated course of high-dose-rate brachytherapy has been the primary focus of treatment delivery. Multicatheter brachytherapy was the initial treatment technique used at the onset of accelerated partial-breast irradiation and is the technique used in the experiences reported with the longest follow-up. Guidelines for implant construction were based on the experience generated from the era prior to the widespread use of electrons, when multicatheter brachytherapy was used to deliver a boost dose to the surgical bed in addition to whole-breast radiotherapy. Building on this experience, coupled with the brachytherapy-only guidelines for sarcoma treatment from Memorial Sloan-Kettering, a dose of 45 Gy low-dose-rate brachytherapy was delivered to the surgical bed plus a 1-to 2-cm margin.[17] Over time, this was converted to high-dose-rate brachytherapy for added control over planning and dose delivery, and for the benefit Page 2 of 10

3 of outpatient treatment and increased safety for the faculty and staff. Although criticized for its operator dependency and associated learn- learning curve when first starting, the incorporation of radiologic imaging in the guidance of catheter placement in concert with 3D treatment planning has greatly reduced these challenges.[ 18,19] Regardless, there will always be some degree of a learning curve when starting, and there is no possible way to remove the distressing appearance of the breast when multiple catheters are in place. MammoSite-The MammoSite Radiation Therapy System was developed to address the difficulties involved in multicatheter brachytherapy with the goal of simplifying the procedure, improving the reproducibility of dose delivery, and therefore, increasing the availability of accelerated partial-breast irradiation. The research and development of this device has focused on the ability to reproduce the target coverage and dosimetry achieved with published multicatheter brachytherapy techniques. The MammoSite Radiation Therapy System is composed of a 15-cm catheter that is 6 mm in diameter (Figure 1). At the distal end of the catheter is a balloon that can be symmetrically inflated to a sphere with a 4- to 5-cm diameter, or a larger size is available that inflates to 5 to 6 cm. The balloon is placed and inflated in the lumpectomy cavity with the catheter exiting either through the lumpectomy incision or a separate exit wound. Placement is easily accomplished at the time of lumpectomy or postlumpectomy and placed by the involved surgeon or radiation oncologist. When properly placed, treatment is delivered to a uniform 1-cm depth from the balloon surface.[20,21] Since the time of US Food and Drug Administration approval in May 2002, use of the system has been adopted in many locations across the country. It is estimated that more than 4,000 balloons have been used for treatment since that time. 3D Conformal External-Beam Radiotherapy The latest partial-breast technique to be investigated is 3D conformal external-beam radiotherapy. The ability to deliver a similarly conformal dose to the target with a noninvasive approach is attractive to both patients and physicians. Pilot studies have been completed, and a national phase I/II trial has recently been completed.[ 22,23] Unique to this treatment approach is the challenge of adjusting for patient setup error and breathing motion, and assuring that the homogeneous dose delivered is radiobiologically equivalent to the relatively inhomogeneous dose delivered with brachytherapy. The William Beaumont Hospital recently published an update of their pilot experience Page 3 of 10

4 with 3D conformal partial-breast irradiation. A total of 31 patients have been treated with a median follow-up of 10 months, and 15 patients have been followed for at least 1 year. The described approach includes strict normal tissue dose restrictions, defining the clinical target volume (CTV) as the lumpectomy cavity plus 1 to 1.5 cm, and the planning target volume (PTV) as the 1-cm expansion of the CTV. This additional PTV margin was applied to address the potential for setup error and breathing motion. A treatment scheme of 34 Gy in 10 fractions was initially used for six patients and then altered to 38.5 Gy in 10 fractions. The reported acute toxicity was minimal with no grade 3 toxicities, 3 grade 2, 19 grade 1, and 9 patients with no acute toxicities. Additional follow-up is needed, although it should be noted that the dose scheme used and volumes treated with this technique parallel the brachytherapy partial-breast experience, for which acceptable late toxicity has been reported with 5-year follow-up.[24] Intraoperative Radiotherapy Beyond the United States, treatment approaches have predominantly been intraoperative, delivering a large single-dose fraction to the target at the time of lumpectomy. Concerns have been voiced regarding the ability to properly select patients and delineate and cover the target, and the risk of fibrosis resulting from the dose delivered as a large single fraction. Despite these concerns, it is hard to argue the attractiveness of a treatment approach that completes all local therapy in one trip to the operating room. To date, the early reports from these investigations have not described excessive failures or soft-tissue toxicity.[25,26] At the University College of London, this treatment is completed with the placement of a soft x-ray device into the lumpectomy cavity to deliver 21 Gy to a 2-mm depth. Intraoperative electrons are used at the European Institute of Oncology, where 21 Gy is delivered to the postlumpectomy breast tissue judged to be at risk for failure. The target is surgically manipulated so that it is easily encompassed within the electron field while temporarily pulling the skin out of the field and placing deep shielding to protect the underlying chest wall and lung. Patient Selection Criteria and Quality Assurance When reviewing the literature, specific attention should be directed to the details regarding patient selection criteria and quality assurance guidelines involved in the treatment experience. In studies for which both of these entities are clearly included, the outcome data are consistent and comparable to the conventional whole-breast external-beam experience (Table 1).[20,22-36] Conservative patient selection criteria have been outlined by both the American Brachytherapy Society (ABS) and the American Society of Breast Surgeons (ASBS).[37,38] Both groups agree that patients should be older than 45 to 50 years and all cases should first be acceptable for conventional breast-conservation therapy. Additional selection criteria include primary lesions that are unifocal, small (ABS suggests < 3 cm, ASBS recommends < 2 cm), resected with negative microscopic margins, and with axillary lymph nodes evaluated and negative. The ABS advises restricting accelerated partial-breast irradiation to patients with infiltrating ductal carcinoma histology only, based on the fact that little data exist to suggest that additional histologies should be included. The ASBS is in concordance with this, but with the addition of ductal carcinoma in situ, extrapolating from data suggesting that wide excision alone may be sufficient treatment.[ 39] The guidelines for quality assurance should include a target definition of at least the lumpectomy cavity plus a 1- to 2-cm margin, and the methodology of treatment delivery describing verification of the prescribed dose to the target volume. All three of these partial-breast treatment approaches allow for thorough evaluation for proper patient selection and subsequent target delineation and assurance of target coverage prior to treatment delivery. Additionally, these approaches allow for dose delivery that is fractionated, reducing the risk of late toxicity, ie, fibrosis or fat necrosis. Future Directions Although accelerated partial-breast irradiation is being offered in an increasing number of facilities across the United States, this treatment approach has not yet been accepted as an alternative method of local management for early-stage breast cancer by the entire breast oncology community. Some physicians believe additional data supporting the concept of accelerated partial-breast irradiation are needed prior to generalized acceptance; however, it should be noted that patients are now seeking out locations that offer accelerated partial- breast irradiation, and an increasing number of physicians are offering this treatment based on current data. Despite the availability of 5-year data and the acceptance of this treatment approach, additional investigation is necessary. Future studies should appropriately focus on the development of well-conducted protocols that will further define the appropriate patient selection criteria and continue the development of treatment techniques. Several phase I/II trials are now being conducted, and many more are in development. Additionally, a national phase III trial which will be jointly managed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG), has been developed and will be open for accrual later this year. Hypofractionated Whole-Breast Irradiation Reduction of treatment time to improve patient access and maximize Page 4 of 10

5 availability of treatment resources has also been the focus of study in Cana da. In a prospective randomized trial, investigators have demonstrated the equivalency of two radiation treatment schemes, thus reducing the treatment time from 5 to 3 weeks while maintaining the conventional whole-breast treatment target.[40] In this trial, 1,234 patients were randomized between a short course of radiotherapy, 42.5 Gy in 16 fractions, and a standard course of radiotherapy, 50 Gy in 25 fractions. All patients were diagnosed with T1/T2 infiltrating breast carcinoma and resected with microscopically negative margins. All patients were axillary node-negative. With a median follow-up of 69 months, they reported the observed local recurrence rate, disease-free survival, overall survival, and cosmetic outcome to be equivalent. Local re- currence rates at the time of the report were 3.2% vs 2.8% for the standard and short treatment courses, respectively. Cosmetic outcome was reported as good/excellent in approximately 75% in both treatment arms. These results have mostly been ignored in the United States, as there continues to be a reluctance to adopt this hypofractionated treatment course. Although there has been some level of academic discussion regarding the possible limitations of these data,[41] it would appear that the motivation to change from a 6-week course that includes a boost to a 3-week course without a boost is lacking. The actual reasoning behind this lack of motivation is uncertain but may be due to the overshadowing anticipation of accelerated partial-breast irradiation, which will reduce the overall treatment time to 5 days. Nevertheless, it should be noted that the NSABP has recently extended their adjuvant external-beam radiotherapy guidelines for all existing protocols to include the Canadian hypofractionated treatment scheme. Intensity-Modulated Radiation Therapy While the Page 5 of 10

6 partial-breast irradiation and hypofractionated treatment approaches discussed previously have the main goal of reducing overall treatment time, the goal of IMRT is improved dose homogeneity, target coverage, and decreased toxicity. IMRT represents an optimized extension of currently employed 3D conformal radiotherapy techniques, offering improved dose conformality, as well as greater dose homogeneity within the target volume and sharper dose gradients at the margins of target tissues. IMRT provides sophisticated, computer-optimized intensity distributions within the fields of multiple dynamic radiation beams. The high degree of conformality possible with IMRT promises improved toxicity profiles through reduced daily and total doses to adjacent normal structures. The main goal of IMRT in the setting of breast cancer is the delivery of a much more homogeneous and/or conformal treatment plan. As compared to today's standard treatment plans, IMRT has the potential to improve target volume coverage, reduce dose inhomogeneities, and significantly reduce doses to normal tissues, such as heart and lung, in patients receiving comprehensive regional nodal radiotherapy. IMRT is uniquely suited to the homogeneous treatment of difficult target geometries, such as that presented by a breast overlying concave chest wall. Advantages of IMRT In the treatment of early-stage breast cancer, the use of IMRT can reduce the volume of lung that would receive the full dose and, in left-sided cases, reduce the volume of heart as compared to standard tangential radiotherapy fields. The application of IMRT to this clinical situation offers the potential for reducing unnecessary dose delivery to heart and lung volumes, while maintaining maximal target coverage.[42] Improved dose distributions in the whole breast can result in clinical improvements, but the need for improved dose distribution is yet more compelling and challenging in the setting of comprehensive radiotherapy to regional nodal areas,[43,44] for which the complexity of treatment planning is greater. It should be realized that when IMRT is used, radiation may be delivered to normal tissues outside of the breast that would typically not have been irradiated.[45] The longterm effect of low-dose irradiation to a greater volume is currently unknown. Given that breast cancer patients generally experience long survival times, they may be at risk for the development of second malignancies or other late complications. As research progresses in this area, clinical judgment will need to balance the potential risks of irradiating greater volumes of soft tissues against the potential benefits of a more homogeneous and conformal dose, with reduced exposure to normal vital structures. Several groups have demonstrated improved dose distributions to the breast using IMRT, as compared to standard planning.[46-55] The largest clinical experience with wholebreast IMRT was recently published by the William Beaumont Hospital group.[56] A total of 281 patients with early-stage breast cancer who elected breast-conserving therapy received whole-breast radiotherapy after lumpectomy using a static multileaf collimator IMRT technique. The technical and practical aspects of implementing this technique on a large scale in the clinic were analyzed, as well as the clinical outcome of the patients. Treatment time was equivalent to conventional wedged-tangent treatment techniques. The median volume of breast receiving 105% and 110% of the prescribed dose was 11% (range: 0%-68%) and 0% (range: 0%- 39%), respectively. No or mild acute skin toxicity was noted in 56% of patients; 43% experienced moderate, grade 2 acute skin toxicity; and only 3 patients (1%) had significant, grade 3 toxicity. Among the 95 evaluable patients, cosmetic results at 1 year were rated as excellent or good in 94 (99%). No skin telangiectasias, significant fibrosis, or persistent breast pain were noted. The authors concluded that the use of intensity modulation using their static multileaf collimator technique for tangential whole-breast radiotherapy was an efficient method for achieving a uniform and standardized dose throughout the whole breast. Techniques Compared The majority of published studies have primarily investigated IMRT in the setting of breast/chest wall-only treatment, rather than the breast/chest wall and regional lymphatics treated in more locally advanced disease. It is the latter scenario that has the more compelling need for improvements in dose distribution, as comprehensive radiotherapy-nvolving breast, chest wall, supraclavicular, and internal mammary nodes-presents a convoluted target volume in close proximity to lung, heart, and medi- astinum.[44,57] Although 3D treatment planning can improve the dosimetric coverage of this complex target volume and reduce normal tissue exposure, conventional techniques have not yet been shown to reproducibly achieve goals of target coverage in all patients. Cho et al[58] compared IMRT and non-imrt techniques in the treatment of the left breast and internal mammary nodes and demonstrated superior breast and internal mammary chain target coverage. Krueger et al[43] used a nine-field axial IMRT plan to demonstrate significantly improved chest wall coverage using IMRT as compared to standard tangents, while minimizing normal tissue complication probabilities for cardiac ischemia. In this setting, IMRT also improved the internal mammary node coverage and significantly reduced normal lung tissue complication probabilities in all patients, despite a wide range of body habitus. The William Beaumont Hospital group is actively investigating the use of active breathing Page 6 of 10

7 control in conjunction with IMRT to incorporate short breath-holds timed to treatment delivery in order to maximally displace heart from chest wall.[59] Their studies comparing this technique to standard radiotherapy demonstrate a significant reduction in mean percentage of heart receiving 30 Gy or greater and in mean percentage of lung volume receiving 20 Gy or greater. However, with their IMRT approach, the radiation dose to contralateral breast was greater than typical. Their preliminary clinical experience treating patients with radiation to the breast only showed the technique to be well tolerated and time-efficient, confirming the practical application of this technology in the clinic.[60,61] Several groups are exploring various versions of whole-breast IMRT,[47,48,52] and several randomized studies have been initiated in Europe and Canada to compare conventional tangential radiotherapy with IMRT for breast-only treatment. These trials should prove useful in quantifying the need and benefits for IMRT in the setting of early-stage breast cancer. Currently, clinical use of IMRT for comprehensive regional-nodal irradiation should still be considered investigational. The impact of breathing motion and treatment setup uncertainties on the accurate delivery of these highly complex treatment fields has not yet been fully evaluated. As IMRT increasingly becomes the "gold standard" of radiotherapy treatment delivery, issues regarding quality assurance, treatment delivery accuracy, and long-term outcome need to be resolved before locoregional breast IMRT can be routinely used in the clinic. Conclusions Conventional radiotherapy techniques for the treatment of breast cancer have yielded excellent local and locoregional control rates, and therefore, have been in use for several decades with minimal modification. With the use of proper surgical and radiotherapeutic techniques, improvements in local control with new technology would be difficult to demonstrate. Therefore, research has focused on improving patient quality of life by reducing the overall treatment time and introducing techniques that may reduce acute and late normal tissue effects. With advances in imaging, treatment planning, and treatment delivery, we now have opportunities to introduce new treatment techniques that promise several advantages while maintaining the familiar high rates of local control. These opportunities exist in both early- and advanced-stage breast cancer. Published data demonstrate that overall treatment time for early-stage breast cancer can be reduced with either accelerated partial-breast irradiation or a hypofractionated course of whole-breast radiotherapy. Additional research will help to further define appropriate patient selection criteria and determine the advantages of the various techniques. Addressing a different concern, IMRT provides the tools to improve dose homogeneity and dose conformality. The introduction of IMRT in the treatment of breast cancer promises reduced soft-tissue toxicity in simple, breast-only treatment and the potential for improved locoregional control without an increase in lung and heart toxicity in locally advanced breast cancer. Additional research and follow-up of IMRT-treated patients is needed to fully evaluate the role of IMRT in the treatment of breast cancer. As the public becomes more aware of these newer treatment techniques, it will be increasingly important for physicians to know how to best incorporate these treatment techniques into clinical practice. Clinicians must also become involved in properly designed clinical studies that will allow the application of these techniques to expand to their full potential and define their limitations. 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