|Year : 2007 | Volume
| Issue : 4 | Page : 231-235
External hypofractionated whole-breast radiotherapy: Now where does accelerated partial breast irradiation stand?
Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai, India
Department of Radiation Oncology, 120, Tata Memorial Hospital, Parel, Mumbai - 400 012
Breast-conserving therapy (BCT) has emerged as a viable option for suitable breast cancer patients who are desirous of preserving the breast. The major advantage of BCT is the good cosmetic outcome with disease-free and overall survival similar to mastectomy. In this article, I have compared two emerging modalities for treating a preserved breast with radiotherapy. These two techniques in breast cancer - accelerated partial breast irradiation (APBI) and hypofractionated whole breast external beam radiotherapy - have their respective merits and drawbacks, and this article attempts to dissect the issue.
Keywords: Accelerated partial breast irradiation, hypofractionated, whole-breast radiotherapy
|How to cite this article:|
Munshi A. External hypofractionated whole-breast radiotherapy: Now where does accelerated partial breast irradiation stand?. J Can Res Ther 2007;3:231-5
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Munshi A. External hypofractionated whole-breast radiotherapy: Now where does accelerated partial breast irradiation stand?. J Can Res Ther [serial online] 2007 [cited 2013 Jun 19];3:231-5. Available from: http://www.cancerjournal.net/text.asp?2007/3/4/231/38999
Breast-conserving therapy (BCT), over the past few years, has found acceptance as an appropriate modality in the management of breast cancer. The major benefit of BCT is the preservation of the affected breast, with consequent advantages in terms of quality of life. It helps women avoid the feelings of disfigurement and mutilation that is associated with modified radical mastectomy.  Large randomized trials have proven the equivalence of BCT compared to mastectomy in terms of long-term disease-free and overall survival rates. ,
The conventional treatment of radiotherapy after breast-conserving surgery requires 6-7 weeks of daily treatment. This long duration of postoperative radiotherapy is often regarded as a deterrent to breast conservation. Any treatment technique or innovation which reduces the treatment time should therefore be of interest to clinicians, patients, and health policy planners alike. In this context two treatment techniques have emerged over the past decade. The first is accelerated partial breast irradiation (APBI). This technique involves irradiation of only a partial volume of the breast with accelerated radiotherapy by methods such as multicatheter brachytherapy, mammosite, or intraoperative electrons. The second is hypofractionated external beam radiotherapy (HERT) to the whole breast. APBI and whole-breast hypofractionated radiotherapy may now compete with each other in potential applications. Interestingly, both these techniques share the common advantage of reduced treatment time.
| > Accelerated Partial-Breast Irradiation|| |
Accelerated partial breast irradiation (APBI) is defined as a radiation technique that employs fractions higher than 1.8-2.0 Gy per day to a partial volume of the breast over a period of less than 5-6 weeks. The rationale of this technique is to treat the lumpectomy cavity and an adjacent margin of 1-2 cm. This includes a range of techniques, such as interstitial implantation, mammosite, targeted intraoperative therapy (TARGIT), and intraoperative electrons, the first two being the most popular. Earlier APBI series had reported unacceptable local control rates and the selection criteria of patients for APBI were modified subsequently. Various guidelines now exist for including patients in APBI protocols (see [Table - 1] and references). Tumor size >3 cm, positivity for extensive intraductal component (EIC), lymphovascular emboli (LVE), positive axillary nodes, and young age are generally recognized as exclusion criteria for APBI techniques. Multicatheter brachytherapy involves placing catheters in two or more planes in the breast, either during or after breast conservation surgery. The aim is to treat a 1-2 cm margin beyond the operative cavity. These catheters remain in place for a few days, during which radiotherapy is delivered either by a low dose-rate (LDR) source or an intermittent (usually twice daily) treatment by a high dose-rate (HDR) source.
Mammosite is a balloon-shaped device inserted during or after surgery. It consists of an inflatable balloon with a central lumen for source delivery (usually HDR). This device treats a 1-2 cm area around the cavity (which is occupied by the inflated balloon). Due to its ease of application, it is the most frequent form of APBI practiced in the United States. ,, The results of newer APBI trials are shown in [Table - 1]. As can be seen, the local failure rates have been <5% at 5 years, a figure that can be compared to that of traditional whole-breast radiotherapy. Besides, APBI does not seem to have any detrimental effect on cosmesis.
Since the treatment time is reduced from 6 weeks to 1 week or less, this technique has the potential to be a landmark in the evolution of radiotherapy in breast cancer.
| > Pitfalls of APBI|| |
Since the maximum evidence in APBI is for interstitial brachytherapy and mammosite, the results of other APBI techniques need to be verified for equivalence in control rates and cosmetic outcomes. The existing local control rates in phase II trials are in fact a surprise if one analyses the mastectomy pathology data. The cardinal mastectomy specimen pathology article by Holland et al. reported that only in 40% of the cases was the tumor confined to the gross tumor mass on histopathology.  In 20% of the cases, there were microscopic foci of disease in the 2-cm margin around the primary tumor. Further, in around 40% cases, foci were present even beyond this 2-cm margin. Half of these foci were invasive cancers, while the rest were ductal carcinomas in situ . As mentioned earlier, APBI techniques treat only a 1-2 cm margin around the excision cavity, with the assumption that all microscopic disease will be covered by this specification. Similarly, a recent study of MRI scans in 267 patients who were undergoing breast conservation surgery showed that 18% had foci of disease outside of the index tumor bed.  It is believed that the foci of tumor cells outside the index quadrant remain dormant and are of little relevance, but no firm evidence is available on this. Hence, while conventional external beam radiotherapy can theoretically take care of the entire breast, APBI can treat only a partial volume of the breast.
There are two randomized trials comparing partial breast and whole breast radiotherapy. The first is a RTOG/NSABP trial, randomizing 3000 patients between standard whole-breast and partial-breast irradiation. The latter was delivered with any one of the three techniques: multicatheter interstitial brachytherapy, mammosite brachytherapy, or 3-D conformal external beam radiotherapy. The second trial is a European trial comparing whole-breast radiotherapy with only interstitial brachytherapy. The results of these will take time to mature and should make us wiser on this issue.
| > Hypofractionated Whole-Breast External Beam Radiotherapy (HERT) in Breast Cancer|| |
Conventionally a dose per fraction of 1.8-2 Gy has been used for treatment of breast cancer. This has emerged from concern that fraction sizes of more than 2 Gy might increase the likelihood of the late effects of breast fibrosis, edema, telangiectasia, and tenderness, thus impairing cosmesis. ,, It is a well-known radiobiological dictum that late sequelae depend upon dose per fraction and total dose Also, tissues with a low alpha/beta ratio have a greater sensitivity to dose per fraction, i.e., if the alpha/beta ratio is low for a particular normal tissue (or for a normal tissue side effect), the dose per fraction should be correspondingly low, so as to minimize the late sequelae. A technique which reduces the treatment time to half (3 weeks instead of the present 6 weeks) while maintaining cosmesis and control rates needs to be viewed with great interest. In this context, recent studies comparing 13-16 fractions of hypofractionated radiotherapy (using larger dose per fraction) with the present 25 fractions have provided critical supportive evidence. , Furthermore, unlike APBI, these studies have been proper randomized controlled trials and thus provide level I evidence.
[Table - 2] summarizes the trials evaluating altered fractionation and cosmesis. For the past few years, Yarnold et al. have been studying the feasibility of HERT after breast conservation surgery.  In a trial reported recently, they analyzed 1410 women with T1-3 N0-1 M0 invasive breast cancer. These subjects were randomized into one of the three radiotherapy regimens.  The primary endpoint was a late change in breast appearance compared to post-surgical appearance, as scored from annual photographs after blinding to treatment allocation. They reported an α/β value of around 3 Gy for late normal-tissue changes in the breast. The local control rates in the three arms were similar. The other randomized trial studied patients with early-stage, lymph node-negative breast cancer treated with BCT in which they compared two fractionation schedules with doses per fraction of 2.6 Gy and 2 Gy.  The local control rate, overall survival, and cosmesis were comparable in the short and long arms. Their study supported the use of a shorter course of radiotherapy for patients with (the most favorable) infiltrating ductal carcinomas. However, more than one-third of the patients were excluded in this trial because of the presence of invasive or intraductal carcinoma at the inked margin of excision or because of a large breast size. Some authors therefore argue that the latter study has limited applicability.
The clear advantages of HERT are its ease of use and wide applicability. HERT also addresses the issue of microscopic foci of disease away from the primary tumor since the entire breast is being treated. HERT, as discussed in the randomized trials, is relevant to a broad spectrum of patients. Various forms of APBI have gained acceptance not because they irradiate only partial volumes of the breast (which, of course, is of considerable interest to clinicians) but because the main advantage with these techniques is that the treatment gets over in less than a week's time compared to the conventional therapy, which can last for 6-7 weeks. In comparison to the stringent selection criteria of partial-breast APBI (invasive or noninvasive), the criteria for HERT are much more generalized and have a broad spectrum. Based on the findings from these two pioneering randomized trials, it appears that a dose per fraction limit of 2.5-3 Gy can be used in external beam radiotherapy of carcinoma breast without compromising cosmesis. For reliable estimates of the fractionation sensitivity of breast cancer, results of the UK START Trial A of 2236 patients (International Standard Randomized Controlled Trial Number 59368779) are eagerly awaited; it includes randomized comparisons of 41.6 Gy in 13 fractions of 3.2 Gy and 39.0 Gy in 13 fractions of 3.0 Gy over 5 weeks with a control schedule of 50 Gy in 25 fractions of 2.0 Gy. The results of the UK START Trial B, which randomly assigned 2215 women to 40 Gy in 15 fractions over 3 weeks or to 50 Gy in 25 fractions over 5 weeks, will attempt to confirm the findings of the Toronto trial. The other current endeavors underway include the randomized UK FAST Trial, which compares two doses (5.7 Gy and 6.0 Gy) delivered in five fractions over 5 weeks with a control dose of 50 Gy in 25 fractions.  The final aim of HERT would be to give a dose of 30-35 Gy over a 1-2 weeks by daily or alternate day fractionation. Once HERT achieves this, it will be par with major APBI techniques in terms of treatment time,and ,using a noninvasive technique, it would be possible to finish the treatment in 5-10 days time!
| > Pitfalls of HERT|| |
These successes of hypofractionated radiotherapy may appear appealing to all oncologists and breast cancer patients, but it may be prudent to add a note of caution. , There remains a last stumbling block for HERT. Over the past two decades, radiation-induced heart disease (RIHD) has become a subject of increasing discussion in articles and editorials. It is a cardinal radiobiologic principle that the late effects on normal tissues are strongly dependent on dose per fraction, so that the higher the dose per fraction (as is the case with hypofractionated regimens), the greater the susceptibility of normal tissues to radiotherapy. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) analysis reported 1% mortality in breast cancer patients at 15 years due to non-breast causes, and an important cause of this could be RIHD.  Hypofractionation, by virtue of inherent radiobiology, can make these figures worse. Furthermore, the cardiac side effects may not emerge until 15 years after treatment and may persist well beyond this period. The hypofractionated schedules have not been in use long enough to provide long-term lung and cardiac morbidity rates. It may be hazardous to increase the dose per fraction in breast cancer without addressing the cardiac effects.  Indeed, fuelled by these concerns, a school of thought suggests using 1.8 Gy per fraction (less than conventional) to prevent cardiac morbidity in breast cancer patients. 
On the other hand, it can be argued that current radiotherapy practice is technically advanced and is more precise than what was practiced two decades back. Radiation oncologists are encouraged by the progress in precision radiation oncology gadgets and technical devices (linear accelerators, 3-D conformal radiotherapy, intensity-modulated radiotherapy, image-guided radiotherapy, proton beam therapy, etc.). Also there is an increasing trend for omission of the internal mammary field (which presumably increased the dose to the heart in earlier reported series). Besides, the earlier studies on RIHD did not have an account of the volume of heart irradiated, preexisting cardiac morbidity, dose and fractionation, or the use of adjuvant chemotherapy that contains potentially cardiotoxic anthracycline. The tools for measuring cardiac morbidity were varied and loosely applied. Some of these (such as perfusion studies) even show some reversibility over time.  Also, recent results as by Overgaard et al. have shown no excess cardiac deaths in patients followed up for over 10 years.  In a SEER study by Giordano, with each succeeding year after 1979, the hazard of death from ischemic heart disease for women with left-sided vs those with right-sided disease declined by 6% (HR = 0.94, 95% CI = 0.91 to 0.98), a standing testimony to the claims of the radiation oncologist. 
[Table - 3] gives in a nutshell the head-to-head comparison of APBI and HERT.
APBI and HERT in breast cancer are techniques that can have widespread implications for breast cancer throughout the world. This is primarily because both reduce the treatment time with radiotherapy to 1-2 weeks from the existing 6-7 weeks. Each of these has definite advantages and limitations. APBI calls for more stringent selection criteria, which may potentially limit its application. However, for a definite subgroup of breast cancers, clinicians and patients will soon have to choose one over the other. These techniques would need to be tested for long-term safety, local and distant control rates, cosmetic outcomes, and quality of life issues. Unfortunately, to understand all these aspects would need follow-up data of close to 10-15 years. As of now, both these techniques should be used only in the context of a clinical trial.
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[Table - 1], [Table - 2], [Table - 3]
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