		Contemporary risk-adapted local therapy for early breast cancer is a complex and evolving paradigm. Shah et al do an excellent job in summarizing the multitude of evidence-based approaches related to risk stratification, treatment options, and results. By also placing these in the context of real-world case examples, clinicians can gain valuable insight into the appropriate application of these multifaceted clinical trial data to manage the individual patient. This review highlights the enormous progress that has been achieved in recent years toward providing women with local therapy options that are safe, effective, convenient, and cost efficient.

	Breast conserving therapy (BCT) offers women the ability to preserve their breast without sacrificing local control or survival. Since its inception, a key component of BCT has been the delivery of adjuvant radiotherapy following breast-conserving surgery (BCS). However, a growing interest remains in determining if there exists a subset of women with low-risk features for whom adjuvant radiotherapy may be omitted following BCS. To date, the data are consistent in demonstrating that adjuvant radiotherapy reduces the rate of local recurrences in all risk groups. In lower-risk groups, modern trials have failed to demonstrate a survival advantage from the local control benefit derived from radiotherapy. Currently, studies are being performed to identify low-risk patients based on tumor genetics, nomograms, and other techniques. In the interim, clinicians now have alternative techniques including hypofractionated whole breast irradiation as well as accelerated partial breast irradiation which allows for a reduction in treatment duration (and possibly treatment volume) while still maintaining local control.

Over the past several decades, breast-conserving therapy (BCT) has emerged as the standard of care in the management of early-stage breast cancer. With greater than twenty-five years of follow-up, multiple randomized trials have demonstrated equivalence in outcomes between mastectomy and BCT, with BCT being shown to improve the quality of life of breast cancer survivors compared with mastectomy.

A key component in the BCT arms of the randomized trials was standard fractionation whole-breast irradiation (WBI) delivered over 5 to 6 weeks. In the decades since the initial randomized trials, adjuvant radiation therapy (RT) has continued to be a key component of the BCT technique to optimize local control. While RT has been shown to enhance local control following breast-conserving surgery (BCS), concerns exist, including acute/chronic toxicities associated with treatment, the duration of treatment, and the potential for overtreatment.

A key question being considered is the role of RT in patients who will not manifest large local control benefits with adjuvant RT compared with BCS with or without endocrine therapy. Multiple attempts have been made to omit RT following BCS, with mixed results. In spite of the lack of clarity, clinicians are facing pressure to tailor RT recommendations based on patient (age, performance status), pathologic (tumor size, margin status, grade, hormone receptor status, lymph node status), and systemic treatment (tamoxifen/aromatase inhibitor utilization) characteristics and to identify low-risk patients for whom RT may not be required. Therefore, the purpose of this clinical review is to evaluate the role of RT in low-risk patients (based on patient and pathologic features) following BCS and to provide common scenarios and recommendations based on current data and guidelines.

The role of adjuvant RT in patients undergoing BCS has been evaluated as part of the randomized trials comparing mastectomy and BCT. NSABP B-06 randomized 1861 women (stage I/II, < 4cm, 62% node negative, all underwent axillary dissection) to mastectomy, BCS, or BCS with adjuvant RT. With 20 years follow-up, the omission of RT following BCS increased the rate of local recurrence, 39% vs 14%.

 Further, the Milan III study randomized nearly 579 women (tumor size <2.5 cm, <70 years old, majority <55 years old, 32% to 44% endocrine therapy, 67% to 72% node negative, all underwent axillary dissection, nodal positivity allowed) to adjuvant RT or observation following quadrantectomy; at 10 years follow-up, adjuvant RT had reduced local recurrences (from 23% to 6%) with the greatest benefit noted in women under 45 years of age.

Similar results were seen with a trial from Sweden, which randomized 381 women (<2cm, node negative) to receive RT following BCS; at 10 years, RT had reduced the rate of local recurrence, from 24% to 8.5%.

 These findings have been replicated by other randomized trials, which have consistently demonstrated an improvement in local control with RT.

 As well, the Early Breast Cancer Trialists Group (EBCTG) meta-analysis has confirmed the improvement in local control and breast cancer mortality with adjuvant RT.

		Table 1. Trials Evaluating the Omission of Radiotherapy With Endocrine Therapy

		ALND indicates axillary lymph node dissection; DFS, disease-free survival; ER, estrogen receptor, PR, progesterone receptor; RT, radiation therapy.

It should be noted that most patients in the older randomized trials did not consistently receive endocrine therapy. With the advent of tamoxifen and aromatase inhibitors and the subsequent publication of NSABP B-14 and the EBCTG meta-analysis, trials were developed evaluating the role of RT in patients receiving endocrine therapy 

NSABP B-21 randomized 1009 women with node negative (following pathologic evaluation) tumors less than 1 cm to tamoxifen, RT, or RT and tamoxifen. At 8 years, the lowest rate of local recurrence was seen in the RT and tamoxifen arm (2.8%), with higher rates seen in the radiation alone (9.3%) and tamoxifen arms (16.5%). Compared with tamoxifen alone, RT reduced the rate of ipsilateral breast tumor recurrence (IBTR) by 49%.

 The CALGB 9343 trial randomized a potentially lower risk group of 636 women over 70 years of age with T1N0 estrogen receptor positive tumors to tamoxifen with or without adjuvant RT following BCS with negative surgical margins. At 10 years, RT further reduced the rate of local recurrence compared with tamoxifen alone (9% vs 2%), although no difference in cause-specific or overall survival (OS) was noted.

 These results were mirrored by a Canadian study that randomized 769 women 50 years or older with node negative tumors less than 5 cm to tamoxifen with or without RT following BCS with negative surgical margins. While an increase in local recurrence was noted in patients receiving tamoxifen alone (8% vs 1%), an increase in disease-free survival was noted, which may be due to the inclusion of younger patients than in the CALGB trial.

 A German 2×2 randomized trial evaluated 361 low-risk women (pT1, estrogen receptor positive, margin negative, node negative) with a randomization for adjuvant RT and tamoxifen. While underpowered, at 10 years, the rates of local recurrence were 34%, 10%, 7%, and 5% for the BCS, BCS + RT, BCS + tamoxifen, and BCS + RT + tamoxifen arms, respectively.

 A more recent Austrian study evaluated 869 women with low-risk breast cancer (tumor <3 cm, ER/PR positive, grade 1/2, node negative, margins negative) and randomized women following BCS to hormonal therapy (tamoxifen or Arimidex) with or without adjuvant RT. At 5 years, RT significantly reduced local recurrences (5.1% vs 0.4%) and overall relapses (6.1% vs 2.1%).

 Taken together, the data support the premise that even with the additional benefit of endocrine therapy, adjuvant RT provides a local control benefit even in low-risk patients.

Clinicians continue to search for a group of low-risk patients for whom RT may not be required following BCS. One method is to apply the clinical and pathologic criteria utilized in the trials themselves, such as those from the CALGB 9343 trial.

These strategies have been incorpora-â€¨ted into evidence-based guidelines, including the National Comprehensive Cancer Network (NCCN) guidelines, which provide a category 1 recommendation to omit radiation in women 70 years of age or older with T1N0 (clinically negative) estrogen receptor positive tumors should they receive adjuvant endocrine therapy. No mention is made of the role of grade or margin status.

 Similarly, nomograms have been developed using clinical and pathologic characteristics to help risk-stratify patients and provide clinicians with an estimate of the risk of local recurrence. One example is the IBTR! nomogram, which includes age, size, margins, lymphovascular invasion, tumor grade, and the utilization of chemotherapy and endocrine therapy.

A more recent technique to identify patients who may not need adjuvant RT is to use tumor genetics rather than clinical and pathologic characteristics. Panels have been developed to evaluate the benefit of systemic therapy and have been validated.

 Studies are currently looking to utilize similar gene panels to identify those patients who benefit most and least from adjuvant RT. Studies with ductal carcinoma in situ (DCIS) scoring, demonstrating an ability to stratify by risk of recurrence in some groups, have been presented recently.

 Beyond omitting RT in low-risk patients, new treatment schedules and techniques are available to shorten the duration of treatment and the volume of normal breast tissue irradiated. One alternative gaining acceptance is the use of hypofractionated whole-breast irradiation 

 A study from the Ontario Clinical Oncology Group randomized 1234 women with T1-2N0 (node dissection required) breast cancer to whole-breast irradiation with either 50 Gy in 25 fractions or 42.5 Gy in 16 fractions. Forty-one percent of women received tamoxifen and 11% received chemotherapy. At 10 years, no difference in local control (7.4% vs 7.5%) or OS was noted and toxicities and cosmesis (70% excellent/good) were comparable.

 These findings were consistent with follow-up from the START A and B trials, which demonstrated comparable local control with hypofractionated regimens compared with standard schedules.

 The START A trial randomized 2236 women (pT1-3a, 30% node positive) to 39 Gy in 13 fractions, 41.6 in 13 fractions or 50 Gy in 25 fractions with all delivered over 5 weeks; no difference in local recurrence (5.2% vs 3.5% vs 3.6%) was noted. The START B trial randomized 2215 women (pT1-3a, 21.5% node positive) to 40 Gy in 15 fractions in 3 weeks or 5 Gy in 25 fractions, with no difference in local recurrence (2.2% vs 3.3%) with reduced adverse events in the hypofractionated arm. Accelerated partial breast irradiation (APBI) is another option that shortens treatment duration and reduces the amount of normal breast tissue treated by irradiation to the lumpectomy cavity and the area surrounding it. APBI can be delivered with interstitial brachytherapy, applicator brachytherapy, or external beam techniques. Randomized data from Hungary have demonstrated equivalence in local control and survival compared with standard fractionation WBI, as has a matched-pair analysis from William Beaumont Hospital with long-term follow-up.

 More recently, applicator-based brachytherapy has emerged as the predominant brachytherapy technique, with follow-up demonstrating low rates of local recurrence and, with the development of multilumen applicators, reduced toxicities.

 Modern randomized studies comparing APBI with WBI are either under way or completed with results expected in the years to come, including the NSABP B-39 and GEC-ESTRO trials.

		Table 2: Randomized Hypofractionated Radiation Therapy Trials

When evaluating the clinical implications of modern data, it is imperative to utilize the data in conjunction with a multidisciplinary evaluation of the patient. The following examples will present common clinical scenarios and treatment recommendations.

Scenario 1: Age 70 years or greater, T1N0, estrogen receptor positive

This group currently represents the subset of patients for whom omitting RT has the greatest support based on the findings of the CALGB trial as well as the evidence-based NCCN guidelines.

 Patients should have negative margins or undergo re-excision, as trials consistently included patients with negative margins. With regard to grade, the majority of patients were grade 1/2 or grade but not evaluated while there was a subset of high-grade patients in the Canadian trial 

. It should be noted that current guidelines do not incorporate grade into the recommendations. For patients seeking an alternative to simply omitting RT, hypofractionation or APBI are reasonable alternatives to standard fractionation, though a subset analysis did find higher local recurrence with hypofractionation in high-grade tumors.

Scenario 2: Age 70 years or greater, T1N0, estrogen receptor negative

In light of estrogen receptor negativity, utilizing endocrine therapy alone following BCS is not an option for this subset of patients. While omitting RT may be an option in patients with poor performance status or significant comorbidities, RT remains the standard for patients in this group including standard fractionation WBI, hypofractionated WBI, and APBI as trials had limited numbers of receptor negative patients.

 While some concern has been raised about estrogen receptor negativity and APBI, current guidelines support the use of APBI in estrogen receptor negative patients.

With regard to margin status, negative margins should be achieved if feasible prior to initiation of RT. Limited data are available on the role of grade in this subset of patients.

Scenario 3: Age 70 years or greater, T2N0, estrogen receptor positive/negative

In patients with larger tumors (T2N0), there are limited data on omitting RT at this time. While some studies included T2 patients, most studies limited tumor size to less than 3 cm, with the exception of the Canadian trial, in which 17% of cases were >2 cm. As such, RT following BCS remains the standard with options including standard fractionation WBI, hypofractionated WBI, and APBI (<3 cm).

 For those patients requiring systemic therapy, less data are available regarding hypofractionated WBI, and subset analysis has shown higher recurrence rates with higher-grade tumors.37 In patients with positive margins, re-excision should be performed if feasible prior to RT with limited data available regarding grade and the omission of RT in this subset of patient.

Scenario 4: Age 50-70 years, T1N0, estrogen receptor positive

To date, the data do not support the omission of RT in this subset of patients. As noted in 

, subsets of patients from each trial with the exception of CALGB 9343 included women in this group, though there were small numbers, particularly less than 60 years old. The Canadian trial that included women 50 years or older not only demonstrated a local recurrence increase but a decrement in disease-free survival and as such it is not considered a standard option in evidence-based guidelines.

 For women 60 to 69 years of age, there are data evaluating the omission of RT, but this is still evolving in light of evidence-based guidelines focusing on women over age 70 years.

 Treatment options include standard fractionation WBI, hypofractionated WBI, and APBI. While the ASTRO guidelines puts patients ages 50 to 59 as a cautionary risk for APBI, the ABS and ASBS consensus statements do not.

As noted above, margin status should be considered as well as grade, particularly in high-grade patients for whom hypofractionated RT is considered.

Scenario 5: Age 50-70 years, T1N0, estrogen receptor negative

Adjuvant RT remains an essential component of BCT in this subset of patients. While standard fractionation WBI remains the standard for these patients, hypofractionated WBI represents an option for those not requiring systemic therapy.

 APBI also represents an option for appropriately selected patients though concerns regarding estrogen receptor negativity exists.

Scenario 6: Age 50-70 years, T2N0, estrogen receptor positive/negative

In this subset of patients, RT remains the standard of care following BCS. Conventional fractionation represents the standard, but hypofractionated RT can be considered in women based on national guidelines as well as dosimetric constraints.

 APBI also represents an option for appropriately selected patients in this subset with tumors less than 3 cm though there remains some debate over suitability in this subset.

 Surgical margins should be negative prior to proceeding with RT.

Trials have confirmed that adjuvant RT following BCS improves local control. However, new data allow for stratifying patients into low-risk cohorts (clinical/pathologic, molecular) who may not require RT or who may be able to receive alternatives to standard RT (eg, hypofractionated or accelerated partial breast irradiation). Future studies are required to provide long-term outcomes for patients in whom RT is omitted based on such stratification criteria.

Summa Health System and Northeast Ohio Medical University (CS, MFB), University of Nebraska Medical Center (VV), 21st Century Oncology/Michigan Healthcare Professionals (FV).

Chirag Shah, MD, Department of Radiation Oncology, Summa Health System, 161 North Forge, Suite G90, Akron, OH 44304, Phone: (330) 375-3557, Fax: (330) 375-3072. E-mail: csshah27@hotmail.com.

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