Accelerated Partial-Breast Irradiation

Accelerated partial breast irradiation (APBI) encompasses several effective approaches available for radiotherapy after breast-conserving surgery in selected patients with early stage breast cancer. These approaches include brachytherapy approaches with commercial balloon-based devices (MammoSite and Contura; Hologic [Marlborough, MA, USA]), commercial interstitial devices (strut adjusted volume implant [SAVI]; Cianna Medical [Aliso Viejo, CA, USA]), other interstitial catheter approaches, and 3-dimensional conformal external beam delivery approaches. ASTRO recently released a consensus statement based on the evidence-based support for APBI, which is an update to the consensus statement published in 2009, and proposed 3 patient groups: suitable, cautionary, and unsuitable.

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  Suitable: patients aged ≥50, negative margins by ≥2 mm, T stage of Tis or T1 (≤2 cm), and DCIS that meets all criteria (screen detected, low to intermediate nuclear grade, size ≤2.5 cm, and negative margins at ≥3 mm).

  
  
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  Cautionary: patients aged 40 to 49 if all other criteria for “suitable” are met as well as patients aged ≥50 if they have at least 1 of the following criteria (size 2.1–3.0 cm, T stage T2, close margins at less than 2 mm, limited/focal lymphovascular space invasion, estrogen receptor negative, clinically unifocal with total size 2.1–3.0 cm, invasive lobular histology, pure DCIS ≤3 cm if criteria for “suitable” not fully met, and extensive intraductal component ≤3 cm).

  
  
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  Unsuitable: patients aged ≤40, as well as patients aged 40 to 49 with no “cautionary” criteria, positive margins, and DCIS with size greater than 3 cm.

For the use of ABPI outside of a clinical trial, the Update Task Force proposed that it is acceptable for patients in the suitable group, that caution and concern should be applied when considering in the cautionary group, and it is not generally considered warranted in the unsuitable group. The American Brachytherapy Society consensus statement for APBI is less strict with respect to overall tumor parameters and defines appropriate patient selection through consideration of the following factors: age ≥50 year old, tumor size ≤3 cm, all invasive subtypes and DCIS, negative surgical margins, no lymphovascular space invasion, and negative nodal status. The RTOG 0413/NSABP B39 trial allowed women with invasive or noninvasive disease less than 3 cm with 1 to 3 positive lymph nodes to be randomized to whole breast or APBI. The results of the RTOG 0413/NSABP B39 trial will give definitive results of the safety and efficacy of APBI in a diverse group of early stage patients compared with WBRT. In the authors’ institution, they offer APBI for patients with early stage invasive cancer or DCIS, age greater than 50, who are lymph node negative, estrogen receptor positive, Her2/neu negative, with less than 3 cm of disease, and negative margins. The authors do use caution in those who have high-grade DCIS due to the lack of available data in these patients.

Brachytherapy for breast cancer was first developed using multicatheter interstitial implants, which are inserted using a free-hand technique often under image guidance. Significant limitations in terms of complexity, user dependence, logistics, conformality (accurate shape and scale), and reproducibility among patients prompted the development of device-based interstitial brachytherapy. Two of the more widely embraced single-entry catheter devices are multilumen balloon based and SAVI with 6 to 9 catheters. In the authors’ experience, multichannel SAVI-based implants markedly reduces the maximum skin and chest wall doses, simultaneously achieving dose coverage to the target volume compared with balloon techniques. Also, differential-source dwell-loading allows modulation in the distribution of the radiation dose that leads to improved dosimetric conformality. SAVI is safe and increases eligibility for APBI over balloon brachytherapy because the device can be safely placed closer to the skin (up to 3 mm) or chest wall with the ability to dose shape precisely. It also has more consistency in the quality of the implant compared with a free-hand technique. Brachytherapy approaches typically deliver less radiation doses to the uninvolved ipsilateral breast, heart, and lung compared with external-beam radiation techniques.

Multiple series have documented excellent clinical outcomes with interstitial APBI and balloon-based brachytherapy. Five-year outcomes demonstrate a 3.8% risk of local recurrence in more than 1400 patients with invasive cancer treated with MammoSite brachytherapy, and in 2.6% at 4 years in 300 patients treated with SAVI brachytherapy. The NRG have reported on their experience of multicatheter brachytherapy with a 5.2% risk of local recurrence at 10 years in 100 patients. A similar low risk of recurrence of 2.6% at 5 years was seen in 300 patients with DCIS treated with MammoSite brachytherapy. It is important to note that these series typically reflect very favorable risk patients; however, there have so far been no safety signals from the RTOG/NSABP trial, suggesting this treatment may even become more widely available if the efficacy continues to be favorable.

Intraoperative radiotherapy is typically a single dose of radiation limited to the tumor bed at the time of breast-conserving surgery. Intraoperative radiotherapy can play a role in the decision of some patients of undergoing breast-conserving therapy over mastectomy, especially when factors such as long travel distances to the hospital, advanced age, or socioeconomic status have a significant influence. However, there are concerns about the efficacy of this modality based on the results of the TARGIT A and ELIOT trials that show a higher local recurrence at short follow-up compared with traditional treatment. In the TARGIT A trial, local recurrence was 3.3% for intraoperative radiotherapy versus 1.3% for whole-breast radiotherapy, with an equivalent breast cancer mortality. In the ELIOT trial, the local recurrence was within the prespecified margin but higher than with whole-breast radiotherapy, 4.4% versus 0.4%, with no difference in overall survival. One of the principal issues with single fraction radiation is the lack of assessment of margin status at the time of treatment. In addition, there are concerns about dose accuracy, given the lack of imaging to assess that the applicator is intimately opposed to the breast tissues. Recent analyses of these trials reported that intraoperative radiotherapy had a significantly higher risk of ipsilateral breast tumor recurrence compared with WBRT but no significantly higher overall mortality. Nonetheless, this treatment has established a foothold globally and in the United States and will likely continue to be used more regularly in selected low-risk patients, albeit with higher potential recurrence rates. However, there is further investigation ongoing to identify the subset of patients who may safely benefit from intraoperative radiotherapy. The previously described consensus guidelines for APBI highlight the importance of the prudent selection of suitable patients with low risk of local recurrence.

External-beam radiotherapy for APBI has been studied with several types of radiation (ie, photons, electrons, and protons) as well as with various types of planning and delivery techniques, that is, 3 dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and TomoTherapy. In general, external-beam radiotherapy offers excellent target coverage and dose homogeneity but inferior conformality, when compared with brachytherapy, leading to increased doses to the uninvolved ipsilateral breast, skin, heart, and lung. Proton therapy may decrease the dose to the uninvolved ipsilateral breast, heart, and lung at the expense of a modest decrease in target coverage and an increased risk of skin toxicity. Some of the early reports from the randomized NSABP B-39/RTOG 0413 protocol have demonstrated that 3D-CRT for ABPI resulted in a high rate of moderate to severe late normal tissue effects (10%), despite the relatively brief median follow-up period (15 months). Finally, there is also interest in stereotactic body radiotherapy via CyberKnife as a means of APBI. CyberKnife radiosurgery for breast cancer is considered experimental today; however, early data demonstrate good feasibility and safety in brief median follow-up period (18 months).

Hypofractionated Whole-Breast Irradiation

Prospective, randomized, phase 3 clinical trials evaluating hypofractionated whole-breast irradiation therapy (HWBI) conducted in Canada and the United Kingdom have matured and reported long-term 10-year or greater results. These studies have established the role of HWBI in early stage breast cancer as an option endorsed by ASTRO in their Choosing Wisely Campaign. Local control has been equal, and cosmetic results and complications have been equal or better with accelerated hypofractionation compared with conventional fractionation with 10-year follow-up. There are many potential benefits, including patient convenience, less cutaneous toxicity, and reduced cost of care. For these reasons, HWBI is now a standard option as an alternative to conventional fractionation for most women.

However, there has been some limitation in the extension of the overall positive results of HWBI to specific subgroups that were underrepresented in these phase 3 trials, including younger women. Based on the available data, HWBI may be safely offered to most women with DCIS or early stage invasive breast cancer treated by conventional whole-breast irradiation. However, there is still controversy about the use of HWBI in women aged less than 50 years, high-grade cancers, or tumors requiring a sequential tumor bed boost or chemotherapy before or after radiation. Large breast size or chest wall separation (distance from the midline to midaxillary line) is also a relative contraindication because of the heterogeneity of dose distribution in the breast—with larger breast size or separation leading to inhomogeneities of greater than 7%. Based on the Canadian experience, most radiation oncologists use a maximum of 7% inhomogeneity for consideration of HWBI. However, improvements in radiation therapy equipment and planning techniques since the conduct of earlier HWBI studies may allow for previously ineligible patients to be considered for HWBI. Finally, HWBI studies have not included coverage of regional nodes, which increases the radiation volumes substantially, and potentially toxicity. Conventional fractionation remains the standard for women who have dose inhomogeneity greater than 7%, require chemotherapy, or need regional node irradiation.