Limited-Field and Whole-Breast Hypofractionated Radiotherapy

With the publication of mature experiences using accelarated partial breast irradiation (APBI) and accelerated whole breast irradiation (AWBI), the use of shortened courses of radiotherapy has become increasingly popular. Dr. Mouw and Dr. Harris describe the potential benefits associated with accelerated treatment, but they also discourage widespread application of these techniques in the absence of long-term randomized data. We agree that controversy will exist until such data are available, and present several points to supplement the discussion of this important topic.

Patient Selection

The most widely used patient selection guidelines for APBI are those published by the American Society for Radiation Oncology (ASTRO).[1] Published data were reviewed and used to determine which patients should be considered “suitable,” “cautionary,” or “unsuitable” for treatment with APBI. It is important to note that many of the factors placing patients in the “cautionary” or “unsuitable” groups (in situ or lobular histology, extensive intraductal component, lymphovascular space invasion, etc.) have not been shown in modern series to be associated with an increased risk of local recurrence after APBI. Subsequent analyses have suggested that these guidelines do not adequately distinguish groups of patients at higher risk for local recurrence with APBI.[2-5] We believe that these guidelines should be updated to incorporate newer data regarding the risk of recurrence.

Treatment Efficacy

Tumor control following APBI and AWBI has been excellent.[6-10] In a recent analysis of the American Society of Breast Surgeons (ASBrS) MammoSite Registry Trial, control at the tumor bed was noted to be equal to or greater than that seen with historical control rates in patients treated with WBI.[11] Dr. Mouw and Dr. Harris discuss several trials, including the earliest APBI experiences at Christie and Leeds Hospitals.[12,13] Just as the earliest trials of breast conservation do not reflect the true efficacy of the technique, the Christie and Leeds APBI experiences do not accurately reflect modern clinical outcomes. As acknowledged by Dr. Mouw and Dr. Harris, these trials have critical flaws in patient selection and treatment delivery and are simply not relevant to a discussion of modern APBI techniques. The meta-analysis demonstrating a higher incidence of local recurrence after APBI should be similarly discounted, as data from the Christie and Leeds experiences constitute the bulk of the analysis.[14]

More recently, a Medicare-claims analysis published this year by Smith and colleagues generated tremendous interest when the authors reported a higher rate of mastectomy following breast brachytherapy (an absolute difference of 1.77%).[15] This retrospective study used billing codes as surrogates for clinical endpoints. It has a number of significant limitations, including treatment era bias, the retrospective nature of the analysis, selection bias, and incomplete treatment data. It is not appropriate to use this type of analysis to drive clinical practice when there are nearly two decades of evidence in the literature supporting use of APBI in appropriately selected and treated patients.

Cosmetic Outcomes and Treatment-Related Toxicities

Cosmetic outcomes following AWBI have been reported as equivalent or improved compared with those of traditional WBI.[7,16,17] Most series reporting cosmetic outcomes after APBI describe 80% to 90% of patients as having good or excellent cosmesis using the Harvard scale. Although some groups have reported decreased cosmetic scores using the 3-D conformal radiotherapy (3D-CRT) form of APBI, an analysis of 1,100 patients treated as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 / Radiation Therapy Oncology Group (RTOG) 0413 phase III trial showed that less than 3% of patients receiving 3D-CRT had a grade 3 or higher skin/tissue toxicity.[18] Although Dr. Mouw and Dr. Harris appropriately describe the risks of infection, fat necrosis, and rib fracture associated with interstitial and balloon-based APBI, the incidences of acute and late toxicity are quite low with modern treatment techniques.[19,20] When balloon devices are placed according to the current standard of care, the incidence of infection is 4.8%.[19] Only 2.6% of patients in the ASBrS trial experienced fat necrosis.[21] In our experience, most side effects related to APBI are mild and have a limited time-course.

In summary, APBI and AWBI are options that potentially offer improved treatment techniques in the delivery of adjuvant radiotherapy following breast-conserving surgery. For appropriately selected patients, similar efficacy can be achieved using an abbreviated treatment schedule, which results in a good-to-excellent cosmetic outcome for the vast majority of patients. We agree that data from randomized trials using contemporary techniques are needed to further characterize the safety and efficacy of APBI. We also believe it is important to note that no modern, prospective data have suggested that APBI is inferior to standard WBI. Until long-term data from these trials are available, the debate will continue. We strongly encourage clinicians to treat patients according to available guidelines and to participate in clinical trials whenever possible.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001.

2. Vicini F, Arthur D, Wazer D, et al. Limitations of the American Society of Therapeutic Radiology and Oncology Consensus Panel guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011;79:977-984.

3. Beitsch P, Vicini F, Keisch M, et al. Five-year outcome of patients classified in the “unsuitable” category using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus Panel guidelines for the application of accelerated partial breast irradiation: an analysis of patients treated on the American Society of Breast Surgeons MammoSite(®) Registry trial. Ann Surg Oncol. 2011;17(Suppl 3):219-25.

4. Zauls AJ, Watkins JM, Wahlquist AE, et al. Outcomes in women treated with MammoSite brachytherapy or whole breast irradiation stratified by ASTRO Accelerated Partial Breast Irradiation Consensus Statement Groups. Int J Radiat Oncol Biol Phys. 2012;82:21-9.

5. Stull TS, Catherine Goodwin M, Gracely EJ, et al. A single-institution review of accelerated partial breast irradiation in patients considered “cautionary” by the American Society for Radiation Oncology. Ann Surg Oncol. 2012;19:553-9.

6. Strnad V, Hildebrandt G, Potter R, et al. Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy alone after breast-conserving surgery. Int J Radiat Oncol Biol Phys. 2011;80:17-24.

7. Whelan TJ, Pignol J, Julian J, et al. Long-term results of a randomized trial of accelerated hypofractionated whole breast irradiation following breast conserving surgery in women with node-negative breast cancer. Int J Radiat Oncol Biol Phys. 2008;72:S28.

8. Polgar C, Fodor J, Major T, et al. Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast carcinoma--5-year results of a randomized trial. Int J Radiat Oncol Biol Phys. 2007;69:694-702.

9. Shah C, Antonucci JV, Wilkinson JB, et al. Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matched-pair analysis. Radiother Oncol. 2011;100:210-14.

10. Arthur DW, Winter K, Kuske RR, et al. A phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and survival outcomes of RTOG 95-17. Int J Radiat Oncol Biol Phys. 2008;72:467-73.

11. Beitsch PD, Wilkinson JB, Vicini FA, et al. Tumor bed control with balloon-based accelerated partial breast irradiation: incidence of true recurrences versus elsewhere failures in the American Society of Breast Surgery MammoSite(®) Registry Trial. Ann Surg Oncol. 2012;27 July [Epub ahead of print].

12. Ribeiro GG, Magee B, Swindell R, et al. The Christie Hospital breast conservation trial: an update at 8 years from inception. Clin Oncol (R Coll Radiol). 1993;5:278-83.

13. Dodwell DJ, Dyker K, Brown J, et al. A randomised study of whole-breast vs tumour-bed irradiation after local excision and axillary dissection for early breast cancer. Clin Oncol (R Coll Radiol). 2005;17:618-22.

14. Valachis A, Mauri D, Polyzos NP, et al. Partial breast irradiation or whole breast radiotherapy for early breast cancer: a meta-analysis of randomized controlled trials. Breast J. 2010;16:245-51.

15. Smith GL, Xu Y, Buchholz TA, et al. Association between treatment with brachytherapy vs whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer. JAMA. 2012;307:1827-37.

16. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008;9:331-41.

17. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008;371:1098-107.

18. Julian TB, Costantino JP, Vicini F. Early toxicity results with 3-D conformal external beam therapy (CEBT) from the NSABP B-39/RTOG 0413 Accelerated Partial Breast Irradiation (APBI) Trial. Int J Radiat Oncol Biol Phys. 2012;66:S235-6.

19. Cuttino LW, Keisch M, Jenrette JM, et al. Multi-institutional experience using the MammoSite radiation therapy system in the treatment of early-stage breast cancer: 2-year results. Int J Radiat Oncol Biol Phys. 2008;71:107-14.

20. Cuttino LW, Heffernan J, Vera R, et al. Association between maximal skin dose and breast brachytherapy outcome: a proposal for more rigorous dosimetric constraints. Int J Radiat Oncol Biol Phys. 2011;81:e173-7.

21. Khan A, Arthur D, Vicini F, et al. Six-year analysis of treatment-related toxicities in patients treated with accelerated partial breast irradiation on the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial. Ann Surg Oncol. 2012;19:1477-83.