Intraoperative Radiotherapy for Breast Cancer: Deceptively Simple?

Dr. Ash and colleagues are to be commended for their thorough review of this emerging technology. Intraoperative radiotherapy (IORT) is an attractive method for delivering partial-breast irradiation, and it deserves serious consideration. The authors do a thorough job of examining the technical aspects required to implement a program. In addition, they are to be commended for treating all patients on protocol, as is appropriate for this experimental therapy.

However, we must take issue with the introductory paragraph, in which Dr. Ash and colleagues state that “survival was not compromised in the cohorts of patients omitting radiotherapy” after breast-conserving surgery, even though local recurrence rates were higher. The authors would do well to remember the lessons learned from the Early Breast Cancer Trialists’ meta-analysis, which demonstrated a survival benefit that is associated with prevention of local recurrence.[1,2] The introductory paragraph sets a misleading tone with respect to the importance of local control in breast cancer. The authors go on to state that partial-breast irradiation via IORT would be an attractive option if it had at least an efficacy equivalent to that of whole-breast irradiation while reducing overall toxicity. It is not at all clear that IORT fulfills this promise. The summarized trials in Table 1 are encouraging; however, the follow-up at the present time is inadequate to prove non-inferiority, particularly when patients are still receiving adjuvant hormonal therapy. Recent long-term follow-up from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial suggests that the benefit associated with endocrine therapy may continue to be realized for several years after cessation of hormonal therapy.[3] These data, revealing the ongoing benefits of endocrine therapy (used in 65% of patients who received targeted intraoperative radiotherapy or whole-breast radiotherapy for breast cancer in TARGIT-A[4] will mean that prolonged follow-up is essential to ensure efficacy.

The authors state that “direct visualization of the target volume at the time of treatment also ensures appropriate coverage of the breast tissue at risk.” However, it is erroneous to conclude that simple visualization of the resection cavity ensures adequate treatment of all “breast tissue at risk.” In fact, one of the main shortcomings of IORT is that the microscopic margins of the resection cavity cannot be determined prior to the delivery of treatment. The ample data regarding inadequate margin clearance and the increased risk of local recurrence[5,6] highlight the importance of obtaining negative surgical margins prior to treatment with radiotherapy. If positive margins are discovered, re-excision is undertaken, and external beam radiation is added. The additional tissue taken at re-excision creates a new resection bed that does not receive a boost. The result is a partially boosted tumor bed for some patients whose initial tissue at risk as identified at the time of IORT was not representative of the true tissue at risk as determined by detailed pathologic assessment. This occurs in a small subset of patients, and the studies are not powered to detect a local recurrence difference in this small but important subset. Nonetheless, the possibility of this eventuality raises concerns.

Furthermore, analysis of the dosimetry of IORT does not inspire confidence. Others[7] have noted that the dosing used in TARGIT-A would be likely to be substantially less effective than external beam radiation, since the 20-Gy dose at the surface attenuates to 5–7 Gy at a 1-cm depth.[4] It is counterintuitive that if 20 Gy in one fraction is equivalent to approximately 58–60 Gy in 2-Gy fractions, that 20 Gy can be given with external beam without an increase in complications for the 14% of patients[8] receiving both external beam radiation and IORT. It would seem more likely that if IORT is eventually shown to be equivalent to external beam radiation, the lower dose to 1 cm of tissue (5–7 Gy) is effective because of the reduction in time for repopulation following surgical excision or other alterations in the cytokine milieu, as suggested by Belletti and colleagues.[9]

The authors discuss physics, radiation oncology, operating room, and shielding considerations for IORT in detail. However, they do not discuss how one approaches the education of our surgical colleagues in the particular requirements of this technique. In the ELIOT trial,[8] surgeons adopted “extensive breast resection” due to the intraoperative nature of the procedure. The procedure also requires intraoperative inking of the tumor bed (as opposed to inking of the excision specimen, as is typically done). Additionally, the procedure requires mobilization of fat and breast tissue off the pectoralis major muscle, as well as away from subcutaneous tissue within a 4- to 5-cm margin from the tumor bed. Moreover, a point not addressed in the intraoperative trials is that of cosmesis, and with such “extensive resection,” one must wonder whether cosmesis will suffer. While TARGIT’s methods[4] state that specimen weight was recorded in both arms, this was not reported in the manuscript. Multidisciplinary cooperation is an essential component of such a program.

Dr. Ash and colleagues close with an analysis of the financial aspects of IORT. While the authors adopt an apologietic tone with regard to the failure of “advances in remuneration for intraoperative radiotherapy” to keep pace with the clinical progress, this is one arena where IORT in fact has the clear lead. If IORT is determined to be effective, with equivalent cancer control, complications, and cosmesis, IORT would be a very attractive treatment choice due to its low cost to the healthcare system. It is encouraging that IORT has shown positive quality-of-life indicators in comparison with external beam radiation.[10] In the current healthcare environment, with its continually escalating costs, a convenient, cost-effective modality would be a welcome addition. However, due to the fact that we do not have mature long-term data regarding efficacy, we are still several years away from declaring IORT to be a viable alternative to the current standard of care in patients with early-stage breast cancer.

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. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087-106.

2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG); Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378:1707-16.

3. Davies C, Pan H, Gray R, et al, on behalf of ATLAS Collaborators Worldwide. ATLAS – 10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease: effects on outcome in the first and in the second decade after diagnosis. San Antonio Breast Conference, December, 2012, San Antonio, TX.

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5. Park CC , Mitsumori M , Nixon A , et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol. 2000;18:1668-75.

6. Lupe K, Truong PT, Alexander C, et al. Subsets of women with close or positive margins after breast-conserving surgery with high local recurrence risk despite breast plus boost radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81:e561-8. Epub 2011 Apr 20.

7. Smith BD, Buchholz TA, Kuerer HM. Intraoperative radiotherapy for early breast cancer. Lancet. 2010;376:1141.

8. Veronesi U, Orecchia R, Luini A, et al. Full-dose intra-operative radiotherapy with electrons (ELIOT) during breast conserving surgery-experience with 1246 cases. ecancermedicalscience. 2008 February 26. DOI: 10.3332/eCMS 2008.65

9. Belletti B, Vaidya JS, D’Andrea S, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res. 2008;14:1325-32.

10. Welzel G, Boch A, Sperk E, et al. Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: results from the randomized phase III trial TARGIT-A. Radiat Oncol. 2013;8:9.