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September 30, 2013

External-Beam Accelerated Partial-Breast Irradiation: Exploring the Limits of Tolerability

Publication: Journal of Clinical Oncology
Radiation therapy is a critical element of breast-conserving therapy that has been shown to yield a substantial improvement in local control and a modest improvement in survival.1 In most studies of adjuvant radiotherapy after breast-conserving surgery, standard fractionation, with doses of 1.8 to 2.0 Gy per treatment, has been used to administer treatment to the whole breast, once a day. This approach relies on the radiobiologic rationale that slowly dividing cells of normal tissues can repair radiation-induced damage between small daily fractions in a way that rapidly dividing tumor cells, which are often characterized by deficiencies in DNA repair, cannot. Thus, fractionation of dose contributes to the therapeutic ratio of radiation treatment.
Because 5 to 6 weeks of standard fractionated treatment are necessary to reach total doses that generally control microscopic disease, concerns have arisen regarding the convenience, access, and cost of this approach. At the same time, evidence has emerged to suggest that breast cancer cells may be more sensitive to larger fraction sizes than previously thought, suggesting that lower total doses of radiotherapy may be equally efficacious if treatment is administered in larger daily fractions. Therefore, interest in hypofractionated schedules of breast irradiation has grown in recent years.
Several studies have explored a variety of schedules for hypofractionated whole-breast irradiation, including a Canadian randomized trial that reported equivalent efficacy and toxicity at 10 years from a schedule of 42.5 Gy in 16 fractions compared with 50 Gy in 25 fractions.2 Randomized trials from the United Kingdom have also demonstrated equivalent outcomes comparing standard whole-breast irradiation with hypofractionated whole-breast irradiation.3,4 Others have been motivated to explore treatment to only part of the breast, inspired by findings that suggest that the majority of local recurrences after breast-conserving surgery occur in the region of the tumor bed. These studies postulate that even more radically hypofractionated and accelerated schedules of treatment, commonly referred to as accelerated partial-breast irradiation (APBI), might be tolerable owing to reduction in the volume of tissue irradiated.
The earliest studies of APBI used brachytherapy5,6,7,8 but, in more recent years, interest in administering APBI via conformal external-beam radiation has grown as a result of improvements in targeting and dosimetric planning. External-beam treatment is noninvasive, allows treatment after full pathologic information is available without subjecting the patient to a second surgical procedure, and may be less operator-dependent compared with the brachytherapy options. The brachytherapy treatment approach typically employs a fractionation scheme of 3.4 Gy delivered twice daily over 5 days, which is radiobiologically equivalent to a standard 5-week course of radiation and minimizes the time exposed to risk of infection, given the indwelling brachytherapy catheters. To replicate this scheme and account for some differences in homogeneity with external-beam techniques, a slight modification in this dose to 3.85 Gy delivered twice daily over 5 days was adopted for the National Surgical Adjuvant Breast and Bowel Project/Radiation Therapy Oncology Group (NSABP/RTOG) trial and was also the schedule tested in the Randomized Trial of Accelerated Partial Breast Irradiation (RAPID) trial reported by Olivotto et al.9
Since initiation of these large, national randomized trials, several reports from single institutions have raised concerns about the possibility that this fractionation schedule for external-beam APBI might be suboptimal. External-beam techniques require a significantly higher integral dose to the normal breast,10 and single-arm trials at Tufts University11,12 and the University of Michigan13 have suggested that rates of adverse cosmetic outcomes might be more substantial than usually observed with standard whole-breast irradiation. However, given the small sample sizes and other limitations of these studies, as well as the fact that similar trials at other institutions have demonstrated excellent cosmetic outcomes, 14,15 the community has been left to anxiously await the analyses of large, well-designed randomized trials to clarify this important issue.
Olivotto et al9 present the results of the interim toxicity/cosmesis analysis in their large, Canadian randomized trial (RAPID) comparing external-beam APBI to whole-breast irradiation (using either standard fractionation or a hypofractionated course of 42.5 Gy). Strengths of their study include its multicenter, randomized design; careful quality assurance; and triangulation of evidence from multiple sources. Specifically, patients were evaluated by trained nurse-observers, patients provided their own perspectives on patient-reported outcomes questionnaires, and they contributed photographs that underwent blinded physician review for cosmetic outcomes. Adverse cosmesis was more common in patients treated with APBI than in those treated with whole-breast irradiation as assessed by the nurses (29% v 17%; P < .001), patients themselves (26% v 18%; P = .002), and blinded-physician reviewers of photographs (35% v 17%; P < .001). The substantial, consistent, and significant differences observed using data from multiple sources are both persuasive and clinically relevant. Particularly interesting was the finding that cosmesis was stable or improved over time in a higher proportion of patients treated with whole-breast irradiation as acute hematomas and edema resolved, and cosmesis deteriorated over time in a larger proportion of APBI patients.
Of note, the findings of this Canadian RAPID trial diverge from preliminary findings obtained to date from an interim analyses of the large and similarly well-designed randomized trial of APBI in the United States, RTOG 0413/NSABP B39. Interim analysis of the subset of patients treated with external-beam APBI in that study did not reveal significant increases in severe toxicity as evaluated by treating providers on routine case report forms, using the Common Terminology Criteria for Adverse Events (CTCAE).16 However, the RAPID trial suggests that adverse cosmesis may not adequately be captured by CTCAE scoring; indeed, they found low rates of severe CTCAE-graded toxicity even in the context of substantial rates of adverse cosmesis. Of note, the NSABP/RTOG trial was also carefully designed to collect the results of global physician cosmetic assessments, patient-reported outcomes, and review of photographs. We eagerly anticipate reviews of these other important end points in this important trial.
It is possible, of course, that even with further review the outcomes in the RTOG/NSABP trial will differ from those in the RAPID trial. Subtle differences in the limits on dose prescription, including definition of the normal breast volume, may affect the development of toxicity in this setting, as may variation in how much the treating providers approached the allowable limits with their treatment plans. It is pointed out in the supplemental tables, however, that major deviation in dose constraints occurred in only 1.8% of patients in the RAPID trial. As Olivotto et al9 note, although there was an excess of adverse cosmetic outcomes in their trial, many patients treated with APBI had good or excellent outcomes. Additional dosimetric studies of the data from both trials would be particularly valuable to illuminate which patients are most likely to experience adverse cosmetic outcomes, information that could then be used to further refine dosimetric parameters for this approach. It may also be valuable to examine actual interfraction intervals in these twice-daily fractionation schemes of APBI, given the possibility raised by radiobiologists that the community may have underestimated the effects of incomplete recovery of normal tissue damage between fractions.17
Of note, these findings should not be extrapolated to the expected outcomes of brachytherapy-based approaches for APBI. Given the steep dose fall-off with brachytherapy, smaller volumes of normal breast are exposed to large doses per fraction of radiation. Other studies have considered outcomes of brachytherapy-based techniques, including a highly publicized observational study of Medicare data published last year.18 In that study, patients undergoing brachytherapy-based APBI had a higher mastectomy rate than those who received whole-breast irradiation (3.95% v 2.18%; P < .001). However, the study by Smith et al18 was a retrospective, observational analysis, subject to the usual caveats that association might not imply causation. Moreover, the study was situated in an era of relatively early experience with brachytherapy, before criteria for appropriate patient selection and risk factors for complications had been articulated,19 so its results may not reflect the toxicity or efficacy of brachytherapy as applied now that experience with this approach is more mature.20 Therefore, the findings of the RTOG 0413/NSABP B39 trial, which allowed both brachytherapy and external beam approaches for APBI, will be extremely valuable in the further evaluation of concerns raised to date about both techniques.
In summary, APBI is a strategy that may make radiation treatment more accessible and convenient for some patients, and it is therefore a worthy subject of ongoing investigation. However, as with any new radiation treatment approach, carefully designed clinical trials are essential to establish appropriate dose, volume, and scheduling parameters for each technique. The interim toxicity results reported by Olivotto et al9 from their experience with external-beam APBI in the Canadian RAPID trial provide compelling evidence that current schedules for APBI approach the steep aspect of the toxicity curve and merit caution before application outside the context of a clinical trial.
Therefore, we firmly believe that patients who wish to be treated with APBI should be enrolled on prospective trials to address many of the unanswered questions, including appropriate patient selection, dose fractionation, and technical issues in APBI. Such clinical trials not only will help to move the field forward but assure through their prospective nature and informed consent that patients are fully aware of the potential risks, benefits, and alternatives. Those patients who wish to pursue partial-breast irradiation outside the context of ongoing protocols should be fully informed of the results of the Canadian trial, as well as the generally nascent and evolving nature of our knowledge regarding this approach. Only with the ongoing support and follow-up of large, carefully designed trials like the Canadian RAPID trial and the NSABP B39/RTOG 0413 can the risks and benefits of various approaches to adjuvant breast irradiation ultimately be defined and appropriately refined.
See accompanying article on page 4038

Authors' Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

References

1.
M Clarke, R Collins, S Darby, etal: 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 366: 2087– 2106,2005
2.
TJ Whelan, JP Pignol, MN Levine, etal: Long-term results of hypofractionated radiation therapy for breast cancer N Engl J Med 362: 513– 520,2010
3.
SM Bentzen, RK Agrawal, etal: The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial Lancet Oncol 9: 331– 341,2008 START Trialists' Group
4.
SM Bentzen, RK Agrawal, etal: The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial Lancet 371: 1098– 1107,2008 START Trialists' Group
5.
PR Benitez, PY Chen, FA Vicini, etal: Partial breast irradiation in breast conserving therapy by way of interstitial brachytherapy Am J Surg 188: 355– 364,2004
6.
RR Kuske, JS Bolton: Radiation Therapy Oncology Group Publication No. 1055: A phase I/II trial to evaluate brachytherapy as the sole method of radiation therapy for stage I and II breast carcinoma 1995 Philadelphia, PA Radiation Therapy Oncology Group
7.
F Perera, F Chisela, J Engel, etal: Method of localization and implantation of the lumpectomy site for high dose rate brachytherapy after conservative surgery for T1 and T2 breast cancer Int J Radiat Oncol Biol Phys 31: 959– 965,1995
8.
C Polgár, Z Sulyok, J Fodor, etal: Sole brachytherapy of the tumor bed after conservative surgery for T1 breast cancer: Five-year results of a phase I-II study and initial findings of a randomized phase III trial J Surg Oncol 80: 121– 128,2002
9.
IA Olivotto, TJ Whelan, S Parpia, etal: Interim cosmetic and toxicity results from RAPID: A randomized trial of accelerated partial-breast irradiation using three-dimensional conformal external-beam radiation therapy J Clin Oncol 31: 4038– 4045,2013
10.
DW Weed, GK Edmundson, FA Vicini, etal: Accelerated partial breast irradiation: A dosimetric comparison of three different techniques Brachytherapy 4: 121– 129,2005
11.
JT Hepel, M Tokita, SG MacAusland, etal: Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation Int J Radiat Oncol Biol Phys 75: 1290– 1296,2009
12.
KL Leonard, JT Hepel, JR Hiatt, etal: The effect of dose-volume parameters and interfraction interval on cosmetic outcome and toxicity after 3-dimensional conformal accelerated partial breast irradiation Int J Radiat Oncol Biol Phys 85: 623– 629,2013
13.
R Jagsi, MA Ben-David, JM Moran, etal: Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation Int J Radiat Oncol Biol Phys 76: 71– 78,2010
14.
FA Vicini, P Chen, M Wallace, etal: Interim cosmetic results and toxicity using 3D conformal external beam radiotherapy to deliver accelerated partial breast irradiation in patients with early-stage breast cancer treated with breast-conserving surgery Int J Radiat Oncol Biol Phys 69: 1124– 1130,2007
15.
PY Chen, M Wallace, C Mitchell, etal: Four-year efficacy, cosmesis, and toxicity using three-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation Int J Radiat Oncol Biol Phys 76: 991– 997,2010
16.
N Wolmark, WJ Curran, F Vicini, etal: Response to “Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation” (Int J Radiat Oncol Biol Phys 76:71-78, 2010) and “Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation” (Int J Radiat Oncol Biol Phys 75:1290-1296, 2009) Int J Radiat Oncol Biol Phys 77: 317,2010
17.
SM Bentzen, JR Yarnold: Reports of unexpected late side effects of accelerated partial breast irradiation–radiobiological considerations Int J Radiat Oncol Biol Phys 77: 969– 973,2010
18.
GL Smith, Y Xu, TA Buchholz, etal: Association between treatment with brachytherapy vs whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer JAMA 307: 1827– 1837,2012
19.
BD Smith, DW Arthur, TA Buchholz, etal: Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO) Int J Radiat Oncol Biol Phys 74: 987– 1001,2009
20.
LW Cuttino, JR White, R Rabinovitch, etal: Accelerated partial breast irradiation: Trial by media or by science? Int J Radiat Oncol Biol Phys 83: 1075– 1077,2012

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 4029 - 4031
PubMed: 24081942

History

Published online: September 30, 2013
Published in print: November 10, 2013

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Reshma Jagsi [email protected]
University of Michigan; Center for Bioethics and Social Sciences in Medicine, Ann Arbor, MI
Bruce G. Haffty
Rutgers Robert Wood Johnson Medical School; The Cancer Institute of New Jersey, New Brunswick, NJ

Notes

Corresponding author: Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, University of Michigan, UHB2C490, SPC 5010, 1500 East Medical Center Dr, Ann Arbor, MI 48109-5010; e-mail: [email protected].

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Manuscript writing: All authors
Final approval of manuscript: All authors

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Reshma Jagsi, Bruce G. Haffty
Journal of Clinical Oncology 2013 31:32, 4029-4031

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