© The Author 2006. Published by Oxford University Press.
EDITORIAL |
Postmastectomy Radiotherapy: Quality Counts!
Affiliation of authors: Department of Radiation Oncology, Duke University Medical Center, Durham, NC
Correspondence to: Leonard R. Prosnitz, MD, Department of Radiation Oncology, Duke University Medical Center, Box 3085 Medical Center, Durham, NC 27710 (e-mail: prosnitz{at}radonc.duke.edu).
It seems like such a simple idea. It is surprising that no one has ever done it before.
In this issue of the Journal, Gebski et al. (1) from Australia revisit the issue of postmastectomy radiation therapy and its effects on survival with a meta-analysis of 36 trials and a reanalysis of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) report (2). What is new is that Gebski et al. make an effort to control for the quality of radiation therapy in these trials.
The trials were categorized as "optimal" with regard to radiation therapy dose and treatment volume (dose of 40–60 Gy and irradiation of chest wall and regional lymph nodes) or inappropriate with doses and/or treatment volumes outside this range. The authors consider the appropriate volume to be all (emphasis ours) areas at risk for local–regional recurrence or involvement, a statement that seems fairly straightforward and a principle that is central to radiation therapy of most other cancers (e.g., head and neck or rectal). By implication, this would include internal mammary lymph nodes and supraclavicular lymph nodes, a conclusion with which we agree but that is nonetheless quite controversial because of concern for cardiac side effects. Omission of only internal mammary lymph nodes did not cause studies to be classified as inappropriate or suboptimal.
There is a potential for bias in these definitions because the authors knew the outcome of the studies. Nonetheless, the definitions are mainstream radiation oncology principles and so are well justified, in our opinion.
The authors further had no opportunity (hardly possible in a meta-analysis) to review treatment records, techniques, and portal films to determine whether the planned doses and fields were actually delivered. When careful quality analysis has been done on radiation therapy in cooperative group trials, major protocol violations have been found in up to 20% of cases.
Additional limitations of this analysis are as follows: 1) The inclusion of many studies in which adjuvant systemic therapy was not used. In a disease with a high frequency of systemic relapse, local–regional therapy is most likely to improve survival when effective systemic therapy is used. 2) The inclusion of patients with various risks of relapse (i.e., high, medium, and low). Potential absolute survival benefits of radiation therapy will be less in the low-risk group. 3) Ten-year analysis may not fully reflect the impact of radiation therapy–related mortality, which is primarily cardiac mortality and usually occurs more than 10 years after treatment. Radiation therapy–induced cardiac damage is largely a technical issue; the heart can, for the most part, be avoided with modern treatment planning. Recent studies have suggested no increase in cardiac deaths after postmastectomy radiation therapy, but further follow-up is desirable (3,4). One can account for length of follow-up by performing meta-analyses subdivided by year of onset of the trial.
The first two limitations mentioned above dilute the potential survival benefits from radiation therapy, making them more difficult to detect. Ten-year analysis may understate the adverse effects of radiation therapy and thus falsely elevate the survival benefit. Nonetheless, the authors make a valuable contribution by addressing the quality issue and convincingly demonstrate a statistically significant increase in survival as well as local–regional control in patients treated with optimal postmastectomy radiation therapy, compared with those receiving inappropriate or no postmastectomy radiation therapy. They demonstrate this both in their primary analysis and in their reanalysis of the EBCTCG data.
Some of the concerns raised above have been addressed by others. Whelan et al. (5) analyzed 18 trials in which adjuvant systemic therapy had been used for all patients and found statistically significant improvement in both local–regional control and survival with postmastectomy radiation therapy. The quality of radiation therapy was commented upon but not accounted for in that analysis.
When Van de Steene et al. (6) reanalyzed the 1995 EBCTCG data (7), they attempted to control for quality by examining 11 variables, including size of the trial, radiation therapy dose, target volume, year the trial began, and adjuvant systemic therapy. They found statistically significant survival benefits for the addition of postmastectomy radiation therapy when the trials were recent, large, and used appropriate doses of radiation therapy.
Survival benefits also appear to accrue from the use of radiation therapy after lumpectomy in patients receiving breast-conservation therapy. Some initial reports as well as the EBCTCG analysis suggested the survival gain was minimal (2). More recent updated analyses, however, have shown a benefit, even though the quality has not been controlled and the follow-up is relatively short [median follow-up of 6 years in the Vinh-Hung analysis (8)].
What should we conclude from the Gebski report as well as the literature cited above?
1) The quality of treatment is important for outcome, especially for radiation therapy but, of course, also for other modalities. Meta-analyses that do not take quality into consideration should be regarded skeptically.
2) The evidence is now strong for survival benefits for both postmastectomy radiation therapy and postlumpectomy radiation therapy. Three recent editorials in the Journal also support this point of view (9–11). Local control is important not only for quality of life but also for survival. The notion that it is possible to let cancer recur in the breast without affecting survival has always struck us as implausible. Now the data are emerging that such local recurrence does has an adverse impact on survival.
3) Despite recent data suggesting (but not conclusively proving) that there is no increase in cardiac mortality from modern radiotherapy, radiation oncologists should remain diligent. Our studies have detected asymptomatic cardiac perfusion defects in many patients (12). Advanced planning and delivery tools, such as three-dimensional treatment planning, can keep those problems to a minimum and should be used.
4) Finally, emphasis should now shift to better selecting patients for postsurgical radiation therapy. With the advent of molecular profiling, new classifications of breast carcinoma have been developed and are now being applied to the selection of patients for various chemotherapy regimens (13). The relevance of molecular profiling to the selection of patients for postsurgical radiation therapy in mastectomy patients or in those treated with lumpectomy needs to be investigated.
REFERENCES
(1) Gebski V, Lagleva M, Keech A, Simes J, Langlands AO. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst 2006;98:26–38.
(2) Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757–70.[CrossRef][Web of Science][Medline]
(3) Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 2005;97:419–24.
(4) Prosnitz RG, Marks LB. Radiation-induced heart disease: vigilance is still required. J Clin Oncol 2005;23:7391–4.
(5) Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220–9.
(6) Van de Steene J, Soete G, Storme G. Adjuvant radiotherapy for breast cancer significantly improves overall survival: the missing link. Radiother Oncol 2000;55:263–72.[CrossRef][Medline]
(7) Early Breast Cancer Trialists' Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. N Engl J Med 1995;333:1444–55.
(8) Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004;96:115–21.
(9) Cuzick J. Radiotherapy for breast cancer. J Natl Cancer Inst 2005;97:406–7.
(10) Vallis KA, Tannock IF. Postoperative radiotherapy for breast cancer: growing evidence for an impact on survival. J Natl Cancer Inst 2004;96:88–9.
(11) Whelan T, Levine M. More evidence that locoregional radiation therapy improves survival: what should we do? J Natl Cancer Inst 2005;97:82–4.
(12) Marks LB, Yu X, Prosnitz RG, Zhou SM, Hardenbergh PH, Blazing M, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys 2005;63:214–23.[CrossRef][Web of Science][Medline]
(13) Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 2005;23:7350–60.
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  I. Kunkler, N. Russell, P. Canney, K. Venables, and J. Bartlett Re: Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst, July 19, 2006; 98(14): 1020 - 1021. [Full Text] [PDF]
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