Clinical Update - Breast Cancer
Radiotherapy in Ductal Carcinoma In Situ
Commentary by Associate Professor Geoff Delaney
The articles
- Omlin A, Amichetti M, Azria D et al.
Boost radiotherapy in young women with ductal carcinoma in situ:
a multicentre, retrospective study of the Rare Cancer Network.
Lancet Oncol 2006;7(8):6526
Summary | Commentary - Bijker N, Meijnen P, Peterse JL et al.
Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ:
ten-year results of European Organisation for Research and Treatment of Cancer Randomized Phase III Trial 10853 -
A study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 2006;24:33817
Summary | Commentary
Reviewer
Associate Professor Geoff Delaney is the Director of Radiation Oncology for Liverpool and Campbelltown Hospitals.
Article i
Boost radiotherapy in young women with ductal carcinoma in situ
Summary
Abbreviations
Confidence Interval (CI), Ductal Carcinoma In Situ (DCIS), Gray (Gy), Hazard Ratio (HR)
Study design
This retrospective study included 373 women who were 45 or younger when their DCIS was diagnosed at one of 18 institutions from 11 countries (including Australia). After their surgery, 15% of these women had no radiotherapy, 45% had whole-breast radiotherapy without a boost (median dose 50 Gy [range 4060]), and 40% had whole-breast radiotherapy with a boost (median dose 60 Gy [range 5376]). The primary outcomes were local relapse and local relapse-free survival. Local relapse was defined as any local recurrence of breast cancer (either invasive or in situ). The median follow-up was 6 years.
Findings
Compared with patients who had no radiotherapy, patients who had radiotherapy had lower risks of relapse both without a boost (HR: 0.33; 95%CI: 0.16, 0.71; p=0.004) and with a boost (HR: 0.15; 95%CI: 0.06, 0.36; p<0.0001).
Local relapse-free survival rates at 10 years were:
- 46% (95% CI: 24%, 67%)* for patients with no radiotherapy
- 72% (95% CI: 61%, 83%)* for patients with radiotherapy without boost
- 86% (95% CI: 78%, 93%)* for patients with radiotherapy and boost
*difference between all three groups, p<0.0001.
There was no significant difference in 10-year overall survival rates between the three treatment groups.
Conclusion
The authors concluded that boost radiotherapy should be considered in addition to surgery for breast-conserving treatment for DCIS.
Article i - Boost radiotherapy in young women with ductal carcinoma in situ
Commentary
What does this article add to existing clinical evidence in this area?
The study by Omlin et al.1 evaluated the benefits of radiotherapy, with or without a boost, to conventional breast radiotherapy after breast conserving surgery for DCIS. No randomised trials have evaluated adding a boost for patients with DCIS, although plans are underway for such a trial in Australia and New Zealand.
Three randomised trials have shown that radiotherapy halves local recurrence rates after breast conserving surgery for DCIS.2–4 However, the recurrence rates with radiotherapy reported in these trials have been slightly higher than those in similar patients treated with breast conserving surgery and radiotherapy for invasive cancers. One of the postulated reasons for this is that all three randomised trials used radiotherapy to the whole breast to a total dose of 50 Gy without a boost, and that a boost of radiotherapy to the primary surgical bed might further improve local control.
A boost dose of radiotherapy to the tumour bed, following treatment to the entire breast, has been shown to improve loco-regional control in patients with invasive breast cancer.5 This was particularly evident in patients < 50 years of age (i.e. those patients at greatest risk of local recurrence). In invasive disease, age has been shown to be an important prognostic factor for recurrence. No such randomised trial exists for DCIS patients.
The study by Omlin et al.1 found that additional radiotherapy by way of a radiotherapy boost improves local control for patients < 45 years of age. Ten year relapse free survival was 46% for those patients not receiving any radiotherapy, 72% for patients receiving radiotherapy without a boost and 86% for patients having radiotherapy including a boost. The absence of an overall survival benefit is expected as the study was never powered to detect a survival difference.
This study suggests that a radiotherapy boost may be beneficial in patients < 45 years old but it does not address the issue for older patients.
How adequate was the methodology used in addressing the aims of this study?
This study has several limitations:
- It was retrospective and the use of radiation (and/or a boost) was not randomly allocated resulting in selection bias. However, in this case, selection bias is against radiotherapy (and/or a boost) in that it is more likely to be given to patients with a higher risk of recurrence (larger lesion, higher grade and close or positive surgical margins). Despite these biases against radiotherapy, the study was in favour of radiotherapy boost improving local control, suggesting that the true difference might even be greater. A randomised trial is needed to determine the benefits accurately.
- The follow up in this study is relatively short (median of 72 months). Although this might be acceptable for invasive disease, some DCIS lesions have a very long time to recurrence, particularly those of low grade, and the results may change with longer follow up.
- Patients were accrued over 26 years. During this time, significant changes have occurred in patient assessment, mammography, surgical techniques, specimen handling and radiotherapy techniques. No analysis of recurrence according to year of diagnosis is provided to determine the impact of these changes in practice.
What are the implications of this study for clinical practice in Australia?
Although this study is limited because of its retrospective nature it provides some evidence supporting the use of a radiotherapy boost in patients with DCIS at high risk of recurrence. However, a randomised trial comparing radiotherapy with and without a boost is needed to accurately determine its benefits and harms. This study has also identified that young age and close or positive surgical margins increase the risk of local recurrence in women with DCIS.
Article ii
Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ
Summary
Abbreviations
Confidence Interval (CI), Contralateral Breast Cancer (CLBC); Ductal Carcinoma In Situ (DCIS), Gray (Gy), Hazard Ratio (HR), Local Excision (LE)
Study design
After complete LE, 1010 women with DCIS were randomised to either no further treatment (n=503) or radiotherapy (50 Gy, n=507). The primary outcome was local recurrence-free survival. The median follow-up was 10.5 years.
Findings
The addition of radiotherapy after LE improved:
- 10-year local recurrence-free rates (85% vs 74%; HR:0.53; p<0.0001)
- 10-year DCIS local recurrence-free rates (93% vs 86%; p=0.001)
- 10-year invasive local recurrence-free rates (92% vs 87%; p=0.007)
There were no significant differences at 10 years in the rates of CLBC, distant metastases, or death.
Conclusion
The authors concluded that radiotherapy after local excision reduces the risk of local recurrence compared with local excision alone.
Article ii - Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ
Commentary
What does this article add to existing clinical evidence in this area?
This is an update of the European Organization for the Research and Treatment of Cancer (EORTC) randomised clinical trial assessing the role of post operative radiotherapy following breast conservative surgery in the management of ductal carcinoma in-situ.
The previous publication reported results after a median follow up of 4.25 years6 and this study reports follow up after 10 years.
The main findings were:
- Radiotherapy after local excision reduces the risk of recurrence of invasive cancer or DCIS, even in low risk categories.
- The magnitude of the benefit has increased with longer follow up.
- Radiation had no effect on overall survival. This includes the fact that patients having radiotherapy did not appear to have an increased death rate due to heart disease.
- There was no difference in the pattern of recurrence between invasive or non-invasive recurrence.
- There was no difference in the rates of contra-lateral breast cancer. The previous report of this trial suggested an increased risk of contra-lateral breast cancer, a finding that was always difficult to explain, and was most likely due to the play of chance.
- The overall death rate from DCIS was 2% which was similar to that reported after mastectomy.
- For some groups having local excision and radiotherapy, there was still a recurrence rate of 15% or more. This study did not include the use of radiotherapy boost, which may further decrease local recurrence rates and could be considered for those patients at high risk.
- The risk of recurrence is <10% at 10 years after surgery alone for Grade 1 DCIS with a clinging, micro-papillary pattern and clear surgical margins. Recurrence rates were significantly improved by the addition of radiotherapy. However, for patients with a low risk of recurrence, the absolute benefits are small and might be judged insufficient by patients to warrant treatment.
How adequate was the methodology used in addressing the aims of this study?
This is a well-conducted randomised controlled trial and is likely to reflect the outcomes of treatment in the population at large.
What are the implications of this study for clinical practice in Australia?
This study is not likely to dramatically change practice as it is consistent with current Australian guidelines based on the initial findings of this trial.7 The reassurance that contralateral breast cancer risk does not appear to be increased for patients having radiotherapy for DCIS means that patients can be counselled more easily about the benefits of improved local control. It is important that patients understand the absolute benefits of their proposed radiotherapy and that this depends on their risk of recurrence according to standard pathological features. For patients with a low risk of recurrence, the absolute benefits of radiotherapy are sufficiently small that some women may opt not to have it.
References
1. Omlin A, Amichetti M, Azria D et al. Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network. Lancet Oncol 2006;7(8):6526
2. Bijker N, Meijnen P, Peterse JL et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: ten-year results of European Organisation for Research and Treatment of Cancer Randomized Phase III Trial 10853 - A study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 2006;24:33817
3. UK Coordinating Committee on Cancer Research (UKCCCR), Ductal Carcinoma in situ (DCIS) Working Party on behalf of the DCIS trialists in the U.K., Australia and New Zealand. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the U.K., Australia and New Zealand: randomised controlled trial. Lancet 2003;362:95102.
4. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: An update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 2001;28:40018.
5. Bartelink H, Horiot JC, Poortmans P, et al. European Organization for Research and Treatment of Cancer Radiotherapy and Breast Cancer Groups. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:137887.
6. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: First results of the EORTC randomised phase III trial 10853 EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 2000;355:52833.
7. National Breast Cancer Centre (NBCC). The clinical management of ductal carcinoma in situ, lobular carcinoma in situ and atypical hyperplasia of the breast. National Breast Cancer Centre, 2003, Sydney.
Editor: Dr Karen Luxford, Deputy Director NBCC.
Editorial Committee: Mr John Collins - Surgeon,
Dr Sue-Anne McLachlan - Medical Oncologist,
Dr Sue Pendlebury - Radiation Oncologist,
Dr Martin Stockler - Medical Oncologist
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