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Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5844-5845 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7082
In Reply:Antoni van Leeuwenhoek Hospital; the Netherlands Cancer Institute, Amsterdam, the Netherlands
Fédération Nationale des Centres de Lutte Contre le Cancer, Dijon, France
Bernard Verbeeten Institute, Tilburg, the Netherlands
European Organisation for Research and Treatment of Cancer, Brussels, Belgium The three letters to the editor concerning our report of the 10-year results of the European Organization for Research and Treatment of Cancer boost versus no boost trial focus mainly on the positive effect of the boost dose of 16 Gy at reducing the local recurrence rate after breast conserving therapy with a factor 2.1 The letters also point at the limited increase of fibrosis and its possible pathways. Indeed, experimental studies demonstrated that fibrosis after irradiation is related to TGF-b1 and its associated pathways, that, as suggested by Koc, may be stimulated further by tamoxifen. A separate analysis of our study was performed to investigate factors associated with increased fibrosis in the patients receiving a boost and will be reported soon.2 For this analysis, the patient group was first randomly split into a model-development and a model-validation group. The analyses confirmed that in the test group, the risk of fibrosis for the patients who received tamoxifen was 1.5 times higher than in patients who were not exposed to tamoxifen. However, this factor did not reach statistical significance when the model was tested in the validation group.2 Factors that remained significant in the validation group were the presence of a hematoma after lumpectomy, chemotherapy when given concomitantly with irradiation, and radiotherapy treatment factors associated with inhomogeneous dose distribution in the breast. Our study could not demonstrate any significant difference in the rate of fibrosis when the boost was given with external radiotherapy or with brachytherapy. We agree that the amount of fibrosis and vascular damage caused by irradiation may be reduced by using inhibitors of Rho and ROCK (Rho-kinase). This hypothesis, however, needs yet to be demonstrated in the framework of a clinical trial such as our ongoing randomized phase III trial M02STA. Irradiation of the breast might also negatively impact survival due to possible cardiac damage, as stated by Gultekin et al. With a median follow-up of 10.8 years, we have yet to find any difference in overall mortality nor in non–breast cancer–related mortality between the two treatment arms. We also appreciate the worries expressed by Gultekin et al that due to our publication concerning the 5-year results3, some older patients may temporarily not have benefited from a boost dose. An independent data committee advised us in 2001 to publish the results already at 5 years, as the reduction of local recurrence rate after a boost dose was so impressive in young patients, especially knowing that the delivery of a boost was at that time not standard in large parts of the world. We think therefore that, thanks to our published results, the benefit for younger patients receiving a boost dose outweighs the negative impact for older patients not receiving a boost. The fact that also now, after much longer follow-up, older patients have a significant improvement in local control stresses again the importance of publishing long-term follow-up results of breast cancer treatment; it also emphasizes the need to ensure sufficient statistical power to demonstrate treatment effects in all patient subsets of interest. Another important item stressed by Bourgier et al is the high local recurrence rate observed in young patients in comparison to that in older women. However, we expect that the high local recurrence rates that Arriagada et al4 reported with long-term follow-up will probably not emerge in the contemporary patient population. We expect nowadays a much lower recurrence rate, as much more attention is given to completely resecting the primary tumor and because many young patients now receive adjuvant systemic treatment, which is known to have further reduced the risk of local relapse. In our trial as well, adjuvant chemotherapy as along with hormonal therapy were shown in a previous multivariate analysis to further reduce the local recurrence rate with a factor of nearly 2.5 Finally, we fully agree that better criteria are needed for selecting patients for radiotherapy and especially for guiding on the irradiation dose required for optimal treatment. For this reason, a new trial was started in the Netherlands, as a logical follow-up to the original boost trial. This trial, which is called "young boost trial" and has already accrued 800 patients, recruits patients up to 50 years of age and randomizes them between a low- and high-boost dose. Fresh frozen tumor material for microarrays and blood for proteomics are also collected from these patients. The final aim of the "young boost" trial is indeed to develop and validate a prediction profile for local recurrence that will help in the future to more accurately select the patients who need a higher boost dose. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Bartelink H, Horiot JC, Poortmans PM, et al: Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breastcancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 25:3259-3265, 2007 2. Collette S, Collette L, Budiharto T, et al: Predictors of increased risk of breast fibrosis at 10 years with higher radiation dose in early breast cancer (EORTC trial: boost versus no boost). Eur J Cancer 5:192, 2007 (suppl; abstr 2027) 3. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378-1387, 2001 4. Arriagada R, Le MG, Guinebretiere JM, et al: Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol 14:1617-1622, 2003 5. Antonini N, Jones H, Horiot JC, et al: Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882. Radiother Onc 82:265-271, 2007[CrossRef]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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