Correspondence
Radiotherapy for Breast Cancer
N Engl J Med 2002; 346:862-864March 14, 2002
- Article
To the Editor:
We wonder about the generalizability of the results of the European Organization for Research and Treatment of Cancer (EORTC) trial of supplementary (“booster”) irradiation after lumpectomy (Nov. 8 issue).1 The rate of recurrence of local breast cancer is now very low in women treated with modern surgical techniques, postoperative whole-breast irradiation (without a supplementary dose), and adjuvant systemic therapy. In a recent randomized trial involving 1234 women with node-negative breast cancer treated with lumpectomy, adjuvant systemic therapy (used selectively), and whole-breast irradiation (50 Gy in 25 fractions or 42.5 Gy in 16 fractions), the rate of recurrence in the breast was only 3 percent at five years.2 This rate is lower than that seen in the current EORTC study. Similarly low rates of local recurrence with the use of whole-breast irradiation have been observed in other studies.3,4 The magnitude of the benefit expected with supplementary irradiation in women with such low rates of recurrence is very small and needs to be weighed against an additional week and a half of treatment and the possible decrease in the quality of the cosmetic outcome.1
The beneficial effect of additional radiotherapy in the EORTC trial was mainly observed in younger women, but high rates of local recurrence in young women are unusual. Adjuvant systemic therapy reduces the risk of local or distant recurrence in patients who undergo lumpectomy.3,4 In the EORTC trial, tamoxifen and chemotherapy were used infrequently. Fifty-three percent of the women in our study2 received systemic therapy. The observed rates of local recurrence — 8.9 percent in patients 40 years old or younger, 4.5 percent in those 41 to 50 years old — were lower than that observed in the additional-radiation group of the EORTC trial. Although Bartelink et al. recommend booster treatment for all women younger than 50 years of age, in our view this issue requires further study.
4 ReferencesTim Whelan, B.M., B.Ch.
Jim Julian, M.Math.
Mark Levine, M.D.
McMaster University, Hamilton, ON L8N 3Z5, Canada
tim.whelan@hrcc. on. ca 1
Bartelink H ,Horiot J-C ,Poortmans P , et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378-1387
Full Text | Web of Science | Medline2
Whelan TJ ,MacKenzie RG ,Levine M , et al. A randomized trial comparing two fractionation schedules for breast irradiation postlumpectomy in node-negative breast cancer. Prog Proc Am Soc Clin Oncol 2000;19:2a-2a abstract.3
Fisher B ,Dignam J ,Mamounas EP , et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996;14:1982-1992
Web of Science | Medline4
Fisher B ,Dignam J ,Bryant J , et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529-1542
CrossRef | Web of Science | Medline
To the Editor:
Bartelink et al. evaluated the effect of an additional 16-Gy dose of radiation in patients with breast cancer. In 1985, in a study that involved 463 patients, my colleagues and I showed by multivariate analysis that there was a linear relation between dose and tumor control,1 and we predicted that an additional 15 Gy would halve the risk of local recurrence in patients with subclinical disease. Bartelink et al. calculated this reduction as hazard ratios of 0.59 and 0.51 in univariate and multivariate analyses, respectively.
Bartelink et al. also showed that the additional dose had a larger effect in younger patients, who have a greater risk of local recurrence than older patients. Even if the 5-year rate of recurrence with the additional dose is about 10 percent, the risk might reach 15 to 20 percent at 10 to 15 years. To increase the dose of radiation further does not seem to be a solution, since the authors state that 56 percent of the recurrences in the breast were outside the area that received the additional dose. Furthermore, since the risk of local recurrence in younger patients has been reported to be nine times that in older patients,2 even when an additional dose is given,2 it would be necessary to increase the additional dose by two steps of 15 to 16 Gy each, for a total dose of 95 to 98 Gy — an approach that seems unrealistic.
2 ReferencesRodrigo Arriagada, M.D.
Instituto de Radiomedicina, 6671407 Santiago, Chile
gocchi@ctcinternet.cl 1
Arriagada R ,Mouriesse H ,Sarrazin D ,Clark RM ,Deboer G . Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Int J Radiat Oncol Biol Phys 1985;11:1751-1757
CrossRef | Web of Science | Medline2
Voogd AC ,Nielsen M ,Peterse JL , et al. Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials. J Clin Oncol 2001;19:1688-1697[Erratum, J Clin Oncol 2001;19:2583.]
Web of Science | Medline
To the Editor:
In the study by Bartelink et al., it is unclear why the five-year rates of local recurrence among the 449 women 40 years old or younger — whether they were treated with additional radiation (rate of local recurrence, 10.2 percent) or without additional radiation (19.5 percent) — were higher than the rates of local recurrence in older women. It is possible that some local recurrences outside the tumor-bearing area in women 40 years old or younger were second primary tumors due to a BRCA1 or BRCA2 mutation. Recurrent tumors in the ipsilateral breast in women with a BRCA1 or BRCA2 mutation often have a location and histologic features that are different from those of the primary tumor, and they tend to occur late, with a median time to recurrence of 7.8 years.1 This possibility is supported by the observation that the curves representing the cumulative incidence of local recurrence in women in this age group who received additional radiation and in those who did not continue to separate after five years (Figure 2 of the article). The planned analysis at 10 years, with detailed correlation of incidence with the presence or absence of a family history of breast cancer, will therefore be important in assessing the effect of additional radiation on the long-term risk of tumor recurrence in the ipsilateral breast in women 40 years old or younger.
1 ReferencesIan Kunkler, F.R.C.P.E., F.R.C.R.
Western General Hospital, Edinburgh EH4 2XU, United Kingdom
i.kunkler@doctors. org. uk 1
Turner BC ,Harrold E ,Matloff E , et al. BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations. J Clin Oncol 1999;17:3017-3024
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: A comparison of small differences in rates of local recurrence between trials, as suggested by Whelan and colleagues, is difficult or even impossible, since their study population was about one fifth the size of ours and did not, for instance, include node-positive patients. Moreover, their results are currently available only in abstract form. The rate of local recurrence also depends on the definition used; for example, in our trial, the actuarial rate of local recurrence as a first event was only 5.9 percent in the standard-treatment group and 3.3 percent in the additional-radiation group. We would like to underline the general applicability of the data from our EORTC trial, since it was carried out at 31 centers in nine countries and involved more than 5000 patients. In this trial and in a previous randomized trial,1 we indeed observed a lower rate of recurrence in patients who received adjuvant systemic therapy and radiotherapy. In the multivariate analysis, however, only age and the additional dose of radiation remained significant.
We agree with Arriagada that a halving of the local-recurrence rate with the use of an additional dose of 16 Gy is not sufficient for all patients 40 years of age or younger. As an alternative, higher doses of radiation can be given; adjuvant systemic treatment also contributes to a decrease in the recurrence rate. Intraoperative imaging or guidance techniques with wires or isotopes will lead to more complete excisions and may contribute to better results.2,3
Kunkler comments on the still-unknown cause of the worse prognosis in young women with breast cancer and notes that some of the recurrences in this group may be related to BRCA1 or BRCA2 germ-line mutations. Our extensive analysis of prognostic factors could not explain the effect of age on local control.4 This uncertainty stimulated the use of DNA microarrays containing approximately 25,000 genes from young patients with breast cancer at the Netherlands Cancer Institute to identify subgroups with poor outcomes. The initial results show that gene-expression profiling can identify small tumors that are already programmed for a poor outcome and that it can identify a special gene-expression “signature” in patients with a BRCA1 mutation.5 Further research in this field will lead to the identification of subgroups with specific gene-profile signatures, which may, in turn, allow adaptation of the treatment strategy (adjuvant systemic treatment and, eventually, mastectomy) and selection of the required radiation dose for each individual patient. Until these results are confirmed, we strongly suggest the delivery of an additional, 16-Gy dose of radiation after whole-breast irradiation with 50 Gy in patients 50 years old or younger. The absence of demonstrable radiation-induced damage at five years and the 91 percent five-year survival rate are additional reasons to recommend a few extra days of irradiation in young patients.
5 ReferencesHarry Bartelink, M.D., Ph.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
h.bartelink@nki. nl Jean-Claude Horiot, M.D., Ph.D.
Centre G.-F. Leclerc, 21034 Dijon CEDEX, FrancePhilip Poortmans, M.D.
Dr. Bernard Verbeeten Instituut, 5000 LA Tilburg, the Netherlands1
Bartelink H ,Rubens RD ,van der Schueren E ,Sylvester R . Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer randomized phase III trial. J Clin Oncol 1997;15:207-215
Web of Science | Medline2
Gennari R ,Galimberti V ,De Cicco C , et al. Use of technetium-99m-labeled colloid albumin for preoperative and intraoperative localization of nonpalpable breast lesions. J Am Coll Surg 2000;190:692-698
CrossRef | Web of Science | Medline3
Liberman L ,Kaplan J ,van Zee KJ , et al. Bracketing wires for preoperative breast needle localization. AJR Am J Roentgenol 2001;177:565-572
Web of Science | Medline4
Vrieling C ,Collette L ,Fourquet A , et al. The higher local recurrence rate after breast conserving therapy in young patients explained by larger tumor size and incomplete excision at first attempt? Int J Radiat Oncol Biol Phys 1998;42:Suppl:125-125 abstract.
Web of Science | Medline5
Van't Veer LJ ,Dai H ,van de Vijver MJ , et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530-536
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
P. Graham, A. Fourquet. (2006) Placing the Boost in Breast-conservation Radiotherapy: A Review of the Role, Indications and Techniques for Breast-boost Radiotherapy. Clinical Oncology 18:3, 210-219
CrossRef
