correspondence

the temsirolimus group, but not the combination- Gary Hudes, M.D.
therapy group, had significantly better overall Fox Chase Cancer Center
survival than the interferon group. Contrary to Philadelphia, PA 19111
Ferrettis suggestion, treatment after disease pro- gary.hudes@fccc.edu
gression was left to the discretion of the treating
1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus
physician and was in no way restricted by the interferon alfa in metastatic renal-cell carcinoma. N Engl J Med
study design. 2007;356:115-24.

Local Therapy and Survival in Breast Cancer

To the Editor: One of the shortcomings of the
article on local therapy and survival in breast can-
cer, by Punglia et al. (June 7 issue),1 is the claim
that a decrease in breast-cancer mortality and
overall mortality as a result of radiation therapy
firmly support[s] a causal link between local
control and overall survival in some patients. Al-
though surgical removal of the breast is the most
effective method of local control, the authors
statement that pooled analyses of randomized
trials comparing mastectomy with breast-conserv-
ing therapy have shown equivalent survival is
contrary to that thesis. In the Early Breast Cancer
Trialists Collaborative Group (EBCTCG) 2000 over
view,2 although radiation therapy appreciably de-
creased local recurrence, benefits of only 2.1%
and 1.2% in overall survival and 3.0% and 4.8%
in breast-cancer mortality were noted at 10 and 20
years, respectively. Those modest benefits were
partially offset by small disadvantages in deaths
not related to breast cancer. Those findings, con-
firmed by the Cochrane Collaboration,3 support
one of the principles of the Fisher hypothesis that
variations in local-regional therapy are unlikely
to substantially affect survival.4 Another EBCTCG
meta-analysis showed that systemic therapies not
only decreased local and distant disease but also
substantially improved survival.5 The claim of a
causal relationship between a reduction in local
recurrence and improved survival when surgery
and radiation therapy are used, either alone or in
conjunction with systemic therapy, is tenuous.
Bernard Fisher, M.D.
Stewart J. Anderson, Ph.D.
University of Pittsburgh
Pittsburgh, PA 15213
fisherb2@upmc.edu
1. Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy
and survival in breast cancer. N Engl J Med 2007;356:2399-405.
2. Early Breast Cancer Trialists Collaborative Group. Favour-
able and unfavourable effects on long-term survival of radio-
therapy for early breast cancer: an overview of the randomised
trials. Lancet 2000;355:1757-70.
3. Idem. Radiotherapy for early breast cancer. Cochrane Data-
base Syst Rev 2002;2:CD003647.
4. Fisher B. Laboratory and clinical research in breast cancer
a personal adventure: the David A. Karnofsky memorial lec-
ture. Cancer Res 1980;40:3863-74.
5. Early Breast Cancer Trialists Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival: an overview of the
randomised trials. Lancet 2005;365:1687-717.
To the Editor: Punglia et al. cite the 2005
EBCTCG meta-analysis,1 which showed a 4-to-1
ratio between reduced local recurrences and de-
creased deaths from cancer with postsurgical ra-
diation therapy. One of Punglias coauthors and
others also advocate universal radiation therapy
after breast conservation for ductal carcinoma in
situ (DCIS).2
The 2000 EBCTCG meta-analysis3 showed an
increase in noncancer-related deaths caused by
radiation that offset the advantage of reduced
deaths from breast cancer throughout the 20-year
follow-up period, eventuating in an unchanged
overall survival. The 2005 EBCTCG report1 noted
these increases in deaths from lung cancer (risk
ratio, 1.78) and deaths from cardiovascular causes
(risk ratio, 1.27) with adjuvant radiation therapy,
yet with only a 1% reduction in breast-cancer
mortality at 15 years when the reduction in local
recurrences was less than 10%.
The review by Punglia et al. and the 2005
EBCTCG meta-analysis fail to extrapolate these
data in order to appreciate that, given the mini-
mal risk of death associated with small invasive
breast cancers (T1a or T1b) and DCIS, the added
risk of death from radiation is still present and
may actually reduce overall survival in the current

n engl j med 357;10 www.nejm.org september 6, 2007 1051

The New England Journal of Medicine
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Copyright 2007 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

majority of breast cancers with these favorable In the trials comparing breast-conserving
presentations. therapy and mastectomy, women randomly as-
Blake Cady, M.D. signed to breast-conserving surgery also received
24 Walnut Pl. radiation therapy, whereas those randomly as-
Brookline, MA 02445 signed to mastectomy did not. Therefore, the dif
bcady123@comcast.net
ferences in both 5-year local recurrence and 15-
1. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy year survival were small.
and of differences in the extent of surgery for early breast cancer
Dr. Cady raises an important point namely,
on local recurrence and 15-year survival: an overview of the ran-
domised trials. Lancet 2005;366:2087-106. that radiation therapy can result in increased late,
2. Buchholz TA, Haffty BG, Harris JR. Should all patients under- nonbreast-cancer mortality. This was seen par-
going breast conserving therapy for DCIS receive radiation ther-
ticularly in the older trials of radiation therapy
apy? Yes: radiation therapy, an important component of breast
conserving treatment for patients with ductal carcinoma in situ after mastectomy in which substantial volumes
of the breast. J Surg Oncol 2007;95:610-3. of heart and lung were irradiated, but such effects
3. Early Breast Cancer Trialists Collaborative Group. Favour-
are much less evident in the more recent trials of
able and unfavourable effects on long-term survival of radio-
therapy for early breast cancer: an overview of the randomised radiation therapy after breast-conserving surgery
trials. Lancet 2000;355:1757-70. in which the irradiated volumes of heart and
lung were much smaller. We have stressed to our
The Authors Reply: In response to Drs. Fisher radiation oncologist colleagues that computed-
and Anderson: we believe that the EBCTCG data1 tomographybased simulation is critical for pa-
provide strong evidence of a causal link between tients with left-sided breast cancer so that the
the absolute magnitude of the reduction in local volume of irradiated heart can be assessed and
recurrence at 5 years and the absolute magnitude minimized. On the basis of the accruing data on
of the improvement in 15-year survival. These cardiac toxicity, in patients with left-sided DCIS
data are derived from randomized trials in which in which local radiation therapy would result in
the only difference between treatment groups was substantial heart irradiation, we believe that such
more or less aggressive local therapy, and the radiation therapy should not be used.
linkage is seen consistently across the trials in Rinaa S. Punglia, M.D., M.P.H.
several different treatment comparisons. DanaFarber and Brigham and Womens Cancer Center
The argument for causality is strengthened by Boston, MA 02115
the observed proportionality that is, the great- rpunglia@lroc.harvard.edu
er the absolute reduction in 5-year local recur- Monica Morrow, M.D.
rence, the greater the absolute reduction in 15- Fox Chase Cancer Center
year mortality. And causality is also supported by Philadelphia, PA 19111
the observed time course, such that the reduction Jay R. Harris, M.D.
in local recurrence is seen during the first 5 years
DanaFarber and Brigham and Womens Cancer Center
and the improved survival is seen only in the suc- Boston, MA 02115
ceeding 10 years. Moreover, the effect is substan-
tial. For example, for the trials randomly assign- 1. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy
and of differences in the extent of surgery for early breast cancer
ing patients after breast-conserving surgery to on local recurrence and 15-year survival: an overview of the ran-
receive radiation therapy or not to receive it, the domised trials. Lancet 2005;366:2087-106.
absolute decrease in breast-cancer mortality was 2. Early Breast Cancer Trialists Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
5.4% at 15 years, which is similar to that seen cancer on recurrence and 15-year survival: an overview of the
with adjuvant multiple-agent chemotherapy. 2 randomised trials. Lancet 2005;365:1687-717.

Follow-up of Patients with Early Breast Cancer

To the Editor: In the review of early breast- cle) might have been clearer if raloxifene, which
cancer management by Hayes (June 14 issue),1 does not adversely affect endometrial tissues2,3 as
the effects of selective estrogen-receptor modula- tamoxifen does, had been listed separately, as it
tors on the uterus (shown in Table 5 of the arti- was in Table 4 of the article.

1052 n engl j med 357;10 www.nejm.org september 6, 2007

The New England Journal of Medicine

Downloaded from www.nejm.org by NECULA DANIEL on August 31, 2010. For personal use only. No other uses without permission.
Copyright 2007 Massachusetts Medical Society. All rights reserved.