Download Is Less More? Lessons in Radiation Schedules in

Is Less More? Lessons in Radiation Schedules in
Breast Cancer
Carolyn I. Sartor, Joel E. Tepper
A 1990 National Institutes of Health consensus conference
concluded that appropriate conservative therapy for breast cancer includes postexcision breast radiotherapy. However, patterns-of-care studies show that, although more patients are being
treated with breast-conserving surgery, the use of radiotherapy
in this setting is declining and the likelihood of receiving radiotherapy is related to insurance, race, income, and distance from
radiotherapy centers (1–4). To help alleviate the strain on patient
and institutional resources that a 5- to 6-week radiotherapy treatment course creates, several Canadian institutions have explored
delivery of shorter radiotherapy regimens, demonstrating acceptable cosmesis and local control of breast cancer in prospective
nonrandomized and retrospective matched-control series. Although radiobiologic principles dictate that, given enough dose
per fraction and total dose, radiation therapy delivered in more
rapid treatment schedules can be as effective in controlling tumor recurrence as longer schedules, the issue is whether the
toxicity and cosmesis will remain acceptable.
In this issue of the Journal, Whelan et al. (5) report the initial
results of a randomized comparison of two radiation fractionation schedules—42.5 Gy in 16 fractions over 22 days (2.65
Gy/day) and a standard regimen of 50 Gy in 2-Gy fractions over
35 days—in lymph node-negative, margin-negative breast cancer patients. The shortened course did not result in excess ipsilateral breast tumor recurrence or in worse cosmesis. At a median follow-up of 69 months, the 5 year in-breast recurrence
(invasive and in situ) rates were 4% in both treatment arms. This
recurrence rate is similar to the recurrence rate seen in a nonrandomized prospective trial in Vancouver (6) of 186 lymph
node-negative patients treated with 44 Gy in 16 fractions (2.75
Gy per fraction), which was 6% at a median follow-up of 6.7
years, and to the recurrence rate seen in a retrospective analysis
from Ontario of 294 patients treated with 40 Gy in 16 fractions
(2.5 Gy per fraction), which was 3.5% at a median follow-up of
5.5 years (7).
1114 EDITORIALS
With a larger dose per fraction, poor cosmesis (e.g., fibrosis
and edema), cardiotoxicity, and brachial plexopathy are concerns. Neither supraclavicular nor axillary fields were used in
the present study of lymph node-negative patients, so brachial
plexopathy is not anticipated. The follow-up duration is insufficient to define rates of cardiac injury, which are being followed. Cosmesis, however, was reportable and was not found to
be worse in the shorter-course arm, confirming the acceptable
rates of excellent or good cosmesis demonstrated in the nonrandomized, single-institution studies (6,7).
Does this study set a new standard for adjuvant external beam
radiotherapy for early-stage breast cancer? Perhaps, in certain
situations. Of 3732 screened patients with early-stage, lymph
node-negative breast cancer treated with breast-conserving
therapy, more than one third were not deemed appropriate candidates for the trial. One reason for exclusion was the presence
of invasive or intraductal carcinoma at the inked margin of excision. Margin status may be particularly important for adequate
local control when using shorter radiotherapy regimens that
do not include a boost (additional radiotherapy directed to the
tumor bed after the course of radiotherapy to the entire breast).
In the Ontario study (7), 12 patients with clear margins but with
tumor cells within 2 mm of the margin were treated without a
boost, and two of the 12 patients developed in-breast recurrence
within 5 years. Two other studies (8,9) of shorter radiotherapy
courses, in which negative margins were not required, demonstrated a 12%–13% recurrence rate without a tumor bed boost.
Because the incidence of recurrence in patients excised with
Affiliation of authors: University of North Carolina School of Medicine,
Chapel Hill.
Correspondence to: Carolyn I. Sartor, M.D., University of North Carolina
School of Medicine, Department of Radiation Oncology, Campus Box 7512,
Chapel Hill, NC 27599-7512 (e-mail: [email protected]).
© Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 15, August 7, 2002
close margins was not reported in the present randomized trial,
caution should be exercised in applying these results to patients
with close margins.
Another reason for exclusion from the present study was
large breast size, because earlier studies demonstrated worse
cosmesis with a large dose per fraction in patients with large
breasts. Thus, the results do not apply to large-breasted women.
Other features associated with at least a 10% risk of ipsilateral
breast tumor recurrence within 5 years in nonrandomized studies
of shorter fractionation schemas include lobular histology and
lack of estrogen receptor expression. Therefore, caution should
be exercised when extrapolating the results of Whelan et al. to
patients with these features (7). Furthermore, the results of this
trial do not apply to patients with ductal carcinoma in situ,
because such patients were excluded. Finally, given that only
11% of patients received chemotherapy, the acceptable toxicity
and cosmesis seen with this fractionation may not be obtained in
patients treated with chemotherapy.
Nearly half the patients who met all stated eligibility criteria
declined to participate, illustrating the difficulties in accruing
patients to randomized clinical trials that offer less versus standard radiotherapy. However, this level of nonparticipation may
also reflect physician bias, with unknown selection factors that
could affect the ability to generalize these results to standard
practice. Even though patients with stage T2 tumors (2–5 cm in
greatest dimension) were eligible for the trial, 80% of the patients enrolled had stage T1 tumors (艋2 cm in greatest dimension). Fewer than 20% had high-grade tumors, and fewer than
one third had estrogen receptor-negative disease. These favorable tumor characteristics are reflected in the low use of chemotherapy. The success of reduced fractionation may depend on
careful selection for patients with a low likelihood of a substantial burden of residual malignant cells in the breast after breastconserving surgery.
The Whelan et al. study thus supports the use of a shorter
course of radiotherapy for patients with the most favorable infiltrating ductal carcinomas. However, it may be possible to
make therapy even shorter, more convenient, and perhaps less
expensive. This same subset of patients may be well-treated with
partial breast irradiation, which enables delivery of radiotherapy
over very short periods by using brachytherapy, intraoperative
radiotherapy, or conformal techniques as the sole treatment
modality. Single-institution experience with partial breast
brachytherapy (32 Gy over 4 days), delivered by experienced
clinicians (10), demonstrates excellent local control with preservation of cosmesis and may be technically more generally
applicable if devices are used that simplify brachytherapy, such
as the MammoSite, an applicator for brachytherapy sources (11).
Preliminary results using intraoperative radiotherapy as the sole
treatment for this favorable subset of patients (21 Gy in one
fraction) are promising, raising the possibility of shortening
treatment to a single day for such patients (12). However, all
partial breast radiotherapy techniques (as sole therapy) should be
considered experimental at this time.
The carefully performed and reported study by Whelan et al.
demonstrates that, in carefully selected patients, use of shorter,
less expensive, and more convenient radiotherapeutic approaches can produce excellent local control of breast cancer
with acceptable cosmesis. It is premature to generalize these
results beyond the categories of patients actually treated in the
trial, but, with further technologic and biologic advances, perhaps we can ultimately do even “less.”
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Journal of the National Cancer Institute, Vol. 94, No. 15, August 7, 2002
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