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1061
E D I T O R I A L
Counterpoint
Postmastectomy Radiation
A Modest Benefit Prevails for High Risk Patients
Barbara Fowble,
M.D.
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
T
See reply to counterpoint on pages 1067–8 and
referenced original article on pages 1138–49,
this issue.
Address for reprints: Barbara Fowble, M.D., Department of Radiation Oncology, Fox Chase
Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19104.
Received October 3, 1996; accepted October 12,
1996.
he role of postmastectomy adjuvant radiation in the treatment of
operable breast carcinoma remains controversial. Although multiple prospective randomized trials have demonstrated the ability of
radiation to decrease the incidence of locoregional recurrence, the
absence of a decrease in distant metastases or a significant improvement in survival in the majority of these studies has raised doubts
regarding the overall efficacy of the treatment.1 An additional challenge to postmastectomy radiation has been the development of effective adjuvant chemotherapy or combined chemotherapy and endocrine therapy for the treatment of micrometastatic disease.2 In axillary
lymph node positive patients, some of these regimens3 – 7 have also
demonstrated a modest decrease in the incidence of locoregional
recurrence after mastectomy, whereas others have demonstrated
minimal or no benefit.3,8 – 11 The use of dose-intense regimens with
autologous bone marrow support in patients with 10 or more positive
axillary lymph nodes has not diminished the risk of a locoregional
recurrence in these high risk patients.12 This finding has prompted
the routine use of postmastectomy radiation in patients with 10 or
more positive axillary lymph nodes in the two ongoing prospective
randomized trials evaluating high dose chemotherapy with autologous bone marrow transplantation. These inconsistent results of the
impact of chemotherapy on local control have further confounded
the issue of postmastectomy radiation.
Critics of the postmastectomy radiation randomized trials have
cited the lack of a consistent randomization process and inadequate
stratification, unequal patient distribution among the treatment arms,
and inadequate radiation in terms of total dose and/or the regions
treated. However, the most important criticism is that these trials
have included many low risk patients for whom the benefit of postmastectomy radiation would be minimal in terms of both the prevention of a locoregional recurrence and an improvement in survival.Patients who appear to be at greatest risk for a locoregional recurrence
after mastectomy are those with primary tumors ¢5 cm and/or 4 or
more positive axillary nodes.8,13 – 19 The incidence of isolated locoregional recurrence in these women when they also receive adjuvant chemotherapy is approximately 20 – 30%.8,10,14 – 17,20 – 23
Five prospective randomized trials have specifically addressed the
issue of adjuvant chemotherapy with or without radiation in these
high risk patients.20,24 – 29 All of these trials have demonstrated a decreased incidence of locoregional recurrence with the addition of
radiation. A significant improvement in relapse free survival was re-
q 1997 American Cancer Society
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CANCER March 15, 1997 / Volume 79 / Number 6
ported by two of the trials,24,25,28,29 including one29 in
which radiation resulted in a significant improvement
in 12-year actuarial distant disease free survival. One
trial reported a significant improvement in overall survival,24,25 and three reported an absolute survival benefit
of 6–12%, which was not statistically significant.26 –29
The number of high risk patients randomized in these
trials ranged from 119 to 331. In this issue of Cancer,
Olson et al.30 report the results of a sixth prospective
randomized trial evaluating postmastectomy radiation
in high risk patients who received 6 cycles of cyclophosphamide, doxorubicin, and 5-fluorouracil with tamoxifen and fluoxymesterone after mastectomy. At first
glance, this appears to be another negative trial of postmastectomy radiation. However, further scrutiny raises
significant concerns regarding the conclusions.
Clinical trials provide the ultimate mechanism for
evaluating different therapies. The reporting of clinical
trials, however, has recently received increasing attention.31 – 34 Baar and Tannock35 have demonstrated ways
in which the design and/or analysis of a trial can influence conclusions. Guidelines for reporting clinical
trials have been proposed by several groups31,32,35,36 in
an attempt to minimize the possibility that incorrect
inferences will be drawn from trials. The recommended structure for a report emphasizes a detailed
presentation of the trial design, conduct, and statistical analysis. However, these guidelines have not been
uniformly adopted. The current report of the Eastern
Cooperative Oncology Group (ECOG) randomized trial
of postmastectomy radiation illustrates a number of
the problems that can arise in the design, conduct,
and reporting of a trial.30
The design of a trial reflects the investigators’
assessment of the potential, or lack thereof, for treatment differences. This assessment may underestimate or overestimate the actual treatment effect, resulting in a trial that is not designed to detect any
reasonable difference. In the ECOG trial, the premise
to be tested was that combined chemotherapy and
endocrinotherapy was as effective as postmastectomy radiation in preventing locoregional recurrence
and that early detection of a local recurrence in patients who did not receive radiation would result in
subsequent salvage. The study was designed with an
80% power to detect a 50% improvement in time to
relapse, from a median of 3 years in the observation
group to 4.5 years in the radiation group. However,
the median time to relapse in the observation group
in the actual trial was 5.2 years. A 50% improvement
would result in a projected median time to relapse
in the radiation group of 7.8 years. This is clearly an
unrealistic end point for the evaluation of operable
locally advanced breast carcinoma patients with or
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without radiation. The median survival for the 134
patients who actually received radiation was 9.6
years, as compared with 8.1 years for the 148 patients
assigned to observation (P Å 0.57). The study was
not designed to detect statistical significance for this
modest difference.
Additional factors that could have biased the results of the ECOG trial include the heterogeneity of
the study population, the number of patients who
were never randomized to radiation, and the lack of
compliance in terms of patients actually randomized
to radiation receiving it as well as receiving the prescribed radiation course. Of the 426 patients entered
into the study between 1982 and 1987, 10% were
deemed ineligible. Seventy (18%) of the remaining 383
patients were never randomized after chemotherapy,
and 30 (18%) of the 164 patients randomized to radiation did not receive this treatment. Thirty percent of
the patients who received radiation had major variations from the protocol in their treatment. The nature
of these variations and their potential impact on locoregional control is not stated in the report. Patients
deemed eligible for the study included those with nonmetastatic, noninflammatory, technically resectable,
locally advanced breast carcinoma whose primary surgical procedure was a radical or modified radical mastectomy in which a minimum of 8 lymph nodes were
removed and no gross disease remained. It is difficult
to determine the precise extent of disease with the
information provided in the report. Ninety-six percent
of the patients had a modified radical mastectomy. It
is stated that a portion of the pectoralis major muscle
was excised in ‘‘many’’ cases, but the exact numbers
are not stated. The median pathologic tumor size was
5.5 cm. Ninety-six percent of cases were lymph node
positive, and the median number of positive lymph
nodes was 8. According to the 1992 AJCC-TNM staging
system, 60% were Stage IIA, IIB, or IIIA. Cases in the
‘‘poor’’ TNM risk category were defined as T4c (edema
or satellite skin nodules and extension to the chest
wall). Nine percent of the radiation patients were classified as poor risk, as compared with 7% of the observation patients. The study population, therefore, was
extremely heterogeneous, and it is possible that nonstatistically significant differences in prognostic factors for the two treatment groups could affect the results.
The protocol design required patients who developed an isolated locoregional recurrence in the observation arm to undergo surgical resection where possible, followed by radiation. However, only 8 of the 29
patients (28%) who developed an isolated locoregional
recurrence were registered for radiation. Treatment for
the remaining patients is not described in the report.
W: Cancer
Counterpoint
Since it appears that there was little adherence to the
planned intervention at the time of failure in this
group of women, no conclusions regarding the possibility of salvaging such recurrences can be drawn.
The statistical analysis in the ECOG trial presents
outcome in terms of crude incidence of patterns of
first failure, median time to first failure, median survival, and overall survival. Results are reported in
terms of the intent to treat, in order to provide an
‘‘unbiased analysis of randomized treatment comparisons.’’ However, this approach may not accurately reflect the benefits, or lack thereof, of a treatment when
a significant proportion of patients randomized to one
arm do not receive the assigned treatment. Results
should be presented in terms of both intent to treat
and treatment actually received so that the reader can
assess the clinical relevance of the findings. In the trial,
18% of the patients randomized to radiation did not
receive it. Patterns of first failure are presented for
patients who actually received treatment, those who
refused treatment, and those randomized to observation. Isolated locoregional failure was observed in 4%
of patients who received radiation, 27% of those who
refused treatment, and 20% of those randomized to
observation. Radiation clearly decreased the risk of
isolated local recurrence as a first site of failure. Distant metastases (with or without local relapse) occurred as a first site of failure in 52% of the radiation
patients, 40% of those who refused radiation, and 35%
of the observation arm. The total relapse rate (local
and/or distant) was 58% for patients receiving radiation, 70% for those who refused radiation, and 56%
for the observation arm. Therefore, the group of patients who refused radiation had the highest total relapse rate, and they were included in the primary analysis with patients who were randomized to radiation.
It is noteworthy that patients who refused radiation
had a rate of isolated locoregional recurrence almost
equal to the rate of distant metastases only. This pattern of failure has been observed in certain high risk
groups (namely, patients with T3 tumors and 4 – 7 positive lymph nodes) receiving postmastectomy adjuvant
chemotherapy.1,16
The investigators do provide some evidence that
patients who actually received radiation achieved a
survival benefit. The median survival and overall survival for the 164 patients randomized to radiation was
8.3 years and 46%, as compared with 8.1 years and
47% for those randomized to observation. However,
the median survival for patients who actually received
radiation was 9.6 years. Unfortunately, overall survival
is not reported for these patients, although it was described as not significantly different from the overall
survival of patients in the observation arm. The poten-
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1063
tial survival benefit for patients who actually received
radiation can be estimated from the patterns of failure.
Radiation decreased the incidence of isolated local
failure from 21% (for both observation patients and
patients who refused radiation) to 4%. Distant metastases occurred in 38% of the patients who did not
develop a local failure, and prevention of a local recurrence in these women would not have an impact on
survival. Therefore, the maximum potential survival
benefit would be 11% (17% 0 0.38 1 17 Å 11%), assuming that none of the local failures could be salvaged.
The ECOG study does not provide information regarding the outcome of the 37 patients who did not receive
radiation and who developed an isolated locoregional
recurrence. However, several previous studies37 – 40
have suggested that salvage of an isolated locoregional
recurrence in patients who have received postmastectomy adjuvant chemotherapy is at best 50%. Assuming
a 50% salvage rate, the potential survival benefit from
improved locoregional control with radiation in the
population at risk would be Ç5%. The ECOG study
was not designed to demonstrate that a survival difference of 5% at 10 years between the two arms would
be significant. A study population of approximately
1600 would be required for this magnitude of difference to be statistically significant.41
The competing risk approach has been proposed
as a method to assess better the contribution of various events to overall failure.42 – 45 Competing events in
the course of breast carcinoma include locoregional
failure, distant metastases, contralateral breast carcinoma, second malignancies that are not breast carcinoma, and death unrelated to cancer. Gelman et al44
recommended that analyses of the effect of a treatment on local failure show time to first failure for any
site and the distribution of sites of first failure. Olson
et al.30 have provided this information, and the ECOG
study confirms the observation that as locoregional
failure decreases, distant metastases become the predominant pattern of first failure.40 For the patients who
received radiation, the isolated locoregional failure
rate was 4%, and distant metastases with or without
local failure occurred as first site of failure in 52%. In
contrast, 21% of the observation patients experienced
an isolated locoregional failure, and 36% had distant
metastases. It could be inferred incorrectly that radiation increased the likelihood of distant metastases.
However, as reported by others,37 – 40 patients who develop an isolated locoregional recurrence will subsequently develop distant metastases. Unfortunately,
this information is not provided in the ECOG study,
despite the fact that the protocol required documentation of all sites of failure, both initial and subsequent.
Arriagada et al.40 recently reported the results of the
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Stockholm trial, which randomized 960 women to premastectomy or postmastectomy radiation versus observation. In axillary lymph node positive patients, radiation significantly decreased the 15-year cumulative
incidence of local failure as a first event (10% vs. 37%,
P õ 0.0001). However, in results similar to those of
the ECOG study, patients who received radiation had
an increased incidence of distant metastases as a first
event (43% vs. 34%, P Å 0.83). Following locoregional
recurrence, 66% of the observation group developed
distant metastases, as compared with 82% of the radiation group. Therefore, the total incidence of distant
metastases (as a first or subsequent event) was 72%
for the observation patients and 54% for the radiation
patients. The authors estimated that this difference
would result in a 6% survival benefit for the radiation
patients at 10 years. If similar rates of distant metastases after isolated locoregional failure are assumed for
the ECOG trial, the total incidence of distant metastases would be 55% for radiation patients and 51% for
the observation patients. It is also possible that all of
the patients who experienced an isolated locoregional
recurrence would subsequently develop distant metastases, given the relatively advanced stage of their
initial disease. In this case, the total incidence of distant metastases would be 56% for the radiation patients and 57% for the observation patients. These calculations emphasize the potential for decreasing the
total incidence of distant metastases by improving locoregional control. However, the overall benefit would
be small if distant metastases without local failure continued to be the dominant pattern of failure. The analysis also highlights the importance of presenting distant failures as first events as well as subsequent
events, since both affect survival.
The competing risk approach also includes contralateral breast carcinoma, second nonbreast malignancies, and death from causes unrelated to cancer
as events. The ECOG trial provides no information regarding second malignancies. It is stated that 13 patients died without evidence of recurrent breast carcinoma, but the distribution of these patients between
the two arms is not indicated. The radiation technique
included photon irradiation of the internal mammary
lymph nodes, which has been associated with an increased risk of cardiac mortality (primarily observed
after 10 years).46 – 52 In the ECOG trial, 3 of the radiation
patients experienced Grade 3 cardiac toxicity. Their
outcome is not reported. It is possible that radiation
technique may also have contributed to the deaths
unrelated to cancer in the trial.
Given the considerations discussed herein, what
are the valid conclusions that can be drawn from
the ECOG randomized trial of postmastectomy radi-
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ation? A conservative but reasonable interpretation
is that in this heterogeneous patient population, radiation decreased the incidence of isolated locoregional failure as well as the incidence of persistent
local disease at the time of death, did not increase
the total incidence of distant metastases, and resulted in a prolongation of median survival from 8.1
to 9.6 years. Its impact on overall survival is not
known; the only survival data presented include data
on a significant proportion of women in the radiation arm who never received this treatment. The impact of radiation at the time of local recurrence is
also unknown; it appears that only 28% of these patients received radiation.
The trial was not designed to demonstrate
whether the modest benefit of radiation in this
group of patients achieved statistical significance.
It will be cited by skeptics as another postmastectomy radiation trial with negative results. This
study illustrates the problems that can be encountered in the design, conduct, and analysis of randomized clinical trials. The failure of the investigators to submit a complete report leaves many questions unanswered and does not allow the critical
reader to determine the ‘‘true’’ validity of the trial.
The findings do not support the abandonment of
postmastectomy radiation in high risk patients. The
adoption by investigators, journal reviewers, and
journal editors of standardized guidelines for reporting randomized trials will serve to enhance
medical care for all patients.
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