Download Postmastectomy Radiation Therapy

Chapter
42
Postmastectomy Radiation
Therapy
Atif J. Khan and Bruce G. Haffty
CHAPTER CONTENTS
Rationale for PMRT
Randomized Trials of Adjuvant Systemic Therapy
Alone or in Addition to PMRT
EBCTCG Meta-Analysis
Patient Selection for PMRT
Node-Positive Patients
Introduction
The use of postmastectomy radiation therapy (PMRT) is
perhaps one of the most intensively studied topics in oncology and yet continues to be a cause of considerable debate.
Indeed, some of the first ever prospective randomized trials to be conducted addressed the utility of PMRT. This
area has attracted robust scientific inquiry since the initial
efforts, and has been the subject of over 20 randomized prospective trials. Despite the scientific scrutiny this area has
attracted, important questions still remain to be answered.
This chapter will focus on the topic of PMRT and is
divided into four sections:
1. In the section on the Rationale for PMRT, we will review
the data supporting the efficacy of PMRT as well as the
risks and sequelae of PMRT.
2. Patient selection.
3. Reconstruction and PMRT.
4. Technique of PMRT.
The role of PMRT after neoadjuvant chemotherapy and in
locally advanced and inflammatory breast cancer is discussed in Chapters 57, 58, and 59, respectively.
Rationale for PMRT
The principle that irradiating the chest wall and regional
lymph nodes after mastectomy can reduce subsequent localregional recurrences (LRRs) has been well documented by
multiple older trials comparing mastectomy alone to mastectomy with postoperative radiation. These trials typically
used unsophisticated radiation techniques coupled with
outdated radiation treatment machines that produced orthovoltage x-rays, resulting in less precise delivery of radiation
to target tissues and increased doses to nontarget normal
structures. Naturally, the relevance of these older trials is
limited in the context of modern radiation therapy, but they
Node-Negative Patients
Margin Status
Biologic Classifiers and Risk of LRR
Reconstruction and PMRT
Technique of PMRT
Treatment Volume, Dose and Prescription
adequately demonstrated two important facts: first, PMRT
can effectively reduce the burden of residual local-regional
disease, and second, radiation therapy is more comprehensive and more “radical,” in terms of treatment volume, than
even the most radical surgery. These trials did not demonstrate improvements in survival; benefits in breast cancer
mortality may have been offset by nonbreast cancer–related
morbidity and mortality associated with the radiation techniques employed (1).
The potential improvement in local-regional control
resulting from adjuvant systemic therapy alone can be studied through the numerous trials of systemic therapy versus
nil that have reported patterns of failure (2). Data demonstrating a benefit of systemic cytotoxic chemotherapy on localregional control are somewhat inconsistent, which may be
related to the confounding effects of patient selection, surgery
and radiation delivery. However, the most recent Early Breast
Cancer Trialists’ Collaborative Group (EBCTCG) meta-­analysis
of systemic therapy trials reported statistically fewer isolated
local relapses in patients receiving polychemotherapy (recurrence rate ratio of 0.63 and 0.70 for women younger than 50 and
50–69, respectively) (3). Similarly, adjuvant tamoxifen seems
to improve local-regional control as corroborated by the last
fully reported EBCTCG meta-analysis, which demonstrated
an isolated local recurrence rate ratio of 0.47 with tamoxifen versus without (3). These observations, along with the
demonstrable improvement in survival with systemic agents,
raise the obvious question of the relative additional benefit of
PMRT in patients receiving systemic therapy.
Randomized Trials of Adjuvant Systemic
Therapy Alone or in Addition to PMRT
Several trials have studied the efficacy and incremental benefit of PMRT in the presence of systemic therapy (2). The
most significant contributions have come from the Danish
Breast Cancer Cooperative Group (4,5) and the British
Columbia Cancer Agency (BCCA) (6). The trials conducted
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by these two groups, together with the updated findings of
the EBCTCG meta-analysis of radiation trials discussed later
(7), have decisively altered practice and reaffirmed the role
of PMRT in current breast oncology.
In protocol 82b, the Danish Breast Cancer Cooperative
Group randomized premenopausal women with high-risk
breast cancer after modified radical mastectomy (total
mastectomy and level I and II axillary dissection) to either
nine cycles of cyclophosphamide-methotrexate-fluorouracil
(CMF) chemotherapy or to eight cycles of CMF chemotherapy and radiation therapy to the chest wall and regional
nodes between the first and second cycles of chemotherapy
(4). High-risk status was defined as positive lymph nodes,
tumor size greater than 5 cm, or invasion of the skin or pectoralis fascia. Radiation therapy was delivered to a total dose
of 50 Gy in 25 fractions or 48 Gy in 22 fractions using anterior electron fields to treat the chest wall and internal mammary nodes (IMNs) and a matched anterior photon field to
treat the supraclavicular, infraclavicular, and axillary lymph
nodes. A posterior axillary photon field was used in patients
with a large anterior-posterior (AP) separation. Over 92% of
all patients were treated with megavoltage equipment. The
study enrolled 1,708 patients between 1982 and 1989. With a
median follow-up of 114 months, the irradiated group demonstrated statistically significant improvements in LRR (32%
vs. 9%), disease-free survival (3% vs. 48% at 10 years), and
overall survival (45% vs. 54% at 10 years). Over half of all
LRRs were on the chest wall.
In the companion trial, protocol 82c (5), postmenopausal women younger than 70 with high-risk breast cancer
(defined as in 82b) were randomized after modified radical
mastectomy to receive either 30 mg of tamoxifen daily for
1 year beginning 2 to 4 weeks after surgery alone or with
concurrent radiation therapy delivered to the chest wall
and draining lymph nodes. A total of 1,375 patients were
recruited between 1982 and 1990 and followed for a median
time of 10 years. As in the 82b study, the irradiated group
demonstrated statistically significant improvements in LRR
(35% vs. 8%), disease-free survival (24% vs. 36%) and overall
survival (36% vs. 45%). As in the 82b study, recurrence at all
local-regional subsites was lower with PMRT than without.
Although these well-designed efforts by the Danish group
are not without flaw (as discussed below) they nonetheless
strengthened the theory that, in certain patient subsets,
aggressive local-regional control could result in improvements in survival end points.
The smaller British Columbia trial enrolled 318 node-­
positive premenopausal breast cancer patients and randomized them after modified radical mastectomy to either
radiation therapy or no additional local-regional therapy
(6). Both groups received adjuvant CMF chemotherapy for
12 (first 80 patients) or 6 months. Radiation therapy was
delivered to the chest wall to a dose of 37.5 Gy in 16 daily
fractions through opposed tangential photon fields. The
supraclavicular and axilla nodes were treated with an AP field
and a posterior axillary field, with a target midaxilla dose of
35 Gy. Bilateral IMNs were treated with an additional anterior field to a dose of 37.5 Gy in 16 fractions. All treatments
were delivered with cobalt machines, between cycle four and
five of chemotherapy. After a median follow-up of 20 years,
the 20-year survival free of local-regional disease developing
before systemic was 61% in the chemotherapy alone arm and
87% in the irradiated group. The irradiated group had statistically significant improvements in 20-year event-free survival
(25% vs. 38%), systemic disease-free survival (31% vs. 48%),
breast-cancer specific survival (38% vs. 53%), and overall
survival (37% vs. 47%). There were slightly more nonbreast
cancer deaths in the irradiated group (9% vs. 4%, p = 0.11).
Harris_9781451186277_Chap42.indd 2
There were three cardiac deaths (2%) in the irradiated
group versus one (0.6%) in the control group (p = .62), and
9% of patients in the irradiated group developed arm edema
compared with 3% in the control group (p = .035). This study
corroborated the Danish experience and again demonstrated
some of the most remarkable improvements in survival end
points ever reported for any adjuvant therapy.
Taken together, these studies demonstrated that certain
patient cohorts have a high risk for LRR that is inadequately
addressed by systemic therapy alone. Furthermore, reducing the likelihood of LRR can result in improved survival;
presumably, persistent or recurrent local-regional disease
can be a source of distant metastases and subsequent death.
These studies imply that the benefit of systemic therapy is
primarily to lower the competing risk of distant micrometastases, and that adjuvant local-regional therapy and adjuvant systemic therapy independently benefit these patients
on the principle of spatial cooperation. There is no definitive randomized data supporting any specific sequencing
of systemic therapy and radiation in the postmastectomy
setting; for patients receiving both cytotoxic chemotherapy
and postmastectomy radiation, the prevailing practice typically sequences the cytotoxic chemotherapy first, followed
by radiation. Hormonal therapy, if indicated, may be given
concurrently with radiation or following radiation, though
some clinicians prefer to sequence tamoxifen after the radiation. Although there is little in the way of long-term followup data and additional studies will likely be forthcoming in
the next few years, adjuvant systemic therapy with trastuzumab (typically administered for up to 1 year following
chemotherapy) appears to be safe and effective given concurrently with radiation (8).
EBCTCG Meta-Analysis
The EBCTCG has collected primary data from every randomized trial of adjuvant radiotherapy in breast cancer and periodically reports the ongoing analyses on the benefits and
risks of radiation therapy in these patients. The most recent
full report from 2005 reviewed data on 9,933 patients enrolled
in 25 trials of PMRT, all of which were unconfounded by the
use of systemic therapy (7). Node-positive patients who
had axillary clearance and received radiation therapy after
mastectomy had a 5-year LRR rate of 6%, compared to 23%
for unirradiated controls (15-year rates were 8% vs. 29%).
In every large trial of PMRT in node-positive women, radiation therapy produced a similar proportional reduction in
local recurrence, powerfully demonstrating the comparable
efficacy of radiotherapy in achieving local control across all
time periods. Even more significantly, PMRT also produced
comparable proportional reductions in local recurrence in
all women irrespective of age or tumor characteristics.
Absolute reductions in local recurrence were dependent
on the absolute risk in the control arm (i.e., larger reductions were seen in subsets with greater risk). For patients
with a control risk of local recurrence greater than 10%, the
addition of radiation therapy (RT) improved local recurrence irrespective of systemic therapy. For women with
node-positive disease who were irradiated after mastectomy and axillary clearance, a 17% absolute improvement
in 5-year local control translated into a highly statistically
significant 5.4% absolute improvement in 15-year breast cancer mortality (60.1% vs. 54.7%, 2p = 0.0002, Fig. 42-1) (7), and
a 4.4% absolute improvement in 15-year all-cause mortality
(64.2% vs. 59.8%, 2p = 0.0009) over unirradiated controls.
There was an excess cancer incidence in women studied in the EBCTCG report (including women treated with an
intact breast), mainly in contralateral breast cancer and lung
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C hapte r 4 2
Isolated local recurrence
40
27·6
30
22·8
Mast+AC
29·2%
20
7·8%
10
5·8
0
5
7·5
10
50·9
50
years
Mast+AC
60·1%
%
60
54·7%
Mast+AC+RT
50
Mast+AC
64·2%
63·7
40
34·0
30
32·1
40
35·5
30
33·6
20
20
10
0
59·8%
Mast+AC+RT
49·9
46.7
15-y gain 5·4% (SE 1·3)
Mast+AC+RT
15
Any death
Any death
50
0
%
60
5-y gain 17·1% (SE 0·9)
3
P ostmastectom y Ra d iation T he r ap y
Breast cancer mortality
Breast cancer mortality
Isolated local recurrence
%
60
| Logrank 2p = 0·0002
0
5
10
15
years
10
0
15-y gain 4·4% (SE 1·2)
Logrank 2p = 0·0009
0
5
10
15
years
Figure 42-1 Probabilities for isolated local recurrence, breast cancer mortality, and
any death in node-positive patients treated with postmastectomy radiation therapy after
mastectomy and axillary clearance. (Reproduced with permission from Early Breast
Cancer Trialists’ Collaborative Group. Effects of radiotherapy and differences in the extent
of surgery for early breast cancer on local recurrence and 15-year survival: an overview of
the randomized trials. Lancet 2005;366:2087–2106.)
cancer, and an excess mortality from heart disease and lung
cancer. The averaged detrimental effects were modest, with
15-year absolute loss of 1.8% for contralateral breast cancer
and 1.3% for nonbreast cancer mortality. Importantly, the
proportional excess of nonbreast cancer deaths was greatest 5 to 14 years and more than 15 years after randomization, and the mean dates of randomization for these two
groups was 1975 and 1970, respectively. The authors of the
EBCTCG correctly point out that the late hazards evident in
their report could well be substantially lower for modern
radiation therapy technique and regimens.
The EBCTCG data were presented at the 2007 annual
meeting of the American Society of Clinical Oncology (9).
Since then further analyses have been carried out and prepared for publication (Sarah Darby, personal communication). Although the data are still preliminary, they represent
the first detailed analysis of patients stratified both by extent
of axillary dissection (at least level II vs. less extensive and by
degree of nodal involvement (1–3 vs. 4+), and several pertinent and new findings have been described.
Among women with node positive disease, radiotherapy reduced the rate of any recurrence both for women
who had undergone axillary dissection to at least level II
(recurrence rate ratio: 0.75, 2p < 0.00001), and for women
who had undergone less extensive axillary dissection (0.59,
2p < 0.00001), although the proportional reduction was
larger in the women who had less extensive axillary dissection (2p for difference = 0.003). In addition, the subgroup of
patients with axillary dissection to at least level II and one
to three positive lymph nodes had a statistically significant
improvement in 15-year breast cancer mortality (death rate
ratio irradiated vs. unirradiated: 0.80, 15-year gain 7.9%, 50.2
vs. 42.3%, 2p = 0.01) with PMRT. This proportional reduction
did not differ significantly according to whether or not the
trial policy was to give systemic therapy (usually cmf or, for
ER+, tamoxifen) in both trial arms.
The cohort of women with axillary dissection to at least
level II and four or more positive nodes also enjoyed significant benefits from PMRT in their risk of any recurrence (recurrence rate ratio: 0.79, 2p = 0.0003) and breast cancer mortality
(death rate ratio: 0.87, 2p = 0.04). In contrast to women with
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node ­positive disease, women with node negative disease had
no benefit from PMRT either in terms of recurrence (rate ratio:
1.06, 2p > 0.1) or breast cancer mortality (rate ratio: 1.18 2p > 0.1).
In summary, the EBCTCG update appears to suggest that
women with node positive disease are likely to benefit from
PMRT, even when they have had axillary dissection to at least
level II and probably also in the presence of systemic therapy.
The EBCTCG overview represents one of the most significant contributions to the study of PMRT. However, the relevance of its findings may be limited by the inclusion of older
trials that used fractionation schemes, treatment machines,
and treatment volumes that are antiquated by current standards, as well as by the usual limitations of meta-analyses. To
address these issues, Van de Steene et al. (10) re-examined
the EBCTCG data and identified four factors which selected
for significant improvement in the odds ratio (OR) for survival in the irradiated versus control populations: start date
of the trial (after 1970 [OR 0.935]), number of patients (>600
patients [OR 0.932]), fractionation (conventional [OR 0.896]),
and crude survival on the trial (at least 80% [OR 0.799]).
Excluding trials that began before 1970 and trials with
small sample sizes produced a significant odds reduction of
12.3% ± 4.3% with irradiation (10). Gebski et al. performed a
meta-analysis in which they carefully attempted to control for
the quality of radiation delivery in PMRT trials. The authors
defined optimal dose as being between 40 and 60 Gy delivered
in 2 Gy fractions (nonconventional fractionation schemes
were converted to 2-Gy equivalents using bioeffective dose
calculations) and appropriate treatment volumes as both
chest wall and regional lymphatics (11). The authors reanalyzed data from the EBCTCG applying these criteria. The proportional reduction in local-regional recurrence was greater
for trials with optimal dose and volume (80%), compared to
those with suboptimal dose (70%) or field design (64%). An
improvement in breast cancer mortality was restricted to
those trials that used appropriate doses and fields for irradiation (6.4% absolute increase in survival, p <.001).
The most concerning risk of PMRT for radiation oncologists is the risk of radiation induced cardiac morbidity.
As described above, the EBCTCG meta-analysis as well as
other registry data have detected increased risks of c
­ ardiac
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­ ortality in irradiated patients (7,12,13). In contrast, an
m
analysis of the Danish postmastectomy trials patients by
Hojris et al. (14) found, using a technique of RT that avoided
cardiac irradiation, equal rates of ischemic heart disease
and acute myocardial infarction in the irradiated and unirradiated group. Approximately 3% of patients in both groups
had ischemia-related morbidity at a median follow-up of
117 months and less than 1% of patients in both arms had
death due to cardiac causes. There was no difference in
this study when comparing left- versus right-sided irradiation. However, these numbers may underestimate the true
burden of radiation-related cardiac morbidity due to the
competing risk of breast-cancer death in this high-risk population, and also because this study was an unplanned retrospective report on a prospectively studied patient cohort.
Gyenes et al. (15) reviewed 960 patients treated on the
first Stockholm Breast Cancer trial (modified radical mastectomy alone vs. preoperative vs. postoperative RT accrued
1971–1976) and reported 58 acute myocardial infarctions
(MI) in the study population for a crude rate of 6%. There
were no differences in acute MI or death due to cardiovascular disease (n = 63/960) between irradiated and unirradiated
patients. Importantly, the authors showed that only patients
in the high-dose–volume group had an excess hazard ratio
(HR) of cardiovascular death (HR 2, 95% CI, 1.0–3.9, p = 0.04).
A retrospective study by Harris et al. (16) examined cardiac
events in a series of 961 women irradiated to the intact
breast and reported no interaction between left-sided versus right-sided RT on cardiac mortality or congestive heart
disease. A significant interaction was noted between leftsided RT in the subsequent development of coronary artery
disease (20-year actuarial risk 25% vs. 10% for right-sided,
p <.001) and MI (15% vs. 5%, p <.002). Coexistent hypertension
was an independent hazard for the development of coronary
artery disease.
A study of the Surveillance, Epidemiology and End
Results (SEER) database conducted by Giordano et al. (17)
compared 15-year cardiac mortality rates in left- versus
right-sided breast cancer as a function of the year of diagnosis in patients who received RT. Presumably, patients with
left-sided lesions received more heart irradiation than those
with right-sided lesions. Although the authors demonstrated
excess cardiac mortality in left-sided breast cancer patients
diagnosed between 1973 and 1979 (13% vs. 10%, p = .02),
they found no significant difference in patients irradiated
in the most recent time periods (∼9% for both groups in the
1980–1984 cohort, and 5% to 6% in the 1985–1989 cohort).
Beginning in 1979, the hazard of death from ischemic heart
disease in left-sided breast cancer patients (vs. right-sided)
declined by an average of 6% per year.
In a similar study, Henson et al. (18) evaluated the relative risk (RR) of cardiac disease in women irradiated for leftversus right-sided breast cancer and the relative risk of lung
cancer in the ipsilateral versus contralateral lung in women
irradiated for breast cancer using the SEER public-use data
set. They found that the RR of breast cancer continued to
increase, reaching 1.9 (1.52–2.37) 20 years after diagnosis.
Similarly, the RR of lung cancer increased continuously in
time, peaking at 3.87 (2.19–6.82) for women 20 years after
diagnosis. As noted by the study authors, many women in
this analysis were treated during an age in which IMN nodal
RT was much more common, thus, potentially increasing the
toxicity risks compared to contemporary treatment cohorts.
Furthermore, current techniques that enhance treatment
conformity probably decrease cardiac and lung doses compared to the study cohorts, even when the IMs are treated.
Darby et al. (19) reported a well-executed populationbased case-control study of the risks of cardiac irradiation
Harris_9781451186277_Chap42.indd 4
in patients treated for breast cancer. The mean dose to the
whole heart was 5 Gy in the control cohort, and each excess
Gy in mean dose conferred a 7% RR decrement. Importantly,
no threshold dose for risk was detected. Taken together,
these data stress the potential for cardiac morbidity and
mortality with breast irradiation but are reassuring that
routine contouring of the heart and improvements in imagebased simulation and treatment delivery can substantially
reduce these risks.
Little data exists on the cumulative effects of anthracyclines and radiation therapy on cardiac morbidity and
function. Perhaps the best data on this topic comes from
Fumoleau et al. (20) who reported long-term cardiac function in 3,577 assessable patients randomized on eight French
trials of adjuvant therapy, 2,553 of whom received epirubicin-based chemotherapy. Ninety-seven percent of women on
the epirubicin cohort had adjuvant radiation (to the intact
breast or postmastectomy) and 94% on the nonepirubicin
cohort received RT (with about two-thirds of these receiving
RT to the IMNs). The 7-year risk of left-ventricular dysfunction was 1.36% in the epirubicin arm and 0.2% in the nonanthracycline patients. Age 65 or greater and body mass index
> 27 kg/m2 were additional significant risk factors.
Additional nonlife-threatening late risks of postmastectomy irradiation can include arm edema, fibrosis, shoulder
stiffness, and brachial plexopathy. In an instructive report,
the Danish postmastectomy investigators invited patients
irradiated at Aarhus University Hospital who were alive and
without evidence of disease to participate in a study of the
late effects of PMRT (21). Eighty-four patients accepted the
invitation and were eligible for analysis, and these patients
were carefully assessed for late toxicity based primarily on
LENT-SOMA criteria. More women in the irradiated group
had lymphedema (17% vs. 9%) and impaired shoulder movement (16% vs. 2%) that interfered with work or daily activities. Irradiated patients also had more arm parasthesias
(21% vs. 7%) and more arm weakness (14% vs. 2%). Only the
shoulder function comparison was statistically significant.
Symptomatic pulmonary complications were equal in irradiated and unirradiated patients. In a separate report of 161
patients with neurological follow-up who were irradiated on
the Danish 82 protocols, 5% of patients had disabling and
8% had mild radiation-induced brachial plexopathies (22).
Kuhnt et al. (23) reported acute and chronic reactions in 194
patients receiving PMRT. Twenty-two percent of patients had
any incidence of chronic effects, mostly from arm edema (28
of 43). Five patients had telangiectasia and one patient had
plexopathy.
In conclusion, randomized trials as well as data from
meta-analyses provide a strong rationale for PMRT in
patients with a high likelihood of local-regional residual disease, despite the use of systemic therapy in these patients.
Additional local-regional therapy in the form of RT reduces
LRR rates by a factor of approximately two-thirds, and one
breast-cancer death is averted for every four LRR prevented
by RT. The risks of PMRT are modest but demonstrable, and
cardiac effects may largely be attributable to older technique.
The cardiac and pulmonary toxicities of modern day PMRT
continue to be evaluated and are likely minimal with careful
three-dimensional planning and treatment techniques.
Patient Selection for PMRT
Node-Positive Patients
Node positivity in the axilla is the most significant predictor of LRR after mastectomy. It should be borne in mind,
however, that approximately two-third of LRR occur on the
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| chest wall, and that axillary failures are far less common
(24–27). Accordingly, the degree of node positivity should
be viewed as an adverse feature that confers a higher risk
for overall LRR (i.e., not limited to failure at regional sites).
The Danish and Canadian PMRT trials demonstrated
stable relative risk reductions for all events in all groups
of node-positive patients. However, the conclusion that all
node-positive patients warrant PMRT has been challenged.
There are two general criticisms of these studies which
limit the generalizing of these findings to all node-positive
patients: first, the adequacy of the systemic therapy in the
control arms of these studies; and second, the issue of the
“background risk” in the relevant study populations.
The most recent EBCTCG meta-analysis of systemic therapy showed a significant but minor improvement for anthracycline containing polychemotherapy regimens over CMF
regimens (3). Whether this incremental benefit improves localregional control as well is unknown and is probably unlikely in
patients with high risk for local-regional microscopic residual.
Furthermore, neither the addition of taxanes nor increases in
the intensity or density of chemotherapy have had demonstrable impacts on local-regional control in node-positive patients,
although they do improve survival end points presumably by
addressing micrometases (28–33). In sum, it seems unlikely
that present-day chemotherapy regimens would significantly
alter the findings of the postmastectomy trials. In contrast, the
Danish 82c trial treated postmenopausal patients (untested
for estrogen-receptor/progesterone-receptor [ER/PR] status)
with 1 year of tamoxifen (5), and it is unknown how a longer
duration of hormonal therapy in a population known to be
hormone-receptor positive would modulate the risk of LRR
and thus the benefit of PMRT.
A more significant factor that limits interpretation of
the Danish and British Columbia trials is that node-positive
patients on the control arm of these trials had higher LRR
rates than commonly reported for patients treated in the
United States and elsewhere (4–6,24). This difference is especially obvious in patients with one to three positive lymph
nodes, who represented about 60% of patients on these studies. In the unirradiated Danish population, the 18-year probability of local-regional recurrence (as first site of failure)
was 59% for patients with four or more positive nodes, and
37% for those with one to three positive nodes (34). In the
unirradiated Canadian population, the 20-year isolated LRR
rate was 41% for patients with four or more positive nodes,
and 21% for patients with one to three positive nodes (6).
LRR developing any time before distant failure (i.e., cumulative LRR as first failure) was not reported as a function of
the number of positive lymph nodes, but was 39% for the
entire unirradiated group. In contrast, several large series
of patients treated in the United States and elsewhere have
reported LRR rates in the range of 6% to 13% for patients with
one to three positive nodes (25,26,35,36) (Table 42-1). This
seems to indicate that the background risk for LRR in the
Danish and BC trials was higher than average, and this may
have exaggerated the benefit of PMRT in this population.
Differences in the extent of axillary surgery may partially
explain the differences in the risk of LRR in patients with one
to three positive nodes. Full level I and II axillary dissections
were not performed; a median of seven lymph nodes were
removed in the Danish studies and a median of 11 lymph
nodes were examined in patients on the Canadian trial (4–6).
As such, many of the patients scored as having one to three
positive lymph nodes may have actually had four or more
positive nodes had full axillary dissections been performed.
Tellingly, failure in the axilla either alone or as a component
of LRR represented 43% of all LRR in the Danish studies (24),
compared to 14% in the data cited above (25).
Harris_9781451186277_Chap42.indd 5
P ostmastectom y Ra d iation T he r ap y
5
T ab l e 4 2 - 1
LRR Rates in Patients Not Treated with Radiation
after Mastectomy in Randomized Clinical Trials
Patterns-of-Failure
Studies (Reference)
ECOG (26)
1–3 +LN
≥4 +LN
MD Anderson (27)
1–3 +LN
≥ 4 +LN
NSABP (35)
1–3 +LN
≥4 +LN
IBCSG (38)
1–3 +LN
≥4 +LN
No. of
Patients
LRR Rates at
10 Years (%)
1,018
998
13
29
437
373
13
25
2,957
2,784
13
27
2,402
1,670
17
31
ECOG, Eastern Cooperative Oncology Group; NSABP, National
Surgical Adjuvant Breast and Bowel Project; IBCSG, International
Breast Cancer Study Group.
However, it is important to note that the reports cited
above and in Table 42-1 have reported 10-year local-regional
control rates. The Danish studies report 18-year recurrence
rates, and also document a consistent LRR of about 1% per
year between follow-up years 10 and 25 (24). Similarly, in
the British Columbia (BC) trial, which has reported 20-year
recurrence rates, approximately 20% of LRRs occurred
after follow-up year 10 (6). In addition, other identified and
unidentified risk factors, such as T4 tumors or pectoral fascia invasion, may have been over-represented in the postmastectomy trials (24), increasing the background risk for
local-regional failure. For example, in a combined report of
patients with one to three positive axillary nodes treated on
the control arm of the British Columbia postmastectomy trial
(n = 82) and similar patients treated on prospective systemic
therapy trials at the MD Anderson Cancer Center (MDACC)
(n = 462), statistically significant differences were detected
in patients on the BC trial who were younger (median age 43
vs. 48) and had more lymphovascular invasion (LVI) (52%
vs. 33%), in addition to fewer examined nodes (median 10
vs. 16) (37). The resultant 10-year Kaplan-Meier estimates of
LRR were 21.5% and 12.6% for the BC and MDACC patients,
respectively.
Nonetheless, several reports have demonstrated the
prognostic impact of total dissected nodes, nodal ratio
(number of involved to uninvolved nodes), and number of
total uninvolved nodes on LRR and even overall survival
(25,26,35–40). Attempts by Danish investigators to reanalyze
their patients to include only those with adequate dissections are limited by the fact that these patients were not
stratified by this important risk factor at randomization (41).
This issue remains unclear and, because it has complicated
the interpretation of the existing postmastectomy trials, can
only be addressed in the context of additional large, randomized trials.
Recent reports have demonstrated rather low rates
of LRR in patient populations treated with mastectomy
and highly active systemic agents alone. These reports
challenge the current interpretation of both the PMRT trials and the EBCTCG meta-analysis on the basis of current
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improvements in detection, surgical technique, pathological
review, and adjuvant therapies. Could the “control” risk for
local-regional failure in currently treated patients be much
lower than expected from a review of patient data collected
decades ago? Sharma et al. (42) at the MDACC reported outcomes in a contemporary cohort of women with T1-2 breast
cancer and node-negative or one to three node-­
positive
disease, 1,019 women were treated between 1997 and 2002;
77% of women had adjuvant systemic therapy with a median
follow-up of 7.5 years. The local-regional relapse rate was
exceptionally low—2.3%. Young age was a significant covariate for LRR on multivariate regression analysis. As with any
retrospective analysis, selection biases may have been
operant and contributing the low rate of LRR. As pointed
out by the study authors, there were few women with three
positive lymph nodes in their analysis (<2%) and many
women with T1-2N0-1a with adverse features on pathology
were likely treated with PMRT, thus selecting for a low-risk
group. Nonetheless, the Sharma report offers a tantalizing
prospect—perhaps current cumulative improvements in
screening, surgery, pathological assessment, and adjuvant
systemic therapy combine to significantly reduce the background risk of LR failure. Pointedly, a similar report on identical stage patients treated at MDACC during an earlier time
period (1975–1994) had a 10-year LRR of 14% (25).
Still, there is recent evidence that supports an aggressive treatment approach in patients with intermediaterisk presentations. Abdulkarim et al. (43) reported results
on a retrospective cohort of triple-negative breast cancer
patients (n = 768) and compared outcomes stratified by type
of local-regional therapy. Patients who received breast-conserving therapy (BCT) had better local-regional control and
better survival than patients who received modified radical
mastectomy (MRM) on univariate analysis. On multivariate analysis, initial BCT continued to predict for improved
LRR but not overall survival (OS). Interestingly, in the subset of women with T1-T2N0 disease, patients who received
BCT had better 5-year local-regional control compared to
women who had MRM. Local treatment strategy remained
a predictor of LRR on multivariate analysis in this group.
One possible explanation is the larger, more comprehensive
treatment volume associated with standard radiation fields
compared to mastectomy alone. Similarly, Canadian trials
have reported preliminary MA.20 results in abstract form. In
this trial, high-risk node-negative or node-positive patients
were randomly assigned to whole breast irradiation alone
or including regional draining lymph nodes after breast-conserving surgery. Results on 1,832 randomized patients were
presented at the 2011 annual American Society of Clinical
Oncology (ASCO) meeting (44). With a median follow-up
of 62 months, the addition of regional nodal RT improved
5-year local-regional control, distant disease control (92.4%
vs. 87%, p = 0.002), and overall survival (92.3% vs. 90.7%, p =
0.07). Given these data, it appears that a serious discussion
of PMRT is still warranted in the majority of women with one
to three positive lymph nodes on mastectomy.
Both the American Society of Therapeutic Radiology
and Oncology (ASTRO) and the ASCO as well as other advisory organizations have endorsed the routine use of PMRT
in women with four or more involved nodes and node-positive women with tumors greater than 5 cm, who have a
high (>20% to 25%) risk of LRR without RT. Both societies
recognize the uncertain benefit of PMRT in patients with
T1 or T2 primaries with one to three positive nodes (stage
II) in whom the risk of LRR is intermediate (around 10% to
20%) (45,46). The European SUPREMO trial (Selective Use
of Postoperative Radiotherapy after Mastectomy) is currently open and will attempt to answer this question. This
Harris_9781451186277_Chap42.indd 6
trial randomizes intermediate risk operable breast cancer
(node-positive stage II tumors and node-negative tumors
larger than 2 cm with adverse features [high grade or LVI])
to chest wall irradiation or observation after mastectomy.
Several groups have attempted to identify high-risk
patients within the one to three positive lymph node group
(Table 42-2). Clearly, this group of patients is heterogeneous
in terms of various potential clinicopathological factors that
may allow differentiation into low- and high-risk cohorts.
One of the most significant efforts attempting to identify
these risk factors comes from Wallgren et al. (36) who
reviewed data on over 5,300 patients enrolled on the first
seven trials of the International Breast Cancer Study Group
(IBCSG). These trials of systemic therapy required a minimum of eight dissected lymph nodes and negative margins.
In patients with one to three involved lymph nodes, premenopausal patients with LVI and grade 3 tumors had cumulative incidence functions (CIFs) exceeding 20% for any LRR.
Postmenopausal women with grade 3 tumors and tumors
larger than 2 cm had correspondingly high risk. Collapsing
this information, premenopausal women with one to three
positive lymph nodes had LRR risks ranging from 19% to
27% if they had grade 2 or 3 disease with vascular invasion,
but that risk was less than 15% if they had grade 1 disease
with no vascular invasion. In a subsequent report, the same
group reported results from IBCSG trials 1 through 9 and
demonstrated the significant independent impact, in a multivariate model, of the number of uninvolved lymph nodes
(38). More specifically, in the group of patients with one to
three lymph nodes (n = 2,402), factors that independently
predicted a CIF for LRR exceeding 20% included age younger
than 40, fewer than 10 uninvolved lymph nodes, and LVI.
The investigators at MDACC have reported results from
their cohort of 1,031 patients treated with mastectomy and
doxorubicin-based chemotherapy without subsequent radiation therapy on five prospective trials between 1975 and
1994 (25,39,47). Three factors were significant for isolated
and total LRR on multivariate analysis of the entire group:
T stage, number of involved nodes, and extranodal extension 2 mm or more. Restricting the analysis to patients with
T1or T2 disease and one to three axillary nodes (n = 404,
overall isolated 10-year LRR risk of 10%), multivariate predictors of LRR were fewer examined nodes, higher T stage, and
extracapsular extension (ECE), with isolated 10-year LRR in
excess of 25% for patients with gross ECE (33%) and tumor
size greater than 4 cm (26%) (25). In a more detailed study of
pathologic factors in the same group of patients, Katz et al.
(47) reported that close or positive margins and gross multicentric disease were also predictive of LRR on multivariable. However, in the subgroup of patients with one to three
positive nodes, invasion of skin and nipple, pectoral fascia
invasion, and close or positive margins, but not multicentricity, were significant predictors of higher LRR. In a similar
group of patients, Fowble et al. (48) reported that patients
with multicentric disease without other strong risk factors
for postmastectomy chest wall relapse had a 5-year actuarial
risk of an isolated local-regional recurrence of only 8%.
Truong et al. (40) reported on 821 women with T1 and
T2 primary lesions with 1 to 3 positive lymph nodes treated
with mastectomy and systemic therapy (in 94%) within the
BCCA. Twelve putative clinicopathologic factors were examined for their effect on LRR in a multivariate model. Age less
than 45, nodal ratio greater than 25%, ER negative status,
and medial location independently predicted for isolated
and any LRR, with age having the greatest effect (HR = 3.44).
The authors suggested using age and nodal ratio as first line
discriminants of risk and medial location and ER negative
status as secondary factors.
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C hapte r 4 2
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P ostmastectom y Ra d iation T he r ap y
T ab l e 4 2 - 2
Cofactors Associated with a Greater than 15% LRR after Mastectomy and Chemotherapy in Patients with One
to Three Positive Lymph Nodes
Study
Number of
Patients
Cofactors
End Point
Wallgren et al. (36)
2,404
• 10-year LRF ± DF (isolated LRF
or with simultaneous DF)
Taghian et al. (35)
Recht et al. (26)
2,403
1,018
• Premenopausal, G2 or G3, LVSI
• Postmenopausal, G3
• Postmenopausal, G2, T2 disease
• Age <50, T2 disease
• Premenopausal, T1 disease
Truong et al. (40)
821
Katz et al. (47)
466
Cheng et al. (49)
110
• Age <45a
• 25% of lymph nodes involveda
• ER negative diseasea
• G3 disease
• T2 disease
• LVSI
• Medial tumor locationa
• Tumor size >4 cm
• Invasion of skin/nipple
• Invasion of pectoralis fascia
• Close or positive margins
• Age <40
• Tumor size ≥3 cm
• Presence of LVSI
• Adjuvant hormonal therapy
• 10-year LRF ± DF
• 10-year LRF ± DF (isolated LRF
or with simultaneous DF)
• 10-year LRF ± DF (isolated LRF
or with simultaneous DF)
• 10-year LRF ± DF
• 4-year LRF ± DF (isolated LRF
or with simultaneous DF)
LRF, local-regional failure; DF, distant failure; LVSI, lymphovascular space invasion; ER, estrogen receptor; G2 or 3, grade 2 or 3.
aRetain significance on multivariate analysis.
Recht et al. reported on the outcomes of over 2,000 patients
enrolled on four randomized Eastern Cooperative Oncology
Group (ECOG) studies of systemic therapy. Median follow-up
of the entire group was 12 years and 983 patients had tumors
5 cm or less and one to three positive lymph nodes (LNs). In
a multivariate analysis of all patients, increasing tumor size,
increasing number of positive nodes, ER-negative status and
decreasing number of examined nodes were significant independent predictors of LRR (26). Cheng et al. (49) identified 110
patients with one to three positive axillary nodes treated at their
institution with modified radical mastectomy and systemic
therapy but without radiation, (median number of nodes examined, 17). Sixty-nine patients received adjuvant chemotherapy
and 84 received adjuvant hormonal therapy with tamoxifen.
On multivariate analysis, only tumor size (<3 cm vs. greater)
was significant for LRR. However, the authors found that the
four most significant factors on univariate analysis (age < 40
years, tumor ≥ 3 cm, ER-negative disease, and LVI) could segregate patients into a high-risk group (with three or four factors) and a low-risk group (with two or fewer factors). This
report had relatively small numbers and short median followup (54 months). In a similar Hungarian study, the authors
reported on 249 patients with T1 and T2 tumors with one to
three positive axillary nodes, half of whom were treated with
PMRT (50). Several putative risk factors for LRR were examined in the unirradiated patients on multivariate analysis, and
only age (≤ 45 years) and size (T2) emerged as independent
predictors of LRR. Finally, Cheng et al. (51) have reported on
gene expression profiles that are predictive of LRR after mastectomy, although the number of local-regional events in their
patients with 1–3 positive nodes was small. This promising
Harris_9781451186277_Chap42.indd 7
methodology may serve as a valuable tool of risk assessment
in the future.
Node-Negative Patients
The most recent EBCTCG overview demonstrated a nominal 5-year local recurrence rate of 6% after mastectomy and
axillary clearance in node-negative patients. The addition of
PMRT reduced this rate to 2% (2p = 0.0002), producing a
modest absolute 5-year gain of 4% (7). Given the low overall
risk of LRR in node-negative patients, several investigators
have attempted to identify subsets within this group with
LRR risks high enough to warrant PMRT.
In a multivariate analysis of the IBCSG trial patients
discussed above, LVI was a significant risk factor of LRR
in node-negative patients, as was size greater than 2 cm in
premenopausal node-negative patients (36). Jagsi et al. (52)
reported a retrospective analysis of a cohort of 870 nodenegative patients (excluding T4 patients) treated with modified radical mastectomy without RT at the Massachusetts
General Hospital between 1980 and 2000. A multivariate analysis of several potential risk factors for total LRR
revealed four significant independent predictors: margin status (<2 mm), premenopausal status, size (>2 cm), and LVI,
with these latter two having the greater hazard ratios (3.8
and 3.2, respectively). Ten-year total LRR rates were approximately 20% with two adverse factors and 40% with three
adverse factors. Approximately two-thirds of the patients in
this cohort did not received systemic therapy.
Floyd et al. (53) published data on a multicenter effort
of 70 patients treated with mastectomy, systemic therapy,
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and no radiation for patients with pathological T3N0 disease and reported a 5-year LRR of only 8%. Those who had
LVI had a 21% LRR compared to a 4% rate for those without
LVI. Taghian et al. (54) reported results on 313 patients with
pathological stage T3N0 disease who were treated with mastectomy, systemic treatment, and no radiation on National
Surgical Adjuvant Breast and Bowel Project (NSABP) clinical
trials. The 10-year LRR for this series was only 7%, with 24 of
the 28 LRR developing only on the chest wall.
Truong et al. (55) focused exclusively on patients with
T1or T2 node-negative breast cancer treated within the BCCA
and extracted clinicopathological data on this cohort from
their outcome database. They reported an actuarial 10-year
LRR risk of 8% in 1,505 women treated with mastectomy
without RT. On logistic regression analysis, grade, LVI, T
stage and systemic therapy use were statistically significant
independent predictors of LRR. On recursive partitioning
analysis, the first split occurred at histologic grade 3 (actuarial 10-year rate of LRR 12% vs. 6%). The concomitant presence of LVI increased the Kaplan-Meier estimate for 10-year
LRR to 21% compared to 9% for grade 3 alone. Similarly,
Yildirim et al. (56) reported on 502 patients treated with
MRM for T1 or T2 node-negative disease in their retrospective study from Ankara Oncology Hospital. With a median
follow-up of 77 months, only 3% of patients had LRR. Within
these small numbers, multivariate analysis revealed tumor
size greater than 2 cm and LVI as predictors for high risk of
LRR in women 40 years or younger and tumor size greater
than 3 cm, LVI, grade, and HER2 status, and use of tamoxifen in the older women. Ten-year risks of LRR exceeded 30%
for younger women with both risk factors, and older women
with at least three risk factors.
Margin Status
Margin status is another potential risk factor for LRR in postmastectomy patients. However, information documenting
and quantifying the risk of LRR in these patients is scarce
because margin issues are uncommon after mastectomy.
Furthermore, interpreting the available data is difficult due
to the variable definitions of close or positive margins and
the small denominators in the handful of existing reports.
Perhaps the best effort comes from BCCA who identified 94
women with tumor at the inked margin of resection after
mastectomy in their outcomes database (57). Forty-one of
these patients received PMRT, while 53 did not, and cumulative crude LRR were 11.3% versus 4.9% in unirradiated
and irradiated groups, respectively, with no significant difference between the two groups. Factors that resulted in a
cumulative crude LRR of approximately 20% (17% to 23%)
without RT were age 50 or younger, T2 tumor size, grade 3
histology, and LVI. The corresponding rates with RT were in
the single digits (0% to 9%) but all comparisons were statistically nonsignificant. Also, with a median follow-up time of
about 8 years, none of the 22 women with positive margins
without these associated features had LRR.
Freedman et al. (58) reviewed 34 patients with close or
positive margins after mastectomy whose primary tumor
was smaller than 5 cm with zero to three positive axillary
nodes and who received no postoperative radiation. Five
chest wall recurrences appeared at a median interval of
26 months (range, 7–127 months), resulting in an 8-year
cumulative incidence of a chest wall recurrence of 18%.
The authors reported a relatively high risk of local relapse
among younger women (age 50 or younger) compared to
older women (28% vs. 0 at 8 years, p = .04). In a multivariable analysis by Katz et al. (47) of factors predictive of LRR
in patients treated with mastectomy and chemotherapy
Harris_9781451186277_Chap42.indd 8
­ ithout irradiation, close or positive margins were a sigw
nificant independent predictor of LRR. Although there were
only 29 patients available for this analysis, their 10-year LRR
was 45%; the risk was 33% for those with pectoralis fascia
invasion even when negative margins were achieved.
Childs et al. (59) retrospectively reviewed records on
397 women who were treated at Faulkner Hospital (a Dana
Farber affiliate) with mastectomy but without prior induction chemotherapy or PMRT. Fifty-four (14%) of these had
positive margins and 68 (17%) had close (<2 mm) margins.
The median age was 55 years and the risk profile of the
study cohort was quite low. With a median follow-up of 6.7
years, the 5- and 8-year rates of LRR were 2.4% and 4.5%,
respectively. The 5-year risk of LRR with a positive margin
was 6.2% compared to under 2% for both close and negative margin cases (p = .04). Positive-margin status appeared
to confer higher risks when combined with other adverse
­predictors.
Biologic Classifiers and Risk of LRR
Mamounas et al. (60) explored the significance of the
Oncotype Dx recurrence score on LRR risk in postlumpectomy and postmastectomy patients enrolled on the
NSABP-B-14 and B-20 studies. The Oncotype-Dx assay is a
21-gene expression panel that is a validated discriminator
of distant recurrence risk in tamoxifen treated patients. Of
895 tamoxifen treated patients analyzed, 505 were postmastectomy. The LRR rate was 15.8% in patients with a high
recurrence score (RS) (95% CI, 10.4–21.2) compared to 4.3%
(95% CI, 2.3–6.3). Similar results were noted in the placebo
and chemotherapy+tamoxifen cohorts. Multivariate Cox
regression analysis confirmed the independent significance
of RS. In the subgroup of patients treated with mastectomy
(n = 505), the LRR rates for low, intermediate and high RS
were 2.3, 4.7, and 16.8%, respectively. The RS appeared
to consistently discriminate risk in both older (≥50) and
younger postmastectomy patients. This hypothesis-generating data is consistent with distant failure validation studies
of Oncotype Dx in tamoxifen-treated patients, and demonstrates that LRR rates can even be high in biologicallyselected node-negative populations.
Breast cancer can be classified into biologically distinct subtypes (based on gene expression patterns) with
varying clinical potential (61). These subtypes can be
approximated by assessing expression levels of a handful of
markers; prognostic information on metastasis and death is
conserved even with these subtype constructs (62). Several
groups have examined LRR rates as a function of biologic
subtype.
Kyndi et al. (63) retrieved paraffin-embedded tumor
blocks for 1,078 patients enrolled on the Danish postmastectomy trials who had at least eight lymph nodes examined. Tissue microarrays were constructed from 1,000 of
these patients and then stained with standard immunohistochemical methods for ER, PR, and HER2. Successful IHC for
all three markers was achieved in 996 patients. The median
­follow-up of surviving patients was 17 years. In their multivariate analysis, triple-negative status, and receptor-­negative
or HER2 positive (HER2 driven) were prognostic for LRR and
overall mortality. HER2 driven phenotype was outperformed
only by nodal status as a risk for all end points (LRR, DM,
and mortality). In the subgroup of patients randomized
to observation after mastectomy (n = 510), triple-negative
tumors were associated with inferior overall mortality, DM
rate, and LRR probability. HER2 tumors were associated
with mortality and DM but not LRR. In patients who received
PMRT (n = 486), triple-negative status continued to be
2/10/2014 6:10:38 PM
C hapte r 4 2
| ­ ssociated with worse LRR, but not survival or metastasis
a
rate. Indeed, in patients who received PMRT, triple-negative
status, and HER2 enriched status were the strongest associations with LRR, exceeding even nodal status and tumor
size. Perhaps most startlingly, PMRT only appeared to benefit patients with favorable biologic subtypes (constructed
Luminal A) with no statistical improvement in mortality for
patients with Luminal B, triple-negative, and HER2 subtypes.
Although LRR was improved with PMRT in all subgroups,
except the HER2 enriched subtype, the relative reductions
were higher in the luminal subtypes (HR 0.06–0.09) than in
triple-negative subtype (HR 0.33).
The Kyndi report is provocative and requires careful
thought and interpretation. Foremost, the subset numbers
are limited in their power to detect differences. For example,
the Luminal B (HR+, HER2+) curves appear divergent and
have an HR of 0.65 (0.40–1.04, p = .07). Still, the results of the
paper are hard to ignore and counterintuitive—the benefit
of PMRT appeared to be somewhat restricted to favorable
subtypes. It is plausible that hormone-negative and HER2driven tumors had preexisting micrometastases that were
insufficiently treated with the available systemic therapy
and the limitations of the study design (hormonal therapy
with tamoxifen was guided by patient age rather than receptor status on trial 82c, trastuzumab was not available, etc.).
Additional agents that can be delivered with PMRT may perhaps benefit some of these patients.
Voduc et al. (64) analyzed biologic subtype as a predictor of local-regional recurrence in a cohort of over 4,000
women treated in the BCCA system. Fifty-eight percent of
these women (n = 1492) were postmastectomy patients.
Basal and HER2 positive subtypes predicted for higher rates
of local and regional failure in both postlumpectomy and
postmastectomy cohorts. In the postmastectomy patients,
all non-luminal A subtypes were found to be independent
predictors of chest wall and regional nodal failure on Cox
multivariate analysis. The 10-year local relapse-free survival
for Luminal A patients was 92% while the regional relapsefree survival was 96%. The corresponding rates were 86%
and 88% in Luminal B patients, 83 and 88% for HER2 enriched,
and 80% and 81% for basal subtype.
Dominici et al. (65) reported on a cohort of 819 patients
who underwent mastectomy at the MDACC. Most of these
patients received systemic therapy at the discretion of their
treating oncologists—none received PMRT. The majority of
patients were either T1 (75%) or N0 (72%). Approximately
27% of patients (219 of 819) had one to three positive lymph
nodes. With a median follow-up of 58 months, the 5-year risk
of LRR was only 2.5%. Patients with triple-negative tumors
had a 10.9% incidence of LRR, which was higher than other
phenotype constructs (p <.01). On multivariate analysis, having four or more positive lymph nodes and triple-­negative
status were the strongest predictors of LRR. Triple-negative
status and either lymph-vascular space invasion or lymph
node positivity increased risk of LRR at 60 months to 30%
and 23%, respectively.
Using a three-marker classification, Billar (66) retrospectively analyzed recurrence rates by constructed subtype in
a cohort of 1,061 patients of whom 35% were mastectomy
patients. Local or regional recurrence developed more frequently in patients with “triple negative” phenotype (5.7%)
compared to HER2+ (2.9%) and ER+ (1%), p = .001.
Albert et al. (67) also used a three-marker system to
assess the prognostic value of molecular subtype for localregional control in a retrospective cohort of 756 patients
treated at the MDACC. Notably, they restricted their cohort
to patients with small, node-negative tumors (T1a-b, N0).
Approximately 38% of these patients were treated with
Harris_9781451186277_Chap42.indd 9
P ostmastectom y Ra d iation T he r ap y
9
mastectomy. With a median follow-up of 6 years, the 8-year
LRR rates were 5.8% for triple-negative, 3.5% for hormone+/
HER2- (Luminal A), 13.4% for hormone+/HER2+ (Luminal B),
and 29% for hormone-/HER2+ (HER2 enriched). There were
only 26 patients at risk in the hormone-/HER2+ patients.
Likewise, there were only eight events in the mastectomy
group, making a subgroup analyses impossible.
Finally, Wang et al. (68) successfully completed a multicenter randomized trial in China evaluating the benefit of
PMRT in triple-negative breast cancer patients. Six-hundred
and eighty-one women were randomly assigned to receive
either no further treatment or 50 Gy in 25 fractions to the
chest wall or regional lymph nodes after a mastectomy and
systemic chemotherapy. With a median follow-up of 86.5
months, patients who received PMRT fared much better
than patients randomized to observation in both 5-year
relapse-free (74.6% vs. 88.3%) and overall-survival rates
(78.7% vs. 90.4%). The Wang trial is notable for its randomized design and its strict inclusion of stage I and II patients.
All patients had tumors that were no larger than 5 cm, and
over 60% were node negative. Sixty-two percent were 50 or
younger.
Taken together, these data strongly suggest that PMRT
can reasonably be considered for most women with triplenegative or basal subtype cancers. In our opinion, these
data nonetheless do not warrant routine PMRT.
Reconstruction and PMRT
Many women desire breast reconstruction after mastectomy, and this presents a commonly encountered challenge
in the management of these women should they also require
radiation therapy. A multidisciplinary collaboration is warranted in which the surgical oncologist, reconstructive surgeon, and radiation oncologist confer with each other and
with the patient to ensure an optimal aesthetic outcome
without compromising the proven benefits of timely PMRT.
Breast reconstruction efforts can generally be categorized as either implant-based or autologous tissue reconstructions. In addition, reconstructions can occur at the
time of the mastectomy (immediate reconstructions) or at
some time after mastectomy, usually after the completion
of radiotherapy (delayed reconstructions). Implant-based
approaches are simpler to perform, avoid the potential
morbidities associated with the donor site, and can be
offered to thin women who do not have adequate autologous tissue in potential donor sites. A tissue expander is
placed between the chest wall musculature and serially
inflated until an appropriate tissue envelope is created,
at which time the expander is replaced with a permanent
prosthesis. Typically, implant-based reconstructions occur
immediately after mastectomy because normal tissues can
become less compliant after radiation, making tissue expansion problematic.
Autologous reconstructions are commonly performed
using a transverse rectus abdominus myocutaneous (TRAM)
flap. Alternatively, a latissimus dorsi flap or a flap based
on the deep inferior epigastric perforator (DIEP) artery or
gluteal arteries can be used for the reconstruction. These
reconstructions can be immediate or delayed. In general,
immediate reconstructions are accompanied by a skin-sparing mastectomy, thus preserving sensate skin and a natural
inframammary sulcus for the reconstruction. The important
advantages of an immediate reconstruction are offset by the
potential adverse effects of radiation therapy on the reconstruction, and the negative impact the reconstruction can
have on the design and delivery of PMRT.
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| M A N A G E M E N T O F P r ima r y I nvasive B r east C ance r
PMRT can result in high rates of contracture, fibrosis,
and poor cosmesis in patients who have immediate implantbased reconstructions. Spear et al. (69) reviewed the data
on 40 consecutive patients who had undergone a two-stage
saline implant reconstruction followed by RT and compared
their outcomes to 40 controls. Fifty-three percent of irradiated reconstructions had complications compared to 10% in
controls, including a 33% capsular contracture rate in the irradiated patients compared to zero in the controls (p <.00005).
Krueger et al. (70) reviewed data on 19 patients who had
expander/implant (E/I) reconstructions and radiation therapy and found that 13 (68%) had complications, compared
to 19 of 62 (31%) in unirradiated controls (p = .006). In contrast, the group at Memorial Sloan Kettering Cancer Center
(MSKCC) has reported results for their patients treated on
an institutional algorithm of E/I reconstructions followed by
PMRT and reported excellent disease control, no delays, and
good to excellent aesthetic results in 80% of cases (71). Ho
et al. (72) recently updated results from 151 patients treated
with PMRT at MSKCC after exchange of a tissue expander
with a permanent prostheses. With a median follow-up of 86
months, the 7-year rates of implant replacement and removal
were 17% and 13%, respectively. Disease-related outcomes
were consistent with uncompromised control. Others have
demonstrated that immediate autologous reconstructions
are associated with somewhat lower complications rates
compared to prosthetic reconstructions (73).
Tran et al. (74) compared complication rates in immediate versus delayed TRAM reconstructions in patients who
received PMRT. Twenty-four of 32 patients in the immediate
reconstruction group had contracture, compared to 0 of 70 in
the delayed reconstruction group (p <.0001). Furthermore,
28% of the patients with immediate reconstruction required
an additional flap or prosthesis to improve cosmesis. In an
attempt to reconcile the benefits of immediate and delayed
reconstructions, Kronowitz et al. (75) have published on
the “delayed-immediate” breast reconstruction wherein
patients have a skin-sparing mastectomy, with preservation of sensate skin, and subpectoral placement of a tissue expander (75). After final pathology is reviewed, those
patients not requiring PMRT go on to have an “immediate” (within 2 weeks) autologous reconstruction, while the
remainder have a delayed autologous reconstruction after
RT. The expander is kept inflated throughout chemotherapy
and then deflated before PMRT.
Breast reconstruction can alter the contour of the chest
wall in a way that makes delivery of radiation to the necessary target volume much more challenging. In a recent
report, Motwani et al. (76) reviewed 112 radiation plans
designed to treat postmastectomy breast reconstructions
and found that 52% of these required compromises in field
design due to geometrical constraints imposed by the
reconstruction (33% were scored as moderate compromises
and 19% major compromises). Only 7% of similar plans in
matched controls had compromises due to patient anatomy
(p <.0001). In contrast, the group at MSKCC has demonstrated excellent coverage in a series of 40 patients with E/I
reconstructions treated with intensity modulated radiation
therapy (IMRT) (77).
Technique of PMRT
Treatment Volume, Dose and Prescription
The volumes at greatest risk for recurrence, the chest wall
and the supraclavicular lymph nodes, should always be
included. However, a case can be made for omitting the
Harris_9781451186277_Chap42.indd 10
supraclavicular/high axilla lymph nodes in patients with
high-risk node-negative breast cancer, due to the low risk of
regional failure reported in these patients (52,54). The entire
mastectomy flaps, inclusive of the mastectomy scar and
drain sites, should be treated. Most commonly, a monoisocentric photon technique is used whereby opposed tangent
split beams are employed for chest wall irradiation and are
matched at isocenter to a superior AP supraclavicular field.
The medial border is typically at midsternum and lateral
border is at the mid- or posterior axillary line as clinically
indicated. The inferior edge is 2 cm inferior to the level of
where the inframammary fold existed. The contralateral
breast (if it is intact), can be used to estimate the level of the
inframammary fold. The superior border of the chest wall
fields serves as the match plane and should be marked at
the palpable inferior edge of the clavicular head. The gantry
angles on the tangent fields are then designed as is done in
conventional intact breast tangents, with half-beam or asymmetric-jaws technique to limit posterior divergence into the
lungs. Ultimately, the isocenter should be at mid-separation
(SAD technique) along a straight line connecting the medial
and lateral wires through the central ray of the symmetrical tangents. Typically, 2 to 3 cm of lung in the tangents is
required for adequate coverage of the chest wall. The isocenter is then translated cranially to the match plane, ensuring
that the geometry of the tangents remains stable. Collimator
rotations on the tangent fields (to correct for the slope of
the chest wall) can be avoided by opening the jaws on the
lung side of the tangents by 2 to 3 cm and adding a superior
lung block to ensure 2 to 3 cm of lung throughout the long
axis of the tangent beams-eye view. This eliminates the need
to correct for the angulation of the cranial edge and simplifies the isocentric match with the supraclavicular field. If the
length of a patient’s torso makes coverage of the chest wall
impossible with half of the available beam length, the tangent jaws can be opened (symmetrically or asymmetrically)
and couch rotations can be performed for each tangent to
create a straight nondivergent cranial edge for the tangent
fields. Simple trigonometric calculations can be performed to
calculate the required couch rotation, or the rod-and-chain
technique can be used. All of these steps can be reproduced
virtually on image data acquired at the time of a CT simulation, and fields designed as described above. Alternatively,
the entire chest wall can be treated with electrons, but
variations in patient thickness and slope can make optimal
dosimetry difficult with this technique. In particular, transmission into lung has to be carefully accounted for. CT planning should be strongly considered for all left-sided lesions,
and dose to the cardiac volume should be tracked and constrained. If the heart is placed anteriorly, the medial chest
wall can be treated with an anterior electron field which is
matched to shallower chest wall tangents. The target dose
to the chest wall is 45 to 50 Gy in conventional 1.8- to 2-Gy
fractions. Dose can be prescribed 1.5 cm from the posterior
edge of the tangents at midseparation or at one-third of the
distance from this point to the anterior skin. Alternatively,
dose can be normalized to a treatment isodose line covering
the target volume. Ideally, the treatment volume should be
homogenous for dose, with acceptable ranges within 95% to
107% of prescription dose. Contributions from 15 MV photons should be minimized and bolus placement should be
considered to ensure superficial coverage. Forward-planned
IMRT, electronic compensation, and inverse-planned IMRT
can be important tools for the radiation oncologist to consider in meeting treatment objectives if the conventional
techniques described above result in suboptimal dosimetry. Notably, both the START A and B r­ andomized trials of
2/10/2014 6:10:39 PM
C hapte r 4 2
| hypofractionation allowed PMRT patients, and no special
toxicity concerns were noted (including the risk of brachial
plexopathy) (78,79). The Cancer Institute of New Jersey and
the Huntsman Cancer Institute are accruing patients to a
prospective phase II trial of hypofractionated PMRT that is
expected to complete enrollment in 2014.
The supraclavicular field is typically an AP photon field
with the upper border above the AC joint (or just flashing
the skin), medial border at the vertebral pedicles and lateral border at the coracoid process in patients who have
had complete axillary dissections. Alternatively, the lateral
border can be placed to include the medial two-thirds of the
humeral head if the axilla is undissected or inadequately dissected. Strom et al. (80) found that in their population of
well-dissected axillae (median number = 17), failures in the
low and midaxilla were uncommon (10-year actuarial rate
3%).The AP supraclavicular field is prescribed at a depth
of 3 cm by convention, although in the age of the CT planning, an alternate anatomically defined depth can be used
provided the superficial entrance dose remains acceptable.
Six MV photons are typically used, although higher energies
are reasonable to consider. A posterior axillary boost (PAB)
can be designed to supplement dose to the axillary apex if
the contribution from the AP supraclavicular field to the
midplane is inadequate. The depth of the supraclavicular
prescription point can be altered to increase the midplane
dose; the depth of the supraclavicular and high axilla nodes
are often similar (81). Many centers are now routinely contouring axillary nodal stations as well as the supraclavicular
nodal target, and this practice can be very helpful in treatment planning. Commonly, 50 Gy prescribed to the supraclavicular volume will result in 40 to 45 Gy to the axillary apex
without need for a PAB.
Inclusion of IMNs is widely variable because of the conflicting data on the benefits and risks of irradiating these
nodes. Although microscopic involvement of IMNs can be
high (82), especially in patients with positive axillary nodes
and medial tumors, IMN failures are exceedingly unusual
(0.1% in the ECOG experience) (26). Furthermore, the benefit of routinely irradiating (or dissecting) the IMNs has
never been proven, although it has not been tested in wellcontrolled studies. Advocates of IMN irradiation correctly
point out that the postmastectomy radiation trials discussed earlier did include the IMNs. This issue will not likely
be settled at least until the results of ongoing randomized
trials of regional nodal irradiation are mature. If the IMNs
are to be included, several techniques have been described,
and these were compared by Arthur et al. (83) in a dosimetric study (83) The partially-wide tangents technique, in
which the tangents blocks are altered to deepen coverage
in the upper three intercostal spaces (Fig. 42-2), resulted in
the least amount of incidental heart and lung irradiation. A
popular technique not compared in this study is a 5 to 6
cm wide electron patch matched to the entry point of the
medial tangent and tilted to a gantry angle 5 to 15 degrees
less than the medial tangent (Fig. 42-3). Nine or 12 MeV electrons can be employed to treat at the requisite CT defined
depth. At 80 to 90% of prescribed dose, acute skin reactions
may necessitate substituting the electron field with a photon field in the same geometry to allow skin sparing. The
target dose is 45 to 50 Gy.
The area around the scar is commonly boosted with
an additional 8 to 12 Gy with electrons. An electron “cutout” can be created to treat a 2- to 3-cm margin around
the mastectomy scar and/or drain sites. In patients with
complex scar geometry or extensive chest wall curvature
(especially after reconstruction) a creative way to avoid the
Harris_9781451186277_Chap42.indd 11
P ostmastectom y Ra d iation T he r ap y
11
Figure 42-2 Beam’s eye view reconstruction of a partially wide tangent field.
uncertainty of matching electron fields is to create a customized thermoplastic surface applicator with embedded
afterloading catheters for remote high-dose rate delivery of
dose (84).
The quality of radiation treatment plans can be judged
by prespecified dose-volume histogram parameters that correlate with disease control and/or tissue toxicity thresholds.
The upcoming RTOG1304/NSABP-B51 randomized study of
treatment volume after induction chemotherapy calls for
95% of the prescription dose delivered to 95% of the planning target volume (PTV), no greater than 30% of the lung
receiving greater than 20 Gy, and no greater than 5% of the
heart receiving greater than 25 Gy in left-sided cases. The
mean heart dose should not exceed 4 Gy.
Figure 42-3 Axial view of isodose lines produced from
a postmastectomy radiation treatment plan employing
tangents and a matched electron strip angled toward the
medial tangent.
2/10/2014 6:10:43 PM
12
SECTION VII
| M A N A G E M E N T O F P r ima r y I nvasive B r east C ance r
Management Summary
PMRT improves local-regional control, breast cancermortality, and all-cause mortality in appropriately
selected patients.
In order to improve local-regional control, PMRT should
be recommended for all patients who have a projected
LRR rate of 20% or greater. This includes patients with
four or more involved axillary nodes, patients with one
to three involved nodes and a primary tumor larger
than 5 cm, and patients with T4 disease (skin involvement, and/or involvement of the chest wall).
Patients with T1 or T2 disease and one to three involved
nodes have an intermediate-risk of recurrence (10% to
20%) and should be considered for PMRT if they have
less than 10 nodes removed, a nodal ratio greater than
0.20, age less than 45, positive margins, high grade
tumors, or LVI. More recent data suggests that these
patients might derive the most survival benefit from
PMRT.
• Node-negative patients generally have low rates of
LRR, including those with T3N0 LVI-negative disease.
PMRT can be considered in patients who have at least
three of these additional adverse features: young age,
histologic grade 3, LVI, and T2 size.
• Adverse tumor biology as indicated by either triplenegative phenotype or high recurrence score on
Oncotype Dx assay should be considered, along with
other risk factors, as potential indications for PMRT.
• In assessing the survival benefit of PMRT, it is important
to consider competing risks of mortality. Patients with
a very high risk of DM and older patients derive less
benefit from PMRT than patients with fewer competing risks.
• Adjuvant systemic therapy decreases LRR and efforts
are underway to assess the survival benefit of PMRT
in the context of increasingly-effective systemic
therapy.
• In devising radiation fields, CT planning for left-sided
cases is very important. The heart should be contoured
and the mean cardiac dose limited.
• For patients desirous of reconstruction, a multidisciplinary collaboration is warranted in which the surgical oncologist, reconstructive surgeon, and radiation
oncologist confer with each other and with the patient
to ensure an optimal aesthetic outcome without compromising the proven benefits of timely PMRT.
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