Commentary
Jyoti Mayadev
Megan Daly
Department of Radiation Oncology, University of
CaliforniaeDavis, Sacramento, CA
Allen Chen
Department of Radiation Oncology, UCLA Medical
Center, Los Angeles, CA
Richard Bold
Department of Surgical Oncology, University of
CaliforniaeDavis, Sacramento, CA
Helen Chew
Department of Medical Oncology, University of
CaliforniaeDavis, Sacramento, CA
The Potential Role of Radiation Therapy to the Primary
Site of Disease in Stage IV Breast Cancer Presenting With
Synchronous Metastasis
Introduction
The benefit of local therapy in the form of surgery or radiation
therapy to the chest wall or intact breast remains unproven in pa-
tients diagnosed with stage IV breast cancer.1-9 Traditional therapy
for these patients consisted of primary systemic therapy, with sur-
gery or radiation therapy reserved for palliation of symptomatic local
disease only after control of systemic disease. Stage IV breast cancer
patients constitute a heterogeneous population with regard to mo-
lecular subtype, age, overall disease burden, visceral organ involve-
ment, and treatment response to endocrine therapy, biologic agents,
or chemotherapy, all of which contribute to prognosis. With the
advent of new therapeutic strategies, the 3-year survival rate
increased from 27% to 44% in a French multicenter study.10 With
the increasing efficacy of systemic therapy, a subgroup of stage IV
patients may achieve a complete clinical and radiologic response.
Emerging data, mostly examining the efficacy of surgery, suggest an
overall survival (OS) advantage with aggressive management of the
primary site of disease in stage IV breast cancer.3,8,10-13 Similar
findings to support surgical resection in select stage IV patients have
also been reproduced with the database of the Surveillance,
Epidemiology, and End Results (SEER) Program of the National
Cancer Institute and institutional observational protocols.1,11 The
benefit of radiation therapy to the primary tumor, either following
Submitted: Apr 27 2013; Revised: Jul 24, 2013; Accepted: Aug 26, 2013; Epub: Oct
30, 2013
Address for correspondence: Jyoti Mayadev, MD, Department of Radiation Oncology,
University of CaliforniaeDavis, 4501 X Street, Ground Floor, Suite G-140, Sacra-
mento, CA, 95817
E-mail contact: jyoti.mayadev@ucdmc.ucdavis.edu
10 - Clinical Breast Cancer February 2014
Clinical Breast Cancer Vol. 14, No. 1, 10-2
or replacing surgery, in this cohort of patients remains unknown.
Our clinical commentary visits the role of locoregional therapy of
the primary tumor in patients with metastatic disease at diagnosis.
Further, we explore the existing data and the potential role of ra-
diation in this setting.
Discussion
In the United States, approximately 5% of breast cancer patients
present with metastatic disease annually with a 5-year relative sur-
vival of 23.8%.14 The standard management approach for these
patients with incurable disease has historically consisted of systemic
therapy, with local therapy, including surgery or radiation therapy,
reserved for palliative control of symptoms. However, with signifi-
cant advances in the systemic management of breast cancer, patients
are now living longer with their disease.10 Further, there is signifi-
cant molecular and pathologic heterogeneity among stage IV breast
cancer patients, with established prognostic indicators for longevity
in stage IV patients including oligometastatic disease or bone-
limited metastases. Therefore, the role of local management is
now more germane in well-selected patients for whom local therapy
may impact progression-free survival or OS.
After a mastectomy for locally advanced breast cancer, the chest
wall represents the area at highest risk for locoregional recurrence.
Large, prospective randomized trials have established the benefit
of postmastectomy radiation therapy on local control, disease-free
survival, and OS.15,16 Currently, there is a paucity of data
addressing the role of radiation to the primary site for stage IV
patients, after either breast-conserving surgery or mastectomy,
following systemic therapy.17,18 Further, radiation oncologists are
often faced with a dilemma in consultation for stage IV patients who
1526-8209/$ - see frontmatter Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.clbc.2013.08.010
have no active disease after primary systemic chemotherapy and
secondary surgical resection of the primary. Will radiation benefit
these patients in terms of local control or prevention of a painful
and morbid chest wall recurrence?19 Perhaps radiation will
contribute to an OS benefit, as seen in patients with locally
advanced disease, even those who present with supraclavicular
nodal metastasis. The answers to these pertinent questions are
unknown at this time.
Role of Surgery to the Breast
Several provocative studies have demonstrated the benefit of
surgical resection of the primary tumor in patients with oligome-
tastatic breast cancer. Khan et al. published a seminal study in 2002
evaluating the role of surgical resection of the primary tumor in
patients with stage IV breast cancer using the National Cancer
Database from the American College of Surgeons.11 The median
survival of the entire cohort of patients was 19 months vs. 26
months for those who received a partial mastectomy and 32 months
for those who were treated with a total mastectomy. There was also
a statistically significant difference in 3-year OS for patients who
were treated with a partial mastectomy (28%), compared with those
who were treated with a total mastectomy (32%) and those who
did not have surgery (17%), P < .0001.11 Unfortunately, the use of
adjuvant radiotherapy at the primary site was not evaluated, and
hence the potential benefit of local radiotherapy in this setting
cannot be determined. Subsequently, 14 additional retrospective
studies have explored the use of primary surgery in patients with
metastatic disease from 2002 to 2011, with the majority of the
studies showing an improvement in OS when locoregional therapy
is included. However, there is inherent selection bias in the surgical
group, with younger and more favorable patients being selected for
surgical resection.20 Therefore, these studies suggest, but cannot
conclude on, a survival benefit to primary surgical resection for
select metastatic breast cancer patients.1,2,6,7,21
Collaborative Group Randomized Trials
There are 2 collaborative trials exploring the role of locoregional
therapy in patients with metastatic breast cancer. The actively
accruing Eastern Cooperative Oncology Group (ECOG) E2108, “A
Randomized Phase III Trial of the Value of Early Local Therapy
for the Intact Primary Tumor in Patients with Metastatic Breast
Cancer,” is prospectively evaluating the role of local therapy in
metastatic disease. The primary objective is to determine whether
early local therapy for intact primary disease in women with stage IV
breast cancer whose disease does not progress during initial optimal
systemic therapy will result in prolonged survival compared with
that of women who receive local therapy for palliation only. The
secondary objective is to compare the time to uncontrolled chest
wall disease between patients who receive early local therapy
and patients who receive palliative local therapy. The study also
investigates whether there is a difference in health-related quality of
life between patients who receive early local therapy and those who
receive palliative local therapy. As a developmental therapeutic
strategy, the trial collects biospecimens to determine whether the
circulating tumor cell burden at 6 months following randomization
will be different between the 2 groups. Ultimately, the results
should confirm or dispel findings by earlier, retrospective,
nonrandomized, and data-based studies that suggested the benefits
of aggressive local therapy. Unfortunately, radiation therapy in the
setting of a mastectomy or breast conservation is at the discretion
of the oncology team and therefore, it is unlikely that clear data on
the impact of radiation therapy in this setting will be collected by
this clinical trial.
The second randomized trial is a recently completed collab-
oration between Turkish institutions, “A Randomized Trial
Comparing Locoregional Resection of Primary Tumor with No
Surgery in stage IV Breast Cancer at the Presentation (Protocol
MF07-01): A Study of Turkish Federation of the National Societies
for Breast Diseaes.”22 The primary objective was to assess whether
locoregional treatment of the primary tumor confers an OS
advantage.22 The secondary objectives include assessments of
progression-free survival, quality-of-life, and morbidity related to
locoregional treatment. Locoregional treatments consisted of either
mastectomy or breast-conserving surgery with level I-II axillary
clearance in patients whose lymph nodes are clinically positive for
cancer or whose sentinel lymph node biopsy results are positive for
cancer.22 Radiation therapy to the whole breast followed breast-
conserving surgery.22 Sysetmic therapy was given after surgical
resection in the locoregional arm or immediately in the non-
locoregional treatment arm.22 The study opened in October 2007
and completed its target accrual of 271 patients in November 2012.
Results are pending.
Role of Radiation Therapy to the Primary Site
Although the available surgical data suggest a potential survival
benefit following primary local surgery in select patients with
metastatic breast cancer, the role of adjuvant radiation therapy for
these patients remains largely unexplored.4,17 Unfortunately, there
is no mechanism to differentiate radiation therapy to the primary
site from that to metastatic lesions in large databases such as SEER.
Retrospective studies have shown that radiation therapy is more
often used in those who are treated with surgery (41%) than in a
similar group of stage IV patients treated without surgery (34%).23
There is a paucity of data in the postoperative setting from which to
draw firm conclusions on the role of radiation therapy after surgery.
Furthermore, a thought-provoking scenario would be the
consideration of the use of primary radiation therapy alone for
locoregional control in patients with a disease status whose prog-
nostic benefit depends on systemic therapy. Because of the temporal
benefit of local therapy, primary radiation may be just as effective in
terms of locoregional control as surgery. In a study by Bougier et al.,
radiation therapy without surgical resection provided a local control
benefit and reported metastasis-free progression of 20% to 39%
with OS of 39% to 57% at 3 years.17 Therefore, local radiation
therapy could lead to a prolongation of survival by decreasing the
risk of systemic shedding from the primary site of disease. The
Renee Cancer Center in France performed a retrospective review
of their 581 patients with breast cancer who presented with a stage
IV disease. These patients represented 3% of the center’s the breast
cancer population during the study period. Of these patients, 320
received locoregional therapy as follows: radiation therapy alone in
249 patients (78%), surgery with adjuvant radiation in 41 patients
(13%), and surgery alone in 30 patients (9%).13 Radiation was
prescribed to mean doses of 48.67 Gy (5-50 Gy) to the affected
Clinical Breast Cancer February 2014 - 11
 Radiation Therapy to the Primary Site in Stage 4 Breast Cancer
breast and 48.01 Gy (5-50 Gy) to the axillary and supraclavicular
lymph nodes.13 18 patients received hypofractionated locoregional
radiation. Of the 249 patients receiving radiation alone, 158 pa-
tients (63.5%) were treated with hypofractionated radiation ther-
apy. Additionally, 124 patients (42.7%) received an axillary boost
(mean dose, 16.7 Gy; 9-25 Gy), and 57 patients (20%) received a
boost to the supraclavicular fossa (mean dose, 11.17 Gy; 5-18 Gy).13
The 3-year OS rate was 43% in the group receiving radiation
therapy alone and 26% in those who received surgery and radiation
therapy. However, more patients who received radiation therapy
alone had smaller primary tumors, less nodal burden, bone-only
disease, and less visceral involvement, and more were treated with
endocrine therapy. As with the other trials discussed, the inherent
selection bias confounds interpretation of the role of local therapy.
Debate and inconclusive evidence regarding the role, timing, dose,
and optimal treatment strategy when employing radiation therapy
to the primary site in stage IV breast cancer remain. Whether
patients would benefit from locoregional nodal radiation therapy in
addition to radiation therapy to the chest wall or intact breast after
conservative surgery is currently unknown.
Patient Selection for Radiation Therapy to the
Primary Site
From the existing literature, it is not clear which patients will
benefit from additional locoregional therapy and whether this is
limited to those who present with more-favorable features, such as
low disease burden, estrogen- or progesterone-receptor expression,
or bone-only metastases.3,8 Patient selection for primary radiation
may be the largest confounder in assessments of the effect of
locoregional therapy on disease control. Several studies suggest that
bone-only disease is better controlled when locoregional therapy is
used in the up-front setting.3,8 However, these studies have not
demonstrated an OS benefit to locoregional therapy in those with
bone-only disease.13,24 Because patients with bone-only metastasis
tend to have receptor-positive disease with a more indolent course,
their OS may not be influenced by locoregional therapy. Further-
more, patients traditionally thought to rapidly succumb to
disseminated disease derive a benefit from locoregional therapy with
radiation. According to the article by LeScodan et al., patients with
multiple metastasis and visceral metastasis had an improvement in
3-year OS when treated with locoregional therapy (26.7% vs.
12.3%; P ¼ .003, and 34.2% vs. 17.8%; P ¼ .005, respectively).13
Conclusion
Patients presenting with synchronous metastasis have a historical
median survival of 16 to 29 months.8,10,12,13 There are emerging
retrospective data that challenge the traditional dogma of reserving
local therapy for palliation and demonstrate a survival benefit in
patients treated with aggressive up-front local therapy. However,
interpretation of these nonrandomized, retrospective studies is
confounded by the inherent limitations of such analysis. Prospective
data from randomized trials such as E2108 and the Turkish
Federation study may ultimately provide more-conclusive evidence.
The role of radiation therapy and its decision-making processes,
including the optimal radiation dose, fields, and timing with surgery
is largely unknown. Future strategies examining the role of primary
12 - Clinical Breast Cancer February 2014
tumor control involving radiation therapy could lead to improve-
ment in breast cancer specific survival.
Disclosure
The authors have stated that they have no conflicts of interest.
References
1. Carmichael AR, Anderson ED, Chetty U, et al. Does local surgery have a role in
the management of stage IV breast cancer? Eur J Surg Oncol 2003; 29:17-9.
2. Arriagada R, Rutqvist LE, Mattsson A, et al. Adequate locoregional treatment
for early breast cancer may prevent secondary dissemination. J Clin Oncol 1995;
13:2869-78.
3. Babiera GV, Rao R, Feng L, et al. Effect of primary tumor extirpation in breast
cancer patients who present with stage IV disease and an intact primary tumor.
Ann Surg Oncol 2006; 13:776-82.
4. Bafford AC, Burstein HJ, Barkley CR, et al. Breast surgery in stage IV breast
cancer: impact of staging and patient selection on overall survival. Breast Cancer Res
Treat 2009; 115:7-12.
5. Cady B, Nathan NR, Michaelson JS, et al. Matched pair analyses of stage IV breast
cancer with or without resection of primary breast site. Ann Surg Oncol 2008; 15:
3384-95.
6. Hazard HW, Gorla SR, Scholtens D, et al. Surgical resection of the primary tumor,
chest wall control, and survival in women with metastatic breast cancer. Cancer
2008; 113:2011-9.
7. Leung AM, Vu HN, Nguyen KA, et al. Effects of surgical excision on survival of
patients with stage IV breast cancer. J Surg Res 2010; 161:83-8.
8. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast
tumor improves survival of patients with metastatic breast cancer at diagnosis.
J Clin Oncol 2006; 24:2743-9.
9. Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al. Surgical resection of the
primary tumour is associated with improved survival in patients with distant
metastatic breast cancer at diagnosis. Eur J Surg Oncol 2009; 35:1146-51.
10. Andre F, Slimane K, Bachelot T, et al. Breast cancer with synchronous metastases:
trends in survival during a 14-year period. J Clin Oncol 2004; 22:3302-8.
11. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival
in metastatic breast cancer? Surgery 2002; 132:620-6; discussion 626-7.
12. Khodari W, Sedrati A, Naisse I, et al. AROME (Association of Radiotherapy and
Oncology of the Mediterranean Area;www.aromecancer.org). Impact of loco-
regional treatment on metastatic breast cancer outcome: A review. Crit Rev
Oncol Hematol 2013; 87:69-79.
13. Le Scodan R, Stevens D, Brain E, et al. Breast cancer with synchronous metas-
tases: survival impact of exclusive locoregional radiotherapy. J Clin Oncol 2009; 2:
1375-81.
14. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.
gov). SEER*Stat Database: Mortality - All COD, Aggregated With State, Total
U.S. (1969-2010) <Katrina/Rita Population Adjustment>, National Cancer Insti-
tute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released
April 2013. Underlying mortality data provided by NCHS (www.cdc.gov/nchs).
15. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in
high-risk premenopausal women with breast cancer who receive adjuvant
chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med
1997; 337:949-55.
16. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk
postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast
Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999; 353:1641-8.
17. Bourgier C, Khodari W, Vataire AL, et al. Breast radiotherapy as part of
loco-regional treatments in stage IV breast cancer patients with oligometastatic
disease. Radiother Oncol 2010; 96:199-203.
18. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences
in the extent of surgery for early breast cancer on local recurrence and 15-year
survival: an overview of the randomised trials. Lancet 2005; 366:2087-106.
19. Thariat J, Marcy PY, Lagrange JL. Trends in radiation therapy for the treatment of
metastatic and oligometastatic disease in 2010 [in French]. Bull Cancer 2010; 97:
1467-76.
20. Rashaan ZM, Bastiaannet E, Portielje JE, et al. Surgery in metastatic breast cancer:
patients with a favorable profile seem to have the most benefit from surgery. Eur J
Surg Oncol 2012; 38:52-6.
21. Danna EA, Sinha P, Gilbert M, et al. Surgical removal of primary tumor reverses
tumor-induced immunosuppression despite the presence of metastatic disease.
Cancer Res 2004; 64:2205-11.
22. Soran A OS, Kelsey SF, Gulluoglu BM. Randomized trial comparing locoregional
resection of primary tumor with no surgery in stage IV breast cancer at the pre-
sentation (Protocol MF07-01): a study of Turkish Federation of the National
Societies for Breast Diseases. Breast J 2009; 15:399-403.
23. Gnerlich J, Jeffe DB, Deshpande AD, et al. Surgical removal of the primary tumor
increases overall survival in patients with metastatic breast cancer: analysis of the
1988-2003 SEER data. Ann Surg Oncol 2007; 14:2187-94.
24. Blanchard DK, Shetty PB, Hilsenbeck SG, et al. Association of surgery with
improved survival in stage IV breast cancer patients. Ann Surg 2008; 247:732-8.