The Breast 31 (2017) 192e196

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The Breast
journal homepage: www.elsevier.com/brst

Original article

Is there a role for salvage radiotherapy in locally advanced breast

cancer refractory to neoadjuvant chemotherapy?
R.C. Coelho*, F.M.L. Da Silva, I.M.L. Do Carmo, B.V. Bonaccorsi, S.M. Hahn, L.D. Faroni
Department of Clinical Oncology, Brazilian National Cancer Institute, Rio de Janeiro, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Locally advanced breast cancer (LABC) is a major problem, especially in developing
Received 12 July 2016 countries. The standard treatment for LABC is neoadjuvant chemotherapy, with or without anti-Her2
Received in revised form therapy, followed by surgery, radiotherapy, and adjuvant systemic treatment if appropriate. However,
7 September 2016
there are few data in the literature addressing alternatives when neoadjuvant chemotherapy fails to
Accepted 25 October 2016
Available online 24 November 2016
reduce the tumour for surgery.
Materials and methods: We conducted a retrospective study including all patients who had non-
metastatic LABC treated with neoadjuvant chemotherapy and who were not eligible for surgical resec-
Keywords:
Breast cancer
tion; these patients were submitted to salvage radiotherapy (RTX) between January 2000 and December
Locally advanced 2012 at the Brazilian National Cancer Institute.
Radiotherapy Results: Fifty-seven patients were included, with a median age of 51 (23e72) years. The most frequent
Neoadjuvant chemotherapy clinical stages were IIIA and IIIB, corresponding to 19.3% and 70.2%, respectively; mean tumour size was
Retrospective study 8.74 (3e18) cm, and 44 patients (77.2%) had nodal involvement. Chemotherapeutic regimens containing
anthracyclines were prescribed to 98.2% of the patients. Fifteen patients (26.3%) received taxanes and
anthracyclines. Radiation dose was 50 Gy divided into 25 fractions; 43 patients (75.4%) had their tumours
downsized by RTX and underwent mastectomy. Overall survival (OS) was 38 (23e52) months. Patients
who were submitted to surgery had an OS of 49 (28e70) months and those who were not eligible for
mastectomy after radiotherapy had an OS of 18 (9e27) months.
Conclusion: This retrospective study conrms that RTX is an effective treatment to downsize LABC tu-
mours with low or no response to chemotherapy, thereby enabling surgical resection which may
improve overall patient outcome.
2016 Elsevier Ltd. All rights reserved.

1. Introduction cancer (LABC) is neoadjuvant chemotherapy with or without anti-

Breast cancer (BC) is a major global health problem. In Brazil
57,120 new cases are expected in 2016, corresponding to 28.1% of all
cancers diagnosed in women [1]. BC has a relatively good prognosis
when diagnosed and treated early. Unfortunately, in emergent
countries BC mortality rates remain high; this is probably related to
late diagnosis and limited access to treatments [2,3]. The survival
rates are different around the world, reaching approximately 90%
for white women in the United States and less than 40% in low-
income countries [4,5].
In Brazil about 30% of patients present with locally advanced
tumours [1,2]. The standard treatment for locally advanced breast
* Corresponding author.
E-mail address: rccmed@gmail.com (R.C. Coelho).
Her2 therapy followed by surgery, radiotherapy and adjuvant sys-
temic treatment if appropriate. Some patients with high positive
hormonal receptors can be treated with hormone therapy in a
neoadjuvant setting [6e10]. However, up to one third of LABCs are
resistant to chemotherapy and/or hormone therapy and remain
inoperable. It is possible to treat such patients with radiotherapy in
order to reduce the tumour burden and allow resection [6e8].
At the Brazilian National Cancer Institute (INCA) many patients
have their diagnosis when their disease is locally advanced, and a
signicant proportion of them have poor responses to neoadjuvant
chemotherapy regimens involving anthracyclines taxanes
trastuzumab; thus other therapies are required, such as radio-
therapy, to reduce the tumour burden with the aim of surgical
resection. There are few data in the literature about this subset of
patients.
This retrospective study evaluated the role of neoadjuvant

http://dx.doi.org/10.1016/j.breast.2016.10.026
0960-9776/ 2016 Elsevier Ltd. All rights reserved.
 R.C. Coelho et al. / The Breast 31 (2017) 192e196
radiotherapy as a salvage treatment in order to allow surgery in a
cohort of patients with LABC who remained inoperable after
standard neoadjuvant chemotherapy.
2. Materials and methods
This was a retrospective cohort study which evaluated non-
metastatic LABC patients documented by imaging, treated with at
least one standard neoadjuvant chemotherapeutic regimen, and
not eligible for surgical resection. These patients were treated with
salvage neoadjuvant radiotherapy (RTX), after informed consent,
with the objective of reducing the tumour burden to allow surgery.
Patients treated between January 2000 and December 2012 were
included, aiming for a minimum follow-up of 3 years. All patients
included were from INCA (Rio de Janeiro, Brazil). This study was
approved by the Ethics in Human Research Committee of INCA and
conducted in accordance with the Declaration of Helsinki and Good
Clinical Practice guidelines.
Clinical data were collected from medical records; de-
mographics, Eastern Cooperative Oncology Group (ECOG) perfor-
mance status (PS), clinical and imaging stages, tumour
characteristics, neoadjuvant treatments before radiotherapy, con-
current treatments with radiotherapy, response, surgery feasibility,
surgical complications, and time to recurrence and/or death were
all evaluated.
Local response to treatment was assessed through clinical
evaluation by surgeons according to the International Union
Against Cancer (UICC) criteria as follows: no palpable abnormality
at the site indicated a complete response (CR); reduction of
50% in
the product of the two largest perpendicular dimensions of the
breast mass and regional adenopathy indicated a partial response
(PR); and <50% reduction indicated a minor response. Stable dis-
ease was dened as no change in clinical status, and progressive
disease was dened as tumour growth or the appearance of new
lesions [11].
In general, the rst clinical reassessment to evaluate RTX
response was performed 4e6 weeks after the end of treatment.
Only patients with complete or partial responses were selected for
mastectomy and axillary clearance.
If the patient was not eligible for surgery and had HR disease,
hormonal therapy (HT) was promptly initiated. Thirteen (44.8%) of
those patients with HR disease who were eligible for resection
after RTX received HT before surgery; nine patients (31%) received
tamoxifen, and four (13.8%) received anastrozole. To consider the
tumour as HR, oestrogen and/or progesterone receptor expres-
sion had to be
1% of the biopsy sample [12].
We dened standard chemotherapeutic regimens in our insti-
tution, at the period evaluated by the study, as the use of anthra-
cyclines and/or taxanes with or without trastuzumab.
Standard radiotherapy included the whole breast by tangential
elds and draining nodal chains (three levels of axilla and supra-
clavicular fossa), and was delivered with anteroposterior (AP)/
posteroanterior (PA) elds. All treatment was delivered with three-
dimensional conformal radiotherapy employing multileaf collima-
tors and 6 MV photons. Patients received the dose of 50 Gy divided
into 25 fractions.
In eight patients, radiosensitisation chemotherapy was pre-
scribed concomitantly with radiotherapy. Seven received capeci-
tabine 850 mg/m2 twice daily for 14 days and repeated every 3
weeks during the radiation therapy, and one had cisplatin 30 mg/
m2 weekly during radiotherapy. A separate analysis for these pa-
tients was performed, but the result was not different from that for
the general population. These data are therefore not described.
During follow-up, patients were evaluated regularly with clin-
ical and physical examinations. Contralateral breast mammography
193
was performed yearly. Other radiological exams and/or biopsies
were performed only if there were clinical suspicions of recurrence.
Exclusion criteria included: insufcient records to complete the
required data described above; incomplete staging without bone,
chest and/or abdominal imaging; another primary neoplasm
(except non-melanoma skin cancer); and treatment with neo-
adjuvant radiotherapy alone or after neoadjuvant hormone therapy
without previous chemotherapy. We also excluded patients in
which radiotherapy was performed with palliative intention.
Overall survival was estimated from the time of diagnosis
(conrmed by biopsy) until death or, for living patients, the last
available follow-up; disease-free survival was determined from the
date of surgery to either rst recurrence or death or the date of last
contact for patients who were alive and disease-free. In both cases
the KaplaneMeier method was used. Survival curves were
compared by log-rank test. Association between hormone receptor
status and outcomes were evaluated by Fisher's exact test. The
evaluation of all analyses was performed with the SPSS software,
version 18.0.
We did not perform a separate analysis of inammatory and
non-inammatory breast cancer patients because not all the re-
cords specied clearly whether or not the tumours were
inammatory.
3. Results
Fifty-seven patients met the inclusion criteria and were selected
for this study. Fifty-six patients (98.2%) were women, with a me-
dian age of 51 (23e72) years. Tumour characteristics at diagnosis
and epidemiological data are described in Table 1.
Tumour characteristics at diagnosis are impressive, reecting
the public health reality in Brazil. Clinical stages IIIA and IIIB, ac-
cording to TNM system 7th edition [13], were more frequent, cor-
responding to 19.3% and 70.2% of cases, respectively; the mean
tumour size was 8.74 (3e18) cm, and 44 patients (77.2%) had nodal
involvement.
Chemotherapeutic regimens containing anthracyclines were
prescribed to 98.2% of patients. Fifteen patients (26.3%) received
taxanes and anthracyclines, and one was treated with the combi-
nation of docetaxel and cyclophosphamide. Trastuzumab was
prescribed to only three patients (5%) because we did not have
access to trastuzumab in our institution until 2011.
The medium time to surgery after radiotherapy was 20 weeks. In
43 patients (75.4%) tumours were downsized by RTX and the pa-
tients underwent mastectomy. If separated according to hormone
receptor status, 29 of 32 patients (90.6%) with HR and 14 of 24
(58.3%) with negative hormone receptors (HRe) had a response to
RTX and were eligible for surgery. One patient was not tested for
HR. There were no complete pathological responses. Surgical
complications were frequent; nonetheless no patient died because
of them. The most common events were chronic pain (12e21.1%),
lymphoedema (10e17.5%), wound dehiscence (8e14%) and/or
infection (6e10.5%).
Disease-free survival (DFS) was evaluated in patients who un-
derwent surgery. The medium DFS was 20 months. At the second
and fth years, 45.6% and 35.1% were disease-free, respectively.
Considering the hormone receptor status, patients who were
HR had a DFS of 37 months, while those who were HRe had a DFS
of 15 months.
Nine patients are being followed without recurrence. Eight are
HR and one is triple-negative. The last is currently on the fourth
year of follow-up. Two patients had a mucinous subtype, and two
had HER-2 overexpression and were treated with trastuzumab
(HER-2 was tested in ve of nine patients).
Overall survival (OS) was 38 (23e52) months, varying according
194 R.C. Coelho et al. / The Breast 31 (2017) 192e196

Table 1
Baseline and tumour characteristics of the total study population (n 57).

Characteristics n (57) %

Age, years:
Median 51
Range 23e72
Menopausal status:
Premenopausal 25 43.9
Postmenopausal 30 52.6
Unknown 2 3.5
Education level:
Illiterate 5 8.8
8 years 18 31.6
>8 years 19 33.3
Unknown 15 26.3
Race:
White 26 45.6
Black 7 12.3
Mulatto 15 26.3
Unknown 9 15.8
Tumour size (cm):
Mean 8.74
Range 3e18
Histological subtype:
Invasive ductal carcinoma 50 87.7
Invasive lobular carcinoma 5 8.8
Mucinous carcinoma 2 3.5 Fig. 1. Overall survival according to surgical status (P 0.001 by log-rank test).
Oestrogen receptors:
Positive 30 45.6
Negative 26 52.6
Unknown 1 1.8
according to hormone receptor status. In HR patients, bone me-
Progesterone receptors: tastases were more common, corresponding to 22%, followed by
Positive 18 31.6 lungs 18.8%, lymph nodes 15.6%, liver 12.5%, brain 3.1%, pleura 3.1%
Negative 38 66.7 and skin 3.1%. In HRe patients the lung was the main metastatic
Unknown 1 1.8
site, corresponding to 33.3% of cases, followed by lymph nodes 25%,
Her 2 hyperexpression:
Positive 5 8.8 liver 20.8%, bone 16.7%, brain 8.3%, pleura 8.3% and skin 8.3%.
Negative 13 22.8
Unknown 39 68.4
Differentiation grade: 4. Discussion
G1 2 3.5
G2 14 24.6
G3 16 28.1 Locally advanced breast cancer is a major concern in emergent
Unknown 25 43.9 countries. Many variables are responsible for the late diagnosis,
Ulceration: including low educational status, negligence, limited access to the
Yes 12 21.1 public health system, social disparities and scarce resources [1e5].
No 41 71.9
Unknown 4 7
This study illustrates these problems, and better public health
Clinical staging: policies are needed to improve the prognosis of our breast cancer
IIAeIIB 4 7.1 patients in Brazil and probably also in other developing nations.
IIIA 11 19.3 The limitations in primary care and difculties in accessing the
IIIB 40 70.2
public health system are characterised by the median tumour size
IIIC 2 3.5
of 8.74 cm at the rst evaluation by the physician, and by the mean
waiting time between diagnosis and the start of chemotherapeutic
treatment of 75 (1e669) days. Furthermore, low educational status
to surgical and hormone receptor status. Patients who went to
could act directly as a trigger, generating difculties in under-
surgery had an OS of 49 (28e70) months. At the second and fth
standing and failure to seek surveillance programmes.
years OS in operated patients was 76.7% and 36.4%, respectively. On
Studies have been published evaluating the role, efcacy and
the other hand, those who were not eligible for surgery had an OS
tolerability of neoadjuvant radiotherapy in breast cancer patients
of 18 (6e30) months. Overall survival was 38.8% and 9.7% at the
with and/or without inammatory tumours [14e21]. Nonetheless,
second and fth years. Fig. 1 shows OS according to surgical status.
there are few data in the literature about patients who are initially
In patients who underwent surgery, hormonal status inuenced
refractory to neoadjuvant chemotherapy and who are submitted to
prognosis directly. Those with HR disease had an OS of 59
salvage radiotherapy.
(15e103) months. At the second and fth years, OS was 78.1% and
Huang et al., in a retrospective analysis, found that 32 of 38
48.5%, respectively. As expected, HRe patients had an OS of 25
patients (84%) were able to undergo mastectomy when receiving
(19e32) months. No HRe patient was alive at the fth year, and
neoadjuvant radiotherapy after failure of chemotherapy. For the
only 56.6% were alive at the second year.
whole group, overall survival at 5 years was 46%, with a distant
Prognosis was also inuenced by age, since patients <50 years
disease-free survival rate of 32% [22].
old had an OS of 30 (12e48) months, and those
50 years of age
A phase I/II study performed by Gaui et al. at INCA evaluated the
had an OS of 44 (14e75) months. It is important to note that 16
role of neoadjuvant capecitabine and radiotherapy in patients with
patients (61%) who were <50 years old were HRe compared with
inoperable LABC resistant to anthracyclines. This treatment
ten patients (31%) who were
50 years of age.
rendered 23 of the 28 patients (82%) operable. The ve remaining
The most frequent sites of systemic recurrence differed
patients did not undergo surgery because of disease progression.
 R.C. Coelho et al. / The Breast 31 (2017) 192e196
Treatment was well tolerated with no grade 3 or 4 events [23].
In the present study surgery was performed in 43 patients
(75.4%). The majority of the patients did not have chemotherapy
concomitant with RTX, and the results with regard to surgical
resection were similar to those presented by Gaui et al., raising the
question of whether combining chemotherapy and RTX is really
necessary. Furthermore, if compared to the results of Gaui et al.,
26.3% of patients in our cohort were treated with taxanes and
anthracyclines, which could result in different responses to radio-
therapy [23]. The small number of patients treated with taxanes
and/or trastuzumab, as described before, could be one of the rea-
sons why our cohort was refractory to neoadjuvant treatment.
Nevertheless, our data show the reality in many countries with low
budgets for oncological drugs, especially the more expensive ones
such as monoclonal antibodies.
With regard to tumour prole, almost half of the patients were
HRe. This subset of patients had lower responses to RTX than
HR patients, and consequently had a lower frequency of mas-
tectomies. Furthermore, there was an important difference in DFS
and OS favouring patients who underwent surgery regardless of
hormone receptor status. However, the majority of operated pa-
tients had HR disease, so it is difcult to dene whether salvage
radiotherapy, biological behaviour, or hormonal therapy, or a
combination of these are responsible for favourable outcomes. We
believe that probably all these factors may have made positive
contributions.
This study has limitations such as the retrospective methodol-
ogy, absence of a strict control in the intervention group, missing
data in patients' records, lack of standardised chemotherapeutic
regimens, and absence of a strict interval between the end of
radiotherapy and surgery.
The strongest points of the present study are as follows: (1) it is
the largest retrospective cohort evaluating this subgroup of pa-
tients with LABC refractory to neoadjuvant chemotherapy and
ineligible for surgical resection, and treated with salvage neo-
adjuvant radiotherapy; (2) it demonstrates that radiotherapy can be
an alternative to patients with unresectable tumours after neo-
adjuvant chemotherapy; and (3) it is the rst study, to our
knowledge, to show an overall survival advantage for patients with
tumours resected after neoadjuvant salvage radiotherapy
compared with those who were unresected.
Surgical complications were frequent but not severe, and in our
opinion many patients could have other benets from mastectomy
after RTX in addition to DFS and OS, since it is well known that LABC
patients tend to have pain, bleeding, infections and other symp-
toms that affect quality of life. Furthermore, locoregional control
was good, with only three patients (5.3%) presenting with skin
recurrence.
5. Conclusion
Neoadjuvant radiotherapy is an effective treatment to downsize
breast cancer tumours with low or no response to chemotherapy,
and therefore enables surgical resection which may improve
overall patient outcome.
Funding
This work did not receive any specic grants from funding
agencies in the public, commercial, or not-for-prot sectors.
Ethical approval
This study was approved by the Ethics in Human Research
Committee of the Brazilian National Cancer Institute and conducted
195
in accordance with the Declaration of Helsinki and Good Clinical
Practice guidelines.
Conict of interest statement
The authors declare no conict of interest.
Acknowledgments
Our sincere gratitude T. Castro for her contribution to statistical
analysis. We are also immensely grateful to Dr Jose
Bines for his
support and help. His contribution was unique.
References
[1] Instituto Nacional de Ca ^ncer Jose
Alencar Gomes da Silva Coordenaa ~o de
Preven~ ao e Vigila ^ncia Estimatives. Brazilian Cancer Incidence/Instituto
Nacional de C^
Alencar Gomes da Silva, Coordenaa
ancer Jose ~o de Prevena ~o e
^ncia. Rio de Janeiro: INCA; 2016. 2016, http://www.inca.gov.br/wcm/
Vigila
dncc/2015/por-tipos.asp (Accessed 4 April 2016).
[2] Gonzaga CM, Freitas-Junior R, Curado MP, Sousa AL, Souza-Neto JA, Souza MR.
Temporal trends in female breast cancer mortality in Brazil and correlations
with social inequalities: ecological time-series study. BMC Public Health
2015;15:96.
[3] Ghoncheh M, Mohammadian-Hafshejani A, Salehiniya H. Incidence and
mortality of breast Cancer and their relationship to development in asia. Asian
Pac J Cancer Prev 2015;16(14):6081e7.
[4] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin
2013;63(1):11e30.
[5] Igene H. Global health inequalities and breast cancer: an impending public
health problem for developing countries. Breast J 2008;14(5):428e34.
[6] Giordano SH. Update on locally advanced breast cancer. Oncologist 2003;8:
521.
[7] Shenkier T, Weir L, Levine M, et al. Clinical practice guidelines for the care and
treatment of breast cancer: 15. Treatment for women with stage III or locally
advanced breast cancer. CMAJ 2004;170:983.
[8] Tryfonidis K, Senkus E, Cardoso MJ, Cardoso F. Management of locally
advanced breast cancer-perspectives and future directions. Nat Rev Clin Oncol
2015;12(3):147e62.
[9] Leal F, Liutti VT, Antunes dos Santos VC, Novis de Figueiredo MA, et al. Neo-
adjuvant endocrine therapy for resectable breast cancer: a systematic review
and meta-analysis. Breast 2015;24(4):406e12.
[10] Barroso-Sousa R, Silva DD, Alessi JV, Mano MS. Neoadjuvant endocrine ther-
apy in breast cancer: current role and future perspectives. Ecancermedi-
calscience 2016;10:609.
[11] Hayward JL, Carbone PP, Heusen JC, et al. Assessment of response to therapy
in advanced breast cancer. Br J Cancer 1977;35:292e8.
[12] Hammond MEH, Hayes DF, Dowsett M, et al. American society of clinical
oncology/college of american pathologists guideline recommendations for
immunohistochemical testing of estrogen and progesterone receptors in
breast Cancer. J Clin Oncol 2010;28(16):2784e95.
[13] Edge SB, David RB, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC (american
joint committee on Cancer ) Cancer staging handbook: TNM classication of
malignant tumors. seventh ed. 2010. p. 345e76.
[14] Gerlach B, Audretsch W, Gogolin F, et al. Remission rates in breast Cancer
treated with preoperative chemotherapy and radiotherapy. Strahlenther
Onkol 2003;179(5):306e11.
[15] Chakravarthy AB, Kelley MC, McLaren B, et al. Neoadjuvant concurrent
paclitaxel and radiation in stage II/III breast Cancer. Clin Cancer Res 2006;12:
1570e6.
[16] Silvia C, Formenti, Matthew Volm, Franco Muggia, et al. Preoperative twice-
weekly paclitaxel with concurrent radiation therapy followed by surgery
and postoperative doxorubicin-based chemotherapy in locally advanced
BreastCancer: a phase I/II trial. J Clin Oncol 2003;21:864e70.
[17] Roth SL, Audretsch W, Bojar H, et al. Retrospective study of neoadjuvant
versus adjuvant radiochemotherapy in locally advanced noninammatory
breast cancer : survival advantage in cT2 category by neoadjuvant radio-
chemotherapy. Strahlenther Onkol 2010;186(6):299e306.
[18] Alvarado-Miranda Alberto, Arrieta Oscar, Gamboa-Vignolle Carlos, et al.
Concurrent chemo-radiotherapy following neoadjuvant chemotherapy in
locally advanced breast cancer. Radiat Oncology 2009;4:24.
[19] Lerouge D, Touboul E, Lefranc JP, et al. Combined chemotherapy and preop-
erative irradiation for locally advanced noninammatory breast cancer: up-
dates results in a series of 120 patients. Int J Radiat Oncol Biol Phys
2004;59(4):1062e73.
[20] Bourgier C, Lima Pessoa E, Dunant A, Heymann S, Spielmann M, Uzan C, et al.
Exclusive alternating chemotherapy and radiotherapy in non-metastatic in-
ammatory breast cancer: 20 years of follow-up. Int J Radiat Oncol Biol Phys
2012;82(2):690e5.
re-Calandry A, Benot C, Dubois S, Moreau J, et al. Salvage concomitant
[21] Bellie
196 R.C. Coelho et al. / The Breast 31 (2017) 192e196

chemoradiation therapy for non-metastatic inammatory breast cancer after 2002;53(5):1225e33.

chemotherapy failure. Cancer Radiother 2015;19(8):739e45. [23] Gaui MF, Amorim G, Arcuri RA, et al. Phase II study of second-line neoadjuvant
[22] Huang E, McNeese MD, Strom EA, et al. Locoregional treatment outcomes for chemotherapy with capecitabine and radiation therapy for anthracycline-
inoperable anthracycline-resistant breast cancer. Int J Radiat Oncol Biol Phys resistant locally advanced breast Cancer. Am J Clin Oncol 2007;30(1):78e81.