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Is there a role for salvage radiotherapy in locally advanced breast cancer refractory to neoadjuvant chemotherapy?
The Breast 31 (2017) 192e196
Contents lists available at ScienceDirect
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: Received 12 July 2016 Received in revised form 7 September 2016 Accepted 25 October 2016
Introduction: Locally advanced breast cancer (LABC) is a major problem, especially in developing countries. The standard treatment for LABC is neoadjuvant chemotherapy, with or without anti-Her2 therapy, followed by surgery, radiotherapy, and adjuvant systemic treatment if appropriate. However, there are few data in the literature addressing alternatives when neoadjuvant chemotherapy fails to reduce the tumour for surgery. Materials and methods: We conducted a retrospective study including all patients who had nonmetastatic LABC treated with neoadjuvant chemotherapy and who were not eligible for surgical resection; these patients were submitted to salvage radiotherapy (RTX) between January 2000 and December 2012 at the Brazilian National Cancer Institute. Results: Fifty-seven patients were included, with a median age of 51 (23e72) years. The most frequent clinical stages were IIIA and IIIB, corresponding to 19.3% and 70.2%, respectively; 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 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 confirms that RTX is an effective treatment to downsize LABC tumours with low or no response to chemotherapy, thereby enabling surgical resection which may improve overall patient outcome. © 2016 Published by Elsevier Ltd.
Keywords: Breast cancer Locally advanced Radiotherapy Neoadjuvant chemotherapy Retrospective study
1. Introduction 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 lowincome 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: [email protected] (R.C. Coelho). http://dx.doi.org/10.1016/j.breast.2016.10.026 0960-9776/© 2016 Published by Elsevier Ltd.
cancer (LABC) is neoadjuvant chemotherapy with or without antiHer2 therapy followed by surgery, radiotherapy and adjuvant systemic 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 significant proportion of them have poor responses to neoadjuvant chemotherapy regimens involving anthracyclines ± taxanes ± trastuzumab; thus other therapies are required, such as radiotherapy, 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
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 nonmetastatic 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; demographics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), clinical and imaging stages, tumour characteristics, neoadjuvant treatments before radiotherapy, concurrent 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 disease was defined as no change in clinical status, and progressive disease was defined as tumour growth or the appearance of new lesions [11]. In general, the first 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 HRþ disease, hormonal therapy (HT) was promptly initiated. Thirteen (44.8%) of those patients with HRþ 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 HRþ, oestrogen and/or progesterone receptor expression had to be 1% of the biopsy sample [12]. We defined standard chemotherapeutic regimens in our institution, at the period evaluated by the study, as the use of anthracyclines and/or taxanes with or without trastuzumab. Standard radiotherapy included the whole breast by tangential fields and draining nodal chains (three levels of axilla and supraclavicular fossa), and was delivered with anteroposterior (AP)/ posteroanterior (PA) fields. All treatment was delivered with threedimensional conformal radiotherapy employing multileaf collimators and 6 MV photons. Patients received the dose of 50 Gy divided into 25 fractions. In eight patients, radiosensitisation chemotherapy was prescribed concomitantly with radiotherapy. Seven received capecitabine 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 patients 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 clinical 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: insufficient 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 neoadjuvant 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 (confirmed 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 first 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 inflammatory and non-inflammatory breast cancer patients because not all the records specified clearly whether or not the tumours were inflammatory. 3. Results Fifty-seven patients met the inclusion criteria and were selected for this study. Fifty-six patients (98.2%) were women, with a median age of 51 (23e72) years. Tumour characteristics at diagnosis and epidemiological data are described in Table 1. Tumour characteristics at diagnosis are impressive, reflecting the public health reality in Brazil. Clinical stages IIIA and IIIB, according to TNM system 7th edition [13], were more frequent, corresponding 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 combination 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 patients underwent mastectomy. If separated according to hormone receptor status, 29 of 32 patients (90.6%) with HRþ 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 underwent surgery. The medium DFS was 20 months. At the second and fifth years, 45.6% and 35.1% were disease-free, respectively. Considering the hormone receptor status, patients who were HRþ 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 HRþ 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 five of nine patients). Overall survival (OS) was 38 (23e52) months, varying according
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Table 1 Baseline and tumour characteristics of the total study population (n ¼ 57). Characteristics Age, years: Median Range Menopausal status: Premenopausal Postmenopausal Unknown Education level: Illiterate 8 years >8 years Unknown Race: White Black Mulatto Unknown Tumour size (cm): Mean Range Histological subtype: Invasive ductal carcinoma Invasive lobular carcinoma Mucinous carcinoma Oestrogen receptors: Positive Negative Unknown Progesterone receptors: Positive Negative Unknown Her 2 hyperexpression: Positive Negative Unknown Differentiation grade: G1 G2 G3 Unknown Ulceration: Yes No Unknown Clinical staging: IIAeIIB IIIA IIIB IIIC
n (57)
%
51 23e72 25 30 2
43.9 52.6 3.5
5 18 19 15
8.8 31.6 33.3 26.3
26 7 15 9
45.6 12.3 26.3 15.8
8.74 3e18 50 5 2
87.7 8.8 3.5
30 26 1
45.6 52.6 1.8
18 38 1
31.6 66.7 1.8
5 13 39
8.8 22.8 68.4
2 14 16 25
3.5 24.6 28.1 43.9
12 41 4
21.1 71.9 7
4 11 40 2
7.1 19.3 70.2 3.5
to surgical and hormone receptor status. Patients who went to surgery had an OS of 49 (28e70) months. At the second and fifth years OS in operated patients was 76.7% and 36.4%, respectively. On the other hand, those who were not eligible for surgery had an OS of 18 (6e30) months. Overall survival was 38.8% and 9.7% at the second and fifth years. Fig. 1 shows OS according to surgical status. In patients who underwent surgery, hormonal status influenced prognosis directly. Those with HRþ disease had an OS of 59 (15e103) months. At the second and fifth years, OS was 78.1% and 48.5%, respectively. As expected, HRe patients had an OS of 25 (19e32) months. No HRe patient was alive at the fifth year, and only 56.6% were alive at the second year. Prognosis was also influenced by age, since patients <50 years old had an OS of 30 (12e48) months, and those 50 years of age had an OS of 44 (14e75) months. It is important to note that 16 patients (61%) who were <50 years old were HRe compared with ten patients (31%) who were 50 years of age. The most frequent sites of systemic recurrence differed
Fig. 1. Overall survival according to surgical status (P ¼ 0.001 by log-rank test).
according to hormone receptor status. In HRþ patients, bone metastases were more common, corresponding to 22%, followed by lungs 18.8%, lymph nodes 15.6%, liver 12.5%, brain 3.1%, pleura 3.1% and skin 3.1%. In HRe patients the lung was the main metastatic site, corresponding to 33.3% of cases, followed by lymph nodes 25%, liver 20.8%, bone 16.7%, brain 8.3%, pleura 8.3% and skin 8.3%.
4. Discussion Locally advanced breast cancer is a major concern in emergent countries. Many variables are responsible for the late diagnosis, including low educational status, negligence, limited access to the public health system, social disparities and scarce resources [1e5]. This study illustrates these problems, and better public health policies are needed to improve the prognosis of our breast cancer patients in Brazil and probably also in other developing nations. The limitations in primary care and difficulties in accessing the public health system are characterised by the median tumour size of 8.74 cm at the first 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 could act directly as a trigger, generating difficulties in understanding and failure to seek surveillance programmes. Studies have been published evaluating the role, efficacy and tolerability of neoadjuvant radiotherapy in breast cancer patients with and/or without inflammatory tumours [14e21]. Nonetheless, there are few data in the literature about patients who are initially refractory to neoadjuvant chemotherapy and who are submitted to salvage radiotherapy. Huang et al., in a retrospective analysis, found that 32 of 38 patients (84%) were able to undergo mastectomy when receiving neoadjuvant radiotherapy after failure of chemotherapy. For the whole group, overall survival at 5 years was 46%, with a distant disease-free survival rate of 32% [22]. A phase I/II study performed by Gaui et al. at INCA evaluated the role of neoadjuvant capecitabine and radiotherapy in patients with inoperable LABC resistant to anthracyclines. This treatment rendered 23 of the 28 patients (82%) operable. The five remaining 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 radiotherapy [23]. The small number of patients treated with taxanes and/or trastuzumab, as described before, could be one of the reasons 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 profile, almost half of the patients were HRe. This subset of patients had lower responses to RTX than HRþ patients, and consequently had a lower frequency of mastectomies. 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 patients had HRþ disease, so it is difficult to define 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 methodology, 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 patients with LABC refractory to neoadjuvant chemotherapy and ineligible for surgical resection, and treated with salvage neoadjuvant radiotherapy; (2) it demonstrates that radiotherapy can be an alternative to patients with unresectable tumours after neoadjuvant chemotherapy; and (3) it is the first 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 benefits 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 symptoms 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 specific grants from funding agencies in the public, commercial, or not-for-profit 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. Conflict of interest statement The authors declare no conflict of interest. Acknowledgments Our sincere gratitude T. Castro for her contribution to statistical Bines for his analysis. We are also immensely grateful to Dr Jose support and help. His contribution was unique. References ^ncer Jose Alencar Gomes da Silva Coordenaça ~o de [1] Instituto Nacional de Ca ^ncia Estimatives. Brazilian Cancer Incidence/Instituto Prevenç~ ao e Vigila Alencar Gomes da Silva, Coordenaça ~o de Prevença ~o e Nacional de C^ ancer Jose ^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. Neoadjuvant 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 therapy in breast cancer: current role and future perspectives. Ecancermedicalscience 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 classification 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 twiceweekly 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 noninflammatory breast cancer : survival advantage in cT2 category by neoadjuvant radiochemotherapy. 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 preoperative irradiation for locally advanced noninflammatory breast cancer: updates 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 inflammatory breast cancer: 20 years of follow-up. Int J Radiat Oncol Biol Phys 2012;82(2):690e5. re-Calandry A, Benoît C, Dubois S, Moreau J, et al. Salvage concomitant [21] Bellie
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chemoradiation therapy for non-metastatic inflammatory breast cancer after chemotherapy failure. Cancer Radiother 2015;19(8):739e45. [22] Huang E, McNeese MD, Strom EA, et al. Locoregional treatment outcomes for inoperable anthracycline-resistant breast cancer. Int J Radiat Oncol Biol Phys
2002;53(5):1225e33. [23] Gaui MF, Amorim G, Arcuri RA, et al. Phase II study of second-line neoadjuvant chemotherapy with capecitabine and radiation therapy for anthracyclineresistant locally advanced breast Cancer. Am J Clin Oncol 2007;30(1):78e81.
Contents lists available at ScienceDirect
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: Received 12 July 2016 Received in revised form 7 September 2016 Accepted 25 October 2016
Introduction: Locally advanced breast cancer (LABC) is a major problem, especially in developing countries. The standard treatment for LABC is neoadjuvant chemotherapy, with or without anti-Her2 therapy, followed by surgery, radiotherapy, and adjuvant systemic treatment if appropriate. However, there are few data in the literature addressing alternatives when neoadjuvant chemotherapy fails to reduce the tumour for surgery. Materials and methods: We conducted a retrospective study including all patients who had nonmetastatic LABC treated with neoadjuvant chemotherapy and who were not eligible for surgical resection; these patients were submitted to salvage radiotherapy (RTX) between January 2000 and December 2012 at the Brazilian National Cancer Institute. Results: Fifty-seven patients were included, with a median age of 51 (23e72) years. The most frequent clinical stages were IIIA and IIIB, corresponding to 19.3% and 70.2%, respectively; 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 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 confirms that RTX is an effective treatment to downsize LABC tumours with low or no response to chemotherapy, thereby enabling surgical resection which may improve overall patient outcome. © 2016 Published by Elsevier Ltd.
Keywords: Breast cancer Locally advanced Radiotherapy Neoadjuvant chemotherapy Retrospective study
1. Introduction 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 lowincome 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: [email protected] (R.C. Coelho). http://dx.doi.org/10.1016/j.breast.2016.10.026 0960-9776/© 2016 Published by Elsevier Ltd.
cancer (LABC) is neoadjuvant chemotherapy with or without antiHer2 therapy followed by surgery, radiotherapy and adjuvant systemic 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 significant proportion of them have poor responses to neoadjuvant chemotherapy regimens involving anthracyclines ± taxanes ± trastuzumab; thus other therapies are required, such as radiotherapy, 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
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 nonmetastatic 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; demographics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), clinical and imaging stages, tumour characteristics, neoadjuvant treatments before radiotherapy, concurrent 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 disease was defined as no change in clinical status, and progressive disease was defined as tumour growth or the appearance of new lesions [11]. In general, the first 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 HRþ disease, hormonal therapy (HT) was promptly initiated. Thirteen (44.8%) of those patients with HRþ 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 HRþ, oestrogen and/or progesterone receptor expression had to be 1% of the biopsy sample [12]. We defined standard chemotherapeutic regimens in our institution, at the period evaluated by the study, as the use of anthracyclines and/or taxanes with or without trastuzumab. Standard radiotherapy included the whole breast by tangential fields and draining nodal chains (three levels of axilla and supraclavicular fossa), and was delivered with anteroposterior (AP)/ posteroanterior (PA) fields. All treatment was delivered with threedimensional conformal radiotherapy employing multileaf collimators and 6 MV photons. Patients received the dose of 50 Gy divided into 25 fractions. In eight patients, radiosensitisation chemotherapy was prescribed concomitantly with radiotherapy. Seven received capecitabine 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 patients 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 clinical 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: insufficient 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 neoadjuvant 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 (confirmed 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 first 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 inflammatory and non-inflammatory breast cancer patients because not all the records specified clearly whether or not the tumours were inflammatory. 3. Results Fifty-seven patients met the inclusion criteria and were selected for this study. Fifty-six patients (98.2%) were women, with a median age of 51 (23e72) years. Tumour characteristics at diagnosis and epidemiological data are described in Table 1. Tumour characteristics at diagnosis are impressive, reflecting the public health reality in Brazil. Clinical stages IIIA and IIIB, according to TNM system 7th edition [13], were more frequent, corresponding 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 combination 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 patients underwent mastectomy. If separated according to hormone receptor status, 29 of 32 patients (90.6%) with HRþ 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 underwent surgery. The medium DFS was 20 months. At the second and fifth years, 45.6% and 35.1% were disease-free, respectively. Considering the hormone receptor status, patients who were HRþ 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 HRþ 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 five of nine patients). Overall survival (OS) was 38 (23e52) months, varying according
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Table 1 Baseline and tumour characteristics of the total study population (n ¼ 57). Characteristics Age, years: Median Range Menopausal status: Premenopausal Postmenopausal Unknown Education level: Illiterate 8 years >8 years Unknown Race: White Black Mulatto Unknown Tumour size (cm): Mean Range Histological subtype: Invasive ductal carcinoma Invasive lobular carcinoma Mucinous carcinoma Oestrogen receptors: Positive Negative Unknown Progesterone receptors: Positive Negative Unknown Her 2 hyperexpression: Positive Negative Unknown Differentiation grade: G1 G2 G3 Unknown Ulceration: Yes No Unknown Clinical staging: IIAeIIB IIIA IIIB IIIC
n (57)
%
51 23e72 25 30 2
43.9 52.6 3.5
5 18 19 15
8.8 31.6 33.3 26.3
26 7 15 9
45.6 12.3 26.3 15.8
8.74 3e18 50 5 2
87.7 8.8 3.5
30 26 1
45.6 52.6 1.8
18 38 1
31.6 66.7 1.8
5 13 39
8.8 22.8 68.4
2 14 16 25
3.5 24.6 28.1 43.9
12 41 4
21.1 71.9 7
4 11 40 2
7.1 19.3 70.2 3.5
to surgical and hormone receptor status. Patients who went to surgery had an OS of 49 (28e70) months. At the second and fifth years OS in operated patients was 76.7% and 36.4%, respectively. On the other hand, those who were not eligible for surgery had an OS of 18 (6e30) months. Overall survival was 38.8% and 9.7% at the second and fifth years. Fig. 1 shows OS according to surgical status. In patients who underwent surgery, hormonal status influenced prognosis directly. Those with HRþ disease had an OS of 59 (15e103) months. At the second and fifth years, OS was 78.1% and 48.5%, respectively. As expected, HRe patients had an OS of 25 (19e32) months. No HRe patient was alive at the fifth year, and only 56.6% were alive at the second year. Prognosis was also influenced by age, since patients <50 years old had an OS of 30 (12e48) months, and those 50 years of age had an OS of 44 (14e75) months. It is important to note that 16 patients (61%) who were <50 years old were HRe compared with ten patients (31%) who were 50 years of age. The most frequent sites of systemic recurrence differed
Fig. 1. Overall survival according to surgical status (P ¼ 0.001 by log-rank test).
according to hormone receptor status. In HRþ patients, bone metastases were more common, corresponding to 22%, followed by lungs 18.8%, lymph nodes 15.6%, liver 12.5%, brain 3.1%, pleura 3.1% and skin 3.1%. In HRe patients the lung was the main metastatic site, corresponding to 33.3% of cases, followed by lymph nodes 25%, liver 20.8%, bone 16.7%, brain 8.3%, pleura 8.3% and skin 8.3%.
4. Discussion Locally advanced breast cancer is a major concern in emergent countries. Many variables are responsible for the late diagnosis, including low educational status, negligence, limited access to the public health system, social disparities and scarce resources [1e5]. This study illustrates these problems, and better public health policies are needed to improve the prognosis of our breast cancer patients in Brazil and probably also in other developing nations. The limitations in primary care and difficulties in accessing the public health system are characterised by the median tumour size of 8.74 cm at the first 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 could act directly as a trigger, generating difficulties in understanding and failure to seek surveillance programmes. Studies have been published evaluating the role, efficacy and tolerability of neoadjuvant radiotherapy in breast cancer patients with and/or without inflammatory tumours [14e21]. Nonetheless, there are few data in the literature about patients who are initially refractory to neoadjuvant chemotherapy and who are submitted to salvage radiotherapy. Huang et al., in a retrospective analysis, found that 32 of 38 patients (84%) were able to undergo mastectomy when receiving neoadjuvant radiotherapy after failure of chemotherapy. For the whole group, overall survival at 5 years was 46%, with a distant disease-free survival rate of 32% [22]. A phase I/II study performed by Gaui et al. at INCA evaluated the role of neoadjuvant capecitabine and radiotherapy in patients with inoperable LABC resistant to anthracyclines. This treatment rendered 23 of the 28 patients (82%) operable. The five remaining patients did not undergo surgery because of disease progression.
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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 radiotherapy [23]. The small number of patients treated with taxanes and/or trastuzumab, as described before, could be one of the reasons 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 profile, almost half of the patients were HRe. This subset of patients had lower responses to RTX than HRþ patients, and consequently had a lower frequency of mastectomies. 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 patients had HRþ disease, so it is difficult to define 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 methodology, 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 patients with LABC refractory to neoadjuvant chemotherapy and ineligible for surgical resection, and treated with salvage neoadjuvant radiotherapy; (2) it demonstrates that radiotherapy can be an alternative to patients with unresectable tumours after neoadjuvant chemotherapy; and (3) it is the first 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 benefits 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 symptoms 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 specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Ethical approval This study was approved by the Ethics in Human Research Committee of the Brazilian National Cancer Institute and conducted
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in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Conflict of interest statement The authors declare no conflict of interest. Acknowledgments Our sincere gratitude T. Castro for her contribution to statistical Bines for his analysis. We are also immensely grateful to Dr Jose support and help. His contribution was unique. References ^ncer Jose Alencar Gomes da Silva Coordenaça ~o de [1] Instituto Nacional de Ca ^ncia Estimatives. Brazilian Cancer Incidence/Instituto Prevenç~ ao e Vigila Alencar Gomes da Silva, Coordenaça ~o de Prevença ~o e Nacional de C^ ancer Jose ^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. Neoadjuvant 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 therapy in breast cancer: current role and future perspectives. Ecancermedicalscience 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 classification 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 twiceweekly 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 noninflammatory breast cancer : survival advantage in cT2 category by neoadjuvant radiochemotherapy. 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 preoperative irradiation for locally advanced noninflammatory breast cancer: updates 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 inflammatory breast cancer: 20 years of follow-up. Int J Radiat Oncol Biol Phys 2012;82(2):690e5. re-Calandry A, Benoît C, Dubois S, Moreau J, et al. Salvage concomitant [21] Bellie
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