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Radiation induced angiosarcoma of the breast: outcomes from a retrospective case series

Radiation induced angiosarcoma of the breast: outcomes from a retrospective case series Background: Radiation induced angiosarcoma (RIAS) of the breast is a rare and aggressive complication of radio‑ therapy. Due to the rarity of this disease, much of the evidence for its management is based on case reports or small retrospective series. We sought to describe the management and outcomes of RIAS in a large single‑ institution series. Methods: All patients diagnosed with RIAS between January 2000 and January 2014 were identified from an institu‑ tional database. Results: A total of 49 patients were identified. Median age at diagnosis was 72 years (range 51–93). Median time from completion of radiotherapy to diagnosis of RIAS was 7.5 years. Median tumour size at presentation was 5.0 cm (1.5–19.0). The majority of patients presented with localised disease (47, 95.9%). Of these, 35 (74.5%) were suitable for surgery and underwent surgery with curative intent. Twelve patients presented with localised irresectable disease. Of these, 7 received systemic chemotherapy, with a sufficient response to facilitate surgery in 3 patients. Following potentially curative surgery, 2‑ year local recurrence‑ free was 55.2%. Survival was significantly prolonged in patients presenting with resectable disease (2‑ year overall survival 71.1% vs 33.3%, p < 0.001). Tumour size >5 cm was prog‑ nostic of distant metastases‑ free survival and overall survival. Conclusion: RIAS are rare, aggressive soft‑ tissue lesions with limited treatment options and high‑ rates of both local and systemic relapse. Keywords: Radiation, Angiosarcoma, Breast as a treatment for breast cancer was associated with Background 26-fold increase in the risk of developing angiosarcoma Radiation-induced angiosarcoma of the breast (RIAS) is when compared with non-irradiated controls [5]. The a rare and late complication of radiotherapy for breast prognosis for patients with RIAS remains poor, with cancer. In those patients undergoing breast conserving 5-year overall survival rates ranging from 27 to 48% [2]. surgery with adjuvant radiotherapy, the estimated inci- Surgery, in the form of wide excision or mastectomy, is dence of RIAS is 0.05–0.3% [1–4]. Although still rare, the mainstay of management in localised disease. Some the incidence of RIAS appears to be increasing, perhaps studies have reported an association between R0 margins reflecting the long latency period for the development and improved survival, although this was not demon- of these tumours following the widespread adoption of strated to be independent of other biological factors such adjuvant radiotherapy for breast cancer. In a large popu- as tumour size [6, 7]. Although there is some evidence lation-based cohort study, a history of prior radiotherapy that neoadjuvant chemotherapy may improve outcomes in angiosarcoma, the rarity of this condition limits such *Correspondence: Andrew.Hayes@rmh.nhs.uk evidence to case reports or small retrospective series The Sarcoma Unit, The Royal Marsden Hospital NHS Foundation Trust, [8–12]. The purpose of this study was to describe the London, UK © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 2 of 6 management and outcomes of patients presenting with was defined as the time from histological diagnosis to RIAS of the breast within a large single-institution case the date of death or last follow-up. Survival curves were series. constructed using the Kaplan–Meier method and com- pared with the log-rank test. A univariate Cox regression Methods analysis was used to investigate the following potential All patients treated with a diagnosis of RIAS at The Royal prognostic variables of LRFS, DMFS and OS: age; mar- Marsden Hospital between January 2000 and January gin status; tumour size; treatment (surgery versus surgery 2014 were identified from a prospectively maintained and adjuvant chemotherapy). Potentially confounding database. Ethical approval was obtained from an institu- factors (p  <  0.1) were then combined in a multivariate tional review board. RIAS was defined as a histologically analysis with forward stepwise combination methods. proven diagnosis of angiosarcoma occurring in a patient The results of these analyses are presented as hazard with a history of irradiation of the surgical field following ratios (HR) with 95% confidence intervals (CI). breast-conserving surgery for breast cancer. Results Operative strategy A total of 49 patients with a confirmed diagnosis of RIAS Patients either underwent their initial surgical manage- were identified during the study period. Patient demo - ment at The Royal Marsden Hospital or were referred graphics, primary breast cancer characteristics and treat- following an initial resection elsewhere. All patients ment for primary breast cancer are outlined in Table  1. undergoing surgery at The Royal Marsden Hospital were All patients were female, with a median age at diagnosis discussed at a sarcoma multidisciplinary meeting pre- of RIAS of 72 years (range 51–93 years). The median time operatively. Patients were classified as having resect - from completion of radiation therapy to the diagnosis of able disease if pre-operative assessment indicated that RIAS was 7.5 (range 1–26) years, with a median maximal a 2  cm or greater negative margin could be achieved by tumour dimension of 5.0  cm (range 1.5–19.0  cm). None surgery with or without plastic surgical reconstruction of the patients in this study had active breast cancer at in the form of a single pedicled or free myocutaneous the time of RIAS diagnosis, nor did any develop recur- flap. If the desired negative margins would require more rent breast cancer during follow-up. extensive reconstruction, such as with extensive resur- The majority of patients presented with localised dis - facing by large skin grafting, the patient was classified ease (47 patients, 95.9%). Of these, 35 patients had as having irresectable disease. Rapidly progressive dis- ease, where disease volume increased over a time span of 2–3  weeks from being suitable for mastectomy alone Table 1 Primary breast cancer characteristics and  treat- or in combination with a pedicled flap to requiring more ment in patients who developed RIAS extensive reconstruction, was also judged irresectable in N = 49 (%) oncological terms. Pre-operative 4-quadrant punch biop- sies were performed to confirm that the planned surgical Median age at RIAS diagnosis (range) 72 (51–93) margins were not involved by microscopically occult dis- Primary breast cancer histology ease. Macroscopically complete resection was judged by Infiltrating ductal carcinoma 25 (51.0) the operating surgeon. Histologically, the resection was Infiltrating lobular carcinoma 3 (6.1) classified as R0 (microscopically negative) if the negative Ductal carcinoma in situ 1 (2.0) margins were >1  mm circumferentially or R1 (micro- Unspecified 20 (40.8) scopically positive) if tumour extended to or within 1 mm Surgery for primary breast cancer of the resection margin. Wide local excision ( WLE) 18 (36.7) WLE and axillary lymph node dissection 29 (59.2) Statistical analyses Mastectomy 1 (2.0) The latency period to the development of RIAS was Mastectomy and LD flap reconstruction 1 (2.0) defined as the time from the date of completion of radi - Adjuvant therapies otherapy to the date of a histological diagnosis of RIAS. Chemotherapy 10 (20.4) Local recurrence-free survival (LRFS) was defined as Endocrine therapy 36 (73.5) the time from histological diagnosis to the develop- Trastuzumab 3 (6.1) ment of a local recurrence or last follow-up. Distant Radiation dose (Gy) (range) metastases-free survival (DMFS) was defined as the time Primary median 50 (40–54) from histological diagnosis to the development of dis- Boost median 12.5 (10–16) tant metastases or last follow-up. Overall survival (OS) LD latissimus dorsi Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 3 of 6 resectable disease at presentation and underwent surgery local recurrence were significantly closer than those who with curative intent (74.5%). 25 patients (74.3%) under- did not (median clearance 1.0  cm vs 2.5  cm, p  =  0.003, went their initial operation at The Royal Marsden Hos - unpaired t test). All but 1 patient who developed local pital with 10 patients (25.7%) initially treated elsewhere. recurrence had less than 2  cm clearance. No difference Of the 10 patients undergoing initial surgery elsewhere, in the proportion of patients developing local recurrence 8 had a simple mastectomy, with 2 undergoing mastec- was noted in those undergoing reconstructive surgery tomy with immediate plastic reconstruction with a pedi- and those closed primarily (44.4% vs 55.6%, p  =  0.505, cled flap (20.0%). Of the 25 patients undergoing initial Fisher’s exact test). A further 7 patients developed iso- surgery at The Royal Marsden Hospital, 9 had a simple lated distant metastases, giving a systemic failure rate of mastectomy, with 16 undergoing a mastectomy with 42.9%. 2-year DMFS was 67.3% (95% CI 48.6–80.5). At immediate plastic reconstruction (64.0%). A microscopi- the time of writing, 20 patients had died (57.1%) with a cally complete R0 resection was performed in 32 patients 2-year OS of 71.1% (95% CI 52.9–83.3). (91.4%). No further therapy was given to the majority of Of the 12 patients with irresectable localised disease, these patients, with 2 patients receiving adjuvant chemo- 4 developed distant metastases (33.3%), with a 2-year therapy following surgery. The decision to give adjuvant DMFS of 57.3% (95% CI 21.6–81.7). At the time of writ- chemotherapy was made based on the extent of disease, ing, 11 of these patients had died (91.7%) with a 2-year OS with 1 patient requiring both a pedicled flap and skin of 33.3% (95% CI 10.3–58.8). Overall survival of patients grafting to achieve macroscopic clearance and the other with irresectable localised disease was significantly having a positive deep margin on the chest wall. Inter- shorter than those with resectable disease (median OS estingly, neither of these patients developed local recur- 18 months vs 37 months, p < 0.001, log-rank test) (Fig. 1). rence, though both subsequently relapsed systemically. Univariate analyses were performed to identify prog- The remaining 12 patients with localised disease at nostic factors of oncological outcomes in patients with presentation were considered to have irresectable dis- resectable localised disease at presentation. The results ease (25.5%). Of these, 4 patients declined or were unfit are summarised in Tables 2 and 3. Tumour size and mar- for further intervention and received best supportive care gin status were prognostic of DMFS on univariate analy- (33.3%). Debulking surgery was performed in 1 patient sis. However, with multivariate analysis, only tumour size for symptomatic palliation. This patient presented with remained prognostic of DMFS. Tumour size was also large volume, fungating disease and a mastectomy was prognostic for OS, with no prognostic factors for LRFS performed with no prospect of achieving clearance of all identified. macroscopic skin changes. The remaining 7 patients were treated with systemic therapy, with 2 patients treated Discussion with doxorubicin and 5 patients receiving weekly pacli- The widespread adoption of breast-conserving surgery taxel. A sufficient response, downsizing the tumour to and adjuvant radiotherapy in the management of pri- allow a potentially curative resection to be performed, mary breast cancer has been accompanied by a steady was achieved in 3 patients. Local disease control was achieved in 2 of these patients, although both subse- quently developed distant metastases. Two patients presented with metastatic RIAS. The first patient presented with hepatic metastases and died fol- lowing spontaneous haemorrhage from these lesions 5 months after diagnosis. The second patient with meta - static hilar and axillary lymphadenopathy responded well to paclitaxel chemotherapy and was disease free after 20 months follow-up. Outcomes Of the 35 patients undergoing surgery for locally resect- able disease, 18 developed a local recurrence (51.4%), 8 of whom presented with a synchronous systemic relapse (22.9%). 2-year LRFS was with 51.2% (95% CI 33.2–67.2). Of these 18 patients, 17 had microscopically negative Fig. 1 Overall survival from diagnosis of RIAS in patients with margins following their initial surgery (94.4%). Resec- localised resectable (blue) and localised irrespectable (red) disease (p < 0.001, log‑rank test) tion margins in those patients who went on to develop Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 4 of 6 Table 2 Univariate and multivariate Cox regressional analyses for prognostic factors of distant metastases-free survival in patients with localised resectable RIAS Variable Univariate Multivariate HR (95% CI) p value HR (95% CI) p value Age (years) <70 Reference – * * ≥70 1.06 (0.98–1.15) 0.146 * * Positive margins No Reference – * * Yes 4.20 (1.12–15.67) 0.033 * * Tumour size (cm) <5 Reference – Reference – ≥5 5.70 (1.18–27.50) 0.030 5.70 (1.18–27.50) 0.030 Treatment Surgery Reference – * * Surgery + chemotherapy 2.08 (0.46–9.51) 0.344 * * *Not included in model generated by forward stepwise combination Table 3 Univariate Cox regressional analyses for  prog- more than 90% of patients in the current series. Despite nostic factors of  overall survival in  patients with  localised this, the majority of patients developed local recurrence resectable RIAS with a 2-year recurrence free survival of 55%. RIAS typi- cally present as multifocal lesions and the propensity Variable HR (95% CI) p value for this pathology to form microsatellite deposits may Age (years) contribute to the difficulty in obtaining local control <70 Reference – [3, 6, 14, 15]. The importance of performing a complete ≥70 1.94 (0.77–4.91) 0.161 pathological resection has been stressed in the literature, Positive margins although no standard guidelines regarding the recom- No Reference – mended distance of clearance have been published [3, Yes 1.17 (0.27–5.10) 0.837 16–18]. In the current series, those who developed local Tumour size (cm) recurrence were found to have closer margins than those <5 Reference – who did not, with only 1 of the 18 (5.6%) patients who ≥5 5.18 (1.41–19.0) 0.013 recurred locally having more than 2  cm circumferential Treatment clearance. However, marginal status was not found to Surgery Reference – be independently prognostic of oncological outcomes Surgery + chemotherapy 1.53 (0.35–6.72) 0.575 in this series. This would suggest that the ability to achieve greater margins is dependent on other biologi- cal tumour factors that also determine outcome, such a increase in the incidence of RIAS of the breast. RIAS is size. Accordingly, no difference in local recurrence rates typically a late complication of adjuvant radiotherapy, was noted between patients undergoing plastic recon- with a median latency of 7.5  years in our institutional struction and those closed primarily. It is likely that the series, although there is considerable variation in the major determinant of outcome in RIAS is tumour biol- time to presentation, ranging from 1 to 26  years. These ogy and, although the initial surgery should aim for mac- findings are consistent with those previously reported in roscopic clearance, it should be cautioned that achieving the literature and due to the substantial variability in the greater negative margins does not necessarily equate to latency of this disease, a high index of suspicion is war- improved patient outcomes. ranted for any patient undergoing adjuvant radiotherapy Despite the majority of patients presenting with local- in this context [1, 3, 13]. ised disease that was amenable to surgery, the rates of Surgery, in the form of mastectomy with or with- local and systemic relapse in RIAS are high. Tumour size out plastic reconstruction, is the modality of choice in was identified as the only independent prognostic fac - patients presenting with localised disease and achieved tor of outcomes in this series, being associated with both microscopically complete (R0) resection margins in DMFS and OS. A meta-analysis of patients with RIAS Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 5 of 6 also identified tumour size as an important prognostic The use of neo/adjuvant chemotherapy was also found factor, being associated with LRFS and, alongside patient to be associated with improved local disease control in age, with OS [19]. As may be expected, poorer survival a large retrospective series of patients with radiation- outcomes were noted in patients presenting with locally induced sarcomas of all sites, although not associated advanced disease unsuitable for surgical management in with improved rates of systemic relapse or survival [3]. our series. These factors highlight the importance of early Adjuvant chemotherapy was not found to produce a ben- diagnosis in this patient group. Angiosarcomas often pre- efit in terms of local control or overall survival study of sent insidiously with purple or red skin changes and may high-risk soft-tissue sarcomas treated with surgery and be easily mistaken for bruising or benign skin changes radiation [21]. As such, there is limited evidence to sug- leading to delayed investigation and diagnosis (Fig.  2). gest that neo/adjuvant chemotherapy produces a survival Early detection and prompt referral may potentially benefit in RIAS, although it certainly may be of use as reduce the number of patients presenting with irresect- an induction therapy prior to surgery in those present- able disease and improve both local and distant disease ing with locally advanced disease and may offer patients control. effective disease palliation in addition. Targeted therapies The role of peri-operative chemotherapy in the man - may offer an alternative treatment in patients with pro - agement of RIAS remains to be clarified. In the current gressive disease, with the tyrosine kinase inhibitor pazo- series, of the 7 patients treated with neoadjuvant chem- panib demonstrating activity in both locally advanced otherapy for localised irresectable disease, 3 patients and metastatic angiosarcoma [22]. achieved a sufficient response to facilitate surgery. RIAS are rare, aggressive soft-tissue lesions with lim- Similar results were noted in the Phase II ANGIOTAX ited treatment options and high-rates of both local and study, in which 30 patients with localised irresectable systemic relapse. Neoadjuvant chemotherapy may have a or metastatic angiosarcoma were treated with paclitaxel role in downsizing locally advanced disease although has [20]. Five patients had partial responses, 3 of whom had no proven effect on survival. localised irresectable lesions in the breast that were ren- Authors’ contributions dered resectable following treatment. On histopatho- Study concept and design: AJH, CB, AM, IJ, RJ, KT. Acquisition, analysis and logical assessment of the resection specimens, 2 of these interpretation of data: RC, HS, RS, GS, OA, KK. Drafting, revising and approving manuscript: RC, HS, RS, GS, OA, KT, AM, KK, IJ, RJ, CB, AJH. All authors read and patients had achieved a complete histological response. approved the final manuscript. Competing interests The authors declare that they have no competing interests. Availability of data The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Ethics approval Ethical approval for this study was obtained from an institutional review board. Funding No funding was received for this study. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Received: 16 June 2017 Accepted: 29 July 2017 References 1. Monroe AT, Feigenberg SJ, Mendenhall NP. Angiosarcoma after breast‑ conserving therapy. Cancer. 2003;97(8):1832–40. 2. Sheth GR, Cranmer LD, Smith BD, Grasso‑Lebeau L, Lang JE. Radiation‑ induced sarcoma of the breast: a systematic review. Oncologist. 2012;17(3):405–18. 3. Torres KE, Ravi V, Kin K, Yi M, Guadagnolo BA, May CD, et al. Long‑term Fig. 2 The typical appearances of radiation‑induced angiosarcoma outcomes in patients with radiation‑associated angiosarcomas of the of the breast Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 6 of 6 breast following surgery and radiotherapy for breast cancer. Ann Surg from late tumors in edematous arms to earlier tumors on the thoracic Oncol. 2013;20(4):1267–74. wall. Breast Cancer Res Treat. 2010;122(3):883–7. 4. West JG, Qureshi A, West JE, Chacon M, Sutherland ML, Haghighi B, et al. 14. Seinen JM, Styring E, Verstappen V, Vult von Steyern F, Rydholm A, Suur‑ Risk of angiosarcoma following breast conservation: a clinical alert. Breast meijer AJ, et al. Radiation‑associated angiosarcoma after breast cancer: J. 2005;11(2):115–23. high recurrence rate and poor survival despite surgical treatment with R0 5. Huang J, Mackillop WJ. Increased risk of soft tissue sarcoma after radio‑ resection. Ann Surg Oncol. 2012;19(8):2700–6. therapy in women with breast carcinoma. Cancer. 2001;92(1):172–80. 15. Shah S, Rosa M. Radiation‑associated angiosarcoma of the breast: clinical 6. Jallali N, James S, Searle A, Ghattaura A, Hayes A, Harris P. Surgical man‑ and pathologic features. Arch Pathol Lab Med. 2016;140(5):477–81. agement of radiation‑induced angiosarcoma after breast conservation 16. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous therapy. Am J Surg. 2012;203(2):156–61. angiosarcoma following breast‑ conserving surgery and radiation: an 7. Lindet C, Neuville A, Penel N, Lae M, Michels JJ, Trassard M, et al. Localised analysis of 27 cases. Am J Surg Pathol. 2004;28(6):781–8. angiosarcomas: the identification of prognostic factors and analysis of 17. Brenn T, Fletcher CD. Radiation‑associated cutaneous atypical vascular treatment impact. A retrospective analysis from the French Sarcoma lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Group (GSF/GETO). Eur J Cancer. 2013;49(2):369–76. Surg Pathol. 2005;29(8):983–96. 8. Alvarado‑Miranda A, Bacon‑Fonseca L, Ulises Lara‑Medina F, Maldonado ‑ 18. Lindford A, Bohling T, Vaalavirta L, Tenhunen M, Jahkola T, Tukiainen E. Martinez H, Arce‑Salinas C. Thalidomide combined with neoadjuvant Surgical management of radiation‑associated cutaneous breast angiosar ‑ chemotherapy in angiosarcoma of the breast with complete pathologic coma. J Plast Reconstr Aesthet Surg. 2011;64(8):1036–42. response: case report and review of literature. Breast Care. 2013;8(1):74–6. 19. Depla AL, Scharloo‑Karels CH, de Jong MA, Oldenborg S, Kolff MW, Oei 9. Oxenberg J, Khushalani NI, Salerno KE, Attwood K, Kane JM 3rd. Neoad‑ SB, et al. Treatment and prognostic factors of radiation‑associated angio ‑ juvant chemotherapy for primary cutaneous/soft tissue angiosarcoma: sarcoma (RAAS) after primary breast cancer: a systematic review. Eur J determining tumor behavior prior to surgical resection. J Surg Oncol. Cancer. 2014;50(10):1779–88. 2015;111(7):829–33. 20. Penel N, Bui BN, Bay JO, Cupissol D, Ray‑ Coquard I, Piperno‑Neumann S, 10. Quadros CA, Vasconcelos A, Andrade R, Ramos RS, Studart E, Nascimento et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the G, et al. Good outcome after neoadjuvant chemotherapy and extended ANGIOTAX Study. J Clin Oncol. 2008;26(32):5269–74. surgical resection for a large radiation‑induced high‑ grade breast sar‑ 21. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. coma. Int Semin Surg Oncol. 2006;3:18. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim 11. Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ. Angiosarcoma. Lancet for resected soft‑tissue sarcoma (EORTC 62931): a multicentre ran‑ Oncol. 2010;11(10):983–91. domised controlled trial. Lancet Oncol. 2012;13(10):1045–54. 12. Zemanova M, Machalekova K, Sandorova M, Boljesikova E, Skulte‑ 22. Kollar A, Jones RL, Stacchiotti S, Gelderblom H, Guida M, Grignani G, tyova M, Svec J, et al. Clinical management of secondary angiosar‑ et al. Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue coma after breast conservation therapy. Rep Pract Oncol Radiother. and Bone Sarcoma Group (STBSG) retrospective analysis. Acta Oncol. 2014;19(1):37–46. 2017;56(1):88–92. 13. Styring E, Fernebro J, Jonsson PE, Ehinger A, Engellau J, Rissler P, et al. 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Radiation induced angiosarcoma of the breast: outcomes from a retrospective case series

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Publisher
Springer Journals
Copyright
Copyright © 2017 by The Author(s)
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology
eISSN
2045-3329
DOI
10.1186/s13569-017-0081-7
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Abstract

Background: Radiation induced angiosarcoma (RIAS) of the breast is a rare and aggressive complication of radio‑ therapy. Due to the rarity of this disease, much of the evidence for its management is based on case reports or small retrospective series. We sought to describe the management and outcomes of RIAS in a large single‑ institution series. Methods: All patients diagnosed with RIAS between January 2000 and January 2014 were identified from an institu‑ tional database. Results: A total of 49 patients were identified. Median age at diagnosis was 72 years (range 51–93). Median time from completion of radiotherapy to diagnosis of RIAS was 7.5 years. Median tumour size at presentation was 5.0 cm (1.5–19.0). The majority of patients presented with localised disease (47, 95.9%). Of these, 35 (74.5%) were suitable for surgery and underwent surgery with curative intent. Twelve patients presented with localised irresectable disease. Of these, 7 received systemic chemotherapy, with a sufficient response to facilitate surgery in 3 patients. Following potentially curative surgery, 2‑ year local recurrence‑ free was 55.2%. Survival was significantly prolonged in patients presenting with resectable disease (2‑ year overall survival 71.1% vs 33.3%, p < 0.001). Tumour size >5 cm was prog‑ nostic of distant metastases‑ free survival and overall survival. Conclusion: RIAS are rare, aggressive soft‑ tissue lesions with limited treatment options and high‑ rates of both local and systemic relapse. Keywords: Radiation, Angiosarcoma, Breast as a treatment for breast cancer was associated with Background 26-fold increase in the risk of developing angiosarcoma Radiation-induced angiosarcoma of the breast (RIAS) is when compared with non-irradiated controls [5]. The a rare and late complication of radiotherapy for breast prognosis for patients with RIAS remains poor, with cancer. In those patients undergoing breast conserving 5-year overall survival rates ranging from 27 to 48% [2]. surgery with adjuvant radiotherapy, the estimated inci- Surgery, in the form of wide excision or mastectomy, is dence of RIAS is 0.05–0.3% [1–4]. Although still rare, the mainstay of management in localised disease. Some the incidence of RIAS appears to be increasing, perhaps studies have reported an association between R0 margins reflecting the long latency period for the development and improved survival, although this was not demon- of these tumours following the widespread adoption of strated to be independent of other biological factors such adjuvant radiotherapy for breast cancer. In a large popu- as tumour size [6, 7]. Although there is some evidence lation-based cohort study, a history of prior radiotherapy that neoadjuvant chemotherapy may improve outcomes in angiosarcoma, the rarity of this condition limits such *Correspondence: Andrew.Hayes@rmh.nhs.uk evidence to case reports or small retrospective series The Sarcoma Unit, The Royal Marsden Hospital NHS Foundation Trust, [8–12]. The purpose of this study was to describe the London, UK © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 2 of 6 management and outcomes of patients presenting with was defined as the time from histological diagnosis to RIAS of the breast within a large single-institution case the date of death or last follow-up. Survival curves were series. constructed using the Kaplan–Meier method and com- pared with the log-rank test. A univariate Cox regression Methods analysis was used to investigate the following potential All patients treated with a diagnosis of RIAS at The Royal prognostic variables of LRFS, DMFS and OS: age; mar- Marsden Hospital between January 2000 and January gin status; tumour size; treatment (surgery versus surgery 2014 were identified from a prospectively maintained and adjuvant chemotherapy). Potentially confounding database. Ethical approval was obtained from an institu- factors (p  <  0.1) were then combined in a multivariate tional review board. RIAS was defined as a histologically analysis with forward stepwise combination methods. proven diagnosis of angiosarcoma occurring in a patient The results of these analyses are presented as hazard with a history of irradiation of the surgical field following ratios (HR) with 95% confidence intervals (CI). breast-conserving surgery for breast cancer. Results Operative strategy A total of 49 patients with a confirmed diagnosis of RIAS Patients either underwent their initial surgical manage- were identified during the study period. Patient demo - ment at The Royal Marsden Hospital or were referred graphics, primary breast cancer characteristics and treat- following an initial resection elsewhere. All patients ment for primary breast cancer are outlined in Table  1. undergoing surgery at The Royal Marsden Hospital were All patients were female, with a median age at diagnosis discussed at a sarcoma multidisciplinary meeting pre- of RIAS of 72 years (range 51–93 years). The median time operatively. Patients were classified as having resect - from completion of radiation therapy to the diagnosis of able disease if pre-operative assessment indicated that RIAS was 7.5 (range 1–26) years, with a median maximal a 2  cm or greater negative margin could be achieved by tumour dimension of 5.0  cm (range 1.5–19.0  cm). None surgery with or without plastic surgical reconstruction of the patients in this study had active breast cancer at in the form of a single pedicled or free myocutaneous the time of RIAS diagnosis, nor did any develop recur- flap. If the desired negative margins would require more rent breast cancer during follow-up. extensive reconstruction, such as with extensive resur- The majority of patients presented with localised dis - facing by large skin grafting, the patient was classified ease (47 patients, 95.9%). Of these, 35 patients had as having irresectable disease. Rapidly progressive dis- ease, where disease volume increased over a time span of 2–3  weeks from being suitable for mastectomy alone Table 1 Primary breast cancer characteristics and  treat- or in combination with a pedicled flap to requiring more ment in patients who developed RIAS extensive reconstruction, was also judged irresectable in N = 49 (%) oncological terms. Pre-operative 4-quadrant punch biop- sies were performed to confirm that the planned surgical Median age at RIAS diagnosis (range) 72 (51–93) margins were not involved by microscopically occult dis- Primary breast cancer histology ease. Macroscopically complete resection was judged by Infiltrating ductal carcinoma 25 (51.0) the operating surgeon. Histologically, the resection was Infiltrating lobular carcinoma 3 (6.1) classified as R0 (microscopically negative) if the negative Ductal carcinoma in situ 1 (2.0) margins were >1  mm circumferentially or R1 (micro- Unspecified 20 (40.8) scopically positive) if tumour extended to or within 1 mm Surgery for primary breast cancer of the resection margin. Wide local excision ( WLE) 18 (36.7) WLE and axillary lymph node dissection 29 (59.2) Statistical analyses Mastectomy 1 (2.0) The latency period to the development of RIAS was Mastectomy and LD flap reconstruction 1 (2.0) defined as the time from the date of completion of radi - Adjuvant therapies otherapy to the date of a histological diagnosis of RIAS. Chemotherapy 10 (20.4) Local recurrence-free survival (LRFS) was defined as Endocrine therapy 36 (73.5) the time from histological diagnosis to the develop- Trastuzumab 3 (6.1) ment of a local recurrence or last follow-up. Distant Radiation dose (Gy) (range) metastases-free survival (DMFS) was defined as the time Primary median 50 (40–54) from histological diagnosis to the development of dis- Boost median 12.5 (10–16) tant metastases or last follow-up. Overall survival (OS) LD latissimus dorsi Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 3 of 6 resectable disease at presentation and underwent surgery local recurrence were significantly closer than those who with curative intent (74.5%). 25 patients (74.3%) under- did not (median clearance 1.0  cm vs 2.5  cm, p  =  0.003, went their initial operation at The Royal Marsden Hos - unpaired t test). All but 1 patient who developed local pital with 10 patients (25.7%) initially treated elsewhere. recurrence had less than 2  cm clearance. No difference Of the 10 patients undergoing initial surgery elsewhere, in the proportion of patients developing local recurrence 8 had a simple mastectomy, with 2 undergoing mastec- was noted in those undergoing reconstructive surgery tomy with immediate plastic reconstruction with a pedi- and those closed primarily (44.4% vs 55.6%, p  =  0.505, cled flap (20.0%). Of the 25 patients undergoing initial Fisher’s exact test). A further 7 patients developed iso- surgery at The Royal Marsden Hospital, 9 had a simple lated distant metastases, giving a systemic failure rate of mastectomy, with 16 undergoing a mastectomy with 42.9%. 2-year DMFS was 67.3% (95% CI 48.6–80.5). At immediate plastic reconstruction (64.0%). A microscopi- the time of writing, 20 patients had died (57.1%) with a cally complete R0 resection was performed in 32 patients 2-year OS of 71.1% (95% CI 52.9–83.3). (91.4%). No further therapy was given to the majority of Of the 12 patients with irresectable localised disease, these patients, with 2 patients receiving adjuvant chemo- 4 developed distant metastases (33.3%), with a 2-year therapy following surgery. The decision to give adjuvant DMFS of 57.3% (95% CI 21.6–81.7). At the time of writ- chemotherapy was made based on the extent of disease, ing, 11 of these patients had died (91.7%) with a 2-year OS with 1 patient requiring both a pedicled flap and skin of 33.3% (95% CI 10.3–58.8). Overall survival of patients grafting to achieve macroscopic clearance and the other with irresectable localised disease was significantly having a positive deep margin on the chest wall. Inter- shorter than those with resectable disease (median OS estingly, neither of these patients developed local recur- 18 months vs 37 months, p < 0.001, log-rank test) (Fig. 1). rence, though both subsequently relapsed systemically. Univariate analyses were performed to identify prog- The remaining 12 patients with localised disease at nostic factors of oncological outcomes in patients with presentation were considered to have irresectable dis- resectable localised disease at presentation. The results ease (25.5%). Of these, 4 patients declined or were unfit are summarised in Tables 2 and 3. Tumour size and mar- for further intervention and received best supportive care gin status were prognostic of DMFS on univariate analy- (33.3%). Debulking surgery was performed in 1 patient sis. However, with multivariate analysis, only tumour size for symptomatic palliation. This patient presented with remained prognostic of DMFS. Tumour size was also large volume, fungating disease and a mastectomy was prognostic for OS, with no prognostic factors for LRFS performed with no prospect of achieving clearance of all identified. macroscopic skin changes. The remaining 7 patients were treated with systemic therapy, with 2 patients treated Discussion with doxorubicin and 5 patients receiving weekly pacli- The widespread adoption of breast-conserving surgery taxel. A sufficient response, downsizing the tumour to and adjuvant radiotherapy in the management of pri- allow a potentially curative resection to be performed, mary breast cancer has been accompanied by a steady was achieved in 3 patients. Local disease control was achieved in 2 of these patients, although both subse- quently developed distant metastases. Two patients presented with metastatic RIAS. The first patient presented with hepatic metastases and died fol- lowing spontaneous haemorrhage from these lesions 5 months after diagnosis. The second patient with meta - static hilar and axillary lymphadenopathy responded well to paclitaxel chemotherapy and was disease free after 20 months follow-up. Outcomes Of the 35 patients undergoing surgery for locally resect- able disease, 18 developed a local recurrence (51.4%), 8 of whom presented with a synchronous systemic relapse (22.9%). 2-year LRFS was with 51.2% (95% CI 33.2–67.2). Of these 18 patients, 17 had microscopically negative Fig. 1 Overall survival from diagnosis of RIAS in patients with margins following their initial surgery (94.4%). Resec- localised resectable (blue) and localised irrespectable (red) disease (p < 0.001, log‑rank test) tion margins in those patients who went on to develop Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 4 of 6 Table 2 Univariate and multivariate Cox regressional analyses for prognostic factors of distant metastases-free survival in patients with localised resectable RIAS Variable Univariate Multivariate HR (95% CI) p value HR (95% CI) p value Age (years) <70 Reference – * * ≥70 1.06 (0.98–1.15) 0.146 * * Positive margins No Reference – * * Yes 4.20 (1.12–15.67) 0.033 * * Tumour size (cm) <5 Reference – Reference – ≥5 5.70 (1.18–27.50) 0.030 5.70 (1.18–27.50) 0.030 Treatment Surgery Reference – * * Surgery + chemotherapy 2.08 (0.46–9.51) 0.344 * * *Not included in model generated by forward stepwise combination Table 3 Univariate Cox regressional analyses for  prog- more than 90% of patients in the current series. Despite nostic factors of  overall survival in  patients with  localised this, the majority of patients developed local recurrence resectable RIAS with a 2-year recurrence free survival of 55%. RIAS typi- cally present as multifocal lesions and the propensity Variable HR (95% CI) p value for this pathology to form microsatellite deposits may Age (years) contribute to the difficulty in obtaining local control <70 Reference – [3, 6, 14, 15]. The importance of performing a complete ≥70 1.94 (0.77–4.91) 0.161 pathological resection has been stressed in the literature, Positive margins although no standard guidelines regarding the recom- No Reference – mended distance of clearance have been published [3, Yes 1.17 (0.27–5.10) 0.837 16–18]. In the current series, those who developed local Tumour size (cm) recurrence were found to have closer margins than those <5 Reference – who did not, with only 1 of the 18 (5.6%) patients who ≥5 5.18 (1.41–19.0) 0.013 recurred locally having more than 2  cm circumferential Treatment clearance. However, marginal status was not found to Surgery Reference – be independently prognostic of oncological outcomes Surgery + chemotherapy 1.53 (0.35–6.72) 0.575 in this series. This would suggest that the ability to achieve greater margins is dependent on other biologi- cal tumour factors that also determine outcome, such a increase in the incidence of RIAS of the breast. RIAS is size. Accordingly, no difference in local recurrence rates typically a late complication of adjuvant radiotherapy, was noted between patients undergoing plastic recon- with a median latency of 7.5  years in our institutional struction and those closed primarily. It is likely that the series, although there is considerable variation in the major determinant of outcome in RIAS is tumour biol- time to presentation, ranging from 1 to 26  years. These ogy and, although the initial surgery should aim for mac- findings are consistent with those previously reported in roscopic clearance, it should be cautioned that achieving the literature and due to the substantial variability in the greater negative margins does not necessarily equate to latency of this disease, a high index of suspicion is war- improved patient outcomes. ranted for any patient undergoing adjuvant radiotherapy Despite the majority of patients presenting with local- in this context [1, 3, 13]. ised disease that was amenable to surgery, the rates of Surgery, in the form of mastectomy with or with- local and systemic relapse in RIAS are high. Tumour size out plastic reconstruction, is the modality of choice in was identified as the only independent prognostic fac - patients presenting with localised disease and achieved tor of outcomes in this series, being associated with both microscopically complete (R0) resection margins in DMFS and OS. A meta-analysis of patients with RIAS Cohen‑Hallaleh et al. Clin Sarcoma Res (2017) 7:15 Page 5 of 6 also identified tumour size as an important prognostic The use of neo/adjuvant chemotherapy was also found factor, being associated with LRFS and, alongside patient to be associated with improved local disease control in age, with OS [19]. As may be expected, poorer survival a large retrospective series of patients with radiation- outcomes were noted in patients presenting with locally induced sarcomas of all sites, although not associated advanced disease unsuitable for surgical management in with improved rates of systemic relapse or survival [3]. our series. These factors highlight the importance of early Adjuvant chemotherapy was not found to produce a ben- diagnosis in this patient group. Angiosarcomas often pre- efit in terms of local control or overall survival study of sent insidiously with purple or red skin changes and may high-risk soft-tissue sarcomas treated with surgery and be easily mistaken for bruising or benign skin changes radiation [21]. As such, there is limited evidence to sug- leading to delayed investigation and diagnosis (Fig.  2). gest that neo/adjuvant chemotherapy produces a survival Early detection and prompt referral may potentially benefit in RIAS, although it certainly may be of use as reduce the number of patients presenting with irresect- an induction therapy prior to surgery in those present- able disease and improve both local and distant disease ing with locally advanced disease and may offer patients control. effective disease palliation in addition. Targeted therapies The role of peri-operative chemotherapy in the man - may offer an alternative treatment in patients with pro - agement of RIAS remains to be clarified. In the current gressive disease, with the tyrosine kinase inhibitor pazo- series, of the 7 patients treated with neoadjuvant chem- panib demonstrating activity in both locally advanced otherapy for localised irresectable disease, 3 patients and metastatic angiosarcoma [22]. achieved a sufficient response to facilitate surgery. RIAS are rare, aggressive soft-tissue lesions with lim- Similar results were noted in the Phase II ANGIOTAX ited treatment options and high-rates of both local and study, in which 30 patients with localised irresectable systemic relapse. Neoadjuvant chemotherapy may have a or metastatic angiosarcoma were treated with paclitaxel role in downsizing locally advanced disease although has [20]. Five patients had partial responses, 3 of whom had no proven effect on survival. localised irresectable lesions in the breast that were ren- Authors’ contributions dered resectable following treatment. On histopatho- Study concept and design: AJH, CB, AM, IJ, RJ, KT. 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Clinical Sarcoma ResearchSpringer Journals

Published: Aug 7, 2017

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