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Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review
European Journal of Cancer (2014) xxx, xxx– xxx
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Review
Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review A.L. Depla a, C.H. Scharloo-Karels a, M.A.A. de Jong a, S. Oldenborg a, M.W. Kolff a, S.B. Oei b, F. van Coevorden c, G.C. van Rhoon d, E.A. Baartman d, R.J. Scholten e, J. Crezee a, G. van Tienhoven a,⇑ a
Academic Medical Center, Department of Radiation Oncology and Hyperthermia, Amsterdam, The Netherlands Department of Radiation Oncology and Hyperthermia, Institute Verbeeten, Tilburg, The Netherlands c Department of Surgery, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands d Department of Radiation Oncology, Hyperthermia Unit, Erasmus MC-Cancer Institute, Rotterdam, The Netherlands e Dutch Cochrane Center, Utrecht, The Netherlands b
Received 29 January 2014; received in revised form 28 February 2014; accepted 1 March 2014
KEYWORDS Breast cancer Radiation-induced angiosarcoma Surgery Radiotherapy Local control
Abstract Background: Radiation-associated angiosarcoma (RAAS) of the breast is a rare, aggressive disease. The incidence is increasing with the prolonged survival of women irradiated for primary breast cancer. Surgery is the current treatment of choice. Prognosis is poor. This review aims to evaluate all publications on primary treatment of RAAS to identify prognostic factors and evaluate treatment modalities. Methods: Databases were searched for articles with published individual patient data on prognostic factors, treatment and follow-up of patients with RAAS. A regression analysis was performed to test the prognostic values of age, interval between primary treatment and RAAS, tumour size and grade on the local recurrence-free interval (LRFI) and overall survival (OS). The effects of treatment modalities surgery, radiation (with or without hyperthermia) and chemotherapy or combinations were evaluated. Results: 74 articles were included, representing data on 222 patients. In these patients, the 5year OS was 43% and 5-year LRFI was 32%. Tumour size and age were significant prognostic factors on LRFI and OS. Of all patients, 68% received surgery alone, 17% surgery and reirradiation and 6% surgery with chemotherapy. The remaining 9% received primary treatments
⇑ Corresponding author: Address: Academic Medical Center, Department of Radiation Oncology and Hyperthermia, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Fax: +31 20 6091278. E-mail address: [email protected] (G. van Tienhoven).
http://dx.doi.org/10.1016/j.ejca.2014.03.002 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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without surgery. Surgery with radiotherapy had a better 5-year LRFI of 57% compared to 34% for surgery alone (p = 0.008). The value of other treatment modalities could not be assessed. Conclusions: This systematic review confirms the poor prognosis of RAAS. Tumour size and age were of prognostic value. The addition of reirradiation to surgery in the treatment of RAAS appears to enhance local control. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Angiosarcomas are rare, highly malignant tumours of endothelial cells. They occur most commonly in elderly people, on the face or scalp. The breast is the third most common location [1]. Overall, less than 1% of all soft tissue sarcomas are angiosarcomas [2]. Primary angiosarcoma of the breast is very rare; it accounts for only 1 per 1700–2000 primary breast tumours [3], but in the breast it is one of the most common sarcomas [4]. Secondary angiosarcomas of the breast or chestwall are associated with two presumed aetiologic factors: chronic lymphedema after a mastectomy with lymph node dissection – Stewart–Treves syndrome – and radiotherapy, for which a relative risk of 15.9 was found [5,6]. Often it is hard to define the difference in aetiology, because chronic lymphedema and breast cancer treatment, including radiation, are often inter related. Angiosarcomas secondary to radiotherapy are part of a larger group of radiation-associated sarcomas (RAS). RAS is defined by three characteristics: a sarcoma in the previous field of radiation, a latency period of at least 3 years and a histological distinction from the primary neoplasm [7]. Radiation-associated angiosarcoma (RAAS) is the most common kind of RAS in the breast region [6]. In the Netherlands Cancer Registry 181/321 RAS were located in the chest region, of which 56% were angiosarcomas [8]. The cumulative incidence of RAAS, fifteen years after radiotherapy for breast cancer, is 0.9 per 1000 cases [9]. This incidence is low, but likely to increase since women with breast carcinomas have a gradually improving prognosis and radiotherapy is used more often in their treatment. In addition the increasing use of intensity modulated radiation therapy (IMRT) might lead to a higher chance of tumour induction. With the prolonged survival, the long-term effects of the treatment – including RAAS – will occur more frequently. The reported median latency period between radiation and diagnosis of RAAS is 6–7 years [10]. The tumours often present with a blue/red discoloration of the skin, which may be considered as bruises after a light trauma [11]. Due to the long latency period, the seemingly harmless presentation and the rarity of the tumour, recognition by both patient and physician is often delayed. The prognosis of the RAAS is poor; the 5-year survival rates vary from 28% to 54% [12–14]. Currently,
surgery is considered to be the treatment of choice [15], but the outcome is poor because of high local recurrence rates (54–92%) [11,16]. Due to the rarity of this tumour, other treatment options or – combinations are not yet well investigated. The current systematic review of the literature aims to identify patients in all publications on RAAS and its treatment. With the published individual-patient data, from these studies, the intention is to examine prognostic factors and compare the local control as well as the overall survival after different treatments or combinations of treatment. With this information, hypotheses may be created for future, prospective, studies on the treatment of RAAS. 2. Methods 2.1. Search strategy For this systematic review, a comprehensive literature search has been performed in MEDLINEÒ (via PubMed) and Embase in April 2013. Search strategy and methods of data analysis were determined before the start of the study. All searches were limited to the English language and limited to publication dates from 1985, because the first radiation-associated angiosarcoma was described in 1987 [17,18]. The search strategies are presented in the appendix. The results of both searches were combined and duplicates were removed. To assess whether the search had not missed any relevant articles, a validation set was composed of ten relevant articles, which we had already identified in another study [19]. These ten articles were then complemented with five other relevant articles that were identified via Google Scholar by the use of the references of the first ten articles. Using this method, a validation set of 15 articles was built [10,20–33] and we assessed whether the performed search included those 15 articles. 2.2. Selection criteria Selection of the articles was done using the following selection criteria: – Angiosarcoma of the thorax region. – Radiation-associated: angiosarcoma after radiation for primary breast cancer.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx
– Therapy for RAAS and local recurrence after treatment were described in detail. – These data could be extracted from the articles on an individual patient level.
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One reviewer (A.D.) performed the first round of selection by title. Further selection of the articles on abstract and whole article, was done by two reviewers (A.D. and G.T.). Since RAAS of the breast is such a rare tumour, and all articles were case histories or relatively small observational series, no selection criteria were set for the level of evidence of the articles.
All groups in which surgery was used – with or without another treatment modality – were also analysed in a univariate regression, since these groups allow comparison. A second multivariate analysis correcting the various treatments for the prognostic factors was intended, but appeared not to be possible due to too many missing values. Kaplan–Meier curves were calculated to visualise the treatment effects on OS and LRFI. The Log-Rank test was used to assess any differences between treatments. A p-value of less than 0.05 was considered significant. All tests were performed using SPSS20.
2.3. Data extraction
3. Results
The following individual patient data were extracted from the articles per patient:
3.1. Literature search
– Age (years): age of patient at time of diagnosis of RAAS. – Interval (years): time between radiotherapy for primary breast cancer and the diagnosis of RAAS. – Tumour size (cm). – Tumour grade (high/intermediate/low): grade of malignancy of the angiosarcoma. – Primary treatment RAAS (surgery, radiotherapy, chemotherapy, hyperthermia or combinations). – First recurrence (no/local/regional/distant) after treatment for RAAS. – Time to local/regional and/or distant recurrence (months). – Time to death or last follow-up (months). – Follow-up status: no evidence of disease/alive with disease/death of angiosarcoma/death of intercurrent disease.
After having removed duplicates the search resulted in 779 potentially eligible articles. Of those, 74 were included [10,17,19,20,23–92]. The PRISMA (Preferred Reporting Items of Systematic reviews and Meta-Analyses) based study flow of the searches is presented in Fig. 1 [93]. Overall, 12 retrospective series of patients with RAAS were found, of which the smallest described five patients and the largest 24. The other 62 papers were case reports describing one to four patients. Nine patients described in four case reports were reported double and the duplicates were removed. Total number of patients included for further analysis was 222, of whom 80 were described in case reports and 142 in retrospective case series. In the retrospective case series, median follow-up was about twice as long as in the case reports. 3.2. Patient characteristics
Details on radiation dose were not assessed since these were only available in the minority of patients. After obtaining these published individual patient data, the set was checked for double reporting of cases by comparing age and interval between primary breast cancer and RAAS. Double reported cases were removed from the dataset. 2.4. Data analysis All data obtained from the articles were listed in a database. Patient and tumour characteristics as well as outcome parameters for the whole cohort were analysed. Univariate regression analysis of the potential prognostic significance for overall survival (OS) and local recurrence-free interval (LRFI) was performed for the variables age, interval between breast cancer and RAAS, tumour size and tumour grade. The variables that appeared to have a significant effect were subsequently tested in a multivariate model.
Not every variable was described for all patients; in particular tumour grade was missing for more than half of the patients (Table 1). The majority of patients (201, 91%) was treated with surgery (Table 2). Surgery alone, was performed as primary treatment for RAAS in 150 patients (68%). Of those, 129 patients had received mastectomy (86%), 14 patients ‘wide excision’ (9%) and seven patients ‘excision’ (5%). Surgery combined with reirradiation was performed in 37 patients (17%). Of those, mastectomy was used as surgical treatment in all, but one patient who underwent tumour excision. In this group, surgery with reirradiation was included as well as surgery combined with reirradiation and hyperthermia. Hyperthermia was given in addition to radiotherapy in 11 patients (30%). One study with eight patients used hyperfractionated and accelerated radiotherapy (HART) combined with surgery [27]. Radiotherapy was given either before
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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Fig. 1. Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) flow diagram.
Table 1 Patient characteristics. Variable
n
Age (yrs) Interval (yrs) Tumour size (cm) Tumour grade
208 208 142 94
Median (min–max)/distribution
Low: 22%
69 (36–96) 6 (1–24) 4.5 (0.1–34) Intermediate: 28%
High: 50%
Abbreviations: n = number of patients the variable was known for, yrs = years, cm = centimetre, min = minimum, max = maximum.
(30%) or after surgery (70%). Surgery combined with chemotherapy was performed in 14 patients (6%) The remaining patients were treated with radiotherapy and hyperthermia alone (6%). or received just chemotherapy (3%). 3.3. Treatment results Data on outcome parameters were obtained for almost all patients (Table 3). Irrespective of the type of treatment received, the 5-year OS was 43% and the 5-year LRFI 32%. Of the 144 (65%) recurrences, 131 (90%) were
local. Two patients experienced a regional recurrence. Only 3% of the patients died of intercurrent disease. 3.4. Prognostic factors and treatment results Interval between breast cancer and RAAS, tumour size and age were significant prognostic factors for local recurrence (hazard ratio (HR) 0.93, 1.09 and 1.02, respectively) and mortality (HR 0.92, 1.09 and 1.03, respectively) in univariate analysis (Tables 4 and 5). The prognostic impact of grade of the tumour was not found to be significant, probably because of the high
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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Table 2 Treatments. Treatment
Number of patients per treatment n (%)
Patients from retrospective reviews n (number of studies)
Patients from case reports n (number of studies)
SUR SUR + RT (±HT) SUR + CT RT (±HT) CT SUR + CT + RT
150 (68%) 37 (17%) 14 (6%) 14 (6%) 6 (3%) 1 (0.5%)
85 36 5 14 1 1
(10) (5) (3) (3) (1) (1)
65 1 9 0 5 0
(48) (1) (9)
Total
222 (100%)
142
(12)
80
(65)
(5)
Abbreviations: SUR = surgery, RT = radiotherapy, HT = hyperthermia, CT = chemotherapy, n = number of patients.
Table 3 Outcome. Variable
n
Outcome
Site of first recurrence
222
No Local Distant
5-year LRFI 5-year OS Follow-up status
222 222 215
Alive Died
35% 59% 6% 32% 43% 58% 42%
Abbreviations: n = number of patients the variable was known for, LRFI = local recurrence-free interval, OS = overall survival.
number of missing values for this variable (Table 1). In multivariate analysis tumour size was the main prognostic factor, both for local control and overall survival and age remained prognostic for overall survival. Univariate analysis of the three surgery groups showed the following: median follow-up for all patients alive at the end of follow-up after surgery only was 24 months, for surgery with radiotherapy it was 52 months and for surgery with chemotherapy 16 months. A significant effect of adding radiotherapy to surgery on LRFI was found (HR 0.46) and no difference with respect to OS (HR 0.99) (Tables 4 and 5; Figs. 2 and 3). For surgery only we found a recurrence rate of
65%, of which 91% were local. For surgery with radiotherapy the recurrence rate was 51%, of which 68% local. So local recurrence rates were 59% and 35% respectively. Median LRFI for surgery was 12 months, the median LFRI was not reached for surgery + radiotherapy. The 5-year LRFI was 34% and 57%, respectively (Fig. 2). The group that received surgery with chemotherapy showed no significant difference compared to surgery alone, neither for LRFI, nor for OS (Tables 4 and 5). Multivariate analysis with correction for prognostic factors was attempted, but appeared unreliable due to too many missing values. The prognostic factors were slightly better in the surgery with radiotherapy group compared to the other two groups (Table 6). For the remaining 21 patients (9%) various other treatment strategies had been used without surgery. Most likely, these were patients who were medically inoperable or had an irresectable tumour and had a worse prognosis to start with. Most of these patients were treated with radiotherapy and hyperthermia alone (14 patients). In this group, local recurrence occurred in 13 patients. The median LRFI was 0.5 months and the median OS 10 months. Only six patients received chemotherapy alone (3%); three of them had progressive disease during treatment. The other three patients had a local recurrence after 2, 6 and 12 months. All six of them died of disease.
Table 4 Prognostics on local recurrence. Factor
Univariate HR (CI 95%)
p-Value
Age (yrs) Interval (yrs) Tumour size (cm) Tumour grade Inter versus low High versus low
1.02 (1.00–1.04) 0.93 (0.87–0.99) 1.09 (1.05–1.12)
(n = 208) (n = 208) (n = 142) (n = 94)
1.23 (0.60–2.53) 1.28 (0.67–2.47)
0.029 0.015 0.000 0.751 0.567 0.456 0.037 0.010 0.969
(n = 201)
0.46 (0.26–0.84) 0.99 (0.48–2.04)
Treatment S + RT versus S S + CT versus S
Multivariate (n = 128) HR (CI 95%) 1.02 (1.00–1.05) 0.94 (0.87–1.01) 1.07 (1.04–1.11)
p-Value 0.110 0.080 0.000
Abbreviations: HR = hazard ratio, CI 95% = confidence interval 95%, S = surgery, RT = radiotherapy ± hyperthermia, CT = chemotherapy, yrs = years, cm = centimetre, inter = intermediate, n = number of patients in analysis.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx Table 5 Prognostics on mortality. Factor
Age (yrs) Interval (yrs) Tumour size (cm) Tumour grade Inter versus Low High versus Low Treatment S + RT versus S S + CT versus S
Univariate
Multivariate (n = 121)
HR (CI 95%)
p-Value
HR (CI 95%)
1.03 (1.01–1.05) 0.92 (0.84–1.00) 1.09 (1.05–1.12)
(n = 201) (n = 201) (n = 135) (n = 87)
2.18 (0.71–6.70) 2.17 (0.74–6.43)
0.009 0.062 0.000 0.344 0.174 0.160 0.898 0.650 0.885
(n = 186)
0.87 (0.49–1.56) 0.93 (0.34–2.57)
1.03 (1.00–1.07) 0.92 (0.82–1.02) 1.07 (1.03–1.11)
p-Value 0.048 0.103 0.000
Abbreviations: HR = hazard ratio, CI 95% = confidence interval 95%, S = surgery, RT = radiotherapy ± hyperthermia, CT = chemotherapy, yrs = years, cm = centimetre, inter = intermediate, n = number of patients in analysis.
Fig. 2. Local control, surgery versus surgery + radiotherapy.
4. Discussion In this systematic review all case reports and smaller or larger series with sufficient published individual patient data of patients with RAAS from 1985 to 2013 are identified, leading to a cohort of 222 patients. In this cohort the overall prognosis, prognostic factors and the influence of treatment related factors of RAAS are studied, of course with the limitations of an observational review.
Our results indicate an overall survival of 43% at 5 years, consistent with the literature that was not included in this review (28–54%) [12,14]. The overall 5year LRFI was 32%. We found tumour size and age to be of prognostic value for LRFI. These results are in contrast with those of Torres et al., who found neither age, grade, margin status or tumour size prognostic for LRFI [14]. Though surgery is usually mentioned as standard treatment, we found a high, mostly local-, recurrence
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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Table 6 Characteristics per Treatment. Variable
Surgery (n = 150)
Surgery + RT (n = 37)
Median/distribution Age (yrs) Interval (yrs) Tumour size (cm)
69 6 4.5
Tumour grade
Low Inter High
Articles
CR: 49 RR: 10
n
Median/distribution
(36–91) (1–24) (0.3–20)
150 150 90
71 7 3.0
25% 29% 46%
84
Low Inter High
(65 pts) (85 pts)
–
CR: 1 RR: 5
Surgery + CT (n = 14) n
Median/distribution
(38–96) (4–18) (0.1–34)
23 23 26
67 7 4.0
0% 0% 100%
1
Low Inter High
(1 pt) (36 pts)
–
CR: 9 RR: 3
n
(49–85) (1–10) (1.2–15.0)
14 14 9
0% 33% 67%
6
(9 pts) (5 pts)
–
Abbreviations: n = number of patients the variable was known for, yrs = years, cm = centimetre, CR = case report, RR = retrospective review, inter = intermediate, RT = radiotherapy ± hyperthermia, CT = chemotherapy.
rate (65%) after this treatment, consistent with current literature [11,22]. Our results suggest that adding reirradiation to surgery improves the local control. This is an encouraging result, but it should be interpreted with caution, since bias could be part of the explanation. The most important forms of bias we need to take into account are selective publication and selective indication. Selective publication is plausible since we included a lot of case reports. Selective indication may take part because all studies were retrospective observations of patients or cohorts. As a result, the
groups were not 100% comparable. The surgery with radiotherapy group had a slightly better profile with smaller tumours and a larger interval (Table 6). This difference in prognostic profile might partly explain the difference in outcome between the two groups. We attempted a multivariate analysis taking the differences in prognostic factors into account, but that resulted in unreliable analyses because of too many missing data. In addition, the two groups we compared differed in size: the surgery only group was almost four times larger than the surgery + radiotherapy group. Finally, the
Fig. 3. Overall survival, surgery versus surgery + radiotherapy.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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follow-up in case reports was shorter, and since the surgery only group consisted of more case reports, median follow-up was twice as long in the surgery + radiotherapy group than in the surgery only group. Though we investigated a large set of patients (222), the level of evidence is at best level 3. Yet, no higher level of evidence has been published on RAAS. Comparing our results to other large studies on RAAS, that have not been included in our systematic review because they did not contain enough information on individual patients, we find similar outcomes as for our surgery only group (local recurrence rate (LRR) of 59% with a median LRFI of 12 months). A large study on RAAS in the Netherlands described 31 patients in a retrospective review, who all underwent surgical tumour resection [11]. The LRR in this study was 61%, with a median LRFI of 6 months. Another retrospective review on RAS treated with surgery – of which 12 angiosarcomas – found a LRR of 76%, with a median LRFI of 13 months [94]. Billings et al. found a LLR of 64% in a group of 22 patients treated with surgery alone [22]. In view of this consistently reported high local recurrence rate of surgery alone, and despite the above mentioned limitations, the observed improvement in local control from additional reirradiation needs further (preferably prospective) investigation. Some studies claim an effect of adding chemotherapy to surgery in the treatment of angiosarcomas [14,95]. Torres et al. published the largest study, a retrospective review on 95 patients with RAAS [14]. In this study 42% of the group was treated with surgery alone and 51% of the patients were treated with surgery and chemotherapy. The LRR for the whole group was 48%. A lower LRR was found for the group that received adjuvant chemotherapy. Our results do not support these claims (a hazard ratio around 1, not significant), but the number of patients receiving chemotherapy in addition to surgery in our cohort is very limited, and the patients were mainly derived from case reports. We cannot draw conclusions on patients treated without surgery, since these groups were too small and probably limited to patients with irresectable tumours or who were medically inoperable. In conclusion, the results from this review on 222 patients suggest that the addition of reirradiation to surgery might be of benefit for the local control of RAAS. However, this result warrants further investigation, preferably in a prospective setting. Conflict of interest statement None declared. References [1] Rubin R, Strayer DS. Blood vessels. In: Rubin’s pathology. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 425.
[2] Bardwil JM, Mocega EE, Butler JJ, Russin DJ. Angiosarcomas of the head and neck region. Am J Surg 1968;116:548–53. [3] Enzinger FM, Weiss SW. Soft tissue tumors. St. Louis: Mosby; 1995, p. 641–77. [4] North JH, McPhee M, Arredondo M, Edge SB. Sarcoma of the breast: implications of the extent of local therapy. Am Surg 1998;16:338–47. [5] Stewart TW, Treves N. Lymfeangiosarcoma in postmastectomy lymphedema. Cancer 1949;1:64. [6] Huang J, Mackillop WJ. Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 2001;92:171–80. [7] Cahan WG, Woodard HW, Higinbotham NL, Stewart FW, Coley BL. Sarcoma arising in irradiated bone: report of 11 cases. Cancer 1948;1:3–29. [8] The Netherlands Cancer Registry. http://www.ikcnet.nl/page.php?id=2896&nav_id=160 [Accessed July, 2010]. [9] Yap J, Chuba PJ, Thomas R, et al. Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 2002;52:1231–7. [10] Tomasini C, Grassi M, Pippione M. Cutaneous angiosarcoma arising in an irradiated breast. Case report and review of the literature. Dermatology 2004;209:208–14. [11] Seinen JM, Styring E, Verstappen V, et al. Radiation-associated angiosarcoma after breast cancer: high recurrence rate and poor survival despite surgical treatment with R0 resection. Ann Surg Oncol 2012;19:2700–6. [12] Fraga-Guedes C, Gobbi H, Mastropasqua MG, Botteri E, Luini A, Viale G. Primary and secondary angiosarcomas of the breast: a single institution experience. Breast Cancer Res Treat 2012;132:1081–8. [13] Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the breast. Cancer 2005;104:2682–8. [14] Torres KE, Ravi V, Kin K, et al. Long-term outcomes in patients with radiation-associated angiosarcomas of the breast following surgery and radiotherapy for breast cancer. Ann Surg Oncol 2013;20:1267–74. [15] Weiss SW, Golblum JR. Chapter 25. In: Soft tissue tumors. St. Louis: Mosby; 2001. [16] Jallali N, James S, Searle A, Ghattaura A, Hayes A, Harris P. Surgical management of radiation-induced angiosarcoma after breast conservation therapy. Am J Surg 2012;203:156–61. [17] Body G, Sauvanet E, Calais G, Fignon A, Fetissof F, Lansac J. Angiosarcome cutane´ de sein apre`s ade´nocarcinome mammaire ope´re´ et irradie´. J Gynecol Obstet Biol Reprod 1987;16:479–83. [18] Strobbe LJ, Peterse HL, van Tinteren H, Wijnmaalen A, Rutgers EJ. Angiosarcoma of the breast after conservation therapy for invasive cancer, the incidence and outcome. An unforseen sequela. Breast Cancer Res Treat 1998;47:101–9. [19] De Jong MA, Oldenborg S, Bing Oei S, et al. Reirradiation and hyperthermia for radiation-associated sarcoma. Cancer 2012;118:180–7. [20] Marchal C, Weber B, de Lafontan B, et al. Nine breast angiosarcomas after conservative treatment for breast carcinoma: a survey from French comprehensive cancer centers. Int J Radiat Oncol Biol Phys 1999;44:113–9. [21] Cha C, Antonescu CR, Quan ML, Mary S, Brennan MF. Longterm results with resection of radiation-induces soft tissue sarcomas. Ann Surg 2004;239:903–9. [22] Billings SD, Mckenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol 2004;28:781–8. [23] Thijssens KMJ, van Ginkel RJ, Suurmeijer AJH, et al. Radiationinduced sarcoma: a challenge for the surgeon. Ann Surg Oncol 2005;12:237–45. [24] Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol 1994;102:757–63.
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A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx [25] Catena F, Santini D, Di Saverio S, et al. Skin angiosarcoma arising in an irradiated breast: case-report and literature review. Dermatol Surg 2006;32:447–55. [26] Lamblin G, Oteifa M, Zinzindohoue C, Isaac S, Termine L, Bobin JY. Angiosarcoma after conservative treatment and radiation therapy for adenocarcinoma of the breast. Eur J Surg Oncol 2001;27:146–51. [27] Palta M, Morris CG, Grobmyer SR, Copeland EM, Mendenhall NP. Angiosarcoma after breast-conserving therapy: long-term outcomes with hyperfractionated radiotherapy. Cancer 2010;116:1872–8. [28] Feigenberg SJ, Mendenhall NP, Reith JD, Ward JR, Copeland EM. Angiosarcoma after breast-conserving therapy: experience with hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 2002;52:620–6. [29] Sener SF, Milos S, Feldman JL, et al. The spectrum of vascular lesions in the mammary skin, including angiosarcoma, after breast conservation treatment for breast cancer. J Am Coll Surg 2001;193:22–8. [30] Brenn T, Fletcher CDM. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol 2005;29:983–96. [31] Fodor J, Orosz Z, Szabo´ E, et al. Angiosarcoma after conservation treatment for breast carcinoma: our experience and a review of the literature. J Am Acad Dermatol 2006;54:499–504. [32] Rao J, DeKoven JG, Beatty JD, Jones G. Cutaneous angiosarcoma as a delayed complication of radiation therapy for carcinoma of the breast. J Am Acad Dermatol 2003;49:532–8. [33] Molitor JL, Spielmann M, Contesso G. Angiosarcoma of the breast after conservative surgery and radiation therapy for breast carcinoma: three new cases. Eur J Cancer 1996;32A:1820. [34] Anania G, Parodi PC, Sanna A, et al. Radiation-induced angiosarcoma of the breast: case report and self-criticism of therapeutic approach. Ann Chir 2002;127:388–91. [35] Aneiros-Fernandez J, Arias-Santiago S, Sotillo R, MenjonBeltran S, Concha A. A woman with reddish nodule on the skin of the breast. Dermatol Online J 2011;17:11. [36] Anzalone CL, Cohen PR, Diwan AH, Prieto VG. Radiationinduced angiosarcoma. Dermatol Online J 2013;19:2. [37] Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur J Dermatol 1999;9:118–21. [38] Baack T, Wenz F. Secondary cancers after radiotherapy may appear early and atypical. Strahlenther Onkol 2012;188:91–2 [author reply 92–3]. [39] Badwe RA, Hanby AM, Fentiman IS, Chaudary MA. Angiosarcoma of the skin overlying an irradiated breast. Breast Cancer Res Treat 1991;19:69–72. [40] Biswas T, Tang P, Muhs A, Ling M. Angiosarcoma of the breast: a rare clinicopathological entity. Am J Clin Oncol 2009;32:582–6. [41] Bolin DJ, Lukas GM. Low-grade dermal angiosarcoma of the breast following radiotherapy. Am Surg 1996;62:668–72. [42] Bonetta A, Pagliari C, Morrica B. Post-radiation angiosarcoma of the breast: a clinical case. Tumori 1995;81:219–21. [43] Buatti JM, Harari PM, Leigh BR, Cassady JR. Radiationinduced angiosarcoma of the breast. Case report and review of the literature. Am J Clin Oncol 1994;17:444–7. [44] Cafiero F, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: diagnostic and therapeutic implications – two case reports and a review of the literature. Cancer 1996;77:2496–502. [45] Chahin F, Paramesh A, Dwivedi A, et al. Angiosarcoma of the breast following breast preservation therapy and local radiation therapy for breast cancer. Breast J 2001;7:120–3. [46] Chiarelli A, Boccone P, Goia F, et al. Gingival metastasis of a radiotherapy-induced breast angiosarcoma: diagnosis and multidisciplinary treatment achieving a prolonged complete remission. Anticancer Drugs 2012;23:1112–7.
9
[47] Chuo CB, Corder AP. An unusual case of metastatic postirradiation breast sarcoma. Breast 2002;11:350–2. [48] Colville RJ, Ramsden A, Malcolm A, McLean NR. Angiosarcoma of the breast after quadrantectomy and postoperative radiotherapy for carcinoma. Br J Plast Surg 2000;53:622–4. [49] Cunha AL, Amendoeira I. High-grade breast epithelioid angiosarcoma secondary to radiotherapy metastasizing to the contralateral lymph node: unusual presentation and potential pitfall. Breast Care (Basel) 2011;6:227–9. [50] Cwikiel M, Stene-Hurtzen C, Albertsson M, Andersson T, Johansson-Terje I. Angiosarcoma as a sequela of breast cancer treatment with lumpectomy and radiotherapy. Breast 1997;6:307–9. [51] De Bree E, van Coevorden F, Peterse JL, Russell NS, Rutgers EJ. Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: genetic predisposition? Eur J Surg Oncol 2002;28:392–5. [52] De Giorgi V, Santi R, Grazzini M, et al. Synchronous angiosarcoma, melanoma and morphea of the breast skin 14 years after radiotherapy for mammary carcinoma. Acta Derm Venereol 2010;90:283–6. [53] Del Mastro L, Garrone O, Guenzi M, et al. Angiosarcoma of the residual breast after conservative surgery and radiotherapy for primary carcinoma. Ann Oncol 1994;5:163–5. [54] Deutsch M, Rosenstein MM. Angiosarcoma of the breast mimicking radiation dermatitis arising after lumpectomy and breast irradiation: a case report. Am J Clin Oncol 1998;21:608–9. [55] Deutsch M, Safyan E. Angiosarcoma of the breast occurring soon after lumpectomy and breast irradiation for infiltrating ductal carcinoma: a case report. Am J Clin Oncol 2003;26:471–2. [56] Esler-Brauer L, Jaggernauth W, Zeitouni NC. Angiosarcoma developing after conservative treatment for breast carcinoma: case report with review of the current literature. Dermatol Surg 2007;33:749–55. [57] Ferna´ndez Ortega A, Gil Gil JM, Urruticoetxea A, Serra Payro´ JM. Angiosarcoma of the breast. Two cases following breast conserving treatment for invasive carcinoma. Clin Transl Oncol 2006;8:536–9. [58] Gambini D, Visintin R, Locatelli E, et al. Paclitaxel-dependent prolonged and persistent complete remission four years from first recurrence of secondary breast angiosarcoma. Tumori 2009;95:828–31. [59] Hanasono MM, Osborne MP, Dielubanza EJ, Peters SB, Gayle LB. Radiation-induced angiosarcoma after mastectomy and TRAM flap breast reconstruction. Ann Plast Surg 2005;54:211–4. [60] Hildebrandt G, Mittag M, Gutz U, Kunze ML, Haustein UF. Cutaneous breast angiosarcoma after conserving treatment of breast cancer. Eur J Dermatol 2001;11:580–3. [61] Hoffmann G, Mylonas I. Therapy of radiation-induced angiosarcoma of the breast in an elderly patient. Arch Gynecol Obstet 2013;287:827–31. [62] Hogewind BF, Boutkan HB, de Jager-Nowak HK, Merkus JW. Angiosarcoma following breast-conserving therapy. Ned Tijdschr Geneesk 2004;148:995–7. [63] Iga N, Endo Y, Fujisawa A, et al. Two cases of cutaneous angiosarcoma developed after breast cancer surgery. Case Rep Dermatol 2012;4:247–9. [64] Kelly NP, Siziopikou K. Pathologic quiz case: a 68-year-old woman with bluish discoloration of the skin of the breast. Arch Pathol Lab Med 2002;126:989–90. [65] Kunkel T, Mylonas I, Mayr D, Friese K, Sommer HL. Recurrence of secondary angiosarcoma in a patient with post-radiated breast for breast cancer. Arch Gynecol Obstet 2008;278:497–501. [66] Lindford A, Bo¨hling T, Vaalavirta L, Tenhunen M, Jahkola T, Tukiainen E. Surgical management of radiation-associated cutaneous breast angiosarcoma. J Plast Reconstr Aesthet Surg 2011;64:1036–42.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx
[67] Linthorst M, van Geel AN, Baartman EA, et al. Effect of a combined surgery, re-irradiation and hyperthermia therapy on local control rate in radio-induced angiosarcoma of the chest wall. Strahlenther Onkol 2013;189:387–93. [68] Mano MS, Fraser G, Kerr J, et al. Radiation-induced angiosarcoma of the breast shows major response to docetaxel after failure of anthracycline-based chemotherapy. Breast 2006;15:117–8. [69] Mehta RS, Mikhail M. Post-irradiation cutaneous angiosarcoma. Cases J 2008;1:241. [70] Mills TD, Vinnicombe SJ, Wells CA, Carpenter R. Angiosarcoma of the breast after wide local excision and radiotherapy for breast carcinoma. Clin Radiol 2002;57:63–6. [71] Moe M, Bertelli G. Breast angiosarcoma following lumpectomy and radiotherapy for breast cancer: a case with short latent period and false negative result on biopsies. Ann Oncol 2007;18:801. [72] Moreno-Merlo F, Hanna W. Cutaneous angiosarcoma after breast-conserving surgery and radiotherapy. Breast J 1998;4:460–4. [73] Moskaluk CA, Merino MJ, Danforth DN, Medeiros LJ. Lowgrade angiosarcoma of the skin of the breast: a complication of lumpectomy and radiation therapy for breast carcinoma. Hum Pathol 1992;23:710–4. [74] Nakamura R, Nagashima T, Sakakibara M, et al. Angiosarcoma arising in the breast following breast-conserving surgery with radiation for breast carcinoma. Breast Cancer 2007;14:245–9. [75] Otis CN, Peschel R, McKhann C, Merino MJ, Duray PH. The rapid onset of cutaneous angiosarcoma after radiotherapy for breast carcinoma. Cancer 1986;57:2130–4. [76] Provencio M, Bonilla F, Espana P. Breast angiosarcoma after radiation therapy. Acta Oncol 1995;34:969. [77] Raina V, Sengar M, Shukla NK, et al. Complete response from thalidomide in angiosarcoma after treatment of breast cancer. J Clin Oncol 2007;25:900–1. [78] Roncadin M, Massarut S, Perin T, et al. Breast angiosarcoma after conservative surgery, radiotherapy and prosthesis implant. Acta Oncol 1998;37:209–11. [79] Roukema JA, Leenen LP, Kuizinga MC, Maat B. Angiosarcoma of the irradiated breast: a new problem after breast conserving therapy? Neth J Surg 1991;43:114–6. [80] Scott MT, Portnow LH, Morris CG, et al. Radiation therapy for angiosarcoma: the 35-year University of Florida experience. Am J Clin Oncol 2013;36:174–80. [81] Shaikh NA, Beaconsfield T, Walker M, Ghilchik MW. Postirradiation angiosarcoma of the breast: a case report. Eur J Clin Oncol 1988;14:449–51.
[82] Shrestha DB, Ravichandran D, Pittam M. Discolouration of breast skin following breast conservation therapy for breast cancer: a cautionary tale of two patients. Int J Clin Pract 2010;64:112–3. [83] Taat CW, van Toor BS, Slors JF, Bras J, Blank LE, van Coevorden F. Dermal angiosarcoma of the breast: a complication of primary radiotherapy? Eur J Clin Oncol 1992;18:391–5. [84] Tahir M, Hendry P, Baird L, Qureshi NA, Ritchie D, Whitford P. Radiation-induced angiosarcoma following conservative surgery for lobular breast cancer. Breast J 2008;14:390–1. [85] Timmer SJ, Osuch JR, Colony LH, Edminster RR, Gayar H, Igram R. Angiosarcoma of the breast following lumpectomy and radiation therapy for breast carcinoma: case report and review of the literature. Breast J 1997;3:40–7. [86] Tomasello L, Gardin G, Boccardo F. Secondary breast angiosarcoma: lethal response to anti-angiogenic therapy with paclitaxel chemotherapy. A case report. Anticancer Res 2006;26:4775–7. [87] Weber B, Marchal C. Three cases of breast angiosarcomas after breast-conserving treatment for carcinoma. Radiother Oncol 1995;37:1063–4. [88] West J, Liao SY, Cho D. Angiosarcoma after breast conservation: diagnostic pitfalls. Clin Breast Cancer 2008;8:94–6. [89] Williams EV, Banerjee D, Dallimore N, Monypenny IJ. Angiosarcoma of the breast following radiation therapy. Eur J Surg Oncol 1999;25:221–2. [90] Williams SB, Wyld L, Reed M. Cutaneous angiosarcoma after breast conserving treatment for bilateral breast cancers in a BRCA-1 gene mutation carrier: a case report and review of the literature. Surgeon 2009;7:250. [91] Yim KL. Secondary angiosarcoma occurring after conservative treatment for breast adenocarcinoma. Ann Oncol 2009;20:14–5. [92] Zucali R, Merson M, Placucci M, Di Palma S, Veronesi U. Soft tissue sarcoma of the breast after conservative surgery and irradiation for early mammary cancer. Radiother Oncol 1994;30:271–3. [93] Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Ann Intern Med 2009;151. [94] Blanchard DK, Reynolds C, Grant CS, Farley DR, Donohue JH. Radiation-induced breast sarcoma. Am J Surg 2002;184:356–8. [95] Fury MG, Antonescu CR, Van Zee KJ, Brennan MF, Maki RG. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J 2005;11:241–7.
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Review
Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review A.L. Depla a, C.H. Scharloo-Karels a, M.A.A. de Jong a, S. Oldenborg a, M.W. Kolff a, S.B. Oei b, F. van Coevorden c, G.C. van Rhoon d, E.A. Baartman d, R.J. Scholten e, J. Crezee a, G. van Tienhoven a,⇑ a
Academic Medical Center, Department of Radiation Oncology and Hyperthermia, Amsterdam, The Netherlands Department of Radiation Oncology and Hyperthermia, Institute Verbeeten, Tilburg, The Netherlands c Department of Surgery, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands d Department of Radiation Oncology, Hyperthermia Unit, Erasmus MC-Cancer Institute, Rotterdam, The Netherlands e Dutch Cochrane Center, Utrecht, The Netherlands b
Received 29 January 2014; received in revised form 28 February 2014; accepted 1 March 2014
KEYWORDS Breast cancer Radiation-induced angiosarcoma Surgery Radiotherapy Local control
Abstract Background: Radiation-associated angiosarcoma (RAAS) of the breast is a rare, aggressive disease. The incidence is increasing with the prolonged survival of women irradiated for primary breast cancer. Surgery is the current treatment of choice. Prognosis is poor. This review aims to evaluate all publications on primary treatment of RAAS to identify prognostic factors and evaluate treatment modalities. Methods: Databases were searched for articles with published individual patient data on prognostic factors, treatment and follow-up of patients with RAAS. A regression analysis was performed to test the prognostic values of age, interval between primary treatment and RAAS, tumour size and grade on the local recurrence-free interval (LRFI) and overall survival (OS). The effects of treatment modalities surgery, radiation (with or without hyperthermia) and chemotherapy or combinations were evaluated. Results: 74 articles were included, representing data on 222 patients. In these patients, the 5year OS was 43% and 5-year LRFI was 32%. Tumour size and age were significant prognostic factors on LRFI and OS. Of all patients, 68% received surgery alone, 17% surgery and reirradiation and 6% surgery with chemotherapy. The remaining 9% received primary treatments
⇑ Corresponding author: Address: Academic Medical Center, Department of Radiation Oncology and Hyperthermia, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Fax: +31 20 6091278. E-mail address: [email protected] (G. van Tienhoven).
http://dx.doi.org/10.1016/j.ejca.2014.03.002 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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without surgery. Surgery with radiotherapy had a better 5-year LRFI of 57% compared to 34% for surgery alone (p = 0.008). The value of other treatment modalities could not be assessed. Conclusions: This systematic review confirms the poor prognosis of RAAS. Tumour size and age were of prognostic value. The addition of reirradiation to surgery in the treatment of RAAS appears to enhance local control. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Angiosarcomas are rare, highly malignant tumours of endothelial cells. They occur most commonly in elderly people, on the face or scalp. The breast is the third most common location [1]. Overall, less than 1% of all soft tissue sarcomas are angiosarcomas [2]. Primary angiosarcoma of the breast is very rare; it accounts for only 1 per 1700–2000 primary breast tumours [3], but in the breast it is one of the most common sarcomas [4]. Secondary angiosarcomas of the breast or chestwall are associated with two presumed aetiologic factors: chronic lymphedema after a mastectomy with lymph node dissection – Stewart–Treves syndrome – and radiotherapy, for which a relative risk of 15.9 was found [5,6]. Often it is hard to define the difference in aetiology, because chronic lymphedema and breast cancer treatment, including radiation, are often inter related. Angiosarcomas secondary to radiotherapy are part of a larger group of radiation-associated sarcomas (RAS). RAS is defined by three characteristics: a sarcoma in the previous field of radiation, a latency period of at least 3 years and a histological distinction from the primary neoplasm [7]. Radiation-associated angiosarcoma (RAAS) is the most common kind of RAS in the breast region [6]. In the Netherlands Cancer Registry 181/321 RAS were located in the chest region, of which 56% were angiosarcomas [8]. The cumulative incidence of RAAS, fifteen years after radiotherapy for breast cancer, is 0.9 per 1000 cases [9]. This incidence is low, but likely to increase since women with breast carcinomas have a gradually improving prognosis and radiotherapy is used more often in their treatment. In addition the increasing use of intensity modulated radiation therapy (IMRT) might lead to a higher chance of tumour induction. With the prolonged survival, the long-term effects of the treatment – including RAAS – will occur more frequently. The reported median latency period between radiation and diagnosis of RAAS is 6–7 years [10]. The tumours often present with a blue/red discoloration of the skin, which may be considered as bruises after a light trauma [11]. Due to the long latency period, the seemingly harmless presentation and the rarity of the tumour, recognition by both patient and physician is often delayed. The prognosis of the RAAS is poor; the 5-year survival rates vary from 28% to 54% [12–14]. Currently,
surgery is considered to be the treatment of choice [15], but the outcome is poor because of high local recurrence rates (54–92%) [11,16]. Due to the rarity of this tumour, other treatment options or – combinations are not yet well investigated. The current systematic review of the literature aims to identify patients in all publications on RAAS and its treatment. With the published individual-patient data, from these studies, the intention is to examine prognostic factors and compare the local control as well as the overall survival after different treatments or combinations of treatment. With this information, hypotheses may be created for future, prospective, studies on the treatment of RAAS. 2. Methods 2.1. Search strategy For this systematic review, a comprehensive literature search has been performed in MEDLINEÒ (via PubMed) and Embase in April 2013. Search strategy and methods of data analysis were determined before the start of the study. All searches were limited to the English language and limited to publication dates from 1985, because the first radiation-associated angiosarcoma was described in 1987 [17,18]. The search strategies are presented in the appendix. The results of both searches were combined and duplicates were removed. To assess whether the search had not missed any relevant articles, a validation set was composed of ten relevant articles, which we had already identified in another study [19]. These ten articles were then complemented with five other relevant articles that were identified via Google Scholar by the use of the references of the first ten articles. Using this method, a validation set of 15 articles was built [10,20–33] and we assessed whether the performed search included those 15 articles. 2.2. Selection criteria Selection of the articles was done using the following selection criteria: – Angiosarcoma of the thorax region. – Radiation-associated: angiosarcoma after radiation for primary breast cancer.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
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– Therapy for RAAS and local recurrence after treatment were described in detail. – These data could be extracted from the articles on an individual patient level.
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One reviewer (A.D.) performed the first round of selection by title. Further selection of the articles on abstract and whole article, was done by two reviewers (A.D. and G.T.). Since RAAS of the breast is such a rare tumour, and all articles were case histories or relatively small observational series, no selection criteria were set for the level of evidence of the articles.
All groups in which surgery was used – with or without another treatment modality – were also analysed in a univariate regression, since these groups allow comparison. A second multivariate analysis correcting the various treatments for the prognostic factors was intended, but appeared not to be possible due to too many missing values. Kaplan–Meier curves were calculated to visualise the treatment effects on OS and LRFI. The Log-Rank test was used to assess any differences between treatments. A p-value of less than 0.05 was considered significant. All tests were performed using SPSS20.
2.3. Data extraction
3. Results
The following individual patient data were extracted from the articles per patient:
3.1. Literature search
– Age (years): age of patient at time of diagnosis of RAAS. – Interval (years): time between radiotherapy for primary breast cancer and the diagnosis of RAAS. – Tumour size (cm). – Tumour grade (high/intermediate/low): grade of malignancy of the angiosarcoma. – Primary treatment RAAS (surgery, radiotherapy, chemotherapy, hyperthermia or combinations). – First recurrence (no/local/regional/distant) after treatment for RAAS. – Time to local/regional and/or distant recurrence (months). – Time to death or last follow-up (months). – Follow-up status: no evidence of disease/alive with disease/death of angiosarcoma/death of intercurrent disease.
After having removed duplicates the search resulted in 779 potentially eligible articles. Of those, 74 were included [10,17,19,20,23–92]. The PRISMA (Preferred Reporting Items of Systematic reviews and Meta-Analyses) based study flow of the searches is presented in Fig. 1 [93]. Overall, 12 retrospective series of patients with RAAS were found, of which the smallest described five patients and the largest 24. The other 62 papers were case reports describing one to four patients. Nine patients described in four case reports were reported double and the duplicates were removed. Total number of patients included for further analysis was 222, of whom 80 were described in case reports and 142 in retrospective case series. In the retrospective case series, median follow-up was about twice as long as in the case reports. 3.2. Patient characteristics
Details on radiation dose were not assessed since these were only available in the minority of patients. After obtaining these published individual patient data, the set was checked for double reporting of cases by comparing age and interval between primary breast cancer and RAAS. Double reported cases were removed from the dataset. 2.4. Data analysis All data obtained from the articles were listed in a database. Patient and tumour characteristics as well as outcome parameters for the whole cohort were analysed. Univariate regression analysis of the potential prognostic significance for overall survival (OS) and local recurrence-free interval (LRFI) was performed for the variables age, interval between breast cancer and RAAS, tumour size and tumour grade. The variables that appeared to have a significant effect were subsequently tested in a multivariate model.
Not every variable was described for all patients; in particular tumour grade was missing for more than half of the patients (Table 1). The majority of patients (201, 91%) was treated with surgery (Table 2). Surgery alone, was performed as primary treatment for RAAS in 150 patients (68%). Of those, 129 patients had received mastectomy (86%), 14 patients ‘wide excision’ (9%) and seven patients ‘excision’ (5%). Surgery combined with reirradiation was performed in 37 patients (17%). Of those, mastectomy was used as surgical treatment in all, but one patient who underwent tumour excision. In this group, surgery with reirradiation was included as well as surgery combined with reirradiation and hyperthermia. Hyperthermia was given in addition to radiotherapy in 11 patients (30%). One study with eight patients used hyperfractionated and accelerated radiotherapy (HART) combined with surgery [27]. Radiotherapy was given either before
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Fig. 1. Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) flow diagram.
Table 1 Patient characteristics. Variable
n
Age (yrs) Interval (yrs) Tumour size (cm) Tumour grade
208 208 142 94
Median (min–max)/distribution
Low: 22%
69 (36–96) 6 (1–24) 4.5 (0.1–34) Intermediate: 28%
High: 50%
Abbreviations: n = number of patients the variable was known for, yrs = years, cm = centimetre, min = minimum, max = maximum.
(30%) or after surgery (70%). Surgery combined with chemotherapy was performed in 14 patients (6%) The remaining patients were treated with radiotherapy and hyperthermia alone (6%). or received just chemotherapy (3%). 3.3. Treatment results Data on outcome parameters were obtained for almost all patients (Table 3). Irrespective of the type of treatment received, the 5-year OS was 43% and the 5-year LRFI 32%. Of the 144 (65%) recurrences, 131 (90%) were
local. Two patients experienced a regional recurrence. Only 3% of the patients died of intercurrent disease. 3.4. Prognostic factors and treatment results Interval between breast cancer and RAAS, tumour size and age were significant prognostic factors for local recurrence (hazard ratio (HR) 0.93, 1.09 and 1.02, respectively) and mortality (HR 0.92, 1.09 and 1.03, respectively) in univariate analysis (Tables 4 and 5). The prognostic impact of grade of the tumour was not found to be significant, probably because of the high
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Table 2 Treatments. Treatment
Number of patients per treatment n (%)
Patients from retrospective reviews n (number of studies)
Patients from case reports n (number of studies)
SUR SUR + RT (±HT) SUR + CT RT (±HT) CT SUR + CT + RT
150 (68%) 37 (17%) 14 (6%) 14 (6%) 6 (3%) 1 (0.5%)
85 36 5 14 1 1
(10) (5) (3) (3) (1) (1)
65 1 9 0 5 0
(48) (1) (9)
Total
222 (100%)
142
(12)
80
(65)
(5)
Abbreviations: SUR = surgery, RT = radiotherapy, HT = hyperthermia, CT = chemotherapy, n = number of patients.
Table 3 Outcome. Variable
n
Outcome
Site of first recurrence
222
No Local Distant
5-year LRFI 5-year OS Follow-up status
222 222 215
Alive Died
35% 59% 6% 32% 43% 58% 42%
Abbreviations: n = number of patients the variable was known for, LRFI = local recurrence-free interval, OS = overall survival.
number of missing values for this variable (Table 1). In multivariate analysis tumour size was the main prognostic factor, both for local control and overall survival and age remained prognostic for overall survival. Univariate analysis of the three surgery groups showed the following: median follow-up for all patients alive at the end of follow-up after surgery only was 24 months, for surgery with radiotherapy it was 52 months and for surgery with chemotherapy 16 months. A significant effect of adding radiotherapy to surgery on LRFI was found (HR 0.46) and no difference with respect to OS (HR 0.99) (Tables 4 and 5; Figs. 2 and 3). For surgery only we found a recurrence rate of
65%, of which 91% were local. For surgery with radiotherapy the recurrence rate was 51%, of which 68% local. So local recurrence rates were 59% and 35% respectively. Median LRFI for surgery was 12 months, the median LFRI was not reached for surgery + radiotherapy. The 5-year LRFI was 34% and 57%, respectively (Fig. 2). The group that received surgery with chemotherapy showed no significant difference compared to surgery alone, neither for LRFI, nor for OS (Tables 4 and 5). Multivariate analysis with correction for prognostic factors was attempted, but appeared unreliable due to too many missing values. The prognostic factors were slightly better in the surgery with radiotherapy group compared to the other two groups (Table 6). For the remaining 21 patients (9%) various other treatment strategies had been used without surgery. Most likely, these were patients who were medically inoperable or had an irresectable tumour and had a worse prognosis to start with. Most of these patients were treated with radiotherapy and hyperthermia alone (14 patients). In this group, local recurrence occurred in 13 patients. The median LRFI was 0.5 months and the median OS 10 months. Only six patients received chemotherapy alone (3%); three of them had progressive disease during treatment. The other three patients had a local recurrence after 2, 6 and 12 months. All six of them died of disease.
Table 4 Prognostics on local recurrence. Factor
Univariate HR (CI 95%)
p-Value
Age (yrs) Interval (yrs) Tumour size (cm) Tumour grade Inter versus low High versus low
1.02 (1.00–1.04) 0.93 (0.87–0.99) 1.09 (1.05–1.12)
(n = 208) (n = 208) (n = 142) (n = 94)
1.23 (0.60–2.53) 1.28 (0.67–2.47)
0.029 0.015 0.000 0.751 0.567 0.456 0.037 0.010 0.969
(n = 201)
0.46 (0.26–0.84) 0.99 (0.48–2.04)
Treatment S + RT versus S S + CT versus S
Multivariate (n = 128) HR (CI 95%) 1.02 (1.00–1.05) 0.94 (0.87–1.01) 1.07 (1.04–1.11)
p-Value 0.110 0.080 0.000
Abbreviations: HR = hazard ratio, CI 95% = confidence interval 95%, S = surgery, RT = radiotherapy ± hyperthermia, CT = chemotherapy, yrs = years, cm = centimetre, inter = intermediate, n = number of patients in analysis.
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A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx Table 5 Prognostics on mortality. Factor
Age (yrs) Interval (yrs) Tumour size (cm) Tumour grade Inter versus Low High versus Low Treatment S + RT versus S S + CT versus S
Univariate
Multivariate (n = 121)
HR (CI 95%)
p-Value
HR (CI 95%)
1.03 (1.01–1.05) 0.92 (0.84–1.00) 1.09 (1.05–1.12)
(n = 201) (n = 201) (n = 135) (n = 87)
2.18 (0.71–6.70) 2.17 (0.74–6.43)
0.009 0.062 0.000 0.344 0.174 0.160 0.898 0.650 0.885
(n = 186)
0.87 (0.49–1.56) 0.93 (0.34–2.57)
1.03 (1.00–1.07) 0.92 (0.82–1.02) 1.07 (1.03–1.11)
p-Value 0.048 0.103 0.000
Abbreviations: HR = hazard ratio, CI 95% = confidence interval 95%, S = surgery, RT = radiotherapy ± hyperthermia, CT = chemotherapy, yrs = years, cm = centimetre, inter = intermediate, n = number of patients in analysis.
Fig. 2. Local control, surgery versus surgery + radiotherapy.
4. Discussion In this systematic review all case reports and smaller or larger series with sufficient published individual patient data of patients with RAAS from 1985 to 2013 are identified, leading to a cohort of 222 patients. In this cohort the overall prognosis, prognostic factors and the influence of treatment related factors of RAAS are studied, of course with the limitations of an observational review.
Our results indicate an overall survival of 43% at 5 years, consistent with the literature that was not included in this review (28–54%) [12,14]. The overall 5year LRFI was 32%. We found tumour size and age to be of prognostic value for LRFI. These results are in contrast with those of Torres et al., who found neither age, grade, margin status or tumour size prognostic for LRFI [14]. Though surgery is usually mentioned as standard treatment, we found a high, mostly local-, recurrence
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Table 6 Characteristics per Treatment. Variable
Surgery (n = 150)
Surgery + RT (n = 37)
Median/distribution Age (yrs) Interval (yrs) Tumour size (cm)
69 6 4.5
Tumour grade
Low Inter High
Articles
CR: 49 RR: 10
n
Median/distribution
(36–91) (1–24) (0.3–20)
150 150 90
71 7 3.0
25% 29% 46%
84
Low Inter High
(65 pts) (85 pts)
–
CR: 1 RR: 5
Surgery + CT (n = 14) n
Median/distribution
(38–96) (4–18) (0.1–34)
23 23 26
67 7 4.0
0% 0% 100%
1
Low Inter High
(1 pt) (36 pts)
–
CR: 9 RR: 3
n
(49–85) (1–10) (1.2–15.0)
14 14 9
0% 33% 67%
6
(9 pts) (5 pts)
–
Abbreviations: n = number of patients the variable was known for, yrs = years, cm = centimetre, CR = case report, RR = retrospective review, inter = intermediate, RT = radiotherapy ± hyperthermia, CT = chemotherapy.
rate (65%) after this treatment, consistent with current literature [11,22]. Our results suggest that adding reirradiation to surgery improves the local control. This is an encouraging result, but it should be interpreted with caution, since bias could be part of the explanation. The most important forms of bias we need to take into account are selective publication and selective indication. Selective publication is plausible since we included a lot of case reports. Selective indication may take part because all studies were retrospective observations of patients or cohorts. As a result, the
groups were not 100% comparable. The surgery with radiotherapy group had a slightly better profile with smaller tumours and a larger interval (Table 6). This difference in prognostic profile might partly explain the difference in outcome between the two groups. We attempted a multivariate analysis taking the differences in prognostic factors into account, but that resulted in unreliable analyses because of too many missing data. In addition, the two groups we compared differed in size: the surgery only group was almost four times larger than the surgery + radiotherapy group. Finally, the
Fig. 3. Overall survival, surgery versus surgery + radiotherapy.
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A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx
follow-up in case reports was shorter, and since the surgery only group consisted of more case reports, median follow-up was twice as long in the surgery + radiotherapy group than in the surgery only group. Though we investigated a large set of patients (222), the level of evidence is at best level 3. Yet, no higher level of evidence has been published on RAAS. Comparing our results to other large studies on RAAS, that have not been included in our systematic review because they did not contain enough information on individual patients, we find similar outcomes as for our surgery only group (local recurrence rate (LRR) of 59% with a median LRFI of 12 months). A large study on RAAS in the Netherlands described 31 patients in a retrospective review, who all underwent surgical tumour resection [11]. The LRR in this study was 61%, with a median LRFI of 6 months. Another retrospective review on RAS treated with surgery – of which 12 angiosarcomas – found a LRR of 76%, with a median LRFI of 13 months [94]. Billings et al. found a LLR of 64% in a group of 22 patients treated with surgery alone [22]. In view of this consistently reported high local recurrence rate of surgery alone, and despite the above mentioned limitations, the observed improvement in local control from additional reirradiation needs further (preferably prospective) investigation. Some studies claim an effect of adding chemotherapy to surgery in the treatment of angiosarcomas [14,95]. Torres et al. published the largest study, a retrospective review on 95 patients with RAAS [14]. In this study 42% of the group was treated with surgery alone and 51% of the patients were treated with surgery and chemotherapy. The LRR for the whole group was 48%. A lower LRR was found for the group that received adjuvant chemotherapy. Our results do not support these claims (a hazard ratio around 1, not significant), but the number of patients receiving chemotherapy in addition to surgery in our cohort is very limited, and the patients were mainly derived from case reports. We cannot draw conclusions on patients treated without surgery, since these groups were too small and probably limited to patients with irresectable tumours or who were medically inoperable. In conclusion, the results from this review on 222 patients suggest that the addition of reirradiation to surgery might be of benefit for the local control of RAAS. However, this result warrants further investigation, preferably in a prospective setting. Conflict of interest statement None declared. References [1] Rubin R, Strayer DS. Blood vessels. In: Rubin’s pathology. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 425.
[2] Bardwil JM, Mocega EE, Butler JJ, Russin DJ. Angiosarcomas of the head and neck region. Am J Surg 1968;116:548–53. [3] Enzinger FM, Weiss SW. Soft tissue tumors. St. Louis: Mosby; 1995, p. 641–77. [4] North JH, McPhee M, Arredondo M, Edge SB. Sarcoma of the breast: implications of the extent of local therapy. Am Surg 1998;16:338–47. [5] Stewart TW, Treves N. Lymfeangiosarcoma in postmastectomy lymphedema. Cancer 1949;1:64. [6] Huang J, Mackillop WJ. Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 2001;92:171–80. [7] Cahan WG, Woodard HW, Higinbotham NL, Stewart FW, Coley BL. Sarcoma arising in irradiated bone: report of 11 cases. Cancer 1948;1:3–29. [8] The Netherlands Cancer Registry. http://www.ikcnet.nl/page.php?id=2896&nav_id=160 [Accessed July, 2010]. [9] Yap J, Chuba PJ, Thomas R, et al. Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 2002;52:1231–7. [10] Tomasini C, Grassi M, Pippione M. Cutaneous angiosarcoma arising in an irradiated breast. Case report and review of the literature. Dermatology 2004;209:208–14. [11] Seinen JM, Styring E, Verstappen V, et al. Radiation-associated angiosarcoma after breast cancer: high recurrence rate and poor survival despite surgical treatment with R0 resection. Ann Surg Oncol 2012;19:2700–6. [12] Fraga-Guedes C, Gobbi H, Mastropasqua MG, Botteri E, Luini A, Viale G. Primary and secondary angiosarcomas of the breast: a single institution experience. Breast Cancer Res Treat 2012;132:1081–8. [13] Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the breast. Cancer 2005;104:2682–8. [14] Torres KE, Ravi V, Kin K, et al. Long-term outcomes in patients with radiation-associated angiosarcomas of the breast following surgery and radiotherapy for breast cancer. Ann Surg Oncol 2013;20:1267–74. [15] Weiss SW, Golblum JR. Chapter 25. In: Soft tissue tumors. St. Louis: Mosby; 2001. [16] Jallali N, James S, Searle A, Ghattaura A, Hayes A, Harris P. Surgical management of radiation-induced angiosarcoma after breast conservation therapy. Am J Surg 2012;203:156–61. [17] Body G, Sauvanet E, Calais G, Fignon A, Fetissof F, Lansac J. Angiosarcome cutane´ de sein apre`s ade´nocarcinome mammaire ope´re´ et irradie´. J Gynecol Obstet Biol Reprod 1987;16:479–83. [18] Strobbe LJ, Peterse HL, van Tinteren H, Wijnmaalen A, Rutgers EJ. Angiosarcoma of the breast after conservation therapy for invasive cancer, the incidence and outcome. An unforseen sequela. Breast Cancer Res Treat 1998;47:101–9. [19] De Jong MA, Oldenborg S, Bing Oei S, et al. Reirradiation and hyperthermia for radiation-associated sarcoma. Cancer 2012;118:180–7. [20] Marchal C, Weber B, de Lafontan B, et al. Nine breast angiosarcomas after conservative treatment for breast carcinoma: a survey from French comprehensive cancer centers. Int J Radiat Oncol Biol Phys 1999;44:113–9. [21] Cha C, Antonescu CR, Quan ML, Mary S, Brennan MF. Longterm results with resection of radiation-induces soft tissue sarcomas. Ann Surg 2004;239:903–9. [22] Billings SD, Mckenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol 2004;28:781–8. [23] Thijssens KMJ, van Ginkel RJ, Suurmeijer AJH, et al. Radiationinduced sarcoma: a challenge for the surgeon. Ann Surg Oncol 2005;12:237–45. [24] Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol 1994;102:757–63.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
A.L. Depla et al. / European Journal of Cancer xxx (2014) xxx–xxx [25] Catena F, Santini D, Di Saverio S, et al. Skin angiosarcoma arising in an irradiated breast: case-report and literature review. Dermatol Surg 2006;32:447–55. [26] Lamblin G, Oteifa M, Zinzindohoue C, Isaac S, Termine L, Bobin JY. Angiosarcoma after conservative treatment and radiation therapy for adenocarcinoma of the breast. Eur J Surg Oncol 2001;27:146–51. [27] Palta M, Morris CG, Grobmyer SR, Copeland EM, Mendenhall NP. Angiosarcoma after breast-conserving therapy: long-term outcomes with hyperfractionated radiotherapy. Cancer 2010;116:1872–8. [28] Feigenberg SJ, Mendenhall NP, Reith JD, Ward JR, Copeland EM. Angiosarcoma after breast-conserving therapy: experience with hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 2002;52:620–6. [29] Sener SF, Milos S, Feldman JL, et al. The spectrum of vascular lesions in the mammary skin, including angiosarcoma, after breast conservation treatment for breast cancer. J Am Coll Surg 2001;193:22–8. [30] Brenn T, Fletcher CDM. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol 2005;29:983–96. [31] Fodor J, Orosz Z, Szabo´ E, et al. Angiosarcoma after conservation treatment for breast carcinoma: our experience and a review of the literature. J Am Acad Dermatol 2006;54:499–504. [32] Rao J, DeKoven JG, Beatty JD, Jones G. Cutaneous angiosarcoma as a delayed complication of radiation therapy for carcinoma of the breast. J Am Acad Dermatol 2003;49:532–8. [33] Molitor JL, Spielmann M, Contesso G. Angiosarcoma of the breast after conservative surgery and radiation therapy for breast carcinoma: three new cases. Eur J Cancer 1996;32A:1820. [34] Anania G, Parodi PC, Sanna A, et al. Radiation-induced angiosarcoma of the breast: case report and self-criticism of therapeutic approach. Ann Chir 2002;127:388–91. [35] Aneiros-Fernandez J, Arias-Santiago S, Sotillo R, MenjonBeltran S, Concha A. A woman with reddish nodule on the skin of the breast. Dermatol Online J 2011;17:11. [36] Anzalone CL, Cohen PR, Diwan AH, Prieto VG. Radiationinduced angiosarcoma. Dermatol Online J 2013;19:2. [37] Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur J Dermatol 1999;9:118–21. [38] Baack T, Wenz F. Secondary cancers after radiotherapy may appear early and atypical. Strahlenther Onkol 2012;188:91–2 [author reply 92–3]. [39] Badwe RA, Hanby AM, Fentiman IS, Chaudary MA. Angiosarcoma of the skin overlying an irradiated breast. Breast Cancer Res Treat 1991;19:69–72. [40] Biswas T, Tang P, Muhs A, Ling M. Angiosarcoma of the breast: a rare clinicopathological entity. Am J Clin Oncol 2009;32:582–6. [41] Bolin DJ, Lukas GM. Low-grade dermal angiosarcoma of the breast following radiotherapy. Am Surg 1996;62:668–72. [42] Bonetta A, Pagliari C, Morrica B. Post-radiation angiosarcoma of the breast: a clinical case. Tumori 1995;81:219–21. [43] Buatti JM, Harari PM, Leigh BR, Cassady JR. Radiationinduced angiosarcoma of the breast. Case report and review of the literature. Am J Clin Oncol 1994;17:444–7. [44] Cafiero F, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: diagnostic and therapeutic implications – two case reports and a review of the literature. Cancer 1996;77:2496–502. [45] Chahin F, Paramesh A, Dwivedi A, et al. Angiosarcoma of the breast following breast preservation therapy and local radiation therapy for breast cancer. Breast J 2001;7:120–3. [46] Chiarelli A, Boccone P, Goia F, et al. Gingival metastasis of a radiotherapy-induced breast angiosarcoma: diagnosis and multidisciplinary treatment achieving a prolonged complete remission. Anticancer Drugs 2012;23:1112–7.
9
[47] Chuo CB, Corder AP. An unusual case of metastatic postirradiation breast sarcoma. Breast 2002;11:350–2. [48] Colville RJ, Ramsden A, Malcolm A, McLean NR. Angiosarcoma of the breast after quadrantectomy and postoperative radiotherapy for carcinoma. Br J Plast Surg 2000;53:622–4. [49] Cunha AL, Amendoeira I. High-grade breast epithelioid angiosarcoma secondary to radiotherapy metastasizing to the contralateral lymph node: unusual presentation and potential pitfall. Breast Care (Basel) 2011;6:227–9. [50] Cwikiel M, Stene-Hurtzen C, Albertsson M, Andersson T, Johansson-Terje I. Angiosarcoma as a sequela of breast cancer treatment with lumpectomy and radiotherapy. Breast 1997;6:307–9. [51] De Bree E, van Coevorden F, Peterse JL, Russell NS, Rutgers EJ. Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: genetic predisposition? Eur J Surg Oncol 2002;28:392–5. [52] De Giorgi V, Santi R, Grazzini M, et al. Synchronous angiosarcoma, melanoma and morphea of the breast skin 14 years after radiotherapy for mammary carcinoma. Acta Derm Venereol 2010;90:283–6. [53] Del Mastro L, Garrone O, Guenzi M, et al. Angiosarcoma of the residual breast after conservative surgery and radiotherapy for primary carcinoma. Ann Oncol 1994;5:163–5. [54] Deutsch M, Rosenstein MM. Angiosarcoma of the breast mimicking radiation dermatitis arising after lumpectomy and breast irradiation: a case report. Am J Clin Oncol 1998;21:608–9. [55] Deutsch M, Safyan E. Angiosarcoma of the breast occurring soon after lumpectomy and breast irradiation for infiltrating ductal carcinoma: a case report. Am J Clin Oncol 2003;26:471–2. [56] Esler-Brauer L, Jaggernauth W, Zeitouni NC. Angiosarcoma developing after conservative treatment for breast carcinoma: case report with review of the current literature. Dermatol Surg 2007;33:749–55. [57] Ferna´ndez Ortega A, Gil Gil JM, Urruticoetxea A, Serra Payro´ JM. Angiosarcoma of the breast. Two cases following breast conserving treatment for invasive carcinoma. Clin Transl Oncol 2006;8:536–9. [58] Gambini D, Visintin R, Locatelli E, et al. Paclitaxel-dependent prolonged and persistent complete remission four years from first recurrence of secondary breast angiosarcoma. Tumori 2009;95:828–31. [59] Hanasono MM, Osborne MP, Dielubanza EJ, Peters SB, Gayle LB. Radiation-induced angiosarcoma after mastectomy and TRAM flap breast reconstruction. Ann Plast Surg 2005;54:211–4. [60] Hildebrandt G, Mittag M, Gutz U, Kunze ML, Haustein UF. Cutaneous breast angiosarcoma after conserving treatment of breast cancer. Eur J Dermatol 2001;11:580–3. [61] Hoffmann G, Mylonas I. Therapy of radiation-induced angiosarcoma of the breast in an elderly patient. Arch Gynecol Obstet 2013;287:827–31. [62] Hogewind BF, Boutkan HB, de Jager-Nowak HK, Merkus JW. Angiosarcoma following breast-conserving therapy. Ned Tijdschr Geneesk 2004;148:995–7. [63] Iga N, Endo Y, Fujisawa A, et al. Two cases of cutaneous angiosarcoma developed after breast cancer surgery. Case Rep Dermatol 2012;4:247–9. [64] Kelly NP, Siziopikou K. Pathologic quiz case: a 68-year-old woman with bluish discoloration of the skin of the breast. Arch Pathol Lab Med 2002;126:989–90. [65] Kunkel T, Mylonas I, Mayr D, Friese K, Sommer HL. Recurrence of secondary angiosarcoma in a patient with post-radiated breast for breast cancer. Arch Gynecol Obstet 2008;278:497–501. [66] Lindford A, Bo¨hling T, Vaalavirta L, Tenhunen M, Jahkola T, Tukiainen E. Surgical management of radiation-associated cutaneous breast angiosarcoma. J Plast Reconstr Aesthet Surg 2011;64:1036–42.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002
10
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[67] Linthorst M, van Geel AN, Baartman EA, et al. Effect of a combined surgery, re-irradiation and hyperthermia therapy on local control rate in radio-induced angiosarcoma of the chest wall. Strahlenther Onkol 2013;189:387–93. [68] Mano MS, Fraser G, Kerr J, et al. Radiation-induced angiosarcoma of the breast shows major response to docetaxel after failure of anthracycline-based chemotherapy. Breast 2006;15:117–8. [69] Mehta RS, Mikhail M. Post-irradiation cutaneous angiosarcoma. Cases J 2008;1:241. [70] Mills TD, Vinnicombe SJ, Wells CA, Carpenter R. Angiosarcoma of the breast after wide local excision and radiotherapy for breast carcinoma. Clin Radiol 2002;57:63–6. [71] Moe M, Bertelli G. Breast angiosarcoma following lumpectomy and radiotherapy for breast cancer: a case with short latent period and false negative result on biopsies. Ann Oncol 2007;18:801. [72] Moreno-Merlo F, Hanna W. Cutaneous angiosarcoma after breast-conserving surgery and radiotherapy. Breast J 1998;4:460–4. [73] Moskaluk CA, Merino MJ, Danforth DN, Medeiros LJ. Lowgrade angiosarcoma of the skin of the breast: a complication of lumpectomy and radiation therapy for breast carcinoma. Hum Pathol 1992;23:710–4. [74] Nakamura R, Nagashima T, Sakakibara M, et al. Angiosarcoma arising in the breast following breast-conserving surgery with radiation for breast carcinoma. Breast Cancer 2007;14:245–9. [75] Otis CN, Peschel R, McKhann C, Merino MJ, Duray PH. The rapid onset of cutaneous angiosarcoma after radiotherapy for breast carcinoma. Cancer 1986;57:2130–4. [76] Provencio M, Bonilla F, Espana P. Breast angiosarcoma after radiation therapy. Acta Oncol 1995;34:969. [77] Raina V, Sengar M, Shukla NK, et al. Complete response from thalidomide in angiosarcoma after treatment of breast cancer. J Clin Oncol 2007;25:900–1. [78] Roncadin M, Massarut S, Perin T, et al. Breast angiosarcoma after conservative surgery, radiotherapy and prosthesis implant. Acta Oncol 1998;37:209–11. [79] Roukema JA, Leenen LP, Kuizinga MC, Maat B. Angiosarcoma of the irradiated breast: a new problem after breast conserving therapy? Neth J Surg 1991;43:114–6. [80] Scott MT, Portnow LH, Morris CG, et al. Radiation therapy for angiosarcoma: the 35-year University of Florida experience. Am J Clin Oncol 2013;36:174–80. [81] Shaikh NA, Beaconsfield T, Walker M, Ghilchik MW. Postirradiation angiosarcoma of the breast: a case report. Eur J Clin Oncol 1988;14:449–51.
[82] Shrestha DB, Ravichandran D, Pittam M. Discolouration of breast skin following breast conservation therapy for breast cancer: a cautionary tale of two patients. Int J Clin Pract 2010;64:112–3. [83] Taat CW, van Toor BS, Slors JF, Bras J, Blank LE, van Coevorden F. Dermal angiosarcoma of the breast: a complication of primary radiotherapy? Eur J Clin Oncol 1992;18:391–5. [84] Tahir M, Hendry P, Baird L, Qureshi NA, Ritchie D, Whitford P. Radiation-induced angiosarcoma following conservative surgery for lobular breast cancer. Breast J 2008;14:390–1. [85] Timmer SJ, Osuch JR, Colony LH, Edminster RR, Gayar H, Igram R. Angiosarcoma of the breast following lumpectomy and radiation therapy for breast carcinoma: case report and review of the literature. Breast J 1997;3:40–7. [86] Tomasello L, Gardin G, Boccardo F. Secondary breast angiosarcoma: lethal response to anti-angiogenic therapy with paclitaxel chemotherapy. A case report. Anticancer Res 2006;26:4775–7. [87] Weber B, Marchal C. Three cases of breast angiosarcomas after breast-conserving treatment for carcinoma. Radiother Oncol 1995;37:1063–4. [88] West J, Liao SY, Cho D. Angiosarcoma after breast conservation: diagnostic pitfalls. Clin Breast Cancer 2008;8:94–6. [89] Williams EV, Banerjee D, Dallimore N, Monypenny IJ. Angiosarcoma of the breast following radiation therapy. Eur J Surg Oncol 1999;25:221–2. [90] Williams SB, Wyld L, Reed M. Cutaneous angiosarcoma after breast conserving treatment for bilateral breast cancers in a BRCA-1 gene mutation carrier: a case report and review of the literature. Surgeon 2009;7:250. [91] Yim KL. Secondary angiosarcoma occurring after conservative treatment for breast adenocarcinoma. Ann Oncol 2009;20:14–5. [92] Zucali R, Merson M, Placucci M, Di Palma S, Veronesi U. Soft tissue sarcoma of the breast after conservative surgery and irradiation for early mammary cancer. Radiother Oncol 1994;30:271–3. [93] Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Ann Intern Med 2009;151. [94] Blanchard DK, Reynolds C, Grant CS, Farley DR, Donohue JH. Radiation-induced breast sarcoma. Am J Surg 2002;184:356–8. [95] Fury MG, Antonescu CR, Van Zee KJ, Brennan MF, Maki RG. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J 2005;11:241–7.
Please cite this article in press as: Depla A.L. et al., Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.03.002