1832

Angiosarcoma after Breast-Conserving Therapy Alan T. Monroe, M.D. Steven J. Feigenberg, M.D. Nancy Price Mendenhall, M.D. Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida.

BACKGROUND. Angiosarcoma arising in the irradiated breast after breast-conserving therapy is being reported with increasing frequency. As more women undergo breast-conserving therapy, the incidence can be expected to increase. Surgeons, medical oncologists, and radiation oncologists will be faced with difficult management decisions for this aggressive disease. METHODS. A comprehensive review of all English-language reports of angiosarcomas after breast-conserving therapy was performed. Approximately 100 cases were reviewed for treatment details and outcome analysis was performed. RESULTS. Surgical excision is associated with very high rates of disease recurrence (55 of 75 patients with at least 1 year of follow-up; 73%). Local disease recurrences in the tumor bed or along the mastectomy scar are a component of almost all recurrences (96%). Distant metastases develop simultaneously or shortly after local recurrences. Hyperfractionated radiotherapy has successfully prevented local disease recurrences in a limited number of patients. CONCLUSIONS. Angiosarcoma after breast-conserving therapy is increasingly diagnosed in a small but significant portion of breast carcinoma survivors. The aggressive nature of this disease demands further investigation of adjuvant therapy to prevent recurrence of disease after surgery. Cancer 2003;97:1832– 40. © 2003 American Cancer Society. DOI 10.1002/cncr.11277

KEYWORDS: breast neoplasms, angiosarcoma, radiotherapy, surgery, drug therapy.

A

Address for reprints: Nancy Price Mendenhall, M.D.; Department of Radiation Oncology; University of Florida College of Medicine, PO Box 100385; Gainesville FL 32610-0385; Fax: (352) 265-0759; E-mail: [email protected] Received November 6, 2002; accepted December 19, 2002. © 2003 American Cancer Society

ngiosarcomas are malignant tumors with morphologic properties similar to the vascular endothelium.1 They may arise in almost any site but most commonly affect the skin of the face and/or scalp in elderly patients. Overall, less than 1% of all soft tissue sarcomas are angiosarcomas2 and primary angiosarcoma of the breast represents only 1 in 1700 –2000 primary breast cancers.1 Over the past 20 years, breast-conserving therapy has replaced modified radical mastectomy as the standard of care for patients with early-stage breast carcinoma. Angiosarcoma arising in the irradiated breast after breast-conserving therapy has been reported with increasing frequency over a similar time period.3–51 Although angiosarcoma after breast-conserving therapy is uncommon (approximately 100 cases are reported in the literature), the incidence has increased as more women are treated with segmental mastectomy and radiotherapy. The purpose of this study is to review the medical literature and determine optimal management strategies for patients who develop secondary angiosarcoma of the breast.

NATURAL HISTORY Histology Low-grade, well differentiated angiosarcomas resemble normal endothelium both morphologically and functionally. Ultrastructural find-

Angiosarcoma after Breast Conservation/Monroe et al.

ings may include Weibel-Palade bodies (tubular structures found in normal endothelium) and pinocytic vesicles. The majority of angiosarcomas are highgrade tumors with varying degrees of nuclear atypia, hyperchromatic nuclei, large nucleoli, and frequent mitoses. “Blood lakes,” which represent hemorrhage into surrounding stroma, are common features of high-grade angiosarcoma. Immunohistochemical verification of the diagnosis is frequently attempted but is not always successful given the limited sensitivity and specificity of current markers. Factor VIII-associated antigen and CD34 represent the most frequently employed markers. CD31, a platelet-endothelial cell adhesion molecule, is a more sensitive and specific antigen for endothelial differentiation.52 The limited data on the cytogenetics of angiosarcoma show these tumors to have a complex karyotype involving a number of chromosomal deletions and structural rearrangements.18 BRCA1, BRCA2, p53, and the ataxia telangiectasia gene are potential genetic mutations.53

Primary Versus Secondary Angiosarcoma Primary angiosarcoma of the breast arises without a recognized associated factor. Despite its overall rarity, it is one of the most common breast sarcomas.54,55 Primary breast angiosarcoma usually affects women in their 20s or 30s. Axillary lymph nodes are infrequently involved, but the prognosis is poor for women with primary breast angiosarcoma compared with women with invasive ductal breast carcinoma. Chen et al.56 reported a 3-year disease-free survival rate of 14% and Buatti et al.10 reported a mean overall survival period of approximately 2 years. Secondary angiosarcomas have been distinguished from primary angiosarcomas by their association with a number of presumed etiologic conditions. Secondary angiosarcoma was first reported in association with long-standing extremity edema as the Stewart–Treves syndrome.57 This syndrome was described initially in six patients with chronic lymphedema of the upper extremity after radical mastectomy and complete axillary clearance. Chronic lymphedema due to a variety of causes predisposes patients to angiosarcoma. Congenital,58 idiopathic, traumatic, and infectious causes have been implicated.1 Despite the distinction from primary angiosarcoma, the natural history of secondary angiosarcoma is remarkably similar, with a median survival period of 14.5–34 months and a 5-year survival rate of approximately 15%.25,59,60 The distinction between primary and secondary angiosarcoma may prove to be less important as more is learned about the etiology of this rare disease.

1833

EPIDEMIOLOGY The association between radiation and breast angiosarcoma has been established by a number of large cohort population studies. Cozen et al.61 reviewed the incidence of angiosarcoma in a case– control study of women in Los Angeles County with a history of invasive breast carcinoma. The odds ratio was 59 for developing an upper extremity angiosarcoma and 11.6 for developing either a chest wall or breast angiosarcoma. The Surveillance, Epidemiology, and End Results program data compiled by the National Cancer Institute included more than 194,000 women who were treated for breast carcinoma. Among patients in the radiotherapy cohort, the relative risk (RR) of developing angiosarcoma was 15.9.62 Even among patients not receiving radiotherapy, a doubling of the RR was appreciated. This may reflect the role of breast edema as an etiologic factor. Marchal et al.25 surveyed the French Comprehensive Cancer Center experience with angiosarcoma after breast-conserving therapy. Nine cases were reported after more than 18,000 women were treated for an approximate prevalence of 5 per 10,000. As the number of patients treated with breast-conserving therapy increases, the prevalence of secondary angiosarcoma will likely increase proportionately.

ETIOLOGY Despite the apparent correlation between reports of secondary breast angiosarcoma and the increasing use of breast-conserving therapy, a true etiologic effect from radiation has been difficult to establish. Classically defined radiation-induced sarcomas63 included lesions of a different histology arising within a previous radiotherapy field, usually after a latency period of more than 10 years.64,65 In contrast, most recent reports of secondary breast angiosarcoma have been observed with a shorter latency period of approximately 4 –7 years.16,17,47,66 The shorter latency period may reflect a different natural history of angiosarcoma after breast-conserving therapy. Although the preserved breast is the most common site of soft tissue sarcoma in patients receiving radiotherapy for breast carcinoma,29 secondary angiosarcomas may also occur out-of-field. An example is the Stewart–Treves syndrome, which occurs in areas of chronic edema outside the irradiation fields. Radiation exposure alone is unlikely to complete the cause/effect equation. More likely, secondary angiosarcomas have a multifactorial etiology that interacts at the molecular level to produce malignant transformation. Lymphedema has been implicated as a potential

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CANCER April 15, 2003 / Volume 97 / Number 8

causative factor in the development of angiosarcoma. One of the first reported cases of secondary breast angiosarcoma after breast conservation occurred in a patient with an edematous breast 4 years after segmental mastectomy without radiotherapy.6 Molecular mechanisms linking lymphedema and secondary angiosarcoma are not clearly defined. Chronically obstructed lymphatics may induce the growth of collateral vessels, which could cause the transformation to malignant tumors under the influence of vascular growth factors. An alternative mechanism is the notion that chronic lymphedema may interfere with the host’s repair of genetic mutations, rendering an edematous area an “immunologically privileged site.”67 Irradiation may result in a necessary genetic insult or it may simply be a confounding factor that enhances the potential for lymphedema. Persistent edema is reported in approximately 4% of all patients receiving breast-conserving therapy.68 Edema associated with secondary breast angiosarcoma has been reported by 11–30% of reviews in the literature.25,43 However, these numbers likely underestimate the incidence of breast edema. Essentially, all patients treated with breast-conserving therapy have some degree of edema, perhaps transient and subclinical, related to the primary surgical and axillary incisions. The breast, being a dependent organ, frequently harbors significant edema, which is not always apparent because of the decrease in overall breast size related to tumor removal. Although most overt edema resolves within a few months of surgery, some degree of clinically apparent edema frequently lingers for several years. The probability of clinically overt edema is much less in patients receiving breast-conserving therapy for noninvasive disease than for patients with invasive disease. One reason for this may be the effect of axillary surgery on lymphatic drainage. There is no objective measure for breast edema. Therefore, clinicians may often overlook or underestimate its presence. There may be no threshold level of edema that correlates with the development of angiosarcoma. Consequently, careful observation will be important in studying the connection between edema and angiosarcoma.

CLINICAL COURSE Approximately 100 cases of angiosarcoma arising in the irradiated breast after breast conservation are described in the English literature. Clinical presentation may vary significantly among patients. As a result, a delay in diagnosis is, unfortunately, common. Patients typically present with erythematous or violaceous skin lesions that are painless and may be multifocal. Both cutaneous and noncutaneous lesions exist,23 with the

former being more common. Often, a significant portion of the breast is involved with swelling and/or discoloration at the time of diagnosis. Because of their ecchymotic appearance, lesions may be attributed to trauma and may not brought to the attention of the treating physician. Radiographic assistance in making the diagnosis has been limited. Mammography may reveal skin thickening and/or an ill-defined superficial mass, but findings are often nonspecific. Nearly 33% of patients with breast angiosarcomas have negative mammograms.69 Magnetic resonance imaging (MRI) scans play an increasing role in breast imaging and has been regarded as a promising modality with which to verify clinically suspicious lesions. Lesions are markedly enhancing70 with low-signal T1 weighting and high-signal T2 weighting. Although experience is limited, excellent correlation between MRI scan findings and mastectomy specimens has been demonstrated. Imaging may serve a confirmatory role. However, the ultimate diagnostic tools for a patient previously treated with breast-conserving therapy are a physical examination followed by the performance of a biopsy of the suspicious lesion.The clinical course of angiosarcoma is highly dependent on tumor grade. A lowgrade angiosarcoma exhibits an indolent, smoldering clinical course similar to that of benign atypical vascular lesions.17 However, local recurrences of lowgrade angiosarcoma have been reported.27 Conversely, high-grade angiosarcomas are highly aggressive tumors characterized by explosive growth and relentless local recurrences within months of radical resection. A poorly differentiated histology is a negative prognostic indicator for patients with angiosarcoma.71 Low-grade angiosarcomas may transform into a high-grade angiosarcomas.

THERAPEUTIC OUTCOMES Surgery Despite the high probability of local disease recurrence, the mainstay of treatment has been a simple mastectomy or a wide local excision. A review of all reported cases in the English literature with at least 1 year of follow-up reveals that 55 of 75 patients (73%) developed tumor recurrences after surgery (Table 1). The majority of tumor recurrences occurred within 1 year (84%) of surgery. Only two patients experienced a recurrence more than 2 years after surgery. Fortythree of 45 patients (96%) had local recurrences in the tumor bed or along the mastectomy scar and for 37 of 45 patients (82%), this was the only site of failure. Very few cases of surgical salvage after local tumor recurrence have been reported in the literature. Even after obtaining negative margins through radical sal-

Angiosarcoma after Breast Conservation/Monroe et al.

1835

TABLE 1 Review of the Literature

Grade

Time to first recurrence (mos)

Location of first recurrence

Treatment of first recurrence

DM

Follow-up (mos)

Negative

High

—

None

—

—

NED (6)

SM SM SM

— Negative Close

— — NR

— — 4

— — —

SM

Negative

Low

—

— — Abdomen and thigh —

— NED (6) —

120

— None Local (scar) ⫹ DM None

54 72

62 72

SM SM

NR Negative

Int High

12 6

Local (scar) Local (scar)

— —

76

11

SM

Negative

High

3

—

NED (26 mos) NED (36 mos after salvage) Died 2 mos later

69 48 69

48 77 42

— — —

— — —

— — —

3 — —

Local and c/l breast Site unknown None —

CW resection RT and hyperthermia None — — —

— — —

Dead 9 mos later NED (14) —

71

111

SM

Negative

High

—

None

—

—

79

52

SM

—

—

8

—

—

Dead intercurrent disease (23) —

Feigenberg et al., 200216 Feigenberg et al., 200216 Feigenberg et al., 200216 Fineberg and Rosen, 199417 Fineberg and Rosen, 199417 Fineberg and Rosen, 199417 Gil-Benso et al., 199418 Givens et al., 198919 Hildebrandt et al., 200120 Joshi et al., 199521 Layfield and Dodd, 199722 Majeski et al., 200023 Marchal et al., 199925

73

66

SM

Close

High

1

C/l breast and axilla Local scar

RT hfx ⫹ WLE

—

NED (38 after RT)

72

77

SM

Negative

Low

2

Local scar

—

NED (39 after RT)

76

56

SM

Positive

Low

1.5

—

NED (22 after RT)

80

63

RM (doxorubicin)

NR

High

⬍9

Local scar and flap Local

RT (50 Gy, 1.5 Gy b.i.d.) RT —

—

74

46

SM

NR

High

—

—

—

—

Died with local disease only NED (2)

73

42

—

NR

High

—

—

—

—

66

60

SM

NR

Int

5

62 79

150 66

MRM SM

— Negative

High Low

— 4

— 80

84 84

SM SM

Negative —

High Low

3 —

Local (tumor bed) — Local (CW) ⫻ 3 C/l breast —

73 50

63 108

Negative —

NR —

26 ?

Marchal et al., 199925 Marchal et al., 199925 Marchal et al., 199925 Marchal et al., 199925 Marchal et al., 199925

63 80 80 68 53

74 67 77 76 57

— — — — —

— — — — —

Marchal et al., 199925 Marchal et al., 199925 Mills et al., 200251 Mills et al., 200251 Molitor et al., 199726

77 71 78 77 71 59

57 75 79 96 86 78

SM Extended RM (CTX) RM (RT) RM (RT) RM (RT) RM (RT) RM (RT and chemotherapy) RM RM RM SM SM SM

— — — Negative Negative NR

Molitor et al., 199726 Molitor et al., 199726

66 49

48 54

SM SM

Moskhaluk et al., 199227 Parham and Fisher, 199728 Parham and Fisher, 199728 Pendlebury et al., 199529

62

88

79

120

68

60

SM

63

85

—

Patient’s age (yrs)

Time to AS (mos)

Treatment of AS (adjuvant)

Margins

79

54

SM

48 54 95

67 78 48

Bolin and Lukas, 19968 Bonetta et al., 19959 Buatti et al., 199410

71

Chahin et al., 200112

References Autio and Kariniemi, 19993 Badwe et al., 19915 Benda et al., 19876

73

Cwikiel et al.,

Del Mastro et al., 199413 Deutsch and Rosenstein, 199814 Edeiken et al., 199215

—

NED (12)

SM

—

Died 2 weeks after diagnosis No follow-up

— WLE

— SCF at 3rd LRR

— Alive with disease (23)

SM (⫹margin) —

— —

No follow-up No follow-up

Local (CW) ?

WLE —

— —

NED Dead (5.5)

11 3.7 8.6 16 7.3

? ? ? ? ?

— — — — —

— — — — —

Dead (11.5) Dead (15.5) Dead (15.5) Dead (17) Dead (23)

— — — High High High

7.6 ? 2.9 — — 9

— — WLE — — —

— — — — — Spine and lung

Dead (25.5) Dead (5.3) NED (32) NED (14) NED (15) Dead (14 after SM)

NR NR

Int Low

— 4

? ? Local None None Local (CW) and DM None Local

— Chemotherapy

— —

WLE

—

Low

24

Local

WLE

—

SM

Negative

High

—

Local vs. DM

—

—

NED (18) Dead of regional disease (19 after SM) At 6 mos LRR treated with SM; NED (96) NED (13)

Negative

Low

—

None

—

—

—

—

—

—

—

—

Liver metastasis at diagnosis

Dead 2 mos later (continued)

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CANCER April 15, 2003 / Volume 97 / Number 8

TABLE 1 (continued)

Margins

Grade

Time to first recurrence (mos)

SM with removal of prosthesis

NR

High

1

Local

72 75

WLE SM (neoadjuvant chemotherapy)

Negative NR

Int Int

3 6

71

60

SM

—

Int

Rubin et al., 199035 Sener et al., 200136

67 67 73

84 84 132

SM RM SM

Negative — Negative

Sener et al., 200136

72

96

WLE

Sener et al., 200136 Sener et al., 200136

80 72

79 54

Sessions and Smink, 199237 Shaikh et al., 198838

76

References

Patient’s age (yrs)

Time to AS (mos)

Treatment of AS (adjuvant)

Perin et al., 199730

46

60

Polga´ r et al., 200131 Provencio et al., 199532

71 79

Roukema et al., 199134

Location of first recurrence

Treatment of first recurrence

DM

Follow-up (mos)

4 cycles of chemotherapya

—

Local Local (scar)

RM CW resection

— Yes sites unknown

—

—

—

—

2nd recurrence 8 mos later (CW and c/l breast); treated surgically. 3rd recurrence 1 mo later (LR and R pleural effusion); treated with highdose ifosfamide; Died 6 mo later. NED (36) Died 11 mos after LRR with local and distant disease —

— Low High

— — 3

— — RT

— — —

NR

High

2

None None Local (CW and c/l breast) Local

—

MRM (RT, 70 Gy) SM

Positive Positive

High NR

— 3

Local Local ⫻ 2

RM followed by paclitaxel ⫻ 3 Thalidomide —

54

SM

—

—

—

—

77

48

WLE

—

Int

—

Slotman et al., 199439

79

52

SM

NR

NR

2

SCF and pleural effusion Local (scar)

39

72 — 75

56 75 83

SM SM SM

Negative — NR

— — High

— — —

None None None

53

29

SM

—

High

6

57

69

SM

NR

Low

—

Local (mast scar) None

Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843 Strobbe et al., 199843

— — — — — — — — — — — — — — — — — — —

144 76 78 29 121 98 65 72 84 36 106 60 55 68 84 99 74 52 70

— SM SM SM SM SM SM SM SM SM SM SM SM SM SM SM SM SM SM

— Negative Positive Positive Positive Positive Positive Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative

— 6 18 6 12 12 5 6 6 3 — — 3 78 — — — — 16

Strobbe et al., 199843

—

89

SM

Negative

43

—

81

SM

Negative

43

Strobbe et al., 1998

—

58

SM

Positive

Taat et al., 199244

70

66

SM

Positive

— High High High High High High Int Int Int Int Int Low Low Low Low Low Low Low/ int Low/ int Low/ int Low/ int —

Turner and Greenall, 199145

66

108

WLE

—

—

2

Slotman et al., 1994 Solin et al., 200140 Stokkel and Peterse, 199241 Stokkel and Peterse, 199241 Stokkel and Peterse, 199241 Stotter et al., 198942 Strobbe et al., 199843

Strobbe et al., 1998

NED (12) NED (84) Dead (9) LRR and pleural effusion NED (14 after RM)

—

— C/l axilla at 2nd recurrence —

— — —

—

—

—

RT and hyperthermia — — —

— — — —

Developed c/l axilla 6 mos later NED (24) NED (86) NED (21)

CW resection

—

—

—

Dead 2 weeks postoperatively NED (82)

— Local Local Local Local Local Local Local Local Local None None Local Local None None None None Local

— — — — — — — — — — — — — — — — — — —

— — — — — — — — — — — — — — — — — — —

— Dead (8) Dead (24) Dead (6) NED (13) NED (14) NED (6) Dead (35) Dead (8) NED (15) NED (50) NED (50) NED (36) NED (82) NED (12) NED (26) NED (47) NED (5) Dead (38)

—

None

—

—

NED (48)

—

None

—

—

NED (66)

2

Local

—

—

Dead (8)

5

Local (mast scar) Local

RT and hyperthermia MRM and doxorubicin and ifosfamide

—

Dead (1 after RT) Died secondary to local disease (continued)

Angiosarcoma after Breast Conservation/Monroe et al.

1837

TABLE 1 (continued)

Grade

Time to first recurrence (mos)

Location of first recurrence

Treatment of first recurrence

DM

Follow-up (mos)

—

—

—

—

—

—

No follow-up

SM

Negative

Low/ int

16

Local (mastectomy scar)

CW resection

—

77

SM

Negative

—

None

—

—

59

84

SM

Negative

—

None

—

—

NED (7)

60 64

44 41

SM SM

Negative NR

Low/ int Low/ int Low Int

2nd and 3rd LRR treated with RT and hyperthermia. Dead (local disease) NED (30)

— 13

None Local (CW)

— —

72

59

SM

NR

Int

4

Local (scar) and b/l lung

— WLE and RT (60 Gy) Chemotherapy

NED (5) NED (13 mo after salvage) Died shortly after salvage chemotherapy

Patient’s age (yrs)

Time to AS (mos)

Treatment of AS (adjuvant)

Margins

Veosoulis and Cunliffe, 200046 Wijnmaalen et al., 199348

45

96

SM

57

66

Wijnmaalen et al., 199348 Wijnmaalen et al., 199348 Williams et al., 199949 Zucali et al., 199450

72

Zucali et al., 199450

References

—

AS: angiosarcoma; NR: not reported; SM: simple mastectomy; RM: radical mastectomy; MRM: modified radical mastectomy; CW: chest wall; WLE: wide local excision; c/l breast: contralateral breast; LRR: locoregional recurrence; hfx: hyperfractionated; SCF: supraclavicular fossa; b/l lung: bilateral lung; (scar): recurred in surgical scar; mast scar: mastectomy scar; DM: distant metastasis; NED: no evidence of disease; RT: radiotherapy; int: intermediate; CTX: chemotherapy; b.i.d.: twice per day; c/l axilla: contralateral axilla. a Four cycles of chemotherapy: doxorubicin, ifosfamide, and dacarbazin.

vage surgery by simple mastectomy, radical mastectomy, or chest wall resections, additional local tumor recurrences are common (14 of 29 patients [48%]). This is important because distant metastases rarely developed as a site of first failure and there is a window of opportunity for controlling disease locally before dissemination occurs. Distant metastases rarely were present at initial presentation (1 of 96 patients [1%]). Instead, they develop simultaneously or shortly after the first local tumor recurrence (6 of 45 patients [13%]) or, occasionally, after multiple local recurrences (three patients). If local control can be attained, the incidence of distant metastasis may be reduced and survival rates may improve.

Radiotherapy Given the difficulty in achieving local disease control with surgery alone, adjuvant radiotherapy seems logical. Several investigators used adjuvant radiation in standard regimens in an attempt to improve local control. The explosive growth suggests a high growth faction and a potential role for hyperfractionated radiotherapy. At the University of Florida, results with accelerated hyperfractionated postoperative radiotherapy are encouraging.16 Radiation portals should encompass the entire chest wall or breast with a generous margin. Because the disease occurs in the dermal lymphatics, which have no valves, margins must be even more generous than margins for carcinomas or other sarcomas. Typically, fields include a minimum of 8 –10-cm margins

around macroscopic disease. The regional lymph nodes are uncommon sites of tumor recurrence, but are at risk in patients with extensive disease. Only one incidence of tumor recurrence in the ipsilateral supraclavicle has been documented in the literature (Table 1). In addition, one treatment failure in the untreated axillary lymph nodes has been observed in our institution. If disease is extensive and is in close proximity to draining lymphatics, consideration should be given to elective treatment of the lymph nodes. Because radiation is often delivered to previously irradiated surrounding tissue, we recommend preoperative radiation followed by surgical resection. This allows removal of tissue at high risk for late complications and placement of autologous tissue flaps as needed. Preoperative radiation also avoids the potential negative effect of local hypoxia within the tumor bed, minimizes the potential for seeding at the time of surgery, and may allow lower radiation doses.

Chemotherapy The most common site of “distant” failure is the contralateral breast, which in most cases is probably local extension through dermal lymphatics. The role of chemotherapy in angiosarcoma patients has not been established, as usually only short-lived responses are reported in the literature.16 Paclitaxel has shown substantial activity in angiosarcoma patients with involved sites other than the breast72 and warrants further investigation. Vascular targeting agents are intriguing new agents that selectively destroy existing

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CANCER April 15, 2003 / Volume 97 / Number 8

tumor vasculature, thereby inducing rapid tumor necrosis. Currently, a Phase I/II clinical trial is being planned at the University of Florida to assess the efficacy of vascular-targeting agents in conjunction with accelerated hyperfractionated radiotherapy in treating angiosarcoma.

RECOMMENDATIONS Angiosarcoma is increasingly diagnosed in a small but significant portion of breast carcinoma survivors. As more women are treated with breast-conserving therapy for early-stage breast carcinoma, the incidence of angiosarcoma of the breast is expected to rise. Early clinical detection will require a high index of suspicion by health-care providers. Patients should be advised to alert their physician of skin changes and biopsies of suspicious lesions should be performed promptly. Avoiding diagnostic delay is important because of the potentially aggressive kinetics of this disease. A combination of hyperfractionated radiotherapy and surgery provides the most promising results for patients with high-grade angiosarcoma. The role of systemic therapy is unclear at this time. The limited prevalence of disease will probably preclude randomized clinical trials. Therefore, it is important to report small successful experiences to aid the clinician in managing these infrequent problems.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

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Enzinger FM, Weiss SW. Soft tissue tumors. St. Louis: Mosby, 1995:641– 677. 2. Bardwil JM, Mocega EE, Butler JJ, Russin DJ. Angiosarcomas of the head and neck region. Am J Surg. 1968;116:548 –553. 3. Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur J Dermatol. 1999; 9:118 –121. 4. Aydogdu M, Trams G. Angiosarcoma of the breast after conservatively operated breast carcinoma—a sequela of adjuvant radiotherapy? [German]. Geburtshilfe Frauenheilkd. 1996;56:60 – 62. 5. Badwe RA, Hanby AM, Fentiman IS, Chaudary MA. Angiosarcoma of the skin overlying an irradiated breast. Breast Cancer Res Treat. 1991;19:69 –72. 6. Benda JA, Al-Jurf AS, Benson AB III. Angiosarcoma of the breast following segmental mastectomy complicated by lymphedema. Am J Clin Pathol. 1987;87:651– 655. 7. Body G, Sauvenet E, Calais G, Fignon A, Fetissof F, Lansac J. Cutaneous angiosarcoma of the breast following surgery and irradiation of breast adenocarcinoma [Angiosarcome cutane´ du sein apre`s ade´ nocarcinome mammaire ope´ re´ et irradie´ ]. J Gynecol Obstet Biol Reprod (Paris). 1987;16:479– 483. 8. Bolin DJ, Lukas GM. Low-grade dermal angiosarcoma of the breast following radiotherapy. Am Surg. 1996;62:668 – 672. 9. Bonetta A, Pagilari C, Morrica B. Post-radiation angiosarcoma of the breast: a clinical case. Tumori. 1995;81:219-221. 10. Buatti JM, Harari PM, Leigh BR, Cassady JR. Radiation-

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22.

23.

24.

25.

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