© 2007 European Society for Medical Oncology
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Liposomal doxorubicin is active in Stewart–Treves syndrome
In 1948, Stewart and Treves described some cases of lymphangiosarcoma arised in women who had previously undergone radical mastectomy and axillary node dissection for breast cancer [1]. After this first report, this rare clinical entity has been called Stewart–Treves syndrome (STS). Following mastectomy, patients affected by STS develop purple-colored multifocal raised cutaneous lesions progressing to ulceration in the lymphoedematous upper limb within a median of 10 years (range: 5–27 years) [2]. So far, 
300 cases of STS have been reported [3]. Lymphonodal dissection complicated by lymphedema has been associated with increased risk for STS, while the role of radiation therapy or cardiovascular diseases remains unclear. The molecular pathogenesis of STS is still undefined. It has been indicated that growth factors and cytokines are released as consequence of the lymphatic block and that these factors might in turn support proliferation of vessels and lymphatics, as observed in edematous tissue [4]. At present, there is no standard treatment for STS [3]. Limited disease may undergo amputation surgery which appears the best option for a prolonged survival [2, 3]. Radical surgery has a role even beyond the intent of cure with palliative benefits on severe pain and bleeding. However, after amputation of upper limb, the disease often relapses on the surgical site and spreads to the chest wall and/or to lungs. STS is poorly responsive to chemotherapy, whose role in the neo-adjuvant, adjuvant or palliative setting is still undefined. A recent report has indicated activity of liposomal doxorubicin in a patient affected by STS [5]. At present, however, the overall clinical management of STS is unsatisfactory, the prognosis is poor and more information on the role of chemotherapy are eagerly awaited.
A 81-year-old woman, who had undergone Patey mastectomy and axillary node dissection for medullary breast cancer in 1991, was referred to our institutions for a significant lymphedema of left arm, reduced arm function, intense pain and a raised, swollen and ulcerated area with multifocal hemorrhagic or solid purple-colored lesions (Figure 1A). Some lesions were also observed on the scapular area and the patient's performance status (PS) was reduced (PS = 3, World Health Organization). Whole body computed tomography (computed tomography scan) showed a large infiltrated area in the left arm (Figure 1D), but did not reveal distant lesions.
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Histological examination of a skin biopsy disclosed tumor cells in the context of a lymphovascular growth pattern, compatible with lymphangiosarcoma. High histologic grade, marked nuclear pleomorphism and high mitotic activity of malignant epithelioid cells infiltrating the skin and the presence of numerous small vascular channels were observed (Figure 1F). Immunohistochemistry was negative for epithelial markers and positive for endothelial markers CD31 and CD34 (not shown). All clinical and histological findings excluded a carcinoma, a melanoma or a Kaposi’s sarcoma and allowed the diagnosis STS.
The patient underwent up-front chemotherapy with pegylated liposomal doxorubicin (Caelyx®, Schering-Plough, Milan) 30 mg/m2 for five consecutives cycles every 21 days. After the beginning of the treatment, a progressive significant reduction of solid lesions (Figure 1B), enhancement of arm function and an increased PS (PS = 2) was observed. At the end of treatment, the clinical and radiological response to Caelyx was almost complete (Figure 1C and E). Pegylated liposomal doxorubicin was well tolerated without any adverse cardiac event. Palliative upper limb amputation was excluded for unacceptable risk conferred by the preexisting serious hypertensive cardiomyopathy and coronary artery disease. The progression-free survival was 7 months. No benefits were achieved by a second-line treatment with eight courses of weekly paclitaxel (Taxol, Bristol-Myers Squibb, Rome) 60 mg/m2. The patient was then referred to a palliative program and died 10 months after the beginning of chemotherapy.
Systemic anthracyclines are a conventional therapeutic option for sarcoma. A suggestive hypothesis is that, anthracyclines carried by liposomes, which are the archetypal and simplest form of nanovectors, may significantly enhance the drug activity in STS taking benefit of the slow vascular and extravascular flow in the affected lymphoedematous limb and leaky cancer neovasculature. The presence of large fenestrations in tumor vessels significantly enhances permeability and allows local retention of liposomal nanovectors with the final result of an efficient passive targeting and increased therapeutic effects. A remarkable point is, in our case, the lack of cardiac toxicity of pegylated liposomal doxorubicin even in the presence of a serious heart disease, which precluded amputation surgery. Taking all together, we propose pegylated liposomal doxorubicin as a primary treatment of STS, to be ideally followed by radical surgery, considering the excellent and rapid tumor regression. In this specific context, the evaluation of new targeted therapies, including anti-vascular endothelial growth factor monoclonal antibodies and/or small tyrosine kinase inhibitors alone or in combination with pegylated liposomal doxorubicin, would be of great interest. Long-term control of STS by systemic chemotherapy alone does not appear infact achievable for the rapid onset of chemoresistence and the early spread to distant sites.
1 Medical Oncology Unit, University of Magna Græcia and T. Campanella Cancer Center, Campus Germaneto, Viale Europa, 88100 Catanzaro
2 Pathology Unit
3 Breast Unit, "Pugliese-Ciaccio" Hospital, Catanzaro, Italy
* (E-mail: oncologia{at}unicz.it)
Footnotes
Pierfrancesco Tassone, Pierosandro Tagliaferri and Iole Cucinotto equally contributed to the work.
References
1. Stewart F, Treves N. Lymphangiosarcoma in post-mastectomy lymphedema. Cancer (1948) 1:64–81.[CrossRef][Web of Science][Medline]
2. Kaufmann T, Chu F, Kaufman R. Post-mastectomy lymphangiosarcoma (Stewart-Treves syndrome): report of two long-term survivals. Br J Radiol (1991) 64:857–860.
3. Ocana A, Delgado C, Rodriguez CA, et al. Case 3. Upper limb lymphangiosarcoma following breast cancer therapy. J Clin Oncol (2006) 24:1477–1478.
4. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphedematous extremities. Cancer (1972) 30:562–572.[CrossRef][Web of Science][Medline]
5. Goetze S, Schmook T, Audring H, et al. [Successful treatment of Stewart-Treves syndrome with liposomal doxorubicin]. J Dtsch Dermatol Ges (2004) 2:49–52.[Medline]
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