SEARCH

SEARCH BY CITATION

Keywords:

  • angiosarcoma;
  • docetaxel;
  • paclitaxel;
  • radiation dermatitis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Effective treatment options are limited for patients with cutaneous angiosarcoma (AS). Docetaxel, a member of the taxane family of drugs, reportedly has been effective in the treatment of lung, head and neck, and breast cancers. Another taxane drug, paclitaxel, reportedly had unique activity in the treatment of AS of the scalp and neck and acquired immunodeficiency syndrome-related Kaposi sarcoma. Therefore, the authors hypothesized that docetaxel may be of value in the treatment of cutaneous AS that is resistant to conventional therapy. However, there were only 3 case reports of the successful treatment of AS in elderly patients using docetaxel in combination with surgery and radiotherapy.

METHODS.

This was a retrospective trial. After written informed consent was obtained, docetaxel was administered intravenously at a dose of 25 mg/m2 for 1 hour weekly over a period of 8 weeks on the basis of previous reports. This treatment regimen was received by 9 patients with cutaneous AS who were treated at Kobe University Hospital between January 2003 and October 2006.

RESULTS.

Six of the 9 patients who received treatment achieved major responses, including 2 complete responses and 4 partial responses. Neutropenia and peripheral neuropathy were not prominent, although severe radiation dermatitis enhanced by the docetaxel was observed in 3 patients. There were no deaths attributable to this therapy.

CONCLUSIONS.

The current study demonstrated that docetaxel was effective in patients with cutaneous AS. Cancer 2007. © 2007 American Cancer Society.

Angiosarcoma (AS) of the scalp is a rare disease for which there has been no effective chemotherapy. Therefore, a combination of resection with a wide and deep margin and radiation has been recommended.1 However, the outcomes of such combination therapy have been poor.2 In the 1990s, 2 taxanes (paclitaxel and docetaxel) demonstrated good efficacy in patients with breast cancer.3, 4 Paclitaxel has unique activity not only in breast cancer but also in AS5, 6 and Kaposi sarcoma,7 and it has been demonstrated that paclitaxel is effective in the treatment of AS. However, few patients who received treatment with docetaxel have been reported.8–10 Therefore, we reviewed our experience of chemotherapy in adult patients with cutaneous AS using docetaxel.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We reviewed the medical records of 9 patients with cutaneous AS who received treatment with docetaxel at Kobe University Hospital between January 2003 and October 2006. All patients provided signed, written informed consent before chemotherapy. The review included 7 patients with AS of the scalp and neck, 1 patient with epithelioid hemangioendothelioma, and 1 patient with Stewart-Treves syndrome of both legs after total hysterectomy. The clinical characteristics of our patients are summarized in Table 1. The mean age was 72.7 years (range, 56–91 years). The patient with epithelioid hemangioendothelioma had multiple metastatic lung tumors. Because of the severe nature of their disease, 8 of 9 patients previously or simultaneously had received other therapies (surgery and/or irradiation and/or immunotherapy with interleukin 2 [IL2]). In Patients 1, 2, 3, 4, 6, and 7, we evaluated the effect of the drug on the basis of measurements of the size and greatest dimension of residual tumors after irradiation or surgery. In Patients 2, 3, and 4, the size of metastatic (satellite) lesions outside of the radiation therapy area also was evaluated. Because, in Patient 5, the lesion of malignant epithelioid hemangioendothelioma on the patient's scalp was removed completely with surgery, we measured the number and size of multiple lung metastases to evaluate the effect of docetaxel.

Table 1. Characteristics of Patients With Angiosarcoma Treated With Docetaxel
PatientAge, ySexPrimary siteRemote metastasisTime to PD, moResponseNext RxTime to PD after PTX, moOperationRadiationIL2Side effectsRemarks
  1. PD indicates progressive disease; Rx, therapy; PTX, paclitaxel; IL2, interleukin 2; W, woman; PR, partial remission; M, man; CR, complete remission; NC, no change; RD, radiation dermatitis.

175WScalp15PRPTX5YesYesYes  
268MScalp22CRPTX4NoYesNoRD 
382MScalp3NCPTX5NoYesYesRD 
461MNeck3PRPTX6NoYesYesRD 
556WScalpLung>16NC YesNoNo Epithelioid
677MScalp>14CR NoYesYes  
783WScalp>13PR YesNoYes  
862WLeg1PDPTX4YesYesYes Stewart-Treves
991WFace>3PR NoNoNo  

Docetaxel (Taxotere; Sanofi-Aventis, Tokyo, Japan) was administered intravenously at a dose of 25 mg/m2 for 1 hour weekly over a period of 8 weeks. Docetaxel was given every week except for Weeks 4 and 8. Thereafter, if the patient experienced stable disease or a better response, then additional treatment was administered. Patients were premedicated with dexamethasone (8 mg orally) for 3 days before chemotherapy, and 8 mg dexamethasone were administered orally twice over the next 24 hours, as reported previously.11 Clinical evaluations were done after each course of chemotherapy. In all patients, radiologic evaluation consisted of computed tomography scans, a magnetic resonance imaging, and, if necessary, bone scintigraphy.

Responses were assessed according to the following definitions: A clinically complete response (CR) was defined as the disappearance of all evidence of measurable disease and assessable tumor for at least 1 month. A partial response (PR) was defined as a decrease ≥50% in the sum of the products of greatest perpendicular dimensions of all measurable lesions that lasted for at least 1 month. Stable disease (SD) was defined as a response less than a PR but with no disease progression for at least 1 month. Progressive disease (PD) was defined as any increase ≥25% in the size of measurable lesions.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Response

Of the 9 patients who received docetaxel, 6 patients had a major response (2 CRs and 4 PRs). Two patients had SD, and 1 patient with Stewart-Treves syndrome of both legs after total hysterectomy had PD.

The observed response duration to docetaxel was from 1 month to 22 months (average, 9.5 months). Two patients (Patients 2 and 6) who achieved a CR had primary lesions of the scalp. Although Patient 2 attained a CR for 22 months, he discontinued therapy with docetaxel for personal reasons. However, he restarted docetaxel because of a local recurrence. Docetaxel monotherapy also was effective for recurrent lesions. After Patient 2 achieved a CR for 9 months after restarting docetaxel, recurrent lesions appeared on his cheek. Patient 6 achieved a CR for 14 months. In Patients 1 and 4, who achieved a PR for 15 months and 3 months, respectively, local recurrence occurred on the face, head, and neck. The cause of death in Patient 1 was unclear; however, we could not find any clinical symptoms or radiologic evidence of lung metastasis. In Patient 5 (the patient with epithelioid hemangioendothelioma), we evaluated the effect of docetaxel based on the size of multiple lung metastases. The greatest measurable dimensions of the metastases have not changed for 16 months and have shown no local recurrence. In 5 of 9 patients, we administered paclitaxel weekly as second-line therapy. The patient with Stewart-Treves syndrome achieved SD for 4 months after the administration of paclitaxel, although the docetaxel was ineffective.

Toxicity Evaluation

Docetaxel toxicity was assessed in all 9 patients. Myelosuppression was not prominent; therefore, granulocyte-colony stimulating factors or platelet transfusions were not administrated for any patient in this series. No neuropathy was observed. Patients 2, 3, and 4 were treated simultaneously with radiation therapy for their temporal areas. Docetaxel is well known for its ability to enhance the effectiveness of irradiation in cutaneous and mucosal tumors.12 These patients had severe radiation dermatitis on their cheeks and neck and had widespread erosion and ulcers on their buccal mucosa, gingiva, and tongue.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Angiosarcoma in the elderly is an aggressive neoplasm. Local recurrence and early metastasis to the lung are not uncommon and are associated with a poor prognosis.2 Although surgery, wide-field radiation, and systemic doxorubicin administration are recommended, only 20% of patients are disease free at 5 years.5 Recently, paclitaxel and docetaxel, members of the taxane family, have been used especially in the treatment of breast cancer3, 4 and lung cancer.4 However, in reports of studies conducted at the Mayo clinic13 and in Europe,14 it was concluded that docetaxel was rather ineffective in soft tissue sarcomas, including AS, and could not be recommended for further use. Therefore, the application of docetaxel for AS was discontinued. In Japan, we started to use docetaxel for AS in 2001, because it also proved to be effective in the treatment of advanced-stage acquired immunodeficiency syndrome-related Kaposi sarcoma.15 Based on the finding that the origin of both Kaposi sarcoma and AS is the endothelial cell, it is conceivable that the antiangiogenic activity of paclitaxel and docetaxel is a mechanism that contributes to its efficacy in angiosarcoma.5 Recently, there have been a few reports showing the efficacy of docetaxel for AS.8–10 In the current report, we describe our experience of favorable clinical response in 6 of 9 patients who were treated with docetaxel.

The reasons for the discrepancy between the results from the European study and our current results are unclear. Although their protocol was different from ours, the number of patients with AS was too small in the European study to determine which protocol yielded a better outcome. In patients who were treated with paclitaxel, Fata et al. reported that 1 patient, who had progressed on a 3-hour infusion (every 3 weeks) of paclitaxel, experienced a CR when switched to the weekly, low-dose schedule.5

In our current series, there were no withdrawals because of safety concerns. The most severe side effect experienced by our patients was radiation dermatitis on the scalp, neck, and oral mucosa. Although local irradiation was indispensable in the treatment for AS because of the enhanced effect of irradiation by docetaxel, 3 of our patients had wide-spread dermatitis and erosion and had ulcerations of the skin and oral mucosa, which disturbed their oral ingestion for 2 months.

Although the administration of a regular dose of docetaxel (60–75 mg/m2) every 3 weeks often induced neutropenia and peripheral neuropathy, we adopted a weekly low-dose therapy (25 mg/m2) with no severe side effects.15 In 5 of 9 patients, therapy with docetaxel was discontinued and switched to therapy with paclitaxel. At the beginning of chemotherapy (8 weeks) with paclitaxel, the drug seemed to be an active chemotherapeutic agent in patients with AS who had received previous treatment with docetaxel-based chemotherapy. However, several months later, it appeared that AS became resistant to the therapy with paclitaxel in all patients. Consistent with a previous study,16 it is likely that the pattern of prior response to docetaxel may determine the likelihood of disease response to paclitaxel. These 2 agents differ somewhat in their in vivo and in vitro activities and in some cell lines and in some human cancer specimens; and docetaxel has demonstrated a greater ability to inhibit tumor cell growth compared with paclitaxel.16 The sequence of drug administration has been worthy of study in cancer chemotherapy. Currently, which taxane is the optimal choice in the treatment of AS as front-line therapy remains a matter of controversy.

To date, except for Patient 1, we have observed no clinical symptoms or radiologic evidence of lung metastasis. It is noteworthy that docetaxel potently may suppress lung metastasis of AS, which is the most direct and frequent cause of death from AS.

In conclusion, docetaxel is an effective and safe chemotherapeutic agent for the treatment of patients with cutaneous AS. However, as a caveat, we should add that our study was not homogeneous, the number of the patients was small, and some of these patients may require follow-up therapy with paclitaxel. Which drug can yield the best outcomes as initial therapy remains unknown. Future clinical research should explore the most appropriate regimens with docetaxel in the treatment of cutaneous AS.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES