. Authors may own ... mas represent a small subgroup of soft tissue sarcomas
361
Paclitaxel and Pegylated-Liposomal Doxorubicin Are both Active in Angiosarcoma Keith M. Skubitz, M.D.1 Philip A. Haddad, M.D.2 1
Department of Medicine, the University of Minnesota Medical School, Masonic Cancer Center, Minneapolis, Minnesota.
2
Department of Medicine, Louisiana State University, Health Sciences Center, Shreveport, Louisiana.
BACKGROUND. Paclitaxel has unique activity in angiosarcomas of the face and scalp, but its activity in angiosarcomas originating at other sites is less well defined. Paclitaxel and pegylated-liposomal doxorubicin (PLD) are highly effective in Kaposi sarcoma (KS). Because of the efficacy of PLD in soft tissue sarcoma in general, and in KS in particular, coupled with potential similarities in KS and angiosarcoma, and the apparent activity of paclitaxel in angiosarcomas, the authors treated patients with angiosarcoma with either paclitaxel or PLD as initial chemotherapy. METHODS. To better define the efficacy of these agents in angiosarcoma, the authors reviewed their experience with paclitaxel and PLD in patients with angiosarcoma treated between 1994 and 2004. RESULTS. They identified seven patients with angiosarcoma treated with paclitaxel, and six treated with PLD. Only one patient in the series had an angiosarcoma of the scalp. Two patients receiving paclitaxel had received previous therapy with PLD, and four of six patients treated with PLD had previously received paclitaxel. Of the eight patients treated with paclitaxel, five had major responses (three had partial responses [PR] and two had complete disease remission [CR]) and three had progressive disease (PD). Of the 6 patients who received PLD, 3 had a PR for 6, 19, and ⬎20 months, respectively, 2 had stable disease for 7 and 11 months, respectively, and 1 had PD. CONCLUSIONS. The current study demonstrated the activity of PLD (five of six patients experienced clinical benefit) and extended the data on paclitaxel in angiosarcoma, both of the face and scalp, as well as angiosarcoma originating at other sites. Cancer 2005;104:361– 6. © 2005 American Cancer Society. KEYWORDS: sarcoma, angiosarcoma, paclitaxel, pegylated-liposomal doxorubicin, chemotherapy.
S
The authors thank D. Northfelt for a critical review of the article and M. Hajak, N. Gaspar, and S. McGraw for data capture. Address for reprints: Keith M. Skubitz, M.D., Department of Medicine, University of Minnesota Medical School, Masonic Cancer Center, P.O. Box 286, Minneapolis, MN 55455; Fax: (612) 6261441; E-mail:
[email protected] Authors may own publicly traded stock in Bristol Meyers Squibb and Johnson & Johnson. Received September 15, 2005; revision received March 11, 2005; accepted March 11, 2005.
oft tissue sarcomas comprise a heterogeneous group of mesenchymal tumors. This heterogeneity can be identified by light microscopy,1,2 and further heterogeneity can be identified by analyses of gene expression.3– 6 Importantly, even within a histologic category, there may be marked heterogeneity in biologic behavior. Angiosarcomas represent a small subgroup of soft tissue sarcomas that typically occur on the scalp or face7 and in postradiation fields,8 although they may occur at other sites as well.9,10 Although the response rates of soft tissue sarcomas to chemotherapy in general is ⬍ 40%, reports suggest that paclitaxel may be uniquely effective in angiosarcomas. In a Phase I trial of continuous infusion paclitaxel, 1 of 1 patient with angiosarcoma obtained a dramatic partial response (PR) that persisted for 12 months.11 Also, in a Phase II trial of paclitaxel for soft tissue sarcoma, 1 of 1 patient with angiosarcoma also had a dramatic response that lasted for 6 months.12 A retrospective review of patients receiving paclitaxel for
© 2005 American Cancer Society DOI 10.1002/cncr.21140 Published online 9 June 2005 in Wiley InterScience (www.interscience.wiley.com).
362
CANCER July 15, 2005 / Volume 104 / Number 2
angiosarcoma of the head and neck revealed that 8 of 9 patients had a major response and 1 of 9 patients had a minor response with a median duration of 5 months.13 Paclitaxel also has activity in Kaposi sarcoma (KS).14 –16 Pegylated-liposomal doxorubicin (PLD) is highly effective and has only minor toxicity in patients with KS, a tumor composed primarily of abnormal endothelial cells.17–19 PLD is a formulation in which doxorubicin is contained in liposomes that are coated with methoxypoly-(ethylene glycol). The methoxypoly(ethylene glycol) confers a decreased uptake by the reticuloendothelial system, a long half-life in blood (approximately 50 – 60 hours), and a different toxicity from nonpegylated liposomes.20 –22 The toxicity profile of PLD is, in general, more similar to that of continuous infusion doxorubicin than bolus doxorubicin.23,24 It delivers more doxorubicin to KS lesions than does administration of free doxorubicin, and it also delivers more doxorubicin to KS lesions than to normal adjacent skin.25 PLD also has demonstrated activity in soft tissue sarcomas.26 –28 Because of the efficacy of PLD in soft tissue sarcoma in general, and in KS in particular, coupled with potential similarities in KS and angiosarcoma, and the apparent activity of paclitaxel in angiosarcomas, we have treated patients with angiosarcoma with either paclitaxel or PLD as initial chemotherapy. To better define the efficacy of these agents, we reviewed our experience with paclitaxel and PLD in adult patients with angiosarcoma.
MATERIALS AND METHODS We identified 8 patients with angiosarcoma treated with paclitaxel, and 6 patients with angiosarcoma treated with PLD at the University of Minnesota between 1994 and 2004. The current review included the patient with angiosarcoma of the kidney who was enrolled in our Phase I study of continuous infusion paclitaxel11 and who also was enrolled in our Phase II study of PLD in patients with sarcomas.26 Patient characteristics are listed in Table 1. The sample comprised 4 men and 4 women with a median age of 60 years (range, 37– 87 years). In contrast to earlier reports, only one patient in our series had an angiosarcoma of the scalp. Six patients had metastatic disease. All patients had highgrade angiosarcomas. Three patients receiving paclitaxel had received previous chemotherapy (Patient 1, previously treated with both doxorubicin and ifosfamide-based chemotherapy,24,29 and Patients 6 and 8 previously treated with PLD). Four of the six patients treated with PLD had previously received paclitaxel. Seven of the 8 patients treated with paclitaxel
received paclitaxel at a dose of 140 mg/m2 given by continuous infusion (6 patients received the drug over 6 days and 1 patient received the drug over 7 days) and 1 received weekly paclitaxel at a dose of 100 mg/m2. Antihypersensitivity medication was given to the first patient (continuous infusion over 7 days) and also to the patient receiving weekly paclitaxel, but not to the other patients. Paclitaxel given by continuous infusion was administered on an outpatient basis to patients using a wearable ambulatory infusion pump. Each 48 hours, the paclitaxel dose was mixed in 480 mL, and the bags were changed every 48 hours. Antiemetic drugs and premedications were not used for patients receiving infusional paclitaxel. Five of the 6 patients treated with PLD initiated therapy on a 28-day interval (initial dose of 50, 50, 50, 45, and 45 mg/m2), and 1 received treatment every 2 weeks (20 mg/m2) in combination with interferonalpha (IFN-␣) at 6 million U subcutaneously 3 times a week. No premedication or antiemetic medication was given with PLD. Standard Cancer and Leukemia Group B response criteria were used for all patients except for patients with primary angiosarcomas of the scalp and breast. For these 2 patients, complete disease remission (CR) was defined as the complete clinical resolution of all lesions for ⱖ 4 weeks.
RESULTS Response Of the eight patients treated with paclitaxel, five had major responses (three had PRs and two had CRs) and three had progressive disease (PD). The two patients achieving a CR included a primary lesion of the scalp and a primary lesion of the breast in a previously irradiated field for an early-stage breast tumor. The patient who received weekly paclitaxel for the scalp angiosarcoma achieved a CR after three cycles, whereas the patient receiving infusional paclitaxel achieved a CR after three cycles of the regimen. Each of these two patients received local radiotherapy after paclitaxel. Response durations are shown in Table 1. Of the 6 patients who received PLD, the following results were obtained: 2 had a PR for 6 and 19 months, respectively; 1 had a slowly evolving response, achieving a PR at 12 months, continuing for ⬎ 20 months; 2 had stable disease (SD) for 7 and 11 months, respectively; and 1 had PD. For the 3 patients achieving SD, the tumor demonstrated PD over ⬍ 2 months, 2, and 2 months before receiving PLD. Patient 8 received PLD every 2 weeks with IFN-␣ 3 times a week, and obtained a PR for 5 months, at which time PLD was discontinued and he was treated with IFN-␣ alone. PD was noted 6 months later (at 11 months) and PLD was
51/M
76/F
87/F
51/M
37/M
65/F
75/F 60/M
1
2
3
4
5b
6
7 8
Scalp Right atrium
Thigh
Pulmonary valve
— —
—
—
—
—
Breasta
Right atrium
—
CAD IMV
Prior Rx
Thigh
Kidney
Primary site
P/100 mg/m2 weekly PLD/20 mg/m2 q 2 wks ⫹ ␣ IFN 6 milllion U TIW
P/140 mg/m2/civi 7 days q 4 wks P/140/civi over 6 days q 4 wks P/140/civi over 6 days q 4 wks P/140/civi over 6 days q 4 wks P/140/civi over 6 days q 4 wks PLD/45 mg/m2
Initial Rx/dose
3 15
5
2
9
6
6
12
No. of cycles
CR PR
PR
PD
CR at 18 mo PR
PR
PR
Response
NED at 12 mo —c
6 mo
P/140/civi over 6 days q 4 wks — P/140/civi over 6 days q 4 wks
PLD/50 mg/m2
⬍ 2 mo
— 2
1
7
21
PLD/50 mg/m2
10 mo
11
PLD/45 mg/m2
—
2
No. of cycles
PLD/50 mg/m2
Next Rx/dose
—
NED at 18 mo
6 mo
12 mo
Time to PD
— PD
PD
SD
PR
—
SD
PD
Response
— 2 moc
⬍ 1 mo
7 mo
⬎ 20 mo
—
11 mo
2 mo
Time to PD
P: paclitaxel; CAD: continuous infusion doxorubicin/dacarbazine (see Skubitz et al.24); IMV: continuous infusion isfosfamide and oral VP-16 (see Skubitz et al.29); PR: partial response; CR: complete disease remission; PD: progressive disease; SD: stable disease; PLD: pegylated-liposomal doxorubicin; q: every; M: males; F: females; Rx: therapy; civi: continuous intravenous infusion; IFN-␣: interferon-alpha; TIW: 3 times a week; NED: no evidence of disease; wks: weeks; mo: months. a Occurred in previously irradiated site. b Patient 5 subsequently achieved a PR after IMV lasting ⬎ 14 months. c PR at 3 months, PLD stopped at 5 months, IFN-␣; continued. PD at 11 months and PLD restarted with IFN-␣, yielding a PR at 13 months with continued PR at 19 months when PLD alone was received. PD was noted at 20 months and IFN-␣ was added, but disease progressed and paclitaxel was begun.
Age/ gender
Pt. no.
TABLE 1 Characteristics of Patients Treated with P or PLD
Paclitaxel and PLD in Angiosarcoma/Skubitz and Haddad 363
364
CANCER July 15, 2005 / Volume 104 / Number 2
again given with IFN-␣. Two months later, a PR was again observed. Thereafter, the tumor continued to shrink as the patient received PLD alone at 19 months. At 20 months PD was noted, and IFN-␣ was added but PD occurred. Thus, clinical benefit was seen in five of six patients treated with PLD.
Toxicity Continuous infusion paclitaxel was generally well tolerated. Similar to previous reports,11 no neuropathy was observed, neither premedications nor anti-emetics were needed, myelosuppression was not prominent, and hair loss was often only mild thinning of hair. The patient who received weekly paclitaxel, who also had diabetes, required dose reduction after two cycles due to neurotoxicity. PLD also was generally well tolerated. Similar to previous reports,26 –28 the most common toxicities were hand-foot syndrome, mucositis, and fatigue. Hair loss was sometimes observed in the axillary and pubic areas but not on the scalp. Dose modification (dose reduction or increase in treatment interval or both) due to mucositis or hand-foot syndrome was needed in two of five patients receiving the monthly schedule.
DISCUSSION Angiosarcoma represents an uncommon subtype of soft tissue sarcoma. Angiosarcoma of the scalp commonly occurs in elderly people or in the postirradiation setting.30 Lymphedema may also predispose to the development of angiosarcoma.31,32 Surgery followed by radiotherapy has been a standard approach for resectable lesions. Until recently, there has been no highly active chemotherapy for angiosarcoma. KS is also derived from endothelial cells and has been associated with human herpes virus-8 infection. Although taxanes have been found to have limited activity in soft tissue sarcomas in general, responses to paclitaxel in angiosarcoma have been observed,11–13 and paclitaxel appears to be highly active in angiosarcomas of the scalp and face.13 PLD has activity in soft tissue sarcomas in general,26 –28 and is highly active in KS.17–19,25,33 Both KS and angiosarcoma are tumors of endothelial cells and may, therefore, share some biologic properties. We treated six patients with angiosarcomas with PLD, either as first-line therapy or in patients who experienced PD while receiving paclitaxel. The current report demonstrates activity of PLD, and confirms and extends the data on paclitaxel activity in angiosarcoma, both of the face and scalp as well as angiosarcoma originating at other sites. All but one of the patients who received pacitaxel
in the current report were treated with paclitaxel as a continuous infusion. One patient received weekly paclitaxel due to logistical concerns. Continuous infusion paclitaxel has some advantages compared with shorter infusions. With continuous infusion over 6 days, no premedication was necessary, eliminating the side effects of corticosteroids. Nausea medications were not needed, hair loss was usually only thinning of hair, myalgias and neuropathy were not observed, neutropenia was not a prominent complication, and growth factors were not used. However, continuous infusion paclitaxel does require stable intravenous access. In addition, it also requires the patient to pick up a new bag of paclitaxel every 48 hours, although it is possible that paclitaxel is stable for longer periods of time at concentrations feasible for this approach. There are theoretic advantages of infusional paclitaxel as well.11 In particular, one would expect a longer exposure of low growth fraction tumors to a drug to be more efficacious, and in vitro studies suggest that longer exposure to paclitaxel yields a greater tumor cell kill. It is noteworthy that in one study,13 a patient who had PD of an angiosarcoma while receiving a 3-hour infusion every 3 weeks, experienced a CR when switched to a weekly schedule. Weekly drug administration is more similar to continuous infusion of a drug than administration every 3 weeks. New formulations of paclitaxel that have long half-lives and do not require cremaphor, such as paclitaxel linked to poly-L-glutamic acid34 and nanoparticle paclitaxel,35 may provide the advantages of infusional paclitaxel with a short intravenous infusion. Although paclitaxel appears to have unique activity in angiosarcomas of the face and scalp, its activity in angiosarcomas originating at other sites is less well defined. In a previous report, 2 of 4 patients with angiosarcoma of other sites who received paclitaxel each achieved a PR of 4.5 months.13 In the current report, one patient with a primary tumor of the scalp and one patient with a primary tumor in the breast each achieved a CR, whereas PRs were observed in three of six patients with angiosarcomas in other locations. PLD is highly active in KS.17–19,25 Four case reports suggest activity of PLD in angiosarcoma of the scalp as well. One patient who had failed to respond to radiotherapy and “polychemotherapy” had a rapid and dramatic improvement after administration of PLD.36 One patient who had failed to respond to radiotherapy achieved a PR after two cycles and a CR after six cycles.37 One patient achieved a PR with 20 mg/m2 PLD per month and then had SD with no further shrinkage of the tumor at 21 months, and was then given radiotherapy with control at the time of the
Paclitaxel and PLD in Angiosarcoma/Skubitz and Haddad
report at 24 months after the radiotherapy.38 Another report described a patient response to PLD combined with IFN-␣, in whom subsequent PD developed when PLD alone was received. The patient then had a subsequent PR when IFN-␣ was given in combination with PLD.39 This patient was human immunodeficiency virus negative, and human herpsevirus type-8 was detected by polymerase chain reaction in the tumor sample and blood mononuclear cells. Finally, another patient with angiosarcoma of the scalp has been described who achieved a CR with concomitant PLD and radiotherapy.40 In the current report, five of six patients treated with PLD experienced a meaningful response. SD occurred in three of five patients, each of whom had demonstrated PD while receiving paclitaxel. Of two patients not previously treated, one achieved a PR with PLD alone and one received a PR with PLD in combination with IFN-␣. One patient with an angiosarcoma of the scalp who responded to the related taxane, docetaxel, has been reported.41 In addition, gemcitabine has activity in KS,42 and gemcitabine alone and in combination with docetaxel has activity in soft tissue sarcomas.43– 46 Thus, gemcitabine and docetaxel may also prove useful in the treatment of angiosarcomas. Finally, vinorelbine 30 mg/m2 weekly was reported to induce a meaningful response in a patient with an angiosarcoma in a Phase II trial of patients with soft tissue sarcomas.47 Thus, both paclitaxel and PLD appear to have activity in angiosarcoma. Significant responses to angiosarcomas originating at sites other than the scalp and face were also observed. Both continuous infusion paclitaxel and PLD also have low toxicity profiles. Which therapy would yield the best outcome as initial therapy is unknown. There may also be benefit of combination therapy with these two agents in some cases of this disease as well.
REFERENCES 1. 2.
3. 4. 5.
6.
7.
Weiss SW, Goldblum, JR. Enzinger and Weiss’s soft tissue tumors. St. Louis: Mosby, 2001. Brennan M, Singer, S, Maki R, O’Sullivan, B. Sarcomas of the soft tissues and bone: soft tissue sarcoma. In: DeVita, VT, Jr, Itellman, S, Rosenberg, SA, editors. Cancer: principles and practice of oncology. Philadelphia: Williams and Wilkins, 2005:1581–1638. Skubitz KM, Skubitz AP. Characterization of sarcomas by means of gene expression. J Lab Clin Med. 2004;144:78 –91. Skubitz KM, Skubitz AP. Differential gene expression in leiomyosarcoma. Cancer. 2003;98:1029 –1038. Segal NH, Pavlidis P, Antonescu CR, et al. Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am J Pathol. 2003;163:691–700. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 2002;359:1301–1307. Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face
8. 9.
10. 11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
365
and scalp, prognosis and treatment. Cancer. 1987;59:1046 – 1057. Nanus DM, Kelsen D, Clark DG. Radiation-induced angiosarcoma. Cancer. 1987;60:777–779. Mark RJ, Poen JC, Tran LM, Fu YS, Juillard GF. Angiosarcoma. A report of 67 patients and a review of the literature. Cancer. 1996;77:2400 –2406. Budd GT. Management of angiosarcoma. Curr Oncol Rep. 2002;4:515–519. Skubitz KM. A phase I study of ambulatory continuous infusion paclitaxel. Anticancer Drugs. 1997;8:823– 828. Casper ES, Waltzman RJ, Schwartz GK, et al. Phase II trial of paclitaxel in patients with soft-tissue sarcoma. Cancer Invest. 1998;16:442– 446. Fata F, O’Reilly E, Ilson D, et al. Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer. 1999;86:2034 –2037. Gill PS, Tulpule A, Espina BM, et al. Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 1999;17:1876 –1883. Saville MW, Lietzau J, Pluda JM, et al. Treatment of HIVassociated Kaposi’s sarcoma with paclitaxel. Lancet. 1995; 346:26 –28. Welles L, Saville MW, Lietzau J, et al. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol. 1998;16:1112–1121. Northfelt DW, Dezube BJ, Thommes JA, et al. Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDSrelated Kaposi’s sarcoma after failure of standard chemotherapy. J Clin Oncol. 1997;15:653– 659. Madhavan S, Northfelt DW. Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst. 1995;87:1556 –1557. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylatedliposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998;16:2445–2451. Gabizon AA, Barenholz Y, Bialer M. Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing a polyethylene glycol-derivatized phospholipid: pharmacokinetic studies in rodents and dogs. Pharm Res. 1993;10:703–708. Gabizon A, Catane R, Uziely B, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res. 1994;54:987–992. Northfelt DW, Martin FJ, Working P, et al. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol. 1996;36:55– 63. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. 1991;83:926 –932. Skubitz KM, Hamdan H, Thompson RC. A phase I study of ambulatory continuous infusion chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (ciCAD) for soft tissue sarcomas. J Infus Chemother. 1992;2:97–105.
366
CANCER July 15, 2005 / Volume 104 / Number 2
25. Northfelt DW. Stealth liposomal doxorubicin (SLD) delivers more doxorubicin (D)X) to AIDA-related Kaposi’s sarcoma (AIDS-KS) lesions than to normal skin [abstract]. Proc Am Soc Clin Oncol. 1994;13:51. 26. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Invest. 2003;21:167–176. 27. Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37:870 – 877. 28. Toma S, Tucci A, Villani G, Carteni G, Spadini N, Palumbo R. Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG). Anticancer Res. 2000;20:485– 491. 29. Skubitz KM, Hamdan H, Thompson RC Jr. Ambulatory continuous infusion ifosfamide with oral etoposide in advanced sarcomas. Cancer. 1993;72:2963–2969. 30. Stone NM, Holden CA. Postirradiation angiosarcoma. Clin Exp Dermatol. 1997;22:46 – 47. 31. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphoedematous extremities. Cancer. 1972;30:562–572. 32. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol. 1998;38(2 Pt 1):143–175; quiz 176 –178. 33. Northfelt DW, Kaplan L, Russell J, Volberding PA, Martin FJ. Pharmacokinetics and tumor localization of DOX-SL (stealth liposomal doxorubicin) by comparison with Adriamycin in patients with AIDS and Kaposi’s sarcoma. In: DD Lasic, FJ Martin, editors. Stealth liposomes. Boca Raton: CRC Press, 1995:257–266. 34. Skubitz KM, Kudelka A, Bolton MG. Phase I study of CT2103/cisplatin in patients with solid tumors [abstract]. ECCO 12. Eur J Cancer (Suppl). 2003;12:S168. 35. Ibrahim NK, Desai N, Legha S, et al. Phase I and pharmacokinetic study of ABI-007, a cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8:1038 –1044. 36. Ockenfels HM, Brockmeyer NH, Hengge U, Goos M. Cuta-
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
neous angiosarcoma: a novel therapy with liposomal doxorubicin? J Eur Acad Dermatol Venereol. 1996;6:71–75. Eiling S, Lischner S, Busch JO, Rothaupt D, Christophers E, Hauschild A. Complete remission of a radio-resistant cutaneous angiosarcoma of the scalp by systemic treatment with liposomal doxorubicin. Br J Dermatol. 2002;147:150 –153. Wollina U, Fuller J, Graefe T, Kaatz M, Lopatta E. Angiosarcoma of the scalp: treatment with liposomal doxorubicin and radiotherapy. J Cancer Res Clin Oncol. 2001;127:396 – 399. Jackel A, Deichmann M, Waldmann V, Bock M, Naher H. Regression of metastatic angiosarcoma of the skin after systemic treatment with liposome-encapsulated doxorubicin and interferon-alpha. Br J Dermatol. 1999;140:1187–1188. Lankester KJ, Brown RS, Spittle MF. Complete resolution of angiosarcoma of the scalp with liposomal daunorubicin and radiotherapy. Clin Oncol (R Coll Radiol). 1999;11:208 –210. Isogai R, Kawada A, Aragane Y, Tezuka T. Successful treatment of pulmonary metastasis and local recurrence of angiosarcoma with docetaxel. J Dermatol. 2004;31:335–341. Brambilla L, Labianca R, Ferrucci SM, Taglioni M, Boneschi V. Treatment of classical Kaposi’s sarcoma with gemcitabine. Dermatology. 2001;202:119 –122. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824 –2831. Okuno S, Edmonson J, Mahoney M, Buckner JC, Frytak S, Galanis E. Phase II trial of gemcitabine in advanced sarcomas. Cancer. 2002;94:3225–3229. Patel SR, Gandhi V, Jenkins J, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol. 2001; 19:3483–3489. Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol. 2004;22:1706 –1712. Fidias P, Demetri, G, Harmon D. Navelbine shows activity in previously treated sarcoma patients: Phase II results form MGH/Dana-Farber/Partner’s Cancer Care Study [abstract]. Proc Am Soc Clin Oncol. 1998;17:1977.
