Antiangiogenic Therapy With Pioglitazone, Rofecoxib, and Trofosfamide in a Patient With Endemic Kaposi Sarcoma

Background  Kaposi sarcoma (KS) in patients who are seronegative and seropositive for human immunodeficiency virus is currently the most common malignant tumor in central Africa. It accounts for 50% of all tumors reported in central African countries. Owing to the rising number of patients and the limitations of current therapies, there is an urgent demand for new strategies to treat KS.

Observation  We describe a 42-year-old dark-skinned patient from Mozambique with endemic KS. The tumor was first diagnosed 8 years earlier when an ulcerated nodule appeared at his right ankle joint. Subsequently, multiple reddish brown nodules appeared on both feet and the left thigh. Results of dermatohistopathological analysis confirmed the diagnosis of KS. Topical therapies including cryotherapy, carbon-dioxide laser, and photodynamic therapy could not prevent new recurrences and further cutaneous dissemination. Therefore, a novel antiangiogenic systemic therapy was started that was previously shown to be effective in angiosarcomas other than KS. The regimen consists of the biomodulators pioglitazone hydrochloride and rofecoxib combined with a metronomic (daily) low-dose chemotherapy with trofosfamide. We observed a partial remission, which has been stable for 18 months. No significant toxic effects were observed.

Conclusion  The suggested antiangiogenic strategy has the potential to become a cheap, practical, feasible alternative treatment for endemic KS, particularly suitable for the outpatient setting.

Kaposi sarcoma is a malignant multilocular neoplasm originating from primitive mesenchymal cells that share many features with endothelial cells and smooth muscle cells.^1,2 The etiology of KS is still unknown; however, an association with human herpesvirus 8 infection has been postulated.^1,2 The first cases of KS were described by Moritz Kaposi in 1872 and termed sarcoma idiopathicum multiplex haemorrhagicum.³ To date, the following 4 clinical distinct subtypes of KS are discriminated: classic sporadic KS, endemic African KS (eKS), human immunodeficiency virus (HIV)–associated epidemic KS, and iatrogenic- and transplant-related KS in immunosuppressed patients.⁴ Endemic KS is further subdivided into the benign nodular type, most commonly appearing as papules or nodules on the extremities; the infiltrative type with fibrotic lesions in muscles and bones; and the aggressive disseminated types with mucocutaneous, visceral, or lymphatic involvement, affecting mostly African children and adolescents with poor prognosis. The diagnosis of KS can easily be established owing to its characteristic dermatohistopathological features. A typical feature consists of densely packed CD31/CD34-positive spindle-shaped cells with numerous mitoses forming slitlike neovascular leaky lumina with extravasation of erythrocytes.¹

At present, the treatment of KS is palliative.^2,4 Considering the rising number of patients in Africa and the limitation of local therapies, particularly in cases of disseminated tumors or lesions at mechanically exposed parts of the body such as the soles, there is an urgent worldwide demand for a systemic treatment of KS with an acceptable level of toxicity and long-term palliative effects at low cost.

We treated a dark-skinned 42-year-old patient born in Mozambique who had lived in Germany for 18 years. His family history was negative for cancer and nonrelated internal diseases. A tumor 3 cm in diameter had been removed by excision with subsequent skin grafting 6 years ago. The diagnosis of KS had been established by results of dermatohistopathological analysis. Results of repeated HIV testing remained negative. Previous staging examinations had not shown any visceral involvement. Five years later, multiple pea-sized, dark red lesions appeared on the left knee and right ankle joint, which were first treated with cryotherapy. One year later, 2 more lesions were treated with carbon-dioxide laser therapy. The patient was admitted to our department when multiple new reddish brown nodules of up to 1 × 1 cm appeared on the dorsal side of the left foot. Immediately after local treatment efforts with photodynamic therapy,⁵ we observed 4 new tumors with diameters of up to 4 cm on the left foot, 3 new lesions on the right foot, and another large tumor on the left thigh (Figure 1A).

Results of a complete blood cell count and analysis of serum samples, blood clotting factors, and urine status were normal. Serologic testing for HIV and syphilis yielded negative results; however, human herpesvirus 8–IgG positivity indicated a previous human herpesvirus 8 infection. Panendoscopy and computed tomography of the chest and abdomen revealed no signs of visceral KS.

An excisional biopsy from the dorsal side of the left foot reconfirmed the previous diagnosis of KS. We found spindle-shaped cells with high mitotic activity forming numerous slitlike lumina filled with red blood cells and typical extravasation (Figure 2A). In addition, staining of the spindle-shaped cells that was positive for anti-CD31 and CD34 was seen (Figure 2B-C).

A systemic antiangiogenic therapy was initiated in accordance with a phase 2 study protocol that had already shown antitumoral effects in other multiply pretreated sarcomas and malignant melanomas.⁶ This regimen has been approved by the local ethics committee, and written consent was obtained before inclusion. This therapy combines the orally administered biomodulating drugs pioglitazone hydrochloride (45 mg/d) and rofecoxib (25 mg/d) with metronomically (ie, daily applied) low dosages of oral trofosfamide (50 mg given three times a day). Within 8 weeks of treatment, the patient showed an almost complete clinical remission (Figure 1B). After 18 months of continued treatment, we still observed a stable remission and no signs of visceral involvement. The regimen did not cause subjective or objective adverse effects in this patient.

Therapy for eKS is difficult and remains palliative. Different therapeutic options may be considered. Topical therapies include cryotherapy, multiple excisions, laser therapy (argon laser for smaller lesions and carbon-dioxide laser for bigger lesions), intralesional application of interferon alfa, vinblastine sulfate, radiation therapy, and photochemotherapy.⁴ However, the rate of local recurrences remains high after topically targeted therapies.² Dissemination of the tumor or systemic involvement requires a systemic therapeutic approach. In this case, the current options consist of interferon alfa, liposomal daunorubicin hydrochloride, vinblastine, vincristine sulfate, and dacarbazine.² However, the clinical outcomes are relatively poor, and the long-term palliative treatment of these patients is frequently limited by hematologic and/or cardiological (eg, anthracylines) toxic effects. The antiangiogenic potential of protease inhibitors in HIV-seropositive or HIV-seronegative individuals with KS has been recently suggested as an additional new treatment option.⁷

The rationale of the new therapeutic approach used in the case described herein is also based on the paradigm of antiangiogenic therapy. This approach uses endothelial cells of the host as a “more reliable” therapeutic partner, ie, a strategy that acts independently of the genetic instability and heterogeneity of the tumor itself.⁸ It is therefore thought to be effective also in multiply pretreated cancers and rather independent of chemoselection and chemoresistance.⁶ For this purpose, a low-dose metronomic (daily) chemotherapy has proved to be especially suitable, because it inhibits most effectively proliferating endothelial cells in tumor angiogenesis almost without noxious adverse effects on other host endothelia.⁹ To increase this effect, this base regimen can be combined with biomodulators, which exhibit a synergistic antiangiogenic potential.^6,8 Theoretically, in angiosarcomas, the antiangiogenic therapy could target the transformed endothelial tumor cells and the vasculature that supports the tumor. A previous study by Vogt et al⁶ reported the successful treatment of angiosarcomas other than KS with a triple combination of the biomodulators pioglitazone and rofecoxib and a metronomically applied low-dose chemotherapy with trofosfamide. Because KS originates from primitive mesenchymal cells that share many features with endothelial cells, we were encouraged to try this novel regimen in this case of a progressive disseminated course of eKS.

Pioglitazone is a peroxisome proliferator-activated receptor γ agonist. It belongs to the nuclear hormone receptor/transcription factor superfamily. Originally, this thiazolidinedione derivative was developed for modulation of metabolic mechanisms in the treatment of patients with type 2 diabetes mellitus. However, more recently, it was shown that thioglitazones can also suppress tumor growth and metastasis by means of antiangiogenic effects. In part, the selective antitumoral effects can be explained by the fact that tumor-induced endothelial sprouts often exhibit a relative overexpression of peroxisome proliferator-activated receptor γ compared with normal endothelium.^10,11 Rofecoxib is a nonsteroidal anti-inflammatory drug that is supposed to act as a selective inhibitor of cyclooxygenase 2 (inducible prostaglandin synthase 2), which is up-regulated in numerous tumor entities in the tumor cells and in the microvasculature.¹² Cyclooxygenase 2 inhibitors can suppress tumor-associated angiogenesis partly by interference with the prostaglandin metabolism. In addition, further cyclooxygenase 2–dependent and –independent mechanisms are possibly responsible for rofecoxib-induced apoptosis of the tumor cells themselves. The currently discussed mechanisms are, for instance, modulation of Akt-kinase, mitogen-activated protein kinases, and peroxisome proliferator-activated receptor δ.^13-15 Trofosfamide is a well-established chemotherapeutic agent, an alkylating oxazaphosphorine, which is available as an oral formulation.¹⁶

The combined treatment was well tolerated by our patient, and no adverse effects were observed. Previously observed adverse effects were mild leukopenia, peripheral edema, thrush, renal dysfunction, infection, and fever, which could be well controlled.⁶ Taken together, this antiangiogenic regimen could become a feasible low-cost alternative for the palliative treatment of eKS and should therefore be further evaluated in larger trials.

Correspondence: Thomas Vogt, MD, Department of Dermatology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany (thomas.vogt@klinik.uni-regensburg.de).

Accepted for Publication: May 14, 2004.

Financial Disclosure: None.