Kaposi's sarcoma

Kaposi's sarcoma is a malignant tumor that is one of the major complications with AIDS. This disease is common in male homosexuals, and HHV-8 has been indicated to play a role in its pathogenesis. In treating the lesions that spread over the skin of the entire body, and visceral lesions, mainly of the lung, multidrug chemotherapy has been commonly used, but there are many problems such as myelosuppression and the treatment results are poor in HIV patients with advanced disease. In recent years, however, progress has been made with highly active antiretroviral therapy (HAART), and the prognosis in cases of HIV infection is improving. Moreover, HAART is now coming to be seen as a treatment option for Kaposi's sarcoma itself. In addition, with the use of new drugs such as liposomal doxorubicin, the therapeutic strategy for Kaposi's sarcoma is undergoing great changes.     

Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome).

Palmar-plantar erythrodysesthesia (PPE), also called hand-foot syndrome or hand-to-foot syndrome, is a distinctive and relatively frequent dermatologic toxic reaction associated with certain chemotherapeutic agents. Pegylated liposomal doxorubicin (PLD), a long-circulating formulation of doxorubicin in which doxorubicin hydrochloride is encapsulated within pegylated liposomes, is approved to treat patients with metastatic breast cancer, advanced ovarian cancer, and acquired immunodeficiency syndrome-related Kaposi's sarcoma. The incidence of PPE is increased in patients receiving PLD compared with conventional doxorubicin. In studies that utilized the currently approved dose of PLD (50 mg/m(2) every 4 weeks), approximately 50% of all patients receiving PLD experienced PPE, and approximately 20% experienced grade 3 PPE. The pathophysiology of PPE, as it occurs with any drug with which it is associated, is not well understood. Studies evaluating the development of PPE specifically associated with PLD have not fully elucidated the mechanism; however, data support the roles of drug excretion in sweat and local pressure as contributors. When PPE develops, clinical interventions with respect to altering PLD administration include dose reduction, less frequent dosing, and ultimately, drug withdrawal with several consequences on treatment efficacy. This article will review the available data regarding the etiology and potential management strategies of PPE associated with PLD.     

Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal Doxorubicin

Pegylated liposomal doxorubicin (PLD) is a liposomal formulation with a distinct pharmacokinetic profile characterized by an extended circulation time and a reduced volume of distribution. Biodistribution animal studies indicate preferential accumulation of PLD into various implanted mouse-human tumors, with an enhancement of liposomal drug tumor levels compared with free drugs. The extended circulation time of pegylated liposomes and their ability to extravasate through the leaky vasculature of tumors results in the enhanced delivery of liposomal drug and/or radiotracers to the tumor site in patients with cancer. In malignant effusions, Kaposi sarcoma skin lesions, and a variety of solid tumors there is evidence of selective tumor uptake detected by various methods. Pegylated liposomal doxorubicin has been approved for clinical use in a variety of neoplastic conditions because of its antitumor efficacy and unique safety profile with an impressive reduction of cardiac toxicity in comparison with conventional doxorubicin.     

Graduated Systemic Treatment of AIDS-Associated Kaposi Sarcoma

Kaposi sarcoma is a mesenchymal tumor involving blood and lymphatic vessels. It is the most common malignancy in HIV-infected patients and is classified as one of the AIDS-defining diseases. First described as early as 1872, it is only in recent years that deeper insights into the pathogenesis of Kaposi sarcoma have been gained; Kaposi sarcoma represents an extraordinary example of viral oncogenesis and growth control by the immune system. Although the incidence of HIV-related Kaposi sarcoma as the initial manifestation of AIDS has recently decreased, the overall prevalence of the disease remains stable. To date, AIDS-associated Kaposi sarcoma (AIDS-KS) remains a major cause of severe disease complications and fatal outcome in HIV-positive homosexual men. The initial success of systemic interferon-α (IFNα) treatment in AIDS-KS occurred before the identification of the human herpes virus (HHV)-8 (Kaposi sarcoma herpes virus [KSHV]) and in the absence of a coherent view of Kaposi sarcoma pathogenesis. Over the past several years a more comprehensive understanding of how Kaposi sarcoma develops and why the neoplasm occurs at increased virulence in HIV-infected persons has been established. HHV-8 can be found in all types of Kaposi sarcoma, whether related to HIV or not. In the era of highly active antiretroviral therapy (HAART), regression of AIDS-KS has been observed with pure antiretroviral therapeutic regimens. A revival of local therapy of Kaposi sarcoma may occur, if HAART therapy is shown to prevent spreading of Kaposi sarcoma disease. In fact, Kaposi sarcoma is not so much the result of immunodeficiency but the result of immune activation triggered by inflammatory cytokines, which can be partly antagonized by IFNα. In advanced Kaposi sarcoma, conventional chemotherapy used to be a double-edged treatment strategy as it counteracts the reconstitution of the immune system. However, novel agents, for example, pegylated liposomal doxorubicin or daunorubicin, selectively target the tumor with better response rates and less cumulative toxicity than with all other chemotherapies. This article reviews the rationale for and results with graduated systemic therapy of patients with AIDS-KS to yield a more comprehensive treatment approach for this extraordinary malignancy.     

Pegylated liposomal doxorubicin HCL (PLD; Caelyx/Doxil): experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer.

BACKGROUND: We hypothesized that a response to pegylated liposomal doxorubicin (PLD, Caelyx/Doxil) followed by maintenance is beneficial and safe in recurrent ovarian cancer. PATIENTS AND METHODS: Sixteen patients have received PLD for more than 1 year for recurrent ovarian (14) or fallopian tube (2) cancer. All had stable disease or better responses to PLD + carboplatin (5) or topotecan (9) doublets or to PLD alone (2). PLD maintenance therapy 30-40 mg/m(2) was given every 4-8 weeks. This analysis focuses on cardiac status, overall tolerance, and time to recurrence. RESULTS: Termination of PLD was due to progression in all patients. Noteworthy was the lack of cumulative myelosuppression and, with one exception, clinical cardiac toxicity. This patient was hospitalized with cardiogenic shock and fever complicating grade 4 pancytopenia from topotecan ten months after discontinuation of PLD. Seven patients continue to receive PLD after a median of 1680 mg/m(2) (1180-2460 mg/m(2)). Four of these had documented relapses after 3-6 years on maintenance occurring in the setting of lengthening of the treatment interval. Maintenance PLD was reinstituted after 'reinduction' with a platinum. CONCLUSIONS: PLD appears to be safe as long-term maintenance in ovarian cancer and may be important for a continued response.     

Autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model

Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW-982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G(2)-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted.     

The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a G protein-coupled receptor (vGPCR) that has been implicated in the initiation of Kaposi's sarcoma, identifying vGPCR as an attractive target for preventing Kaposi's sarcoma. However, as only a fraction of cells in advanced Kaposi's sarcoma lesions express vGPCR, it is unclear whether this unique viral oncogene contributes to Kaposi's sarcoma progression. We therefore set out to determine whether the few cells that express vGPCR in established tumors represent an appropriate therapeutic target for the treatment of patients with preexisting Kaposi's sarcoma. To this end, we generated endothelial cell lines stably expressing vGPCR or key KSHV latently expressed proteins (vCyclin, vFlip, and LANA1). The endothelial cell line expressing vGPCR was rendered sensitive to treatment with the nucleoside analogue ganciclovir by using a bicistronic construct coexpressing the herpes simplex virus 1 thymidine kinase. S.c. injection into nude mice with mixed-cell populations formed tumors that approximate the ratio of vGPCR-expressing and KSHV latent gene-expressing cells. These mice were then treated with ganciclovir to specifically target only the vGPCR-expressing cells. Surprisingly, despite the expression of KSHV latent genes in the vast majority of tumor cells, specifically targeting only the few vGPCR-expressing cells in established tumors resulted in tumor regression. Moreover, we observed an increase in apoptosis of latent gene-expressing cells after the pharmacologic deletion of the vGPCR-expressing cells. These findings indicate that vGPCR may play a key role in Kaposi's sarcoma progression and provide experimental justification for developing molecular-based therapies specifically targeting vGPCR and its effectors for the treatment of Kaposi's sarcoma patients.     

Long-term chemotherapy of HIV-associated Kaposi's sarcoma with liposomal doxorubicin

The aim of this study was to examine the outcome, adverse events and clinical complications of long-term chemotherapy with pegylated liposomal doxorubicin (PegLiposomal DOX) for human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS) in the pre-highly active antiretroviral therapy (HAART) era. A phase II study over a 4-year period in a tertiary care university hospital was carried out. 52 acquired immunodeficiency syndrome (AIDS)-patients with advanced KS received long-term chemotherapy (71+/-51 weeks) with a mean of 22.8+/-18.2 cycles and a mean cumulative liposomal doxorubicin dose of 456+/-364 mg/m(2) (120-1040 mg/m(2)). Tumour burden, duration and dosage of PegLiposomal DOX, adverse events, opportunistic infections, immunological parameters and HIV load were measured. A complete (10%) or partial response (56%) was achieved while on chemotherapy. 10 patients (19%) showed stable disease. Tumour progression was observed in 8 patients (15%). Importantly, chemotherapy with PegLiposomal DOX was also successful after previous cytostatic therapy with bleomycin and vincristine. The most common adverse events included leucopenia, neutropenia, anaemia, and increased liver function tests. 34 patients (65%) developed new opportunistic infections and 29 patients (56%) died during the study period. To conclude, pegylated liposomal doxorubicin is a safe and effective drug for long-term chemotherapy of advanced (AIDS) KS without adverse effects on CD4 cell counts and HIV viral load.     

Spotlight on Polyethylene Glycol-Liposomal Doxorubicin in Solid and Hematological Malignancies and AIDS-Related Kaposi’s Sarcoma

Polyethylene glycol (PEG)-liposomal doxorubicin (Doxil®, Caelyx®²) is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localization to tumors. In a large randomized trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3–27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumor activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomized study. In patients with advanced AIDS-related Kaposi’s sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46–77% in randomized trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumor response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin’s lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. Conclusions: Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent’ s tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi’s sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin’s lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.     

Effect of treatment on health-related quality of life in acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma: a randomized trial of pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine

The purpose of this study was to determine whether health-related quality of life (HRQL) would be improved in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma treated by pegylated-liposomal doxorubicin (PLD) as compared to those treated by a conventional combination of doxorubicin, bleomycin, and vincristine (ABV). One hundred thirty-three patients received PLD and 125 patients received ABV every 2 weeks with a planned total of 6 cycles. Patients completed a 30-item AIDS-related HRQL questionnaire before beginning treatment (baseline), every 2 weeks while on treatment, and about 21 days after the end of treatment. Twenty-two items, involving nine domains, were analyzable. While on treatment, PLD-treated patients with partial clinical responses achieved statistically significant greater improvement (compared to baseline) in general health than did ABV-treated patients with partial clinical responses (ρ = 0.008). By the end of treatment, the overall group of patients receiving PLD showed statistically significant greater improvement in pain and energy/fatigue than did the group receiving ABV (ρ = 0.01-0.002). In addition, duration of clinically significant improvement in global QL was longer in the PLD arm.     

Management of AIDS-related Kaposi's sarcoma: advances in target discovery and treatment

Kaposi's sarcoma is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness by the Centers for Disease Control guidelines. Recent advances in the elucidation of the pathogenesis of KS are uncovering potential targets for KS therapies. Such targets include the processes of angiogenesis and cellular differentiation and the Kaposi's sarcoma herpesvirus/human herpesvirus-8. With the increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining Kaposi's sarcoma cases and a regression in the size of existing Kaposi's sarcoma lesions, most, if not all, Kaposi's sarcoma patients should be advised to take antiretroviral drugs that will maximally decrease HIV-1 viral load. Five agents are currently approved by the US FDA for the treatment of Kaposi's sarcoma; alitretinoin gel for topical administration; and liposomal daunorubicin, liposomal doxorubicin, paclitaxel and interferon-alpha for systemic administration. Many more agents, particularly angiogenesis inhibitors and other pathogenesis-targeted therapies are in early clinical development. Over the next 5 years, we may see even more of these pathogenesis-targeted therapies in trials and just as important we may identify, develop and validate clinically practical tools for assessing the biological effects of these therapies. The next 5 years may also bring a better understanding of the pharmacokinetic interactions among the many agents in the Kaposi's sarcoma and AIDS armamentariums.     

Management of AIDS-related Kaposi's sarcoma

The advent of highly active antiretroviral therapy (HAART) has lead to a substantial reduction in the prevalence, morbidity, and mortality associated with AIDS-related Kaposi's sarcoma. Similarly, concomitant advances in chemotherapy and supportive-care protocols have allowed for Kaposi's sarcoma to be managed more effectively in comparison with the pre-HAART era. Furthermore, developments in our understanding of the pathogenesis of Kaposi's sarcoma have identified several molecular targets that can potentially provide new therapeutic strategies. This Review discusses the role of conventional chemotherapeutic and immunomodulatory agents in the treatment of Kaposi's sarcoma and summarises the current status and future prospects of novel molecularly targeted agents in the treatment of this disease.     

Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.

BACKGROUND: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Women (n=509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. RESULTS: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR)=1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR=3.16; 95%CI 1.58-6.31; P<0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. CONCLUSIONS: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.     

AIDS-related cancers in the era of highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) has shown great efficacy in reducing human immunodeficiency virus levels, increasing immunity, and prolonging the survival of persons with acquired immunodeficiency syndrome (AIDS). The risk of life-threatening infections has been greatly reduced. However, the impact of HAART on the incidence of malignancy has been less clear. Published studies generally show that the risk of developing Kaposi's sarcoma declined by about two-thirds between 1994 and 1995 and from 1996 onward (considered the HAART era). Even before 1994, the risk for Kaposi's sarcoma in persons with AIDS had declined considerably and this cancer has now become relatively uncommon. The mechanism by which this decline in incidence was achieved appears to involve improved immunity. Data on the reduction in the risk for non-Hodgkin's lymphoma are mixed. Several studies conducted between 1997 and 1999 found no reduction in the risk for non-Hodgkin's lymphoma, although the most recent data (from 1997 to 1999) show a 42% decrease in risk. Even with a one-third reduction, the risk for non-Hodgkin's lymphoma remains considerably elevated. This high risk may be related to the fact that HAART therapy does not restore the immune system to normalcy. The increased lymphocyte turnover, with its accompanying risk of genetic errors, may increase the risk of developing non-Hodgkin's lymphoma. Most reports have insufficient data to analyze the impact of HAART therapy on incidence of central nervous system lymphomas, but recent data (from 1997 to 1999) showed a significant reduction in that risk. The mechanism by which this might occur is unclear because the central nervous system is an immunologic sanctuary. The relatively low incidence of other cancers in persons with AIDS makes it difficult to gauge the effect of HAART on their incidence, but to date, no significant trends have been reported for specific tumor types or for the overall risk of non-AIDS-related cancers.     

Chemotherapy for hormonally refractory advanced prostate carcinoma. A comparison of combined versus sequential treatment with mitomycin C, doxorubicin, and 5-fluorouracil.

One hundred forty-two patients with progressive, hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were randomized to receive either combination chemotherapy with 5-fluorouracil (5-FU), doxorubicin, and mitomycin C (FAM) or sequential chemotherapy with the same agents, i.e., mitomycin C, followed by doxorubicin on disease progression, followed by 5-FU. Objective tumor regressions were observed in 10 of 70 (14%) patients receiving the FAM treatment arm and 10 of 72 (14%) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone, 3 (12.5%) achieved objective tumor regression. There were no responses among five patients who received tertiary therapy with 5-FU alone. The median survival time for all patients treated with the combination arm was 8.7 months, compared with 7.1 months for patients who received the FAM arm (P = 0.025). However, this modest survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients. The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer.     

聚乙二醇化脂质体多柔比星联合异环磷酰胺治疗晚期转移性软组织肉瘤

背景与目的：软组织肉瘤一旦出现远处转移,预后极差,中位生存时间不到1年。多柔比星联合异环磷酰胺(ifosfamide,IFO)(AI方案)是晚期软组织肉瘤常用的一线联合治疗方案。聚乙二醇脂质体多柔比星(pegylated liposomal doxorubicin,PLD)活性成分为盐酸多柔比星,药物包裹在脂质体中,可减少多柔比星的临床毒性反应。该研究探讨PLD联合IFO治疗晚期转移性软组织肉瘤的临床疗效和安全性。方法：选取晚期转移性软组织肉瘤患者25例,使用PLD联合IFO方案,PLD剂量30 mg/m²,静脉滴注,第1天;IFO剂量1.8 g/m²,静脉滴注,第1~5天;美司钠360 mg/m²,用IFO时0、4和8 h,21 d为1个周期。结果：所有患者化疗1~8个周期,中位周期数4。25例患者中部分缓解9例(36%),疾病稳定12例(48%),疾病进展4例(16%),疾病控制率(完全缓解+部分缓解+疾病稳定)为84%(21/25)。中位无进展生存时间为7.3个月(95%CI：4.6~10.0个月)。由于失访病例较多,中位总生存时间未随访到。化疗后3/4级不良反应包括白细胞下降(20%)、粒细胞下降(28%)、贫血(4%)和呕吐(4%)。只有1例患者治疗过程中予以减量。结论：临床应用PLD联合IFO方案治疗晚期转移性软组织肉瘤疗效确切,且毒性反应较轻,值得进一步深入研究。     

Liposomal pegylated doxorubicin versus low-dose recombinant interferon Alfa-2a in the treatment of advanced classic Kaposi's sarcoma; retrospective analysis of three German centers

BACKGROUND: Classic Kaposi's sarcoma (KS) is a rare neoplasm, predominantly occurring in older subjects of Eastern Europe or Mediterranean descent. While single lesions may be treated by simple excision, laser therapy, cryotherapy, or intralesional therapy, advanced or disseminated disease requires systemic treatment. Several studies reported the effectiveness of pegylated liposomal doxorubicin (PLD) and low-dose recombinant interferon alfa-2a (IFNalpha) in the treatment of AIDS-associated KS. OBJECTIVE: The aim of this retrospective analysis of three German centers was to compare the effectiveness and tolerability of PLD with IFNalpha in patients with advanced classic KS. METHODS: Retrospective analysis of 18 Caucasian patients who had been treated for histologically proven classic KS, with either with PLD or IFNalpha was performed. Twelve patients received 20 mg/m2 of PLD monthly, and the number of cycles was adapted to the clinical response. Dose reduction or increased cycle length was conducted if toxicity intervened. In 6 patients, 3 million U of IFNalpha was injected subcutaneously 3 times a week. IFNalpha -therapy was adapted according to the clinical response. RESULTS: In the 12 KS patients treated with PLD, complete response (CR) was achieved in 8 (67 percent), major response (MR) in 3 (25 percent), and minor response (mR) in 1 (8 percent). Stable disease (SD) or progression of disease (PD) was not observed. An initial response was noted after 4-16 weeks of treatment (mean 8.6 weeks), the mean cumulative dose of PLD was 571.5 mg/m2 (range, 40 to 1496 mg/m2), and the mean follow-up was 13 months. Neutropenia (33 percent) related to PLD was the most common adverse event (4/12). Vomiting occurred in 3 (25 percent) patients; none of these were severe. Six patients were treated with IFNalpha. MR was achieved in 1 (17 percent), mR in 4 (67 percent) and SD in 1 of 6 patients (17 percent), neither had CR or PD. An initial response was observed after 8-17 weeks of treatment (mean 12.7 weeks). Fever occurred in 4 patients (67 percent). Flu-like symptoms in 3 patients (50 percent) related to IFNalpha were the most common adverse events. Mean follow-up was 6.3 months. The differences in response to treatment between PLD and IFNalpha, in general, were significant with p < 0.05 (T-test for independent samples). Comparing weeks to respond and treatment efficiency data were significant with p < 0.001 (Fisher's exact): response to PLD was up to one-third faster than IFNalpha. Calculating different stages of response (MR, CR, etc.), PLD also was clearly superior (p = 0.018) to IFNalpha (Fisher's exact). CONCLUSION: This retrospective analysis of patients with classic KS confirms the efficacy and safety of PLD. The benefits of PLD, including the monthly application, the high response even after previous treatments have failed, and the low rate of side effects even in elderly individuals, outweigh the risks. PLD is superior to IFNalpha and should be considered as an promising option in the treatment of advanced classic KS.     

Cost-effectiveness analysis of pegylated-liposomal doxorubicin and liposomal daunorubicin treatments in patients with Kaposi's sarcoma

Economic evaluations of new AIDS treatment drugs are important. For physicians treating patients with Kaposi's sarcoma, these issues are especially meaningful since cancer treatment costs for this group of patients are high. Kaposi's sarcoma is the most frequently occurring neoplasm in AIDS patients, affecting about 15% of this population. In our study, a retrospective economic evaluation has been made based on data from two randomized phase III clinical studies of severely immune-compromised HIV-infected individuals and which compares liposomal doxorubicin with liposomal daunorubicin. We have estimated the cost and cost effectiveness of the two drugs. The costs per complete or partial response are USS 18340 for daunorubicin and USS 8871 for doxorubicin. The incremental cost per additional responder by using liposomal doxorubicin instead of liposomal daunorubicin is USS 1910. Sensitivity analysis shows that these results hold over a wide range of assumptions.     

Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells

More than 80% of patients with extremity sarcoma ultimately develop metastases to pulmonary sites. Doxorubicin alone or in combination with other chemotherapeutic agents may result in partial or complete tumor response for sarcoma pulmonary metastases. Regardless of the response, there has been no proven survival benefit from cytotoxic chemotherapy in the treatment of localized or metastatic soft tissue sarcoma. Insulin-like growth factor-I receptor (IGF-I-R) activation may contribute to resistance to chemotherapy in mesenchymal neoplasia. IGF-I-R activation by its ligand decreases in vitro cytotoxic response of sarcoma to doxorubicin, the most active agent against soft tissue sarcoma in adults. Furthermore, IGF-I-R is frequently overexpressed in soft tissue sarcoma and may predict poor response to traditional chemotherapy. The effect of doxorubicin on a human soft tissue sarcoma cell derived from a dedifferentiated lung metastasis was evaluated using titrated doxorubicin doses with and without exogenous IGF-I (100 ng/ml). Western blot analysis was performed to evaluate levels of phosphorylated IGF-I-R under control and experimental conditions. In vitro proliferation assays were performed. Nuclear activation through IGF-I receptor mediated pathways prior to exposing sarcoma cells to doxorubicin altered the pattern of response to doxorubicin with enhanced mitogenesis (>2-fold) and blunted doxorubicin cytotoxicity (>10% change in IC50). These data suggest that activation of IGF-I receptor in sarcoma cells is a potential mechanism for tumor resistance to doxorubicin. Inhibition of IGF-I receptor activation represents a novel approach to enhance the degree and duration of response to traditional chemotherapy against soft tissue sarcoma.