Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet).

Anthracyclines are valuable cytotoxic agents in cancer treatment. However, their usefulness is limited by cumulative dose-dependent cardiotoxicity that may manifest as life-threatening congestive heart failure. To avoid cardiotoxicity, the use of doxorubicin is typically capped at a safe cumulative dose. Liposomal formulations may reduce cardiac risks whilst maintaining anti-cancer efficacy. Efficacy and safety studies of non-pegylated liposomal doxorubicin (NPLD) in metastatic breast cancer (MBC) are reviewed, along with studies that examine efficacy and cardiac tolerability in combination with newer agents such as paclitaxel and trastuzumab. These show that cardiac safety of liposomal doxorubicin is similar to that of epirubicin in cumulative dose, but that the formulation, unlike epirubicin, has similar anti-cancer efficacy to doxorubicin at equimolar doses. Liposomal doxorubicin may have a better therapeutic index than non-liposomal anthracyclines. This justifies further studies in patients where cumulative cardiotoxicity is a concern, as does study of its use with other potentially cardiotoxic agents.

A phase I/II trial of pixantrone (BBR2778), methylprednisolone, cisplatin, and cytosine arabinoside (PSHAP) in relapsed/refractory aggressive non-Hodgkin's lymphoma.

The purpose of the study was to evaluate the safety, efficacy, and pharmacokinetics of pixantrone (BBR2778) when substituted for etoposide in the ESHAP regimen in patients with aggressive relapsed or refractory non-Hodgkin's lymphoma. Nineteen patients received protocol therapy, consisting of pixantrone 80 mg/m2 over 1 h on day 1, methylprednisolone 500 mg on days 1 - 5, cisplatin 25 mg/m2 on days 1 - 4, and cytarabine 2000 mg/m2 on day 5. Cycles were repeated every 21 days, in the outpatient setting. Dose limiting toxicity, consisting of bone marrow suppression, occurred at the first dose level (80 mg/m2), which was defined as the recommended dose. Grade 3 and 4 toxicities were mainly hematologic. Only one patient had grade 4 febrile neutropenia. No significant decreases in ejection fraction greater than 20% occurred. Overall response rate was 58%, with 37% complete and 21% partial responses. Six of the 11 responders (55%) underwent stem cell transplant. Median time to progression and overall median survival were 5.7 months and 14.5 months, respectively. There is no significant interaction between pixantrone and the combined drugs. The recommended dose of pixantrone in combination with methylprednisolone, cytarabine, and cisplatin (PSHAP) is 80 mg/m2. PSHAP is an active salvage regimen and should be further evaluated as a pretransplant cytoreductive regimen.

High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin's lymphoma.

No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.

Interleukin 8 is an autocrine growth factor and a surrogate marker for Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common tumor associated with HIV-1 infection. Here, we report the expression, regulation, and biological effect of interleukin (IL)-8 in KS. AIDS-KS cell lines expressed higher levels of IL-8 than either human umbilical vein endothelial cells (HUVECs), human aortic smooth muscle (AoSM) cells or fibroblast cells (T1). The inflammatory cytokine IL-1beta up-regulated IL-8 expression in a time- and concentration-dependent manner in KS cell lines. IL-8 antisense oligonucleotides specifically reduced IL-8 mRNA and protein levels and inhibited KS cell growth in a dose-dependent manner. In addition, supernatant from a KS cell line induced the growth of HUVECs and angiogenesis in chicken chorioallantoic membrane assays, both of which were inhibited by IL-8 neutralizing antibody. Serum levels of IL-8 were also elevated in KS cases compared with matched controls. Modulation of IL-8 may thus be of therapeutic value in this disease.

Clinical aspects and management of AIDS-related Kaposi's sarcoma.

AIDS-related Kaposi's sarcoma (KS) is a tumour of vascular endothelium, which is seen predominantly in men who have sex with men. The majority of affected individuals have advanced immunosuppression at the time of the initial KS diagnosis. The disease may present with cutaneous lesions, or with involvement of visceral organs, of which the gastrointestinal tract is most common. KS may also present with lymphoadenopathy or with isolated lymphoedema, even in the absence of cutaneous lesions. Affected individuals are uniformly co-infected with HIV and with Human Herpesvirus type 8 (HHV8). HHV8 is present within KS tissues, and is aetiological in the pathogenesis of disease, along with aberrant cytokine expression, production of multiple angiogenic peptides, and immune dysregulation. While not presently curable, multiple treatment options exist and must be evaluated in terms of the specific needs of the individual patient. Various local therapies are aimed at eradicating small lesions, while acknowledging that the KS in general, or its likelihood of recurring will be unaffected. Systemic chemotherapy is used to treat extensive visceral involvement. Knowledge of the pathogenesis of disease has led to the development of novel treatment strategies, aimed at HHV8 as the target of therapy, or at the inflammatory cytokine or angiogenic milieu necessary for KS growth. Use of highly active anti-retroviral therapy, aimed at controlling the underlying HIV infection, has been associated with a dramatic decrease in the incidence of KS, and may also be useful in the treatment of existing KS disease.

Incidence and management of AIDS-related lymphoma.

Over time, the spectrum of the acquired immune deficiency syndrome (AIDS) epidemic has changed, especially with the advent of highly active antiretroviral therapy (HAART). The goal of this article is to delineate changes occurring in the incidence and management of lymphoma over the course of the AIDS epidemic. Lymphoma usually occurs rather late in the course of human immunodeficiency virus (HIV) infection and is the cause of death in up to 20% of HIV-infected individuals. It is seen in all population groups at risk for HIV and is more common in men than in women. It is usually diagnosed in patients with markedly decreased CD4 cell counts, consistent with prolonged periods of HIV infection and subsequent immunosuppression. Recent data from several large series have demonstrated a substantial decline in the median CD4 cell count among patients with newly diagnosed AIDS-related lymphoma despite the recent widespread use of HAART. While still somewhat controversial, use of HAART has generally not produced a significant decline in the incidence of AIDS-related lymphoma. Patients treated with low-dose vs standard-dose chemotherapy for AIDS-related lymphoma have achieved similar response and survival rates, although standard-dose therapy is associated with greater toxicity. Adapting therapy to prognostic factors has not produced a significant improvement in survival. Use of antiretroviral therapy along with chemotherapy appears safe, and may be associated with longer survival. An infusional regimen called EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin HCl) shows promise in the future management of AIDS-related lymphoma. No regimen is currently considered the standard of therapy for patients with relapsed AIDS-related lymphoma, and survival is short in this setting.

Liposomal daunorubicin in the treatment of relapsed or refractory non-Hodgkin's lymphoma.

PURPOSE: To assess the efficacy and toxicity of liposomal daunorubicin administered as a two-hour intravenous infusion to patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Eligible patients had relapsed or refractory NHL with measurable or evaluable disease, and low grade, select intermediate grade, or mantle cell pathologic types. Prior exposure to an anthracycline or anthracenedione was allowed. Liposomal daunorubicin at a dose of 100 mg/m2 was given intravenously over a minimum of 120 minutes every 3 weeks. as a single agent. RESULTS: Thirty-three patients were accrued: twenty-three (70%) had low-grade histologies; six (18%) had intermediate-grade histologies (follicular large-cell and diffuse small cleaved); and four (12%) patients had mantle-cell lymphoma. Eighteen (55%) had received two or more prior regimens; fourteen (42%) received a prior anthracycline. A median of six cycles of liposomal daunorubicin were administered (range 1-15). Of 31 patients evaluable for response, 2 complete and 10 partial remissions were documented for a major response rate of 39% (95% confidence interval (CI): 22%-58%). The median duration of response was 19.5 months (range 4.3-41.1+). Six responders (50%) had received a prior anthracycline; one responder had mantle-cell histology. The major toxicities were grade 3 or 4 neutropenia in 26 patients (79%), mild to moderate nausea in 22 (67%), and fatigue in 16 (48%). CONCLUSIONS: Liposomal daunorubicin at 100 mg/m2 every three weeks has activity in patients with relapsed or refractory NHL, including patients with prior exposure to an anthracycline. Further studies of liposomal daunorubicin in combination with other agents are warranted.

Evolving characteristics of AIDS-related lymphoma.

Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P =.25), in Latino/Hispanic individuals (P <.0001), and in those who acquired human immunodeficiency virus (HIV) heterosexually (P =.01). These changes were similar in both countywide, population-based analyses and in those from the single institution. The median CD4(+) lymphocyte count at lymphoma diagnosis has decreased significantly over the years, from 177/dL in the earliest time period (1982-1986), to 53/dL in the last time period from 1995 to 1998 (P =.0006). The pathologic spectrum of disease has also changed, with a decrease in the prevalence of small noncleaved lymphoma (P =.0005) and an increase in diffuse large cell lymphoma (P <.0001). Despite changes in the use of antiretroviral or chemotherapy regimens, the median survival has not significantly changed.

Kaposi sarcoma is a therapeutic target for vitamin D(3) receptor agonist.

Kaposi sarcoma (KS) is responsive to a number of different steroid hormones, such as glucocorticoids and retinoids. An active metabolite of vitamin D, 1alpha,25 dihydroxyvitamin D(3), was used to study the effect of this steroid hormone in KS. Steroid hormones exert their effect through their cognate nuclear receptors, which for vitamin D metabolites is the vitamin D receptor (VDR). It was first shown that KS cell lines and primary tumor tissue express high levels of VDR, whereas endothelial cells had minimal expression and fibroblasts had no expression. Second, KS cell growth was inhibited by VDR agonist 1alpha,25 dihydroxyvitamin D(3) with a 50% inhibitory concentration of 5 x 10 -8 mol/L, whereas endothelial cells and fibroblast cells showed no response. Studies on the mechanism of KS tumor growth inhibition by 1alpha,25 dihydroxyvitamin D(3) showed that production of autocrine growth factors interleukin (IL)-6 and IL-8 was reduced in a dose-dependent manner, whereas no effect was observed on vascular endothelial growth factor and basic fibroblast growth factor. Transcription initiated at the IL-6 promoter was repressed by VDR agonist. The DNA sequences required to mediate this repression were localized to nucleotides -225/-110 in the 5'-flanking region. The antitumor activity of VDR agonists was also confirmed in KS tumor xenograft and after topical application in patients with KS. 1alpha,25 Dihydroxyvitamin D(3) and its analogs may thus be candidates for clinical development in KS.

Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin's disease: a prospective, multi-institutional AIDS clinical trials group study (ACTG 149).

To ascertain the results of standard ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) in HIV-infected patients with newly diagnosed Hodgkin's disease (HD), a nonrandomized, prospective, multiinstitutional clinical trial was conducted by the AIDS Clinical Trials Group (ACTG), in HIV-infected patients with Hodgkin's disease. All patients received the standard ABVD regimen, with granulocyte-colony-stimulating factor (G-CSF). Antiretroviral therapy was not used. Between May, 1992 and August, 1996, 21 patients were added to the study and treated. The median CD4 count was 113 cells/mm3, and 29% had a history of a clinical AIDS-defining condition before diagnosis of HD. Systemic "B" symptoms were present in 90% at diagnosis. Stage IV HD was present in 67%, with bone marrow involvement in 12 (57%). Nodular sclerosis HD was present in 38%, with mixed cellular disease in 31%. Among all patients entered and treated, complete remission (CR) was attained in 9 (43%; 90% confidence interval [CI], 24%-63%), whereas partial response occurred in 4 (19%), leading to an overall objective response rate of 62% (90% CI, 42%-79%). Despite routine use of G-CSF, 10 patients (47.6%) experienced life-threatening neutropenia, with absolute neutrophil counts <500 cells/mm3. In all, nine opportunistic infections occurred in 6 patients (29%) during the study or shortly thereafter. Median survival was 1.5 years. Results of this study suggest that alternative treatment strategies should be explored, including use of chemotherapy together with antiretroviral therapy.

Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposi's sarcoma.

PURPOSE: Although advances have been made in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) with systemic chemotherapy, less toxic therapies are needed. IM862 is a naturally occurring peptide with antiangiogenic properties and was thus studied in patients with AIDS-KS. PATIENTS AND METHODS: IM862 was given as intranasal drops at a dose of 5 mg. Patients were randomized to two dosing schedules given in repeated cycles until disease progression or unacceptable toxicity: 5 days of therapy followed by 5 days off (n = 18) and every other day dosing (n = 26). RESULTS: Forty-two male patients and two female patients with a median age of 38 years (range, 22 to 53 years) were accrued. Twenty-one patients (47%) had more than 50 mucocutaneous lesions, 14 (32%) had lymphedema, and none had visceral involvement. Thirty-three patients (75%) had received prior systemic chemotherapy. Twenty-four patients (55%) had CD4(+) lymphocyte count

Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi's sarcoma.

PURPOSE: Liposomal anthracyclines are the present standard treatment for advanced AIDS-related Kaposi's sarcoma (KS). No effective therapies have been defined for use after treatment failure of these agents. A phase II trial was thus conducted with paclitaxel in patients with advanced KS to assess safety and antitumor activity. MATERIALS AND METHODS: A regimen of paclitaxel at a dose of 100 mg/m(2) was given every 2 weeks to patients with advanced AIDS-related KS. Patients were treated until complete remission, disease progression, or unacceptable toxicity occurred. RESULTS: Fifty-six patients with advanced AIDS-related KS were accrued. Tumor-associated edema was present in 70% of patients and visceral involvement in 45%. Forty patients (71%) had received prior systemic therapy; 31 of these were resistant to an anthracycline. The median entry CD4(+) lymphocyte count was 20 cells/mm(3) (range, 0 to 358). A median of 10 cycles (range, 1 to 54+) of paclitaxel was administered. Fifty-nine percent of patients showed complete (n = 1) or partial response (n = 32) to paclitaxel. The median duration of response was 10.4 months (range, 2.8 to 26.7+ months) and the median survival was 15.4 months. The main side effects of therapy were grade 3 or 4 neutropenia in 61% of patients and mild-to-moderate alopecia in 87%. CONCLUSION: Paclitaxel at 100 mg/m(2) given every 2 weeks is active and well tolerated in the treatment of advanced and previously treated AIDS-related KS. The median duration of response is among the longest observed for any regimen or single agent reported for AIDS-related KS. Paclitaxel at this dosage and schedule is a treatment option for patients with advanced AIDS-related KS, including those who have experienced treatment failure of prior systemic therapy.

AIDS-related lymphoma.

The incidence of intermediate and high grade B-cell non-Hodgkin's lymphomas in HIV-infected individuals is approximately 60 times greater than in the general population. These AIDS-related lymphomas (AIDS-NHL) are a late manifestation of HIV infection and may increase in frequency as patients live longer with highly active antiretroviral therapy and effective prophylaxis of opportunistic infections. AIDS-NHL have unique clinical and pathological features that are different from non-Hodgkin's lymphomas in the general population. Histologically AIDS-NHL are either high (2/3) or intermediate (1/3) grade lymphomas. Clinically AIDS-NHL have a preponderance for extranodal involvement with central nervous system being the most common site for this. In addition to the clinical and pathological features of AIDS-NHL, a current knowledge of their pathogenesis and treatment options are presented in this review.

Cladribine in the treatment of advanced relapsed or refractory low and intermediate grade non-Hodgkin's lymphoma.

BACKGROUND: Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic activity against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies. METHODS: The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/kg daily for 5 consecutive days, repeated every 4 weeks. RESULTS: Twenty-eight patients (16 males, 12 females) with a median age of 58 years (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B-symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient with intermediate grade diffuse large cell lymphoma, and three of six patients who had had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea. CONCLUSIONS: Cladribine is an active single agent in the treatment of patients with refractory or relapsed advanced stage indolent lymphoma, with major responses in one third of patients.

Emerging treatments for epidemic (AIDS-related) Kaposi's sarcoma.

Kaposi's sarcoma (KS) is an opportunistic tumor that develops with increased frequency (100,000-fold) after HIV infection. KS causes significant morbidity from mucocutaneous involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evaluated in patients with limited tumor burden. These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the dipeptide IM 862, TNP-470, Col-3, and thalidomide; 2) topical and systemic retinoids; 3) antiviral agents specific for Kaposi's sarcoma herpesvirus and human herpesvirus-8, or HIV; and 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneous disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal anthracyclines and paclitaxel, with and without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies.

Phase II trial of liposomal daunorubicin in the treatment of AIDS-related pulmonary Kaposi's sarcoma.

PURPOSE: Kaposi's sarcoma (KS) is the most common tumor in patients with AIDS and can be fatal in patients with lung involvement. Systemic chemotherapy is the most effective treatment for pulmonary KS. We thus conducted this study to determine the efficacy of liposomal daunorubicin in the treatment of patients with pulmonary KS. METHODS: Patients with biopsy-proven, symptomatic pulmonary KS were accrued. Liposomal daunorubicin was given at a dose of 60 mg/m2 intravenously every 2 weeks. Response was monitored by chest radiographs, pulmonary function tests, arterial blood gases, and grading of pulmonary symptoms. RESULTS: Fifty-three male patients were accrued. The median CD4+ lymphocyte count was 13/microL (range, 0 to 200); 70% reported a prior AIDS-defining opportunistic infection. All patients were symptomatic, with cough reported in all patients, shortness of breath in 94%, and hemoptysis in 55%. The mean study entry diffusing capacity of carbon monoxide (DLCO) was 58.5% (percent of predicted). The median dose of liposomal daunorubicin delivered was 360 mg/m2 (range, 60 to 1,380). More than 75% of patients had complete or partial resolution of baseline pulmonary symptoms. Complete or partial improvement in DLCO was observed in 22%; complete or partial resolution of radiographic abnormalities was reported in 32%. The most common treatment-related toxicity was neutropenia, which occurred in 85%. There were no instances of cardiac toxicity observed, even at high cumulative doses. CONCLUSION: Liposomal daunorubicin at 60 mg/m2 is safe and active in patients with pulmonary KS. Trials combining liposomal daunorubicin with other active agents in KS should be considered.

AIDS-Related malignancies.

Neoplasms are a common complication of HIV-infected individuals. The increased survival rates of those with HIV infection may allow the emergence of an increased number of cancers. The new therapeutic regimens may slow the rate of progression by partially restoring the integrity of the immune system.

Immunotoxin combined with chemotherapy for patients with AIDS-related non-Hodgkin's lymphoma.

BACKGROUND: The objective of this study was to develop and test a combined therapeutic approach for patients with AIDS-related lymphoma (ARL), employing agents with independent mechanisms of action and nonoverlapping toxicity. This study was designed to test the feasibility and tolerance of combining low dose chemotherapy with infusional immunotoxin in the treatment of ARL patients. METHODS: Previously untreated patients received low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, and vincristine (m-BACOD) on a 21- to 28-day schedule. Patients who did not have progressive disease by Cycle 3 received anti-B4-blocked ricin (anti-B4bR), a murine monoclonal antibody linked to modified ricin, 20 microg/kg/day for 7 days administered by continuous infusion on an outpatient basis. A repeat cycle of anti-B4-bR was administered during Cycle 4 of chemotherapy based on tolerance. Patients received two cycles of chemotherapy beyond complete remission up to eight cycles. Study endpoints were toxicity, development of human antimurine antibody (HAMA) and human antiricin (HARA), tumor response, and survival. RESULTS: Twenty-six of 44 patients received the immunotoxin therapy. Anti-B4-bR infusion was associated with transaminase elevation (Grade 3) in 14 of 26 patients (58%), and flulike symptoms were common. HAMA or HARA was observed in 8 patients (31%). The overall response rate was 57% (13 complete responses and 12 partial responses). The median survival for all patients was 8.9 months. CONCLUSIONS: This study demonstrates the safety and feasibility of using chemotherapy and immunotoxin therapies in combination and supports their further evaluation to improve the outcomes of patients with ARL.

Phase I study of human chorionic gonadotropin given subcutaneously to patients with acquired immunodeficiency syndrome-related mucocutaneous Kaposi's sarcoma.

BACKGROUND: In vitro and in vivo clinical studies have shown that certain preparations of human chorionic gonadotropin have antitumor activity against Kaposi's sarcoma, the most common tumor in patients infected with human immunodeficiency virus type 1 (HIV-1). METHODS: A phase I trial was conducted in 18 male patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma. Successive cohorts of six patients each received human chorionic gonadotropin (A.P.L.; Wyeth-Ayerst, Radnor, PA) subcutaneously at doses of 5000 IU daily (level I), 10,000 IU three times a week (level II), or 10,000 IU daily (level III). Toxic effects, changes in reproductive hormone levels, HIV-1 RNA plasma levels, and response to therapy were evaluated. RESULTS: A.P.L. treatment was well tolerated at all dose levels, and no maximum-tolerated, dose-defined toxic effects were observed at the highest dose tested. The most common side effects were weight gain, increased libido, and increased energy. A persistent increase in testosterone level and a persistent decline in luteinizing hormone and follicle-stimulating hormone levels were seen over time. Major responses were observed in six patients. Partial remissions (> or =50% decrease in lesion numbers, volume, or surface area) were observed at dose level I and dose level II (two patients each); biopsy-confirmed complete remissions (resolution of all lesions) were observed at dose level III (two patients). All but one major response have persisted from 207 to more than 515 days. Nine patients had stable disease lasting 10 weeks or longer. CONCLUSIONS: A.P.L. given at daily doses ranging from 5000 to 10,000 IU has antitumor activity in patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma. A.P.L. can be given for more than 1 year with minimal side effects. Larger efficacy studies are warranted.

Treatment of epidemic (AIDS-related) Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common tumor seen in patients with HIV-1 infection. KS causes significant morbidity and mortality through involvement of the skin and visceral organs. The optimal treatment for KS depends on the extent of the disease and immunologic status. However, with knowledge gained on the pathogenesis of disease, newer therapies and compounds are being developed. Early disease patients are best treated with either local therapy or agents that have low toxicity and can be delivered long term. Advanced disease, such as in patients with widespread mucocutaneous disease, lymphedema, and visceral disease, are treated most effectively with cytotoxic agents such as liposomal anthracyclines, vinca alkaloids, or paclitaxel. Future treatment developments are focusing on the role of effective anti-HIV therapy and anti-human herpesvirus (HHV)-8 therapy in an effort to interfere with key steps in the etiology of KS to control the disease. Secondly, agents that focus on the interruption of autocrine and paracrine growth factors such as vascular endothelial cell growth factor and basic fibroblast growth factor, interleukin-6, and interleukin-8 are of therapeutic interest. Some of these compounds currently under evaluation include antiangiogenesis inhibitors and retinoids.