Progressive Kaposi Research Articles

A Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab followed by Bevacizumab Monotherapy in Patients with Advanced Kaposi Sarcoma.

VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma. Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone. Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T1). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%-74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months-not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension (n = 5), neutropenia (n = 6), gastrointestinal hemorrhage (n = 1), and cerebral ischemia (n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy. Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone.

Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults.

Background Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.Objectives To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.Selection criteria Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.Data collection and analysis Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.Main results We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.Authors' conclusions The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.

Cellular immune responses and disease control in acute AIDS-associated Kaposi's sarcoma

Kaposi's sarcoma-associated herpesvirus (KSHV) specific T cell responses and KSHV viremia were analyzed in seven HIV-infected patients with active Kaposi's sarcoma lesions who initiated highly active antiretroviral therapy, and were compared between patients with improved Kaposi's sarcoma and those with progressive Kaposi's sarcoma requiring further systemic chemotherapy. Patients with controlled Kaposi's sarcoma disease demonstrated undetectable Kaposi's sarcoma viremia together with KSHV-specific CD8 T cells secreting interferon-gamma and tumor necrosis factor-alpha, whereas progressors showed increasing viremia with weak or no T-cell responses. These data point toward a potential role of KSHV-specific immunity in the control of AIDS-associated Kaposi's sarcoma.

Sirolimus monotherapy for Kaposi's sarcoma in an HIV-negative patient

A 63-year-old HIV-negative homosexual man was treated for 16 weeks with mycophenolate mofetil for biopsyproven membranous glomerulopathy with nephrotic proteinuria. An extensive search for a viral or malignant cause for the membranous glomerulopathy had not shown any possibilities other than immunity against hepatitis B virus (negative for hepatitis B surface antigen [Hbs-Ag] and for antibodies against hepatitis B e antigen [anti-Hbe], positive for antibodies against hepatitis B core and surface antigens [anti-Hbc and anti-Hbs, respectively]). Antibodies against HIV types 1 or 2 were absent (microparticle enzyme immunoassay HIV1/2, Abbot Diagnostic Division, Hoofddorp, Netherlands). Mycophenolate mofetil was discontinued in November, 2004, because of noncompliance. Earlier in the course of his disease, the patient was given corticosteroids, which were stopped because the patient did not show a clinical response and had psychiatric adverse eff ects. Several months after mycophenolate mofetil was stopped, he developed a few skin lesions on both wrists. Excisional biopsy of a skin lesion showed spindle cells compatible with Kaposi’s sarcoma. Immunohistochemical staining showed expression of human herpesvirus 8 (HHV8). Immunohistochemical staining for HHV8 of the former renal biopsy was negative. Treatment did not yet seem warranted. In March, 2005, he underwent an axillobifemoral bypass after occlusion of an aorta-bifemoral bypass. Because of an infectious complication, the wound in his left groin was re-explored. Soon after, he developed rapidly progressive Kaposi’s sarcoma on both legs. The largest lesions appeared near to the surgical wound (fi gure A). HHV8 PCR showed 10 000 copies/mL but repeated tests for HIV infection remained negative. Immunoglobin concentrations and the ratio of CD4 to CD8 cells were normal. Subsequently, severe lymphoedema developed in his left leg (fi gure B), which was complicated by recurrent episodes of erysipelas. Repeated courses with amoxicillin and clavulanic acid, or fl ucloxacillin, were given successfully. Blood, urine, and wound cultures remained negative. Deep venous thrombosis or occlusion of the arterial bypass was excluded with repeated ultrasonography and magnetic resonance angiography. Because the Kaposi’s lesions were extensive and located around a surgical wound covering an arterial bypass, systemic treatment seemed warranted. Radiotherapy was not an option. Chemotherapy was contraindicated because of his poor performance status, renal failure, and the infected wound. Inspired by a report in kidney transplant recipients, we started the patient on a course of low-dose sirolimus (target blood concentration 5 μg/L). After 6 weeks, lymphoedema and skin lesions clearly regressed and some lesions spontaneously ruptured. HHV8 viral load was not signifi cantly altered (from 1×10 to 0·6×10 copies/mL). During the following months, the lesions continued to regress (fi gure), and kidney function decreased from a calculated creatinine clearance of 12 mL/min to 9 mL/min (<1 mL/min per month). In the months before the start of sirolimus treatment, creatinine clearance decreased with a rate of about 2 mL/min per month. Proteinuria was massive (13 g per 24 h) but stable, and total cholesterol concentrations remained in the high normal range with statin therapy. However, 6 months after the start of sirolimus treatment, end-stage renal failure ensued (as expected Lancet Oncol 2006; 7: 875–76

Immune Reconstitution Inflammatory Syndrome Associated with Kaposi Sarcoma during Potent Antiretroviral Therapy

Rapidly progressive Kaposi sarcoma (KS) lesions with lymphadenopathy and tissue swelling occurred in a patient during antiretroviral treatment, despite an increased CD4(+) lymphocyte count and decreased HIV-1 level and KS-associated herpesvirus replication, suggesting immune reconstitution inflammatory syndrome. Inflammation resolved coincident with decreases in the CD4(+) lymphocyte count during paclitaxel treatment, whereas KS cleared only after prolonged antiretroviral therapy and chemotherapy.

Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma.

To evaluate the clinical and biological impact of protease inhibitors on HIV-associated Kaposi's sarcoma. A cohort of 10 patients included prospectively from April 1996 to June 1997 were studied in one institutional centre after initiation of protease inhibitors. All patients but one (stable disease) had progressive Kaposi's sarcoma. Three out of 10 patients had stopped specific chemotherapy for Kaposi's sarcoma for more than 4 weeks, three were still under chemotherapy, and four had never received specific treatment of Kaposi's sarcoma. Plasma HIV viral load, human herpesvirus (HHV)-8 viraemia in peripheral blood mononuclear cells (PBMC), and CD4 cell count were sequentially assessed from the beginning of therapy. For six patients, a semiquantitative evaluation of HHV-8 viral load in the Kaposi's sarcoma lesions was performed during treatment using polymerase chain reaction. After initiation of HIV triple therapy with protease inhibitors, we observed six complete responses, two partial responses, and two patients with progressive disease. All patients had undetectable plasma HIV viral load within 2 months of treatment. Undetectable HHV-8 viraemia in PBMC occurred in seven out of eight patients with partial or complete response and in none of the progressive patients. A decrease or negation of HHV-8 viral load in Kaposi's sarcoma lesions was observed in two complete responders. Our results suggest that antiviral therapy with protease inhibitors are clinically efficient in HIV-associated Kaposi's sarcoma and that there exists a correlation between clinical response and negation of HHV-8 viraemia.

Treatment of Kaposi’s Sarcoma with Interferon-α and Other Biological Response Modifiers

As yet, the pathogenesis of Kaposi’s sarcoma in the setting of AIDS is not completely understood. Patients who present with Kaposi’s sarcoma as the initial manifestation of AIDS and have CD4+ cell counts of at least 2 × 108/L, no constitutional symptoms and no previous zidovudine therapy may be considered for monotherapy with high dosage interferon-α. Dosage schedules of 27 to 36MU daily or 36MU 3 times weekly are frequently employed. Response rates in this subgroup of patients are in the range of 40 to 60%, of whom one-third are histologically documented complete responders. These responses are durable; several reports have associated tumour responses with decreases of the HIV-1 p24 antigen, low incidence of opportunistic infections and prolonged survival. Combined treatment with zidovudine 500 to 800mg daily and interferon-α 9 to 18MU daily leads to tumour responses similar to those observed with single agent high dosage interferon-α. With this combination, response rates up to 30% have been also achieved in patients with a CD4+ cell count of <2 × 108/L. However, no conclusive data exist as to whether the addition of interferon-α to long term treatment with zidovudine is effective in developing or progressive Kaposi’s sarcoma.

Neopterin and alpha-interferon in patients affected by Kaposi's sarcoma from Africa

The presence of circulating alpha-interferon and neopterin was investigated in sera of 47 patients affected by African Kaposi's sarcoma, both HIV-seropositive ( 13 patients) and HIV-seronegative ( 34 patients). For comparison, analyses were also performed in 20 HIV-seropositive symptomatic African subjects as well as in 20 African and 20 Italian healthy individuals. Alpha-interferon and neopterin levels appeared significantly higher in comparison with healthy control groups ( P < 0.001) but not with HIV-seropositive African individuals without Kaposi's sarcoma. Moreover, alpha-interferon and neopterin levels were significantly higher in progressive Kaposi's sarcoma ( 27 patients) than in regressive Kaposi's sarcoma ( 20 patients) ( P < 0.001). A significant correlation between alpha-interferon and neopterin was observed ( r = 0.57; P < 0.01). Furthermore, alpha-interferon levels of HIV-seropositive Kaposi's sarcoma patients resulted significantly higher in comparison with the seronegative ones ( P < 0.05). It is concluded that alpha-interferon and neopterin may be reliable prognostic markers in Kaposi's sarcoma patients.

INTERFERON FOR AIDS-RELATED KAPOSI'S SARCOMA.

Two studies in this issue of the Lancet show that high-dose recombinant alpha-interferon is effective in treating AIDS-related Kaposi's sarcoma. de Wit and colleagues used alpha-interferon to treat 28 homosexual men with AIDS and progressive Kaposi's sarcoma. Between four and 40 weeks, 46 percent of the evaluable …

Interferon-induced 2'-5' oligoadenylate synthetase during interferon-alpha therapy in homosexual men with Kaposi's sarcoma: marked deficiency in biochemical response to interferon in patients with acquired immunodeficiency syndrome.

Titers of circulating interferon (IFN) and the activity of 2'-5' oligoadenylate (2-5A) synthetase, an enzyme specifically induced by IFN, were measured in 28 homosexual men with acquired immunodeficiency syndrome (AIDS) who received one- to six-month courses of antineoplastic therapy with IFN-alpha and in homosexual and heterosexual controls. Fifteen of the patients and two of seven healthy homosexual men had high endogenous levels of 2-5A synthetase. IFN therapy induced further increases in this enzyme in only 10 of the 28 patients with AIDS. Furthermore, peripheral blood cells from all but one of the patients with AIDS and homosexual controls tested were markedly deficient in their ability to respond to IFN in vitro, as measured by increased levels of 2-5A synthetase. We did not find a statistical correlation between cytomegalovirus viremia and pretherapy endogenous circulating IFN, nor any apparent correlation between disseminated infection with cytomegalovirus and either basal levels of 2-5A synthetase or changes in enzyme level during therapy. Pretherapy circulating IFN was significantly correlated with progressive Kaposi's sarcoma during therapy, but rises in levels of 2-5A synthetase were not sufficient to predict a good clinical response.

A comparison of cyclophosphamide, vincristine, and prednisone (COP) with nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) in the treatment of nodular, poorly differentiated, lymphocytic lymphoma

This study was designed to test the efficacy and toxicity of COP (cyclophosphamide, vincristine, and prednisone) and MOPP (nitrogen mustard, vincristine, prednisone, and procarbazine) in 13 previously untreated patients with disseminated, nodular, poorly differentiated, lymphocytic lymphoma, and to test for patient cross-resistance to the regimens. Complete remission was initially achieved in six of eight patients on COP and three of five on MOPP. Three patients were crossed over to the alternative induction regimen because of progressive disease after an initial partial response; one was crossed over because of toxicity. On crossover, four patients achieved complete remission, two on either regimen. Durations of unmaintained complete remission range from 6-46+ months, with 8/13 still in their first complete remission. Only one patient has died, while in remission, from progressive Kaposi's sarcoma; one was lost to follow-up while in complete remission at 44 months; the others (85%) remain alive 33-54 months from the initiation of chemotherapy. MOPP was significantly more toxic with respect to thrombocytopenia, duration of myelosuppression, and cumulation of toxicity. Because of its more acceptable toxicity, COP is recommended as initial therapy for patients with nodular, poorly differentiated, lymphocytic lymphoma. MOPP or another regimen of non-crossresistant combination chemotherapy would be more appropriate for primary treatment failures.