tretinoin and Sarcoma--Kaposi

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.. 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.. 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.. 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.. 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.. 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, vincr. 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.

Topics: Alitretinoin; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bleomycin; Doxorubicin; Drug Therapy, Combination; Etoposide; HIV Infections; Humans; Liposomes; Observational Studies as Topic; Randomized Controlled Trials as Topic; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin; Vincristine

Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). Studies are being carried out to determine how best to utilize this characteristic in treatments for conditions such as chronic hand dermatitis.. To review the literature on alitretinoin.. The scope of the review encompasses ways that alitretinoin is currently and may potentially be utilized.. Orally administered alitretinoin is a safe and effective treatment for chronic hand dermatitis. Topical treatment with alitretinoin can be expanded into other areas such as photoaged skin and cutaneous T-cell lymphoma. Despite these benefits, oral alitretinoin will face a difficult path attaining approval for use in the US.

Topics: Administration, Oral; Alitretinoin; Antineoplastic Agents; Hand Dermatoses; Humans; Receptors, Retinoic Acid; Sarcoma, Kaposi; Tretinoin

More therapeutic options are needed for bone and soft tissue sarcomas, especially for patients with metastatic disease. Recent randomized clinical trials conducted in colon, breast and lung cancer have shown the anti-vascular endothelial growth factor agent, bevacizumab, alone or in combination with chemotherapy, improves response and survival. Preclinical studies have demonstrated the anti-tumor effects of varied anti-angiogenic agents in sarcoma cell lines and tumor models.. Preclinical studies in sarcomas have evaluated the role of targeted agents including platelet-derived growth factor, matrix metalloproteinases, urokinase receptor and varied small-molecule tyrosine kinase inhibitors. Novel angiogenesis inhibitors are being studied in the treatment of sarcoma, including monoclonal antibodies against vascular endothelial growth factor, cis- and trans-retinoic acids, thalidomide, and tyrosine kinase inhibitors. Phase I, II and III clinical trials continue to evaluate these agents alone, in combinations together and combined with standard chemotherapy. We review herein the preclinical rationale and clinical trial results of anti-angiogenesis therapy in the treatment of soft tissue and bone sarcoma.. Preclinical mechanistic study and clinical trials are continuing in order to evaluate the therapeutic role and ultimately validate the efficacy of the varied anti-angiogenesis agents in soft tissue and bone sarcoma.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Sarcoma; Sarcoma, Kaposi; Thalidomide; Tretinoin; Vascular Endothelial Growth Factor A

In many countries, Kaposi's sarcoma (KS) is the commonest malignancy among individuals infected with the human immunodeficiency virus-1 (HIV) and is a cause of substantial morbidity and mortality.. The aim of this review was to assess the effectiveness of current therapeutic regimens for the treatment of HIV associated KS, with a focus on options that may be available in resource poor settings.. We searched Cochrane HIV/AIDS Group trials register, Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2002), MEDLINE, EMBASE, AIDSLINE, CINAHL, CANCER LIT, AIDSDRUGS, AIDSTRIALS, African index medicus, physicians data query protocols, United Kingdom Co-ordinating committee on Cancer Research Register of Cancer trials, proceedings and abstracts from AIDS and cancer conferences. The search was conducted between 1st October 2001 and completed 14th December 2002. We also contacted experts in the field of cancer.. Randomised trials of therapy for KS in HIV infected adults.. All reviewers assessed trial quality and extracted data. We contacted study authors for additional information.. Five trials involving 915 people were included. Two trials involving 499 people compared pegylated liposomal doxorubicin (PLD) to a standard regimen among patients with advanced KS were analysed together. There was no difference in mortality between the two regimens RR1.26 (95% confidence interval (CI) 0.83 to 1.91). The response to PLD was superior to that of the control regimen RR 2.16, (95% CI 1.68 to 2.78). Two other trials involving 402 people demonstrated that topical alitretinoin was effective treatment compared to placebo among patients with cutaneous Kaposi's sarcoma. The results were analysed separately due to heterogeneity; (1) the relative risk (RR) was 5.34 (95%CI 2.16 to 13.21) and (2) RR 1.96, 95% CI 1.27 to 3.01). The final trial compared different radiotherapy regimens for treatment of cutaneous KS. The initial complete response of lesions to 20Gy given in 10 fractions or 40Gy in 20 fractions was similar and slightly superior to that of lesions treated with 8Gy as a single fraction, RR 1.58, (95% CI 1.01 to 2.48) and RR 1.65, (95% CI 1.06 to 2.57) respectively.. Alitretinoin gel is effective in treating cutaneous KS, PLD is effective treatment for advanced KS and radiotherapy appears effective in treating cutaneous lesions. Apart from the trial of radiotherapy no trials applicable to developing settings were identified.

Topics: Alitretinoin; Antineoplastic Agents; Doxorubicin; HIV Infections; Humans; Liposomes; Randomized Controlled Trials as Topic; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Kaposi's sarcoma (KS) is the most common malignancy associated with HIV infection and is considered an AIDS defining condition by the US Centers of Disease Control Guidelines. Several advances in the treatment of AIDS-related KS have been achieved over the past few years, even though a gold standard therapy for KS has not yet been defined and treatment must be tailored to individual needs. Since the availability of highly active antiretroviral therapy (HAART), a dramatic clinical response has been documented in patients with KS, making HAART an essential approach in the management of KS in most, if not all, patients with AIDS-related KS. However, in case of aggressive, visceral, and/or life-threatening KS, more complex therapeutic schedules have to be taken into account, including chemotherapy, radiotherapy, and/or immunotherapy. In general, systemic treatment for KS is limited to widespread, symptomatic disease, whereas local interventions are indicated for minimal, cosmetically troublesome lesions. Among new cytotoxic agents, liposomal anthracyclines and paclitaxel are highly effective molecules for KS and have been approved by the US Food and Drug Administration (FDA) as first-line and second-line monotherapy, respectively, for advanced KS. Furthermore, a greater understanding of the pathogenesis of KS has lead to the development of an array of new experimental agents. Many antiangiogenic agents such as AGM 1470 (TNP 470), thalidomide, and glufanide disodium (IM 862) have produced encouraging responses in patients with KS and large clinical trials are in progress. Retinoic acids may also block neoangiogenesis as well as proliferation of KS cells in vitro, and they have been used either systemically or topically with a high response rate. Thus, a topical compound 0.1% alitretinoin gel was approved in 1999 by the FDA for the treatment of skin lesions associated with KS. Human chorionic gonadotropin, a hormonal agent, has shown a strong inhibitory activity in KS cells, but its role in the regression of KS lesions is not clear. Finally, the identification of a novel gamma-herpesvirus, human herpesvirus-8, as a causative agent for KS, together with novel antiangiogenic compounds, such as metalloproteinase inhibitors, may offer promising targets for the therapy of KS.

Topics: AIDS-Related Opportunistic Infections; Angiogenesis Inhibitors; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Humans; Interferons; Paclitaxel; Sarcoma, Kaposi; Tretinoin

The past several years have seen demonstrable progress in the therapy of Kaposi's sarcoma (KS). Liposomal anthracyclines and paclitaxel have been found to be highly effective chemotherapeutic agents for this disease. Recent advances in our understanding of the pathogenesis of KS have led to the consideration of various new experimental agents. Two antiangiogenesis agents, TNP-470 and thalidomide, have been determined to induce some responses in KS, and others are now in early clinical trials or in preclinical development. Oral 9-cis retinoic acid has been shown to have anti-KS activity, and preliminary studies suggest that a urinary protein found in preparations of human chorionic gonadotropin also has activity. Effective anti-HIV treatment has been shown to affect the growth of KS, and the discovery of a new herpesvirus as a causative agent for KS has offered new potential targets for attack.

Topics: Administration, Oral; Alitretinoin; Anthracyclines; Antineoplastic Agents; Cyclohexanes; Humans; Immunosuppressive Agents; Liposomes; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sarcoma, Kaposi; Sesquiterpenes; Thalidomide; Tretinoin

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.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Angiostatins; Antineoplastic Agents; Antiviral Agents; Chorionic Gonadotropin; Collagen; Drug Therapy, Combination; Endostatins; Herpesvirus 8, Human; HIV-1; Peptide Fragments; Plasminogen; Sarcoma, Kaposi; Tissue Inhibitor of Metalloproteinases; Tretinoin

Kaposi's sarcoma (KS) is the most common tumor associated with AIDS. A growing number of patients with this tumor are presenting at later stages of HIV with more rapidly progressive, extensive, or symptomatic KS or with tumors involving visceral organs. Chemotherapy treatment is effective in inducing tumor regression, reducing edema, and ameliorating symptoms caused by these tumors. Side effects and toxicities from these agents, however, can be quite pronounced, especially in patients with advanced AIDS Antiretroviral therapy, prophylaxis for opportunistic infections, and the use of hematopoietic growth factors should be routinely included in the management of these patients. Newer chemotherapeutic agents and combination regimens may be more effective or less toxic than previously evaluated regimens.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antineoplastic Agents; Drug Therapy, Combination; Hematopoietic Cell Growth Factors; Humans; Liposomes; Neoplasm Staging; Phototherapy; Sarcoma, Kaposi; Tretinoin

Dermal dendrocytes represent a population of resident cells of the dermis identified recently by virtue of the immunohistochemical expression of the coagulation factor XIIIa (fXIIIa). These dendritic cells of bone-marrow origin bear particular histoenzymatic and immunohistochemical features, some of which are shared with antigen-presenting cells; however, they are clearly distinct from epidermal Langerhans cells. Dermal dendrocytes could act as macrophages, antigen-presenting cells or participate in the homeostasis of macromolecules of the dermis. These cells give rise to some cutaneous tumours and seem involved in inflammatory dermatoses where they act by means of cytokine production; they could even represent targets of HIV infection. Future functional studies will hopefully lead to a better understanding of their precise role in normal and diseased skin, which remains presently partly speculative.

Topics: Acquired Immunodeficiency Syndrome; Cytokines; Dermatitis; Granuloma; Histiocytoma, Benign Fibrous; HLA-DR Antigens; Humans; Sarcoma, Kaposi; Skin; Skin Neoplasms; Skin Physiological Phenomena; Transglutaminases; Tretinoin; Ultraviolet Rays; Vasculitis, Leukocytoclastic, Cutaneous

To evaluate the safety, dose tolerance, and anti-tumor effects of 9-cis-retinoic acid in the treatment of Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS).. Phase 2, open-label clinical trial of oral doses of 9-cis-retinoic acid increasing in 40-mg increments every 2 weeks from 60 mg/m(2) per day to a maximum of 140 mg/m( 2) per day.. Five hospital or health maintenance organization outpatient clinics.. Fifty-seven adult male patients with human immunodeficiency virus and biopsy-proven KS.. Safety was evaluated by adverse events, physical examination, laboratory test abnormalities, treatment-limiting toxic effects, and reasons for early withdrawal. Response (>/=50% improvement) was evaluated by an overall KS response and by the area and height from 6 index lesions selected at baseline.. Patients tolerated 60 and 100 mg/m(2) per day. Most patients found 140 mg/m(2) per day intolerable owing to headache. Common treatment-related adverse events were headache, xerosis, rash, alopecia, and hyperlipemia. The patient response rate for the overall KS disease was 19% (11/57), including 1 patient with clinically complete response. The response rate assessed by measuring 6 index lesions during treatment was 39% (22/57). Sixteen responding patients (73%) were refractory to at least 1 previous anti-KS therapy. Patients with CD4( +) counts of 150 cells/ micro L or lower were as likely to respond as patients with counts of higher than 150 cells/ micro L. The median time to response was 8.5 weeks (range, 4.0-21.1 weeks). The median duration of treatment was 15.1 weeks (range, 0.14 to >/=62 weeks).. 9-cis-retinoic acid capsules have moderate activity and provide durable responses, but substantial toxic effects at higher doses limit its suitability as an anti-KS therapy.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alitretinoin; Antineoplastic Agents; Biopsy, Needle; Capsules; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Risk Assessment; Sarcoma, Kaposi; Single-Blind Method; Skin Neoplasms; Survival Rate; Treatment Outcome; Tretinoin

A multicenter trial was conducted to determine the efficacy and toxicity of escalating dosages of liposomal tretinoin (all-trans-retinoic acid) administered once or three times weekly in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma.. Seventy-six patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma were randomized to receive the study drug either once (n = 30) or 3 times weekly (n = 46). The starting dosage was 60 mg/m(2), which was escalated to 90 mg/m(2) and then 120 mg/m(2) if the drug was well tolerated (

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Antineoplastic Agents; Drug Carriers; Female; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Liposomes; Male; Middle Aged; Quality of Life; Sarcoma, Kaposi; Treatment Outcome; Tretinoin

To assess the efficacy, safety and tolerance of oral 9-cis-retinoic acid in HIV-infected patients with Kaposi's sarcoma.. Sixty-six patients with AIDS-related Kaposi's sarcoma were enrolled at 14 centers; 60 received the study medication and were analyzed and, of these, 45 (75%) had received prior therapy for Kaposi's sarcoma. Once daily oral 9-cis-retinoic acid (alitretinoin, Panretin) was administered at doses up to 140 mg/m2. Most patients (72%) received a maximum dose of 100 mg/m2. Response was assessed using AIDS Clinical Trials Group (ACTG) criteria.. The median age was 38 years and the median absolute CD4 cell count was 194 x 10(6) cells/l (range 6-784 x 10(6)). Despite the use of three- and four-drug antiviral regimens (83%), the median HIV RNA at baseline was 8701 copies/ml [range < 500 (lower limit of detection) to 4.24 x 10(6)]. The tumor response rate was 37% (95% confidence interval 25-49). Tumor response was associated with improved quality-of-life measures. There was a significant increase in interleukin 6 (IL-6) levels from baseline to week 4. Responders had significantly lower baseline soluble IL-6 receptor levels (P = 0.029) than non-responders. The median time to response was 9 weeks (mean, 13 weeks; range, 4-36). HIV RNA levels did not change significantly during therapy nor did they correlate with tumor responses. Study drug was discontinued by 28 patients for adverse events, which included headache (13) and skin toxicity (10).. Oral 9-cis-retinoic acid is an active antitumor drug for AIDS-related Kaposi's sarcoma. Treatment is associated with skin and constitutional toxicity and further studies are needed to improve its long-term tolerance.

Topics: Administration, Oral; Adult; Alitretinoin; Antineoplastic Agents; CD4 Lymphocyte Count; Drug Tolerance; Female; HIV Infections; Humans; Interleukin-6; Male; Middle Aged; Receptors, Interleukin-6; RNA, Viral; Safety; Sarcoma, Kaposi; Tretinoin

This randomized, double-blind and vehicle-controlled phase III study was conducted to evaluate the efficacy and safety of alitretinoin gel 0.1% for the topical treatment of the cutaneous lesions of AIDS-related Kaposi's sarcoma (KS).. Patients received treatment with alitretinoin gel (n = 62) or vehicle gel (n = 72) twice daily for 12 weeks. The primary efficacy endpoint was the cutaneous KS tumor response rate according to AIDS Clinical Trials Group (ACTG) objective criteria applied to topical therapy, with the patient as the unit of analysis.. Treatment of patients with alitretinoin gel resulted in a significant antitumor effect. The overall patient response rate (complete plus partial response) was 37% (23 of 62) for the alitretinoin-treated patients and 7% (5 of 72) for the vehicle-treated patients (p = 0.00003). The difference in response rates for the 2 treatment groups remained significant even after taking into consideration numerous variables, including age (p = 0.00001), Eastern Cooperative Oncology Group (ECOG) status (p = 0.00002), CD4+ cell count (p = 0.00002), history of opportunistic infection (p = 0.00002), aggregate area of indicator lesions (p = 0.00005), number of raised indicator lesions (p = 0.00002), prior therapy for KS (p = 0.00003), and number of drugs (p = 0.00002) used in concomitant antiretroviral therapy. Generally, treatment with alitretinoin gel was well tolerated. The overall incidence of adverse events was similar for the 2 treatment groups. Adverse events related to treatment with alitretinoin gel tended to be mild to moderate in severity and limited to the site of application. The most frequent adverse event occurring at the application site following alitretinoin gel treatment was irritation coded as rash (32%).. The results of this study provide convincing evidence of the superiority of alitretinoin gel over vehicle gel for the treatment of the cutaneous lesions of AIDS-related KS.

Topics: Administration, Topical; Adult; Alitretinoin; Antineoplastic Agents; Double-Blind Method; Drug Administration Schedule; Female; Gels; Herpesvirus 8, Human; Humans; Male; Palliative Care; Pharmaceutical Vehicles; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS).. Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated.. Nine academic clinical centers.. One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS.. AIDS Clinical Trials Group response criteria.. Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity.. Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.

Topics: Administration, Cutaneous; Adult; AIDS-Related Opportunistic Infections; Alitretinoin; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Gels; Humans; Male; Middle Aged; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin; United States

Kaposi's sarcoma (KS) is the most frequent malignancy in patients with HIV. Given the promise that retinoids show in the treatment of various hyperproliferative skin disorders and in vitro evidence of inhibition of proliferation of KS cells, a randomized, controlled clinical trial was conducted.. A 12-week, multicenter, randomized, double-blind, vehicle-controlled safety and efficacy evaluation of topical alitretinoin 0.1% gel applied to cutaneous KS lesions was conducted in HIV-infected patients. The primary efficacy endpoint was the patient's response rate, as determined by evaluating six index lesions representative of the patient's overall KS cutaneous disease using AIDS Clinical Trials Group (ACTG) response criteria applied to topical therapy. Of 268 patients entered in the blinded treatment phase of the study (alitretinoin group, n = 134; vehicle group, n = 134), 47 patients (35%) treated with alitretinoin 0.1% gel had a positive response, compared with 24 patients (18%) treated with vehicle gel. Of 184 patients receiving open-label alitretinoin treatment following the blinded phase of the trial, 90 patients (49%) met criteria for a positive response. This superior efficacy of alitretinoin gel over vehicle gel was maintained when the data were adjusted or analyzed for age, race, Kamofsky scores, baseline CD4+ lymphocyte counts, number of raised lesions at baseline, and aggregate area of index lesions. Alitretinoin 0.1% gel was superior to vehicle gel regardless of the number of concurrent antiretroviral therapies. Most adverse events were mild to moderate in severity, limited to the application site, and reversible on reduction in frequency or suspension of application. Relatively few patients (7%) discontinued alitretinoin therapy because of to related adverse events.. The results show that alitretinoin gel application is safe and generally well tolerated, and they indicate the superiority of alitretinoin 0.1% gel over vehicle gel in the treatment of cutaneous AIDS-related KS lesions.

Topics: Administration, Topical; Adult; Aged; AIDS-Related Opportunistic Infections; Alitretinoin; Anti-HIV Agents; Antineoplastic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Gels; Humans; Male; Middle Aged; Sarcoma, Kaposi; Tretinoin

To assess the efficacy and safety of all-trans-retinoic acid (ATRA), a retinoid with antitumour activity that inhibits in vitro the growth of Kaposi's sarcoma cells, in patients with low-risk AIDS-associated Kaposi's sarcoma.. Non-randomized phase II study, using a group sequential procedure to determine whether the response rate to ATRA was above 10%.. Nine referral French centres.. Twenty HIV-seropositive men with CD4 cells > or = 200 x 10(6)/l, low-risk Kaposi's sarcoma [T0I0S0 according to the classification of AIDS Clinical Trials Group (ACTG)] not previously treated with systemic anti-Kaposi's sarcoma agents, and with at least four measurable lesions were included.. ATRA was given orally 45 mg/m2 daily for 12 weeks.. Tumour response evaluated according to ACTG criteria.. Nineteen patients were evaluated for response: partial response, stabilization and progression were found in eight (42%), seven (37%), and four (21%) patients, respectively. Gradual flattening and lightening of lesions was observed in responders after at least 2 months of ATRA. All patients with partial response at week 12 pursued ATRA for another 15+/-7 weeks. Further improvement was observed in six patients. Median duration of response was 332 days. Cheilitis, transient headaches and skin dryness were the main toxicities noted. No significant changes in HIV viral burden or serum interleukin-6 pathways were observed.. ATRA is well tolerated and effective enough in Kaposi's sarcoma patients to warrant further evaluation.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Antineoplastic Agents; Cytokines; Female; Follow-Up Studies; HIV-1; Humans; Male; Middle Aged; Sarcoma, Kaposi; Tretinoin; Viral Load

A phase I/II study of oral all-trans-retinoic acid (ATRA; tretinoin), administered every other week alone and then in combination with interferon (IFN) alfa-2a, was undertaken to evaluate the activity, toxicity, and pharmacokinetics of this regimen in patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS).. Thirteen patients with HIV-associated KS, eight of whom had more than 100 CD4 cells/microL, were entered. The protocol initially called for patients to receive 150 mg/m2/d of ATRA every other week. However, this regimen was associated with headaches, and the initial dose of ATRA was reduced to 40 mg/m2/d orally in three divided doses, increasing to a maximum of 100 mg/m2/d. After 12 weeks, IFN alfa-2a could be added.. The principal toxicities from ATRA were headaches (12 patients) and dry skin or lip (seven patients). Of 12 assessable patients, 10 had progressive disease and two had stable disease on ATRA alone. One of eight assessable patients who went on to receive ATRA plus IFN alfa-2a had partial response (PR). There were no overall changes in the serum HIV p24 antigen (Ag) level or CD4 count during treatment with ATRA alone. Peak ATRA levels decreased during the week of continuous ATRA therapy, but rebounded when treatment was resumed after a week without the drug.. Intermittent ATRA therapy was reasonably well tolerated and provided a means to circumvent the low plasma exposure found with continuous ATRA therapy. However, we were unable to document antitumor activity in patients with HIV-associated KS.

Topics: Adult; Combined Modality Therapy; Drug Administration Schedule; Headache; HIV; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Least-Squares Analysis; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Remission Induction; Sarcoma, Kaposi; Tretinoin; Virus Replication

Administration of all-trans-retinoic acid (ATRA) on a continuous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to determine if administration of ATRA on an intermittent schedule could overcome the rapid decrease in plasma drug concentration and provide repetitive periods of higher plasma drug exposure.. ATRA was administered on repetitive cycles of 7 consecutive days of drug followed by 7 days without drug. On the days of pharmacokinetic monitoring, following an overnight fast, a fixed single oral dose of 40 mg/m2 was administered and frequent plasma samples were obtained over 8 hours. Patients had pharmacokinetic studies performed on the first and seventh days of the first week, and on the first day of the third and eleventh weeks. ATRA was measured in plasma with a reverse-phase high-performance liquid chromatography (HPLC) assay.. Plasma exposure to ATRA as measured by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mumol/L.min on day 1 to 18 +/- 4 mumol/L.min by day 7. Plasma ATRA concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to those achieved on day 1 of treatment, with mean AUCs of 177 +/- 39 and 128 +/- 30 mumol/L.min, respectively.. An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. Phase II trials to evaluate the role of intermittent schedules of administration for ATRA are planned.

Topics: Acquired Immunodeficiency Syndrome; Adult; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Half-Life; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Sarcoma, Kaposi; Tretinoin; Up-Regulation

Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antineoplastic Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pilot Projects; Receptors, Interleukin-2; Sarcoma, Kaposi; Survival Analysis; Treatment Outcome; Tretinoin

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; HIV Seropositivity; Humans; Male; Middle Aged; Prospective Studies; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Gels; Humans; Male; Sarcoma, Kaposi; Skin Neoplasms; Treatment Failure; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Counseling; Drug Interactions; Humans; Sarcoma, Kaposi; Tretinoin

Topics: Administration, Topical; Aged; Aged, 80 and over; Alitretinoin; Antineoplastic Agents; Female; Gels; Humans; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Gels; Humans; Sarcoma, Kaposi; Tretinoin

Topics: Administration, Cutaneous; AIDS-Related Opportunistic Infections; Alitretinoin; Anti-HIV Agents; Dermatologic Agents; Drug Administration Schedule; Humans; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

Unlike solid organ transplantation, Kaposi's sarcoma (KS) occurs rarely following hematopoietic stem cell transplantation (HSCT). In fact, only 5 cases of KS have been reported after allogeneic or autologous HSCT. The usual treatment combines a substantial decrease in, or elimination of, immunosuppressive therapy along with local measures such as surgical excision, cryotherapy or radiation therapy. A 46-year-old woman with chronic myelogenous leukemia who had received an allogeneic HSCT previously from an HLA-identical sibling, presented on day +814 with human herpes virus-8-associated KS involving her left lower extremity. She had been on continuous immunosuppressive therapy since her transplant because of chronic graft-versus-host disease. The intensity of immunosuppressive therapy was decreased once a diagnosis of KS had been established. However, the nodular lesions continued to progress in size and number. Therefore, a course of irradiation was administered to sites of bulk disease on her legs. Furthermore, thalidomide was initiated along with a topical retinoid, alitretinoin 0.1% gel applied twice daily to the nonirradiated lesions. This approach yielded a partial response in both irradiated and nonirradiated lesions over the course of the following 7 months. Both thalidomide and alitretinoin 0.1% gel appear to be beneficial in HSCT-associated KS and exhibit tolerable side effects.

Topics: Administration, Oral; Administration, Topical; Adult; Alitretinoin; Antineoplastic Agents; Child; Female; Hematopoietic Stem Cell Transplantation; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Polymerase Chain Reaction; Sarcoma, Kaposi; Thalidomide; Tretinoin

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Agents; Dermatologic Agents; Drug Approval; Gels; Humans; Sarcoma, Kaposi; Tretinoin

Topics: Administration, Topical; AIDS-Related Opportunistic Infections; Alitretinoin; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Gels; Humans; Sarcoma, Kaposi; Tretinoin; United States; United States Food and Drug Administration

The Food and Drug Administration (FDA) recently enacted rules requiring drug companies to provide physicians with information on pediatric use of their products. Also, Nevirapine (Viramune) was recently approved for pediatric use. An FDA advisory panel has also recommended approval of Panretin (9-cis retenoic acid) gel as a second-line treatment for Kaposi's sarcoma.

Topics: Antineoplastic Agents; Child; Dermatologic Agents; Drug Approval; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Sarcoma, Kaposi; Tretinoin; United States Food and Drug Administration

Ligand Pharmaceuticals has received FDA approval for Panretin Gel (alitretinoin) for topical treatment of Kaposi's sarcoma. The company has also filed for approval in Europe and Canada. The gel is applied twice daily, and a 4- to 6-month course of therapy costs between $3,900 and $5,800. The main side effect is skin irritation; 7 percent of patients withdrew from trials because of skin toxicity. Panretin capsules have been tested in phase II clinical trials. Results of 2 trials with 402 patients were presented at the Retroviruses conference.

Topics: Acquired Immunodeficiency Syndrome; Administration, Topical; Antineoplastic Agents; Dermatologic Agents; Drug Approval; Gels; Humans; Sarcoma, Kaposi; Tretinoin; United States Food and Drug Administration

Topics: Acquired Immunodeficiency Syndrome; Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Interferon-alpha; Male; Sarcoma, Kaposi; Tretinoin

Retinoids, a group of natural and synthetic vitamin A analogues the receptors of which belong to the superfamily of steroid receptors, can exert profound effects on growth and/or differentiation of embryonic and neoplastic cells. Kaposi's sarcoma (KS), previously a rare multicentric neoplasm, has become epidemic with HIV infection, although the etiology of KS remains obscure. In the present study, the effects of two potent retinoids, all-trans-retinoic acid (RA) and 13-cis-RA, on the expression of retinoic acid receptor alpha and the growth of AIDS-related KS (AIDS-KS) cells were examined. The proliferation of AIDS-KS cells was significantly inhibited by RA and 13-cis-RA in a dose-dependent manner with 50% inhibitory concentration of 1.4 x 10(-10) M and 4.7 x 10(-9) M, respectively, which correlate with their potency. Growth inhibition was time dependent with maximal inhibition of 90% after 3 days of treatment with 10(-8) M RA. Growth inhibition by RA was further potentiated by forskolin (1 microM), an intracellular cyclic AMP-inducing agent. Moreover, RA treatment blocked the proliferative effect of oncostatin M and tumor necrosis factor alpha, two major KS autocrine growth factors. The effects of RA were accompanied by a dramatic increase in nuclear staining for retinoic acid receptor alpha and in the relative number of strongly positive retinoic acid receptor alpha nuclei. Finally, RA induced morphological changes as KS cells became more flattened, better spread, and more adhesive to the substrate. These results suggest that retinoids inhibit proliferation of AIDS-KS cells and further support their utility as therapeutic agents in AIDS-KS.

Topics: Acquired Immunodeficiency Syndrome; Animals; Cell Adhesion; Cell Division; Cell Nucleus; Cyclic AMP; Drug Synergism; Growth Inhibitors; Growth Substances; Humans; Kinetics; Mice; Oncostatin M; Peptides; Rats; Receptors, Retinoic Acid; Sarcoma, Kaposi; Tretinoin; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

A panel of retinoid compounds (tretinoin, isotretinoin, acitretin, and RO13-1470) were tested for inhibitory activity against Kaposi's sarcoma cell (KSC) cultures in vitro. Tretinoin was found to be the most effective retinoid tested, inhibiting the growth of KSC in vitro while having no effect on the expression of interleukin-6 and basic fibroblast growth factor, two important cytokines involved in KSC growth. Tretinoin also did not appear to downregulate the expression of receptors for these two cytokines. At low concentrations (10(-9) M), acitretin and tretinoin selectively inhibited growth of early passage KSC. At higher concentrations (10(-6)-10(-5) M), retinoid treatment induced a pattern of DNA degradation and morphological changes in KSC characteristic of apoptosis (programmed cell death). The inhibitory activity of tretinoin on KSC growth was decreased if human serum (but not fetal calf serum) was present in the growth medium, and partially restored by removal of serum lipids. These data suggest that retinoids possess potential as therapeutic agents in Kaposi's sarcoma.

Topics: Acitretin; Benzoates; Cell Division; Fibroblast Growth Factor 2; Humans; Interleukin-6; Isotretinoin; Male; Receptors, Fibroblast Growth Factor; Receptors, Interleukin; Receptors, Interleukin-6; Retinoids; RNA, Messenger; Sarcoma, Kaposi; Tretinoin; Tumor Cells, Cultured

Topics: Adult; HIV Infections; Humans; Male; Middle Aged; Neoplasm Staging; Remission Induction; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Topics: Drug Eruptions; Humans; Isotretinoin; Male; Pilot Projects; Sarcoma, Kaposi; Tretinoin