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Topical/Intralesional Treatment
Researchers Report New Treatment Findings
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Pathogenesis:
Kaposi's sarcoma (KS) remains the most commonly diagnosed malignancy in HIV-infected people. Although the incidence of KS as an AIDS-defining illness among gay and bisexual men has declined, an increasing proportion of AIDS deaths are now due to KS. Most often initially involving the skin, KS lesions usually present as red to purple nodules or plaques, that can appear in several parts of the body simultaneously, sometimes with associated edema.
The etiology of KS remains unknown, but evidence suggests that the disease is promoted by the effects of immunosuppression and immune activation, possibly combined with a sexually transmissible infectious agent.
In two recently published studies, herpes virus-like DNA sequences, dubbed human herpes virus 8 (HHV8 or KSHV), have been isolated from KS lesions from patients and in KS-derived cell cultures. In the first study, Chang et al., used representational difference analysis, which incorporates repeated PCR amplifications of short DNA fragments of diseased and nondiseased tissue. Herpes virus-like DNA sequences were isolated from 90% of KS tissues. These sequences were not present in tissue DNA from HIV-negative patients, but were present in15% of DNA samples from non-KS tissue of HIV-positive patients. In the second study (Moore et al.) herpes virus-like DNA sequences were identified in 10 of11 tissue samples from HIV-positive patients with KS, in all 6 samples from patients with classic KS, and in all 4 samples from HIV-negative men with KS. Because of the association of a herpes virus with KS, and anecdotal reports of KS regression during foscarnet treatment for CMV, a trial of foscarnet for the treatment of KS is currently underway.
Other agents suspected of causing KS in the past include cytomegalovirus (CMV), hepatitis B virus, human herpes virus 6 (HHV6), human papillomavirus 16 (HPV 16), HIV, and Mycoplasma penetrans.
There is increasing evidence that circulating growth factors appear to play a key role in the pathogenesis of HIV-related KS. A number of cytokines and viral products produced by retrovirally infected cells (or by the KS cells themselves) are potent growth factors for KS cells in vitro. These include the HIV-1 tat protein, basic fibroblast growth factor (bFGF), the cytokines IL-1, TNF and IL-6, and others. The Community Research Initiative on AIDS (CRIA) located in New York City is currently conducting a study of growth factors isolated from tissues of patients with KS.
Some evidence suggests that KS may not in fact be a true malignancy but rather an angiogenic disorder(a disorder in the formation of blood vessels) with widespread cellular proliferation occurring in response to circulating growth factors. Trials are underway of TNP-470 and SP-PG (Tecogalan DS-4152), which inhibit angiogenesis in vitro.
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Sites of Disease:
KS most commonly involves the skin, although involvement of the lymph nodes, the oral cavity, and gastrointestinal tract are often seen at presentation. Lesions are found in the GI tract in 40% of cases at diagnosis, up to 80% at autopsy, and are frequently asymptomatic. Pulmonary involvement, often occurring late in the disease, may cause severe respiratory symptoms and is associated with a poor prognosis.
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Diagnosis:
Biopsy confirmation establishes histological diagnosis. Suspected pulmonary lesions can be detected by bronchoscopy, but are generally not biopsied due to low yield and risk of hemorrhage. Chest x-rays and pulmonary gallium scans can also be used for evaluation. The concurrent presence of pulmonary infiltrates and nodular densities on chest x-ray, the lack of uptake of gallium in the pulmonary parenchyma and the presence of blood streaked sputum is virtually diagnostic for pulmonary KS when infectious causes have been ruled out. KS involving the gastrointestinal tract is best diagnosed visually on endoscopy (biopsies are frequently negative because the lesions are sub-mucosal).
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Treatment:
Therapeutic approaches must take into account that there is no curative therapy, that the natural course of the disease may be quite variable and that a large number of systemic approaches have immunosuppressive effects. Many factors must be evaluated in developing a treatment strategy; the extent and location of lesions, the presence of tumor-associated symptoms (e.g. pain, edema, GI bleeding), symptoms of HIV infection, and the status of the patient's immune system. Generally, KS patients with CD4+ cells >200/mm3, with no previous opportunistic infections, and few constitutional symptoms have a better prognosis. The primary indication for treatment may be cosmetic or emotional. Minimally myelosuppressive treatment may be more appropriate for patients receiving antibiotic therapy (e.g., ganciclovir) for an opportunistic infection when more aggressive myelosuppressive chemotherapy (which might be more effective in controlling the tumor) could compromise the antibiotic treatment.
For rapidly progressive and/or disseminated mucocutaneous disease, or when tumor compromises the function of vital organs, systemic chemotherapy may effect rapid tumor regression and may be life saving. Among the drugs reported to be effective as single agents or, more commonly, as part of a combination regimen are liposomal doxorubicin, liposomal daunorubicin, bleomycin, doxorubicin, etoposide, vinblastine and vincristine. Hemopoietic growth factors such as G-CSF and GM-CSF should be administered, when indicated, to control bone marrow toxicity (neutropenia) while maintaining therapy.
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Systemic Treatment:
Under the Food and Drug Administration's (FDA) Accelerated Approval mechanism, liposomal doxorubicin (DOXIL®) has been approved for the treatment of KS in patients who have failed conventional treatment. Results from a phase III randomized clinical trial comparing liposomal doxorubicin 20 mg/m2 to adriamycin 20 mg/m2, bleomycin 10 mg/m2, and vincristine 1 mg (ABV) in patients with extensive, progressive mycocutaneous and/or visceral KS were recently reported (Northfelt et al.). Patients were treated every two weeks for up to 6 cycles. The median CD4+ count at entry was 13.5 cells/mm3, in the liposomal doxorubicin group and 14.0 cells/mm3 in the ABV group. 51/118 (43.2%) randomized to receive liposomal doxorubicin reported partial response versus 27/110 (24.5%) in the ABV group (P = 0.005). The median duration of partial response was 107 day and 92 days, respectively. Fewer toxicities (fever, nausea, neuropathy, hair loss and leukopenia) were reported in the doxorubicin group.
Several phase II clinical trials have been performed to study the efficacy and safety of liposomal doxorubicin. In one trial (Stewart et al.) of 247 patients with moderate to severe KS, response data after six cycles of liposomal doxorubicin therapy were available in 133 patients. Of these, 3 (2.3%) achieved a complete response, and 81 (60.9%) had a partial response. 38 (28.6%) had stable disease after six cycles of liposomal doxorubicin therapy, and 11 patients (8.3%) had progression in their KS.
An open-label randomized safety and efficacy trial (ACTG 286) comparing liposomal doxorubicin monotherapy to liposomal doxorubicin in combination with bleomycin and vincristine as first-line chemotherapy for KS is currently enrolling. This trial is trying to determine if lipisomal doxorubicin will be more effective as part of a combination regimen.
The Oncologic Drug Advisory Committee to the FDA has recommended full approval for liposomal daunorubicin (Daunoxome). Ross et al. have reported the results of a clinical trial comparing liposomal daunorubicin (40 mg/m2) versus adriamycin (10 mg/m2), bleomycin (15 mg) and vincristine (1 mg) for the treatment of KS. A total of 227 patients with greater than or equal to 25 mucocutaneous lesions or symptomatic visceral involvement were treated with Daunoxome (n=116) and ABV (n=111). Complete responses were reported in 3/116 (2.6%) patients receiving liposomal daunorubicin and 1/111 (0.9%) patients receiving ABV. Partial responses reported were 26/116 (22.4%) in the liposomal daunorubicin group and 30/111 (27.0%) in the ABV group. Stable disease rates were 72/116 (62.l%) and 64/111 (57.6%), respectively. Adverse events (fatigue, neuropathy, and, hair loss) were significantly less frequent in the liposomal daunorubicin group.
An open-label trial of liposomal daunorubicin for the treatment of pulmonary KS is currently underway. For patients with advanced KS who do not qualify for an ongoing study of liposomal daunorubicin, a compassionate use program is available.
Recombinant human alpha interferon has been approved for the treatment of KS in a subset of AIDS patients with CD4+ cell count greater than 200/mm3. Tumor regression is generally seen after 2 to 3 months of treatment in patients who lack systemic "B" symptoms (fever, weight loss, night sweats), have no history of prior opportunistic infections and have a CD4+ cell count > 200/mm3, at the start of treatment. Major side effects observed in approximately 80% of patients include flu-like syndrome (requiring dose reduction in 25% of subjects) and neutropenia.
Although recombinant human alpha interferon was approved for use at high doses as monotherapy, the results of more recent studies suggest that it may be effective at much lower doses when combined with nucleoside analogues. Beaulieu et al. randomized 118 patients to receive either a moderate dose of interferon (8 MU SC/day) or a low dose of interferon (1 MU SC/day) added to AZT (500 mg/day). While the overall response rate was higher in the moderate group (P = .07), only 10 patients completed 4 months of interferon 8 MU/day without requiring dose reduction. Response rates were also seen in the low dose interferon group when used in combination with AZT.
Interferon is currently being studied in combination with ddI (ACTG 206). Patients are randomized to receive ddI with low dose (1 MU) or moderate dose (10 MU) alpha interferon. Krown and co-workers report that significant responses have been seen in some patients receiving low dose (1 MU SC/day) interferon in combination with ddI (200 mg/day).
A study of paclitaxel (Taxol®) was recently completed by Yarchoan et al. Twenty-nine patients with advanced KS were treated with paclitaxel 135 mg/m2 IV every 21 days with escalation as tolerated to a maximum dose of 175 mg/m2. Fourteen patients (41%) had received prior chemotherapy. The objective response rate in 28 evaluable patients was 7l%; one complete response and 19 partial responses. Five of six patients with pulmonary KS had a partial response of their lung disease. Median progression-free survival among responders was greater than 8 months. Paclitaxel was well tolerated, with neutropenia being dose-limiting.
Other treatments under investigation in clinical trials for KS include alpha interferon in combination with ddI, interferon alpha-2B in combination with AZT and ddC, all-trans-retinoic acid (alone and in combination with alpha interferon), and IL2. A clinical trial is underway at the University of Southern California of human chorionic gonadotropin (hCG) for the treatment of KS.
A trial is currently underway to evaluate low-dose oral etoposide for the treatment of relapsed or progressed KS after systemic chemotherapy.
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Researchers Report New Treatment Findings
Researchers report in the New England Journal of Medicine that injections of a hormone produced during pregnancy can shrink the skin tumors of Kaposi's sarcoma. Parkash S. Gill of the University of Southern California School of Medicine in Los Angeles and colleagues found that, after receiving thrice-weekly injections of the hormone human chorionic gonadotropin (hCG) for two weeks, many small tumors shrank, and some disappeared. The larger the amount of hCG injected, the greater the effect it had on the tumors.
However, some of the patients' tumors returned two to three months after the treatment had cleared them. The finding could lead to an effective treatment for Kaposi's sarcoma, but the role of hCG itself is questionable, because it is expensive and because the number and size of such tumors varies widely.
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Topical/Intralesional Treatment:
Lesions of the face or other exposed parts of the body may be treated with local therapy. Preliminary analysis of a dose finding study has shown that intralesional recombinant platelet factor 4 (rPF4) administration led to an anti-tumor response in KS treatment (Staddon et al.). Results of the trial were based on data from seven patients with KS. When rPF4 was administered via intralesional injection, there were 2 complete responses, 2 partial responses, 2 with stable disease and 1 with progressive disease. No complete responses and only one partial response was reported in the non-injected, proximal and distant control lesions.
Other localized treatments under investigation for cutaneous KS include cryotherapy (topical liquid nitrogen), photodynamic therapy in combination with polypophyrin, and 9-cis-retinoic acid.
Radiation therapy (RI) can be used for intraoral or pharyngeal KS; localized, cosmetically problematic KS (e.g., the nose or ears); painful or bulky localized cutaneous KS; and lymphedema of the face and extremities. Radiation therapy can be an effective method of reducing facial edema and treating lymphedema due to KS. Substantial regression in oral KS has been reported; however side effects such as mucositis (mucous membrane inflammation) are common, can be severe, and may be life-threatening. Late effects of radiation therapy may include fibrosis with skin ulceration. Lesions may recur within radiated areas.
REFERENCES:
Bonhomme L et al. Topical treatment of epidemic Kaposi's sarcoma with
all-trans-retinoic acid. Ann Oncol 2:234-235, 1991.
Bonhomme L et al. Systemic treatment of AIDS-associated Kaposi's sarcoma (KS)
with all-trans-retinoic acid (ATRA). Abstract PO-B12-1562, IX Intl Conf AIDS.
Berlin, 1993.
Chak L et al. Radiation therapy for acquired immunodeficiency syndrome-related
Kaposi's sarcoma. J Clin Oncol 6: 863-7, 1988.
Chang Y et AL. Identification of herpes virus-like DNA sequences in
AIDS-associated Kaposi's sarcoma. Science 266:1865-9, 1994.
Dennis et al. A phase II study of oral etoposide (VP-16) in AIDS-related Kaposi's
Sarcoma. PB #0118. X Intl Conf AIDS, Yokohama, 1994.
Ensoli B et al. Synergy between basic fibroblast growth factor and HIV-1 Tat
protein in induction of Kaposi's Sarcoma. Nature 271:674-680, 1994.
Krown SE et al. Interferon-alpha, zidovudine, and granulocyte-macrophage
colony-stimulating factor: a phase I AIDS Clinical Trials Group study in patients
with Kaposi's sarcoma associated with AIDS. J Clin Oncol 10: 1344-51, 1992.
Huang L et al. Presentation of pulmonary KaposiÕs Sarcoma. Abstract #PB0110, X
Intl Conf AIDS, Yokohma, 1994.
Milliken ST et al. A phase II study of stealth liposomal doxorubicin HCL (S-DXR)
in HIV associated Kaposi's sarcoma (KS). Abstract PO-B12-1570, IX Intl Conf AIDS,
Berlin, 1993.
Moore PS and Chang Y. Detection of herpes virus-like DNA sequences in Kaposi's
sarcoma in patients with and without HIV infection. NEJM 332:1181-5, 1995.
Nair BC et al. Identification of a major growth factor for AIDS-Kaposi's sarcoma
cells as Oncostatin M. Science 255: 1430-2, 1992.
Northfelt DW et al. Randomized comparative trial of Doxil vs, adriamycin,
bleomycin, and vincristine (ABV) in the treatment of severe AIDS-related Kaposi's
sarcoma. American Society of Hematology, 1995.
Ross M et al. Personal testimony to the Food and Drug Administration's Oncology
Drug Advisory Committee. June 8,1995.
Simpson JK et al. Liposomal doxorubicin: initial experience in a major London
centre. Abstract PO-B12-1603, IX Intl Conf AIDS, Berlin, 1993.
Staddon et al. A randomized dose finding study of recombinant platelet fact 4
(rPF4) in cutaneous AIDS-related Kaposi's Sarcoma (KS). Proc Am Soc Clin Onco
13:50, 1994.
Stewart S et al. Efficacy and safety of Stealth liposomal doxorubicin (DOX-SL) in
AIDS-related Kaposi's Sarcoma. Abstract #PO-B123, X Intl Conf AIDS, Yokohama,
1994.
Von Roenn J et al. All-trans-retinoic acid (TRA) in the treatment of
AIDS-associated Kaposi's sarcoma. Abstract PO-B12-1571, IX Intl Conf AIDS,
Berlin, 1993.
Yarchoan R et al. Activity of paclitaxel for the treatment of HIV-associated
Kaposi's sarcoma.1995 Meeting of the Laboratory of Tumor Cell Biology. Abstract
#52, Bethesda, 1995.
OTHER REPORTS:
Marco M et al. The KS Project Report: current issues in research and treatment of
Kaposi's Sarcoma. Treatment Action Group, 1994.
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Sarcoma Menu
Boent P et al. Local peri-lesional therapy with rGM-CSF for Kaposi's sarcoma.
Lancet 341: 1154, 1993.
Huang YQ et al. HPV-16-related DNA sequences in Kaposi's sarcoma. Lancet 339:
515-518, 1992.
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