ACQUIRED IMMUNODEFICIENCY SYNDROME–ASSOCIATED KAPOSI'S SARCOMA

MANAGEMENT OF THE HN-INFECTED PATIENT, PART I1

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ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED KAPOSI’S SARCOMA Biology and Management Susan E. Krown, MD

Kaposi’s sarcoma (KS), one of the first conditions to be recognized as an opportunistic sequela of infection with the human immunodeficiency virus type 1 (HIV), remains the most common neoplasm associated with acquired immunodeficiency syndrome (AIDS). Over the past 15 years, considerable progress has been made in describing its epidemiologic and clinical features, in elucidating its pathobiology, and in developing therapeutic approaches. Despite therapeutic advances, the treatment of KS remains palliative, but a clearer understanding of KS pathogenesis holds promise for eventual curative or even preventive therapy. This article reviews current knowledge about the epidemiology, natural history, pathogenesis, and treatment of AIDS-associated KS and considers future therapeutic opportunities. EPIDEMIOLOGY In the period before AIDS, KS was rare in most of the world except in parts of Africa where KS is endemic.168Among the general population in the United States, age-adjusted incidence rates per 100,000 have been reported as 0.29 in men and 0.07 in women12; in Europe, KS incidence rates range from 0.1 in England to 1.0 in parts of Italy and Considerably higher rates have been described in patients with renal transplant-associated iatrogenic immunosuppression; reported KS incidence in this setting has ranged from 0.1% in

From the Department of Medicine, Memorial Sloan-Kettering Cancer Center; and Cornell University Medical College, New York, New York ~~

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Scandinavia)b to 0.6% in the United and to 5% in Saudi Arabia.127 Although these high incidence rates for KS in allograft recipients and the occasional observation of spontaneous regression in such patients when immunosuppression is withdrawn'22 highlight the strong association between immunosuppression and KS, it is noteworthy that endemic African KS is not associated with immun~suppression.~~ An analysis of linked AIDS and cancer registry data estimates a 73,000-fold increase in KS incidence in homosexual HIV-infected men compared to the general U.S. pop~lation,'~, 35 with 15% to 20% of this group presenting with KS in recent Although KS is relatively less common in other HIV transmission groups (i.e., 1%to 3% of persons other than male homosexuals), the linked AIDS and cancer registry data nevertheless indicate a 10,000-fold increase in KS in HIV-infected women and nonhomosexual men.14 Among members of all HIV transmission groups, the proportion reported to present with KS has been steadily declining. Early in the epidemic, when relatively few HIV-infected patients had progressed to severe immunosuppression, KS accounted for 30% to 40% of initial AIDS diagnoses.27Several theories have been advanced to explain the decline in the proportion of KS as a presenting AIDS-associated illness, including expansion of the AIDS case definition to include conditions that may be diagnosed earlier than KS, a decrease in the identification or reporting of relatively minor KS lesions, and a decline in exposure to environmental factor(s) predisposing to KS development. Some studies, in which patients were carefully monitored for KS as a presenting or secondary complication of HIV infection, suggest that KS incidence may be more stable than generally believed. These include reports from the Multicenter AIDS Cohort Study in the United Statesmand the Danish Study Group for HIV Infection,102neither of which documented a decline in KS. Racial, genetic, and hormonal factors have also been reported to be associated with the observed frequency of HIV-associated KS in various transmission groups. Although the linked AIDS and cancer registry data indicate that the proportion of African-American homosexual men who develop KS is about half that of white homosexual men,14 other studies have not uniformly confirmed this finding.78It has been suggested that KS may be more difficult to recognize in African-American patients or that access to medical attention may be less likely for socioeconomic reasons,14 resulting in artifactually low reporting rates. Early indications that certain HLA types were more commonly associated with KS in HIV-infected patientsIz4,125 have not been confirmed in later studies,18 and the basis for differences in the incidence of KS in different ethnic groups and different parts of the world is not understood. KS is three to four times more common in men than in women without imrnunosuppression.lz,41 Among iatrogenically immunosuppressed individuals without HIV infection, however, and among HIV-infected persons other than homosexual men, KS incidence rates only slightly favor men.I3 Although a possible biologic basis for the somewhat lower incidence of KS in women was suggested by the observations that explanted KS cells could not be established in pregnant mice and human chorionic gonadotropin inhibited the growth of KS-derived spindle cells in vitro,lO' in African women with HIV infection, pregnancy was not associated with protection from KS development or progression.lZ8 The higher incidence of KS in HIV-infected homosexual men, together with reports that the incidence of KS was higher in women who acquired HIV infection through sex with bisexual men compared to women from other transmission groupss, 122 and anecdotal reports that KS may also occur at a higher than expected frequency in homosexual men who are not HIV has

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led to a search for sexually related environmental or infectious factors that might contribute to KS development. Although most of the factors previously implicated (e.g., cytomegalovirus, human papillomavirus, human herpesvirus-6, inhaled nitrites) are no longer considered to play a central role, if any, in the cause of KS, recent data (see under Pathogenesis) have provided more compelling evidence for human herpesvirus-8 (HHV-8)as an important causative factor in the development of KS. CLINICAL MANIFESTATIONS AND PATIENT EVALUATION

The most common site of initial KS presentation is the skin, but occasionally cutaneous involvement is absent or is preceded by visceral, oral, or nodal KS. Cutaneous lesions may vary in size, characteristics,and number. Although some patients may have only a few isolated lesions, in others hundreds of widespread lesions may be present. KS lesions may be macular, plaquelike, papular, or nodular and may range in size from a few millimeters to huge, confluent plaques or nodules of 10 cm or more (Fig. 1). Lesions may be pink, red, purple, or brown, and the color may darken as the lesion ages. In black or olive-skinned people, lesions may be very dark, almost black. Occasionally, KS may be subcutaneous, without visible overlying skin pigmentation. With treatment, red or purple lesions may become brown or tan, KS nodules or papules may flatten, and large plaques may show central clearing with residual pigment at the lesion periphery. KS is often complicated by edema. This is generally nonpitting and is most common on the feet and legs but may also occur in the periorbital region, the external genitalia, or other body sites. Severe edema may result in diffuse serous drainage with accompanying protein and fluid loss, ulceration, and secondary bacterial infection. The degree of edema may be disproportionate to the number

Figure 1. Kaposi's sarcoma of the face, showing diffuse involvement of the nose, smaller, nodular lesions on the cheeks, and mild facial edema.

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of skin lesions and is rarely accompanied by massive proximal lymph node enlargement. Oral cavity KS occurs in about one third of patients but may be asymptomatic and overlooked. Hard palate involvement with KS is most common and may consist solely of flat, red-to-purple discoloration. Nodular lesions of the hard and soft palate may occur, however, and these may become exophytic, ulcerate, and bleed. KS can also involve the gums, tongue, tonsils, pharynx, and trachea; may interfere with eating and speaking; and may lead to tooth loss or obstruct the upper airways. Gastrointestinal KS has been reported in 40% of patients at initial diagnosis and in up to 80% at autopsy and may occur without cutaneous KS7, 38, 94 In most cases, gastrointestinal involvement is asymptomatic, but KS can cause obstruction, bleeding, and pain and can occur throughout the upper and lower gastrointestinal KS involvement of the lung parenchyma, the bronchial tree, or the pleura is usually symptomatic and may be occurring more commonly as survival with KS is prolonged. Clinically, patients may present with cough, hemoptysis, or shortness of breath. Radiographically, ill-defined nodules, interstitial infiltrates, and pleural effusions may be seen, although some patients with endobronchial KS may have a normal chest x-ray study. Lymph node involvement with KS is common. Although on histologic examination lymph nodes are usually only focally involved, on occasion lymph node enlargement can be attributed solely to replacement by KS. KS has been described to. involve many other visceral organs (e.g., liver, spleen, bone marrow, heart, pericardi~m),7~ but a diagnosis of KS in these organs is only rarely made antemortem. KS can present throughout the course of HIV infection. It may occur as the initial AIDS diagnosis at a time when immune function is relatively preserved and other opportunistic diseases are rare but becomes more common as immunocompetence declines.79,'03, 143 The anatomic distribution, rate of progression, and secondary sequelae of KS vary. Although in some patients KS involvement is minimal, inconspicuous, and slowly progressive, in others KS may be widespread, functionally or cosmetically debilitating, and rapidly progressive. Distinctive anatomic lesion distributions may occur (see Fig. l),with some patients showing primarily distal lower extremity lesions; others showing lesions of the nose, periorbital tissues, and ears; and others presenting with involvement of the inguinal, suprapubic, and genital regions, often accompanied by edema. Some patients present with widespread skin lesions that spare the face, hands, or feet. More rapid progression of KS during acute opportunistic infections is a frequent clinical observation that may be related to the increased production of inflammatory cytokines or HIV activation (or both) associated with such episodes. Rare episodes of spontaneous KS regression have been reported,I3O but these are generally incomplete and transient. The varied clinical presentations of KS may be associated with different sequelae that affect the quality of life. Edema of the extremities, genitalia, or periorbital tissues may cause functional disabilities; respiratory compromise may accompany lung or pleural KS; and nutritional deficiencies may complicate oral or gastrointestinal tract KS. Pain may complicate edema or cutaneous lesions, particularly those on the soles of the feet. Social isolation is a frequent sequela of lesions on exposed areas of the body, and even less obvious lesions often provoke anguish and depression in patients who are constantly presented with a visible reminder of their illness. Several staging systems for KS have been proposed. The most widely used

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system, developed by the AIDS Clinical Trials Group (ACTG), divides patients into good-risk or poor-risk groups based on the extent of the tumor (T), immune system status based on CD4 count (I), and the severity of systemic HIV-associated illness (S).90 A prospective analysis of the ability of this staging system to predict survival in 294 patients with KS entered on ACTG therapeutic trials has shown that T and I are the most important predictors of survival and that tumor extent adds to the predictive value of the CD4 count in patients with CD4 counts of 100/mm3 or more93(Krown SE, et al: Unpublished observations). A suggested evaluation of the patient with KS is outlined in Table 1 and includes a thorough examination of the skin and oral cavity, a rectal examination, a chest roentgenogram, and procedures to evaluate signs and symptoms suggestive of visceral KS involvement. PATHOGENESIS

Although several gaps exist in understanding of KS pathogenesis, a model that includes exposure to an infectious agent, altered expression and response to cytokines, and modulation of KS growth by HIV gene products has gradually emerged over the past several years. This model explains, at least partially, not only the frequent occurrence of KS, but also its unusually aggressive behavior in HIV-infected individuals. HIV infection is clearly not required for the development of KS, and molecular studies have failed to identify HIV in KS tissue, making this virus unlikely to play a direct oncogenic role in the cause of KS.” A more indirect role for HIV in altering the natural history of KS is suggested, however, by a number of observations. Transgenic mice bearing the HIV transactivating gene, tat, transiently develop KS-like angiogenic lesions,’65 and the gene product, the Tat protein, has been shown to be released in a biologically active form by HIVinfected CD4 cells and m0nocytes.4~Extracellular Tat binds to cell surface adhesion proteins of the integrin family that are strongly expressed on KS-derived spindle cells: stimulates proliferation of the spindle and induces them to produce inflammatory cytokines that may drive proliferation and angiogenesis through autocrine-paracrine HIV may also contribute more generally to the development and progression of KS through CD4 cell depletion, with a decrease in immune surveillance mechani~rns,’~~ and more specifically by stimulating the excess production of angiogenic lymphokines and monokines, including interleukin (1L)-1, IL-6 and tumor necrosis factor (TNF) levels of which are increased in patients with progressive HIV infection and further increased during acute opportunistic infections.2,17, 23, lZ3 Techniques first developed in the late 1980s to isolate and support the longterm in vitro growth of spindle cells from human KS lesionP, 137 permitted subsequent studies of the roles of cytokines and other growth factors that may support KS development and progression in vivo. Supernatants from retrovirusinfected T cells, which contain multiple cytokines, were required for the longterm maintenance of these cultures, and purified recombinant cytokines of the types contained in these supernatants, including IL-1, TNF, IL-6 and oncostatinM, were shown to increase KS cell proliferati~n.~,’~~,~~~,~~~ The KS-derived spindle cells themselves also produce a wide variety of cytokines and growth factors capable of stimulating KS growth through autocrine and paracrine pathways. These include several types of heparin-binding fibroblast growth factors, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-beta, IL-1, IL-6, and granulocyte macrophage-colony-stimulating

Table 1. EVALUATION OF PATIENTS WITH KAPOSI’S SARCOMA Initial Evaluation History General medical history with specific attention to: Lesion duration and rate of lesion development Gastrointestinal and respiratory symptoms Other KS-related signs/symptoms (e.g., pain, edema, depression) Specific symptom review (e.g., neuropathy, cardiac, hepatic, renal) HIV treatment history Opportunistic disease history KS treatment goals Physical examination Complete physical examination, with specific attention to: Skin: Include scalp, ears, feet, anogenital area; note lesion distribution, character, size, and number Oral cavity Rectal examination Edemdulceration Lymph nodes: note asymmetry, marked enlargement Chest Abdomen Nervous system, especially peripheral nerves Performance status Diagnostic tests Lesion biopsy: Confirm KS and rule out other pigmented lesions (e.g., bacillary angiomatosis) Chest radiograph Stool occult blood test Complete blood count and differential Liver chemistries CD4 count Node biopsy as indicated by physical findings Gastrointestinal and/or pulmonary evaluation as indicated (see below) Evaluation of Abnormal Findings Suggesting Gastrointestinal or Pulmonary Kaposi’s Sarcoma Gastrointestinal* Unexplained pain, bloating, dysphagia, bleeding Upper and/or lower gastrointestinal endoscopy Biopsy of characteristic pigmented (red/violaceous) lesions Positive biopsy: Definitive KS Nondiagnostic biopsy: Presumptive K S t Pulmonary* Effusion, nodules and/or infiltrates on chest radiograph; unexplained cough, wheezing, dyspnea, hemoptysis Individualized workup, that may include: Thoracentesis: sterile, cytologically nondiagnostic, often sanguineous exudate Bronchoscopy: red endobronchial lesions are presumptive KS; endobronchial or transbronchial biopsy specimens often nondiagnostic Gallium scan: Usually negative in KS Thallium scan: Usually positive in KS Other nondiagnostic tests that may be useful in narrowing the differential diagnosis andor providing a more quantitative evaluation of lesion size may include computed tomography scan, pulmonary function tests, sputum examination, and culture ‘Other gastrointestinal conditions may need to be evaluated and ruled out (e.g., enteric infections). Contrast x-ray studies and computed tomography scans generally fail to visualize gastrointestinal KS and are nondiagnostic. tKS lesions of the gastrointestinal tract may be submucosal, and endoscopic biopsy is often negative. *Infectious or inflammatory conditions may coexist with pulmonary KS. KS = Kaposi’s sarcoma.

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factor (GM-CSF):8, Io7 each of which is capable of stimulating angiogene~is;~a histologic hallmark of KS lesions. Both vascular endothelial growth factor (also known as vascular permeability factor) and IL-1 have been implicated in causing the edema and tissue swelling that accompanies some cases of KS.42,147It has been shown further that normal cells of vascular endothelial origin that are first activated by fibroblast growth factors and cytokines from retrovirus-infected T cells become responsive to the stimulatory effects of Tat on proliferation, cell migration, and angiogenic differentiati~n.~~, 52 Although the precise tissue derivation of the KS cell is in some doubt, a vascular endothelial cell origin has long been favored. The identification of significantly higher numbers of KS-like spindle cells in the circulation of HIVinfected individuals with KS and those at high risk for KS (i.e., homosexual and bisexual men) compared to non-HIV-infected controls and HIV-infected heterosexual may help to explain the multifocal presentation of the disease and provides clues to the origin of KS cells. These circulating spindle cells can be cultured from peripheral blood using conditioned medium from activated lymphocytes and express markers of both monocyte-macrophages and endothelial cells, suggesting a derivation from a circulating mesenchymal progenitor cell, possibly a p e r i ~ y t e . ~ ~ As described previously, epidemiologic studies have long suggested that KS, especially in the setting of iatrogenic or acquired immunodeficiency, might be linked to a transmissible cofactor. The identity of the cofactor remained elusive until 1994, when sequences of a novel human herpesvirus were identified in lesions from AIDS-associated KS.30The viral sequences had significant homology to genes encoding the minor capsid and tegument proteins of two lymphotropic gamma herpesviruses, the Epstein-Barr virus and Herpesvirus saimiri,30,113 both of which show oncogenic activity. Sequences of the new virus, termed Kaposi's sarcoma herpesvirus (KSHV) or HHV-8, were subsequently identified in essentially all KS lesions examined from AIDS patients113, 142 as well as in lesions from patients with the classic and endemic (non-HIV-associated) African forms of KS and in KS lesions from homosexual men without evidence of HIV infect i ~ n . ~113, ' , 142 HHV-8 sequences have also been detected in clinically uninvolved and in more than half of peripheral skin from about 20% of patients with KS30,113 blood mononuclear cell samples from patients with KS but only 8% of peripheral blood mononuclear cell samples from HIV-infected patients without KS.I7O In some of the latter patients, KS subsequently deve10ped.I~~ Although these data suggest the possibility that HHV-8 is the inciting factor in KS pathogenesis, studies demonstrating the presence of the virus in pathologic lesions other than KS, although not incompatible with a causative role, raise the alternative possibility that HHV-8 is a more ubiquitous virus that is present as a passenger in many types of proliferative lesions. Viral sequences have been detected in non-KS dysplastic and malignant skin lesions arising in organ transplant recipient^,'^^ angioimmunoblastic lymphaden~pathy,'~multicentric Castleman's disease (a polyclonal lymphoproliferative disorder with associated vascular hyperpla~ia),'~~ and hyperplastic lymph nodes of patients with HIV infection.= Additionally a more specific association has been found between HHV-8 and an unusual form of AIDS-related non-Hodgkin lymphoma.29These non-Hodgkin lymphomas are B-cell neoplasms that arise in the pleura, pericardium, and peritoneum and contain 40 to 80 times the number of HHV-8 sequences per cell than KS lesions.29Although HHV-8 DNA is apparently not present in spindle cell cultures derived from KS lesions,' viral sequences have been detected in CD19+ B cells from KS patients,' and the virus has now been transmitted in vitro to CDlPenriched, but not CD19-depleted, cord blood

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mononuclear cells, indicating B-cell lymphotr~pism.'~~ The virus has been detected, however, in spindle cells and vascular endothelial cells within paraffinfixed KS nodules using a sensitive polymerase chain reaction in situ hybridization technique.21Although the causative role of HHV-8 in KS is as yet unsettled, it is noteworthy that a retrospective review has indicated a reduced risk of developing KS in patients who received foscarnet (but not other antiherpes drugs):' and anecdotal reports have appeared describing resolution of KS in some patients receiving foscarnet therapy.'I4 TREATMENT OF KAPOSI'S SARCOMA Local Therapy

Several treatments aimed at local control of KS lesions may provide cosmetic and functional relief for patients with KS. Treatments reported to induce KS regression include liquid nitrogen ~ryotherapy'~~; intralesional injections of vinblastine,22interferon-alpha (IFN-X)?~myeloid colony stimulating factors,'8 sclerosing agents,Io0recombinant platelet factor 4,'54 and human chorionic gonadotropin6*";topical applications of synthetic retinoidsZ0;photodynamic therapy9; and radiation therapy.'58Of these approaches, cryotherapy, intralesional vinblastine, and radiation therapy are widely used, conventional approaches, with the remainder considered investigational. Although local approaches have the advantage over systemic therapies of inducing minimal systemic side effects and being completed in a relatively short time, particularly when the number of KS lesions is small and the rate of new lesion development is slow, they also have certain limitations and disadvantages. The benefits of local treatments are confined to the treated lesion or area, and lesion regrowth may occur within, or adjacent to, the treated area. Local therapy may be complicated by ulceration and secondary infection, radiation-induced fibrosis and mucositis, and pain (a frequent consequence of intralesional vinblastine therapy). Even in the best of circumstances, there is usually residual evidence of the disease process, including scarring and changes in skin pigmentation, which may be cosmetically suboptimal but which may be more amenable to camouflage with cosmetics than the untreated, raised, violaceous KS lesions. Although radiation therapy is often successful in achieving local control of KS lesions and may be particularly well suited for those patients with advanced HIV disease who have locally symptomatic KS, a relatively short life expectancy, or contraindications to systemic therapy, for those patients with a better longterm prognosis in whom chemotherapy is likely to be required at a later date, the possibility should be kept in mind of radiation recall reactions ,after systemic 156 Swift158 has administration of agents such as anthracyclines or ble~mycin."~, reviewed the relative merits of different radiation dosing schedules for KS, concluding that patients with a poor long-term prognosis (i.e., a life expectancy <4 months) are best managed with a single-dose fraction of 8 Gy to small areas (or short fractionated courses to larger areas or mucosal surfaces) to provide rapid symptom palliation. For patients in whom a longer survival is anticipated, however, the available evidence suggests that more protracted, fractionated radiation courses result in better long-term disease Swift'58 has suggested a total dose of 24 Gy in 2 Gy fractions, which is low enough to permit safe retreatment in the event of local recurrence but which may be less likely to be complicated by late local toxicities than the higher-dose (i.e., 40 Gy) fractionated regimens used by others.'55

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Systemic Chemotherapy

Evaluation of Response: A Caution Standard oncologic criteria, which generally rely on changes in bidimensionally measured lesion diameters, have not proved adequate for assessing the response of KS to treatment. Raised cutaneous lesions, which are most accessible for evaluation, often show flattening, central clearing, and a decrease in volume without a change in measured two-dimensional diameters. Visceral KS is even more difficult to quantify either because invasive procedures (e.g., gastrointestinal endoscopy or bronchoscopy) are required or because radiographic studies show poorly circumscribed lesions. Although specific criteria for KS evaluation were published by the ACTG in 198990and later underwent several refinements, difficulties still exist in evaluating the success of therapeutic interventions. The ACTG response criteria, which include defined decreases in cutaneous lesion size or number (or both) or complete flattening of previously raised lesions, represent an improvement over the prior situation, in which response criteria were often ambiguous and varied between studies. When these criteria are strictly applied, however, clinically minor changes in cutaneous lesions are sometimes interpreted as disease progression, even when the patient is experiencing cosmetic or symptomatic relief. In the author’s experience, this is particularly true when evaluating lesion flattening because minimal changes in lesion volume may mean the difference between a lesion being completely flat on one visit and barely palpable (i.e., raised) on the next. In interpreting the results of the sections that follow, the reader is therefore cautioned that direct comparisons of published response rates are difficult on several accounts, including the use of different response criteria, what is likely to be varying rigorousness with which response criteria are applied, the inclusion in different studies of patients with different severities of both KS and HIV infection, and nonuniform HIV treatment and infection prophylaxis that may have influenced both the tolerance of and response to KS therapy. In the future, the relative merits of various chemotherapeutic regimens for KS will ideally be decided on the basis of a more global assessment of clinical benefit that includes response rate as one of several factors, but the development of techniques to assess such overall benefits is currently in its earliest phases.

Single-Agent Therapy A variety of single chemotherapeutic agents have been reported to induce KS regression. The earliest reported study of chemotherapy for AIDS-associated KS described a 76% response rate in patients receiving intravenous etoposide at a dose of 150 mg/m2/day for 3 days, every 4 weeks.97A later phase I study of weekly oral etoposide over a dose range of 150 to 400 mg induced a response rate of 36% without clear evidence for a dose-response relationship.1z1A lower dose of oral etoposide (25 mg/m2 twice a day) administered on a more frequent schedule (7 days, every 2 weeks) was, however, associated with a response rate A 40% partial response rate has been reported with the use of less than 14Y0.l~~ of another topoisomerase I1 inhibitor, teniposide, administered intravenously at a dose of 360 mg/m2 every 3 Vinblastine, at an initial dose of 4 mg/week intravenously with weekly increments of 2 mg/week as tolerated (median 6 mg/week), induced a response in 30% of Another vinca alkaloid, vincristine, given intravenously at a dose of 2 mg/week for the first 2 to 5 weeks and every 2 weeks thereafter

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induced responses in 61% of patients and reversed thrombocytopenia in several KS patients with a concurrent idiopathic thrombocytopenic purpura-like syndrome.In9Doxorubicin at a weekly intravenous dose of 15 mg/m2 reportedly induced an objective response rate of only lo%, along with an 18% incidence of dose-limiting n e ~ t r o p e n i aThe . ~ ~ low objective response rate in this study may be partially attributable to the reliance on response criteria that excluded flattening of raised lesions.55In another study in which response criteria designed specifically for KS were used, a response of 48% was reported when doxorubicin was administered every 2 ~ e e k s . 6Bleomycin ~ administered by intramuscular injection at a dose of 5 mg/day for 3 days every 3 weeks induced responses in 71% of patients.26As a continuous intravenous infusion, bleomycin induced responses in 48% of patients at a dose of 6 mg/m2/day for 4 days every 4 and in 65% of patients treated at 20 mg/m2/day for 3 days every 3 Two liposomally encapsulated anthracyclines, doxorubicin and daunorubicin, have received approval by the US. Food and Drug Administration for treatment of AIDS-associated KS. Liposomal encapsulation, which encloses drugs in a spherical lipid bilayer, was developed as a technique to prolong the circulating half-life of drugs, achieve higher tumor drug concentrations, and decrease toxicity in nontarget organs.24Clinical studies of both liposomal doxorubicin (Doxil) and daunorubicin (DaunoXome) have confirmed prolonged serum half-lives (measured in hours rather than the few minutes for unencapsulated drug), high drug concentrations within KS lesions (compared to both uninvolved skin and to tumor concentrations after free doxorubicin), and a modified toxicity profile.62,I l 9 Although both agents frequently induce neutropenia,I9,69, 73, ns they rarely induce significant alopecia or nausea and vomiting,36, 69, 169 and high doses have been administered without evidence for typical anthracycline-induced cardiac toxicity.ln.62, 136 In its liposomal formulation, doxorubicin appears to have minimal vesicant activity after accidental 163 Doxil administration has, however, been associated rarely extra~asation.”’~, with the hand-foot syndrome (painful erythema and desquamation of the palmar and plantar surfaces)71and with an acute infusional reaction occurring within minutes of starting the infusion characterized by intense flushing, a sensation of choking, and back pain.’” Some patients have been successfully rechallenged after infusional reactions by slowing the infusion rate. Approved doses and schedules of administration for these agents are 20 mg/m2 intravenously every 3 weeks for Doxil and 40 mg/m2 every 2 weeks for DaunoXome. Although the results of many, generally small trials with these drugs have been published, extremely high initial response rate estimates, sometimes exceeding 90%,19,32, 43, 62, 73, 80, 112, 157 have not been confirmed in larger randomized trials in which these agents were compared with standard combination chemotherapy regimens and response criteria were ’ more strictly applied.69, It is likely, however, that the high initial response rates estimate the proportion of patients with a decrease in tumor bulk, which may be associated with disease palliation even in the absence of well-documented 50% tumor regression. Of particular note is the observation that some patients whose tumors progressed during treatment with regimens containing unencapsulated conventional doxorubicin subsequently responded to a liposomally encapsulated formulation. Combination Therapy Several combination drug regimens have been used successfully to treat KS. Before the development of liposomal anthracyclines, the general consensus was

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that combination regimens induced higher overall response rates with longer median response durations than single agents, but few prospectively randomized studies were conducted. Median response durations were not uniformly reported but when cited generally averaged 6 to 7 months, with a range of 5 to 9 months. In the first combination chemotherapy regimen reported in the literature, Laubenstein and colleagues97achieved a 90% response rate using doxorubicin 40 mg/m2 on day 1, vinblastine 6 mg/m2 on day 1, and bleomycin 15 units on days 1 and 15 of a 28-day treatment cycle. A 43% response rate was reported for a regimen of vinblastine at a dose of 0.1 mg/kg alternating weekly with vincristine at a dose of 2 mg.83Bleomycin and vincristine has been a frequently used and relatively nonmyelotoxic combination. In one study, bleomycin was administered at a dose of 30 mg with vincristine at a dose of 2 mg, every 3 to 4 If neuropathy developed, vinblastine at a dose of 2.5 to 5 mg was substituted for vincristine. A 57% partial response rate was observed, and 28% of patients developed n e ~ r o p a t h y A .~~ combination of bleomycin 10 units/m2 with vincristine 1 to 2 mg given every 2 weeks has been more frequently used in practice, with one small study demonstrating a 72% response rate with minimal associated myelosuppression and An intensive multiagent regimen for KS was described in 1987 by Gelmann and c0lleagues,5~who administered doxorubicin 20 mg/m2, vinblastine 4 mg/m2, and bleomycin 15 units/m2 on day 1; actinomycin D 1 mg/m2, vincristine 1.4 mg/m2, and dacarbazine 375 mg/m2 on day 8; and bleomycin 15 units/m2 on day 15 and repeated the treatment cycle every 28 days. Although a high response was documented (72%), the rate of opportunistic infection was also high, and response duration was short. A subsequent study by Sloand and colleagues15oin patients with pulmonary KS used a similar intensive regimen together with antiretroviral therapy, Pneumocystis carinii prophylaxis, and growth factor support with granulocyte-colony-stimulating factor (G-CSF). Although the response rate was high (83%),the response duration was only 2 to 3 months, suggesting that even with full supportive measures, intensive chemotherapy may be counterproductive. The most widely reported regimen combines doxorubicin, bleomycin, and vincristine (ABV). Doxorubicin 20 mg/m2, bleomycin 10 units/mz, and vincristine 1.4 mg/m2 (maximum 2 mg) given every 2 weeks was reported by Gill and to induce a response rate of 88%, and Gill's study of the same regimen in patients with pulmonary KS yielded a response rate of 80%.60 In both studies, patients received either the combination regimen or doxorubicin alone at the same dosage and schedule. The single-agent response rates to doxorubicin were 48% and 14%. Other studies using the ABV combination but with different doxorubicin doses have also been reported. In a group of 30 patients with pulmonary KS, a regimen of doxorubicin 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg given every 4 weeks induced a partial response rate of 64Y0.~~ Gill and co-workers66have also reported a 90% response rate in a small group of patients who received an ABV regimen using only 10 mg/m2 of doxorubicin every 2 weeks. Most of the aforementioned studies of the ABV combination were conducted at single institutions before the widespread availability of antiretroviral therapy and the routine use of P. carinii prophylaxis. More recent multicenter studies have been conducted to evaluate the tolerance and efficacy of this regimen in conjunction with these now-standard treatments for HIV-infected patients. In one phase 1/11 trial, successive patient cohorts were treated with bleomycin 10 U/m2, vincristine 1.4 mg/m2 (maximum 2 mg), and increasing doses of doxorubicin (0, 10, or 15 mg/mz) every 2 weeks, together with zidovud-

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ine at a dose of 600 mg/day and standard P. carinii pro phyla xi^.^^ A 71% overall response rate was observed, along with a lower incidence of opportunistic infection than observed historically when similar chemotherapy regimens were used without zidovudine or P. carinii prophylaxis. This study, which did not use hematopoietic growth factors to treat or prevent neutropenia, demonstrated a maximum tolerated doxorubicin dose of 10 mg/m2.63 Subsequent studies demonstrated that higher doxorubicin doses and more intensive regimens could be tolerated together with zidovudine when recombinant hematopoietic growth factors were used either prophylactically or therapeutically for neutropenia, but there was no evidence that use of these hematopoietins led to increased response rates or survival?, In another prospectively randomized study, an ABV regimen using a doxorubicin dose of 20 mg/m2 was administered every 2 weeks with either didanosine or zalcitabine to advanced KS patients who had not received chemotherapy previously.11oResponse rates of 58% and 60% were seen in the two groups. Treatment was generally well tolerated using these less myelosuppressive nucleoside analogue reverse transcriptase inhibitors, and the incidence of both peripheral neuropathy and opportunistic infection was low."O The results of two large multicenter trials were reported in which patients with advanced KS and no prior systemic chemotherapy were randomly assigned to receive either an ABV regimen or a liposomal anthracycline every 2 weeks. In one study, an ABV regimen using a doxorubicin dose of 20 mg/m2 was compared to Doxil alone at the same dose.118In this trial, Doxil was found to be more effective than ABV, with respective response rates of 43.2% and 24.5?'0."~ In the other study, an ABV regimen using doxorubicin at a dose of 10 mg/m2 was compared to DaunoXome alone at a dose of 40 mg/mz.69Equivalent re. ~both ~ studies, the liposomal sponse rates of 28% and 25% were d o c ~ m e n t e dIn agents induced significantly less alopecia and peripheral neuropathy than ABV. The considerably lower response rates reported for ABV in these intensively monitored studies, compared to those previously reported for this regimen, are noteworthy. It is likely that these low response rates underestimate the proportion of patients in whom KS was effectively palliated and that they reflect the rather poor ability of current response criteria to capture relevant data on quality of life and overall clinical benefits. These data underscore the difficulties faced in determining optimal chemotherapeutic management of advanced KS. Interferon Therapy

IFN-a induces KS regression when used either as a single agent or as part of certain combination regimens. Early trials demonstrated activity when IFN-a was administered at high doses (e.g., 36 million units daily or 30 million units/ mz three times a week), without other antiretroviral or chemotherapeutic agents, to patients with CD4 + lymphocyte counts of 200/yL or more and no history of 54, n, opportunistic infections or systemic symptoms of advanced HIV infection.49, y2, 131, 134 In these good-risk patients, tumor regression was seen even among those with extensive cutaneous KS and oral or gastrointestinal involvement. Although response rates as high as 70% were reported in small studies that included subsets of good-risk patients, a more realistic estimate of the response rate is probably in the range of 25% to 30%.88Among patients showing IFN-induced tumor response, the median duration of benefit averaged 6 to 12 months for partial responders and up to 2 years for complete responders, with occasional responses persisting for 3 years or more. The clinical usefulness of IFN-a was limited, however, by the restricted subset of patients likely to derive benefit, the

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relatively slow rate at which lesions regress during IFN therapy compared to directly cytotoxic therapies, and the high cost and toxicities (fatigue, malaise, anorexia, neutropenia, and hepatotoxicity) associated with high-dose IFN treatment. Several relatively unsuccessful attempts were made to improve IFN-a efficacy by combining it with chemotherapeutic agents. Concurrent IFN/chemotherapy treatments failed to improve response rates and were associated, in some 87, 146 IFN-a was also ineffective in maintaining cases, with increased toxicities.49, response when administered following chemotherapy-induced KS regre~sion.~~ More recent studies have shown that lower IFN-a doses can induce KS regression and can do so in patients with lower CD4+ lymphocyte counts, when administered together with nucleoside analogue reverse transcriptase in86,89 hibitor~.~ ~ , ~Over ~ , an IFN dose range of 4 to 18 million U/day, IFN-a with zidovudine induced overall response rates exceeding 40%?3,56, 86, 89 Among patients with CD4 + lymphocyte counts below 200/pL, who consistently showed response rates below 10% when treated with high-dose IFN-a monothera ~ y , the 4 ~ IFN-a and zidovudine combination induced KS regression in 25% to 30% of patientss3,89 Although the high rate of dose-limiting neutropenia observed with the IFN-a and zidovudine combination was shown to be responsive to treatment with recombinant GM-CSF?l, 142 more recent studies have substituted less myelosuppressive nucleoside analogues for zidovudine. In an ongoing, randomized, multicenter ACTG study, the combination of IFN-a with didanosine has been well tolerated; therapeutic responses have been observed when didanosine was combined with daily doses of either 1 million or 10 million units of IFN-a, but it is too early to tell whether there are differences in efficacy between the two IFN-a dosage levels. Although IFN-a therapy has not been associated with major or consistent improvements in the immunologic perturbations associated with HIV infection, several studies of both IFN-a monotherapy and combined IFN-a/nucleoside therapy have demonstrated evidence for HIV suppression, measured by p24 antigen suppression or HIV culture, or both.40,86, 89,91, 95,141 IFNs are multifunctional cytokines with a wide variety of effects on cell growth and function. The precise mechanisms accounting for IFN-a's therapeutic effects on KS are unclear, but several of its known properties may affect the pathogenic processes currently implicated in KS development. IFN-a inhibits HIV repli~ation~~ and has synergistic inhibitory effects when combined with 166 Inhibition of various nucleoside analogue drugs used to treat HIV infection.74, HIV might lead indirectly to KS inhibition, by decreasing the production of both extracellular Tat and angiogenesis-promoting cytokines that are mitogenic for KS cells in vitro. IFN-a treatment has also been reported to increase the in vivo production of the naturally occurring antagonists of both IL-1 and TNF (i.e., the IL-1 receptor antagonist and the soluble form of the TNF p55 receptor).161, In both experimental and in patients with hemangiomas,5O IFN-a has proved effective as an inhibitor of angiogenesis, which may be mediated not only via its inhibitory effects on TNF and IL-1, but also by down-regulation of basic fibroblast growth factor expression? IFN-a also induces the in vitro activation of natural killer cells with cytotoxicity against KS-derived target cells13zand has been reported to inhibit experimental infection with Herpesvirus saimiri, a virus with close structural homology to HHV-tI4Further insights into the mechanisms by which IFN-a mediates KS regression in vivo may provide leads for development of more effective, IFN-containing regimens.

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Investigational Approaches to Therapy

Although a detailed description of the many therapeutic approaches currently being tested or contemplated for KS is beyond the scope of this article, several merit brief mention. Among the newer chemotherapeutic agents, the early indications are that paclitaxel (Taxol) has significant anti-KS activity. Preliminary studies indicate high response rates, even in patients with poor prognosis who had received prior chemotherapy, when paclitaxel was administered either at a dose of 135 mg/m2 over 3 hours every 3 weeks140or at a lower (and better tolerated) dose of 100 mg/m2 over 3 hours every 2 weeks.@Pertinently, paclitaxel also shows angiogenesis inhibitory activity in ~ i t r 0 . Another l~~ class of chemotherapeutic agents, the camptothecins, are inhibitors of topoisomerase I and inhibit HIV integrase, an enzyme that facilitates integration of proviral DNA into the host genome.98A multicenter trial of 9-aminocamptothecin has been initiated that will evaluate treatment effects on both KS and HIV viral load. The recognition that new blood vessel formation is an integral feature of KS has stimulated the development of a number of novel therapeutic approaches targeting angiogenic cytokines and growth factors. Among the agents currently being evaluated in clinical trials are synthetic retinoids (which have inhibitory effects on KS cell lines in ~ i t r and o ~ which ~ can down-regulate both IL-6 receptor '~~ (an orally bioavailable inhibiexpressionlZoand IL-6 p r o d ~ c t i o n ) ,vesnarinone tor of IL-6 and TNF-a production in vitro), IL-4 (which inhibits IL-6 production by monocytes in vitroIm),and thalidomide (which exerts antiangiogenesis effects through a variety of mechanisms that include inhibition of TNF-a production and basic fibroblast growth factor-induced vascular pr~liferation~~). Of particular note is 9-cis-retinoic acid (9-cisRA), which, in contrast to previously tested retinoids, interacts with both the retinoic acid receptors (RARs) and a unique set of receptors, the RXRs.I5' Preliminary studies suggest that 9-cisRA may have substantial local anti-KS activity when applied over cutaneous lesions, and trials of the drug administered by the oral route are beginning. Several other compounds that inhibit basic fibroblast growth factor-induced angiogenesis in experimental models have been tested in early-phase clinical trials in KS, without evidence to date for substantial single-agent anti-KS activity, although some suggestions of activity have been observed in as yet unfinished studies of the fumagillin analogue, TNP 47O.lz6,139 An alternative basic fibroblast growth factor-directed strategy has been suggested by experiments demonstrating that low concentrations of antisense oligodeoxynucleotides directed at basic fibroblast growth factor block KS spindle cell growth in culture and inhibit angiogenesis and the formation of KS-like lesions in nude mice.47Additional future targets for anti-KS therapy include the tyrosine kinase transmembrane receptors for fibroblast growth factor, platelet-derived growth factor, or oncostatin-M; distinctive cell surface proteins and adhesion molecules expressed on activated endothelial cells; matrix metalloproteinases that facilitate basement membrane disruption and capillary budding; and HHV-8, the putative KS herpesvirus. A recent review describes a detailed rationale for these and other potential approaches to KS therapy.% Developing an Overall Treatment Strategy

There is no single best treatment for KS. In making decisions about the choice of therapy, many factors need to be taken into account. The severity of the KS and the rapidity with which it is progressing obviously require consideration:

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Specific symptoms and sites of disease (e.g., severe edema, pain, pulmonary involvement) or rapid KS progression generally mandates a more aggressive, cytotoxic approach, whereas slowly progressive, asymptomatic mucocutaneous KS without symptomatic visceral involvement or KS confined to restricted anatomic areas may permit the use of local measures, IFNs, or even investigational drugs, often in succession. In this latter group of patients, differences in treatment philosophy exist, with some physicians advocating the use of local approaches for as long as possible to avoid systemic toxicities and others interpreting current concepts of KS pathogenesis and its multifocal presentation as more supportive of a systemic approach. The treatment goals of individual patients also need to be considered. For some patients, even those with quite widespread disease, immediate cosmetic issues or the desire to avoid alopecia or systemic side effects may be a primary concern. For others, long-term control of disseminated disease or strategies to prevent KS progression may be the primary goal. Achieving these different goals may require different therapeutic strategies, even for patients with similar disease presentations. An open discussion between the patient and physician describing the risks and benefits of various treatments, the varying natural history of KS, general concepts of KS pathogenesis, and the patient's long-term prognosis and goals is extremely useful in helping the patient and physician select an appropriate KS therapeutic strategy. The severity of the underlying HIV infection and its associated non-KS complications also requires consideration. Specific problems (e.g., moderate to severe peripheral neuropathy, diminished cardiac or pulmonary function, severe liver disease) may eliminate certain treatments from consideration ( e g , vinca alkaloids, anthracyclines, bleomycin, IFN). When life expectancy is extremely short (i.e., less than 3 to 4 months) because of other HIV-related complications, local symptom palliation should probably be the primary goal of KS therapy. The mere presence of a low CD4 count should not, however, be used as a rationale to avoid systemic chemotherapy when symptoms otherwise warrant its use. It should be recognized that the chemotherapy regimens shown to provide effective KS palliation with tolerable side effects were tested in groups ~ ,I1O, 118 and of advanced KS patients with median CD4 counts below 50/ P L , ~69, there is little objective evidence that such therapy substantially increases the risk of opportunistic infections when adequate supportive care, infection prophylaxis, and antiretroviral therapy are given along with chemotherapy. Indeed, despite evidence that patients in the post-zidovudine era are presenting with KS at a later stage of HIV infection, a study from University of California, Los Angeles, has shown an apparent improvement in survival for KS patients over the past 10 years, when the data were adjusted for presenting CD4 count and HIV disease stage.Io6 Although financial issues should not be a primary consideration in the selection of appropriate therapy, cost is clearly becoming an increasing concern for patients, physicians, medical institutions, and third-party payers. Certain of the therapeutic options discussed here, for example, liposomal anthracyclines, paclitaxel, hematopoietic growth factors, IFNs, and even frequent local injections, may be quite expensive, and data addressing their potential long-range impact on outcomes and the overall costs of medical care are lacking. As part of an overall treatment strategy for KS, prophylaxis for and prompt recognition and treatment of opportunistic infections are essential. Such infections may not only stimulate KS progression, but also lead to frequent delays in the administration of KS treatment. Although a similar rationale exists for concomitant antiretroviral treatment, and anecdotal reports suggest that the new

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protease inhibitors occasionally induce KS regression, potential drug interactions are a concern. Patients receiving systemic KS treatment require monitoring and treatment for myelosuppression, especially neutropenia, and adequate attention to nutritional support and pain control is required for all patients regardless of the treatment selected. SUMMARY AND FUTURE DIRECTIONS

KS is a clinically heterogeneous tumor that may occur throughout the course of HIV infection. A variety of standard therapeutic approaches are available that can induce tumor regression and provide effective and often long-term KS palliation, but such therapy is not curative. Although advances in the treatment of HIV infection, together with the prophylactic use of antimicrobial agents, aggressive management of acute opportunistic infections, and therapeutic adjuncts such as nutritional support, have contributed to an overall improvement in survival for HIV-infected patients with and without KS, there are as yet no data indicating that specific antitumor therapies result in longer survival for KS patients, possibly because factors other than KS have until recently been the primary survival determinants. The finding that tumor stage is independently correlated with survival93(Krown SE, et al: unpublished observations)and recent therapeutic advances leading to improvements in overall survival for patients with advanced HIV infection may permit the design of studies to address specificallythe effects of current KS treatments on survival in comparably staged patients receiving optimal HIV therapy. Advances in understanding the factors contributing to KS development and progression have suggested a large number of potential targets for therapeutic intervention directed at both viral and host factors. Although tremendous opportunities exist to exploit these new insights for therapeutic benefit, the multiplicity of factors implicated in KS pathogenesis may imply that combinations of approaches targeting different factors may be required for effective or optimal tumor control. In this context, it should probably be no surprise that the antiangiogenesis approaches tested thus far have proved disappointing insofar as their single-agent activity against KS is concerned. The effectiveness of IFN-a against KS may be testimony to its potential activities against multiple factors contributing to endothelial cell proliferation and angiogenesis, and the superior results obtained with IFN-a/nucleoside analogue combination therapy may be taken as further support for the soundness of a multitargeted approach to KS therapy. This type of approach is being developed further through a new trial combining IFN-a, stavudine, and an HIV protease inhibitor, and there exist other potential combinations with similar rationales. It should be cautioned, however, that such combinations involve more than simply combining a seemingly infinite group of agents and that serious potential exists for adverse drug interactions that require careful monitoring in the context of approved protocols. The identification of cells with characteristics suggestive of KS precursors in the circulation of HIV-infected patients considered at high risk for the development of KSZ5and the equally intriguing observation that the presence of HHV-8 in peripheral blood mononuclear cells may precede the development of overt KS’” hold promise for the future identification of specific high-risk populations in whom prophylactic strategies could be tested. It is conceivable that such patients would be more likely than those with established, advanced KS to benefit from interventional strategies aimed at blocking the myriad factors that result in KS development. It is likely, however, that such targeted preemptive

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interventions are many years off and will first require proof of safety and at least some degree of efficacy in established disease.

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