REVIEW Pegylted liposoml doxorubicin in the tretment of AIDS-relted Kposi s srcom Ashish Udhrin 1 Keith M Skubitz 2 Donld W Northfelt 3 1 Deprtment of Medicine, Myo Clinic Arizon, AZ, USA; 2 Division of Hemtology, Oncology, nd Trnsplnttion, University of Minnesot, MN, USA; 3 Division of Hemtology Medicl Oncology, Myo Clinic Arizon, AZ, USA Abstrct: Kposi s srcom is vsculr tumor of skin nd viscer first described in 1872. Prior to the 1980s, this disese ws rrely seen in the Western world, but ws quite prevlent in Sub-Shrn Africn countries. Since the onset of the HIV pndemic in the 1980s, the incidence of Kposi s srcom hs incresed mrkedly in Afric nd continues to be significnt problem in ssocition with AIDS in Western countries. Mny therpies hve been demonstrted to be effective in the tretment of HIV-relted Kposi s srcom, including litretinoin gel, interferon lph, nd vrious forms of cytotoxic chemotherpy. Antiretrovirl therpy combined with cytotoxic gents hs yielded significntly greter efficcy thn chemotherpy lone. However, s reviewed in this report, pegylted liposoml doxorubicin hs been estblished s the tretment of choice for ptients with AIDS-ssocited Kposi s srcom in Western countries. Compelling preclinicl nd clinicl evidence, reviewed herein, hs demonstrted tht the nnoprticle (pegylted liposome) delivery system of this formultion leds to greter tumor locliztion of doxorubicin nd consequent improved efficcy, s well s reduced toxicity. Keywords: liposoml doxorubicin, pegylted liposoml doxorubicin, Kposi s srcom, liposoml dunorubicin, liposoml nthrcyclinces Correspondence: Donld W Northfelt Division of Hemtology Medicl Oncology, Myo Clinic Arizon, AZ, USA Tel +1 480 301 8000 Fx +1 480 301 7006 Emil northfelt.donld@myo.edu Introduction Kposi s srcom (KS) is the most common mlignncy seen in ptients with humn immunodeficiency virus infection, occsionlly s the initil mnifesttion cquired immunodeficiency syndrome (AIDS) (Wng et l 1995). Prior to the AIDS epidemic, KS ws uncommon, occurring primrily in men in Afric, the Mediterrnen re, or Estern Europe (Mitsuysu 2000). Although it ws n exceedingly common compliction of AIDS in western countries in the 1980s t the onset of the epidemic, in the 1990s the incidence of AIDS-relted KS (AIDS-KS) in developed countries decresed drmticlly; between 1990 nd 1997, tht decline ws 10% per yer. An dditionl decline in the incidence of AIDS-KS occurred in ssocition with widespred implementtion of highly ctive ntiretrovirl therpy (HAART) in the lte 1990s. Also, it hs been speculted tht sfer sexul prctices mong homosexul men my hve led to reduced trnsmission of humn herpesvirus-8 (HHV-8), the virus ssocited with ll forms of KS, nd tht the introduction of more effective ntiretrovirl tretments with ssocited reduction in immunodeficiency my lso hve resulted in more effective immune response to HHV-8. Any or ll of these fctors could ccount for the observed decline in incidence of AIDS-KS over the course of the epidemic. Nevertheless, AIDS-KS continues to be dignosed mong HIV-infected persons. Control of HIV infection is not uniformly chieved with HAART, either becuse of drug resistnce nd/or s result of poor dherence to prescribed drug regimens. Additionlly, some ptients continue to develop AIDS-KS despite effective HIV suppression. Furthermore, rtes of AIDS-KS continue to rise in prts of Afric where rtes of both HIV nd HHV-8 infection re high nd HIV tretment is not widely vilble. Interntionl Journl of Nnomedicine 2007:2(3) 345 352 2007 Dove Medicl Press Limited. All rights reserved 345
Udhrin et l Clinicl presenttion of AID-KS AIDS-KS is multifocl, systemic disese tht usully first ppers s pink, red, purple, or brownish-blck nodules, mcules, ptches, or plques on the skin or, less often, on the orl mucos (Wng et l 1995). In the setting of HIV infection, AIDS-KS lesions often occur on the upper body, especilly the hed nd neck. Disese confined to the lower extremities is more common in non-hiv-ssocited KS (Misuysu 2000). Orl lesions hve reportedly ccounted for 22% of the sites of initil presenttion in AIDS-KS. Lesions of AIDS-KS my develop in the lungs, gstrointestinl trct, nd lymph nodes nd hve lso been described in the gllbldder, on the mucos of the vocl cords nd conjunctiv, genitli, liver, spleen, hert, bone, thyroid glnd, nd/or bone mrrow (Wng et l 1995). Depending on their loction nd size, AIDS-KS lesions my be disfiguring nd cn cuse edem, pin, gstrointestinl bleeding, nd tooth loss, nd cn led to nutritionl deficiencies nd disfigurement with consequent socil isoltion. Moreover, lesions in criticl sites cn interfere with eting, speking, brething, nd sometimes produce ftl consequences (Peters et l 1991; Wng et l 1995). The course of the disese vries from development of single or few indolent lesions with miniml progression over time, to ggressive, debilitting, widespred disese with severe complictions emerging within short time (Wng et l 1995; Krown 2004). Rtionle for use of liposoml nthrcyclines in tretment of AIDS-KS Severl liposoml nthrcycline products hve been investigted for the tretment of AIDS-KS. In prticulr, polyethylene glycol-coted ( pegylted ) liposoml product with trde nmes Doxil or Celyx (doxorubicin HCl liposome injection [PLD]; the former distributed in the US by Tibotec Therpeutics, Division of Ortho Biotech Products, LP, Bridgewter, NJ; the ltter distributed outside the US by Schering-Plough Corp.), received ccelerted pprovl from the United Sttes Food nd Drug Administrtion (US FDA) in November 1995 for tretment of ptients with AIDS-KS whose disese either hd progressed on prior combintion chemotherpy or who were intolernt of such therpy (Doxil 2001). In April 1996, the non-pegylted liposoml product, DunoXome (DNX, dunorubicin citrte liposome; Giled Sciences, Foster City, CA) ws pproved s tretment of AIDS-KS for which no prior chemotherpy hd been dministered ( first-line tretment) (DunoXome 1996). Results of phse II tril in AIDS-KS ptients were lso reported for non-pegylted formultion of liposoml doxorubicin, Myocet (liposome-encpsulted doxorubicin citrte complex; Medeus Phrm, Stevenge, Herts UK) (Cheung et l 1999), but this gent is not pproved for tretment of AIDS-KS in the US. Encpsultion of conventionl doxorubicin within liposomes ws expected to preferentilly distribute drug into tumors with leky blood vessels, condition which it ws believed would fcilitte the extrvstion of liposomes into tumor strom (Allen nd Mrtin 2004). Becuse AIDS-KS lesions contin dilted vsculr spces filled with extrvsted erythrocytes, good drug uptke due to similr extrvstion of liposomes ws nticipted. Pegyltion of liposomes ws expected to offer dvntge over conventionl liposomes by preventing erly clernce of circulting liposomes by mcrophges of the reticuloendothelil system. This would theoreticlly led to longer circultion time for the liposomes nd thereby enhnce their opportunity to trverse tumor vsculture where extrvstion could occur. In vitro studies demonstrted the ntitumor ctivity of conventionl doxorubicin in KS-derived cell cultures (Logn et l 1991). Other in vitro studies showed tht exposure to PLD inhibited the prolifertion of KS-derived cells to greter extent thn the prolifertion of endothelil cells, monocytes, nd smooth muscle cells (Sturzl et l 1994). It ws lso shown tht PLD incresed the expression of monocyte chemottrctnt protein-1 in KS cells, substnce believed to led to incresed migrtion of monocytes into the tumor (Sturzl et l 1994). Before initition of clinicl studies, it ws shown in niml models of KS tht PLD ws preferentilly tken up into tumor tissue (Hung et l 1993). Using model of KS derml lesions in trnsgenic mice bering the HIV tt gene (Vogel et l 1998; Hung et l 1993), pegylted liposomes were shown to extrvste into the interstitil spces between spindle-shped KS cells. Liposomes were found predominntly within the lesion in the region djcent to the epidermis, with dense concentrtions round bnorml blood vessels. In ddition, electron microscopy showed tht some mcrophges nd spindle cells hd ingested intct liposomes. Skin biopsies of ptients under tretment with PLD provided dditionl evidence for the preferentil tumor uptke observed in niml models (Vil et l 2004). When encpsulted in pegylted liposome, doxorubicin concentrtions in KS lesions reched 10 20 times those in norml skin (Northfelt et l 1995). In ddition, it ws shown tht more doxorubicin ws delivered to AIDS-KS lesions when dministered s PLD thn s conventionl doxorubicin. Kposi s lesions from 18 ptients were biopsied 72 hours fter intrvenous injection of either PLD 346 Interntionl Journl of Nnomedicine 2007:2(3)
Pegylted liposoml doxorubicin for Kposi s srcom or conventionl doxorubicin (Northfelt et l 1996). Regrdless of the dose, tissue levels of doxorubicin were pproximtely 5 11 times higher in the AIDS-KS lesions of ptients treted with PLD compred with AIDS-KS lesions in ptients given comprble doses of conventionl doxorubicin. Efficcy of liposoml nthrcyclines in clinicl trils of tretment for AIDS-KS Results of phse I/II trils of PLD in reltively unselected cohorts of ptients with AIDS-KS demonstrted overll response rtes (complete nd prtil response [CR + PR]) rnging from 38% to 100% (Sturzl et l 1994; Hengge et l 1993, 2001; Simpson et l 1993; Bogner et l 1994; Jmes et l 1994; Wgner et l 1994; Bergin et l 1995; Hrrison et l 1995; Goebel et l 1996; Northfelt et l 1997; Grunug et l 1998; Newell et l 1998; Nuncez et l 2001). To illustrte these findings we will focus on the tril reported by Northfelt et l (1997) (Tble 1), which provided the dt tht led to initil pprovl of PLD by the United Sttes Food nd Drug Administrtion (US FDA). It ws limited to ptients who hd experienced disese progression or intolerble toxicities during tretment with the combintion of doxorubicin, bleomycin, nd vincristine (ABV) or the combintion of bleomycin nd vincristine (BV) chemotherpy. The 53 ptients enrolled in this tril received 20 mg/m 2 of PLD intrvenously once every 3 weeks; 19 ptients (36%) chieved PRs nd one chieved complete clinicl response. Among those who hd previously experienced disese progression when receiving Tble 1 Effi ccy of pegylted-liposoml doxorubicin in the tretment of AIDS-relted Kposi s srcom fter filure of stndrd chemotherpy (Northfelt et l 1997) Best response All ptients Doxorubicin (n = 53) filure (n = 28) Complete clinicl 1 (2%) 0 Prtil 19 (36%) 9 (32%) Stble 19 (36%) 14 (50%) Progression 14 (26%) 5 (18%) Medin time (dys) to PR 109 109 Medin durtion (dys) of PR 128 127 Medin time (dys) to tretment Filure 134 148 Ptients whose AIDS-KS progressed on combintion regimen contining doxorubicin. conventionl doxorubicin-contining regimen (eg, ABV rther thn BV), the PR rte ws 32%. Medin durtion of response nd time to tretment filure in ll ptients ws 128 nd 134 dys, respectively. Of the 53 ptients, 48 hd rised indictor lesions t bseline; complete flttening of these lesions occurred in 48% of these ptients nd 68% chieved prtil or complete responses. Forty-eight of the ptients hd red or purple indictor lesions t bseline; in 56% of these ptients the lesions chnged to less noticeble color, nd 82% of these ptients chieved prtil or complete responses. Among the 23 ptients with edem t study entry, study therpy reduced edem in 83%, nd 100% of those chieved PR or CR. Of the 22 ptients with pin t bseline, 45% (70% of whom ttined PR or CR) hd pin reduction. These pprent benefits of PLD did not result in PR or CR in some ptients becuse they filed to fulfill some other qulifiction for response, such s no progression t other sites. Although not ddressed specificlly in the study described bove, other observtions demonstrted tht PLD could be effective in relieving symptoms nd possibly prolonging survivl of ptients with pulmonry AIDS-KS. In retrospective nlysis of 20 ptients, including nine who hd received prior chemotherpy, 11 of 16 ptients whose tumors could be evluted hd improved findings on chest rdiogrphy, nd the verge rteril prtil pressure of oxygen (po 2 ) for ll ptients rose to 76 from 55.5 mmhg (p < 0.01). Dyspne nd/or cough resolved in 12 of 16 ptients who hd been symptomtic before tretment (Grunug et l 1998). The evidence supporting the use of PLD lone s first-line therpy is derived from two rndomized trils in which ptients on the control rm received either ABV or BV (Tble 2) (Stewrt et l 1998; Northfelt et l 1998). In the tril conducted by Stewrt et l (1998) 241 ptients who hd received no prior cytotoxic chemotherpy were rndomized to receive either PLD 20 mg/m 2 or BV (bleomycin 15 mg/m 2 nd vincristine 1.4 mg/m 2 ). Both regimens were dministered intrvenously every 3 weeks for six cycles. Overll best response (CR plus PR) ws significntly higher with PLD (58.7% vs 23.3%; p < 0.001), s ws end-of-tretment response (38.8% vs 14.2%; p < 0.001). The end-of-tretment response reflected the ptient s sttus t the time further therpy ws discontinued; the response designtion ws scored within 21 dys of the lst dose of therpy nd must hve been sustined for t lest 4 weeks. The verge time to response ws 49 dys with PLD vs 57 dys with BV. The men durtion of response ws similr for the groups (160 dys with PLD vs 157 dys with BV). PLD produced significntly greter improvements in lesion thickness, nodulrity, edem, color, Interntionl Journl of Nnomedicine 2007:2(3) 347
Udhrin et l Tble 2 Response rtes in rndomized trils compring liposoml nthrcycline with ABV or BV, b Stewrt et l 1998 Northfelt et l 1998 PLD (Doxil) BV P vlue PLD (Doxil) ABV P vlue (n = 121) (n = 120) (n = 133) (n = 125) CR, % 6 1 <0.001 1 0 NS PR, % 53 22 <0.001 45 25 <0.001 CR + PR, % (95% CI) 59 (50 67) 23 (16 31) 46 (37 54) 25 (17 32) Stble disese, % 38 68 53 67 Progressive disese, % 0 4 2 8 Not ssessble, % 3 5 0 0 Best response during tretment. b Prtil response defi ned s bsence of new cutneous or orl lesions, new viscerl sites of involvement, or the ppernce or worsening or tumor-ssocited edem or effusions plus t lest one of the following: 50% decrese in the sum of the products of the skin lesions, complete fl ttening of greter thn 50% of ll previously rised skin lesions, 50% decrese in the sum of the products of the lrgest perpendiculr dimeters of prospectively selected indictor skin lesions, or the ptient met the criteri for Complete Clinicl Response, except tht residul tumor-ssocited edem or effusion ws present. The response ws required to persist for t lest 4 weeks. Abbrevitions: ABV, doxorubicin, bleomycin, vincristine; BV, bleomycin, vincristine; CR, complete response; PR, prtil response; NS, not signifi cnt. pin, nd size thn did BV. Among those treted with PLD, the incidence of pulmonry symptoms (dyspne, cough, chest pin, or effusion) dropped from 23.1% to 10.6% (p = 0.002), while for those on the BV regimen, pulmonry symptoms decresed from 24.4% to 20.2% (p = 0.25). The incidence of gstrointestinl symptoms relted to AIDS-KS (bleeding, erly stiety, or dysphgi) decresed from 16.3% t bseline to 3.8% with PLD tretment (p < 0.001), nd from 17% to 9.4% (p = 0.06) with BV tretment. Mortlity ws similr in the two groups: 15.7% with PLD vs 14.2% with BV, with men time to deth of 239 dys versus 160 dys, respectively. Only three of the deths were cused by KS nd none ws ttributed to the tretments studied. This study, s well s most of the others trils described here, ws conducted before the introduction of HAART. Becuse survivl of AIDS-KS ptients is determined primrily by opportunistic infections nd other non-ks complictions of AIDS, the durtions of survivl in these studies is shorter thn might be expected tody with vilbility of more effective tretment of the underlying disese. In the second rndomized tril of first-line therpy with PLD for AIDS-KS (Northfelt et l 1998), lso performed before the introduction of HAART, 258 ptients with no prior chemotherpy were rndomized to receive either PLD (20 mg/m 2 ) or ABV (conventionl doxorubicin 20 mg/m 2, bleomycin 10 mg/m 2, nd vincristine 1 mg), dministered every 2 weeks. The overll response ws significntly better with PLD thn with ABV (45.9% vs 24.8%; p < 0.001) (Tble 2). The time to response ws gin shorter with PLD (medin, 39 dys vs 50 dys with ABV; p = 0.014). Compred with PLD, more thn three times s mny ptients discontinued ABV becuse of n dverse event (37% vs 11%). PLD-treted ptients remined on tretment longer either becuse it ws well tolerted or becuse they responded to tretment. More rpid dropout of ptients in the ABV tretment group might hve influenced cumultive response rtes, but the study did not exmine this possibility. Significnt differences between the tretments fvored PLD in the frequency with which lesions decresed in size, indictor lesions flttened, lesion color returned closer to tht of norml skin, pulmonry dysfunction improved, pin decresed, hed nd limb mobility improved, exercise tolernce incresed, sleep disturbnces decresed, nd sense of socil wellbeing incresed. The tretments showed no significnt differences in reduction of lesion edem or pin, or ptients bility to wlk or wer clothing more esily. Neither the medin durtion of response (PLD, 90 dys; ABV, 92 dys; p = 0.234) nor the medin overll survivl (both groups, 160 dys differed between tretment groups. Ptients enrolled in the tril compring PLD with ABV (Northfelt et l 1998) were sked to complete 30-item AIDS-relted helth-relted qulity of life questionnire before tretment (bseline), every 2 weeks during tretment, nd pproximtely 21 dys post-tretment (Osob et l 2002). Twenty-two items were ssessed within 9 domins: generl helth, pin, socil functioning, nd overll qulity of life (1 item ech); mentl helth (5 items); energy/ftigue (4 items); helth distress (4 items); nd cognitive functioning (4 items). Scores t bseline nd end of tretment were trnsformed to scle from 0 to 100, with higher scores indicting better helth. In ech of the domins there ws n improvement in helth-relted qulity of life ssocited with PLD tretment, nd six of these nine chnges were sttisticlly significnt (Tble 3) (Osob et l 2001). In contrst, ABV tretment resulted in improved helth-relted qulity of life in only two domins nd in worsened helth-relted qulity of life in three domins, two of which were significntly reduced. 348 Interntionl Journl of Nnomedicine 2007:2(3)
Pegylted liposoml doxorubicin for Kposi s srcom Tble 3 Chnges in helth-relted qulity-of-life prmeters in ptients with Kposi s srcom PLD (Doxil) (n = 118) ABV (n = 114) Domin No. of Chnge P No. of Chnge P P vlue ptients from vlue b ptients from vlue b between bseline bseline groups c Generl helth 91 3.3 NS 85 3.3 0.05 0.02 Pin 73 8.3 0.01 74 0 NS 0.01 Cognitive functioning 70 5.0 0.008 61 0 NS NS Mentl helth 93 3.3 0.03 89 0 NS NS Overll qulity of life 90 4.0 0.05 85 2.0 NS NS Socil functioning 76 10.0 0.004 69 0 NS 0.03 Energy/ftigue 93 3.3 NS 88 5.0 0.004 0.002 Helth distress 91 8.3 <0.001 88 1.4 NS NS Helth trnsition 76 4.0 NS 78 1.4 NS NS Scores t bseline nd end of tretment rnged from 0 to 100, with higher scores nd positive chnges Indicting better helth. b Wilcoxon signed-rnk test compring the chnge from bseline to the end of the tretment within tretments. c Wilcoxon rnk-sum test compring the chnge from bseline to end of tretment between tretments. Abbrevitions: ABV, doxorubicin, bleomycin, vincristine; NS, not signifi cnt. There ws significnt difference between the two tretments in four domins: generl helth, socil functioning, nd energy/ftigue. A cliniclly significnt improvement ws defined s chnge of 10 points or more from bseline in the overll qulity-of-life score, nd more ptients in the PLD group thn the ABV group chieved this endpoint (65% vs 43%, p = 0.0008). The durtion of cliniclly significnt improvement in overll qulity of life ws lso longer in the PLD-treted group thn in the ABV group (p = 0.049). To determine whether the ddition of other gents to PLD might led to improved tretment outcome, the AIDS Clinicl Trils Group performed study which rndomized ptients who hd not received prior chemotherpy to receive tretment with PLD (20 mg/m 2 ) either lone or in combintion with BV (bleomycin 10 U/m 2, nd vincristine 1 mg), dministered every 2 weeks (Misuysu et l 1997). Among 126 evluble ptients, overll responses were similr in the two groups: 79% with PLD lone versus 80% when combined with BV. Five ptients in ech group experienced CR. Medin time to tumor progression or deth ws lso similr: 29 nd 32 weeks, respectively. Ptients treted with PLD lone showed trend towrd better survivl t the time of n interim nlysis; with the single-gent, qulity of life decresed less rpidly during tretment. The uthors concluded tht dding BV to PLD offered no dditionl benefit. Sfety of pegylted liposoml doxorubicin in clinicl trils Toxicities observed in phse I/II studies of PLD for KS re shown in Tble 4 (Hengge et l 1993; Bogner et l 1994; Hrrison et l 1995; Goebel et l 1996; Northfelt et l 1997; Grunug et l 1998; Newell et l 1998). Neutropeni ws progressive with succeeding courses of PLD nd ws the most common dose-limiting side effect, with n incidence tht rnged from 28.6% to 85% in vrious trils. This wide vrition ws likely relted to the degree to which AIDS hd compromised the mrrow in ddition to the effects of prior chemotherpy. In these trils, the overll incidences of lopeci nd nuse nd vomiting were low (generlly <20%). In contrst to studies of ptients with solid tumors in which PLD ws dministered t higher dose, the incidences of hnd-foot syndrome (HFS; 0% 2%) nd infusion rections (0% 15%) were reltively low. Infusion rections to PLD were chrcterized by some or ll of the following: flushing, tchycrdi, dyspne, hypertension or hypotension, chest pin, bdominl pin, nd bck pin. Tble 4 Effi ccy of pegylted-liposoml doxorubicin in the tretment of AIDS-relted Kposi s srcom fter filure of stndrd chemotherpy: dverse events (Northfelt et l 1997) Event All events Severe (n = 53) (% ptients) (% ptients) Any dverse event 76% 30% Leukopeni 40% 17% Nuse nd/or vomiting 19% 0% Alopeci 9% 0% Astheni 9% 2% Fever 8% 2% Dirrhe 6% 2% Thrombocytopeni 6% 2% Adverse events occurring in 5% of ptients, thought to be possibly or probbly relted to pegylted-liposoml doxorubicin. Interntionl Journl of Nnomedicine 2007:2(3) 349
Udhrin et l A similr sfety profile ws observed in the phse III rndomized comprisons of PLD nd either BV or ABV (Stewrt et l 1998; Northfelt et l 1998). Compred with these combintion regimens, PLD ws ssocited with reduced incidence of nuse/vomiting, lopeci, nd neuropthy (from vincristine, which is used in both the BV nd ABV regimens) (Tble 5). In the tril of PLD vs ABV (Northfelt et l 1998) myelosuppression nd fever were less severe with PLD, but this did not trnslte into reduced incidence of infection. In the comprison with BV (Stewrt et l 1998), PLD ws more myelosuppressive becuse neither bleomycin nor vincristine is ssocited with substntil bone mrrow toxicity. HFS ws uncommon with the PLD doses nd schedules used in these trils. No cses occurred in either group of one tril (Stewrt et l 1998), nd in the other tril, 4% of PLD-treted ptients nd 1% of ABV-treted ptients experienced HFS (Tble 5). Mucositis, stomtitis, nd infusion rections such s dyspne nd hypotension occurred more frequently on the PLD rms; infusion rections tht occurred with BV consisted primrily of fever nd rigors. Comprtive tril: PLD vs DNX PLD ws initilly grnted ccelerted pprovl by the US FDA, when the only dt vilble for regultory review were from uncontrolled trils in ptients with AIDS-KS which ws refrctory to conventionl therpy, or in ptients who were intolernt of conventionl chemotherpy regimens. At the request of the US FDA, double-blind rndomized tril of PLD nd DNX tretment for AIDS-KS ws undertken primrily to confirm erlier dt for PLD, rther thn s comprison between the two drugs (Henry et l 2002). In this tril ptients were rndomized in 3:1 rtio to receive PLD or DNX, respectively. The nture of the tril nd the smll number of ptients enrolled precluded robust sttisticl nlysis, nd p vlues were not clculted. For enrollment ptients were required to hve t lest one KS-relted symptom t bseline so tht clinicl benefit could be ssessed. Ptients were initilly eligible only if they were refrctory to conventionl chemotherpy, but the tril ws ultimtely mended to llow ptients without or with limited prior chemotherpy becuse of slow ccrul to the study. As result, 7 of 80 ptients enrolled hd received prior chemotherpy. Ptients were rndomized to PLD 20 mg/m 2 or DNX 40 mg/m 2 given intrvenously every 2 weeks for up to six cycles. Although sttisticl tests were not performed, differences in clinicl benefit nd tumor response tended to fvor PLD (n = 60) over DNX (n = 19) mong the ptients who received t lest one dose of study tretment (Tble 6). Clinicl benefit ws defined s improvement from bseline in t lest one Tble 5 Incidences (%) of dverse events in rndomized trils compring liposoml nthrcycline with ABV or BV Stewrt et l 1998 Northfelt et l 1998 PLD (Doxil) BV P vlue PLD (Doxil) ABV P vlue (n = 121) (n = 120) (n = 133) (n = 125) Neutropeni grde 3/4 72 51 <0.001 36 42 Neutropeni grde 3 29 13 Neutropeni grde 4 6 14 G-CSF required 44 53 Fever 16 25 0.08 0 4 Sepsis 7 2 6 2 OIs 50 30 <0.002 37 30 Orl cndidisis 31 17 0.02 Anemi 18 15 10 11 Thrombocytopeni 15 12 3 6 Alopeci 3 8 1 19 <0.001 Neuropthy ll grdes 3 14 <0.005 6 14 0.002 Constiption 2 11 <0.01 Nuse (ll grdes) 12 17 Nuse/vomiting grde 3/4 16 25 15 34 <0.001 Stomtitis grde 3/4 7 5 5 2 0.026 Infusion rections 4 6 5 0 Skin rsh 12 9 Hnd-foot syndrome 4 1 Includes 2 skin rshes in PLD treted ptients not clled hnd-foot syndrome but totlly consistent with the syndrome. Notes: Unless noted, differences re not sttisticlly signifi cnt. Abbrevitions: ABV, doxorubicin, bleomycin, vincristine; BV, bleomycin, vincristine; G-CSF, grnulocyte colony-stimulting fctor; OI, opportunistic infection. 350 Interntionl Journl of Nnomedicine 2007:2(3)
Pegylted liposoml doxorubicin for Kposi s srcom AIDS-KS symptom ctegory tht lsted for 28 dys or longer in the bsence of disese progression or severe drug-induced toxicity. Using this definition, 80% of PLD-treted ptients nd 63% of DNX-treted ptients experienced clinicl benefit. The definition of sustined clinicl benefit ws more restrictive, nd involved improvement in t lest one symptom ctegory for 28 dys or longer with no worsening of other symptom ctegories nd no increse in medicl interventions either before or during tht period. Sustined clinicl benefit ws observed in 37% of PLD-treted ptients nd 16% of DNXtreted ptients. An externl HIV/AIDS expert who ws blinded to tretment lloction determined tht clinicl study photogrphs showed clinicl efficcy rtes of 35% for PLD nd 38% for DNX. Prtil tumor response ws defined s one or more of the following: (1) no new lesions (skin or orl), no new viscerl sites of involvement, no ppernce or worsening of tumorssocited edem or effusions, nd 50% or greter decrese in the number of ll previously existing lesions lsting for t lest 4 weeks; (2) complete flttening of t lest 50% of ll previously rised lesions; (3) 50% decrese in the sum of the products of the lrgest perpendiculr dimeters of the indictor lesions; or (4) the ptient met the criteri for complete clinicl response except residul tumor-ssocited edem or effusion. Using these criteri, 55% of ptients in the PLD group nd 32% of ptients in the DNX group hd PR to liposoml nthrcycline therpy. There ws positive correltion between clinicl benefit nd tumor response (Person correltion coefficient, 0.25; p = 0.028). Ninety-two percent of ptients who responded to PLD experienced clinicl benefit, nd 42% of responders in the PLD group experienced sustined clinicl benefit. There were concerns tht the introduction of HAART, which occurred round the time the study begn to enroll ptients, might hve confounded the results of the study. An dditionl nlysis of the dt thus considered ntiretrovirl therpy to be potentil confounding fctor if it ws begun within 28 dys of study entry or ws chnged during the study. The observed rtes of clinicl benefit were not significntly different between ptients who met these criteri for potentilly confounding tretment nd those who did not (26% nd 35%, respectively; p = 0.461). Differences in the nture nd frequency of side effects from the two drugs were smller thn might hve been expected from indirect comprisons drwn from dt shown in Tbles 6 nd 7. HFS nd infusion rections were seen only with PLD. In ll but one of the ptients who experienced HFS or infusion rections, the rections were grde 1/2, nd none of the rections cused ptients to discontinue tretment. Conclusion Mny new nd interesting gents re under development for treting AIDS-KS, including ngiogenesis inhibitors, loclly pplied nd orl retinoids, more effective nti-retrovirl gents, nd drugs trgeting HHV-8. However, liposoml nthrcyclines re still considered by mny to be the initil drugs of choice for this disese when it is dvnced nd symptomtic. Phse 1 clinicl trils confirmed tht delivery vi pegylted liposomes does concentrte doxorubicin in AIDS-KS lesions more effectively tht does tretment with conventionl doxorubicin, s well s concentrting doxorubicin to greter degree in AIDS-KS lesions thn in djcent norml skin (Northfelt et l 1993, 1995). A number of phse II clinicl trils demonstrted substntil effectiveness nd good tolerbility of PLD in tretment of AIDS-KS, even in ptients who hd previously been treted with conventionl chemotherpy, including conventionl doxorubicin (Sturzl et l 1994; Hengge et l 1993, 2001; Simpson et l 1993; Bogner et l 1994; Jmes et l 1994; Wgner et l 1994; Bergin et l 1995; Hrrison et l 1995; Goebel et l 1996; Northfelt et l 1997; Grunug et l 1998; Newell et l 1998; Nuncez et l 2001). Finlly, in phse III clinicl trils in which PLD compred with conventionl tretment with BV or ABV, PLD ws ssocited with higher response rte, shorter time to response, nd less toxicity in ptients with AIDS-KS (Stewrt et l 1998; Northfelt et l 1998). PLD lso improved severl domins of helth-relted qulity of life compred with ABV (Osob et l 2001). 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