Barnardt, P

Georgiev, GD

English

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HIV AND CANCERP Ilarnardt, ME CkE, Dip On<ol ChzmorhuG D Georgiev, MD, MMuI (RaJ On<ol)lJep<rnmnu of1I<ldiatiml 0naJIDgy,1Y~ Ho,piud, 1Yg~,wCopePALLIATIVE TREATMENT FOR HIV-RELATEDKAPOSrS SARCOMANOVEMBER ~003METHODSOur study included 54 males and 46 females with HIV-related KS, who were seen and treated between April 1995and November 2002. The mean age for the group as awhole was 35.8 years (range 21 - 60 years), the mean agefor females being 34.2 years (range 21 - 58 years) and themean age for males 37.1 years (range 21 - 60 years). Of thepatients 69 were black, 27 of mixed racial origin and 4white. The male/female ratio was 1.1:1. Sixty-one patients(61%) presented with KS as their AIDS-defining illness and39 developed KS during the course of their HIV disease. Tenpatients (IO%J were homosexual men. Fifty-three patients(53%) were treated for concomitant pulmonarytuberculosis (PTB) [fable n.Optimal or standard therapy for AIDS-related KS has notbeen defined. The major goals of treatment are palliation ofsymptoms, shrinkage of tumour to alleviate oedema andpsychological stress, and prevention of disease progression.All patients presented with generalised mucocutaneous KSlesions and 56 had additional generalisedlymphadenopathy. Fifteen patients had systemic diseaseThis ongoing study evaluated the effectiveness of palliativetreatment in patients with HIV-related KS in the absence ofART.The HIV situation has changed since antiretroviral therapy(ARn became available: deaths from AIDS-related illnesseshave been reduced by 75%. A projected reductionin new KS cases of 50 - 90% and regression of existing KSis now a recognised benefit of ART.' The clinical responsecorrelates with a decrease in the HIV viral load and anincrease in the CD4+ count'People with AIDS are at considerably higher risk ofdeveloping cancer than the general population. Frisch et01.' reported that most of the cancers observed in HIV/AIDSpatients were those already considered to be AIDS-definingcancers (87%), notably Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHl).Objective. To evaluate palliative treatment withchemotherapy and/or radiotherapy in patients withHIV-related Kaposi's sarcoma (KSJ. The primary end-point was symptom relief; the secondary end-pointwas tumour response to treatment and overallsurvival.Methods. This study indudes 100 patients with HIV-related KS. Combination chemotherapy wasadministered with ABV (doxorubicin, bleomycin andvincristine) (33 patients), or vinblastine and bleomycin(Vbl-B) (48 patients), depending on the CD4+ count atpresentation. Radiotherapy was administered to 31patients.Results. Symptomatic relief was noted within 4 weeksof chemotherapy and response after 8 weeks. Twenty-nine patients (29'lbJ had partial responses, 8 patients(8'!bJ achieved complete responses, and 37 patients(37llbJ had stable disease. Twenty-six patients (26llb)had disease progression. The response rate was 37%,with dinical benefit achieved in 74% of patients.Patients who received radiation therapy for bleedingand painful ulcers had complete responses. Twenty-seven patients (27%) received 8 Gray (GyJ singlefractions. Two lower-half bodies (8 GyJ and one upper-half body (6 GyJ were irradiated. Five patients receiveda course of radiation for nasopharyngeal and skeletallesions (20 Gy), rectal lesions (30 Gy) and an eyelidlesion (12 Gy). Forty-two patients (42%) are alive, witha median survival of 11.2 months (range 2 - 49months). Fifty-eight patients (58llb) died due toprogression of HIV disease or associated opportunisticinfections with a median overall survival of8.8 months(range 1 - 31 monthsJ.Conclusion. In the absence of antiretroviral therapythe care and prognosis of HIV-related Kaposi'ssarcoma remains dismal. However, symptomatic reliefand an improved quality of life can still be offered.THE SOUTHERN AfRICAN JOURNAL OF HIV MEOICINE ----------Fig. 1.1<5: X-ray image ofskeletal involvement.Fig. 2. 1<5: Clscan image ofrecral mass.Radiotherapy was offered to patients with CD4+ counts< 50 cellsl~l, performance status 2 - 3, bleeding, painfululcerative lesions, and generalised, painful limb oedema.ThirtY-one parienrs received concomitant radiation therapythe CD4+ count was between 30 and 100 cells/~1. ABV wasadministered 10 33 pa ients, as first-line therapy in 23cases and as second-line treatment for fulminating andprogressive disease in 10. Forty-eight patients received theVbl-B combination. A cycle of treatment consisted of day 1and day 15 every 4 weeks. A median of 5 cycles wasadministered (range 1 - 15 cycles). A total of 206 cycles ofchemotherapy was administered over the study period.92111126746927461395310422100TotalMale FemaleNumber 54 4liAge (years)Mean 37.1 34.2Range 21 - 60 21 - 58Ethnic groupBlack 33 36Mixed race 17 10Caucasian 4KS presentationAIDS-defining 37 24HN late presentation 17 22S",gingGood risk 19 7Poor risk 35 39CD4+ count (cells/Ill)BeginningMean 214 125Range 2 - 750 0-409EndMean 171 105Range 3 - 769 0-409Systemic involvementLung 6 3Rectum 2Spleen 1Uver 1Skeletal 1Pericardiac effusionOpportunistic infectionsTuberculosis 22 31Candidiasis 4 6Herpes zoster 4C neofarmons 2Pneumocystis corinii 2J, ~ ",gtH 2003 --------------TABLE I. PATIENT CHARACTERISTICSthat involved the liver (1 case), spleen (1). lung (9), rectum(2), pericardial effusion (1) and skeletal involvement (1)[Rgs 1 and 2)Because of the multicentric nature of KS, the standardrumour-node-metastases (TNM) staging system used forsolid rumours cannot be applied to KS. Patients wereassigned to receive treatment according 10 he AIDSClinical Trial Group [AClG) staging system developed by theNa ional Insrirute of Allergy and In'ectious Diseases.Pa ients were classified in good or poor risk groups basedon tumour extent immune sratus measured by the CD4+count (>1< 200 cells/~ll. and evidence of HIV-associatedsystemic symplOms:' In this patient population there were26 patients (26010) with good risk sratus while 74 (74010)presented with advanced poor risk KS. All patients with aCD4+ count < 200 cells/~1 received sulphamethoxazole +trimethoprim [Bactrim) as part of Pneumocystis cariniiprophylaxis.Patients received chemotherapy with either thecombination ABV (doxorubicin 10 mglm', bleomycin10 mglm' and vincristine 2 rng) every 2 weeks if rhe CD4+coum was> 100 cells/~l, or the combinarion vinblastine6 mglm' and bleomycin 10 mglm' (Vbl-Bl every 2 weeks ifOveraD Survival1-....,··-PoorR,.p"O.OOO6KS is the most common malignancy associated with HIV.The single most important risk factor for the developmentof AIDS-related KS is immune suppression." Therecognition that effective antiretroviral regimens areassociated with both a decrease in new AIDS-defining KScases and a regression in the size of existing KS esionsresulted in the recommendation mat' I -positive patien sbe treated wi:h antireuoviral orugs. ART prolo gs the timelO treatment 'a'lure 0' anti-KS rherapies. In paf(icular, sincethe use of pro ease inhibitors a 30 - 50~o reduction of KShas oeen observeo in rhe USA ana Europe." The resolutionof immune suppress'on witn ART mignt a so aFect KS..··· Itis thought mer prmease inhibitors may inhibir the KS-associated herpesvirus proreins, but it is more likely that KSregression is linked to adecrease in rhe HIV replicarion withan associated decrease of cytokine levels leading to therestoration of immune funC'Cion:DISCUSSIONFig. 3. Overall survival of 100 parienrs I/irh HIV-refared KSstrarified according to good ana poor risk groups.Because of :he unpreaic:ab e responses of KS :0 ART,spec'rc loca ara/or systemic treraoy 's often :rs:ilU!ed.Forry-two (42%) of this patient population are currentlyalive, with a median survival of 11.2 months (range 1 - 49months). Fifty-eight patients (58%) died due to progressionof their HIV disease or associated opportunistic infections- pneumonia (10 cases), Cryptococcus neoformonsmeningitis (2), Mycobacterium tuberculosis (6), sys emiccandidiasis (3) and fever of unknown origin I2l. with amedian overall survival of 8.8 montns (range 1 - 31months) (Fig. 3).Twenty-nine patients (29%) had partial responses, while 26(26%) experienced disease progression. Eight pa ients (80/0)achieved comple:e responses and 37 [37%) ad stabledisease, with an overall response or 740'0.In this stuoy 61~o of patients presented with KS as theirAIDS-defining illness. Thirty-nine pa ients developed KS asparr of the natural course of HIV, a mean of 31.6 monthsafter diagnosis (range 6 - 120 months).RESULTSAll 100 patients are evaluable for response and 58 patientsfor overall survival. All patients receiving treatment hadsymptomatic relief within the first two administrations (4weeks) and responses within the first twO cycies (8 weeks)0' chemotherapy. Patients generally toleratedchemomerapy well. aema otoxicity requiring treatmentdelays were ooserved in 6 patients w:th graae 3ne tropenia. All 27 patients receiving 8 Gy 'ractiorsresponoeo 'or the indications of pain and bleeding ulcers.Five pOlients receiving a pro racteo course of irradiation allhad complete responses. Three patients receiving naif-bodyradiation had partial symptomatic relief. Two patients whoreceived radiation therapy for bleeding oropharyngeallesions experienced prolonged radiarion-induced mucositis,grade 3 [World Health Organsation). The duration ofresponse for campi ere resoonaers was 9.1 months (2.5 - 30montns), woile :he d rae'on 0' symp:orrar'c re 'ef was 4.1,"on:'s (1 - 8 mon:rs).The CD4+ count was done at the start of treatment andrepeated after every second cycle of cytotoxic treatmenLThe mean CD4+ count was 172.8 cells/~1 [range 0 - 750cells/~1) at onser, and a depletion of 18.8% of the CD4+count was observed by the end of treatment, with a meanof 140.3 cells/~1 (range 0 - 769 cellsl I). The studysuggested that women present at a younger age (mean34.2 years, range 21 - 58 years) and with more advanceddisease (mean CD4+ count 125 cells/~l, range 0 - 409cells/~l) than males, for whom the median age atpresentation was 37.1 years (range 21 - 60 years) and themean CD4+ count 214 cells/~1 (range 2 - 750 cells/~I).while 9 had radiation therapy as their only form oftreatment. Single 8-Gray (Gy) fractions were given in 27patients and were repeated in 9 patients on day 28. Twolower-half bodies [8 Gy) and one upper-half body (6 Gy)were irradiated. A protracted course of irradiation withcobalt-60 was administered to 5 patients: 1with bleedingrectal KS received 30 Gy (3 Gy x 10 fractions); 2 withbleeding nasopharyngeal KS received 20 Gy (4 Gy x 5fractions); 1 with humerus involvement received 20 Gy (4Gy x 5 fractions); and 1 with eyelid involvement receivedconsolidation radiation with 12 Gy (3 Gy x 4 fractions)electrons, after a pa rtia I response to 4 cycles of ABV.The ACTG Oncology Committee evaluates tumourresponses on the basis of total-body cu aneous lesionco ntS, changes in lesio character (fiat or raised) andbidimensional measurements of marker lesio s. Partialresponses (PR) are based on a 500,'0 reduction in the totalnumber of lesions or a 500/0 decrease in the n mber ofraised lesions. Response is never based on improvement ofsymptoms or visceral disease alone.';Optimal ART with maximal viral suppression, preventionand treatment of opportunistic infections is an essentialelement of KS treatmentMany chemotherapeutic agents are active against KS, bothas single agents and in combination. In most series, theoverall response rates range from 25% to 76%, althoughmost have been partial responses."" In our series, anoverall clinical benefit rate of 74% was observed withchemotherapeutic agents, even though the currentsystemic treatment for KS revolves around liposomalanthracyclines and paclitaxel.Neither ART nor liposomalanthracyclines are standardtreatment in the publichealth sector. The absence ofART is reflected in the overallsurvival of AIDS-related KSpatients, with a medianoverall survival of 8.8 months(range 1 - 31 months).The absence of improvedsurvival rates for AIDS-related KS patients isgenerally attributed to thedecline in CD4+ count.Chemotherapy can depleteCD4+ counts by up to 50%independent of HIV and thuslimit the CD4+ protectiveeffect of ART." This studyshowed a decline of 18.8% inthe CD4+ count from a meanof 1728 cells/~l to a mean of 140.3 cells/~1.In spite of significantly improved overall survival rates forpatients with AIDS, the survival of patients with KS hasremained poor. A European AIDS cohort study reported amedian survival of 17 months for patients with KS."Fernandez Guerrero et 0/.' reported that the mediansurvival of patients with KS on ART was 49 months incomparison with 12 months for patients who did notreceive ART. In our study 42% of patients are alive with amedian survival of 11.2 months (range 2 - 49 months). Fourpatients with amedian survival of 29.5 months are on ART.Fifty-eight patients (58%) died due to progression of theirHIV and HIV-related illnesses, with a median overallsurvival of 8.8 months (range 1 - 31 months). Thirty-nineper cent of deaths were due to opportunistic infections:pneumonia, Cneoformons meningitis, systemic candidiasisNOVEMBER 2003and M. tuberculosis. Twelve patients died of progressive KS.The high proportion of patients (61%) presenting with KSas their AIDS-defining illness reflects the ignorance andstigma about HIV/AIDS that still persist in communities.This emphasises the need for continuous education andinformation as a priority of HIV/AIDS prevention. Despitethe high frequency of KS, the referral system seemsinadequate as a limited number of patients are referred fortreatment Factors that could account for this includephysician perception of the disease, or patients with poorperformance status andadvanced disease atpresentation.Survival rates are still failingto improve among ourpatients owing to advanceddisease, accompanied byopportunistic infections, andthe absence of ART. However,symptomatic relief and animproved quality of life canstill be offered to a patientpopulation that largelyremains marginalised.REFERENC£SI. frisch M, Biggar RJ. Engels EA. Goeden: n.Association of canm' with AIDS-relatedimmun05Uppr~n in adults. JAMA 200);285: 1736-1745.2. Tirelli U. Bemardi 0, Spina M, Vacrh~ E.A1DS-related rumo~: integrating antiviraland anticancer Mapy. 0nr0I Hemotol2002;41: 299-315.3. Caudan AM, Avma S. Calabro I.., ~ alAntiretroviral therapy with HIV-protea~inhibitors in W: ueaonent of AIDS-relatedKaposfs sarcoma: dinical and biological correlations. 13th International AIDSConftrtnct, Durban, 9 - 14 July 2Cro (abstract 3163).4. Krown SE. Mwoka C. Wcrnz .)C, er aL Kaposts san:oma in the: acquimf immuneddicietK:y syndrome: A proposal for uniform evaluation,r~ and mgingCJ'ittria. JOinOncoi 1998; 7: 1201-1207.5. Krown SE, Tl5!il M, Huang 1 ValidatiM of tf1( Aids Oinical Trial Group (ACrGJstaging dasWcation for AIDS-associated Kaposi's 'iaItOttli (AidsIKS}. j Din 0nc0I1997; 15: 3085-3092.6. Biggar RJ. Rabkin se. The qlirl~iOOgy of AI DS-rdattd nmpl:isms. HematoI 0trc0JOinNorthAm 1966; 10: 997-101Q7. Oezube BJ. New therali15 for the treatrntnt of A1DS-tdattd Kapos"'s sarcoma. CurrOpin 0tlC'0I2OOJ; 12{5): 445-449.a Bowtt' M, Fox P, Fin:: Ko er aL HAART prolongs time to treatmmr failure in Kaposrssarcoma. JAcqui, Immunt Defic Syndr Hum Reuoviroll999; 21: A 24.9. Fttnandez Gumtro M, Ftrez Casas A, Garcia Ddgado R, Gotgolas M. Impact ofhighly activI= antireuoviral lho'apy in the outrome of patimlS with Aids-rd.dttdlCaposi's sarcoma. 13th International AIDS Confmnct. Durban, 9 - 14 July 2CXXJ(abstract 3156).10. Van Roenn JH. Kaposi's sarcoma: Evaluation and treatmml In: Tk AmericanSociety of Oinirol Oncology Educational Book (34). Philaddphia: WB Saunder'j,1988: 7!H1&.11. Amman K. O1ang Y. Kaposi's sarcoma. NEngJJMed 200J; 324(14): 1027-1036.11 Madall CL. Reisher TA, Brown MR, erallymphocyte deplnion during tre:atmmtwith intensive chemotherapy for cancer. Blood 1994; 84: 2221-222a13. Hermons P, lungrm J, Sommereyns B, et al Survival of European patients withKaposi's sarcoma as AlOS-defining condition during the first decade of AIDS. AIDS1997; 11: 529-531.m SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE

Palliative treatment for HIV-related Kaposi's sarcoma

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Palliative treatment for HIV-related Kaposi's sarcoma

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