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© 2003 American Society for Clinical Oncology AIDS-Related Kaposi’s Sarcoma: Evaluation of Potential New Prognostic Factors and Assessment of the AIDS Clinical Trial Group Staging System in the Haart Era—the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naïve From AntiretroviralsFrom the Division of Medical Oncology A, National Cancer Institute, Aviano; Epidemiology Unit, National Cancer Institute, Aviano; Division of Infectious Diseases, IRCCS Spallanzani, Rome; II Division of Infectious Diseases, Sacco Hospital, Milan; Infectious Diseases Clinic, University of Bologna, Bologna; Division of Infectious Diseases, Santa Croce Hospital, Ravenna; Division of Infectious Diseases, S. Salvatore Hospital, Pesaro; Infectious Diseases Department, University of Torino, Torino; Division of Infectious Diseases, Cuggiono Hospital, Cuggiono; Infectious Diseases Clinic, Sacco Hospital, Milan, Italy. Address reprint requests to Umberto Tirelli, MD, National Cancer Institute, Via Pedemontana Occidentale 12, 33081 Aviano (PN), Italy; email: oma{at}cro.it.
Purpose: To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposi’s sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. Patients and Methods: We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. Results: In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-naïve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P = .007), 83% for S0 patients and 63% for S1 patients (P = .003), and 83% for I0 patients and 71% for I1 patients (P = .06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P = .0001). Conclusion: In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).
KAPOSI’S SARCOMA (KS), a potentially life-threatening multifocal neoplasm, is the most common AIDS-associated malignancy.1 KS has been associated with AIDS since the beginning of the epidemic, and the risk of KS has progressively increased during the human immunodeficiency virus (HIV) epidemic until the mid-1990s when, coincident with the introduction of highly active antiretroviral therapy (HAART), a sharp decline of KS incidence was observed.2,3 Durable suppression of HIV replication by HAART is associated with CD4 cell recovery and with a decrease in morbidity and mortality rates due to opportunistic infections and HIV-related cancers.4 In particular, the widespread use of HAART is associated with a favorable impact on epidemiologic characteristics and on the therapeutic management of KS.5–11 The suppression of HIV by HAART could influence various factors that stimulate KS growth — directly, by causing a decrease in the level of HIV Tat protein and inflammatory cytokines, and indirectly, by improving immune function. Furthermore, protease inhibitors have been reported to have direct antiangiogenetic activity,12 which is an important element in the pathogenesis of KS. On the basis of these considerations, it is likely that the development of KS during HAART has been profoundly modified and that the natural history and prognostic factors for survival have also changed. Thus far, the effects of HAART on the natural history and prognostic factors of KS have not been documented in sizable cohort studies. Assessment of prognostic factors for AIDS-KS in the era of HAART is a crucial issue, considering that so far, the AIDS Clinical Trials Group (ACTG) staging system for AIDS-KS has been used to provide accurate prognostic information on which therapeutic decisions and clinical trial planning are based. The ACTG staging system for AIDS-KS was defined in 1988 and classified patients into good- or poor-risk groups based on tumor extent (T), immune system status (I), as measured by CD4 T-lymphocyte count, and evidence for HIV-1–associated systemic illness (S).13 Subsequently, Krown et al14 validated the proposed staging system showing that the ACTG TIS classification effectively predicted survival of patients with AIDS-KS. The study was conducted before the introduction of HAART; data were collected from 281 patients within 34 ACTG trial sites from April 1989 to January 1995. To date, no study has focused on the assessment of prognostic factors since the introduction of HAART, and, in particular, we do not know whether the ACTG staging system for AIDS-KS is still appropriate and useful in predicting survival in the era of HAART. To assess potential new prognostic factors and to validate the ACTG staging system in the era of HAART, we collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian HIV cohort studies since January 1996.
Our analysis included data from two prospective cohort studies: the Italian Cooperative Group on AIDS and Tumors (GICAT) and the Italian Cohort of Patients Naïve from Antiretrovirals (ICONA). GICAT has recruited 2,500 HIV-positive patients affected by cancer, from many centers throughout Italy since 1986, and many of them have been enrolled in clinical trials. ICONA is a multicenter observational study which has recruited 4,000 HIV-positive patients naïve for antiretrovirals at enrollment, from 65 infectious disease centers in Italy since 1997. We included in the analysis all patients with an initial diagnosis of KS made in January 1996 or later, the date at which HAART became widely available in Italy, and the following criteria were required: histologically confirmed KS, serologic evidence of HIV infection, at least one follow-up visit after KS diagnosis, and treatment with HAART before and/or after KS diagnosis. Two hundred eleven patients met the inclusion criteria and entered the study. Epidemiologic and HIV-related clinical data (age at time of KS diagnosis, sex, race, HIV exposure category, HIV stage at KS diagnosis, immunologic and virologic information at KS diagnosis, antiretroviral therapy history, vital status, eventual cause of death) were available in the ICONA database and GICAT case report forms. A questionnaire was sent to the ICONA and GICAT participating centers to collect retrospectively the following additional information (data available for all patients): KS staging (according to the ACTG criteria), visceral involvement, diagnostic procedures used to assess visceral involvement, type of KS treatment, and, when needed, follow-up update (data required for 139 patients). Although the staging procedures were probably not uniform among the various centers, the following criteria were required to define KS gastrointestinal (GI) tract involvement: positive endoscopic evaluation, and, when endoscopy was not performed, oropharyngeal KS with signs and symptoms of GI disease and without microbiologic evidence of GI tract infection. For KS pulmonary involvement, the following criteria were required: positive bronchoscopic evaluation or evidence of interstitial infiltrates on chest radiograph with positive thallium scan and without microbiologic evidence of pulmonary infection.
Patients were staged according to the ACTG criteria, which are based on the evaluation of tumor extension (T), CD4 cell count (I), and patient’s systemic status (S). Good tumor extension risk (T0) was defined as KS confined to the skin and/or lymph-nodes and/or minimal oral cavity involvement and poor tumor extension risk (T1) as extensive oral disease, the presence of tumor-associated edema or ulceration, or GI or other visceral disease. Good immune system status risk (I0) was defined as CD4 cell count greater than 200/µL, and poor immune system status risk (I1) as CD4 cell count
Information on survival was obtained through an active follow-up on verification of vital status of the patients up to April 15, 2002, and survival was measured from the date of diagnosis to death. Survival analysis was computed by the Kaplan-Meier method,15 and the log-rank test was used to test the difference between subgroups. Differences between subgroups were also tested in univariate analysis using the Cox proportional hazards model to compute the hazard ratio (HR) and corresponding 95% confidence interval (CI).16 Covariates that were significant in the univariate analysis were also tested in the multivariate model.16 As a final step, a Cox proportional hazards model was fitted with interaction terms between some covariates. In all cases, statistical significance was claimed for P
General Characteristics The general characteristics of the 211 patients with KS are presented in Table 1  . One hundred fifty-nine patients were recruited from the GICAT, and 52 from the ICONA. One hundred ninety patients were male and 123 patients (59%) were older than 35 years, with a median age at KS diagnosis of 37 years (range, 20 to 80 years). The majority of patients (52%) were homosexual or bisexual, and 17% and 25% were drug users and heterosexual, respectively. Fifty-one patients (24%) had experienced an AIDS-defining disease before KS diagnosis. Most patients had severe immune system impairment and uncontrolled HIV viremia at KS diagnosis, with a median CD4 cell count of 86 cells/µL (range, 0 to 1,117 µL) and median HIV viremia of 89,000 copies/mL (range, <50 to >1,000,000 copies/mL). Regarding KS staging, 136 patients had poor-risk tumor extension (T1), 148 patients had less than 200 CD4 cells/µL (I1), and 125 patients had poor-risk systemic disease (S1). Only 17 patients had no poor-risk features (T0, I0, S0), whereas 48 patients had all of the poor-risk features (T1, I1, S1). Visceral disease was present in 73 patients, with GI tract involvement in 51 patients (documented by endoscopy in all patients) and pulmonary involvement in 31 patients (bronchoscopically confirmed in 20 patients). Sixty-nine patients received chemotherapy, with most of them being enrolled onto clinical trials. The most frequent combination regimens were: paclitaxel-vinorelbine (33 patients), liposomal daunorubicin (19 patients), and doxorubicin-bleomycin-vincristine (14 patients). Twenty patients underwent radiation therapy.
After a median follow-up of 24 months (range, 1 to 72 months), median survival was not yet reached. The survival rate at 3 years was 75%. KS progression was the most common cause of death, representing 70% of deaths (33 patients), whereas opportunistic infections were the cause of death in 30% of cases (14 patients).
Antiretroviral Therapy
Prognostic Factors
The correlation between survival and TIS variables is presented in Table 2
In the multivariate analysis, the Cox proportional hazards regression model was fitted to evaluate the relationship between TIS variables and survival. On the basis of the univariate analysis, we used a CD4 cell count level cut-point of 100 to discriminate good-risk (I0) and poor-risk (I1) immunologic groups. In the multivariate model, only tumor stage (P = .01) and systemic disease (P = .02) remained independent predictors of survival, whereas the CD4 count did not predict survival significantly. The increased hazard for patients with T1 (as compared with T0) was 2.59 (95% confidence interval (CI), 1.25 to 5.38) and for patients with S1 (as compared with S0) was 2.10 (95% CI, 1.14 to 3.88). To analyze the interaction between tumor stage (T) and systemic disease (S) and its effect on survival, a Cox proportional hazards model was fitted (Table 3 ). When considering patients with good tumor and systemic disease stage (T0S0) at risk 1 (as reference category), both subjects with good tumor extension and poor systemic disease stage (T0S1) and subjects with poor tumor extension and good systemic disease stage (T1S0) did not show a significantly increased HR for death (HR = 1.70, 95% CI, 0.46 to 6.33; and HR = 2.14, 95% CI, 0.70 to 6.49; respectively). However, when considering patients in whom both the tumor and systemic disease stages were poor (T1S1), the HR was significantly increased in comparison with those with T0S0 (HR = 5.68, 95% CI, 1.97 to 16.38), suggesting an additive interaction. Our analysis identifies two different risk categories: a good-risk group (T0S0, T1S0, T0S1) and a poor-risk group (T1S1) (Fig 5). The 3-year survival rate of patients with T1S1 was 53%, significantly lower than the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P = .0001). The median survival for patients with T1S1 was 38 months, whereas the median survival for patients with T0S0, T1S0, and T0S1 has not yet been reached.
Clinical practice and many reports in the literature indicate that KS patients with pulmonary involvement show a particularly aggressive and life-threatening clinical course. For this reason, we explored the possibility that patients with pulmonary disease had a significantly worse survival compared with the other patients with a poor-risk tumor stage disease, but without pulmonary involvement. In the univariate analysis, the median survival of the 31 patients with pulmonary disease was 26 months, while the median survival of patients without pulmonary disease has not yet been reached. The 3-year survival rate of 46% for patients with pulmonary involvement was significantly lower than the 77% survival rate for patients without pulmonary involvement (P = .0002) (Fig 6 ).
In light of this finding, we investigated the possibility that the presence or the absence of pulmonary involvement (indicated in the text as Tp1 and Tp0, respectively) and its interaction with the other TIS variables would provide a better discrimination between risk categories compared to the original ACTG tumor stage (T0, T1). In the multivariate analysis, a Cox proportional hazards regression model was fitted to evaluate pulmonary disease (Tp), immune system status (I), and systemic disease (S) variables. Pulmonary involvement (P = .001) and systemic disease (P = .03) were significantly associated with poorer survival, whereas immune system level of CD4 cells/µL  100 was not (P = .22). Table 4 shows the analysis of the interaction between Tp and S and its effect on survival. Among patients without pulmonary involvement (Tp0), S1 (Tp0S1) patients showed significantly increased hazard ratios for death (HR = 2.68, 95% CI, 1.27 to 5.63) compared with S0 (Tp0S0) patients. Among patients with good-risk systemic disease (S0), those patients with pulmonary involvement (Tp1S0) showed significantly increased hazard ratios (HR = 4.98, 95% CI, 1.93 to 12.85) compared with patients without pulmonary involvement (Tp0S0). Patients with both Tp1 and S1 evidenced the highest risk for death, with an HR of 7.65 (95% CI, 3.24 to 18.04) compared with Tp0S0 patients. This analysis identifies four risk categories with progressively increasing hazard ratios for death: Tp0S0 (HR = 1), Tp0S1 (HR = 2.68), Tp1S0 (HR = 4.98), and Tp1S1 (HR = 7.65).
The relationship between KS and HAART has been widely investigated since the introduction of HAART in 1995, and many aspects are being progressively clarified. The introduction of HAART has altered the course of KS, and in particular has significantly influenced epidemiologic, clinical, and therapeutic aspects. The incidence of KS has dropped sharply since the introduction of HAART,2,3 the use of HAART prolongs overall survival of KS patients and is associated with an 80% reduced risk of death among KS patients,17 KS responds to HAART in > 50% of patients,5–7 and HAART is associated with prolonged time to treatment failure in KS patients treated with systemic treatments.18 There are several possible explanations for these findings: the inhibition of HIV replication and the production and release of the HIV-1 Tat protein, a KS progression factor, the improvement of protective immune responses against human herpesvirus 8 (HHV8), and the direct antiangiogenic effects of some protease inhibitors.19,20 To date, however, there are no data in the literature which evaluate potential new prognostic factors for survival in the era of HAART, and, in particular, we do not know whether the traditional ACTG staging system, based on tumor extent, immune system level, and systemic symptoms, still provides correct and useful prognostic information in patients treated with HAART. Krown et al have validated the ACTG staging classification as a valid predictor of survival in the pre-HAART era, and showed that CD4 and tumor stage yield the most predictive information. This study has been crucial for the management of KS patients, because it provided useful information for clinical and therapeutic decisions. In light of these considerations, we have collected epidemiologic and clinical data on KS diagnosed in 1996 or later within two large HIV cohort populations, with the aim of assessing potential new prognostic factors and of validating the ACTG staging system in the era of HAART. All patients recruited in our study received HAART, either before or after the KS diagnosis. We believe that the population is well suited to the purpose of the study, since it comprises patients with different baseline characteristics: those from the ICONA cohort with mainly untreated and less advanced KS and those from the GICAT cohort with advanced KS enrolled in chemotherapeutic trials. Furthermore, all patients not enrolled in therapeutic trials entered the two cohorts without being subjected to exclusion criteria, so that they represented a comprehensive KS population. A potential bias of our study may be the fact that patients who never received HAART were not included in the analysis, therefore potentially excluding patients within the most favorable risk categories. However, we think this is negligible because the majority of patients with KS begin HAART independently of KS and HIV-related parameters. In fact, only three patients were excluded from the analysis because they never received HAART. Unfortunately, information on HHV8 was not available in our study. Effective biologic markers of KS could be a valid tools in determining the prognosis of KS patients. Several studies have indicated that HHV8 load is associated with KS clinical stage and disease progression and is able to provide clinically useful information.21,22
Analysis of our data indicated that sociodemographic factors such as sex and age (in quinquennia), HIV-related factors (level of HIV viremia), and HAART-related factors (HAART-naïve v HAART experienced at KS diagnosis, type of HAART combination) do not provide prognostic information. What our data indicate is that in the post-HAART era, the factors included in the ACTG staging classification that are most predictive for survival have been modified. In the univariate analysis, neither the CD4 cell cut-points of These findings differ substantially from the pre-HAART results of the Krown14 et al study, in which the CD4 count gave independent predictive information, and tumor stage provided additional predictive information in patients with a good immune system status. We believe that HAART is probably responsible for the alteration of the prognostic value of the ACTG classification in our study. The sociodemographic and clinical characteristics of our patients are similar to those of Krown et al study.14 In analogy to our study, which recruited patients mostly from the GICAT cohort in which half the patients had been enrolled in clinical trials and treated with chemotherapy, the study of Krown et al14 included all patients from ACTG therapeutic trials in which nearly 50% of patients had been treated with systemic chemotherapy. Furthermore, the distribution of risk categories was similar in the two studies, with most patients in the poor-risk category for each of the TIS variables. The finding that the level of immune deficiency does not provide prognostic information in the era of HAART is not surprising. The rapid immune reconstitution due to HAART may be a reasonable explanation. Most cases of KS are the first AIDS-defining event and often are diagnosed in patients unaware of their HIV seropositivity. Therefore, patients initiate HAART at KS diagnosis and this leads in the majority of cases to a significant immune restoration. The relative increase of CD4 lymphocyte counts after introduction of HAART has been reported to have an independent prediction value for KS response.23 However, in our analysis we did not observe any survival benefit in patients who began HAART after KS diagnosis compared to patients who were already receiving HAART. Of note, in our series, KS progression was the most common cause of death (70% v 30% of patients who died of opportunistic infections). Conversely, opportunistic infections were the most common cause of death in the pre-HAART era, because of the poor immune status that exposed KS patients to the infectious complications of HIV more rapidly and significantly than to the tumor progression itself. In the HAART era the increase of the CD4 cell level is associated, in patients with KS, with a markedly decreased risk of HIV-related infections and consequently KS survival is more influenced by T stage than by I stage. The subgroup of patients with pulmonary involvement showed the most unfavorable survival. Pulmonary involvement is a sign of an aggressive clinical course and usually represents late-stage disease, which is less likely to be influenced by immune restoration. There are, however, some studies that report prolonged survival in patients with pulmonary KS undergoing chemotherapy and HAART.24 In the light of our results, we propose a refinement in the application of AIDS-KS staging system, in which the immune system should be eliminated as a prognostic determinant, and only tumor extension and systemic disease should be considered as survival predictive variables. Two survival risk categories are identified: poor risk (T1S1) and good risk (T0S0, T1S0, T0S1). Furthermore, pulmonary involvement predicts survival better than tumor extension and identifies the poorest risk category, independent of the S variable. It is noteworthy that survival analysis of the interaction between pulmonary disease and systemic disease seems to provide a better risk distribution between groups, with progressive HR for death (Tp1S1>Tp1S0>Tp0S1>Tp0S0), as compared with the interaction between classical tumor extension and systemic disease. Further studies are clearly needed, in particular with the aim of determining new prognostic factors, which are more likely to be associated with KS (ie, HHV8) than with HIV infection.
Members of the the Italian Cooperative Group on AIDS and Tumors (GICAT): D. Bernardi, M. Berretta, R. Cinelli, G. di Gennaro, M. Michieli, I. Milan, M. Rupolo, O. Schioppa, C. Simonelli, M. Spina, G. Vultaggio, M. Zanetti (Aviano); P. Blanc (Bagno Ripoli); G. Carosi, M. Puoti (Brescia); G. Rizzardini, C. Zeroli (Busto Arsizio); B.M. Celesia, L. Nigro (Catania); A. Tocchetti (Como); A. Pan (Cremona); F. Mazzotta (Firenze); S. Grisorio (Foggia); P. Tundo (Galatina); A. Albini (Genova); M. Fasan, G. Landonio, A. Lazzarin, C. Pastecchia, A. Ridolfo (Milano); A. Dolara (Monza); V. Montesarchio (Napoli); P.L. Garavelli (Novara); F. Di Lorenzo, S. Mancuso (Palermo); G. Chichino, R. Maserati (Pavia); D. Padrini (Piacenza); B. Adriani (Prato); C. Lovigu (Sassari); S. Di Lorenzo (Sondalo); I. Dal Conte, E. Nigra, F. Lipani, A. Sinicco (Torino); P. Delle Foglie (Trento); A. Vaglia (Treviso); P. Viale (Udine); E. Raise (Venezia). Members of the Italian Cohort of Patients Naïve from Antiretrovirals (ICONA) Study Group: Ancona: M. Montroni, G. Scalise, A. Zoli, S. Di Cesare. Aviano (PN): U. Tirelli, G. Nasti. Bari: G. Pastore, N. Ladisa, G. Minafra. Bergamo: F. Suter, C. Arici. Bologna: F. Chiodo, F.M. Gritti, V. Colangeli, C. Fiorini, L. Guerra. Brescia: G. Carosi, G.P. Cadeo, F. Castelli, C. Minardi, D. Vangi. Busto Arsizio: G. Rizzardini, G. Migliorino. Cagliari: P.E. Manconi, P. Piano. Catanzaro: T. Ferraro, A. Scerbo. Chieti: E. Pizzigallo, F. Ricci. Como: D. Santoro, L. Pusterla. Cremona: G. Carnevale, D. Galloni. Cuggiono: P. Viganò, M. Mena. Ferrara: F. Ghinelli, L. Sighinolfi. Firenze: F. Leoncini, F. Mazzotta, M. Pozzi, S. Lo Caputo. Foggia: G. Angarano, B. Grisorio, S. Ferrara. Galatina (LE): P. Grima, P. Tundo. Genova: G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo. Grosseto: M. Toti, S. Chigiotti. Latina: F. Soscia, L. Tacconi. Lecco: A. Orani, P. Perini. Lucca: A. Scasso, A. Vincenti. Macerata: F. Chiodera, P. Castelli. Mantova: A. Scalzini, G. Fibbia. Milano: M. Moroni, A. Lazzarin, A. Cargnel, G.M. Vigevani, L. Caggese, A. d’Arminio Monforte, F. Tordato, R. Novati, A. Galli, S. Merli, C. Pastecchia, C. Moioli. Modena: R. Esposito, C. Mussini. Napoli: N. Abrescia, A. Chirianni, C. Izzo, M. Piazza, M. De Marco, V. Montesarchio, E. Manzillo, S. Nappa. Palermo: A. Colomba, V. Abbadessa, T. Prestileo, S. Mancuso. Parma: C. Ferrari, P. Pizzaferri. Pavia: G. Filice, L. Minoli, R. Bruno, R. Maserati. Perugia: S. Pauluzzi, F. Baldelli. Pesaro: E. Petrelli, A. Cioppi. Piacenza: F. Alberici, A. Ruggieri. Pisa: F. Menichetti, C. Martinelli. Potenza: C. De Stefano, A. La Gala. Ravenna: T. Zauli, G. Ballardini. Reggio Emilia: G. Magnani, M.A. Ursitti. Rimini: M. Arlotti, P. Ortolani. Roma: L. Ortona, F. Dianzani, G. Ippolito, A. Antinori, G. Antonucci, S. D’Elia, P. Narciso, N. Petrosillo, V. Vullo, A. De Luca, L. Del Forno, M. Zaccarelli, P. De Longis, M. Ciardi, G. D’Offizi, P. Noto, M. Lichtner, M.R. Capobianchi, E. Girardi, P. Pezzotti, G. Rezza. Sassari: M.S. Mura, M. Mannazzu. Torino: P. Caramello, A. Sinicco, M.L. Soranzo, L. Gennero, M. Sciandra, B. Salassa. Varese: P.A. Grossi, C. Basilico. Verbania: A. Poggio, G. Bottari. Venezia: E. Raise, S. Pasquinucci. Vicenza: F. De Lalla, G. Tositti. Taranto, Italy: F. Resta, A. Chimienti. London, UK: A. Cozzi Lepri
This study was supported by Istituto Superiore di Sanitá, Fondo Sanitarion Nazionale, and Associazione Italiana per la Ricerca sul Cancro grants.
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24. Holkova B, Takeshita K, Cheng DM, et al: Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi’s sarcoma treated with chemotherapy. J Clin Oncol 19:3848–3851, 2001 Submitted October 29, 2002; accepted May 5, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
70%; poor systemic disease risk (S1) was defined as a history of opportunistic infection, B symptoms, other HIV-related illness, and Karnofsky score lower than 70%. 
