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Long-Term Prognosis of HIV-Infected Patients with Kaposi Sarcoma Treated with Pegylated Liposomal Doxorubicin

  1. L. Martín-Carbonero1,
  2. R. Palacios5,
  3. E. Valencia1,
  4. P. Saballs6,
  5. G. Sirera7,
  6. I. Santos2,
  7. F. Baldobí12,
  8. M. Alegre8,
  9. A. Goyenechea3,
  10. J. Pedreira13,
  11. J. González del Castillo4,
  12. J. Martínez-Lacasa9,
  13. A. Ocampo14,
  14. M. Alsina10,
  15. J. Santos5,
  16. D. Podzamczer11,
  17. J. González-Lahoz1, and
  18. Caelyx/Kaposi's Sarcoma Spanish Groupa
  1. 1Hospital Carlos III, Madrid
  2. 2Hospital de la Princesa, Madrid
  3. 3Fundación Jiménez Díaz, Madrid
  4. 4Hospital Clínico Universitario San Carlos, Madrid
  5. 5Hospital Universitario Virgen de la Victoria, Málaga
  6. 6Hospital del Mar, Madrid
  7. 7Hospital Germans Trias i Pujol, Madrid
  8. 8Hospital Sant Pau, Madrid
  9. 9Hospital Mutua de Terrassa, Madrid
  10. 10Hospital Clínico, Madrid
  11. 11Hospital Universitario de Bellvitge, Barcelona
  12. 12Hospital Clínico, Valencia
  13. 13Hospital Juan Canalejo, La Coruña
  14. 14Hospital Universitario Xeral-Cies, Vigo, Spain
  1. Reprints or correspondence: Dr. Luz Martín-Carbonero, Dept. of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain (lmcarbonero{at}gmail.com).
 
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Abstract

Introduction. Incidence of Kaposi sarcoma (KS) in human immunodeficiency virus (HIV)-infected persons has dramatically decreased in the highly active antiretroviral therapy era. However, this tumor still represents the most common cancer in this population.

Objectives. The objectives of this study were to evaluate long-term prognosis of HIV-infected patients with KS who had received pegylated liposomal doxorubicin (PLD) and, more specifically, to assess tumor relapse rate, mortality, and cause of death in these subjects.

Design. This study was a retrospective review of all patients with KS who had received PLD in centers belonging to the Caelyx/KS Spanish Group. Kaplan-Meier analysis and univariate and multivariate Cox-regression analysis were used to assess the rate of and factors associated with relapse and death through January 2006.

Results. A total of 98 patients received PLD from September 1997 through June 2002. Median follow-up after initiation of treatment was 28.7 months (interquartile range, 6.6–73.2 months); during follow-up, 29 patients died (a mortality rate of 14.6% per year). In 9 patients (31%), the cause of death was related to the appearance of other tumors (including 7 lymphomas, 1 gastrointestinal adenocarcinoma, and 1 tongue epidermoid cancer). Death caused by progression of KS occurred in 3 cases. Death risk was inversely related to CD4+ cell counts at the end of follow-up (hazard ratio for every increase in CD4+ cell count of 100 cells/µL, 0.7; 95% confidence interval, 0.5–0.9). A relapse study was performed for 61 patients who had complete or partial response to PLD and who attended a control visit after treatment completion. After a median follow-up of 50 months (interquartile range, 17.2–76 months), 8 patients (13%) had experienced relapse; 5 of these patient experienced relapse within the first year after stopping PLD. The only factor that was independently related to risk of relapse was having a CD4+ cell count >200 cells/µL at baseline (hazard ratio, 6.2; 95% confidence interval, 1.2–30). Lower CD4+ cell count at the end of follow-up was marginally associated with relapse (hazard ratio for every increase in CD4+ cell count of 100 cells/µL, 0.7; 95% confidence interval, 0.6–1.01).

Conclusions. Treatment of KS with PLD in HIV-infected patients is followed by a low relapse rate, with most relapses occurring during the first year after stopping chemotherapy. However, the mortality rate in this population was high, in part because of an unexpectedly high incidence of other tumors, mainly lymphomas.

Since the introduction of HAART, the incidence of Kaposi sarcoma (KS) in HIV-infected persons has decreased dramatically in developed countries. However, KS continues to complicate HIV infection and still represents the most common cancer in this population [1–5].

The current first-line therapy for advanced KS in HIV-infected patients is liposomal anthracyclines, which has been shown to perform better if combined with HAART [6]. This approach has demonstrated im-proved response rates and better tolerance than conventional chemotherapy alone [7–9]. Pegylated liposomes were developed to improve the efficacy and safety of standard anthracyclines by stabilizing drug in plasma, prolonging circulation time, and optimizing diffusion onto tumor vasculature [10]. Thus, pegylated liposomal doxorubicin (PLD) plus HAART provides response rates >70%, with little toxicity [11–14]. However, the long-term efficacy of this combination in terms of prevention of KS relapse or global survival has been poorly studied. The main objective of this study was to assess KS relapse rate and mortality among HIV-infected patients who received PLD after receiving a diagnosis of KS.

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Patients and Methods

The Caelyx/KS Spanish Study Group conducted 2 trials involving HIV-infected subjects with KS, in which response to at least 1 cycle of PLD was analyzed. The first cohort consisted of 77 patients who, from September 1997 through January 2000, participated in a prospective, noncomparative, phase IV, multicenter study of PLD efficacy and safety [11]. The second cohort was recruited from June 2000 through June 2002 to compare KS response to PLD plus HAART (21 patients) [12]. The current study is a retrospective analysis of KS relapse rate at completion of the last PLD cycle among patients included in any of these trials who responded to PLD and had at least 1 control visit after treatment. Mortality after the administration of the first PLD cycle was also analyzed.

Inclusion criteria before PLD administration were similar in both cohorts: <10 skin lesions or mucosal/visceral involvement, always with histological confirmation. KS stage was determined on the basis of the modified classification made in 1997 by the AIDS Clinical Trials Group Oncology Committee [15, 16]: T0, skin and/or lymph node tumor extent only; T1, non-lymph node visceral disease, tumor-associated edema or ulceration, or oral involvement; I0, CD4+ cell count >200 cells/µL; I1, CD4+ cell count ⩽200 cells/µL; S0, no other symptomatic illness; S1, presence of other symptomatic illness. Complete response to PLD was defined as an absence of detectable residual disease; if pigmented lesions persisted, a biopsy sample free of malignant lesions was required. A partial response was defined as either a flattening of at least 50% of nodular lesions or a decrease in the number and/or size of the previous lesions by 50%. Patients with improvements in elevation, number, or size of the lesions of <50% were considered to be nonresponsive. For relapse analysis, we only included patients who had complete response or partial response to initial treatment with PLD. Relapse of KS was defined as the appearance of new lesions or the worsening of previous lesions at any time after completion of PLD therapy. Any cause of death was registered if death occurred after the first dose of PLD was administered.

Clinical charts for patients who had participated in the 2 former studies were reviewed. Variables considered in the study were age, sex, risk-group, baseline CD4+ cell count and plasma HIV RNA level, type of HAART (if administered), and type of clinical event. Age was included in the analysis as a categorical variable (<50 years of age or <50 years of age), because this cutoff value represents a meaningful prognostic factor for KS outcome [17]. KS stage and prognosis were evaluated on the basis of the AIDS Clinical Trials Group Oncology Committee staging system, with poor prognosis associated with any status worse than T0-I0-S0 [15]. Patients' follow-up lasted until KS relapse, death, or until the last available visit for patients remaining free of symptoms. HIV RNA level was analyzed at local laboratories using validated techniques, including PCR Amplicor (Roche Diagnostic Systems), branched-DNA Quantiplex (Chiron), and NASBA (Organon Teknika). CD4+ cell count was determined at local laboratories by flow cytometry. Presence of human herpesvirus 8 (HHV-8) DNA was determined from stored and frozen (at −80°C) PBMCs with an in-house PCR method using primers and conditions described elsewhere [11].

Results are expressed as medians and interquartile ranges (IQRs) for continuous variables and as percentages for categorical variables. Characteristics of both cohorts at the time of KS diagnosis were compared using a nonparametric test (Mann-Whitney U test) for continuous variables and the χ2 test for categorical data. Kaplan-Meier analysis was used to describe incidence of KS relapse (for the period after the final PLD dose) and overall mortality (for the period after the first PLD dose). For patients without clinical events, time was censored at last visit before the end of the follow-up period (i.e., January 2006). Factors associated with KS relapse or death were assessed by a Cox proportional hazard regression model. Those factors with a P value <.2 in univariate analysis were included in multivariate analysis using a stepwise selection procedure. The level of significance was defined as P<.05. Statistical analysis was performed using SPSS, version 15.0 (SPSS).

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Results

Patient characteristics. A total of 98 HIV-infected patients with KS received PLD as part of 2 clinical trials. The demographic and clinical characteristics of the patients at the time of initial diagnosis of KS and their response to PLD are shown in table 1. Most of the patients (96%) were male, all of the patients were white, and the median age was 40 years. Median values for CD4+ cell counts and HIV RNA levels were 150 cells/µL and 4.2 log copies/mL, respectively. Fifty-two (75%) of 69 patients who underwent testing for HHV-8 DNA had positive test results. KS stage was heterogeneous among participants: 16 (16%) of 98 had the best (T0-I0-S0) and 17 (17%) of 98 had the worst (T1-I1-S1) prognostic factors. Twenty-nine patients (29%) had visceral involvement (gastrointestinal in 20 and pulmonary in 9). All patients were receiving HAART at the time of PLD administration; 84 (85%) were receiving protease inhibitors (PIs), and 14 (15%) were receiving nonnucleoside reverse-transcriptase inhibitors.

The median number of PLD cycles administered was 9 (IQR, 6–14 cycles). Complete response was achieved by 48 patients (49%), and partial response was achieved by 27 patients (28%). Lack of KS response to PLD was detected in 13 patients (14.5%), and 7 patients died while receiving PLD. The remaining 3 patients did not complete PLD therapy. Patient characteristics were comparable between the 2 cohorts, with the exception of more patients with T0 stage and a higher mean HIV RNA level in the second cohort.

Relapse study. Of the 75 patients with complete or partial response to initial PLD, 61 had data included in the present study from a control visit after completion of therapy. Median duration of follow-up since last PLD dose was 50 months (IQR, 17–76 months). KS relapse was observed in 8 patients (13.5% per year); 5 relapses occurred during the first year after stopping chemotherapy (figure 1). Compared with sustained responders, patients who had tumor relapse were more often classified as I0 at KS diagnosis (94% vs. 77%; P=.1) but had lower CD4+ cell counts at the end of follow-up (316 cells/µL vs. 488 cells/µL; P=.07) and less of an increase in CD4+ cell counts, compared with baseline values (23 cells/µL vs. 248 cells/µL; P=.018). Of note, long-term PLD toxicity was detected in only 1 patient who developed ventricular dilatation and mild dysfunction 3 years after having received 20 cycles.

Figure 1
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Figure 1

Kaplan-Meier analysis of estimates of disease-free survival among 59 HIV-positive patients who attained Kaposi sarcoma response to pegylated liposomal doxorubicin (PLD).

Univariate and multivariate Cox regression analyses are presented in table 2. The only factor that was independently associated with relapse was KS stage I0 (CD4+ cell count, >200 cells/µL) at diagnosis (OR, 6.2; 95% CI, 1.2–30). There was also a trend towards greater incidence of KS relapse among patients with lower CD4+ cell counts at the end of follow-up (OR for every decrease in CD4+ cell count of 100 cells/µL, 1.4; 95% CI, 0.9–1.7).

Figure 2
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Figure 2

Kaplan-Meier analysis of estimates of overall survival among 98 patients who received at least 1 cycled of pegylated liposomal doxorubicin (PLD).

Table 1
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Table 1

Demographic and clinical characteristics of HIV-infected patients with Kaposi sarcoma and response to pegylated liposomal doxorubicin (PLD).

Table 2
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Table 2

Cox-regression analysis of factors associated with Kaposi sarcoma relapse after discontinuation of therapy with pegylated liposomal doxorubicin (PLD).

Mortality study. A total of 29 patients (30%) died during a median follow-up period of 28.7 months (IQR, 6.6–73.2 months) after first PLD dose, constituting a death rate of 14.6% per year. Eight patients died while receiving PLD cycles, 9 died during the first year after stopping PLD therapy, and 12 died >1 year after completion of PLD therapy (figure 2).

Causes of death are summarized in table 3. Three deaths were associated with KS progression, and 8 patients died of infectious complications. Among the remaining 18 patients, an unexpectedly high rate of tumor-related death was found, with 9 cases (50%) diagnosed, including 3 cases of non-Hodgkin lymphoma, 3 cases of primary effusion lymphoma, 1 case of brain lymphoma, 1 case of gastrointestinal adenocarcinoma, and 1 case of tongue epidermoid carcinoma. The rate of lymphoma-related death was 2.3% per year on follow-up. Interestingly, all patients with lymphoma also had test results positive for HHV-8. Cox regression analysis showed that CD4+ cell count at the end of follow-up was the only factor associated with cancer-related death (table 4).

Table 3
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Table 3

Cause of death in 29 HIV-infected patients with Kaposi sarcoma.

Table 4
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Table 4

Cox-regression analysis of factors associated with survival among HIV-infected patients with Kaposi sarcoma.

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Discussion

Since the introduction of HAART, the prognosis of KS has changed dramatically in the developed world [13]. In fact, in patients who do not have extended disease, HAART alone may suffice to provide complete KS response [18]. However, in a previous report, we determined that the combination of HAART plus PLD has greater efficacy than HAART alone [12], with complete or partial response being attained in <75% of patients [11–14].

Our study provides information on the long-term prognosis of KS after PLD in a significantly large sample of patients during a long follow-up period. The rate of relapse among patients who responded to LDP therapy (for which there is very little published data in the literature) was 13.5% per year, with most relapses occurring within the first year after therapy was discontinued. As expected, time free of symptoms is the best predictor of cancer remission [17]. It was intriguing that greater CD4+ cell counts prior to initiation of PLD therapy were associated with greater KS relapse rate. As a possible explanation, it may be that patients with low CD4+ cell counts developed KS mainly as a result of being immunosuppressed, whereas in individuals with a better immune status at the time of KS diagnosis, it was the oncogenic effect of HHV-8 that was the predominant triggering factor. Somewhat confirming this hypothesis, patients with CD4+ cell counts of <200 cells/µL at KS diagnosis showed greater immune recovery during HAART than did individuals who had CD4+ cell counts of <200 cells/µL at the time of KS diagnosis. Also, having higher CD4+ cell counts at the end of follow-up showed a trend toward less frequent KS relapse.

The antiangiogenic properties of PIs have been shown to reduce the development and progression of KS-like lesions in mice [19]. These drugs also promote HHV-8 clearance [20, 21]. However, the clinical significance of this observation is uncertain, because no differences in tumor response have been reported between PI-based HAART regimens and HAART regimens that were not PI-based [22, 23]. We did not find differences in relapse rates among patients treated with nonnucleoside reverse-transcriptase inhibitors and patients treated with PIs, although our study was not designed for this purpose, and our study involved a significantly lower number of patients treated with nonnucleoside reverse-transcriptase inhibitors than patients treated with PIs.

The mortality rate observed in our cohort of HIV- infected patients (14.6% per year) was higher than expected for a study conducted in the HAART era. As a comparison, the mortality rate reported by the HIV Outpatients Study decreased from 7% per year in 1996 (before the HAART era) to 1.3% per year in 2004 (in the HAART era) [24]. Although the baseline characteristics of this cohort are not detailed, it is expected that survival would be better in this cohort, compared with in our cohort, because all of the patients in our cohort had developed an opportunistic infection and were, in general, severely immunosuppressed. A recent study involving patients with KS [17] reported mortality rates that were lower than those in our cohort. However, the baseline characteristics of analyzed patients in the study by Stebbing et al. [25] indicated that they had a better KS prognosis (T1 in 34% of patients, S1 in 26%, and visceral involvement in 12%) than did the patients in our cohort (T1 in 53% of patients, S1 in 38%, and visceral involvement in 30%).

The CD4+ cell count at the end of follow-up was the only factor associated with mortality in our study. In other series that were published before the HAART era [15, 16], patient age, advanced tumor stage (T1), and symptomatic illness (S1) were also factors associated with mortality. It may be that widespread provision of HAART, as was the case in our cohort, has tempered the negative impact of these factors. A recent study [17] provides a novel prognostic index for AIDS-associated KS to be applied in the HAART era, and also includes data regarding opportunistic events and grade of immune recovery. Unfortunately, we were not able to refer to this index in the present study, because not all needed data were available for retrospective review. We cannot exclude the possibility that PLD therapy has a negative impact on survival, which may be mediated by blunted immune reconstitution or severe toxicity. Although only a comparative study could answer this question (with ethical issues being a possible impediment to performing such a study), the fact that the number of treatment cycles was not associated with morbidity or mortality is a relevant argument in favor of PLD safety.

The incidence of lymphoma was particularly high in our cohort. Since the introduction of HAART, the rate of non-Hodgkin lymphoma among HIV-infected patients has decreased to 0.1%–0.6% per year of follow-up [1, 3, 26]. In contrast, the rate of non-Hodgkin lymphoma in our series was 2.3% per year. The oncogenic effect of HHV-8—which has been associated with primary effusion lymphoma (of which we had 3 cases), multicentric Castleman disease, and plasmoblastic lymphoma—together with the severe immunosuppression of most of our patients can explain this observation [27–31]. In fact, all patients with lymphoma also had test results that were positive for HHV-8 DNA. It is also known that having had a tumor is a predisposing factor for the development of a second tumor [32]; this risk can be higher in immunosuppressed patients who harbor an oncogenic virus, such as HHV-8.

The main limitation of our study is its retrospective nature. Also, 2 different cohorts of patients were reviewed, the first of which was recruited in the early years of the HAART era and the second of which was recruited later. We assessed the relevance of this difference by comparing the baseline characteristics of patients in both cohorts to find similar values. We also did not find significant differences in relapse or survival rates between the cohorts.

In conclusion, the rate of relapse of KS is low among HIV-infected patients who are treated with PLD plus HAART; in most cases, relapse occurs within the first year after stopping chemotherapy. In contrast, we found a significant risk for lymphoma and a greater-than-expected mortality rate in this population, in which the oncogenic effect of HHV-8 and severe immunosuppression may play a role.

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Members of the Caelyx/KS Spanish Group

Coordinators. Juan González-Lahoz (Hospital Carlos III, Madrid, Spain) and Daniel Podzamczer (Hospital Universitario de Bellvitge, Barcelona, Spain).

Participants. Ana Goyenechea and Miguel Górgolas (Fundación Jiménez-Díaz, Madrid, Spain); Elena Ferrer (Hospital Bellvitge, Barcelona, Spain); M. Eulalia Valencia, Marina Núñez, and Luz Martín-Carbonero (Hospital Carlos III, Madrid, Spain); Mercé Alsina (Hospital Clínico Barcelona, Barcelona, Spain); Juan González del Castillo and M. Jesús Téllez (Hospital Clínico Madrid, Madrid, Spain); M. José Galindo and Francisco Baldobí (Hospital Clínico, Valencia, Spain); José López Aldeguer (Hospital de la Fe, Valencia, Spain); Alfonso Berrocal (Hospital General Universitario, Valencia, Spain); Guillem Sirera (Hospital Germans Trias I Pujol, Badalona, Spain); Jose Domingo Pedreira (Hospital Juan Canalejo, La Coruña, Spain); Pedro Saballs (Hospital del Mar, Barcelona, Spain); Javier Martínez-Lacasa (Hospital Mutua de Tarrasa, Barcelona, Spain); Ignacio Santos and Jesús Sanz (Hospital de la Princesa, Madrid, Spain); Marta Alegre (Hospital Sant Pau, Barcelona, Spain); Joaquín Torres and Miguel Colmenero (Hospital Virgen de la Macarena, Sevilla, Spain); Jesús Santos and Rosario Palacios (Hospital Virgen de la Victoria, Málaga, Spain); and Antonio Ocampo (Hospital Xeral-Cies, Vigo, Spain).

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Acknowledgments

We thank Julie Sheldon and Pablo Barreiro for their assistance in translation of the manuscript and their suggestions regarding human herpesvirus 8.

Financial support. Schering-Plough, the Asociación de Investigación y Educación en Sida, and the Red Temática Cooperativa de Investigación en SIDA, Fondo de Investigación Sanitaria, Spain.

Potential conflicts of interest. All authors: no conflicts.

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Footnotes

  • ↵a Members of the study group are listed at the end of the text.

  • Received October 29, 2007.
  • Accepted January 9, 2008.
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  1. Clin Infect Dis. (2008) 47 (3): 410-417. doi: 10.1086/589865
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