Paclitaxel for anthracycline-resistant AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations

J. Stebbing1,2, A. Wildfire1, S. Portsmouth1, T. Powles1, C. Thirlwell1, P. Hewitt3, M. Nelson1, S. Patterson2, S. Mandalia1, F. Gotch2, B. G. Gazzard1 and M. Bower1,+

1 Departments of Oncology and HIV Medicine, Chelsea and Westminster Hospital, London; 2 Department of Immunology, Division of Investigative Science, Faculty of Medicine, Imperial College of Science Technology and Medicine, Chelsea and Westminster Hospital, London; 3 Bristol-Myers Squibb Pharmaceuticals Limited, London, UK

Received 13 March 2003; revised 23 May 2003; accepted 12 August 2003


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 References
 
Background:

Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi’s sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-{alpha} (TNF-{alpha}), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12.

Patients and methods:

Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m2 every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel.

Results:

The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-{alpha} levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-{alpha}, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy.

Conclusions:

Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

Key words: AIDS, angiogenesis, cytokines, human immunodeficiency virus, Kaposi’s sarcoma, paclitaxel


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 References
 
Although the incidence of Kaposi’s sarcoma (KS) in established market economies has fallen since the introduction of highly active antiretroviral therapy (HAART), it remains the most common tumour in individuals with HIV infection [1, 2]. Moreover, in many cases KS has been successfully treated with HAART alone [37]. Recent data support a role of CD16/56 natural killer cells and CD8 cytotoxic T lymphocytes in the decline in incidence and the regression of individual lesions in patients with immune reconstitution following HAART therapy [8, 9].

Aggressive KS is a significant cause of morbidity and mortality in those in whom HAART is failing due to antiretroviral resistance, intolerance or adherence issues, and in some patients with good serological parameters (undetectable HIV-1 viraemia and CD4 cell counts >400/mm3) who presumably have failed to reconstitute a full immunological repertoire [1012].

The optimal first-line chemotherapy for AIDS-KS is liposomal anthracyclines [1315]. Other cytotoxic agents tested include vinca alkaloids [16, 17], bleomycin [18] and etoposide [19]. Paclitaxel has been shown to have single-agent activity against KS in phase II studies that have included some patients who had previously received anthracylines [2023]. Toxicity from these agents is often significant, particularly in individuals who are immunologically suppressed due to HIV-1 infection. Indeed in the pre-HAART era, patients with KS had a high mortality predominantly from other opportunistic infections [24]. There was also a reluctance to treat KS with systemic ‘palliative’ chemotherapy, since there was no evidence of sustained remissions and there was a high risk of adversely influencing the HIV disease [25, 26]. For this reason, we followed changes in lymphocyte subsets as this has implications for prophylaxis of opportunistic infection.

Recent data from experiments in mice have indicated a central role of angiogenesis and angiogenic factors in the aetiopathogenesis of KS [27]. These experiments, more than three decades after Folkman [28] showed that tumour growth was dependent on the formation of new blood vessels, found that systemic administration of the protease inhibitors (PIs) saquinavir and inidinavir to nude mice blocked the development of, and induced regression of, angioproliferative KS-like lesions promoted by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF), or bFGF and VEGF combined. These drugs were also found to block bFGF- or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to that of paclitaxel, used as a positive antiangiogenic control. We therefore wished to observe whether in vivo human measurements of a large number of cytokines implicated in tumour growth and angiogenesis change during treatment of KS.

In December 1999, TAX/22-99.002, a pan-European phase IIIb open-label protocol for previously treated AIDS-KS was initiated in our unit. The trial was prematurely closed in June 2000 as a result of poor recruitment rates at other centres. Treatment using the same protocol was continued for other patients. We describe the efficacy and safety of paclitaxel, administered at 2-week intervals to patients who had liposomal anthracycline-resistant KS, defined as progression on liposomal anthracycline treatment or progression within 6 months of treatment. We also evaluated plasma angiogenic marker and growth factor concentrations before treatment with liposomal anthracycline, at relapse and following therapy with paclitaxel.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 References
 
Patients and therapy
From December 1999 to January 2002, 17 individuals with anthracycline-resistant histologically confirmed KS were treated at the Chelsea and Westminster Hospital with paclitaxel 100 mg/m2 administered intravenously over 3 h every 2 weeks. Patients were pre-medicated with intravenous dexamethasone 10 mg, ranitidine 50 mg and chlorpheniramine 10 mg. Patients were treated until maximal response or disease progression or they wished to stop due to toxicities or other reasons. All patients were receiving HAART according to clinical protocol [29, 30], which had remained stable for a minimum of 4 weeks before enrolment. In addition, prophylaxis against opportunistic infection with Pneumocystis carinii was prescribed to patients with CD4 cell counts <200 cells/mm3 and Mycobacterium avium complex prophylaxis to those with CD4 cell counts <50 cells/mm3.

All individuals gave written informed consent and the study received ethical approval in accordance with the Helsinki Declaration. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0. Disease evaluation (including bidimensional measurements of cutaneous lesions) was recorded every other cycle using the amended AIDS Clinical Trial Group (ACTG) response assessment [31]. A Gehan two-stage design with 95% power at a 10% standard error was used. It was originally intended to recruit nine patients and if there were no objective responses or stabilisation of disease, the trial was to be terminated. There was a 5% probability that this would occur with a response or disease stabilising rate of 30%.

Immunological parameters
Total lymphocyte and subset analysis was carried out using whole blood stained with murine anti-human monoclonal antibodies to CD4, CD8, CD16/56 and CD19 (TetraOne; Beckman Coulter, High Wycombe, UK) and were evaluated on an Epics XL-MCL (Beckman Coulter) flow cytometer. Viral loads in patient plasma were measured using the Quantiplex HIV RNA 3.0 assay (Chiron bDNA; Chiron Diagnostics, Halstead, UK) with a lower limit of detection of 50 HIV-1 copies/ml. These parameters were measured before and at the end of chemotherapy and then at 1, 3 and 12 months thereafter.

Cytokines and statistical analysis
Plasma samples were collected in heparinised tubes at the start of therapy with anthracyclines, at relapse and immediately following the completion of treatment with paclitaxel. They were stored at –80°C and analysed together on single plates for each cytokine to reduce variability in results, using quantitative sandwich immunoassay kits. Enzyme-linked immunosorbent assays (ELISAs) were carried out for VEGF (Amersham, Little Chalfont, UK; lower limit of detection 8 pg/ml, upper limit of detection 2000 pg/ml), bFGF (Immunotopics, San Clemente, CA, USA; 3–2470 RU/ml), tumour necrosis factor-{alpha} (Roche, Mannheim, Germany; 20–864 pg/ml), interleukin (IL)-2 (Diaclone, Besancon, France; 10–1000 pg/ml), IL-6 (Diaclone; 1–49 pg/ml) and IL-12 (Diaclone; 10–1000 pg/ml).

Due to variability in plasma levels, a variance-stabilising transformation was made on these data. Non-parametric statistical methods were used for between-group comparisons and the Kruskal–Wallis one-way analysis of variance test was used to compare the initial three results arms (pre-anthracycline, at relapse, post-paclitaxel) at each time period. All non-parametric data are presented as medians with interquartile ranges. Data were further analysed for trends over time using repeated-measures ANOVA with the MIXED procedure in SAS. Between- and within-patient adjusted slopes over time were estimated on log10-transformed plasma levels for each of the study arms and these are presented with 95% confidence intervals (CIs). All P values presented are two-sided.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 References
 
Patients
The mean age of the patients was 38 years (range 27–45) and 15 (88%) were male (Table 1). Only one patient, who had previous cryptosporidial diarrhoea for 1 month, did not have KS as their first AIDS-defining illness. All patients had an Eastern Cooperative Oncology Group/Zubrod performance status of 0–1. Four patients (24%) had visceral KS and a further six (35%) had nodal disease or tumour-associated oedema. The ACTG staging of our cohort [31] was: T0I0 in seven patients (41%), T0I1 in two patients (12%), T1I0 in five patients (29%) and T1I1 in three patients (18%). The median number of years on HAART before paclitaxel therapy was 3 (range 1–6). The median CD4 cell count at entry was 287/mm3 (range 60–671) and 10 (59%) had undetectable HIV-1 RNA loads. There was no correlation between stage of KS and immunological or virological parameters. Six patients (35%) had progressed during liposomal anthracycline therapy (five Daunoxome, one Caelyx) and 11 (65%) within 6 months of completing treatment with liposomal anthracyclines (all Daunoxome) despite continuing HAART therapy.


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Table 1. Characteristics of 17 patients with Kaposi’s sarcoma who were refractory to liposomal anthracycline treatment and received paclitaxel
 
At enrolment, 12 patients (71%) were receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART, three (18%) PI-based HAART and two (12%) a combination including both NNRTI and PI. For six patients (35%) this was their first HAART regimen. One patient decided to stop HAART during chemotherapy. A total of 193 cycles of paclitaxel were given and the median number of cycles per patient was 12 (range 1–22).

Response
The response rate as measured by ACTG criteria on an intention-to-treat basis was 71% (95% CI 60% to 81%); in total 12 patients showed a partial or complete response (Table 2). One patient had progressive disease during treatment and this patient died 4 weeks after his second cycle of paclitaxel due to multicentric Castleman’s disease. A further four patients (24%) had stable disease during treatment. Figure 1 demonstrates the time to progression in this group of patients. The median time to progression for all patients is 0.5 years and for those with a complete or partial response to treatment it is 1.4 years. This compares with a median time to progression for the same patients of 0.5 years on liposomal anthracyclines (Figure 1).


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Table 2. Responses to treatment with paclitaxel
 


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Figure 1. Time to progression during treatment with paclitaxel or previous therapy with liposomal anthracyclines.

 
Changes in CD4, CD8, CD16/56 (natural killer cells) and CD19 (B cells) lymphocyte subset cell counts during and for up to 1 year following chemotherapy were not significant, neither during the paclitaxel chemotherapy nor following completion of the chemotherapy. Similarly, plasma HIV-1 viral loads did not change significantly during or after treatment (data not shown).

Toxicity
There were no cases of cessation of treatment due to toxicity alone. The most common toxicities were grade I anaemia, and neuropathy (29%) and grade II nausea/vomiting (29%), fatigue (23%) and alopecia (17%) (Table 3). One patient with grade III neuropathy had had a grade II antiretroviral-related neuropathy previously. Grade III neutropenia occurred in four patients. One patient with grade IV neutropenia (the only grade IV toxicity recorded) was admitted with a fever, which resolved with antibiotics. This patient was also the only individual who received granulocyte colony-stimulating factor (G-CSF) during the study and developed nail dystrophy (another individual had paronychia). Overall, six patients had either a 1-week delay in treatment or a 25% dose reduction. No patients developed opportunistic infections during treatment and HAART was continued unchanged in 16 patients (94%).


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Table 3. Toxicity in all 17 patients with Kaposi’s sarcoma
 
Cytokines
Table 4 shows the median cytokine levels in all patients and those who responded and those who did not respond at all three time points studied. Levels of IL-2 and IL-12 were undetectable in most individuals (data not shown). There were no statistically significant differences in all patients from baseline measurements to relapse, in all patients from baseline to post-paclitaxel therapy and from relapse to post-paclitaxel therapy (Figure 2). There was, however, a trend towards increased levels at relapse and a decrease following paclitaxel. In addition, we observed a statistically significant increase in VEGF levels (P = 0.017) between baseline and relapse in those individuals who subsequently responded to paclitaxel. There was also a statistically significant decrease in IL-6 levels (P = 0.045) in responders, between baseline and post-paclitaxel samples.


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Table 4. Absolute values of angiogenic markers and cytokines at three time points in all patients, those who showed a response and those who did not
 


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Figure 2. Mean changes in all patients from baseline to relapse (top), from baseline to post-paclitaxel (middle) and from relapse to post-paclitaxel (lower). Error bars are 95% confidence intervals. bFGF, basic fibroblast growth factor; IL-6, interleukin-6; TNF-{alpha}, tumour necrosis factor-{alpha}; VEGF, vascular endothelial growth factor.

 
We therefore analysed the data for those individuals who showed a response to paclitaxel (n = 12) and those who did not (n = 5), using samples from relapse after anthracyclines to after paclitaxel (Figure 3). Once again, no statistically significant changes were noted, although there were trends towards decreased levels in both groups following paclitaxel.



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Figure 3. Mean changes in responders (diamonds) and non-responders (squares), between levels of cytokines at relapse post-anthracycline therapy and levels post-paclitaxel. Error bars are 95% confidence intervals. bFGF, basic fibroblast growth factor; IL-6, interleukin-6; TNF-{alpha}, tumour necrosis factor-{alpha}; VEGF, vascular endothelial growth factor.

 
As previous data [27] indicated specific antiangiogenic effects of PIs, we analysed plasma levels for those individuals on PIs (n = 11) at the time of chemotherapy and those patients not receiving PIs (n = 6). There were no significant changes between baseline and relapse (Figure 4, top). We did, however, observe a statistically significant decrease (P = 0.043) in bFGF levels between relapse following anthracyclines and after paclitaxel in those individuals who were receiving a PI-based regimen (Figure 4, bottom). The sample size was not large enough for further subdivisions of responders and non-responders, on and off PIs. Analysis of differences between T1 KS and T0 KS revealed significantly higher VEGF levels at all three time points in those with more advanced KS.



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Figure 4. Mean changes in those individuals receiving (diamonds) and not receiving (squares) a protease inhibitor (PI), before and after therapy with anthracyclines (top) and before and after therapy with paclitaxel (lower). Error bars are 95% confidence intervals. bFGF, basic fibroblast growth factor; IL-6, interleukin-6; TNF-{alpha}, tumour necrosis factor-{alpha}; VEGF, vascular endothelial growth factor.

 
Discussion

In patients with aggressive and extensive mucocutaneous disease or with visceral KS, systemic chemotherapy and HAART is the treatment of choice [32]. This trial specifically investigated the use of a paclitaxel in patients who were unsuccessfully treated with optimal first-line chemotherapy. One phase II study of paclitaxel (135 mg/m2 every 3 weeks) for KS enrolled 28 patients and reported a response rate of 71%. This included four patients (14%) who had received anthracyclines, but no patients received HAART [21]. A second, larger study of 56 patients included 20 (36%) who received a PI at some stage during the study and 40 (70%) who had received prior therapy for KS, which included liposomal anthracyclines in 17 (30%). The overall objective response rate was 59% (amended ACTG criteria), and a median response duration of 10.4 months [22]. A further open-label multicentre trial enrolled 107 individuals; the response rate was 56% and PI use (77% of patients) had a significant impact on survival. The main side-effect reported in these studies was neutropenia. Our study and subgroup analysis of these previous trials demonstrate that paclitaxel is a safe and effective therapy in patients with anthracycline-resistant AIDS-KS, with a response rate of 71%.

Analysis of angiogenic marker and growth factor concentrations was confounded by marked heterogeneity in levels, a situation previously observed in other studies [33]. Levels of bFGF, VEGF, IL-6, IL-2 and IL-12 did not correlate with response to treatment, although trends towards decreased levels were observed in both responders and non-responders. Levels of IL-6 were significantly decreased by the end of therapy with paclitaxel and recent work has indicated that this may be a surrogate marker of KS-associated herpesvirus (KSHV) viral load (J. Wilkinson, personal communication). This is also consistent with other recent data showing that increased levels of IL-6 are correlated with a negative outcome in both KSHV-related [34] and -unrelated conditions [35].

The lack of differences in plasma levels in the other cytokines between responders and non-responders indicates that while paclitaxel has antiangiogenic effects in a mouse model of KS [27] and can lead to a decrease in angiogenic cytokines, there is only a tenuous relationship with tumour response in humans. Consistent with the mouse model, however, bFGF levels were significantly decreased in those individuals on HAART containing a PI. In addition, those with more aggressive KS were noted to have higher levels of VEGF. A more accurate method of studying the biological effects may involve the examination of biopsy material before and after treatment to assess the vascularity and the expression of angiogenic markers by in situ hybridisation techniques.

The mechanism of paclitaxel activity in KS has been investigated using other models of experimental KS induced by the inoculation of KS-derived spindle cells into nude mice and primary cultures of KS spindle cells [36]. Paclitaxel has been found to (i) promote regression of KS lesions in vivo, (ii) block the growth, migration and invasion of KS spindle cells in vitro, and (iii) promote apoptosis and reduction of the antiapoptotic Bcl-2 protein within these lesions. Recently, its antiangiogenic properties have been described in detail [27], while anthracyclines have not been shown to have the same effect [37]. However, the clinical importance of paclitaxel-induced changes in plasma angiogenic marker levels remains questionable.

It has been reported that the majority of affected individuals have advanced immunosuppression at the time of the initial KS diagnosis [38]. Our cohort was not profoundly immunosuppressed, with a median CD4 cell count at entry of 287/mm3 and 59% with undetectable HIV-1 RNA loads. Furthermore, there was no significant fall in lymphocyte subsets or rise in viral loads or opportunistic infections during chemotherapy or for up to 1 year after completion of paclitaxel. In contrast, Gill et al. [22] reported 51 AIDS-defining opportunistic infections in the 56 patients treated with paclitaxel (10.5/100 patient months on paclitaxel), only 36% of whom received HAART, and Welles et al. [21] reported 27 opportunistic infections (8.4/100 person months on paclitaxel) among her cohort, none of whom received HAART. Thus the concomitant use of HAART and paclitaxel appears to be safe and not detrimental to immune function, despite initial concerns over pharmacological interactions [39].

Overall, paclitaxel was well-tolerated. As previously reported for this group of patients, the major toxicity was neutropenia, although only 23% developed grade III or IV neutropenia and only one patient required G-CSF support. There were no treatment-related deaths and the only other grade III toxicity reported was peripheral neuropathy.

In conclusion, this trial has provided convincing evidence that paclitaxel has activity against anthracyline-resistant AIDS-KS and may safely be administered with HAART. Moreover, there were no significant adverse effects on immune or virological parameters.


    Acknowledgements
 
This study was supported by a grant from the UK Medical Research Council (G84/5631), the Junior Research Committee at the Chelsea and Westminster Hospital, and Bristol-Myers Squibb, Europe, Waterloo, Belgium. Martin Gore and Tim Eisen provided the idea for cytokine measurement.


    Footnotes
 
+ Correspondence to: Dr M. Bower, Department of Oncology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44-20-8237-5054; Fax: +44-20-8746-8863; E-mail: m.bower{at}ic.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 References
 
1. Brodt H, Kamps B, Gute P. Changing incidence of AIDS-defining illness in the era of antiretroviral combination therapy. AIDS 1997; 11: 1731–1738.[CrossRef][ISI][Medline]

2. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000; 92: 1823–1830.[Abstract/Free Full Text]

3. Conant MA, Opp KM, Poretz D et al. Reduction of Kaposi’s sarcoma lesions following treatment of AIDS with ritonovir. AIDS 1997; 11: 1300–1301.[ISI][Medline]

4. Murphy M, Armstrong D, Sepkowitz KA et al. Regression of AIDS-related Kaposi’s sarcoma following treatment with an HIV-1 protease inhibitor. AIDS 1997; 11: 261–262.[ISI][Medline]

5. Vaccher E, di Gennaro G, Nasti G et al. HAART is effective as anti-Kaposi’s sarcoma therapy only after remission has been induced by chemotherapy. J Acquir Immune Defic Syndr 1999; 22: 407–408.[ISI][Medline]

6. Winceslaus J. Regression of AIDS-related pleural effusion with HAART. Highly active antiretroviral therapy. Int J STD AIDS 1998; 9: 368–370.[ISI][Medline]

7. Lebbe C, Blum L, Pellet C et al. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi’s sarcoma. AIDS 1998; 12: F45–F49.[CrossRef][ISI][Medline]

8. Osman M, Kubo T, Gill J et al. Identification of human herpesvirus 8-specific cytotoxic T-cell responses. J Virol 1999; 73: 6136–6140.[Abstract/Free Full Text]

9. Sirianni MC, Vincenzi L, Topino S et al. NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi’s sarcoma. Eur J Immunol 2002; 32: 2711–2720.[CrossRef][ISI][Medline]

10. Hermankova M, Ray SC, Ruff C et al. HIV-1 drug resistance profiles in children and adults with viral load of <50 copies/ml receiving combination therapy. J Am Med Assoc 2001; 286: 196–207.[Abstract/Free Full Text]

11. Lederman MM. Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 2001; 15 (Suppl 2): S11–S15.[CrossRef][ISI][Medline]

12. Nasti G, Errante D, Santarossa S et al. A risk and benefit assessment of treatment for AIDS-related Kaposi’s sarcoma. Drug Saf 1999; 20: 403–425.[ISI][Medline]

13. Gill PS, Wernz J, Scadden DT et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J Clin Oncol 1996; 14: 2353–2364.[Abstract]

14. Northfelt DW, Dezube BJ, Thommes JA et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol 1998; 16: 2445–2451.[Abstract]

15. Stewart S, Jablonowski H, Goebel FD et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol 1998; 16: 683–691.[Abstract]

16. Kaplan L, Abrams D, Volberding P. Treatment of Kaposi’s sarcoma in acquired immunodeficiency syndrome with an alternating vincristine–vinblastine regimen. Cancer Treat Rep 1986; 70: 1121–1122.[ISI][Medline]

17. Nasti G, Errante D, Talamini R et al. Vinorelbine is an effective and safe drug for AIDS-related Kaposi’s sarcoma: results of a phase II study. J Clin Oncol 2000; 18: 1550–1557.[Abstract/Free Full Text]

18. Gill P, Rarick M, Bernstein-Singer M et al. Treatment of advanced Kaposi’s sarcoma using a combination of bleomycin and vincristine. Am J Clin Oncol 1990; 13: 315–319.[ISI][Medline]

19. Laubenstein LJ, Krigel RL, Odajnyk CM et al. Treatment of epidemic Kaposi’s sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol 1984; 2: 1115–1120.[Abstract]

20. Saville MW, Lietzau J, Pluda JM et al. Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet 1995; 346: 26–28.[CrossRef][ISI][Medline]

21. Welles L, Saville MW, Lietzau J et al. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol 1998; 16: 1112–1121.[Abstract]

22. Gill PS, Tulpule A, Espina BM et al. Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 1999; 17: 1876–1883.[Abstract/Free Full Text]

23. Tulpule A, Groopman J, Saville MW et al. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002; 95: 147–154.[CrossRef][ISI][Medline]

24. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338: 853–860.[Abstract/Free Full Text]

25. Uthayakumar S, Bower M, Money-Kyrle J et al. Randomized cross-over comparison of liposomal daunorubicin versus observation for early Kaposi’s sarcoma. AIDS 1996; 10: 515–519.[ISI][Medline]

26. White R. Liposomal daunorubicin is not recommended in patients with less than advanced HIV-related Kaposi’s sarcoma. AIDS 1997; 11: 1412–1413.[ISI][Medline]

27. Sgadari C, Barillari G, Toschi E et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 2002; 8: 225–232.[CrossRef][ISI][Medline]

28. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182–1186.[ISI][Medline]

29. Gazzard B, Moyle G. 1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Writing Committee. Lancet 1998; 352: 314–316.[CrossRef][ISI][Medline]

30. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2001; 2: 276–313.[CrossRef][Medline]

31. Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1997; 15: 3085–3092.[Abstract]

32. Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi’s sarcoma. Eur J Cancer 2001; 37: 1288–1295.[CrossRef][ISI][Medline]

33. Stebbing J, Benson C, Eisen T et al. The treatment of advanced renal cell cancer with high-dose oral thalidomide. Br J Cancer 2001; 85: 953–958.[CrossRef][ISI][Medline]

34. Menke DM, Chadbum A, Cesarman E et al. Analysis of the human herpesvirus 8 (HHV-8) genome and HHV-8 vIL-6 expression in archival cases of Castleman disease at low risk for HIV infection. Am J Clin Pathol 2002; 117: 268–275.[CrossRef][ISI][Medline]

35. Rallidis LS, Zolindaki MG, Manioudaki HS et al. Prognostic value of C-reactive protein, fibrinogen, interleukin-6, and macrophage colony stimulating factor in severe unstable angina. Clin Cardiol 2002; 25: 505–510.[ISI][Medline]

36. Sgadari C, Toschi E, Palladino C et al. Mechanism of paclitaxel activity in Kaposi’s sarcoma. J Immunol 2000; 165: 509–517.[Abstract/Free Full Text]

37. Vacca A, Ribatti D, Iurlaro M et al. Docetaxel versus paclitaxel for antiangiogenesis. J Hematother Stem Cell Res 2002; 11: 103–108.[CrossRef][ISI][Medline]

38. Frisch M, Biggar RJ, Engels EA et al. Association of cancer with AIDS-related immunosuppression in adults. J Am Med Assoc 2001; 285: 1736–1745.[Abstract/Free Full Text]

39. Schwartz JD, Howard W, Scadden DT. Potential interaction of antiretroviral therapy with paclitaxel in patients with AIDS-related Kaposi’s sarcoma. AIDS 1999; 13: 283–284.[CrossRef][ISI][Medline]





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