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Paclitaxel Is Safe and Effective in the Treatment of Advanced AIDS-Related Kaposi's Sarcoma

From the Departments of Medicine and Pharmacy, University of Southern California, Kenneth Norris Cancer Hospital and Research Institute, Los Angeles, CA; Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT; Department of Medicine, Harvard University, New England Deaconess Hospital, Boston; and Massachusetts General Hospital, Boston, MA.

Address reprint requests to Parkash S. Gill, MD, Kenneth Norris Cancer Hospital and Research Institute, 1441 Eastlake Ave, MS-34, Los Angeles, CA 90033; email parkashg{at}hsc.usc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Liposomal anthracyclines are the present standard treatment for advanced AIDS-related Kaposi's sarcoma (KS). No effective therapies have been defined for use after treatment failure of these agents. A phase II trial was thus conducted with paclitaxel in patients with advanced KS to assess safety and antitumor activity.

MATERIALS AND METHODS: A regimen of paclitaxel at a dose of 100 mg/m² was given every 2 weeks to patients with advanced AIDS-related KS. Patients were treated until complete remission, disease progression, or unacceptable toxicity occurred.

RESULTS: Fifty-six patients with advanced AIDS-related KS were accrued. Tumor-associated edema was present in 70% of patients and visceral involvement in 45%. Forty patients (71%) had received prior systemic therapy; 31 of these were resistant to an anthracycline. The median entry CD4⁺ lymphocyte count was 20 cells/mm³ (range, 0 to 358). A median of 10 cycles (range, 1 to 54+) of paclitaxel was administered. Fifty-nine percent of patients showed complete (n = 1) or partial response (n = 32) to paclitaxel. The median duration of response was 10.4 months (range, 2.8 to 26.7+ months) and the median survival was 15.4 months. The main side effects of therapy were grade 3 or 4 neutropenia in 61% of patients and mild-to-moderate alopecia in 87%.

CONCLUSION: Paclitaxel at 100 mg/m² given every 2 weeks is active and well tolerated in the treatment of advanced and previously treated AIDS-related KS. The median duration of response is among the longest observed for any regimen or single agent reported for AIDS-related KS. Paclitaxel at this dosage and schedule is a treatment option for patients with advanced AIDS-related KS, including those who have experienced treatment failure of prior systemic therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
KAPOSI'S SARCOMA is the most common tumor in patients with human immunodeficiency virus type 1 (HIV-1) infection. AIDS-related Kaposi's sarcoma (KS) is a multifocal tumor that most often involves the skin, although almost every organ can be involved. Involvement of the lungs and gastrointestinal tract is common and may result in substantial morbidity and mortality.¹

Factors that influence prognosis in patients with KS include the severity of underlying immune deficiency, history of opportunistic infection, bone marrow function, concurrent medications, and visceral involvement.^2,3 Patients with advanced KS can be treated palliatively with cytotoxic chemotherapy.^4-14 Active agents include Vinca alkaloids, bleomycin, etoposide, daunorubicin, and doxorubicin. Newer agents include the liposomal-encapsulated formulations of daunorubicin and doxorubicin.^10-14 Both liposomal-encapsulated agents have shown antitumor activity similar to multiagent systemic chemotherapy, with reduced toxicity.^11,13,14 Despite treatment advances with these newer agents, nearly one half of patients fail to respond to liposomal anthracyclines, and the duration of response is short, at medians of 3 to 6 months.^11-14 Other therapies are thus needed for patients with advanced KS, particularly those for whom prior systemic therapy, including treatment with liposomal anthracyclines, has failed.

Paclitaxel has previously shown potent antitumor activity in several tumor types.^15-18 Paclitaxel exerts its antitumor effects by several mechanisms, most prominently by polymerizing microtubules, inhibiting cell division, and inducing cell death.¹⁷ Paclitaxel has also been shown to inhibit angiogenesis in preclinical models.^19,20 The current recommended doses and schedules of paclitaxel for refractory ovarian and breast cancer vary from 135 to 210 mg/m² given over 3 to 96 hours.^16,17 Alternative dosing schedules are currently under investigation.²¹

Preliminary studies have shown that very low concentrations of paclitaxel could induce tumor cell death in KS tumor models (Bhalla et al, manuscript submitted for publication), and these levels were substantially lower than those described in other tumor types.²² We hypothesized that low doses of paclitaxel may be active in the treatment of KS. To test this hypothesis, we conducted a trial of paclitaxel at a dose of 100 mg/m² given every 2 weeks to patients with advanced AIDS-related KS.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Criteria
Patients were required to have serologic evidence of HIV-1 infection and advanced biopsy-proven KS defined by greater than 25 mucocutaneous lesions, presence of tumor-associated edema, or symptomatic visceral disease. Prior therapy for KS with local or systemic agents was allowed. Patients were required to have a Karnofsky performance status (KPS) score 60% and adequate hepatic, renal, and bone marrow function (platelet count > 75,000/mm³ and an absolute neutrophil count > 1,000/mm³). Concurrent use of granulocyte colony-stimulating factor (G-CSF) and antiretrovirals was allowed. The study was approved by the institutional review boards of the participating institutions, and all patients signed an informed consent prior to study entry.

Tumor evaluation was performed using the AIDS Clinical Trials Group (ACTG) staging criteria.³ As many as to 50 cutaneous lesions were counted and assessed as raised or flat. If there were more than 50 cutaneous lesions, a representative anatomic area (or areas) was selected and the lesions were counted and characterized. In addition, five discrete, nodular indicator lesions were selected, and the sum of the products of their largest perpendicular diameters was recorded. When possible, indicator lesions and sites of significant disease (ie, areas of confluent disease) and lesion on the face and extremities were photographed at study entry and at restaging visits performed every 4 weeks. Symptomatic visceral disease was evaluated by appropriate imaging techniques at baseline and at maximal response. Laboratory studies and evaluation of treatment-related toxicities and intercurrent illnesses were performed before each treatment visit.

Patients who received prior systemic therapy were evaluated to determine if they were resistant or intolerant to prior systemic therapy. Resistance was defined as the development of progressive disease as a reason for stopping the preceding systemic therapy. Intolerance was defined as unacceptable toxicity as the reason for stopping the preceding systemic therapy.

Treatment Plan
Paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NJ) was administered at a dose of 100 mg/m² intravenously over 3 hours every 2 weeks. Patients were premedicated with dexamethasone 20 mg, cimetidine 100 mg/m², and diphenhydramine 50 mg, all given intravenously before the infusion of paclitaxel. If no hypersensitivity reaction was noted after the first treatment, subsequent doses of dexamethasone were reduced to 8 mg intravenously. Cycles were repeated every 14 days provided hematologic function was adequate (absolute neutrophil count > 1,000/mm³; platelet count > 50,000/mm³). Growth factor support was given as needed. Dose modifications were required for severe peripheral neuropathy, hepatic (total bilirubin > 3.0 mg/dL or transaminases > 5 times upper limit of normal) and renal dysfunction (creatinine > 3.0 mg/dL), or cardiac toxicity.

Patients were continued on treatment until the occurrence of complete remission, intolerable toxicity, disease progression, or patient decision to stop therapy. However, in several cases after prolonged treatment interruption for reasons other than progression or toxicity, treatment was resumed after the first sign of progression as judged in the best interest of the patient by the treating physician.

Efficacy Criteria
The AIDS Clinical Trials Group (ACTG) response criteria were used for assessment of tumor response.³ Complete response was defined as resolution of all disease for 4 weeks or more without evidence of new disease. In patients with residual pigmentation, all lesions must have been completely flat, with pathologic documentation of no disease in a representative lesion. Partial response was defined as a reduction in the product of the bidimensional measurements of target lesions by 50% or more or complete flattening of one half or more lesions, without evidence of new disease, lasting for 4 weeks or more. Progressive disease was defined as the development of new lesions, increase in the bidimensional measurements by 25% or more, a change in 25% of previously flat lesions to raised lesions, development of new or worsening of existing tumor-associated edema, or development of new or progressive visceral disease. Stable disease was defined as not fulfilling criteria for complete response, partial response, or progressive disease.

Clinical records, photographs, chest x-rays, and results of other diagnostic tests were reviewed for efficacy by disease site such as face, extremities/feet, lung, tumor-associated edema, and pain. These were graded as resolved, decreased, stable, or progressive.

Duration of objective and clinical response was calculated from the date of therapy initiation to the date of progressive disease. Responding patients who did not progress were censored at the last follow-up or at the time therapy was changed. All patients were observed until April 1997. Survival was calculated from the first day of treatment to the day of death, and patients who were still alive or lost to follow-up were censored at the last date when they were known to alive.

Study data for response, duration of response, improvement of lung involvement, and tumor-associated edema were reviewed by expert investigators who did not participate in the trial.

Statistical Analysis
This study was designed as a nonrandomized phase II trial. Patients were stratified by prior systemic therapy. All patients were monitored for clinical adverse events, and these were graded using the Southwest Oncology Group (SWOG) toxicity scoring criteria.²³ Survival curves using the method of Kaplan and Meier were constructed for all time-to-event analysis.²⁴ Dose-intensity was calculated using the method of Hryniuk.²⁵

	RESULTS

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Study Patients
Patient characteristics are listed in Table 1. The median time from diagnosis of KS to study entry was 14 months (range, 0 to 125 months). For patients who had received prior systemic therapy, this interval was considerably longer (median, 21 months; range, 6 to 125 months). All patients had one or more poor risk features according to the ACTG TIS (tumor, immune, systemic) staging system for Kaposi's sarcoma.³ The median CD4⁺ lymphocyte count was 20 cells/mm³ (range, 0 to 358 cells). A prior history of opportunistic infection(s) was reported in 75% of patients. A KPS score of 70% or lower was documented in 46% of patients. Most patients with prior systemic therapy had previously received two or more (range, one to six) prior treatment regimens. Thirty-three patients had received at least one anthracycline-containing regimen. Thirty-eight patients (95%) were considered resistant and/or intolerant to prior therapy, and 31 (94%) were resistant and/or intolerant to a prior anthracycline chemotherapy.

Paclitaxel Dosing
The median number of paclitaxel cycles delivered was 10.5 (range, one to 54+). Paclitaxel doses were reduced in four patients: for neutropenia in two patients and for HIV-related complications in two patients. Treatment was delayed for more than 4 days in 47% of all courses. Treatment was delayed mainly in an effort to prolong treatment intervals after significant improvement in disease. Although the planned dose-intensity for this study was 50 mg/m²/wk, because of the treatment delays, the actual median dose-intensity per patient was 39 mg/m²/wk. Prior systemic therapy or treatment with a prior anthracycline did not affect the delivered dose-intensity. More than one half of patients (56%) had started G-CSF before entry onto the study because of concurrent or previous myelotoxic therapy. Overall, G-CSF was used in 55% of all paclitaxel cycles.

Tumor Response and Duration of Response
Major responses were documented in 59% of all patients (95% exact confidence interval, 45% to 72%) (Table 2). The onset of a major response occurred after a median of 6.1 weeks (range, 4 to 36 weeks). Response rates were similar in patients with any prior systemic therapy (55%) or prior systemic treatment with an anthracycline (49%) (Table 2). Moreover, no statistically significant differences were observed in the response rates when subset analysis was performed looking at prognostic features at study entry such as KPS, CD4⁺ lymphocyte count, presence of visceral disease, or prior B symptoms (Table 3). The median duration of response for the entire group was 10.4 months (range, 2.8 to 26.7+ months) (Fig 1). The duration of response was similar when stratifying patients by prior systemic therapy.

View larger version (10K): [in this window] [in a new window]   Fig 1. The median duration of overall response in responding patients (n = 33) was 10.4 months (95% confidence interval, 7.4 to 16.6). Number of events = 20.

Treatment efficacy and duration of improvement were analyzed separately for facial involvement, foot involvement, and tumor-associated edema, because these disease sites impact social well-being and ambulation. Photographs of these disease sites were evaluated in conjunction with clinical documentation. Facial disease, which included swelling secondary to edema and lesions on the face, improved in 72% of patients. Improvement or resolution of facial disease occurred in 83% (10 of 12) of partial responders as well as 60% (three of five) of patients with stable disease as their best objective response. Plantar lesions, characterized by presence of lesions with or without associated swelling, improved in 91%. All patients who achieved partial remission or stable disease showed improvement in plantar disease. Improvement in facial and foot KS is notable for a median duration of improvement in excess of 1 year.

Tumor-associated edema improved in 79% of patients, with complete resolution in 28% lasting a median of 16.6 months. Notably, 10 of 11 patients who reported stable disease as their best response showed complete resolution or improvement in tumor-associated edema. These data show that treatment with paclitaxel is associated with durable benefit in patients with facial disease and disease that impacts on ambulation, such as plantar KS and tumor-associated edema.

Sixteen patients had pulmonary KS at study entry: 12 were symptomatic and four were asymptomatic after response to prior therapy. Seven had objective response with improvement or resolution of both pulmonary symptoms and repeat radiographic studies. Two patients showed disease progression, whereas the remaining seven had no change in pulmonary disease. Nine patients had a diagnosis of gastrointestinal KS at study entry; seven of these patients had symptomatic disease. Resolution or improvement of symptoms with or without repeat endoscopy showed improvement in five patients and no change in four.

Overall, 20 patients received a protease inhibitor at any time during this trial, including 18 of the 33 responders. Fifteen responders started protease inhibitor therapy after a response was documented, and thus the initial responses assessed in this trial are independent of any effect of protease inhibitors. Furthermore, five patients started treatment with a protease inhibitor only after disease progression was documented. Therefore, in 13 of 33 responders could treatment with a protease inhibitor have any impact on the duration of response.

Survival
The median survival for the study population was 15.4 months (Fig 2). The median survival was similar when analyzing subsets of patients who received prior systemic therapy or a prior anthracycline. The survival in patients with pulmonary KS was also analyzed separately, because pulmonary KS can be fatal. The median survival for patients with pulmonary KS was 5.8 months from study entry. Notably, all of these patients had failed prior systemic therapy and they had a longer time from their original KS diagnosis (median, 16.5 months) when compared with other patients (median, 13.7 months).

View larger version (9K): [in this window] [in a new window]   Fig 2. Overall survival of the 56 patients treated with paclitaxel. The median survival was 15.4 months (95% confidence interval, 9.1 to not reached). Number of deaths = 26.

At the time of analysis, 23 patients have died: 10 from HIV-related complications, five from both KS and HIV-related complications, four from KS, two from paclitaxel-induced neutropenia, and two from complications of progressive AIDS-related non-Hodgkin's lymphoma.

Adverse Effects
Adverse effects are listed in Table 4. Grade 4 neutropenia was observed in 35% of patients. This is notable because 28 patients were on G-CSF before study entry due to neutropenia from either underlying bone marrow dysfunction or use of other myelotoxic agents. Fifteen patients started G-CSF while on study; 13 patients never required G-CSF during the trial. Two deaths during the trial were secondary to neutropenia and sepsis.

Neuropathy was reported by 52% of patients, of mild-to-moderate severity in all but one patient; no patient discontinued paclitaxel for neuropathy. Seventeen patients reported neuropathy before study entry. Other factors contributing to neuropathy include underlying HIV disease, prior use of Vinca alkaloids, and concurrent use of neurotoxic antiretroviral agents such as didanosine, zalcitabine, and stavudine.

A total of 51 AIDS-defining opportunistic infections were documented in these patients, for a total incidence rate of 10.5 per 100 patient months (Table 5). The most common infections documented were cytomegalovirus, pneumocystis carinii pneumonia, and esophageal candidiasis. The overall incidence of opportunistic infections is listed in Table 6.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Treatment of advanced AIDS-related KS has changed with the advent of liposomal anthracyclines, daunorubicin, and doxorubicin.^9-14 These agents have antitumor activity comparable to standard combination chemotherapy with doxorubicin, bleomycin, and vincristine, with a reduction in certain toxicities, such as alopecia. Response rates vary from 28% to 46% as first-line treatment, with median response durations of 90 to 175 days. When used as second-line treatment, liposomal doxorubicin is associated with a response of rate of 38%, with a median duration of response of 128 days. Thus there is a need for other therapies. The current study demonstrates that paclitaxel is active in patients who had received prior anthracyclines and is associated with relatively durable response.

Paclitaxel at a dose of 100 mg/m² every 2 weeks was well tolerated. The major side effects were neutropenia, peripheral neuropathy, and hair loss. The majority of patients in this study had poor bone marrow function at study entry requiring G-CSF use. Despite such a population, only 35% of the patients experienced grade 4 neutropenia.

The role of highly active antiretroviral therapy was examined as a possible confounding effect, particularly protease inhibitor use, because these agents have been shown anecdotally to induce response in patients with KS.^26-28 Protease inhibitor use was limited to a minority of patients (20 patients or 36%) at any time during the trial. No patient received a protease inhibitor before study entry. We have documented that only three patients started a protease inhibitor before major response, and only 13 of the responders received a protease inhibitor before disease progression. Thus the response rate or duration of response is independent of protease inhibitor use.

Low-dose paclitaxel administered every 14 days was active in these advanced and heavily pretreated patients. The response rate of 59% is unprecedented in patients with advanced KS, the majority of whom experienced treatment failure with prior systemic therapies, including anthracyclines. All patients had one or more poor risk factors, generally predicting for short survival. Although the response rates in patients who had no prior therapy were slightly higher than in those who received prior cytotoxic therapy, the differences were not statistically significantly, most likely due to the small study size. The median duration of response at 10.4 months is the longest reported with any therapy for KS, either as first- or second-line therapy.

Our study design differs from that of a recent report by Welles et al,²⁹ in which paclitaxel was given to KS patients at conventional doses of 135 mg/m² every 3 weeks with a cross-over design to a 96-hour continuous infusion in nonresponders. Although their response rate was similar, their patient population differed slightly in that all had good performance status scores and most had not received systemic chemotherapy. Only 17% had received an anthracycline compared with 59% of patients in our study.

Early studies with liposomal daunorubicin in KS patients who received prior systemic therapy have shown activity, but the median duration of response was short, at 4 months.¹⁰ Similarly, the median duration of response with liposomal doxorubicin after failure of prior systemic therapy was 128 days.¹² We found that patients who have received prior liposomal anthracyclines had a major response rate of 49%. Furthermore, the median duration of response in these patients was 10.5 months. The duration of response is particularly important because nearly one half had visceral disease, which is typically associated with short survival. The median survival of 5.8 months was better than that which is expected after first-line treatment. Large, randomized studies with liposomal doxorubicin and daunorubicin report visceral involvement of the lungs and gastrointestinal tract in approximately one third of patients.

Paclitaxel is thus active in a population of patients who have limited therapeutic options and who have experienced treatment failure with multiple prior regimens, including anthracyclines. The median survival of 15.4 months in this patient population with advanced, widespread disease is better than any historical data reported thus far. These data are the basis for further studies to define the minimal active dose of paclitaxel, to determine the response rates and tolerance in combination with liposomal anthracyclines, and to study paclitaxel as first-line treatment for patients with KS.

	ACKNOWLEDGMENTS

 
Supported in part by a research grant from Bristol-Myers Squibb Pharmaceutical Research Institute and by the Bridges and Larson Foundation

We thank Dharshika Dharmapala, Kathleen Shea, Serena Vergara, RN, Walter Howard, PA-C, Maria Palmer, PA-C, Robert Mocharnuk, MD, and Julio Hajdenberg, MD, for their expert patient care. We also thank Sue Huybensz and the clinical research staff at Bristol-Myers Squibb Pharmaceutical Research Institute for their invaluable assistance with this study. Lastly, we thank our patients for their participation in our research studies and the excellent nursing and support staff at the 5P21 AIDS clinic, New England Deaconess Hospital, and Massachusetts General Hospital.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 24, 1998; accepted February 18, 1999.

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