This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Evans, S. R. Articles by Von Roenn, J. H. Search for Related Content PubMed PubMed Citation Articles by Evans, S. R. Articles by Von Roenn, J. H.

Phase II Evaluation of Low-Dose Oral Etoposide for the Treatment of Relapsed or Progressive AIDS-Related Kaposi’s Sarcoma: An AIDS Clinical Trials Group Clinical Study

From the Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard School of Public Health, and Sections of Hematology and Oncology, Department of Medicine, Boston Medical Center and Boston School of Medicine, Boston, MA; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and Department of Medicine, Northwestern University Medical School and The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL.

Address reprint requests to Jamie H. Von Roenn, MD, Department of Medicine, Division of Hematology and Medical Oncology, Northwestern University Medical School, 676 N Saint Clair St, Suite 850, Chicago, IL 60611; email: j-vonroenn{at}northwestern.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Liposomal anthracyclines and paclitaxel are considered the best available cytotoxic therapies for Kaposi’s sarcoma (KS), but relapse is common. To identify new interventions for relapsed or progressive KS, a phase II study of low-dose etoposide to assess its toxicity and efficacy was conducted.

PATIENTS AND METHODS: Thirty-six patients with high-risk KS were treated with oral etoposide 50 mg/d for 7 consecutive days of every 2-week cycle. All patients’ disease had relapsed or progressed after prior combination chemotherapy or anthracycline therapy. For patients without a complete or partial response after two cycles of therapy and no toxicity greater than grade 2, the dose of etoposide was escalated to 100 mg/d orally on days 1 to 7 of each 14-day cycle. Treatment-related and disease-specific quality of life was evaluated using patient reports on the General Health Self-Assessment Form and a KS-specific measure.

RESULTS: One patient achieved a complete response, 12 patients had a partial response (overall response rate, 36.1%), and stable disease was observed in 12 patients (33.3%). Tumor responses were seen in all disease sites. Fourteen patients had their dose escalated, of whom five responded. The median time to response was 17.7 weeks; the median duration of response was 25 weeks. The most frequent hematologic abnormality was neutropenia, which was grade 4 in seven patients and grade 3 in six. Opportunistic infections occurred in eight patients during the treatment period. Both response to treatment and toxicity influenced patient-reported quality of life.

CONCLUSION: We conclude that low-dose oral etoposide at a dose of 50 mg/d is safe and effective for the treatment of refractory or progressed AIDS-related KS and has an overall positive effect on the quality of life of responding patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
KAPOSI’S SARCOMA (KS) is the most common malignancy associated with human immunodeficiency virus (HIV) infection.¹ Although the incidence of KS dramatically decreased beginning in the early 1990s, it continues to cause morbidity, and occasionally mortality, in patients with AIDS.^2,3

When KS is widely disseminated, symptomatic, or involves the viscera, cytotoxic chemotherapy is generally considered the treatment of choice. Response rates ranging from 27% to 80% have been documented for a variety of single agents.^4-14 Among these, the liposomal anthracyclines and paclitaxel are currently considered the most effective agents.^10-14 Although these agents induce high response rates, complete responses are relatively uncommon, responding subjects often relapse, and some patients fail to respond. Thus, new therapeutic interventions are needed.

Etoposide was one of the first drugs shown to be active against AIDS-related KS.^9-15 Early in the AIDS epidemic, before the introduction of any antiretroviral drugs, Laubenstein et al⁹ evaluated etoposide at a dose of 150 mg/m² intravenously given on 3 consecutive days every 4 weeks in 41 subjects with AIDS-associated KS. Most of these subjects had limited KS, had no prior opportunistic infections, and had received no prior therapy. The response rate was high, approaching 90% in asymptomatic patients, with a median response duration of 9 months. However, neutropenia and gastrointestinal toxicity were common, and alopecia was observed in all patients.

In a phase I study that enrolled primarily high-risk patients, oral etoposide given as a single, once-weekly dose to patients with KS induced a response rate of 36% and minimal toxicity.¹⁶ Neutropenia was the most frequent dose-limiting toxicity and occurred after a median of 10 weeks of treatment. The observation that low-dose etoposide given over an extended period resulted in an apparent improvement in the therapeutic index in patients with solid tumors led to the development of this phase II study in patients with relapsed or refractory AIDS-associated KS.¹⁷ Etoposide, 50 mg/d by mouth, was administered for 7 consecutive days of each 14-day cycle. The primary objectives of this trial were to assess the impact of daily low-dose oral etoposide on toxicity, tumor response rate, and overall quality of life in patients with AIDS-related KS.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Adult patients ( 12 years of age) with biopsy-proven KS that had relapsed or progressed after prior combination chemotherapy or single-agent anthracycline therapy were eligible for this study. Patients with 15 mucocutaneous lesions and/or symptomatic mucosal disease and/or visceral KS and/or lymphedema were accrued at sites participating in the AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases. Additional eligibility criteria included a Karnofsky performance status 60%, documentation of HIV infection, and the following laboratory parameters: hemoglobin 8 g/dL; absolute neutrophil count 1,000/µL; platelets 75,000/µL; creatinine 1.5 times the upper limit of normal or estimated creatinine clearance of more than 50 mL/min; AST, ALT, and alkaline phosphatase less than five times the upper limit of normal; and bilirubin less than 2 mg/dL. Patients were excluded if they were pregnant or had received prior therapy with etoposide or any antitumor drugs within 14 days before study entry, prior radiation therapy within 7 days before study entry, or therapy with any investigational agent other than antiretroviral agents available by treatment investigational new drug within 14 days before study entry. Additional exclusion criteria included acute opportunistic infections requiring treatment with myelosuppressive antibiotics; neuropsychiatric history or altered mental status that would prevent informed consent or compliance with the protocol; the presence of other active malignancies except basal cell carcinoma of the skin or carcinoma-in-situ of the cervix; or peripheral neuropathy grade 3. The study was approved by the institutional review boards of the participating institutions, and all patients gave informed consent before study entry.

Schedule of Events
Clinical assessments, including a history and physical examination focused on HIV and KS-related signs and symptoms, tumor assessments, performance status, quality-of-life assessment, and complete blood count with differential and platelets, were performed before each 2-week treatment cycle for the first 6 months and every 4 weeks thereafter. Serum chemistries were performed at baseline and every 4 weeks, and a chest radiograph was obtained at baseline in all patients and before every other cycle for those patients with pulmonary KS. All eligible subjects experiencing an adverse event before completion of two cycles of therapy with oral etoposide were considered assessable for toxicity. Using an intent-to-treat analysis, all eligible subjects were considered assessable for antitumor response.

Tumor Evaluation and Definition of Response
Patients were assessed for the number, character, and distribution of mucocutaneous KS lesions and the presence of tumor-associated edema at study entry and every 4 weeks while on therapy. For patients with 50 total skin and oral lesions, all lesions were counted, and the number of raised and flat lesions was enumerated. For patients with more than 50 lesions, three representative anatomic areas were chosen for these evaluations. In all patients, up to five indicator lesions were selected and measured bidimensionally at each tumor evaluation.

Complete response was defined as the absence of any detectable residual disease persisting for at least 4 weeks, including tumor-associated edema. Patients with residual pigmented lesions required biopsy of a representative lesion to document a complete response. Patients with known visceral disease required repeat radiographic or endoscopic evaluation to document resolution of baseline abnormalities.

Partial response was defined as the absence of new mucocutaneous lesions, new visceral sites of involvement, or the appearance or worsening of tumor-associated edema or effusions and a 50% or greater decrease in the number or size of previously existing lesions or complete flattening of more than 50% of previously existing nodular lesions lasting for at least 4 weeks.

Progressive disease was defined as a 25% or more increase in the size of previously existing lesions and/or the number of new lesions, or new or increasing tumor-associated edema lasting at least 1 week that interfered with the subject’s normal activities. Stable disease was defined as disease not meeting the criteria for progression or response.

Statistical Considerations and Study Design
Descriptive statistics were used to describe the study population and incidence of adverse events. Continuous variables were summarized by displaying descriptive statistics. The Kaplan-Meier method was used to display time-to-event variables. If the treatment dispensing date was missing, the starting date was used for time-to-event variables. Otherwise, the registration date was used. Simon’s optimal two-stage design was used in this trial, and confidence intervals (CIs) for the response rate were appropriately adjusted.¹⁸

Responses from the General Health Self-Assessment Form (functional, emotional, work/social, health care utilization, and symptom distress) and KS-specific measures (pain, dissatisfaction with appearance, distress, and edema) were transformed to a scale from 0 to 100, where a higher score indicated a better quality of life. For each subject, a mean summary score was computed for each component. Changes in quality of life were computed as the changes in the mean response of all items within each subsection of the instrument.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Thirty-six patients were accrued onto the study between January 1995 and March 1998 from 11 ACTG centers. Baseline characteristics of the patients enrolled are listed in Table 1. The study enrollment was 97% male and 61% white. All patients enrolled on this trial had "poor-risk" KS as defined by ACTG staging criteria.¹⁹ All patients had received prior chemotherapy. Twenty-nine subjects were receiving stable antiretroviral therapy, which was defined as an unchanged HIV medication regimen for at least 1 month before the study. Five patients were on stable highly active antiretroviral therapy (HAART) at the time of enrollment. Fourteen subjects had some change in their HIV regimen during the study. Prior opportunistic infections were reported by 27 patients (75%). Data on baseline CD4 count were not collected as part of this study. HIV viral load was not considered a standard test when this study was conducted.

Response
Using an intent-to-treat analysis that included all enrolled patients, a complete response was documented in one patient (2.8%), partial response in 12 (33.3%), and stable disease in 12 (33.3%) (Table 2). The overall objective response rate was 36.1% (13 of 36) (95% CI, 21.8% to 55.3%). A secondary analysis, which included only assessable subjects as defined in the protocol (ie, completed two cycles), demonstrated an objective response rate of 44.8% (13 of 29) (95% CI, 26.4% to 64.5%). As listed in Table 2, responses were seen in 12 of the 31 patients with tumor-associated edema, two of 10 patients with visceral disease, and seven of 21 patients with oral cavity lesions. For patients without a complete or partial response after two cycles of therapy and no toxicity greater than grade 2, the dose of etoposide was escalated to 100 mg/d orally on days 1 to 7 of each cycle. Fourteen patients had their dose escalated, of whom five later responded. Flattening of previously raised lesions was the most common criterion on which response was based. None of the 13 responders’ disease progressed during a median follow-up time of 23 weeks. However, 17 of 23 nonresponders showed progression.

The median time to response was 17.7 weeks. The median follow-up time was 14.9 weeks. Because none of the responders’ disease progressed during the study follow-up period, the duration of tumor response was censored for all responders. Study treatment was discontinued for toxicity by one subject (2.8%), for non–protocol-related death by three subjects (8.3%), for clinical end point by 26 subjects (72.2%), at the request of the patient by four subjects (11.1%), at the request of the physician for one subject (2.8%), and for protocol violation by one subject (2.8%).

Toxicity
The toxicity of chronic oral etoposide in patients with refractory and/or progressed AIDS-related KS was mild to moderate. No significant change in performance status was observed in patients on-study. One patient experienced grade 4 fever, and 12 experienced severe (grade 3) treatment- or disease-related, nonlaboratory toxicity (achiness, pain, or discomfort, four; agitation, one; irregular heart rhythm, one; difficulty with concentration, one; seizure, one; paresthesias, one; decreased appetite, one; chills/night sweats, one; diarrhea, two; fever, one; rash, one; nausea, one; and mucositis, one). Most of the 12 patients experienced multiple, concurrent grade 3 toxicities. Grade 2 nausea with or without vomiting was observed in five patients. Laboratory toxicities are listed in Table 3. One or more life-threatening (grade 4) laboratory toxicities were experienced by 10 patients and included neutropenia in seven, and alkaline phosphatase, gamma-glutamyl transferase, anemia, lipase, and thrombocytopenia in one each. Grade 2 or 3 neutropenia was documented in eight patients, and grade 2 or 3 anemia was observed in three patients. Fifteen subjects experienced a laboratory toxicity of grade 3 or higher. Seventeen patients reported use of granulocytic colony-stimulating factor (one of these reported use only at baseline).

Survival
Fifteen patients died during the course of the trial, 10 while on study. Progressive KS was the cause of death for two patients; Pneumocystis carinii pneumonia was the cause of death for two patients; and one patient each died from Mycobacterium avium-intracellulare infection and cytomegalovirus encephalitis. Non–HIV-related causes accounted for two deaths, and secondary HIV progression led to death in the remaining subjects. The median survival time, censoring surviving patients at the time of last contact, was estimated to be 41 weeks.

Quality-of-Life Data
Baseline characteristics. At baseline, the study sample demonstrated consistently low health perceptions across the five items (overall, functional, emotional, personal life, and work and social role) constituting the health perceptions scale, with an overall mean of 46. Similarly, mean functional, emotional and cognitive, and work/social role scores were all less than 60% of the maximum, indicating that patients were functioning at relatively low levels consistent with the severity and stage of their disease before treatment. As listed in Table 4, the symptom distress scores (general and KS-specific) indicated the greatest distress associated with dissatisfaction with appearance, pain and edema, overall discomfort, weakness and fatigue, and trouble sleeping. The least distress was associated with hair loss, chest pain, eye trouble, and diarrhea.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Etoposide is a highly schedule-dependent agent. Once-daily doses give results superior to intermittent administration.^17,20,21 Slavin et al¹⁷ randomly assigned previously untreated subjects with small-cell lung cancer to receive the same total dose of etoposide given either as a single 24-hour intravenous infusion or as five daily 2-hour infusions. The 24-hour schedule induced a response rate of 10%, whereas the 5-day schedule induced responses in 89% of the patients. Pharmacokinetic analysis revealed that although both groups achieved a similar area under the curve, serum concentrations of etoposide more than 1 µg/mL were maintained for twice as long with the 5-day treatment compared with the 1-day treatment. This suggests that prolonged maintenance of low plasma concentrations of etoposide is more important than peak concentrations. Reduced hematologic toxicity and gastrointestinal toxicity have been observed when low-dose oral etoposide was administered as a single agent to previously untreated elderly subjects with small-cell lung cancer. Our results confirm the beneficial therapeutic index of low-dose chronic etoposide administration.

Prolonged survival is rarely the primary purpose of treatment for KS. Symptomatic relief of pain, tumor-associated edema, or disfiguring lesions are more often the major objectives of therapy. This led us to attempt an evaluation of the net impact of therapy by using quality of life as an integrated measure of therapeutic effectiveness. It was hypothesized that the beneficial effects of therapy in those patients whose tumors regressed would outweigh any negative side effects from chemotherapy, and that these positive effects would be associated with corresponding positive changes in functional, emotional, and social health. Both treatment response and toxicity influenced patient-reported quality of life. At baseline, patients had a low functional status and experienced significant pain. Responding patients reported relief of pain and improved quality of life, whereas treatment toxicity adversely affected these parameters. However, for responding patients, the overall effect was positive. The importance of integrating quality-of-life measurements into the evaluation of the therapeutic efficacy of treatments for KS should not be underestimated. In current multicenter phase III trials, overall quality of life and symptom improvement and their relationship to response are being systematically evaluated.

In conclusion, our results support the use of chronic, low-dose oral etoposide for the treatment of previously treated AIDS-associated KS. Although the incidence of AIDS-associated KS has declined in developed countries since the introduction of effective antiretroviral therapy,^22,23 advanced KS requiring chemotherapy still occurs, and second-line therapy is needed for those who relapse after treatment with liposomal anthracyclines and/or paclitaxel. For such patients, low-dose chronic administration of etoposide may be a useful option. Oral etoposide may be of even greater value in underdeveloped areas of the world, particularly in sub-Saharan Africa, where access to cancer and HIV treatments are limited and both HIV and human herpesvirus 8 seroprevalence rates are high.²⁴ In such settings, an effective, minimally toxic, easily administered therapeutic agent may be of particular importance.

	ACKNOWLEDGMENTS

 
Supported by the National Institutes of Health grant no. AI-38858 to the AIDS Clinical Trials Group.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Ledergerber B, Telenti A, Egger M: Risk of HIV related Kaposi’s sarcoma and non-Hodgkin’s lymphoma with potent antiretroviral therapy: Prospective cohort study. BMJ 319: 23-24, 1999[Free Full Text]

2. Brodt HR, Kamps BS, Helm EB, et al: Kaposi’s sarcoma in HIV infection: Impact on opportunistic infections and survival. AIDS 12: 1475-1481, 1998[CrossRef][Medline]

3. Jones JL, Hanson DL, Dworkin MS, et al: Incidence and trends in Kaposi’s sarcoma in the era of effective antiretroviral therapy. J Acquir Immune Defic Syndr 24: 270-274, 2000[Medline]

4. Volberding PA, Abrams DI, Conant M, et al: Vinblastine therapy for Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Ann Intern Med 103: 335-338, 1985[Medline]

5. Lewis B, Abrahms J, Ziegler J, et al: Single agent or combination chemotherapy of Kaposi’s sarcoma (KS) in acquired immune deficiency syndrome (AIDS). Proc Am Soc Clin Oncol 2: 59, 1983 (abstr C-232)

6. Reiber E, Mittelman A, Wormser GP, et al: Vincristine and Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Ann Intern Med 101: 876, 1984 (letter)[Medline]

7. Goss PE, Shepherd FA, Burkes R, Paul K: Phase II study of epirubicin in the treatment of Kaposi’s sarcoma and AIDS (EKS). Proc Am Soc Clin Oncol 8: 2, 1989 (abstr 5)

8. Gill Parkash S, Rarick M, McCutchan JA, et al: Systemic treatment of AIDS-related Kaposi’s sarcoma: Results of a randomized trial. Am J Med 90: 427-433, 1991[Medline]

9. Laubenstein LS, 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 2: 1115-1120, 1984[Abstract]

10. 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. J Clin Oncol 16: 683-691, 1998[Abstract]

11. 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 16: 2445-2451, 1998[Abstract]

12. Northfelt DW, Dezube BJ, Thommes JA, et al: Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma after failure of standard chemotherapy. J Clin Oncol 15: 653-659, 1997[Abstract/Free Full Text]

13. 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 17: 1876-1883, 1999[Abstract/Free Full Text]

14. 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 16: 1112-1121, 1998[Abstract]

15. Schwartsmann G, Sprinz E, Kromfield M, et al: Clinical and pharmacokinetic study of oral etoposide in patients with AIDS-related Kaposi’s sarcoma with no prior exposure to cytotoxic therapy. J Clin Oncol 15: 2118-2124, 1997[Abstract/Free Full Text]

16. Paredes J, Kahn JO, Tong WP, et al: Weekly oral etoposide in patients with Kaposi’s sarcoma associated with human immunodeficiency virus infection: A phase I multicenter trial of the AIDS Clinical Trials Group. J Acquir Immune Defic Syndr 9: 138-144, 1995

17. Slavin ML, Clark PI, Joel SP, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7: 1333-1340, 1989[Abstract]

18. Simon R: Optimal two stage design of phase II clinical trials. Control Clin Trials 10: 1-10, 1989[Medline]

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

20. Slavin ML: The clinical pharmacology of etoposide. Cancer 67: 319-329, 1991[CrossRef][Medline]

21. Clark PI, Cottier B, Joel SP, et al: Prolonged administration of single-agent oral etoposide in patients with untreated small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 9: 226, 1990 (abstr 874)

22. Jones JL, Hanson DL, Dworkin MS, et al: Incidence and trends in Kaposi’s sarcoma in the era of effective antiretroviral therapy. J Acquir Immune Defic Syndr 24: 270-274, 2000[Medline]

23. Jacobson LP, Tamashita TE, Detels R, et al: Impact of potent antiretroviral therapy on the incidence of Kaposi’s sarcoma and non-Hodgkin’s lymphomas among HIV-1-infected individuals: Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr 21: S34-S41, 1999 (suppl 1)

24. Chokunonga E, Levy LM, Bassett MT, et al: Cancer incidence in the African population of Harare, Zimbabwe: Second results from the cancer registry 1993-1995. Int J Cancer 85: 54-59, 2000[CrossRef][Medline]

Submitted December 10, 2001; accepted May 2, 2002.

This article has been cited by other articles:

				T. J. Smith, J. Khatcheressian, G. H. Lyman, H. Ozer, J. O. Armitage, L. Balducci, C. L. Bennett, S. B. Cantor, J. Crawford, S. J. Cross, et al. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline J. Clin. Oncol., July 1, 2006; 24(19): 3187 - 3205. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Evans, S. R. Articles by Von Roenn, J. H. Search for Related Content PubMed PubMed Citation Articles by Evans, S. R. Articles by Von Roenn, J. H.