Kaposi's sarcoma and non-Hodgkin's lymphoma incidence trends in AIDS Clinical Trial Group study participants.

Combination therapy with protease inhibitors and nucleoside analogues dramatically suppresses plasma HIV-1 RNA and delays progression to AIDS, but the impact on HIV-associated malignancy remains to be established. We therefore examined incidence trends of Kaposi's sarcoma and non-Hodgkin's lymphoma in patients with advanced HIV infection in nine AIDS Clinical Trial Group studies of antiviral therapies for HIV and cytomegalovirus infections. Among a total of 6587 patients enrolled between November 1987 and February 1997, there were 280 cases of Kaposi's sarcoma and 68 cases of non-Hodgkin's lymphoma. Incidence rates per 100 person-years of both malignancies declined in concert with decreases in mortality, but the decreases in Kaposi's sarcoma were more profound and consistent than the decreases in non-Hodgkin's lymphoma. These data suggest that current therapies have ameliorated the incidence of Kaposi's sarcoma, but may not have had an equal effect on non-Hodgkin's lymphoma.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy.

PURPOSE: To determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy. METHODS: Fifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks. RESULTS: Nineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorubicin. Patients obtained clinical benefits such as flattening of lesions (48%), improved lesion color (56%), relief of pain (45%), and loss of edema (83%). Forty-nine percent of patients had more than one clinical benefit. The most common adverse effect was leukopenia, which occurred in 40% of patients. Only 15% of patients had nausea and/or vomiting, none of which was severe; 9% experienced alopecia, also generally mild. CONCLUSION: Pegylated-liposomal doxorubicin offers a new alternative for treatment of patients who have experienced failure of standard chemotherapy for AIDS-KS.

Non-AIDS-defining malignancies in patients with HIV infection.

HIV-infected individuals are at an increased risk for development of cancers other than the three AIDS-defining malignancies. Two non-AIDS-defining cancers, germ cell tumors and Hodgkin's disease, have been reported in the setting of HIV infection with increased frequency compared with their incidence in the general population. Other non-AIDS-defining malignancies frequently reported in the setting of HIV infection include lung cancer, squamous and basal cell carcinomas of the skin, anal carcinoma, and pediatric leiomyosarcomas.

Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma.

PURPOSE: To compare the safety and efficacy of liposomal daunorubicin (DaunoXome; NeXstar Pharmaceuticals, Inc, Boulder, CO) with a reference regimen of doxorubicin, bleomycin, and vincristine (ABV) in advanced AIDS-related Kaposi's sarcoma (KS). PATIENTS AND METHODS: In a prospective randomized phase III trial, 232 patients were randomized to receive DaunoXome 40 mg/m2 or a combination regimen of doxorubicin 10 mg/m2, bleomycin 15 U, and vincristine 1 mg, administered intravenously every 2 weeks. Treatment was continued until complete response (CR), disease progression, or unacceptable toxicity. RESULTS: Of 232 patients randomized, 227 were treated: 116 with DaunoXome and 111 with ABV. The overall response rate (CR or partial response [PR]) was 25% (three CRs and 26 PRs) for DaunoXome and 28% (one CR and 30 PRs) for ABV. The difference in response rates was not statistically significant. The median survival time was 369 days for DaunoXome patients and 342 days for ABV patients (P = .19). The median time to treatment failure was 115 days for DaunoXome and 99 days for ABV (P = .13). ABV patients experienced significantly more alopecia and neuropathy (P < .0001). DaunoXome patients experienced more grade 4 neutropenia (P = .021). Cardiac function remained stable, with no instances of congestive heart failure on either treatment arm. CONCLUSION: In this large phase III trial, the efficacy of DaunoXome was comparable to that of ABV. Response rates, time to treatment failure, and overall survival were similar on both treatment arms. DaunoXome is a safe and effective primary therapy for advanced AIDS-related KS.

Anorexia/cachexia in patients with HIV: lessons for the oncologist.

Early intervention and attention to nutritional status are essential in patients with cachexia. Identification of reversible causes of decreased energy intake and/or weight loss is the first step in treatment. When such factors cannot be identified, pharmacologic interventions should be considered. To date, megestrol acetate is the most effective appetite stimulant. Appetite and weight gain occur to a greater and more rapid degree as megestrol dose increases. Unfortunately, the weight gain is due predominantly to an increase in fat mass. Whether this is due to a lack of exercise in the face of increased caloric intake and/or to the hypogonadal effects of megestrol acetate is being tested in ongoing clinical trials. Anabolic agents, particularly growth hormone, are exciting potential therapies. No data are yet available on alternate doses and schedules of growth hormone or on its effect in patients with decreased oral intake. Current studies addressing combination therapy with anabolic agents and appetite stimulants should clarify their respective therapeutic roles.

Treatment strategies for epidemic Kaposi's sarcoma.

As the AIDS epidemic progresses, Kaposi's sarcoma continues to contribute substantially to the morbidity suffered by AIDS patients. Advances in our understanding of the pathogenesis of Kaposi's sarcoma have resulted in treatment strategies that are being investigated in the laboratory and clinic. Agents that affect the abnormal cytokines associated with Kaposi's sarcoma or inhibit angiogenesis are in early clinical trials. The recent discovery of a putative Kaposi's sarcoma virus may lead to new preventive or therapeutic strategies. Interferon, usually in combination with an antiretroviral nucleoside analogue, remains an important therapeutic option for patients with relatively intact immune function. For patients with more advanced immune suppression, chemotherapy is usually given, although there is no standard treatment regimen. New chemotherapeutic agents, including the use of liposomal encapsulated anthracyclines and topoisomerase-1 inhibitors, are being evaluated.

Hospice and palliative care: attitudes and practices of the physician faculty of an academic hospital.

It has been suggested that physicians, particularly in academic hospitals, are resistant to the hospice approach to palliative care for terminally ill patients. It is of interest, therefore, to assess the attitudes and practices of the physician faculty of an academic hospital where a hospice program has been in existence for more than 10 years. This was assessed with two faculty surveys. All 966 physician faculty that were on staff at Northwestern Memorial Hospital in the fall of 1993 were sent a survey about their opinion of hospice care (Survey A). Then, all physicians who had referred patients to the hospice program between September 1993 and September 1994 at Northwestern Memorial Hospital received a survey letter after the death of their patient (Survey B). Seventy-seven percent of faculty physician respondents to Survey A had either referred patients, or knew of colleagues who had referred patients to a hospice program. Ninety-four percent of those who answered "yes" to the question about referrals reported satisfaction with their care. Ninety-four percent would refer patients in the future and 96 percent thought the hospice program was a valuable resource to the medical center. Of the respondents to Survey B, nearly 100 percent thought the referral had been handled in an "excellent" or "good" fashion, that communication with hospice staff was "excellent" or "good," that symptom control was "excellent" or "good," that their patients and families had received "excellent" or "good" psychosocial support, and that their patients and families were satisfied with the hospice care they received.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS and palliative medicine: medical treatment issues.

Caring for patients with AIDS in hospice programs presents numerous challenges. These go beyond the strictly medical decisions discussed in this article to include unique problems with social support, emotional support, and bereavement. This discussion centers on medical issues as they are commonly encountered. They can be stumbling blocks, or even surrogates, for addressing the other important issues at the end of life. Communication between all people involved in the multidisciplinary treatment of these patients is essential. Common goals should be identified and general approaches agreed upon among the physicians, nurses (clinic, hospice, home care), therapists, clergy, and volunteers. In this way we feel that the principles of hospice and palliative care can be effectively applied to most patients with endstage AIDS.

Housestaff training in cancer pain education.

A program for improving housestaff education in cancer pain control was piloted on an inpatient oncology unit during academic year 1992-93. Housestaff (four or five first-year residents and two more senior residents per month) received a three-day lecture series each month. A total of 32 housestaff participated. A questionnaire (Test A) about cancer pain was administered before the series. The subjects scored 58% correct (range 49-69). When Test A was repeated at the end of each rotation, the subjects scored 83% correct (range 82-86, p < 0.0001). A quiz on analgesic dosing (Test B) was also administered. The subjects scored 38% (range 20-56) before the lectures, 81% (range 72-93) immediately after the lectures, and 57% (range 44-67) at the end of the rotation. The authors conclude that this pilot project improves knowledge about cancer pain, but sustained reinforcement is needed if analgesic dosing skills are to be maintained.

A hospice/palliative medicine rotation for fellows training in hematology-oncology.

A clinical hospice/palliative medicine rotation for physicians enrolled in a three-year hematology/oncology fellowship was established in academic year 1993-1994 as a way to accomplish important training goals in pain management and the palliative care of patients with terminal illness. This study was conducted to obtain initial information about its effectiveness. Ten fellows, one at a time, evaluated new hospice/palliative medicine consultations, supervised the care of patients on an inpatient hospice/palliative care unit, and visited patients at home. For the first 13 months, seven fellows were assigned to this rotation for one month each, and three fellows were assigned to spend two separate months each. A self-report evaluation of the experience was administered at the end of each service month. In five of these 13 evaluations, the fellows reported their skills in managing pain and symptoms to be much improved, and in eight they indicated their skills were improved; none stated that there had been no change. Comfort and skill with discussing death, dying, and advanced directives with patients and families were reported by the fellows to be much improved in nine evaluations, improved in three, and unchanged in one. In nine evaluations, the fellows reported their understanding of hospice/palliative care as a program and approach to patient care was much improved; in two, improved; and in two, unchanged. All of the fellows would recommend this rotation to other fellows. A clinical rotation in palliative medicine and hospice care is a useful addition to the curriculum of fellows training in hematology-oncology.

Randomized trials of megestrol acetate for AIDS-associated anorexia and cachexia.

Involuntary weight loss is a frequent complication of acquired immune deficiency syndrome (AIDS) and ultimately affects the majority of patients. The deleterious effects of weight loss on immune function and the physical and psychological sequelae of severe weight loss are well recognized. Megestrol acetate induces appetite stimulation and nonfluid weight gain in patients with advanced hormone nonresponsive cancers. In a pilot study, megestrol acetate produced nonfluid weight gain in patients with AIDS. Two double-blind randomized placebo-controlled trials of megestrol acetate for the treatment of AIDS-related anorexia and cachexia have shown improvements in body weight with treatment. In a multicenter trial reported by Flynn et al. at the 7th International Conference on AIDS (1992), 65 patients with AIDS and weight loss of > 10% of ideal body weight were randomized to placebo or megestrol acetate 800 mg/day. Megestrol acetate-treated patients had a significantly greater mean maximum weight gain (p = 0.027) and appetite stimulation (p = 0.021) than did placebo-treated patients. In a second, larger randomized placebo-controlled trial, 271 patients with AIDS, anorexia and cachexia were randomized to receive placebo or multiple doses of megestrol acetate at 100, 400 or 800 mg/day for 12 weeks. A maximum weight gain of at least 5 lb (2.25 kg) was observed in 64.2% of patients in the 800-mg megestrol acetate group compared with 21.4% in the placebo group (p < 0.0001). Mean maximum weight change from baseline to last evaluation was +8.3 lb in the 800-mg group and -1.1 lb in the placebo group (p < 0.001). Mean change in lean body mass from baseline to last evaluation was +2.5 lb in the 800-mg group versus -1.7 lb in the placebo group (p < 0.001). A significant improvement in appetite was seen in patients receiving 800 mg megestrol acetate compared with patients receiving placebo. No significant toxicity was observed with megestrol acetate therapy. Megestrol acetate is an effective treatment for some patients with AIDS-related anorexia and cachexia.

Megestrol acetate in patients with AIDS-related cachexia.

OBJECTIVES: To compare the effects of oral suspensions of megestrol acetate, 800 mg/d, and placebo on body weight in patients with acquired immunodeficiency syndrome (AIDS)-related weight loss. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient community and university patient care setting. PATIENTS: Consecutive patients with AIDS who had substantial weight loss and anorexia were enrolled. Of 271 patients, 270 and 195 were evaluable for safety and efficacy, respectively. INTERVENTIONS: Patients were randomly assigned to receive placebo or megestrol acetate (100 mg, 400 mg, or 800 mg) daily for 12 weeks. MAIN OUTCOME MEASURES: The primary efficacy criterion was weight gain. Patients were evaluated at 4-week intervals for changes in weight and body composition, caloric intake, sense of well-being, toxic effects, and appetite. RESULTS: For evaluable patients receiving 800 mg of megestrol acetate per day, 64.2% gained 2.27 kg (5 pounds) or more compared with 21.4% of patients receiving placebo (P < 0.001). An intent-to-treat analysis showed significant differences (P = 0.002) between those receiving placebo and those receiving 800 mg of megestrol acetate for the number of patients who gained 2.27 kg (5 pounds) or more (8 of 32 [25%] compared with 38 of 61 [62.3%], respectively). Compared with patients receiving placebo at the time of maximum weight change, evaluable patients receiving megestrol acetate, 800 mg/d, reported improvement in overall well-being and had an increase in mean weight gain (-0.725 compared with 3.54 kg [-1.6 compared with +7.8 pounds]; P < 0.001), lean body mass (-0.772 compared with +1.14 kg [-1.7 compared with +2.5 pounds]; P < 0.001), appetite grade (P < 0.001), and caloric intake (-107 compared with +645.6 calories/d; P = 0.001). CONCLUSIONS: In patients with AIDS-related weight loss, megestrol acetate can stimulate appetite, food intake, and statistically significant weight gain that is associated with a patient-reported improvement in an overall sense of well-being.

Management of HIV-related bodyweight loss.

Involuntary bodyweight loss is a frequent manifestation of HIV infection and ultimately affects the majority of patients. Because it portends a poor prognosis and adversely affects quality of life, nutritional intervention has an important role in the care of all HIV-infected persons. The mechanism of HIV-related bodyweight loss is multifactorial and includes complex interactions between decreased caloric intake, malabsorption and metabolic and/or hormonal abnormalities. Treatment of reversible and identifiable causes of bodyweight loss such as opportunistic infections and adverse effects of therapy are essential for the maintenance of bodyweight. For patients with anorexia of unclear aetiology, there are effective appetite stimulants available. Enteral and parenteral alimentation are under evaluation for their role in maintenance and/or repletion of bodyweight for patients with HIV infection.