Susan E. Krown

Preliminary Observations on the Effect of Recombinant Leukocyte a Interferon in Homosexual Men with Kaposi's Sarcoma

Preliminary clinical trials have shown that both natural and recombinant-DNA-produced human interferons are occasionally capable of inhibiting the growth of some tumors.1 2 3 4 Although the tumors ...

Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.

PURPOSE Three trials were conducted to define the efficacy and toxicity of interferon alfa-2a in the treatment of metastatic renal cell cancer. Univariate and multivariate analyses were performed to identify prognostic factors for survival. PATIENTS AND METHODS Prospectively, 159 patients were treated with interferon alfa-2a. In the first trial, 42 patients received 50 x 10(6) U/m2 intramuscularly three times per week. In the second trial, 64 patients received gradually escalating doses of interferon alfa-2a from 3 to 36 x 10(6) U subcutaneously administered daily. The third trial was randomized; 25 patients received daily interferon alfa-2a alone and 28 were treated with daily interferon alfa-2a and 0.15 mg/kg vinblastine every 3 weeks. RESULTS The overall response proportion was 10% (two complete and 14 partial responses). The median response duration was 12.2 months. The median survival duration was 11.4 months, with 3% of patients alive at 5 or more years. A univariate statistical analysis showed that a Karnofsky performance status > or = 80, prior nephrectomy, and interval from diagnosis to treatment of longer than 365 days were significant prognostic factors for survival. In a multivariate analysis, only prior nephrectomy and Karnofsky performance status > or = 80 were shown to be independent predictors of survival. CONCLUSION Interferon alfa-2a had minimal antitumor activity in patients with advanced renal cell carcinoma and long-term survival was achieved in a small proportion of patients. The need for continued investigation and the identification of more effective therapy for advanced renal cell carcinoma is evident from the poor overall survival rate observed in these 159 patients. The investigation of new agents and of interferon alfa-2a in combination with other agents remains a priority.

Selective CD4+ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications

PURPOSE Standard schedule temozolomide (TMZ; daily for 5 days every 4 weeks) is often used in melanoma patients, but phase III data show that it is no more effective than standard dacarbazine. Extended TMZ dosing regimens may be superior by delivering the drug continuously at a higher dose over time. Using an extended dosing schedule, we noted a high incidence of lymphopenia and occasional opportunistic infections (OIs). Here we report our retrospective experience in the first 97 patients. MATERIALS AND METHODS TMZ was administered at 75 mg/m(2)/d orally for 6 weeks every 8 weeks, although nine patients were treated continuously without a break. Seventeen patients were treated with TMZ alone; 73 patients received TMZ with thalidomide; seven patients received TMZ with low-dose interferon alfa. RESULTS Median duration of TMZ treatment was 113 days; 29% received > or = 24 weeks of therapy. Lymphopenia was seen in 60% of patients (absolute lymphocyte count < 800/microL) with a median of 101 days to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4(+) compartment preferentially. There were two documented OIs (Pneumocystis and Aspergillus pneumonia) as well as other infections indicative of T-cell dysfunction in another 21 patients. CONCLUSION TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

AIDS-related Kaposi's sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee.

PURPOSE To prospectively validate the AIDS Clinical Trials Group (ACTG) staging classification for AIDS-associated Kaposis sarcoma (KS). PATIENTS AND METHODS Two hundred ninety-four consecutive patients enrolled in eight ACTG therapeutic trials for AIDS-associated KS were staged prospectively according to tumor extent (T), severity of immunosuppression (I), and other systemic human immunodeficiency virus type 1 (HIV-1)-associated illness (S) and were observed for survival. Patients were classified as good risk (subscript 0) or poor risk (subscript 1) for each variable according to published ACTG criteria. Univariate and multivariate analyses were used to evaluate the associations between TIS variables and survival; additional analyses were conducted to improve the predictive value of the staging system. RESULTS Survival was significantly shorter for patients in the poor-risk category for each of the TIS variables. Respective median survivals for patients in the good- and poor-risk categories were 27 and 15 months for T (P < .001); 40 and 13 months for I (P < .001) when I0 included CD4 counts > or = 200/microL and 22 and 16 months for S (P = .04). Multivariate analysis indicated that severity of immunosuppression gave the most predictive information but also showed that T provided significant additional predictive information in patients whose immune function was least impaired. Refined Cox models using a CD4 count of 150/microL rather than 200/microL to distinguish I0 and I1 yielded a simplified model with better fit to the observed data. CONCLUSION The ACTG TIS classification predicts survival in patients with AIDS-associated KS; CD4 count and tumor stage provide the most predictive information. However, a lower CD4 count than the one originally proposed provides better discrimination between prognostic groups.

Interferon-α with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS).

Abstract Objective:To evaluate safety, tolerance, and potential efficacy of interferon-α and zidovudine combination therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrom...

Kaposi's sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon.

The efficacy of recombinant leukocyte A interferon (rIFN-alpha A [Roferon-A, Hoffman-La Roche, Nutley, NJ]) treatment of Kaposis sarcoma in patients with acquired immunodeficiency syndrome was evaluated in sequential trials using high doses (36 X 10(6) units) and low doses (3 X 10(6) units) of interferon. A major response was seen in 38% of patients treated at the high dose, with a median response duration of 18 months. At the low dose, the major response rate was 3%; dose escalation to 36 X 10(6) units resulted in an additional major response rate of 17% in low-dose nonresponders, with a median response duration of 10 months. Four of 11 patients who achieved a complete response remain free of disease, whereas all partial responders have shown disease progression. Unacceptable toxicity occurred in 27% of patients initially treated at the high dose and only in 10% of those who had progressive dose escalation up to 36 X 10(6) units. Prior opportunistic infections correlated negatively with therapeutic response, whereas large tumor burden and gastrointestinal involvement did not. Responding patients showed a significantly longer survival and a lower incidence of subsequent opportunistic infections than nonresponders. However, from our study we cannot determine whether rIFN-alpha A has an effect on the natural history of Kaposis sarcoma in patients with the acquired immunodeficiency syndrome.

Malabsorption and Mucosal Abnormalities of the Small Intestine in the Acquired Immunodeficiency Syndrome

Diarrhea and weight loss may accompany the acquired immunodeficiency syndrome. We studied 30 patients with the syndrome, 20 of whom had diarrhea and weight loss and 10 of whom did not. Patients with identifiable enteric infections or small intestinal Kaposis sarcoma were excluded. Malabsorption was common in the patients with diarrhea and weight loss, as shown by abnormal D-xylose and 14C-glycerol-tripalmitin absorption tests. In these patients, duodenal biopsy specimens showed a histiocytic infiltrate containing numerous acid-fast organisms in 5 and a mild-moderate chronic inflammation in 13. In asymptomatic patients, duodenal biopsy specimens were normal in 6 and showed chronic inflammation in 4. These results suggest that malabsorption is common in patients with the acquired immunodeficiency syndrome with chronic diarrhea and may contribute to their weight loss.

Matrix Metalloproteinase Inhibitor COL-3 in the Treatment of AIDS-Related Kaposi’s Sarcoma: A Phase I AIDS Malignancy Consortium Study

PURPOSE Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are overexpressed in Kaposis sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). PATIENTS AND METHODS COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF. RESULTS Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m(2)/d. Prior KS therapy was reported by 17 patients (94%). COL-3-related grade 3 or 4 adverse events were reported by six patients and included photosensitivity, rash, and headache. There was one complete response and seven partial responses, for an overall response rate of 44%, with a median response duration of 25+ weeks. The median COL-3 half-life was 39.3 hours (range, 4.1 to 251.1 hours). There was a significant difference between responders and nonresponders with respect to the change in MMP-2 serum levels from baseline to minimum value on treatment (P =.037). CONCLUSION COL-3 administered orally once daily to patients with AIDS-related KS is reasonably well tolerated. The most common adverse event was dose-related photosensitivity. Antitumor activity was noted. Further evaluation of COL-3 for the treatment of KS is warranted.

A Population-based Analysis of Temporal Trends in the Incidence of Squamous Anal Canal Cancer in Relation to the Hiv Epidemic

Squamous cell carcinoma of the anal canal (SCCA) is etiologically linked to human papillomavirus, and its incidence is increased among the immunosuppressed. We used data from the Surveillance, Epidemiology, and End Results program to analyze the incidence of SCCA in relation to 3 separate periods during the HIV epidemic: the pre-HIV era (1973-1981), the HIV era (1982-1995), and the highly active antiretroviral treatment (HAART) era (1996-2001). The incidence per 100,000 population of SCCA increased from 0.6 in the pre-HIV era to 0.8 in the HIV era and to 1.0 in the HAART era. The gap in SCCA incidence between women and men decreased from a ratio of 1.6:1 in the pre-HIV era to 1.5:1 in the HIV era and to 1.2:1 in the HAART era. There was a significant increase in incidence rates among men and women aged 30 to 54 years in the HAART era compared with the HIV era. Men were more likely to be diagnosed with early-stage disease, but they were less likely than women to receive radiation therapy. The incidence of SCCA has particularly increased among men and those between 30 and 54 years of age since the introduction of HAART.

Highly Active Antiretroviral Therapy in AIDS-Associated Kaposi's Sarcoma: Implications for the Design of Therapeutic Trials in Patients With Advanced, Symptomatic Kaposi's Sarcoma

TO THE EDITOR: The article by Dr Krown provides very appropriate and timely considerations with regard to the management of patients with advanced, symptomatic, AIDS-related Kaposi’s sarcoma (AIDS-KS) in the era of highly active antiretroviral therapy (HAART) and suggests, on the basis of a comprehensive review of the literature, that in T1 (according to the AIDS Clinical Trials Group [ACTG] staging classification) symptomatic KS patients, concomitant chemotherapy should be added to HAART without awaiting a response to HAART. Moreover, the author, referencing our study, states that “T1 and T0 groupings have been associated with distinct survival distribution.” In response, we would like to clarify our data as reported by Dr Krown. We believe that our data may help to better define which group of patients within the T1 category need a timely institution of chemotherapy concomitantly to HAART, and for which group it is too risky to await a possible response to HAART. In our study, we collected clinical and survival data from 211 patients with AIDS-KS enrolled in two prospective cohort studies beginning in 1996, the time when HAART became available in Italy, with the aim of validating the ACTG staging system for AIDS-KS in the HAART era. All patients received HAART. Our analysis identified two different risk categories: a good-risk group (T0S0, T1S0, and T0S1) and a poor-risk group (T1S1). The 3-year survival rate of patients with T1S1 was 53%, significantly lower than the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P .0001). Therefore, the T category alone does not provide an appropriate survival discrimination, as occurred in the pre-HAART period. When we considered only patients with pulmonary involvement (namely,Tp1) as compared with T1 patients without pulmonary disease (namely,Tp0), the 3-year survival rate was 46% for Tp1 and 77% for Tp0 patients (P .0002), indicating that patients with pulmonary involvement identify the group of patients with the poorest prognosis, independent of the other ACTG variables. Therefore, we believe that we were able to identify, within the T1 category, a specific subgroup of KS patients (ie, T1S1, Tp1) with an unfavorable survival rate in whom HAART and concomitant chemotherapy should be used.