N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial.

BACKGROUND: Because of the single-agent activity of irinotecan hydrochloride, combination of irinotecan and docetaxel treatment against metastatic breast cancer (MBC) should be evaluated. PATIENTS AND METHODS: Single-stage phase 2 study of irinotecan and docetaxel to evaluate tumor response, toxicity, time to progression, and overall survival was carried out. Regimen of docetaxel (25 mg/m(2)) and irinotecan (70 mg/m(2)) was administered on days 1 and 8 of each 3-week cycle. Patients had histologically confirmed breast adenocarcinoma and metastatic cancer measurable with RECIST. RESULTS: Of 70 patients enrolled, 64 were assessable. Prior treatment with an anthracycline and a taxane was required. Eighteen (28%) patients [95% confidence interval (CI) 15% to 31%] had tumor response, plus four patients had stable disease (less than 30% decrease in sum of longest diameter and less than 20% increase) for >6 months. The clinical benefit rate was 34% overall. Median duration of tumor response was 6.7 months (95% CI 4.2-37.7 months); median follow-up was 18.6 months (range 8.5-37.7 months). The most common severe adverse events included fatigue [n = 16 (25%)] and neutropenia [n = 13 (20%)]. CONCLUSIONS: Weekly dosing of combination of irinotecan and docetaxel is active against MBC. However, the response rate to our regimen was not significantly better than single-agent docetaxel. Other schedules of irinotecan plus docetaxel should be considered for future studies.

Changes in the cell surface protein composition of human alveolar macrophages induced by smoking.

The cell surface proteins of human alveolar macrophages obtained from nonsmokers have been compared to those of alveolar macrophages obtained from smokers. Proteins of nonsmokers' alveolar macrophages surface labeled with 125I differed from those of smokers' alveolar macrophages, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Three major radiolabeled proteins with molecular weights of 183,000, 80,000, and 30,000 were identified in fresh smokers' cells. The major radiolabeled protein of nonsmokers' macrophages had an apparent molecular weight of approximately 183,000. Affinity chromatography suggested the Mr 183,000 protein is a mannose receptor. In contrast, the molecular weight of the major radiolabeled protein of smokers' alveolar macrophages was approximately 30,000; the Mr 183,000 protein was less prominent. When nonsmokers' alveolar macrophages were cultured in vitro before 125I labeling, the cell surface protein pattern changed to resemble that of smokers' alveolar macrophages; the Mr 183,000 protein could no longer be detected on the cell surface, whereas a Mr 80,000 protein was increased in quantity and a new Mr 30,000 protein was detected. Nonadherent macrophages showed similar changes in their surface-labeled proteins but also contained a new prominently labeled Mr 70,000 protein. Limited proteolysis peptide mapping with five different enzymes did not reveal any evidence of homology among the Mr 183,000, 80,000, 70,000, and 30,000 proteins. The differences in cell surface protein composition between alveolar macrophages of smokers and nonsmokers may reflect their functional capabilities or their state of "activation" and may be mechanistically important in the development of various pulmonary diseases seen in smokers including cancer. These results also demonstrate that major changes in the surface proteins of the human alveolar macrophage plasma membrane can occur rapidly following manipulation.

Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy.

PURPOSE: To determine how men infected with the human immunodeficiency virus (HIV) tolerate and respond to treatment for malignant germ cell tumors (GCTs), and how GCT histology and stage compare among HIV-infected versus non-HIV-infected men. PATIENTS AND METHODS: Two hundred ninety-four cases of GCT diagnosed or treated from 1980 to 1993 were reviewed. Nine new cases among HIV-infected men were identified; these were analyzed together with six cases previously reported from our institution. RESULTS: Low-stage tumors (stages I and IIA) comprised 67% of HIV-infected and 63% of non-HIV-infected cases. Sixty-seven percent of HIV-infected cases were seminomas versus 51% of non-HIV-infected cases. Ten patients had AIDS at the time of GCT diagnosis. Five patients underwent radiation therapy and one patient underwent retroperitoneal lymphadenectomy without complications. Seven patients received chemotherapy with four cycles of cisplatin, etoposide, and bleomycin (PEB) or cisplatin, vinblastine, and bleomycin (PVB) without excess cytopenias or new opportunistic infections. Of seven patients treated for advanced disease, there were five complete and two partial responses. Six patients have died of AIDS at a median of 20 months after diagnosis of GCT. The median follow-up time for surviving patients has been 42 months (range, 8 to 87) and all but one remain without evidence of active disease. In no case was a patient's HIV disease classification altered by antitumor therapy. CONCLUSION: The natural history of GCTs is comparable in HIV-infected and non-HIV-infected men and standard therapy including orchiectomy, retroperitoneal lymph node dissection, radiation therapy, and chemotherapy is well tolerated.

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.

PURPOSE: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS). PATIENTS AND METHODS: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes. RESULTS: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin. CONCLUSION: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

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.

Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial.

PURPOSE: Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma. PATIENTS AND METHODS: Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity. RESULTS: The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections. CONCLUSION: Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.

Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma.

OBJECTIVE: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency disease (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. METHODS: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proven cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first two doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. RESULTS: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (Cmax,avg) and dose intensity. CONCLUSIONS: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both Cmax,avg and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.

Extrapulmonary pneumocystosis: clinical features in human immunodeficiency virus infection.

Pneumocystis carinii infection is reported with increasing frequency as a cause of disease outside of the respiratory tract in patients with human immunodeficiency virus (HIV) infection. Extrapulmonary pneumocystosis is not limited to patients in any discrete risk group for HIV infection. Patients with HIV infection who develop extrapulmonary pneumocystosis frequently do not have concurrent P. carinii pneumonia. Signs and symptoms of extrapulmonary pneumocystosis are nonspecific but when present are frequently referable to the tissues or organs involved. Extrapulmonary pneumocystosis can be diagnosed by examination of tissue biopsies from affected sites using standard histologic techniques. Therapy with antimicrobial agents used to treat P. carinii pneumonia has been effective in some patients. An association between use of aerosolized pentamidine for prevention of P. carinii pneumonia and development of extrapulmonary pneumocystosis has been suggested but remains unconfirmed. Other factors such as the use of zidovudine and duration of immunodeficiency may also be important to the pathogenesis of extrapulmonary pneumocystosis. Further studies are needed to better identify risk factors that may predispose patients to the development of extrapulmonary pneumocystosis.

The usefulness of diagnostic bone marrow examination in patients with human immunodeficiency virus (HIV) infection.

To determine the utility of bone marrow examination for the diagnosis of opportunistic infections and lymphoma in patients with known or suspected human immunodeficiency virus (HIV) infection, we retrospectively reviewed the medical and laboratory records of all patients undergoing diagnostic bone marrow examinations at San Francisco General Hospital between January 1, 1988 and December 31, 1989. All marrow examinations of patients with known or suspected HIV infection in which specimens were examined histopathologically and/or microbiologically for opportunistic pathogens or lymphoma were analyzed. Bone marrow examination resulted in the diagnosis of mycobacterial infection in 16% of the patients studied. Blood culture was 77% sensitive and bone marrow culture was 86% sensitive for detecting disseminated mycobacterial infection. This difference was not statistically significant (p greater than 0.05). Disseminated fungal infections occurred in less than 5% of the patients studied, and most were rapidly and accurately detected by examination of stained bone marrow samples. No case of lymphoma was diagnosed by bone marrow examination. Bone marrow examination may be useful for diagnosing opportunistic infections in patients with HIV infection. Mycobacterial blood cultures have a sensitivity comparable to bone marrow cultures in detecting disseminated mycobacterial infections, are less invasive, and may be less costly. Marrow examination is not useful for diagnosing lymphoma but can determine the extent of lymphoma that has been diagnosed by other means.

Treatment of Kaposi's sarcoma. Current guidelines and future perspectives.

Kaposi's sarcoma is the most common malignancy associated with HIV infection, and the morbidity and mortality attributable to AIDS-related Kaposi's sarcoma (AIDS-KS) may be increasing. No curative therapy is available for AIDS-KS, but palliative therapy can eliminate or reduce cosmetically unacceptable lesions, reduce painful or unsightly oedema or lymphadenopathy, shrink symptomatic oral lesions and relieve symptoms caused by visceral involvement. Strategies currently employed to treat the various clinical problems encountered in AIDS-KS include single- and multi-agent cytotoxic chemotherapy, treatment with interferon-alpha, radiotherapy, and other local therapies. Current clinical research is focusing on use of liposome-encapsulated cytotoxic agents and treatment with substances that inhibit angiogenesis. Any treatment plan for AIDS-KS must be flexible and must be based on the patient's overall clinical and immunological status as well as therapeutic goals. Limited local disease is usually amenable to treatment with local measures. Extensive, symptomatic AIDS-KS warrants systemic treatment. The response of mucocutaneous lesions to low dose systemic cytotoxic chemotherapy is typically excellent. Treatment with interferon-alpha may also be beneficial in this setting. Multi-agent chemotherapeutic regimens are usually reserved for treatment of patients most severely affected by AIDS-KS. It is hoped that liposome-encapsulated cytotoxic chemotherapy and antiangiogenic therapies will prove more effective and less toxic than the treatment strategies currently in use.

Cytomegalovirus pneumonitis. An unusual cause of pulmonary nodules in a patient with AIDS.

A patient with AIDS and a history of non-Hodgkin's lymphoma developed a generalized illness associated with the appearance of multiple pulmonary nodules on a chest radiograph. Cytomegalovirus infection was demonstrated by needle aspiration cytology. The patient's symptoms and radiographic abnormalities resolved completely on ganciclovir therapy. This unusual case (1) broadens the differential diagnosis of nodular pulmonary disease in patients with AIDS and (2) suggests that cytomegalovirus can cause clinically significant lung disease which may respond to standard antiviral therapy in patients with AIDS.

Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma.

A study of the plasma pharmacokinetics, tumor localization, and safety of a single dose of doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol (PEG-liposomal doxorubicin) was conducted in patients with Kaposi's sarcoma (KS) as a manifestation of acquired immune deficiency syndrome (AIDS). Eighteen patients with AIDS-KS diagnosed by examination of biopsy specimens were randomly assigned to receive either standard doxorubicin or PEG-liposomal doxorubicin. Consecutive participants were entered at three dose levels (10, 20, and 40 mg/m2) in ascending fashion. Clearance of PEG-liposomal doxorubicin was 0.034 L/h/m2 to 0.108 L/h/m2, volume of distribution (Vd) was 2.2 L/m2 to 4.4 L/m2, and half-lives (t1/2) of the initial decline in the plasma concentration-time curve and of the terminal decline were 3.77 hours and 41.3 hours, respectively. Seventy-two hours after administration, doxorubicin levels observed in lesions of patients receiving PEG-liposomal doxorubicin were 5.2 to 11.4 times greater than those found in patients given comparable doses of standard doxorubicin. PEG-liposomal doxorubicin and standard doxorubicin were roughly equipotent in producing toxicity. Encapsulation in liposomes containing surface-bound PEG significantly limits the distribution and elimination of doxorubicin, results in greater accumulation of the drug in KS lesions 72 hours after dosing than does standard doxorubicin, and may improve drug efficacy and therapeutic index in the treatment of AIDS-KS.

Treatment of AIDS-related Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common malignancy seen in association with AIDS. Important epidemiologic trends in the occurrence of AIDS-associated Kaposi's sarcoma (AIDS-KS) have been identified, and the molecular processes associated with the development of KS are being studied intensively. It is hoped that these studies will ultimately lead to an understanding of the etiology of the disease and to a rational approach to therapy. Treatment with conventional chemotherapy, radiation therapy, biologic therapy, and various local treatment modalities is effective for palliation of clinical problems associated with AIDS-KS, although the toxicities of these approaches may be problematic. Therapy for AIDS-KS must be individualized, with appropriate consideration given to the patient's overall clinical and immunologic status.

Anal neoplasia. Pathogenesis, diagnosis, and management.

Prolonged, severe immunodeficiency provides the necessary milieu for the emergence of anogenital neoplasia caused by human papillomaviruses. Anal neoplasia is likely to become a more common manifestation of HIV disease as patients with profound immunodeficiency, who would have succumbed to opportunistic infections earlier in the epidemic, are now surviving for extended periods of time because of increasingly effective antiretroviral, prophylactic, and antimicrobial therapies. The screening and treatment strategies described for use in HIV-infected patients with anal neoplasia are currently being investigated and refined.

Cervical and anal neoplasia and HPV infection in persons with HIV infection.

Prolonged, severe immunodeficiency provides the necessary milieu for the emergence of anogenital neoplasia caused by human papillomaviruses. Cervical and anal neoplasia are likely to become more common manifestations of HIV disease as patients with profound immunodeficiency, who would have succumbed to opportunistic infections earlier in the epidemic, are now surviving for extended periods of time because of increasingly effective antiretroviral, prophylactic, and antimicrobial therapies. Cervical cancer in the setting of HIV infection appears to be a more aggressive disease, less likely to be successfully treated by standard therapies, and consequently associated with a poorer prognosis than in comparable non-HIV-infected women. Anecdotal observations suggest that anal cancer in HIV-infected persons may share these features. Strategies need to be developed for earlier detection and treatment of neoplasia and anogenital cancer in the setting of HIV-induced immunodeficiency.

Cancers not associated with immunodeficiency in HIV infected persons.

Kaposi's sarcoma, non-Hodgkin's lymphoma, and cervical carcinoma are the malignancies most clearly associated with HIV infection. Other malignancies with no established association with immunodeficiency, in particular, lung cancer and germ-cell malignancies, also occur in persons with HIV infection, and there is clear overlap in the demographic characteristics of patients with these tumors and HIV-infected individuals. Compared with lung cancer in the general population, lung cancer in HIV-infected patients presents at a younger age, with more advanced disease, and more commonly with adenocarcinoma. No correlations between degree of immunodeficiency and stage of lung cancer at presentation or duration of survival have been established. Patients with and without HIV infection who develop germ-cell malignancies are similar in presentation and tumor histology. Treatment for germ-cell malignancies is well-tolerated and appropriate for HIV-infected patients.

Evaluation and treatment of later manifestations of HIV infection.

An increasing number of primary care physicians will be called on to care for patients with AIDS as the epidemic of HIV infection progresses in the United States. In this article, the more common conditions responsible for significant morbidity and mortality in patients with AIDS have been discussed. It should be apparent that many of these conditions are treatable, either palliatively or with curative intent. Primary care physicians who are familiar with the diagnostic evaluation and therapy of these diseases will therefore be well equipped to provide vital medical care to severely immunocompromised patients with HIV infection.

Anal neoplasia in persons with HIV infection.

AIDS: Aside from the neoplasms that are clearly related to immunodeficiency, such as non-Hodgkin's lymphoma and Kaposi's sarcoma, numerous observations have also shown an association between HIV infection and the incidence of cervical and anal neoplasms. Human papillomavirus (HPV) is the etiologic factor in anogenital neoplasms, although the mechanisms of the association are not clearly understood. It is believed that several HPV genes are critical in the malignant cell transformation process. An etiologic similarity exists between cervical and anal neoplasms, and the risk factors for the former appear to be the same for the latter, such as history of anal or genital warts, history of sexually transmitted diseases (STDs), and certain sexual practices. In addition, a number of studies have shown a relation between HIV-induced immunodeficiency, HPV infection, and the development of anal neoplasms. In a study of 210 men, anal intraepithelial neoplasia was more common in HIV-infected patients than non-HIV-infected patients. Additional risk factors for abnormal cytology included CD4 count under 200, and a history of smoking. Patients who receive surgical treatment for anal carcinoma have been shown to have poor outcome and short survival. Standard treatments, including ablation, surgery plus radiotherapy for small localized lesions, and radiotherapy plus chemotherapy, are preferable for anal neoplasia. Due to the increasing incidence of HPV infection as a manifestation of HIV disease, strategies for screening and treating these patients must be refined.^ieng