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Purpose: To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma., Patients and Methods: Twenty-seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrone (16, 20, 24, 28, or 32 mg/m2) plus cyclophosphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3,600 mg/m2. All patients also received filgrastim 5 micrograms/kg administered subcutaneously beginning on day 2 and continuing until the post-nadir absolute neutrophil count (ANC) was > or = 10,000/microL. Treatment was repeated every 3 weeks if the ANC was > or = 2,000/microL and platelet count > or = 90,000/microL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose-limiting toxicity during the first cycle., Results: The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematologic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11%) had a > or = 10% decrease in the left ventricular ejection fraction (LVEF), one patient (4%) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had not received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45%), and the median response duration was 5 months., Conclusion: In combination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.

Acute rhabdomyolysis has rarely been reported after cytotoxic chemotherapy, including cytarabine and 5-azacytidine. We observed a case of acute rhabdomyolysis and renal failure after treatment with mitoxantrone and cyclophosphamide. No other cause of muscle injury could be identified, although biochemical analysis of a muscle biopsy specimen revealed a deficiency of muscle phosphorylase activity. Retreatment with doxorubicin and paclitaxel was not associated with recurrent rhabdomyolysis.

Infection with HIV is associated with an increased risk of systemic and primary central nervous system non-Hodgkin's lymphoma. Patients with systemic non-Hodgkin's lymphoma usually present with high- or intermediate-grade histology and extranodal dissemination. Although the prognosis for such patients is poor, some patients clearly benefit from combination chemotherapy, and several new treatment approaches appear promising. Primary central nervous system lymphoma usually occurs in patients with more profound immunosuppression and is associated with a dismal prognosis. Selected patients with good performance status may benefit from therapy, particularly if opportunistic infections have been few and nondebilitating. Finally, Hodgkin's disease has been reported in patients with HIV infection, particularly in patients with a history of intravenous drug use, and it is more likely to present with advanced-stage disease and unfavorable histology.

Based on their single-agent activity in metastatic breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and doxorubicin have been alternated and combined in Eastern Cooperative Oncology Group studies to identify a tolerable dose and schedule. A pilot trial in patients who had received no more than one prior chemotherapy regimen alternated paclitaxel 200 mg/m2 and doxorubicin 75 mg/m2 every 3 weeks. Seven of 12 patients had objective (complete plus partial) responses. A second (phase I) trial combined doxorubicin as an intravenous push and paclitaxel as a 24-hour continuous infusion. To evaluate the effect of the schedule on toxicity, the drug administration sequence (doxorubicin-->paclitaxel or paclitaxel-->doxorubicin) was alternated both between and within patients. initial doses were paclitaxel 150 mg/m2 and doxorubicin 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively. Dose-limiting mucositis was seen at the second dose level when paclitaxel preceded doxorubicin, suggesting an important role for the administration sequence in determining toxicity (and possibly efficacy) in this regimen. These results support the sequence of doxorubicin 50 mg/m2 followed by paclitaxel 150 mg/m2 as the maximum tolerated dose. This combination has been incorporated as a treatment arm in an ongoing randomized prospective phase III Intergroup trial. By comparing the combination with both drugs as single agents (with crossover to the opposite agent at disease progression), investigators will attempt to assess response, toxicity, and time to progression as well as the degree of cross-resistance between the two agents. Given the poor prognosis of patients with advanced breast cancer, the three arms also will be evaluated in terms of patients' quality of life.

We performed a pilot trial of high-dose mitoxantrone 15 mg/m2 by i.v. infusion daily on days -6 to -4 and busulfan 1 mg/kg orally every 6 h (16 doses) on days -7 to -4 plus autologous bone marrow transplantation (BMT) in 10 patients with advanced cancer to determine the safety and feasibility of the combination. The median age of the study group was 42 years, all were women and all had progressed after prior chemotherapy (including doxorubicin in seven cases). Disease types included adenocarcinoma of the breast (n = 6) or ovary (n = 3), and non-Hodgkin's lymphoma (n = 1). The median time to an absolute neutrophil count > or = 0.5 x 10(9)/L and platelets > or = 50 x 10(9)/L were 16.5 and 28 days, respectively. There was a high degree of severe regimen-related toxicity, including severe mucositis (n = 7) and veno-occlusive disease (VOD) of the liver (n = 3). Three patients developed multisystem failure and died within 90 days of autologous BMT from complications related to VOD of the liver (n = 2) or septic shock (n = 1). We conclude that the dose and schedule of busulfan and mitoxantrone used in this study was associated with a high degree of unacceptable regimen-related toxicity.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to enter routine clinical practice, has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer. Given this activity, it seemed logical to attempt to combine paclitaxel with doxorubicin, the other most active single agent in metastatic breast cancer. The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination. In the first trial, paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2, respectively, for patients who had received no more than one prior chemotherapeutic regimen. Therapy was well tolerated in this setting. At these doses, paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin. Objective responses (complete and partial responses) were seen in seven of 12 patients; two other patients had improved disease (relief of pain in bony metastases). A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination. In this phase I trial, doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion. The sequence of drug administration (D-->P or P-->D) was alternated both between and within patients, so that we might evaluate the effect of administration schedule on toxicity. Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively, of paclitaxel and doxorubicin. In addition, patients received granulocyte colony-stimulating factor 5 micrograms/kg/d. While therapy at the initial dose level was well tolerated, dose-limiting mucositis was seen at the second dose level, although only when paclitaxel preceded doxorubicin. This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and (perhaps) efficacy, a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer. Based on this study, we identified the sequence of doxorubicin (50 mg/m2) followed by paclitaxel (150 mg/m2) to be the maximum tolerated dose. This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group.

Treatment with interleukin-2 (IL-2) used alone or in combination with lymphokine-activated killer (LAK) cells is known to be an active therapy for patients with advanced renal cell carcinoma and melanoma. To further explore the activity of IL-2/LAK cell therapy in patients with advanced cancer of various primary sites, the Extramural IL-2/LAK Working Group (ILWG) initiated two phase II trials of high-dose IL-2/LAK therapy: one in patients with advanced breast carcinoma, and one in patients with advanced cancer arising in other sites. Patients with advanced renal cell carcinoma, melanoma, colorectal carcinoma, and lymphoma (Hodgkin's and B-cell non-Hodgkin's) were not eligible for the latter trial, but were treated on other ILWG trials that have been reported previously. Sixty-nine patients received high-dose IL-2 (600,000 IU/kg administered by a 15-min intravenous infusion every 8 h) on days 1-5 and days 11-15. Leukapheresis was performed for collection and ex vivo expansion of LAK cells on days 7-10, and the LAK cells were reinfused on days 11, 12, and 14. The studies were designed to determine whether treatment with IL-2/LAK resulted in at least a 40% response rate, a level of activity that was believed to be sufficient to justify the toxicity and cost of IL-2/LAK therapy. An adequate number of patients with carcinoma of the breast (N = 12), pancreas (N = 8), ovary (N = 7), and lung (non-small cell; N = 6) were accrued to assess response; most of these patients had prior chemotherapy that had failed.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To evaluate the activity and toxicity of combined high-dose cisplatin, dacarbazine (DTIC), and tamoxifen chemotherapy and high-dose bolus interleukin-2 (IL-2) in patients with metastatic melanoma., Patients and Methods: Patients with metastatic melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal organ function were enrolled onto this multiinstitutional Cytokine Working Group trial. Patients received intensive chemoimmunotherapy consisting of cisplatin (50 mg/m2) and DTIC (350 mg/m2) intravenously (IV) on days 1 to 3 and 43 to 45, IL-2 600,000 IU/kg IV every 8 hours on days 12 to 16 and 26 to 30 (maximum, 28 doses), and tamoxifen 20 mg orally each day. Patients were evaluated for response at day 63 of each cycle, and responding patients were given a second cycle of therapy beginning on day 71 to 85., Results: Thirty-eight patients were entered onto this study. Toxicities were as expected for the chemotherapy and immunotherapy components of this regimen. Overlapping toxicity consisted primarily of thrombocytopenia (76% of patients required platelet transfusions), neutropenia, anemia, fatigue, and weight loss. Despite these cytopenias, bleeding and infectious complications were rare. There were no treatment-related deaths. Three patients achieved a complete response (CR; 8%), and 13 achieved a partial response (PR). The overall objective response rate was 42% (95% confidence interval [CI], 26% to 58%). Six additional patients had greater than 50% tumor reduction at day 63, which did not persist until a subsequent evaluation. The median duration of response was 5 months (range, 2 to 20+), and the median survival duration was 11 months., Conclusion: This intensive treatment regimen appears to possess activity in metastatic melanoma comparable, but not superior, to that of other less intensive cisplatin- and IL-2-based chemoimmunotherapy regimens. Although the toxicity and complexity of this regimen make it unsuitable for phase III testing and impractical for more widespread use, the results of this study support a potential favorable interaction between IL-2 and chemotherapy in this disease and highlight the need for appropriately designed phase III trials.

Based on our prior data suggesting a therapeutic advantage for infusional administration of cyclophosphamide (C), doxorubicin (D), and etoposide (E) in patients with relapsed and resistant non-Hodgkin's lymphoma (NHL), we administered C (750 mg/m2), D (50 mg/m2), and E (240 mg/m2) via continuous intravenous infusion over 96 hours as first line therapy for 21 patients with intermediate- or high-grade non-Hodgkin's lymphoma associated with human immunodeficiency virus (HIV) infection. Treatment was repeated every 28 or more days. The median CD4 count of the study group was 87/ul, and the median serum lactate dehydrogenase was 383 IU/L. Extranodal disease, lymphomatous marrow involvement, and lymphomatous meningitis were present at diagnosis in 90%, 33%, and 10% of patients, respectively. Complete response (CR) occurred in 13 patients (62%, 95% confidence intervals 41%, 81%) and partial response occurred in five patients (24%). The estimated median survival of the study group was 18.0 months. Hematologic toxicity required dose reduction for 47% of cycles and for 79% of patients who received at least two cycles. The mean dose intensity for C, D, and E were 73%, 70%, and 73% of the intended dose intensity, respectively. Opportunistic infection included oral/esophageal candidiasis (N = 7), herpes labialis (N = 3), pulmonary Mycobacterium avium-intracellulare (N = 1), candidemia (N = 1), pneumonitis (N = 1), and disseminated aspergillosis than resulted in a single treatment-related death (5%). Treatment resulted in a significant decrease in the CD4+ lymphocytes, as well as total lymphocytes, T lymphocytes, and CD8+ lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Echinomycin is a novel bifunctional intercalating agent derived from Streptomyces echinatus. A phase II clinical trial of echinomycin in patients with advanced, measurable colorectal cancer was initiated to determine the efficacy and toxicities of this agent. Echinomycin, 1.5 mg/m2, was given initially as a 30- to 60-min infusion every 4 weeks. After 4 episodes of anaphylaxis had occurred among the first 14 patients, the schedule was changed to a 24-h infusion, and an additional 16 patients were treated on this schedule. Treatment was given every 3 weeks. A total of 30 patients were eligible and evaluable; there were 3 (10%; 90% confidence interval, 3%-23%) clinical responses lasting 3, 3+, and 12 months, respectively. The most serious toxicity encountered was anaphylaxis, which occurred in 5 patients, although with no serious sequelae. A premedication regimen with dexamethasone, diphenhydramine, and cimetidine and a change of the duration of the infusion to 24 h reduced the incidence of this complication. Grade 2-3 vomiting occurred among earlier patients treated; however, with the 24-h schedule this toxicity was substantially reduced. The sole important case of hematologic toxicity was a single patient with grade 3 thrombocytopenia. Echinomycin employed in this dose and schedule had modest activity against colorectal cancer, comparable with that observed with 5-fluorouracil. Further studies in patients with gastrointestinal malignancies using a 24-h infusion with a dexamethasone premedication regimen similar to that employed prior to administration of taxol may be warranted.

Women diagnosed with primary breast or lung cancer and recorded between 1972 and 1989 in our tumor registry were identified. Of 4,123 lung cancer patients and 3,537 breast cancer patients, 42 patients with both diagnoses were identified. The two malignancies were diagnosed simultaneously in five patients, lung cancer was diagnosed first in six patients and breast cancer was diagnosed first in 31 (p < 0.001). Nineteen of those 31 patients received adjuvant radiotherapy for breast cancer and developed lung cancer a median of 17 years later. Of the 19 irradiated patients who subsequently developed lung cancer, 15 did so in the ipsilateral lung and only four had lung cancer contralateral to the previously irradiated site (p < 0.001). Adjuvant radiotherapy for breast cancer as delivered decades ago may be an etiologic factor for lung cancer.

Purpose: To compare the response rate, survival, and toxicity of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus interferon alfa-2a (IFN-alpha) with high-dose IL-2 alone in patients with advanced melanoma in a randomized phase III trial design., Patients and Methods: Eighty-five patients with advanced melanoma were randomly assigned to receive IL-2 6 X 10(6) U/m2 per dose every 8 hours as tolerated for a maximum of 14 doses on days 1 through 5 and 15 through 19, or IL-2 4.5 X 10(6) U/m2 per dose, plus IFN-alpha 3 X 10(6) U/m2 using an identical schedule. A planned interim analysis was performed after 85 patients were entered, which forms the basis for this report., Results: Partial response (PR) occurred in two of 44 patients (5%; 95% confidence interval, 1% to 15%) receiving IL-2 alone, compared with four of 41 patients (10%; 95% confidence interval, 3% to 23%) receiving IL-2/IFN-alpha (P = .30). There were no complete responses (CRs). The median duration of response was 11.5 months (range, 2.0 to 15.7+). There was no significant difference in the median survival duration for patients receiving IL-2 alone (10.2 months) compared with patients receiving IL-2/IFN-alpha (9.7 months). The median and mean number of doses of IL-2 were equivalent in both groups, as was toxicity. There were three treatment-related deaths, two in the IL-2-alone arm and one in the IL-2/IFN-alpha arm. The trial was terminated after the first interim analysis based on predefined early-stopping rules, which included termination if the response rate in the IL-2/IFN-alpha arm was less than 25%., Conclusion: Using the preparation, dose, and schedule of IL-2 in our trial, IFN-alpha failed to enhance significantly the response rate to high-dose IL-2 in the treatment of patients with advanced melanoma.

Purpose: To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-alpha) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-alpha on 5-FU pharmacokinetics., Patients and Methods: Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-alpha, 5 x 10(6) IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-alpha administration using the paired t test., Results: The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-alpha 2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-alpha was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-alpha on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-alpha administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1)., Conclusion: IFN-alpha substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-alpha-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-alpha to enhance the toxic effects of 5-FU.

alpha-Interferon (IFN-alpha) enhances the activity of 5-fluorouracil in patients with advanced colorectal carcinoma. Preclinical evidence suggests a similar potential role for IFN-alpha combined with cyclophosphamide, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) in advanced adenocarcinoma of the breast. To determine a maximum tolerated dose of IFN-alpha that could be combined with CAF and that did not compromise CAF dose intensity and to determine the effect of IFN-alpha on the pharmacokinetics of doxorubicin, a phase I study of IFN-alpha plus CAF was performed by the Eastern Cooperative Oncology Group. Nine patients with advanced breast cancer received CAF (cyclophosphamide at 100 mg/m2/day p.o. on days 1-14, doxorubicin at 30 mg/m2 and 5-fluorouracil at 500 mg/m2 i.v. bolus on days 1 and 8) plus IFN-alpha (1 milliunit/m2, n = 6, or 2 milliunits/m2, n = 3) given s.c. on days 1, 3, 5, and 8 (1 h prior to the doxorubicin and 5-FU injection on days 1 and 8) of each cycle every 28 or more days. Escalation of the IFN-alpha dose occurred in cohorts of 3-6 patients if a dose-limiting toxic event (neutropenic fever, platelet nadir of < 25,000/microliters, > 2-week treatment delay, or a > 50% dose reduction in day 8 CAF) occurred during the first two cycles in 0 of 3 or 1 of 6 patients. During cycle 1, IFN-alpha was omitted on day 1, and multiple plasma samples were drawn on day 1 (without IFN-alpha) and day 8 (with IFN-alpha) after each doxorubicin injection and were analyzed for plasma doxorubicin concentration. The maximum tolerated dose of IFN-alpha by our criteria was 1 milliunit/m2, and neutropenia was the predominant toxic effect that precluded IFN-alpha dose escalation. The dose intensity of CAF achieved with IFN-alpha was identical to that for CAF alone observed in prior studies. IFN-alpha had no significant effect on the pharmacokinetics of doxorubicin, although 3 of 7 patients studied had reduced doxorubicin clearance, ranging from 32% to 69%. Alternative CAF drug delivery schedules (all drugs given i.v. every 3-4 weeks) that are more amendable to hematopoietic growth factor support may be more suitable to combine with higher doses of IFN-alpha that may produce modulation.

Purpose: This study attempted to determine the efficacy of cyclophosphamide (C), doxorubicin (D), and etoposide (E) administered as a continuous intravenous (IV) infusion (infusional CDE) over 4 days in patients with relapsed or resistant non-Hodgkin's lymphoma (rNHL) and in patients with previously untreated (uNHL) who had poor prognostic features., Patients and Methods: Fifty-eight patients with rNHL and 10 patients with uNHL received infusional CDE every 28 or more days; all but one had intermediate- to high-grade histology. The cumulative doses of C, D, and E administered per treatment cycle were 750 mg/m2, 50 mg/m2, and 240 mg/m2, respectively. In the rNHL group, all patients had previously received C, most (81%) had received D, and a minority (16%) had received E., Results: Objective response occurred in 30 patients with rNHL (52%; 95% confidence interval, 39% to 65%); 10 patients had a complete response (CR) (17%; 95% confidence interval, 7% to 27%). Eleven patients (19%) remain progression-free (median follow-up, 22 months; range, 10+ to 38+), and six patients (10%) are disease-free (median follow-up, 25 months; range, 10+ to 38+). Among 10 patients with uNHL, eight (80%) had a CR, and none have relapsed (median follow-up, 11 months; range, 9+ to 24+). Toxicity was primarily hematologic. Two treatment-related deaths (3%) occurred, both attributable to infection in the relapsed or resistant group., Conclusion: Infusional CDE produced a CR in substantial proportion of patients who had previously been exposed to at least two of the agents administered as an IV bolus, suggesting a schedule-dependent effect in favor of the infusional administration of certain cytotoxic agents in patients with lymphoid neoplasms. In addition, infusional CDE was effective and tolerable in patients with poor-prognosis NHL when used as initial therapy, and merits further study in that setting.

Fourteen patients with poor-prognosis intermediate- to high-grade non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection (12 patients) or human T-cell leukemia virus type I (HTLV-I) infection (two patients) received cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and etoposide 240 mg/m2 administered as a continuous intravenous (IV) infusion over 4 days (infusional CDE); treatment was repeated every 28 or more days for up to six cycles. All HIV-positive patients had at least one poor prognostic feature, which included either extranodal disease (10 patients), Karnofsky performance status less than 70% (six patients), a CD4 count less than 100/microL (six patients), or a prior history of acquired immunodeficiency syndrome (AIDS; one patient). Both HTLV-I-positive patients had an elevated serum lactate dehydrogenase (LDH) level, a poor prognostic feature in that setting. Complete response (CR) occurred in 10 patients (71%; 95% confidence interval, 48% to 95%) and partial response (PR) occurred in three patients (21%), yielding an overall objective response rate of approximately 93%. The estimated Kaplan-Meier median survival was 17.4 months; seven of 12 HIV-positive patients are alive and disease-free with a median follow-up of 15 months (range, 7 to 24 months). Hospitalization was required after 19% of treatment cycles due to fever associated with granulocytopenia. Documented or suspected opportunistic infection occurred in five patients (36%), bacteremia occurred in three patients (21%), and candidemia occurred in one patient (7%). There was one treatment-related death attributable to disseminated aspergillosis. This pilot study suggests that infusional CDE may be a highly active regimen capable of producing durable remissions in a high proportion of patients with HIV-related NHL. Further study is required to confirm this observation.

The interferons enhance the cytotoxicity of antimetabolites, alkylating agents, and plant antibiotics against cultured human tumours in vitro and in vivo. Five clinical trials in humans with advanced colorectal carcinoma have demonstrated responses ranging from 26 to 63% in patients treated with 5-fluorouracil (5-FU) plus interferon-alpha (IFN-alpha), suggesting improved response with the combination as compared with 5-FU alone. In addition, responses have been observed in patients with adenocarcinomas of the lung, pancreas, breast, and kidney, squamous cell carcinoma of the oesophagus, and urothelial carcinoma treated with 5-FU/IFN-alpha. However, enhanced 5-FU-related toxicity was observed in these studies, as has been observed when 5-FU is combined with other modulating agents, such as leucovorin. While some studies suggested that enhanced 5-FU-related toxicity was associated with an IFN-alpha-induced reduction in 5-FU clearance when 5-FU was given as an intravenous (i.v.) bolus (750 mg/m2 IV weekly) or as a high-dose five-day continuous infusion (CI) (750 mg/m2/day x 5 days), another study found enhanced 5-FU toxicity in the absence of pharmacokinetic perturbation when 5-FU was given as a low-dose prolonged CI (300 mg/m2/day x 28 or more days).(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral fungal infection is becoming an increasingly recognized entity in immunocompromised patients on post-mortem examination. In order to determine the frequency of clinically significant cerebral fungal infection and define its clinical characteristics in a cohort of immunocompromised patients at high risk of fungal infection, the records of 118 patients with acute leukemia were examined for 57 clinical and laboratory features. The characteristics of 26 patients with systemic aspergillosis and acute leukemia were compared to 92 patients with acute leukemia in a control group. Eight of 118 patients (7%) had cerebral infection (seven Aspergillus, on Candida). Patients with systemic aspergillosis were more likely than patients in the control group to have focal neurologic findings (p = 0.02), confusion (p = 0.04), and abnormal computerized tomography (CT) of the brain characterized by single or multiple, enhancing or non-enhancing hypodense lesions (p = 0.02). Patients with systemic aspergillosis were more likely to die in complete remission than patients in the control group (p = 0.003); three of six patients with aspergillosis who died in remission expired as a consequence of cerebral infection. Cerebral infection complicated systemic Aspergillus infection in seven of 26 patients (27%), versus one of 16 patients with systemic Candida infection (6%) (p = NS). The authors conclude, therefore, that systemic aspergillosis complicating acute leukemia is more likely to be associated with confusion, focal neurologic findings, and abnormal CT scan of the brain, and that these findings suggest the presence of cerebral infection. In addition, cerebral infection commonly complicates the course of systemic aspergillosis, and is a significant cause of morbidity and mortality in patients with acute leukemia. A high index of suspicion is needed to insure early diagnosis and appropriate therapy, particularly in those who achieve remission of their leukemia.

Marrow red cells (MRBCs) from 56 autologous bone marrow harvests were rescued after processing and transfused as the sole transfusion support after surgery. There was no correlation between volume of harvest and total mononuclear cell (MNC) count. The marrow collection induced a significant decrease in hematocrit values (mean, 6.1; range, -0.3-12.3; p less than 0.001) unrelated to the patient's diagnosis, age, or gender. Processing of the marrows resulted in a mean transfused MRBC mass of 258 mL (range, 101-494 mL), representing 78 percent (range, 43-100%) of the MRBC mass collected. The amount of MRBCs transfused correlated with total MNC count (p less than 0.01). All autologous MRBC transfusions were well tolerated. It can be concluded that autologous MRBC transfusions are safe and may eliminate the need for homologous blood transfusions after marrow harvest.

Colonic ischemia (CI) is a rare complication of high-dose interleukin-2 (IL-2) immunotherapy. This complication occurred in three of 141 patients (2.1%) with metastatic cancer treated with high-dose IL-2 therapy; CI only developed in patients receiving interferon-alpha (IFN) with IL-2 (three of 21, 14%) compared with none of 120 in those patients receiving IL-2 alone (P equals 0.0009). Severe diarrhea (greater than or equal to 7 bowel movements/day) also was significantly more common in patients receiving IFN with IL-2 (six of 21, 29%) than in those receiving IL-2 alone (three of 120, 2.5%, P equals 0.001) and preceded the clinical diagnosis of CI in all three patients. Three of nine patients with severe diarrhea had CI. Hematochezia occurred in four patients, all of whom received IFN with IL-2; three had CI, and the other patient had nonspecific colitis. Differences in vasopressor use did not explain the increased risk of CI in patients receiving IFN; those receiving IFN with IL-2 required phenylephrine less often than patients receiving IL-2 alone (P equals 0.01). The administration of lymphokine-activated killer (LAK) cells had no significant effect on the incidence of CI, severe diarrhea, peritonitis, or vasopressor use; two of three patients with CI, however, had their ischemic episode within 24 hours after the last of three LAK cell infusions. In conclusion, CI is an unusual complication of high-dose IL-2 and IFN immunotherapy. In patients receiving such combination therapy, severe diarrhea is a risk factor for the subsequent occurrence of CI.

A 61-year-old woman underwent a left radical nephrectomy for Stage II anaplastic Wilm's tumor. She received no adjuvant therapy. One year later computerized tomography (CT) of the abdomen revealed a mass in the left renal fossa and retroperitoneal adenopathy. A CT-guided needle biopsy was nondiagnostic. The patient had progressive disease after treatment with dactinomycin, doxorubicin, and vincristine, but achieved a complete response after treatment with cisplatin and etoposide. The therapy of Wilms' tumor in adults is discussed.

Ten previously untreated patients with gastric cancer were treated with etoposide, 120 mg/m2 intravenously (i.v.) on days 4, 5, and 6, Adriamycin, 20 mg/m2 i.v. on days 1 and 7, and cisplatin, 40 mg/m2 i.v. on days 2 and 8 (EAP). Etoposide, 240 mg/m2 on days 4, 5, and 6, was administered orally instead of intravenously in alternating cycles, and pharmacokinetic studies were performed in those who had previously undergone gastrectomy or who had tumor infiltrating the stomach to determine oral bioavailability. Nine patients had advanced measurable gastric cancer, and one patient had an elevated carcinoembryonic antigen after surgery for synchronous gastric and colon cancer. The median age was 54 years (range 38-69), and the median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0-3). Nine of 10 patients had poorly differentiated adenocarcinoma. Twenty-four cycles were administered to 10 patients, and hematologic data were available for 23 courses. ECOG grade 4 neutropenia and thrombocytopenia developed in 19 (83%) and 8 (53%) courses, respectively. Thirteen courses (54%) were complicated by fever requiring parenteral antibiotics. Two patients (20%) died due to neutropenic sepsis. The profound myelotoxicity observed in our study prompted us to terminate the investigation prior to completing accrual. The oral bioavailability of etoposide was 21% and 36% in the two patients who had had prior gastrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)