Faculty Bibliography

Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming 'cleavable complex,' a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 'free' topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy

Background: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). Objective: To evaluate intravenous cidofovir as a treatment for CMV retinitis. Design: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Setting: Ophthalmology and AIDS services at tertiary care medical centers. Patients: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Intervention: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Measurements: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Results: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.2), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mu mol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Conclusions: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients

Topotecan, a topoisomerase-1 inhibitor, may have greater therapeutic index when given by prolonged infusion. In an earlier phase I trial of escalating low-dose infusion (MTD = 0.53 mg/m2/d x 21d) for previously treated pts (JCO; 12:553 1994), 3/6 heavily treated ovarian cancer pts responded. We administered 60 cycles of TPT to 16 pts in a phase II study starting at 0.4 mg/m2/d x 21 days. All pts had one prior platinum-containing chemotherapy regimen with progression or recurrence (early less than 6 mo vs later). All pts had PS 0-1, normal heme parameters and Creat less than 1.6. Measurable disease (greater than 2 cm on CT scan) was required. Four pts were able to be escalated to 0.5 mg/m2/d for 11 cycles and 6 were reduced to 0.3 in 15 cycles. Responses are presented in a table. Four pts had stable disease (3 still on rx), and 6 PD. Overall response rate is at least 37% (95% CI =12-62%). Hematologic toxicity included leukopenia and neutropenia gr 3 = 4 pts (7%) and gr 4 = 1 pt (2%) but no grade 3 or 4 thrombopenia. Eight pts required blood transfusions. Non-heme toxicity included grade 1 nausea = 7 pts and gr 2 =3 pts; grade 1 fatigue =5 and gr 1 alopecia = 4 pts. Two catheter related thromboses occurred; 2 had sepsis. Weekly PBMC topo-1 levels were obtained for pharmacodynamic studies (abstract submitted). This response rate is among the highest reported for second-line therapy of ovarian cancer and is seen in both platinum resistant and refractory disease. Data on these and additional pts currently being accrued will be presented. (C) American Society of Clinical Oncology 1997

In non-small cell lung cancer (NSCLC), accurate staging is critical in deciding between potentially curative surgery and palliative treatment. Image registration, or fusion, combines the unique functional information provided by SPECT imaging with the excellent anatomic detail offered by computed tomography (CT) or magnetic resonance imaging to better characterize the information provided by each separate modality. In this study, we explored the role of fusion of immunoscintigraphy SPECT with CT in the staging of NSCLC. We fused chest CT with 99mTc-labeled IMMU-4 anti-carcinoembryonic antigen Fab\' antibody fragment SPECT in 14 patients with NSCLC using a landmark-based algorithm. The algorithm\'s accuracy was a measure from the center-to-center distance and the percentage overlap of two regions of interest: one drawn on CT and warped onto SPECT, the other drawn directly on the SPECT. We found that the average center-to-center distance was 1.3 +/- 0.8 pixels. Average overlap was 46 +/- 20%. CT-SPECT fusion helped differentiate tumor from normal blood pool, necrotic areas within viable tumor, tumor recurrence from scar, and malignant lymphadenopathy from hyperplasia. We conclude that fusion of CT and SPECT augments the information provided by each separate modality. Future clinical applications of fusion in NSCLC staging using immunoscintigraphy appear promising

EDA is an analog of methotrexate which has clinical activity in a variety of solid tumors. We are studying EDA in combination with DOX to assess the toxicities and the maximally tolerated dose (MTD). Without G-CSF, the MTD was EDA 40 mg/m2 iv q 2 wk and DOX 30 mg/m2 iv q 4 wk. A 25% dose-escalation of both drugs resulted in dose-limiting neutropenia in 3/6 evaluable patients. Subsequently, G-CSF was added to the regimen on days 3-13. In addition, all patients received ice chip cryotherapy with EDA infusion. After these modifications, 6 patients (M/F; 5/1) have entered the trial. Median age 53 (range 44-61); median PS of 1. All had prior chemotherapy (2 greater than or equal to 2 regimens); 3 prior radiation. A total of 19 cycles were given. There were no significant toxicities noted during cycle 1 of chemotherapy with EDA 50 mg/m2 and DOX 37 mg/m2 + G-CSF. One patient developed grade 1 mucositis after cycle 4 requiring dose reduction and subsequent elimination of day 15 EDA. Despite this, he developed grade 3 mucositis and grade 4 neutropenia after cycle 7 requiring day 1 dose reduction of both EDA and DOX. Three patients have received at least 1 cycle of chemotherapy with EDA 62 mg/m2 and DOX 47 mg/m2 + G-CSF. There were no significant toxicities identified. The doses of both EDA and DOX can be escalated by the addition of G-CSF. Ice chip cryotherapy appears to reduce the severity of mucositis with this regimen. Dose escalation is continuing. Phase II studies are planned in soft tissue sarcoma and colon cancer. (C) American Society of Clinical Oncology 1997

R24, a murine monoclonal antibody, has been shown to mediate complement- and antibody-dependent cellular cytotoxicity (ADCC) of melanoma tumor targets. We conducted a Phase Ib clinical trial using granulocyte-macrophage colony-stimulating factor (GM-CSF) and R24 in 20 patients with metastatic melanoma. The purpose of this study was to test the hypothesis that treatment with GM-CSF could up-regulate monocyte and granulocyte ADCC and that the combination of GM-CSF plus R24, which mediates ADCC, would lead to enhanced anti-tumor activity in patients with melanoma. GM-CSF was administered by subcutaneous injection daily for 21 days at a dose of 150 micrograms/m2/day. R24 was administered by continuous intravenous infusion on days 8-15 at three dose levels: 0, 10, and 50 mg/m2/day. All 20 patients received one cycle of treatment only. Immune parameters measured were monocyte and granulocyte direct cytotoxicity and ADCC. All patients were evaluable for toxicity. Fifteen patients were evaluable for immune response. Treatment with GM-CSF alone was well tolerated. Toxicity from the combination of GM-CSF plus R24 included diffuse urticaria, nausea and vomiting, hypertension, and hypotension. Hypotension was the dose-limiting toxicity. Two patients on the 50-mg/m2/day dose level of R24 achieved a partial response lasting 2+ and 5+ months. Treatment with GM-CSF led to a statistically significant enhancement of monocyte and granulocyte direct cytotoxicity and ADCC. The maximally tolerated dose of R24 given at this schedule combined with GM-CSF is < 50 mg/m2/day. We conclude that GM-CSF given by subcutaneous injection at 150 micrograms/m2 x 21 days can enhance effector cell ADCC and direct cytotoxicity and that the combination of GM-CSF and R24 can be therapeutic

Adrenal cortical carcinoma is well known to extend into the renal veins and inferior vena cava. It is less known that neoplasms metastatic to the adrenal might also extend into the renal vein and cava. Only a few reports in the literature document this extension. We report a case of metastatic neoplasm to the adrenal extending into the inferior vena cava

Twenty-four patients with solid malignancies were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) on a Phase 1b trial. The objective of the study was to evaluate the effects of GM-CSF on peripheral blood monocyte activation. GM-CSF was administered by subcutaneous injection daily for 14 days. Immune parameters measured were monocyte cytotoxicity against the human colon carcinoma (HT29) cell line, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and in vitro TNF-alpha and IL-1 beta induction. All patients were evaluable for toxicity. Fifteen patients were evaluable for immunologic response. Treatment with GM-CSF led to a statistically significant enhancement in direct monocyte cytotoxicity against HT29 cells. There was no increase in serum TNF-alpha or IL-1 beta and no consistent in vitro induction of TNF-alpha or IL-1 beta from monocytes posttreatment. Treatment was well tolerated overall. We conclude that treatment with GM-CSF can lead to enhanced monocyte cytotoxicity. Further studies are in progress to evaluate the effect of GM-CSF on other parameters of monocyte functions