Faculty Bibliography

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 with a modification at the N10 position designed to improve the therapeutic index by increasing membrane transport and polyglutamylation. EDA has clinical activity in a variety of solid tumors. We are conducting a Phase I study of EDA in combination with DOX. The starting dose of EDA was 40 mg/m2 iv q 2 wk and DOX 30 mg/m2 iv q 4 wk with a 25% escalation of both drugs until MTD. To date, 13 patients (M/F; 8/5) have entered the trial. Median age 61 (range 25-78) yr; median PS of 1. Prior treatment: 8 prior chemotherapy (CT; two greater than or equal to 2 regimens); 4 prior RT. A total of 32 cycles were given. Nonhematologic (2 grade 3) and hematologic (grade 4) toxicity during cycle 1 of CT is presented in a table. At the first dose level 1 patient required a subsequent 50% dose reduction of EDA secondary to grade 3 mucositis at cycle 5. At the second dose level, 2 patients developed neutropenic fever during cycle 1. An additional patient developed neutropenic fever after cycle 2. One patient who received prior pelvic RT developed grade 3 vomiting and abdominal pain after cycle 2 and 3 and was found to have progressive rectal ca in the GI tract. Grade 1-2 mucositis was noted in 3 patients. Other toxicities were mild. The MTD of combination EDA/DOX was at 40 mg/m2/30 mg/m2, respectively, with dose-limiting myelosuppression. We are now entering patients to define the MTD with G-CSF. Phase II trials are planned. (C) American Society of Clinical Oncology 1997

We report the results of an ongoing Phase II study of paclitaxel (Taxol) and DDP in women with metastatic breast cancer. Paclitaxel is administered at 200 mg/m2 iv 24 hr infusion on d1, bolus DDP at 75 mg/m2 d2; G-CSF 5 mcg/kg SQ qd d3 until WBC recovery, with premedications of dexamethasone, cimetidine, and diphenhydramine. Eligibility criteria are: age greater than 18, ECOG PS less than or equal to 2, measurable/evaluable disease, adequate BM, liver, and renal functions, no prior paclitaxel or DDP, and informed consent. Pts may have received adjuvant (adj) therapy (Rx) greater than 1 yr prior to enrollment and less than or equal to 1 prior chemotherapy (CT) regimen for metastatic disease. 27 pts are enrolled on study. Pt characteristics: median age 50 (range 25-69), stage IV 23, stage IIIB, prior adj CT 18, CT 2, hormone 9. Disease sites include lung 13, bone 11, soft tissue 12, lymph node 11, and liver 3 (19 pts have greater than or equal to 2 sites). 27 pts received 111 cycles, median of 5 cycles/pt. Of 21 evaluable pts, there were 2 CR, 9 PR, 9 SD, and 1 PD (overall response rate 52%) [1 pt was non-evaluable (toxic death in cycle 1); 5 pts are too early]. The median duration of response is 3+ months (range 1-12+ months). 16/27 pts (59%; (33/111 cycles)) had grade 4 neutropenia. 17 pts had grade greater than or equal to 2 fatigue (WHO). 9/27 (33%; 12 cycles) required RBC Tx. 8 pts went off study because of cumulative neuropathy. Other off study reasons: 5 PD, 1 toxic death (sepsis), anaphylaxis to DDP-1, and 2 pts went to surgery. Conclusion: Paclitaxel/DDP is an active regimen as first line therapy for metastatic breast cancer, but acute myelosuppression and cumulative neurotoxicity are limiting. (C) American Society of Clinical Oncology 1997

PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer

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

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

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

Topotecan (TPT), a semi-synthetic, water soluble analog of camptothecin (CPT), acts by topoisomerase-1 inhibition. Previous studies with CPT analogs in human xenograft-bearing mice show that prolonged depot administration at nontoxic doses were curative (Giovanella et al, Science, 246:1046, 1989). We treated 33 patients (pts) (16 F, 17 M) with prolonged continuous infusion using ambulatory CADD pumps delivering 7 cc/day (d) with cassette changes every 3 d. Cohorts of 4-6 pts began at a dose of 0.2 mg/m2/day x 7 days with escalation to 10, 14, 17, and 21 days q 28 d. Further escalations were 0.3, 0.4, and 0.53 mg/m2/d x 21 d q 28 d. Disease sites included colon ca (13), NSCLC (4), sarcoma (3), gastric (3), ovarian (3), pancreatic (2); H and N, breast, renal, melanoma, anal (each 1). Median age was 63 (range 29 -79) yr; PS 1 (0-2); prior chemo = 33 (med 2 regimens); prior RT=10. A total of 72 cycles (med 2, range 1-6) were given for a total of 1090 pt-days of infusion. One infectious complication was seen (Mediport-pocket), 4 pts required transfusion; one pt with 3 prior chemo regimens and pelvic RT developed gr 4 leukopenia and thrombocytopenia at the 0.4 mg/m2 x 21 d level. No other hematologic toxicity has been observed. Nonhematologic toxicity included fatigue only. Steady state plasma conc for the active lactone form of TPT at 0.4 mg/m2/d was 1.4 +/- 0.29 ng/ml (N=3) and 4.4 +/- 0.99 (N=3) at the 0.53 level. Best responses were 1 PR (NSCLC), 1 mixed response (breast), 11 stable, 15 progression and 5 too early. TPT administration by this schedule is feasible and safe; we continue to accrue. Dose-limiting heme toxicity has not yet been reached, yet dose intensity (2.8 mg/m2/wk) exceeds that achieved using the recommended Phase II 1.5 mg/m2/d x5 schedule (1.9 mg/m2/wk). Once an MTD is reached, Phase III trials comparing this schedule to the daily x5 bolus schedule will be warranted. (C) American Society of Clinical Oncology 1997

In the era before the acquired immunodeficiency syndrome, Kaposi's sarcoma was a rare cutaneous event. Most reported cases usually originated from one of two geographic regions, an induced immunosuppressed state, or sporadically with various neoplasms that have been known to cause immunosuppression. Since the first cases described with acquired immunodeficiency syndrome in 1981 from New York and San Francisco, this uncommon disorder has had an increased incidence that crosses geographic boundaries. This article describes the current understanding of the pathogenesis of Kaposi's sarcoma and treatments used to ameliorate this disorder

BACKGROUND: Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipeptide (MDP), a component of bacterial cell walls that has potent in vitro monocyte-activating properties. We conducted a phase II clinical trial of MTP-PE in 30 patients with metastatic melanoma. PURPOSE: Our purpose was to define a clinical response rate for this agent in patients with advanced melanoma and to evaluate the agent's immunomodulatory properties. METHODS: Patients were randomly assigned to 1- or 4-mg dose levels of MTP-PE and received the drug intravenously once a week for 12-24 weeks. Immunological monitoring consisted of measurement of plasma tumor necrosis factor-alpha (TNF-alpha), neopterin, interleukin-1-beta, interleukin-6 (IL-6), and beta 2-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mononuclear cells; and measurement of in vitro monocyte cytotoxicity against SKMel28 targets cells. RESULTS: MTP-PE was well tolerated; fever and chills were the major toxic effects. Plasma TNF-alpha levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-alpha levels after MTP-PE administration continued through week 12, but changes were of a lower magnitude after week 1. Plasma neopterin levels were significantly increased 24 hours after treatment at weeks 1, 6, and 12. A marked increase in IL-6 and a modest rise in beta 2-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1 beta were observed. In the cytotoxicity assay, monocyte cytotoxic activity was significantly increased at weeks 4 and 6. Surface immuno-phenotyping revealed a consistent transient reduction in the number of circulating monocytes 2 hours after MTP-PE was administered. In addition, we observed a down-regulation (i.e., a decrease) in the expression of Leu M3 and HLA-DR on monocytes, 2 hours after MTP-PE treatment, followed by a recovery 24 hours after treatment. No objective clinical responses were seen in this advanced disease population. CONCLUSIONS: We conclude that MTP-PE has pleiotropic and potentially beneficial biologic effects and that further clinical investigations of MTP-PE are justified. IMPLICATIONS: In view of the clear immunomodulatory actions seen in our study and in earlier clinical trials, we believe that MTP-PE deserves further study in the adjuvant setting