Faculty Bibliography

18006 Backgound: In a stratified randomized study comparing dacarbazine (DTIC) and oblimersen (Obl) with DTIC alone in metastatic melanoma, overall survival (OS) was increased in the Obl+DTIC group (P = .077). We report results from a multivariate analysis, including prognostic factors. METHODS: The study enrolled 771 patients; 2.2% data were missing. Stratification factors included elevated LDH (>1.1 ULN), performance status (PS) >0, and metastatic site (MET): MET A = liver, MET B = other visceral, MET C = skin, subcutaneous, or lymph nodes only. Each stratification factor was evaluated using monovariate analysis for treatment interaction. Cox model included treatment, any identified factor, gender, or interaction term for OS and progression-free survival (PFS), and a logistic regression for response rate (RR). RESULTS: The stratification factor with the greatest impact on survival was elevated LDH (HR 2.212, P < .0001), followed by PS > 0 (HR 1.497, P < .0001), MET A (HR 1.456, P < .0001), and MET C (HR 0.670, P < .0004). Interaction significance between treatment and LDH, PS, MET A, and MET C were 0.023, NS (0.279), NS (0.419), and NS (0.329), respectively. MET B was used as the reference category for MET A and MET C. CONCLUSION: As expected, all stratification factors were prognostic, with LDH being the most important factor (HR 2.2). The addition of Obl to DTIC treatment improved outcomes for all efficacy end points. A statistical interaction between Obl treatment and LDH was found for survival. Multivariate analysis was significant in all efficacy end points. Patients with abnormal baseline LDH, already understood to have a poor prognosis, were unlikely to benefit from this therapy and should not be included in future trials of combination oblimersen treatments. [Table: see text] No significant financial relationships to disclose.

18001 Background: Bcl-2 inhibits apoptosis, confers resistance to chemotherapy in many cancers, is often over-expressed in advanced melanoma, and is a prime candidate for pro-apoptotic targeted therapy. Recent studies by the EORTC and others show that lactate dehydrogenase (LDH) is a powerful prognostic determinant in advanced melanoma patients (pts). The chief treatment effect of oblimersen (Obl) + dacarbazine (DTIC) was obtained from the largest cohort of normal LDH pts studied to date; detailed efficacy and safety data are reported. METHODS: Previously untreated pts (N = 771) were randomized to receive DTIC 1000 mg/m2 IV Q 3W alone or preceded by Obl (7 mg/kg/d x 5D). Pts were stratified pre-randomization by performance status, liver metastases, and visceral metastases and/or elevated LDH. Serum LDH was /=6 mo (9.6% vs 4.0%; P = .014). In contrast, there were no significant differences in outcomes for pts with elevated BL LDH (n = 252). BL LDH was the only stratification variable significantly associated with a treatment interaction effect. Compared with the entire study population, pts with NE LDH in both groups had a lower incidence of treatment-emergent adverse events (TEAEs) with an outcome of death, serious TEAEs, and discontinuations due to TEAEs. CONCLUSIONS: With extended follow-up, this large trial confirms that serum LDH (prospectively stratified pre-randomization) is probably the most important prognostic factor in advanced melanoma. Given the demonstrable lack of benefit and high potential to yield misleading evidence regarding therapeutic activity, pts with elevated LDH should probably be excluded from trials of new therapies until establishing efficacy in pts with nonelevated LDH. No significant financial relationships to disclose.

AIM: To investigate the value of whole body positron emission tomography/computed tomography (PET/CT) in screening for metastatic choroidal melanoma in patients initially diagnosed with choroidal melanoma. METHODS: 52 patients with choroidal melanoma underwent whole body PET/CT as part of their metastatic investigation. PET/CT scans were used as a screening tool at the time of their initial diagnosis. A physical examination, liver function tests, and a baseline chest x ray were also obtained. PET/CT images (utilising intravenous18-fluoro-2-deoxyglucose (FDG)) were studied for the presence of metastatic melanoma. The standards for reference were further imaging and/or subsequent biopsies. RESULTS: Two of 52 (3.8%) patients were found to have metastatic melanoma before treatment. The most common sites for metastases were the liver (100%), bone (50%), and lymph nodes (50%). Brain involvement was also present in one patient. One patient (50%) had involvement of multiple sites. Haematological liver enzyme assays were normal in both patients. PET/CT showed false positive results in three patients (5.7%) when further evaluated by histopathology and/or additional imaging. In seven patients (13.4%) PET/CT imaging detected benign lesions in the bone, lung, lymph nodes, colon, and rectum. CONCLUSION: PET/CT imaging can be used as a screening tool for the detection and localisation of metastatic choroidal melanoma. Liver enzyme assays did not identify liver metastases, while PET/CT revealed both hepatic and extrahepatic metastatic melanoma. PET/CT imaging may improve upon the conventional methods of screening for detection of metastatic disease in patients initially diagnosed with choroidal melanoma.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea

Breast involvement with non-Hodgkin's lymphoma (NHL) is rare. Patients with AIDS have an increased incidence of NHL, often with high-grade histology, extranodal presentation and aggressive clinical course. Lymphoma of the breast in patients with HIV-1 infection has not been reported. We reviewed our tumor registry database of all AIDS-associated NHL and report on the clinical presentation and long-term outcome of 3 patients with AIDS who presented with lymphomatous involvement of the breast