Leonard P. James

Variability of Lung Tumor Measurements on Repeat Computed Tomography Scans Taken Within 15 Minutes

PURPOSE We use changes in tumor measurements to assess response and progression, both in routine care and as the primary objective of clinical trials. However, the variability of computed tomography (CT) -based tumor measurement has not been comprehensively evaluated. In this study, we assess the variability of lung tumor measurement using repeat CT scans performed within 15 minutes of each other and discuss the implications of this variability in a clinical context. PATIENTS AND METHODS Patients with non-small-cell lung cancer and a target lung lesion ≥ 1 cm consented to undergo two CT scans within a period of minutes. Three experienced radiologists measured the diameter of the target lesion on the two scans in a side-by-side fashion, and differences were compared. RESULTS Fifty-seven percent of changes exceeded 1 mm in magnitude, and 33% of changes exceeded 2 mm. Median increase and decrease in tumor measurements were +4.3% and -4.2%, respectively, and ranged from 23% shrinkage to 31% growth. Measurement changes were within ± 10% for 84% of measurements, whereas 3% met criteria for progression according to Response Evaluation Criteria in Solid Tumors (RECIST; ≥ 20% increase). Smaller lesions had greater variability of percent measurement change (P = .005). CONCLUSION Apparent changes in tumor diameter exceeding 1 to 2 mm are common on immediate reimaging. Increases and decreases less than 10% can be a result of the inherent variability of reimaging. Caution should be exercised in interpreting the significance of small changes in lesion size in the care of individual patients and in the interpretation of clinical trial results.

A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer

INTRODUCTION We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. METHODS This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m(2) on days 1 and 3 with IV topotecan at 1.25mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate. RESULTS Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). CONCLUSION Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.

Pralatrexate with Vitamin Supplementation in Patients with Previously Treated, Advanced Non-small Cell Lung Cancer: Safety and Efficacy in a Phase 1 Trial

Introduction: Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m2 every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities. Methods: Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m2 every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response. Results: Thirty-nine patients were treated for a median of two cycles (range 1–16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m2 and >190 mg/m2) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m2 were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1–20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m2. Conclusions: Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m2. A similar safety profile was observed in patients treated at 230 mg/m2, although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.