• Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

      Eisen, Tim; Thatcher, Nick; Leyvraz, Serge; Miller, Wilson H; Couture, Felix; Lorigan, Paul C; Lüthi, François; Small, David; Tanovic, Adnan; O'Brien, M; et al. (2009-04)
      OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n = 13) or limited-stage disease (n = 7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.
    • Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors.

      O'Connor, James P B; Naish, Josephine H; Parker, Geoff J M; Waterton, John C; Watson, Yvonne; Jayson, Gordon C; Buonaccorsi, Giovanni A; Cheung, Susan; Buckley, David L; McGrath, Deirdre M; et al. (2009-11-15)
      PURPOSE: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS: DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.