No abstract

No abstract

Background: Treosulfan (Ovastat®), a bifunctional alkylating cytostatic, indicated for the treatment of advanced ovarian carcinoma, was recently found to be active in human lung and breast carcinoma xenografts. Moreover, toxicological evaluation as well as clinical experience revealed the lack of significant nonhematological toxicity which makes treosulfan a promising candidate for high-dose chemotherapy combined with autol-ogous blood stem-cell reinfusion. As a prerequisite for clinical high-dose studies, a formal phase I dose escalation without stem-cell reinfusion was conducted to reassess the maximum tolerated dose and dose-limiting toxicity of treosulfan after intravenous short-term infusion. Patients: A total of 12 patients with chemotherapy-refractory advanced cancer were entered at 3 dose levels (8 g; 10 and 12.5 g/m2 treosulfan i.v). Most patients suffered from advanced small-cell lung cancer (5 patients) or ovarian carcinoma (3 patients). Results: The maximum tolerated dose of treosulfan in this group of heavily pretreated patients was 10 g/m2. The dose-limiting toxicity was reversible thrombocytopenia. There were no nonhematological side effects exceeding WHO grade 2. Conclusions: This phase I dose escalation trial confirmed the lack of significant nonhematologic side effects of treosulfan although a dose of 12.5 g/m2 was infused. A subsequent phase I study of high-dose treosulfan followed by peripheral blood progenitor cells has therefore been initiated.

IntroductionUnderstanding prognosis – especially long-term outcome – in advanced non-small-cell lung cancer(NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care.MethodsPrognostic factors influencing overall (OS) and progression-free survival (PFS) in 2082 patients with Wild-type(WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP-registry recruiting in over 150 centers. Analysis for pretherapeutic factors was based on results from Cox proportional hazard models.ResultsCurrent M-descriptors of UICC-8 staging system were validated: M1a and M1b patients had significantly longer time to events compared to M1c (OS/PFS, medians 16.4/7.2; 17.8/6.7; 10.9/5.4 months). OS and PFS were influenced by number and location of metastatic organ systems. M1c and ≥4 metastatic organs involved had shorter OS and PFS than M1c with 1 to 3 organs (OS HR 1.69, p<001; PFS HR 1.81, p<001). M1b-liver metastases had shorter OS/PFS than M1b-involving other organs (OS HR 2.70, p=006; PFS HR 2.48, p=007). Based on number of involved organs(orgsys) and liver metastases, two risk groups (Low-risk: M1a, M1b-non-liver, M1c-1-3-orgsys-non-liver; High-risk: M1c-liver, M1b-liver, M1c-4+-orgsys) with significantly different prognosis could be amalgamated (OS/PFS, medians 14.3/6.5; 7.7/4.1 months). Other favourable factors were female gender and ECOG 0 with age showing no impact. T1- or N0-status were associated with longer OS than T2-4 or N2-3.ConclusionIn this large observational dataset, we further defined factors for outcome in WT-NSCLC - including increased number of involved metastatic organ systems and liver metastases - as those with overall poorer prognosis and reduced survival chance.