gms | German Medical Science

Background: Doublet chemotherapy (DCT) is considered standard but often clinical inappropriate. Newer agents (D; G) have shown favourable toxicity and significant efficacy given as SA 1st- and 2nd-line. It is reasonable to assume that sequencing of D and G could be an equally effective alternative to DCT for palliation. Design of drug sequences probably matters and radomized trials should be conducted to compare its best version to doublet standards.

Treatment: From 1998 to 2004 a total of 819 pts have been included in 3 studies: two (S1; S2) to identify an optimal SA-sequence; and one (S3) to compare sequential SA to a platin-free doublet. For pts selection common eligibility criteria were employed, including histologically confirmed stage „wet IIIB“ or IV, performance status (PS) 0-2, and no prior chemotherapy. S1/S2 were to determine whether G or D with introduction of the opposite agent in case of disease progression is feasible. Treatment feasibility (TF) was defined as the pts’-ability to receive ≥2 cycles (cyc) of 1st-line and in case of progression ≥2 cyc of 2nd-line therapy and to survive at least 7 months (mos). In S1 a weekly regimen (for G 1000 mg/m² and for D 35 mg/m², days 1, 8, 15; q4w) and in S2 a 3-weekly regimen (for G 1250 mg/m², days 1, 8 and for D 100 mg/m², day 1; q3w) were applied. In S3 pts received 3-weekly G 1000 mg/m², days 1, 8 and D 75 mg/m², day 1 either concomitantly (6 cyc) or sequentially (G 3 cyc → D 3 cyc). Primary endpoint was clinically relevant haemato-toxicity (CRHT) defined as thrombocytopenia requiring platelet transfusions, anaemia with RBC-transfusions or febrile neutropenia with i.v. antibiotics (IVAB).

Results: 85% of pts had stage IV disease and 85% PS≤1. TF for S1 was 28% (G→D) and 20% (D→G) (ns). Median survival (MS) was 9.0/5.0 mos (p=.03), and median time to progression (TTP) was 4.3/2.2 mos. TF for S2 was 38% (G→D) and 49% (D→G) (p=.04). MS was 6.3/8.6 mos, and TTP was 2.4/3.3 mos. In S3 CRHT occurred less frequently under SA therapy (p<.001) and transfusions and IVAB treatment days again were less common. QoL also favoured SA therapy. MS was 7.3(G+D )/7.4(G→D) mos, response rate was 33%/22% (p=.05) and TTP was 6.3/4.9 mos (p=.04).

Conclusion: Sequencing modern SA is effective and well tolerated. By using D and G our weekly regimens seems less feasible than the 3-weekly regimens, and its comparison to a non-platin doublet is associated with reduced CRHT, less IVAB, a better QoL, and is more cost-effective.