Lung Cancer 34 (2001) S37–S46 Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer S. Tumolo a, *, G. Toffoli b , S. Saracchini a , G. Lo Re a , G. Bruschi a , M.G. Boccieri a a U.O. Oncologia and Pneumologia, AOS -S. Maria degli Angeli, ia Montereale 24, 33170 Pordenone, Italy b Centro di Riferimento Oncologico, ia Pedemontana Occidentale 12, 33081 Aiano, Italy Abstract In the last years, the main topoisomerase I inhibitors (TP1-I) (i.e. topotecan and irinotecan) have been used in combination chemotherapy in non-small cell lung cancer. Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Topoisomerase inhibitors; Topotecan; Irinotecan; Combination chemotherapy; Efficacy; Toxicity; Non-small cell lung cancer www.elsevier.com/locate/lungcan 1. Introduction Topoisomerase I inhibitors (TP1-I) are a new class of antineoplastic agents currently under study in the clini- cal setting. The knowledge of the structure – activity relationship of the parent compound camptothecin has led to the development of effective analogues with tolerable toxicity. TP1-I includes topotecan (TPT) and irinotecan (CPT-11) as well as less known drugs such as 9-aminocamptothecin (9-AC) and exatecan mesylate (DX-8951f). The use of 9-AC resulted in a partial response (PR) in five out of 58 (8.6%) patients with non-small cell lung cancer (NSCLC) treated at 1100 – 1416 g/m 2 /day ×3 as continuous i.v. infusion [1]. This modest activity of 9-AC as a single agent reduces its use in combination therapy. DX-8951f was used in 23 patients with NSCLC at a dose of 0.5 mg/m 2 i.v. daily for 5 days, with a PR in three out of 16 assessable patients (remission rate, RR =18%) [2], and could be suitable in the future for combination chemotherapy. We know that NSCLCs express a relatively great amount of the topoiosomerase I enzyme [3], and clinical studies have demonstrated that TP1-I are effective in NCSLC (RR =11% in 115 patients for TPT [4] and RR =15–32% for CPT-11 [5,6]). Several pre-clinical studies have provided the ratio- nale for antitopoisomerase I combination chemother- apy [7–13] (Table 1). In particular, TP1-I could increase the cytotoxic effect of platinum derivatives by interfering with DNA repair [7,13]. On the other hand, the recent observation indicating that oxaliplatin can stimulate topoisomerase I [14,15] strongly suggests a biochemical mechanism for synergy with this combina- tion and indicates that oxaliplatin has to be followed by CPT-11 for synergy. Some further considerations could be made about the rationale for combination therapy: 1. Paclitaxel blocks the cells in mitosis, and this mitotic arrest can be irreversible, with consequent apopto- sis, or temporary, with arrested cells re-entering the S-phase. Consequently, initial treatment with pacli- taxel followed by TPT kills the synchronised surviv- ing cell population re-entering the S-phase, whereas an initial treatment with TPT could synchronise cells in the G2-M phase, in which paclitaxel is more active [4]. 2. Tolis et al. [12] have recently demonstrated that TPT and gemcitabine have additive effects in exper- imental models and concluded that it could be re- * Corresponding author. Tel.: +39-0434-399-612; fax: +39-0434- 399-187. 0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0169-5002(01)00403-2