CISPLATIN AND VINORELBINE FOLLOWED BY IFOSFAMIDE PLUS EPIRUBICIN VS THE OPPOSITE SEQUENCE IN ADVANCED UNRESECTABLE STAGE-III AND METASTATICSTAGE-IV NON-SMALL-CELL LUNG-CANCER - A PROSPECTIVE RANDOMIZED STUDY OF THE SOUTHERN ITALY ONCOLOGY GROUP (GOIM)

A multicentric, prospective phase III study was carried out with the a im of testing the so-called 'worst drug rule' hypothesis, which sugges ts the use of an effective but 'less active' regimen that first eradic ates tumoral cells resistant to a second effective and 'more active' r egimen. With respect to this hypothesis, we considered the cisplatin p lus vinorelbine regimen (CCDPNNR) as the more active regimen compared with the non-cisplatin-containing regimen of ifosfamide plus high-dose epirubicin (IFO/EPI). Thus, a randomized study was carried out to com pare the sequential strategy of three cycles of CDDPNNR followed by th ree cycles of IFO/EPI with the opposite sequence in advanced non-small -cell lung cancer. A total of 100 consecutive previously untreated pat ients with stage III-IV non-small-cell lung cancer were centrally rand omized in two arms according to stage of disease and the performance s tatus. Patients allocated to arm A received CDDP (100 mg m(-2) on day 1) plus VNR (25 mg m(-2) i.v. on days 1 and 8) every 21 days for three cycles (step 1) followed, after restaging, by three cycles of IFO (2. 5 g m(-2) with mesna on day 1) plus high-dose EPI (100 mg m(-2) on day I) every 21 days (step 2). Patients in arm B received the opposite se quence. Type and rates of objective response were evaluated after step 1 and step 2 in agreement with WHO criteria and an intent-to-treat an alysis. Patients were also analysed for toxicity patterns, time to pro gression and survival. After the first three cycles (step 1), overall response rate (ORR), calculated according to an intent-to-treat analys is, was 47% and 21% for arm A and arm B respectively (P = 0.0112). ORR for stage III patients was 55% and 14% for arm A and B respectively ( P = 0.0097). In stage IV patients ORR was higher in arm A than in arm B (42% vs 28%) but not statistically significant (P = 0.4). Clinical r esponses to the shift of chemotherapy (step 2) showed that no patient pretreated with CDDPNNR and subsequently treated with IFO/EPI showed f urther response, whereas in the inverse sequence arm CDDPNNR was able to induce 26% partial response (PR) rate in patients pretreated with I FO/EPI, This difference was statistically significant (P = 0.037). The overall median time to progression (TTP) of arm A and arm B did not s ignificantly differ (6 vs 4 months; P = 0.665). However, median TTP of stage III patients was, respectively, 7 months for arm A and only 3 m onths for arm B. This difference was statistically significant (P = 0. 049). Median overall survival (OS) was 9 and 7 months respectively for arm A and arm B. Despite this trend the difference was not significan t (P = 0.328). Median OS of stage III patients showed a statistically significant advantage for arm A over arm B (13 vs 7 months, P = 0.03). In addition, no statistically significant difference in OS was record ed for stage IV patients (both arms 7 months, P = 0.526). Our data do not confirm Day's 'worst drug rule' hypothesis, at least in patients w ith advanced non-small-cell lung cancer treated with the above-mention ed regimens. The combination of CDDP and VNR seems more active, at lea st in terms of response rate, than the IFO/EPI, which performed poorly .