Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: A randomized trial

Summary A multicentric, prospective phase IlIl study was carried out with the aim of testing the so-called 'worst drug rule' hypothesis, which suggests the use of an effective but 'less active' regimen that first eradicates tumoral cells resistant to a second effective and 'more active' regimen. With respect to this hypothesis, we considered the cisplatin plus 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 compare the sequencial strategy of three cycles of CDDPNNR followed by three cycles of IFO/EPI with the opposite sequence in advanced non-small-cell lung cancer. A total of 100 consecutive previously untreated patients with stage III-IV non-small-cell lung cancer were centrally randomized in two arms according to stage of disease and the performance status. 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 1) every 21 days (step 2). Patients in arm B received the opposite sequence. Type and rates of objective response were evaluated after step 1 and step 2 in agreement with WHO criteria and an intent-to-treat analysis. Patients were also analysed for toxicity patterns, time to progression and survival. After the first three cycles (step 1), overall response rate (ORR), calculated according to an intent-to-treat analysis, was 47% and 21% for arm A and arm B respectively (P= 0.0112). ORR for stage Ill 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 responses to the shift of chemotherapy (step 2) showed that no patient pretreated with CDDPNNR and subsequently treated with IFO/EPI showed further response, whereas in the inverse sequence arm CDDPNNR was able to induce 26% partial response (PR) rate in patients pretreated with IFO/EPI. This difference was statistically significant (P= 0.037). The overall median time to progression (UTP) of arm A and arm B did not significantly differ (6 vs 4 months; P= 0.665). However, median UTP of stage Ill patients was, respectively, 7 months for arm A and only 3 months 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 significant (P = 0.328). Median OS of stage Ill 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 recorded 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 with advanced non-small-cell lung cancer treated with the above...

Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

Cisplatin and vinorelbine followed by ifosfamide plus epirubicin vs the opposite sequence in advanced unresectable stage III and metastatic stage IV non-small-cell lung cancer: a prospective randomized study of the Southern Italy Oncology Group (GOIM)

Colucci

Gebbia²,

Galetta

et al. 1997

“…Noteworthy, we were able to increase both gemcitabine and vinorelbine in about a quarter of patients treated with GV. On the other hand, vinorelbine in the MILES trial produced an unexpectedly longlasting MST, not only longer than the combination, but also greater than that obtained in the previous ELVIS study (Elderly Lung cancer Vinorelbine Italian Study Group, 1999), and even superior to those (ranging from 30 to 32 weeks) reported with this drug in three large randomised trials unrestricted to elderly patients (Depierre et al, 1994;Le Chevalier et al, 1994;Crawford et al, 1996).…”

Section: Discussionmentioning

confidence: 66%

Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients

Comella

Frasci

Carnicelli³

et al. 2004

The aim of this study was to assess whether a combination of gemcitabine (GEM) with either paclitaxel (PTX) or vinorelbine (VNR) could be more effective than GEM or PTX alone in elderly or unfit advanced non-small-cell lung cancer (NSCLC) patients. A total of 264 NSCLC patients aged 470 years with ECOG performance status (PS)p2, or younger with PS ¼ 2, were randomly treated with: GEM 1200 mg m À2 on days 1, 8 and 15 every 28 days; PTX 100 mg m À2 on days 1, 8 and 15 every 28 days; GEM 1000 mg m À2 plus PTX 80 mg m À2 (GT) on days 1 and 8 every 21 days; GEM 1000 mg m À2 plus VNR 25 mg m À2 (GV) on days 1 and 8 every 21 days. In all arms, an intra-patients dose escalation was applied over the first three courses, provided that no toxicity of WHO grade X2 had previously occurred. At present time, 217 (82%) patients had died. The median (months) and 1-year survival probability were 5.1 and 29% for GEM, 6.4 and 25% for PTX, 9.2 and 44% for GT, and 9.7 and 32% for GV. Multivariate analysis showed that PSp1 (hazard ratio (HR) ¼ 0.67; 95% CI 0.51 -0.90), and doublet treatments (HR ¼ 0.76; 95% CI 0.59 -0.99) were significantly associated with longer survival. Doublets produced no more toxicity than single agents. GT should be considered a reference regimen for elderly NSCLC patients with PSp1.

“…Comparisons between cisplatin containing double therapy and monotherapy with the non-platinum agent Results of trials comparing monotherapy with vindesine (Elliott et al, 1984;Einhorn et al, 1986), etoposide (Rosso et al, 1990), teniposide (Splinter et al, 1996), and vinorelbine (Depierre et al, 1994;Le Chevalier et al, 1994) with the respective agent combined with cisplatin showed consistently higher response rates in the combination therapy arm, but only about half showed a survival benefit for the combination (Table 2). Similarly, preliminary analysis of a multicenter phase III trial comparing docetaxel vs docetaxel plus cisplatin in patients with inoperable advanced and metastatic NSCLC showed no survival advantage but a significant improvement in objective response rate with combination therapy (Georgoulias et al, 2002; Table 2).…”

Section: Cisplatin and Carboplatinmentioning

confidence: 99%

Platinum drugs in the treatment of non-small-cell lung cancer

Cosaert

Quoix

2002

The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with nonresectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours.