Anthracyclines in non-small-cell lung cancer: do they have a therapeutic role?

Owing to its low level of activity together with its potential cardiotoxicity, doxorubicin (DXR) has been considered as having a marginal role in the treatment of NSCLC. Its analogue, epirubicin (EPI), has also shown a poor antitumor activity in the treatment of NSCLC when used at 'standard' doses (= 90 mg/m2). On the contrary, high-dose epirubicin (HD-EPI) (> 90 mg/m2) has demonstrated antitumor activity as a single agent in the treatment of advanced NSCLC in six small phase II studies (mean 25%, range 17%-36%).

A series of consecutive studies on the activity of HD-EPI alone or in combination regimens were carried out at the Division of Medical Oncology of S. Orsola-M. Malpighi Hospital. After activity was confirmed in advanced disease with doses between 120 and 165 mg/m2 (PR in 6 of 24 = 25%), a phase II study was carried out on the combination of HD-EPI 120 mg/m2 + cisplatinum (CP) 60 mg/m2 in stage IIIB-IV NSCLC. PR was achieved in 54% of 35 patients with a median survival of nine months. A subsequent multicenter phase III trial compared HD-EPI and vinorelbine (VNR), both combined with CP. Two hundred twenty-eight patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 plus CP 60 mg/m2 on day 1 or VNR 25 mg/m2 on day 1 and 8 plus CP 60 mg/m2 on day 1. Both treatments were recycled every 21 days. Eligible patients were 212 and 210 patients evaluable for objective response (100 on HD-EPI and 110 on VNR), respectively. The CR + PR rate was 32% vs. 26% (P = NS) for a median duration of nine and eight months, respectively. Median survival was 10 and 9.5 months, respectively. Grade III-IV leucopenia occurred in 38% and 21% on HD-EPI and VNR, respectively (P = 0.01), thrombocytopenia in 6% and 0% (P = 0.02), anemia in 8% and 7% (NS). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88% vs. 33% on HD-EPI and VNR, respectively). Supraventricular arrhythmia occurred in three patients on HD-EPI; a > 15% LVEF decrease by MUGA scan was observed in 22.5% and 14% patients on HD-EPI and VNR, respectively (NS). No congestive heart failure was observed.

EPI can be safely administered at a dose of 120-135 mg/m2 in non-pretreated patients showing a significant antitumor activity in NSCLC. If the cumulative dose of 800-900 mg/m2 is not exceeded, clinical manifestations of cardiotoxicity are very rare. However, grade 3-4 myelotoxicity and alopecia are very common and can limit the use of this drug in the palliative treatment of this disease. Interesting results are observed in an ongoing pilot study that employed HD-EPI + CP + VNR + G-CSF in the induction therapy of locally advanced NSCLC.