Differences in Treatment-related Toxicities
Small-cell Lung Cancer
In the aforementioned study for extensive stage SCLC, toxicities were also compared between JCOG 9511 and SWOG 0124. Significant differences in hematological toxicities were observed in both cisplatin and etopsode (PE) and cisplatin and irinotecan (PI). Grade 3 or higher neutropenia and anemia were observed in 92 and 32% of Japanese patients treated with PE, respectively; this was 68 and 12% in the US patients, respectively (p < 0.001). As for PI regimen, frequency of neutropenia and anemia were 65 and 28% in the Japanese study, and 34 and 6% in the SWOG study (p < 0.001), respectively.
Non-small-cell Lung Cancer
In the previously mentioned Phase I study of crizotinib in patients with ALK gene rearrangement, the pharmacokinetics (PKs) and toxicity of crizotinib has also been reported in Abstract form. Differences in the PKs of crizotinib between Asians (n = 12) and non-Asians (n = 17) were reported with the steady-state mean area under the concentration–time curve (AUCT) of crizotinib 65% higher in Asian patients. The steady-state mean AUCT of crizotinib adjusted to body weight and body surface area was 26 and 46% higher, respectively, in Asian patients compared with caucasian patients. Crizotinib was well tolerated by both Asian and non-Asian patients, with Asian patients experiencing more low-grade but fewer severe events. As crizotinib is metabolized by CYP3A isozymes, which have no known polymorphisms between Asians and non-Asians, the basis of PK differences is currently unknown.
In the NSCLC common-arm analysis, toxicities were also analyzed from the two Japanese studies (FACS and JMTO LC0003) and the US SWOG 0003 study. In the common arm regimen of paclitaxel plus carboplatin, grades 3/4 neutropenia were comparable between the Japanese studies (88% in FACS and 70% in LC0003) and were significantly greater than in SWOG 0003 (38%) (p < 0.001). Neutropenic fever was more frequent in FACS (27%) and JMTO LC0003 (12%) compared with SWOG 0003(2%) (p < 0.001). Grade 3/4 anemia was greater in FACS (15%) compared with the two other trials (8% in JMTO LC0003 and 7% in SWOG 0003) (p = 0.03).
A pooled analysis on toxicity of Asian versus caucasian patients based on 12 Phase II trials and 38 Phase III trials of NSCLC with a total of 11,271 patients has been reported recently. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, the OR of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian (mostly caucasian). In the treatment of cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV) and carboplatin plus paclitaxel (CP), the ORs were 1.55–3.45 (p < 0.001), 2.99–4.43 (p < 0.001) and 4.79–6.22 (p < 0.001), respectively. Grade 3/4 anemia was also significantly higher in Asians with CG (OR: 3.10–3.27; p < 0.001), CV (OR: 1.99–2.43; p < 0.001), and CP (OR: 1.34–1.52; p = 0.001–0.004). However, no significant difference was observed in thrombocytopenia with CG (OR: 0.66–2.04; p < 0.001–1.000), CV (OR: 0.42– 0.57; p = 0.097–0.323), or CP (OR: 1.21–1.39; p = 0.114–0.152). Given these results, potential and significant differences in hematological toxicities, in particular in neutropenia and anemia, exist between Asian and caucasian patients treated with cytotoxic chemotherapy.
Future Oncol. 2012;8(4):451-462. © 2012 Future Medicine Ltd.