A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer

Abstract

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 Â 2 Gy) alone with WBRT þ topotecan (RCT; 0.4 mg m À2 day À1 Â 20). A total of 320 patients with CNSmetastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3 -752/4 -433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3 -399/4 -228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment.

Whole Brain Radiotherapy Plus Chemotherapy in the Treatment of Brain Metastases from Lung Cancer: A Meta-analysis of 19 Randomized Controlled Trails

“…There were 1471 citations yielded, of which 1440 were removed during abstract review stage as being duplications or irrelevant to the specific question. The remaining 31 studies were to full text screening, and 19 RCTs were included (He et al, 2003;Guerrieri et al, 2004;Ge et al, 2005;Gao et al, 2009;Neuhaus et al, 2009;Dong et al, 2010;Gao, 2011;Pan et al, 2004;Peng et al, 2008;Postmus et al, 2000;Sun et al, 2009;Verger et al, 2005;Xiao et al, 2001;Xie et al, 2007;Zeng et al, 2009;Zhao et al, 2007;Zhu et al, 2009).…”

“…The specifics of the chemotherapy regimens were listed in Zhao et al, 2007;Peng et al, 2008;Gao et al, 2009;Zeng et al, 2009;Zhu et al, 2009;Dong et al, 2010;Gao, 2011), one study according to RECIST (Sun et al, 2009), and 3 studies with unspecified the evaluation criteria (Postmus et al, 2000;He et al, 2003;Neuhaus et al, 2009). The assessments of the 19 studies by two independent reviewers were consistent.…”

“…Figure 2 showed the results of authors' judgement of risk of biases. According to the bias risk assessment tool in the Cochrane systematic reviews handbook (Higgins et al, 2011), 6 RCTs (Postmus et al, 2000;Guerrieri et al, 2004;Verger et al, 2005;Zhao et al, 2007;Gao et al, 2009;Neuhaus et al, 2009) were randomized correctly using the method of random sequence Generation, one study (Xiao et al, 2001) was randomized incorrectly by grouping the patients in the order of admission, and the remain 12 RCTs were just mentioned "randomized" but unclear how to performed. Five RCTs used correct allocation concealment strategies (He et al, 2003;Ge et al, 2005;Sun et al, 2009;Xie et al, 2007;, but the other 14 failed to describe the methods of allocation concealment.…”

“…Three RCTs (erger et al, 2005;Gao et al, 2009;Neuhaus et al, 2009) reported the occurrence of thrombocytopenia. The results of meta-analysis by using random-effects model (p = 0.009, I 2 = 79%) showed that the incidence of thrombocytopenia in WBRT plus chemotherapy group was 5.83 times than WBRT alone group, but the difference was not statistically significant (RR = 5.83, 95% CI = 0.39 -86.59; P = 0.20) (Figure 5).…”

“…2003; Guerrieri et al, 2004;Li et al, 2004;Pan et al, 2004;Ge et al, 2005;Verger et al, 2005;Xie et al, 2007;Zhao et al, 2007;Fan et al, 2008;Peng et al, 2008;Wang et al, 2008;Gao et al, 2009;Neuhaus et al, 2009;Sun et al, 2009;Zeng et al, 2009;Zhu et al, 2009;Dong et al, 2010;Gao, 2011;Guo, 2011). However, not all the results show the differences have statistical significance, and the sample sizes of some studies are small.…”