Whole-brain radiotherapy is currently the standard treatment for brain metastasis from lung cancer and can increase patient survival up to 3–6 months
[6, 7]. However, the rate of complete remission is low, with 30–50% of patient deaths caused by uncontrolled and recurrent intracranial lesions
[8, 9]. The possible reasons are insufficient dose for local tumour during whole-brain irradiation and the limited utility of chemotherapy in this area due to the blood–brain barrier.
Three-dimensional conformal radiotherapy is a newly developed radiation therapy technology that can maximise the radiotherapy dose to tumour but not normal tissues and can increase treatment efficacy
. The results of RTOG9508 indicated that, for the patients with 1–3 brain metastases, whole-brain irradiation plus boost precision radiotherapy significantly improved the efficacy and local control rate compared with whole-brain irradiation alone, with 1-year local control rates of 82% and 71%, respectively. Efficacy was even better for patients with a single brain metastasis. Further analysis found that, for patients with localised lesions ≥ 2 cm and ≤ 3 metastases, whole-brain radiotherapy plus localised boost irradiation showed good efficacy
. Similarly, Casanova et al.
 found that whole-brain radiotherapy plus localised boost irradiation achieved good efficacy for patients with 1–3 brain metastases from lung cancer, with a 1-year local control rate of 75.2%. Univariate analysis revealed that the local dose was positively correlated to the survival.
Stafinski et al.
 reported that whole-brain radiotherapy plus boost precision irradiation for brain metastases (no other distant metastasis) from lung cancer had an effective rate of 91%, which was significantly higher than that of the radiotherapy-alone group of 62%. The 2-year local control rate of 51% and the 2-year survival rate of 23% were also significantly higher than those of the whole-brain radiotherapy-alone group. For patients with other concomitant extracranial metastases, whole-brain irradiation plus boost precision radiotherapy only improved local control; it did not affect survival, suggesting the importance of systemic concurrent chemotherapy for controlling extracranial metastases.
A previous study found that chemotherapy concurrent with whole-brain irradiation may improve treatment efficacy
. Topotecan is a semi-synthetic camptothecin derivative. As an inhibitor of topoisomerase I, topotecan can pass through the blood–brain barrier and exerts a radiosensitising effect, with 33–63% efficacy for brain metastasis tumour
[13, 21–23]. Combining whole-brain irradiation with a maximum daily tolerated dose of topotecan at 0.4–1.0 mg/m2/d
[14, 15, 24] can improve the local control rate of brain metastases, and patients can tolerate it, with myelosuppression as the main side effects. Hedde et al.
 applied topotecan combined with whole-brain radiotherapy in patients with brain metastases from lung or breast cancer and achieved a treatment efficacy of 72%. Mirmiran et al.
 also applied topotecan combined with whole-brain radiation therapy for lung cancer patients with brain metastases with a dose for whole-brain irradiation of 30 Gy/10 times, and the median PFS time of 60 days and the MST of 102 days were not significantly improved compared with the results of previous studies. The possible reason could be insufficient radiotherapy and chemotherapy doses. Therefore, the effect of topotecan combined with concurrent radiation therapy to treat brain metastases from lung cancer has not yet been thoroughly assessed.
Whole-brain irradiation plus local conformal boost can improve local tumour control, but there is no conclusive evidence showing that it improves survival. The application of concurrent chemotherapy drugs can treat extracranial lesions and further improve the local control of intracranial lesions. Consequently, whole-brain irradiation plus 3-D conformal boost radiotherapy with concurrent chemotherapy would theoretically improve survival. To our knowledge, there are no reports on whole-brain irradiation plus 3-D conformal boost radiotherapy with concurrent chemotherapy to treat intracranial metastasis from lung cancer. Although the maximum tolerated dose of topotecan had been reported
[14, 15, 24], we considered that the maximum tolerated dose for the western population may not be applicable to the Asian population due to physical differences between the populations, and this consideration was also based on our previous study results on concurrent chemotherapy and radiotherapy
[25, 26]. Therefore, we conducted a phase I clinical study using whole-brain irradiation plus 3-D conformal boost, combined with weekly topotecan chemotherapy. The patients with brain metastases from lung cancer in this study had ≤ 3 intracranial metastases that were ≥ 2 cm in diameter. We found that the maximum tolerated dose of topotecan for Chinese patients was 1.75 mg/m2/w
. Based on this result, we performed this phase II clinical study.
Our study met its primary endpoint, which was that concurrent chemoradiotherapy significantly improved PFS for patients with brain metastases from lung cancer. Compared with the radiotherapy-alone group, concurrent conformal radiotherapy significantly improved intracranial lesion control. The 1- and 2-year intracranial lesion local control rates of the concurrent chemoradiotherapy and radiotherapy-alone groups were 75.9% and 65.2% and 41.6% and 31.2% (χ2 = 3.892, p = 0.049), respectively. No difference in overall survival (OS) was found between the two groups, with the possible reason being that CRT failed to significantly reduce extracranial lesion progress. No difference in the extracranial lesion control rate was found between the two groups (χ2 = 0.610, p = 0.435), and the main cause of death in patients in both groups was distant metastasis. Compared with radiotherapy alone, CRT failed to significantly improve OS, the NSCLC in the CRT group obtained an average MST of 10 months and a 1-year OS of 33.8%. These results are comparable with the therapeutic outcomes of whole-brain irradiation combined with concurrent temozolomide (TMZ) chemotherapy and targeted therapy, which produced MSTs of 6.3 and 4.0 months and 1-year OS rates of 20.0% and 37.5%, respectively
. The comparable results confirmed the validity of the treatment plan in our research. Our study showed that the application of localised boost irradiation technology and concurrent topotecan chemotherapy achieved better local control of intracranial lesions but did not improve the extracranial lesion control rate. Arrieta et al.
 reported that whole-brain irradiation with concurrent chemotherapy and chest chemoradiotherapy can be applied to strengthen the control of extracranial lesions for lung cancer patients with brain metastases without metastasis in other organs. In this small retrospective study, the treatment plan provided very good efficacy, with PFS and OS of 8.43 ± 1.5 months and 31.8 ± 15.8 months, and the 1- and 2-year PFS and OS were 39.5% and 24.7% and 71.1% and 60.2%, respectively. The study also confirmed the importance of strong concurrent chemoradiotherapy on extracranial lesions to improve lesion control rate.
How to effectively control extracranial lesions is the direction of the future research. The combination of radiotherapy and two-drug chemotherapy should theoretically reduce the possibility of distant metastasis. Tang et al.
 applied docetaxel and cisplatin concurrent with whole-brain radiation therapy and found that 1-year survival rate of 65% in the concurrent chemoradiotherapy group was significantly higher than the 30% survival rate in the radiotherapy-alone group. In recent years, the targeted drugs gefitinib and erlotinib showed good efficacy in the treatment of NSCLC
 and some studies showed efficacy for brain metastases from lung cancer
[31–34]. In the future, whole-brain irradiation with concurrent targeted therapy could be used to improve the systemic tumour control rate, thereby improving overall survival.