Background
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, and approximately 36%-44% of patients with NSCLC present with brain metastases during the course of disease[
1]. During the past 50 years, whole brain radiotherapy (WBRT) has been the standard treatment for brain metastases, but its therapeutic effects are suboptimal with intracranial control rate (ICR) of 60% and median survival of 3–6 months[
1,
2]. Stereotactic radiosurgery (SRS) is beneficial in patients with limited number and volume of metastases and it has become increasingly available as an alternative focal treatment to surgery, but its therapeutic effects decrease with increasing number and volume of lesions[
3]. Furthermore, SRS is not recommended in patients with lesions located in or close to critical anatomic structures because of unacceptable risk of severe long-term damage[
3]. Hypofractionated stereotactic radiotherapy (hfSRT) combines the precise beam delivery of radiosurgical technique with the radiobiological advantages of fractionation, and has shown the results comparable to SRS[
4].
Noncoplanar arcs, noncoplanar fixed fields and intensity modulation are the most frequently used stereotactic radiotherapy techniques. It has been reported that intensity-modulated radiotherapy (IMRT) technique results in improved dose conformity as compared to the other two techniques for the hemisphere and irregular tumor targets, and may increase the therapeutic ratio of treating large and/or irregularly shaped intracranial lesions[
5]. Image guided intensity-modulated radiotherapy (IG-IMRT) is a new technique of radiotherapy. It improves the accuracy of treatment delivery by using cone beam computed tomography (CBCT) with x-ray volumetric images (XVI) to give the 3-dimensional anatomic information in the treatment position and to reduce setup uncertainty[
6]. With these advantages, it is possible to administer hfSRT with IG-IMRT to brain metastases with non-invasive head fixation such as thermoplastic mask[
6,
7].
Several prospective trials proved the superiority of WBRT plus focal radiotherapy boost in patients with limited number and volume of brain metastases[
8,
9], and even in patients with a large number and volume of brain metastases, several studies indicated that focal hfSRT may be effective[
10,
11]. Radiotherapy schedules of most previous reports were WBRT plus sequential SRS/hfSRT boost. Recently, some reports showed that WBRT plus simultaneous in-field boost (SIB) with helical tomotherapy were effective and tolerable for brain metastases[
12‐
15]. In our department, 40 Gy/20 f (5 f/week) used to be the standard schedule of WBRT, and some NSCLC patients with brain metastases received SIB with IG-IMRT in the fourth week of WBRT if they had no or only mild neurological symptoms during the first three weeks. Therefore, we conducted this retrospective study to evaluate the efficacy and toxicities of WBRT plus SIB with IG-IMRT for NSCLC patients with brain metastases.
Discussion
WBRT plus sequential focal SRS/hfSRT boost is one of the most widely used therapeutic strategies for patients with limited brain metastases. However, evidence on efficacy and toxicities of WBRT plus simultaneous hfSRT are emerging recently. The phase I trial of WBRT plus SIB with helical tomotherapy showed that the delivery of 60 Gy/10 f synchronously with WBRT of 30 Gy was tolerable in patients with 1–3 brain metastases, and the Phase II trial is ongoing to examine its efficacy[
12,
13]. Just like helical tomotherapy, the Synergy IGRT system used in our study is one of integrated image-guided intensity-modulated-capable radiotherapy platforms. However, different from the more advanced arc-based IMRT such as helical tomotherapy, the radiation technology used in our study was a step-and-shoot IMRT which was more common and economically feasible in developing countries. Furthermore, only NSCLC patients were eligible in our study, and they were more homogeneous with respect to previous reports of WBRT plus SIB with helical tomotherapy, which enrolled patients without prescribing a limit to pathological type of primary cancer[
12‐
14].
The reported one-year ICR and median survivals of patients with limited brain metastases received WBRT plus sequential focal hfSRT boost were 66%-86% and 7.5-13 months[
16‐
20]. Unlike reports above, approximately half of patients in our study had multiple (≥3) or large (≥3 cc) intracranial lesions, which were always excluded in other studies. However, the median survival and one-year ICR of whole patients in our study were 10 months and 62.9%, which were close to previous data in above studies. Several grading systems are available for brain metastases, such as Graded Prognostic Assessment (GPA), Recursive Partitioning Analysis (RPA) and SIR. Higher level of RPA and lower scores of GPA and SIR are associated with worse survival of patients with brain metastases[
21‐
24]. Similarly, the survival was better in RPA class II, GPA scores 1.5-3.5, and SIR >5 patients in our study. However, possibly because of the limited number of enrolled patients, only differences in survivals between patients with SIR ≤5 and >5 were statistically significant. The number of lesions is another important factor affecting radiotherapy efficacy, and patients with limited number of brain metastases seem to have better outcomes. It has been reported that median survivals were 6.5-16 months following WBRT plus focal radiotherapy boost in patients with single intracranial lesion, corresponding to 5.8-13months in patients with multiple intracranial lesions[
8,
9,
16,
17]. Similarly, patients with number of lesions <3 showed better outcomes in our study, and the median survival was comparable to the data reported by other investigators[
11,
17,
20].
Several studies showed that the radiosensitivity of brain metastases is associated with the mutation status of epidermal growth factor receptor (EGFR)[
25‐
27]. Compared to patients with the wild-type, those with activating EGFR mutations had higher response rates and better survival following WBRT (54%
VS. 24%,
P = 0.045; 17.3 months
VS. 6.6 months,
P = 0.121)[
26]. EGFR-TKI, either alone or combined with WBRT, is effective in brain metastases of NSCLC especially for EGFR-mutated patients[
26,
28,
29]. From the phase I and II trials of WBRT with concurrent and maintenance erlotinib in NSCLC with brain metastases, erlotinib in combination with WBRT was well tolerated and had a favorable efficacy. Moreover, EGFR-mutated patients had a better survival compared to those with wild-type (median survival: 19.1 months
VS. 9.3 months)[
29,
30]. In present study, history of EGFR-TKI treatment was also a favorable prognostic factor for survival, and the median survival of 11 patients received concurrent and maintenance EGFR-TKI treatment was as long as 18 months. EGFR mutation status is not available in our study. However, most patients who received EGFR-TKI in this study were female (72.7%) and had adenocarcinoma (81.8%). Considering the evidence that Asian, female, non-smoking, and adenocarcinoma patients were more likely to be EGFR mutated, and rates of EGFR mutation in brain metastases of NSCLC were 44%-63% in East Asian population[
31,
32]. We speculated that EGFR mutations might contribute to the better survival in the EGFR-TKI treated patients in present study.
Considering the concurrent WBRT, intracranial lesions received total boost doses of 30 Gy/5 f in our study. By using the α/β ratio of 12 Gy and LQC model (BED = nd [1 + d/(α/β)-d
2/(α/γ)]), which was indicated to be suitable for calculating BED value of SRS or hfSRT for brain metastases[
33], the BED value of total boost were 43.33 Gy, which was comparable to other reports of brain metastases treated by hfSRT[
12,
13,
16‐
20,
34]. Late radiation toxicity of 13.8% grade 3 cognitive impairment in our group was comparable to previous data of 6%-11% grade 3 late toxicities from other studies[
16,
17]. The incidence of radiation necrosis was one of the major concerns in late toxicities from WBRT plus focal radiotherapy boost, but it was quite infrequent in our study, and was similar to other reports of WBRT plus focal hfSRT boost[
10,
16‐
18]. Leukoencephalopathy and cognitive impairment were primary late toxicities in present study, and only history of EGFR-TKI treatment was a risk factor for grade 2 leukoencephalopathy in multivariate analysis, which had not been reported by other studies. Patients who received EGFR-TKI treatment had the longer survival, which might partly explain the higher incidence of late toxicities in these patients. It has been reported that the EGFR-TKI plus concomitant WBRT may have synergy effect in brain metastases from NSCLC, the ORR, ICR, and IC-PFS were significantly higher in gefitinib plus WBRT compared with gefitinib alone (ORR: 64.4%
VS. 26.7%,
P < 0.001; DCR: 71.1%
VS. 42.2%,
P = 0.006; IC-PFS: 10.6 months
VS. 6.57 months,
P < 0.001)[
35]. It is a reasonable assumption that the EGFR-TKI plus concomitant brain radiotherapy might also have synergy neurotoxicity, and it might be another reason for the higher incidence of late toxicities in patients with EGFR-TKI treatment. However, considering the limited number of patients in our study, it may need more preclinical and clinical data to support this assumption.
This retrospective study had many limitations such as heterogeneity and limited number of enrolled patients, lack of phase I data, lack of health-related quality of life (HRQoL) data, and lack of neurocognative testing data. We look forward to that the ongoing phase II trial of SIB with helical tomotherapy for 1–3 brain metastases will give us more information[
13].
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Competing interests
There is no actual or potential conflict of interest in this study.
Authors’ contributions
LZ participated in its design and drafted the manuscript. JL helped to review medical records and draft the manuscript. JX helped to analyze the data of local tumor control and survival. YX helped to review medical records. YG and LD helped to draft the manuscript and participated in coordination. SW helped to analyze the data of dosimetry. RZ helped to analyze the data of dosimetry. ZD helped to review medical records. YL designed the study and participated in coordination. All authors read and approved the final manuscript.