WBRT has been used as a standard treatment for BM patients for decades. However, the relationships of WBRT total dose with intracranial tumor control and survival are rarely studied in NSCLC BM patients alone. These profiles are significantly complicated by factors of age, KPS, tumor type, BM lesion number, extracranial metastatic status, local RT modalities, among others . Through this retrospective multivariable analysis, we found that compared to none, WBRT dose ≥30 Gy was invariably associated with improved OS and iPFS. This finding further warrants clinical trials for confirmation. Whether and how the lower WBRT < 30 Gy provide benefits is still unknown and should be further investigated in controlled studies.
This study used a recent large dataset from the real world. Due to differences in healthcare system and socio-cultural reasons, WBRT was administered for only 43% of all NSCLC BM patients newly treated in 2013–2015 at a single cancer institution in China. In this study, patients with WBRT 30–39 and ≥ 40 Gy had estimated MTS of OS of 10.3 and 11.9 months, respectively. Compared to non-WBRT patients, patients with WBRT ≥30 Gy had extended MTS of 4.5–6 months. Similar survival results have also been reported in other Chinese studies [27, 28]. Xiang et al. reported that 135 NSCLC BM patients with WBRT-based combined therapies had MTS of OS as 9.3 months, 1-year and 2-year survival rates as 46.3 and 16.1%, respectively . Zhu et al. reported that 29 inoperable NSCLC BM patients treated with WBRT 40 Gy/20f plus simultaneous in-field boost IMRT 20Gy/5f had estimated MTS of OS and of iPFS as both 10 months . Neither of two studies above enrolled non-WBRT patients. In our study, there were 58% (n = 344) NSCLC BM patients without WBRT as the analysis control.
Whether and how WBRT improves survivals of BM patients at low dose is a difficult question. Further studies on pathophysiology and radiobiological mechanisms of WBRT on BM are required. Through the most recent Cochrane database systematic review, Tsao et al. concluded that the HR of OS with lower biological WBRT doses as compared with control of 30Gy/10f was 1.21 (1.04–1.40, p = 0.01) and with higher biological WBRT doses vs. 30 Gy/10f was 0.97 (0.83–1.12, p = 0.65); both are regarded to have “moderate-certainty” evidences . In addition to WBRT dose, many other multifactorial and interrelated complexes can contribute to survival: such as genetic mutation and blood-brain barrier interactions with local treatments (e.g. RT or surgery) or drugs [20, 26, 27]. Thus far, WBRT administered after local surgery or SRT for patients with 1–3 BM has been evidenced to reduce neurologic death and intracranial relapse but not overall mortality [14, 29]. Currently, many studies have indicated a tendency of longer OS for WBRT-based RT regimens compared to chemotherapeutic ones [18, 20]. However, in the recently published QUARTZ trial, Mulvenna et al. concluded that WBRT provides no better survival than optimal supportive care (OSC) in NSCLC BM patients considered unsuitable for surgical resection or SRT . In this trial, 538 patients in 2007–2014 were randomly assigned into OSC or OSC + WBRT (20Gy/5fr) arms; both arms had the similar MSTs (8.5 and 9.2 weeks, respectively) with an insignificant HR of 1.06 (95% CI 0.90–1.26, p = 0.81) . We noticed that the QUARTZ trial treatment regimens served more palliative than curative purposes and that BM patients were recruited over 8 years and had quite short life expectancy period. Nonetheless, we believe our study population was far more representative of the real world of NSCLC BM patients in recent years and the conclusion should be applicable to the general NSCLC BM patients.
Many trials have failed to define the optimal dose and schedule of WBRT for OS or tumor control [7, 18, 20]. Most of them used various dose-fractionation schedules of WBRT 20–40 Gy/10 - 20f and had different endpoints making comparison and generalization of the dose-effect profile difficult. Indeed, given that WBRT dose of either 30Gy or 40Gy is biologically regarded to be well below the lethal RT dose (presumably over 50 Gy) of tumor, the majority of WBRT regimens in those trials were intended only for palliative purposes [7, 11, 12, 18]. Two RTOG trials in the early 1970s each enrolling over 900 BM patients had concluded that multiple WBRT schedules (low vs. high of 20–40 Gy) and time periods (short vs. long of 2 to 4 weeks) had similar tumor response rate, palliative effects, and time to progression and survival ; randomly-added ultra-short WBRT schedules (10Gy/1f vs. 12Gy/2f vs. 20Gy/5f) led to the same survival time but shorter time to brain tumor progression . Kurtz et al. conducted one randomized control trial (RCT) in 255 highly-selected BM patients with good prognosis to conclude that WBRT 50Gy/20f and 30Gy/10f schedules had similar effects of symptom palliation, time to progression, cause of death, and survival . Another trial comparing WBRT 32Gy plus 24.4 Gy to a boost field in 1.6 Gy fractions (b.i.d.) with WBRT 30Gy/10f among 445 patients had demonstrated that the accelerated hyper-fraction of WBRT made no difference on survival time . However, one trial indicated that WBRT 40Gy/20f (b.i.d) in 113 patients had similar OS but higher tumor control rate (56% vs. 36%) and lower neurological mortality (32% vs. 52%, p = 0.03) than WBRT 20Gy/4f, . Another trial involving 533 patients showed that WBRT 30Gy/10f compared to WBRT 12Gy/2f had a slight but statistically better OS (p = 0.04) .. These trials support our conclusion that WBRT doses ≥30 Gy provide better intracranial tumor control.
How the local treatment of BM (surgery, SRT or boost RT) impacts the dose-effect survival profiles of WBRT is infrequently studied. Some published trials showed that combining SRT or surgery with fixed-dose-schedule of WBRT had improved OS and reduced local failure in patients with single metastasis only [16, 34]. Andrews et al. conducted one RCT of 333 patients with 1–3 BM lesions and found that compared to WBRT alone, SRS + WBRT (37.5Gy/15f) had a better local control rate at 1 year follow-up (82% vs. 71%, p = 0.01) and better OS for single metastasis patients only (MTS 6.5 vs. 4.9 months, p = 0.04) but not in the entire cohort (6.5 vs. 5.7 months, p = 0.14); for NSCLC BM patients only, their MTS of ‘SRS + WBRT’ and ‘WBRT alone’ patients were estimated as 5.0 vs. 3.9 months (p = 0.05), respectively . Patchell et al. conducted another RCT by assigning 48 patients with single BM into surgery + WBRT (36 Gy/12f) vs. WBRT alone and found significant advantages of lower local failure (20% vs. 52%, p < 0.02) and longer MTS (40 weeks vs. 15 weeks, p < 0.01) for the surgery + WBRT patients . However, one trial by Mintz et al. failed to show the benefit of improving OS (MST 5.6 months vs. 6.3 months, p = 0.24) by having surgery first for the single BM patients who had the universal WBRT 30Gy/10f . To determine the effects of adding boost RT to WBRT, Antoni et al. retrospectively analyzed 208 BM patients (137 from lung cancer) with RPA II and 1–2 metastases and found that patients with boost RT 9Gy/3f had MST of 2.2 months longer (5.9 vs. 3.7 months, p = 0.03) and higher local tumor control rates at 6-, 12- and 24-month (p = 0.03) than patients with WBRT (30Gy/10f) alone . In this study, we had 15 SRT patients (only one had subsequent WBRT) and 32 surgical patients (14 of them had WBRT before or after BM surgery). Through multivariable analyses, we found that SRT was associated with better OS but not iPFS, and the boost ≥50 Gy was associated with better OS than iPFS (Table 3).
Other factors affecting OS and iPFS were also identified in this study. Chemotherapy and targeted therapy were found to be quite effective in improving OS and iPFS (p < 0.001). While female, young age, good KPS, short NSCLC history, and primary tumor resection were associated with improved survival, the presence of extracranial metastasis and BM lesions ≥4 predicted poorer survival. These findings were consistent with other studies [4, 37,38,39,40,41,42]. In this study, instead of using calculated GPA or RPA score, we decided to use individual covariates in Cox models to better estimate the independent dose-survival effect of WBRT. The adjustment analyses by RPA, Lung-GPA or Lung-molGPA confirmed that OS and iPFS profiles of WBRT dose level have not changed. The survival profiles of these common prognostic indices were also found to be consistent with other studies [4, 6, 41].
We recognize that our current study has both limitations and strengths. In addition to the hidden selection biases of any retrospective analysis, weaknesses include: (1) the resultant link of delivered ‘RT boost’ and higher WBRT dose could compromise their independent benefit profile evaluation in somewhat way even through multivariate and stratified analyses; (2) the BED of WBRT was not calculated for use; we were concerned with the accuracy and validity of using traditional linear-quadratic formula and citing a specific α/β value for BED calculation among these NSCLC BM patients who received heterogeneous modalities of RT rather than the fixed-schedule of universal WBRT; as aforementioned, the actual percents of 40Gy/20f, 30Gy/10f, and 37.5Gy/15f regimen used were 46, 41, and 5% in 251 WBRT patients; (3) neither neurologic symptoms nor quality of life measurements were collected; (4) Only 4.7% of patients took the ALK gene mutation test; how this low test rate, high positive rate (21%, 6/28) and the rare use of ALK drugs in the Chinese population impact the study results was difficult to assess. Strengths of this study include (1) our cohort study was conducted at a single center between 2013 to 2015 during which the guidelines of NSCLC BM treatment experienced little variation; (2) three other RT modalities in their independent formats were considered in multivariable analyses; (3) individual covariates were also presented in the final models.