Patterns of brain metastasis immediately before prophylactic cranial irradiation (PCI): implications for PCI optimization in limited-stage small cell lung cancer

Small cell lung cancer (SCLC) features a rapid doubling time and an aggressive behavior. Brain is a favored site of metastasis in SCLC, and the 2-year brain metastasis (BM) rate could reach more than 50% – even in SCLC patients who achieved complete remission (CR) after chemotherapy [1].

Prophylactic cranial irradiation (PCI) has been proved to effectively reduce BM and improve survival in limited-stage SCLC (LS-SCLC) patients with a good response to definitive chemoradiotherapy (CRT) [1‐4]. Theoretically, there could be some patients experiencing BM before PCI, due to poor penetration of drugs through the blood-brain barrier. However, most previous studies exploring the value of PCI in SCLC did not enforce brain imaging immediately before PCI [1, 2]. A small-cohort study, employing cranial magnetic resonance imaging (MRI) immediately before PCI in LS-SCLC patients who had achieved CR after CRT, found that 32.5% of the patients developed BM before PCI [5].

Here, we report the prevalence of and risk factors for BM immediately before PCI (pre-PCI BM), based on contrast-enhanced cranial MRIs in a larger cohort from our center. We also investigated the time trend for pre-PCI BM and several radiological features of the intracranial lesions, aiming to explore the potential of PCI optimization for LS-SCLC patients in the MRI era.

Our study corroborates the findings of a previous study in a relatively small cohort [5], which showed that there was a considerable risk of pre-PCI BM in LS-SCLC patients who achieved clinical CR after definitive CRT. Moreover, in both studies patients with pre-PCI BM were rarely neurologically symptomatic. These findings suggest the importance of MRI evaluation immediately before PCI, even in asymptomatic patients. In addition, we investigated the time trend and risk factors for pre-PCI BM and several image features of the intracranial lesions, which were not reported in the previous study [5]. Our findings indicate that some aspects could be optimized in PCI for LS-SCLC.

Treatment duration was often employed to represent the CRT time-intensity and has been revealed as an independent risk factor for OS in SCLC [11]. In the present study, longer CRT-D was found to be a risk factor for poor survival. The inferior survival of patients with longer CRT-D may have been the result of worse performance status, larger tumor burden and poorer compliance. However, it is also plausible that the worse survival in patients with longer CRT-D may be partly derived from a higher pre-PCI BM rate: in this study longer CRT-D was an independent risk factor for pre-PCI BM.

Many studies showed that BM incidence plateaued around 2 years after PCI for SCLC and remained significantly lower than control groups [1‐3, 12]. This phenomenon indicates that the emergence of detectable BMs can be prevented, instead of simply delayed, by PCI. In other words, PCI is a curative rather than palliative therapy for subclinical BMs in SCLC. However, when these BMs become clinically detectable, PCI may only achieve palliative results. As shown in this study, although all of the patients with MRI detected pre-PCI BM received WBRT, the outcomes were significantly worse than in those without pre-PCI BMs.

In the current study, the cumulative incidence of MRI-detected pre-PCI BMs gradually increased along with the time interval between the treatment initiation and pre-PCI MRI, even though clinical CR was achieved for the extracranial disease. We speculate that with the longer treatment courses, there is more time for occult brain lesions to develop and become MRI-detectable, possibly due to the poor penetration of chemotherapy agents through the blood-brain barrier.

Considering all the evidence, we believe that the timing of PCI is crucial for optimal BM prevention. At present, 4–6 cycles of chemotherapy at 21-day intervals concurrently with TRT was recommended for LS-SCLC [13, 14], which would take 2–3.5 months if administered on schedule. In this study, the cumulative incidence of pre-PCI BM was 6.67% at the fourth month after initial treatment, which increased to 12.20% only 1 month later; it gradually increased further to 21.82% at the ninth month from treatment initiation. Thus, in patients who completed CRT on schedule, the pre-PCI BM risk is relatively low, and they can receive PCI after CRT completion. However, for patients whose CRT courses are prolonged to more than 4 months, postponing PCI further may expose them to higher risk of pre-PCI BM. Investigations of moving PCI up and before CRT completion in these patients are warranted.

Nonetheless, the timing of PCI should be weighed against neurotoxicity, because neurocognitive deficits have been reported to be more severe when PCI is delivered concurrently with chemotherapy [15, 16]. The HA technique was found to better preserve neurocognitive functions in WBRT [17, 18], and thus has garnered increasing interest recently. However, the intracranial seeding pattern immediately before PCI was previously unreported. Therefore, we investigated the risk of pre-PCI BMs in the HA region, to explore the safety of HA-PCI for LS-SCLC patients. In contrast to a previous study [19], our cohort is more likely to represent the pattern of de novo LS-SCLC BM distribution owing to the pre-PCI MRI, and that all patients included had limited diseases outside the brain. Consistent with the previous study [19], our results also showed that the risk of BM in the HA region is low.

SRT is a curative approach with lower toxicity for BMs from solid tumors, which is extensively employed in clinical practice. The idea of reserving PCI in LS-SCLC, and using salvage SRT when BMs emerge, had been raised [20]. In the present study, we investigated the image features of the intracranial lesions to explore the technical feasibility of applying SRT for the BMs detected before PCI. However, there are no standard criteria for BM SRT at present. BM numbers of 1–3 or 4 were traditionally thought to be most suitable, but there is increasing evidence to support that SRT could benefit patients with more than 4 BMs. The present highest-level evidence comes from the multi-institutional prospective observational study conducted by the JLGK Society (JLGK0901) [10], which demonstrated that the therapeutic effect of SRT in patients with 5–10 BMs is comparable to that in those with 2–4 BMs. We employed the JLGK0901 eligibility criteria for evaluation of SRT feasibility in this study and found that 33.3% of the patients did not meet the criteria. This indicates that it is not appropriate to abandon PCI in these patients.

In summary, our findings suggest that PCI is still of importance for LS-SCLC, and patients should undergo MRI evaluation immediately before PCI. Studies exploring the possibility of moving PCI up and before CRT completion in LS-SCLC patients with prolonged CRT-D, and the feasibility of HA-PCI to reduce neurotoxicity, are warranted.