The Dandelion Dilemma of Brain Metastases: Treating the Whole Lawn or the Weeds Separately

Approximately, 40% to 60% of patients with small cell lung cancer (SCLC) develop brain metastases (BMs),1
^,2
^,3
and fewer than 15% survive beyond 2 years.4
^,5
 Whereas upfront stereotactic radiosurgery (SRS) has become the preferred treatment for brain metastases arising from most solid tumor histologies,6
SCLC remains an exception where whole brain radiotherapy (WBRT) has remained the standard of care.7
 This practice is influenced by the understanding that brain metastases in SCLC are rarely limited in number and that WBRT for SCLC, particularly in the setting of prophylactic cranial irradiation (PCI), has been shown to be effective with acceptable neurocognitive outcomes. Due to increasing awareness of the effect on neurocognitive function (NCF) and quality of life (QoL)8
and the increasing use of SRS, many are rethinking the practice of WBRT for SCLC brain metastases.

Clinical Trials
Multiple randomized trials have demonstrated improved central nervous system (CNS) control with strategies incorporating WBRT but improvement in NCF and QoL and equivalent overall survival (OS) with SRS alone.9
However, patients with SCLC were excluded from these landmark trials due to factors including: 

• Historically poor prognosis of patients with SCLC BMs;
• Concerns for higher propensity for CNS progression than in many other solid tumors;
• Short interval, multi-lesion CNS progression specific to patients with SCLC histology; and
• The widespread prevalence of PCI, which has limited both the ability to study SRS without prior brain radiation and to randomly assign patients to arms that included WBRT.10
  ^,11

Due to the paucity of data on first-line SRS for SCLC, WBRT has endured as the preferred treatment strategy for patients with one or more brain metastases. 

With emerging data, the role of PCI in the modern era continues to evolve. The landmark EORTC trial12
showed a benefit in OS for patients receiving PCI after a good response to systemic therapy. However, a recent Japanese trial by Takahashi et al.13
has challenged this historic benefit by showing no survival difference despite a reduction in CNS progression events (33% vs. 59% at 1 year; p < 0.001). Notably, most patients in the EORTC trial did not have any baseline brain imaging (63%), whereas all patients in the Takahashi trial had baseline and surveillance MRIs every 3 months for the first year. The increased MRI surveillance is thought to have permitted earlier and more effective salvage therapy. In response to this conflicting Level 1 evidence, the National Comprehensive Cancer Network (NCCN) SCLC guidelines changed PCI from a category 1 recommendation to an optional treatment strategy for extensive-stage SCLC (ES-SCLC) and added recommendations for brain surveillance (MRI preferred over CT in the United States but both equally acceptable in Africa) in all patients at the same interval regardless of PCI delivery.7
^,14
 

The potential benefit of PCI in ES-SCLC has been further complicated with randomized trials demonstrating improved disease-free survival and OS with the addition of immune checkpoint inhibitors (ICI) to platinum-based chemotherapy.7
^,15
^,16
^,17
However, the inconsistent use of PCI in the ICI trials limits our understanding of the benefit of using this combination. Future development of systemic agents with enhanced CNS activity in SCLC18
is a promising option to address CNS micrometastases,19
which has historically been achieved primarily with PCI/WBRT. Improved prognosis in the modern era has given momentum to look for strategies addressing the effect on NCF and has further intensified the already shifting practice patterns20
involving a decrease in PCI in the context of increased brain MRI surveillance. Together, these data suggest value in re-evaluating the role and therapeutic ratio of PCI in the modern era. The results of the currently ongoing SWOG 1827 trial, “MRI Brain Surveillance Alone Versus MRI Surveillance and Prophylactic Cranial Irradiation: A Randomized Phase III Trial in Small-Cell Lung Cancer (MAVERICK),” assessing the role of PCI for both limited-stage (LS-SCLC) and ES-SCLC in the era of ICI, MRI surveillance, and early salvage radiation therapy are eagerly awaited.21

Although the data on first-line SRS are more limited in SCLC compared with other solid tumors, the results from the recently published First-Line Radiosurgery for Small Cell Lung Cancer (FIRE-SCLC) study, the largest analysis comparing upfront SRS (without prior PCI or WBRT) for SCLC BMs (710 patients) with WBRT (219 patients), have been encouraging. The authors concluded a similar median OS (6.5 for upfront SRS vs. 5.2 months for WBRT; p = 0.003) against a trade-off of shorter time to CNS progression (9.0 months vs. not reached for WBRT; HR 0.38; p < 0.001). The more frequent use of surveillance MRI in the SRS versus WBRT cohort (89% vs. 46% had at least one follow-up MRI) could have resulted in observed differences in time to CNS progression as well as permitting more disease-altering salvage interventions among the upfront SRS cohort (16% with WBRT and 33.5% with SRS). Because the last year of treatment on FIRE-SCLC was 2018, contemporary interpretation of FIRE-SCLC remains limited in the context of the results from IMpower 133 in 2018 and CASPIAN in 2019.12
^,22
^,16
^,17
 Despite the use of propensity score matching, the likelihood of bias due to the non-randomized nature of the study exists. 

Despite promising outcomes by FIRE-SCLC and the authors suggesting the existence of subset of patients with SCLC brain metastases who demonstrate adequate survival to potentially benefit from a strategy of SRS alone,11
the widespread adoption of upfront SRS on a global scale is limited by current practice patterns, availability, and accessibility. PCI is the standard of care for LS-SCLC and a standard treatment option in ES-SCLC with global variation in use.7
^,22
^,23
^,24
^,25
 Approximately, three-fourths of the patients in the upfront SRS group were from Japan, which has the largest concentration of MRIs in the world (52 MRI units per million capita) and guidelines strongly recommending against PCI. 26
^,27
On the other hand, the close MRI surveillance needed for PCI might not be a realistic goal for low-to-middle income countries, despite NCCN ES-SCLC guidelines for Africa suggesting both PCI and MRI or CT surveillance as standard options after response to systemic therapy.14
Notably, the region has a sobering 0.5 MRI units per million capita. The financial toxicity of MRI active surveillance; decreased sensitivity of a standard MRI for detecting small BMs compared with high resolution thin slice, double-dose, or triple-dose MRI28
; and lower sensitivity for CT29
poses a limit on increased adoption of upfront SRS. Considering the benefit in intracranial control by PCI coupled with the financial and/or logistical challenges associated with adherence to imaging surveillance in the absence of PCI, some providers might favor PCI, especially in low-resource settings. Conversely, others might lean toward upfront SRS, particularly for patients with a single-lesion metastasis or small numbers of brain metastases and those who might be at increased risk for toxicity from WBRT, including elderly patients and those with a poor performance status.

Assessing QoL Factors
As providers assess the various treatment options, attention is shifted to maximizing NCF in addition to optimizing other standard endpoints. Although NCF and QoL can be affected by several factors such as intracranial disease, treatments, and comorbidities, adverse effects have been described for patients receiving cranial irradiation, with increased rates in older patients and those receiving higher doses.30
^,31
To mitigate this toxicity, several trials in ES-SCLC are exploring the value of hippocampal avoidance (HA) with PCI or WBRT and comparing WBRT with SRS. With no guidance yet from randomized trials, increasing clinical expertise has, however, altered the balance of clinical equipoise as some clinicians make the switch to SRS or HA-PCI or HA-WBRT for selected patients. As the results of trials are awaited, the uncertainty in outcomes emphasizes the need to engage in informed decision-making with the patient on an individual basis to discuss all available options including associated benefits, risks, and adherence to routine MR surveillance, even if the options are recommended by guidelines. Where available, patients should be offered clinical trials to decrease this uncertainty. 
 

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