A Phase III Trial of Hippocampal-sparing Prophylactic Cranial Irradiation (HS-PCI) in Locally Advanced (Stage IIIA/IIIB) Adenocarcinoma of the Lung

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) have an increased risk of developing central nervous system (CNS) metastases during the course of their disease. The brain is the most common site of failure after first-line therapies (independent of combined sequential or consolidation chemotherapy). Recent studies employing multimodal therapy have reported overall brain metastasis rates ranging from 22% to 55%, and the rates for brain as first site of relapse range from 16% to 43%.

Prophylactic cranial irradiation (PCI) results in a 2-3 fold lower incidence of brain metastasis. However, randomized studies have failed to demonstrate improved overall survival (OS) after PCI.

One of the major weaknesses of these trials is the unselected mixed pool of stage III patients (stage III A and B, lymph node status N0 to N2, squamous and non-squamous histology etc.). A broad variety of studies have shown that a certain subset of patients with NSCLC (e.g. cancers with adenocarcinoma histology, multilevel nodal involvement) are at highest risk for brain metastases. Furthermore, the risk for brain metastases appears to be specifically higher in younger patients (age <60 years), although this collective commonly undergoes more frequently chemotherapy and/or more aggressive regimens than elderly patients.

Prevention of CNS metastases, even for LA-NSCLC patients with other sites of failure, will improve quality of life and, for patients controlled extracranially, will improve survival. Meta analyses performed on data from several Radiation Treatment Oncology Group (RTOG) studies have shown that longer survival for patients with LA-NSCLC treated with either radiation alone or radiochemotherapy is associated with an increased incidence of CNS metastases. Although the addition of chemotherapy to radiation therapy reduces extracranial distant metastases and improves survival it does not alter brain relapse rates. Even though the addition of modern targeted therapy using small-molecules or antibodies may further improve the outcome, the CNS remains the most common site of failure under targeted therapy, although no evidence for resistance in histological workups of metastases has been found. This emphasizes the urgent need for treatment directed at chemotherapeutically inaccessible (or dormant) micrometastases that are a priori dispersed within the brain. As the median time for relapse in the CNS is approximately 6 months after first-line therapy, the treatment of micrometastases should be meaningfully initiated even during or shortly after first-line therapy.

Irradiation of the brain does not only bear the risk of inducing acute (partially mass-associated) side effects such as nausea, vomiting and fatigue, but also causes long-term neurocognitive deficits. Although neurocognitive disorders after PCI/Whole brain radiotherapy (WBRT) also have a multifactorial etiology based on a patient's individual medical history (preceding chemotherapy, pre-existing vascular damage e.g. from smoking, local reactions/edema), it is currently believed that they are mostly caused by a loss of neural stem cells in the hippocampal areas. Multipotent and self-renewing neural stem cells are found in the subgranular zone of the adult hippocampus and in the subventricular zone of the lateral ventricles. The hippocampus plays an important role in memory consolidation and emotional learning (contextual fear conditioning). The disruption of neurogenesis in the subgranular zone or damage to the hippocampus can lead to impaired short- and long-term memory, learning and contextual fear conditioning. In line with this, irradiating the brain decreases neurogenesis in the hippocampus which leads to impaired hippocampal-dependent learning and memory.