Prophylactic Cranial Irradiation in Small-Cell Lung Cancer: Update on Patient Selection, Efficacy and Outcomes
Lung Cancer: Targets and Therapy
Abstract: Over 10% of small-cell lung cancer (SCLC) patients have brain metastases (BM) at initial diagnosis; more than 50% will develop BM within 2 years. BM are detected in up to 80% of all patients at autopsy. After primary treatment, prophylactic cranial irradiation (PCI) has been established as standard of care in SCLC patients responding to initial therapy. Based on level I evidence, PCI significantly decreases the risk of intracranial relapse and shows a modest survival benefit after 3 years. However, the role of PCI in defined patient subgroups such as resected SCLC, elderly and extensive stage patients with access to magnetic resonance imaging surveillance and stereotactic radiotherapy is yet to be fully clarified. Furthermore, strategies to effective prevention of neurocognitive decline after PCI remain unclear. All these factors significantly impact treatment decision making and should be evaluated in prospective settings. New concepts such as hippocampal avoidance and drug neuroprotection prevent chronic neurocognitive effects reducing treatment-related side effects of PCI. The aim of this review is to present a summary and update of the latest evidence for patient selection, efficacy and outcome of PCI.
Keywords: PCI, small-cell lung cancer, treatment, patient selection, neurocognition
Small-cell lung cancer (SCLC) is an aggressive type of cancer associated with poor prognosis due to rapid growth and early distant and loco-regional dissemination.1,2 Combined modality treatment, consisting of chemotherapy and thoracic radiotherapy (TRT) delivered concurrently or sequentially, is the standard of care for primary disease.3 Patients who respond to initial therapy without developing symptomatic brain relapse will be treated with prophylactic cranial irradiation (PCI).4–6 In an earlier study in extensive stage (ES)-SCLC, PCI significantly reduced the incidence of symptomatic brain metastases (BM) by approximately 25%, which translated into improvement in median overall survival.6
Patients with limited stage (LS) achieve a median survival of 16–20 months and a 5-year survival rate of 10%–20%. The administration of PCI has been investigated in several studies and has been proven to be an independent prognostic factor.6–8 In 2008, a small retrospective study first reported about the role of repeat contrast-enhanced cranial MRI immediately before the start of PCI for detection of occult intracranial relapse in patients who completed chemoradiotherapy.9 A randomized Phase 3 study by Le Péchoux et al established PCI with a total dose of 25 Gy delivered in 10 once-daily fractions as standard of care due to significant increase in mortality in the higher dose arm of 36 Gy.10Interestingly, a pooled analysis by the North Central Cancer Group revealed a survival difference between PCI total dose of 25 and 30 Gy probably associated with higher rates of adverse events in the 30 Gy group.11 Other prognostic factors such as age, sex, performance status and response to initial treatment were also reported to have an impact on patient outcome.12–16
Following 2 previous publications by Slotman et al, chemotherapy followed by TRT and PCI in treatment responders was established as the new treatment standard for ES disease.6,17 However, a recent Phase 3 study conducted by Takahashi et al at 47 institutions in Japan included an active MRI surveillance program before and after PCI and could not confirm a survival benefit of PCI in ES disease with confirmed absence of BM.18 However, TRT was not an obligatory part of multimodal treatment in the study and has to be taken into account when interpreting the data.
Although the delivery of PCI in both LS- and ES-SCLC is considered to be well established, treatment-related side effects need further extensive investigation. PCI is known to be associated with acute side effects including alopecia, nausea, headache, fatigue as well as chronic neurologic sequelae such as decline in neurocognitive function.19 Several strategies such as hippocampal avoidance and/or drug neuroprotection are currently being investigated in order to limit potential side effects.20–23
The aim of this review is to present a summary of the latest evidence for various patient subgroups, efficacy and outcome of PCI considering new technical and imaging opportunities.