Phase III Trial of Prophylactic Cranial Irradiation with or without Hippocampal Avoidance for SMALL-CELL LUNG Cancer

Abstract

Purpose/Objective(s): Clinical evidence suggests that radiation dose received by the hippocampus during whole brain radiotherapy may play a role in radiation-induced neurocognitive decline. To prospectively evaluate the neurocognitive (NC) benefit of hippocampal sparing (PCI-HA), we have developed a phase III clinical trial (PREMER) to test hippocampal sparing during PCI. Materials/Methods: 118 patients undergoing PCI were randomized to receive PCI (nZ60) or PCI-HA (nZ58). The hippocampus was contoured, and hippocampal avoidance regions were created using a 5-mm volumetric expansion around the hippocampus. Linear accelerator ebased intensitymodulated radiotherapy and Volumetric Modulated Arc Therapy treatment plans were generated for a prescription dose of 25 Gy in 10 fractions. The main objective was NC function at 3 months assessed by Free and Cued Selective Reminding Test (FCSRT). The FCSRT is a well-validated and reliable assessment of memory, including encoding, retrieval, and retention of new information over time. Results: These treatment modalities spared the hippocampus, with a D100 of 8.4 AE 2.0 Gy and a maximum dose of 14.5 AE 3.3 Gy. There was a decline in free delayed recall in PCI vs PCI-HA arm at 3 months (21.7 vs 5.1%; p 0.01; OR 5 [IC 95% 1.36-18.87]) at 6 months (32.6 vs 7.3%; p 0.008; OR 6.1 [IC 95% 1.60-23.29]) and at 12 months (18.5 vs 3.8%; p 0.09; OR 5.7 [IC 95% 0.61-52.42])

Current Management and Progress in Radiotherapy for Small Cell Lung Cancer

“…A phase II trial ( 90 ) and subsequent study from Redmond et al demonstrated that conformal avoidance of the hippocampus during WBRT/PCI was associated with improved memory and QoL, with only 10% of patients developing new BM in the underdosed area, which were amenable to stereotactic radiosurgery (SRS) ( 59 , 90 ). The recently completed phase III PREMER-TRIAL also demonstrated that compared to conventional PCI, hippocampal avoidance PCI improved free delayed recall at 3 months (21.7 vs. 5.1%), 6 months (32.6 vs. 7.3%), and 12 months (18.5 vs. 3.8%) ( 91 ). These encouraging results have led to the development of NRG-CC003, an active, randomized phase II/III trial of WBRT with or without hippocampal avoidance in patients with both LS-SCLC and ES-SCLC (NCT02635009).…”

Prophylactic cranial irradiation or MRI surveillance for extensive stage small cell lung cancer

“…Given the importance of the PCI question to the majority of SCLC patients without brain metastases at diagnosis, MAVERICK is a pragmatic trial designed to minimize barriers to accrual allowing varying and evolving SCLC practice patterns including immunotherapy, consolidative thoracic radiation for ES-SCLC, HA-PCI, memantine, and salvage therapies including WBRT, HA-WBRT, and SRS at the discretion of the treating physician. This trial is supported by a recent patterns of care survey amongst 487 radiation oncologists which reported that routine recommendation for PCI in ES-SCLC had dropped from 72% to 44% following the Japanese trial, and that 82% of respondents would be willing to enroll patients with either LS and/or ES SCLC on a trial comparing MRI surveillance with and without PCI (42)(43)(44). An important design feature of the MAVERICK trial is the prerandomization stratification by LS-SCLC and ES-SCLC which will ensure balance between the arms while allowing investigators to enroll the patients with the stage of SCLC for which they have equipoise on the PCI question (i.e., LS-SCLC, ES-SCLC, or both).…”

“…The phase II portion of NRG CC003 was designed to determine whether the 12-month intracranial relapse with HA-PCI was non-inferior to standard PCI, and the ongoing phase III component is designed to determine whether HA-PCI can reduce the likelihood of 6-month cognitive deterioration on the Hopkins Verbal Learning Test-Revised (HVLT-R). Of note, prior smaller randomized trials of PCI vs. HA-PCI have returned conflicting results regarding the cognitive impact of HA-PCI (42,43).…”

Intracranial failure after hippocampal-avoidance prophylactic cranial irradiation in limited-stage small-cell lung cancer patients

“…Although two patients (10% of their cohort) developed metastasis in an under-dosed brain region, the tumors were effectively treated with SRS. De Dios et al also reported that the PCI group showed a significant decline in memory compared to the HA-PCI group 17 . Moreover, a recent randomized phase III trial suggested that there was no significant difference in the incidence of brain metastases between standard PCI and HA-PCI according to their abstract 18 .…”