Early Hippocampal Avoidance Prophylactic Cranial Irradiation in Patients With LD SCLC

About 15% of all lung cancers are small cell lung cancer (SCLC). SCLC is a high-grade, neuroendocrine carcinoma of the lung. Limited disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port. About 30% of all SCLC are LD at diagnosis. The median overall survival (OS) in LD SCLC is approximately 20 months, with an expected 5-year survival of less than 15%.

SCLC is characterized by rapid growth and early dissemination. The standard treatment of LD SCLC involves multimodality therapy with concurrent thoracic radiotherapy (tRT) and chemotherapy (CHT) with cisplatin and etoposide.

Recurrence in the brain is usually the primary site of treatment failure in SCLC and is associated with significant morbidity; and consequently often the cause of death. Occult early dissemination of SCLC has frequently occurred prior to the time of diagnosis. In patients with brain metastasis two randomized trials showed an overall 5-year rate of brain metastasis of 59% without prophylactic cranial irradiation (PCI) compared to 43% with PCI. However the rate of brain metastasis with PCI is still very high.

About 50% of patients with SCLC will develop brain metastases some time during the course of their disease. Therefore PCI is recommended in case of good response to CHT and tRT. PCI has shown to improve overall survival in patients with LD who have achieved a complete or partial remission after initial chemoradiotherapy. CHT might achieve insufficient drug levels in the brain. Therefore, an up-front PCI could treat occult brain metastases at a preclinical state and may increase the permeability of the blood-brain barrier for CHT products.

When evaluating PCI it is important to weigh the reduced incidence of brain metastases against the potential risk of deficits resulting from the treatment itself, including deteriorations in neurocognitive functions (NCF) or quality of life (QoL).

A possibility to reduce long-term neurocognitive effects due to PCI is the sparing of the hippocampus. Recent technological advancements in radiation oncology delivery enable the avoidance of the hippocampus. A PCI with hippocampus avoidance (HA-PCI) can reduce memory loss due to radiation.

Prospective neurocognitive testing has been increasingly used in trials for patients with CNS tumors and in patients with brain metastases in order to determine the risks versus benefits of different treatment approaches. For this trial, the choice for NCF assessments follows the recommendation provided by Meyers and Brown (2006). This neurocognitive battery for the use in multinational drug trials with neurocognitive endpoints consists of four standardized psychometric instruments, i.e. the Hopkins Verbal Learning Test, the Controlled Oral Word Association Test (COWAT) and the Trail Making Part A and Part B (TMT A/B). These tests have been shown to be sensitive to the neurotoxic effects of cancer treatment in clinical trials and cover several cognitive functions (memory, verbal fluency, visual-motor speed, executive function). In addition, published normative data are available that take into account age, and where appropriate, education and sex. To minimize the effects of repeated administration alternate forms can be used and test administration is highly standardized. The same battery of tests has been used in trials conducted by the Radiation Therapy Oncology Group (RTOG) (e.g. Wolfson 2011), and one or several of these three tests were applied in most of the studies mentioned above. Using the same tests across trials is important in order to be able to compare results of different trials. It has been shown that performing a cognitive test battery consisting of five cognitive tests (and a QoL assessment) in a multi-site trial and cooperative group setting (i.e. a RTOG trial) in patients with brain metastases is feasible.

NCF can be affected by a number of factors such as the volume of brain metastases, disease progression, other treatments (e.g. surgery, chemo- or endocrine therapy), medications and psychological factors such as anxiety and distress. These factors should be considered when evaluating the actual neurocognitive effect of concomitant CHT, tRT and PCI.

Rationale for performing the trial PCI is part of the standard treatment of LD SCLC as the rate of developing brain metastases is very high and PCI has shown to increase overall survival. PCI is given to patients presenting a good response to CHT and tRT. However the overall 5-year rate of brain metastasis with PCI is still very high.

As long as safety data are lacking on PCI administered concurrently with CHT and tRT, PCI is given after the end of CHT in the clinical practice. Therefore the aim of this phase II trial is to evaluate to what extent early HA-PCI given concomitant to CHT and tRT impairs NCF and whether this neurotoxicity can be considered acceptable to evaluate this question in a phase III trial.