Early Hippocampal Avoidance Prophylactic Cranial Irradiation in Patients With LD SCLC
Condition: Small-Cell Lung Cancer
MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma
Study type: Interventional

Summary: 
      The main objective of this trial is to assess NCF after early HA-PCI concomitant to the
      second cycle of CHT and to tRT for patients with LD SCLC.
    

Detailed description: 
      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.
    

Intervention name(s): Irradiation: HA-PCI
Intervention type(s): Radiation
Intervention description(s): 25 Gy in 10 daily factions, five times a week
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Early prophylactic; cranial irradiation; hippocampal avoidance; limited disease small-cell lung cancer