MTE 04.02 General Principles of PCI in the Treatment of SCLC

Abstract

The brain is a well-recognized sanctuary site for micrometastases in patients with small cell lung cancer (SCLC) treated with chemotherapy. The administration of prophylactic cranial irradiation (PCI) in patients responding to chemotherapy reduces the incidence of clinically detectable brain metastases in patients with both limited1 and extensive disease.2,3 In patients with limited disease, this translated into a survival benefit in a meta-analysis of 987 complete responders, but in patients with extensive disease, one trial of 286 responders to chemotherapy showed a survival benefit2, whilst in another of 224 patients it did not.3 The design of this latter trial suggested that regular surveillance with MRI and treatment at the time of metastasis detection might be an equally effective strategy. This could reduce the incidence of the most serious toxicity of PCI which is delayed neurotoxicity. Limiting the total dose is another possible means of reducing neurotoxicity. A randomized trial of three dose prescriptions restricted to patients with limited disease showed no difference in rate of brain metastases between 25 Gy in 10 fractions versus two higher dose schedules, but there was a higher mortality associated with the higher doses, due to an unexplained increase in disease progression.4 In spite of this high level evidence there are still numerous uncertainties facing the clinician when deciding whether to recommend PCI. 1. Is the classification limited versus extensive disease still appropriate when selecting patients? 2. Are there subgroups of patients with metastatic disease more likely to benefit from PCI than others because their overall prognosis is better?5 3. Should there be an upper age limit? 4. Are pre-existing neurologic conditions or paraneoplastic syndromes contraindications? 5. In patients with extensive disease, is pretreatment MRI required? 6. Is MRI surveillance cost effective? 7. Is there a role for hippocampal sparing techniques or neuroprotective agents? 8. Is there a place for lower dose/shorter fractionation schedules? 9. In patients with extensive disease having consolidative chest irradiation, is there any difference between giving PCI simultaneously versus sequentially? 10. What will be the role of PCI in the era of immunotherapy? Question 7 is currently the subject of an actively recruiting randomized trial (NRG-CC003), but for the other questions, physician and patient discretion will be required for the foreseeable future. 1. Auperin, A., et al., Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med, 1999. 341: 476-84. 2. Slotman, B., et al., Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer N Engl J Med, 2007. 357: 664-672. 3. Takahashi, T., et al., Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2017. 18: 663-671. 4. Le Pechoux, C., et al., Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol, 2009. 10:467-74. 5. Eberhardt, W.E., et al., The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol, 2015. 10:1515-22. small cell lung cancer, prophylactic cranial irradiation