FDG-PET/CT as a Predictor of Outcome in EGFR-Mutant Non-Small-Cell Lung Cancer

ctivating mutations in the epidermal growth factor receptor (EGFR) are found in approx- imately 10% to 15% of non-small-cell lung cancer (NSCLC) patients in the United States and up to 35% of those in East Asia. 1,2 Patients with this mutation are more likely to be female, Asian, and nonsmokers than the general lung cancer population. For patients with these mutations, treatment with EGFR tyrosine kinase inhibitors (TKIs) erlotinib, afa- tinib, or gefitinib is associated with higher response rates and improved progression-free sur - vival (PFS) compared with standard platinum-based doublet chemotherapy. 3,4 Unfortunately, acquired resistance to these TKIs inevitably develops. A variety of resistance mechanisms have been identified, including a secondary mutation in EGFR, T790M. 5-7 Resistance to TKIs usually occurs at a median of 9 to 13 months after treatment initiation although there is a wide range. In this regard, some patients have progression of disease years after initiation of TKI therapy while others have rapid progression and widespread disease after only a few months. Currently, there are no reliable clinical tools to predict outcomes for patients with EGFR mutations treated with TKIs. In this issue of the Journal of Thoracic Oncology, Keam et al. report on the relation between FDG-PET/CT metabolic parameters and outcomes in patients with EGFR-mutant lung cancer receiving gefitinib as first-line treatment at a single center in South Korea. Seventy-five patients with stage IIIB or IV chemotherapy naive NSCLC were identified from a retrospective database. All patients had one of the two most common activating EGFR mutations—either a deletion in exon 19 or the L858R missense mutation in exon 21. Patients with these mutations are known to respond well to EGFR TKIs. 1 Outcomes for patients enrolled on this trial were similar to historical controls, with an overall response rate of 69%, median PFS 11.5 months, and median overall survival (OS) 26.7 months. Keam et al. performed whole-body FDG-PET/CT in all patients before initiation of therapy and found that total lesion glycolysis (TLG), a measure that reflects both tumor bulk and metabolic activity, was significantly associated with PFS and OS. Patients with the highest TLG had a PFS of only 7.2 months, compared with patients with low TLG with PFS 24.2 months. SUVmax was also associated with PFS, but the correlation was not as strong, and there was no significant association between SUVmax and OS. Interestingly, response rates were not different between those with high TLG and those with low TLG. Similar to many retrospective studies, the temporal performance of the imaging in the study by Keam et al. was not standardized and there was a large range between the FDG-PET/CT acquisition and the initiation of gefitinib therapy (range 0-46 days, median 19 days). Because of the considerable variation of tumor metabolic activity at different time points, this inconsistency in the performance of the baseline FDG-PET/CT is a potential limitation of the applicability of the imaging analysis and conclusions drawn. In addition, in terms of methodology, the use of a single threshold (50% of SUVmax for each lesion) to determine volume is prone to error, primary due to the value being affected by lesion