Non‐small cell lung cancer: One size doesn't fit all (2012)

Management of lung cancer in the past was based on clinical parameters that included disease stage and histology. Patients who did not have small cell lung cancer were labeled collectively as having non-small cell lung cancer (NSCLC) and all treated with the same chemotherapy, since clinical trials had shown no differential effect of chemotherapy on outcomes for the various histological subtypes. As a result of this broad approach the median survival of patients with advanced stage disease was limited to 10 months and many patients suffered from treatment toxicity without experiencing any benefit. Recent advances in molecular diagnosis have obliged doctors to move away from the one-size-fits-all approach. We have entered an era when the right treatment at the right time should be selected for each patient, aiming for maximal efficacy with minimal toxicity. The current issue of Asia-Pacific Journal of Clinical Oncology (APJCO) publishes five articles on personalized medicine for lung cancer that demonstrate the significant contribution made by Asian investigators in this arena. Tomita et al.1 reported on pre-operative evaluation of prognostic markers that included quantitative assessment of fluorodeoxyglucose on a positron emission tomography (PET) scan. The 5-year survival rate of patients with a pre-operative standardized uptake value (a high maximum standardized uptake value [SUVmax]) of >6.6 was significantly lower than in those with a low SUVmax (63 vs 87%, respectively, P = 0.0004). In addition, high pre-operative serum CEA was associated with a significantly worse survival than normal carcinoembryonic antigen (CEA) (51 vs 83%, P < 0.0001). Moreover, the combined use of pre-operative SUVmax and CEA level might be a strong prognostic marker for survival. These results are provocative but the study is limited by the small sample size and arbitrary definition of the cut-off value. SUV is a semi-quantitative measurement of tumor metabolic activity as reflected by glucose uptake. SUVmax on PET is a potential surrogate of cellular function while serum CEA could reflect tumor volume. However, in either case, a standardized cut-off value has never been recognized. This study generates an attractive hypothesis that needs to be validated in a large prospective study. Personalized therapy may also be applicable in patients with stage III locally advanced disease. Concurrent chemoradiation is the current standard therapy. Surgical resection after chemoradiation remains controversial. Isobe et al.2 are among the first to report on the importance of a complete pathological response to chemoradiotherapy for the long-term survival of patients with stage III NSCLC. Among 27 patients who had surgical resection after induction chemoradiotherapy seven attained a complete pathological response. The median survival of this small subset of patients was 77 months and six were still alive at the time of the report. Comparatively, the median survival of patients without a complete pathological response was significantly shorter. This finding is logical but the question is how we may apply this knowledge clinically. Surgical resection is not feasible for all patients; thus we need a surrogate. A post-chemoradiation decline in SUV on PET scan is correlated with pathological complete remission and favorable prognosis. A reduction in SUVmax of more than 80% was highly predictive of complete pathological response.3 However, what this study failed to address is whether surgical resection has added value to patients who already had a complete pathological response. If it does, PET could be a useful tool for selecting patients for surgical resection after chemoradiation. Activating mutations of the epidermal growth factor receptor (EGFR) gene represents the first predictive biomarker for the use of EGFR tyrosine kinase inhibitors (TKI) for patients with advanced stage metastatic lung cancer.4 While data supporting the clinical use of activating the EGFR mutation is overwhelming,5-8 universal testing is limited to major hospitals where EGFR mutation analysis is readily available. Many Asian centers still use clinical parameters, including histology and smoking status, as selection criteria. Wu et al.9 confirmed that the Chinese subgroup from the Iressa Pan-Asia Study (IPASS) share similar efficacy and safety with the overall study population. China enrolled the largest proportion of patients in IPASS (372 out of total of 1217) but provided the lowest proportion of tumor samples for biomarker analysis (38 vs 56% in the overall IPASS population). This has limited the statistical power of using the EGFR mutation as a predictive factor in this subgroup. In contrast, the other two studies by Liam et al. and Boyer et al.10, 11 did not attempt to collect tumor samples. TRUST is a phase IV prospective study on the use of erlotinib in an unselected NSCLC population.11 The tumor response rate was 28%. Progression-free and overall survival was 2.7 and 6.9 months, respectively. The Malaysian study is a retrospective analysis of patients with adenocarcinoma.10 The tumor response rate was 37% and median progression-free survival was 6.5 months. The differences in treatment outcomes to EGFR TKI between these studies is best explained by the difference in the incidence of the EGFR mutation in each study population. The incidence of the EGFR mutation in both the Chinese subgroup of IPASS and the Malaysian study is likely to be above 50%, while it is expected to be lower in the Australian population. These studies have reinforced the fact that patients should be selected by biomarkers and not according to clinical parameters. Personalized medicine is now standard for the management of lung cancer. EGFR mutation analysis is mandatory for selecting patients for EGFR TKI. For patients with early stage disease, a PET scan could be a useful tool to predict survival. We are clearly making steady progress in the management of NSCLC and the studies reported in this issue of APJCO contribute to these improvements.