Locally advanced non–small cell lung cancer: What is the optimal concurrent chemoradiation regimen?
ABSTRACTThe optimal chemoradiation regimen for patients with locally advanced non–small cell lung cancer (NSCLC) has yet to be defined. Disease and patient heterogeneity prevent a “one size fits all” approach to treatment. Concurrent chemoradiation up front is the definitive strategy for patients with unresectable stage III NSCLC; the addition of consolidation chemotherapy following definitive treatment has produced conflicting results with respect to overall survival. Biologic therapies have yet to show value as add-on treatment to chemoradiation.
LITTLE PROGRESS WITH BIOLOGIC THERAPIES
The improvements observed when combining chemotherapy with radiation therapy in sequence with systemically active doses of third-generation agents have come at a price of increased toxicity, and most patients will still suffer relapse and ultimately die of metastatic disease. A significant proportion of patients will not be fit enough for more aggressive regimens.
The addition of thalidomide as an immunomodulator agent to chemoradiation did not improve overall or progression-free survival; it was also associated with a higher rate of grade 3+ toxicities in patients with stage IIIA/B NSCLC.18
In CALBG 30407, a regimen of pemetrexed disodium and carboplatin together with radiation therapy with or without cetuximab was studied in patients with stage III unresectable NSCLC.19 Median survival was 22.3 months with pemetrexed-carboplatin; the addition of cetuximab conferred no significant benefit, with maintenance beyond 4 cycles being unfeasible in nearly 50% the patients enrolled.
Integrating the vascular endothelial growth factor inhibitor bevacizumab into combined modality therapy was tested in SWOG 0533. The study consisted of 3 treatment arms in which bevacizumab was introduced at different times in the concurrent chemoradiation setting in patients with stage III NSCLC. Accrual into the trial was terminated because of an unacceptable level of toxicity. Despite the risk stratification, restrictive eligibility criteria, and careful bevacizumab deployment, the approach still proved to be unfeasible.
The small-molecule epidermal tyrosine kinase inhibitors gefitinib and erlotinib had demonstrated efficacy as single agents, but the randomized SWOG 0023 trial of maintenance gefitinib after concurrent chemoradiation and consolidation therapy with docetaxel was terminated early when an interim analysis suggested lack of efficacy of maintenance gefitinib.
CONCLUSIONS
Stage III NSCLC is a heterogeneous disease with considerable variations in prognosis and treatment options. The goals of treatment are local control through the use of radiation therapy and chemotherapy and eradication of distant micrometastases through chemotherapy. For patients with good performance status, concurrent chemoradiation is the standard of care.
Phase 3 trials of full-dose chemotherapy, as either induction or consolidation, have not optimized outcomes. Integration of targeted agents is now under investigation. Any future progress will likely rely on molecular selection, which will require accruing a large number of patients into many clinical trials.
