Is heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials?

Abstract

The current standard of care for the management of inoperable stage 3 non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (cCRT) using radiotherapy dose-fractionation and chemotherapy regimens that were established 3 decades ago. In an attempt to improve the chances of long-term control from cCRT, dose-escalation of the radiotherapy dose was assessed in the RTOG 0617 randomised control study comparing the standard 60 Gy in 30 fractions with a high-dose arm receiving 74 Gy in 37 fractions. Following the publication of this trial the thoracic oncology community were surprised to learn that there was worse survival in the dose-escalated arm and that for now the standard of care must remain with the lower dose. In this article we review the RTOG 0617 paper with subsequent analyses and studies to explore why the use of dose-escalated cCRT in stage 3 NSCLC has not shown the benefits that were expected. The overarching theme of this opinion piece is how heterogeneity between stage 3 NSCLC cases in terms of patient, tumour, and clinical factors may obscure the potential benefits of dose-escalation by causing imbalances in the arms of studies such as RTOG 0617. We also examine recent advances in the staging, management, and technological delivery of radiotherapy in NSCLC and how these may be employed to optimise cCRT trials in the future and ensure that any potential benefits of dose-escalation can be detected.

Comparison of efficacy and safety between simultaneous integrated boost intensity-modulated radiotherapy and conventional intensity-modulated radiotherapy in locally advanced non-small-cell lung cancer: a retrospective study

“…A retrospective analysis utilizing National Cancer Data Base enrolled 33,566 patients with stage III NSCLC treated by thoracic radiation, and the results showed that patients with dose of ≥66Gy had increased OS than those with dose of 59.4-60Gy (median: 21.1 vs 18.8 months) [18]. Dose-escalation is still a feasible tool to improve outcome if the toxicity can be well controlled [19]. SIB-IMRT seems to be a useful technique for dose-escalation, in which the increased dose was only delivered to GTV/PGTV [20].…”

An overview on personalisation of radiotherapy prescriptions in locally advanced non-small cell lung cancer: Are we there yet?

“…Furthermore, a true person-centred approach is lacking in this research, with the majority of studies and proposals aiming to simply escalate dose without a focus on the patient characteristics. A recent publication [39] highlights the vast heterogeneity within this population and the myriad of factors that are not yet considered in our treatment approach. This may well provide a starting point for improved patient stratification and thus personalisation.…”

Rationale for concurrent chemoradiotherapy for patients with stage III non-small-cell lung cancer

“…Incorporating these potential advances with recent developments in disease staging, diagnostic imaging and molecular profiling could create comprehensive investigational strategies to improve outcomes in future stage III NSCLC clinical trials. [44][45][46][47][48][49] ADJUVANT IMMUNOTHERAPY AFTER CONCURRENT CHEMORADIOTHERAPY IN STAGE III NSCLC The synergistic effect between radiation and immune-checkpoint modulations has been demonstrated in multiple preclinical studies, [50][51][52][53][54][55][56][57] and more recently in the clinical setting following the publication of the Phase 3 PACIFIC trial results. 49 The use of immune-checkpoint antagonists, specifically anti-PD-1 and anti-PD-L1 therapeutics, has resulted in improved OS in patients with metastatic lung cancer, and has transformed the therapeutic landscape in the first-58 and second-line treatment settings.…”