Elsevier

Lung Cancer

Volume 118, April 2018, Pages 139-147
Lung Cancer

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

https://doi.org/10.1016/j.lungcan.2018.02.006Get rights and content

Highlights

  • A review of concurrent chemoradiotherapy in stage 3 non-small cell lung cancer.

  • Recent trial data suggests a detriment to dose-escalated radiotherapy in this setting.

  • Large degree of heterogeneity in patient, tumour and clinical factors between cases.

  • Heterogeneity may be limiting the ability to detect benefits of dose-escalation.

  • Technology advances may better stratify cases and allow safer dose-escalation.

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.

Section snippets

Current standard of care in inoperable stage 3 NSCLC

Following the failure to demonstrate the superiority of 74 Gy in 37 fractions in RTOG 0617, the standard of care for inoperable stage 3 NSCLC patients with good performance status remains 60 Gy in 30 fractions of 2 Gy concurrently with chemotherapy. This dose is based on a study from 1980 that found 60 Gy (2 Gy/fraction) to be more efficacious than lower doses in terms of local control and survival [10]. Over the following 3 decades trials have persistently demonstrated the additional benefit

Staging and anatomical heterogeneity

The American Joint Committee on Cancer (AJCC) staging for stage 3 NSCLC is presented in Fig. 1A [18]. Stage 3 encompasses a diverse spectrum of clinical presentations. It can refer to a small peripheral primary with chest wall involvement and solitary hilar node or a large 10 cm tumour centrally located invading the mediastinum with diffuse mediastinal and supraclavicular lymph node involvement (Fig. 1B). Such diverse presentations are because the TNM classification was primarily created to

Diagnostic heterogeneity

Heterogeneity in diagnostic radiology between centres can affect trial outcome interpretation in two categories, pre-treatment staging determination and post-treatment recurrence detection. The last decade has seen the introduction of FDG PET-CT into routine clinical practice for the staging of potentially radically treatable NSCLC. PET-CT increases the detection of nodal and metastatic disease to reduce the incidence of occult metastatic disease in staging groups [32]. Using PET data in

Genetic and histopathological heterogeneity

Due to the carcinogenic effect of cigarette smoke, lung cancers have one the highest mutational burdens of any cancer [34]. Therefore mutational drivers of lung cancer are heterogeneous and known therapeutically targetable drivers such as EGFR, EML4-ALK and ROS1 affect only a small proportion of cases, particularly in smokers. In one study patients with tumours harbouring activating mutations in EGFR who receive cCRT have longer local control and fewer local relapses than those without

Radiotherapy heterogeneity

Within the same dose-fractionation, the delivery of radiotherapy varies greatly between centres regarding technology used, target volumes, organs at risk (OAR) tolerances, set-up protocols and care throughout treatment. Within departments, where the above variables are expected to be constant, there is often great variability between clinicians in terms of target delineation [39]. Therefore radiotherapy for stage 3 NSCLC is delivered in a very heterogeneous manner that could confound trial

Clinical response heterogeneity

There is conflicting data on the prognostic value of tumour shrinkage during and immediately post-cCRT for stage 3 NSCLC. In one retrospective study the GTVs pre-treatment and 1-month post-treatment, as assessed by CT, were analysed for 157 patients [21]. This showed, in concordance with previous studies, that patients with smaller pre-treatment GTVs had better survival. However they also found a trend to worse OS with a larger volume reduction ratio (indicating better short-term response to

Currently available solutions and future directions

Despite the disappointing results of RTOG 0617, a number of studies are currently evaluating treatment intensification in stage 3 NSCLC. As things stand currently there are 2 key questions. Firstly is there enough evidence of a potential benefit to dose-escalation in stage 3 NSCLC cCRT to justify further trials? Secondly how could these new trials be optimised to ensure a benefit (or conclusive negative result) is detected? Regarding evidence of potential benefit from dose-escalation, the

Conclusion

We have highlighted multiple levels of heterogeneity between cases of stage 3 NSCLC and for future studies a priority is to ensure better equality in trial arms for newly identified prognostic factors. It may be argued that using large numbers of patients in randomised arms protects against some of these factors. However these potentially confounding factors need to be considered at the trial planning stage so that the benefits of stratification can be realised and factors that may result from

Conflict of interest

None declared.

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