ReviewIs heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials?
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.
References (72)
Dose escalation in lung cancer: have we gone full circle?
Lancet Oncol.
(2015)- et al.
How can we optimise concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer?
Lung Cancer
(2014) - et al.
Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients
Lung Cancer
(1999) - et al.
Results of a phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non–small-cell lung cancer
Int. J. Radiat. Oncol.
(2006) - et al.
Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study
Lancet Oncol.
(2015) - et al.
Gefitinib (G) versus vinorelbine + cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): A randomized, phase III trial (CTONG 1104)
J. Clin. Oncol.
(2017) - et al.
New radiotherapy approaches in locally advanced non-small cell lung cancer
Eur. J. Cancer
(2014) - et al.
Tumor volume combined with number of positive lymph node stations is a more important prognostic factor than TNM stage for survival of non–small-cell lung cancer patients treated with (chemo)radiotherapy
Int. J. Radiat. Oncol.
(2008) - et al.
A validated prediction model for overall survival from stage III non-small cell lung cancer: toward survival prediction for individual patients
Int. J. Radiat. Oncol.
(2015) - et al.
Metabolic tumor volume is an independent prognostic factor in patients treated definitively for non–small-cell lung cancer
Clin. Lung Cancer
(2012)