Management of stage I and II nonsmall cell lung cancer

Introduction

Surgical intervention remains the gold standard for the approximately 30% of NSCLC patients who present with resectable stage I and II disease [18] and who are functionally operable (level C evidence) [5, 15, 19]. The extent of resection and precise surgical approach are the subject of discussion. Additionally, with the advances in newer ablative techniques, their role in early stage disease is currently debated, especially in medically compromised patients. In this section, the indications for sublobar resections (SLR), sleeve resections and MIT by video-assisted thoracic surgery (VATS) and robot-assisted thoracic surgery (RATS) are discussed.

Conservative interventions: SLR and bronchoplastic procedures

Lobectomy has remained the standard of care for resection of early stage NSCLC since the prospective randomised Lung Cancer Study Group trial, comparing lobectomy with SLR (anatomical segmentectomy or wedge resection) for stage I NSCLC, which was published in 1995 [20]. The limited resection group had a three-fold increased incidence in local recurrence (p=0.008), a 30% increase in overall death rate (p=0.08) and a 50% increase in cancer-related death (p=0.09) compared with patients undergoing lobectomy (level B evidence). It is important to note that the limited resection arm included anatomical segmentectomies as well as non-anatomical wedge resections, and tumours up to 3 cm were eligible.

Since this study, there has not been another published prospective trial on this topic. Several single centre retrospective studies have been published with conflicting conclusions [21, 22]. Landreneau et al. [23] performed a propensity-matched comparison between anatomical segmentectomy versus lobectomy for clinical stage I NSCLC. The study reported no significant difference in locoregional recurrence (p=1.00) or in 5-year disease-free survival (DFS) (p=0.47). Yano et al. [24] published a multi-institutional retrospective study (n=1737) on limited resections (segmentectomy or wedge resection) for cT1 N0 M0 NSCLC. Computed tomography imaging was used to determine the invasive potential of the tumour on the basis of the ratio of consolidation (C) to the maximal tumour diameter (T) (C/T ratio). Tumours were classified “invasive” if the C/T ratio was >0.25 and “non-invasive” if C/T ≤0.25. Overall survival and DFS after limited resection were 94.0% and 91.1% at 5 years, respectively. C/T ≤0.25 predicted for good outcome, especially in cT1a N0 M0 disease. In a meta-analysis by Cao et al. [25] data were reviewed of intentional SLRs versus lobectomy for early stage NSCLC. Patients who underwent SLR for small, peripheral NSCLC after intentional selection rather than ineligibility for larger resections, achieved similar long-term survival outcomes as those who underwent lobectomies (level C evidence). However, patients included in this meta-analysis were a highly selected cohort and these results should be interpreted with caution. Two large prospective trials are currently ongoing (CALGB 140503 and JCOG0802/WJOG4607L), comparing segmentectomy versus lobectomy in NSCLC and the results are eagerly awaited (table 4) [26, 27].

SLR is a valid alternative to lobectomy in lung cancer patients who meet the following criteria: stage IA disease, tumours up to 2 cm in diameter, peripheral tumour location and predominantly ground-glass (non-solid) appearance on computed tomography imaging (level C evidence) [19]. Anatomical segmentectomy is preferred over wedge resection since the latter is associated with higher rates of locoregional recurrence in stage IA NSCLC [28, 29]. Although, in case of a predominant ground glass opacity clinical stage IA adenocarcinoma, a wedge resection might be performed with a T1a tumour, and segmentectomy for a T1b tumour due to the low-grade malignancy and favourable prognosis (level C evidence) [30]. When dealing with a solid-type, clinical stage IA NSCLC, a lobectomy is recommended [31].

The second ESMO consensus conference on lung cancer concluded that SLR is acceptable for pure ground glass opacities and adenocarcinoma in situ with minimal invasion [15]. Lobectomy is still the preferred treatment for tumours ≤2 cm with solid appearance on computed tomography (level C evidence). Either open thoracotomy or VATS can be utilised as per experience of the thoracic surgeon.

Next to the aforementioned distal lung parenchyma saving procedures, proximal bronchoplastic interventions as sleeve resections may be the treatment of choice in early stage NSCLC with proximal bronchial involvement or positive N1 nodes around a lobar bronchus [32, 33]. In this way, a pneumonectomy is avoided. Conservative resections are more often performed in carcinoids or in patients with impaired pulmonary reserve [34].

Minimally invasive surgery

MIT like VATS or RATS have been widely implemented as standard treatment for early stage NSCLC. Both procedures are equivalent in outcome (level C evidence) [35]. A retrospective analysis on the National Cancer Database (USA) looked at perioperative outcomes and survival of patients with clinical T1–2, N0 M0 NSCLC undergoing open or MIT: VATS and RATS [36]. This is an oncology database established by the American College of Surgeons and the American Cancer Society with data from hospital registries that are collected in more than 1500 Commission on Cancer-accredited facilities. Shorter median length of stay (5 versus 4 days; p<0.001), and improved 2-year survival (87% versus 86%; p=0.04) were observed when an MIT was used. There was no significant difference in nodal upstaging rates and 30-day mortality between the two groups. Comparing both MITs, there was no significant difference between VATS and RATS in regards to nodal upstaging, 30-day mortality and 2-year survival rates.

It is important to consider the role of nodal dissection, for which precise criteria have been established, to accurately stage the extent of cancer spread pathologically [37]. Medbery et al. [38] conducted a retrospective analysis on the same National Cancer Database and reported nodal upstaging was more frequent in patients treated with lobectomy by thoracotomy than by VATS (12.8% versus 10.3%; p<0.001). This difference was non-significant in patient groups treated in academic research facilities [38].

Differences in quality of life measures following open compared with VATS anatomical resection were assessed in a prospective study and were found to be similar in both patient groups (level C evidence) [39]. In addition the patient-reported physical component summary and pain scores after thoracotomy and VATS were also similar in both groups during the first 12 months after surgery [39].

Introduction

In addition to the advances in surgery over recent years, there have been dramatic developments in radiotherapy for NSCLC patients. Radiotherapy is established as an alternative curative treatment option for patients with early stage disease, particularly in patients who are considered medically inoperable due to co-morbidities. In this section, we compare local ablative therapies for stage I NSCLC and discuss the role of radiotherapy in a multidisciplinary setting as adjuvant and definitive treatment for stage I and II NSCLC.

Comparison of local ablative treatments for stage I NSCLC

Whenever there is a contraindication for surgery, radiotherapy may offer a valid alternative. To date, no valid prospective randomised controlled trial (RCT), comparing surgery and SBRT in medically operable patients with early stage NSCLC, has been completed; therefore, the question of whether SBRT yields similar results as complete surgical resection, remains unanswered (level C evidence) [40]. A recently performed propensity matched comparison between surgery and SBRT in over 117 000 patients with stage I NSCLC, derived from the National Cancer Database demonstrated that, although 95% of patients received surgery, the median overall survival favoured the surgical group (62.3 versus 33.1 months; p<0.001) [40]. The main limitation of such analysis is the difficulty in attributing improved outcome to patient selection or better cancer control, particularly since causes of death are unknown. Unfortunately, prospective RCTs, comparing surgery and SBRT in medically operable patients with early stage NSCLC, have all been terminated prematurely due to poor accrual (table 5).

A recent combined analysis of patients randomised in both the Dutch ROSEL trial and the US STARS trial comparing SBRT with lobectomy demonstrated a significant 3-year overall survival advantage in favour of SBRT (95% versus 79%; p=0.037) in the 58 included patients [41]. DFS was similar in both groups; however, severe grade 3 or more toxicity was lower in the SBRT group (10% versus 44%). Despite small numbers the data suggest “at least clinical equipoise between the two treatment modalities” (level B evidence). However, as discussed in several letters to the Editor, it should be noted that mortality in the surgical arm was unacceptably high, that histology was not obtained in every case and that direct comparison of locoregional control between surgery and radiotherapy is not possible [43–49]. Further interest lies in comparing SBRT to surgical resection (lobectomy or SLR) in patients considered “high-risk” for surgery. There are ongoing studies, assessing randomisation in this setting, currently recruiting (table 6).

The use of radiofrequency ablation (RFA) might rival with SBRT or SLR in early stage NSCLC. One study has compared the selection criteria and short-term outcomes in three prospective clinical trials that used SBRT (Radiation Therapy Oncology Group (RTOG) trial 0236), SLR (American College of Surgeons Oncology Group (ACOSOG) trial Z4032) and RFA (ACOSOG trial Z4033) [50]. The overall 90-day mortality for SBRT, surgery and RFA was 0%, 2.4% and 2.0%, respectively (p=0.5) (level C evidence). The RFA trial included older patients with more impaired lung function. Another study has assessed the outcomes of SLR, RFA and radiation treatment in 116 patients with histologically proven stage I NSCLC from a prospective database [51]. The hazard ratio for primary tumour recurrence adjusted for age and tumour size was 2.73 (95% CI 0.72–10.27) for SLR versus radiotherapy and 7.57 (95% CI 1.94–29.47) for SLR versus RFA. SLR was associated with a higher primary tumour control rate compared with RFA or radiotherapy but no differences were observed in overall survival or DFS (level C evidence). Interpretation of data from both these studies is limited as baseline patient characteristics were not comparable and treatment was not randomly assigned. In particular in the second study the radiotherapy group included patients treated with both SBRT (57%) and conventionally fractionated radiotherapy (43%). The median tumour size was significantly larger in the radiotherapy group compared with the other two groups. A large prospective RCT is required to assess the benefits of RFA in comparison with SBRT and surgery.

Adjuvant radiotherapy in resected early stage NSCLC

A meta-analysis of data from nine randomised trials of adjuvant radiotherapy after resection of stage I–III NSCLC revealed a significant absolute detriment of 7% increased mortality at 2 years with the addition of radiotherapy (level A evidence) [52]. Subgroup analyses suggested that the adverse effect was greatest for patients with stage I and II disease and therefore adjuvant radiotherapy is not recommended for completely resected early stage disease [15, 53].

Definitive radiotherapy for stage I NSCLC

SBRT makes use of advanced radiotherapy planning and delivery techniques to permit high doses of radiation per fraction to be given accurately to small discrete targets with high conformality and rapid dose fall-off within the surrounding normal tissues. The majority of published studies of lung SBRT are single-centre retrospective series (level C evidence). There are technical variations in practice in the literature including whether the reported radiation dose is prescribed to the 100% or to the isodose covering the target, in the type of planning algorithms software and whether a heterogeneity correction was applied. Additionally, there are variations in patient selection, including whether there was pathological confirmation of the treated lesion, staging, including whether the mediastinum was invasively staged and in the computed tomography scanning follow-up intervals for assessment of local disease control. Bearing these limitations in mind, promising outcomes are observed with SBRT; for example, a systematic review of published studies of SBRT for peripherally positioned stage I NSCLC reports 2-year local disease control rates of 91% and 2-year overall survival rates of 70% (level C evidence) [54].

Importantly, it is the position of the steep dose fall off within normal tissues that determines the potential toxicity. While toxicity with lung SBRT is generally low with grade 3 or higher rates usually <4% [55–57], the exception is for centrally placed lesions as highlighted in a single centre phase II study. Patients with centrally located tumours were treated with a schedule of 60–66 Gy in three fractions (54 Gy in three fractions equivalent with heterogeneity correction) and after 4 years follow-up had an 11-fold higher risk of developing grade 3–5 toxicities when compared with patients with peripherally located tumours [58]. This led to the initial definition of the “no fly zone” (the volume encompassing 2 cm in all directions around the proximal bronchial tree) used in the RTOG 0236 trial [57] and subsequent SBRT studies (level C evidence).

Various dose fractionation schedules are reported in the literature varying between one and 10 fractions with higher number of fractions predominantly being used for more centrally located lesions; however, the optimal dose remains unknown and is complicated by the variation in dose prescription methods used in the literature, making comparison of outcomes challenging (level C evidence). While schedules with a biologically equivalent dose (BED) of 100 Gy₁₀ or more are associated with high local disease control rates [59, 60], a meta-analysis suggests the highest biologically equivalent schedules (>146 Gy₁₀) may be associated with lower survival rates than the medium-high schedules (106–146 Gy₁₀) (level C evidence) [61].

To address the dose question for peripheral tumours, the randomised phase II RTOG 0915 trial compared 48 Gy in four fractions (BED 105 Gy₁₀) to a single 34 Gy fraction (BED 150 Gy₁₀) [62]. One-year overall survival was 85% in the single-fraction arm and 91% in the four-fraction arm with similar toxicity and local tumour control rates (level B evidence). Further follow-up is awaited to decide whether the single-fraction schedule will be compared to the RTOG 0236 schedule of 54 Gy in three fractions in a phase III setting for peripheral lesions. For central lesions, the initial results from the RTOG 0813 study investigating maximum tolerated dose for central lesions using five fractions, presented in abstract form, suggest that the highest investigated dose level of 60 Gy in five fractions is associated with a 7.2% risk of severe dose limiting toxicity [63]. Data on efficacy of the various dose levels in the phase II component of the study are awaited prior to decision about the dose to be considered in a phase III setting [63]. The European Organisation for Research and Treatment of Cancer (EORTC) LungTech trial (NCT01795521) investigating the safety of 60 Gy in eight fractions for centrally lesions is actively recruiting. When comparing studies with treatment of central lesions it is also important to note that there is more than one definition of a “central” lesion in the literature [64].

For inoperable patients, in comparison with standard fractionation radiotherapy, the Scandinavian phase II SPACE RCT compared 3D conformal radiotherapy with 70 Gy in 7 weeks with SBRT to 66 Gy in three fractions in inoperable patients with stage I peripheral lesions. Initial results, in abstract form, with a median follow up of 37 months reveal no significant difference in DFS or overall survival (level B evidence) [65]. However, the patients in the SBRT arm experienced significantly less any-grade pneumonitis (19% versus 36%) and oesophagitis (8% versus 30%) with improved dyspnoea, cough and chest pain quality-of-life measures. The phase III RTOG 0902 CHISEL trial (NCT01014130) completed recruitment and the results are awaited. There has been no direct comparison between SBRT and RFA in inoperable patients with early stage NSCLC; however, due to the greater body of evidence in the literature to support SBRT as definitive treatment for NSCLC, SBRT is considered the most appropriate therapy for inoperable patients with stage I NSCLC (level C evidence).

Despite SBRT being well tolerated, patient selection remains important. The majority of published SBRT trials included lesions up to 5 cm in diameter. Larger lesions are included in multiple retrospective series and can be considered for SBRT if dose constraints to surrounding normal tissues can be met. Alternative more protracted schedules can also be considered, for example 60 Gy in 15 fractions [66] or 70 Gy in 17 fractions [67]. As for medically inoperable patients with poor lung function and multiple co-morbidities and advanced age, SBRT needs to be weighed up against the risks of no treatment. The median survival of patients with routinely detected clinical stage I and II disease is approximately 10 months [68], and population-based studies of elderly patients with early stage NSCLC suggest that the observed improvement in overall survival over time is limited to patients treated with radiotherapy, including SBRT, rather than surgery or to those not treated radically (level C evidence) [69]. Therefore, advanced age alone should not exclude patients from SBRT. With co-morbidities, there are no absolute contraindications to SBRT and, in general, patients with ECOG performance status of 0–2 or poor lung function [70, 71] should be considered for treatment. An important relative contraindication to SBRT, however, is active interstitial lung disease with higher than expected reported cases of severe or fatal pneumonitis in retrospective series [72, 73].

Up to 20% of patients treated with SBRT will relapse with distant metastases after treatment [74, 75]. There is no proven role for adjuvant chemotherapy following SBRT particularly in patients with larger lesions (≥4 cm) that would be considered for adjuvant therapy following resection. A study in this patient population would be interesting. However, given the majority of these patients are considered medically inoperable, many may not be suitable candidates for platinum-based systemic therapy.

In summary, SBRT is the standard of care for medically inoperable patients with early stage peripheral NSCLC [15, 16]. In comparison with surgery in operable patients, SBRT remains an alternative and offers at least clinical equipoise with surgery, especially in those considered “high risk” for surgery until further evidence is available comparing the two modalities. Prospective trial data are awaited to determine the optimal dose schedules, in particular for central lesions [15, 76].

Definitive (chemo)radiotherapy for stage II NSCLC

For the relatively small proportion of patients with medically inoperable stage II NSCLC not suitable for SBRT, usually because of ipsilateral hilar nodal involvement, the standard of care is treatment with chemo-radiotherapy (CRT) using conventional fractionation and platinum-based regimens [77–79]. The role of concomitant compared with sequential chemotherapy in this patient group is less clear. In the landmark meta-analysis of over 1200 patients with stage I–III disease, concomitant CRT was associated with a 4.5% benefit in overall survival at 5 years compared with a sequential approach at the expense of a significant increase in acute oesophageal toxicity from 4% to 18% [80]. However, less than 3% of the patients included in the analysis had stage I–II with the vast majority having stage III disease (level B evidence). The added benefit of accelerated radiotherapy in the sequential setting is also less clear in stage II disease (level C evidence). The large meta-analysis assessing accelerated hypo- or hyper-fractionated radiotherapy schedules compared to conventionally fractionated treatment in over 2000 patients with NSCLC [81] demonstrated that accelerated schedules were associated with a 2.5% improvement in overall survival at 5 years. However, again only a small proportion of included patients, <20%, had stage I–II disease (level C evidence). Given the paucity of data on definitive CRT specifically in inoperable patients with stage II disease, a population-based outcomes study (>550 patients) was recently performed in this patient group [82]. Stage II NSCLC patients treated with concomitant or sequential CRT were included and a median overall survival of 20.5 months was found. This figure approximates to survival figures in stage III disease from historic phase III trials (level C evidence). There is likely to be adverse selection bias for these patients with stage II disease given they were considered medically inoperable.

In summary, patients with inoperable stage II disease should be treated with definitive radiotherapy and consideration of the addition of chemotherapy concomitantly or sequentially should be given based on fitness to tolerate treatment. Further studies are required to assess the benefits of CRT in this population specifically. Additionally, the role of treatment dose intensification with isotoxic radiotherapy schedules [83], oncogene targeted systemic therapies, DNA damage repair and immune checkpoint inhibitors needs to be explored.

Salvage surgery after stereotactic radiotherapy

For recurrent or persistent NSCLC after SBRT, salvage surgery is a valid therapeutic option when a complete resection is feasible and cardiopulmonary functional assessment shows no contra-indication for the anticipated resection. Although surgical salvage is a relatively new concept in thoracic surgery, recent data show that it is feasible in selected patients, not only for NSCLC but also for lung metastases (level E evidence) [49, 84]. Technical difficulties in performing the resection are limited on the condition that the hilum and mediastinum are not irradiated beforehand. More long-term data are needed to determine its role more precisely.

Introduction

In contrast to the previous sections (locoregional treatment), in this section systemic therapy is reviewed. Platinum-based chemotherapy, targeted agents, immunotherapy and anti-angiogenic agents as adjuvant therapies for resected early stage NSCLC are discussed.

Adjuvant platinum-based chemotherapy

The RCTs of adjuvant cisplatin-based chemotherapy versus observation in patients with resected stage I–III NSCLC demonstrate statistically significant benefit for the addition of systemic therapy (level A evidence) [85–89]. An overview of these trials is provided in table 7. A meta-analysis of pooled data (n=4584) revealed a 5.3% (overall survival) and 5.2% (DFS) improvement at 5 years with the addition of cisplatin-based chemotherapy [90]. However, a statistically significant interaction between disease stage and chemotherapy effect was observed. In stage IA, a potential detrimental effect was found with the addition of chemotherapy. In stage IB, a trend was seen favouring the addition of systemic therapy (level B evidence). A subsequent study of adjuvant carboplatin/paclitaxel in patients with resected stage IB NSCLC demonstrated no overall survival benefit; however, an unplanned retrospective subgroup analysis revealed a benefit for patients with tumours ≥4 cm [91]. Therefore, the ESMO guidelines state that adjuvant chemotherapy can be considered for the latter [15]. As mentioned previously, in the forthcoming eighth TNM edition, it is proposed to reclassify tumours ≥4 cm as T2b [6] and, subsequently, these are grouped as stage IIA instead of stage IB [7].

Recently, a Cochrane meta-analysis on adjuvant chemotherapy (without radiotherapy) in resected NSCLC was performed: 35 trials were identified and an analysis based on 8447 participants showed a clear benefit of adjuvant chemotherapy (HR 0.86, 95% CI 0.81–0.92; p<0.0001) with a 5-year absolute survival benefit of 4% (level A evidence) [92]. The most studied adjuvant drug combination is cisplatin/vinorelbine, although the Cochrane meta-analysis showed little variation in effect between different regimens (level A evidence). Moreover, an exploratory analysis of the E1505 trial (adjuvant chemotherapy±bevacizumab in early stage resected NSCLC) presented at the American Society of Clinical Oncology (ASCO) 2016 annual conference showed no difference in DFS or overall survival for the four different cisplatin-based chemotherapy regimens (cisplatin with investigator's choice: vinorelbine, docetaxel, gemcitabin or pemetrexed) [93].

No difference in survival has been demonstrated between neoadjuvant and adjuvant treatment (level B evidence) [94, 95]. Due to adjuvant trial results, most neoadjuvant trials were closed prematurely [95]. A potential advantage of neoadjuvant chemotherapy is that compliance may be better. Due to their clinical condition, more patients are likely to complete four cycles of neoadjuvant chemotherapy, compared with the 50–70% completing four treatment cycles demonstrated in most adjuvant studies [95, 97].

Patients enrolled in clinical trials are highly selected and often younger, with good performance status and fewer co-morbidities compared with patients in the general population. In a retrospective analysis of the Ontario Cancer Registry, it was shown that adjuvant chemotherapy had a detrimental effect in patients with severe co-morbidities (Charlson score 3+) [98]. A subgroup analysis of the JBR 10 study demonstrated that elderly (>65 years) had the same amount of benefit with adjuvant chemotherapy than younger patients, without additional toxicity [99]. In the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis the same was true for patients aged >70 years [100]. Interestingly, in both studies the elderly received on average fewer chemotherapy cycles and reduced cisplatin dose. Improved overall survival was noted for elderly (age >65 years) with stage I (tumour ≥4 cm) in a Surveillance, Epidemiology and End Results (SEER) -Medicare analysis (n=3289) although adjuvant chemotherapy was associated with an increased number of serious adverse events [101]. However, data on patients aged >75 years are lacking as this group was under-represented in clinical trials (level B evidence). In clinical trials, adjuvant chemotherapy is started within 6–8 weeks of surgery. In daily practice, 35% of patients start adjuvant chemotherapy >10 weeks after surgery; however, this did not appear to have a negative impact on survival [98].

The meta-analysis showed a clear overall survival benefit for adjuvant chemotherapy and it is advised in all current guidelines [100]. However, tools to optimally select patients who benefit from chemotherapy are warranted, especially since the updated survival analysis of the International Adjuvant Lung Cancer Trial (IALT) showed that the survival benefit did not persist after 5 years of follow-up, mainly due to increased non-lung cancer mortality in patients treated with adjuvant chemotherapy (level B evidence) [102]. The histological NSCLC subtype has not been shown to be a predictive factor of benefit from adjuvant chemotherapy and, as yet, there is no fully validated biomarker to identify patient subgroups who may derive particular benefit [92]. The IALT biomarker group has studied predictive value of several biomarkers including excision repair cross-complementation group 1 (ERCC1) and P53. ERCC1 expression seemed to be a predictive marker for response to platinum-based chemotherapy, with only ERCC1-negative tumours benefitting from adjuvant chemotherapy [103]. Although the randomised adjuvant Tailored Postsurgical Therapy in Early Stage NSCLC (TASTE) trial showed that a biology-driven randomised adjuvant trial is feasible, the planned phase III trial was terminated due to inaccuracy of the ERCC immunohistochemical staining classification [104]. Until now, no potential predictive biomarker has been validated in an RCT and none can be used to select patients who benefit from adjuvant chemotherapy. Invasive components of the tumour (vascular, lymphatic or perineural invasion) are also of prognostic significance in early stage NSCLC. Although not evaluated in RCTs, it is possible that resected early stage patients with adverse prognostic factors would benefit more from adjuvant treatment than those without. In a meta-analysis (22 studies, a total of 25 280 patients with resected stage I NSCLC), visceral pleural invasion was associated with death (HR 1.427, 95% CI 1.221–1.669; p<0.001) and recurrence (HR 1.600, 95% CI 1.284–1.995; p<0.001) [105]. This increased risk was found for all subgroups including patients with tumours <2 cm.

Comparable results were found in another analysis including 13 cohort studies (27 171 patients) (level C evidence) [106]. Lymphovascular invasion (LVI) was also associated with a worse prognosis in a recent meta-analysis including resected stage I patients (20 studies, 8032 patients) [107]. Risk of death was significantly higher in patients with LVI (HR 1.81, 95% CI 1.53–2.14) (level C evidence). Conflicting studies exist on the prognostic significance of perineural invasion [108, 109]. A newer method to evaluate prognosis is the use of an immunoscore. For example, it has been shown that stromal CD8⁺ tumour-infiltrating lymphocytes density had a prognostic impact across all stages in multivariate analysis in a study including 797 resected stage I–IIIA NSCLC patients [110]. 5-year overall survival was 61%, 50% and 41% for CD8⁺ high, intermediate and low scores, respectively (p<0.001) (level C evidence).

Adjuvant targeted agents

The effect of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was tested in the BR19 study [111]. Unselected patients with completely resected stage IB-IIIA NSCLC were randomised between gefitinib or placebo for 2 years. This study was closed prematurely; however, it showed no benefit for adjuvant gefitinib (level B evidence) [111]. In addition, no benefit was shown in the subgroup with an activating EGFR mutation (n=15). With the proven efficacy of EGFR-TKIs in mutation-positive advanced disease, the role of adjuvant erlotinib versus placebo has been explored in patients with completely resected EGFR-expressing (immunohistochemistry) or EGFR-amplified (fluorescence in situ hybrisation) stage IB to IIIA disease [112]. Adjuvant erlotinib for 2 years did not prolong DFS in the EGFR mutation-positive NSCLC. Although there was a trend to improved DFS with gefitinib in the EGFR-activating mutation positive subgroup (n=161, HR 0.61 95% CI 0.38–0.98; p=0.039), this was not statistically significant due to hierarchical testing (level B evidence). Discussion points are the dose and duration of treatment. It might be that, in line with results in breast cancer, the treatment period was too short. Currently, there is no role for TKIs in the adjuvant setting, but further research in the EGFR mutant positive patients is warranted and trials are ongoing (table 8).

Adjuvant immunotherapy

Another promising adjuvant systemic therapy being investigated is immunotherapy. One of these approaches is targeting MAGE-A3. MAGE-A3 is expressed in 35% of NSCLC patients. A phase II RCT showed that in patients with stage IB–II resected NSCLC expressing MAGE-A3 the HR for DFS was in favour of treatment with recombinant MAGE-A3 protein in combination with an immunostimulant; however, this was not statistically significant (HR 0.75, 95% CI 0.46–1.23; p=0.248) [113]. In the phase III MAGRIT RCT, presented at ESMO 2014 13 824 patients were screened for MAGE-A3 and 2270 were randomised between adjuvant MAGE-A3 immunotherapy or placebo. Unfortunately, MAGE-A3 immunotherapy did not improve outcome (level B evidence) [114]. The full paper has not been published yet.

Other interesting immunotherapy strategies currently being explored in several phase III RCTs are the use of checkpoint inhibitors. As these studies started enrolment in 2015, results are expected within a few years. An overview of these studies is provided in table 9.

Adjuvant anti-angiogenic agents

As angiogenesis is one of the hallmarks of cancer and important for growth and metastatic potential of tumours, the addition of bevacizumab to platinum-based chemotherapy was tested in a phase III RCT (E1505, n=1501) and presented at the World Lung Cancer Conference 2015 [93]. Patients with resected IB (>4 cm) to IIIA NSCLC were treated with four cycles of cisplatin with either vinorelbine, pemetrexed, docetaxel or gemcitabine, and randomised between addition of bevacizumab for 1 year or chemotherapy alone. At time of interim analysis (all patients randomised), no difference was observed in the primary endpoint overall survival (HR 0.99 (95% CI 0.81–1.21; p=0.93)) (level B evidence) and in the secondary endpoint DFS (HR 0.98 (95% CI 0.84–1.14; p=0.75)). As low molecular weight heparin may also improve outcome, it was tested in the NVALT-8 trial (n=202) whether the addition of nadroparin to adjuvant chemotherapy (cisplatin combined with pemetrexed (non-squamous) or gemcitabine (squamous) improved DFS in resected stage I–IIIA NSCLC patients. Results were presented at the ASCO 2016 conference: no significant differences in DFS were found, which is different from the results in the abstract [115].

In summary, international guidelines recommend the use of adjuvant platinum-containing chemotherapy in patients with completely resected stage II disease and consideration of its use in patients with resected stage IB disease with a primary tumour ≥4 cm. According to the proposed 8th TNM edition, these are all grouped in stage II [15, 53]. Age is not a selection criterion per se, but co-existence of severe comorbidity may lead to detrimental outcome. Currently no predictive biomarkers of clinical benefit are available and new treatment strategies, such as EGFR-TKIs, angiogenesis inhibitors and immunomodulation have not yet resulted in improved outcome, but additional trials are ongoing.