The standard dose regimen with standard 2D radiation therapy was established by the RTOG 7301 at 60 Gy in 2 Gy/fx [35]. However, median survival was about 10 months, with 3-year survival <10 %. Several other studies conducted in the 1980 sattempted to increase the dose to improve local control. They showed a strong correlation between total dose and local control and overall survival of locally advanced NSCLC [36]. The randomized phase I/II RTOG 8311 trial tested dose escalation (60, 64.8, 69.6, 74.5, and 79.2 Gy) using a hyperfractionated 1.2 Gy twice-daily regimen in 848 patients. The 69.6 Gy group had better outcomes than the lower doses groups. It was assumed that doses above 70 Gy did not increase survival further as a result of radiation-induced lung toxicity because of the volume of normal lung tissue irradiated [37]. Later studies increased the total dose with conformal irradiation [2] from 65 to 102 Gy with acceptable acute grade 3–4 lung and esophageal toxicity rates (4−12 %) with little reporting of late toxicities [38, 39]. Compared to historical results, dose escalation protocols produced higher local control rates (50−60 %) than standard radiotherapy, with 2-year survival rates around 40 %. The higher esophageal toxicity did not result in significant radiation protraction or interruption. Acute heart toxicities occurred in 8 % of a cohort of 50 patients treated with total doses up to 74 Gy [38, 39]. A retrospective study conducted by the Memorial Sloan Kettering in 2007 included 82 patients with inoperable NSCLC Stage I-IIIB [40]. A dose ≥80 Gy was used conformal radiation therapy with sequential chemotherapy. For stage III, 5-year local control and survival rates were 39 and 31 %, with advantage benefit of dose escalation consistent with other studies. Kong et al. [41] showed a benefit of dose escalation on 5-year survival with corresponding improvements with dose in local control. Further, phase I studies like one published by Rosenzweig et al. including 104 patients (65 % stage III and 6 % recurrent) receiving conformal irradiation without elective nodal irradiation showed significantly improved overall survival with dose ≥80.0 Gy, with induction chemotherapy given to 16 % of patients and no concurrent chemotherapy [42]. Crude late pulmonary toxicity was 7 %. The maximal tolerated dose with a normal tissue control probability (NTCP) constraint of 25 % was 84.0 Gy. The RTOG 84–07 (1984–1989) concomitant boost phase I/II trial used 45 Gy on large fields including primary + regional nodes and a 18 Gy boost on primary and involved nodes only to a total dose of 63 Gy. Dose was escalated from 63 to 70.2 Gy/5.5 or 5 weeks [43]. Acute and late toxicities increased within reasonable rates but survival was not statistically different between arms. For patients with Stage III/KPS > 70/no weight loss (i.e. eligible for CALGB 8433) 2-year overall survival was about 20 %.

Later trials, like the CALGB 30105 phase II trial, used dose-intense chemoradiation combinations. The CALGB used induction chemotherapy followed by concurrent chemoradiation in stage III NSCLC with dose-escalated thoracic conformal radiotherapy (74 Gy, once daily, 2 Gy per fraction) in both arms [44]. Patients were randomized between carboplatin/gemcitabine, which arm was closed prematurely due to an unacceptably high rate of grade 4–5 pulmonary toxicity attributed to radiosensitization by gemcitabine. The carboplatin/paclitaxel arm yielded a median survival of 24 months with a 12 % rate of grade 3 or higher pulmonary toxicity [44]. These promising results formed the basis for the experimental arm of the phase III RTOG 0617 trial.

The Randomized Phase III RTOG 0617 compared Standard- Dose (60 Gy) Versus High dose (74 Gy) Conformal Radiotherapy with in patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer. The 2 × 2 factorial design consisted of weekly concurrent carboplatin–paclitaxel chemotherapy with randomization between 60 Gy or 74 Gy, and two cycles of Concurrent and Consolidation Carboplatin/Paclitaxel with or without cetuximab. The high dose arm was closed prematurely after showing 85 documented events and a likely detrimental effect with high dose radiotherapy, which correlated with patient-reported deteriorated quality of life [104]. Updated analysis after 207 events demonstrated a significant increased risk of death in the high dose arms (median survival 28.7 months (60 Gy arm) vs. 19.5 months (74 Gy), p = 0.0007), with a 37 % increased risk of local failure in the high dose arms. There were also a trend for more treatment-related deaths in the high dose arms (10 vs. 2) [105]. Why the RTOG 0617 trial is not consistent with the results of previous phase II trials remains investigational and methodological issues are being looked for. While the exact reasons for such deleterious effects are yet unknown, it was shown that these results are consistent with patient-reported quality of life (ASTRO 2013). Hypotheses include accelerated repopulation due to protracted irradiation, increased reported protocol deviations, under-reporting of lung and cardiac treatment-related deaths in patients who received excessive radiation dose to heart and lung in the high dose arms, and a possible negative interaction between cetuximab and high dose radiotherapy.

Altered fractionation regimens using concomitant boost or hyperfractionated and/or accelerated radiation therapy have been conducted in locally advanced lung cancer. The CHART (Hard hyperfractionation through Continuous Hyperfractionated Accelerated RadioTherapy) trial has demonstrated that overcoming the accelerated repopulation effect by delivering 54 Gy three times daily in 12 consecutive days results in a significant survival benefit compared to conventional regimens [45]. However, logistics of delivering irradiation thrice daily for 12 days limited its use in routine practice. Alternatively, many combinations using either different timings or different drugs were subsequently used to improve local control, distant control and survival. Several phase II trials like the RTOG 9204 (twice daily irradiation with chemotherapy) showed improved local control at the expense of higher esophageal toxicities [46]. More recently, an individual patient data meta-analysis of 10 randomized trials (2,000 patients) comparing hyperfractionated and/or accelerated radiotherapy to conventional fractionation has confirmed the advantage of altered fractionation, increasing 5-year survival rates by 3 %. Dose escalation and dose redistribution based on functional imaging is at the heart of the EU Framework Program 7 (FP7) funded PET Boost trial (ClinicalTrials.gov Identifier: NCT0102482). The overall treatment dose is escalated by increasing the dose-per-fraction until specified dose constraints are met. The patients are randomized to receive the standard regimen (66 Gy given in 24 fractions of 2.75 Gy) with either an integrated boost to the primary tumor as a whole or to the 50 % SUVmax area of the primary tumor based on the pre-treatment FDG-PET CT scan.

If local control may be improved by radiotherapy dose escalation according to several studies, toxicity, including esophageal toxicity, and more particularly pulmonary toxicity seems to be related to radiation volume. In locally advanced non-small cell lung cancer, eliminating elective nodal irradiation allows to maximize tumor dose and minimize normal tissue toxicity in combined modality treatments. The use of staging modalities such as positron emission tomography allows encompassing the tumor volume with more accuracy. Several retrospective, randomized phase III studies and a meta-analysis of 1,705 patients from 4 RTOG trials (7811, 7917, 8311, 8407) have confirmed that involved-field irradiation results in a regional nodal failure rate of less than 10 % [47–49] and suggest that it can be performed in routine practice. To that extent, PET CT is highly recommended for suitable diagnostic work up and pre therapeutic staging [50].

Pemetrexed inhibits enzymes involved in nucleotide synthesis by acting as afolate competitor. Compared to gemcitabine, pemetrexed, in association with cisplatin, increased overall survival in metastatic non-squamous NSCLC [60]. Preclinical studies have shown that pemetrexed is a potential radiosensitizer with radiosensitization depending on drug concentration and tumor type, with an enhancement ratio as high as 1.6 in the LXI lung tumor cell line [61]. Several phase I and II studies have demonstrated that combining pemetrexed with concurrent radiation only yielded moderate toxicities [62–64], was efficient in locally advanced stage III NSCLC and can be safely given at full systemic doses with thoracic radiation therapy [65, 66]. The negative CALGB 30407 trial included squamous NSCLC where activity of pemetrexed is known to be limited [66]. Subsequent trials only included non-squamous NSCLC. The PROCLAIM phase III trial started in 2008, and compared cisplatin plus pemetrexed to cisplatin plus etoposide with concurrent 66 Gy thoracic radiation therapy followed by consolidation chemotherapy [67]. Its aim is to determine if concurrent pemetrexed/cisplatin would translate into a survival benefit. The study enrolled nearly 600 patients. There was a similarly high dose-intensity in both arms, and preliminary results demonstrated significantly lower incidences of overall adverse events and some toxicities including granulocytopenia and infections in the pemetrexed/cisplatin arm [106]. Full presentation of the study results including potential late toxicities is awaited.

More recently, in 2010, the French Thoracic Oncology Group (IFCT) started the IFCT 0803 phase III trial, comparing cisplatin plus pemetrexed with concurrent 66 Gy thoracic irradiation, with or without cetuximab [68]. This “best of” trial combined all up-to-date advances together, i.e. chemoradiation, induction chemotherapy, high dose irradiation (66 Gy), pemetrexed, cetuximab, and a platinum-based doublet. The IFCT 0803 trial just terminated accrual of 106 patients. Garrido et al. recently presented the data of the pemetrexed-cisplatinum (500 mg/m², 75 mg/m² d1 q21d) induction and chemoradiation phase II study in non-squamous NSCLC. Progression free survival (1-year rate of 51 %) was similar to that observed in other cisplatinum-based induction and concurrent protocols. The overall response rate was 59 % with 13 % having progressive disease. Dose-intensity was maintained in 71 % of patients. Grade 3–4 toxicities (esophagitis, neutropenia) during the chemoradiation phase were around 10 %, which is generally considered acceptable for locally advanced NSCLC undergoing radical chemoradiation.

Cetuximab is a monoclonal antibody targeting epidermal growth-factor receptor (EGFR). There have been suggestions, in the FLEX phase III for example, that patients who had a higher expression of EGFR in their tumors (as measured by immunohistochemistry) had a better response than patients with low expression [69]. There was also a strong rationale from preclinical studies [67] and the RTOG 0324 study, to add cetuximab to chemoradiation. Preliminary results from the RTOG 0617 trial at the 15th World Conference on Lung Cancer (Abstract PL03 2013) however suggest that there is no clinical benefit from the addition of cetuximab to chemoradiation in patients with unresectable stage III NSCLC.

Furthermore, the addition of cetuximab is associated with increased toxicity. The cetuximab analysis was carried out on 465 patients, with a median follow-up of 19 months. Weekly cetuximab was added to weekly chemotherapy with carboplatin and paclitaxel, given concurrently with radiation. Median overall survival for patients treated with chemoradiation with or without cetuximab was 23 months, the 18-month overall survival rate 60 %, and median progression-free survival 10 months in both arms. Overall combined adverse events were reported by 85 % of patients treated with chemoradiation with cetuximab vs 70 % without cetuximab, while overall non hematological adverse events were reported by 71 % vs. 51 % of patients, respectively (p <0.0001).

Patients with EGFR-mutated locally advanced NSCLC have lower local recurrence rates following radiotherapy and/or chemotherapy, raising the hypothesis that EGFR mutation might confer sensitivity to some EGFR inhibitors in a way that is synergistic with irradiation [70, 71]. Tolerance studies have shown that standard dose of EGFR inhibitors such as erlotinib or gefitinib could be given during chemoradiation without significantly increasing toxicities [72, 73]. However, so far, most studies investigating the use of EGFR-tyrosine kinase inhibitors with chemoradiation have been rather disappointing, with survival rates lower or close to those seen with chemoradiation alone [73–77]. In particular, the SWOG S0023 study, comparing gefitinib and placebo after cisplatin/etoposide/63 Gy and consolidation docetaxel in stage III NSCLC, showed an increased mean survival time in the placebo arm (35 versus 23 months in the experimental arm), leading to premature trial closure [74]. Similarly, the use of gefitinib after resection of stage III NSCLC was not associated with increased survival [78]. These study results suggest that the use of EGFR-TKI in an EFGR mutation unselected stage III NSCLC population is not warranted and future study should focus on the integration of EGFR-TKI to chemotherapy in patients with activating EGFR mutations.

Available evidence clearly indicates that the mutational landscape, including EGFR mutations [79–86] and ALK translocations [87, 88], of non-small cell lung cancers is relevant to therapeutics to yield personalized medicine.

One recent breakthrough was the discovery of chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) in non small cell lung cancers, which can be targeted using oral ALK inhibitors such as crizotinib. Crizotinib was shown superior to standard chemotherapy in patients with previously treated and untreated, advanced non-small-cell lung cancer with ALK rearrangement [107]. Further, preliminary retrospective data suggest that crizotinib not only can be delivered during irradiation but also yields interesting control rates in oligoprogressive lung cancer treated with chemoradiation [89, 90]. Clinical trials in stage III ALK positive NSCLC would be of interest, although their conduction is a challenge due to the low incidence of this rare molecular alteration comprising only 4 % of NSCLC patients. A randomized phase II trial in molecularly selected patients with stage III NSCLC is currently ongoing (RTOG1306).

Anti-angiogenics such as bevacizumab have shown promises in metastatic setting when combined with chemotherapy in NSCLC and has become a first-line therapy in many facilities [91, 92]. However, when used in a radiotherapy setting, bevacizumab is associated with major toxicities, including tracheo-esophageal fistulae, pulmonary hemorrhage, particularly in squamous histology tumors [93, 94], with no survival benefit. As such, there are currently no ongoing trial using bevacizumab concurrently with radiotherapy with lung cancer and its use should be avoided in this setting. Others anti-angiogenics have been assessed in association with chemoradiation or radiation therapy alone in NSCLC. The use of the anti-angiogenic agents (AE-941 or thalidomide) was associated with increased toxicity, mainly thrombo-embolic events, but did not increase survival [95, 96].

Many other targeted agents have been tested in clinical trials, such as efaproxiral, which reduces hemoglobin oxygen-binding affinity, increasing tissue pO2, as a mean to overcome tumor hypoxia. In this study, efaproxiral, combined with radiotherapy after induction chemotherapy resulted in 20.6 months survival, with low toxicity incidence, which makes it a promising drug [97]. A new vaccine to MUC-1, L-BP25, has shown great promise in stage IIIB and IV NSCLC in a phase II trial, with an increase in median survival (30.6 versus 13.3 months) in stage IIIB disease [98]. Based on these results, the phase III START trial randomized 1320 patients with unresectable stage III NSCLC who had disease control after first line chemo-radiotherapy to receive either L-BP25 (Stimuvax) or placebo after priming with cyclophosphamide 300 mg/m² [108]. The primary endpoint overall survival was not met (25.6 vs 22.3 months, HR 0.88, p = 0.12). However, when analyzing the large subgroup of patients (n = 806) who have received standard concurrent chemoradiotherapy as opposed to sequential treatment, overall survival was increased in the vaccination arm by almost 10 months (30.8 vs 20.6 months, HR 0.78, p = 0.016). Following this encouraging observation a phase III study (START 2) including only patients treated with standard concurrent chemoradiotherapy has been initiated.

Another phase III study investigating the use of GV 1001, a telomerase peptide vaccine, after chemoradiation is planned, following a phase II study showing a significant increase in overall survival (19 versus 3.5 months) in immune responders [99].