Keywords

1 Standard Treatment of Locally Advanced Unresectable Non-small Cell Lung Cancer

Locally advanced unresectable non-small cell lung cancer (NSCLC), stage IIIA with bulky N2 and stage IIIB diseases, accounts for approximately one fourth of all patients with NSCLC [1, 2]. The disease of this stage is characterized by a large primary lesion and/or involvement of the mediastinal or supraclavicular lymph nodes as well as occult systemic micrometastases in the majority of patients. The standard treatment for patients with a good performance status has been concurrent chemoradiotherapy [3, 4]. A platinum doublet using a third-generation anticancer agent combined with thoracic radiotherapy has yielded a median overall survival time of 22–30 months and long-term survivors of about 20 % [5], but the effect of platinum-based chemotherapy has reached a plateau [6–8]. Since about one third of patients had a relapse within a radiation field, enhanced local treatment may improve survival of these patients. However, a phase III trial of high-dose versus standard-dose thoracic radiotherapy using three-dimensional conformal radiotherapy or IMRT concurrently combined with chemotherapy (RTOG0617) showed poorer survival in the high-dose arm probably due to excessive toxicity to normal tissues [9]. Thus, new types of agents are needed for patients with locally advanced NSCLC to lead a longer and fuller life. Current research focuses on molecular targeted agents, especially epidermal growth factor receptor (EGFR)-directed agents and angiogenesis inhibitors.

2 Monoclonal Antibodies Against EGFR

In tumor cells, EGFR has an important role in cellular proliferation, inhibition of apoptosis, migration and invasion, and angiogenesis through activation of many signaling pathways including the RAS-mitogen-activated protein kinase pathway and phosphatidylinositol-3-kinase-AKT pathway [10]. Activation of EGFR signaling can be mediated by ionizing radiation as well as oncogenic EGFR. The activated EGFR signaling leads to radioresistance by inducing cell proliferation and apoptosis inhibition and enhancing DNA repair [11, 12]. The relationship between EGFR expression and radioresistance was shown among several murine carcinoma cell lines [13, 14], and a transfection study confirmed this relationship [15]. Several in vitro and in vivo studies showed synergistic effect of anti-EGFR antibody cetuximab and radiation [13, 16, 17]. This synergistic activity was obtained only in cetuximab-sensitive cell lines [17].

A benefit of the cetuximab and radiation combination was also demonstrated in a clinical setting; a combination of cetuximab and radiotherapy resulted in a significant improvement in 5-year overall over radiotherapy alone (45.6 % vs. 36.4 %) in a randomized phase III trial of locally advanced head and neck cancer [18]. However, the addition of cetuximab to chemoradiotherapy failed to show any survival benefits in either head and neck cancer (RTOG 0522) [19] or esophageal cancer (RTOG 0436) [20].

Safety of cetuximab combined with thoracic radiotherapy was firstly evaluated in SCRATCH study (n = 12), showing that the early and late toxicities of concurrent cetuximab and thoracic radiotherapy were acceptable, although one patient died of bronchopneumonia [21]. The following phase II trials of concurrent cetuximab and thoracic radiation with induction or consolidation platinum-doublet chemotherapy showed a median OS of 17.0 months or 19.4 months, respectively, with one death of pneumonitis in each study [22, 23]. A phase I trial of cetuximab in addition to chemoradiotherapy with cisplatin and vinorelbine showed that cetuximab could be safely added to chemoradiotherapy with grade 3–4 toxicity in 12 of 25 patients and one treatment-related death of hemoptysis 4 months after radiotherapy [24]. Phase II trials confirmed the toxicity profile of cetuximab combined with chemoradiotherapy, but median overall survival times seemed no improvement when compared with chemoradiotherapy without cetuximab (Table 9.1) [22, 23, 25–28]. A randomized phase II trial of carboplatin, pemetrexed, and thoracic radiotherapy with or without cetuximab (CALGB30407) showed no difference in failure-free survival, overall survival, or grade 3 or severe toxicity except for skin rash between the arms [27]. A landmark phase III trial of paclitaxel and carboplatin chemotherapy combined with thoracic radiotherapy of 60 Gy (n = 151), 74 Gy (n = 107), 60 Gy with cetuximab (n = 137), or 74 Gy with cetuximab (n = 100) (RTOG0617) showed an identical median overall survival of 25.0 months in patients receiving cetuximab and 24.0 months in patients who did not (HR 1.07, 95 % CI 0.84–1.35; p = 0.29). The overall incidence of grade 3 or worse toxicity for patients receiving chemoradiotherapy with cetuximab and chemoradiotherapy alone was 86 % and 70 %, respectively (P < 0.0001).

Table 9.1 Phase II trials of cetuximab and thoracic radiotherapy or chemoradiotherapy in patients with non-small cell lung cancer
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3 EGFR Tyrosine Kinase Inhibitors

EGFR tyrosine kinase inhibitors (TKIs) are another class of agents that inhibit EGFR, especially EGFR with somatic mutations in its tyrosine kinase domain [29, 30]. The EGFR mutations sensitize tumor cells to ionizing radiation by 500- to 1000-fold through the delayed repair of DNA double-strand breaks when compared with EGFR wild-type tumor cells [31, 32]. Several lines of studies showed that gefitinib and erlotinib potentiated radiation effects in NSCLC with EGFR wild type in vitro and in vivo by suppressing cellular DNA repair capacity and G2/M phase cell cycle arrest [33–38]. For EGFR-mutated cells, there are no experimental studies that tried to investigate the interaction between EGFR-TKIs and radiation.

There are several feasibility and phase II trials of EGFR-TKIs combined with thoracic radiotherapy or chemoradiotherapy in patients with unresectable stage III NSCLC (Table 9.2) [39–45]. These studies showed that these attempts were all feasible with acceptable toxicity, but the efficacy was disappointing in all but one trial. Komaki R et al. reported a phase II trial of erlotinib concurrently with weekly carboplatin and paclitaxel chemotherapy and thoracic intensity-modulated radiation therapy at a total dose of 63 Gy in 35 fractions followed by carboplatin and paclitaxel chemotherapy in 46 patients with previously untreated unresectable stage III NSCLC [45]. In the amended protocol, the primary endpoint of this study was time to progression, and the authors hypothesized that combining erlotinib and chemoradiation would increase the median time to progression from 15 to 25 months. The survival results looked promising at a glance; the median OS in this study was 36.5 months, and 2- and 5-year OS rates were 67.4 % and 35.9 %, respectively. None of these survival parameters differed by EGFR mutation status. The time to progression, however, was only 14 months with a distant failure noted in 59 % of patients. They concluded that the time to progression did not meet the assumption and more effective systemic therapy was needed.

Table 9.2 Epidermal growth factor receptor-tyrosine kinase inhibitors: feasibility and phase II trials
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Another approach to unresectable stage III NSCLC is to add an EGFR-TKI as a maintenance therapy after completion of a standard chemoradiotherapy. A phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in unresectable stage III NSCLC showed that the gefitinib arm was inferior in overall survival to the placebo arm (median survival: 23 months versus 35 months, p = 0.013) [46]. This unexpected outcome could not be explained by excessive toxicity in the gefitinib arm, because grade 4 toxicity was noted only 2 % of patients and no toxic death in the gefitinib arm. One possible explanation was an imbalance in prognostic factors including smoking history, tumor EGFR mutation status, and K-ras mutation status, which might have contribution in poorer outcome in the gefitinib arm. Finally, the possibility that gefitinib somehow stimulated tumor growth either directly or indirectly cannot be excluded [47]. Erlotinib as maintenance treatment after concurrent chemoradiotherapy seemed also not promising in patients with stage III NSCLC not selected by EGFR mutations [48].

4 Angiogenesis Inhibitors

Angiogenesis is the essential process for further growth after tumors reach a diameter of 1–2 mm to maintain blood supply to the tumors. Angiogenesis is also critical for the efficacy of radiotherapy through several mechanisms. Tumor vascular bed is abnormal and irregular in its structure and function with the incomplete and heterogeneous oxygen supply. This leads to hypoxic radioresistance of tumor cells through lack of oxygen to facilitate DNA damage by radiation-induced free radicals and upregulation of hypoxia-inducible factor-1α (HIF-1α) [49]. In addition, radiation directly induces HIF-1α expression in tumor cells. The HIF-1α renders tumor cell phenotype suitable for proliferation by transcriptionally activating several genes, as well as induces tumor cells to secrete vascular endothelial growth factor (VEGF) [50], which serves to enhance endothelial cell radioresistance and angiogenesis after radiation [51, 52]. It was shown that tumor response to radiotherapy was closely related to endothelial cell apoptosis [53].

The rationale of combining angiogenesis inhibitors and radiation is vascular normalization, the remodeling of a dysfunctional tumor vasculature to a normal phenotype to restore tumor perfusion and oxygenation, and inhibition of radiation-induced angiogenesis signaling for repopulation of tumor cells after radiation [54]. Numerous preclinical models showed synergistic effects of the two modalities in a dose- and schedule-dependent manner, probably because disruption of tumor vessels hampers proper perfusion and aggravates tumor tissue hypoxia [55–58]. Thus, the vascular normalization window, the transient period of vessel normalization during anti-angiogenesis therapy, is important for the clinical application of angiogenesis inhibitors during radiotherapy, but it is difficult to determine when the normalization window occurs in patients, because the tumor growth kinetics in patients differ from those in animal models [54].

Early clinical investigations of bevacizumab and chemoradiotherapy were closed early due to severe toxicity. A phase II trial of carboplatin, pemetrexed, and bevacizumab induction for two cycles followed by thoracic radiotherapy at a dose of 61.2 Gy in 34 fractions concurrently combined with the same chemotherapy in patients with stage III NSCLC showed that of five patients enrolled, two developed tracheoesophageal fistula, and one died of bilateral pulmonary hemorrhage, left ventricular dysfunction, and subsequent pneumonia [59]. Socinski et al. reported a phase I/II trial of carboplatin, paclitaxel, and bevacizumab for two cycles followed by chemoradiotherapy with weekly carboplatin, paclitaxel and biweekly bevacizumab, and thoracic radiotherapy at a dose of 74 Gy in 37 fractions. Patients in cohort 1 received no erlotinib, whereas patients in cohorts 2 and 3 also received erlotinib at 100 and 150 mg, respectively. Of 45 patients enrolled, one developed grade 3 pulmonary hemorrhage and another developed tracheoesophageal fistula [60]. A phase I trial of induction cisplatin-based doublet chemotherapy and subsequent thoracic radiotherapy to a total dose of 66 Gy in 33 fractions concurrently combined with escalating doses of bevacizumab showed that four of six patients developed pneumonitis [61]. These trials clearly showed that concurrent bevacizumab and thoracic radiotherapy was too toxic. Another feasibility trial of chemoradiotherapy followed by consolidation docetaxel and bevacizumab resulted in two grade 3 pneumonitis and two fatal pulmonary hemoptysis among 21 patients assessable for safety [62]. Thus, even after completion of chemoradiotherapy, bevacizumab develops serious toxicity.

5 The Current Issues and Future Directions

The current review disclosed many issues on incorporation of molecular-targeted agents into the treatment of unresectable stage III NSCLC. One strategy for the treatment of stage III disease has been selecting a drug with a survival benefit demonstrated in patients with stage IV NSCLC. In addition, special importance has been placed on synergistic effects shown by preclinical studies. However, these strategies used for conventional cytotoxic chemotherapy require amendment because little is known about combined effects and optimal schedule of molecular-targeted agents and radiation. Identification of patient populations most likely to benefit is also an important subject for both clinical and basic researchers. The EGFR mutation status is crucial when selecting treatment for patients with stage IV NSCLC, but its significance in the treatment of stage III NSCLC remains unknown, because no preclinical or clinical studies showed combined effects of EGFR-TKIs and radiation on EGFR-mutated tumors. Toxicity enhancement by the combination of molecular-targeted agents and radiation also requires further investigation. Observation of tumor-bearing mice treated with a molecular-targeted agent and radiation to the tumor is not enough to evaluate toxicity. Precise experiments focused on toxicity may be more helpful to predict toxicity of the combination in humans.