Radiation Therapy as a Backbone of Treatment of Locally Advanced Non-Small Cell Lung Cancer Aaron M. Laine, Kenneth D. Westover, and Hak Choy Locally advanced non-small cell lung cancer (LA-NSCLC) is a heterogeneous disease, encompassing stage IIIA, for which surgery in combination with chemotherapy and/or radiation therapy (RT) represents a potential treatment approach for select patients, and stage IIIB, for which chemoradiation represents the standard of care. Recent advances in systemic cytotoxic and molecularly targeted therapies coupled with technologic innovations in radiotherapy have the potential to improve outcomes for this patient population. Many ongoing clinical trials use specific genetic mutations or histologic status to determine the combination of targeted therapies and RT, as well as to determine the optimal chemoradiotherapy platforms. Additionally, use of modern RT techniques has improved outcomes for some patients with limited metastatic disease, thereby prompting further studies on how to best integrate aggressive management of oligometastases using RT with chemotherapeutic regimens. Semin Oncol 41:57-68 & 2014 Elsevier Inc. All rights reserved.

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dentifying lung cancer patients before they progress to locally advanced disease remains one of the foremost challenges to improving outcomes for lung cancer patients. Forty to fifty thousand patients with locally advanced non-small cell lung cancer (LA-NSCLC) are diagnosed annually in the United States, representing approximately 35% of all newly diagnosed cases.1 Many of the advances in the treatment of this disease have come from studies involving combined modality therapy (CMT), where a combination of chemotherapy with radiation treatments have made a significant impact in the outcome of these patients.2 However, despite encouraging improvements in survival, the absolute overall survival (OS) of patients with LA-NSCLC remains poor. Improving outcomes for patients with locally advanced disease is an area of ongoing research and significant advances have been made in the treatment of this patient population over the past few decades. Active areas of research include determining the appropriate sequencing of systemic

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX. Conflicts of interest: none. Address correspondence to Hak Choy, MD, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 5801 Forest Park Rd, Dallas, TX 75390-9183. E-mail: hak.choy@ utsouthwestern.edu. 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2013.12.012

Seminars in Oncology, Vol 41, No 1, February 2014, pp 57-68

treatments with radiation therapy (RT) in the combined modality setting, discovery of novel agents, and technological advances aimed at improving delivery of radiation treatments. Treatment paradigms now incorporate factors beyond age, performance status (PS), and non-small cell histology into the decisionmaking process such as genetic alterations. We have arrived at an era where patients benefit from individualized therapeutic strategies based on the molecular characteristics of tumor tissue.3 The handful of success stories in this regard provide reason to expect that additional research will lead to better outcomes and more effective clinical trial design for a greater number of patients in the future. In addition, technological improvements in RT are expanding the ability to target tumors with more precision and higher doses, enhancing treatment options for patients. This has effectively expanded the number of clinical situations where RT may be beneficial. In this review, we will discuss the role of radiotherapy in the treatment of LA-NSCLC, current strategies for combined modality therapy, the role of targeted therapies, the treatment of limited metastatic disease, and potential future directions under investigation.

ROLE OF RADIOTHERAPY Definitive RT was the standard of care for patients with LA-NSCLC until clinical trials demonstrated improved survival with CMT. RT without chemotherapy remains the preferred definitive approach 57

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for poor-risk patients who are not candidates for CMT. RT can also have a role in selected patients with isolated thoracic recurrence after previous therapy. Other benefits of RT include palliation of tumor-related symptoms, local control of tumor growth and a potential survival advantage.

Dose Escalation The use of RT alone for LA-NSCLC consistently resulted in a median survival of about 10 months and 5-year survival rates of 5%.4–7 In the 1970s, the Radiation Therapy Oncology Group (RTOG) performed a phase III trial (RTOG 73-01) to evaluate the role of RT dose on local control rates and OS.8 Patients were randomly assigned to treatment with 40, 50, or 60 Gy in 2-Gy daily fractions. Local control rates were significantly better with the highest dose (52% v 62% v 73%, respectively), although median survival rates were similar (10.6 months v 9.5 months v 10.8 months, respectively).8 This established 60 Gy in 30 fractions as the standard RT dosefractionation schema. Early RT portals were designed to cover primary tumor, ipsilateral supraclavicular nodes, ipsilateral hilum, and contralateral mediastinum. This approach was termed elective nodal radiation therapy (ENI). However, as it became apparent that ENI results in additional toxicity and that local failure is closely related to poor patient outcomes, treatment planning shifted towards involved field irradiation (IFI).9 Concerns over the potential for nodal recurrences with IFI were answered by a prospective randomized trial from China where LA-NSCLC patients were treated with 68–74 Gy IFI or 60–64 Gy ENI.10 At 5 years, significant improvements were seen in the IFI arm with regard to overall response rates (90% v 79% ), local control (51% v 36% ), and the rates of pneumonitis (17% v 29% ). OS was improved for patients treated with IFI with 2-year rates at 39.4% versus 25.6%. While there are limitations to this study, the results are intriguing and suggest that failure to cover elective nodes is unlikely to compromise clinical outcomes. In addition to determining the optimal treatment volume, there was interest in exploring the role of dose escalation in the improvement of local control rates.11 Early phase I/II trials suggested that increasing the dose to 74 Gy could improve the median survival times to 24 months.12–15 These promising results, in addition to a pooled analysis of cooperative group studies,16 suggested the need to compare, with the backdrop of CMT, dose-escalated RT to standard RT doses in a randomized trial. This question was addressed in a phase III trial (RTOG 06-17) that randomly assigned patients with LANSCLC to one of two chemotherapy regimens and

A.M. Laine, K.D. Westover, and H. Choy

to either standard-dose RT (60 Gy in 30 daily fractions) or high-dose RT (74 Gy in 37 daily fractions). Survival was compared between the 74-Gy group and the 60-Gy group, and OS was better in the lower dose group (median survival of 28.7 months in 60-Gy group v 19.5 months in 74-Gy group and an estimated 18-month OS of 66.9% v 53.9%).17 Patients in the high-dose group had a 56% greater risk for death than those in the standarddose group and a 37% greater risk for local progression. However, even though 17 patients died in the 74-Gy arm compared with seven in the 60-Gy arm, the toxicity rates were no different between the two dose groups. The final results of this trial will surely be scrutinized, but the standard dose of RT for LA-NSCLC remains 60 Gy.

Altered Fractionation Schedules Multiple trials have explored the use of altered dose fractionation schedules to improve the therapeutic index of RT. These approaches have included hyperfractionation (two or three fractions per day with a lower dose per fraction over the standard treatment duration), accelerated fractionation (using a standard fraction size and total radiation dose, given over a shorter overall time) or a combination of both. Randomized studies have not shown a survival benefit to hyperfractionated radiation with concurrent chemotherapy delivered either continuously or as a split course compared with standard chemoradiotherapy.18,19 However, studies have demonstrated improved outcomes when using a hyperfractionated accelerated radiotherapy (HART) approach. Continuous HART, delivering 54 Gy in 36 fractions of 1.5 Gy over 12 days, resulted in improved survival compared with conventional RT alone (2-year OS 29% v 20%).20 Similarly, Eastern Cooperative Oncology Group (ECOG) 2597, which randomly assigned patients to HART (1.5 Gy three times per day for 2.5 weeks) after two cycles of carboplatin/paclitaxel or standard RT (64 Gy in 2 Gy daily fractions) with the same chemotherapy, revealed an numerically improved median survival for the HART arm (20.3 v 14.9 months, P ¼ .28) and 3-year OS (23% v 14%).21 The most informative results come from a metaanalysis of eight randomized trials that examined individual patient data from 2,000 patients, in which patients were randomly assigned to an altered regimen or conventional fractionation.22 The analysis was limited to trials where chemotherapy was identical in both treatment arms. Modified fractionation resulted in a small, but significant, improvement in 5-year OS (10.8% v 8.3%; hazard ratio 0.88). A higher rate of severe esophageal toxicity (19% v 9%) was observed in the modified fraction group.

Radiation therapy of locally advanced NSCLC

Widespread adoption of modified RT schedules over conventional once-daily treatment have been limited due in part to the logistical challenges to the patient and treatment centers to deliver HART, as well as the higher rates of toxicity.

Hypofractionation Hypofractionated radiation—the delivery of fewer, larger (42 Gy) doses of radiation—provides another potential means to increase dose-intensity. This approach has become more feasible with the advent of three-dimensional planning technologies that allow for more conformal radiation delivery, thereby decreasing RT volumes and normal tissue doses. Few studies have used hypofractionation with modern RT techniques for LA-NSCLC. Two prospective phase II studies evaluating concurrent platinumbased chemotherapy concurrently with 2.4–2.75 Gy per day have reported an encouraging 20-month median survival.23,24 Additional studies using modern RT techniques are currently ongoing in the cooperative group setting, as well as in single institutions. Of note the NCT01459497 is a phase III trial comparing a hypofractionated course of 60 Gy in 15 fractions over 3 weeks to conventional RT (60 Gy in 30 fractions) without concurrent chemotherapy for poor performance status, stage II–III NSCLC patients. An example of a hypofractionated treatment plan is shown in Figure 1.

Isolated Thoracic Recurrence Approximately one-third of stage I and stage II NSCLC patients who relapse following surgical resection have an isolated recurrence in the ipsilateral thorax.25 RT alone or with chemotherapy may salvage carefully selected patients with an isolated thoracic recurrence. In a single-institution, retrospective review in which 29 patients were treated of a 13-year period with definitive RT (median dose of 66 Gy), the actuarial rate of local control was 62% at 2 years and the 2-year OS rate was 38%.26 Most subsequent relapses were at distant sites.

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Additionally, this study reviewed seven earlier series and found that median survival ranged from 11–19 months and 2-year OS rates from 10%–40%. This suggests that for patients who have a stage I or II pattern of recurrence who are not candidates for further resection, RT alone is a reasonable salvage treatment option. For patients who recur in a stage III pattern, definitive chemoradiotherapy should be considered.

COMBINED CHEMOTHERAPY AND RADIATION THERAPY Since the mid 1990s, chemotherapy and RT have been combined in an effort to treat both locoregional and microstatic disease in patients with LANSCLC. Initially, sequential therapy (chemotherapy followed by RT) was used to avoid overlapping toxicities and clinical trials established the efficacy of this sequence compared to RT alone. However, studies that followed compared sequential to concurrent chemoradiotherapy and demonstrated a benefit for the concurrent approach.

Sequential Therapy Initial results were encouraging when the Cancer and Leukemia Group B (CALGB) trial 8433, which randomized patients to conventional RT (60 Gy in 30 fractions) or two cycles of cisplatin and vinblastine followed by conventional RT, demonstrated an improvement in median survival of 13.7 months (compared to 9.6 months for conventional RT alone) and 5-year OS of 17% (compared to 6%).5 These results were confirmed in an Intergroup trial, which randomized patients to conventional RT (60 Gy in 30 fractions), hyperfractionated RT (69.6 Gy in 58 fractions of 1.2 Gy twice daily), or chemotherapy (vinblastine and cisplatin) followed by conventional RT.27 The median survival was significantly improved in the sequential arm compared to either RT arm (13.2 v 11.4 and 12 months). The 2-year OS rates were 32% versus 19% and 24%, respectively. Additionally, two-

Figure 1. An image-guided radiotherapy (IGRT) treatment plan using a hyprofractionated approach for a patient with LA-NSCLC. The dose prescribed was 60 Gy in 15 fractions. Note the conformality of the high-dose region treating the tumor. (A) Axial image. (B) Sagittal image. (C) Coronal image.

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meta analyses confirmed that 1- and 2-year survival rates were improved with a sequential approach.28,29

Concurrent Chemoradiotherapy In an effort to improve local-regional tumor control, concurrent administration of chemotherapy and RT was studied. This approach was anticipated to have great potential based on the hypothesis that it would provide early treatment of micrometastatic disease and exploit the synergistic effects of chemotherapy and RT, while also delivering treatment in the shortest time. The superiority of concurrent chemoradiotherapy compared with sequential therapy has been demonstrated in two large, multicenter phase III trials. RTOG 9410 was a three-arm trial in which patients received either induction cisplatin and vinblastine followed by conventional RT alone, cisplatin and vinblastine concurrently with conventional RT, or cisplatin and etoposide concurrently with hyperfractionated twice-daily RT to a dose of 69.2 Gy.18 The clinical outcomes were significantly improved in the concurrent arm compared to the sequential arm with regards to median survival (17.0 v 14.6 months), 4-year OS (17% v 12%), and local control (66% v 59%). Acute grade 3 or higher nonhematologic toxicity was increased in the concurrent arm (48% v 30%), but the rates of late toxicity were similar. These results were confirmed by the West Japan Lung Cancer Group in which patients were assigned to either concurrent chemotherapy (two cycles of cisplatin, mitomycin, and vindesine) plus split-course RT (two courses of 28 Gy in 2-Gy fractions, separated by 10 days) or two cycles of the same chemotherapy regimen followed by RT alone (56 Gy in 28 fractions).30 Results favored the concurrent arm in regards to response rate (84% v 66%), median survival (17 v 13 months), and 5-year OS (16% v 9%). The optimal chemotherapy regimen for use in conjunction with concurrent thoracic RT is not known due to a paucity of randomized trials comparing different chemotherapy regimens in the LANSCLC setting. The two chemotherapy regimens that have been most commonly used are the combination of cisplatin and etoposide31 and the weekly carboplatin and paclitaxel32 regimens. In a recent Japanese study, concurrent carboplatin and paclitaxel had the lowest rates of grade 3–4 neutropenia and equal outcomes (median survival of 22 months) compared to those receiving mitomycin, vindesine and cisplation or irinotecan and cisplatin.33 Some argue, however, that cisplatin-based regimens may lead to improved outcomes over carboplatin-based regimens.34 Results of a recently completed phase III

A.M. Laine, K.D. Westover, and H. Choy

study comparing these two regimens are eagerly anticipated (NCT01494558). More recently, the use of pemetrexed plus cisplatin has become more prevalent, particularly in patients with nonsquamous NSCLC.35,36 With modern staging techniques, improved supportive care, and less squamous cell histology, patients with LA-NSCLC who undergo CMT obtain median survival rates ranging from 21– 26 months in current trials.37

Induction Chemotherapy Followed by Chemoradiotherapy The use of induction chemotherapy prior to concurrent chemoradiotherapy was associated with increased toxicity, but no survival advantage, reduction in distant metastasis or decrease in locoregional progression. These findings were observed in at least one phase III (CALGB 39081)32 and one randomized phase II (Locally Advanced Multi-Modality Protocol [LAMP])38 studies that used primarily a carboplatin/ paclitaxel regimen. In the CALGB 39081 phase III study, patients received two cycles of induction therapy with carboplatin and paclitaxel followed by chemoradiotherapy versus chemotherapy alone for LA-NSCLC.32 There was no statistically significant difference in the median survival (14 v 12 months), or 2-year OS (29% and 31%). Radiation-related toxicities were not significantly different between the two arms. Due in part to these two studies, induction chemotherapy is not routinely employed in the treatment of LA-NSCLC. However, in certain instances, induction chemotherapy prior to definitive therapy should be considered if the gross disease cannot be safely encompassed in a RT portal without leading to unacceptably high risk of radiationassociated side effects (ie, pneumonitis). In such cases definitive therapy can be used if an adequate response to induction therapy is obtained.

Consolidation Therapy The exact role of consolidation chemotherapy after chemoradiotherapy remains uncertain. Initial promising results of the phase II SWOG S9504 (median survival of 26 months)39 leant support to the concept that administration of consolidation chemotherapy might improve survival in LANSCLC. This was further addressed in the phase III Hoosier Oncology Group trial, which randomized patients to concurrent chemoradiotherapy with cisplatin and etoposide followed by three cycles of docetaxel consolidation or observation.31 The trial was stopped early based upon a planned interim analysis that met the predefined rule for futility. There was no difference in the median survival of patients receiving consolation therapy (21.2 months) versus the observation arm (23.3 months). Similarly,

Radiation therapy of locally advanced NSCLC

there was no difference in progression-free survival (PFS) with or without consolidation therapy (10.8 v 10.3 months). There were higher rates of treatmentrelated toxicities in the docetaxel arm, including death (5.5% v 0%). An additional phase III trial using consolidation cisplatin/vinorelbine or observation after concurrent chemoradiation with the same chemotherapy regimen did not demonstrate improved PFS or OS.40 Based on these results, when cisplatin-containing regimens are used during concurrent therapy, there appears to be no conclusive role for consolidation therapy. However, the question arises: if the standard for stage IV disease is to administer four to six cycles of chemotherapy, how are only two cycles of chemotherapy, as given with concurrent RT, sufficient to treat micrometastatic disease? Based on this line of reasoning, the use of consolidation therapy following concurrent chemoradiation is routine in clinical practice. When weekly radiosensitizing low-dose carboplatin and paclitaxel are administered concurrently with thoracic RT, consolidation therapy with full systemic doses is often given to address concern for systemic disease. Several studies have demonstrated improved survival outcomes for this approach.38,41 Based on the recent phase III Intergroup trial (RTOG 0617), two cycles of consolidation carboplatin and paclitaxel is the standard when a concurrent carboplatin/paclitaxel regimen is employed.17

MOLECULAR THERAPEUTIC AGENTS Scientific investigation has identified a number of molecular pathways that may be responsible for oncogenesis, cancer cell progression and growth, and cancer cell resistance to radiation or other cytotoxic agents. Therefore, these pathways are being explored as potential targets for augmentation of radiation response or chemotherapy response. The result has been an explosion of new molecularly targeted agents with potential value for selected lung cancer patients. Indeed, some of these agents have also been tested for use as primary therapy for lung cancer patients demonstrating the appropriate molecular profile. The expanding list of molecular targets for NSCLC includes epidermal growth factor (EGF) and its receptor (EGFR), vascular endothelial growth factor (VEGF) and its receptor (VEGFR), anaplastic lymphoma kinase (ALK) fusion protein (EML4-ALK), B-Raf, PIK3CAgene, ErbB2 (Her2/neu), mammalian target of rapamycin (mTOR), and various other molecules that regulate different steps in their signal transduction pathways.42 While the preclinical data suggests that all of these pathways contain potentially viable targets to be exploited in improving

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therapeutic efficacy, not all targeted agents have proven to be beneficial in the clinical setting. A handful of agents have now been granted US Food and Drug Administration (FDA) approval for cancer therapy, while many other agents are undergoing clinical trials to determine their efficacy when used in combination with other cytotoxic agents, including ionizing radiation. Some agents are potentially single pathway targeting agents, and others target multiple molecular signaling pathways. The most clinically advanced agents target EGFR, VEGF/ VEGFR, and ALK1 pathways. Molecular agents that have been studied in conjunction with radiation treatments in the clinical setting are outlined in Table 1.

EGFR Targeting EGFR is one of the model paradigms for combining RT with molecular based therapeutics. EGFR plays an important role in tumor growth and response to cytotoxic agents, including ionizing radiation. The receptor is frequently expressed at high levels in many types of cancer, which is often associated with more aggressive tumors, poor patient prognosis, and tumor resistance to treatment with cytotoxic agents including radiation.43–46 Preclinical data have generally supported a strong rationale for combining EGFR inhibitors with RT. Broadly speaking, two mature strategies for inhibiting EGFR include use of monoclonal antibodies (mAB) against the EGFR receptor (cetuximab and panitumumab) and small molecule tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib). Cetuximab is a chimeric mouse anti-EGFR mAB, and is perhaps the most widely studied and developed mAB in this class. While the main study which defined the role of cetuximab in conjunction with RT is based on positive experience in head and neck squamous cell carcinoma patients,47 this agent also has been studied extensively in NSCLC patients. Of note, recent phase II studies were reported by the RTOG and CALGB groups.48,49 In the randomized phase II CALGB study, two novel chemotherapy regimens were given concurrently with RT to LANSCLC patients. The first group received concurrent carboplatin and pemetrexed with 70 Gy of thoracic RT. The second group received the same but also added cetuximab. Both groups received four cycles of pemetrexed as consolidation therapy. The carboplatin/pemetrexed/RT arm demonstrated 18-month OS of 58%, and the group with cetuximab, demonstrated 18-month OS of 54%. The final interpretation was that the combination of thoracic RT, pemetrexed, carboplatin, with or without cetuximab is feasible and fairly well tolerated.49

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Table 1. Clinical Trials Using Molecular Compounds With Combined Chemoradiotherapy for LA-NSCLC Study

Agent

RTOG 0324, Cetuximab phase II47 CALGB 30407, Cetuximab phase II48

Study Design Carboplatin/paclitaxel/cetuximab/ RT→carboplatin/paclitaxel x 2 cycles Carboplatin/pemetrexed/RT ± cetuximab

Gefitinib

Chemo/RT -4 docetaxel x 3 cycles→gefitinib v placebo

CALGB 30106, Gefitinib phase II57

Poor-risk group: carboplatin/paclitaxel →RT/ gefitinib →gefitinib Good-risk group: carboplatin/paclitaxel →RT/ gefitinib/carboplatin/paclitaxel →gefitinib

SWOG 0023, phase III56

University of Chicago, phase I58 Spigel et al, phase II=

Group 1: carboplatin/paclitaxel →carboplatin/ paclitaxel/RT/erlotinib Group 2: cisplatin/etoposide/RT/erlotinib →docetaxel Bevacizumab Carboplatin/pemetrexed/bevacizumab/RT → carboplatin/pemetrexed/bevacizumab →bevacizumab

Erlotinib

In the RTOG study, patients were treated with combination of paclitaxel/carboplatin and cetuximab with 63 Gy of RT. All patients received a loading dose (400 mg/m2) of cetuximab 1 week prior to RT, and patients received carboplatin/paclitaxel/cetuximab for two additional cycles after completion of RT. This study demonstrated a median survival of 22.7 months, and 2-year OS of 49.3%.48 Based on these very promising results, cetuximab was included in the recent RTOG 0617 trial. Current randomization includes chemotherapy plus cetuximab plus RT versus chemotherapy plus RT, followed by adjuvant chemotherapy versus chemotherapy plus cetuximab. Results of this study are eagerly anticipated. Gefitinib is approved for use as single agent in treatment of chemotherapy-refractory NSCLC.50 This agent demonstrated promise in phase II studies (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL]-1, and IDEAL-2),51,52 but had disappointing results in phase III trials (‘Iressa’ NSCLC Trials Assessing Combination Treatment [INTACT]-1, and INTACT-2) where it failed to demonstrate additional benefit to standard chemotherapy for advanced lung cancer patients.53,54 However, a subset of patients was noted to have a significant response to gefitinib, and subsequently this led to discovery that mutations in the EGFR tyrosine kinase domain may predict for positive response to gefitinib.55,56

Findings Median OS: 27.7 mo 2-yr OS: 49.3% Without cetuximab: 18 mo, OS 58% With cetuximab: 18 mo, OS 52% With gefitinib maintenance: median OS 23 mo Placebo: median OS 35 mo Poor-risk group: PFS 13.4 mo, median OS 19 mo Good-risk group: PFS 9.2 mo, median OS 13 months Group 1: median OS 13.7 mo Group 2: median OS 10.2 mo 2/5 patients developed tracheo-esophageal fistulae

SWOG performed a large phase III trial where stage III NSCLC patients were treated with standard chemoradiotherapy followed by consolidation with docetaxel for three cycles. The patients were then randomized to maintenance therapy with placebo, or gefitinib. At interim analysis, patients on the gefitinib maintenance arm had worse OS (23 v 35 months), and therefore the study was closed.57 Based on this trial, routine use of EGFR-targeted therapy using TKIs after definitive chemoradiation in an unselected patient population is not supported. CALGB 3010658 was a phase II study designed to evaluate the addition of gefitinib to sequential or concurrent chemoradiotherapy in unresectable NSCLC patients. Patients were categorized into poor-risk (≥2 and ≥5% weight loss) and good-risk strata (performance status [PS] 0-1, weight loss o5%). All patients received induction chemotherapy with two cycles carboplatin and paclitaxel plus gefitinib. Gefitinib was removed from induction in May 2004 when the SWOG trial did not demonstrate a benefit to adding gefitinib with chemotherapy. The poor-risk group received 66 Gy of thoracic RT with concurrent gefitinib. Good-risk stratum patients received the same RT and gefitinib but also received weekly carboplatin and paclitaxel. Consolidation gefitinib was given until progression. For poor-risk patients, PFS was 13.4 months, and median

Radiation therapy of locally advanced NSCLC

OS was 19 months. In good-risk stratum, PFS was 9.2 months, and median OS was 13 months. Thirteen of 45 tumors had activating EGFR mutations, and 2/ 13 had T790M mutations. Seven of 45 tumors had KRAS mutations. When analyzed by these molecular phenotypes, no significant difference in outcome was noted. Interestingly, individuals in the poor risk stratum who received RT plus gefitinib after induction chemotherapy demonstrated promising survival and PFS outcomes. This will likely lead to further studies designed to elucidate the role of gefitinib and RT in poor PS patients with LA- SCLC. Meanwhile, the good-risk stratum patients did not demonstrate an improved outcome, suggesting that addition of gefitinib to chemotherapy/RT regimen may not be beneficial in this patient population. This is consistent with studies of erlotinib and chemoradiation therapy.59 Erlotinib is also an EGFR TKI that has been studied for the treatment of LA-NSCLC. Findings from two large phase III studies, The Tarceva Lung Cancer Investigation (TALENT)60 and Tarceva Responses in Conjunction with Paclitaxel and Carboplatin (TRIBUTE)61 trials demonstrated no significant improvement in outcomes with the addition of erlotinib to chemotherapy in patients with advanced lung cancer. Similar to the gefitinib studies, the lack of demonstrable global benefit to erlotinib pointed to the need for stringent patient selection criteria. In the TRIBUTE study, addition of erlotinib to carboplatin and paclitaxel improved PFS and OS only in the subset of never smokers. National Cancer Institute (NCI) Canada conducted a phase III study of patients with stage IIIB or IV NSCLC, who had failed one or two prior chemotherapy regimens. Patients were randomized to receive erlotinib or placebo. Despite the fact that EGFR status was not part of the enrollment criteria for this study, OS was improved with erlotinib (6.7 v 4.7 months), and response rate, time to symptomatic progression, and PFS were also improved. An exploratory subgroup analysis showed that EGFR amplification status did correlate with survival.62 Since EGFR TKIs appear to be most effective in never-smokers and in patients with EGFR mutations, this question was studied in a phase II study by the CALGB group (CALGB 30406). This study evaluated patients who were never/light-smokers, and patients were randomized to erlotinib alone, or erlotinib, carboplatin, paclitaxel. This study has only been reported in an abstract form. At a median follow-up of 30 months, there was no statistically significant difference in PFS with the addition of erlotinib. However, patients with EGFR mutation had significantly improved PFS and OS in both treatment groups compared to patients who did not harbor the EGFR mutation.63

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Choong et al59 reported on a ping-pong phase I study of erlotinib with chemoradiotherapy. One group received induction carboplatin and paclitaxel followed by carboplatin/paclitaxel/RT and erlotinib, while a second group received cisplatin/etoposide/ RT and erlotinib followed by docetaxel. Erlotinib dose was escalated from 50 mg to 150 mg in three levels in each arm. Median survival in each group was 13.7 months and 10.2 months, respectively, with patients who developed rash showing an improvement in OS and PFS. This study demonstrated tolerability of the regimen, but also resulted in disappointing survival data, once again pointing to the need for improved patient selection when using EGFR-based treatments. Tremendous efforts have been made to establish the role of combining anti-EGFR–targeted compounds with radiation and chemoradiation therapy in many different malignancies. The paradigm for success is the demonstrable benefit of adding mAB cetuximab with RT for patients with locally advanced head and neck cancer. Interestingly, cetuximab is being investigated as a promising agent for combination with chemotherapy/RT in locally advanced NSCLC (RTOG 0617) based on data from RTOG 0324. Meanwhile, in LA-NSCLC patients, antiEGFR TKIs have shown no demonstrable benefit in the maintenance/adjuvant setting after chemoradiation treatments. Perhaps unsurprisingly, a general them from these trials is that patient selection for EGFR mutations or amplification is important when designing studies involving EGFR-targeted agents. An interesting question arises: how does treatment for lung cancer change the responsiveness of cancer cells to EGFR targeted agents. Along these lines, it may be reasonable to re-evaluate biomarkers after chemoradiation treatments to determine which subset of patients may benefit from further therapy with anti-EGFR agents. Clearly, in designing future studies involving anti-EGFR treatments in combination with RT consideration should be given to using focused patient selection criteria at various time points throughout the treatment cycle to maximize chances of providing benefits for patients.

Anti-angiogenesis Agents Perhaps no other molecular targets have been investigated for possible tumor treatment strategies more than inhibitors of tumor angiogenesis or agents that act on the tumor vasculature. Inhibitors of angiogenesis have undergone extensive preclinical testing, with some agents moving into clinical trials. Even though there were concerns that an anti-angiogenic agent may impair the efficacy of

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radiotherapy via the enhancement of hypoxia, interestingly, the first clinical trial with a specific inhibitor of angiogenesis, angiostatin, showed a synergistic effect with radiation.64 A model of normalization of tumor vasculature has been described by Jain.65 In this model, pro-angiogenic factors from tumors can cause abnormal neovascularization, and inhibition of tumor angiogenesis transiently normalizes the tumor vasculature. This, therefore, has the counterintuitive effect of decreasing tumor hypoxia and improving effectiveness of RT. Preclinical studies have been performed in support of this hypothesis, and a phase I study of bevacizumab with 5fluorouracil and RT preoperatively in locally advanced rectal cancer patients also supports this notion.66 Similar to the EGFR inhibitors, anti-angiogenic compounds can broadly be classified as monoclonal antibodies directed against anti-angiogenic molecules or their receptors (mAB) (bevacizumab) or TKIs with narrow or broad-spectrum activity against one or more of these receptors (sorafenib, sunitinib, pazopanib). In NSCLC, studies with bevacizumab have been performed with radiation. Efforts to improve the therapeutic ratio by addition of bevacizumab to chemoradiation therapy have been attempted in multiple studies for both small cell lung cancer and NSCLC patients. Unfortunately, these studies demonstrated an association between bevacizumab and the incidence of tracheo-esophageal fistula in both small cell and NSCLC cases.67 Therefore, in the setting of lung cancer, patient selection factors (location of tumor, histology of tumor), and timing of integration of bevacizumab with RT needs to be considered, when designing further studies. Studies are underway aimed at determining potential role and sequencing of bevacizumab, when used with combined modality therapy, in patients with NSCLC. Thalidomide has also been found to have potent immunomodulatory effects as well as antiangiogenic properties.68 ECOG 3598 was a randomized study comparing chemoradiation with or without thalidomide in patients with LA-NSCLC. Patients underwent either carboplatin/paclitaxel with or without thalidomide for two cycles, followed by either weekly carboplatin/paclitaxel with RT with or without thalidomide. Additionally in the thalidomide group, patients could be treated with adjuvant thalidomide for up to 2 years. There was no difference in PFS or OS with addition of thalidomide.69 While this may suggest nonefficacy of such combination therapy regimen, another possibility is that such negative studies may point towards a need for a better patient selection when using specific agents.

A.M. Laine, K.D. Westover, and H. Choy

ALK Inhibitors The ELM4-ALK fusion oncogene has become a very important potential biomarker for patients with NSCLC.70 While several ALK inhibitors have been identified, clinical experience is longest with crizotinib. Crizotinib is effective as an ALK inhibitor in NSCLC patients harboring ALK translocations.71 In a phase I trial of 82 patients selected for ALK translocation (out of more than 1,500 patients), an impressive response rate of 57% was noted.72 Based on this very promising phase I study, this agent has entered phase III studies directly. This agent has received FDA approval for patients with NSCLC with ALK translocation. There are no significant data to suggest a radio-sensitizing or synergistic effect when combined with RT concurrently. Given the high response rates with agents like crizotinib and the observation that targeted molecular therapy does not provide durable control, one potential strategy under consideration is to follow crizotinib therapy with consolidative RT.

TREATMENT OF OLIGOMETASTATIC DISEASE In general, the prognosis for metastatic NSCLC is poor. However, clinical evidence suggests that an intermediate, or oligometastatic, state may exist when metastasis are limited in number and/or location, making it possible that local therapy with surgery or radiation may provide a benefit.73–76 This is consistent with findings for NSCLC77,78 and several trials have explored the role of hypofactionated image guided radiotherapy (HIGRT) or stereotactic ablative body radiotherapy (SABR) in the treatment of oligometastatic disease. The North Cancer Treatment Group phase III trial explored the role of treating all known sites of disease (limit of one to three metastatic sites) with RT following four to six cycles of systemic therapy would result in improved survival (NCT00776100). Patients were randomized to observation or RT to all sites of disease. The RT fractionation was either 60 Gy in 2-Gy fractions or 45 Gy in 3-Gy fractions. Unfortunately, the study was closed due to poor accrual. The protracted courses of RT may have contributed. The University of Chicago performed a phase II trial in patients with one to five NSCLC metastasis (NCT00887315). Patients either received RT to all known sites of metastasis during the third and fourth cycle of systemic therapy (cisplatin and docetaxel) or chemotherapy alone. RT was given in 5 Gy fractions to a total dose of 50 Gy. Unfortunately, this study too had difficulty accruing and closed prior to meeting the accrual goal.

Radiation therapy of locally advanced NSCLC

A single-arm phase II study at Wake Forest University of treating all visible extracranial metastasis after completion of systemic therapy with SABR is ongoing (NCT01185639). Patients receive three to six cycles of systemic therapy and must have stable disease or partial response before treatment with RT. This study differs from the two above in that it employs SABR, which allows the delivery of metastasis-directed therapy quickly. Recently, reports from a phase II trial combining SABR and erlotinib have generated interest.79 Stage IV NSCLC patients with six or fewer sites of extracranial disease who failed first-line systemic therapy received SABR to all sites of clinically apparent disease combined with erlotinib therapy. Frequent SBRT fractionation schemes used included 33 Gy in 11-Gy fractions and 40 Gy in 8-Gy fractions. Twentythree patients who had progressed through platinum-based chemotherapy, 14 with paclitaxel and seven with pemetrexed, as part of the doublet regimen were treated. Lung parenchyma and mediastinal lymph nodes represented most common sites of irradiation. The median PFS was 10.7 months and median OS was 20.8 months. A majority of patients progressed in new sites with only four patients failing locally. Overall, the therapy was well tolerated. Debulking gross disease with local therapy resulted in a median PFS of nearly a year with patients relapsing most commonly in new rather than existing sites and demonstrated that cytoreduction with SABR may aid systemic agents in prolonging survival. Further trials exploring this hypothesis would be of interest.

CONCLUSIONS Biomarkers, molecular therapeutics, advanced imaging technology, and experience with integration of chemotherapy and radiation treatments have made personalized medicine for NSCLC more feasible. As new biomarkers are discovered, the use of such personalized strategies will become more applicable to a larger number of patients. Although not discussed above, the role of immunomodulatory therapy also may play a larger role in the treatment of NSCLC in the future since initial studies of immunomodulatory agents in combination with cytotoxic agents have provided early promising results.80 Incorporation of such agents into a concurrent chemoradiotherapy regimen is currently being considered. Despite significant advances in the treatment of LA-NSCLC, for the majority of patients, it remains a deadly disease. Improvement of our therapeutic development strategy, in order to maximize the chance of future success for our patients, should be our driving force.

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