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# Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy

*Sameera S. Kumar 1 , Kristin A. Higgins 2 and Ronald C. McGarry1 \**

*1Department of Radiation Medicine, University of Kentucky, Lexington, KY, United States, 2Department of Radiation Oncology, Winship Cancer Institute of Emory University, The Emory Clinic, Atlanta, GA, United States*

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an "abscopal effect" although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This "quadmodality" approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy.

Keywords: stereotactic body radiation therapy, immunotherapy, radiation therapy, non-small cell lung cancer, stage III

### CHEMORADIATION IN STAGE III NON-SMALL CELL LUNG CANCER (NSCLC)

One hundred years ago, lung cancer was a rare malignancy (1). Lung cancer today is the leading cause of cancer death in the United States, with over 158,000 estimated deaths in 2016 (2). Forty percent of these patients present with locally advanced disease (3). Approximately 80–90% of newly diagnosed lung cancers are classified as NSCLC, primarily consisting of adenocarcinoma, squamous cell carcinoma, or large cell carcinoma histologies. Historically, surgery has been the gold standard for newly diagnosed NSCLC with early-stage resectable disease, resulting in 5-year overall survival

#### *Edited by:*

*John Varlotto, University of Massachusetts Medical Center, United States*

#### *Reviewed by:*

*Eric Chi-ching Ko, Weill Cornell Medical College, United States Nitin Ohri, Albert Einstein College of Medicine, United States*

> *\*Correspondence: Ronald C. McGarry<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology*

*Received: 31 July 2017 Accepted: 17 August 2017 Published: 04 September 2017*

#### *Citation:*

*Kumar SS, Higgins KA and McGarry RC (2017) Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy. Front. Oncol. 7:197. doi: 10.3389/fonc.2017.00197*

rates (OS) of 50–70%. However, for patients with more locally advanced NSCLC, 5-year OS after treatment with definitive radiation therapy and concurrent chemotherapy remains modest, at approximately 15–20% (4). Prior to the advent of cytotoxic chemotherapy, lung cancer at all stages was treated surgically or by radiation alone (5, 6). TNM staging was introduced in 1974 and it helped shape the way lung cancer was managed. Stage III lung cancer, though heterogeneous in its classification, includes non-metastatic but locally advanced disease with involvement of N1–N3 nodal stations and/or T3 and T4 primaries. Presently, stage III lung cancer is managed with a combination of chemotherapy, radiation therapy, and sometimes surgery but the two major challenges in improving outcomes of the treatment of this disease remain local control and metastatic spread.

## CHEMORADIOTHERAPY (CRT) DOSE ISSUES

Multiple studies have examined the issue of the optimal dose of radiotherapy in NSCLC but are complicated by the heterogeneity of the disease itself in terms of size and location of the primary tumor, number and size of involved lymph nodes, and the patient's comorbidities, all of which limit the treatment tolerability and risks. Delivery of tumoricidal doses to the primary tumor and involved lymph nodes is balanced by treatment-related toxicities, namely esophagitis, pneumonitis, and cardiac injury.

An early dose-finding study by the Radiation Therapy Oncology Group (RTOG) 7301 study was conducted from 1973 to 1978 and studied four different doses and schedules: 40 Gy split course, 40 Gy continuously, 50 Gy, and 60 Gy. All doses were given in 2 Gy fractions. The optimal dose was determined to be 60 Gy (7).

Further improvements in survival were sought by the incorporation of chemotherapy. The Cancer and Leukemia Group B 8433 study solidified chemotherapy's importance in the treatment of locally advanced lung cancer. In this phase III study, 155 patients with stage III NSCLC were randomized to receive 60 Gy in 30 fractions or induction chemotherapy consisting of two cycles of cisplatin and vinblastine followed by 60 Gy in 30 fractions. Both median OS (13.8 versus 9.7 months) and 3-year OS were improved in the CRT arm (23 versus 11%) (8). Likewise, a European Organisation for Research and Treatment of Cancer study showed a benefit to concurrent CRT by randomizing patients to split-course radiotherapy alone to a dose of 55 Gy, split-course radiotherapy plus low-dose daily cisplatin, and split-course radiotherapy plus higher dose weekly cisplatin. The most salient differences were seen between concurrent daily CRT and radiation alone with the 3-year OS for CRT being 16 versus 2% for radiotherapy alone. This difference was thought to be due to an improvement in local control, as the 2-year local control in the daily CRT arm was 31 versus 19% in the radiotherapy alone arm (9).

Only one phase III trial has compared the traditional standard of 60 Gy to a modestly escalated dose regimen of 74 Gy. Based on the results of RTOG 0117 suggesting that 74 Gy represented a maximum tolerated dose of CRT for most patients, RTOG 0617 compared 60 versus 74 Gy both combined with weekly carboplatin and paclitaxel. In this four-arm study, a second randomization of cetuximab versus observation was also studied. Unfortunately an interim analysis showed that the 74 Gy arm had increased risk of death, with a median survival of 20 months for patients receiving 74 Gy versus 29 months for patients receiving 60 Gy, leading to early termination of the study (10). There was no benefit to local control. Of note, the 60 Gy arm had the highest median survival demonstrated within a phase III trial for this patient population. On multivariate analysis, increased dose to the heart, represented as heart V5 and V30 (the percent volume receiving ≥5 and ≥30 Gy, respectively), maximum esophagitis grade, planning target volume, and radiation dose (74 Gy) were all shown to negatively impact overall survival. There were no statistically significant differences in ≥grade 3 toxic effects between the groups; however, heart-specific toxicities were not assessed in this trial. Ultimately this underlines the difficulty of dose escalation with conventional radiation therapy fractionation techniques in the general population of patients with stage III NSCLC, opening the door for new strategies to improve outcomes for locally advanced disease. Often the argument is put forth that surgery is the ultimate form of local control and indeed 5-year local control rates for locally advanced NSCLC after CRT have been reported as low as 15%, but at least some of this is possibly biased by the selection of more resectable patients receiving surgery (11). Improving local control of the primary lesion in NSCLC does influence overall survival, as demonstrated by a meta-analysis of concurrent CRT versus sequential chemotherapy and radiation (12). Thus, if radiation techniques could be optimized and local control improved, one could expect to see improvement in longterm patient survival.

### INDIVIDUALIZED CRT

Since most dose-escalation studies have produced problematic results in relatively unselected patients, can escalated radiation doses safely be delivered to patients by adaptive radiotherapy either during or after conventional radiotherapy? Additionally, in an era of intense research into molecular markers and innovative systemic therapies, how can combination strategies best be utilized to improve both local control and risk of metastasis?

Radiation Therapy Oncology Group 9311 was an early multi-center dose-escalation trial of 179 patients which used radiotherapy alone (13). The treatment was individualized based on the volume of lung receiving 20 Gy or more (V20). Those with a V20 less than 25% were dose-escalated to 90.3 Gy. Those with a V20 of 25–36% were dose-escalated to 83.8 Gy. Both schemes were performed at 2.15 Gy per fraction. Two treatment-related deaths occurred in the 90.3 arm and this dose was labeled as too toxic. Elective nodal coverage was not allowed, but still the isolated nodal failure rate was less than 10%. For the group with a V20 less than 25%, 83.8 Gy was found to be safe and for the group with a V20 of 25–36% 77.4 Gy was found to be safe.

More recently Kong et al. reported results of a phase II study of mid-treatment positron emission tomography-computed tomography (PET/CT) adapted radiotherapy with concurrent chemotherapy (14). Briefly, in this study, 43 patients with unresectable stage II–III NSCLC received radiotherapy with doses individualized for an allowable mean lung boost dose of up to 20 Gy which would produce a risk of pneumonitis up to 17.5%. Radiation was delivered in 30 fractions with all patients receiving 2.1–2.85 Gy/fraction for the initial dose up to approximately 50 Gy EQD2 with the adaptive phase of the treatment of 2.85–5.0 Gy/fraction for a total radiation dose of up to 86 Gy in an attempt to deliver >100 Gy BED10. Weekly carboplatin and paclitaxel were given concurrently. After a median follow-up of 47 months, the 2-year infield and overall local regional tumor controls were 82 and 62%, respectively; and median OS was 25%. Overall these results are consistent with most other stage III studies. This promising strategy of mid-treatment PET with dose escalation is currently being evaluated in the RTOG 1106 randomized trial, which recently completed accrual. Though local control has improved with these trials, metastatic disease still remains an important site of failure.

Stereotactic body radiation therapy (SBRT) has changed the standard of care for early-stage lung cancer, and data are emerging showing applicability to the stage III NSCLC population. The evidence for a role of SBRT in the stage III lung cancer population is summarized within this review.

### BIOLOGICALLY EFFECTIVE DOSE (BED) AND SBRT

The success of SBRT treatments in early-stage NSCLC likely reflects the radiobiologic properties of high radiation doses. Higher radiation doses result in exponential increases in cell kill, and may also have an ablative effect on tumor vascularity and stroma (15, 16). A method of dose modeling based on the linear quadratic model of cell killing, referred to as the BED, takes into account the radiation dose per fraction and the inherent radiation response of a particular tissue (17). As derived from linear quadratic curves, mathematically two different dose and fractionation schemes can be compared theoretically for tumor control probability. An important assumption of this model is referred to as the α/β ratio, simplistically thought of as the ratio of cell killing based on single hit and multi-hit kinetics that leads to local control of a cancer mass (primarily from cell culture experiments, animal data and clinical observation). Nevertheless, tumor control probabilities are more complicated than a simple mathematical statement since tissues are complicated structures with underlying vasculature, stroma, and tumor cells, all of which interact (18). Many of the α/β assumptions are, therefore, also based on long clinical observation of tumor control and normal tissue toxicities. The BED equation can be expressed as BED = *nd*(1 + *d*/α/β) where *n* = the number of fractions, *d* = the dose/fraction, and α/β = alpha-beta ratio. Often early-reacting tissues/tumor cells are considered to have an α/β of approximately 10 whereas late reacting tissues are assigned an α/β of approximately 3. Based on these assumptions, Martel et al. constructed a mathematical model which predicted that in NSCLC a dose 84 Gy must be achieved for a local progression-free survival (PFS) of greater than 30 months (19). A retrospective study found that the doses of at least 70 Gy at 1.8–2 Gy per fraction provided better local control and survival for tumors less than 100 cc (20). Using 2 Gy fractions, a dose of 70 Gy has a BED of 84 Gy.

Based on the success of Gamma Knife treatment of brain lesions, extremely hypofractionated extracranial stereotactic radiotherapy programs began in the 1990s and are commonly known as SBRT or stereotactic ablative radiation therapy. SBRT treatments, because of the high dose per fraction, are able to achieve a much higher BED to localized volumes than conventional radiation delivered at 2 Gy/fraction. Multiple studies have demonstrated that a higher BED is correlated with improved local control and survival (21–24). Onishi et al. have shown that in early-stage lung cancer, superior local control and survival are achieved with treatment regimens that reach a BED of 100 Gy or greater (21). Specifically in lung cancer, SBRT delivers a high dose per fraction, with robust immobilization that minimizes intra-fraction motion and tumor-related internal motion, allowing for overall reduction in size of treatment volumes and overall treatment time.

In the seminal clinical reports by Blomgren and Lax, the philosophy and treatment parameters for the hypofractionated highly conformal treatment of localized disease that we use today were elucidated (25). In an *ad hoc* manner, they treated a number of different sites of localized disease most notably early-stage lung cancers settling on a dose of 60 Gy in three fractions of 20 Gy each with excellent local control and minimal toxicity. Their studies defined the parameters required for safe and precise delivery that we utilize in SBRT delivery today. Presciently, they speculated that "this new technique may also be used for delivering boost doses with a high precision after conventional radiation therapy" (26).

## SBRT CLINICAL TRIALS IN EARLY-STAGE LUNG CANCER

In an effort to better define SBRT doses for localized disease, Timmerman et al. performed a phase I-II dose-escalation study for SBRT to the primary tumor in patients with stage I NSCLC using the concept derived from Swedish studies (27). Inhomogeneity corrections to correct for lung density were not performed. Separate cohorts of patients were followed with the dose-escalation ending at 60 Gy in 20 Gy fractions with no doselimiting toxicity. Termination of the dose escalation for these smaller tumors was based on modeling of cell kill. For larger tumors (up to 7.0 cm) a dose-limiting toxicity (pneumonitis) was reached at 72 Gy in 24 Gy fractions. This experience laid the groundwork for further national clinical trials evaluating SBRT as a therapy for medically inoperable early-stage NSCLC, and ultimately changed the standard of care for these patients. Currently, SBRT is defined as 1–5 treatments of high-dose radiation delivered to tumors, typically measuring up to 7 cm, with registration of the patient's anatomy to a 3-D coordinate system either physical or within the planning system. SBRT is considered an ablative treatment intended to disrupt cellular clonogenicity, and lead to cell death. Robust immobilization, control of internal organ and tumor motion, sharp dose gradients, and high dose per fraction (≥600 cGy) for five or fewer fractions have been considered to define SBRT.

The first North American prospective cooperative group clinical trial evaluating SBRT, RTOG 0236 began accrual in 2004 and only allowed "peripherally located" tumors as defined by being outside 2 cm of the proximal bronchial tree or mediastinum (commonly referred to as the "no fly" zone). This study accrued 59 patients, treated with 18 Gy × 3 (total 54 Gy with heterogeneity corrections) to the primary tumor, and demonstrated 3-year local control (involved tumor and primary lobe) of 91% for patients with T1-2, N0 medically inoperable lung cancer (28). Three-year local–regional control was 87%, and distant failure rate was 22%. Overall survival was 56%. Results from longer follow-up have shown higher rates of local failure, primarily due to intralobar recurrences, with 5-year local recurrence rates of 20% (29). Importantly, these clinical outcomes are far better than historical studies treating medically inoperable early-stage lung cancer with conventionally fractionated radiation (2 Gy/fraction), with dismal local control of the primary tumor of 50% or less (30). Grade 3 and higher adverse events occurred in approximately 15% of patients enrolled in RTOG 0236.

For centrally located tumors, RTOG 0813 was a phase I-II study for T1-2, N0 medically inoperable lung cancer 5 cm or less in size, centrally located within or touching the 2 cm bronchial tree "no fly" zone. The primary endpoint was to establish the optimal SBRT dose for centrally located tumors. With dose cohorts of 10 Gy × 5, 10.5 Gy × 5, 11 Gy × 5, 11.5 Gy × 5, and 12 Gy × 5, it was found that the highest dose cohort had a 7% probability of a dose-limiting toxicity (31). RTOG 0915 was a randomized phase II study designed to test 34 Gy × 1 versus 12 Gy × 4 for noncentrally located tumors, with a primary endpoint of determination of the regimen with the lowest rates of protocol specified adverse events at 1 year. One year adverse events were 10% for the 34 Gy arm, and 13% for the 48 Gy arm (32).

It thus appears that there are multiple hypofractionated schemes that are acceptable using SBRT techniques to achieve high degrees of local control but they all have one thing in common: BED > 100.

### SBRT TOXICITY

Though grade 3–5 toxicities with SBRT are overall low, Timmerman et al. retrospectively found in the initial single institution phase II study that 20–22 Gy × 3 was overly toxic for tumor in a central location, defined as within 2 cm from the proximal bronchial tree. In this phase II study, 2-year freedom from severe toxicity was 83% in patients with peripheral tumors and 54% for patients with central tumors (33). A separate single institution study recently showed a 3.7% fatal toxicity rate for SBRT with central tumors, with tumors abutting the proximal bronchial tree having significantly more grade 3+ adverse events (31 versus 7%) (34).

This suggests that tumor location with regards to the potential for late toxicity attributable to SBRT may be important as described above, but the RTOG 0813 SBRT dose-escalation study shows that central tumors may be safely treated to significant SBRT doses (31). As data and experience accumulates, dose-limiting organs within the hilum and mediastinum are becoming better defined and with care, SBRT can be utilized to treat "central" tumors safely.

Nonetheless, a large body of literature is accumulating confirming that SBRT treatment is well tolerated and safe in patients who are medically inoperable with early-stage lung cancer and produces excellent results. The question of applying SBRT to a stage III population with centrally located mediastinal lymph nodes as well as primary tumors remains pertinent. The studies summarized below describe the experience of SBRT in the locally advanced, stage III patient population.

### DOSE-ESCALATED HYPOFRACTIONATED RADIATION (SBRT) IN STAGE III NSCLC

Investigators at the University of Kentucky completed a prospective study evaluating the feasibility of conventional CRT followed by a SBRT boost to the primary tumor as a method to dose escalate in patients with residual disease following CRT (35). In this study, patients with stage IIIA and IIIB NSCLC received CRT (median dose of 59.4 Gy) followed by a whole body fluorodeoxyglucosepositron emission tomography (FDG-PET) scan 1 month after treatment. Eighty-nine percent of patients received concurrent, platinum-based chemotherapy during CRT. Patients were eligible for SBRT if they had evidence of residual disease at the primary tumor location that was ≤5 cm in greatest dimension. Patients with progressive metastatic disease, contralateral lung disease or residual disease in the hilum or mediastinum were not eligible (defined as SUV ≥ 2). SBRT doses were 6.5 × 3 for centrally located primary tumors, and 10 Gy × 2 for non-central tumors. With these dose schemas, the cumulative BED10 to the primary tumor was 110 Gy for non-central tumors and 102 Gy for centrally located tumors. Sixty-two patients were screened, and 37 patients were ultimately eligible and enrolled. Approximately 31% of patients screened had new metastatic disease and an additional 31% had persistent nodal disease on post-treatment FDG-PET. The primary endpoint of this study was to assess the proportion of patients who developed ≥grade 3 radiation pneumonitis, according to the RTOG acute and late radiation morbidity scoring criteria. Overall, 11.4% of patients experienced radiation pneumonitis consistent with rates found in most studies of conventional CRT suggesting no increase risk with the SBRT boost. Two patients developed fatal pulmonary hemorrhage felt to be possibly related to treatment but careful analysis showed that these cases were more likely to have been related to squamous cell cavitary recurrences involving the hilum (36). Statistically there were no differences dosimetrically between patients who developed a fatal hemorrhage from those who did not. Local recurrence remained the most significant predictor. The central structures including the bronchial walls, pulmonary arteries, and aorta were contoured and the individual doses delivered to these structures were compared as well as the location of the PTV to the hilum. This small series of patients suggested that it is prudent to restrict the maximum radiation dose to the pulmonary artery to less than 185 Gy cumulative BED3, and to less than 120 Gy BED3 for the 5 cc volume; as well as limiting the maximum dose to the bronchial wall to less than 175 Gy BED3. The equivalent dose on a per fraction basis would be equivalent to limiting each of these structures to less than 700 cGy per fraction times 3, or 900 cGy per fraction times 2 for the boost, assuming that the patient has previously received between 60 and 66 Gy using standard fractionation. The most recently reported long-term follow-up of this study shows a crude local control rate of 78%. Median overall survival was 25 months. There were no significant late toxicities seen within the study population (37).

Second, a recent phase I study by Higgins et al. (in press) evaluated the optimal SBRT dose after 44 Gy CRT. Inclusion criteria included stage IIIA or IIIB NSCLC, with a primary tumor of 8 cm or less and no N1 or N2 nodal station >5 cm in maximum dimension. This multi-institution phase I study enrolled 15 patients, and dose-escalated a SBRT boost according to the following dose cohorts: 9 Gy × 2, 10 Gy × 2, 6 Gy × 5, 7 Gy × 5. Patients received 44 Gy with weekly carboplatin and paclitaxel, and then underwent a second computed tomography (CT) simulation after 40 Gy was delivered. The SBRT boost was then planned to encompass all residual primary and nodal disease as seen on the planning CT simulation. This volume was then dose-escalated according to the dose assignment of the patient. The maximum tolerated dose was determined to be 6 Gy × 5. There was one treatment-related grade 5 toxicity at this dose level, and 10 Gy × 2 is felt to be the most optimal SBRT boost dose, as no grade 3 or higher toxicities were seen in patients treated within the dose cohort. For all patients, actuarial local regional control at 3 years was 59%, and 3-year overall survival was 39% (38).

In an additional phase I study by Hepel et al., 12 patients with stage III NSCLC who had a primary tumor volume <120 cc (approximately 6.0 cm) and nodal disease volumes <60 cc received CRT to a dose of 50.4 Gy in 28 fractions (39). The study used a dose-escalation design to identify the maximum tolerated dose. SBRT dose was escalated from 16 Gy in two fractions to 28 Gy in two fractions in 2 Gy/fraction increments, resulting in four potential dose cohorts. The endpoint was dose-limiting toxicity occurring within 4 weeks of SBRT. A standard phase I cohort design was used. SBRT cohort doses started at 800 cGy × 2 fractions and escalated by 200 cGy/fraction to a final dose of 1,400 cGy × 2 for a total SBRT boost of 28 Gy. No early grade 3–5 toxicities were noted and at a median follow-up of 16 months, 1 year local–regional control was 78% with 100% at ≥24 Gy. Overall survival at one year was 67%. One late fatal pulmonary hemorrhage was noted and it was determined that the patient's 4 cc proximal bronchial-vascular tree dose was substantially higher than all patients reported at 30.2 Gy for the SBRT boost and 73.5 Gy for the total treatment. A total BED computation was not available to assess all patient doses.

It is clear from these studies and RTOG 0813, contouring of at risk structures and applied dose constraints (see above estimates) particularly for the pulmonary vasculature need to be respected in the treatment plan.

#### IMMUNOTHERAPY IN NSCLC

The use of immunotherapy in NSCLC is rapidly burgeoning. Early vaccine trials and trials with interferon therapy for those who were suffering from NSCLC have been largely negative and led to the hypothesis that NSCLC was believed to be largely non-immunogenic. Clearly, the immune response must be tightly controlled to prevent rampant autoimmunity. Multiple mechanisms to regulate immune responses have been shown to exist including innate tolerance to self-antigens, a network of both B and T suppressor cells and more recently elucidation of molecular regulatory mechanisms including checkpoint inhibitors. Immune checkpoint inhibitors have shown some promise in modulating the tumor microenvironment so that evasion of the immune system is more difficult.

Surveillance and destruction of tumor cells is postulated to be effected by the immune system and the vanguard of early tumor control may be the natural killer cell although its full role is yet to be elucidated. Once a tumor is established, control may be mediated by activated T-lymphocytes including CD4+ and CD8+ cells. The CTLA-4 and programmed death ligand 1 (PD-1) pathways are two T-cell inhibitory pathways that may modulate immune responses to lung antigens in the presence of an increasing burden of malignant cells possibly in an effort to prevent damage to host normal tissues. Inadvertently this may result in suppression of the immune system favoring tumor cell survival and growth. A CTLA-4 monoclonal antibody which is currently in use is ipilimumab, currently indicated in the treatment of melanoma. The PD-1 receptor ligands include PD-L1 and PD-L2. Nivolumab and pembrolizumab are two PD-1 inhibitors which have been FDA approved for clinical use in lung cancer.

Several seminal trials suggested the utility of blocking the PD inhibitory pathway by monoclonal antibodies to harness the immune system in control of NSCLC. The Checkmate 057 phase III clinical trial randomized 582 patients with non-squamous metastatic NSCLC who had progressed during or after platinumbased chemotherapy to salvage docetaxel chemotherapy or nivolumab. Median OS was longer in the nivolumab group (12.2 versus 9.4 months). Patients with even <10%, but greater than 1% PD-L1 expression showed a benefit with nivolumab over docetaxel (40). A second study, Checkmate 017, studied 272 patients with metastatic squamous cell NSCLC who progressed through platinum-based first-line chemotherapy. Those who received nivolumab had a median OS of 9.2 months versus those who received docetaxel, with a median OS of only 6.0 months (41). The use of nivolumab as a first-line agent was explored in the phase III Checkmate 026 trial in which 541 patients with previously untreated metastatic NSCLC with at least 1% PD-L1 expression were randomized to nivolumab or standard-of-care platinum doublet chemotherapy. Both PFS and OS were not significantly different between the two arms (42).

The KEYNOTE-010 trial enrolled over 1,000 patients with previously treated advanced NSCLC with at least 1% PD-L1 expression. They were randomized to two different doses of pembrolizumab or docetaxel. Median OS was 10.4 months with 2 mg/kg of pembrolizumab, 12.7 months with 10 mg/kg of pembrolizumab, and 8.5 months with docetaxel, which was statistically significant. An even greater survival benefit was seen in those with >50% tumor PD-L1 expression: 14.9 months with 2 mg/kg of pembrolizumab, 17.3 months with 10 mg/kg of pembrolizumab, and 8.2 months with docetaxel, which was also statistically significant (43). As a first-line therapy, the phase III KEYNOTE 024 trial explored the use of pembrolizumab in advanced NSCLC with at least 50% PD-L1 staining versus cytotoxic chemotherapy, which was up to the discretion of the treating physician. Only 30% of the patients had the required 50% or greater PD-L1 staining tumors. In those patients, pembrolizumab was seen to significantly increase the 6-month OS (80.2 versus 72.4%) (44).

PD-L1 reactive monoclonal antibodies are currently being explored in NSCLC. Atezolizumab is one such IgG1 agonist to PD-L1. In the OAK trial, 1,225 patients with advanced NSCLC were randomized to salvage chemotherapy with docetaxel or atezolizumab. Greater OS was seen with atezolizumab regardless of PD-L1 expression (13.8 versus 9.6 months) (45).

To date, there are only limited data from phase III trials regarding immunotherapy for stage III NSCLC. The phase III START trial enrolled 1,514 patients with stage III NSCLC who had received CRT and had not progressed within 1–3 months. Patients were randomized to either placebo or tecemotide, an anti-MUC-1 immunotherapy designed to stimulate a T-cell response against the MUC-1 protein. There was no OS difference between the placebo group and the tecemotide group, except in a subgroup receiving concurrent CRT. In this case, the tecemotide group did have an improved OS (46), suggesting a possible synergistic interaction between the radiation and the drug. Belagenpumatucel-L is a tumor vaccine of four allogeneic NSCLC cell lines. In a phase III trial, 270 stage III or IV patients who were treated with platinum-based chemotherapy and who had not progressed were randomized to receive placebo or belagenpumatucel-L. There were no differences in OS or PFS between the two arms (47). A killed *Mycobacterium vaccae* named SRL172 was the subject of a phase III clinical trial published in 2004. A total of 419 patients were treated with 6 cycles of mitomycin, vinblastine and cisplatin or carboplatin with or without monthly administration of SRL172. There were no differences in overall survival, but patients in the SRL172 arm reported better quality of life (48). A metaanalysis of 20 trials by Zhou et al. found an OS benefit to immune checkpoint inhibitors and therapeutic vaccine (49).

### RATIONALE FOR THE USE OF IMMUNOTHERAPY WITH RADIOTHERAPY

Immunogenic cell death is a postulated mechanism of radiation injury. Classically it is thought that the immune system must recognize either foreign (e.g., viruses) or mutated antigens on tumor cells to initiate an immunostimulatory response. Thus far, no simple antigen has been identified since in many ways, cancer cells are "self." Roszik et al. found a significant relationship between the predicted tumor mutation load and clinical benefit from ipilimumab, T-cell therapy, and pembrolizumab suggesting mutated proteins or DNA-protein complexes may be immunostimulatory (50). Unlike conventional apoptosis, when due to an immunogenic cell death apoptosis causes a release of molecules which may lead to an inflammatory or augmented immune response (51, 52). Damaged cells produce damage-associated molecular patterns which lead to uptake and subsequent presentation of tumor antigen by dendritic cells. Radiation has been shown to release or upregulate immune and tumor-related molecules such as major histocompatibility complex, tumor markers, adhesion molecules, cytokines, and many others (53). Single doses of 15–25 Gy induced strong T-cell responses, but these immune responses were dampened by the use of fractionated radiation or chemotherapy (54). Unfortunately, since lymphocytes are so radiosensitive, only a low integral dose is needed to kill any surrounding tumor lymphocytes. There is some evidence that ablative radiation fraction sizes (at least 6 Gy) or high linear energy transfer radiation causes increased release of immunogenic antigens. Mouse studies have shown evidence of the abscopal effect after use of large fractions (55, 56). A paper by Lugade et al. looked at 15 Gy in a single fraction versus 15 Gy in 5 fractions of 3 Gy in in a mouse melanoma model. They found that both fraction sizes lead to tumor-infiltrating lymphocytes that were capable of lysing tumor cell targets, but that the larger fraction size produced better results (57). A strong antitumor immunogenic response was observed in mouse models after being treated with a carbon ion beam. This resulted in fewer contralateral squamous cell tumors, which is thought to be due to an immune-mediated abscopal effect (58). Strictly defined, the abscopal effect is the resulting shrinkage or disappearance of metastatic deposits following treatment of the primary tumor mass. Clinically the abscopal effect is rarely seen, with fewer than 50 documented cases in the literature (59). Barid et al. propose that this is because while radiotherapy provides available antigen, it does not provide the necessary co-stimulation of T cells or cytokine release (60). Thus, this presents an opportunity for the combined use of radiotherapy and immunotherapy.

Both laboratory and clinical evidence exist regarding the advantage of combined radiotherapy and immunotherapy. In a murine model of metastasis, squamous cell carcinoma cell lines were inoculated into the mouse thigh typically requiring ≥106 tumor cells to ensure tumor growth. Most of these cells die and release tumor lysis products which may bias treatment results. Mice were treated with a single 6 Gy dose of carbon ions and 36 h later treated with α-galactosylceramide-pulsed dendritic cells. Compared to the untreated control mice, these mice developed significantly fewer pulmonary metastases (61). Intravenous administration of isolated dendritic cells with either carbon beam therapy or photon beam therapy was compared in a murine model. Both types of irradiation produced an antimetastatic effect, but carbon ions did so at a lower BED (62). Sharabi et al. examined the effect of SBRT in murine melanoma or breast cancer and found that the effect of radiation was enhanced in the presence of a PD-1 inhibitor or regulatory T-cell depletion (63). Some studies suggest that an immune-mediated abscopal effect is increased with fractionated radiotherapy using large fractions in addition to a CTLA-4 inhibitor as opposed to single-dose radiotherapy (64). Indeed, further mouse studies confirmed that fractionation using "medium-sized doses" (7.5 Gy per fraction) provided both low numbers of regulatory T-cells and the best control of the tumor (65).

Clinical studies also show encouraging results of the use of combined radiation and immunotherapy. Abscopal effects in humans after SBRT with or without immunotherapy have been reported in both renal cell carcinoma and melanoma (66–68). The KEYNOTE-001 study predated the KEYNOTE-010 study. KEYNOTE-001 was a phase I clinical trial which enrolled 495 patients with advanced NSCLC. They were treated with pembrolizumab at doses of 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. The objective response rate was found to be 19.4% and OS was 12 months. In patients with at least 50% expression of PD-L1 median overall survival was not reached. It was deemed to have an acceptable side effect profile and the most common side effects included fatigue, itching, and decreased appetite (69). An analysis of the trial was done and showed that in 97 patients who had prior radiation PFS and overall survival were significantly longer, especially for those who received extracranial radiotherapy (70). In the PACIFIC study, a phase III study for stage III unresectable lung cancer, patients in the experimental arm received chemoradiation followed by durvalumab for 12 months. In a preliminary report, Astra Zeneca suggests an improvement in PFS in the immunotherapy arm was seen, however, these data have yet to be presented (71). Currently, there are several ongoing clinical trials investigating the use of immunotherapy with radiotherapy. These trials include agents such as cancer vaccines, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors (**Table 1**). This table was generated by searching the ClinicalTrials.gov database with search terms such as "radiation," "chemoradiation," "thoracic RT," and several variations. The results were then manually filtered for the inclusion of Immunotherapy.

#### SUMMARY

Treatment of locally advanced lung cancer has not made great strides since the 1990s when cytotoxic chemotherapy was combined with radiation. The two major stumbling blocks to improvements in survival of these patients are local control and distant metastasis. It is clear that SBRT for stage I NSCLC is one of the most important treatment advancements in decades with excellent outcomes of high local tumor control and survival with low toxicity.

Cytotoxic chemotherapy remains an important modality in more advanced disease but has reached a point where major improvements are unlikely and despite systemic therapy, metastatic disease is a prominent cause of death in locally advanced NSCLC patients.

We need more innovative approaches to management of this disease. Evidence is accumulating that dose escalation of radiotherapy improves local control of much of the microscopic and gross disease in the chest. Since dose escalation by conventional radiation delivery has been compromised by toxicity, the careful delivery of hypofractionated radiation therapy (SBRT) to the sites of gross disease should improve local control by ablating any residual viable cancer cells. The initial studies of SBRT boost while small, show this approach is safe and feasible, but the impact of this approach on survival in the management of stage II-III awaits larger studies.

The sequencing and combination of this "quadmodality" approach is still being explored. In the Phase I/II studies described above, concurrent chemoradiation to a dose of 44–60 Gy was used which was followed by an SBRT boost. The trials showed favorable toxicity profiles using this approach. Fractionated chemoradiation promotes immunotolerence through the killing of lymphocytes by the chemotherapy and radiation therapy, but SBRT has been shown to induce strong T-cell responses. Thus ideally the patient would undergo concurrent chemoradiation to a dose of 44–60 Gy, have an approximately 2-week break to allow for SBRT treatment planning and recovering from leukopenia, then get an SBRT boost. In order to capitalize on the immunostimulatory effects of the SBRT, the immunotherapy should be administered soon (within 1 week) of the SBRT boost. Cranial stereotactic radiosurgery with concurrent immunotherapy appears to be well tolerated, but data on lung SBRT and concurrent immunotherapy is still developing. Theoretically, there could be an increased risk for toxicity, especially induced auto-immune effects, due to this quadmodality approach. Indeed, the SBRT boost followed by immunotherapy may prime the immune system to attack not only tumor cells but normal tissue as well.

From a metastatic viewpoint, immunotherapy is an exciting option that is still in its infancy. There are adequate early and non-clinical data suggesting that hypofractionated radiation and immunomodulation may be synergistic. Thus, a more cogent approach to trials addressing both local control and metastatic

TABLE 1 | Active clinical trials involving the use of both radiotherapy and immunotherapy such as cancer vaccines, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors in Stage III non-small cell lung cancer (NSCLC).

disease may become "quadmodality" and include combining chemotherapy, conventionally fractionated radiation therapy, immunotherapy and SBRT dose intensification to ablate the residual primary tumor mass. Given the continued devastating effect of lung cancer on the world, such trials need to be developed promptly.

### AUTHOR CONTRIBUTIONS

Contributors who meet fewer than all four of these criteria for authorship should not be listed as authors, but they should be acknowledged: substantial contributions to the conception or

#### REFERENCES

design of the work; or the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved (SK, KH, and RM).

#### ACKNOWLEDGMENTS

The University of Kentucky Markey Cancer Center's Research Communications Office assisted with manuscript preparation.

inoperable stage I non-small cell lung cancer. *Chest* (2003) 124:1946–55. doi:10.1378/chest.124.5.1946

induced by carbon-ion irradiation. *J Radiat Res* (2017):1–10. doi:10.1093/ jrr/rrx005

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2017 Kumar, Higgins and McGarry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Radiotherapy for Oligometastatic Lung Cancer

*Derek P. Bergsma1 , Joseph K. Salama2 , Deepinder P. Singh1 , Steven J. Chmura3 and Michael T. Milano1 \**

*1Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, United States, 2Department of Radiation Oncology, Duke University Health System, Raleigh, NC, United States, 3Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, United States*

Non-small cell lung cancer (NSCLC) typically presents at an advanced stage, which is often felt to be incurable, and such patients are usually treated with a palliative approach. Accumulating retrospective and prospective clinical evidence, including a recently completed randomized trial, support the existence of an oligometastatic disease state wherein select individuals with advanced NSCLC may experience historically unprecedented prolonged survival with aggressive local treatments, consisting of radiotherapy and/or surgery, to limited sites of metastatic disease. This is reflected in the most recent AJCC staging subcategorizing metastatic disease into intra-thoracic (M1a), a single extra thoracic site (M1b), and more diffuse metastases (M1c). In the field of radiation oncology, recent technological advances have allowed for the delivery of very high, potentially ablative, doses of radiotherapy to both intra- and extra-cranial disease sites, referred to as stereotactic radiosurgery and stereotactic body radiotherapy (or SABR), in much shorter time periods compared to conventional radiation and with minimal associated toxicity. At the same time, significant improvements in systemic therapy, including platinum-based doublet chemotherapy, molecular agents targeting oncogene-addicted NSCLC, and immunotherapy in the form of checkpoint inhibitors, have led to improved control of micro-metastatic disease and extended survival sparking newfound interest in combining these agents with ablative local therapies to provide additive, and in the case of radiation and immunotherapy, potentially synergistic, effects in order to further improve progression-free and overall survival. Currently, despite the tantalizing potential associated with aggressive local therapy in the setting of oligometastatic NSCLC, well-designed prospective randomized controlled trials sufficiently powered to detect and measure the possible added benefit afforded by this approach are desperately needed.

Keywords: lung cancer, non-small cell lung cancer, oligometastases, stereotactic body radiotherapy, oligometastatic disease

### INTRODUCTION

Although lung cancer incidence and mortality are declining, due in large part to public health smoking cessation efforts, it remains the leading cause of cancer-related mortality both in the United States and worldwide (1). The majority of lung cancer patients have non-small cell lung cancer (NSCLC) and commonly present with metastases involving distant organ sites. Historically, palliative treatment with chemotherapy has been the standard of care for metastatic NSCLC, and outcomes with this approach have been frustratingly dismal, resulting in a median overall survival (OS) of only

#### *Edited by:*

*John Varlotto, University of Massachusetts Medical Center, United States*

#### *Reviewed by:*

*Vivek Verma, University of Nebraska Medical Center, United States John Austin Vargo, West Virginia University Hospitals, United States*

*\*Correspondence: Michael T. Milano<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology*

*Received: 28 July 2017 Accepted: 28 August 2017 Published: 19 September 2017*

#### *Citation:*

*Bergsma DP, Salama JK, Singh DP, Chmura SJ and Milano MT (2017) Radiotherapy for Oligometastatic Lung Cancer. Front. Oncol. 7:210. doi: 10.3389/fonc.2017.00210*

8–10 months (2). However, in the past 5 years, clinical trials evaluating the efficacy of targeted therapy with receptor tyrosine kinase inhibitors (TKIs) and immunotherapy with checkpoint inhibitors represent a breakthrough in the care of advanced NSCLC offering improvements in progression-free survival (PFS) and OS (3–5). Despite these advances, long-term PFS remains limited to a relatively small subset of metastatic NSCLC patients.

Radiation therapy, a critical component of curative treatment for non-metastatic NSCLC, has classically been reserved for tumor-related symptom palliation in the metastatic disease setting. The past decade has brought about dramatic improvements in the planning and delivery of radiation treatments due to technical advancements in computing power, diagnostic imaging, and motion management. This has led to the increased use of precisely targeted highly conformal radiation, often in large doses per treatment.

Hypofractionated image-guided radiotherapy (HIGRT), typically referred to as "stereotactic radiosurgery" (SRS) when delivered to an intracranial target in one or more fractions or "stereotactic body radiotherapy" or "stereotactic ablative radiotherapy" (SBRT or SABR) when given to extra-cranial body sites in one or more fractions, has been shown to result in high rates of treated tumor control (6–8) with a favorable toxicity profile and improved convenience (9) when compared to conventionally fractionated external beam radiation (EBRT). Although not yet elucidated entirely, it is postulated that hypofractionated radiotherapy may accomplish tumor killing *via* different biological mechanisms than conventional fractionation, one being the possible infliction of endothelial or vascular damage (10, 11).

The role of radiotherapy, delivered as SBRT or conventionally fractionated EBRT with or without systemic therapy, is rapidly evolving with dramatically increased utilization in the treatment of advanced NSCLC patients with limited sites of metastatic disease termed "oligometastases" (12). Despite these advances, the appropriate selection of oligometastatic patients for curativeintent local treatment, optimal integration of radiotherapy with systemic therapy, and the added long-term benefit such as aggressive treatment approach provides have not been sufficiently clarified.

#### THE OLIGOMETASTATIC STATE

One of the hallmarks of cancer is the development of pioneer cells that are able to release from the primary tumor site and metastasize to regional lymph nodes and/or distant organs *via* the lymphatics, blood stream, or direct extension (13). The risk of subclinical dissemination in solid tumors, even in the setting of apparently localized disease, is variable and dependent on tumor histology, size, grade, stage, genetics, and a host of other factors, many of which are not yet understood. Hellman and Weichselbaum postulated the existence of an oligometastatic state in which tumors develop sites of distant metastasis in a single or limited number of organs as a function of the underlying biology of tumor cells and the unique receptiveness of distant organ sites ("seed and soil") (14). This concept of oligometastases is derived from the spectrum theory that bridges the gap between the Fisher and Halstedian viewpoints on cancer. Fisher argued many tumors are micro-metastatic from inception even when presenting without clinical/radiographic evidence of distant metastatic disease (15), whereas Halsted postulated orderly spread from the primary tumor into regional lymph nodes and ultimately distant organs (16). In the spectrum theory of cancer, the oligometastatic state may reflect patients with more indolent disease courses that may be cured or rendered disease free for long time intervals with aggressive local treatment of distant metastases. We will further discuss the rationale and review the ever-growing clinical evidence supporting an aggressive treatment approach in select NSCLC patients presenting with oligometastatic disease.

Historically, before the development of systemic therapies with increased efficacy, aggressive metastasis-directed treatments were relied upon to palliate, and occasionally cure, patients with limited metastases (17). In the setting of systemic therapy, which may be able to sterilize micrometastases, control of clinically detectable tumors is perhaps of even more importance. Although prospective clinical trials do not routinely report PFS of individual metastases, observational studies report that the predominant pattern of recurrence in patients with oligometastatic NSCLC treated with first-line systemic therapy appears to be local only (18, 19). This pattern of progression would support the potential PFS benefit of delivering aggressive local therapy to all appreciable metastatic sites, as well as the thoracic primary, if feasible. As unchecked growth of oligometastases may culminate in progressive organ dysfunction eventually leading to death, improved PFS with aggressive local therapy may ultimately result in longer OS. In recent decades, the bulk of published clinical series have included patients with oligometastatic sarcoma, colorectal, or breast cancer (20–22); however, there are an increasing number of single institution studies, the majority retrospective, which report long-term PFS and OS associated with aggressive treatment to all known sites of disease in oligometastatic NSCLC (23).

One of the difficulties in interpreting and applying the available data to predict which patients will benefit from an aggressive treatment approach including local therapies is establishing the appropriate cutoff to define the oligometastatic state. Nearly all published studies of oligometastatic NSCLC have limited inclusion to patients with ≤5 metastases; however, the majority enrolled patients with ≤3 metastases and over half of all patients included in a recent meta-analysis had only a single metastasis (24). The oligometastatic state is believed to be a relatively common presentation of advanced NSCLC; however, its exact incidence is dependent on the cutoff used for its definition. The relative prevalence of oligometastatic disease in advanced NSCLC has been reported to range from 26 to 50% using cutoffs of ≤3–5 metastases (18, 25). The reported rates of oligorecurrence after definitive surgical treatment of NSCLC are even higher, with 33–50% of patients recurring with ≤3 lesions (26, 27). It is important to note that the studies reporting rates of oligometastases are likely subjected to selection bias as patients with more metastatic burden may be less likely to be enrolled on protocols and/or treated at tertiary or quaternary referral centers that often report their large institutional experiences.

In general, patients with fewer metastases tend to have better outcomes than those with a more widespread presentation irrespective of the potential impact of aggressive metastasisdirected local therapy. This has been shown in multiple retrospective studies (25, 27, 28) including a comprehensive analysis of advanced NSCLC patients treated on consecutive Southwest Oncology Group prospective protocols that revealed a significantly longer OS in patients developing a single metastasis (8.7 months) vs multiple metastases in a single organ (6.2 months) or multiple organs (5.1 months) (28). Some argue that oligometastases do not reflect a more indolent biology but rather lead-time bias in which patients are found to have metastatic disease at an earlier point in the natural history of their disease. However, this explanation cannot fully account for the long-term survival of some individuals with oligometastatic disease with up to one-quarter of patients surviving long-term with aggressive treatment to all sites of disease (24, 29). The recent 8th edition of the AJCC staging manual now considers a single extrathoracic metastasis to be M1b vs more widespread extrathoracic M1c disease (30). The M1a substage interestingly includes patients with potentially more metastatic burden than M1b, such as numerous lung metastases and/or malignant pleural effusion(s), as long as it is contained to the thorax.

Another important consideration when defining the oligometastatic state is appropriate patient evaluation/staging. Advancements in modern diagnostic imaging, including more widespread use of brain MRI and FDG-PET/CT, have improved the detection of both intra- and extra-cranial metastatic disease. MRI is superior to CT in staging the brain and may detect the presence of metastases, particularly small lesions, unappreciated by CT (31). The use of PET/CT staging is associated with improved OS, likely due in part to stage migration where patients are bumped into a higher stage category by the detection of otherwise clinically unapparent metastases (32, 33). Based on published studies, approximately 15% of NSCLC patients initially thought to be stage I–III may be upstaged to stage IV with use of PET/CT in addition to contrast CT imaging alone (34, 35). Furthermore, modern imaging may detect widespread metastases in patients thought to have oligometastatic disease, thereby avoiding aggressive metastasis-directed local therapy in those who are unlikely to have a PFS benefit. It is important to consider that the bulk of published studies in oligometastatic NSCLC included patients treated before the routine use of PET/CT for staging (24).

Despite a strong focus on using a strict number of metastases to define oligometastatic disease, other factors including age and performance status, volume of disease, histology, tumor location(s), rate of progression, and genetics may be important in predicting benefit from aggressive local therapy (36). For appropriate clarification of distinct clinical scenarios, oligometastatic disease can be subdivided based on the development of metastases in relation to initial diagnosis and systemic therapy (37). Synchronous or *de novo* oligometastases refers to presentation with a limited number of lesions at initial diagnosis, while oligorecurrence is the metachronous development of new metastases after definitive treatment of initial locoregional thoracic disease. Patients with more widespread presentation experiencing relative disease stability on "mostly effective" systemic therapy aside from a limited number of persistent or recurrent/growing metastases may be referred to as having oligoresistance (or "induced oligometastases") and oligoprogression disease, respectively. The latter two scenarios are fairly common in the setting of oncogene-addicted NSCLC (those patients with ALK rearrangements or EGFR mutations) and are due predominantly to acquired resistance to treatment with TKIs in progressing/resistant tumor clonogens (38).

Timing does appear to be important and an improved prognosis has been observed in patients presenting with oligorecurrence compared to those with *de novo* oligometastases as evidenced by an individual patient data meta-analysis by Ashworth and colleagues including 757 oligometastatic NSCLC patients treated with ablative treatments to all sites of disease which reported the latter to be associated with a HR of 1.96 (*p* < 0.001) on multivariate analysis (24). It is worth mentioning that a more recent publication did not show worse OS outcomes in synchronous patients if treated with aggressive thoracic therapy (ATT) (39). Additional adverse prognostic factors for OS reported in the meta-analysis by Ashworth (24) included higher thoracic stage and/or mediastinal node positivity, presence of brain metastases, non-adenocarcinoma histology, and non-surgical treatment. Nearly 90% of patients included had a single metastatic lesion and the presence of >1 oligometastatic lesion and/or multiple organ involvement was significantly associated with worse PFS. As alluded to previously, there is evidence to support the premise that larger volume, rather than number, of metastases is more predictive of worse outcome. A retrospective study conducted at MD Anderson Cancer Center including 1,284 patients with advanced NSCLC found that the number of extra-cranial metastases correlated with OS; however, among patients with brain- or lung-only metastases, there was an even stronger association with cumulative metastatic tumor volume (40).

### DEFINITIVE RADIOTHERAPY-BASED TREATMENT OF OLIGOMETASTASES

Historically, surgical resection has been the preferred metastasisdirected treatment for patients with limited metastases from NSCLC (41). Surgery has the attributes of being both diagnostic, by providing pathologic confirmation of metastatic disease, and therapeutic, by eliminating tumor and/or alleviating tumorrelated symptoms (42, 43). The benefit of aggressive metastasisdirected therapy was first shown in patients with limited brain metastases. Patchell and colleagues (44) performed a phase III randomized controlled trial evaluating the impact of surgical resection added to palliative whole brain radiotherapy (WBRT) in a predominantly NSCLC population of patients with a single brain metastasis reporting resected patients lived significantly longer (40 vs 15 weeks, *p* < 0.01). Following this, a number of studies examined the effect of extra-cranial metastasis-directed therapy, typically consisting of surgery and/or radiotherapy, with nearly two-thirds of patients included in a recent meta-analysis of oligometastatic NSCLC patients managed with surgery as the primary treatment. Although surgery was found to be significantly associated with improved OS, there was a strong potential selection bias favoring outcomes in the surgical group (for example, medical co-morbidities) (24).

Unfortunately, many patients with oligometastases present with one or more unresectable deposits and/or may be poor operative candidates due to advanced age and/or medical comorbidities. There is interest in utilizing less invasive, potentially ablative techniques to treat oligometastases including thermal, cryo-, chemical, or irreversible electroporation ablation, but experience with these techniques is limited and restricted to select institutions (45). Furthermore, their role in the treatment of oligometastatic disease, NSCLC, or otherwise is not well defined.

The ability of modern radiotherapy techniques to deliver potentially ablative HIGRT doses, including SRS and SBRT, to numerous organ sites throughout the body has allowed for the aggressive treatment of unresectable metastases. Techniques intrinsic to SRS were initially developed to treat small targets in the brain that were not amenable to conventional surgery (46), however, have since been greatly refined due to improved brain imaging, treatment planning software allowing for MRI-CT image fusion and accurate dose calculation, more widely available LINAC-based delivery, and non-invasive immobilization. SRS alone has replaced WBRT as the recommended upfront treatment for NSCLC patients with oligometastases in the brain (47).

Extra-cranially, SBRT is associated with treated tumor control rates rivaling surgery, often in excess of 90%, among NSCLC patients when escalated to a biologically effective dose (BED) of at least 100 Gy (6, 48). As these treatments deliver very high, potentially ablative, doses of radiation to tumor, often near critical normal organs (i.e., spinal cord, kidney, bowel, and heart), the safe delivery of HIGRT is highly dependent on effective patient immobilization, accurate and reproducible image-guided setup, and respiratory motion analysis and management. As the technical expertise and availability of equipment required to deliver HIGRT rapidly expands, there are a growing number of institutions reporting their experiences, both retrospective and prospective, using these techniques in advanced stage NSCLC patients to target metastases located throughout the body (see **Table 1**).

### TREATMENT OF INDIVIDUAL ORGAN SITES

#### Brain

Brain metastases ultimately develop in 30–50% of NSCLC patients and are typically associated with a very poor prognosis. The increased availability of brain MRI as well as improved systemic therapies that improve survival but often poorly penetrate the blood–brain barrier have led to an increase in the number of NSCLC patients ultimately diagnosed with brain metastases (59). Historically, upfront WBRT constituted the standard of care treatment for brain metastases, despite a lack of proven OS benefit, due to its ability to provide improved central nervous system (CNS) control and decrease the risk of neurologic death, at the risk of potential late neurocognitive toxicity, compared to optimal supportive care (OSC). The utility of WBRT has come under significant scrutiny, particularly based on the results of a recently published phase III, non-inferiority, randomized trial from the United Kingdom (UK) (QUARTZ) which compared WBRT to OSC in NSCLC patients with brain metastases unsuitable for surgical resection or SRS. The study authors concluded that although the OSC alone arm did not meet the predetermined primary endpoint of non-inferiority in regard to quality-adjusted life-years, the absolute benefits of WBRT were clinically insignificant and it should not routinely be used to treat this patient population. Proponents of WBRT argue that the patients enrolled on the QUARTZ trial had extremely poor prognosis, evidenced by the reported median OS of 8–9 weeks, which precluded significant benefit from WBRT. In fact, the prognosis for NSCLC patients with brain metastases varies widely and the anticipated benefit of WBRT may be more substantial in patients with a greater ratio of intra- to extra-cranial disease burden who are at high risk of severe mortality and/or mortality with uncontrolled progression of CNS metastases (60). Furthermore, select patients with adequate performance status, limited brain metastases, and low burden extra-cranial disease may experience improved survival from the improved brain control associated with aggressive CNS-directed local therapies including surgery and/ or SRS (61). An aforementioned trial demonstrated that in good performance status patients with a single intracranial metastasis, adding surgical resection to WBRT significantly improved OS (44). Similarly, RTOG 9508 studied the impact of SRS boost after WBRT for patients with 1–3 newly diagnosed brain metastases and revealed an OS benefit with the addition of SRS in patients with a single brain metastasis, mean survival time (MST) of 6.5 vs 4.9 months (*p* = 0.039), as well as in NSCLC patients, MST of 5.9 vs 3.9 months (*p* = 0.012) (62).

The benefit afforded by the addition of upfront WBRT to surgical resection and/or SRS has been intensely studied given the potential for prolonged survival in the most favorable subset of NSCLC patients with brain metastases as well as the appreciable risk of late neurocognitive toxicity with WBRT (61). The Alliance group recently published the results of a trial comparing upfront SRS with or without WBRT in patients (approximately two-third NSCLC) with one to three brain metastases and reported no detriment to OS and less cognitive deterioration in the SRS alone group (63, 64). Furthermore, two additional randomized trials each enrolling surgically resected patients with limited brain metastases, one (in which 20% had NSCLC) comparing SRS vs observation (65) and the other (in which 58% had NSCLC) SRS with or without WBRT (66), show adjuvant SRS may provide an optimal balance between maximizing brain metastasis control in the resection cavity and preservation of neurocognition without compromising survival provided patients are followed closely with salvage therapy (either additional SRS or WBRT) initiated at the time of intracranial progression.

An additional consideration in the treatment of brain oligometastases includes the relatively lower prescribed dose, limited by potential toxicity including the risk of radionecrosis, and resulting high local failure rates associated with single fraction SRS for large lesions (>2 cm). Recently published retrospective data show a multifraction SRS (three to five fractions) approach yields increased local control (LC) and decreased risk of radionecrosis in large brain metastases compared to single fraction SRS (67). There are also emerging data supporting the premise that the cumulative volume of intracranial metastatic burden

Yes

Yes

Yes NA

Yes

Yes 70% chemo

16% chemo

100% upfront

chemo

13.5

> NA

> > 17

NA

NA

> 12

2 years 25%

(oligorecurrence)

NA

NA

17% G3+

vs 43% (*de novo*

oligometastases)

Median

Median

74 months

20 months

TABLE 1 | Summary of select studies of high dose radiation therapy as part of an aggressive local treatment approach targeting oligometastases from non-small cell lung cancer.

Reference

Gomez

et al. (49)

Iyengar

et al. (50)

Collen

et al. (51)

et al. (52)

Griffioen

et al. (53)

et al. (54)

Hasselle

et al. (55)

Jabbour

et al. (56)

Cheruvu

Retrospective

Retrospective

Retrospective

*aA single patient had multiple organ involvement.*

*bA single patient underwent surgical ablation.*

*Adapted from Bergsma et al. (23).*

2011

2010

2006

*LCT, local consolidative therapy; SBRT, stereotactic body radiotherapy.*

96

44

23 ≤8

> 1

≤2 Yes

> No

> No

SBRT

Various

Various Yes

Yes

Yes

et al. (29)

Yano

Khan

et al. (57)

et al. (58)

Weickhardt

De Ruysscher

may matter more than brain metastasis number and OS may not be inferior for patients with 4–10 vs 2–3 brain metastases (68). Overall, although the presence of brain metastases has historically felt to be an adverse prognostic factor (24), the development and widespread implementation of SRS has proven to be a powerful tool in the radiation oncologist's armamentarium for the treatment of oligometastatic NSCLC within the brain.

#### Lung

For decades, pulmonary metastasectomy has been utilized for lung metastases from several cancer types, predominantly sarcoma and colorectal cancer. Published experiences confirm that resection can lead to prolonged PFS and OS in selected patients. Pulmonary oligometastases in NSCLC patients have been reported to carry a favorable prognosis that is now reflected in the recently published 8th edition of the TNM classification for lung cancer that separates intra-thoracic metastases, including metastatic lung or pleural nodules, as M1a rather than M1b or M1c (69). The safety and efficacy of SBRT delivered to primary NSCLC tumors and lung oligometastases has been well studied in multiple prospective studies (7, 70). Rusthoven and colleagues reported an actuarial 2-year LC of 96% in a prospective phase II study enrolling patients with one to three lung metastases from various solid tumor primaries (13% from primary lung cancer). Treatment was very well tolerated with only 8% grade 3 events and no grades 4 or 5 toxicity reported. A more recent retrospective study of SBRT for lung oligometastases limited to NSCLC reported 88.9% LC and 74.6% OS at 2 years with no grade 4 pulmonary toxicity, chest pain, or rib fractures (71). Of note, the use of PET/CT along with pathological confirmation (if acceptable risk) can be quite helpful as the presence of a contralateral lung nodule in newly diagnosed advanced NSCLC can be difficult to differentiate between a metastasis and a synchronous lung primary (72). Robust motion management is critical when delivering lung SBRT as metastases may be subjected to significant respiratory-induced motion and resulting target uncertainty which can be minimized by abdominal compression, breath hold, respiratory gating, real-time tumor tracking, and/or generation of an internal target volume based on four-dimensional CT at time of simulation (73).

## Adrenal Glands

Adrenal gland metastases may be present in 5–10% of NSCLC patients (74) at initial presentation and solitary metastases occur in approximately 2–3% of cases. As solitary adrenal masses found on CT may in fact be benign adenomas, further diagnostic workup with PET/CT or dedicated MRI and possible histological confirmation should be pursued (75). Surgery with adrenalectomy of solitary metastases has been reported to provide favorable outcomes in NSCLC patients per several single and multi-institutional series (76) and conventionally fractionated EBRT can be used for palliation of pain with good response rates as measured by analgesic requirements (77). The use of SBRT in the treatment of adrenal oligometastases is gaining traction as an alternative to adrenalectomy resulting in high rates of palliation and LC rates (≥74%) which appear to correlate well with greater BED (78). Definitive radiation for adrenal metastases is an attractive non-invasive alternative particularly given the not infrequent adverse pathological features of positive margins and incomplete resections seen after adrenalectomy. Treatment appears to be well tolerated with only rare severe toxicity (79, 80); however, care must be taken during treatment planning as adrenal metastases may also exhibit significant motion with respiration and are often near the kidney, spinal cord, and sensitive gastrointestinal organs including the liver, colon, stomach, and small bowel.

#### Liver

Liver involvement at diagnosis is a relatively uncommon presentation of advanced NSCLC with hepatic metastases reportedly occurring in less than 5% of new diagnoses (81). Histology plays a role in the comparative number of metastases with solitary presentation in 50% of patients with squamous cell carcinoma vs 5% of those with adenocarcinoma. Ultimately, the development of hepatic metastases is not uncommon in the natural history of advanced stage NSCLC. Although there is a wealth of data establishing the benefit of partial hepatectomy for isolated or limited liver metastases from colorectal cancer, the published experience of surgical resection for liver metastases from NSCLC, oligometastatic, or otherwise is lacking. The safety and efficacy of SBRT delivered to hepatic oligometastases from solid tumors has been well established in both retrospective and prospective (82) series with Goodman and colleagues reporting 91% LC at 4 years with only 4.9% grade 3 or greater liver toxicity (83). A major limitation of using these studies in the context of oligometastatic NSCLC is the wide variety of tumor histologies included, with NSCLC comprising a minority of treated cases (21% of patients enrolled on the prospective phase I/II trial by Rusthoven and colleagues); however, a large retrospective study from Moffitt Cancer Center showed that liver metastases of NSCLC origin may exhibit relative radiosensitivity compared to other histologies (84). Contrast (ideally tri-phasic) should be given at simulation to help delineate the target given the similar CT density of metastasis and normal liver. Fiducials may be helpful in aligning to the target for image guidance radiotherapy and motion assessment and management is mandatory due to potential for respiratory-induced tumor motion during treatment (85).

### OTHER SITES INCLUDING BONE, KIDNEY, SPLEEN, SKIN, AND LYMPH NODES

There is relatively little data on management of oligometastatic NSCLC involving these sites with the majority being surgical series for solitary bone (86) or skin (87) lesions. Although not limited to patients with oligometastases, Gerszten and colleagues report a single institutional experience detailing outcomes in 500 cases of spine radiosurgery documenting remarkable 100% longterm radiographic control and 93% long-term pain improvement in a subset of 80 lung cases (88). A recent retrospective study from Mayo Clinic analyzed outcomes after SBRT for non-spine bone oligometastases reporting a 91.8% LC at 1 year and acceptable acute and late toxicities; however, a minority of patients included had NSCLC (89). RTOG 0631 is a randomized phase II/III study of image-guided SRS/SBRT for localized spine metastasis, not limited to NSCLC patients, which has recently closed after adequate accrual with the primary endpoints of feasibility and palliation of pain (NCT00922974). Although the use of SRS or SBRT for bone metastases is promising, more studies are needed evaluating its impact in the context of oligometastatic NSCLC.

## ROLE OF ATT

The potential benefit of aggressive therapy directed to the primary tumor (and involved nodes) has been proven in the setting of multiple histologies of advanced stage cancers. For example, in metastatic renal cell carcinoma, randomized controlled trials have shown the significant OS advantage of cytoreductive nephrectomy added to immunotherapy (90). For advanced NSCLC patients with *de novo* oligometastases or oligorecurrence including initial thoracic disease, unchecked growth of locoregional chest disease may lead to significant tumor-related morbidity including cough, pain, shortness of breath, endobronchial obstruction causing airway collapse or post-obstructive pneumonia, superior vena cava syndrome, and/or severe hemoptysis, which may ultimately result in death. Radiotherapy can alleviate symptoms associated with bulky thoracic disease and is often utilized in the palliative treatment of advanced NSCLC patients.

Historical trials conducted by the RTOG in the 1970s showed that dose escalation up to 60 Gy utilizing conventional fractionation, relative to lower doses, led to improved thoracic tumor control in inoperable NSCLC patients treated with definitive radiotherapy (91). The optimal dose of chest radiotherapy in the setting of oligometastatic NSCLC has been debated given the need to balance palliation, including prevention of morbidity related to thoracic disease progression, while also minimizing treatment toxicity and duration as prolonged breaks in systemic therapy could heighten competing risks of systemic disease progression. A large retrospective study using the National Cancer Database evaluated the comparative effectiveness of chest radiotherapy dose escalation and found a positive association between improved survival and higher-dose radiotherapy (BED above 50 Gy) (92). However, a recent meta-analysis of 14 randomized controlled trials with 3,576 patients concluded there was no strong evidence to support extended fractionation schedules of radiotherapy to palliate thoracic symptoms in incurable NSCLC patients as all patients (including those receiving shorter treatment schedules) appeared to benefit in regard to palliation with no apparent difference in OS (93). Of note, patients with good performance status had longer 1-year OS with more fractions (33.3 vs 25.6%); however, the relative effect was not reported due to a high level of heterogeneity. Acute toxicity was an issue with higher radiotherapy doses though most patients were treated before the era of 3D conformal radiotherapy that has the potential to decrease exposure of normal organs to the full prescribed dose.

Although robust prospective randomized evidence is lacking, Li and colleagues recently published a meta-analysis that included 7 retrospective observational cohort studies and 668 synchronous oligometastatic NSCLC patients, of whom 227 (34.0%) received ATT consisting of surgery and/or radiotherapy to a total dose more than 40 Gy (94). Receipt of ATT was associated with significantly improved OS (HR 0.48, *p* < 0.00001) in the entire cohort, as well as in subgroup analyses of patients with single organ metastases (HR 0.42, *p*< 0.00001), solitary (HR 0.49, 95% CI 0.31–0.75) or two to four brain metastases (HR 0.44, 95% CI 0.26–0.73), and patients with thoracic stage I–II (HR 0.38, *p* = 0.004) or stage III (HR 0.32, *p* = 0.01) disease. Pooled cumulative OS at 3 years was significantly higher in the ATT group (23.0 vs 3.7%). A recent prospective phase II study by Li and colleagues evaluating the efficacy and toxicity of definitive thoracic concurrent chemoradiation (BED ≥ 60 Gy) followed by consolidation chemotherapy for oligometastatic NSCLC (≤5 metastases) enrolled 64 patients yielding encouraging 14-month median PFS and 26-month median OS at a median follow-up of 28 months (95). These prospectively accrued data are consistent with PFS and OS outcomes reported in other retrospective studies of ATT in oligometastatic NSCLC (25, 96, 97). While most published studies employed conventionally fractionated radiotherapy schedules with sequential or concurrent chemotherapy, HIGRT has also been used as definitive local treatment of smaller primary lung tumors in the oligometastatic setting (51, 53). Whether treatment is surgical or radiotherapy based, the use of ATT for controlling presenting or potential symptoms of thoracic disease is an integral component of an aggressive treatment approach for oligometastatic NSCLC patients with synchronous presentation given the potential for prolonged survival and significant morbidity and/or mortality resulting from uncontrolled locoregional progression.

### USE OF RADIOTHERAPY WITH SYSTEMIC THERAPY

Systemic therapy is the standard palliative treatment option for reasonably fit NSCLC patients presenting with either synchronous or metachronous disseminated disease with the agent (chemotherapy, TKIs, or immunotherapy with checkpoint inhibitors) selected based on histological and genotypic information about the primary and/or metastatic tumor. Randomized trials supporting the use of these systemic therapies typically included patients with widespread, rather than limited, metastases. Regardless, the promise of improved systemic control only heightens the importance of effective local treatment modalities to address isolated persistent or progressive metastases. For example, oligoprogression is well documented during treatment of onco-addicted NSCLC (ALK gene rearrangements or EGFR mutations) with TKIs such as crizotinib for ALK+ and erlotinib for EGFR mutated NSCLC. In these patients, local ablative treatment with HIGRT has allowed continuation of targeted therapy with greater than 6 months of additional disease control (50, 54).

The optimal integration of definitive local therapy with systemic therapy in oligometastatic NSCLC is not yet certain. It is common clinical practice to address limited brain metastases with upfront SRS or surgery (if symptomatic or warranted for diagnosis) followed by SRS or WBRT with initiation of systemic therapy or definitive thoracic therapy (if brain only metastases and synchronous presentation); however, medical oncologists typically treat patients with extra-cranial oligometastases with upfront systemic therapy. As alluded to earlier, the use of induction systemic therapy may allow for selection of patients who are less likely to develop new metastases and may experience improved PFS after consolidation with aggressive local therapy to the chest and limited residual metastases (typically ≤3) (49). The selective use of aggressive metastasis-directed and thoracic therapy in non-progressing patients is a potential source of selection bias in published retrospective studies, namely immortal time bias, which is best controlled for with a randomized controlled study. The recently reported multicenter, phase II randomized controlled trial by Gomez and colleagues utilized local consolidative therapy (LCT) of all active disease and reported a dramatic median PFS benefit (11.9 vs 3.9 months, *p* = 0.0054) compared to maintenance treatment in oligometastatic NSCLC patients (46 of 49 *de novo*) with three or fewer metastatic disease lesions without progression after first-line systemic therapy (49). These randomized prospective data reinforce the sum of available retrospective evidence signaling the significant PFS benefit of adding aggressive local therapy to standard systemic treatment for patients with NSCLC oligometastases.

It should be noted that the administration of systemic therapy may be associated with significant acute toxicities, including chemotherapy-related nausea and myelosuppression and autoimmune phenomena related to immunotherapy, which adversely affect patient quality of life. In the setting of oligometastatic NSCLC, Collen and colleagues reported the results of a small prospective study that showed receipt of induction chemotherapy prior to undergoing SBRT was not prognostic for LC or PFS (51). It is possible that select patients may experience prolonged PFS with aggressive local therapy directed at all metastatic sites in lieu of systemic therapy; however, it is reasonable to consider chemotherapy, or other appropriate systemic agents, as upfront treatment in oligometastatic patients given the OS benefit afforded in both early (adjuvant after resection in node positive and/or larger primary tumors) and advanced stage NSCLC (98). This treatment approach is reflected in the NCCN guidelines version 1.2017. As mentioned earlier, the use of aggressive local therapy in the setting of oncogene-addicted NSCLC is an area of significant interest as studies have reported excellent PFS and OS with the addition of SBRT to erlonitib in patients progressing after first-line platinum-based chemotherapy (50). Salvage of oligoprogression in the setting of advanced NSCLC with a driver mutation may allow continuation of otherwise efficacious and well-tolerated systemic therapy in patient who may not have other effective treatment options (99). Reported toxicities of the above approaches have been quite low with rare reports of severe (grades 4–5) adverse events.

Although the benefit of aggressive primary and metastasisdirected local therapy in the metastatic setting has commonly felt to be due to improved LC of targeted gross tumor(s), Gomez and colleagues reported a significantly prolonged time interval to the appearance of a new lesion among patients randomized to LCT (11.9 vs 5.7 months) (49). This is a provocative finding that suggests an aggressive local treatment approach may alter the natural history of metastatic disease either by limiting the potential for later spread or stimulating systemic immune-surveillance. Furthermore, there are fascinating reports of radiation inducing an "abscopal effect" whereby treating a single lesion results in regression of metastases far away from the treated site, however, these remain mostly anecdotal at present. Preclinical studies show synergistic antitumor effects with radiotherapy *via* proimmunogenic properties resulting from increased tumor antigen presentation and activation of cytotoxic T cells (100) and emerging clinical data also support this concept with a recent study reporting previous treatment with extra-cranial radiotherapy was associated with significantly improved median OS (11.6 vs 5.3 months, *p* = 0.034) among patients treated with pembrolizumab on the KEYNOTE-001 phase I trial (101). Importantly, predominantly retrospective data to date suggest that the contemporaneous administration of immunotherapy and intracranial SRS or palliative dose extra-cranial radiotherapy is relatively safe without dramatically increased risk of synergistic toxicity; however, efficacy nor the safety of more aggressive extra-cranial dose schedules has not been studied (102, 103). There may even be a detrimental effect of more protracted palliative radiotherapy schedules given the extreme radiosensitivity of circulating lymphocytes and our growing understand of the importance of the immune system in combatting metastatic disease (104).

### FUTURE DIRECTIONS AND ONGOING PROSPECTIVE TRIALS

The emerging evidence supports the existence of a subset of advanced NSCLC patients who will benefit from definitive local treatment to limited sites of disease with unparalleled PFS and OS. The challenge has been defining the appropriate patient population and proving the added benefit of aggressive local therapy in a randomized fashion. The phase II study by Gomez and colleagues represents the first randomized controlled trial addressing the question at hand and supports the premise that select advanced NSCLC patients may progress predominantly in known disease sites and aggressive thoracic and metastasisdirected local therapy can result in improved PFS. As follow-up remains short (median of 12.4 months), it is unclear whether the PFS benefit observed will translate into improved OS. It is possible that crossover of patients in the maintenance arm to LCT after progression could minimize the potential OS benefit similar to that seen in randomized trials of targeted agents in NSCLC (105). In addition, as the study was powered to assess the primary outcome, PFS, and was closed early at the recommendation of the data safety monitoring committee due to an overwhelming probability of concluding in favor of the LCT group, it may be insufficiency powered to measure a true difference in OS between arms. Regardless of whether an improvement in OS is ultimately shown, an improvement in PFS is certainly meaningful as a prolonged disease-free interval off of systemic therapy may represent a significant quality of life benefit to the patient.

Further randomized studies are necessary. NRG Oncology has recently opened NRG-LU002 (NCT03137771), a randomized phase II/III trial enrolling NSCLC patients with ≤3 oligometastatic sites that will build upon the experience of Gomez and colleagues and seeks to evaluate the PFS and OS benefit, if it exists, of consolidative SBRT and definitive thoracic therapy after first-line/induction systemic therapy in a national cooperative group setting. SABR-COMET (NCT01446744) is another multiinstitutional randomized phase II trial that has completed accrual of 99 patients (not limited to NSCLC histology) with ≤5 metastases and a controlled primary tumor. Patients were randomized to standard of care with or without SBRT consolidation to all sites of known disease with OS as the primary outcome measure. SARON (NCT02417662) is a UK-based multicenter randomized phase III study enrolling (target of 340) patients with oligometastatic NSCLC and examining the feasibility, safety, and efficacy of consolidation with SBRT or conventional RT to primary and sites of metastases after standard platinum-based doublet chemotherapy. CORE (NCT02759783) is another randomized phase II trial (anticipated accrual of 206 patients) that has opened in the UK enrolling breast, prostate, and NSCLC patients with oligorecurrence and is evaluating the impact of adding SBRT to standard of care with PFS as the primary outcome. These larger randomized studies should increase the power to uncover an OS benefit with the addition of SBRT as comprehensive local therapy in the setting of oligometastatic NSCLC.

Additional questions remain unanswered beyond the measurable added benefit, if any, of an aggressive treatment approach including definitive local therapy. Both SABR-COMET and the randomized phase II study by Gomez and colleagues were evaluating the use of definitive local therapy to sites of limited disease as consolidation after upfront systemic therapy. However, the optimal timing of aggressive local treatment remains undefined. The ongoing Chinese OITROLC trial (NCT02076477) may help answer this question as it randomizes oligometastatic patients (≤5 distant organ metastases) between upfront definitive local therapy to the primary and all sites of metastases vs a consolidative approach after two cycles of induction chemotherapy with 3-month response rate as the primary outcome and 3-year PFS and toxicity as secondary outcomes. As use of SBRT combined with erlotinib showed remarkable outcomes in oligoprogressive metastatic NSCLC (50), a pilot study from Memorial Sloan Kettering Cancer Center (NCT02450591) is now evaluating outcomes when SBRT or surgery is added to erlotinib for newly diagnosed oligometastatic lung adenocarcinoma harboring a sensitizing EGFR mutation with the goal to evaluate feasibility and PFS.

Although crucial before more broadly adopting an aggressive local therapy approach to oligometastatic disease, the safety and optimal dose fractionation when treating multiple oligometastases in various organ sites remains unknown as the bulk of published literature studied the use of SBRT for single metastases within individual organs (8, 106). NRG BR001 (NCT02206334), a phase I study enrolling patients with oligometastatic NSCLC, prostate, or breast cancer, attempts to clarify the tolerability of SBRT when treating patients with multiple metastases at pre-defined doses in seven organ sites including bone and lymph nodes, where little safety data currently exist.

The era of personalized medicine has arrived in the field of oncology, ushered in by advances in imaging and molecular biology. Broad molecular profiling is expected to be a key component of future advancements in the care of patients with NSCLC. Prospective clinical trials are underway to generate clinical and molecular predictors, including comprehensive molecular profiling and/or primary tumor microRNA expression, to guide selection of patients for oligometastases-directed ablative therapy (107, 108). Further investigation, including independent validation, is needed before clinical implementation. Given the transition toward earlier incorporation of immunotherapy, such as the upfront administration of pembrolizumab in some newly diagnosed advanced NSCLC patients, there is considerable interest in combining immunotherapy and radiotherapy to improve outcomes and perhaps even induce the abscopal effect (109). A web search of http://clinicaltrials.gov revealed that there are now at least 14 actively recruiting studies evaluating immunotherapy in NSCLC as of March 31, 2017. These studies will hopefully add knowledge as to the added benefit and optimal incorporation of radiation with immunotherapy, including the most appropriate timing, sequencing, and dosing of each.

Despite the emerging evidence supporting the use of aggressive local treatments in addition to standard of care systemic therapy for oligometastatic NSCLC, as well as the increasing availability of non-invasive potentially ablative radiotherapy techniques, there are practical limitations that must be considered as our society increasingly recognizes the rising costs of health care in the modern era and begins to transition toward a value-based reimbursement model for providers and hospital systems (110). "Payers," including governmental and private health insurers, are increasingly emphasizing an evidence-based approach to justify potentially costly treatments in patients with relatively poor prognosis. This can make obtaining insurance approval for novel and/or investigational uses for expensive treatment modalities, including SRS or SBRT, an onerous challenge for the treating radiation oncology team, as well as increase the financial burden and stress patients and their families experience during cancer treatment (111). This new reality reinforces the need for high level evidence to justify and guide the recommendation for aggressive local treatments in the setting of oligometastatic NSCLC.

## CONCLUSION

Tremendous developments in the field of oncology within the past decade, including improvements in imaging and radiotherapy technique allowing for the safe delivery of potentially ablative doses of radiation with minimal toxicity or interruption in quality of life or systemic therapy, have ushered in the next frontier of NSCLC treatment. A steadily increasing number of published retrospective and prospective clinical experiences, including the first successfully completed randomized trial, support the concept that NSCLC patients with limited metastatic disease, termed as oligometastases, will experience improved outcomes with aggressive local treatment with surgery and/or radiation therapy targeting all sites of appreciable disease. The challenge for the oncology community moving forward is to design and accrue to prospective randomized controlled trials that will allow for an accurate assessment of the added benefit of aggressive local therapy as well as the optimal integration with existing and emerging systemic therapies.

## AUTHOR CONTRIBUTIONS

DB wrote the initial draft of this review, with edits and revisions from each of the other authors: JS, DS, SC, and MM.

#### REFERENCES

be used for precision medicine. *Cancer Lett* (2016) 382:118–26. doi:10.1016/j. canlet.2016.01.041

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2017 Bergsma, Salama, Singh, Chmura and Milano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

## The Potential of Heavy-Ion Therapy to Improve Outcomes for Locally Advanced Non-Small Cell Lung Cancer

*Stephen G. Chun1 \*, Timothy D. Solberg2 , David R. Grosshans 1 , Quynh-Nhu Nguyen1 , Charles B. Simone II 3 , Radhe Mohan1 , Zhongxing Liao1 , Stephen M. Hahn1 , Joseph M. Herman1 and Steven J. Frank 1*

*1 Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States, 2Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States, 3 Maryland Proton Therapy Center, University of Maryland Baltimore, Baltimore, MD, United States*

Keywords: carbon, heavy ion, locally-advanced lung cancer, hypofractionation, immune therapy

#### *Edited by:*

*John Varlotto, UMass Memorial Medical Center, United States*

#### *Reviewed by:*

*John M. Holland, Oregon Health & Science University, United States*

*\*Correspondence: Stephen G. Chun<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology*

*Received: 31 July 2017 Accepted: 21 August 2017 Published: 05 September 2017*

#### *Citation:*

*Chun SG, Solberg TD, Grosshans DR, Nguyen Q-N, Simone CB II, Mohan R, Liao Z, Hahn SM, Herman JM and Frank SJ (2017) The Potential of Heavy-Ion Therapy to Improve Outcomes for Locally Advanced Non-Small Cell Lung Cancer. Front. Oncol. 7:201. doi: 10.3389/fonc.2017.00201*

The treatment of unresectable locally advanced non-small cell lung cancer (LA-NSCLC) remains a daunting challenge. To date, the best median survival achieved in a randomized prospective bi-modality clinical trial for LA-NSCLC is 28.7 months for patients who received standard chemoradiotherapy on NRG Oncology RTOG 0617 (1). Emerging data from RTOG 0617 and other institutions have also implicated radiation dose to the heart as a driver of cardiovascular events, survival, and patient-reported quality of life (2–5). To improve survival and quality of life for LA-NSCLC, it is critical to explore emerging therapeutic technologies. One such technology is radiation therapy delivered with heavy ions, such as carbon ions. Heavy-ion therapy has both unique biological and physical advantages that may improve local control while also reducing radiation exposure to nontarget organs at risk such as the heart. With the technology implemented at several Asian and European centers in conjunction with the planned development of several therapeutic heavy-ion centers in the United States, there will be real opportunity to exploit this technology to gain ground and improve the therapeutic ratio in LA-NSCLC.

LA-NSCLC is highly resistant to conventionally fractionated radiation therapy with cooperative group studies showing locoregional failure rates greater than 60% after definitive chemoradiation (6). From a radiation biology standpoint, there is considerable rationale to support use of heavy-ion therapy to improve local control for these patients. Upon encountering target tissue, interaction of charged heavy ions with matter yields the highest linear energy transfer (LET) of any currently available form of clinical radiation (7). This in turn results in unique clustered DNA lesions, resulting in a lower oxygen enhancement ratio and higher relative biological effectiveness (RBE) that is on the order of threefold greater than photon radiotherapy (7). Early preclinical data have also suggested tumors with EGFR mutation may be more susceptible to heavy-ion therapy than photon irradiation, suggesting that heavy-ion therapy may provide opportunities to further tailor radiation therapy in the heterogeneous genetic landscape of LA-NSCLC (8). Taken together, these properties suggest that heavy ions could improve local control by overcoming DNA repair pathways that confer radiation resistance and provide patient-tailored options for LA-NSCLC.

The physical properties of heavy-ion therapy also provide dosimetric advantages for LA-NSCLC (9). With particle therapy, the energy deposited in tissue increases with depth eventually coming to an abrupt stop, known as the Bragg peak. Using particles, practitioners have the ability to stop the dose deposition at a specified point, reducing or eliminating exposure to tissues distal to the target volumes. These advantages are particularly relevant to recent findings in RTOG 0617 where the importance of radiation conformity to prevent pneumonitis and reduce cardiac doses has been established (10, 11). Just as proton therapy can reduce cardiac doses in comparison to photon therapy (12), heavy ions also have the potential to further reduce cardiac and pulmonary doses (9, 13). First, the Bragg Peak can reduce radiation doses distal to the target to a far greater degree than photon irradiation. Second, heavy ions exhibit less scattering than protons because of their mass, resulting in a sharper lateral penumbra than proton or photon radiotherapy. Third, pencil beam scanning and arc technologies are expected to provide unprecedented geometric avoidance of non-target organs at risk. The combination of these physical advantages with motion management and Monte Carlo algorithms for plan optimization has potential to produce dramatic improvements in the conformity of the high, intermediate, and low dose regions. While proton therapy exhibits some of these characteristics such as the Bragg Peak, proton therapy has more lateral scattering and lacks the LET of heavy-ion therapy.

In the era of anti-PD-1-/PDL-1-targeted therapies, another important biological advantage of heavy-ion therapy is its potential immunostimulatory effects. While radiation therapy is known to have complex reactions with the immune system and tumor microenvironment, heavy ions have may have unique immune effects that are distinct from photons or proton therapy. Because of their high LET and RBE, preclinical evidence suggests that heavy ions induce non-apoptotic cell death that is independent of the typical p53, bax/bcl, and p21 signal transduction cascades (14, 15). These alternative forms of cell death could provide more diverse tumor epitopes for cytotoxic T-cells to prime immune responses. Another immunological advantage of heavy-ion therapy stems from the unique physical properties discussed earlier. Reducing low and intermediate dose exposure has the potential to reduce integral dose that can cause lymphopenia and hematologic toxicity (16–18). In RTOG 0617, Grade 3+ hematological toxicity was observed in 56% of patients with only one-third of patients completing consolidative chemotherapy (1), highlighting the need to reduce the myelosuppressive effects of definitive chemoradiotherapy. Thus, by reducing lymphopenia from exposure of circulating lymphocytes and also stimulating the local production of immunological epitopes, heavy-ion therapy might be a potent weapon to illicit *in situ* vaccine responses.

Conventionally fractionated radiation therapy as a single modality has dismal cure rates (19), and the primary benefit of concurrent chemotherapy in historic combined modality trials has been to improve local control (20–22), which comes at the cost of myelosuppression, esophagitis, and peripheral neuropathy in LA-NSCLC. However, heavy-ion therapy can deliver doses to tumor targets with greater potency than concurrent chemoradiation without the systemic side effects of chemotherapy. This raises the question of whether heavy-ion therapy can obviate the need for concurrent cytotoxic therapy. Concurrent chemotherapy has significant downsides including high rates of severe esophagitis and immunosuppression. A Phase I–II of carbon ion therapy for patients with LA-NSCLC who were medically unfit to receive concurrent chemotherapy from the Research Institute for Charged Particle Therapy in Chiba, Japan showed promising results (23). In this study, dose was escalated from 68 to 72 cobalt Gy equivalents without dose limiting toxicity. Oncological outcomes were also favorable with a 2-year local control rate of 93.1% and overall survival of 51.9%. There has also been success using carbon ion therapy without cytotoxic chemotherapy for medically inoperable early-stage NSCLC (13, 24–26). Exploration of heavy-ion technology as a strategy to avoid concurrent cytotoxic chemotherapy should be encouraged as a way to reduce toxicities and health-care costs for patients without compromising oncological efficacy.

Currently used fractionation schedules for carbon therapy differ greatly from standard photon techniques. Given differential biological effects on tumors normal tissues as a function of dose per fraction, hypofractionated approaches are commonplace in the practice of heavy-ion therapy. The use of hypofractionated treatment schedules may allow for a greater number of patients to be treated at select centers at a reduced cost. Coupled with the potential for reduced toxicity and improved outcomes, this could make heavy-ion therapy a cost effective treatment, despite the high upfront costs of building such facilities likely on the order of \$200–300 million (USD).

As the number of heavy-ion therapy centers is expected to increase in the United States in the coming years, there will be opportunity to explore its role for LA-NSCLC. We have outlined rationale for robust exploration of heavy-ion therapy in LA-NSCLC for the purpose of improving what are presently suboptimal outcomes in this population.

#### AUTHOR CONTRIBUTIONS

All authors have contributed to conceptualization and writing of this manuscript.

#### REFERENCES

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2017 Chun, Solberg, Grosshans, Nguyen, Simone, Mohan, Liao, Hahn, Herman and Frank. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Radiation Therapy in Extensive Stage Small Cell Lung Cancer

*Branislav Jeremic1 \*, Antonio Gomez-Caamano2 , Pavol Dubinsky 3 , Nikola Cihoric4 , Franesc Casas5 and Nenad Filipovic1*

*1BioIRC Centre for Biomedical Research, BioIRC, Kragujevac, Serbia, 2Hospital Clínico Universitario, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain, 3East Slovakia Institute of Oncology, Louis Pasteur University Hospital, Kosice, Slovakia, 4Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland, 5Hospital Clínic de Barcelona, Barcelona, Spain*

Lung cancer is the major cancer killer in the Western world, with the small cell lung cancer (SCLC) representing around 15–20% of all lung cancers. Extensive disease small cell lung cancer (ED SCLC) is found in approximately two-thirds of all cases, composed of both metastatic (M1) and non-metastatic (but presumably with tumor burden too large for locoregional-only approach) variant. Standard treatment options involve chemotherapy (CHT) over the past several decades. Radiation therapy (RT) had mostly been used in palliation of locoregional and/or metastatic disease. In contrast to its established role in treating metastatic disease, thoracic RT (TRT) had never been established as important part of the treatment aspects in this setting. In the past two decades, thoracic oncologists have witnessed wide introduction of modern RT and CHT aspects in ED SCLC, which led to more frequent use of RT and rise in the number of clinical studies. Since the pivotal study of Jeremic et al., who were the first to show importance of TRT in ED SCLC, a number of single-institutional studies have reconfirmed this observation, while recent prospective randomized trials (CREST and RTOG 0937) brought more substance to this issue. Similarly, the issue of prophylactic cranial irradiation was investigated in EORTC and the Japanese study, respectively, bringing somewhat conflicting results and calling for additional research in this setting. Future studies in ED SCLC could incorporate questions of RT dose and fractionation as well as the number of CHT cycles and type of combined Rt-CHT (sequential vs concurrent).

 While its incidence is declining in men, it continues to rise in women (3). In spite of significant efforts and refinements in staging system (4), division by "extensiveness" of the disease is still widely used. Extensive disease small cell lung cancer (ED SCLC) is found in approximately two-thirds of all cases, composed of both metastatic (M1) and non-metastatic (but presumably with tumor burden too large for locoregional-only approach) variant. Standard treatment options involve chemotherapy (CHT) over the past several decades (5). Various efforts to optimize treatment outcome with CHT, such as maintenance CHT or higher CHT doses unequivocally failed (6–10). With CHT, the median survival times (MST) are 9–12 months, while 5-year survivals of only 1–2% (9, 11–13).

#### *Edited by:*

*John Varlotto, University of Massachusetts Medical School, United States*

#### *Reviewed by:*

*John Austin Vargo, West Virginia University Hospitals, United States Nitin Ohri, Albert Einstein College of Medicine, United States*

> *\*Correspondence: Branislav Jeremic<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology*

*Received: 05 July 2017 Accepted: 26 July 2017 Published: 11 August 2017*

#### *Citation:*

*Jeremic B, Gomez-Caamano A, Dubinsky P, Cihoric N, Casas F and Filipovic N (2017) Radiation Therapy in Extensive Stage Small Cell Lung Cancer. Front. Oncol. 7:169. doi: 10.3389/fonc.2017.00169*

Radiation therapy (RT) had mostly been used in palliation of locoregional and/or metastatic disease. In contrast to its established role in treating metastatic disease, thoracic RT (TRT) had never been established as important part of the treatment aspects in this setting. This was largely due to conflicting reports in the past several decades about its usefulness in controlling intrathoracic tumor burden (14–17), and predominantly metastatic nature of the disease. It is likely that inferior diagnostic and staging tool as well as outdated RT and CHT aspects such as 2D RT planning, modest RT doses, and non-platinum-based CHT significantly contributed to poor RT performance in this setting.

## THORACIC RT

In the past two decades, thoracic oncologists have witnessed wide introduction of modern RT (3D planning, altered RT fractionation) and CHT (platinum-based) aspects in ED SCLC. This has resulted in more frequent use of RT and, importantly, rise in the number of clinical studies addressing the issue of optimization of treatment approaches by focusing on important aspects of RT.

The turning point in the history of modern treatment of ED SCLC occurred with the publication of seminal paper of Jeremic et al. (13) in 1999. It was the very first study which tested, in a prospective randomized Phase III fashion, standard treatment option (CHT) vs CHT and TRT, with a prophylactic cranial irradiation (PCI) given in both arms. This trial was based on observations from the past studies that, in ED SCLC, there were frequent intrathoracic failures, which also frequently occur even in patients who achieved initial complete response (CR) after CHT. Hence, study of Jeremic et al. (13) had its premises in the following: (1) significant proportion of patients with ED SCLC experience intrathoracic (locoregional) treatment failure, which cannot be successfully treated with second line CHT, (2) these failures may also become the source of subsequent metastatic disease (in patients with previous non-metastatic ED SCLC) and lead to death, (3) TRT could control intrathoracic tumor burden, (4) if successful, this may lead to improved and prolonged intrathoracic tumor control, and, if significant, may lead to an improvement in overall survival. Ultimate question, overshadowing all these considerations was: which subgroup of patients may have been suitable for testing the place and role of TRT in ED SCLC.

In the Jeremic trial (13), subjects were adult treatment-naive patients with good PS and biopsy-proven ED SCLC. All patients initially received three cycles of standard-dose cisplatin/etoposide (PE) regimen, after which complete patient reevaluation and restaging was performed both at local (intrathoracic) and the distant level. Randomization included only patients who achieved either a CR at both local and distant level, labeled as CR/CR or those who achieved a partial response (PR) within the thorax accompanied with the CR elsewhere (labeled as PR/CR). They received either accelerated hyperfractionated RT (Acc Hfx RT) and concurrent low-dose daily CHT, given on each RT day, followed by PCI, and then by additional two cycles of PE (group I) or four additional cycles of PE and PCI (Group II). Patients achieving worse response were not randomized. Total tumor dose was 54 Gy in 36 fractions, 1.5 Gy BID, while PCI dose was 25 Gy in 10 daily fractions. When deemed appropriate, palliative RT was given to patients with metastatic lesions with 30 Gy in 10 daily fractions.

A total of 210 patients entered this study. TRT added to CHT offered superior outcome over CHT alone in terms of both the MST and 5-year survival rates [17 vs 11 months (*p* = 0.041), and 9.1 and 3.7%, respectively]. Similar was observed for the local recurrence-free survival (the median time to local recurrence, 30 vs 22 months, and 5-year local recurrence-free survival, 20 vs 8.1%, respectively; *p* = 0.062), but RT added to CHT did not offer better distant metastasis-free survival (*p* = 0.35).

To enlighten the effects of TRT on local (intrathoracic) level, local CR rates were evaluated after three cycles of induction CHT at week 9 (i.e., just before the randomization), week 15 (i.e., when either Acc Hfx RT/CE in group I or 2 additional cycles of PE in group II were administered), and at week 21 (2 more cycles of CHT in each group). Local CR rate was similar after 9 weeks (47 vs 44%, *p* = 0.77), but after week 15, the local CR rate became significantly higher in group I than in group II (96 vs 61%, *p* = 0.000007). This was maintained at week 21 (96 and 66% for the two groups, respectively; *p* = 0.00005). Therefore, fourth and the fifth cycles of CHT barely improved response in group I once Acc Hfx RT/CE had been given. Similarly, the sixth and seventh cycles of PE in group II brought only a few percent increase in response rates. What these results imply is that perhaps one may not need more than 3–4 CHT cycles in this patient population, possible food for thoughts for future trials.

Jeremic et al. (13) were the first to show that TRT plays indispensible role in the treatment of patients with ED SCLC after initial CHT. Beside primary study endpoints, an analysis of various pretreatment prognostic factors showed that higher KPS score and no significant weight loss were strong prognosticators of improved treatment outcome. As a potential guide for future studies, the number of metastases independently influenced survival. It was shown that metastatic tumor burden should be taken into account since patients with ≥2 metastases had significantly worse outcome than those with only one metastasis. Since approximately 90% of all patients in the study of Jeremic et al. (13) had 1–2 metastases, subsequent discussions in this field frequently labeled this disease extent as *limited extensive disease*.

Overall impact of the study of Jeremic et al. (13) was not easy to comprehend in the years following its publication. However, 10 years after its publication, the study of Ou et al. (18) retrospectively analyzed the data from several counties in southern California with estimated population of 6.2 million. Of a total of 3,428 ED SCLC patients, RT was given to 1,204 (35.1%) patients. For this group, the 2-year, and MST were 9.3%, and 8 months, respectively, being significantly better than in those who did not receive RT (3.8%, and 4 months, respectively; *p* < 0.0001). Analysis of prognostic factors showed that delivered RT exerted independent and positive influence of on treatment outcome (*p* < 0.001).

A recent survey of 473 practicing US radiation oncologist attempted to identify the current pattern of practice of TRT in ED SCLC (19). In spite of great variation in the patient selection and doses of RT used, TRT was recommended after systemic CHT by 96% of the respondents. The type of the institution influenced the decision with patients treated in private clinics being more likely to receive TRT than patients treated at academic centers (*p* = 0.0101). Interestingly, lower TRT recommended doses were associated with respondents claiming higher self-rated knowledge of individual clinical trials.

Past several years also brought studies that investigated the same issue. In a prospective study from Canada (20), the median time to disease progression was 8.4 months and the MST was 13.7 months. Additionally, two single-institutional, retrospective studies showed the same. In the Chinese study (21), for TRTtreated group MST was 17.2 months, and 5-year survival was 10.1%, respectively (*p* = 0.0001), while another Canadian study (22) reported on MST of 14 months and 2-year survival of 14% for TRT/CHT treatment.

Recently, in an EORTC (23) prospective phase III study patients with World Health Organization PS of 0 to 2 and confirmed ED SCLC without clinical evidence of brain, leptomeningeal, or pleural metastases, who achieved any response to 4–6 cycles of PE were treated with either TRT (30 Gy in 10 fractions) or no TRT, while all patients receiving PCI. Overall survival was longer in the TRT arm (*p* = 0.066), whereas 12-, 18-, and 24-month survival rates in the 2 arms were 33, 16, and 13% vs 28, 16, and 3%, respectively. Although the trial was negative for the primary endpoint of 1-year overall survival, significance was achieved at 18 months (*p* = 0.03) and was maintained at 24 months (*p* = 0.004). MST from the time of randomization was 8 months, but when calculated from diagnosis, it was 12 months. Progression-free survival was longer in the TRT arm (*p* = 0.001). Intrathoracic progression (isolated or accompanied by progression elsewhere or as the first site of disease progression) was seen less frequently in the TRT arm. Almost a 50% reduction in intrathoracic recurrences (80 vs 44%, respectively; *p* = 0.001) was observed.

Although EORTC study (23) characteristics (study design, patient eligibility, treatments offered) differed from those of Jeremic et al. (13) (**Table 1**), it is tempting to discuss and compare the two studies (**Table 2**) in order to obtain better perspective for future studies planning and execution. EORTC study (23) reconfirmed the importance of local control as initially suggested by Jeremic et al. (13). However, more intensive TRT given with concurrent CHT in a shorter OTT in the study of Jeremic

*CHT, chemotherapy; TRT, thoracic radiotherapy; fx, fraction; BID, hyperfractionation (2 fx a day); QD, conventional fractionation (1 fx a day); PCI, prophylactic cranial irradiation.*

et al. (13) may have led to faster improvement in local control which, in turn, may have led to faster improvement in the overall survival. More intensive tumor cell kill was accompanied with somewhat higher incidence of acute toxicity, which in both studies was acceptable and, in the study of Jeremic et al. (13), only high-grade acute esophageal toxicity was significantly more frequent in the TRT group. What this attempted comparison hints at is the large gap in both the patients' and the treatment aspects when considering the two studies' characteristics (13, 23) perhaps being at the two extremes, hence the necessity to fill in the existing gap with more clinical research.

One such attempt have been materialized in the Radiation Therapy Oncology Group study 0937 (24) during which patients with 1–4 extracranial metastases were deemed eligible after achieving either CR or PR to initial CHT. Patients received either PCI alone or PCI + TRT to the thorax and metastases. PCI was given with 25 Gy in 10 daily fractions in 2 weeks, while TRT was given with 45 Gy in 15 daily fractions in 3 weeks. Between March 2010 and February 2015, a total of 86 patients were randomized. The study crossed the futility boundary for OS and was closed at planned interim analysis prior to meeting accrual target. With the median follow-up of 9 months, 1-year overall survival was similar between the groups: 60.1% (95% CI: 41.2–74.7%) for PCI and 50.8% (95% CI: 34.0–65.3%) for PCI + + TRT (*p* = 0.21). Three and 12-month rates of progression were 53.3 and 79.6% for PCI, and 14.5 and 75% for PCI + TRT. Time to progression favored PCI + TRT (*p* = 0.01). Not to be forgotten, there were some imbalances in the two groups, which might better explain the negative results for overall survival despite improvements in thoracic control, including the higher number of patients with PR vs CR to CHT and 2–4 vs 1 metastases in the group receiving RT. Treatment-related toxicity was also similar between the two arms. The authors concluded that overall survival exceeded predictions for both arms with the consolidative RT delaying progression but not improving the 1-year overall survival.

Although this trial will definitely be seen as a negative trial, it brought several important findings. The first site of failure after CHT is likely to be in sites of presenting disease; RT to these sites

*LC, local control; OS, overall survival; OTT, overall treatment time; TRT, thoracic radiotherapy; CHT, chemotherapy.*

Jeremic et al. RT in ED SCLC

alters failure patterns; late RT without concurrent CHT is not durable; and, oligometastatic ED SCLC survival seems to again approach that of LD SCLC, confirming the postulates and results of Jeremic et al. (13). Ineffective RT dose and schedule, advanced age, and an imbalance in disease burden in the two groups all likely contributed to lack of survival advantage with consolidative RT in this trial. In addition, considering all trial aspects, authors suggested that perhaps a more appropriate treatment for this patient population with low volume systemic disease could have been early RT concurrent with cycle three or four of CHT in patients with a favorable response to cycles one and two of CHT followed by PCI, similar to the Jeremic trial (13).

### PROPHYLACTIC CRANIAL IRRADIATION

Contrary to the place and role of PCI in limited disease SCLC, where several PRCTs and MAs exist, in ED SCLC data concerning it is much more limited. A large PRCT of EORTC included responders to 4–6 cycles of CHT (25). In this trial, patients were randomized to receive either PCI (20 Gy in 5 daily fractions or 30 Gy in 12 daily fractions) or observation. PCI offered significantly lower cumulative risk of brain metastasis at 1-year (14.8 vs 40.4%, *p* < 0.001), which led to an improvement in the progression-free survival (14.7 vs 12 weeks, respectively, *p* = 0.02). Finally, PCI led to an improvement in 1-year overall survival (27 vs 13%, respectively, *p* = 0.003) as a consequence of improved CNS control.

The same EORTC trial (25, 26) collected self-reported patient data using both Quality of Life Questionnaire C30 and Quality of Life Questionnaire Brain Cancer Module while investigating the effect of PCI on quality of life (QoL). In the first report, sideeffects of PCI, including fatigue and hair loss, were significantly more severe in the group of patients receiving PCI (25). However, no significant differences were seen in the remaining endpoints. Importantly, in a subsequent report, there was a limited effect of PCI on these factors, none reaching the level of clinical significance as (26). Severe worsening in global health status (35 vs 22%) from base line up to 3 months was observed in the PCI group; however, one must not forget that there was a 94% participation rate at baseline, followed by poor compliance during the followup (60 and 55% at 6 weeks and 3 months, respectively). However, the control arm was significantly superior when an exploratory analysis of other symptom scale factors was performed.

These results have profoundly influenced the practice of RT in ED SCLC as PCI was overwhelmingly accepted as standard of treatment in this setting (5, 27). However, fresh data from a Japanese trial (28) seem to question that, in that trial, patients with any response to platinum-based doublet CHT and no brain metastases on MRI received PCI (25 Gy in 10 fractions) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrollment. The primary endpoint was overall survival. 224 patients were randomly assigned. In the planned interim analysis, of the first 163 enrolled patients, Bayesian predictive probability of PCI being superior to observation was 0.011%, resulted in early termination of the study because of futility. In the final analysis, the MST was 11.6 months in the PCI group and 13.7 months in the observation group (*p* = 0.094). The most frequent grade ≥3 adverse events at 3 months were anorexia, malaise, and muscle weakness in lower limbs, which were all similar between the two groups. No treatment-related deaths occurred in either group.