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Feature articles about advances, challenges, or other aspects of radiation oncology that impacts or has potential impact in thoracic oncology.

Prophylactic Cranial Irradiation in Locally Advanced NSCLC Falls Flat

Fig. 1A. Neurotoxicity in the Patients Who Received Prophylactic Cranial Irradiation
Fig. 1B. Neurotoxicity in the Control Group

By John Armstrong, MD, FRCPI, DABR, FFRRCSI

RTOG 0214, a phase III randomized trial, is the biggest trial to date testing prophylactic cranial irradiation (PCI) in locally advanced NSCLC.1 The trial, presented at the IASLC World Conference on Lung Cancer this past September, evaluated patients with stage III NSCLC whose disease had not progressed after treatment with surgery and/or radiation therapy with or without chemotherapy. PCI failed to improve survival, which could have been due to a number of factors, despite a reduction in brain metastases for patients who received PCI.

Dr. John Armstrong

Study Details
Participants were stratified by stage (IIIA vs. IIIB), histology (nonsquamous vs. squamous), and therapy (surgery vs. none) and were randomly assigned to PCI or observation. The primary endpoint of the study was overall survival (OS). Of the 356 patients entered, 340 were eligible for analysis. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients.

The trial failed to meet accrual targets and was underpowered to detect a significant survival difference. PCI had no effect on OS. PCI did, however, significantly reduce the risk of brain metastases; patients in the observation arm were 2.33 times more likely to develop brain metastases than those in the PCI arm (p = 0.004). Nevertheless, there was a relative lack of efficacy in reducing brain metastases. The 10-year risk was 28.3% without PCI versus 16.7% with PCI. Thus, PCI yielded an absolute risk reduction of 11.6%. This means that PCI benefits just one in 8.6 patients. In contrast, in limited-stage small cell lung cancer (where PCI improves OS), PCI reduced the risk of brain metastases from 58% to 33%. For SCLC, PCI benefits one in four patients.2

Inadequate Effect Within the Brain
Completion of imaging prior to random assignment is important. The trial mandated CT scans or brain MRIs with or without contrast. However, CT imaging can miss a significant number of brain metastases detectable by MRI. The trial MRIs were done with and without contrast but were not necessarily volumetric studies. Therefore, an unknown number of patients on both arms of the trial probably had small, undetected brain metastases at enrolment.

In this group of patients with NSCLC, the risk of developing brain metastases was 28.3% without PCI versus 58% in the SCLC metanalysis.2 The biologic basis for PCI is that the brain represents a sanctuary site (perhaps because of the blood–brain barrier), where cancer cells survive the effects of chemotherapy. However, the relatively low baseline risk in this series suggests that the brain is not a sanctuary site and that failure in the brain is a manifestation of general failure of systemic control.

The reduction of risk from 28.3% without PCI to 16.6% denotes a 40% control rate. Therefore, PCI failed to eliminate 60% of occult or microscopic brain metastases. The dose used was 30 Gy in 15 fractions, which is probably a very low biologic dose. When biologically effective dose (BED) is calculated using an estimated alpha/beta ratio of 3.9 for NSCLC, we can compare this schedule to other commonly used fractionation schedules.3 The 60 Gy/30 fractions RTOG standard dose for the locally advanced NSCLC gives a BED of 90.77 Gy. The 50 Gy in 25 fractions used by the Lung Cancer Study Group randomized trial of postoperative radiation had a BED of 75.64 Gy.4 That dose was very effective in controlling microscopic or occult disease remaining after surgery in the mediastinum. Consequently, a similar BED might well be required to control similar disease within the brain. Yet the 30 Gy in 15 fractions used in RTOG 0214 has a BED of only 45.38 Gy. Therefore, it is not surprising that it was not particularly effective in achieving this objective.

Neurotoxicity
The main concern about PCI is the risk of neurotoxicity. These concerns prevented the investigators from using a higher dose. A recently published smaller randomized trial in the Netherlands presented comprehensive data regarding incidence and durability of several aspects of neurotoxicity (Fig. 1).5

Perspective on the Future of PCI
RTOG 0214 is the largest trial to address this topic. The investigators should consider amalgamating their data with data from the other trials to perform a metanalysis. At present, there is no evidence that PCI improves survival, so it cannot be recommended. Future trials testing other therapies for locally advanced NSCLC could incorporate translational analyses, which might, in theory, identify a phenotype where the risk of brain metastases is so high that PCI (or alternatively routine volumetric MRIs in follow up) might be reconsidered.6 Meanwhile, the recently reported trial of adjuvant immune therapy (PACIFIC ) suggests that immune therapy may be as effective in the brain as elsewhere in the body. In the PACIFIC trial, the incidence of brain metastases was 5.5% using consolidative durvalumab after definitive chemoradiation versus 11% without.7

About the Author: Prof. Armstrong is a professor at St. Luke’s Radiation Oncology Network, Dublin, Ireland.

References:
1. Sun A, Hu C, Gore E, et al. 10-Year Updated Analysis of NRG Oncology/RTOG 0214: A Phase III Comparison of PCI vs. Observation in Patients with LA-NSCLC. Presented at: IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada.

2. Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with smallcell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476-484.

3. Santiago A, Barczyk S, Jelen U, Engenhart-Cabillic R, Wittig A. Challenges in radiobiological modeling: can we decide between LQ and LQ-L models based on reviewed clinical NSCLC treatment outcome data? Radiat Oncol. 2016;11:67

4. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. Lung Cancer Study Group. N Engl J Med. 1986 Nov 27;315(22):1377-1381

5. De Ruysscher D, Dingemans AC, Praag J, et al. Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non- Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study. J Clin Oncol. 2018;36(23):2366-2377.

6. Grinberg-Rashi H, Ofek E, Perelman M, et al. The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain. Clin Canc Res. 2009;15(5):1755-1761.

7. Antonia S, Villegas A, Daniel D et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919-1929

Utility and Controversies Surrounding Use of New Techniques in Radiotherapy

By Suresh Senan, MRCP, FRCR, PhD

Improved delivery of radiotherapy has contributed to the recent changes in guidelines for patients with lung cancer. The clinical impact of some technical advances has been modest, but the cumulative effect of many developments has led to more precise treatment delivery, and has increased the confidence of clinicians to adopt new techniques. The impact of new technology is best illustrated by referring to selected clinical stages.

Early-stage Peripheral NSCLC

The poster child of new technology is image-guided stereotactic ablative radiotherapy (SABR or SBRT), which is a technique for delivering high-dose, high-precision radiation. In early-stage peripheral non-small cell lung cancer (NSCLC), 5-year in-field tumor control rates of 90% have been reported, and the introduction of SABR has been associated with improved cure rates at the population level. The superiority of SABR over conventional radiotherapy has been established in two randomized trials, results from one of which was presented at the IASLC 18th World Conference on Lung Cancer [Ball D, WCLC 2017]. SABR resulted in superior freedom from local failure (HR = 0.29, 95% CI 0.130, 0.662, P=0.002) and also longer overall survival (HR = 0.51, 95% CI 0.51, 0.911, P=0.020).

Minimal requirements for SABR planning and delivery were recently published by the European Society for Radiotherapy and Oncology, and include use of 4-D planning computed tomography (CT) scan and a standard linear accelerator with a cone-beam CT scan. Newer developments include the clinical introduction of magnetic resonance imaging-guided SABR, which is undergoing evaluation in high-risk tumors such as centrally located NSCLC. The use of protons (charged particles) was considered previously to be a promising development for treating lung tumors, due to its ability to decrease radiation doses to surrounding organs. However, the options for managing tumor motion at current proton centers is generally inferior to that available on a standard linear accelerator. At present, there are limited prospective data supporting a role for protons in early-stage NSCLC.

Locally Advanced Lung Cancer

Since the introduction of CT-based treatment planning and improved set-up protocols, concurrent chemo-radiation (CT-RT) has become established as the standard of care for most fit patients who present with locally-advanced NSCLC. Patients undergoing standard concurrent CT-RT to 60 Gy in the RTOG 0617, study achieved 5-year overall and progression free rates of 32% and 18%, respectively.1 The median overall survival of 28.7 months in this trial has also established a new benchmark. The role of intensity modulated radiotherapy (IMRT) remains a topic of debate, particularly as population studies suggest that benefits of IMRT are limited to larger central (T3-4) tumors. Results of RTOG 0617 support use of IMRT in locally-advanced NSCLC as this reduces rates of radiation pneumonitis, and was associated with a better quality of life in the first 12 months post CT-RT.

Some, but not all studies, suggested that delivery of higher radiation doses to the heart are associated with a poorer overall survival. However, other studies suggest that delivered heart doses may be a surrogate for other prognostic factors in stage III NSCLC, such as the extent and location of mediastinal nodal involvement, especially subcarinal nodes, rather than an independent predictor of outcome. The increased cardiac toxicity has also been correlated with the use of doses higher than the standard 60 Gy for CT-RT, and with schemes using non-standard fractionation schemes (>2 Gy, once daily).

Proponents of proton radiation have therefore advocated its use as a means to decrease both lung and cardiac toxicity. The number of proton centers worldwide is increasing in a roughly exponential fashion, with approximately 20 operating centers, and 53 in development. However, little consensus has been reached for using proton therapy for common types of cancer in adults. A prospective randomized trial led by the MD Anderson Cancer Center compared the use of IMRT versus proton therapy in locally advanced NSCLC, and reported no differences in treatment failures, which were defined as either grade ≥3 pneumonitis or local failure at 1 year.2 Proponents of protons have argued that the use of a newer delivery technique (intensity-modulated proton therapy) will improve outcomes, and the results of ongoing comparative trials are awaited. Treatment of mobile tumors in the lung and liver using protons remains a challenge, and only a minority (27%) of European proton and carbon ion therapy centers currently treat such tumors.3

Changing Paradigms in Locally Advanced Lung Cancer

The published results of the PACIFIC trial have called into question the previous focus on delivery of ever higher radiation doses. PACIFIC evaluated consolidation durvalumab or placebo every 2 weeks for a year, following CT-RT in patients with unselected stage III NSCLC after concurrent CT-RT to a dose of 54-66 Gy.4 Consolidation durvalumab resulted in an increase in median PFS to 16.8 versus 5.6 months (HR 0.52) with the differences in PFS sustained at 12- and 18-month landmarks. Durvalumab also resulted in a superior median time to death or distant metastases (23.2 vs 14.6 months; P < .001), and little increase in grade 3/4 treatment related toxicity. The above findings indicate that the addition of durvalumab consolidation to standard radiation doses combined with two cycles of platinum-containing chemotherapy, is sufficient to improve both local and distant tumor control. This, in turn, raises the question whether the focus of radiation research should simply be to limit radiation doses to 60 Gy, while further optimizing the integration of immune-oncology and other systemic approaches into CT-RT of stage III NSCLC. ✦

References
1. Bradley JD, Hu C, Komak RU, et al. Long-term results of RTOG 0617: A randomized phase 3 comparison of standard dose versus high dose conformal chemoradiation therapy +/- cetuximab for stage III NSCLC. J Am Coll Radiol. 2017:99, S105 (suppl)
2. Liao Z, Lee J, Komaki R, Gomez D, O’Reilly M, Allen P, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol. 2016;34 suppl 15:8500.
3. Weber DC, Abrunhosa-Branquinho A, Bolsi A, et al. Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire. Radiother Oncol. 2017;124:185-189.
4. Scott J. Antonia SJ, Villegas A, Davey Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017 Sep 8. doi: 10.1056/ NEJMoa1709937. [Epub ahead of print]

Patients with EGFR Mutation Should Postpone Brain Radiation for CNS Metastases: Pro and Con

By Pranshu Mohindra, MD, MBBS, DABR®, Lecia Sequist, MD, and Laurie E. Gaspar, MD, MBA

Since the initial approval of erlotinib, an oral tyrosine kinase inhibitor (TKI), for treatment of patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC), multiple additional treatment agents targeting EGFR mutation are now recommended for use in clinical practice.1 Estimated median survival for patients with previously untreated EGFR-mutant positive (EGFRmt (+)) NSCLC can extend well beyond 2 years; however, this increase in longevity has been linked with an increased incidence of brain metastases (BM).2,3 While whole-brain radiotherapy (WBRT) was previously considered the standard of practice, the concern for neurocognitive side effects has led to the decreased use of WBRT in favor of stereotactic radiosurgery (SRS), as supported by phase-III trials that do not demonstrate a detriment in survival.4-6

EGFRmt (+) NSCLC provides a unique therapeutic setting where even with a diagnosis of BM, extended survival may be seen.7 A debate was conducted at the recently concluded 2017 IASLC meeting in Chicago, reviewing the pros and cons of withholding radiation therapy in patients with EGFRmt (+)-NSCLC diagnosed with BM. Key highlights from the debate presented by Dr. Lecia Sequist (Pro) and Dr. Laurie Gaspar (Con) are excerpted below.

Pro: Dr. Lecia Sequist 

1. A multi-institutional retrospective study evaluated upfront radiation (WBRT or SRS) approaches versus upfront EGFR-directed therapy approaches for these patients and showed a significant detriment in overall survival (OS) by delayed use of either of the radiation options.8 However, there are limitations in this experience, with other literature review showing mixed results:

• The presence of central nervous system (CNS)-only disease in 76% of the patients likely biased the outcomes in favor of upfront radiation.
• Also, SRS was planned only at intracranial progression, not as planned consolidation of residual disease.
• In a literature review of other institutional experiences, mixed results were observed, with 2 other studies showing survival advantage with use of radiation, 1 study showing survival advantage with TKI alone, and 3 other studies showing no significant differences, although a trend of a 4- to 7-month survival improvement with radiation was noted.

2. All published studies to date used erlotinib- or gefitinib-based therapy, which have demonstrated less CNS penetration compared to newer EGFR TKIs. Outcomes are superior in the osimertinib era.

• AURA 2 study, a phase II study evaluating use of AZD9291 (osimertinib) in EGFR and T790M mutation positive tumors after previous EGFR TKI therapy, demonstrated a 54% overall response rates (ORR) within the brain (2016 World Conference on Lung Cancer, Vienna, Austria).
• The phase I BLOOM study evaluated the use of osimertinib in patients with EGFRmt (+) leptomeningeal disease. Among 21 patients, efficacy assessments confirmed radiological response in 7 and cytological CSF clearance in 2 patients (2016 ASCO Annual Meeting, Chicago, US).
• AURA 3 study demonstrated that the ORR in brain with osimertinib in comparison with chemotherapy in patients with progression after first-line TKI therapy were 70% vs. 31%, p = 0.015 (2017 ASCO Annual Meeting, Chicago, USA). In a follow-up detailed report of this phase 3 study, analysis of 144 patients with T790M-positive advanced NSCLC who develop BM demonstrated a significant improvement in progression-free survival (PFS) favoring osimertinib as against platinum-pemetrexed chemotherapy doublet: 8.5 months vs 4.2 months (HR, 0.32; 95% CI, 0.21 to 0.49).9
• In the FLAURA study comparing osimertinib to standard therapy (erlotinib or gefitinib) in EGFRmt (+) -NSCLC, in patients with BM (n = 116), the median PFS with osimertinib versus standard therapy was 15.2 months vs. 9.6 months (HR, 0.47; 95% CI, 0.30-0.74; P = 0.0009). The rates of CNS progression were 6% versus 15%, respectively (2017 ESMO Congress, Madrid, Spain).

Bottom line: Given the risk of radionecrosis or steroid dependence from SRS or cognitive decline from WBRT, and in light of particularly encouraging outcomes from recent studies evaluating osimertinib in BM, I support use of upfront systemic therapy to offer patients an opportunity for response and thereby delay the risk of side effects from the use of radiation therapy. I also favor consideration of SRS to any significant residual CNS lesions after initial response to TKIs, a sequence and therapeutic strategy employed increasingly at most academic centers, an approach that has not been permitted in most published studies.

Con: Dr. Laurie E. Gaspar 

1. The prognosis of EGFRmut (+) BM and the time to salvage SRS/ WBRT is not as good as perceived, especially if BM occur while on TKI.

• In the Massachusetts General Hospital experience, patients with EGFRmt (+) or ALK translocation who developed BM in the setting of prior TKI therapy had worse OS than those not on TKI prior to the BM diagnosis (median OS 9m vs. 19.6 m, p < 0.001).10 Further, after cranial radiotherapy, EGFR mutation status did not impact OS.10
• In a multi-institutional retrospective database, median OS after diagnosis of BM for EGFRmt patients was 23 months (17 months for TKI treated versus 30 months for TKI-naive patients, p < 0.01). When time-dependent analysis was performed, extended survival associated with EGFRmt (+) NSCLC was only noted in TKI-naive patients relative to those who developed BM while on TKI therapy.11
• Even on the AURA 3 study, despite the 70% ORR, median PFS for patients whose disease had progressed on first-line TKI and develop CNS disease was only 8.5 months.9
• In a phase-II Japanese study using gefitinib in EGFRm-NSCLC with brain metastases, despite a 87.8% ORR, the median time on gefitinib was only 10.6 months with intracranial progression being the most common cause of withdrawal.12

2. While neurocognitive effects following WBRT are well known, there are no comparable data on the neurocognitive effects of TKI.

3. In afatinib-treated patients in the LUX-Lung 3 and LUX-Lung 6 trials, the benefit of afatinib appeared higher in patients with prior WBRT with median PFS in entire cohort ranging from 8.2 to 11 months.13

4. Results reported in the study by Magnuson et al are compelling across all prognostic subpopulations.8 This multi-institutional retrospective study evaluated upfront radiation (WBRT or SRS) approaches versus upfront EGFR-directed therapy approaches for these patients and showed a significant detriment in OS by delaying implementation of either of the radiation options. Key findings are:

• Median OS for upfront-SRS, upfront-WBRT and upfront EGFR-TKI, with SRS or WBRT at intracranial progression, were 46, 30, and 25 months, respectively, p < 0.001.
• In both radiation cohorts, 50% of patients were symptomatic at the time WBRT was initiated, compared to only 12% of patients in the EGFR-TKI cohorts.
• Even after controlling for variables that constitute the Disease Specific Graded Prognostic Assessment (DS-GPA) score7 and the EGFRm status, upfront SRS was independently associated with improved OS relative to EGFR-TKI and delayed radiation (adjusted HR, 0.39; 95% CI, 0.26 t 0.58, p < 0.001).
• Prior EGFR-TKI use and EGFR-TKI resistance mutations were exclusions, thereby suggesting the benefit of radiation was even more pronounced in the better prognostic group.

5. The biggest concern is the overall quality of life for patients with BM and the symptoms and sequelae from the metastatic intracranial burden. Bottom line: The argument for upfront radiation is especially strong for SRS, as opposed to WBRT, so why wait and let a BM get larger or more symptomatic, and not be amenable to SRS? At the University of Colorado, these patients are given upfront SRS if possible, and then proceed to TKI. If SRS is not thought to be reasonable, then the TKI is started and SRS or WBRT is deferred until progression.

Audience response: There was a lively discussion followed by an informal vote that (predictably) declared no clear winner. ✦

References
1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Smal Cell Lung Cancer version 9.2017, Natl. Compr. Cancer Network. (2017). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (accessed October 21, 2017).
2. Jackman DM, Miller VA, Cioffredi LA, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009; 15:5267-5273.
3. Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014; 9:195-199.
4. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol. 2009; 10:1037–1044.
5. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA. 2016; 316:401–409.
6. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC•3): A multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017; 18:1049–1060.
7. Sperduto PW, Yang TJ, Beal K, et al. Estimating survival in patients with lung cancer and brain metastases: An update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA). JAMA Oncol. 2017; 3:827–831.
8. Magnuson WJ, Lester-Coll NH, Wu AJ,et al. Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptormutant non-small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol. 2017; 35:1070–1077.
9. Mok TS, Wu YL, Ahn MJ, AURA3 Investigators, et al., Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017; 376:629–640.
10. Mak KS, Gainor JF, NiemierkoA, et al. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with nonsmall cell lung cancer treated with radiotherapy for brain metastases. Neuro Oncol. 2015; 17:296–302.
11. Sperduto PW, Yang TJ, Beal K, et al. The effect of gene alterations and tyrosine kinase inhibition on survival and cause of death in patients with adenocarcinoma of the lung and brain metastases. Int J Radiat Oncol Biol Phys. 2016; 96:406–413.
12. Iuchi T, Shingyoji M, Sakaida T, et al. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013; 82:282–287.
13. Schuler M, Wu YL, Hirsh V, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016; 11:380–390.

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