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

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.

Proton-Beam Therapy Versus Photon-Beam Therapy: The Debate Continues

Comparison of relative depth dose distributions of photons versus protons. Source: J Clin Oncol. 2014 Sep 10;32(26):2855-63.

By Cynthia L. Kryder, MS, CCC-Sp

For patients who present with inoperable, locally advanced lung cancer, photon-based chemoradiation remains the standard of care. Despite advanced radiation-delivery techniques, such as multi-leaf collimators, intensity-modulated radiotherapy (IMRT), and imageguided radiotherapy (IGRT), radiation oncologists continue to explore ways to extend the ALARA principle, that is, the desire to deliver tumoricidal radiation doses to intended targets while minimizing the radiation doses to adjacent healthy tissues. This has led radiation oncologists to investigate the potential of proton beam radiation therapy. In patients with non-small cell lung cancer (NSCLC), proton-beam therapy may enable safe dose escalation while sparing chest organs at risk and simultaneously maintaining adequate target coverage. In so doing, the collateral damage of standard radical thoracic radiotherapy can, theoretically, be mitigated.

Photons Versus Protons

Although the therapeutic index of modern, highly conformal photon radiotherapy has increased, the physics of photons make it impossible to avoid the exit dose downstream from the target, which is a physical limitation of the photon beam. In comparison, protons travel through tissue quickly and stop abruptly when reaching tissues at a very specific depth. Unlike photons, which deposit their radiation doses close to their entrance into the body, protons deposit most of their energy at the end of their paths, in a phenomenon known as the Bragg peak, the point at which the majority of energy deposition occurs. Before the Bragg peak, the deposited dose is about 30% of the Bragg peak maximum dose. Thereafter, the deposited dose falls to practically zero, yielding a nearly nonexistent exit dose. The integral dose with proton therapy is approximately 60% lower than any photon-beam technique.1 Thus, proton therapy delivers radiation to tumors and areas in very close proximity, decreasing integral radiation dose to normal tissues and theoretically avoiding collateral damage.

Despite these potential advantages, a fundamental issue with protons is the ability to stop the proton at the tumor. As any external beam travels through the body toward its target, it passes through tissues of different densities. Protonbeam therapy is much more sensitive to tissue density than photon therapy. Likewise, at greater depths the lateral margins of the proton beam become less sharp due to considerable scattering.2 Any change in tissue composition, such as organ motion, lung expansion, or alteration in bone position from one treatment to the next, can affect target coverage and dose to surrounding structures. To account for tissue heterogeneity and to reduce the potential for tumor underdosing, radiation oncologists often add a margin of uncertainty, meaning that the beam is designed to overshoot the target to guarantee good coverage.3 This could, however, negate the tissue-sparing advantage of proton-beam therapy and/or dilute its therapeutic effects.

Another difference between photon beam therapy and proton-beam therapy is the expense. Proton-beam therapy is an expensive technology. Including a cyclotron, multistory gantries, and several treatment rooms, the average cost for a proton facility ranges between US$140 million and US$200 million.

Assessing the Clinical Advantage of Proton-Beam Therapy

Given its lower integral dose and steeper dose gradient, proton therapy is an appealing therapeutic option. However, dosimetry advantages alone will not be enough to convince payors and patients to adopt this costly technology. Proton beam therapy must demonstrate a measurable clinical advantage when compared with standard photon therapy.

Clinical trials are underway to do just that. Zhongxing Liao, MD, of the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center, is the principal investigator of a multi-center, prospective, randomized phase III trial that will compare overall survival after photon versus proton chemoradiotherapy in patients with unresectable locally advanced NSCLC.4 This randomized trial will compare the overall survival (OS) in patients with stage II-IIIB NSCLC after image-guided, motion-managed photon radiotherapy (Arm 1) or after image-guided, motion-managed proton radiotherapy (Arm 2), both given with concurrent platinum-based chemotherapy. A total of 560 patients are expected to be enrolled. The primary endpoint is OS; secondary endpoints include 2-year progression-free survival, adverse events, quality of life, cost-effectiveness, and changes in pulmonary function.

A second ongoing trial seeks to determine whether the dose of radiation to the tumor, but not the surrounding healthy tissue, could be increased by using IMRT or intensity-modulated proton beam therapy (IMPT).5 In phase I of the study, investigators will identify the maximum tolerated dose (MTD) of IMPT and IMRT. In phase II, researchers will compare the efficacy of IMPT and IMRT when both treatments are combined with standard chemotherapy. The primary outcome measure is MTD; the secondary outcome measure is progression-free survival.

Future Outlook

The ability of proton-beam therapy to precisely target tumors and spare underlying tissues from radiation exposure in patients with a variety of cancers has already been demonstrated. Exactly if and how proton-beam therapy fits into the treatment of patients with lung cancer remains to be determined. Harnessing the power of proton-beam therapy in the treatment of NSCLC may be challenging given that protons must be delivered to the lungs, which are targets in motion that are surrounded by tissues of different densities. Future studies will need to assess not only side effects and outcomes, but they will also need to provide data to support the development of dose algorithms and motion-management techniques.

Given the capital investment and operating costs associated with protonbeam therapy, examining the economic advantages and liabilities of this new technology is necessary. Clear data about its cost effectiveness based on different clinical and treatment scenarios will enable providers, payors, and patients to make informed decisions about treatment. ✦

Expert Comment
The photon versus proton conundrum continues in the latter part of 2017, and it now must evolve in the context of promising new data with immune enabling drugs such as checkpoint inhibitors. Personally, I believe it is unlikely that further dose escalation to the target area will result in significant benefits in local control and overall survival from a radiobiologic perspective despite potential advantages in dose deposition by proton therapy, so newer directions are needed. From a cost perspective, is a 140-200 million monetary outlay for protons the way to get us to the promised land? Or will molecular and immunological discoveries offer the best avenue for success? Perhaps radiation, whether through protons or photons, will be the match rather than the flame for immune enabling drugs; therefore, dose escalation may be less important. Building on the theme of potential clinical advantages between photon or proton intensity modulated therapy, the question is whether less integral dose scatter within normal tissue with the use of protons will result in less chronic immunosuppression and thus potentiate checkpoint inhibition over photon irradiation. This is an amazing opportunity to study the changes in lymphocyte:neutrophil ratios during and after treatment. The bar has jumped with the anticipated results of the PACIFIC trial in locally advanced NSCLC, and we must jump with it. —David Raben, MD

References

1. Mitin T, Zietman A. Promises and pitfalls of heavyparticle therapy. J Clin Oncol. 2014;32:2855-2863.
2. Goitein M. Magical protons? Int J Oncol Biol Phys. 2008;70:654-656.
3. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57:R99–R117.
4. ClinicalTrials.gov [website]. Comparing photon therapy to proton therapy to treat patients with lung cancer. Last updated June 10, 2016. https:// clinicaltrials.gov/ct2/show/NCT01993810. Accessed July 24, 2017.
5. ClinicalTrials.gov [website]. Intensity-modulated scanning beam proton therapy (IMPT) with simultaneous integrated boost (SIB). Last updated July 22, 2016. https://clinicaltrials.gov/ct2/show/NCT01629498. Accessed July 24, 2017.

2018 ASTRO Guideline for Palliative Thoracic Radiation Therapy for NSCLC: The Balance Between Curative and Palliative Radiotherapy

By Shalini K. Vinod, MBBS, MD

The standard of care for patients with inoperable stage III NSCLC is curative radiotherapy and concurrent chemotherapy.1 However, there are numerous factors that may preclude this approach, including poor respiratory function and large tumor volume—both of which are surrogates for unacceptable radiation doses to normal lung tissue resulting in high risk of pulmonary toxicity. Other more subjective factors include Eastern Cooperative Oncology Group performance status (ECOG PS), comorbidities, and age. In practice, 57% to 61% of patients with stage III NSCLC are treated with palliative radiotherapy.2,3 Patients not suitable for curative treatment usually receive single-modality palliative treatment given sequentially, with the order of treatment based on patient symptoms and disease burden.

Until now, international guidelines have not specifically addressed palliative treatment of stage III NSCLC due to a paucity of evidence. The American Society for Radiation Oncology (ASTRO) has updated its palliative radiotherapy guideline to recommend palliative hypofractionated radiotherapy and concurrent chemotherapy for patients with stage III NSCLC who are deemed unsuitable for curative therapy.4 Patients must be fit for chemotherapy, have an ECOG PS of 0 to 2, and a life expectancy of at least 3 months. This guideline change is largely based on the publication of two randomized controlled trials.5,6 Both trials tested the efficacy of palliative hypofractionated radiotherapy and concurrent chemotherapy; however, the standard arms differed, with palliative radiotherapy featured in one5 and palliative chemotherapy in the other (Table).6

Supporting Data
Nawrocki et al. conducted a phase II trial of patients with stage III NSCLC unsuitable for curative treatment on the basis of FEV1 less than or equal to 40% and/or tumor diameter greater than 8 cm.5 Random assignment was to radiotherapy alone or two cycles of chemotherapy followed by concurrent radiotherapy. Patients receiving chemoradiotherapy had a significantly better median and 2-year survival and a similar rate of symptom relief compared to radiotherapy alone. Toxicity was greater in the chemoradiotherapy arm, with six early deaths (12%) versus 0 (0%) in the radiotherapy arm.

Strom et al. randomly assigned patients with stage III NSCLC unsuitable for curative treatment on the basis of one or more adverse prognostic factors (tumor size of 8 cm or greater, ECOG PS of 2 or greater, or weight loss of 10% or greater) to four cycles of chemotherapy or the same regimen with radiotherapy between cycles 2 and 3.6 Overall survival was significantly better with chemoradiotherapy (Table). Treatment-related mortality was similar; however, there were more hospital admissions and esophagitis in the chemoradiotherapy arm.

Neither study mandated PET staging, which could result in imbalances in otherwise unrecognized stage IV disease between arms. Differences in treatment on progression can also affect survival. Patients in the control arm of the study by Nawrocki et al.5 were less likely to receive palliative chemotherapy upon disease progression. Considering that these patients were chemo naive, one would have expected the majority of them to receive chemotherapy upon progression; however, this did not occur due to poor performance status. Interestingly, the converse was true in the study by Strøm et al.6, in which significantly more patients in the chemotherapy- alone arm received both further chemotherapy and radiotherapy. Despite some differences in eligibility criteria, the improvement in median and 2-year survival seen with concurrent palliative chemoradiotherapy in both studies was remarkably similar.

There is now evidence to support the use of concurrent chemotherapy and palliative radiotherapy in improving survival, symptoms, and quality of life in patients with stage III NSCLC who are unsuitable for curative treatment. –Shalini K. Vinod, MBBS, MD

Remaining Questions and Challenges
There is now evidence to support the use of concurrent chemotherapy and palliative radiotherapy in improving survival, symptoms, and quality of life in patients with stage III NSCLC who are unsuitable for curative treatment. However, the challenge remains in identifying patients who would be eligible for this approach without denying them the possibility of curative chemoradiotherapy. Curative radiotherapy in stage III NSCLC is underutilized, and this guideline should not be used as an excuse to treat patients palliatively. Tumor size alone should not be used as an indication for palliative treatment7 unless a safe radiotherapy plan respecting normal tissue tolerances cannot be generated. Similarly, it may be safe to treat patients with poor pulmonary function if the tumor volume, hence radiotherapy field is small. Performance status is a clearer indication of the ability to tolerate curative treatment; however, the survival benefit seen in Strom et al. was not seen in the subgroup with an ECOG performance status of 2 or greater. Significant weight loss is associated with poor prognosis and is often a marker of systemic disease, which would not have necessarily been detected in these studies in the absence of PET staging.

For patients with stage III NSCLC who are deemed unsuitable for curative treatment, concurrent chemotherapy and palliative radiotherapy is superior to either single modality alone. However, the optimal chemotherapy agents, radiotherapy doses, and scheduling are yet to be determined. Given the uncertainties in selecting patients for this treatment strategy, decisions are best made in the setting of a multidisciplinary team. ✦

About the Author: Professor Vinod is a radiation oncologist at Liverpool Hospital, Sydney, Australia, and a conjoint professor at the University of New South Wales.

References:
1. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187-199.

2. Vinod SK, Wai E, Alexander C, Tyldesley S, Murray N. Stage III non-small-cell lung cancer: population-based patterns of treatment in British Columbia, Canada. J Thorac Oncol. 2012;7(7):1155-1163.

3. Vinod SK, Simonella L, Goldsbury D, Delaney GP, Armstrong B, O’Connell DL. Underutilization of radiotherapy for lung cancer in New South Wales, Australia. Cancer. 2010;116(3):686-694.

4. Moeller B, Balagamwala EH, Chen A, et al. Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. Pract Radiat Oncol. 2018; pii: S1879-8500(18)30069.

5. Nawrocki S, Krzakowski M, Wasilewska-Tesluk E, et al. Concurrent Chemotherapy and Short Course Radiotherapy in Patients with Stage IIIA to IIIB Non-small Cell Lung Cancer Not Eligible for Radical Treatment: Results of a Randomized Phase II Study. J Thorac Oncol. 2010;5(8):1255- 1262.

6. Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013;109(6):1467-1475.

7. Ball DL, Fisher RJ, Burmeister BH, et al. The complex relationship between lung tumor volume and survival in patients with non-small cell lung cancer treated by definitive radiotherapy: A prospective, observational prognostic factor study of the Trans-Tasman Radiation Oncology Group (TROG 99.05). Radiother Oncol. 2013;106(3):305-311.

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