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PCI Decreases the Risk of Brain Metastases in Patients with Locally Advanced NSCLC

Dr. Elizabeth Gore

By Elizabeth Gore, MD
Posted: May 27, 2019

IN REFERENCE TO: 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-11DLCRG-02 study. J Clin Oncol. 2018;36(23):2366-2377.

Dr. De Ruysscher et al. are commended for completing a well-designed phase III trial of prophylactic cranial irradiation (PCI) in patients with radically treated stage III NSCLC.1 The primary endpoint was incidence of symptomatic brain metastases at 2 years. The vast majority of patients were treated to 30 Gy in 10 or 12 fractions. The incidence of brain metastases at 2 years was 7% with PCI and 27.2% with observation (p = 0.001), consistent with the findings in RTOG 0214, another contemporary phase III study comparing PCI and observation in patients with stage III NSCLC.2 RTOG 0214 demonstrated a 1-year incidence of brain metastases of 7% with PCI versus 18% with observation (p = 0.004). Many other trials have consistently shown a decrease in brain metastases with PCI for NSCLC, although none have demonstrated improvement in overall survival. Completing a trial adequately powered to show a survival advantage has proven to be challenging for many reasons including imperfect selection criteria, physician bias, PCI toxicity, and patient reluctance to undergo randomization.

Prevention by some clinicians is viewed as less relevant now with the availability of MRI surveillance and early detection of brain metastases with effective and potentially curative treatment(s) now available. Aggressive treatment has changed the previously accepted perception of short survival once brain metastases are diagnosed. Also, trials with newer systemic therapies demonstrate blood–brain barrier penetration with decrease in the incidence of brain metastases; they can also effectively treat known metastases with the expectation of less central nervous system toxicity than PCI.

Mitigating Even the Acceptable Adverse Events from PCI
An interesting and important finding in this trial is the difference in physician- and patient-reported adverse events (AEs). Except for vomiting, all AEs were under reported by physicians relative to patients. Interestingly, fatigue and memory loss were more likely to be underreported by physicians for patients in the observation arm, emphasizing the need for patient-reported outcomes and pointing to a possible physician bias favoring observation. It has been suggested that even without improvement in survival, delay or prevention of brain metastases is clinically meaningful due to the deleterious effect of brain metastases on quality of life. In this trial, quality of life was worse at 3 months in the PCI arm and then returned to the same level as the observation arm thereafter. This occurred despite the significantly higher rate of symptomatic brain metastases in the observation arm, although it is unclear if AEs of brain metastases were captured in this analysis.

Although trials have consistently demonstrated that the toxicity of PCI is acceptable,3 toxicity remains a primary concern and limitation to the acceptance of PCI. Measures, such as use of pharmacologic agents and radiation therapy techniques that may mitigate or minimize the side effect of PCI, should be undertaken. Hippocampal avoidance (HA) whole-brain radiation therapy may play an important role based on the encouraging results of NRG CC001, which evaluated HA wholebrain radiation therapy for documented brain metastases,4 and the anticipated outcomes of a similar trial, NRG CC003 (NCT02635009), which is evaluating HA with PCI for small cell lung cancer. Additionally, careful selection of patients for PCI should incorporate known, preexisting toxicity risks including established microvascular disease, impaired baseline neurologic function, and residual side effects from primary therapy, particularly fatigue and memory impairment.

In this study, treating approximately five patients with PCI prevented one case of symptomatic brain metastases. Many more patients would need to be treated to result in cure or increased survival of even one patient. Better understanding of tumor and host factors that increase risk of brain failures will improve this ratio and perhaps identify a cohort of patients with locally advanced disease and perhaps a subset of patients with early-stage disease who are at high risk for brain metastases and for whom brain-directed therapy is clearly indicated.

PCI is effective, but there is no proven benefit in terms of overall survival, and therefore it is not currently considered standard of care. As stated by the authors, the pros and cons of PCI necessitate a shared-decision process between patients and physicians. ✦

About the Author: Dr. Gore is a professor and medical director of Radiation Oncology, Zablocki VA Medical Center, Medical College of Wisconsin

References:
1. 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-11DLCRG-02 study. J Clin Oncol. 2018;36(23):2366-2377.

2. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non–small-cell lung cancer: Primary analysis of Radiation Therapy Oncology Group Study RTOG 0214. J Clin Oncol. 2011;29(3):272-278.

3. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non–small-cell lung cancer: Neurocognitive and quality-of-life analysis. J Clin Onc. 2011;29(3):279-286.

4. Gondi V, Pugh S, Brown PD, et al. Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001. Int J Radiat Oncol Biol Phys. 2018;102(5):1607.

Brain Metastases in NSCLC: Is Delaying Upfront Radiation a Viable Option?

Dr. Arya Amini & Dr. Chad G. Rusthoven

By Arya Amini, MD, and Chad G. Rusthoven, MD
Posted: August 19, 2020

Approximately 10% of patients diagnosed with metastatic NSCLC present with brain metastases, and another 30% develop brain metastases during the course of their illness.1 Traditionally, the treatment for brain metastases included surgery, whole-brain radiotherapy (WBRT), or stereotactic radiosurgery (SRS). Due to neurocognitive effects from WBRT, SRS has now emerged as first-line therapy in many patients with limited brain metastases. Ongoing trials are evaluating the definition of “limited,” which may evolve from the current clinical thresholds ranging from four or fewer to 10 or fewer lesions.2 An ongoing randomized phase III clinical trial is comparing SRS to WBRT in patients with five to 15 brain metastases (NCT03550391).3 In patients who are not candidates for SRS, WBRT is still the “standard” and is typically used in patients with numerous brain metastases not amenable to SRS and/or those presenting with leptomeningeal disease. To counteract the potential neurocognitive side effects from WBRT, hippocampal sparing and memantine are viable options for these patients and should be considered, on the basis of randomized data.4 Lastly, in patients with one or more lesions causing current or impending mass effect and symptoms, or in settings where tissue confirmation is needed, surgery should be considered.

Revisiting the Gold Standard
SRS has emerged as the gold standard for limited brain metastases after multiple randomized trials demonstrated improved cognition and quality of life compared to strategies incorporating WBRT. There has been a growing interest, however, in parallel strategies involving systemic therapy upfront with radiation deferred. Despite the improved side-effect profile of SRS compared to WBRT, SRS can nevertheless pose certain risks, including central nervous system (CNS) necrosis, and can be associated with cognitive and quality-of-life effects when numerous lesions are treated. Therefore, potentially delaying or avoiding radiation may have its benefits. Whereas historically, chemotherapy had low CNS penetration and objective response rates (ORRs), novel agents have been introduced in the past decade with clinically meaningful intracranial response rates in advanced NSCLC. These include EGFR TKI agents such as third-generation osimertinib, which has shown encouraging ORRs and reduction in CNS progression compared to first- and second-generation EGFR TKIs.5 ALK inhibitors have demonstrated similarly encouraging CNS ORRs in the range of 60% to 80%. Pembrolizumab, a PD-1 inhibitor, has been approved for treatment in metastatic NSCLC without targetable mutations, on the basis of phase III randomized data demonstrating improved OS compared to chemotherapy.6-8 In a single-arm, phase II study in patients with metastatic NSCLC with at least one untreated brain metastasis receiving pembrolizumab alone, the CNS response rate approximated 30%.9 Additional data suggest that when combining pembrolizumab with chemotherapy, CNS response rates increase to approximately 40%.10

Although the improved CNS response rates with newer agents are encouraging, there is currently a paucity of high-level evidence to ensure that the outcomes achieved with an initial strategy of systemic therapy alone are equivalent to systemic therapy plus tumor-directed radiation across various clinical settings. Moreover, SRS has traditionally been combined with the most effective systemic therapies available, and the emergence of newer agents with increased CNS activity does not necessarily preclude the benefit of durable local tumor control achieved with SRS. Although the growing interest in a strategy of first-line systemic therapy alone is underscored by ongoing trials enrolling patients with untreated asymptomatic brain metastases (EA516/ S1709 INSIGNA; NCT03793179),11 there are also data suggesting inferior outcomes when upfront radiation is omitted in favor of TKIs alone. Additional analyses suggest potential synergy between radiation and immune checkpoint inhibitors, especially in those with larger lesions potentially causing mass effect or in neurologically critical locations.12,13

Collaborative Decision Making
In a rapidly evolving field, where the development of new therapies with enhanced CNS activity has outpaced clinical trial efforts to evaluate systemic agents with and without brain radiation, our institutions have taken a multidisciplinary approach involving input from both medical oncologists and radiation oncologists. In patients with NSCLC with targetable molecular alterations, such as EGFR and ALK, who have asymptomatic but extensive brain metastases that would normally require WBRT, our groups will often favor a strategy of a CNS-active TKI alone with close clinical and brain MRI monitoring. In some cases, this strategy can lead to “downstaging,” where patients who previously may have required WBRT at presentation can subsequently undergo SRS to isolated deposits of residual disease. In patients who are candidates for upfront SRS, strategies instituting TKIs alone or TKI plus SRS may be reasonable, depending on the clinical scenario. However, early radiation or surgery is usually preferred for tumors that are: symptomatic; have poor prognostic characteristics such as larger size, significant edema, or impending mass effect; or are located in eloquent and higher-risk areas (e.g., in the brainstem or near optic pathways). In patients without targetable mutations, it is important to note that the response rates to immunotherapy are generally lower than those observed with CNS-active TKIs for targetable NSCLC mutations; thus, the threshold to forgo early radiation should be higher in these patients, and close monitoring remains imperative.

Multidisciplinary input and close monitoring are essential particularly when using systemic therapy alone upfront.

In the coming years, prospective trials are needed to assess the optimal timing of radiation for patients with brain metastases who are candidates for CNS-active systemic therapies, to determine whether SRS can be safely delayed without affecting neurocognitive function, quality of life, and survival. In the meantime, early local therapy for brain metastases remains the gold standard, and as such, multidisciplinary input and close monitoring are essential, particularly when using upfront systemic therapy alone. ✦

About the Authors: Dr. Amini is with the Department of Radiation Oncology, City of Hope National Medical Center. Dr. Rusthoven is an associate professor in the Department of Radiation Oncology at the University of Colorado Cancer Center.

References:
1. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698-2705.

2. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387-395.

3. Canadian Cancer Trials Group. Stereotactic radiosurgery compared with hippocampalavoidant whole brain radiotherapy (HA-WBRT) plus memantine for 5-15 brain metastases. https://clinicaltrials.gov/ct2/show/NCT03550391. Published June 8, 2018. Updated March 25, 2020. Accessed March 31, 2020.

4. Brown PD, Gondi V, Pugh S, et al. Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. 2020;38(10):1019-1029.

5. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50.

6. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.

7. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1- positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.

8. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051.

9. Goldberg SB, Gettinger SN, Mahajan A, et al. Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab. J Clin Oncol. 2018;36(suppl 15):2009.

10. Powell SF, Rodriguez Abreu D, Langer CJ, et al. Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: pooled analysis of KEYNOTE-021, 189, and 407. Ann Oncol. 2019;30(suppl 5):v602- v660.

11. National Cancer Institute. Firstline pembrolizumab alone or in combination with pemetrexed and carboplatin in induction/maintenance or postprogression in treating patients with stage IV non-squamous non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT03793179. Published January 4, 2019. Updated March 26, 2020. Accessed March 31, 2020.

12. Shepard MJ, Xu Z, Donahue J, et al. Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study. J Neurosurg. 2019;1-8.

13. Singh C, Qian JM, Yu JB, Chiang VL. Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases. J Neurosurg. 2019;132(2):512-517.

Utility and Controversies Surrounding Use of New Techniques in Radiotherapy

By Suresh Senan, MRCP, FRCR, PhD
Posted: December 2017

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
Posted: December 2017

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.

CONVERT: An International Randomized Trial of Concurrent Chemo-Radiotherapy Comparing Twice-Daily and Once-Daily Radiotherapy Schedules in Patients with Limited-Stage Small Cell Lung Cancer and Good Performance Status

Source: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30318-2/fulltext

By Prof. Corinne Faivre-Finn

The optimal timing and schedule of thoracic radiation in the management of limited-stage small cell lung cancer (LS-SCLC) continues to provoke debate. Since the publication of Intergroup 0096 in 1999, there had been controversy about the standard chemo-radiotherapy (cCTRT) regimen in LS-SCLC.1 Although twice-daily (BD) radiotherapy (RT) was associated with a higher survival compared to once-daily (OD) RT, concerns regarding toxicity (i.e., a third of the patients developing grade 3 or more esophagitis), together with logistical issues in the delivery of BD RT and criticism about the low dose of RT used in the control arm of Intergroup 0096, led to the limited adoption of this regimen in routine practice.2

The CONVERT trial is the first multicenter, international, randomized phase III trial aiming to establish a standard chemo-radiotherapy regimen in LS-SCLC. It is the largest-ever trial completed in this group of patients. We reported the trial results at the 2016 Annual Meeting of the American Society of Clinical Oncology.3

In CONVERT, patients with LS-SCLC were randomized 1:1 to receive either 45 Gy in 30-BD fractions over 3 weeks or 66 Gy in 33-OD fractions over 6.5 weeks, starting on day 22 of cycle 1 chemotherapy (four to six cycles of cisplatin and etoposide, according to investigator’s prespecified choice), followed by prophylactic cranial irradiation, if indicated. RT was planned using either 3-D conformal or intensity-modulated radiation therapy (IMRT). The primary endpoint of the study was 2-year survival and all analyses were by intention to treat. The study enrolled 547 patients recruited from 73 centers in seven European countries and Canada between 2008 and 2013.

Patient characteristics were well balanced in both arms of the study. Median age was 63 years (15% were older than 70 years), almost 50% were female, and the majority of patients had a performance status of 0 or 1 and were ex-smokers or current smokers.

At a median follow-up of 45 months, 2-year survival was 56% compared to 51%, and median overall survival was 30 months compared with 25 months in the BD RT and the OD RT arms, respectively, a difference that did not prove to be statistically significant. Furthermore, no statistically significant differences between the two groups were reported in terms of local or metastatic disease progression.

Acute toxicity rates were not significantly different between the two groups, with the exception of more neutropenia in patients treated with BD RT. Nor was there any difference in terms of acute esophagitis or pneumonitis. There was one death in the BD group and two in the OD group due to radiation pneumonitis. Few patients developed severe late toxicity.

In conclusion, OD RT did not result in a superior survival or worse toxicity than BD RT. The survival for both regimens was higher than previously reported, possibly due to more frequent PET/CT staging, and radiation toxicities were lower than expected, likely due to using modern RT techniques. The implications of CONVERT are important. The OD arm did not show superior survival as originally postulated. Because CONVERT was not an equivalency trial, the only study to date that has shown superiority for one RT regimen over another in LS-SCLC was the Intergroup 0096 trial; because there were no major differences in toxicity, 45 Gy in 30-BD fractions should continue to be regarded as standard of care. However, OD RT at a dose of 66 Gy in 33 fractions can certainly be considered an alternative regimen if 45 Gy in 30-BD fractions cannot be delivered due to patients’ choice, departmental logistics, or other factors.

References
1. Turrisi AT, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999; 340:265–271.

2. Komaki R, Khalid N, Langer CJ, et al. Penetration of recommended procedures for lung cancer staging and management in the United States over 10 years: a quality research in radiation oncology survey. Int J Radiat Oncol Biol Phys. 2013; 85:1082-1089.

3. Faivre-Finn C, Snee M, Ashcroft A, et al. CONVERT: An international randomised trial of concurrent chemo-radiotherapy (cCTRT) comparing twice-daily (BD) and once-daily (OD) radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status (PS). J Clin Oncol. 2016; 34 (15) suppl: 8504.

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