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

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Living in the “Gray Zone”: Entering a New Age in Radiation Therapy for Patients with Lung Cancer

Fig. 1. Clinical Case: Stage IIIB NSCLC
The top panel of Figure 1 shows radiation dose distribution overlaying CT imaging of a patient with stage III NSCLC treated with 60 Gy VMAT technique, compared to the lower panel showing the same 60 Gy with proton technique. There is higher dose to the contralateral lung and heart, with a comparison DVH shown on the far right.

Posted: October 2018

Patients with stage III or more advanced lung cancer tend to be older and less healthy than patients with other stage III cancers. Because of this, selection of optimal therapies for individual patients, including stereotactic body radiation therapy (SBRT), is more nuanced. With the advent of improvements in technology, more multidisciplinary approaches to decision making, and changing recommendations on fractionation, numerous factors influence radiation therapy selection and delivery often in the absence of an abundance of data. In addition, the rapid addition of immunotherapy in locally advanced NSCLC has resulted in even more questions and potential for rapid change in best practices.

Dr. Kristin Higgins

In the following interview, Kristin Higgins, MD, associate professor and medical director of radiation oncology of The Emory Clinic at Winship Cancer Institute’s Clift on campus, explains her approaches to therapeutic decision making and provides an overview of the state of the art in radiation oncology technology.

Multidisciplinary Care for Patients with Early-Stage Disease
The current standard of care for early-stage NSCLC is surgical resection. However, many patients aren’t optimal surgical candidates, whether it’s because of damage to their lungs from years of smoking, risks associated with anesthesia, or potential perceived postoperative toxicities. These patients live in a gray zone of sorts. They are clearly not surgical candidates, and for them, the standard of care is sterotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR). There are often disagreements across subspecialties about nodule management for these patients because no trials that directly compare surgery with SBRT have met their accrual goals, many closing early or prematurely. The ongoing Veterans Aff airs Lung Cancer or Stereotactic Radiotherapy (VALOR) trial within the Veterans Affairs system is comparing SBRT with surgery for a high-risk population, but this is not open to patients who do not have a military service history.

In the meantime, we base our decisions for this high-risk population on the data we have available to us and on the best interest of the patient. More often, we’re trying to involve the patient in a multidisciplinary discussion that involves the surgeon, the radiation oncologist, and the medical oncologist so that the patient can hear the pros and cons for each potential treatment scenario and can participate in decision making. I think this shared approach is a good way to determine appropriate therapy for each individual patient when there is no black or white answer.

Treating Stage III Disease
The average age of a patient at lung cancer diagnosis is 70,1 which means that decisions regarding concurrent therapy should not be based solely on age. It’s important that decision making about combined modality treatment is a thoughtful process that involves geriatricians in the evaluation of candidacy, especially because the management of the side effects from combined-modality therapy has so drastically improved over time. If you look at RTOG 0617 for example, the rates of high-grade pneumonitis and esophagitis were only approximately 7% in the standard-dose arm,2 which was a decrease from the approximately 15% to 20% or higher rates observed in the first generation of combined modality trials for stage III lung cancer.3

There is great interest in immunotherapy and combination immunotherapy/radiation clinical trials for lung cancer, especially in the locally advanced setting. The standard of care has really shifted and now includes consolidated immunotherapy for stage III disease based on the positive PFS results of the phase III PACIFIC trial which, as presented at the 19th World Conference on Lung Cancer in September, also demonstrated a highly significant OS advantage. However, despite the emergence of immunotherapy in stage III NSCLC, a lot of questions remain. How do you approach immunotherapy in an elderly patient, for example, who may not be a candidate for combined- modality treatment? We’ve seen exciting results with immunotherapy given in the consolidative setting, but can it be moved into the concurrent setting? What is the optimal radiation dose/fractionation regimen to use with immunotherapy? There are developing clinical trials designed to answer these and other emerging questions around immunotherapy and locally advanced NSCLC.

Proton Therapy’s Unproven Benefits
Proton therapy is being more widely used in the management of many cancers throughout the United States, with more and more proton centers coming online. The randomized phase III NRG 1308 trial (NCT01993810) is evaluating proton versus photon therapy for unresectable stage II and III NSCLC. The study design has recently been revised to include co-primary endpoints of overall survival, development of grade 2 or greater cardiac toxicity, and grade 4 or greater lymphopenias. RTOG 0617 demonstrated that a higher dose of radiation led to decreased survival. Importantly, this study also showed that when the radiation dose to the heart increased, there was a greater risk of mortality.2 With lung cancer, radiation dose to the heart is an obvious concern given the close proximity of lung tumors to cardiac structures. Using protons in stage III lung cancer makes a lot of sense from that standpoint because you can deliver an adequate dose to the tumor but decrease the bystander radiation dose to the heart, which cannot be done as well with standard photon techniques including intensity modulated radiation therapy (IMRT).

Until we see the results of this trial, however, I think that proton therapy should still be used wisely in patients in a clinical trial, which is really the best way to explore this technology.

Clinical Trials Versus the Real Word: Technology Must Be Biology Driven
In radiation oncology, we are technologically driven. We try to use our technologies to make our therapy more precise and accurate, but it is important to remember that these costly improvements must be clinically meaningful. Applications of technologies must lead to improvements in meaningful outcomes for our patients, such as reduced side effects, improved quality of life, and, of course, improved survival. To tackle some of these challenges, next-generation linear accelerators are being developed. They are more costly than standard linear accelerators, but they offer features such as built-in MRI, which allows tumor imaging in real time as the radiation beam is being directed at the tumor. One such accelerator, marketed by ViewRay, has been approved by the U.S. Food and Drug Administration (FDA). There’s also a next-generation machine, which is not yet FDA approved, that combines a linear accelerator with PET and can yield biologically guided radiation therapy, in which the photon beam is sent from the linear accelerator directly to the PET signal within the tumor.

The use of these next-generation machines could be advantageous in that you can potentially dose escalate tumors that are near critical organs because you can see the organs in real time and adapt the radiation to the exact anatomy of the patient at the time of treatment. Th is is especially helpful in pancreatic cancers, for example, and these machines are being used in prospective clinical trials. For lung cancer, this newer technology would potentially allow us to better target tumors during the respiratory cycle and to more safely dose escalate or treat multiple sites of metastatic disease simultaneously.

In addition to using trial data to prove that technologic improvements result in improved patient care, it is also important that we design radiation trials so that they are reflective of a real-world population. Future trials should be framed around the typical patient with lung cancer—elderly and often with a comorbid conditions, such as heart disease or diabetes—because, otherwise, we won’t be able to translate our findings from clinical trials with stricter inclusion criteria into real-world care.

Palliative Radiation SBRT
The American Society for Radiation Oncology consensus guideline for palliative thoracic radiation therapy for NSCLC recommends a longer course of 30-42 Gy delivered at 2.8-3 Gy per day fractions if the patient has a preserved performance status in order to achieve durable tumor control; however, many patients have performance statuses that fluctuate.4 There are clinical situations where shortened courses of one to five fractions are the best option in highly symptomatic patients. Additionally, when treating metastatic disease—particularly bone metastases—clinical trials have shown no difference in pain reduction with single fraction versus more prolonged treatment courses. The utilization of single-fraction treatments for palliation has been more slowly adopted in the United States, compared with Europe for example, for unclear reasons. I think we should base our decisions on individual patient presentations.

We are using SBRT more frequently for patients with stage IV disease to try to improve progression-free survival based on multiple studies showing improvement in this endpoint. NRG LU002 (NCT03137771) is examining administration of SBRT to the primary and metastatic sites of disease after first-line chemotherapy or immunotherapy, using a hypofractionated approach. I think stage IV palliative radiation therapy is becoming more nuanced than palliative radiation therapy for other disease stages because we are using ablative fractionation regimens to achieve local control of the primary and distant disease sites, if they’re limited, which has been a real change in the field for stage IV lung cancer. As our patients are living longer with more effective systemic therapies, there may be more of a role for radiation to local sites of disease. The data from NRG LU002 and other trials will help us make these determinations.

Immunotherapy and Early-Stage Disease
There are also trials being designed to examine whether immunotherapy after SBRT or SBRT alone is better for patients with early-stage disease who are not surgical candidates. These studies may help to further improve the outcomes of patients who are medically inoperable. Also, there are single institutions at large academic centers that are evaluating the optimal timing of immunotherapy, the optimal radiation therapy fractionation regimen, and biomarkers for the optimal selection of patients who receive immunotherapy with radiation. Overall, this is an amazingly exciting time for thoracic radiation oncologists. Through innovation and collaboration, we’ve made quite a bit of progress in the treatment of lung cancer with radiation therapy, but the field awaits continued improvements. We are certainly on the right track and hope that we can continue to improve the lives of our patients with lung cancer. ✦

References:
1. American Cancer Society. Key Statistics for Lung Cancer. https://www.cancer.org/cancer/ small-cell-lung-cancer/about/key-statistics.html. Accessed July 20, 2018.

2. 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.

3. Curran WJ, Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103(19):1452-1460.

4. Moeller B, Balagamwala EH, Chen A, et al. Palliative thoracic radiation therapy for nonsmall cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. Practical Radiation Oncology. [Epub ahead of print April 2018].

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

By Shalini K. Vinod, MBBS, MD

Posted: October 2018

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.

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
Posted: December 2018

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

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.

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