By Cynthia L. Kryder, MS, CCC-Sp
Posted: October 2017

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.

By Leah Lawrence

Posted: June 2018

The use of trimodality therapy—the combination of chemoradiotherapy followed by surgery—remains controversial for patients with locally advanced cN2-N3 NSCLC.

According to the National Comprehensive Cancer Network guidelines, definitive chemoradiation therapy is the standard of care for the majority of patients with stage III NSCLC, and trimodality treatment is used only in selected patients with minimal N2 disease.

Results of the Intergroup 0139 study, one of the first randomized studies of concurrent chemoradiotherapy and trimodality approaches, showed that the 5-year progression-free survival was improved in patients who underwent trimodality treatment compared with bimodality therapy alone (hazard ratio = 0.77; 95% CI[0.62, 0.96]); however, this benefit did not translate into an overall survival advantage.¹

“In a subset analysis of the study, they showed that patients who underwent a lobectomy did have a survival benefit with trimodality treatment, but this was an unplanned analysis,” said Melissa A.L. Vyfhuis, MD, PhD, of the University of Maryland Medical Center.

The lack of overall survival benefit may have, in part, been due to the trial’s high mortality rate seen with pneumonectomies. Furthermore, in the trial, they used a lower radiation dose of 45 Gy prior to surgical resection to offset the chance of an increase risk in morbidity or mortality associated with higher doses, according to Dr. Vyfhuis. “In the setting of stage III disease, we now know that [45 Gy] is not sufficient for cure,” Dr. Vyfhuis said. Practically speaking, if the tumor is deemed not resectable after such a low dose of radiation, then the patient would have to go back and receive additional radiation therapy, but now having sustained a significant break (typically 1 to 2 weeks) in their radiation treatments, which could affect clinical outcomes.

According to Dr. Vyfhuis, at the University of Maryland, she and her colleagues give a definitive dose of radiation (≥ 60 Gy) with concurrent chemotherapy, even if a patient was scheduled to undergo surgery; however, she acknowledged that not a lot of institutions routinely offer this dose as part of trimodality therapy.

“At University of Maryland, our surgeons have extensive experience operating on patients after the administration of a definitive dose (≥ 60 Gy) of radiation. This has resulted in low rates of postsurgical morbidity and mortality, especially for those patients undergoing a lobectomy,” Dr. Vyfhuis explained.

Dr. Vyfhuis and colleagues recently published the results of a study that showed that trimodality treatment with a radiation dose of at least 60 Gy significantly improved survival and freedom from recurrence in patients with locally advanced NSCLC.²

In our experience, patients who attain mediastinal nodal clearance after neoadjuvant chemoradiation, no matter how bulky or extensive the disease was initially, can benefit from trimodality therapy.
–Melissa A.L. Vyfhuis, MD, PhD

The retrospective analysis included data from 355 consecutive patients with locally advanced NSCLC treated with curative intent between January 2000 and December 2013. Those patients who received trimodality therapy had a significantly longer median survival compared with patients with either unplanned or planned bimodality treatment (59.9 vs. 20.1 vs. 17.3 months, respectively; p < 0.001). The addition of surgery also benefited patients with stage IIIb (p < 0.001) and N3 (p = 0.010) nodal disease, especially when mediastinal nodal clearance was achieved.

“A median survival of approximately 60 months is essentially unheard of in stage III disease,” Dr. Vyfhuis said, adding that as a retrospective study some selection bias may be present. “In our experience, patients who attain mediastinal nodal clearance after neoadjuvant chemoradiation, no matter how bulky or extensive the disease was initially, can benefit from trimodality therapy.”

How Does It Fit?
The current standard of care for patients with stage III NSCLC may soon be changing however, according to Martin J. Edelman, MD, chair of the department of hematology/oncology at Fox Chase Cancer Center, and formerly of the University of Maryland Greenebaum Comprehensive Cancer Center.

In 2017, results of the phase III PACIFIC trial showed that the administration of the anti–PD-1 antibody durvalumab after definitive chemoradiotherapy more than tripled the median progression-free survival compared with chemoradiotherapy followed by placebo (16.8 vs. 5.6 months; p < 0.001).³ The results were presented at the 2017 European Society for Medical Oncology Congress and published in The New England Journal of Medicine. Based on these results, the standard of care today for a patient with locally advanced NSCLC is chemoradiotherapy followed by immunotherapy, according to Dr. Edelman.

“The trial was done predominantly in Europe, a little bit differently than we might have done it in the United States, but results were impressive,” Dr. Edelman said. “We do not yet have overall survival results, but I would be surprised if they do not echo the substantial improvements in progression-free survival that was published.”

The integration of immunotherapy into treatment regimens for patients with stage III disease only further complicates matters. Many questions remain, Dr. Edelman said.

“We still do not know the optimal chemotherapy regimen to use in combination with radiation,” Dr. Edelman said.“We feel following chemoradiotherapy with immunotherapy is good, but do not know if immunotherapy should follow immediately.”

Trimodality care should be restricted to experienced institutions that have high volume and an experienced multimodality team.
–Martin J. Edelman, MD

With so many questions remaining about bimodality therapy, it is hard to know where surgery would fit in.

According to Dr. Edelman, an ideal candidate for trimodality treatment would be someone who is relatively fit, with an otherwise good performance status. Ideally, the patient would require a lobectomy and not a pneumonectomy or another type of complex procedure, and would have mediastinal nodal disease that is not bulky. “Those patients in the correct hands should have a very low operative mortality,” Dr. Edelman said. However, outside of these situations, the standard of care remains bimodality therapy, he added.

“The problem with trimodality studies is how one integrates all three modes of treatment is very difficult, and each study has to be evaluated by itself because no two of them held all features constant,” Dr. Edelman explained.

When he was at the University of Maryland, using a radiation dose of 60 Gy with chemotherapy was feasible. If a patient did not go on to surgery, this meant that the proper definitive radiation dose had been administered. However, this approach may not be feasible in all institutions.

“Trimodality care should be restricted to experienced institutions that have high volume and an experienced multimodality team,” Dr. Edelman said. “Patients who are felt to be suitable for this treatment should be selected prior to initiation of any treatment.” ✦

References:
1. Albain KS, Swann RS, Rusch VR, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small cell lung cancer. Lancet. 2009;374:379-386.
2. Vyfh uis MAL, Bhooshan N, Burrows WM, et al. Oncological outcomes from trimodality therapy receiving definitive doses of neoadjuvant chemoradiation (≥60 Gy) and factors influencing consideration for surgery in stage III non-small cell lung cancer. Adv Radiat Oncol. 2017;2:259-269.
3. Antonio SJ, Villegas, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer. N Engl J Med. 2017;377:1919-1929.

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.

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].

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.

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.

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