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.
By CynthiaL.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.
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
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.” ✦
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. ✦