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

Utility and Controversies Surrounding Use of New Techniques in Radiotherapy

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

Improved delivery of radiotherapy has contributed to the recent changes in guidelines for patients with lung cancer. The clinical impact of some technical advances has been modest, but the cumulative effect of many developments has led to more precise treatment delivery, and has increased the confidence of clinicians to adopt new techniques. The impact of new technology is best illustrated by referring to selected clinical stages.

Early-stage Peripheral NSCLC

The poster child of new technology is image-guided stereotactic ablative radiotherapy (SABR or SBRT), which is a technique for delivering high-dose, high-precision radiation. In early-stage peripheral non-small cell lung cancer (NSCLC), 5-year in-field tumor control rates of 90% have been reported, and the introduction of SABR has been associated with improved cure rates at the population level. The superiority of SABR over conventional radiotherapy has been established in two randomized trials, results from one of which was presented at the IASLC 18th World Conference on Lung Cancer [Ball D, WCLC 2017]. SABR resulted in superior freedom from local failure (HR = 0.29, 95% CI 0.130, 0.662, P=0.002) and also longer overall survival (HR = 0.51, 95% CI 0.51, 0.911, P=0.020).

Minimal requirements for SABR planning and delivery were recently published by the European Society for Radiotherapy and Oncology, and include use of 4-D planning computed tomography (CT) scan and a standard linear accelerator with a cone-beam CT scan. Newer developments include the clinical introduction of magnetic resonance imaging-guided SABR, which is undergoing evaluation in high-risk tumors such as centrally located NSCLC. The use of protons (charged particles) was considered previously to be a promising development for treating lung tumors, due to its ability to decrease radiation doses to surrounding organs. However, the options for managing tumor motion at current proton centers is generally inferior to that available on a standard linear accelerator. At present, there are limited prospective data supporting a role for protons in early-stage NSCLC.

Locally Advanced Lung Cancer

Since the introduction of CT-based treatment planning and improved set-up protocols, concurrent chemo-radiation (CT-RT) has become established as the standard of care for most fit patients who present with locally-advanced NSCLC. Patients undergoing standard concurrent CT-RT to 60 Gy in the RTOG 0617, study achieved 5-year overall and progression free rates of 32% and 18%, respectively.1 The median overall survival of 28.7 months in this trial has also established a new benchmark. The role of intensity modulated radiotherapy (IMRT) remains a topic of debate, particularly as population studies suggest that benefits of IMRT are limited to larger central (T3-4) tumors. Results of RTOG 0617 support use of IMRT in locally-advanced NSCLC as this reduces rates of radiation pneumonitis, and was associated with a better quality of life in the first 12 months post CT-RT.

Some, but not all studies, suggested that delivery of higher radiation doses to the heart are associated with a poorer overall survival. However, other studies suggest that delivered heart doses may be a surrogate for other prognostic factors in stage III NSCLC, such as the extent and location of mediastinal nodal involvement, especially subcarinal nodes, rather than an independent predictor of outcome. The increased cardiac toxicity has also been correlated with the use of doses higher than the standard 60 Gy for CT-RT, and with schemes using non-standard fractionation schemes (>2 Gy, once daily).

Proponents of proton radiation have therefore advocated its use as a means to decrease both lung and cardiac toxicity. The number of proton centers worldwide is increasing in a roughly exponential fashion, with approximately 20 operating centers, and 53 in development. However, little consensus has been reached for using proton therapy for common types of cancer in adults. A prospective randomized trial led by the MD Anderson Cancer Center compared the use of IMRT versus proton therapy in locally advanced NSCLC, and reported no differences in treatment failures, which were defined as either grade ≥3 pneumonitis or local failure at 1 year.2 Proponents of protons have argued that the use of a newer delivery technique (intensity-modulated proton therapy) will improve outcomes, and the results of ongoing comparative trials are awaited. Treatment of mobile tumors in the lung and liver using protons remains a challenge, and only a minority (27%) of European proton and carbon ion therapy centers currently treat such tumors.3

Changing Paradigms in Locally Advanced Lung Cancer

The published results of the PACIFIC trial have called into question the previous focus on delivery of ever higher radiation doses. PACIFIC evaluated consolidation durvalumab or placebo every 2 weeks for a year, following CT-RT in patients with unselected stage III NSCLC after concurrent CT-RT to a dose of 54-66 Gy.4 Consolidation durvalumab resulted in an increase in median PFS to 16.8 versus 5.6 months (HR 0.52) with the differences in PFS sustained at 12- and 18-month landmarks. Durvalumab also resulted in a superior median time to death or distant metastases (23.2 vs 14.6 months; P < .001), and little increase in grade 3/4 treatment related toxicity. The above findings indicate that the addition of durvalumab consolidation to standard radiation doses combined with two cycles of platinum-containing chemotherapy, is sufficient to improve both local and distant tumor control. This, in turn, raises the question whether the focus of radiation research should simply be to limit radiation doses to 60 Gy, while further optimizing the integration of immune-oncology and other systemic approaches into CT-RT of stage III NSCLC. ✦

1. Bradley JD, Hu C, Komak RU, et al. Long-term results of RTOG 0617: A randomized phase 3 comparison of standard dose versus high dose conformal chemoradiation therapy +/- cetuximab for stage III NSCLC. J Am Coll Radiol. 2017:99, S105 (suppl)
2. Liao Z, Lee J, Komaki R, Gomez D, O’Reilly M, Allen P, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol. 2016;34 suppl 15:8500.
3. Weber DC, Abrunhosa-Branquinho A, Bolsi A, et al. Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire. Radiother Oncol. 2017;124:185-189.
4. Scott J. Antonia SJ, Villegas A, Davey Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017 Sep 8. doi: 10.1056/ NEJMoa1709937. [Epub ahead of print]

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

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

By Cynthia L. Kryder, MS, CCC-Sp
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


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.

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

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

By Prof. Corinne Faivre-Finn

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

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

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

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

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

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

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

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

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

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

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