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Abstract:
As technology has advanced, modern radiotherapy (RT) techniques, such as conformal radiotherapy (CRT), intensity-modulated radiation therapy (IMRT), and proton therapy (PT), have become available. In this session, the advantages of these techniques in the treatment of early-stage and locally-advanced lung cancer will be presented, along with their uncertainties. Conformal RT uses CT scans to create 3-dimensional images of the tumor and normal tissues, which leads to more accurate treatment planning. It also uses multiple radiation beams from various angles to concentrate the radiation dose to the tumor while reducing the dose to normal tissues. Furthermore, conformal RT improves tumor control and reduces toxicity compared to 2-dimensional RT (1). IMRT is a sophisticated form of CRT, which enables us to more exactly concentrate and shape the dose distribution to the tumor and spare normal tissues. It can also partially intensify doses to individual areas deemed to be more aggressive or radioresistant. PT uses charged particles, which have a unique physical characteristic called the Bragg peak. The Bragg peak describes a certain tissue depth at which the protons stop just after transferring most of their energy. This feature is particularly convenient for tumors located close to critical normal tissues. PT is commonly adopted for pediatric, central nervous system, and intraocular malignancies. Stereotactic body radiation therapy (SBRT), also called stereotactic ablative radiation therapy (SABR), is characterized by accurate target definition, precise tumor positioning, steep dose gradients outside targets, and very high dose per fraction. SBRT can be delivered using either CRT or IMRT. In the treatment of peripheral early-stage lung cancer, SBRT is widely adopted as a standard treatment and is considered better than conventional fractionated RT. PT can also be used in this setting, despite similar outcomes as SBRT (2); however, a recent systematic review of cost-effectiveness analyses did not support the use of PT (3). To improve outcomes in locally-advanced lung cancer, IMRT and PT have been actively investigated. Several in silico studies have suggested the superiority of IMRT over CRT, and PT over IMRT, but this remains to be demonstrated clinically. Subgroup analyses of RTOG 0617, which compared a high dose (74 Gy) vs. a standard dose (60 Gy) and allowed both CRT and IMRT, showed similar efficacy, less radiation pneumonitis, and better compliance of consolidative chemotherapy favoring IMRT over CRT, despite there being more advanced cases in the IMRT group (4). The study authors generated a hypothesis that dose intensification by IMRT may result in better efficacy with less toxicity. However, we could not determine the true difference between IMRT and CRT among patients who received the standard dose, which is our current practice, because their analysis included both high- and standard-dose arms; the differences might be more prominent in the high-dose arm. These investigators also suggested that increasing the radiation dose to the heart may worsen survival, so dose constraints to the heart became stricter thereafter. Results of a Bayesian phase II randomized trial of IMRT vs. PT were reported at the ASCO Annual Meeting earlier this year (5). The primary endpoint was incidence and time to protocol failure, defined as Grade 3 or higher pneumonitis or local failure. The observed local failure rates at 12 months were similar (13% vs. 12%). The investigators assumed Grade 3 or higher pneumonitis of 15% in the IMRT arm and 5% in the PT arm; however, they observed 6.5% in the IMRT arm, which was lower than the assumed probability, and 10.5% in the PT arm, higher than expected. Because this was a phase II trial with some limitations, firm conclusions could not be drawn. However, PT failed to suggest a clinical benefit over IMRT. A meta-analysis of the phase III trials conducted by the Radiation Therapy Oncology Group between 1968 and 2002 showed that new treatments were demonstrated to be better than existing ones in only 6 of 59 comparisons. In addition, overall survival of all of the accrued patients did not differ between groups, while the odds ratio of 1.76 for treatment-related death was significantly higher for the new treatments (6). These results clearly showed that “New is not always better.” We need to identify the subpopulations for whom new techniques are more effective and to demonstrate these have true value with scientifically strong evidence, instead of just believing in their efficacy, complaining about the challenges associated with evaluating them, or advertising them directly to patients. Figure 1 References 1. Chen AB, Neville BA, Sher DJ, et al. Survival outcomes after radiation therapy for stage III non-small-cell lung cancer after adoption of computed tomography-based simulation. J Clin Oncol 2011;29:2305-2311 2. Grutters JP, Kessels AG, Pijls-Johannesma M, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol 2010;95:32-40 3. Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer 2016;122:1483-1501 4. Chun SG, Hu C, Choy H, et al. Outcomes of intensity modulated and 3D-conformal radiotherapy for stage III non-small cell lung cancer in NRG Oncology/RTOG 0617. J Thorac Oncol 2015;10:S213 5. Liao ZX, Lee JJ, Komaki R, 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; abstr 8500) 6. Soares HP, Kumar A, Daniels S, et al. Evaluation of new treatments in radiation oncology: are they better than standard treatments? JAMA 2005;293:970-978

Abstract:
Lung cancer is the most frequent cancer and the leading cause of cancer mortality. Lung cancer treatment results in terms of patients' long-term survival and cure are far from ideal. Radiotherapy as one of the lung cancer standard treatment modalities can be applied with curative or palliative intent. Radiotherapy treatment intent depends on tumor extent (disease stage), tumor location, patient’s performance status and comorbidities, availability of modern radiotherapy treatment machines and their technical and software capabilities (1-4). Radiotherapy with curative intent is indicated as an alternative to surgical treatment in patients having the early stage disease (generally stages I and II) or a locally more advanced disease (stage III). In early stage disease patients, which are the group with the best prognosis, radiotherapy can be applied as, for example, the sole treatment modality in the form of hypofractioned stereotactic ablative radiotherapy (SABR) for patients with lymph node-negative peripheral non-small cell lung cancer (NSCLC). For patients having inoperable locally advanced lung cancer (stage III) the five-year overall survival rate is at around 15-20%. Therefore, the two remaining standard treatment modalities, chemotherapy and radiotherapy with curative intent, are used and combined whenever possible. Concomitant chemoradiotherapy is the treatment of choice since it gives better results, but in practice a significant number of patients is not fit for this approach. Therefore, the alternative in unfit patients is sequential chemoradiotherapy or radiotherapy alone. In patients having concomitant chemoradiotherapy there are no results in favour of induction or consolidation chemotherapy. It might be that a novel immunotherapy approach with anti-PD-1 or anti-PD-L1 inhibition will in the future improve the survival rate of this group of patients and patients with the metastatic disease (1-4). The effectiveness of radiotherapy depends on the total radiation dose being delivered accurately. For most tumors there is a dose-response effect, i.e. the higher the dose, the higher the chance of local tumor control and cure. The first trial that in the case of lung cancer demonstrated this relationship was published by Perez et al (RTOG 71-01 trial) (5). In this dose escalation trial, the dose of 60 Gy in comparison with the dose of 50 and 40 Gy was found, evaluated clinically, to have a lower incidence of local failures (33% versus 39% versus 44% to 49%). The survival of patients according to treatment regimen was not statistically significantly different. The one-year and two-year survival rates for all groups were, respectively, 45% and 25%. On the basis of this trial the dose of 60 Gy in 30 fractions (60 Gy/30x) or higher has since that time been the optimal standard radiotherapy treatment, although patient outcomes were objectively very poor. It should be mentioned that from today's perspective the radiotherapy techniques that were then used (2D radiotherapy planning and relatively large tumor/target volumes) are not recommendable nowadays in radiotherapy treatments with curative intent (3,4). The objectively unsatisfactory clinical outcomes in terms of local tumor control, progression free survival (PFS) and overall survival (OS) after radiotherapy +/- chemotherapy treatments are probably the consequence of the inadequate radiation dose to the tumor tissue. However, the usage of higher doses is limited by the radiation tolerance of surrounding normal tissues and organs (3,4). In clinical radiotherapy, the radiation tolerance of normal tissues and organs surrounding the tumor limits the radiotherapy dose that can be given safely. As the dose is increased, the incidence and severity of normal tissue damage rises. When severe, normal tissue damage can produce life threatening morbidities. Multiple parameters such as total radiation dose, fraction size, overall treatment time, volume and type of normal tissues to be irradiated, definition of target volume, and quality control of radiotherapy techniques should be taken into account. A reduction of radiotherapy-related toxicity is fundamental to the improvement of clinical results in lung cancer as well as other types of cancers. Organs at risk of lung cancer radiotherapy include the lungs, heart, spinal cord, and esophagus. Present knowledge of radiation toxicity is derived from conventional and newer 3D-conformal radiotherapy (3D-CRT) data. The QUANTEC project (6) produced data that are currently used to predict the side effects of radiotherapy and the plausibility of evaluated treatment plans. Before being approved all radiotherapy treatment plans have to be evaluated for the probability of organ-specific radiation toxicity (3,4). Thanks to the evolving radiation imaging and computer technology, a number of innovations in radiotherapy have been introduced in radiotherapy practice within the several past decades. Conventional 2D treatment simulation has been replaced with computer tomography (CT) planning, with volumes delineated according to the International Commission on Radiation Units and Measurements (ICRU) report and ICRU supplements. This CT-based planning together with the possible implementation of other imaging methods such as PET/CT and MRI have enabled more precise target borders and volume determination with the consequence of radiotherapy treatment plans having better tumor dose conformity and sparing the surrounding normal tissues (3,4). Due to a better delineation of tumor margins and reduced rates of radiation-associated toxicity, the current standard radiation treatments based on the implementation of these various technical and technological advances in radiation planning and delivery have allowed the design of clinical studies with radiotherapy dose escalations and modified fractionation schemes. The goal of radiation treatment is to improve clinical outcomes while reducing the damage to the normal tissues. Newer radiotherapy equipment, techniques and treatment planning software can, due to a better delineation of tumor margins and reduced rates of radiation-associated toxicity, allow tumor dose escalation to improve local control and possible tumor cure. Improvements in radiotherapy technique are achieved by using functional images for target definition (PET/CT), 4D-computed tomography (4D-CT), intensity modulated radiation therapy (IMRT) and adaptive radiotherapy. (3,4) Several studies have shown a better response with dose escalation in NSCLC. Doses of up to 74 Gy can be delivered when normal tissue constraints are considered. The phase I/II RTOG 9311 trial reported the outcome of a dose-escalated 3D conformal radiotherapy in stage I-III NSCLCs stratified at escalation dose level according to parameters V20 Gy (percentage of the total lung volume that received > 20 Gy). The results of this trial showed that radiation dose escalation was considered safe when using 3D conformal techniques to 83.8 Gy in patients with a V20 < 25% and 77.4 Gy in patients with V20 between 25 and 36% (7). In the RTOG 0617 trial two schedules were compared: 60 Gy (in 6 weeks) versus 74 Gy (in 7.5 weeks) in a 2×2 design where patients were also randomized to receive or not receive cetuximab. Surprisingly, the higher dose arm was not associated with improved survival at 1 year but, rather, showed a contrary trend. The trial showed an OS of 28.7 months for patients who received standard dose radiotherapy compared with 20.3 months for those who received high dose radiotherapy. Median survival in patients who received cetuximab was 21.3 months compared to 24.0 months in those who did not receive cetuximab (p = .29) (8). The use of IMRT allows clinicians to obtain better radiotherapy planning parameters such as V20 and mean lung dose and to reduce the probability of development of lung toxicity - radiation pneumonitis. As reported in literature, V20 values of 35–37% and the MLD value of 20–23 Gy have been considered safe but 10–15% of patients can still develop a severe radiation pneumonitis when lower doses are delivered (9). The concomitant use of chemotherapy with radiotherapy can achieve a better overall response, albeit with an increased number of treatment related toxicities – esophagitis and pneumonitis in 10 to 40% of patients (7-9). The use of radiotherapy after chemotherapy with delivered escalated doses of 74 Gy and 86 Gy is associated with a higher incidence of bronchial stenosis (4% and 25%, respectively) and can increase when radiotherapy is used concurrently with chemotherapy. For patients with a locally advanced NSCLC stereotactic ablative radiation treatment (SABR) can be used as a boost to the primary parenchymal lesion. SABR treatment was added after the conventional chemo-radiation (60 Gy/ 30 fractions) treatment: the prescription dose varied from 10 Gy in 2 fractions in peripheral lesion to 6.5 Gy in 3 fractions in the central tumors. After a median follow-up of 13 months local control was 82.9% and there were no patients with a radiation pneumonitis grade 4 or 5 (10). Proton therapy is a new potential therapeutic approach to the treatment of NSCLC. Protons have the potential role of reducing the dose to the normal tissue, in particular to the lung and the heart. Initial studies have demonstrated that in patients receiving a concomitant treatment of chemo-radiotherapy the overall survival is influenced by the mean dose to the heart and the lung (3,4,11). As previously described, the univariate and multivariate analysis of RTOG 0617 demonstrated that lung V5, heart V5 and heart V30 were considered predictors of OS. Intraluminal (IL) high-dose rate (HDR) brachytherapy, as the exclusive conformal brachytherapy technique, avoids the previously mentioned dose constraints and could be applied in highly selective cases with significant predominantly endobronchial or endotracheal tumors as a ¨boost” of 10-15 Gy after external beam radiation therapy (EBRT) (60 Gy/30 fractions) or in a palliative setting in recurrent tumors after EBRT in various fractionation schemes according to the American Brachytherapy Society (ABS): 10-15 Gy in one fraction or IL high-dose rate (HDR) alone 22,5 Gy/3 fractions, 24Gy/4 fractions, 30 Gy/6 fractions. Brachytherapy is recommended if there is a collapsed lung at the first presentation because of improved re-expansion rates using IL HDR over EBRT (4,12,13). In conclusion, remarkable technological advances in the planning and delivery of radiotherapy allows us to do more, which raises hopes that this will be translated into improved clinical outcomes for patients having lung cancer. References: 1. Non-Small Cell Lung Cancer Treatment (PDQ®) - Health Professional Version. Available from https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq 2. Small Cell Lung Cancer Treatment (PDQ®) - Health Professional Version. Available from https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq 3. Baker S et al. Radiat Oncol. 2016;11:115. doi: 10.1186/s13014-016-0693-8. 4. Giaj-Levra N et al. Cancer Invest. 2016;34:80-93. doi: 10.3109/07357907.2015.1114121. 5. Perez CA et al. Cancer. 1980;45:2744-53. 6. Marks LB et al. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S70-6. doi: 10.1016/j.ijrobp.2009.06.091. 7. Bradley J et al. Int J Radiat Oncol Biol Phys 2005;61:318–28. 8. Bradley JD et al. Lancet Oncol. 2015;16:187-99. doi: 10.1016/S1470-2045(14)71207-0. 9. Graham MV et al. Int J Radiat Oncol Biol Phys 1999;45:323–9. 10. Feddock J et al. Int J Radiat Oncol Biol Phys 2013;8:1325–31. 11. Oshiro Y et al. J Radiat Res 2014;55:959–65. 12. Stewart A et al. Brachytherapy, 2016:15:1-11. 13. Langendijk H et al.. Radiother Oncol 2001; 58: 257–68.

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