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A. Frobe

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    YI02 - Basics of Radio-Oncology (ID 406)

    • Event: WCLC 2016
    • Type: Young Investigator Session
    • Track: Radiotherapy
    • Presentations: 1
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      YI02.03 - Dose Limitations for Radiotherapy of Lung Cancer (ID 6912)

      14:30 - 15:45  |  Author(s): A. Frobe

      • Abstract
      • Presentation
      • Slides

      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 2. Small Cell Lung Cancer Treatment (PDQ®) - Health Professional Version. Available from 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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