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S. Senan



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    E08 - Early Endobronchial Tumours (ID 8)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      E08.4 - RT Approaches for Early Stage Central Tumours (ID 411)

      15:05 - 15:25  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract
      Stereotactic ablative radiotherapy (SABR) is an established treatment modality in the curative treatment of early stage peripheral non-small cell lung cancer (NSCLC). The local control rates of SABR in many publications have exceeded 90% when tumors of up to 5 cm were treated, with corresponding regional nodal failure rates of approximately 10%. SABR has been reported in many series to have only modest early and late toxicity, generally maintaining pulmonary function and preserving health-related quality of life. Following the publication of an phase II study, which showed an 11-fold increase in severe toxicity in the subgroup of patients with centrally located lung tumors that had been treated with a high dose per fraction, these central locations had been considered to be a ‘no fly zone’ for SABR [Timmerman 2006]. Although several subsequent single center studies have shown that SABR performed with an adapted fractionation scheme using daily fractions of 6.0–7.5 Gy to total doses of 48–60 Gy has been both effective and safe, the results of the ongoing Radiation Therapy Oncology Group (RTOG) phase II trial (0813) for SABR in central tumors, have to be awaited to determine the maximum tolerated dose which can be delivered in five fractions. A recently published systematic review of the literature identified a total of 20 studies reporting on the outcome of SABR in 315 patients with centrally located early stage NSCLC, including two phase II studies [Senthi 2013]. The overall survival rates reported for centrally located tumors appeared to be similar to those of peripheral tumors. Similar to what has been described for peripheral lesions, central tumors showed a dose–response relationship for local control, with four studies reporting improved outcomes with a biological effective dose of 100 Gy~10~ or higher compared to lower doses. In those studies where fractionation schedules with a biological effective dose of 100 Gy~10~ or higher were used, the local control rates exceeded 85%. Post-SABR grade 3 or 4 toxicity occurred in 8.6% of central tumors treated with SABR, and the risk of treatment-related mortality was less than 1% if the biological effective dose for late responding tissues (BED Gy~3~) remained below 210 Gy~3~. In conclusion, SABR for central tumors has been shown to be both effective and safe, provided that appropriate risk-adapted fractionation schemes are used and careful contouring of organs at risk with quality assurance of all aspects of treatment planning and delivery are taken into account. The results of the RTOG dose-finding phase II study 0813, in which already 120 patients are entered, will further strengthen the data on the use of SABR for centrally located tumors.

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    MS15 - Extending the Limits of Combined Modality Treatment for NSCLC (ID 32)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Combined Modality
    • Presentations: 1
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      MS15.2 - Dose Escalation of Radiation in Combined Modality Therapy of NSCLC (ID 527)

      14:27 - 14:50  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract
      Chemo-radiotherapy (CT-RT) is the presently the standard of care in patients presenting with a stage III-N2 NSCLC, with surgery being considered an option in selected patient subgroups [ESMO Guidelines 2013]. Improved local disease control in stage III disease translated into improved overall survival [Auperin A, 2010; Machtay M, 2012]. The best median survival reported to date in a randomized phase III trial of concurrent CT-RT is 28.7 months in RTOG 0617, when concurrent carboplatin-paclitaxel was combined with delivery of 60 Gy in once-daily fractions of 2 Gy [Bradley J, 2013]. At this dose, 25% of patients developed a local failure at 18 months follow-up. Therefore, both the optimization of radiation delivery and dose escalation are areas of active research. Evidence supporting radiation dose escalation comes from retrospective analyses and pooled studies. The randomized RTOG 0617 study compared 60 Gy (in 6 weeks) versus 74 Gy (in 7.5 weeks), in a 2x2 design where patients were also randomized to receive additional cetuximab or none [Bradley J, ASCO 2013]. Analysis of the impact of cetuximab has yet to be reported, but a difference in favor of the 60 Gy arm was seen for progression-free survival (36.6% vs. 26.3% at 18 months), median overall survival (28.7 vs. 19.5 months). A higher incidence of grade 3 esophagitis in the 74 Gy arm (21% vs. 7%, p=0.0003) was not unexpected, but the higher rates of local disease progression (34.3% vs. 25.1%, HR = 1.37, p = 0.0319) was a surprise. The latter raises the possibility of unsafe planning practices being applied when higher (and more toxic) doses have to be delivered. On multivariate analysis, factors predictive of a poorer overall survival were higher radiation doses, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volumes receiving >5 Gy. While publication of full data from the RTOG 0617 study is awaited, some issues related to toxicity and techniques should considered (below). 1. Improved radiotherapy planning using intensity modulated radiotherapy (IMRT) has permitted some parameters for lung toxicity (V20, mean lung dose) to be improved. However, not all recent or ongoing studies have applied constraints for lung volumes undergoing low-dose irradiation (V5). Furthermore, the choice of chemotherapy may increase lung toxicity, as reported by a recent meta-analysis showing that the risk of radiation pneumonitis is highest after concurrent CT-RT in patients aged >65 years, who also received carboplatin-paclitaxel [Palma D, 2012]. This meta-analysis revealed that predictors of fatal pneumonitis were use of daily dose fractions exceeding 2 Gy, the V~20~ parameter, and lower-lobe tumor locations. 2. Cardiac doses exceeding 5 Gy correlated with poorer survival in RTOG 0617 trial, and future studies must pay more attention to cardiac toxicity. Following concurrent CT-RT, cardiac doses of 45 Gy or higher correlated with myocardial hypoperfusion [Gayed 2006], and a higher risk of ischemic heart disease and cardiac dysfunction was seen patients undergoing CT-RT for left-sided lung cancer [Hardy D, 2010]. 3. After radiation doses of 74 Gy and 86 Gy delivered after chemotherapy, the incidence of bronchial stenosis was 4 and 25%, respectively, (Millar KL, 2005]. This complication may increase in incidence if higher doses of radiation are administered concurrent with chemotherapy. 4. When evaluating the results dose escalation studies, one must also consider the impact of tumor volume on survival in stage III NSCLC. For example, planning target volumes (PTV) correlated significantly with overall survival, with PTV values <350cc, 350-700cc, >700-1050cc and >1050cc having corresponding median overall survivals of 35.6 months (95% CI=0-71.3), 24.2 months (95% CI=18.3-30.2), 15.7 months (95% CI=10.5-20.9) and 10.3 months (95% CI=6.0-14.7), respectively [van Reij E, 2013]. Survival for tumors measuring 350-700cc differed significantly from the groups 700-1050 and >1050 cc (p=0.039 and p=0.002, respectively). In addition, larger tumor volumes are also associated with an increased risk of dying in the first 18 months, independently of T and N stage, but not beyond that time point [Ball D, 2012]. The latter finding suggests that a better characterization of tumor characteristics that correlate with radiocurability should be a research priority. 5. In RTOG 0617, the dose of 74 Gy arm was delivered in 7.5 weeks. A recent meta-analysis suggested that the accelerated delivery of radiation, i.e. delivering a higher higher dose in a shorter overall time, led to superior tumor control [Mauguen 2013]. Such accelerated delivery can be delivered using multiple fractions per day, or larger doses/fraction, both approaches which can increase the toxicity of concurrent CT-RT. For some subgroups of stage III-N2 disease, e.g. large volume tumors, where the benefits of concurrent CT-RT are modest [Wiersma T, 2013], sequential delivery may be a less toxic manner for investigating dose escalation. 6. Tumor volumes not infrequently regress during a course of CT-RT, and may also shift in position during the course of treatment [Lim G, 2011]. Volumetric imaging on modern treatment machines can allow for such changes to be detected, and treatment plans be adapted when required. Many recent clinical studies have not studied this aspect of treatment delivery. With dose escalation in fractions of 2 Gy falling out of favor, some groups are exploring the ‘dose painting’ hypothesis [Bentzen S, 2011]. Briefly, the former assumes that local recurrences arise from relatively radiation-resistant sub-regions; that reliable spatio-temporal mapping of such sub-regions is possible (e.g. using FDG-PET); that boosting radiation delivery to these egions improves local tumor control with acceptable side effects. Others groups are exploring the use of protons to improve local control in stage III NSCLC. A critical evaluation of the results emerging from ongoing trials is required, even if early outcomes from pioneering centers appear promising. Quality assurance data from radiotherapy trials, in which a broad range of institutions participate, reveals that a failure to comply with protocol requirements is associated lead to decreased survival, poorer local control and potentially increased toxicity [Weber DC, 2012].

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    O10 - Stereotactic Ablative Body Radiotherapy (ID 104)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      O10.08 - DISCUSSANT (ID 3930)

      17:30 - 17:45  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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