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  • Dec 20, 2019
    Long-term results of RTOG 0617: Radiation dose escalation +/- cetuximab for stage III NSCLC

    The dosing for stage III non-small cell lung cancer has been established at 60Gy since RTOG 7301. Trialists looked to dose escalation as a possibility, comparing 74Gy to60Gy in 2Gy fractions together with carboplatin paclitaxel. There was also a cetuximab component to the 2x2 trial. The 2015 publication of two-year follow-up results showed decreased overall survival with the dose escalation arm (median survival 28.7mo vs 20.3 mo). The use of cetuximab conferred additional toxicity without any overall survival difference. Updated five-year follow up confirmed these findings with the standard arm having better 5yr survival (32% vs 23%). Interestingly, even local failure trended to improvement with the standard lower dose. There was some speculation as to whether treatment noncompliance with the high dose arm contributed to the worse outcomes, but there was no difference when analyzing only the protocol compliant population. Multivariate analysis points to cardiac dose as a potential culprit for the decreased survival, but this still doesn’t explain the trend towards decreased local control.

    (Open Access)

    Reference (PubMed Link): Bradley JD, Hu C, Komaki RR, et al. Long-term results of NRG oncology RTOG 0617: Standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage iii non-small-cell lung cancer. J Clin Oncol 2019:Jco1901162.

    Key Institution: Multi-Institutional (US, Canada)
    Keywords: Clinical practice, nonsmall cell lung cancer, dose-escalation, cetuximab, RTOG, NRG Oncology

  • Nov 20, 2019
    Effects of checkpoint inhibitor pembrolizumab on advanced lung cancer not altered much by SBRT

    This multi-institutional phase 2 study randomized 92 patients with advanced non-small cell lung cancer (NSCLC) regardless of PD-L1 status. Pembrolizumab was either given along (control arm) or after radiotherapy (8 Gy x 3) to a single tumor site. The main outcome was improvement in overall response rate (ORR). 76 patients were randomized to the control arm and 36 to the experimental arm. The ORR at 12 weeks was 18% in the control arm vs 36% in the experimental arm (P = 0.07). Median progression-free survival was 1.9 months vs 6.6 months (P = 0.19). No increase in treatment-related toxic effects was observed in the experimental arm. The study concluded that stereotactic body radiotherapy prior to pembrolizumab was well tolerated, and suggested that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC towards a more inflamed tumor microenvironment. 

    Reference (PubMed Link): Theelen W, Peulen HMU, Lalezari F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: Results of the pembro-rt phase 2 randomized clinical trial. JAMA Oncol 2019.

    Key Institution: Multi-Institutional (The Netherlands)
    Keywords: Non-small cell lung cancer, pembrolizumab, stereotactic body radiotherapy 

  • Nov 1, 2019
    Large increase in apparent diffusion coefficient (ADC) on MRI predicts local failure after lung SBRT

    This prospective clinical study of patients receiving SABR for lung cancer set out to test the hypothesis that apparent diffusion coefficient (ADC) on MRI imaging is a useful radiomic marker of locoregional failure. ADC in this context is thought to be a marker of increased cellularity potentially indicative of persistent tumor.

    The investigators took baseline MRI ADC measurements pre-treatment and then again at one month post-treatment. All patients were being treated with thoracic SABR for early-stage (12 patients) or oligometastatic (1 patient) NSCLC. Images were analyzed by 2 blinded radiologists, and results were highly concordant between the 2 (Pearson Correlation <0.85). They found a mean 18% increase in ADC from pre to post treatment. Interestingly, only 2 of their patients experienced locoregional failure, and both of these patients exhibited a 1 month post-treatment ADC increase of >40%, whereas 0/10 recurrence-free patients broke this 40% cutoff. This effect was found to be statistically significant. 

    Post-SABR changes in lung anatomy and associated fibrosis are a major limitation of interpreting post-treatment tumor response. Indeed, tumors may be obscured by areas of inflammatory consolidation. PET scan does little to address this limitation, as inflammatory areas are often PET-positive. In that context, the present study is among the first to evaluate MRI radiomic assessment of treatment response and correlate this to patient outcomes. Their result is certainly interesting in that they were able to show a cut point of the data which correctly assigned 100% of their patients into future recurrence or not. 

    Although this was a well-designed prospective trial, the obvious limitation of this study is sample size. The study was closed early due to poor accrual. An additional potential limitation only partially addressed by the authors is that MRI is a historically limited modality to evaluate the thorax. However, the use of breathhold imaging allowed for usable data for the study. 

    Although this is certainly an interesting result, it is hypothesis-generating and not hypothesis-testing. Indeed, it is premature to make major clinical determinations based on an absolute number of 2 recurrence events. More prospective studies are needed to evaluate this finding further, testing whether the observed predictive value for recurrence persists in larger patient populations. It is plausible that application of these findings in future can lead to early intervention and personalized adaptive therapy in the immediate post-SABR period before traditional methodology would detect treatment failure.

    Reference (PubMed Link): Sampath S, Rahmanuddin S, Sahoo P, et al. Change in apparent diffusion coefficient is associated with local failure after stereotactic body radiation therapy for non-small cell lung cancer: A prospective clinical trial. Int J Radiat Oncol Biol Phys 2019;105:659-663.

    Key Institution: University of Iowa
    Keywords: NSCLC, SABR, apparent diffusion coefficient, MRI

  • Aug 20, 2019
    One versus three fractions of SBRT for peripheral stage I-II NSCLC

    This is a phase II multi-institutional randomized trial evaluating single fraction SBRT 30 Gy versus three fraction 60 Gy for peripheral NSCLC in medically inoperable patients. The primary endpoint of this study was grade three or higher thoracic toxicity and other adverse events. Secondary endpoints included local control, progression free survival, overall survival, and quality of life. 

    From 2008 to 2015, 98 patients were randomized and reported with 53.8 months median follow up. There were ten patients lost to follow up, 9 of which were on the three fraction arm.  

    For the primary endpoint, 16% on the single fraction arm and 12% on the three fraction arm experienced a grade three thoracic adverse event, no grade 4-5 were reported. There were no statistically significant differences in local control, progression free survival, and overall survival endpoints. The OS at 2 years was 73% versus 62% and PFS at 2 years was 65% versus 50% for single and three fraction arms, respectively.  On quality of life questionnaires patients in the single fraction arm reported significantly better dyspnea at six months and better social functioning at three and six months. There was no change in pulmonary function tests compared with baseline in both arms. 

    In conclusion, this is a phase II randomized study compared single versus three fraction SBRT for peripheral NSCLC in medically inoperable patients. The primary endpoint, grade 3 thoracic adverse events, was not significantly different between arms, nor were any of the secondary endpoints of local control, progression free survival, and overall survival. Patients who received single fraction SBRT reported improved dyspnea and social functioning in follow up questionnaires.  This study concludes that single fraction is safe and effective, although one should note that efficacy was limited to secondary endpoints.

    Reference (PubMed Link): Singh AK, Gomez-Suescun JA, Stephans KL, et al. One versus three fractions of stereotactic body radiation therapy for peripheral stage i to ii non-small cell lung cancer: A randomized, multi-institution, phase 2 trial. Int J Radiat Oncol Biol Phys 2019;105:752-759.

    Key Institution: Multi-institutional/USA 
    Keywords: Single fraction, SBRT, NSCLC 

  • Jul 30, 2018
    Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer Findings from NRG Oncology RTOG 0618 Trial

    This trial evaluated the use of SBRT for early stage lung cancer patients who were operable, whereas historically SBRT was reserved for medically inoperable patients. The primary endpoint was local control, and survival, adverse events, and the incidence of surgical salvage, as secondary endpoints.

    With median follow up of 48.1 months, 26 of 33 enrolled patients were evaluable. Of those evaluable 23/26 were T1 and 3 were T2. The median FEV1 and DLCO were 72% (38-136) and 68% (22-96), respectively.

    One patient had primary tumor recurrence; 4 year local control 96%. OS and DFS at 4 years was 56% and 57%, respectively. LRC at 4 years was 88% (3 regional failures) and DM rate was 12% (5 patients). Grade 3 AE rate 14%, no grade 4.

    SBRT appears to have a high probability of tumor control, low morbidity, and little need for surgical salvage in patients with early-stage operable lung cancer.

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    Journal & Date: JAMA Oncol. 2018 May 31. doi: 10.1001/jamaoncol.2018.1251. [Epub ahead of print]
    Key Institution: UTSW, Dallas TX, USA
    Keywords: SBRT, SABR, early stage NSCLC, medically operable

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