RTOG 0617 compared standard-dose (60 Gy) with high-dose (74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non–small-cell lung cancer (NSCLC). This was a report of long-term outcomes. Median follow-up was 5.1 years. There were 3 grade 5 adverse events in the standard arm and 9 in the high dose arm. Treatment-related grade >=3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the standard arm v 12.1% and 17.4% in the high dose arm, respectively (P = .0005 and .0001). There was no difference in pulmonary toxicity, with grade >=3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. 

This was a large multi-center randomized trial examining the benefit of two methods of treatment intensification for advanced NSCLC. Notably the trial preceded the PACIFIC trial, which established chemoradiation with adjuvant immunotherapy as the new standard of care for this disease state. Unfortunately, neither method of treatment intensification (cetuximab or dose-escalated radiation) succeeded in improving outcomes and these strategies may have even worsened outcomes. The exact reason for this remains uncertain, though differences in heart dose may partially explain this. 

Overall, this was a well-designed randomized trial, which importantly demonstrates the challenges of improving outcomes in NSCLC through treatment intensification. While the addition of immunotherapy to chemoradiation has been shown to be beneficial for patients with this condition, the results of RTOG 0617 suggest that efforts to make further outcome improvements should proceed with caution.  

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 2020;38:706-714.

Key Institution: Multi-Institutional
Keywords: NSCLC, randomized trial, treatment intensification, dose escalation, cetuximab 

Twenty-one participants had locally advanced, unresectable, stage III NSCLC, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function.

Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Progression-free survival was good, with relatively few serious immune-related adverse events.

Consolidative immunotherapy following chemoradiation for locally advanced NSCLC was shown to improve survival in the PACIFIC trial. The use of concurrent immunotherapy with radiation in intriguing but there is little data regarding safety and efficacy. This Phase 1 study demonstrates that concurrent chemoimmunoradiotherapy is tolerable in this population, with further studies required to evaluate efficacy.

(Open Access)

Reference (PubMed Link): Jabbour SK, Berman AT, Decker RH, et al. Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol 2020;6:1-8.

Key Institution: Multi-Institutional (Royal Marsden Hospital, Institute of Cancer Research, London, UK)
Keywords: Immunotherapy, Chemoradiotherapy, Locally Advanced Non-small Cell Lung Cancer 

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

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 

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

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 

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.

PDF

This paper is a NCDB analysis of early-stage NSCLC that shows improved 30-day mortality with SABR vs. surgery. The authors identified 76,623 patients who were treated with surgery or SABR for early-stage NSCLC (T1-T2a N0 M0) and compared their 30-day and 90-day post-treatment

Patients with SABR had significantly improved mortality at both 30-days and 90-days compared to patients who received surgery in both unmatched and propensity-matched analyses. Elder patients (>70 years) had greatest mortality benefit with SABR vs. surgery. Patients treated with pneumonectomy had worst absolute mortality as would be expected. These results strongly show that SABR may be safer than surgery especially in the peri-treatment period and for elderly patients, as we would intuitively expect. This is despite SABR patients typically being chosen because they are poor operative candidates, thus generally being frailer. This study has limitations as a retrospective NCDB analysis, with the cohorts not being perfectly matched, as shown in table 1 with nearly every pre-treatment treatment/site/stage/epidemiologic factor being significantly different between the surgery and SABR groups. Also, the authors limit the analysis to only T1-T2a patients and don’t include T2b N0 patients who are also generally strong candidates for both lobectomy and for SABR. In addition, there is no data on survival/mortality beyond the 90 day period; it would be interesting to see if any of the early mortality trends continued subsequently and if that also correlated with age. Still, despite these limitations, this paper is probably the largest and strongest to date showing that for older patients SABR may be strongly preferable to surgery to decrease risk of peri-treatment mortality. It is thus potentially practice-changing especially for older patients who are borderline surgical candidates, as physicians may be more likely to recommend SABR based on the results of this study.

PDF