The Pro Side of PORT
One of the most anticipated clinical trials in stage III NSCLC, the LungART trial,1 was presented at the European Society for Medical Oncology Annual Meeting in September 2020. This trial was designed to test the hypothesis that for resected N2-positive NSCLC, postoperative radiation (PORT) would improve disease-free survival (DFS). The randomized data on PORT in resected N2 disease has been sorely needed, as practice patterns have varied for many years across institutions, regions, and countries for this subset of patients.
Notably, the 1998 PORT meta-analysis drew attention because it showed that PORT did not improve OS in resected, stage I-III NSCLC and that it in fact increased mortality, presumably due to late side effects of mediastinal radiation.2 This analysis has many shortcomings, mainly data from patients treated on antiquated equipment without modern technologies that are currently used in radiation oncology practice. Since the publication of the PORT meta-analysis, several other retrospective analyses have shown that perhaps PORT does improve survival in N2 disease.3,4,5 Many radiation oncologists in the United States have routinely recommended PORT to patients with mediastinal involvement because of a perceived benefit, in spite of no randomized data. Thus, the radiation oncology community has waited anxiously for the publication of the LungART trial, which audaciously undertook the task of determining if modern-day PORT is beneficial in patients with N2 disease.
The LungART trial began in 2010 and enrolled 501 patients throughout five European countries. This study was designed to test the hypothesis that PORT would improve DFS in patients with pathologically proven N2 disease. Results showed a 3-year DFS of 47.1% in the PORT arm and 43.8% in the control arm (HR 0.85, 95% CI [0.67-1.07]; p = 0.16). Three-year OS was 66.5% in the PORT arm, compared with 68.5% in the control arm. Mediastinal relapse was reduced by nearly 50% in patients receiving PORT; however, patients receiving PORT also experienced high rates of death secondary to cardiopulmonary toxicity. The authors therefore concluded that PORT should not be routinely administered in patients with pN2 resected NSCLC.
First, the study team should be congratulated for successfully conducting this important trial. A trial of this scale requires immense dedication—we thank you for your efforts in answering this scientific question for our patients with lung cancer.
One issue with interpreting the results of LungART is the fact that this trial occurred over a decade (August 2007 to July 2018). During this time, major advances were developing in both the local and systemic treatment of NSCLC. In terms of radiation therapy, the major shift that occurred was a transition from delivery of PORT primarily with 3D conformal radiation technique (3D-CRT) to the use of intensity-modulated radiation therapy (IMRT). The use of IMRT allows for reductions in the volume of the heart that receives radiation as well as lower lung doses, including lung V20 and mean lung dose.6 LungART required 3D-CRT, and only for select cases IMRT was allowed at the approval of the principal investigator. Use of IMRT in unresectable stage III NSCLC has been shown in some retrospective studies to improve quality of life,7 reduce radiation pneumonitis,6,8 and improve OS.9 It should not be understated that the use of 3D-CRT in this trial likely contributed to more cardiopulmonary toxicity than we would see when delivering PORT with the IMRT technique. Another trend over the lifetime of the LungART trial has been a shift away from including elective nodal volumes in radiation field design. When delivering definitive radiation for unresectable stage III NSCLC, all current NRG oncology protocols disallow elective nodal treatment, as doing so substantially increases the radiation field size and could potentially increase heart and lung toxicity.
To provide context for the high rates of cardiopulmonary toxicity seen in LungART: the first major phase III trial to show that radiation doses to the heart predict mortality was RTOG 0617, which was published in 2015.10 RTOG 0617 and subsequent studies have shown that radiation dose to the heart increases risk of death and cardiac events, and these toxicities occur at a much earlier time point than what was previously thought.11,12 Thus, when LungART was initially developed, our understanding of cardiac toxicity from radiation was much less developed than our understanding of it is now. In addition there is a developing body of research demonstrating the immunosuppressive effects of mediastinal radiation that is more pronounced with less conformal radiation fields—introducing an additional “immune system” organ at risk that would not have been accounted for in the LungART trial, and that immune system could be an avoidance structure in radiation planning.13 Current clinical trials underway for stage III unresectable NSCLC, such as RTOG 1308 (NCT01993810) incorporate more stringent constraints to the heart as well as a planned analysis that will study immunosuppression and cardiac toxicity as primary endpoints.
Another point worthy of consideration is the statistical design of the LungART trial. After the target accrual was changed from 700 to 500, the hypothesis was revised to detect a 12% benefit in DFS rather than the 10% difference designated at the outset of the trial. This magnitude of DFS improvement is quite ambitious and unlikely to materialize, particularly given an over-performance of the control arm from that which was originally hypothesized.
The generalizability of the LungART trial is perhaps most challenged by the evolution of systemic therapy for NSCLC over the last decade. Immunotherapy has revolutionized the treatment of unresectable stage III NSCLC and stage IV NSCLC, leading to substantial improvements in survival. In addition, targeted therapy has led to major improvements in outcomes both in stage IV14 and within the resectable patient population, with the ADAURA study showing significant improvements in DFS when osimertinib was given adjuvantly to patients with EGFR mutations.15 In addition, the impact of the combination of chemotherapy and immunotherapy on major pathologic response rates as well as a 2-year PFS of 77% for resectable stage III disease are major advances, as demonstrated in the recently published NADIM trial.16 The impact of local therapy on DFS will be most pronounced when the risk of distant relapse is mitigated—we have yet to understand what the optimal combination of systemic therapy is in resectable NSCLC, and the coming years will see data from studies that will undoubtedly change our current paradigms.
So where does that leave radiation in the treatment of resected stage III NSCLC? First, it is imperative that the field of radiation oncology continues to strive to better understand cardiopulmonary toxicity related to thoracic radiation. We have a pool of extremely talented young investigators who are devoted to further understanding what cardiac structures are most at risk, developing biomarkers for cardiopulmonary toxicity, and understanding what patient-specific factors lead to heightened risk of toxicity. We will continue to make strides in understanding and mitigating cardiopulmonary toxicity as a field, and I look forward to these developments that merge technology and biology.
As the treatment paradigm for resectable NSCLC is further refined, radiation will continue to play a role. Although not indicated for every patient, those believed to be at highest risk for regional nodal relapse may benefit from the regional control provided by PORT. Future analyses, retrospective and multi-institutional, may be useful to understand which patients do benefit from PORT in the context of optimal adjuvant systemic therapy and radiation planning technologies. As radiation technologies and systemic therapies evolve, we will continue to see opportunities for PORT to positively impact unique subsets of patients.
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