The role of surgery in patients with pre-resection documented N2 disease remains a subject of controversy. In some institutions, any clinical N2 disease identified preoperatively is considered non-surgical and these patients are offered upfront definitive chemoradiation therapy (DefCRT) without planned resection. In other institutions, a selective approach to N2 patients will consider surgery as part of a multimodality approach where surgery may be offered first followed by adjuvant cytotoxic chemotherapy (AC) with or without sequential post-operative radiation therapy (PORT), or where surgery will be offered after induction chemotherapy or induction chemoradiation therapy. Due to variability in N2 disease presentation, factors determining this selective approach vary between institutions and may include the bulk of N2 nodal involvement (size), extent of N2 involvement (single vs multistation, microscopic vs macroscopic), the presence or absence of extracapsular nodal involvement, the need to perform a pneumonectomy or not, and mediastinal sterilization after induction therapy. Historically, response to induction therapy with clearance of N2 nodal involvement following induction therapy has been shown to bode for a better prognosis after surgical resection. Unfortunately, even after complete resection following induction therapy, many patients develop distant metastases, with brain metastases prevailing. In 2018, the PACIFIC trial showed that adding an immune checkpoint inhibitor (IO) durvalumab for up to one year after completion of DefCRT in non-surgical stages cIIIa and cIIIB patients led to a significant and unprecedented overall survival in this population of patients. (Antonia, NEJM 2018) In patients with resectable NSCLC (cIIIA and less), recent small phase I clinical trials of either single-agent induction IO (Forde, NEJM 2018) or concurrent induction chemoimmunotherapy (Provencio, JTO abst. 2018) given before surgery have demonstrated feasibility, acceptable toxicity, and unprecedented pathological response rates. It remains to be seen if these pathologic responses will translate into improved overall survival in this patient population. Extrapolating from these early observations, one may think that induction IO (likely with concurrent cytotoxic chemotherapy) may possibly allow us to offer surgery to a larger proportion of patients with clinical N2 disease in the future as we observe higher response rates to induction therapies which may translate in better survival. Others may want to extrapolate from the Pacific trial results and hypothesize that surgery followed by adjuvant IO may become a desirable option. Though encouraging, there is a paucity of data to help guide us in the incorporation of IO therapy perioperatively for patients with clinical N2 disease. As such, the role for IO in multimodality treatment for N2 disease remains undefined. Unknown are the true impacts of periop IOs in this patient population and what is the optimal combination and timing of these multimodality treatments. There are more unanswered questions than established guidelines: (1) whether “IO first then surgery” is superior to “surgery first then adjuvant IO”, (2) whether an induction IO strategy followed by resection would be superior to DefCRT followed by IO in this population of potentially resectable cN2 IIIA patients, (3) if induction IO is shown to be superior, how many cycles preop, (4) do we need to continue IOs post op, if so, for how long, (5) whether there will be a role for surgery after major response to IO, and (6) how will we select patients for resection when major pathological response rates will be in the 80% range (7) do we need to utilize biomarkers, tumor mutation burden, or genotyping in patient selection, (8) What is the best biomarker to predict response, among other questions . The easy answer at this stage is to treat these patients on trials where the impact of IOs can be rigorously studied. Ideally, I personally would want to compare: (1) Induction vs adjuvant IOs for surgical patients with cN+ disease, (2) Induction IO followed by resection vs DefCRT followed by IO. The duration of periop IO also needs to be evaluated and these studies should include cost analysis as well. For the surgeons, as systemic treatments improve, our duty is to perform sound oncological surgery with minimal morbidity and minimal to absent mortality. I believe that preop IO may allow us to consider surgical resection for a larger proportion of cIIIA N2 patients in the future. Immunotherapy, stage IIIA NSCLC, surgery
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Feb 17, 2021
Phillip M Rappold + 3
Open Access
