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Chemoimmunotherapy has given medical oncologists a major weapon against resectable non-small cell lung cancer (NSCLC), but what does this treatment approach really mean for surgeons? "Advances in chemoimmunotherapy will allow surgeons to play a greater role in more advanced disease stages, with a curative intent in mind," explained Mariano Provencio-Pulla, MD, PhD, of the Instituto Investigacion Sanitaria Puerta de Hierro-Segovia de Arana, Hospital Universitario Puerta de Hierro-Majadahonda, in Madrid, and colleagues.

"Beyond the impact on resectability, neoadjuvant chemoimmunotherapy has an influence on surgical practice and the potential to improve surgical outcomes," the team wrote in a review in the on treatment sequencing in resectable lung cancer.

Provencio-Pulla's group, including co-author Jonathan D. Spicer, MD, PhD, of McGill University Health Centre in Montreal, highlighted that "adjuvant treatment allows the fastest time to surgery and longer treatment duration for systemic control," and pointed out that less than 10% of patients fail to progress to surgery after neoadjuvant therapy.

The authors also explained that in the clinic, "one of the most important arguments for neoadjuvant chemotherapy/immunotherapy is its biologic efficacy," and cited positive pathologic complete response (pCR) in trials such as NADIM, , and. Other advances with a neoadjuvant strategy are disease downstaging, increased R0 surgery, a reduction in surgical time, along with the extent and invasiveness of surgery.

In a talk, Spicer -- distinguished scientist in Surgical Research and a co-investigator for CheckMate 816 -- discussed how pre-operative surgery has broadened the horizons for lung cancer resection.

What's been the historical relationship between resectable NSCLC surgery and chemotherapy?

Spicer: The notion of systemic therapy for operable lung cancer is not a new concept. I think [systemic therapy] is germane to every form of cancer that we operate on. We realize that ... it's a systemic disease, and by adding some sort of systemic therapy, in this case chemotherapy [based on 1994 studies in the and the ], we improve outcomes. Despite that, the landscape for operable lung cancer has remained dominated by surgery alone as the primary modality of therapy, and ... the concept of getting systemic therapy before the operation didn't really take off.

There are a lot of reasons for that; chemotherapy on its own is not the most effective for downstaging so it didn't historically have an impact on the conduct of the operation. Some patients might not have made it to the operating room, so there's really this idea that the sooner the patient gets resected, the better ... and that you could look after the systemic treatment issues in the postoperative phase.

We know lung surgery tends to be a morbid intervention and a lot of patients feel like their disease is cured ... the desire to go on to postop chemo in the lung space has been historically low. Even as , many patients who met indications for systemic chemotherapy would not go on to receive it, and those numbers haven't changed all that much in [2016-2019].

What studies signaled the "new era of therapy for resectable NSCLC"?

Spicer: The team at Johns Hopkins has really led the way for immunotherapy in lung cancer, having done most of the pivotal trials. In -- they only had 20 patients -- they accrued them over the better part of 3 years. But what struck everyone was 45% of those 20 patients had what was called a major pathological response [MPR] after only two doses [of nivolumab] ... historically, [patients] who received chemotherapy, maybe three or four cycles, would have a 15% incidence of MPR. So these two doses, which are far less toxic than any amount of chemotherapy, really had a dramatic impact, and this was in a cohort of patients that were totally unselected for biomarkers; they took all comers.

I think this [trial] woke everyone up ... "Maybe [immunotherapy] is going to be a very important part of our practice."

In parallel to that, there were a number of surgical publications indicating that operating on patients who had received immunotherapy, usually in the oligometastatic setting, was extremely challenging. There was much more in these challenging, risky operations, so I think as a community, thoracic surgery was reticent [about pre-op immunotherapy].

Despite that, there were other phase II trials that produced interesting, compelling results: One out of Columbia [University] ... combined . This was an academic trial with a great surgical team; 97% of those [30 patients] made it to the operating room, and had a high complete resection rate [87%], and 57% [experienced MPR] -- so even more than with nivolumab alone -- and almost half had no residual tumor.

Probably the most influential trial has been from the . When I see what they've done in Spain, it gives me hope that we can do some really amazing things in Canada as well. In this trial, 83% had MPR and 63% had pCR, which is striking; nearly two-thirds of the patients who had no residual cancer at resection -- there were only five patients who didn't make it to surgery, but you can see [in the trial data that] some are going quite far with no evidence of progression, recurrence, or death.

Were these patients possibly cured by systemic treatment alone? I suppose time will tell.

What about the CheckMate 816 trial and its impact on lung cancer surgery?

Spicer: The ... pCR was wildly positive [24% for nivolumab plus chemotherapy versus 2.2% chemotherapy alone]; a 14-fold difference [odds ratio 13.94] ... in terms of event-free survival [EFS], we had almost 20 points in difference at 2 years, which corresponds to 11 months of extra life in the experimental arms versus the controls arms. I think this is what really has people saying CheckMate 816 EFS is one of the most significant improvements in the care of patients who undergo surgery for lung cancer.

Really, our efforts as surgeons in the last little while has been on reducing morbidity. There's really little in the operating room that is changing the long-term survival of patients. We try and take out all the disease, and do it in the least morbid way, but now with these new agents, we're really making a difference.

This is the first time we sort of see pre-operative intervention having a beneficial effect on the conduct of surgery, and this is in a community of surgeons ... that is notoriously conservative, where the adoption of minimally invasive surgery has been rather slow, and there is a dogma to resect the disease at first presentation rather than tailor the operation to radiographic response.

But in terms of the data we have, the effects seem to be most notable in the stage IIIA patients, which is understandable because these are patients with the heaviest burden of disease, who might need the most extensive resection, who may be approached by an open [surgical] technique more frequently. In CheckMate 816, you see a relatively striking reduction in the need for open surgery in the chemo-nivo group.

What for you has been the most interesting shift in post-treatment resection?

Spicer: What I find most stimulating from a surgical standpoint is that these treatments are pushing us to do more and more interesting pulmonary-preserving operations. Data from the where they looked at patients who underwent either pneumonectomy or some kind of sleeve lobectomy ... it was fascinating in their data to see that, more and more over time, they adopted sleeve resections, but that there was a time-era effect [later era versus earlier era] in terms of complications, indicating that it takes time to learn how to do these operations safely for patients.

So volume is important, and good teams that know how to conduct these complicated operations are available. That seemed to translate into better overall survival, recurrence-free survival, indicating that the operations were more effective from an oncologic standpoint.

Read the review here.