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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

Surgery vs. Non-Surgical Treatment of Stage IIIA N2 NSCLC: The Debate Continues
Author
Howard (Jack) West, MD

There is still plenty of active debate about whether patients with stage III NSCLC who have mediastinal lymph nodes, the ones in the middle of the chest between the lungs but on the same side as the main tumor, should receive surgery in some circumstances or not. There was a trial done in the US that I described in a previous post, essentially demonstrating a better progression-free survival for patients who received "induction" chemo and concurrent radiation followed by surgery and then more chemo compared with chemo and higher dose radiation, but no surgery; however, overall survival was not significantly better for the arm that had surgery because much of the benefit against the cancer was nullified by the risk of dying from treatment, which was notably higher on the surgical arm, particularly if patients required a pneumonectomy, the removal of a whole lung. In the wake of these trial results, some experts feel that without a significant benefit shown for surgery, patients with stage IIIA N2-node positive NSCLC should not have surgery and should instead receive chemo/radiation, others still favor surgery if patients are up for it, and some people still consider it so complex that they individualize recommendations for each patient based on their health, the bulk of the mediastinal disease), the number of nodal areas involved, and the extent of surgery that would be required. I would say that stage IIIA NSCLC remains the most controversial setting in lung cancer management, even with the results of this trial, which produced results as clear as mud and hasn't yet been published with full data.

Another trial looking at the same popualtion was very recently published by van Meerbeeck and colleagues (abstract here) from the European Organisation for Research and Treatment of Cancer (EORTC) - Lung Cancer Group, a cooperative group in Europe similar to SWOG, ECOG, and CALGB in the US. In this trial, 579 patients with stage IIIA N2 NSCLC started with induction chemotherapy for three cycles, then had a CT scan to assess their response to induction chemotherapy. If they didn't progress, patients were randomized to receive subsequent definitive radiation or surgery. The trial design is shown here:

EORTC 08941 schema (click to enlarge)

The chemo used was a platinum with gemcitabine for 40%, a platinum with a taxane (taxol or taxotere) for 21%, and the rest just a mix of this and that. The response rate, which is the proportion of patients who had at least a 50% shrinkage of measurable disease, ws 61%. A few patients came off of the trial because of refusal to continue, the decision that there were still inoperable, or side effects. They ended up with 332 patients randomized to radiation or surgery after chemo, and a few patients on each arm refused or didn't get that treatment for one reason or another. Among the patients who had surgery, nearly half required a pneumonectomy, which is really a huge proportion. The 30-day mortality (death within a month of surgery) was 4%, which is not especially high for so many pneumonectomies. Similar to the experience in the US-based Intergroup trial, patients who had a lobectomy had a markedly better result than patients who required a pneumonectomy; in addition, patients who had nodal "downstaging", so that they no longer had any mediastinal nodes with cancer in them, did much better than the patients who still had N2 nodes involved with cancer. That's a recurring theme in management of stage IIIA N2 NSCLC.

EORTC 08941 Slide 3

Keep in mind, though, that the people with the biggest cancers were the ones most likely to require a pneumonectomy, and the more responsive cancers were the ones most likely to be downstaged to N0/N1 instead of N2 after induction therapy.

Radiation was generally very well tolerated, with just 1% of patients with serious esophagitis, 4% with significant pneumonitis; a single patient (<1%) died of radiation pneumonitis. Radiation was also given post-operatively to 40% of the patients on the surgical arm, so this is a bit of an imbalance, in that more than a third of the patients on the surgical arm actually received all three lines of treatment, but the patients assigned to chemo/radiation didn't also get surgery added on.

The overall results of the trial showed no differences between the two arms, with about a quarter of the patients in both arms showing no evidence of progression after two years, a median overall survival in the 16-18 month range, and a 5-year survival of about 15%.

EORTC 08941 Slide 2 EORTC 08941 Survival Curves

So the two arms are equal, but both arms underperformed the Intergroup trial done in North America (described previously), in which the two arms also were not significantly different, and the median overall survival was 22-24 months for both groups, with a 5-year overall survival of 20 and 27% for the 2 arms (the higher survival was in the chemoradiation followed by surgery arm, but it was not statistically significantly better). In trying to figure out why the results appeared to be less impressive overall in the European trial, it is important to remember that many trials have established that chemoradiation given at the same time is consistently associated with better survival (but more serious side effects) than chemo followed by radiation, which was used in the EORTC trial. The EORTC trial also allowed either cisplatin- or carboplatin-based chemotherapy, while the North American Intergroup trial allowed cisplatin only, which many experts (including this one) suspect may be a little better in the curative setting. It's also important to note that the patients on the European trial may have had bulkier mediastinal disease than the ones in the North American trial, although there was definitely a wide range in both. The EORTC trial did pneumonectomies in 47% of patients, and now many people believe that if you need a pneumonectomy after induction therapy, you shouldn't do surgery. Only about 36% of surgeries in the North American Intergroup trial were pneumonectomies (which is still a huge proportion in a US-based surgical trial, but stage IIIA patients are much more likely to need a pneumonectomy than stage I or II patients), and these were the patients who did poorly on both trials. It's possible that the patients on the North American Intergroup trial were less likely to have bulky, poorer risk disease that required a pneumonectomy, that responses were better after induction chemoradiation than after chemo alone, and/or that the skill level of surgery in the North American trial was a little higher (lobectomy is a more labor-intensive surgery than pneumonectomy -- I'm not trying to slander here, but just raising the possibility).

Overall neither trial is perfect, but they both showed very similar results, with the non-surgical arm performing similarly to the one that included surgery. Essentially, people can still find some evidence to support whatever they were inclined to believe. There's certainly no approach that clearly beat another, so people are still likely to choose based on the strengths of the center where they are receiving treatment as well as the preferences of the patients and their doctors.

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