Point/Counterpoint: Does surgery play a role in N2 disease treatment following induction therapy?

POINT: Surgery has its uses for some

BY DR. STEPHEN G. SWISHER

When talking about the role of surgery after induction therapy with persistent N2 disease, one must acknowledge that this is such a heterogeneous disease. You can have single-station N2; resectable, bulky multistation N2; and so on. Then there’s unresectable stage IIIA, but let’s focus mainly on resectable stage IIIA disease.

I can’t tell you how many audiences I’ve faced that absolutely believe the myth that surgery plays no role in Stage IIIA non–small cell lung cancer based on data from stage IIIA disease patients randomized to chemoradiation followed by surgery. The problem with these study results is the high mortality in the pneumonectomy subset. There’s no difference in the overall survival of the two groups, but that doesn’t mean that everyone in that group wouldn’t benefit from surgery.

The curve showed that pneumonectomy did not benefit after chemoradiation in a non–high-volume center. You can see a steep drop in the mortality early on, but it catches up again at the end. If you look at the overall 5-year survival rate, even in the pneumonectomy subset, you’re looking at 22% vs. 24%.

But in the lobectomy set, you see something completely different. You’ve got a doubling of survivors and no mortality early on, and a doubling of 5-year survival from 18% to 36%.

And yet, people continue saying that there’s no role for surgery. Well, I think there is a role for surgery, and there are subsets of N2 for which surgery can be particularly beneficial. We have to move more toward what the medical oncologists do, which is personalize therapy and look at subsets of N2 disease so that we know which patients we can benefit and which ones we can’t.

Moving on to the second myth: Surgery plays no role in N2 residual disease after induction therapy. This myth is based on the results of a couple of prospective studies in the 1980s and ’90s that showed residual N2 disease after chemo- and radiotherapy leads to survival of 16-35 months in most cases. I’d say that those results are true, but it’s not to say there aren’t subsets within these populations that benefited. With preoperative chemo and radiation, it’s basically the same thing ­^– poor prognoses in patients with N2 or N3 disease, so the standard becomes never to operate on these individuals.

A European study prospectively took 30 patients and treated them with induction chemotherapy. They saw a 5-year survival rate of 62% if a patient downgrades to lymph node–negative disease and the positron-emission tomographic (PET) findings were good. But they also saw a subset with a small amount of disease within the lymph nodes at the N2 stage and a poor response on PET; Their 5-year survival rate was around 19%. So I’d argue that PET response and the number of lymph nodes involved are the key criteria, and you shouldn’t routinely deny surgery to these patients.

Our experience at MD Anderson Cancer Center over the last 10 years has been to treat N2 and N3 admissions, with surgery, followed by postoperative radiation of 50 Gy. We’re able to achieve very-low morbidity with this regimen, and no mortality after 30 and 90 days. Just to show the heterogeneity: Single-station, microscopic N2 disease should really be resected.

You just can’t lump together everyone with residual N2 after induction therapy, since PET-CTs and most other diagnostic procedures have high false-negative rates. And like I’ve said, it doesn’t matter because N2 disease is really a subset disease. Microscopic N2 disease behaves in a completely different way than does macroscopic, multiple-level N2 disease. And even more important is how the patient’s primary tumor responds to the chemotherapy or chemoradiation; that will tell you how well they’re going to do even if they have a small amount of residual disease in the lymph nodes.

Dr. Swisher is at the University of Texas MD Anderson Cancer Center in Houston. He disclosed that he is a consultant/advisory board member for GlaxoSmithKline.

COUNTERPOINT: Surgery seems to have little value, adds risk.

BY DR. SCOTT J. SWANSON

Dr. Swisher and I probably agree more than we disagree, but I’m going to start by saying that N2 disease is bad, and most of these populations are heterogeneous. But if you feel that a curve toward the bottom of a graph is good, then you should think twice. Anywhere from a 15%-30% survival rate is not great and shows that we have a long way to go. The overall impression among oncologists in several countries is that it’s not really clear whether surgery adds value. Even in very good centers like MD Anderson where there is minimal risk, surgery inherently still involves some risk.

So then, what do we do with persistent N2 disease? I’d say that most of the time, it should be treated with chemotherapy or chemotherapy and radiation. In some cases, N2 disease can be treated with a creative, mutation-driven immunotherapy approach. Most of the time though, surgery is just not a good idea.

Interestingly, about one-third of lung cancer patients present with stage IIIA disease, so it’s important that we as a medical community sort out these treatment options. I think we’re all in agreement that single-station, microscopic, PET-negative/CT-negative disease is not the same as extranodal or multistation PET-positive disease, so we’ve got to begin to substratify N2 disease.

In an intergroup trial of about 200 patients per arm published in the Lancet, patients went to surgery if they didn’t regress after evaluation. The progression-free survival rate did seem to favor surgery; and, if you look at the lobectomy subset, the results are certainly strong. But again, we’re dealing with curves that are pretty low. The pneumonectomy subset drops off and then starts to catch up, but clearly pneumonectomy was a problem in this multicenter trial. The most important graph to this debate shows subjects that persistently had nodal disease had very poor survival. It’s hard to argue for surgery when results show that only about 24% of them are going to be alive down the road. If oncologists across most of the United States say they believe that surgery isn’t a good idea, we’re not going to use this graph to change their minds; we need to change our way of thinking.

So the conclusion to take away from that presentation is that N0 status at surgery significantly predicts greater 5-year survival. So, conversely, surgery is not helpful for the patient with node-positive disease. Surgical resection should only be considered if lobectomy is the operation in question. Pneumonectomy carries risk, and surgery has no beneficial value, compared with chemotherapy unless the patient has been downstaged.

Our experience at Brigham and Women’s Hospital in Boston is similar to Dr. Swisher’s at MD Anderson. During the first 8 years of our thoracic division, we looked at 103 patients who had surgery after induction therapy for N2 disease. The induction plan in those patients was chemotherapy only for 75, radiation only for 18, and chemoradiation for 10. Almost 40% of patients had pneumonectomies, and the rest had lobectomies.

Mortality was 3.9%, major morbidity was 7%, and about 30% were downstaged. Those 5-year survival rates were about 36%. Persistent nodal disease, either N1 or N2, was seen in about 75%, and most of them were N2; the 5-year survival rate there was about 9% with a median of about 15.9 months. Beauty is in the eye of the beholder, so you may look at that and say that 15.9 months isn’t bad, but there’s still a huge subgroup that’s node positive, so here I’d say that pushing surgery is not the best strategy. We also found in this group that adenocarcinomas were much harder to clear.

We’re on very-safe ground to push surgery in the node-negative group, but you’ve got to be careful in the node-positive group.

Survival is relatively limited in N2 disease in general. Surgery may be of value if you downstage the patient, if you’re doing a lobectomy or if you see squamous cell carcinoma. Going forward, we really ought to focus our attention on identifying responders more reliably and improving downstaging – with different or individualized chemotherapy, or perhaps even immunologic therapy.

For the present, we can talk about radiation dosing. High-dose radiation is clearly a viable option for some patients. In addition, we can improve identification of N2 subgroups. Not all N2 disease is the same, so it should not be treated the same across the board.

Dr. Swanson is at Brigham and Women’s Hospital in Boston. He disclosed that he is a consultant/advisory board member for Covidien and Ethicon Endo-Surgery.

This article grew out of the debate by Dr. Swisher and Dr. Swanson at the annual meeting of the Society of Thoracic Surgeons.

POINT: Surgery has its uses for some

BY DR. STEPHEN G. SWISHER

When talking about the role of surgery after induction therapy with persistent N2 disease, one must acknowledge that this is such a heterogeneous disease. You can have single-station N2; resectable, bulky multistation N2; and so on. Then there’s unresectable stage IIIA, but let’s focus mainly on resectable stage IIIA disease.

I can’t tell you how many audiences I’ve faced that absolutely believe the myth that surgery plays no role in Stage IIIA non–small cell lung cancer based on data from stage IIIA disease patients randomized to chemoradiation followed by surgery. The problem with these study results is the high mortality in the pneumonectomy subset. There’s no difference in the overall survival of the two groups, but that doesn’t mean that everyone in that group wouldn’t benefit from surgery.

The curve showed that pneumonectomy did not benefit after chemoradiation in a non–high-volume center. You can see a steep drop in the mortality early on, but it catches up again at the end. If you look at the overall 5-year survival rate, even in the pneumonectomy subset, you’re looking at 22% vs. 24%.

But in the lobectomy set, you see something completely different. You’ve got a doubling of survivors and no mortality early on, and a doubling of 5-year survival from 18% to 36%.

And yet, people continue saying that there’s no role for surgery. Well, I think there is a role for surgery, and there are subsets of N2 for which surgery can be particularly beneficial. We have to move more toward what the medical oncologists do, which is personalize therapy and look at subsets of N2 disease so that we know which patients we can benefit and which ones we can’t.

Moving on to the second myth: Surgery plays no role in N2 residual disease after induction therapy. This myth is based on the results of a couple of prospective studies in the 1980s and ’90s that showed residual N2 disease after chemo- and radiotherapy leads to survival of 16-35 months in most cases. I’d say that those results are true, but it’s not to say there aren’t subsets within these populations that benefited. With preoperative chemo and radiation, it’s basically the same thing ­^– poor prognoses in patients with N2 or N3 disease, so the standard becomes never to operate on these individuals.

A European study prospectively took 30 patients and treated them with induction chemotherapy. They saw a 5-year survival rate of 62% if a patient downgrades to lymph node–negative disease and the positron-emission tomographic (PET) findings were good. But they also saw a subset with a small amount of disease within the lymph nodes at the N2 stage and a poor response on PET; Their 5-year survival rate was around 19%. So I’d argue that PET response and the number of lymph nodes involved are the key criteria, and you shouldn’t routinely deny surgery to these patients.

Our experience at MD Anderson Cancer Center over the last 10 years has been to treat N2 and N3 admissions, with surgery, followed by postoperative radiation of 50 Gy. We’re able to achieve very-low morbidity with this regimen, and no mortality after 30 and 90 days. Just to show the heterogeneity: Single-station, microscopic N2 disease should really be resected.

You just can’t lump together everyone with residual N2 after induction therapy, since PET-CTs and most other diagnostic procedures have high false-negative rates. And like I’ve said, it doesn’t matter because N2 disease is really a subset disease. Microscopic N2 disease behaves in a completely different way than does macroscopic, multiple-level N2 disease. And even more important is how the patient’s primary tumor responds to the chemotherapy or chemoradiation; that will tell you how well they’re going to do even if they have a small amount of residual disease in the lymph nodes.

Dr. Swisher is at the University of Texas MD Anderson Cancer Center in Houston. He disclosed that he is a consultant/advisory board member for GlaxoSmithKline.

COUNTERPOINT: Surgery seems to have little value, adds risk.

BY DR. SCOTT J. SWANSON

Dr. Swisher and I probably agree more than we disagree, but I’m going to start by saying that N2 disease is bad, and most of these populations are heterogeneous. But if you feel that a curve toward the bottom of a graph is good, then you should think twice. Anywhere from a 15%-30% survival rate is not great and shows that we have a long way to go. The overall impression among oncologists in several countries is that it’s not really clear whether surgery adds value. Even in very good centers like MD Anderson where there is minimal risk, surgery inherently still involves some risk.

So then, what do we do with persistent N2 disease? I’d say that most of the time, it should be treated with chemotherapy or chemotherapy and radiation. In some cases, N2 disease can be treated with a creative, mutation-driven immunotherapy approach. Most of the time though, surgery is just not a good idea.

Interestingly, about one-third of lung cancer patients present with stage IIIA disease, so it’s important that we as a medical community sort out these treatment options. I think we’re all in agreement that single-station, microscopic, PET-negative/CT-negative disease is not the same as extranodal or multistation PET-positive disease, so we’ve got to begin to substratify N2 disease.

In an intergroup trial of about 200 patients per arm published in the Lancet, patients went to surgery if they didn’t regress after evaluation. The progression-free survival rate did seem to favor surgery; and, if you look at the lobectomy subset, the results are certainly strong. But again, we’re dealing with curves that are pretty low. The pneumonectomy subset drops off and then starts to catch up, but clearly pneumonectomy was a problem in this multicenter trial. The most important graph to this debate shows subjects that persistently had nodal disease had very poor survival. It’s hard to argue for surgery when results show that only about 24% of them are going to be alive down the road. If oncologists across most of the United States say they believe that surgery isn’t a good idea, we’re not going to use this graph to change their minds; we need to change our way of thinking.

So the conclusion to take away from that presentation is that N0 status at surgery significantly predicts greater 5-year survival. So, conversely, surgery is not helpful for the patient with node-positive disease. Surgical resection should only be considered if lobectomy is the operation in question. Pneumonectomy carries risk, and surgery has no beneficial value, compared with chemotherapy unless the patient has been downstaged.

Our experience at Brigham and Women’s Hospital in Boston is similar to Dr. Swisher’s at MD Anderson. During the first 8 years of our thoracic division, we looked at 103 patients who had surgery after induction therapy for N2 disease. The induction plan in those patients was chemotherapy only for 75, radiation only for 18, and chemoradiation for 10. Almost 40% of patients had pneumonectomies, and the rest had lobectomies.

Mortality was 3.9%, major morbidity was 7%, and about 30% were downstaged. Those 5-year survival rates were about 36%. Persistent nodal disease, either N1 or N2, was seen in about 75%, and most of them were N2; the 5-year survival rate there was about 9% with a median of about 15.9 months. Beauty is in the eye of the beholder, so you may look at that and say that 15.9 months isn’t bad, but there’s still a huge subgroup that’s node positive, so here I’d say that pushing surgery is not the best strategy. We also found in this group that adenocarcinomas were much harder to clear.

We’re on very-safe ground to push surgery in the node-negative group, but you’ve got to be careful in the node-positive group.

Survival is relatively limited in N2 disease in general. Surgery may be of value if you downstage the patient, if you’re doing a lobectomy or if you see squamous cell carcinoma. Going forward, we really ought to focus our attention on identifying responders more reliably and improving downstaging – with different or individualized chemotherapy, or perhaps even immunologic therapy.

For the present, we can talk about radiation dosing. High-dose radiation is clearly a viable option for some patients. In addition, we can improve identification of N2 subgroups. Not all N2 disease is the same, so it should not be treated the same across the board.

Dr. Swanson is at Brigham and Women’s Hospital in Boston. He disclosed that he is a consultant/advisory board member for Covidien and Ethicon Endo-Surgery.

This article grew out of the debate by Dr. Swisher and Dr. Swanson at the annual meeting of the Society of Thoracic Surgeons.

POINT: Surgery has its uses for some

BY DR. STEPHEN G. SWISHER

When talking about the role of surgery after induction therapy with persistent N2 disease, one must acknowledge that this is such a heterogeneous disease. You can have single-station N2; resectable, bulky multistation N2; and so on. Then there’s unresectable stage IIIA, but let’s focus mainly on resectable stage IIIA disease.

I can’t tell you how many audiences I’ve faced that absolutely believe the myth that surgery plays no role in Stage IIIA non–small cell lung cancer based on data from stage IIIA disease patients randomized to chemoradiation followed by surgery. The problem with these study results is the high mortality in the pneumonectomy subset. There’s no difference in the overall survival of the two groups, but that doesn’t mean that everyone in that group wouldn’t benefit from surgery.

The curve showed that pneumonectomy did not benefit after chemoradiation in a non–high-volume center. You can see a steep drop in the mortality early on, but it catches up again at the end. If you look at the overall 5-year survival rate, even in the pneumonectomy subset, you’re looking at 22% vs. 24%.

But in the lobectomy set, you see something completely different. You’ve got a doubling of survivors and no mortality early on, and a doubling of 5-year survival from 18% to 36%.

And yet, people continue saying that there’s no role for surgery. Well, I think there is a role for surgery, and there are subsets of N2 for which surgery can be particularly beneficial. We have to move more toward what the medical oncologists do, which is personalize therapy and look at subsets of N2 disease so that we know which patients we can benefit and which ones we can’t.

Moving on to the second myth: Surgery plays no role in N2 residual disease after induction therapy. This myth is based on the results of a couple of prospective studies in the 1980s and ’90s that showed residual N2 disease after chemo- and radiotherapy leads to survival of 16-35 months in most cases. I’d say that those results are true, but it’s not to say there aren’t subsets within these populations that benefited. With preoperative chemo and radiation, it’s basically the same thing ­^– poor prognoses in patients with N2 or N3 disease, so the standard becomes never to operate on these individuals.

A European study prospectively took 30 patients and treated them with induction chemotherapy. They saw a 5-year survival rate of 62% if a patient downgrades to lymph node–negative disease and the positron-emission tomographic (PET) findings were good. But they also saw a subset with a small amount of disease within the lymph nodes at the N2 stage and a poor response on PET; Their 5-year survival rate was around 19%. So I’d argue that PET response and the number of lymph nodes involved are the key criteria, and you shouldn’t routinely deny surgery to these patients.

Our experience at MD Anderson Cancer Center over the last 10 years has been to treat N2 and N3 admissions, with surgery, followed by postoperative radiation of 50 Gy. We’re able to achieve very-low morbidity with this regimen, and no mortality after 30 and 90 days. Just to show the heterogeneity: Single-station, microscopic N2 disease should really be resected.

You just can’t lump together everyone with residual N2 after induction therapy, since PET-CTs and most other diagnostic procedures have high false-negative rates. And like I’ve said, it doesn’t matter because N2 disease is really a subset disease. Microscopic N2 disease behaves in a completely different way than does macroscopic, multiple-level N2 disease. And even more important is how the patient’s primary tumor responds to the chemotherapy or chemoradiation; that will tell you how well they’re going to do even if they have a small amount of residual disease in the lymph nodes.

Dr. Swisher is at the University of Texas MD Anderson Cancer Center in Houston. He disclosed that he is a consultant/advisory board member for GlaxoSmithKline.

COUNTERPOINT: Surgery seems to have little value, adds risk.

BY DR. SCOTT J. SWANSON

Dr. Swisher and I probably agree more than we disagree, but I’m going to start by saying that N2 disease is bad, and most of these populations are heterogeneous. But if you feel that a curve toward the bottom of a graph is good, then you should think twice. Anywhere from a 15%-30% survival rate is not great and shows that we have a long way to go. The overall impression among oncologists in several countries is that it’s not really clear whether surgery adds value. Even in very good centers like MD Anderson where there is minimal risk, surgery inherently still involves some risk.

So then, what do we do with persistent N2 disease? I’d say that most of the time, it should be treated with chemotherapy or chemotherapy and radiation. In some cases, N2 disease can be treated with a creative, mutation-driven immunotherapy approach. Most of the time though, surgery is just not a good idea.

Interestingly, about one-third of lung cancer patients present with stage IIIA disease, so it’s important that we as a medical community sort out these treatment options. I think we’re all in agreement that single-station, microscopic, PET-negative/CT-negative disease is not the same as extranodal or multistation PET-positive disease, so we’ve got to begin to substratify N2 disease.

In an intergroup trial of about 200 patients per arm published in the Lancet, patients went to surgery if they didn’t regress after evaluation. The progression-free survival rate did seem to favor surgery; and, if you look at the lobectomy subset, the results are certainly strong. But again, we’re dealing with curves that are pretty low. The pneumonectomy subset drops off and then starts to catch up, but clearly pneumonectomy was a problem in this multicenter trial. The most important graph to this debate shows subjects that persistently had nodal disease had very poor survival. It’s hard to argue for surgery when results show that only about 24% of them are going to be alive down the road. If oncologists across most of the United States say they believe that surgery isn’t a good idea, we’re not going to use this graph to change their minds; we need to change our way of thinking.

So the conclusion to take away from that presentation is that N0 status at surgery significantly predicts greater 5-year survival. So, conversely, surgery is not helpful for the patient with node-positive disease. Surgical resection should only be considered if lobectomy is the operation in question. Pneumonectomy carries risk, and surgery has no beneficial value, compared with chemotherapy unless the patient has been downstaged.

Our experience at Brigham and Women’s Hospital in Boston is similar to Dr. Swisher’s at MD Anderson. During the first 8 years of our thoracic division, we looked at 103 patients who had surgery after induction therapy for N2 disease. The induction plan in those patients was chemotherapy only for 75, radiation only for 18, and chemoradiation for 10. Almost 40% of patients had pneumonectomies, and the rest had lobectomies.

Mortality was 3.9%, major morbidity was 7%, and about 30% were downstaged. Those 5-year survival rates were about 36%. Persistent nodal disease, either N1 or N2, was seen in about 75%, and most of them were N2; the 5-year survival rate there was about 9% with a median of about 15.9 months. Beauty is in the eye of the beholder, so you may look at that and say that 15.9 months isn’t bad, but there’s still a huge subgroup that’s node positive, so here I’d say that pushing surgery is not the best strategy. We also found in this group that adenocarcinomas were much harder to clear.

We’re on very-safe ground to push surgery in the node-negative group, but you’ve got to be careful in the node-positive group.

Survival is relatively limited in N2 disease in general. Surgery may be of value if you downstage the patient, if you’re doing a lobectomy or if you see squamous cell carcinoma. Going forward, we really ought to focus our attention on identifying responders more reliably and improving downstaging – with different or individualized chemotherapy, or perhaps even immunologic therapy.

For the present, we can talk about radiation dosing. High-dose radiation is clearly a viable option for some patients. In addition, we can improve identification of N2 subgroups. Not all N2 disease is the same, so it should not be treated the same across the board.

Dr. Swanson is at Brigham and Women’s Hospital in Boston. He disclosed that he is a consultant/advisory board member for Covidien and Ethicon Endo-Surgery.

This article grew out of the debate by Dr. Swisher and Dr. Swanson at the annual meeting of the Society of Thoracic Surgeons.