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Lung cancer is not the most common cancer in either men or women. Prostate cancer is certainly number one in men and breast cancer is number one in women.

 It cuts lung cancer at approximately half; so you can see breast cancer is much more common than lung cancer. However, if you look at the deaths from cancer, lung cancer, it is by far the biggest killer in both men and women.

If you look at the changing incidence of lung cancer in men, the United Kingdom is actually decreasing quite substantially from the earlier 1960s and '70s. In the United States, it actually leveled off in the 1980s, and it has started to decline in the last couple of years, and in France it is still rising. So it really just depends on where you are and on your habits. In women, the United States is still going up. It hasn't showed any sign of leveling off. The United Kingdom has already leveled off and started to decline a little bit. In France, it is has always been low.

Types of lung cancer. There are two major types: non-small cell and small cell. Approximately 75-80% of the tumors that we see are non-small cell, while only 20-25% are small cell itself. If we look at the small cell subtypes, previously the vast majority of those particularly with the disease found in males was squamous cell cancer, but more recently the majority of them are adenocarcinomas, and 40% of all lung cancers are adenocarcinomas. So this has really shot up and changed the nature of the disease as well. Squamous cell is only 17% of all lung cancers.

In smokers, particularly males, squamous cell is a fairly predominant tumor type. But if we look at nonsmokers, Aden carcinoma is by far the most common subtype. The same is true of females, even to a greater extent. In smokers, adenocarcinoma is more common in females.

Staging. The T-stage is based on the size, the location, the amount of atelectasis and a few other things. The N-stage is fairly simple. N1 is intrapulmonary lymph nodes, N2 is outside and N3 is outside the chest and M1 is self-explanatory.

Stage 1 and 2 are localized to the lung itself. Stage 3A is more advanced with metastases in general or chest wall invasion and 3B is your unresectable tumors. T3N0 is tumors that involve the parietal pleura either on the chest wall, the diaphragm or the mediastinum, now it is considered to be stage 2 as well since the survival is actually better. In these two groups up here, TI and T2, each one has been divided into A and B. Now, there is 1A, 1B, 2A, 2B and then T3 can be observed in 2B as well.

Stage1 tumors have to be less than 3 cm and it can't involve a major lobar bronchus and create lobar atelectasis or consolidation, and it can't have any lymph node involvement either in the lung or outside. T2, they are just bigger lesions. Either greater

than 3 cm or those that involve the visceral pleura and that cause lobar atelectasis. Segmental atelectasis is the T1 finding. Stage 2 is the same two groups except for there is intrapulmonary lymph node involvement so that the criteria are the same. This is 2A, this is 2B but there is intrapulmonary lymph nodes either along the segmental bronchi or either the lobar bronchi that are involved. Also, again, 2B consists of T3, which is tumors that are involved in the parietal pleura or 2 cm with carina.

3A is locally advanced. T3N0 again goes to the 2B now but T3N1 and 2, T3 involves basically anything that has parietal pleura. if you see something with complete collapse of the lung, by definition they have to have a T3 disease.

The other component of a 3A is N2 disease and that means now lymph nodes up in this area that are involved. So you can kind of get a feeling from the number of different subgroups in this phase that there are a lot of different patient populations in here. N2 disease is a lot different from T3 disease so implications in terms of survival and treatment are also different.

3B again is something that is unresectable in general which includes N3 disease which is either contralateral, if you have a tumor over here, contralateral lymph node involvement on the opposite side or a scalene lymph nodes in this particular area or you have a T4 lesion which is either a tumor growing into a major structure like an aorta, esophagus, left atrium or some major unresectable organ or a malignant pleural effusion.

One of the things surgeons keep in mind is the spread of tumors along lymph node chains. If you have an upper lobe lesione and up along the peritracheal nodes here so

the subparietal nodes are oftentimes spared or the left side is spared. If you have a middle lobe or lower lobe lesion, it tends to drain not down here actually but to the subparietal lymph nodes and then up along the right side. On the left side actually, the lower lobe tends to drain to the subparietal nodes and then switches over to the righ side as well so you get more contralateral involvement of the left lower lobe. The left upper lobe tends to drain along this direction. Just like the right upper lobe it also goes to the AP window which is on the left side.

So when you see a report where someone on mediastinoscopy biospies a mediastinal lymph node, it is not accurate enough. It doesn't tell you enough information to really be able to treat the patient as well as they can be treated. Stage 1, clinically the survival is the best - 50-55%. Stage 2 drops down to 30% or less. Stage 3A is 15 or less and Stage 3B and 4 are dismal. So if you have an accurately staged 1 patient, either T1 or T2, survival is 60-75% or even 80% for small lesion so that is fairly reasonable.

But you the T1N0s are 75-80%. That is a pretty reasonable survival but that means even when we start getting T2, no lymph node involvement, this is a larger tumor or visceral pleural involvement it drops down in the 50s so you are really just flipping a coin to see whether patients survive and then when you drop down to stage 2, it goes down below the 30s. Generally 52 is kind of high, but it is 30-40% in most stage 2 tumors. The 3A it drops from the 30s down to as low as 15% depending upon which 3A we are talking about. Then 3B and 4 are dismal - less than 10%. Patients unfortunately present mostly with advanced 3B or 4 disease half the time and then half the remaining patients would be the early resectable disease, stage 1 or 2 or locally advanced, which is potentially resectable, but may not be good to resect necessarily.

Distance spread for lung cancer as everybody knows is brain, bone, liver adrenals, lymph nodes as well as the lungs. Those are the most common sites. But the problem from the surgical standpoint is that no matter what you do from a surgical standpoint, two-thirds or more of the patients fail distantly. So no matter what you do, except for the small subgroup of patients with very small primary lesions that we find early incidentally, the vast majority of the patients are bound to recur. Adjuvant therapy was instituted because of the high risk of recurrence.

The Lung Cancer Study Group as well as the Veterans' Group and other groups studied postoperative chemotherapy, postoperative radiation, postoperative chemotherapy and radiation and then more recently looking at preoperative therapy, either chemotherapy or chemo radiotherapy.

Postoperative adjuvant radiation therapy and has a benefit for stages 2 to 3A from postoperative treatment which increased local control from around 80-85% up to 97% or better. But the problem is it doesn't translate into increased survival because of the fact that it is not a local problem that kills the patient. It is the systemic metastases.

Postoperative chemotherapy was looked at extensively and people always bring up the point that this is CAP chemotherapy and most of the postoperative trials were done with chemotherapies that are not used any longer because they are inferior and so nobody really knows now whether postoperative chemotherapy would work or not. There are some people that are starting to look at that again. But this is one study, again by the Lung Cancer Study Group looking at Phase 2 and 3 patients, the immunotherapy control arm which is basically no therapy and did not see significant overall survival advantage although the disease-free survival was slightly prolonged.

The dismal result of all of these trials led people to try and think of new ways to give therapy and one of the newer ways was neoadjuvant therapy, also called preoperative therapy induction therapy. That is giving some kind of therapy prior to definitive local control measures. Local control measures can either be radiation or surgery but some of the therapy given before that. So in terms of surgery, neoadjuvant therapy that has been looked at includes both chemotherapy, chemoradiotherapy and radiation therapy alone.

There have been a number of preoperative radiation trials looking at preoperative radiation by itself prior to surgical resection and those haven't shown any benefit. In fact, even in Pancoast's tumors, the classic treatment that was developed back in the '50s and '60s was to treat these patients with preoperative radiation therapy then resection. That is still done in most places now. But the more that we view their data in terms of the radiation therapy and in looking at intraoperative administration, preoperative or postoperative, patients did the same no matter what they did so that the combination of chemotherapy and radiation is important but the order is not necessarily important. So there are some areas like in St. Louis where they don't get preoperative therapy, just resect the tumor and give them postoperative therapy and it seems to work out the same. So preoperative radiation has never really been shown to be definitively better than the surgery alone with postoperative adjuvant if needed. So what I want to do is look at some of the data from stage 3A disease and what I mean by 3A, there are a lot of different types of 3As. They used to be T3N0 which is now 2B but I am going to talk about them anyway because all of the trials have included those patients. You can see survival for those patients with T3N0 is 40-50%. Usually closer to 50% so that is why they have been changed recently to 2B because their survival really doesn't fit into 3A. Then N2 disease is not even a single disease. An N2 can be a micrometastatic deposit in one lymph node or it can be bulky disease in multiple station lymph nodes and their survival is dramatically different as well.

N2 positive patients. If you look at just a single station, that is one lymph node area on that map that has been involved with tumor and the rest of them were all biopsied and negative, which gives you about a 35% survival with surgery alone. If you look at a single station lymph node excluding the subcarinal area which tends to be a somewhat bilateral station and more difficult and poor prognostically input implications is actually a better survival if you can eliminate those patients and look at a single station that is not subcarinal. Up to 45%. Then if you look at patients with more than one area involved, they go down to 9%. If you again exclude the subcarinal area, it goes up to 22% so you can see that depending on which group you look at you can have anywhere from less than 10% survival up to 45% survival.

In terms of preoperative or induction therapy, there are a number of advantages that have been proposed. One of them is that you treat the patient then when primary tumor size is as small as it can be, malignant metastases are also presumably small and they would be several months later. You potentially might decrease surgical seating which may or may not happen. The disadvantages that have been worried about have been the increased morbidity and mortality from the surgical procedure, which actually has not turned out to be the case, and delayed primary tumor control. That, as you can see from the other data, is not the biggest worry. The metastatic disease is what kills the patient so that has turned out not to be the case.

There are other factors in all of this. When the Lung Cancer Study Group evaluated their adjuvant trials, one of the primary things and possible reasons for failure was that the patients didn't tolerate the therapy very well. After undergoing a major operation and trying to recover from that and then getting chemotherapy. Also patients psychologically weren't ready to take more chemotherapy because their tumor was already out and they would give up easily and say, "I don't want anymore chemotherapy because my tumor is gone. It may not be there anymore and I don't want anymore." So, preoperative therapies tend to get a higher dose intensity of chemotherapy than postoperative treatment so that may be one of the key reasons why the preoperative seemed to be work better.

The two randomized trials looking at preoperative induction chemotherapy prior to surgical resection in 3A patients. A trial from Barcelona that was published in the New England Journal a few years ago but these were both small trials. They were both designed to have 120 patients in them. They were both stopped after 60 patients by independent review boards that thought that the results were so compelling that it was not ethical to continue the trials so that each had only 60 patients, here 30 on each arm, this is 32 and 28. This arm is surgery alone and in Barcelona everybody got radiation so it's surgery plus radiation versus chemotherapy plus surgery plus radiation.

At the M.D. Anderson they got surgery and chemotherapy prior to surgery. Some of these patients also got radiation if they had close margins or residual disease in their lymph nodes. The chemotherapy was used, and actually again the greatest chemotherapy, in Barcelona they used cyclophosphamide and cisplatin and in M.D. Anderson they used cyclophosphamide which was pretty worthless, cyclophosphamide and cisplatin.

So these aren't the kinds of modern regimens that everybody used but still the results are kind of interesting. The third trial at NIH that never really reached the pinnacle of significance because it only had about 27 patients in it. It showed the same trend as these two studies. The multiple number of phase 2 trials that were done also showed the same kind of results in a nonrandomized fashion.

But if you look at the results here in surgery alone, 85% of resectable in Barcelona, the median survival time is only 8 months and 10 months in M.D. Anderson. These were criticized a little bit saying, "Well this is not what we would expect because surgical time is usually longer than that". But this data has been looked at in terms of the Lung Cancer Study Group, they included thousands of patients and it is actually consistent with those controls for this stage of disease. If you look at chemotherapy prior to therapy, the median survival time is at 26 months for Barcelona and actually it is up to approximately 60 months or 5 years in M.D. Anderson. So that is pretty compelling and you would think that this would be a reasonable thing to do although people now have discounted a lot of this because some of the data that was collected regarding K-RAS expression in these patients and both of these groups went back and looked at the K-RAS expression and it was not balanced between the two groups. So now people just throw out all of the results because of that which I think is a little bit unfair because that was one of the goals of the trial was to better the K-RAS. This is just to show you so you can see it. This survival curve is from the M.D. Anderson trial and you can see this is surgery alone and you do get a few survivors. It levels off and this is with chemotherapy prior to surgery. Again, it is leveling out and there is definitely a big difference between the two curves. It is not one of those curves where they come down and then they eventually meet down here with the same survival. It levels off and is definitely different. Then you look at the Barcelona and it is hard to see but it is the same thing basically. Surgery alone comes down here and then surgery plus chemotherapy levels off here with a definite distinct difference in survival.

So it looks like it works. The issue of primary control is one that we brought up. Whether surgery is necessary in a lot of these patients because they have high dose radiation therapy along with therapy producing, at least in some patients or advanced patients, similar results. So the question still is open whether surgery is needed or whether you can do the same thing with radiotherapy. The only data that we know of at least in earlier stage disease was small lesions. We know that surgery is far superior to the radiation therapy but in more advanced lesions like the 3A and 3B, radiotherapy has been fairly equivalent to surgery but that is because the systemic disease is not controlled. So if you start to control system disease, then it may end up eventually being proven that surgery has always been a better local control modality than radiotherapy.

This is a trial that is ongoing but it is looking at the question whether chemoradiotherapy is better than chemotherapy alone in a preoperative setting. So they are randomizing patients to receive again unusual chemotherapy, mitomycin, vizicin and cisplatin and actually get a different chemotherapy cisplatin to this group and they get radiation therapy to this group as well and do surgery and then follow it up with either radiation or chemotherapy. So it is kind of an unusual trial but some of the data in terms of the resectable and the disease free survival so far has been different in favor of the radiotherapy arm. But this is very early on and the endpoints they looked at are really endpoints of local control and not necessarily systemic control. So resectability response ranks a little bit higher with that we would expect with radiotherapy so there is really no definitive evidence right now that radiotherapy in a preoperative setting adds anything to chemotherapy. I think it detracts from the induction therapy because what you really want to know is how well the systemic disease is going to respond to the chemotherapy and not whether a local tumor can respond to radiotherapy because that is what really determines survival. So patients who respond dramatically to chemotherapy are the ones that we can be more aggressive on in terms of resecting patients and the radiotherapy kind of confounds that by covering up possible therapy failures.

What I had mentioned before is there are some special considerations about bronchial obstruction. The fact that if you have an obstructed bronchus and potential infection beyond that, if you treat patients like that preoperatively, there were a number of deaths when that first started being done in Toronto. It was responsible for the major part of the mortality of this kind of approach until it was realized they shouldn't do that. So if you do have a bronchial obstruction, it is best to either relieve it either with surgery or radiation or something prior to giving chemotherapy or at least know what the problem is and cover it with antibiotic.

The major thing is to avoid a lot of hydration in patients perioperatively because the chemotherapy patients for some reason are more susceptible to having postoperative noncardiogenic pulmonary edema which is catastrophic in patients who are undergoing pneumonectomies or big resections. Having had chemotherapy makes them more susceptible to that so we need to be aware of that and keep their fluids down, quite dry.

Now, just some data regarding 3B which is classically considered unresectable. These there is a trial Suave 8805 which looked at actually 3A and 3B disease and treated it with chemotherapy, radiotherapy and there is an induction protocol. The reason this is important is because this is what is being used now in trials with 3A disease - a similar regimen. Then they were reevaluated and patients that seemed to have a good response and were in good shape underwent surgical resection and this was the results from that trial. The interesting and surprising thing about this trial was that patients with 3B disease in green had similar survivals as those with 3A with this induction and treatment. All of these patients underwent more aggressive surgery where they had to do bilateral lymph node resections and that kind of thing but it kind of gives you an idea that if you can give a good and early induction chemotherapy regimen and control systemic metastases and potentially some of the disease that was thought to be unresectable previously may actually be resectable.

You can't apply this widely. You have to select the patients very carefully and also stage them very accurately and staging always, at least for most of these trials, includes mediastinoscopy and PET scans are now being used more widely to try and also stage patients. But we have also found that a lot of false negatives and false positives PET scans so that still hasn't been proven. So I think mediastinoscopy is still required in all of these patients to really know what the risk of recurrence is and how it should be treated. M1 disease. Patients with M1 disease occasionally are surgical candidates.

 It is not very common but patients particularly with solitary brain metastases and solitary adrenal metastases have been shown to have a more favorable prognosis at least in terms of resection candidates than in other patients with more widely metastatic disease.

These are theories looking at solitary brain mets and survival after surgical resection of the brain met and the primary lung cancer. You can see the five year survival varied anywhere from 9% to 34%. So, depending on again the prognosis and the type of disease that is a reasonable survival. It is more like 3A survival - patients with 3A disease. So people have used this to go ahead and do primary resections in the presence of solitary resectable brain metastasis. Again, what we are doing now is to

apply the same approach to 3A disease to this category as well and that is these patients have about the same survival as the patients with 3A disease, again because of systemic recurrence. Two-thirds or more of these patients are going to have a systemic recurrence versus any problem in primary brain site or primary lung site.

So we are now actually taking patients with solitary brain mets, resecting the brain metastasis, giving them chemotherapy again in an induction setting and then going back and resecting the primary lung lesion. Again in the same way of trying to improve survival.

The Memorial data with multiple metastases. They had 231 patients with different numbers of resections including up to three or four resections of solitary brain metastases over time. They found that the poor prognostic factors were multiple metastases, incomplete resection, male gender, infratentorial location was an important one and the presence of other systemic metastases obviously as well as advanced age.

This looks at some of the breakdown of the 182 patients with a single resection and their disease free survival was only five months and their median survival was 14.6 months which is a little bit better than we would expect otherwise. I will show you in a minute some radiation controlled studies. Actually, patients had two and three resections and their survival was as long as 42 months so it shows that some patients who do have limited numbers of metastases can be controlled with surgery alone.

Again, this is not patients who received chemotherapy, so that, potentially, these patients could have a higher survival if they had chemotherapy as well. The five year survival is 12.5% which is a little bit less than a lot of the other series but it shows that it is better than the general systemic metastasis. Two-thirds died again with systemic disease which again includes chemotherapy.

The RCOG study, 8528 looked at just brain irradiation along with the lung primary without surgery. You can see that their survival at one year was only 20 to 33%. The early stage lung cancer. This is kind of group where people have been treated for years with surgery alone, whether it is stage 1 or stage 2. Anything with disease in the lung has been treated surgically. As you remember from the survival curve that I showed earlier, the disease survival can be as low as 30-40% in the stage 2 subgroup so this is not a really outstanding survival with surgery alone. Again, the standard approach has been surgery, definitive therapy, radiation therapy if patients refused surgery or seemed inoperable. The Lung Cancer Study Group has shown with a randomized trial that the standard surgery should be a lobectomy or pneumonectomy, which is far better than limited resection including segmentectomies or wedge incisions. The local recurrence rate goes from about 6% with a lobectomy to as high as 38% with a wedge resection. The survival is inferior with those lesser resections so most surgeons now feel lobectomy is the least you should be doing. Memorial's data from stage 2 disease and shows over 39% five year survival so this group does not have great survival. We have started thinking that we shouldn't accept

this as acceptable to surgery alone and apply other therapies. What we looked at more recently is new adjuvant therapies in high risk early stage lung cancer which includes all of these early lung cancer stages except T1N0. So, if there is a small peripheral primary that is easily resectable, we still do that. But anything more than that, we actually now are giving chemotherapy prior to surgical resection. These are the number of centers that are all participating. This is a multicenter study that we are doing now in the phase 2 setting. Giving carboplatin and Taxol prior to resection is what all these places that are participating are giving.

The schema of the trial is to give them two cycles of carboplatin and Taxol and then, if they have progression of the disease when they go off treatment, if they respond or it is a stable disease, which everybody has, they go on to surgical resection and then three postoperative cycles of chemotherapy.

So in the future, we are looking at this poor prognostic early stage disease looking at getting chemotherapy to T2 and N1 patients as well as T3 disease with complete chest wall involvement. We limit it to solitary brain or adrenal metastases but Memorial is actually giving chemotherapy in a preoperative setting to patients who have a solitary metastases anywhere that is resectable. Then there is 3B and M1 disease that don't really have protocols but they eventually show some improvement. A special type of laser bronchoscope can isolate early lesions and we are looking into screening for lung cancer patients who are at high risk because of a previous lung cancer or are high risk for other reasons. One of the arms of the screening is doing monoclonal antibody screening of sputa looks very promising to identify patients with early changes in the mucosa prior to any overt cancer. Then another one is looking at this light bronchoscopy which is a type of blue light laser which will make neoplastic changes or pre-malignant lesions become autofluorescent. This you can see is the white light bronchoscopy for these areas. You can't really see much abnormal in these areas but here you can see an extensive brown area and over here there is more of a brown area here which are potential lesions that might develop into tumors. So these can be hopefully related early and avoid big resections. The other part of this treatment would be to use photodynamic therapy to ablate these mucosal changes before they become a tumor, but it is still experimental. You may have heard the Japanese reports of using photodynamic therapy for early lung cancer  and these are the kinds of patients that they were attempting to use it in. Problems occur with patients with solid masses in their lung and other things, people that are pulmonary cripples who can't have surgery and they want to know about photodynamic therapy. It is really not something that has been able to treat solid lesions.

 The best thing to do is to find any lesion, which in the United States are rare to find this early lesion and treat it with photodynamic therapy. But it is something that might in the future, photodynamic therapy is very limited and used rarely to treat patients who have had high dose radiation and have recurrence in their airway and have a tumor growing in their airway that is not treatable by any other means, which is rare. This is Natan trial which is ongoing now which is looking at N2 disease which is again, there are several questions regarding how best to treat patients with metastases but they take what you might consider inoperable N2 disease with bulky nodes and definite N2 involvement to be treated with radiotherapy which used to be the primary treatment modality. Well, now it is chemoradiotherapy and that is one reason why the trial is failing recently knowing how randomized it is.

The other group is chemotherapy followed by surgery followed by chemotherapy. So this was to look at this new way of induction chemotherapy versus the old standard. This started a number of years ago but may actually be changed to a different trial because they can't really finish it. The Interview trial from NCI which is now looking at the question of surgery, as a modality. This randomizes the chemoradiotherapy or local modality therapy in the definitive option and then the other arm is chemoradiotherapy prior to surgery. This is slowly accumulating patients.