Barret’s and cancer. What do you do if you find a Barrett’s?

What do you do if you find a Barrett’s? What I like to do is to look very carefully for any suspicious nodularity or stricture at endoscopy and to first biopsy any nodule or stricture. Benign ulcers usually are benign. Then, sample the whole of the Barrett’s esophagus by taking four-quadrant biopsies, as shown with these little x’s, all the way down the Barrett’s esophagus to try to find anything that might be hidden there.

What are we looking for? Well, besides cancer, we are looking for dysplasia, which is a precancerous condition. This is taken from a resection specimen, to get a nicer picture, but this is a Barrett’s, and if you look at this side of this villous-like structure, you will see the obvious goblet cells here. Here, the nuclei are at the base of the cells in order and that is non-dysplastic here. Now, when we look at the other side of this villous structure here, there are more nuclei. The nuclei are above other nuclei; that is, they are stratified. This is low-grade dysplasia; that is non-dysplastic Barrett’s, low-grade dysplasia. The same is true here; this is non-dysplastic here and this is low-grade again. There are too many nuclei here and the nuclei are stratified. This is common and we have found low-grade dysplasia in about a third of our patients and high-grade dysplasia in considerably less than 5%. Here is high-grade dysplasia. On this side you will see lots of nuclei; large, densely-staining nuclei, not much cytoplasm and the nuclei extend up to the lumen surface of the cells. On this side, it is even worse; there is very high-grade dysplasia with malignant-looking cells. These really are cancer cells to look at, but my pathologist colleague tells me that because they actually haven’t broken through the basal lamina, which is there and here, this is by definition high-grade dysplasia and not invasive adenocarcinoma; it is sometimes difficult to tell the difference on a biopsy.

If you were to operate on someone with high-grade dysplasia in different series, anywhere from about 10 to 50% of patients in whom the endoscopist has found Barrett’s high-grade dysplasia and not seen a cancer, cancer is found in 10% to 50% in the resected specimen, depending on how carefully it has been looked for. Some of these patients have a cancer right now; others will get a cancer later.

Barret’s and cancer. Combination treatments

The same patient, approximately one year later, had another endoscopy and he had developed a Barrett’s esophagus in the meantime. Here on the right is the typical epithelium found in a Barrett’s esophagus – glandular; note the goblet cells. You can see the little sort of oval holes in the cells here. This is intestinal metaplasia; this is not the normal type of epithelium found at the upper end of the stomach . This is the hallmark of Barrett’s esophagus and the type of epithelium that most adenocarcinomas of the esophagus are found to occur in.

Here are some endoscopic pictures; we are looking down in about the mid esophagus here at an untreated patient with Barrett’s esophagus. You will see these erosions, these triangular, pale-centered, bright-red margined lesions in the squamous mucosa. This is typical reflux esophagitis. If you look further down here, however, you will see red mucosa which covers a long segment of the lower esophagus and that is the Barrett’s mucosa. Here, on the retroflexed view, looking upward, is the hiatal hernia that this patient had.

Supposing we treat a patient like this effectively to prevent reflux, either with proton pump inhibitors, such as omeprazole, or with a laparoscopic Nissen. What will happen? What will probably happen is that you will control their heartburn and acid reflux and their esophagitis will resolve if you endoscope them again, but the Barrett’s is almost certain to remain. It may develop squamous islands. These are squamous islands partially occupying some of the area of columnar mucosa. Doing an anti-reflux operation, or controlling with Prilosec, has not been shown to reduce the cancer risk in the remaining Barrett’s esophagus, so you still have to keep on with surveillance.
Breast cancer
What is the risk of adenocarcinoma in patients with Barrett’s? There are many series; these are just three of the larger, more recent series, number of patients followed, number of follow up years median and the number of cancers per patient years. Take the top series of 166 patients, followed for an average of 9.3 years, one cancer per 180 follow up years, or out of 180 patients, one would get cancer each year. That looks bad, but it isn’t quite as bad as you might think. Some patients we see with Barrett’s really feel sure that they are going to die of cancer, but that is just not the case.

Here are four series, one of which was a paper I had in the New England Journal in 1985; these are longer follow ups. These are patients followed up 3-cm Barrett’s or longer, the number of follow up years and if you follow people for long enough, a proportion will die of a cause of some sort. If you follow everyone in this room for 100 years, you would get 100% mortality. So if you follow people with Barrett’s long enough, people will die of something. These are the numbers of those who died and these are the numbers of those who died of cancer of the esophagus; it was between 2.5 and 6%, roughly about 5%. Therefore, in these series, with the present methods of management, only about 5% of patients with a long-segment Barrett’s actually died of esophageal cancer. We sometimes find early cancers in these people, and at least four other patients in these different series developed a cancer but did not die of the cancer, they died of something else. That is quite different from a cancer causing an obstructive mass in the esophagus. So, 95% of patients with Barrett’s will not die of esophageal cancer.

Combination treatments.

It has been shown that postoperative radiation and chemotherapy do not increase survival in adenocarcinoma. Preoperative chemotherapy alone is not helpful, although there is a recent paper in the New England Journal of a large multi-center study confirming that again. Presently, preoperative, so-called neoadjuvant, chemotherapy plus radiotherapy looks somewhat more promising,. with radiation being given to improve control over local disease, and sometimes by the time the operation is done, about 20 to 25% of patients do not have any tumor left, and with chemotherapy to control micrometastases, which are present in so many of these patients, but of course can’t be seen but show up as distant metastases at a later date. Thinking was changed by this paper from Walsh and his colleagues in Dublin, Ireland, which appeared in the New England Journal in 1966. They took about 113 patients and randomized them to either have surgery alone or to have surgery preceded by multimodal therapy, which was 5-FU plus cisplatin plus radiation to the primary tumor. As you will see, by three years the survival was much better in the patients given the neoadjuvant preoperative therapy compared to proceeding immediately to surgery.

While it is fairly difficult to do radiation and chemotherapy, it has its own problems and complications and this paper, it was decided at our institution, was not enough to change the entire thinking and to proceed on this one paper alone. There was a smaller one from the University of Michigan with a similar trend to give everyone preoperative therapy. So the present situation is that we surgeons, oncologists and radiation therapists are collaborating with multiple other North American centers in the CALGB-97 study, which is attempting to reproduce this study with preop chemo and radiation followed by surgery versus surgery alone. We are randomizing patients into that study, but it will be several years before the results are finally determined.

I’m afraid that for many patients, possibly half of all patients with adenocarcinoma of the esophagus presenting with symptoms, an operation is not possible because of distant metastases, because of age or other medical conditions, and sometimes all that can be done is the endoscopic placement of a metal spring stent to enable them to be swallow, as is being done here.

Let’s go back to Barrett’s esophagus, the place where most adenocarcinomas of the esophagus begin. Normally, all of your esophagus is lined with pale pink squamous mucosa and the Z line, the junction, should be at the lower end of the esophagus. In Barrett’s esophagus, a variable length of lower esophagus is lined with red columnar epithelium, easily seen at endoscopy. Barrett’s esophagus is an acquired condition and is associated with severe gastroesophageal reflux. Most patients will have a weak lower esophageal sphincter and over 90% of patients will also have a sliding hiatal hernia. These are at least two of the factors that probably cause reflux to occur, reflux then damaging the normal squamous lining here, which becomes replaced later by columnar. This is an acquired condition and this is an interesting and unusual patient, but we are showing a typical finding, a patient with reflux symptoms. On the left here, biopsy from the lower esophagus shows squamous epithelium with changes of esophagitis, elongated papillae and a thickened basal cell here.

Barrett’s esophagus and adenocarcinoma

The first slide to give you a typical history is a patient I saw about a year ago, a man of 61, who came with a complaint of three months of increasing dysphagia for solid foods, which were sticking at the chest level. When asked, he also had a 30-year history of heartburn and sour reflux, for which he had never sought other treatment except taking antacids, so this had never been investigated. In the population, there are many people with heartburn who have not had it investigated. A barium x-ray was done at his home hospital and this showed an esophageal ulcer with what was called edema. However, they recognized that it wasn’t just edema and did an endoscopy at his home hospital, which showed an adenocarcinoma and a Barrett’s esophagus which had not been recognized previously.

The results of treatment of patients of this type are unfortunately not very good. This shows the results of surgical resection in seven fairly large series. Here are the numbers of patients who had resection for adenocarcinoma of the esophagus and here is the mortality rate. While these series may have been written a few years ago, the median mortality here was about 8%. Here is the complication rate. The median complication rate here was about 40%, with such problems as anastomotic leaks, pneumonia, postoperative strictures and empyemas. This is difficult surgery. For all that the patients went through, and the surgeons, the five-year survival was not very great. The median five-year survival for patients presenting with a mass in the esophagus which was an adenocarcinoma in these series was about 15%. How could we do better? This is a very brief review of a lot of literature in the oncology and radiation area.

Non-Small Cell Lung Cancer. What is happening for at least N2

What is happening for at least N2 IIIa disease right now is a very important trial that accepts concomitant chemo-radiotherapy – that’s the SWOG regimen, platinum, etoposide, radiation – and then asks, “Do these patients really need surgery? Do they benefit from that or is chemo-radiotherapy just as good?” So they randomized on the standard arm to receive 45 gray of radiation with two cycles of platinum, etoposide and then surgery versus that same initial chemo-radiotherapy and then a chemo-radiotherapy boost. This trial is in progress and hopefully will complete in the very near future.

What about classical adjuvant chemotherapy for earlier stage disease, stage I or stage II? This is a very typical design. You would look at surgery and radiation, in some cases surgery alone, versus surgery, radiation and chemo. Well, to make it brief, to date there is no proven role for adjuvant chemotherapy. I’m showing you this trial as the most recent example of a negative trial. This was a large U.S. intergroup trial, designed just as this: surgery, radiation, surgery, radiation with platinum, etoposide. Two cycles concurrent and two cycles adjuvant afterwards. Preliminary analysis shown at ASCO this year, long term follow-up already. Median 41 months and median survival identical, 38 months on both arms. The only thing that is encouraging about this is that the median survival was really high on both arms. Surprisingly so, maybe, and the five year survival rate particularly encouraging at 39% and 33%. But this does not support a role for adjuvant chemotherapy, not yet.

This is a positive trial, a European trial, that actually suggests that induction chemotherapy may be of benefit in stage Ib to IIIa where patients had either surgery or MIP, mitomycin ifosfamide, platinum, and then surgery. And radiation was given to some patients according to individual preference. In this trial, if you look at the two and three year survival, there is a suggestion of benefit. But it’s confounded by a number of things. The number of patients getting radiation on the surgical arm is much higher and paradoxically we now think that adjuvant radiation for at least some of these patients actually decreases their chances of survival or cure rather than increasing it. That’s again fairly recent literature looking at the role of radiation. So I’m showing you this to say that not all data are negative, but it’s certainly not yet conclusively supporting induction chemotherapy.

Now finally then, looking at current affairs here, here in early stage disease – much like in the advanced stages – we are looking at the newer regimens and what is called the bi-modality lung oncology trial, or BLOT. Bi-modality because it is chemo and surgery, looks at induction chemotherapy with carboplatin and paclitaxel in stage Ib through IIIa disease. This has been piloted in 94 patients with an objective response rate of the chemotherapy of 54%, which is not bad, and based on this the phase III trial has been activated where patients received either surgery or induction, not adjuvant, carbo and paclitaxel for three cycles.

Non-Small Cell Lung Cancer. So you can summarize

So you can summarize then that induction chemotherapy is established, that concomitant chemo-radiotherapy is probably also established and may be even a little bit better, but we don’t know yet. I think the RTOG trial is important for that. And that we now need to integrate the new drugs and maybe find out; is induction better than concomitant, but should maybe both be given? This is the first such trial that tried to evaluate should both be given, giving induction and then radiation versus radiation with weekly carbo at low doses. So this is going back to the single agent concept. And you see no difference. That’s actually consistent with cisplatin literature, that single agent radiation sensitization is simply not enough to make a difference. Median survival, 13 months in both arms as you would expect in an induction chemotherapy trial.

In CLGB we’ve now looked at giving induction and concomitant but multi-agent therapies. And several other groups are looking at this and then adding the new drugs into this menu. We have some preliminary data that suggests that this can be done. We’ve looked at gemcitabine in this setting, paclitaxel and vinorelbine. All three are feasible but how good they are and what kind of long term survival rates we get, we are not sure of yet. So this was a randomized phase II trial, about 60 patients per arm, and we do now that all three arms are feasible and that these new drugs may have a role in stage III disease, much as they do in stage IV disease.

So in the last few minutes then, let’s move down to the earlier stage disease settings. If chemotherapy has a role in stage IV for palliation and in stage IIIb to increase survival, then moving to the earlier stages you have fewer patients to evaluate, you bring in surgery as a third modality, randomized trials are very few and the conclusions are much less clear. So I just want to leave you with a few impressions. This is stage IIIa disease where again you have large primary lymph nodal disease but usually the surgeon has an option of at least attempting a curative intent resection. There have been two very small trials that are frequently cited that have looked at induction chemotherapy for stage IIIa disease and in this case surgery versus chemotherapy, followed by surgery. If you look at the three year survival there was a large difference favoring induction chemotherapy. A very similar trial from Spain, published in the New England Journal 1994, again about 30 patients – these are much harder to do these trials than stage IV or IIIb – surgery followed by radiation, versus chemotherapy followed by surgery and radiation. You look at the median survival, eight versus 26 months, and again a suggestion also of long term benefit. But both are very small trials and I could show you similar small trials that did not show that benefit. So for IIIa disease, induction chemotherapy, we’re really not sure yet.

Concomitant chemo-radiotherapy.Non-Small Cell Lung Cancer

So what about concomitant chemo-radiotherapy? We mentioned that toxicities are higher with concomitant therapies. So in the head and neck that’s mucositis, and soft tissue. And you can observe patients for that. In the lung it’s esophagitis which is very unpleasant and hard to monitor. And it can be radiation pneumonitis and radiation pneumonitis can be fatal. So that concomitant approaches to the lung have been tested with a great deal of caution, historically. The majority of trials therefore looked at single agents including some inactive agents. Now that didn’t make a whole lot of sense, but cisplatin in four trials and cisplatin is – we know from stage IV disease – a 12% active drug. Three of these trials showed no benefit and one showed a little bit of benefit, and I want to show it to you because it is frequently cited. It’s by Shaka-Koenig, New England Journal 1992 and it looked at radiation therapy given for two weeks at slightly larger fractions of free gray and then a four week break, and then another two weeks of treatment. So this is not an orthodox control arm because it’s larger fractions but low total dose of 55 gray given over a prolonged course of time. To this they then added – either weekly or daily – cisplatin. In both cases it amounted to the same total dose of 30 mg per meter square per week, or 6 daily times 5. So there is some beauty in this in terms of its design. It would be great to do in, say, animals. But in humans this was compromised by the fact that this is unorthodox radiation and really very low dose cisplatin. Four times 30 is 120, that’s just a little bit more than you would give as one single modality administration. Now this trial is cited as positive because of long term benefit here for the two platinum arms, and maybe short term benefit with the daily cisplatin, but I’m not sure it is. Because the other three cisplatin trials were negative and the control arm did exceedingly poor, and I just explained to you why; because it wasn’t standard radiation.

Now concomitant chemo-radiotherapy looks more promising when multi-agent drugs have been used. Where you can still get that sensitization or better local control, but you also add at least the potential for some systemic activity. SWOG has been the ones who have done the most trials of this in the United States, looking at platinum VP-16 and concurrent radiation. Recently there are Japanese data that I’ll show you that have looked at the MVP regimen, of mitomycin, Velban platinum with either concurrent or sequential radiation. So here’s the SWOG experience. Platinum, etoposide for two cycles with radiation and then two additional cycles in the adjuvant setting. The white curve here are patients with un-resectable disease. The yellow curve are patients who had resectable disease but got a little bit of this treatment before resection. You look at the three year survival – it’s over 20% – suggesting that this is an active principle, to give concurrent multi-agent drugs with radiation therapy. This is unpublished information that Dave Kandara gave me.

RTOG has looked at this a little bit further, in terms of; if concomitant treatment is good and induction chemotherapy is good, can you say is one better than the other? So the control arm here is induction chemotherapy followed by radiation versus concomitant chemo-radiation, and the third arm of cisplatin and oral etoposide with hyperfractionated radiation. So this is a trial that doesn’t look at new drugs necessarily, but tries to optimize how do we give combined modality therapy. You can see that there are positive data for either one of these, induction or concomitant, but the trial tries to establish which is the best way to do this. It’s completed and probably will have some data on this next year.
Cancer information
Now the Japanese have already established such a trial and that was published in JCO last month, or two months ago, and it looked at un-resectable disease. And either gave MVP concurrent with radiation or for two cycles as induction and then radiation alone. So it looked at multi-agent chemotherapy, induction versus concomitant and this is the outcome. Three year survival, 14% versus 22%, or median survival 13 versus 16 months. Clearly suggesting that induction chemotherapy here is as good as it was in the North American trials – median survival of 13 to 14 months – and concomitant, when using multi-agents, may be a little bit better. This is the survival showing this, 13 versus 16 months median survival. Long term follow-up and the curves do not come back together.