Loco-Regional Control: Patterns of Failure by Leonard L Gunderson, MD

SLIDES & TRANSCRIPTS
Tuesday, March 6

Loco-Regional Control: Patterns of Failure
Leonard L. Gunderson, MD

Slide 1: Introduction

As pointed out by Jack Macdonald yesterday, we are talking from the perspective of, postoperatively, radiation plus chemotherapy being the standard. I will present data from phase III trials including the positive pre-op trial so that, as we get into the question period, we can talk about issues of sequencing as well as treatment intensity and radiation technique.

Slide 2: Adjuvant Chemoradiation

The possibility of adjuvant chemoradiation has been of interest for some time, in view of the trial from Mayo Clinic, which was positive as designed with regard to adding post-op, 5FU of radiation over a surgery-long control arm. The confusing part of that study is that the randomization was done before informed consent. There was an unbalanced randomization and part of the patients opted not to receive the treatment.
While intent to treat was a five-year survival as shown, that was statistically significant, the actual treatment was a 20 versus 12 percent survival. As designed, it was a positive study, but as carried out it was not a positive study.

Slide 3: Pre-op Trial

Another study of interest is the published pre-op trial from Bejing, a fairly large study looking at moderate dose pre-operative radiation without chemotherapy, and also relatively modest irradiation fields. The trial was conducted in patients with cardia lesions only.

Slide 4: Study Results

When they looked at results, they found a positive survival advantage, a p for significance as shown, and tabular format here, 30 versus 20 percent survival. Even though there were improvements in disease control with the addition of treatment, they were still with fairly high tumor bed and nodal failure rates, possibly due to the modest fields and the modest dose radiation that was utilized.

Slide 5: Pre-op Treatment

It showed that the pre-op treatment could be carried out safely with no increase in anastomotic leak rates or operative mortality.

Slide 6: Dublin Data

The other pre-op data of interest, of course, is the Dublin data, which included adenocarcinomas of esophagus and the cardia randomized to surgery, versus pre-op chemoradiation of adult fractionation. That is not normally used in the United States.

Slide 7: Dublin Data

Whether analyzed by intention to treat or actual treatment, it showed an advantage to the pre-op chemoradiation over surgery alone, with the concerns of this study being the five-year survivals in the surgery alone arm, which were quite low compared to what most people feel that they can achieve. It was a trial that was positive as designed by both intent to treat as well as actual treatment for pre-op chemoradiation.

Slide 8: Intergroup Trial

In the United States, we would prefer to go the direction of a confirmatory Intergroup trial based on the interest in the initial small-institution study from Mayo, and pilot data showing that 5FU leucovorin was tolerable during irradiation.
Steve Smalley did the quality control parts of the radiation fields, which were mandatorily designed during the first cycle of chemotherapy that was given before the combined chemoradiation. This was a subject of plenary discussion at the ASTRO meeting this past year, and a paper is nearly ready for submission on technique issues in patients who received post-op chemoradiation.

Slide 9: Patients at Risk

The survival results were shown yesterday by Jack and re-shown by Scott and showed an advantage in both disease free and survival, and with patterns of relapse -- represented on this slide, as opposed to Jack's slide yesterday -- representing percent of patients at risk, not of those who relapsed, of patients at risk with a 19 percent local failure rate with surgery along versus seven percent with post-op chemoradiation. One has to take the patterns of relapse with somewhat a grain of salt, since mandatory CT studies were not a part of this particular trial.

Slide 10: Studies of Interest

So, we look at the three trials that have statistical significance, but with predominance at the larger pre-op trial from Bejing and United States. Both showing survival advantages, with the Bejing pre-op trial and the Mayo post-op trial with smaller doses showing very high levels of loco-regional relapse.
It certainly gives merit for a discussion of some of the studies that are of interest as we look down the road for replacement studies.

Slide 11: Possible Study

Thrown into that are the ECF data shown yesterday by Jack Macdonald showing that, for metastatic disease, ECF showed an advantage to FAM-TX. It raises the question of a number of possibilities for a gastric adjuvant replacement study. One, alternate chemotherapy, both for the systemic component as well as during irradiation, where one might see an arm of the standard arm in 116 of bolus 5FU leucovorin as both the systemic maintenance chemo before and after, is combined chemoradiation.

The chemo during irradiation would also be the bolus 5FU leucovorin, versus an ECF regimen where the 5FU is given as infusion, and therefore, during irradiation would be PVI infusion 5FU. The systemic component would be the ECF chemotherapy. That is an arm that is being piloted now in phase II fashion, to see if it can be taken into a phase III. Based on the pre-op Bejing trial, a positive trial for pre-op, it brings into question ultimately, if one could do it pre versus post-op and those sorts of questions with regard to sequencing issues. With regard to the regional failure problems in the abdomen, demonstrated in the surgery alone patterns of failure data I pointed out, as well as fairly high regional failure rates in the Intergroup trial, it certainly raises the issue of evaluating interperitoneal treatment, which will be the subject of Dave Kelsen's presentation to us.

Slide 12: Data That Supports Evaluating Pre-op Treatment

The other data, as I said, that supports evaluating pre-op treatment in this group of patients includes the Walsh data that I showed you, with a survival advantage, the ERBA data for esophagus, which 75 of their 100 patients had adenocarcinomas versus 25 percent having squamous, showing a suggesting difference which, by the log table, did not reach statistical significance and, by the Cox regression, just barely reached it at the time of their ASCO 97 presentation.
It certainly helps support the suggestion that pre-operative regimens could justifiably be looked at, but practically, those things aren't going to happen in U.S. trials based on patterns of referral at the present time.

Slide 13: Supportive Data

For the locally advanced group of patients, I don't want to take the time to discuss all of the supportive data as far as trials that have suggested changes in results. Jack yesterday presented data showing that external irradiation plus chemotherapy has been shown, with locally advanced disease that would have positive margins if surgery were done up front, or unresectable if surgery were done up front, that irradiation plus chemotherapy can yield about a 10 to 20 percent five-year survival.

The Japan trials with stage IV disease pseudorandomized with the surgery alone. Zero percent long-term survival versus 15 to 20 who got interoperative radiation.
The European neoadjuvant chemo shows the ability to downstage and have a higher percentage of patients with complete resection, but still, as I showed you, with very high rates of loco-regional relapse in the downstage patients who were able to proceed to surgery. The data in these sorts of trials certainly raise issues of trials that could be done and haven't been done in this country since the GITSG, basically, closed up shop.

We haven't had any phase III or even phase II randomized trials. We could evaluate the potential of neoadjuvant chemo or neoadjuvant chemoradiation and allowing an inter-op electron boost. When we look at sequencing issues, it was interesting, in a group of papers that we updated -- Mayo data that were published in 2000 -- when we looked at our patients with either resection up front and microscopic or gross residual, versus those in whom resection wasn't felt to be feasible up front, and who got chemoradiation before an attempt at surgery, and interoperative electrons in a select group of these patients, that the people who got surgery up front, even a marginal gross total resection didn't translate into an improvement in long-term survival when looking at patients in whom surgery was not done up front.

Slide 14: Sequencing Issues

So, sequencing issues are certainly ones that would be of interest to address, perhaps in a trial where half the patients would get randomized to neoadjuvant chemo alone, whether the ECF or the regimen is open for discussion, versus the other half getting combined chemoradiation, two cycles of chemoradiation, resection with the first group getting post-op chemoradiation, the second group getting post-op chemo, but to address the issue of intensity and sequencing to some degree.

Slide 15: Study Results

So, the Japanese results are showing the potential value of inter-op boost in the locally advanced group of patients. Published Mayo data with the total group of 60 patients with locally advanced disease, not including the 28 with microscopic residual in whom we looked at dose escalation as a function of local regional control, showed an advantage to those patients that got an inter-op electron boost in addition to external. There was also an advantage in the subset of patients with loco-recurrent disease, which was just over 20 patients, 21 to be exact, with the inter-op boost over and above the external appearing to translate into improved survival as well, but in a non-randomized setting.

Slide 16: Treatment Algorithms

In summary then, with regard to treatment algorithms for chemoradiation, when surgery precedes chemotherapy, we get resection negative margins, no further treatment for those confined to the node negative, but certainly the need for replacement studies for those with high risk for relapse locally and systematically. In resected but residual they are looking at irradiation plus chemo but unresectable for cure, preferably going back to a regimen of pre-op chemoradiation allowing intra-op electrons as an option and maintenance chemotherapy and evaluating that.

Slide 17: Irradiation Technique

For irradiation technique, in the last portion of my presentation, I wanted to concentrate on some of the issues that Steve Smalley raised at his ASTRO plenary session presentation.
In the Intergroup 116 trial, where Steve did the yeoman's task of evaluating all irradiation fields before they could proceed on to treatment, what was required in there was, in all patients, coverage of the primary tumor bed, the regional lymphatics, as well as the duodenal stump or remaining stomach, but with the realization that one needed to preserve at least two-thirds of one kidney.

Slide 18: Semi-design in Trial

Part of the justification for the semi-design in this trial were patterns of relapse in the Minnesota re-operative series, with this now superimposing the bed failures, which are the darker circles, the nodal failures which are the open circles, and a potential idealized field, but not intending that this be the field that everybody try to utilize because it is going to differ based on site within a patient.
This showed that the idealized field, one could usually end up with preservation of two thirds of the right kidney for proximal lesions, two thirds of the left kidney for distal lesions.

Slide 19: Generalized Field Intent

This being from the 0116 protocol, it is showing the generalized field intent, with these being blocks to preserve areas that didn't need to be treated, showing the stomach general position before resection and showing that approximately two thirds of the left kidney may be in the field, but then one needs to preserve two thirds of the right, but with the realization that that may differ from sequence to sequence.

Slide 20: Up-front Review

Had that up-front review not been done, 35 percent of patients would have had a major or minor deviation that could have affected outcome. By doing the up-front review, only 6.5 percent of patients ended up with such a deviation.
So, it was people who wouldn't make the changes that Steve had suggested, with it being a combination of tumor bed errors, node errors, failure to include the anastomosis or differentiated duodenal area, or over-treating critical structures.

Slide 21: Deviation

The biggest deviation was in those patients with the proximal lesions of GE junction or cardia, and very few problems with the mid-gastric lesions, higher risk, again, with the distal lesions. The conclusion from his presentation is that future trials will need to utilize the prospective field design, just like the current trials have done.

Slide 22: Mayo Analyses

In our Mayo analyses we looked at the issue of multiple fields versus parallel to post-fields, as far as treatment tolerance. I had treated a majority of the over 100 patients that were looked at in our two combined papers, but in this post-op irradiation paper there was a group of 63 patients with only 18 having parallel to post fields, and the rest being treated with multiple fields. When one analyzed treatment tolerance of grade IV or grade V toxicity, they were finding statistical significance and advantage to the multiple field approach, where you are going to avoid the hot spots that you can see with parallel to post treatment. This shows you an example of a lateral field that would be combined with the sort of APPA field that you saw from the diagram of Dr. Smalley from the 0116 protocol.

Slide 23: Example

This is another example. It is showing an APPA field combined with a lateral field with regard to a patient with an EG junction but extending a fair amount into the stomach with some bulky nodes as well, so there is a need to include virtually all nodal sites in the initial field design.

Slide 24: Treatment Field Optimization

About a year ago, Joel Tepper contacted Steve and me and said, we need to think about treatment field optimization. Some people were having concerns about putting patients on the study because of the mandatory, fairly standard field approach, of including bed, remaining stomach, and all nodal sites that you could safely treat in all patients. So, Joel pushed, based on surgical literature, suggesting a difference in risk of nodal involvement based on site of primary within the stomach, but with the realization that, based on prominent submucosal and sub-serosal lymphatics, that even with a distal lesion you can have splenic hilar involvement and with a proximal lesion you can still have porta hepatis and pancreatic duodenal involvement.

There are a number of papers included among them, Tavre Acasos' paper back in 1971, that did look at site versus incidence, breaking it down by cardia, fundus, corpus and antral lesions. He certainly showed that, with the cardia lesion, there was a higher incidence of nodes in the vicinity, but still with eight percent in pancreatico-duodenal and nine percent with porta hepatis. You can look at the different sites of lesions and see the variations in nodal disease as one goes through this. There is a shift, but still with some risk of nodal involvement independent of site.

Slide 25: Optimized Irradiation Fields

In trying to put into play the question of optimized irradiation fields, Joel and I decided that it made the most sense -- and it is being put into play in the phase II study of ECF -- to add it to radiation. That is a CALGB pilot, but Mayo has been invited to join that. We are putting into play a tabular format of field design, whether one includes the stomach, bed and nodes, based on both TNN stage as well as the site of the primary lesion. While I don't have time to go into detail about this format today, we will use the next slide just as an example. The desire, if one can safely do it, is to treat the remaining stomach in most patients, but with the realization that with an EG junction lesion, you definitely need to be able to block the right kidney.

So, you would bend over backwards to find that, even if the TN stage suggested you needed to include it, you need to exclude two thirds of the kidney, which is usually going to be the right. With cardia lesions, it is preferred again to treat the remaining stomach. You are usually going to be blocking the right as opposed to the left.
With distal gastric lesions, you are usually going to be sparing two thirds of the left kidney. Occasionally, a patient's anatomy differs, and this is where the treating radiation oncologist cannot just blindly put into play the issues of treatment, but needs to take into consideration TN stage.

Slide 26: Four Tables

What we did was put together four tables. I will just go through two of them as examples for you, breaking it up by region. This is a body, middle third, cardia proximal a third, taking TN stage, and looking at the question of remaining stomach, tumor bed volumes, nodal volumes. For the middle third of patients, they are treating the remaining stomach in all T stages, including nodal volumes primarily in those with adherence to surrounding structures that may play nodes at risk that the surgeon may or may not have removed with an incomplete dissection.

For the node positive patients, they are always treating essentially all of the draining nodal areas that are at some risk, based on a central location of the tumor.
As you can see, where for the cardia proximal third lesions, the nodal drainage differs and some optional node sites then exist. Where we do see the pancreatic or duodenal and porta hepatis nodes, in patients that have an adequate surgical dissection of a D-1 plus D-2 with examination of 10 to 15 nodes and have only one or two nodes involved, the exclusion of these nodes is quite appropriate. It spells out in more detail than the initial protocol did what is appropriate for each site, for each stage, and hopefully will present less of a technique problem. Steve is actually worried that it might present more problems, but I think with some of the footnotes that Joel and I have added to our tables -- you have to have an adequate number of nodes involved and the like -- that this might end up being easier to transport irradiation fields across the United States. With this having been identified with regard to yes, we have improved treatment, yes, there are some concerns about field design and here is how we are going to approach it, I would like to turn the time over to Dave Kelsen for a discussion of intraperitoneal therapy issues.