Balancing Morbidity and Outcome

SLIDES & TRANSCRIPTS
Monday, June 17

Balancing Morbidity and Outcome

Brian O'Sullivan

Slide 1:

Thank you very much, Scott. I would like to thank Ernie and Murray and Scott for inviting me, and to the committee for nominating me for this lecture. When Sam and Burt were speaking this morning, I was wondering if I was going to have anything left to talk about. Maybe what I will do, I will talk about surgery, since you guys talked about radiation treatment, and see what we can do in terms of looking at this difficult question.

Slide 2:

This slide sort of gives us a little bit of a road map of what we will be going through in the next 20 minutes. I would like to talk a little bit about this issue about avoidance of radiotherapy which, of course, applies both to the spectrum of very early disease as well as extensive tumors. The types of surgical management, whether we are talking about conservative versus ablative treatments, or amputation, mutilation, however you wish to talk about it -- I prefer ablative -- and delivery of radiation treatment and, specifically, scheduling of treatment.

We will focus a little bit on pre-op and post-operative radiotherapy and the outcome of our trial. I want to make the point that I believe that brachytherapy is important.
The reason I say this is, I got assaulted about two months ago in Europe for not mentioning brachytherapy. Brachytherapy is part of the armamentarium. It is just as good as external beam, from the knowledge we have on outcome of this disease.
We will focus on acute issues as well as late morbidity issues in external beam -- again, focusing a little bit from the standpoint of our trial.

Special sites, such as retroperitoneal, I will touch on. I will also give you a description of some of the new methods of radiation treatment delivery that provide a good opportunity for preserving normal tissue and improving outcome.

I think we also need to acknowledge that we need good methods that we consistently apply to look at heterogeneity of outcome and assessment of outcome, and we will touch on that toward the end of the talk. Then, also the prospects for multimodality protocols. I am also focusing primarily on local management issues, not on systemic issues in terms of morbidity.

Slide 3:

Now, we have seen this data already. The numbers of randomized trials, in fact, are six for local management of soft tissue sarcoma.

Sam mentioned these already, and we also have the retroperitoneal NCI randomized trial. Fred Alber presented at ASCO some years back pre-op RT with intravenous versus intraarterial adriamycin, and then we have our own NCI trial.

All of these -- except for the retroperitoneal one -- we had high rates of local control, good survival at the rate of 70 percent, as you would expect in this disease, and provide the prospect of good functional preservation with radiotherapy combined with surgery, as evidenced by the classic landmark trial comparing it against amputation, which was acknowledged earlier today.

Slide 4:

I think we should still focused on the fact -- this is the last sarcoma patient I saw, a few days ago, with Jay Wonder -- a superficial lesion, nice plane, right up against the knee. We managed this with surgery alone, as we would with about 30 percent of our patients at Princess Margaret. I think we shouldn't just get off on thinking about radiotherapy always in these cases, and I think Sam made that point very nicely this morning.

Slide 5:

The issue about the omission of radiotherapy is interesting because it applies at both ends of the spectrum, the very contained early tumor and the very extensive tumor at the far end of the spectrum.
If you don't give radiotherapy, you end up balancing issues, comparing local control and tissue preservation. It is this buffer area in here where we use radiotherapy. We are not exactly certain where these question marks or arrows should actually be placed. If you take it this way too far, you are certainly going to presumably maintain local control, but it will be at the expense of tissue preservation. If you go from the left too far, you will probably begin to lose local control at some point, or you will have to do extensive tissue resection. Eventually, if you don't do radiotherapy at all, you will bump into the amputation group. So, we have this paradox of radiotherapy being omitted at both ends for entirely different reasons, when we look at data.

Slide 6:

There is quite a good literature that is emerging. This was talked about earlier today. There are several other papers that I haven't put on here.

Slide 7:

I just focus on the Boston paper that Sam mentioned earlier because there were some nice points made from it.

This is Beth Valdenes paper that Sam did show. We have a local control that is very substantial -- 93 percent -- consistent with other approaches for soft tissue sarcoma with a modest only distant failure rate, which of course exemplifies the selective nature of these cases. This comprised about 30 percent of their patients who did not receive radiotherapy, which would be very similar to our own experience and probably many other big groups throughout the world.

Slide 8:

Further study is needed to carefully define the subset of patients and identify the optimal surgery that should be used, when we don't use radiotherapy. I think there is focus here for study, I think. It is very difficult to do a trial because of the selection characteristics, and I think that should be something that we talk about later this afternoon.

Slide 9:

The Scandinavian sarcoma group, of course, took a different approach. This was Clement Trovik thesis published last year in the Scandinavian Orthopedic Journal. It shows about a quarter of their patients only received adjuvant radiotherapy.

There is a cost for this, of course -- a higher rate of local occurrence, an initial amputation rate of about 9 percent. Their final amputation rate is about 12 percent, because about one-fifth of their cases required amputation for salvage. We don't know anything about the function of these patients to be able to make a judgment as to the outcome of the other patients who had surgical management without amputation but without radiotherapy either. Presumably there were extensive resections.

Now, one of the problems here: this is not population-based, and he makes this point very nicely. Only the Swedish sarcoma registry is actually population-based. The others are put together from interested centers, although it does comprise a lot of Scandinavian sarcomas that would be ordinarily registered. He gives a nice description of this if you are interested.

Slide 10:

Looking over toward our own side of the Atlantic, this is our own geographic area in Ontario, the Ontario Cancer Registry for a similar time period, a similar number of cases, almost 1,500 patients, looking at amputation rates, primary amputation rates, across different regions. There is only one that was statistically significant compared to the others. The benchmark here for statistics was the Toronto area, where they had about a six percent amputation rate. This is all comers. This is not just patients registered at the Princess Margaret.

You notice that there seems to be a slight difference for hospitals that see less than 20 cases and that is for the total amount. We would see a lot more than 50, but 50 cases contributed to the very large sample that you see here. Hospitals that see a modest number tend to have a higher incidence of amputation rate. We also see that there is some improvement as time goes by, over the years, coming in about five percent, which in fact is the result that we have at Princess Margaret. This is data that is in press in Sarcoma.

We have currently actually gone after all these patients. We have a grant funded for a big outcomes study on every one of these patients. We are also looking at the survivors to be able to look at functional outcome, which Aileen Davis is doing as part of the grant. So, over the next couple of years we should have a fair amount of data on the outcome and treatment of every single one of these patients and every surgical procedure and every surgeon and institution that was involved in the management being identified.

Slide 11:

Just changing tack a little bit to the issue about scheduling of radiotherapy -- this is our pre-operative versus post-operative radiotherapy trial from the Canadian Sarcoma Group. That is NCI Canada. Just for interest, this just came out online in the Lancet last week. You can get it, if you register, free online for PDF, and it will come out a week from Saturday in the print version. The next few slides are all available on the paper that is taken straight, actually, from the manuscript.

Slide 12:

This trial took about three years to accrue about 190 patients. It was closed -- I just want to emphasize this -- after a planned interim analysis showed a significant difference between two arms for the primary endpoint of the study, which was acute complications defined as a repeat trip to the operating room to repair the wound or prolonged wound care, prolonged dressings and deep wound packing that might be required over a period of time up to four months after surgical management.
The trial was closed because it was constructed so that, when there was no value in continuing after the primary question was addressed the trial was closed. It was not closed because of specific morbidity. This was part of the protocol design.

We could not have run an equivalence study in Canada. It would have taken about 1,000 patients for us to do a local control equivalence study, and we would never have been able to do that trial. We would still be accruing and still would be accruing for several more years, if we hadn't designed it in this fashion.
In addition, this, we felt, was a relevant endpoint, as much as the functional outcome and late toxicity issues that I will address momentarily.

Slide 13:

We're presenting 3.3 years median follow-up in this study. Most of you are aware we use 2 Gray fractions -- standard conventional radiotherapy, 50 Gray as a phase I in both arms of the study, and the post-operative arm received a post-operative boost by reducing field technique to 16 Gray, or to 20 Gray if there was gross residual disease, which, in fact, there wasn't in any patient.

The pre-operative arm did receive the boost as well if margins were positive which was the case in 12 percent of the cases.

Slide 14:

The acute wound complication, which was the primary endpoint of the study that we see here, was twice as high in pre-operative radiotherapy compared to post-op -- 35 percent versus 17 percent. I would emphasize, though, that there are still 17 percent of post-operative patients who had a wound complication.

The other point of interest is that this seems to be an entirely lower-limb problem. The one patient in the upper extremity, one could argue based on the details, whether it even was a wound complication. It was mainly an infection in the fungating tumor when the patient first presented, but by the criteria it was a wound complication.

Slide 15:

This was statistically significant and the reason for the closure of the trial. The logistic regression for wound complication shows that the variables, pre-op versus post-op, are statistically significant in both univariate and multivariate analysis, as were gross specimen size and volume. That is the volume of the specimen removed and whether the lesion was in the upper or the lower extremity.

All these other factors, including the type of reconstruction done and the center, did not have an effect in terms of the risk of wound complications.

Slide 16:

In addition, if you look at functional status and health status, the patients treated with post-operative radiotherapy had higher function at six weeks after surgery.

That was based on the MSTS, the truncal extremity salvage score, which is a validated, patient-derived instrument for looking at function, and the SF-36 bodily pain score. One year afterwards, there was no difference between either arm of the study.

Slide 17:

If you look at local control -- 93 percent in both sides. If you look at survival, there is an interesting difference in survival which is statistically significant, which we don't have a good explaination for, in favor of the pre-operative arm.

Slide 18:

If you look at death from sarcoma, it is increased in the post-operative arm, but death from other cause mainly drives the movement to statistical significance, in the sense that there is a small number of deaths. If you take them out, this does not appear statistically significant. The departure in the survival curve happens at about 2.5 years, although it was seen on the interim analysis originally as well. So, we have to follow this group of patients in the future.

Now, this data here does not appear in the Lancet article, and refers to late effects two years after radiotherapy. You will notice that the pendulum is now swinging. Post-operative radiotherapy has twice the risk of fibrosis, RTOG grade 2 or greater.

That is significant. Edema is also three times more likely to take place in the post-operative arm. On multivariate analysis, you can see fibrosis is related independently to the field area and maximum radiation dose. Edema is related to field area. These effects are confounded by the maximum dose and field sizes associated with the post-operative arm, and we can't put the schedule of radiation into the multivariate analysis because of that.

Slide 19:

In conclusion, there is increased acute morbidity with preoperative radiotherapy, which appears to be limited to lower extremity. Pre-op is detrimental to function up to six weeks afterwards but then becomes comparable, and that is followed out to a year later. Local control is equivalent.

Reduced fibrosis and edema occurred with pre-operative radiotherapy and we have to wait on late effects, and then there is an improved survival for pre-operative radiotherapy although the reason for that is unknown.

Now, it is important to recognize that the trial was not planned with the idea of doing survival at a specific point in time. One would really not be able to rationalize this based on the trial design, any survival advantage. So, it would have to be regarded as a secondary end point component.

Local anatomic factors should also determine the choice of treatment. I can elaborate on that afterwards, but in particular, since upper extremity has virtually no risk of wound complication, and there is a brachial plexus up there and a lot of lung and things up there, we would actually strongly favor giving pre-op in the upper extremities, especially in the high upper extremity.

Slide 20:

Now, just to change a little bit, because we do have long-term data from our own institution, when Bob and I started working together back in the mid-1980s, we started prospective functional, and outcome assessment. We have 16 years of follow-up on our patients with outcome assessment, including function and late tissue toxicity.

This data is on 364 patients from 1986 to 1998 -- lower extremity soft tissue sarcoma treated with limb salvage and external beam, no adjuvant chemotherapy, and was put together by Ginger Holt, one of our surgical fellows, presented recently at the NSTS earlier this spring.

Slide 21:

You will notice the radiation regime. Low dose -- 50 Gray -- is associated with a two percent fracture rate. And high-dose -- 60 to 66 Gray -- is associated with a 10 percent fracture rate. It is also important to note that the time-to-fracture ranged from 12 to 153 months, which is 13 years.

It does not apply, in fact, to all these patients. So, as we follow these patients out, we probably would see a higher number of fractures in the high-risk ones. In the low-risk ones, it tends to happen to patients who have undergone periosteal stripping.

Slide 22:

So, the conclusion from this study is that significantly higher incidence of radiation-induced fractures appear to happen, at least in our data, with higher doses of radiation when compared to lower doses, and it is usually pre-op versus post-op. Women who undergo extensive periosteal stripping and high sarcomas combined with radiation are at particular risk.

Slide 23:

Now, the challenge of retroperitoneal sarcoma was identified earlier this morning by both speakers, and especially by Burt. We recognize that surgical resection is the mainstay, that post-operative radiotherapy may delay local failure, or time to local failure, and that the local recurrence rates remain prodigious and it is often the cause of death in these patients.

Slide 24:

Just to recap what Burt said, the tumor often provides as best tissue expansion, moving the normal tissue out of the way, the kidney moved to one side and bowel, et cetera, if you look at the same case with contrast in the bowel post-operatively, you will see why we have huge problems delivering post-operative radiotherapy. This bowel is fixed in the area where the tumor was originally, making it extremely difficult, if not prohibitive, to give radiotherapy to some of these patients. Of course, that becomes a big problem in terms of any of the outcome studies for this group of patients.

Slide 25:

Recently, we have presented and published this paper, which was the results of a pre-op study with brachytherapy in selective cases. We started off using brachytherapy in all patients, but, toward the second half of accrual in the study, we omitted it because of toxicity.

This was published in the Annals of Surgical Oncology very recently, and the point I just make on this that I think is of interest, is that, for the first time, we see a break in our data -- at least, between primary and recurrent presentations. As Burt already said, the first go at this might actually be your best time, and this might be something we are seeing here. Certainly we have not seen this before in our data in the past.

Slide 26:

The conference chairman, Murray Brennan, has very nicely summarized this in a nice editorial that Murray I believe everything you say in it. He summarizes the issues.

Pre-operative radiotherapy is very well tolerated. Every single patient had a grade 2 or less bowel toxicity. When the bowel was pushed out of the way, it makes it very easy to give this treatment. There was significant toxicity from brachytherapy. Brachytherapy is likely of limited value. That would be my own bias as well. That may be in part because many of these cases were low-grade liposarcomas, which we know from the Memorial trial are a problem group in terms of efficacy from brachytherapy. He does point out that the follow-up is modest. I think that is very true and we need to follow this in time.

He also points out that external beam is likely the best adjuvant candidate, especially for the low-grade tumors. I like your points about our excuses that the trial may take too long, but, of course, we look back in time at lost opportunity. This would be one group of patients that perhaps there is a trial, if we could get together, and put our efforts to take the long view and see whether we could impact on outcome in this group of patients.

Slide 27:

For example, a trial such as this, which Peter Pisters has been proposing through the Intergroup format, he has been doing most of the heavy lifting to try to get all of us up and going on this trial.

This would compare pre-operative external beam versus surgery alone. There are some contentious issues -- whether you include the boost, whether you include the low grades only, or also have the high grades, whether we have primary versus recurrent cases, whether you allow chemotherapy. There is a whole dialogue going on at the moment over this trial, which we forsee ACOSOG potentially taking a leadership role and bringing it through Intergroup to all the groups involved, if at all possible. I think this would be a valuable attempt, based on what we have seen from what Murray said and is certainly the view of our own group in terms of management, especially of the low-grade tumors. The high-grade tumors, there is the possibility I accept of treating these with chemotherapy as well as radiotherapy.

Slide 28:

Now, I just wanted to say a little bit on new technologies. There is a host of different things that have come to the fore.
I know you talk about molecular target all morning; but there are other targets as well -- the physical targets that we have to deal with as radiation oncologists. These have taken a major change as well in recent times with the advent of computerized radiation treatment delivery. I won't go through all of these in detail, but let me just comment a little bit on the opportunities presented by intensity modulated radiotherapy in soft tissue sarcoma.

Slide 29:

The concept of a sliding window, shown here, can be achieved by using these metal veins that can come in and out electronically and are controlled by computer.
What this can provide is variable fluence intensity across the radiation beam.

That is, it can break up the beam into all the little beamlets. You see these little squaress? They all have different intensities of radiation treatment going through them, at least being exposed. The way they do this is by having different traverse times for these metal leaves that come in and out through the multi-leaf columnation. This is in fact the helios 120 MLC which is in fact the state of the art MCL which is now being equipped on most of the Verion units.

IMRT involves providing variable fluence, or variable intensity of beam, where we deliver different intensity across the profile of the beam using multileaf collimation, as opposed to the flat fluence, which occurs in most normal radiotherapy.

Slide 30:

There are a whole lot of little elegant words that get used. Some of these have been invented by physicists, who have really done most of the preliminary work, Cliff Ling at Memorial has been one of the main ones.

He described these words, "dose painting", where you can see how they can differentially dose a target, as opposed to the solid 66 Gray that we used to have to do where you can block it off, maybe.

Within the target you can in fact give 66 Gray and phase it out to lower doses in whatever way you want. In addition, we can dose sculpt. We can create concave shaped volumes like this, in three dimensions, which is impossible with anything other than intensity modulated radiotherapy. Conformal radiotherapy can provide shaping by blocking; but it can't provide this sort of concave distribution that you can see here. What we can do by this process is provide exquisite dose conformation around targets. In fact, we can treat anything that we want, if we can actually visualize it. So, imaging is an extremely important component of the new era of radiotherapy in terms of dose delivery and accurately localizing tissues and tumors.

Slide 31:

You can see examples of this here. This was presented at CTOS by our group last year. We have treated a number of patients with high-resolution intensity modulated radiotherapy for retroperitoneal sarcoma, which would be our preferred way of treating, especially high up on the right side of the abdomen, when the disease is hooded by the liver and you can't separate it from the liver, unless you do a very sophisticated form of dose sculpting.

Slide 32:

Another example you can see here with a girl with transgression of the interosseous membrane. It is from a synovial sarcoma. Right down on the vessels,

Slide 33:

we have dose-painted around this lesion. You can see we have been able to protect the subcutaneous tissues all around and bring it right out to where the olecranon is in the elbow region. This paper actually has been submitted. We have got two-year follow-up on this patient, who remains well although margins were positive on the vessels. We did give an intensity modulated radiotherapy boost as well afterwards.

Slide 34:

You can see the intensity profile on one of the beams for that patient. These peaks of radiation dose, and valleys here can be illustrated on the dosimetry that you can see here and here, and in fact -- I have actually brought the real beam and the dose as it crosses in this patient. You can see the fluence map as it crosses across in this patient. So, this is the actual beam being used to treat this patient.

Slide 35:

If you look at a non-intensity-modulated beam, that would be the same sort of conformal shape of it -- you don't get any modulation in it. It is just a flat profile across the beam.

One thing we have is about six of these beams all taking account of the different profile intensity of dose that is provided by each of them, and it is a very complex iterative process to derive the target eventually, but you can really get a very significant shaping around virtually any structure, if you can adequately target it or at least identify it.

Slide 36:

You can see another example. We have got another one on the lung and a very large lesion in the deltoid area.

Again, capitalizing on the fact that this is using a large-bore CT scanner, which would not ordinarily been able to be done previously because of the narrowness of the gauge of the CT scanner; but the patient could actually have their arm laid out in the treatment position, and we were able to sculpt right around the lung in this fashion.

Slide 37:

Advantages of sparing subcutaneous tissue? This is a patient I treated about 15 or 14 years ago, who had a very intense reaction with cyvadic and radiotherapy at the same time. Fourteen years later, there was an abrupt-onset honeycombing and edema in the subcutaneous tissues related to this radiation effect and moist desquamation. She actually did extremely well for many, many years, with very little in the way of sequelae except for telangiectasias, and then resulted in this problem.

I think we do have the opportunity to put protocols together where we can spare subcutaneous tissue when we are using combined chemoradiotherapy protocols. There is also the possibility of introducing new complications in the same fashion.

Slide 38:

Now, measurement tools, just to sum up a little bit. We need good prospective and uniformly used measurement tools. For functional assessment, I don't know what everybody wishes to use, but they should be used uniformly.

There is the MSTS, there is the Toronto extremity salvage score which Eileen Davis put together which is what we would normally use.

Grading of late effects, I think, should be emphasized.

Slide 39:

There was a meeting earlier this year that was sponsored by NCI, CTEP, and NCI radiation research branch with a number of participant organizations. A number of people in this room were actually at this meeting.

It was chaired by Andy Trotti, who has done a superb job of putting this together. The idea was to develop adverse effects criteria for a new version of the CTC criteria, which would include surgery.

Slide 40:

We had a musculoskeletal group which Tom Galante, put together; fibrosis, Aileen Davis chaired that. Surgical effects was David Jaques, and lymphedema, Andrea Chavelle. This should come out next year.

Slide 41:

In conclusion, I think we need improved criteria for treatment selection. We want to consider improved techniques for all modalities, in terms of improving the balance of morbidity and outcome.

Better diagnostic tools -- we have been hearing about pathology and radiology this morning. I would emphasize strongly that we need those in order to optimize the other approaches. Improved measurement tools that understand heterogeneity of disease and tissue response. Tissue response is not uniform for all patients, especially with radiation morbidity. Of course, we need to develop multi-modality protocols. Thank you very much for your attention.