|
So my portion
really deals with the ones that are diagnosed pathologically with
tissue, because I think last night the consensus seemed to be that
we couldn't simply treat with radiation therapy for lesions that
were growing by CT, with the present state of the science. Hopefully
that will change sometime because I think radiation oncologists
are still getting patients referred who cannot even tolerate, or
perhaps it is in the eye of the referring physician, cannot even
tolerate a needle biopsy for risk of pneumothorax. So, this is a
real issue for radiation oncologists. Hopefully our pathology colleagues,
our imaging colleagues are going to come up with some other marker
or imaging study. But for now we are dealing with biopsy proven
cancers. Then I sort of divided patients up between those with good
pulmonary function tests and those with poor PFT's. For the good
pulmonary function tests I still think the standard appears to be
lobectomy, but with the idea that we want to do lung preservation
because these are patients with a high risk of future malignancies.
I still heard the question being asked about limited surgery such
as a wedge resection or segmentectomy. For those patients then I
think the question comes up can surgery alone do that. Maybe for
the very small lesions that is enough. We were hearing about 20%
to 30% recurrence rates following wedge or even post-op radiation.
So, obviously if that still held true for the very small lesions
then maybe surgery alone isn't enough in which case the one area
that I don't think we have talked about, and I don't know of any
good studies in it is pre-op external beam radiation. Certainly
if these lesions were plentiful that would be a worthwhile area
to study. Then Alex Chen gave a very good talk I think last evening
about intraoperative I-125 where it was embedded into a vicryl mesh
and put into the resected area into the segmented or wedge resection
scar and in 50 patients no local recurrences and no post-op complications
that were unexpected. So I think compared to the perhaps the 20
to 30% expected local recurrence rate that was quite interesting
and should probably be followed up. For those patients with poor
pulmonary function tests it is a different problem. Presumably they
cannot have lobectomy and then you are talking about either limited
surgery and again then you get into the surgery alone, pre-op radiation
or the intra-op brachytherapy, but limited surgery could also be
compared to stereotactic radiosurgery. Bob Timmerman gave a very
good presentation of 20-some patients with early lung cancers being
treated with stereotaxic radiosurgery. They were not all less than
1 centimeter in size though, so even in these larger lesions there
was I think near 100% local control.
You cannot get much better than that and very little in the way
of treatment morbidity. So, his dose escalation study is ongoing
still because there hasn't been the expected pneumonitis and that
is with three fractions. So, we are talking then about a less inconvenient
schedule, low risk and a higher local control rate than we are experiencing
with conventional radiation. But I have put conventional XRT down
on here because I think it is still the standard treatment. I do
stereotactic radiation as well, but patients coming to me with early
lesions that would still be what I am suggesting they have outside
of a study. So, the other thing I didn't put in my slide and I apologize
is radiofrequency ablation which obviously is another method of
lung sparing and suitable for early disease. I didn't work it in
there, but I would be the first one to suggest that that is, also,
a comparable modality. I will stop there.
DR. SAXMAN:
Thank you, Laurie. Any other comments, anything anyone would like
to add?
DR. MICHAELS:
You didn't have postoperative radiation therapy for patients who
undergo limited surgery.
DR. GASPAR: That was because of the talk last night from Jeff Bogart
suggesting that there was still 20 to 30% local recurrence rate
when they did it for T1, T2 lesion. So, perhaps it might be different
for the even earlier lesions but I felt that that question had sort
of been looked at and it would be difficult to take that forward.
Do you disagree?
DR. MICHAELS:
As I said yesterday I think one thing that we don't really know
is what is the appropriate target volume. Is treating the suture
line the right thing to do versus trying to extend a wedge resection
to segmental resection or to a lobectomy by radiation.
DR. GASPAR: I think it would be difficult to design studies to answer
that question though because then you could argue why not have done
a lobectomy, you know, if you are talking about doing a more generous
radiation. I hear what you are saying, but I didn't think it was
the question today.
DR. SAXMAN: Yes, Eric?
DR. HOFFMAN: I didn't really comment last night because I think
the time was getting late, but I would just like to reiterate that
there are many areas in lung imaging where the ability to gate and
control lung volume and so forth is highly important and it seems
like it should be a straightforward simple subject. Anybody that
gets involved in it realizes it is not straightforward and easy
at all, and I think that this is an area where there is cross interest.
I think there should be some great focus on how to gate and know
lung volume accurately, that when you do cardiac imaging you would
think that the heart would be harder. It is a lot easier. You follow
the ECG and if it is regular you find a point in that cycle. People
have been measuring lung volumes for many years, but in a pulmonary
function laboratory setting if you are 10% off who cares to some
extent. In imaging if you are 1% off it makes a major difference
in many applications. So, I think that is an area that really needs
some attention.
DR. GASPAR: There are commercial products and home-grown products
everywhere. The problem I think will be having some consistency
among them. Some people do breath holding respiratory gating. Some
people do expiration or mid, shallow breathing. There are so many
different versions of it, none of which I think is proven to be
better than the other.
PARTICIPANT: People sort of showed us Sensor Medics' product that
we have worked closely with Sensor Medics trying to help them develop
it, and I am not sure that I would promote it that much as a final
answer.
DR. GASPAR: We can always treat. The attention of the respiratory
gating is trying to come up with a small volume again and the way
we compensate for it outside of the respiratory gating is just to
add more. As far as we know that still has to be what we do. We
are kind of worried about pulling the tighter margins until we have
a better imaging relationship.
DR. SAXMAN: Rich, last comment?
DR. CUMBERLIN: I wanted to get to the issue of clinical trials because
that is what we are doing here. We came to a consensus last night
that the appropriate clinical trial would be patients that have
these subcentimeter lesions and would go to surgery but are medically
or otherwise inoperable. Now, suppose we do this trial and we find
out that we give a 95% complete response rate; these response rates
are durable and the patients die within 2 years of cardiac disease
or, whatever. If we have those kinds of results what do we next?
Do we leave it at that for the medically inoperable or do we compare
it to surgery and if so under what circumstances? That might be
worth a little discussion right here, since we have everybody, every
specialty represented. I think it would be a good thing to do.
DR. GASPAR: That was sort of what I was suggesting by limited surgery
versus stereotactic radiosurgery concept. You know we still have
the Phase II data to mature perhaps, but I think that is a reasonable
approach. I don't think you can then go back and compare that to
lobectomy. You know, if you have chosen your patients as an inoperable
group.
DR. SAXMAN: I think what Rich is suggesting is moving this at some
point in time into the operable patients and asking the question
of limited resection versus local therapy with radiation, either
stereotactic radiosurgery or whatever.
DR. GASPAR: I think that would be difficult to study for operable
patients, you know, speaking as a non-surgeon. What I hear the surgeons
say is, and it would be difficult to sell to a patient yet, I think
is to talk about doing lobectomy versus stereotactic radiation or
conventional radiation alone. I think it would be a hard sell. I
think you have to deal first with the inoperable patients or the
marginally resectable.
DR. RUSCH: It is very important in a trial like that that you collect
at least some information from the initial biopsies. Again, going
back to the issue of repository concept because you need to be able
to distinguish which patients might have a complete and sustained
response to radiation and also that you have long-term follow-up
with late radiation effects and effects on pulmonary function that
are well measured because otherwise future questions potentially
comparing that approach to some other approach, whether it is RFA
or surgery or whatever just cannot be well designed.
DR. STEVENS: I just wanted to clarify one point and that is I think
that our consensus is going to be that the standard of care today
is going to be what 66 Gray or so, 60-plus Gray in 30 fractions
for these small lesions without treating the mediastinum or the
hilum. Do you agree with that, Laurie?
DR. GASPAR: I think the first thing would be -
DR. STEVENS: No, no, in the unresectable patients.
DR. GASPAR: Then I have to agree that that would still be the standard.
DR. STEVENS: And then the next step will be to compare radiotherapeutic
interventions of various sorts and in the next couple of years we
should probably do that.
DR. GASPAR: Within the trial setting I think you can compare the
standard fractionated x-ray beam with stereotactic radiosurgery.
DR. STEVENS: Would it be reasonable to start doing a Phase I, II
trial in the RTOG to at least start accruing those 60 to 66 Gray
patients in the near term? Is that something that we should focus
on at RTOG?
DR. GASPAR: I guess the question is are we going to see enough patients
at this time referred to radiation oncology prior to resection or
lobectomy.
DR. STEVENS: And it is hard to know.
DR. GASPAR: Right, it is hard to know and so sometimes when there
are those questions I guess the best thing is to open a study sometime
to get an idea of the numbers, but I think that is what Roger Byhart
and the committee asked me to report back to them what we thought
should be done.
If I could ask the surgeons would they support such a study, a Phase
II study in inoperable patients, radiation alone.
PARTICIPANT: Comparing two different radiation modalities?
DR. GASPAR: No, I think we are talking about just a Phase II study
of conventional fractionation is what Greg -
PARTICIPANT: In patients who are medically inoperable that makes
a lot of sense.
DR. SAXMAN: Thank you. We need to move on. Deja vu all over again,
I guess from this morning, but I am sure that based upon the discussion
this morning Paul has some other thoughts. So, we will let Paul
summarize the chemotherapy discussion section.
DR. BUNN: One of the things I think that struck all of our attention
is the studies that were presented all had a handful of patients.
So, you know, there aren't zillions of these patients actually and
these patients are valuable resources that cannot be wasted. I think
in terms of coordination the patients that are going to go on trials
like we just heard I am not sure the mechanisms that were set up
to look at screening are the appropriate mechanisms. Maybe they
are, but we need to figure it out because really the question is
we are not going to create a new mechanism and the question is when
the patients are identified are they going to be followed by those
registries or then are they going to go to ECOG and SWOG and RTOG
or what is the central mechanism for collecting these patients and
following these patients? So, to me a big thing is to figure out
once patients are identified who is going to follow them, and this
is not 6 months of follow-up. We are talking 10 years of follow-up.
So, there has to be some statistical center that has the expertise
and the experience with following patients coming from all across
the country. It seems to me we need to figure out once patients
are identified, these are patients who have got these small nodules,
they cannot be lost. They have to be followed by somebody, and we
have to figure out who it is that is going to follow them.
Is it some Intergroup mechanism? Are they all going to be followed
by ECOG? Are they all going to be followed by ACOSOG? Are they all
going to be followed by SWOG? Who cares, but there needs to be a
coordinated way of identifying these patients and following them
clinically forever. Otherwise they are going to be completely wasted.
Patients are valuable resources that cannot be wasted, and all of
them should be entered on a clinical trial which may only be a follow-up
cohort clinical trial but all of these patients once they are identified
should go on to some kind of a follow-up study. Now, my interpretation
of the consensus was that indeterminate nodules, people that have
small nodules that cannot be biopsied and we don't know what they
are, whether they are solid or partly solid should go on to some
kind of a cohort study which is a cohort registry follow-up study.
My conclusion is that those tumors that are biopsied and are of
uncertain invasiveness should also go on to some kind of a cohort
registry trial and should be followed without any definitive extra
studies. This may not be a uniform or a unanimous consensus, but
I believe those that do have invasive cancer should be eligible
for therapy trials and should be entered on therapy trials. I think
those that are medically inoperable should have the type of study
that has just been discussed. I, personally wouldn't have any problem
putting a patient like that on stereotactic radiosurgery trial.
I think it would be completely appropriate. My own view is those
that have definitive therapy or are going to have definitive therapy
and have definitive invasive cancer should be eligible for trials.
I think that a trial could be done and should be done looking at
either a COX-2 inhibitor or an EGF inhibitor. There was some debate
about the study design. Personally I think the best study design
would actually be to treat them for 6 weeks and see what happens
to the nodule. Then when you took it out you could do a zillion
biomarkers to figure out if your agent was doing something, not
only to shrink it but biologically what you wanted to have happen.
Those patients are going to be followed anyway. They need to be
followed, and I personally believe that you could follow these biomarkers
in a randomized way so that half the patients were getting COX-2
or EGFR inhibitor and half weren't and you could see what happened.
You could correlate the biologic markers with both recurrence and
second primaries. So, I, also, think that some pilot trials in these
patients of the type that Dr. Mulshine was talking about would be
reasonable as well, but again no single institution and probably
no single cooperative group as it currently exists would have enough
patients for any of these trials. So, we need some kind of mechanism
that once these patients are identified that they are going somewhere
to be followed and going somewhere where they can go on a clinical
trial and again I don't know whether that ACOSOG, ECOG or who that
is but I think for the NCI that is really a point of discussion.
It could be one of the registries but there needs to be some way
where these patients are followed and eligible for trials.
DR. SAXMAN: Any other comments?
PARTICIPANT:
I just wanted to mention that I thought Dr. Reeves' data and the
ability to measure 3 to 5% change in a lesion is ground breaking
in terms of our ability to do 6-week trials or 2-month trials or
whatever the ethics or standard of care would allow in whatever
setting it allows it. You have the ones that are biopsied and proven
cancer. Certainly you have disrupted the lesion, but you still probably
have an opportunity to see what happens to that lesion over 6 to
8 weeks and everything that we know about pre-cancer, cancer is
the best parameter for integrating what is happening is change in
lesion size that measures the dynamics of cell division and cell
death. It is probably going to predict better than anything else
we can measure and certainly whatever else we measure in terms of
the biomarkers could be correlated with that phenomenon. So, I just
think when people can measure 3 to 5% change in volume that that
kind of research needs to really be fostered and encouraged.
DR. BUNN: I agree and then you take the nodule out so the pathologist
can correlate what actually happened with whatever intervention
you did with the changing size in the nodule when you have the nodule
in the pathologist's hands.
PARTICIPANT: I would like to second that. I agree absolutely with
what Gary has said and Dr. Korn I think has left but we have been
chatting with him with Claudia and David about coming up with some
new trial structures to take advantage of that brief exposure with
the drug evaluating response in that setting. I would also point
out that Larry Summers and some of the people working with Dave
Schrump have been looking at virtual bronchoscopy and I think that
is going to give you another target to look at in terms of looking
at endobronchial response and we have got to develop new trial mechanisms
around that to address this area.
DR. BUNN: But again the question was raised in the radiotherapy
section are there enough patients and that is a major issue. Certainly
I can tell you the University of Colorado doesn't have enough patients
to do a trial, but certainly if there was a mechanism for every
patient like this that we identify or gets referred to us we would
love to put them into the registry for the indeterminate nodules
and the non-invasive cancers and a treatment algorithm. Nasser indicated
that at Cornell, and I don't know if somebody from Cornell can correct
him, but he was saying at Cornell you are probably talking 10 of
these patients a year. That is probably true for all our institutions.
So, this is going to have to be coordinated nationally by the NCI
through one mechanism or another. David Harrington, can ECOG do
this? Would ECOG be willing to do this?
DR. HARRINGTON: It turns out that with these sorts of patients the
follow-up is less difficult for us than the registration especially
when patients like this are seen by many different modalities. ECOG
is primarily a medical oncology group. So, it is the entry point
that is the tough point, capturing patients who are seen by many
different specialties. The follow-up mechanisms exist in any of
the groups, I think. It is a well-oiled machine, but it is getting
them in there first that is the hard part.
DR. BUNN: Yes, and the question is how do we coordinate this? Do
they go from one registry in there into one registry and follow
them forever in clinical trials? How to get it incorporated into
those registries? I don't know. I think that is something the NCI
needs to be discussing.
PARTICIPANT: Also, I would agree with the small number. We only
had three out of our first year of 1500 patients and also from our
standpoint our expertise in fine needle biopsy is not at the clinic.
So, we don't have David unless he wants to come to Rochester in
January to do that for us. So, our problem is that biopsy is more
than likely going to be done fluoroscopically. So, the pre-op treatment
would be thrown out for us, and we would be in that postoperative
for the COX inhibitor. But it is going to be a small number. So,
I think it is the Intergroup or the American College of Surgeons
that is going to be the key.
PARTICIPANT: First of all I wouldn't let David go up there in January
but I really think that is why in an institution doing screening,
they should be collaborating and that is really the place that you
can identify them. Then if we can develop a follow-up to the other
organizations that would be very good, but it is relatively easy
to do at the screening setting and particularly with the growth
that you can then assess in a central fashion.
PARTICIPANT: One thing we didn't really touch upon is just how difficult
it is to get tissue from these patients for the pre- and post-assessment
process. If we are talking about lesions of less than a centimeter
even if you spin it down or have a cell block you are not going
to be able to do hundreds of biomarker studies. So, probably if
we are going to do trials where we want to follow biomarkers we
want to do them in larger lesions like for example head and neck
tumors larger than 3 centimeters, 6 centimeter tumors before we
get to this stage. We want to have a pretty clear plan of exactly
what we want to look at given the paucity of tissue we are going
to get from the pre-biopsy.
DR. SAXMAN: Thank you. I would just make one comment, Paul. I think
you are absolutely right that the NCI needs to assist in coordinating
these efforts but I hear that ASCO has a president who has an intense
interest in lung cancer and I think that one possibility is that
ASCO could take some type of leadership role in some part of these
efforts as well. That they be something worth considering at some
future date.
PARTICIPANT: Scott, I think that is exactly correct. I think that
as long as our next president of ASCO is here the other issue is
that I understand he has reasonable credibility with the pharmaceutical
industry and they are really not participating in this opportunity
because of the problems with liability and the trial design and
the FDA validation. We need to have some further dialogue around
those points to try to decompress those issues. I think one incredibly
important document that the Institute of Medicine just published
is about health care delivery in the United States and a lot of
the problems that they identified as being really particularly severe
are choke points for the development of this kind of prevention
research. I think the big thing that they point out is that infrastructure
isn't in place to coordinate these things and the second thing is
there are disincentives for pharmaceutical participation in some
of these areas. I think that has got to be addressed.
DR. SAXMAN: Okay, thank you. I wanted to spend the last few minutes,
we are out of time, discussing some people's feelings about how
this forum worked and how valuable this was. I think because we
are out of time and I promised to end at noon that we will use the
evaluation forms for that. So, please, if you would take care to
make comments about the value of this forum for you and the issues
that came out of this and comment as to how you think this might
be better. Before you leave if you would please join me again in
thanking all of the people that put this together, not only the
NCI staff but all of the planning teams and all of the speakers
and everyone. I think they all did a terrific job.
(Applause.)
DR. SAXMAN: Everyone have a safe trip, and thank you very much.
TOP
|
Okay,
we will go on to the summary of the radiotherapy section. Laurie
Gaspar is going to summarize the radiotherapeutics from last evening.
On
this slide is the only thing I really want to talk about in the
imaging area. You know radiation oncologists are very image oriented
people but I was very struck by the sophistication that is developing
in radiology. Right now our software programs for radiation oncology
autocontour normal structures but don't do computer-assisted drawing
of the target. So, that seems a little unusual, and it seems to
me that we are almost there to be able to use computer-assisted
drawing to define our targets because we have a major problem in
differentiating atelectasis from the tumor itself and as well follow-up
patients following radiation treatment. How do you distinguish radiation
fibrosis from tumor progression? So, perhaps our imaging colleagues
are going to help us with that. Then respiratory gating is one of
the issues that I suppose is more central to radiation oncology
in that radiation delivery has to be given during a period of time
for which patients cannot breath hold.