Clinical Applications of P.E.T. in Oncology

Speakers

• Dr Joe Connors MD: Medical Oncology, Vancouver Cancer Centre
• Dr Simon Sutcliffe: CEO, BC Cancer Agency
• Dr Peter Conti, MD: Associate Professor of Radiology, Clinical Pharmacy and Biomedical Engineering USC
• Dr Richard Wahl, MD: Director of Nuclear Medicine, John Hopkins University
• Dr Richard Baum, PhD: Chairman PET Centre, Zentralklinik, Bad Berka, Germany
• Dr Edward Coleman, Professor of Radiology, Duke Medical Centre

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Dr Connors: Just quickly to re-summarize what I was proposing is that we would use PET scanning in two I think fairly well described situations:

• The staging indication would be in specifically patients with early staging disease, with aggressive histology lymphoma, where our treatment plan is brief chemotherapy and radiation and where realization of more advanced disease would lead to an extended course of chemotherapy—so a major treatment change. We would not be using it for the indolent lymphomas or Hodgkin’s lymphoma for two different reasons:
  1. We need more information about which indolent lymphomas might have accurate uptake, and
  2. In Hodgkin’s lymphoma, our success rate is high enough that we don’t need an additional staging test.
• For advanced disease the crucial issue is discerning the identity of residual masses and here one could say instead of what I have said before where I said at advance disease post treatment evaluation to add radiation, it could be add any additional treatment. If we had sufficient confidence in the test, we might for instance add high dose chemotherapy and stem cell transplantation if we in fact quite strongly believe to the positive predictive value, but any rate, the simplest situation to understand is the addition of radiation and we would use it to evaluate residual masses. A patient in complete remission by CT scanning then wouldn’t fall into this category where the overall yield seems to be too low to justify routine PET scanning for that population. For advanced disease where we planned radiation but we are concerned that it may confer undue toxicity we would use PET scanning to eliminate the use of the radiation in those patients where PET scanning is negative and you saw from Dr Voss’s results that that is actually the use to which we have most frequently put PET scanning to use so far and then...
• Finally, in highly selected patients where potentially the patient has relapsed and the other tests we have available are not yielding an unequivocal answer we would use PET scanning to help to understand the whole situation.

So those are the indications.

Dr Sutcliffe: Thanks very much, could I perhaps pose those to our expert panel for comment?

Dr Wahl: I would just comment that in the low grade lymphomas one of the papers that you refer to looking at the mucosa associated lymphoid tumours or lymphomatized tumours—those were mainly gastric I think in that paper for 10 of them, those are small volume tumours. I think that it is pretty clear that PET is not indicated in that kind of tumour especially in the stomach because the background uptake is fairly high. I think that most other studies though, when you look at larger volume, even lower grade lymphomas, several you didn’t reference have shown reasonably high sensitivities of FDG. In those tumours you will have a higher incidence of false negativity but I’m not quite as pessimistic as you. I think the ones you selected, the ones particularly in the stomach are a particularly bad performing group partly because of the low volume so when we had looked at lower grade lymphomas we had fairly high success rate and certainly with gallium I believe they are more commonly negative, so I would agree with you that these lower grade lymphomas may not be well imaged but we have had abundant cases particularly cases we treated. With radioimmunotherapy when the FDG uptake has been intense and I think the real issue is how is it going to change your management of those? So I’m not as pessimistic about the low grade lymphomas as you were from the data that you selected.

The data on bone marrow involvement, 16% of your patients had additional sites of bone marrow involvement identified which you thought was not significant, there was another paper from Ohm, Germany I think that showed about 20% may be higher incidence of finding bone marrow lesions by PET when the bone marrow biopsy was negative so this is for 1 in 4 or 1 in 5 patients and that just depends on how the treatment is going to change, but if you think that bone marrow biopsy is important for staging the marrow then the fact that you find 1 in 4 or 1 in 5 additional patients with PET might be important depending on how treatment is changed.

Again, I thought that you may be being more conservative than I would have been in terms of indications in the lower grade patients other than that the cure rates of 97% are pretty important but my sense from our oncologists and radiation oncologists is that there is a little bit of a tendency to move to less chemo therapy in some of the Hodgkin’s lymphomas because of the higher incidence of side effects down the line years later for patients that have had both chemo and radiation and maybe the radiation for cure is still not such a bad thing to look at. I know that this has been there are different groups who have different view points but my sense right now is that, having seen several cases of failure just outside of the radiation field, that if somebody is thought to be curable with radiation therapy alone then doing an initial PET may be quite a reasonable thing to do to define that field because it is your one chance, it is your best chance for cure. It is hard to match fields afterwards so I think as least there is some opinion in the US that trying to plan those fields for initial curative radiation therapy is really where PET can make a big difference if you find a little bit more extended tumour so those are just some comments—I generally agree with you.

Dr Connors: You are correct we have to put these things in the local context. We don’t manage any patients with Hodgkin’s disease with radiation therapy alone in all patients receive some systemic chemotherapy and it is in that context that I didn’t think it would add to our usefulness. With regard to the indolent lymphomas, that also has to be placed in context because 90% of these patients with advanced disease as defined by other modalities of investigation. So it would still be a rather small and confined group where one would have to think through particularly what the consequences of missing the advanced disease which would then only be discovered when they relapse after some rather well tolerated field of radiation so I did try to err on the side of being quite conservative here so that any indications that we do come up with are highly defensible. Thanks for your comments.

Dr Coleman: Yes, I agree with the comments that have been made. I think that you are being conservative in its utilization and certainly there is nothing wrong with that to start out. Get experience. I do strongly recommend that FDG-PET replace gallium, I think that for those of us who have been doing Gallium scans for years, just the quality of the information, the accuracy of the information is just much better with the FDG-PET than with gallium so if nothing else for those patients who now have been getting gallium scans, they should be getting FDG-PET scans, then the information will be much better.

Dr Baum: Just a small remark concerning gallium. I think one should also mention the radiation burn for the patient: comparing gallium with FDG-PET, especially in young patients was longer follow up period and repeated scans, it comes to an essential amount of radiation from gallium, If you use 5 MC per dose it is some 4 to 5 folds the radiation exposure as compared to F18 FDG-PET.

Dr Conti: Just in our own clinical experience in Los Angeles, I think the issue of lymphoma and advanced disease needs to be perhaps be reconsidered in the sense that looking at disease even if it is advanced at the time of diagnosis as a baseline for level of measurement and our understanding of the metabolic presentation of the cancer, because when you go back and evaluate residual disease these cancers do vary even within cell type in their intensity of uptake. So in our experience it is usually very useful to have that prior study to refer back to, as opposed to deciding not to do the PET scan and then being considered down the road for whether or not there is residual disease—you have no base line at that point.

Dr Connors: I agree and I think as we gain more experience that that might well be another way that we would use PET scanning and also worth commenting about the ability to distinguish the different histological types at presentation because a substantial fraction of patients who appear to have indolent or low grade disease on presentation actually harbour islands of transformed disease. I myself would be particularly curious as a research question as to whether PET scan positivity in diagnosis for indolent lymphomas might not actually predict for such islands of more aggressive disease, something that we will be able to find out in the future.

Floor: Joe, I just wanted to ask in reference to the second and third point—both of these would be CT positive patients that you had referred to in both in our group and in the literature, there was one group that had 5 negative PETs; I mean they were all negative PET–positive CT and negative PET and 19 of them, of these 5 had an unpleasant outcome I don’t remember if they relapsed or died or something. That is a fairly high rate of bad outcome for that group that you would not be offering them treatment. Do you remember that slide and I just wonder at what level of false negative that you would be willing to accept for this group when most of them presumably would be eligible for a localized treatment plan in addition to their chemo? The 25% relapse, I do not know right there does that not make you nervous or what you would do about that. I presume you would not have offered these people additional localized therapy and is that enough level of comfort?

Dr Connors: First of all, the recommendation that I am making is that we undertake to do a PET scan in this situation because the patient has a positive PET scan so that is evidence of residual disease at the end of their treatment. Whether we would be willing to rely on the negative PET scan is a good question—this study had the lowest negative predicted value out of any of the studies reviewed and I’d want to put all of the studies together—rather than basing my conclusions on a single one. Remember that in lymphomas we do have back up treatment and so experiencing a relapse may not have some of the implications that it would in a solid tumour especially these patients that were patients with Hodgkin’s lymphoma they would still have a 60 or 70% chance of being cured with back up treatment and so it may make good sense especially if this figure is more like the 5% to 10% that has been found in the studies with a larger number of patients. To observe these patients for the minority that relapse, embark on more intensive treatment at that time. Because we would not be offering additional treatment, and this would be the group that we would learn about most quickly and we would find out if in fact this was an error in decision-making and realise that and could revise our treatment approaches after that.

Dr Wahl: Just a comment: the other issue and this particular paper there, the number of instances of CT negative, PET positive was very low in this study, but there was an article in the JCO in January of this year (2001) where if I recall correctly there were something like a 15%–20% incidence of PET positive, CT negative cases. Which was higher than most studies, but in that particular study those cases which were CT negative, PET positive had a very early frequency of relapse and I have a slide and will show you that later, so obviously neither a negative PET nor a negative CT are completely indicative of good long term survival—I think both can miss low tumour burden due to the physics of the detection of the method, so your negative studies will—you are not going to find a 3mm focus lymphoma in general I would think, especially if it has been metabolically stung by chemotherapy. So these aren’t like an in vivo PCR of the whole body, so I think it is fair to say that negative or both are not necessarily going to carry a negative predictive value, but this is particularly bad, this is worse than the average study as was pointed out, with a quarter progressing.

Dr Sutcliffe: It would seem then that the indications that have been put up are:

1. Recognised within the context of our own local management plans
2. Would be recognised as being conservative relative to the evidence but supportable by the evidence that is available in the literature and practise.

It would seem a fairly strong recommendation that if you have PET capability, there is no reason to be doing Gallium scans in lymphoma any more and just as I am allowed the prerogative it raises the interesting question at some time from a health system perspective whether staging of lymphoma would go over to PET based evaluation and one would in fact reduce the frequency in which one is doing other types of investigations, the argument I image would be weak at moment from an economic perspective but that could presumably change over time and acceptance by the profession.