Hello, I'm Kirk Frey, chief of the division of nuclear medicine and molecular imaging at the University of Michigan Health System. This lecture will be the fourth in a series on the use of FDG-PET imaging in the evaluation of non-small cell lung cancer. And this lecture will consider some evolving concepts in the use of FDG-PET in treatment response monitoring. These are my disclosures which I do not expect will have an impact on the topics we're going to discuss. Let's begin this lecture with the posing of a question that hopefully will be addressed and answerable by the materials we'll consider. For impact on adaptive therapy planning, FDG-PET is needed, a, at completion of treatment, b, during the delivery of therapy, c, before and during the delivery of therapy, or d, at intervals following achievement of a complete response. The learning objectives for this lecture are that participants will achieve an understanding of therapy response monitoring with the use of FDG-PET imaging, and an understanding of possible use of FDG-PET in adaptive treatment planning. This comes from a summary published in the Journal of Nuclear Medicine and Molecular Imaging in 2009 by Dr. Hicks from Australia which summarized, at that time, all of the evidence based reports, dealing with the use of F-FDG PET in monitoring response of patients to therapy for non-small cell lung cancer. And as you can see, many studies of substantial size were summarized here. In virtually all of them, there was evidence that the PET imaging was able to capture an aspect of therapeutic response despite a disparity of techniques used, a disparity of response characteristics that were applied, and of course, the disparity in specific patient populations that were enrolled. But this kind of information gives hope that FDG-PET imaging may have a role in telling us about how individual patients may respond to the chosen therapy or surgically unresectable disease. Therapeutic response idea is actually best articulated perhaps in response to treatment of high grade neoplasms, especially high grade lymphomas. And in this context, it has become now a standard of practice to monitor the early response to chemotherapy, and that's usually after two cycles of chemotherapy, or in some of the data we'll look at here, in the use of radiation therapy after approximately 50% of the intended total dose has been delivered. The presence of a metabolic complete response, abbreviated here mCR, predicts a durable therapeutic response in that patient. Early metabolic complete response identifies patients who may not need more aggressive or intensive treatment modification. And finally, stable disease or progression despite therapy can be used to change therapy, i.e., adaptive therapy protocols, where a new, or different, or salvaged therapeutic approach is engaged without waiting for completion of the ineffective treatment that's been delivered. This is a cartoon example from work published by Dr. Wahl and his colleagues that shows how this works. So if we start on the left of this figure, with no chemotherapy or radiotherapy yet delivered, we have a metabolic intensity in the tumor which we presume is reliably imageable and which we have detected with PET. Now if one waits until the completion of the delivery of, say, a cycle of six courses of chemotherapy, we may achieve aside our toxic effect, a cell kill effect that reduces the number of surviving cancer cells to fewer than our threshold for detection in PET imaging. So that patients who have a modest but incomplete response may not be distinguishable from those that had a better but incomplete response, or those who had a cell kill response to therapy such that at the end of a sixth cycle they presumably have no residual surviving neoplasm. So these three conditions cannot be resolved one from another by FDG-PET imaging at the end of therapeutic strategy. However, if one images early in the delivery of therapy, say here, after two chemotherapy cycles, or perhaps in some instances even after one, one can detect the early evolution of an undetectable residual tumor mass which is indicative then of a very aggressive and favorable response. And the assumption then is that further delivery of the same therapy for additional cycles will reduce the viable mass of tumor to a level that may either constitute a cure, or at the very least, a long-term durable response. So this is the underlying theory for use of interim PET imaging during the delivery of therapy to measure their response in the tumor. There have been other papers that indicate similar kinds of use of FDG-PET. In the planning and delivery of therapy this, from an Israeli group, demonstrates in the primary lesion in lung cancer, these are isotherms in therapeutic delivery. And here is a map in this represented as individual patient of the recurrence of tumor and its metabolic intensity. And what these investigators discovered is that areas of recurrent tumor after delivery of completion of radiotherapy are often subtended by the areas where the initial metabolic activity in the cancer was at its highest. And the receiver operating characteristic curve analysis of this suggests the possibility of use of FDG imaging intensity prior to therapy to guide the pattern of radiotherapy delivered in order to maximize the value of therapeutic response. Work in our own laboratory related to the early response monitoring of radiotherapy is summarized here in this paper by Dr. Spring Kong. Patients with nonsurgical, non small-cell lung carcinoma were imaged with FDG-PET prior to the delivery of radiotherapy and then midway during a therapeutic course of radiotherapy, and again at the end of completion of radiotherapy. And what was identified in these studies is that a considerable metabolic response to therapy was detectable after delivery of only slightly more than half the total dose, and that this was highly predictive of the overall outcome at the end of therapy. So this suggests the possibility that interim imaging during the delivery of, say, radiotherapy as in this case might serve as a tool for refocusing the remaining radiation dose to target those areas that have not yet completely responded. The question we posed at the beginning of this lecture was that for impact on adaptive therapy planning, FDG-PET is needed, a, at completion of the treatment, b, during the delivery of therapy, c, before and during the delivery of therapy, or d, at intervals following achievement of a complete response. And I think it's clear from the presentation that we've seen, the correct answer is c, that in order to use the FDG-PET response in the delivery of adaptive therapy one needs an image at the outset and midway or during the delivery of therapy to evaluate the patient's response and perhaps to replan the remaining therapeutic delivery. The take home points from this module concern future directions in the use of FDG-PET to assess and predict therapeutic response and to assist with the development of adaptive further therapy approaches. Prospective studies of metabolic tumor response characteristics are, however, needed. I thank you for your attention to this fourth lecture on the use of FDG-PET imaging in the evaluation of non-small cell lung cancer, and thank you again.
