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An earlier indication of whether chemotherapyterm benefits non–small cell lung cancer patients—provided by positron emission tomography (PET) imaging—can guide doctors in offering them better care, according to researchers in the May Journal of Nuclear Medicine.
“Our study demonstrates that patients who respond to chemotherapy can be identified early in the course of their treatment, and these patients will generally exhibit prolonged overall survival,†explained Claude Nahmias, professor of radiology and medicine at the University of Tennessee Medical Center in Knoxville. “Although we studied a relatively small number of patients—and our results should be interpreted with caution—it is clear that a repeat PET study with the radiotracer fluorodeoxyglucose (FDG) at the end of the first cycle of chemotherapy would allow the identification of those patients for whom the therapy was futile,†he said. “The ability to provide an early indication of therapeutic response has the potential to improve patient care by identifying those patients who do not benefit from their current treatment,†explained Nahmias. “Patients would benefit from either having chemotherapy and its associated toxic side effectsterm stopped or going on to a different, and hopefully more adequate, therapeutic approach,†added the co-author of “Time Course of Early Response to Chemotherapy in Non–Small Cell Lung Cancer Patients With 18F-FDG PET/CT.â€
Non–small cell lung cancer is the most common type of lung cancer, usually growing and spreading more slowly than small cell lung cancer. -Lung cancer is the second most common cancer and the most common cause of cancer-related death in both men and women in the United States. In 2007, about 213,380 new cases of lung cancer (both small cell and non-small cell) are expected in the United States, and about 160,390 people will die of this disease. For most patients with non–small cell lung cancer, current treatments do not cure the cancer.
“With non–small cell lung cancer—since the relatively modest increase in survival must be balanced against the toxicity of the chemotherapeutic treatment—the case for monitoring therapeutic response is especially compelling,†said Nahmias. “To assess the response to chemotherapy in patients with advanced non–small cell lung cancer, all of the studies published thus far have evaluated the patients at one, or at most two, time points after the initiation of chemotherapy,†said Nahmias. “In our study, we evaluated 15 patients weekly—for seven weeks—as they started their chemotherapy regiment. In spite of the persuasive findings of several studies investigating PET for monitoring response to cancer therapy, until now no published reports have clearly demonstrated that PET results were used to alter treatment,†he noted.
PET is a powerful molecular imaging procedure that noninvasively demonstrates the function of organs and other tissues. When PET is used to image cancer, a radiopharmaceutical (such as FDG, which includes both a sugar and a radionuclide) is injected into a patient. Cancer cells metabolize sugar at higher rates than normal cells, and the radiopharmaceutical is drawn in higher amounts to cancerous areas. PET scans show where FDG is by tracking the gamma rays given off by the radionuclide tagging the drug and producing three-dimensional images of their distribution within the body. PET scanning provides information about the body’s chemistry, metabolic activity and body function.
“Our result—that PET studies one and three weeks after initiation of cancer therapy can predict success or failure of the therapy—should be validated in a larger study in which patients are enrolled with the intention of applying it in patient management,†said Nahmias. He added, “I am forever grateful to all the patients who came back week after week to undergo our PET scans.â€
“Time Course of Early Response to Chemotherapy in Non–Small Cell Lung Cancer Patients With 18F-FDG PET/CT†appears in the May issue of the Journal of Nuclear Medicine, which is published by SNM, the world’s largest molecular imaging and nuclear medicine society. Other co-authors are Wahid T. Hanna, Misty J. Long, Karl F. Hubner and David W. Townsend, departments of Medicine and Radiology, University of Tennessee, Knoxville, and Lindi M. Wahl, Department of Applied Mathematics, University of Western Ontario, London, Canada.
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Pet Imaging vs. Cell Culture Assay
Cell culture assay results of "fresh" tumor (not passaged) specimens with Sutent (a new multi-targeted kinase inhibitor approved for use as a second-line drug for tumors that are non-responsive to Gleevec) have shown tumor cell clusters treated with this drug sometimes take up copious amounts and sometimes have taken up little or none. This drug inhibits several proteins involved in triggering replication in cancer cells. With a new pre-test (EGFRx Assay), it is possible to see which cells have taken it up and which haven't.
Drug resistance/response is multifactorial. It matters not that a particular intracellular molecular target is present, if the drug can't even get into the cell to interact with that target or if it gets in but is metabolized or actively extruded out of the cell (a common mechanism of drug resistance). What is measured with the EGFRx Assay is the net result of everything.
The proto-oncogene KIT, a tyrosine kinase that is inhibited by Gleevec, is overexpressed in a majority of GISTs. Some patients have suffered relapses due to acquired point mutations in KIT, which prevents Gleevec from binding to the protein. Similar mutations have been characterized in EGFR from Iressa-resistant lung cancer patients.
It is not known why Gleevec (and most other drugs) either works or doesn't work. The advantage of the EGFRx Assay is that there is a good idea of what will happen. The disadvantage is that it is not known why the drug worked or why it didn't work, only that it worked. The EGFRx Assay uses a combination of the morphologic endpoint (DISC) and one or more of the metabolic endpoints (MTT, ATP, resazurin) to test the targeted molecular drugs.
The kinases act on and modify the activity of specific proteins. So people will try and get some sort of gene-based test to measure the expression-mutation of these kniases. But something more elemental is going on. Does the drug even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate?
Some clones of tumor cells don't accumulate these drugs. These cells won't get killed by it. But you wouldn't pick this up with an assay which only measured the kinases themselves. The new EGFRx Assay measures the net effect of everything which goes on (Whole Cell Profiling). Are the cells ultimately killed, or aren't they?
Also, the ability of various agents to kill tumor and/or microvascular cells (anti-angiogenesis) in the same tumor specimen is highly variable among the different agents. There are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.
A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents. The Microvascularity Viability Assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect.
The principles and methods used in the Microvascularity Viability Assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.
It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.
Sutent is conveniently pigmented brilliant yellow. Easy to see which cells have taken it up. In the attached photomicrographs (two magnifications), it is fairly easy to see that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The Assay measures the net effect of everything which goes on. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome.
Each of the new targeted drugs are not for everybody. According to the National Cancer Institute, those who benefit substantially from "targeted" drugs is approximately 10% to 20%. What if you are one of those few? This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first.
Photomicrographs:
[url]http://weisenthal.org:80/slide.057.jpg[/url]
[url]http://weisenthal.org:80/slide.058.jpg[/url]