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"Men of science in this city are awaiting with the utmost impatience the arrival of English technical journals which will give them the full particulars of Professor Roentgen's great discovery of a method of photographing opaque bodies," reported the January 16, 1896, edition of The New York Times of Wilhelm Roentgen's discovery of rays that could penetrate flesh and photograph bone. The finding -- which in 1901 earned Roentgen the first Nobel Prize in physics -- began a medical revolution that continues to this day.
"Advances in imaging technology -- and in the ways we apply it -- are having a major impact on cancer care," said Hedvig Hricak, Chairman of Memorial Sloan-Kettering Cancer Center's Department of Radiology. "We are able to detect cancer at smaller and smaller sizes. Imaging findings frequently provide crucial information for treatment selection, treatment planning, and assessment of response. And imaging is increasingly being used to guide minimally invasive procedures, changing the nature of surgical practice. Furthermore, imaging is accelerating our understanding of the biology of cancer and hastening the development of new drugs."
Testifying to the increasing importance of imaging in cancer care, Memorial Sloan-Kettering's Department of Radiology has grown dramatically in recent years. The number of faculty members has doubled, from 32 in 1999 to 64 in 2005, while the total staff has grown to 480, a figure that includes the technicians and nurses who are an integral part of the department.
Diagnosis: The First Step
Today, imaging technologies are improving the way many types of cancer are diagnosed and staged. The impact has been especially significant in prostate and breast cancers.
The imaging revolution in prostate cancer began in the late 1980s with the arrival of computed tomography (CT). "Prior to this, it was very difficult to visualize tumors in the pelvis or to assess their response to treatment," explained Howard I. Scher, Chief of Memorial Sloan-Kettering Cancer Center's Genitourinary Oncology Service. With the advent of spiral CT, which takes continuous wraparound images, physicians are now able to detect a tumor measuring a centimeter or less. "As the technology improves, our ability to detect cancer and to monitor treatment effects has improved. It's like getting a bigger magnifying glass," Dr. Scher observed.
In addition, as clinicians have incorporated the use of magnetic resonance imaging (MRI) into prostate examinations, its benefits over conventional examinations are becoming clear. In older men with a condition called benign prostatic hypertrophy, a noncancerous enlargement of the gland, x-ray images may appear as "smorgasbords" of slightly, but not sharply, distinct tissues, explained Peter T. Scardino, Chairman of the Department of Urology. New research from Drs. Scardino, Hricak, and their colleagues suggests that endorectal MRI (MRI performed with a coil placed in the rectum) to detect cancer in the gland is more accurate than the digital rectal exam, the standard physical examination for prostate tumors. "Unless the cancer is large, with ultrasound or a physical exam you have no idea that any abnormality is there," Dr. Scardino said.
MRI paired with spectroscopy (MRSI) adds a chemical dimension to anatomical imaging that further enhances clinicians' ability to accurately diagnose cancer. MRSI excites protons in the molecules inside prostate cells and measures levels of the molecules choline and citrate. In men with prostate cancer, choline levels surge and citrate levels fall, reflecting the nutritional demands of the tumor; the ratio of the two molecules can indicate the presence of cancer. "When you see an abnormal spectroscopy, that is probably a high-grade cancer, a larger cancer, and a more aggressive cancer," said Dr. Scardino.
Studies by Memorial Sloan-Kettering Cancer Center radiologists, including Liang Wang, under the direction of Dr. Hricak, and medical physicists Kristen L. Zakian and Amita Dave, among others, have shown that MRI and MRSI greatly assist in staging prostate cancers and predicting the success of treatment. The two techniques markedly improve clinicians' ability to identify indolent prostate cancers -- small, slow-growing tumors that may not require immediate treatment. In a recent Memorial Sloan-Kettering Cancer Center study, for example, the accuracy of prediction of indolent prostate cancer was 75 percent for MRI and 85 percent for a combination of MRI and MRSI. Other studies have found that MRI/MRSI adds to the predictive powers of prostate cancer nomograms, statistical models that help doctors choose the best treatment for patients. Today, an MRI/MRSI scan is available to virtually every man treated for prostate cancer at the Center.
Memorial Sloan-Kettering Cancer Center researchers and clinicians also are applying MRI and improving its use in diagnosing and staging breast cancer. According to D. David Dershaw, Director of Breast Imaging, this year Center radiologists will review some 4,000 breast MRIs, more than any other breast cancer MRI program in the United States. Dr. Dershaw and Elizabeth A. Morris, Director of Breast MRI, along with radiologists Laura Liberman and Lia Bartella, have conducted some of the seminal research on the use of MRI in breast cancer diagnosis. Their work shows that it has a higher sensitivity for the detection of cancers, particularly preinvasive ductal carcinoma in situ, in which tumor cells are confined to the ducts of the breast. They also have pioneered the use of MRI-guided breast biopsies, allowing physicians to more precisely remove tissue for diagnosis without surgery, as well as to localize lesions seen only on MRI for those women who will go on to have surgery.
Spectroscopy may eliminate the need for some breast biopsies altogether, offering instead a kind of "instant pathology report" based on a tissue's chemical signature. "Preliminary data suggest that the spectroscopic pattern might be able to detect which lesions are definitely not cancer," Dr. Dershaw said. "And if we can determine that a patient definitely doesn't have cancer, that person needn't go through a biopsy."
However, the bulk of breast cancer imaging remains the province of mammography, which relies on x-rays to detect abnormal tissues, and in particular, calcium deposits that may signal cancer. Indeed, Larry Norton, Deputy Physician-in-Chief for Breast Cancer Programs, predicts mammography -- which recently has been augmented by digital imaging and computer-guided interpretation -- will continue to be the standard method of diagnosing breast cancer. MRI and spectroscopy will supplement, not replace, the technology, most often in women at high risk of the disease. "Mammography is good enough that it's unlikely we're going to be able to replace it in the near future with anything else," Dr. Norton said.
Treatment: Planning the Attack…
"Imaging has enabled us to understand the anatomy of breast cancer and at the same time has had a direct impact on our ability to intervene," Dr. Norton explained. "It has helped diagnosis and has guided therapy for quite some time. And as the technology advances, it is helping us more and more." One example: breast conserving surgery, which avoids removing the whole breast, was made possible by screening mammography that can identify miniscule tumors when they are relatively easy to remove. "The revolution in breast conservation was totally dependent upon the revolution in breast imaging," Dr. Norton said.
In prostate cancer, computer software overlays spectroscopic evidence on top of an MRI of the prostate gland, offering surgeons a detailed view of where a tumor is located. This information is crucial to planning surgery that minimizes the chances of sexual dysfunction and urinary incontinence, two frequent consequences of prostate cancer surgery. "When I operate, I want to be sure to 'get around' the cancer, while preserving the nerves responsible for sexual function and the urinary sphincter responsible for continence," Dr. Scardino explained. "When we do MRSI, it helps me decide how widely I have to dissect near these crucial nerves."
A recent Memorial Sloan-Kettering study by Drs. Hricak, Scardino, and others of surgical planning for 135 men who had MRI before radical prostatectomy found that with the MRI findings surgeons made better decisions about whether to remove important nerves and blood vessels during the operation.
Going forward, Memorial Sloan-Kettering Cancer Center's Center for Image Guided Intervention, now in the planning stages, will house image-generating technology and offer patients minimally invasive treatment options -- radiotherapy and high-frequency ultrasound, for example -- that work together to optimize care. "The future of cancer care lies in minimally invasive, image-guided approaches to diagnosis and treatment," Dr. Hricak said.
Dr. Norton agreed. "Much of the diagnosis of cancer, as well as the therapy for it, will be conducted by image-guided technologies," he said. The result, he added, will be a greatly streamlined experience for patients. "I can easily see the day when somebody comes in, gets a screening test, is diagnosed with early stage breast cancer, undergoes therapy, and leaves cured in time for dinner."
Spectroscopy has the potential to detect the earliest signs that a treatment may be working, even before the effect of therapy is noticeable on MRI. "The early data suggest that there's a modification in the choline peak in breast cancers after the first dose of chemotherapy in patients for whom chemotherapy will be effective," Dr. Dershaw explained. "So, even before there are changes in the volume of a tumor there may actually be a change in its biochemistry."
Nevertheless, assessing tumor volume can provide critical information about how well a treatment is working. While imaging devices can provide rough estimates of tumor size by measuring diameter and circumference, these estimates are not fine enough for small tumors and can't detect early changes in tumor size. Now, Memorial Sloan-Kettering Cancer Center investigators are developing computer algorithms that accurately measure the volume of lung tumors, liver metastases, and lymph nodes on CT.
"We're finding that volume provides different and likely more-accurate information about the change in the size of the tumor," said Lawrence H. Schwartz, Director of Magnetic Resonance Imaging and Director of the Computational Imaging Analysis Laboratory, who collaborated with medical physicist Binsheng Zhao and other researchers to create these algorithms. Early studies indicate that the computer programs can detect decreasing lung-tumor volume within about one month of starting treatment. Eventually, Dr. Schwartz said, the models may be able to detect changes after just one treatment. "We're also developing algorithms for other types of cancers, including those of the prostate and liver, and modifying them to handle data from MRI and positron emission tomography (PET) scans."
Another way to monitor therapy is through molecular imaging methods that open a window into the chemical workings of cells. PET is the molecular imaging tool most widely used in both clinical practice and basic research. "PET plays an integral role in the management of several forms of cancer, including lung, colorectal, and lymphoma," said Steven M. Larson, Chief of Memorial Sloan-Kettering's Nuclear Medicine Service. "And it's developing as a major component in the management of other cancers, such as those of the head and neck and breast."
PET scans detect radioactive versions of certain molecules, called radiolabels. The most widely used radiolabel is fluorodeoxyglucose (FDG), a modified form of blood sugar tagged with radioactive fluorine. FDG is taken up by cancer cells hungry for energy and acts as a sort of glowing food dye for tumors, permitting clinicians to observe chemical reactions inside cells as they occur in real time. "The rate of uptake is a very accurate predictor of whether a tumor is biologically aggressive," said Dr. Larson. "That makes PET a tremendous tool for clinicians because it can improve the staging of tumors and helps us monitor treatment effectiveness."
At Memorial Sloan-Kettering Cancer Center PET is also typically combined with CT, adding metabolic information to CT's structural images. "In prostate cancer, for example, PET/CT is helpful in detecting which tumors in the skeleton are growing; and with new tracers, we will be able to determine a tumor's specific molecular signature without doing an invasive biopsy," said Dr. Scher.
Research: The Future
Just as imaging has become central to modern cancer diagnosis and care, these technologies are invaluable assets for basic scientists. From real-time monitoring of tumors in animals to tracking the behavior in cells of molecules with therapeutic potential, imaging offers researchers new insights into the fundamental biology of tumors.
To better observe the molecular activity of cancer with PET, it is necessary to create novel tracers and probes. Here, Dr. Larson and his colleagues are broadening the library of these substances. In recent years, for example, they have been working to develop a test to image the presence of HER2, a protein receptor found on the surface of epithelial cells in the breast. Breast cells that overproduce HER2 receptors divide faster than normal and contribute to tumor growth. However, a drug called trastuzumab (Herceptin®) counteracts excess HER2. "If we can see the overexpression of HER2, we can direct treatments to it," Dr. Larson said. Tracking the protein visually should also be valuable for monitoring the effectiveness of trastuzumab treatment.
Another probe developed by Dr. Larson's team, along with researchers from Washington University in St. Louis and the University of Illinois at Urbana-Champaign, is FDHT, a radiolabeled form of the sex hormone testosterone called dihydrotestosterone. Because prostate tumors divide more rapidly in the presence of testosterone, an androgen, many men with prostate cancer are given anti-androgen therapy to deny their tumors this growth signal. Yet in some men the treatment fails over time, and the remaining prostate cells become sensitive to very small amounts of testosterone. A successful androgen receptor probe could allow physicians to observe this effect in its earliest stages and enable them to intervene to prevent the cancer from recurring.
Several imaging techniques that may be applied to a variety of cancers are being investigated by Memorial Sloan-Kettering Cancer Center molecular imaging expert Vladimir Ponomarev. Dr. Ponomarev is collaborating with Michel Sadelain, Head of the Sloan-Kettering Institute's Laboratory of Gene Transfer and Gene Expression, on using PET to visualize T cells that are genetically modified to seek out a key prostate cancer protein, PSMA. The technology will soon be studied in a small clinical trial of men with prostate cancer who have been treated with PSMA-specific T cells. "We want to image not only the location of the T cells but whether they are actively doing their job," Dr. Ponomarev said. "We can then correlate the results with clinical outcomes and predict how patients will respond to the treatment."
In addition, Dr. Ponomarev is helping to develop DNA probes that can be seen with both PET and optical imaging machines that detect either fluorescence or bioluminescence — the emission of visible light by cells. "Marrying these two technologies allows us to monitor the same molecular and biological processes much more efficiently," Dr. Ponomarev said. "So the transition between a preclinical experiment and the clinic would be very rapid."
"Ultimately, we want to be able to diagnose, treat, and follow patients without ever having to cut into the skin," concluded Dr. Hricak, "and we are approaching that day. Not only are we beginning to make diagnoses and monitor treatment efficacy on the molecular level, but biologic imaging is being employed to identify the molecules implicated in the development of different cancers. We can then determine what drug is needed to target a particular problem and work to develop that drug. We're also moving into the realm of truly minimally invasive treatment. For instance, clinicians are now experimenting with MRI-guided high-intensity focused ultrasound treatment for breast and prostate cancers, using finely tuned sound waves to ablate, or burn away, tumors. The future is extremely promising and exciting."
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