Proton MR Spectroscopy for Assessment of Tumor Extent in Metastatic and Primary Neoplasms of the Brain: Potential Applications as an adjunct to Gamma Knife Planning and Patient Prognosis
Ronald Alberico, MD, Director Neuroradiology, Head/Neck Imaging
This study aims to better define tumor extent and grade using proton MR spectroscopy (MRS), and evaluate the technique as an adjunct to conventional MR imaging for improved gamma knife patient selection and treatment planning.
Because of superior spatial and contrast resolution, contrast-enhanced magnetic resonance imaging (EMRI) is currently the method of choice for evaluation of both primary and metastatic neoplastic disease of the brain. Although EMRI has had tremendous impact on our ability to detect and localize brain tumors, it can lack specificity and does not accurately depict the extent of neoplastic disease.
MRS uses signal generated from a pre-selected volume of interest in a patient's brain to measure relative concentrations of various metabolites, (like choline), in that volume.
Multiple studies have proven the efficacy of MRS in predicting tumor recurrence after surgery and radiotherapy and have shown some utility in predicting the grade of primary brain tumors. Improved accuracy in terms of tumor margins could significantly effect therapeutic decisions in brain tumor patients. More accurate detection of tumor margins may enhance gamma knife treatment planning and potentially improve patient outcome.
Adaptation of Compounds Originally Designed for Photodynamic Therapy to Function as Tumor-Avid Gadolinium-Based Contrast Media for Magnetic Resonance Imaging
Zachary D. Grossman, MD, FACR, Chairman, Ravindra Pandey, PhD, Associate Professor of Radiology and Radiation Biology, Bing Ma, PhD, Guolln Li, Graduate Student, Ronald Alberico, MD, Director Neuroradiology, Head/Neck Imaging, Peter Loud, MD, Director of Ultrasound
Although many tumors are sufficiently vascular to "enhance" their signal on MR Imaging when an intravascular contrast medium is circulating, there are, to date, no effective contrast media that selectively accumulate in tumors, over time, in an inverse relationship to their intravascular concentration. The diagnostic imaging group has combined forces with the chemistry section of the photodynamic therapy team to create gadolinium-based contrast media which, after peripheral intravenous injection, will selectively target and progressively accumulate in tumors. This goal has already been achieved with a variety of tumor-avid porphyrin-based agents, now FDA-approved for clinical photodynamic therapy; therefore, we reasoned that the classic MR contrast atom, gadolinium, could be chemically linked to porphyrin-type compounds, so as to produce a tumor-avid MR contrast agent.
A wide variety of compounds previously created for photodynamic therapy were screened by their inventor, Ravindra Pandey, Ph.D., to select those most suitable for gadolinium labeling. Then, various labeling methods were attempted, in order to establish which would result in the most stable bond. Finally, rats were implanted with a common soft tissue tumor, baseline MR images were created, and the animals were subsequently injected intravenously with the gadolinium-labeled porphyrin. Repeat MR images immediately after gadolinium injection, one hour later, and up to three days later have revealed significant enhancement of tumor signal compared to normal soft tissue background, blood, and signal from other organs. These findings will soon be reported and open the door for the creation of multiple other tumor-avid gadolinium-based porphyrins, with appropriate molecular alterations to enhance tumor avidity.
Adaptation of Compounds Originally Designed for Photodynamic Therapy to Function as Tumor-Avid Radiopharmaceuticals, labeled with Technetium-99M and Indium-111
Zachary D. Grossman, MD, FACR, Chairman, Ravinda K. Pandey, PhD, Bing Ma, PhD, Guolin Li, Graduate Student, Dominic Lamonica, MD, Director of Nuclear Medicine
For over 30 years, the prime tumor imaging agent for Nuclear Medicine has been gallium-67 (Ga67). This radionuclide circulates, protein-bound, and has a strong affinity for certain proteins (notably lactoferrin) which are known to exist in sizeable concentrations within many tumors, particularly lymphoma. Nonetheless, Ga67 is a nonspecific agent which accumulates in normal structures (nasal mucosa, breast, lacrimal glands, gastrointestinal tract) and in many inflammatory conditions; therefore, various receptor-specific agents have recently been devised. Despite the preliminary success of receptor-based agents configured as monoclonal antibodies or small peptides (for example, somatostatin receptor agents), a better, more generally applicable tumor-avid agent would be an extremely valuable diagnostic agent for radionuclide diagnosis. Therefore, we reasoned that the binding of common radionuclides, particularly indium-111 or technetium-99m, to porphyrin-based tumor-avid agents originally created for photodynamic therapy, might be feasible.
Multiple binding methods for both indium-111 and technetium-99m were explored in order to select the most stable chelate, and multiple porphyrins were screened. After both in vivo and in vitro stability of the labeled chelates was established, rats were implanted with a common soft tissue tumor, radionuclide-labeled porphyrin was injected intravenously, and at various intervals animals were sacrificed and extensive radiobiodistribution studies were performed. Preliminary data reveal strong tumor avidity of the radionuclide-labeled porphyrins, compared to blood, muscle, and softtissue background. These studies will soon be reported and open the door for creation of multiple other tumor-avid radiopharmaceuticals based upon similar porphyrin congeners.
New York Early Lung Cancer Action Protect (NY-ELCAP)
Donald Klippenstein, MD, Vice Chair, Diagnostic Radiology, Alan Litwin, MD, Body Imaging, Ultrasound
The Early Lung Cancer Action Project (ELCAP) demonstrated that low-dose chest computed tomography (CT) screening conducted on persons with a high risk for lung cancer has the potential to markedly increase the detection of small, early lung cancer. In a study of 1,000 individuals with 10 pack-year histories of cigarette smoking reported in Lancet (July 10, 1999; 354, pages 99-105), Henschke et al showed that malignancies detected by the CT screening were missed on high quality chest radiographs 85 percent of the time, confirming the expectation that, relative to traditional chest radiography, CT-based screening markedly enhances the detection of small non-calcified nodules and, thus, of lung cancer at earlier and more curable stages relative to what is known to prevail in absence of screening.
Roswell Park Comprehensive Cancer Center, as a member institution of the Academic Medicine Development Company (AMDeC), was one of 12 institutions participating in the New York Early Lung Cancer Action Project (NY-ELCAP) to validate the results obtained by Henschke et al. The NY-ELCAP will enroll 10,000 women and men aged 60 and older who have a 10 pack-year history of cigarette smoking, no prior cancer and are fit to undergo thoracic surgery, if warranted. A baseline and one year follow-up low dose screening chest CT will be provided free of cost to qualifying participants in this study. Donald Klippenstein, MD, will serve as the Principal Investigator at Roswell Park for the NY-ELCAP.
Prognostic Implications of Initial Radiogallium Imaging In Low-Grade Non-Hodgkin's Lymphoma
Dominick Lamonica, MD, Director, Nuclear Medicine, Ming Liu, MD, Clinical Fellow, Research Associate, Theresa Hahn, Ph.D., Postdoctoral Associate, Zachary Grossman, MD, Chair, Diagnostic Imaging, Myron Czuczman, MD, formerly of Roswell Park
Combination chemotherapy has been shown to increase the rates of remission and 5-year survival in patients with non-Hodgkin's Lymphoma. However, some patients do not respond to therapy and ultimately die of thelr disease, especially those with Low-Grade Non-Hodgkin’s Lymphoma (LGNHL). Identification of patients at high or low risk at the time of the diagnosis could have important therapeutic implications.
The purpose of this research was to retrospectively study the predictive value of the gallium scan in patients with LGNHL. Forty-five patients with biopsy proven stage III or IV LGNHL (small lymphocytic; follicular, small cleaved and follicular, mixed small and large cell types) had pretreatment Ga67 scans and Induction chemotherapy before July of 1996. Of those with a positive pretreatment Ga67 scan, 71 percent achieved complete or partial remission after induction therapy, while 94 percent of those with a negative scan did so. In addition, duration of remission was markedly different between the two groups. After an average of 7 years, 15% (3 of 20) of patients in the positive scan group I were still alive in complete or partial remission vs. 50% (8 of 16) in the negative scan group.
The diagnostic value of radiogallium imaging for the staging of LGNHL has been questioned in the past, and this retrospective analysis indicates that gallium positivity atdiagnosis carries with it the implication of a more chemoresistant disease that may prove problematic when approached with conventional therapies. Compared to their gallium negative counterparts, such patients exhibit a worse prognosis from the standpoints of response to induction chemotherapy, time to disease progression and overall survival. As such, they should be considered for clinical trials of treatment alternatives.
Radioimmunotherapy of Non-Hodgkin's Lymphoma
Dominick Lamonica, MD, Director, Nuclear Medicine, Myron Czuczman, MD, formerly of Roswell Park, Zachary Grossman, MD, Chair, Diagnostic Imaging, Marion Skipper, RN
Based on their exquisite radiosensitivity, lymphomas have long been considered attractive targets for radioimmunotherapy. These clinical trials will assess the effectiveness of two different antibody preparations [IDEC-2B8: Zevalin®; IMMU-LL2] used in combination chemotherapy for some lymphomas. The antibodies can be used effectively and conveniently in outpatient dosing because they lack gamma radiation.
These phase I/II clinical trials are directed at assessing the place for these agents in current treatment schemas both with and without the use of peripheral stem cell rescue.
Diagnosis of Pulmonary Embolism and Deep Vein Thrombosis using Combined CT Venography and Pulmonary Angiography
Peter A. Loud, MD, Director Ultrasound, Zachary D. Grossman, MD, FACR, Chairman, Donald L. Klippenstein, MD, Vice Chair, Director, CT & Body Imaging
Deep venous thrombosis and its most serious complication, pulmonary embolism, are causes of significant worldwide morbidity and mortality. Certain groups, including cancer patients, are at particularly high risk. CT Pulmonary Angiography is being used increasingly to evaluate suspected pulmonary embolism because it accurately defines emboli and reveals other nonembolic causes of thoracic symptoms. A large number of patients still require separate testing of the veins for deep vein thrombosis after pulmonary imaging. This leads to a delay in diagnosis and initiation of therapy.
In 1998, we devised a new imaging test, Combined CT Venography and Pulmonary Angiography, which allows evaluation for both pulmonary embolism and deep vein thrombosis in a single examination (Loud, et al AJR 170:951-954, 1998). A follow up preliminary study of this technique in 71 patients showed it to be highly sensitive and specific for diagnosis of deep vein thrombosis (Loud et al, AJR, 174:61-65,2000).
We are currently evaluating a large group of patients imaged with combined CT venography and pulmonary angiography. In addition to analysis of deep vein thrombosis location and extent, we are performing a comparative study with tower extremity venous sonography to further assess the accuracy of the technique. Preliminary results show the addition of CT venography leads to a significant increase in the number of positive studies compared to CT pulmonary angiography alone. Another important advantage of CT venography is the ability to detect deep vein thrombosis in the abdomen and pelvis as well as in the lower extremities. Based on our initial results obtained at Roswell Park Comprehensive Cancer Center, a number of institutions around the country have begun using the technique on a routine basis.
Computed Tomography in the Evaluation of Gastrointestinal Metastases from Melanoma
Peter A. Loud, MD, Director, Ultrasound, Donald L. Klippenstein, MD, Vice Chair, Director, CT & Body Imaging
Malignant melanoma, a disease which is increasing in frequency, is one of a few neoplasms which commonly metastasize to the gastrointestinal tract. Patients may have symptoms of bowel obstruction, gastrointestinal bleeding and pain. Computed tomography is frequently used to evaluate melanoma patients. With a review and evaluation of the CT features of gastrointestinal metastases from melanoma, and the records of Roswell Park patients with pathologically confirmed melanoma metastases, we may find correlations. Clarification of typical CT findings should allow more accurate diagnosis of this disease and may lead to better ways to optimize CT imaging to detect gastrointestinal metastases.
Prospective Comparison of Digital Subtraction Angiography. Helical CT Angiography and Gadolinium Enhanced MR Angiography for Radiosurgical Planning of Arteriovenous Malformation Ablation Using the Leksell Gamma Knife
Ronald A. Alberico, MD, Director, Neuroradlology, Head/Neck Imaging
Current treatment alternatives for intracranial arteriovenous malformations (A VMS) include surgery, embolization, and radiosurgery. Radiosurgical techniques using the Leksell gamma knife have been extensively studied in the last two decades, with strong results. This technique offers a noninvasive alternative to patients who have contraindications to more invasive surgical or endovascular treatment.
Standard gamma knife planning for A VM therapy relies upon detailed images generated by catheter angiography (DSA) combined with either CAT scan (CT) or magnetic resonance imaging (MRI). Using these images, a treatment plan can be generated that will conform to the three-dimensional shape of the lesion and deliver the appropriate dose for the measured lesion volume. Recent advances in MRI and CT have enabled detailed vascular imaging without the need for intra arterial catheter placement. Several reports have demonstrated the efficacy of these techniques in evaluating the intracranial circulation.
DSA has several disadvantages when planning radiosurgery with gamma knife, including the risk of cerebral infarct. Other complications include vascular trauma in the groin, embolic ischemia in the legs and hematoma at the puncture sight. DSA also typically requires approximately 1-2 hours in uncomplicated cases. Any and all of these factors can delay or postpone the planned radiosurgery as well as potentially contribute significantly to overall morbidity. In this study, we will compare CTA and MRA with DSA for planning gamma knife therapy of arteriovenous malformations. It is our hope that this comparison will give insight into the feasibility of gamma knife planning for A VM radiosurgery without catheter angiography.
Radiosurgery Induced Imaging Changes in Cranial Nerve Five: Correlation with Follow-up Interval, Dose and Patient Response
Ronald A. Alberico, MD, Director, Neuroradiology, Head/Neck Imaging
Trigeminal neuralgia is a paroxysmal pain syndrome corresponding to the distribution of the fifth cranial nerve. Patients suffer from severe lancinating pain, with minimal external stimulation of the effected dermatome. In severe cases, patients can suffer from malnutrition and weight loss due to an inability to eat. Fortunately, primary drug therapy is frequently effective in controlling or eliminating the symptoms of this disease. For patients with medically resistant disease, or intolerable side effects from long term medical therapy, several surgical options are available. These include glycerol rhyzolysis, thennal rhizotomy, and peripheral nerve blocks. More effective surgical options are more invasive.
Recently, treatment of medically resistant trigeminal neuralgia with gamma knife radiosurgery has been evaluated. Results have been variable: one large series reports excellent response, while other investigators report different response rates. The differences in reported response rates of trigeminal neuralgia to radiosurgery have been attributed to multiple factors, including differences in prior invasive treatment, dose delivery and target location during radiosurgery, as well as differences in imaging technique before treatment planning. This is particularly important, because some investigators suggest that distortion inherent in MR imaging may affect target position enough to limit its usefulness for radio surgical planning of small targets. Other reports suggest that distortion in MR imaging is minimal and unlikely to adversely affect radio surgical targeting. This controversy suggests that a percentage of treatment failures in radiosurgery of trigeminal neuralgia may have resulted from misplacement of the target volume. For patients with poor clinical response, confirmation of target tissue change on MR imaging has not, to our knowledge, been a routine part of follow-up assessment. Some reports suggest that cranial nerve five may enhance after gamma knife radiosurgery , while others suggest a lack of MR imaging signal changes.
We hypothesize that the effects of radiosurgery on cranial nerve five may include intensity changes within the nerve on MR imaging. The purpose of this retrospective study is to identify and characterize the type of MR intensity changes in cranial nerve five that result from gamma knife treatment of medically refractory trigeminal neuralgia. We plan to retrospectively review MR images and clinic records of 15 patients who underwent gamma knife radiosurgery for trigeminal neuralgia between 11/98 and 7/00. Our hope is to identify imaging changes in the area of treatment that will confirm that this relatively small target was treated as planned. We will attempt to correlate any changes in the images with treatment response and radiation dose.
An Exploratory Study of Proton MR Spectroscopy for the Assessment of Tumor Extent, Proliferative Potential, and Response to Treatment in Primary and Metastatic Neoplasms of the Brain Pre and Post Leksell Gamma Knife Radiosurgery
Ronald Alberico, MD, Director, Neuroradiology, Head/Neck Imaging
This exploratory study will examine the use of a new approach, proton magnetic resonance spectroscopy (MR-S), as an adjunct tool to magnetic resonance imaging (MRI) for improving assessments of tumor margins and proliferative potential. While there are guidelines available to suggest tumor behavior (tumor proliferation potential, tumor grade, death of tumor cells) from MR spectral data, MR-S is currently an emerging field, and the utility of this methodology in the proposed context is not known. This is essentially a pattern-seeking study of a promising new technology, with no effect on patient diagnosis or treatment, with minimal patient risks and costs.
Primary and secondary CNS tumors offer a particular challenge when being evaluated by non-invasive techniques. MRI has become the accepted modality for serial follow-up and is presently a reliable means by which tumor response to treatment is measured. To date, MRI enhancement patterns have been the standard by which tumor extent has been measured. However, MRI enhancement patterns provide little information regarding metabolic characteristics and growth potential in various intracranial tumors. The lack of specificity of MR imaging results in an inability to confidently determine the efficacy of adjuvant therapy, such as radiation and chemotherapy.
To circumvent these difficulties, a non-invasive imaging modality can be utilized to measure biological factors without the need for tissue sampling. MR-Spectroscopy (MR-S) has been proven as a reliable indicator of tumor activity. Additionally, individual spectral MR-S Assessment of Tumor extent Pie and Post Gamma Knife characteristics can offer information in the follow up period, monitoring response to treatment. Each spectral image provides a "fingerprint" describing behavioral characteristics (ie. tumor proliferation, tumor grade, and cell death in response to radiation) potentially improving the accuracy of tumor characterization. The increase in accuracy could effect patient selection and treatment planning with the Gamma Knife.