The Holden Comprehensive Cancer Center at the University of Iowa, Iowa City, founded in 1980, was designated a National Institutes of Health Cancer Center in 2000, with the designation being renewed in 2005. The center coordinates patient care, research, and education in cancer performed by faculty from 38 departments in six of the University’s colleges.

In May 2005, the department of radiation oncology, a center of excellence in image-guided radiation therapy, moved to a new facility. The department offers external-beam, intensity-modulated, and stereotactic therapy, as well as brachytherapy and radiosurgery, and has most of its own imaging (as well as planning and delivery) equipment. For example, it is home to a large-gantry, multidetector-array (20-row) CT scanner with respiratory gating that is capable of capturing slices as thin as 0.6 mm and creating three-dimensional volumes. With appropriate adjustments in the software, this scanner can obtain as many as 40 rows of data. The large gantry permits imaging of patients in the positions in which they will be treated, which is often impossible with standard gantries. For example, breast-cancer patients often lie with their arms above their heads and bent so that their elbows protrude; this position cannot be accommodated by conventional scanners. The department also has a 3T MRI scanner used for both imaging and spectroscopy. Between 15% and 20% of patients have an MRI scan, and many departments might prefer to use someone else’s scanner for this work. As John Bayouth, PhD, director of medical physics, explains, “We want images of high signal-to-noise ratio and high spatial resolution, which means we need scanning parameters slightly different from what one would use in diagnostic imaging. This requirement translates into much longer scanning times, but that is a luxury we are able to accommodate because we have the scanner in our department.”

A PET/CT scanner has also been planned for within the clinic. The technology will allow for respiratory-correlated imaging of radionuclides.

EQUIPMENT NEEDS

John M. Buatti, MD

“On-site imaging with the best equipment is essential, as these images are the basic template for all of treatment planning and delivery,” according to John M. Buatti, MD, professor and head of radiation oncology. High-resolution imaging is needed, not only to define the precise initial boundaries of the tumor, but also to ensure that it remains within the portals during treatment. “For every patient, the more information you can gain from imaging, the more information you have for appropriate decision making and treatment planning,” Buatti comments. Moreover, he says, “The hand-me-down imaging equipment from radiology departments that many radiation oncologists made do with in the past is inadequate for current planning techniques.” Bayouth adds, “Today, medical physicists can generate radiation dose distributions that conform three dimensionally to the shape of the tumor as identified by the physicians, and we can shape these distributions with extraordinary precision. For example, we can create a dose distribution in the shape of your coffee cup without irradiating the coffee inside.”

The importance of high-resolution imaging in treatment is further illustrated by a radiosurgery procedure performed by the department for a benign disease, trigeminal neuralgia. Pain relief is achieved by delivering 90 Gy of radiation to the trigeminal nerve at the point where it branches off from the brain stem. “You want to be able to do this with submillimeter positioning and accuracy,” Bayouth says.

Delineating tumors using high-resolution imaging is improving disease control while reducing damage to normal tissues. For example, the overall control rate for meningioma is now 95% to 98%, with little collateral damage. Again, with intensity-modulated radiation therapy, it has been possible to increase the dose to a prostate tumor to as much as 90 Gy, yet create less rectal toxicity than is seen in association with classic external-beam protocols delivering much lower radiation doses.

“It may seem counterintuitive that you can shrink the field and improve the outcome, but it is true,” Buatti says. “That has been our experience: smaller fields with more accurate delivery.” Direct randomized comparisons of the older and newer protocols are neither possible nor acceptable. Even though they might be desirable from a scientific point of view, they are not needed. Buatti points out, “There is no randomized comparison of the accuracy of fields set up by physical examination versus fluoroscopy or by fluoroscopy versus CT, but there is no question that the newer methods are superior.”

LOOKING AHEAD

John Bayouth, PhD

Further refinement of tumor identification is still needed; for this reason, the future of treatment planning clearly lies with molecular imaging.

“If the physicians can tell me who the bad guys are and where they are, I can hit them, but if the physicians are uncertain who and where the bad guys are, I cannot. This is the weak link, at present, in the radiotherapy process,” Bayouth comments. “Now, because we cannot accurately identify the entire tumor with respect to the normal tissue, we have to irradiate volumes that contain normal tissue, increasing toxicity, and we reduce the chances that we will include all of the diseased tissue in the treatment volume, resulting in poorer local control. Emerging techniques that may allow us to identify the extent of the disease better are likely to be the key in the next significant step toward reducing the uncertainty in radiation therapy.”

Better definition may be possible with MR spectroscopy and PET/CT. Radiopharmaceuticals under development can, for example, define a tumor’s blood flow and areas of angiogenesis and hypoxia. “Hypoxic regions of a tumor are more resistant to radiation. If we know where they are, a priori, we can design our dose distributions to exploit that knowledge,” Bayouth says.

Tumors are nonuniform in their sensitivity to radiation because, by their nature, they are usually histologically heterogeneous. For example, subvolumes within the prostate may be more likely to contain cancer, and with MR spectroscopy data obtained using a 3T scanner, such areas can be located for targeting with higher doses, without the distortion of the gland created by the traditional endorectal coils. Moreover, “There is absolutely no reason to think the characteristics of a tumor remain constant throughout the course of a 6-week to 8-week treatment,” Bayouth says. “Our next questions are, ‘How does the tumor change during treatment?’ and ‘How can we adapt our plan to accommodate those changes?’ We are studying the utility of replanning: acquiring imaging throughout treatment to understand better when we need to change the plan. How often we need to do this is one of the questions we are asking.”

EQUIPMENT SOURCE

Although the department of radiation oncology traditionally dealt with another vendor of imaging equipment, “There was a tremendous commitment by Siemens to the development of image-guided radiation therapy,” Buatti says. “The fact that Siemens offered a common platform for all of the image equipment and the treatment delivery was a strength. In addition, our new department is completely paperless, and using their information system within the radiation oncology product for all of our information needs was achievable. We have implemented it, and all of our expectations have been borne out: they made the commitment, and they came through on it.”

Free Radical and the Radiation Biology Program

Free radicals are highly reactive atoms having at least one unpaired electron. Biologically, free radicals of oxygen are of particular interest, as they are believed to be involved in aging and many diseases. Free radicals also interest radiation oncologists, as they are responsible for as much as 80% of radiation damage to normal and malignant tissues.

The Free Radical and Radiation Biology Program, carried out in a complex of five interdisciplinary laboratories at the University of Iowa, Iowa City, studies the physical, chemical, and biological changes induced in tissues by radiation, with a particular focus on free radicals. The director of one of these laboratories, Larry W. Oberley, PhD, originated the theory that an imbalance of oxidation and reduction (redox) reactions within a cell, in large part as the result of a deficiency of the enzyme superoxide dismutase, is critical to malignant transformation.1 He later demonstrated that the malignant phenotype can be reversed by increasing cellular superoxide content.2 His laboratory demonstrated that metastases tend to differ from their primary cancers in their tolerance for oxidative stress,3 implying a different response to radiation and chemotherapy. A newly published article4 from this laboratory describes the use of a redox signature score to identify those large B-cell lymphomas with a poor prognosis. This study was part of the Leukemia/Lymphoma Molecular Profiling Project.

Frederick E. Domann, PhD, directs another laboratory in the program. His special interest is the regulation of gene expression in cancer. One of the findings of this group is that overexpression of the oncogene v-Ha-Ras increases superoxide production, with profound consequences for the cellular redox environment5 and thus, perhaps, radiation and drug sensitivity. This group has also suggested that head and neck cancers might be treatable with radioactive iodine after delivery to the tumor of the sodium iodide symporter gene, a technique these scientists call genetically targeted radiotherapy.6

Douglas R. Spitz, PhD, directs a laboratory devoted to elucidation of the abnormal metabolic patterns characteristic of cancer cells. One of its discoveries is that cancer cells are more susceptible to glucose-deprivation-induced oxidative stress.7 This is among the discoveries being subjected to translational research in the radiation oncology department. Clinical trials are attempting to exploit deoxyglucose (which, in fluoridated form, is used for positron-emission tomography) as a radiation sensitizer. The cellular transport machinery perceives this compound as glucose and brings it into the cell. Such uptake is greater in cancer cells, with their voracious appetites. The cell’s glucose-metabolizing enzymes cannot process the analog, however, so it accumulates, unused and blocking utilization of glucose itself. The hope is that the compound will enhance radiation damage to cancers relative to normal cells.

The radiation oncology department also is looking at other ways of preventing damage to normal tissues by radiation and free radicals. One possible way is with amifostine,8 recently cleared by the US Food and Drug Administration to protect against salivary gland damage in patients being treated for head and neck cancer. University of Iowa researchers are quantifying the effects obtained with this drug.

—J. G. Bronson

REFERENCES

  1. Oberley LW, Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res. 1979;39:1141-1149.
  2. Oberley LW. Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomed Pharmacother. 2005;59:143-148.
  3. Oberley TD, Zhong W, Szweda LI, Oberley LW. Localization of antioxidant enzymes and oxidative damage products in normal and malignant prostate epithelium. Prostate. 2000;44:144-155.
  4. Tome ME, Johnson DB, Rimsza LM, et al. A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis. Available at: www.bloodjournal.org/cgi/content/abstract/2005-02-0487v1. Accessed September 14, 2005.
  5. Yang JQ, Li S, Huang Y, et al. v-Ha-Ras overexpression induces superoxide production and alters levels of primary antioxidant enzymes. Antioxid Redox Signal. 2001;3:697-709.
  6. Gaut AW, Niu G, Krager KJ, Graham MM, Trask DK, Domann FE. Genetically targeted radiotherapy of head and neck squamous cell carcinoma using the sodium-iodide symporter (NIS). Head Neck. 2004;26:265-371.
  7. Spitz DR, Sim JE, Ridnour LA, Galoforo SS, Lee YJ. Glucose deprivation-induced oxidative stress in human tumor cells: a fundamental defect in metabolism? Ann N Y Acad Sci. 2000;899:349-362.
  8. Andreassen CN, Grau C, Lindegaard JC. Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol. 2003;13:62-72.

Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.