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A publication of

LOMA LINDA UNIVERSITY MEDICAL CENTER

Volume 2, Number 2 Spring 2009

Breast cancer treatment with proton radiation: a patient's perspective

Cancer treatment is in many ways a partnership between the patient and the care team. At the James M. Slater, M.D. Proton Treatment and Research Center, the patient-physician relationship is one of mutual respect, and sometimes produces bonds of affection as well. at is the case with one breast-cancer patient at Loma Linda University Medical Center (LLUMC), Mrs. Ann Hughes, of Redlands, California (Fig. 1). Mrs. Hughes received proton radiation therapy as part of her treatment program for breast cancer. Surgery and radiation therapy play complimentary roles in the management of earlystage breast cancers. It has been known for decades that lumpectomy (removal of the local tumor mass combined with axillary dissection) and postoperative radiation therapy result in disease-control rates similar to those historically associated with more-extensive surgical procedures, such as partial, simple, or radical mastectomy. Conventional radiation therapy in these situations, however, is associated with a risk of side effects owing to some of the radiation dose reaching the heart, lung, and/or opposite breast. With those risks in mind, radiation oncologists at the James M. Slater center proposed the use of proton beams to deliver the radiation component of the multidisciplinary treatment. e program, led by Dr. David A. Bush of the department of radiation medicine, was described in 2007, in a peer-reviewed article (Bush DA, Slater JD, Garberoglio C, Yuh G, Hocko JM, Slater JD. A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal x-ray therapy. Cancer Journal 2007;13(2):84-86). at article referred to a clinical study in which radiation oncologists collaborated with the department of surgical oncology at LLUMC to offer lumpectomy and axillary dissection, Please turn to page 2

U Breast cancer treatment with proton radiation: a patient's perspective Page 1 U Research toward treatment of focal epilepsy Page 4 U Ongoing research in radiation protection Page 8 U Alumni Postgraduate Convention Page 11

Fig. 1. Mrs. Ann Hughes, of Redlands, California, shares a lighthearted moment with her radiation oncologist, David A. Bush, M.D., at one of her regular follow-up visits.

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Protons for breast cancer; a patient's perspective...

the experience they have had at Loma Linda University Medical Center. Mrs. Hughes is a professional hair stylist. At one time she owned her own shop, but now is associated with the Salon Museum in Redlands. She has a devoted clientele; some of her customers have used her services for more than three decades. Indeed, she called her former business, "Ann and Friends." "A hair salon is a kind of community center," Mrs. Hughes noted. "Barber shops are probably the same. People come to greet old friends and exchange news and views. And it was in one of those exchanges that I learned about proton therapy." In 2006, Mrs. Hughes's annual mammogram revealed that a mass, biopsied a year earlier and found not to be cancer, looked suspicious. A second biopsy revealed cancer cells. Her first reaction, as is true of most people, was fear and uncertainty. She shared her news with some of her customers, and one of them, who worked for LLUMC, asked her, "Have you thought of protons?" "Up to that time, I'd never heard of proton radiation therapy," Mrs. Hughes said. "But I called Loma Linda and eventually was connected with Dr. Bush's Nurse Coordinator, Gail Verrecchio (Fig. 3). Gail was just wonderful to me: she spent a lot of quality time with me in discussing the proton breast study; she explained it fully and then asked me if I would like to be a participant. I was quite glad to accept that invitation."

Fig. 2. Dose distributions using protons (left) and x-rays (right) for partial breast treatment of a left-sided lesion. Note that the entire proton dose distribution is conformed within the treated breast. Beam arrangements include left lateral, anterior, and two axial oblique beams. Red and blue contours outline the tumor bed and clinical target volume, respectively.

Continued from page 1 followed by proton radiation therapy, to patients with stage T1 breast cancer. e study described in the article has since closed. However, a successor study is underway as this issue goes to press. According to Dr. Bush, Loma Linda physicians use protons for two main reasons. e first is the superior conformability that protons afford. Dr. Bush noted, "When I refer to conformal radiation, I don't just mean conformation to the target volume. I also mean excluding radiation from as much normal tissue as possible. You might call this exclusive conformability, to coin a phrase." Asked to elaborate, Dr. Bush commented, "At Loma Linda we take the attitude that unnecessary radiation should be eliminated as much as possible, not just reduced. In the case of breast cancer, some of that unnecessary radiation goes to the heart and lung, or causes severe skin damage, when photons, such as X rays, are used (Fig. 2). is is true even with modern methods like IMRT or newer forms of brachytherapy. Protons give us a tool to exclude much more of the normal tissues than photonbased methods can. We demonstrated that in our 2007 paper." e other main reason that protons are used, Dr. Bush went on, is that the total radiation dose can be delivered in a shorter overall time than is possible with externalbeam x-ray therapy. "We call this hypofractionation," Dr. Bush explained. "It means

fewer fractions, or individual proton treatments, with each fraction delivering a greater part of the total dose. e exclusive conformability of the proton beam makes this possible: if we know we can exclude normal structures, we can deliver larger dose fractions without fearing the increased side effects that would happen if we used X rays. We deliver the total dose, 40 Gray, in two weeks; that's half the time it would take with external-beam photons. As our paper showed, our patients have tolerated this treatment very well." Doing well for the patient--controlling the disease while minimizing side effects and thus maintaining quality of life--is the whole point of the program. Mrs. Hughes is one of many patients who testify to their satisfaction with

Fig. 3. Left to right: Gail Verrecchio, R.N., Mrs. Hughes, and Dr. Bush

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Protons for breast cancer; a patient's perspective...

ceiving protons and offered remarks concerning the importance of ongoing research in the treatment of cancer. "I can't say enough about the people at Loma Linda," Mrs. Hughes went on to say, when interviewed for this article. "Dr. Garberoglio was wonderful, and so are my current physicians, my surgeon, Dr. Sharon Lum, and my medical oncologist, Fig. 4. Left: a completed immobilization device with VAC-LOCTM cushions above and below the two-part foam, providing a Dr. Hamid Mircustom mold of the ipsilateral breast; right, a patient in the prone position for proton treatment. shahidi. I enjoy my visits with Dr. Bush, and Mrs. Hughes was referred first to Dr. Car- onds, though. One day the techs invited me to I'm very fond of the whole team. I talk about los Garberoglio, who performed the lumpec- see the control room, so I knew where they this with anyone who asks." tomy and axillary dissection. e operative went. I felt like an old hand by the time I was Dr. Bush described the ongoing clinical inspecimen revealed a small, slow-growing breast done." vestigation. "We've opened up the study from cancer, and her axillary nodes did not contain Summarizing her experience at Loma its original protocol," he said. "Originally, we tumor cells. She was then referred to Dr. Bush. Linda, Mrs. Hughes remarked, "Everyone was accepted patients who had small invasive "He was very thorough, very professional, and just wonderful: very professional, yet very breast cancers and had negative axillary nodes. very reassuring at the same time," she remarked. warm. I liked the Christ-centered environ- We completed that study with 50 patients. When asked to describe her experience re- ment." e Loma Linda staff, she said, "offered We noted that all the patients tolerated the ceiving proton therapy, Mrs. Hughes remarked prayer before surgery, but nobody pushed reli- treatments very well, so we decided to open a that it was an easy one. "e hardest part for gion. It was a pleasant experience in an awful second study with another 50 patients. is me was getting fitted for the immobilization situation. People care here, which is so impor- time, however, we are also accepting into the form, which they called the pod; I had to stay tant when a person is so vulnerable." She re- study patients who have pre-invasive cancers still for about 45 minutes while it was shaped called the 1991 movie, "e Doctor," about a (carcinoma in situ) and patients who have not to fit me." Dr. Bush amplified the description successful surgeon who had no problems until more than three positive axillary nodes. Everyof this part of the procedure: "We fit each pa- he was diagnosed with cancer. e experience thing else in the present investigation, however, tient with a treatment brassiere," he said. "Pa- of a patient's perspective changed him; there- is the same as in the first." tients are placed prone in a cylindrical polyvinyl after, he had the residents wear gowns to begin e previous study, in which Mrs. Hughes chloride shell with the upper and lower body to appreciate what it is like to be a patient. "At participated, and the current one are still in being supported and immobilized with foam Loma Linda," she said, "people get it; they know progress. Because breast cancer tends to be a bead cushions. We immobilize the upper chest how a patient feels. ey have empathy here, chronic disease, long-term follow-up, of at least and breast areas with expandable foam (Fig. 4). and sensitivity." five years duration, is required in order for the It takes a while to make this form, but once it's Mrs. Hughes is now in the follow-up phase investigators to reach conclusions regarding made, it's quite comfortable for the patient even of the study. She comes to Loma Linda every disease control or long-term side effects. "We though it immobilizes her." six months for a physical examination; this will are nearing five years of follow-up visits with Mrs. Hughes verified Dr. Bush's comment. continue until five years have elapsed since her some patients in the first study," Dr. Bush ob"Once that form was made, I had clear sailing. last proton treatment. She also has become a served, "and we are still enrolling and treating I came in every day for two weeks, was there spokesperson for proton therapy and for patients in the second one, so it will be a while for about a half-hour each time, then went breast-cancer research. During Breast Cancer before we can reach some conclusions and pubhome or to work, just as I always do. At first it Awareness month, in October 2008, the Salon lish anything definitive. In our department we felt strange when the techs, who were so nice Museum devoted one day to cancer research, are always cautious about analyzing our data as they placed me in the pod, would just vanish donating proceeds from haircut sales. In a re- outcomes and drawing conclusions from them, and I was left alone in the treatment room. e port on the event in a local newspaper, the San but even so, we are very encouraged at the outactual treatment probably took only a few sec- Bernardino Sun, Mrs. Hughes talked about re- comes we are seeing thus far."

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Progress toward proton treatment of focal epilepsy: a process of translational research

Proton radiation therapy is well known as a highly effective treatment for cancer and benign tumors. However, the precise conformability of the proton beam makes it an effective potential therapy for a number of diseases that arise from localized abnormal tissues. Because the physician can conform a proton beam to encompass a three-dimensional volume tightly, and the beam deposits little radiation in surrounding normal tissues, the physician can use protons to treat small volumes of abnormal or malfunctioning tissue virtually anywhere in the body. e famed neurosurgeon, Wilder Penfield, referred to epilepsy as"wearing the frightening mask of tragedy in her approach to each patient." Epilepsy is a relatively common neurological disorder, affecting millions in the U.S. alone. It often targets the young: about a quarter of the 200,000 newly diagnosed cases each year will be children. Many of us have a family member or close friend who has been diagnosed; more will have observed someone experiencing an epileptic seizure. Everyone with a connection to this disorder, therefore, will understand Dr. Penfield's insight, particularly in regards to patients who develop "intractable" seizures, that is, seizures not responding to currently available anti-epileptic medications. ere are many different types of epilepsy, and over the years the approach to classifying seizure disorders has evolved in parallel with better understanding of the underlying pathophysiology. e most fundamental distinction in classifying an epileptic disorder relates to how much of the brain is affected by the electrical disturbances causing the seizures. Approximately half of the patients who develop epilepsy have "partial" seizures, in which only a part of the brain is involved. is condition most often results from a focal abnormality, an anatomical or biochemical lesion in a specific area of the brain. e precise conformability and tissue-sparing capability of proton radiation therapy makes it a potential therapy for treating focal abnormalities in the brain. is capability underlies a translational research program at the James M. Slater, M.D. Proton Treatment and Research Center, one focused on the use of image-guided, stereotactic proton radiosurgery to treat medically refractory (intractable) partial epilepsy. Dr. Robert D. Pearlstein (Fig. 1), of the department of surgery (neurosurgery), Duke University Medical Center, Durham, North Carolina, and the Radiosurgery Research Program, department of ratients diagnosed with epilepsy will either not respond to or will not tolerate available anti-epileptic medications. e impact of uncontrolled seizures on the quality of life for these patients is substantial, as Dr. Penfield noted so eloquently. erefore, the research team directed by Dr. James M. Slater and Dr. Pearlstein are evaluating the safety and efficacy of treatments that would involve focusing proton radiation on the region of the brain in which patients' seizures are generated. Seizures can originate in any part of the brain, but certain regions are more likely to be associated with them. Examples are the deep-lying structures of the temporal lobe such as the amygdala, hippocampus, and parahippocampal gyrus. Moreover, seizures emanating from the deep temporal lobe often appear not to respond to anti-epilepsy medications. Surgical

Fig. 1. Robert D. Pearlstein, Ph.D.

diation medicine, Loma Linda University, is a leading investigator in the ongoing initiative to develop proton-based treatments for functional brain disorders such as intractable epilepsy.. Published statistics vary, but somewhere in the range of 10% to 30% of all pa-

Fig. 2. Targeting deep-lying (mesial) structures of the temporal lobe. e blue crosshairs that appear in each of the three magnetic resonance (MR) image perspectives in a patient's MR volume point to the hippocampus. Using a process called segmentation, in which the boundaries of an anatomical feature of interest (e.g., a brain region or lesion) are delineated over the entire volume, the shape of the hippocampus can be visualized (lower left) as an elongated region wrapping around the brain stem. (Segmentation and visualization performed using ITK-SNAP v1.8.)

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Progress in proton radiation treatment of focal epilepsy...

treatments targeting the mesial (deep) temporal lobe structures were developed by several groups, including Dr. Penfield's team at the Montreal Neurological Institute, beginning in the 1950s. ese procedures involve removal of the "epileptogenic" tissue in the temporal lobe, sparing the adjacent "eloquent" brain tissues that mediate critical brain functions (such as language comprehension and speech). Several different surgical approaches for treating partial epilepsy originating in the mesial temporal lobe have been developed, including those involving selective resection of the amygdala and hippocampus. All of them have been shown to be effective: about 2 out of 3 patients will become seizure-free following surgery. Even so, most patients will put up with years and years of uncontrolled seizures before finally undergoing surgery; many will never choose this treatment option. e invasiveness of surgery is likely a significant factor in why it is deferred and/or underutilized. e objective of the research program led by Drs. Slater and Pearlstein is to encourage earlier intervention by offering a non-invasive option to patients who would otherwise not consent to surgery. e scientists' studies of protons for treating epileptogenic tissue, have, of course, been done to date in rats, not humans. e reason for conducting extensive preclinical studies before translating the research to a clinical trial is consistent with a principle guiding all translational research conducted at the James M. Slater, M.D. Proton Treatment and Research Center: primum non nocere (first, do no harm). Preclinical studies serve several purposes: they ensure that treatments will provide desired therapeutic effects; they help optimize the conditions for providing the therapeutic effects; they help investigators to understanding the basis of the therapeutic effects. Most importantly, such studies are undertaken to determine the safety of the proposed therapy, in this case, to ensure that treatment effects can be attained without damaging functionally critical brain centers and to characterize the long-term risks of treatment. e target volumes in the animals used for these preclinical studies are substantially smaller than in the human brain (Fig. 3). Indeed, Dr. Pearlstein comments that such small-scale work often reminds him of a 1965 film, Flight of the Phoenix, in which a group of oil-field workers are stranded in the Sahara after a plane crash, without hope for rescue. Among the survivors is an "airplane" designer who proposes that the downed aircraft be used to create a new aircraft to fly the group out of the desert. When ultimately it is revealed that his only experience was in designing model airplanes, the engineer justifies his background

Fig. 3. Rat and human brains, same scale; hippocampi are shown in red. Projection image of human brain created by R.D. Pearlstein, using BrainSuite2 software, which strips the skull and scalp regions from a patient's MR image volume and differentiates grey (green-purple regions) and white matter. [D.W. Shattuck and R.M. Leahy: BrainSuite: an automated cortical surface identification tool. Medical Image Analysis 2002;8:129-142]

by emphasizing that working in reduced scale is far more demanding in comparison to the full-scale effort. So it is with preclinical studies, where treatment targets are measured in millimeters, not centimeters as in clinical applications. Unlike the clinical situation where the pronounced variability in human brain anatomy requires that treatment planning always be guided by imaging studies, the consistent brain anatomy of the animals used for preclinical studies makes it possible to guide proton beams to a target based on published "atlases", neuroanatomical road maps that show the location of brain regions referenced to landmarks located on the animals' skulls. With the support of the department's Physics Core Laboratory, software has been developed that allows the investigators to determine the dose distributions from multiple, intersecting proton beams all referenced to these skull landmarks. ey have developed many different treatment plans such as the one shown in Fig 4 (next page), each designed to test a specific question related to the safety or efficacy of treatments. Each plan is verified using an animal MRI system, one of several advanced technologies available in the Non-invasive Imaging Lab-

oratory, another of the core laboratories that have been created by the department to support basic and translational research efforts at the James M. Slater, M.D. Proton Treatment and Research Center. Photomicrography shows dramatically the ability of the proton beam to destroy targeted tissue while sparing normal tissue close to the target volume. Fig. 5 (next page) demonstrates the effectiveness of proton beams for ablating (destroying) grey matter tissue located deep within the cranial vault of the rat. e animal from which the brain tissue specimen was taken had been treated with 6 intersecting, 2mm-diameter proton treatment beams 15 months before harvesting the brain. e demarcation between the treated volume and the surrounding normal tissue is obvious. A key part of the approach that eventually will be developed for treating epileptic patients with proton radiosurgery is the images upon which the treatments will be based. Investigators at Loma Linda are working constantly to improve the accuracy of functional imaging procedures for locating epileptogenic neural tissue. In the near future they hope to begin translatPlease turn to page 6

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Progress in proton radiation treatment of focal epilepsy...

Continued from page 5 In order to treat a focal abnormality, or any volume of abnormal or cancerous tissue, the physician first must identify and delineate the target volume. Since the projected proton treatment for epilepsy will be guided by images, the guiding imagery must be as precise and faithful as possible to the volume of malfunctioning tissue or anatomical abnormality. However, as Shakespeare might put it, there's the rub. Dr. Pearlstein points out that any image is a representation of physical space; it is not the reality itself. If errors occur in creating the image, then the image will represent the underlying reality inaccurately. Imaging modalities used for treatment planning are subject to physical effects that cause spatial distortions; that is, mismatches can occur between the location of a point in space and its true location. Just as a defect on a lens or mirror that focuses light on the focal plane of a film camera will cause a distorted image on the photographic film, irregularities in the magnetic field of an MR imager or beam hardening within a computed tomography scanner will affect mapping of physical space into the image volume. Such effects such cause uncertainties regarding the true physical location of a target boundary identified within the image. ese uncertainties are quite small, but nonetheless they can be significant when planning treatments for small target volumes located within critical structures. A collaborative research team that includes scientists and engineers at Loma Linda University and Duke University are studying ways to address this problem. One of the approaches involves the development of imaging phantoms (tools used by imaging physicists to simulate a patient undergoing an imaging procedure). A recent paper in the journal, Medical Physics, (Kittle D, Holshouser B, Slater JM, Guenther BD, Pitsianis N, Pearlstein RD, Technical note: rapid prototyping of 3D grid arrays for image guided therapy quality assurance., 2008; volume 35, number 12, pages 5708­5712) describes development of three-dimensional grid phantoms, which are placed within a Leksell stereotactic frame (a device used to immobilize the heads of patients receiving stereotactic radiosurgery or radiation therapy). Such phantoms help to measure imaging-related spatial inaccuracies for image-guided surgery and radiotherapy. e authors examined various rapid-prototyping technologies for fabricating three-dimensional grid phantoms directly from computer-aided design (CAD) drawings. ey used three different fabrication process materials, and tested the phantoms created therefrom to determine the best combination of

Fig. 5. Photomicrograph of grey matter radioablated by proton treatment.

Fig. 4. Proton treatment plan for a rat brain. is horizontal MRI section is taken near the base of the brain. e colored area indicates the volume treated with converging, narrow (2 mm) proton beams.. Note that the radiation dose is confined tightly to the volume of interest, indicated by the pink-red wash.

ing these efforts to the clinic and begin treating patients with epilepsy associated with unilateral mesial temporal lobe sclerosis. e investigators think it possible that, with appropriate proton treatment, most of these patients can have complete control of seizure. To help in planning treatments aimed at that outcome, however, physicians will need as much information as possible regarding the location and behavior of the suspected target tissue deep in the temporal lobe. e epilepsy research team are investigating that aspect of the problem now. Neural activity produces electromagnetic fields that can be detected non-invasively with external sensors. Technologies such as electroencephalography and magnetoencephalography, which detect these electromagnetic fields, are routinely used in clinical monitoring and diagnosis of neurological disease and injury. Using electromagnetic fields for brain imaging is a potentially powerful extension of these technologies. Accordingly, a research team at the James M. Slater center, drawn from both the basic science and clinical arms of the department of radiation medicine and from cooperating departments at Loma Linda University, are assessing the feasibility of an advanced system, based on electromagnetic fields, for real-time imaging of brain function.

build accuracy, surface finish, and stability. One process was superior to the others. Based on their findings, they built a cylindrical grid phantom (Fig. 6), a dense array of uniformly spaced control points that allows investigators to assess distortions within the MR scanner in both the spatial and frequency domains. When the investigators evaluated the spatial uniformity of the grid control point array in their phantom, they found that over 97.5% of the control points were located within 0.3 mm of the position specified in CAD drawings, and none of the points was off by more than 0.4 mm. (To put this into perspective, a human hair is 0.1 to 0.2 mm thick.) As a result of their studies, the investigators concluded that the process of rapid prototyping is a flexible and cost-effective means of developing and fabricating customized grid phantoms for medical physics quality assurance. Magnetic resonance imaging is the preferred method for identifying mesial temporal lobe structures to be ablated with proton beams. Guided accurately by MR images that identify the target volume precisely, physicians and scientists at Loma Linda expect that proton radiation can be used to deliver the dose precisely where it is needed, meanwhile sparing functionally critical surrounding brain tissue. e new device is being employed at the James M. Slater center. Dr. Pearlstein is working with Dr. Barbara Holshouser, the chief MR imaging physicist in the department of radiology at LLU, to assess the accuracy of pre-operative MR images. us far they have used the new head phantom to measure the imaging distortion of specially shaped fiducials contained with the localizer panels of a Leksell frame; the fiducials are used to link image space with treatment space, a critical step in treatment planning. e investigators have been able to identify systematic dis-

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Progress in proton radiation treatment of focal epilepsy...

ical studies with animal models have established the efficacy of proton radiation for ablating brain lesions in small animals. Investigators are now performing translational studies that must be done before clinical trials in humans can begin. e development of tools such as the cylindrical grid phantom is part of that process. To those who suffer from them, the threat of epileptic seizures is akin to waiting for the other shoe to drop. Medications for controlling seizures do not work for everyone who suffers from epilepsy, and surgery, though effective, is for many an unacceptable option. Protons may provide an acceptable alternative treatment for these patients. Preclinical safety and efficacy studies clearly suggest that proton treatments can be used safely and effectively to stop intractable seizures associated with specific types of epilepsy and to prevent development of new epileptic foci in adjacent normal tissue. Translational studies, such as the development of the grid phantom described here, are laying the foundation for clinical research investigations. Continued research is essential, but all indications are promising that further investigations in the use of proton radiation will lead to an effective treatment option for patients with medically refractory epilepsy. e fundamental qualities of the proton beam--the ability to conform the dose to the target and to avoid tissues that should not be irradiated--permit this option. Ongoing research is the key to realizing it in clinical practice.

Fig. 6. e grid phantom developed by the investigators, shown mounted in place within a Leksell frame at a CT (computerized tomography) scanner.

tortions within the image space in the region of the head fixation ring (Fig. 7); they are evaluating distortion correction methods to reduce the magnitude of the imaging abnormalities. Using sophisticated tools and analyses such as those described here, members of the epilepsy translational research team are identifying imaging errors and also means of correcting for them. ese corrections will be vital for image-guided treatment of focal neurological abnormalities such as those that cause epileptic seizures, but in a broader perspective, investigations such as these may apply to proton therapy of many other conditions, such as benign and malignant tumors of the central nervous system or head and neck, for example. Since its founding in 1990, physicians and scientists at the Proton Treatment and Research Center have maintained that proton radiation has many potential applications, and have conducted research with this in mind. Hence, the studies described are part of an ongoing larger research effort to develop proton-based treatments for functional neurological disorders such as medically refractory epilepsy. is effort, supported generously by the Henry L. Guenther Foundation, has proceeded steadily for several years and is but one part of a coordinated program in the neural sciences, with special consideration to the role that protons might play in treating neurological disorders. As noted earlier, the research team have established a foundation for the current work; pre-clin-

Fig. 7. Analyzing spatial disortions detected using the cylindrical grid phantom. e arrows show the direction of the abberation; the colors denote the magnitude of the recorded distortions. Blueshaded arrows indicate treatment space that falls within acceptable tolerance (that is, within submillimeter accuracy). e error vectors eventually will be used to help correct distortions in image space. Courtesy of R. D. Pearlstein.

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Radiation protection: ongoing basic-science research at Loma Linda University

One of the prime concerns of the physicians and scientists at the James M. Slater, MD Proton Treatment and Research Center is exploiting the advantages of proton radiation therapy to the fullest. Proton irradiation offers the inherent advantage of exquisite conformability: the physician can shape the beam in three dimensions, to deliver the needed dose to the targeted volume, and the characteristics of the beam are such that the dose to surrounding normal tissues falls off rapidly. However, normal tissues immediately adjacent to the treatment volume receive some radiation dose and, especially in cases where adjacent tissues are highly radiosensitive, the treating physician would like to lower that dose as much as possible. At the James M. Slater center, proton radiation therapy is used to treat prostate cancer. An optimal radiation dose requires maximal destruction of the tumor while simultaneously affording minimal damage to normal tissues. Accordingly, several dose-escalation studies have been done at the Proton Treatment and Research Center over the past several years; these investigations have established that proton radiation therapy can be used to deliver high doses with minimal likelihood of severe side effects. Still higher doses of radiation, or doses delivered in a shorter overall time, are being contemplated by clinical investigators. Even with protons, such doses may carry some risk of causing side effects because the dose to adjacent tissues will be higher. e nature and duration of the potential side effects depend on the radiosensitivity of the tissue, the total radiation dose, the fractionation scheme, and overall health of the patient. To retain the low incidence of side effects now being seen with proton therapy, investigators are evaluating potential means of protecting normal tissues from radiation. Any form of ionizing radiation damages cells, normal and abnormal alike, in two main ways: directly, by damaging DNA, and indirectly, by inducing the production of reactive oxygen species (ROS). As radiation causes elevation in ROS levels, the ROS in turn affect various cellular processes; accordingly, the fate of the cells ultimately depends on the interaction of ROS with these cellular processes. Cytokines secreted by leukocytes are among the many molecules that are expressed in response to ROS. Since they play important roles in cellular signaling, the pattern of cytokine expression owing to elevated ROS could be especially crucial in the response of cells to radiation. Tumor growth modulation by cytokines can have both direct and indirect effects on angiogenesis (production of blood vessels in a tumor volume), as well as on the anti-tumor immunity of the host. Further, other cytokines, which are important in facilitating immune attacks against tumors, can be compromised by normal-cell exposure to radiation. For reasons such as these, some means of protecting normal cells may be important in cases where adjacent tissues are highly radiosensitive or are exposed to higher total doses, even from highly conformal treatment modalities such as proton radiation therapy. Antioxidants constitute one method of dealing with the ROS problem. Antioxidants are responsible for detoxifying ROS and are the central cellular defense mechanism against oxidative damage. ere are several groups of antioxidants, of which the superoxide dismutases (SODs) comprise one. It has been shown, for example, that elevated levels of SODs have a protective effect against oxidative stress. Several factors have mitigated against the clinical use of endogenous SODs, however, including their short circulating half-lives, hypersensitivity induction, and cost of production. As a result, drugs known as SOD mimetics have been developed in efforts to overcome these limitations. A class of antioxidant drugs known as metalloporphyrins is among these, and a recent paper by investigators at the James M. Slater center deals with a study of a metalloporphyrin antioxidant used in treating a prostate cancer model in laboratory animals (Makinde AY, Luo-Owen X, Rizvi A, Crapo JD, Pearlstein RD, Slater JM, Gridley DS. Effect of a metalloporphyrin antioxidant (MnTE-2-PyP) on the response of a mouse prostate cancer model to radiation. Anticancer Research 2009; 29:107-118). One reason for the research interest in antioxidant radioprotectants is that they have the potential to assist in managing cancers, such as carcinoma of the prostate, that are best treated with high total doses of radiation. Although the cure rate for many such malignancies would be increased by escalating the radiation dose, physicians have to balance that desired result against increasing the risk for normal-tissue injury. Much research shows that local control of prostate cancer, for example, improves significantly when the total radiation dose exceeds 72 gray (usu-

Fig. 1. e chemical structure of the drug studied by the investigators. MnTE-2-PyP is a porphyrin complex with a manganese (Mn+) center and four positively charged imidazole side groups.

ally expressed as Gy, for standard units of radiation dose), but similar data suggest that rates of severe complications also increase. e proton beam, with its highly conformal dose distribution, permits the physician to avoid more of the normal tissues, thus allowing for total doses up to 80 Gy or more. Nonetheless, as noted, some normal tissues are exposed to radiation. erefore, especially at dose levels and fractionation schedules such as are now possible with protons, the physician would like to protect such tissues as much as possible. Hence the interest in radioprotectants by investigators at the Proton Treatment and Research Center. However, for a normal-tissue radioprotectant to be useful during radiation therapy, it must not protect tumor cells. Determining whether this occurs is one major focus of current investigations at Loma Linda. In their study, investigators from the department of radiation medicine and the department of basic sciences (divisions of biochemistry and microbiology) collaborated with colleagues from the department of medicine at the National Jewish Medical and Research Center in Denver, Colorado (Dr. James D. Crapo) and the department of neurosurgery and anesthesiology at Duke University in Durham, North Carolina (Dr. Robert D. Pearlstein). e research emphasized an educational aspect as well: one of the authors, Ms. Adeola Makinde, is a graduate

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student (please see sidebar, page 10). e researchers studied a metalloporphyrin antioxidant, MnTE-2PyP (Fig. 1), combined with radiation on tumor growth using a mouse prostate tumor model known as RM-9. ey used that model because RM-9 cells were originally developed to mimic the characteristics of human prostate cancer as nearly as possible. e cell line has been evaluated extensively for pathological and phenotypic characteristics; such investigations have established that its similarity to human prostate cancer is very close. e MnTE-2-PyP study was part of a longstanding investigation of SOD mimetics at Loma Linda. In previous studies with an SOD mimetic structurally similar to MnTE-2-PyP, administration to RM-9 prostate tumor-bearing mice that also received radiation treatment significantly slowed tumor growth and decreased the expression of hypoxia-inducible factor-1-alpha, an oxygen-regulated transcription factor known to regulate certain cytokines. e investigators speculated that examining the levels of those cytokines might provide insight into the mechanisms responsible for the activity of SOD mimetics in combination with radiation. e major objectives of the MnTE-2-PyP study were to deter-

Fig. 3. Tumor volume in relation to time after treatment. Each point represents the mean ± the standard error of the mean. Significant differences ( p < 0.05) occurred when comparing groups receiving radiation alone (open diamonds) versus no treatment and drug (closed triangles); drug and radiation versus no treatment and drug; and drug and radiation versus no treatment. No significant difference was found comparing radiation alone versus the drug plus radiation (closed circles), but the rate of tumor growth was slowest in the group receiving both treatments.

Fig. 2. AECLTM cobalt-60 irradiator used for irradiating small target fields.

mine whether MnTE-2-PyP can be used in combination with radiation in the RM-9 mouse prostate tumor model and to further investigate possible mechanisms of interaction. In the present research, the emphasis was on leukocyte populations that respond to tissue damage, secrete cytokines, and have anti-tumor properties. e investigators used 8- to 9-week-old mice as their test subjects. ey injected the mice with RM9 prostate tumor cells and grouped them according to whether they were treated with MnTE-2-PyP alone, a single dose of 10 Gy gamma radiation administered via a research-dedicated machine (Fig. 2), or a combination of both. ey euthanized some of the mice 12 days after tumor cell injection to evaluate them for leukocyte populations, red blood cell (RBC) and platelet characteristics, and cytokines; the rest of the test mice were followed for a longer period of time, to assess tumor growth. e scientists found that radiation treatment alone significantly slowed tumor growth. In terms of tumor volume, for example (Fig. 3), they discovered that radiation, whether used with the drug or not, made a significant difference in restraining tumor

size. Adding the MnTE-2-PyP metalloporphyrin did result in slightly slower tumor progression, but the difference between radiation alone and radiation plus the drug was not statistically significant. A similar pattern was seen when the scientists measured survival (Fig. 4, next page). Here again, the difference between animals treated with radiation alone versus radiation plus the metalloporphyrin was not statistically significant, but there was a trend toward a survival advantage in animals given the drug in addition to radiation. e highest fraction of survivors was seen in the group receiving both treatments. In other parameters that the investigators evaluated, however, it appeared that the use of the metalloporphyrin alone did result in some significant outcomes affecting anti-tumoral immunity. ese parameters included production of interleukin-2 (IL2), B cells, T cells, and natural killer (NK) cells. e researchers found that treatment with the MnTE-2-PyP metalloporphyrin alone significantly elevated T cells and NK cells in the spleen, elevated Please turn to page 10

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Radiation protection: ongoing basic-science research...

Student education: an essential part of research

Adeola Y. Makinde Fig. 4. Survival in relation to time after treatment. e fraction of surviving mice in the drug plus radiation group was higher across the entire length of the study. By day 18 there were 0% survivors in the non-treated group, whereas in the drug, radiation alone, and drug plus radiation groups there were 10%, 58%, and 85% survivors, respectively

B cells in the blood and spleen, and enhanced the capacity to produce IL-2 (Fig. 5). All of these factors have the potential to influence anti-tumoral immunity. Adding the drug to radiation did not ameliorate the depression seen in all major leukocyte types, but it did protect the mice against radiation-induced decreases in RBC counts, hemoglobin, and hematocrit. One important cytokine was increased in plasma from both irradiated groups (Fig. 6, next page) and there was a trend for an increase in another important cytokine with radiation alone. e investigators concluded that MnTE-2-PyP did not protect RM-9 prostate tumors against radiation damage. Further, they concluded that it was not toxic under the conditions of their study, and the drug-induced enhancement of certain immune parameters suggested that MnTE-2-PyP may be a beneficial adjunct not only as a normal tissue radioprotectant, but also as a facilitator of anti-tumor immunity. Previous investigations, at Loma Linda University and elsewhere, had established that antioxidant mimetics can protect normal tissues against radiation damage. erefore, one main question the investigaPlease turn to page 11

Fig. 5. e above graphs are similar to those in the authors' published paper but have been simplified for presentation here. Lines atop bars represent standard errors of the mean. Colors represent the treatment (or lack thereof ) arms of the study, as noted at the base of the bottom graph. Note that animals treated with the metalloporphyrin drug only (green bars) showed higher levels of B cells in the blood and spleen; had higher levels of T and NK cells in the spleen; and had a greater capacity to produce the IL-2 cytokine. Each of these factors may have an effect on anti-tumoral immunity. All of the measured differences, in comparison to the other arms of the study, were statistically significant.

e lead author of the peer-reviewed article on which this newsletter story is based, Ms. Adeola Makinde, is a graduate student who works closely with Dr. Daila Gridley in the Radiation Research Laboratories of the department of radiation medicine. Ms. Makinde, who will complete her studies in May 2009, is from Nigeria, where her father is a Seventh-day Adventist pastor and president of Babcock University. Her primacy as author reflects her role in conducting the research and the excellence of her contributions, and also reflects the department of radiation medicine's function as an academic component of Loma Linda University. As a health-sciences university, LLU attracts students from all over the world. Many of them in the basic sciences study radiation (oxidative stress) as part of their requirements for the Ph.D. degree. Many choose to pursue further graduate work with department faculty, and the department includes several such students in any given academic year. Faculty in the department share Dr. James M. Slater's belief that research offers an opportunity for learning, not only for students but for all. Students are learners and collaborators, and their work is recognized in several ways, including publication. Ms. Makinde's work on metalloporphyrins is a sterling example of that process.

Spring 2009

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Radiation protection: ongoing basic-science research...

Continued from page 10 tors asked themselves in the present study was: does MnTE-2-PyP protect tumors? If not, why? at was the fundamental question; if tumor cells were protected against radiation, the agent would seem to have little value for further study. Fortunately, it did not appear to protect tumor tissue. In addition to that fundamental finding, the data obtained by the investigators demonstrated that tumor volumes were significantly reduced by radiation treatment, regardless of whether treatment with the metalloporphyrin was added. e researchers found no statistically significant difference between "radiation" and"drug + radiation" groups. Even so, the rate of tumor growth was slowest in mice receiving both treatments, and mice receiving both treatments survived longest. ese are the kind of findings that, although they do not rise to statistical significance in themselves, intrigue investigators and suggest the need for more study. e investigative team concluded that MnTE-2PyP may be of therapeutic benefit, not only as a nordata reported by the investigators are unique and will stimulate further research with metalloporphyrin antioxidants. "Further research" is, perhaps, the key phrase in this story and in the investigation of metalloporphyrin antioxidants. Studies of metalloporphyrins and other antioxidants have been carried out for several years at the James M. Slater, M.D. Proton Treatment and Research Center. Many of these studies suggest that the tested agents have promise for eventual clinical use, but all investigations thus far are in the basic-research phase. e research teams are still asking fundamental questions and collecting data. When the accumulated evidence seems sufficiently favorable, translational studies will be needed to determine whether clinical research would be feasible. It seems fair to say that the routine clinical use of metalloporphyrins in patients is still years away. Nonetheless, data that have been generated so far at Loma Linda University and at cooperating institutions suggest that more studies of these agents are worth doing. is is being done at the Proton Treatment and Research Center.

Fig. 6. Effect of treatment on expression of the cytokine, vascular endothelial growth factor (VEGF). Groups receiving radiation, with or without MnTE-2-Pyp, demonstrated significantly higher levels of VEGF than did groups not receiving radiation.

mal-tissue radioprotectant, based on its ability to scavenge ROS, but it may also serve to enhance mechanisms that are vital for effective immune responses against neoplastic cells and may decrease risk for anemia in patients undergoing radiotherapy. e

Radiation medicine faculty and staff participate in annual postgraduate convention

e Alumni Postgraduate Convention (APC) is a tradition at Loma Linda University. e event, held this year from March 6 to 9, combines an alumni homecoming for Loma Linda University School of Medicine with a major medical meeting, at which faculty from the various departments at LLU share research findings with alumni and visitors. e department of radiation medicine hosted an informational booth at APC. e booth was staffed by Sharon Jurgens, administrative assistant to Dr. James M. Slater; Sandra Teichman, R.N., B.S.N, publication and protocol coordinator; and Roger Grove, M.P.H., department statistician. Faculty from the clinical and basic-science divisions offered several poster presentations, and Dr. Daila Gridley prepared a poster summarizing several basic-sciences investigations at the Radiation Research Laboratories. Visitors to the booth also were offered copies of various department of radiation medicine publications and Drs. Daila Gridley and Michael Pecaut, who served as information about ongoing clinical and basic-science studies. One clinical topic poster judges, with poster summarizing basic-science ingarnering notable attention was the Phase II trial of lumpectomy and partial vestigations at the Radiation Research Laboratories. breast proton therapy for early stage breast cancer (see story on page 1 of this newsletter). Another popular offering at the booth was a review paper summarizing the clinical applications of proton radiation treatment at Loma Linda University (Technology in Cancer Research and Treatment, 2006;5(2):81-89). e booth and posters were part of the APC Technical & Scientific Exhibit, held on March 8 & 9. Unlike other forms of information sharing, APC offered an opportunity for both participants and visitors to exchange information actively, a valuable way to communicate.

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Patient referral information

For more information or to refer patients, please call the James M. Slater, MD, Proton Treatment and Research Center referral service: USA International Fax inquiry (800) 496-4966, or (800) PROTONS (909) 558-4288 (909) 558-4829

Volume 2, Number 2 EDITORIAL BOARD

Spring 2009

Those requesting information before or after regular business hours may leave a message and will be contacted the next business day. Written inquiries may be directed to: James M. Slater, MD, Proton Treatment and Research Center Loma Linda University Medical Center 11234 Anderson Street Loma Linda, California 92354 Please visit our website at www.protons.com for more information.

Jerry D. Slater, MD (chair, department of radiation medicine); David A. Bush, MD (clinical affairs); Daila S. Gridley, PhD (molecular and radiation biology); Yolanda Magana, RN (administration); Baldev Patyal, PhD (medical physics); Reinhard W. Schulte, MD (translational research); Jon W. Slater (Optivus Proton Therapy, Inc.); Stephen Jacobs (special assistant to the LLUMC president); William Preston, EdD (editor).

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