Fall 2007

Multi-Disciplinary Pancreatic Cancer Clinic

We are pleased to announce the opening of the Multi-Disciplinary Pancreatic Cancer Clinic at The Johns Hopkins Hospital.

The clinic will be held every Tuesday, and the first clinic day will be November 21st, 2006. In one day patients with known or presumed pancreatic cancer will have a comprehensive evaluation by nationally recognized pancreatic cancer clinicians and specialists.

It is our goal that all patients will be seen in the clinic within one week of the referral, as long as all the necessary clinical information has been obtained.

August 2006

Johns Hopkins Institutional Research Grant, May 2006
"Spatial Distribution of Hypoxia and Response to Localized Radiotherapy"

Investigators:
E. Ford, E. Armour, J. Wong (JHU, Radiation Oncology)
M. Pomper (JHU, SAIRP program)
R. Freifelder (UPenn, Cyclotron Production Facility)

This experiment aims to study the distribution of low oxygen regions (hypoxia) within tumors and their response to radiation. Hypoxia is an important property of solid tumors that confers radiorestistance on cells and drives upgregulation of genes associated with poor clinical outcomes. This study employs a well studied human colorectal tumor model, and a novel non-invasive imaging agent, 18F-EF5, which selectively binds to hypoxic regions and can be imaged with positron emission tomography (PET). EF5-PET imaging will allow us to visualize the heterogeneous spatial distribution of hypoxia quantify its response to fractionated localized radiotherapy. These experiments will be a first step toward testing the effectiveness of hypoxia-localized radiotherapy. They will provide knowledge about the interaction of fractionated radiotherapy and the distribution of hypoxia, critical information in the design of future clinical trials.

Upcoming Presentations:

ASTRO 2006

1. Early Experience With Highly Focal Radiation Delivery To The Mouse Brain Using Our Small Animal Radiation Research Platform (SARRP)

2. Repeat Respiratory-Correlated 4-D CT Images to Evaluate Inter/Intra-fractional Changes in Volumes and Trajectories of Pancreatic Tumor/Tumor-bed and Organs at Risk (OAR).

3. Comparison of PET/CT and CT for Delineation of Lumpectomy Cavity for Partial Breast Irradiation

4. Megavoltage CT Assessment Of Volume Changes In Target and Non-Target Tissues of the Head and Neck Over A Standard Course Of Therapy

5. The Small Animal Radiation Research Platform

AAPM 2006

1. Evolution of tumor volume and motion in non-small cell lung cancer during radiotherapy

2. The Small Animal Radiation Research Platform: Benchtop Cone-Beam CT

3. The Small-Animal Radiation Research Platform (SARRP): commissioning a 225 kVp “small-field”

4. x-ray source for Monte Carlo-based treatment planning

5. The Small-Animal Radiation Research Platform (SARRP): Focused Pencil Beam Dosimetry

May 2006

Active Breathing Coordinator (ABC) System

Since October 2004 Dr. John Wong has been the Director of Medical Physics at Johns Hopkins. He was the innovator who designed and clinically implemented the first active breathing immobilizer. As such, with Dr. Wong’s expertise, our present faculty’s interest and our staff’s enthusiasm will permit the rapid educational advance of our clinic with direct benefits to our patients.

The ability to plan and deliver radiation with high precision is only valuable if the tumor is in an identifiable and stationary position. As such, physicians rarely use millimeter precision for tumors in the lungs due to respiratory motion. Because these tumors are moving with respiration, they are difficult to target for precision treatments. Thus, in order to be sure these moving lung tumors receive adequate radiation, larger treatment fields are required.

Unfortunately, these larger fields also result in a greater amount of non-cancerous lung to be treated as well. Tools that would allow physicians to arrest a patient’s breathing at a precise moment and coordinate the delivery of radiation with this pause would be valuable. Such a system would provide far greater accuracy of radiation delivery minimizing radiation to the normal lung thereby reducing side effects. The active breathing coordinator (ABC) is a portable system to achieve this repeatable arrest in breathing essentially freezing the moving tumor.

Impact on patient care

High doses of radiation are known to be more effective at controlling most types of cancer. Johns Hopkins has already made substantial investments in high precision radiation delivery equipment. The benefits possible with this precision equipment have not yet been fully realized for treatment of lung, breast, and liver tumors because of the complex motion inherent in these organs resulting from respiration. Integration of an active breathing coordinator (ABC) will allow for higher, more precise radiation used to treat these tumors as well.

The benefits include:

1. Higher radiation doses for better tumor control

2. Reduced normal lung exposed to radiation when treating patients with lung cancer and breast cancer for better long-term breathing

3. Reduced heart exposure to radiation when treating patients with breast cancer results in reduced coronary vessel injury

4. Reduced normal liver exposed to radiation means better long-term liver function

5. Older children with Hodgkin’s disease would also experience similar benefits with decreased lung and heart irradiation.

For breast cancer patients in particular, this treatment is more effective as that majority of left sided breast patient receiving radiation will have a significant portion of their ascending coronary artery in the field, posing a real risk of cardiac toxicity with time. This is particularly exacerbated with the combined use of chemotherapy and radiation. Also, the ABC breath-hold technique will allow treatment of breast patients with loco-regional nodal disease that is superior then all current methods.

For most tumor types it has been shown that a combination of radiation and chemotherapy, when used simultaneously, results in improved tumor control. Today, certain potent chemotherapy drugs cannot easily be prescribed with radiation in the treatment of lung and liver tumors because of the large radiation fields necessary. The combination of the two would result in substantial side effects to the patient. Incorporation of an ABC could potentially allow the study of these more potent radiation-sensitizing drugs with more precise radiation delivery without fear of substantial side effects.

This would also allow us to study the application of substantially greater doses of radiation without chemotherapy, which today cannot be delivered given the lack of an active breathing control mechanism.

January 2006

RADIATION THERAPY IN PATIENTS WITH CHILDHOOD CANCER

Dr. Moody Wharam and Dr. Ori Shokek recently reported on the outcome of children with
rhabdomyosarcoma (RMS). RMS, a rare pediatric cancer which under the microscope resembles
muscle cells, can arise anywhere in the body. All patients require chemotherapy, but the
decision of how to manage the local site where the tumor arises is often quite challenging.

Dr. Wharam and Dr. Shokek examined the results of children treated on national protocols
without radiation therapy (RT) to the local site and compared them to those treated with RT.
The purpose of the study was to identify certain groups of patients in whom omitting RT
is permissible. Patients with tumors arising in gynecologic sites indeed appeared to fare well.
In contrast, very young patients in whom RT was omitted fared poorly.

The study was presented at national and international pediatric cancer conferences.
Its results will help refine treatment for this uncommon pediatric cancer.

December 2005

Dr. Danny Song, M.D., Assistant Professor of Radiation Oncology and Urology awarded DOD grant
in Prostate Cancer: A “Better Mousetrap” to Make Brachytherapy Even More Precise.

Brachytherapy -- implanting radioactive seeds into the prostate to kill cancer -- has come a long way
since the 1970s, when doctors made an incision in the prostate and tried to space the seeds evenly,
with a “free-hand” approach.

Over the last decade, with the use of CT scans and ultrasound guidance to place the seeds through
the perineum, and the development of dosimetry -- precise placement of the seeds to kill prostate
tissue, but avoid harming nearby organs, such as the bladder and rectum -- brachytherapy has become
much more effective. This is particularly true as more men, with the help of regular PSA screening,
are diagnosed with early-stage prostate cancer, where the cancer is still confined within the prostate.

However, the goal is perfection -- curing prostate cancer with minimal side effects -- and as good as
brachytherapy has become, radiation oncologists and colleagues at Hopkins are working to improve it.
One challenge is that there is no “regulation” prostate -- no standard in size, shape, or tissue
consistency. Every man’s prostate is different. This means that “the highest level of precision
is sometimes difficult to achieve, even for the most experienced physicians,” says Dr. Song.

Sometimes, for example, dense prostate tissue slightly bends the needles used to place the seeds,
and the implanted seeds don’t always end up exactly where they are supposed to be. “In addition, although we use ultrasound to view the prostate during the procedure, seeds cannot readily be seen on the ultrasound image once they have been placed. This means that the results of the implant are not always exactly what was intended -- and yet, when it occurs, this cannot always be identified and corrected in the operating room.”

Treating a moving target

Even with “pre-plan” (a map and radiation dosage guide drawn up before the procedure) and intraoperative “real time” dosimetry, “the treatment plans are based on a fixed organ,” says Dr. Song. “In reality, the prostate gland is mobile. As it is pierced with needles, the prostate gland can move, rotate, and swell. The radioactive seeds can also move, shift and migrate during the procedure. This can make perfect implants difficult.” (This frustrating movement of the prostate, by the way, can also happen during a needle biopsy to look for cancer, and is why doctors now take a dozen samples instead of just a handful.)

What’s needed, continues Dr. Song, is “a better mouse trap” -- improved dosimetry. “We are currently
evaluating two different approaches to help solve this issue.” One potential solution involves
Dr. Dan Stoianovici, Director of Uro-Robotics Laboratory at the Brady Urological Institute.
Stoianovici has been developing an automated method of performing brachytherapy, using a computer-driven, robotically automated brachytherapy seed implant device, which he designed, that can be coupled with continuous real-time MRI imaging.

Another benefit: “The automatic implant device will make the success of treatment independent
from the operator,” says Song. “Dr. Stoianovici's concept and work is revolutionary, and will change the face of prostate brachytherapy.” Another approach involves a device created by Dr. Gabor Fichtinger and colleagues in the Hopkins School of Engineering. “This device links an x-ray machine, which is capable of viewing the seeds but not the prostate, to an ultrasound, which can view the prostate but not the seeds,” explains Song.

Computer software then spots the seeds on the x-ray and projects their location onto the ultrasound, showing exactly where the seeds are. What does this mean? The ability to see in the dark -- to know what’s happening to the ever-changing prostate during the procedure. “The concept,” explains Song, “is that as the seeds are placed, the prostate gland is constantly reimaged and revaluated for adequate dosimetry. If a seed shifts, a ‘cold spot’ would be recognized and treated. This is not possible with current techniques.” The result: “An ideal seed distribution,” says Song.

The next step is to prove that these “better mousetraps” work as well as the Hopkins scientists expect it will. “We have recently been awarded funding through the Prostate Cancer Research Program of the Department of Defense to carry this out this study,” says Song. He and colleagues will conduct a feasibility study, evaluating results in men treated with the new technology. If shown to be effective, this technology will rapidly be made available to all physicians, and their patients, who are using brachytherapy to treat prostate cancer.

November 2005

The following news tips are based on Johns Hopkins Kimmel Cancer Center presentations made at the American Society for Therapeutic Radiation and Oncology 47th Annual Meeting October 16-20, 2005 in Denver, Colorado. For more information or to arrange interviews, contact Vanessa Wasta at 410-955-1287, wastava@jhmi.edu.

HORMONE TREATMENTS BEFORE RADIATION NOW CONSIDERED EFFECTIVE
Mouse Studies Quell Worries from Previous Prostate Cancer Study Radiation oncologists have eagerly anticipated a follow-up to previous studies that implied radiation treatment for prostate cancer was less effective after the use of drugs to suppress hormones. Now, Johns Hopkins Kimmel Cancer Center scientists say their tests provide evidence that hormone therapy will not diminish the value of radiation.

The root of clinicians' concerns began five years ago when studies revealed that suppressing hormones in prostate tumors destroys tiny blood vessels that carry oxygen to cells within the tumor. But oxygen also plays a critical role in biochemical pathways that help radiation kill cancer cells by immobilizing their DNA repair process. If true, these oxygen-depleted tumors would be less likely to respond to radiation.

Theodore DeWeese, M.D., professor and chair of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins, led new tests in more than 50 rats whose prostates closely resemble human ones. "We used several rigorous tests, including a small fiberoptic probe and florescence, to detect oxygen levels in the prostate, and no rat showed any indication of low oxygen levels following hormone suppression," he says.

It is still unclear as to how oxygen remains in the tumor without the small blood vessels, but DeWeese believes that clinicians can be assured that hormone therapy will not cause radiation to be less effective. (Abstract #2399, Proceedings of the American Society for Therapeutic Radiation and Oncology, 2005)

LEUKEMIA DRUG SHOWS MODEST BENEFIT FOR PROSTATE CANCER
Johns Hopkins Kimmel Cancer Center researchers have found that the leukemia drug imatinib (Gleevec), which is being tested in various cancers including colon, ovarian and pancreas, may not work alone against prostate cancer. Previous studies have already found that imatinib is ineffective for metastatic prostate cancer. This new study shows only modest benefits in suppressing PSA levels for some men with localized prostate cancer. But, the researchers say that combining imatinib with other chemotherapy drugs may be something to study.

"Even though Imatinib was tolerable and easy to administer, using this drug alone was not enough to lower the majority of patients' PSA levels," says Theodore DeWeese, M.D., professor and chair of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins.

The study performed by Dr. DeWeese, in collaboration with Dr. Gopal Bajaj, M.D.,
is one of the first to evaluate imatinib in men with non-metastatic prostate
cancer. All 24 patients had rising PSA levels -- a sign of relapse -- despite surgery to remove the prostate or radiation therapy to destroy it. PSA levels in six patients (22 percent) remained stable while receiving imatinib for one year, and two patients (7 percent) experienced a decline in PSA that was not statistically significant. The remaining patients' PSA levels increased while taking the drug.

Other researchers at Hopkins are conducting studies on using the chemotherapy drug docetaxel in men with non-metastatic disease. DeWeese believes that results of this study may help determine if adding imatinib to chemotherapy is worth pursuing for these patients. He says, "With the combination strategy, we may be able to kill cancer cells by two different pathways."
(Abstract #2141, Proceedings of the American Society for Therapeutic Radiation and Oncology, 2005)

RADIATION TECHNIQUE CAN DESTROY VESSEL ABNORMALITY IN BRAIN
Malformed blood vessels in the brain that are larger than the size of a silver dollar were once thought incurable by radiation alone. After a 10-year study, Johns Hopkins Kimmel Cancer Center researchers found that precise radiation techniques can cure or shrink some of these abnormalities.

Arterio-venous malformations (AVMs) are a collection of blood vessels that do not contain the smaller capillaries, which bring oxygen and nutrients to brain tissue. Recently brought to mass attention by a character in the HBO television show "Six Feet Under," AVMs can lead to deadly stroke and neurological problems. Brain surgery can be risky, and cutting off the blood supply to the vessels via embolization does not cure the problem.

Daniele Rigamonte, M.D., professor at Johns Hopkins and senior author of the study, says that image-guided methods that very precisely deliver large doses of radiation therapy have helped to cure more large AVMs. "We are encouraged to find that sterotactic radiosurgery is a relatively safe method, and some large AVMs can be completely obliterated," he says.

AVMs were cured in three of 12 patients treated with stereotactic radiosurgery in the past 10 years with an average of three treatments per year. AVMs in the rest of the group were reduced by an average of 64 percent. Side effects included persistent headaches in two patients and a partial seizure in another patient.

Dr. Rigamonte says that his team will continue to follow these patients to determine how long it takes on average to cure the AVMs.
(Abstract #180, Proceedings of the American Society for Therapeutic Radiation and Oncology, 2005)

--John Hopkins Medical Institutions--