3-DIMENSIONAL CONFORMAL RADIATION THERAPY

The University Hospitals of Cleveland Department of Radiation Oncology is at the forefront in the constantly changing battle to treat malignancies with ionizing radiation. As computer technology evolves and improves, so do the treatment planning capabilities that are available in the Radiation Oncologist’s arsenal. Three-Dimensional Conformal Radiation Therapy (3DCRT) is a technology-driven treatment planning technique that utilizes diagnostic quality Computed Axial Tomography (CAT or CT scans) to create a customized treatment plan for the patient. This planning method allows for more precise delivery of the external beam radiation from high-energy linear accelerators and has forced a rethinking of the traditional planning techniques. By utilizing a full CT dataset, three-dimensional localization and visualization of the target and its relation to the adjacent normal structures is now an integral part of the planning process. 3DCRT can also account for changes in the patient contour and the density variations within the body 

The goal of a course of radiation therapy is to deliver higher total doses to the target volume with relatively lower doses to the normal tissues. 3D Conformal Radiation Therapy techniques utilize multiple beams to focus the high dose on the volume of interest identified by the physician. At the same time, the plans aim to reduce the dose to the normal structures in the area of the target volume. 3DCRT plans can consist of 6-8 beams, or more, and these treatment portals are customized in their energy selection and relative contribution and are highly conformal. By accurately shaping the fields with much smaller margins, usually 0.5-1.5cm on the target volume, the treatment plan is designed to exclude as much normal tissue as possible in order to keep these structures below their tolerance levels. This is done in an effort to reduce side effects and make the treatment more tolerable for the patient. The tighter margins also allow for higher doses to be delivered to the target volume on each fraction. An additional benefit is that higher overall doses are now attainable and these higher doses should improve cure rates. Other imaging modalities such as MR (Magnetic Resonance), PET (Positron Emission Tomography), SPECT (Single Photon Emission Tomography) can be used in conjunction with CT to guided the planning process to accurately deliver more dose to the target region while sparing normal organs. 

At University Hospitals of Cleveland, the entire treatment planning and delivery process is completely automated. From the treatment planning CT to the treatment planning computer and on to the treatment machine, a seamless transfer of information is in place. 3DCRT and other complex radiation treatments are planned and implemented for patients treated at the UHC Ireland Cancer Center and at the satellites within the University Hospitals Health System.

INTENSITY MODULATED RADIATION THERAPY (IMRT)

Intensity Modulated Radiation Therapy (IMRT) gives the physician a powerful tool that utilizes state of the art technology to deliver doses of radiation with intensity and accuracy that were previously unachievable. These advances allow the team of physicians, physicists, dosimetrists and therapists to maximize the dose of radiation to the tumor while sparing the healthy tissue surrounding the cancer. IMRT technology is so advanced that the treatment machine can be programmed to “wrap” the radiation around the tumor while giving neighboring structures much lower doses.

IMRT is being used to increase tumor control and decrease toxicity in body sites such as the brain, head & neck, lung, esophagus, spine, pancreas, liver, bladder and prostate. IMRT is also very useful in treating areas that have already received significant doses of conventional radiation therapy.

The benefits of IMRT include higher daily doses that can control disease more effectively, fewer side effects due to lower doses to normal tissue, and a reduced number of treatments. These combine to allow the patient to maintain strength and lead more normal lifestyles during the course of treatment while increasing the potential for cure.

IMRT utilizes the technology to provide a highly customized treatment that satisfies the prescription better than 3D Conformal RT. In 3DCRT, the dose within the treatment volume is fairly homogeneous, usually +/- 3-5%. With IMRT, the computer can create a plan that has a much more varied dose distribution and can actually focus the hot spots in areas that are chosen by the physician.

The advances in technology that have brought the Multi-Leaf Collimator (MLC) and record and verify to the clinical setting have allowed the advances seen in IMRT. In coordination with the treatment planning computer, the record and verify software drives the treatment machine through the sequence of fields established in the plan. Each IMRT treatment portal actually consists of many individual fields, called beamlets, which are defined by specific MLC settings. IMRT plans generally consist of 3-6 beams, but it is not uncommon to treat with 8, 9 or more each day, depending on the tumor location and the associated limiting structures. Because the dose distribution can be tailored to meet specific criteria set by the physician for both target volumes and critical structures, it is possible to deliver higher daily doses than with 3DCRT while keeping the incidence of side effects at comparable levels. This is arguably the greatest advantage of IMRT over 3DCRT because higher daily doses will allow the patient to complete treatment sooner than traditional dose schedules.


3-D IMAGE FUSION

In order to improve diagnosis and external beam treatment planning, patient images generated from MR, SPECT, PET and CT may be fused or precisely overlaid and aligned by using the MIMTM image display system. This system, which has received FDA clearance, was originally designed and tested by faculty members of the Nuclear Medicine Division of the UHHS Department of Radiology. Used in conjunction with treatment machine-based external markers (fiducial arrays) which were also pioneered at University Hospitals/Case Western Reserve University, these imaged-guided localization methods bring critical support to the IMRT treatment program and has made it possible for our patients to receive the very highest degree of conformal therapy currently available. The radiation oncologist is now able to define treatment volumes for cancerous tumors not only in relation to anatomical structure, but also with knowledge of the functional state of the tumor and surrounding normal tissue. This information provides them with the ability to target highly active areas of tumor growth with “boost” doses of radiation, potentially leading to increased intervals of tumor regression, tumor eradication and curative outcomes.


GAMMA KNIFE RADIOSURGERY

Gamma Knife radiosurgery is a combined neurosurgical/radiation oncology procedure that utilizes a focused beam of 201 independent Co-60 gamma radiation sources to destroy brain cancers and abnormalities with sub-millimeter accuracy. In addition to the treatment of malignant lesions and arteriovenous malformations, the Gamma Knife has also been successfully applied in the treatment of small, benign tumors such as acoustic neuromas and meningiomas, as well as tumors in areas of the brain that are inaccessible to the surgeon’s knife or so close to vital structures that the risk of conventional surgery would out-weigh its potential benefits. The tissue being treated receives the highest dose of radiation, while surrounding tissue is left minimally affected. Depending on the size of the volume being treated, the procedure can take from 15 minutes to several hours. As indicated, the beams can be redirected and the irradiation procedure repeated until the entire disease site is treated.

Treatment with the Gamma Knife is carried out through the cooperative effects of a team of specialist who bring a broad range of expertise to each patient’s treatment. At University Hospitals of Cleveland, the Gamma Knife team includes the neurological surgeon, radiation oncologist, physicist, radiation technologist, gamma knife certified nursing staff and other essential support personnel.

The Gamma Knife program at University Hospitals of Cleveland, which began in 1999, has treated well over 500 patients for approximately twenty different disease indications. In 2004, the Gamma Knife Model C unit was upgraded with a complete source exchange and the latest versions of treatment planning software and hardware were installed.

On the research and development front, new inverse treatment planning and “expert” friendly software has been created. This software accelerates the planning process and allows the computer to arrive at the optimum plan configuration within minutes. These results were published in the International Journal of Radiation Oncology, Biology and Physics (2002) and Medical Physics (2003).
For more information about Gamma Knife, please click on this GAMMA brochure.


BRACHYTHERAPY

Brachytherapy is a type of treatment using sealed radiation sources to deliver a dose at a short distance, usually to an area or volume that is within 6 inches of the radiation sources. “Brachys” is Greek for “near”, thus, the radioactive sources are placed strategically within the tumor tissue (interstitial), inside a diseased cavity (intracavitary) or even on the surface of the disease site. With brachytherapy, a high dose of radiation is delivered to the tumor while the dose levels decrease rapidly in the adjacent healthy tissue. Clinical experience and studies have shown that tumor tissue response may depend on the rate at which the dose of radiation is delivered. Based on this need for tumor/site specific dose delivery, brachytherapy treatments may be divided into High Dose Rate (HDR) or Low Dose Rate (LDR) techniques.

High Dose Rate (HDR) Brachytherapy

During High Dose Rate (HDR) procedures, the radioactive source (Cesium 137) housed within the HDR unit is temporarily placed (on the order of minutes) adjacent to or within the tumor. With HDR techniques, the radiation oncologist can vary the radiation dosage with source placement resulting in more precise treatment doses and while minimizing the dose to healthy tissue in the immediate vicinity. At University Hospitals of Cleveland, the HDR brachytherapy service is treating patients with gynecologic, endobronchial, and head and neck cancers.

Low Dose Rate (LDR) Brachytherapy 

Low Dose Rate (LDR) Brachytherapy procedures rely on the surgical placement of sealed sources of radiation directly in or near the area being treated. LDR treatments are customized to the patient by varying the radiation source strength and placement and can be temporary (on the order of hours or days) or permanent. The University Hospitals of Cleveland LDR Brachytherapy service provides treatment to the following sites, the prostate gland, cervix, eye and intravascular lesions.

Permanent Prostate Seed Implant (PSI)

For this implant, small radioactive seeds (usually Iodine-125 or Palladion-103) are inserted into the prostate gland with the patient under general anesthesia. In the operating room, images of the patient’s prostate are captured using ultrasound. The treatment planning computer software uses these ultrasound images to plan the seed distribution required to effectively treat the patient. A computer printout, or template, is generated which indicates the seed placement coordinates and the radioactive seeds are placed using an ultrasound-guided needle. After the procedure is completed, the patient goes home (same day procedure). The sources remain in tissue permanently and continue to decay delivering the radiation over a period of time, about 1 year for Iodine-125 and 3 months for Palladium-103.

Cervical Cancer using Tandem-Ovoids or Syed Template

Intracavitary gynecologic cancers, usually within the cervix, are treated using a temporary implant. Cesium-137 or Iridium-192 sources are inserted in to the treatment site using a variety of applicators, such as Tandem-Ovoids and a Syed Template. The surgically placed sources remain at the treatment site between 1-5 days and the patients remain in the hospital for the duration of the treatment.

Eye Plaque

Eye plaque radiation treatment is offered for choroidal melanoma in adults. This treatment requires radioactive seeds to be placed in a plaque that will be sutured in place directly over the lesion. The sources imbedded in the plaque direct therapeutic radiation toward the tumor while shielding the orbit and other surrounding anatomy.

Intravascular Brachytherapy (IVB)

This procedure is performed at the Cardiac Catherization Laboratory at University Hospitals of Cleveland. For this procedure, a catheter is inserted into and guided through the femoral artery, into the inferior vena cava and on until it reaches the location within the thorax where the restenosis is located. A train of radioactive sources is temporarily positioned delivering the necessary radiation within minutes. Presently, Beta particles from sealed Sr-90 sources are used to give the high dose rate radiation to the tissue blocking patient’s artery.


INTRAOPERATIVE RADIATION THERAPY (IORT)

University Hospitals of Cleveland (UHC) is the only hospital in Northeast Ohio to offer Intraoperative Radiation Therapy (IORT). Surgeons and Radiation Oncologists are able deliver a high dose of electron radiation to the tumor site right in the operating room. Unlike other facilities that transport patients from the operating room to the radiation oncology department for IORT, UHC utilizes a mobile electron beam accelerator, the Mobetron, to treat patients in the operating room. The ability to treat the patient without having to move them throughout the hospital saves time, reduces the amount of anesthesia required, and lessens the threat of infection. The second unit of its kind in the United States, the UHC Mobetron is used to treat cancers of the stomach, cervix, head and neck, bladder, pancreas, colon, rectum and sarcomas during the surgical procedure.


RADIOLABELLED MONOCLONAL ANTIBODY THERAPY (RIT) 

Over the past several decades, much progress has been made in the area of targeted therapy where a carrier molecule selectively seeks out cancerous tissue. Rather than affecting all cells, normal and abnormal, targeted therapy can be directed at specific cells. A variety of carrier molecules, such as cell specific antibodies, hormones, drugs, signal transmitters and metabolites, have be tested in animal models and in the clinical setting for selective targeting. Since the turn of the century, at least three drugs which are antibody-based have received FDA clearance and are available to treatment mainly blood borne diseases, such as non-Hodgkins B-lymphoma. These include the drugs Rituxan, which is a biologically active cell surface antibody delivered as a native antibody and is rapidly becoming frontline therapy for low-grade lymphoma. Also approved are Zevelin and Bexxar, both of which are radiolabeled antibodies that selectively bring a potentially lethal dose of radiation to cancer cells through a localized radionuclide. Currently, there are several hundred clinical trials conducted world wide for virtually every type of blood borne and solid tumors using radiolabeled antibody targeted therapy.

At University Hospitals of Cleveland, there are several outstanding efforts in this area including:

1. Original discovery of a biologically active antibody, labeled 3F8, which specifically targeted neuroblastoma and carried an I-131 therapy payload.

2. The availability of radiolabeled antibodies or targeting agents which are in use or are proposed:

   1. As a diagnostic imaged-guided scanning agent labeled with In-111 to direct external beam boost therapy to prostate cancer

   2. For the treatment of low-grade lymphoma treatment (3 agents)

   3. In support of a multi-centered clinical trial for the treatment of glioblastoma through the direct infusion of an antibody into the tumor bed by the placement of catheter in the brain to deliver the agent

   4. For Ho-166 therapy used as a preparative regime for bone marrow transplant for patients with multiple myeloma

3. The establishment of a core laboratory to evaluate multi–centered dosimetric information for patients treated with radiolabeled antibodies.
   

PHOTODYNAMIC THERAPY (PDT)

Photodynamic Therapy (PDT) is a powerful technique that is combined with radiation therapy and chemotherapy for the treatment of several types of cancer that occur within 1 cm of an organ’s surface or near the skin. One of the significant effects of this relatively new technique is its fast action, with tumor ablation often occurring within a few days. PDT uses light, generally from a laser, to generate singlet oxygen to kill malignant cells. Singlet oxygen is a highly reactive, cytotoxic form of molecular oxygen.

The treatment begins when a photosensitizing drug is injected into the bloodstream and cells throughout the body selectively absorb the active agent. After a period of time, which varies with the photosensitizer localization properties, the retention of the drug within tumor cells is substantially greater compared to the levels in normal tissue. However, the window of opportunity is small, so treatment must begin promptly. For activation of the photosensitizer, the tumor region is illuminated with a laser whose emission wavelength coincides with the photosensitizer absorption peak. Absorption of light by the tumor-bound photosensitizer in the presence of molecular oxygen initiates a cascade of molecular chemical or charged events that results in the death of the malignant cells.

Advantages of PDT over other techniques are:

• A degree of selectivity of drug binding to tumor tissue

• The absence of systemic toxicity of the drug alone

• The ability to focus the light on the tumor region

• The possibility of treating multiple lesions simultaneously and 

• The ability to retreat a tumor to improve the overall response

Disadvantages of PDT have been shown to be the prolonged skin photosensitivity, at least for the first generation drug Photofrin®, limited depth of penetration of light (generally only up to 1 cm), and the inability to treat widely disseminated disease.

The PDT Center in the Department of Radiation Oncology, University Hospitals of Cleveland has been involved in several treatment protocols using Photofrin (a first generation photosensitizer) and Pc 4 (a second generation photosensitizer).

Pc 4, silicon phthalocyanine, was developed at Case Western Reserve University and University Hospitals of Cleveland and is currently in Phase I-II clinical trial. These trials are designed to test the efficacy of this translational research effort first demonstrated in mice and now used to treat superficial human cancers. The desirable properties of Pc 4 are its chemical purity, its high extinction coefficient, and its rapid clearance from skin that helps limit treatment complications related to the extent and duration of cutaneous photosensitivity.

TOMOTHERAPY