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INTENSITY MODULATED RADIATION THERAPY "IMRT"
For the newly diagnosed prostate cancer patient, IMRT represents yet another technological innovation available in the armamentarium for the treatment of prostate cancer. What is IMRT and what does its application mean in terms of improved treatment for prostate cancer? In the following discussion you will learn about the technology which makes IMRT possible, as well as how the application of this technology may improve treatment outcomes in prostate cancer.
IMRT is the most precise treatment planning and treatment delivery system yet devised, to deliver radiation therapy. IMRT takes advantage of the practical aspects of leading edge technology in computer sciences, medical imaging technology, materials engineering, and medical physics. IMRT is the most precise method to deliver radiation dosage to the prostate, without the need for surgical intervention. It represents the next technological progression in external beam radiation therapy management for many tumors, including prostate cancer. IMRT is truly "THE NEW - NEW THING".
To understand the technological advancement of IMRT over other external beam radiation techniques, one must first consider what went before in the application of radiation therapy for the treatment of prostate cancer: conventional radiation therapy and 3D conformal therapy (3D CRT). Conventional radiation was first noted to be effective in the treatment of periprostate cancer in the late 1960's. Utilizing the existing linear accelerator technology at the time, radiation therapy was delivered to the prostate and periprostatic tissues in an effort to eradicate the cancer, while attempting to spare the sensitive surrounding normal tissues from potential untoward effects of the radiation. If it were not necessary to consider the radiation dose tolerance of the surrounding normal structures, such as the rectum and bladder, radiation therapy in high enough dose, would eradicate the vast majority of prostate cancers. It turns out, however, that the dose limiting feature in the treatment of prostate cancer with conventional radiation therapy, is the tolerance of the adjacent normal tissues of the bladder and rectum. The dose tolerance for these structures is below the dose which is required to eradicate the prostate cancer, with a high degree of probability. The conventional radiation technique utilized a cross-fire, 4 field box technique, which centered on the prostate, but also included substantial portions of the rectum and bladder within the radiation fields. Due to this fact, the dose of radiation to the prostate was limited to a range not higher than 6,800 to 7,000 centigrade.
Although conventional radiation therapy was found to be effective in controlling many prostate cancers, in the late 1980's and the early 1990's, techniques were developed to conform the standard radiation beam to the prostate gland and thus, exclude substantial portions of the dose limiting tissues of the bladder and rectum. The techniques developed, called 3D conformal radiation (3D CRT), utilized CT imaging technology, as well as three-dimensional radiation therapy treatment planning computer programs to develop anatomically shaped radiation beams which conform as much as possible to the shape of the prostate gland, while avoiding the sensitive tissues of the rectum and bladder. Multiple radiation beams (4, 6, or 7), are delivered at various angles, with each beam shaped by beam shaping devices, such as radiation therapy treatment blocks, or multileaf collimators (MLC) to conform the radiation therapy beamed to the prostate target. The beam shape is defined by a 3D computer graphics software, which allows the radiation oncologist to visualize the prostate target via a beam's eye-view (BEV) technique. The anticipated benefits of 3D CRT were felt to be decreased treatment toxicity related to the rectum and bladder, as well the possibility that higher "escalated doses" could be utilized to give a higher probability of tumor control.
Although, to date, there is no long term survival advantage attributed to 3D CRT for the treatment of prostate cancer, clinical trials have established certain facts. First, 3D CRT is associated with less acute side effects of treatment related to bladder irritation, rectal bleeding and diarrhea. Second, 3D CRT has less long term GI side effects, such as chronic rectal bleeding. And third, dose escalation of 10 to 20% is possible, without increasing toxicity to adjacent normal tissues and that dose escalation results in improved biochemical disease free survival as measured by 3 consecutive rises in PSA.
With all the benefits of 3D CRT, the planning techniques have certain shortcomings. 3D CRT planning, utilizes a trial and error methodology. The radiation oncologist and the medical physicist define a treatment technique and use the computer to show the dose the prostate receives by utilizing this predetermined array of treatment fields. If the dose is not acceptable, alternative radiation fields, or beam modification devices are used in an effort to optimize the dose. This planning technique is called "forward planning". Simply put, forward planning takes beam arrangements and beam shaping modifications as defined by the radiation oncologist and shows what those arrangements and modifications yield in terms of dose to the treatment volume. The trial and error process of forward planning at times, must be repeated to obtain optimal dose distribution. Sometimes, optimal dose distributions cannot be achieved, particularly when the targeted structure has highly irregular shapes, with a combination of convex and concave contours (like many prostate glands). Until now, 3D CRT BEV forward planning represented state of the art radiation therapy planning and delivering.
THE IMRT ADVANTAGE
IMRT achieves unprecedented conformity of the radiation dose, by applying two complex concepts.
- Inverse Treatment Planning
- Modulation of the radiation beam, during treatment to change the intensity of the radiation from moment to moment, during the treatment delivery.
INVERSE TREATMENT PLANNING
In the case of IMRT, the trial and error method of forward planning is replaced by a treatment planning process that allows the radiation oncologist to precisely define the dose to the targeted anatomy (in this case the prostate). In addition, the radiation oncologist can designate areas where the radiation dose is not desired, such as to the sensitive structures of the rectum and bladder and therefore limit the dose to those areas. In fact, inverse planning, together with modulation of the radiation therapy beam, can create radiation dose distributions in almost any conceivable pattern (Fig. 1, happy face).
INTENSITY MODULATION OF THE RADIATION THERAPY BEAM
The second crucial concept of IMRT is modulation of the intensity or strength of the treatment beam, which is varied across the treatment target. To accomplish this, the treatment beam is divided into a multitude of pencil sized beamlets. Each beamlet can, in turn, be adjusted or modulated as to its intensity, with some beamlets shining on the target for longer periods of time or with a stronger intensity. It is like using hundreds of flashlights, each with a different low level of brightness, shining on an object in a dark room. When the flashlights are placed appropriately, the object will be lit, but the surroundings in the room will remain relatively dark. With IMRT, we start with a target, which for the sake of this discussion is the prostate, deep inside the body. The IMRT inverse planning computer system then back projects through the patient's tissue (soft tissue, organs, bone, etc.) back to the linear accelerator source, to define a complicated nonuniform radiation exposure plan. With the equipment, which is most commonly in use at this time, the Nomos-Peacock System, the delivery of the radiation plan is accomplished by using a multileaf collimator (MLC), which is attached to the head of the linear accelerator, between the source of the radiation and the patient. The MLC contains a set of tungsten leaves, which divide the conventional treatment beam into smaller beams or beamlets. As the tungsten leaves move, so does the linear accelerator gantry in an arc-like fashion and thus, the beam is modulated to the specifications of the treatment plan.
DEVELOPMENT OF THE IMRT TREATMENT PLAN
The treatment planning process begins in the same way 3D CRT does, with a treatment planning CT scan of the patient immobilized in the treatment position. Anywhere from 35 to 60 CT scan slices are transferred to the IMRT planning computer. The radiation oncologist designates the target volume (the prostate) and the dose that the target volume is to receive. In addition, the radiation oncologist defines maximum tolerance doses to the near by critical structures, such as the rectum, bladder, and the femoral heads. The computer takes all these specifications into account to derive a treatment plan. Also, the computer solves conflicts between specifications of high dose areas (the target volume) and low dose areas, (the nearby sensitive tissues), as well as, takes into consideration uncertainties in the prostates localization and the prostate movement within the body, by adding margins to the clinical tumor volume (CTV) as designated by the prostate gland, to create the planning tumor volume (PTV).
The computer produces the plan, which designates dose coverage specifically called isodose distributions, in axial, sagittal and coronal views (Fig. 2 axial views, sagittal views, and coronal views). In addition, a valuable tool for the radiation oncologist and medical physicist is developed by the computer called a Dose Volume Histogram (DVH). This is a graphic display of the radiation dose versus the volume of the target and the nearby sensitive tissues (Fig. 3 DVH). If the plan shows the appropriate coverage of the target volume (CTV), and adequate sparing of the sensitive tissues, a computer floppy disk is made that will be utilized to execute the delivery of the plan, during the actual treatment of the patient.
IMRT TREATMENT DELIVERY
IMRT treatment delivery is accomplished utilizing a number of technical approaches, including static IMRT delivered with the aid of MLC, dynamic IMRT delivered with the aid of MLC and rotational tomotherapy IMRT delivered with a MIMiC (MULTIVANE INTENSITY MODULATION COMPENSATOR). Each of these techniques require the same step wise image acquisition and planning process and are likely to have similar outcomes of treatment. However, it is the Nomos-Peacock System utilizing the MIMiC that has the largest clinical experience. In addition, it is also the technology utilized by the author of this chapter, so the explanation of the IMRT treatment delivery will focus on the use of this system.
The Nomos-Peacock System (Fig. 4, MIMiC) utilizes a treatment method called tomotherapy, in which treatments are delivered in a series of segments or steps, through the target volume, in a rotational fashion. As the linear accelerator gantry rotates around the patient's target volume, the MIMiC under computer control, modulates the radiation beam in accordance with the dose intensity map developed by the treatment planning computer (Fig. 5 Intensity Map). The MIMiC can treat each segment in .5 cm, 1 cm, or 2 cm slices. The MIMiC treats two slices at a time, so that the target may be treated in 1 cm, 2 cm, or 4 cm slices thicknesses with each step. If the target is larger, or irregularly shaped the treatment table is indexed or stepped between 1 and 6 times, so as to achieve coverage of the prostate target. It is common to utilize between 2 and 3 steps for the treatment of prostate cancer. The indexing or stepping is accomplished by a device called a CRANE, which precisely moves the treatment table between each step. The MIMiC produces beam modification by dividing the collimated larger broad beamed radiation into 40 beamlets using 40 tungsten leaves, each 1 cm wide, 8 cm deep, which moves in and out of the beam's path at extremely high speeds, as the linear accelerator gantry rotates around the patient. This dynamic process allows the intensity of the beam, to vary from zero to 100% for each 5 degrees of rotation of the linear accelerator gantry. While the MIMiC's leaves move extremely rapidly to allow for the dynamic treatment process, other treatment systems utilizing conventional MLC's move much more slowly, thus requiring the use of fixed field treatment techniques, sometimes called "step and shoot".
THE FINER ASPECTS OF IMRT TREATMENT DELIVERY
The more precise one can make the dose distribution, the more precise the treatment set up must be to prevent missing the treatment target. An immobilization device, which is custom molded to each individual patient's pelvis, torso and thighs is fabricated to ensure limitation of the external motion of the patient. In addition, reproducible placement of the patient's hands and feet, are also felt to be critical factors limiting external movement of the patient.
Internal movement of the prostate is a well documented phenomena, which was previously noted in the external beam radiation therapy literature, as well as observed by those radiation oncologist, with extensive experience in interstitial implant techniques, which visualize the prostate in real time, under fluoroscopic and ultrasound control. Methods of internal immobilization of the prostate remain controversial, but include simple use of external immobilization devices only, bladder filling or emptying, rectal balloon to compress the prostate, new ultrasound field placement devices and the use of certain on-line portal imaging devices. At this time, it is unclear which, if any of these modalities is superior in achieving the goal of internal immobilization of the prostate.
RESULTS OF TREATMENT WITH IMRT
Long term data of treatment related side effects and efficacy are simply not available at this time. What we do know now is very encouraging. Well over 1,000 patients have been treated with IMRT, for prostate cancer. Most radiation oncologists and medical physicist agree, that this technology can deliver the intended dose of radiation to the prostate, while minimizing the dose to the bladder and rectum. In fact, a paper presented at the American Association of Physicists and Medicine in 1999, showed that IMRT when compared to 3D CRT delivered 7% higher dose to the prostate, while a 9% lower dose to the bladder and a 12% lower dose to the rectum.
Moreover, several investigators report less gastrointestinal and genitourinary acute toxicity, associated with IMRT, when compared with 3D CRT. Butler published a paper noting that 52% of IMRT patients had no genitourinary toxicity related to treatment, while 56.7% of patients treated with 3D CRT suffered grade 1 toxicity in a series published by Pollack. In the same group of patient's 74% of patients treated with IMRT, experienced no gastrointestinal related acute toxicity, while 66.7% experienced grade 2 acute toxicity, which required medication to control diarrhea with 3D CRT. This information is not derived from randomized data, but does suggest substantially fewer treatment related symptoms in patients receiving IMRT versus patients receiving 3D CRT.
DOSE SPECIFICATION WITH IMRT
Currently no standard convention exists to specify dose when utilizing IMRT. The nominal daily dose and total prescribed treatment dose are felt to be somewhat lower than the actual dose the prostate receives. Also, it should be noted that there is dose inhomogeneity with minimum dose regions as well as maximum dose regions similar to what is seen with interstitial implant dosimetry. Due to this fact, one should be cautious when comparing treatment doses given with IMRT to 3D CRT. Analysis of IMRT dosimetry, utilizing mean average dose methodology, for example shows that IMRT treatment delivers significantly higher dose to the prostate when compared to conventional treatment, even though the same daily prescribed dose is administered. For example, in one model 7,000 centigray prescribed in 35 fractions, with IMRT was equivalent to the dose escalated total of approximately 7,500 centigray, when mean dose methodology was used to determine the prescribed dose. A strategy which takes advantage of this increased daily dose to the prostate, which incidentally is noted to be well tolerated, can decrease the time in which treatment is given. Kuplian has reported this modification of a treatment approach, which is sometimes called accelerated fractionation, which allowed dose escalation treatment to be delivered over less time, but with no greater side effects or morbidity. This approach may have biological advantage in terms of killing cancer cells, as well as economic advantage of shortening the treatment time.
THE PROMISE OF IMRT
The current status with regards to the evaluation of the efficacy and the effectiveness of IMRT in the treatment of prostate cancer is in much the same place 3D CRT was in the mid 1990's. However, it was the patients treated with that new treatment modality then, who comprised the data, which show the benefits of 3D CRT now. IMRT, due to its inherent precision creates new technological challenges, which are being studied and evaluated. The technology of IMRT with its precision of treatment delivery, is particularly suited to the treatment of prostate cancer and it is the view of the author, that it will fast become the technological standard to compare other external beam techniques. Does that mean the end of 3D conformal therapy, or even the replacement of many of the interstitial implants used in the treatment of prostate cancer? IMRT like the other treatment methods will find its niche and will be applied to appropriate clinical situations. The IMRT has clear advantages in terms of its precise delivery of radiation to eradicate cancer. IMRT will move from being "THE NEW - NEW THING", to an accepted and possibly superior treatment modality and its use will elevate the standard of care in the future. |
