Copyright R. Zamenhof, 2013.
Since their discovery in 1896, x-rays and gamma rays have been the cornerstones of diagnostic radiology and radiation oncology. Within the last decade, however, new approaches to radiation oncology with x-rays and gamma-rays have been developed that go even further toward increasing the radiation dose delivered to tumor while reducing the radiation dose delivered to surrounding healthy tissues and organs—which is the primary technical goal of radiotherapy.
Intensity Modulated Radiotherapy (IMRT)
An important development in radiation oncology about a decade ago is called Intensity Modulated Radiotherapy, or IMRT. With this technology, the x-ray beam during a treatment is not of constant intensity, as it was in older technologies, but varies based on the changing irradiation geometry during a treatment delivery. In conjunction with a more established technology called the variable leaf collimator, IMRT is often able to produce better dose distributions within the patient’s body than pre-IMRT technologies. Not all cancer treatments are improved in quality using IMRT, but most are.
Image Guided Radiotherapy (IGRT)
An original deficiency of IMRT was that it relied on the tumor remaining in the same anatomical position during a treatment, as well as maintaining the same location in the body from one treatment fraction to the next. In reality, however, many tumors tend to move around. For example, lung tumors can shift positions with every breath, while tumors of the colon can change position from day-to-day due to migrations of bowel gas. In both cases, this can make “aiming” the radiation treatment very uncertain.
A solution to this problem was developed about a 15 years ago and is called Image Guided Radiotherapy, or IGRT. CT scans of the patient are taken by specialized CT scanners that produce movie-like scans that record, for example, the respiratory movements of lung tumors. Various devices are placed on the patient’s chest to monitor respiratory movement using video cameras while the CT scan is in progress. The same devices are used during actual treatment, and a correlation is established between the instantaneous position of the tumor and the phase of the respiration cycle, which enables IMRT enabled therapy machines to irradiate the tumor only when it is in a predetermined known position.
On Board Imaging
A related development is CT-like imaging devices that are integrated into the treatment machines themselves. Known as on board imaging, or OBI, these devices use the normal rotation around the patient of modern linear accelerators to collect x-ray transmission measurements through the patient that are immediately reconstructed into CT-like images. OBI can detect, for example, shifts in anatomical tumor position from day-to-day as well as during a treatment. With this additional information, tumor location corrections can be applied from one treatment to the next as well as more recently, using specially adapted treatment machines, during the course of each individual treatment. Not all radiotherapy centers yet have OBI capabilities, but many larger facilities and academic centers do.
A completely different approach to radiotherapy, available for many years but in very few treatment centers, is called Proton Therapy. Protons are nuclear particles that can be accelerated to very high energies by machines called cyclotrons or synchrotrons. When a beam of such high-energy protons enters the patient’s body, it delivers its energy quite uniformly within a specifically chosen range of depths that is made to vary as the proton beam rotates around the patient. Unlike beams of x-rays that pass all the way through the body and deliver unwanted dose to healthy tissues beyond the depth of the tumor, proton beams stop abruptly at specified depths; this means that no dose at all is delivered beyond the deepest location of the tumor and, therefore, downstream healthy tissues and organs are protected. Consequently, for many applications in radiotherapy, proton beams are able to deliver radiation with more precise conformation to tumor volume and with less injury to healthy tissues and organs than x-rays. For this reason, protons are an excellent choice for a specific class of tumors, where unwanted radiation outside the tumor volume can lead to especially serious side effects.
Since proton therapy involves very expensive facilities (costing typically $100,000,000 to $150,000,000), insurance companies only cover this treatment for a limited number of cancers where it has been clearly demonstrated that protons are more effective—or at least produce fewer side effects than x-rays. However, with time the cost of proton facilities will no doubt decrease, which should expand the range of applications for which insurance coverage is available. Examples of cancers where protons have been found to be superior to x-rays are tumors of the spinal cord, childhood brain tumors, and prostate tumors.
Today, there are still not many proton treatment facilities in existence: approximately 14 centers in the U.S. with 12 more in the planning or construction stage, with about 49 centers mainly in Europe and Japan.
Using similar principles to proton therapy, one of the latest approaches to particle therapy uses carbon ions in place of protons. Carbon ions, approximately 12 times heavier than protons, require much higher energies and even more costly accelerators than protons, but in return produce even more conformal dose distributions than protons and possess radiobiological characteristics that make them especially suited to treating certain types of highly resistant cancers. Typically, the accuracy of heavy-ion beam delivery is better than 1 mm. Carbon ions also produce biological damage that is virtually unrepairable, so tumors and normal tissues are able to recover much less from this kind of radiation than from x-rays or protons. Because the criteria for beam delivery with heavy-ions are even higher with heavy-ions than with protons (due to the potentially devastating harm the heavy-ions can cause if misdirected), it is considered almost mandatory to mount the beam delivery systems on isocentrically mounted rotating gantries, so that the patient does not move after setup or during changes in beam direction, which would greatly reduce the accuracy of beam delivery. However, because the accelerating energies for heavy-ion beams are very much higher than for protons, the physical size of the gantries needed is enormous. At the present time there is only one clinically operational heavy-ion 360 degree rotating gantry facility in the world: in Heidelberg, Germany. The gantry in this facility weighs 670 tons and the accuracy of beam delivery is stated to be sub-millimeter. The picture at the top of this article shows the massive dimensions of the Heidelberg heavy-ion gantry.
An obvious question arises as to whether even heavier ions could be used which would provide still better radiobiological characteristics and further improved beam delivery accuracy. However, for ions heavier than carbon, these two characteristics in fact rapidly deteriorate, because heavier ions break up into lighter ones as they penetrate through tissue, thereby reducing beam delivery accuracy and the quality of the beam’s radiobiological characteristics.
So far, approximately 13,000 patients have been treated with carbon-ion beams in Japan, Germany, Italy, and China. But the U.S., despite having pioneered heavy-ion treatment at the Lawrence Berkeley National Laboratory in clinical trials that ran from 1975 through 1992, still lacks a clinical treatment capability.
The enormously high cost of heavy ion therapy, many times that for proton therapy, sheds some doubt on whether heavy-ion facilities could ever exist on patient income alone without the large subsidies from government funding that they presently enjoy.
However, from a financial viewpoint, treatment with heavy-ions has one mitigating advantage over treatments with x-rays or even protons. Because of the propensity of heavy–ion beams to cause essentially unrepairable damage, there is less benefit to fractionation than with other forms of radiation. In fact, for some cancers, heavy-ion treatments are delivered in 4-6 fractions rather than the 30-40 fractions that would be used for treating the same cancers with x-rays or protons. This proportionally reduces the cost of the heavy-ion treatments by a factor of approximately 4.
Staff at the National Cancer Institute have estimated that a total of 60 heavy-ion treatment facilities would meet the clinical need for heavy-ion treatment worldwide for the types of cancers for which heavy-ions have been shown to be beneficial.
Fast Neutron Therapy
Fast neutron therapy uses high-energy neutrons in place of x-rays for treating certain cancers for which the dependence of tumor regrowth on the presence of oxygen is a problem for local disease control.
Therapeutic fast neutrons have energies of 50-70 MeV. At these energies, fast neutron beams have penetration in tissue that is similar to 6-10 MeV (i.e., intermediate energy x-ray beams). Fast neutrons interact with tissue primarily by causing recoil of the tissue elements hydrogen, carbon, oxygen, and nitrogen. The radiobiological characteristics of these recoiling ions (with the possible exception of hydrogen) are very well suited for treating certain cancers that depend on the presence of oxygen to survive and grow.
The parameter that defines how much less dose needs to be delivered with fast neutrons vs. x-rays to produce the same effect on tumor is called the relative biological effectiveness, or RBE. But, as fast neutron dose decreases, RBE increases. This leads to potential complications at normal-tissue/tumor boundaries, where a sharp dose gradient exists and one would expect normal tissues to receive significantly less dose than tumor. However, since the physical doses to normal tissues around this boundary are significantly lower, the RBE is significantly higher; which led to unexpected normal tissue complications in the early fast neutron trials in the U.S. Similarly, as the number of fast neutron fractions for a treatment increases, dose-per-fraction decreases and, once again, fast neutron RBE increases.
This latter phenomenon led to the earliest fast neutron trials in the U.S. at the Lawrence Berkley Laboratories in the 1940s being an unmitigated disaster, since fast neutron RBE was determined in in vitro cell cultures, and no allowance for increased RBE was made when fractionated treatments were delivered to the first fast neutron patients.
Fast neutron therapy has been administered to about 30,000 patients in Germany, Russia, South Africa, and the United States. In the U.S., four treatment centers exist in Seattle, Washington, Detroit, Michigan and Batavia, Illinois, although currently only three are actively treating patients.
The efficacy of fast neutron treatments has been convincingly demonstrated for many forms of cancer; but specifically head-and-neck cancers, which often depend on the presence of oxygen to grow, have been excellent candidates for fast neutron therapy.
So why has fast neutron therapy not caught on? The reasons for this are related to technical and financial issues. From a financial viewpoint, as with current x-ray and proton therapy treatments, the fast neutron treatment heads—at least in the U.S. facilities--are mounted on isocentrically rotating gantries. Since the production of fast neutrons for therapy requires the acceleration of either protons or deuterons to high energies, the cost of isocentrically mounted fast neutron treatment heads is equal to the cost of isocentrically mounted proton treatment heads plus the additional hardware necessary to create and shape the fast neutron beam. The resulting cost of an isocentrically mounted fast neutron treatment facility is significantly higher than the cost of a proton treatment facility.
From a technical viewpoint, there have been many enhancements to x-ray therapy over the past 20 years—as described in the earlier sections of this article; for example, IMRT, IGRT, on-board imaging, sophisticated treatment planning software, etc. Because fast neutron treatment facilities are still experimental and highly subsidized, many of the above developments in sophistication of treatment have not percolated down to the fast neutron facilities. Therefore, fast neutron facilities, other than enjoying rotating gantries, have not been able to take advantage of many of the technological treatment enhancements that have helped x-ray therapy.
A new type of x-ray radiotherapy was developed about 15 years ago called Tomotherapy. Tomotherapy machines look a bit like CT or MRI scanners. The patient enters a tunnel on a moveable couch and a built-in CT scanner ensures accurate positioning. The patient then moves slowly through the tunnel while many pencil-sized beams of x-rays are rapidly turned on and off in a carefully programmed sequence while the x-ray source rotates around the patient. For many types of cancers, Tomotherapy can provide a higher quality treatment than IMRT, and at times can almost match the precision of proton therapy.
An interesting innovation in radiotherapy has been the Cyberknife, a robotic radiotherapy system programmed to aim a moving pencil-like x-ray beam at the patient’s body from various directions (see 1st picture above). Like proton therapy, Cyberknife is most useful for treating small primary or metastatic tumors located within particularly sensitive normal tissues. The Cyberknife is usually integrated with an IGRT enabled CT scanner, so its beam can also be programmed to “follow” the movement of a tumor as a treatment progresses.
For small brain tumors, brain metastases (tumors from elsewhere in the body that have spread to the brain), and arteriovenous malformations (AVMs) the Gammaknife has proven itself a very effective form of radiotherapy. Introduced about 20 years ago, the Gammaknife uses 101 individual sources of the radioisotope cobalt-60 that send individual narrow pencil beams of gamma rays (equivalent to x-rays for this discussion) to crossover at a “focal point”. The patient’s head is then oriented and automatically moved so that this focal point is swept throughout the volume of the tumor to be treated, producing a very conformal dose distribution around one or more tumors. The gammaknife procedure requires that the patient have a stereotactic frame placed on his/her head, which involves four screws that penetrate through the scalp and partially into the skull, so that the MRI images initially taken for treatment planning can be spatially correlated with the gammaknife’s internal coordinate system. For this reason, the Gammaknife is designed to do single treatments rather than the 20-40 treatment fractions comprising most radiotherapy regimens. In addition to being an effective treatment for intracranial tumors and metastases, the gammaknife is frequently used to treat trigeminal neuralgia. This nerve disorder causes severe and disabling facial pain. By strategically placing a high-dose lesion on the trigeminal nerve where it exits the spinal cord, the pain signals can be be blocked. Gammaknife provides the highest level of precision necessary to effectively treat trigeminal nerve disorders. This procedure is more frequently being used as the first treatment for trigeminal neuralgia when medications fail to provide adequate pain relief.
Neutron Capture Therapy
The efficacy of radiotherapy in the future will markedly improve when techniques are developed to treat metastatic disease as effectively as local disease. One such emerging technology, still in its early clinical trials, is called neutron capture therapy (NCT), once dubbed “cellular surgery” because of its potential ability to irradiate individual tumor cells rather than visible macroscopic tumor volumes--as all other radiotherapy technologies discussed here are limited to doing. NCT is a very complex form of radiotherapy, combining the principles of chemotherapy (in that individual tumor cells are initially targeted by a chemical compound), and heavy-particle radiotherapy (with the radiobiological advantages brought by that form of therapy.
The patient is initially infused with a chemical compound that has been designed to selectively concentrate in tumor cells—both those within the primary tumor volume as well as the individual islands of cells near the peripheries of primary tumor volumes. Each molecule of the compound is labeled with a number of atoms of boron-10 (typically a “cage” of 12 boron-10 atoms). Boron-10 has an unusually high proclivity for absorbing low energy neutrons, immediately after which it splits into two charged particles: a lithium-7 ion and an alpha particle. These particles have a range in tissue of 4-10 µm, roughly equivalent to a typical tumor cell diameter. After the chemical compound has been given sufficient time to reach an optimal concentration ratio between tumor and normal cells, the local region of the body is irradiated with a specially designed “epithermal” neutron beam from a specially modified research nuclear reactor (in the U.S., research reactors at the Brookhaven National Laboratory and at the Massachusetts Institute of Technology were converted to deliver NCT therapy to patients, but are not active any more).
The epithermal neutrons entering the tissue (after losing most of their energy through collisions) are captured by the boron-10 nuclei, resulting in a cellular level charged particle distribution that mimics the distribution of the boron labeled compound. Consequently, much higher radiation doses can be delivered to tumor cells, both within the primary tumor volume as well as isolated tumor cells near the tumor’s periphery, than to neighboring normal cells.
There have been a number of clinical trials of NCT at some of the 10 or so sites in the world where such technologies exist. NCT has been shown to sometimes provide better therapy for certain tumors than any other radiotherapy available; for example, certain very difficult-to-treat head and neck cancers respond very well to NCT, probably because the radiobiological properties of NCT do not permit the presence of oxygen in tumors to support their regrowth. However, the complexity and very high cost of delivering NCT severely limit its continuing development and its future.
Important advances in radiotherapy and cancer imaging over the past 20 years or so have consistently increased the “therapeutic ratio”, i.e., the ratio of dose to tumor divided by dose to normal tissue; this, in turn, enables more dose to be delivered to tumor for the same level of complications in normal tissues and results in better local tumor control. This, combined with a deeper understanding of the biology of tumors, has further resulted in very significant improvements in local tumor control without concomitant increases in normal tissue complications.
We have discussed a number of advances in radiotherapy technology, including intensity modulated radiotherapy, image guided radiotherapy, on-board fluoroscopic imaging, proton therapy, heavy-ion therapy, fast neutron therapy, tomotherapy, cyberknife, gammaknife, and neutron capture therapy.
The next quantum jump in the efficacy of radiotherapy in the future will most likely be the ability to treat metastatic disease as effectively as we can now treat local disease. Neutron capture therapy promises to achieve this to a certain extent, but its cost will greatly inhibit its further development.
With many of the technologies discussed, the extremely high cost poses a dilemma for society: how much public funding is it reasonable to expend on treating a subset of cancers that respond particularly well to certain very costly new therapies? It is time, indeed, to bring in permanent federal and private sector support for ultra-expensive cancer treatments.
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