Radiation as Cancer Therapy

After many years of work, radiation therapy for cancer with alpha-emitters (brachytherapy) seems feasible, and a Liquid Fluoride Thorium Reactor, or LFTR (pronounced “Lifter”), although originally designed to generate electric power, may be just the engine for generating these much-needed rare isotopes.

Treatment with Radiation Therapy
A man is stabbed with a large knife during an altercation and is brought into the emergency room at the local hospital. There he is found to be bleeding internally and is rushed to the operating room. After suitable preparation and anesthesia, the surgeon prepares to correct the damage from the knife wound. He starts by… cutting the patient open with a knife! So, a knife is neither good nor evil in itself, it depends on who is on the handle. Radiation is that way, too. It is usually thought of as an evil thing that causes cancer, but used correctly, radiation can also diagnose cancer and contribute to its cure. It all depends on how it is used.

Let us first be clear about what is meant by “radiation.” Electromagnetic radiation, first predicted by Maxwell’s equations back at the time of the U.S. Civil War, spans a huge range from ultra-long wavelengths used to communicate with submarines at sea to the extremely high-energy X-ray bursts originating outside our galaxy. The energy of radiation in the visible spectrum (which we call light) is about 1 to 3 electron volts (eV). (The medical world doesn’t know about ergs or joules, and doesn’t understand what a kilowatt hour is, so energy is always stated in electron volts.) “Radiation” can also refer to high-energy (i.e., moving at high velocity) electrons, protons, helium nuclei, and other particles. However, usually the word means electromagnetic radiation or photons.

Traveling out in the direction of high energy, we pass through the R-O-Y-G-B-I-V spectrum into ultraviolet. At about 14eV, a photon has enough energy to ionize hydrogen and oxygen and so we call it “ionizing radiation.” Fortunately, our atmosphere blocks this high-energy ultraviolet, letting through just enough low energy ultraviolet to give us a tan and malignant melanoma. At some arbitrary border – a few hundred eV or so – we call the radiation “soft X-rays.” Naturally, as the energy gets higher we change the name to “hard X-rays,” which for medical use, start at about 20keV or about 104 times the energy (per photon) of visible light.

Low energy medical X-rays (20keV – 60keV) do not penetrate tissue well, but because of their extraordinary sensitivity to the atomic number (~Z3 or ~Z4) of the material that they pass through, they produce very high contrast images and are useful (essential) for dental X-rays and high quality mammograms. (Here comes the cancer thing). Chest X-rays are most valuable in the 60keV to 80keV range although, strictly speaking, this is 60kVp to 80kVp, which means the peak energy is 60keV to 80keV. Manmade sources of X-ray give rise to a spectrum because a working single “discrete” frequency or single “discrete” energy X-ray laser has not been built.
 

CT scans use X-rays that are approximately 120keV. At this energy, the X-rays are far more penetrating that those used for mammograms, but their absorption is much less Z-dependent than their lower energy counterparts. At first blush this would seem to be a bad thing – CT scans are valuable for their ability to distinguish slight variations in electron density (=Z) and thus distinguish different soft-tissue types. However, the number of exposures and the quality of the detectors more than make up for the relatively high energy employed.

In 1896, shortly after Röntgen invented the X-ray tube, it was found that aiming an X-radiation beam at a bleeding tumor would sometimes stop the bleeding and cause the tumor to shrink. Soon the field of radiation oncology began, and the attempt to build X-ray machines with higher energies started. Unfortunately, 250keV to 275keV was all that could be achieved with standard vacuum tube technology. Such beams were not sufficiently penetrating to treat tumors to high dose, and they were still very Z-dependent, which meant that much of the radiation was absorbed by normal bone rather than the tumor. The solution to these problems was to build higher energy X-ray machines, but that could not be done until the perfection of the linear accelerator.

There is an old saying in computer science that it is easier to buy than to build. That is, you should use something that already exists rather than create it anew. It turns out that nature already provided a source of X-rays in the form of radioactive materials, but it was not immediately recognized. By the turn of the 20th century, it was clear that radioactive materials emitted three different kinds of radiation, labeled alpha, beta, and gamma. Beta particles turned out to be electrons, and eventually it was discovered that gamma radiation was identical to x-radiation (?? = x). The term gamma was then reserved for the discrete energy-level radiation provided by nature, but X-rays referred to manmade continuous-spectrum high energy radiation. (Today the original distinction between the two words seems to be blurred with gamma sometimes meaning very high energy X-rays.)

Alexander Graham Bell is believed to be the first to suggest implanting radioactive materials into an unresectable tumor to shrink it. In time this approach, using first radium and later the safer cesium-137, was used to cure some patients with inoperable cancer of the uterine cervix.

The combination of external beam radiation therapy (teletherapy or long distance therapy) and radioactive isotopes implants (brachytherapy or short distance therapy) successfully came together with the production of the first teletherapy machines using cobalt-60. The decay scheme of cobalt-60 is:

⁶⁰Co → ⁶⁰Ni + e– + νe + γ (1.17MeV) + γ (1.33MeV)

Thus, the megavoltage teletherapy machine was born. At megavoltage energies, photons have little or no Z-dependence, so the dose to bone is the same as to the tumor. They are also deeply penetrating. An unexpected benefit of these high-energy gamma rays is that the radiation dose for the first 5mm’s of tissue was much reduced, due to lack of electron equilibrium. The depth-dose curves (below, left) show the effect. Skin-sparing made it possible to treat patients to much higher radiation doses than were previously possible (skin damage often limited the amount of radiation that could be delivered) and increased the range of cancers that could be successfully treated, including head and neck cancers, some lung cancers, and cancer of the prostate. Cobalt-60 also made it possible for some women with breast cancer to substitute a “lumpectomy” and radiation for a mastectomy (removal of the whole breast).

The advent and development of the linear accelerator allowed for radiation energies of up to 15MeV, and that greatly improved radiation dose distributions compared to what could be achieved on Cobalt-60 machines. These new accelerators were mechanically versatile and could shape and modulate X-ray beams and allow them to be directed under image guidance. These accelerators also allow for the direct use of electron beams.

It is with this combination of capabilities that as many as one-half of all cancer patients are now receiving radiation as part of their cancer therapy.

Radiobiological studies and clinical experience have demonstrated that direct electron beam and X-ray beams have similar biologic efficacy, not surprising, because the effect of x-radiation on cells is mediated through electrons. The only real difference between the two is in the radiation dose deposition pattern. Both modalities can be used to kill many tumor types, but other tumor types remain quite radiation resistant. In addition, tumor hypoxia (low oxygen level) and/or a low pH environment can render some normally radiation sensitive tumors radiation resistant. Attempts to overcome some of these difficulties by treating patients simultaneously with radiation and chemotherapy have been partly successful, although failure to kill the entire tumor at radiation-tolerable doses remains a significant clinical problem. For example, in cases of inoperable but still potentially curable lung cancer, more than one-third of the tumors will survive direct assault by high dose radiation.

These inherent biological limitations of X-radiation have led radiobiologists and engineers to study other kinds of radiation and ways to deliver it. Neutrons were found to destroy tumor cells by direct damage to their DNA, as opposed to the indirect damage that is the mechanism of cell-kill from X-rays or electrons. However, being without electric charge, neutrons are difficult to collimate and modulate, so the radiation dose distributions that could be achieved were no better than old cobalt machines could do. A few particle-beam accelerators have been commissioned for clinical use, employing ions as heavy as carbon for treatment. They may well be more effective than conventional X-ray therapy machines, but their multi-hundred-million-dollar cost, and the need to keep a large engineering team on site to maintain them, make them prohibitively expensive.

Advancing techniques in external beam therapy had slowed development of brachytherapy technology, although such therapy is still standard for cancers of the uterine cervix and, in the form of 125I seeds, for prostate cancer. Implants allow for precise placement of radioactive materials, and the resulting radiation dose distribution (essentially an inverse square fall-off) is difficult to approximate with an external beam. However, the inherent biologic limitations of X-ray (or gamma ray) radiation remain.

Alpha particles destroy cells by direct damage to the DNA. There is no radiation resistance, and a single alpha particle can kill a cell, making it a very potent therapy. Thus, alpha emitters used in the form of an implant, or guided to their targets by chemical or biologic carriers, might be an effective form of cancer therapy, different from anything currently available. Progress in this area has been in part limited by the problem of not having a wide choice of alpha emitters easily available.

On May 15, 2013, the Food and Drug Administration (FDA) approved the first alpha particle-emitting drug ever, radium-223 dichloride (Xofigo, Bayer HealthCare Pharmaceuticals Inc.), for treatment of patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 dichloride mimics the effect of calcium and therefore forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases. It is relying on chemical means (its similarity to calcium) to get to its designated site.

In many ways, Ra-223 is an ideal medical agent. Its half-life is 11-1/2 days, long enough so it doesn’t decay before it gets to a hospital, but short enough so that the radioactive radium clears from the body in a short period. Probably more important is that the α-component of the radiation accounts for 93% of the emitted energy, while β-particles account for 4%, and less than 2% is emitted as unwanted low-energy γ radiation.

Another approach to developing alpha-emitting drugs is being undertaken by Actinium Pharmaceuticals Inc. This company is now testing several drugs using alpha-emitters attached to antibodies. Two clinical trials in patients with acute myeloid leukemia (AML) have been conducted at Memorial Sloan-Kettering using such alpha emitters. (AML is a highly lethal disease with few effective drugs available to treat it.) The first trial used a drug named Bismab-A, which is bismuth-213 linked to an antibody known as lintuzumab. Lintuzumab targets the CD33 protein, which is expressed on the leukemia cells, but does not appear in abundance on normal cells.

Although the initial results of using Bismab-A were promising, it was decided not to continue its development because of supply, logistics, and cost reasons. Bismuth-213 must be made from actinium-225, which itself is still in limited supply and the chemical separation of bismuth-213 from actinium-225 can be difficult. Therefore, the second trial used actinium-225, also an alpha emitter, again linked to lintuzumab. Actinium-225 is an attractive alpha emitter because its decay scheme yields four alpha-particles.

The humanized monoclonal antibody, trastuzumab (Herceptin), directed against the HER2/neu antigen, has been very effective in the treatment of a specific subpopulation of women with breast cancer. However, the value of trastuzumab depends on the level of HER2/neu expression on breast cancer cells. Only those patients with a high level of antigenic expression can presently benefit from this treatment. The hope is that an alpha emitter attached to trastuzumab might improve its efficacy and increase the number of patients that could benefit from this therapy. In initial laboratory trials, this approach looks promising and is an example of a new field of cancer treatment now known as radioimmunotherapy. The amount of actinium needed to treat a cancer patient effectively is unknown but probably is about a microgram.

Enter the LFTR Reactor
The liquid fluoride thorium reactor (LFTR; spoken as “Lifter”) is a thermal breeder reactor that uses the thorium fuel cycle in a fluoride-based molten (liquid) salt fuel to achieve high operating temperatures at atmospheric pressure. In a LFTR, thorium and uranium-233 are dissolved in carrier salts, forming a liquid fuel. LFTRs theoretically have huge advantages over traditional U-235 power plants in that they have an ample fuel supply (thorium-232 which is plentiful) and decay products that are much shorter lived than the waste products from their U-235 counterparts. Currently, there is a major effort being made to overcome political and public perception barriers and implement this advanced technology. One advantage of building LFTRs is that their decay products include actinium-225 and bismuth-213 (see picture on the right side). Our preliminary calculations show that a typical LFTR would produce about 1μg (10^-6g) of actinium-225 per day after a year of operation. (The production rate would increase to approximately 10μg after 10 years). The production rate of Ra-225 is similar.

The therapeutic dose of actinium is unknown, but for Ra-223, the only alpha-emitter currently approved for clinical use, it is 1.35μCi/kg, or about 100μCi for a 160 lb patient. If the amount of actinium needed is also about 100μCi then:

10^-4Ci/patient × 17 × 10^-6g/Ci = 1.7 × 10^-9g/patient of ²²⁵Ac.

Therefore, the radioactive by-products from a single LFTR could provide all the actinium and other alpha emitters that would be needed to treat about 100 new cancer patients per day. At present, there is no other good way to obtain these precious isotopes in those amounts.

In summary, radiation therapy for cancer can take many forms. After many years of work, brachytherapy with alpha-emitters seems feasible, and a LFTR, although designed primarily for energy generation, may be just the engine for generating these much-needed and rare isotopes.

Energy from Thorium Foundation
Cleveland, Ohio
www.energyfromthorium.com

About the authors: Julian Rosenman, M.D., Ph.D., is from the University of North Carolina at Chapel Hill and can be reached at julian_rosenman@med.unc.edu. Michael S. Goldstein, J.D. is part of the Energy from Thorium Foundation. William Thesling, Ph.D. is the executive chairman of the Energy from Thorium Foundation (EFTF) and can be reached at bthesling@th90.org. EFTF is a U.S.-based not-for-profit organization dedicated to advancing the research, development and deployment of safe, clean, and affordable energy based on liquid fluoride thorium reactor technology.