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The invention provides a novel means to apply radiation therapy to cancerous tumors not available in the prior art. Currently practiced radiation therapy is limited to two options, external beam X-ray therapy and surgical implantation of solid radioactive needles and rods (seeds). The new approach of this invention is to administer radiotherapy in the form of the radioactive gas Xenon-133, which is infused through a catheter directly into the core of the tumor. This method of radiation therapy allows for a major improvement in target to non-target radiation over external beam X-ray therapy. Also, the excretion of Xenon-133 gas by the lungs eliminates the need for surgical removal of the radiation source as is the case for implanted seeds.
Current methods for radiotherapy of cancerous tumors are hampered by significant target to non-target dosimetry problems. External beam radiotherapy employs X-radiation which must be of sufficient energy to traverse non-diseased tissues prior to reaching the tumor, and most of the radiation then continues through the tumor to expose additional non-diseased tissue to unwanted irradiation. Since only a fraction of the incident radiations are absorbed by the tumor relative to normal tissues, the total radiation which can be administered is limited. An approach which has helped to some degree is multiple angle focusung of the X-ray beams, which improves the target to non-target safety about ten- to twentyfold.
Implantation of radioactive seeds, while more selective than external beam radiotherapy, still suffers from radiation spillover into normal tissue. In addition, seeds may migrate and they must be surgically removed when the radiation treatment is completed.
The method of the current invention involves the site selective infusion of a diffusible radioactive gas, Xenon-133 (Xe-133) into the core of the tumor. One might be tempted to question the usefulness of this approach, because the 0.346 MeV beta emissions from Xe-133 can penetrate tissue only to a depth of about one millimeter, which would restrict its utility to very small tumors. However, Xe-133 exhibits several desirable attributes which make it uniquely valuable when infused into a tumor. First, when infused into the core of the tumor, Xe-133 forms diffusible microbubbles of gas which can spread throughout the tumor [see Exhibit A]. Second, continuous infusion forces the spread of the gas as an expanding sphere completely filling the tumor with the radioactive Xe-133. Third, the Xe-133 gas, having spread to the periphery of the tumor, will be taken up into patent capillaries and carried away thereby protecting adjacent tissues from prolonged radiation exposure. Following its uptake into the capillary blood, Xe-133 will be carried to the lungs and excreted in the expired air. This uptake and excretion represents a safety feature unavialable from any other approach to radiotherapy. The enabling discovery by the inventor was the determination that Xenon exists in tissues as diffusible microbubbles of gas [Exhibit A].
The disease of cancer is most often treated using three modalities alone or in combination, surgery, chemotherapy and radiation. Depending on type and location, tumors are treated by protocols developed from years of trial and error experience. Surgical excision, if practical, is usually the treatment of choice, often followed by chemotherapy and/or external beam radiation therapy. Although many chemotherapeutic combinations and regimens have been developed and remain in use, they generally suffer from lack of target to nontarget specificity with resulting toxicity to essential major organs such as the liver, kidneys and bone marrow. This often becomes the limiting factor in the effective treatment of the primary cancer and/or metastatic sites. External beam radiation, although effective in killing tumor tissue, also carries a major disadvantage in its relative lack of target to non-target specificity. Attempts to improve external beam x-ray beam therapy have included focused beams at varying angels which provides unitary improvement in tumor selectivity for each angle (radiation port) employed. This approach has been further enhanced by a device known as the Gamma Knife which can focus the x-ray beam over multiple angels providing a further improvement in target to non target irradiation. However, Gamma Knife instruments are quite expensive, not widely available and are generally limited to smaller tumors.
Attempts to improve the specificity and selectivity of tumor irradiation have focused on local deposition of radioactive elements (brachytherapy) which emit various types of radiations as they decay over time. Brachytherapy, using radioactive isotope doped rods or needles (seeds) implanted within the tumor, is a direct approach to radiotherapy, but it often contributes significant exposure to adjacent normal tissue. Brachytherapy can become further problematical in cases where these radioactive seeds migrate from their original implantation sites. Other disadvantages are the usual requirement for implanting a number of such seeds to provide comprehensive tumor site irradiation and that these seeds must be surgically removed when the therapy is completed.
Radiation is generally thought to kill cells by destroying the DNA contained in the cell nucleus. There are principally four types of radioactive decay which could effectively kill cells. These are auger electrons, alpha particles, beta particles and gamma rays. Auger electrons are impractical since they travel only micron distances in tissue and would therefore have to be localized within the cell nucleus to be effective, and no specific localization techniqes are available. Alpha particles travel distances of up to about one millimeter in tissue and are highly tissue-destructive radiations. However, they are generally long-life isotopes which, unless effectively and completely removed would irradiate tissues for years with consequent destruction of normal tissue and potential for radiation-induced cancer. There are no effective means available for the selective administration or removal of alpha-emitting isotopes. Radioisotopes best suited for local tumor tissue irradiation are those which emit beta particles (beta rays). The energy of these beta particle emissions are such that tissue penetration can range from about one millimeter up to 3 or 4 centimeters. Again, however, but with few exceptions, only direct introduction into the tumors provides a suitable means for their administration. In addition, those beta emmissions which travel 3-4 centimeters in tissue suffer from the problem of non-target exposure, because sources deposited near the periphery of the tumor will irradiate adjacent non-diseased tissues. The fourth type of isotopic radiation is the gamma ray. Much the same as X-rays, gamma rays generally traverse tissues to such an extent that most of these irradiations escape the body and they demonstrate little target to non-target selectivity resulting in widespread dosimetry problems similar to those for external beam X-ray therapy described above.
An improvement in the art would be the novel use of a radiopharmaceutical which would enhance tumor selectivity over current means, thereby allowing higher doses of radiation well in excess of generally accepted minimum effective tumor-killing doses, while at the same largely sparing radiation to normal tissues. Moreover, following the irradiation, the agent should exit the body without having exposed other critical organs, e.g. bone marrow, liver, kidneys, to dangerous levels of radioactivity. In addition, it would be desirable that the exposure of the tumor to the radioactive agent could be monitored so as to insure its proper distribution and timely removal. It would also be desirable that such candidate radiopharmaceutical should have a half-life which is long enough to allow for production and distribution to the market. The administration of the radiopharmaceutical should be accomplished with equipment available in the art, and there should be means available to trap the radiopharmaceutical as it exits the body so as to aid its disposal and minimize environmental contamination.