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 Table of Contents  
REVIEW ARTICLE
Year : 2010  |  Volume : 6  |  Issue : 3  |  Page : 239-248

External and internal radiation therapy: Past and future directions


1 Agricultural, Medical and Industrial Research School, Nuclear Science and Technology Research Institute, P.O. Box: 31485/498, Karaj, Iran
2 Faculty of Engineering, Research and Science Branch, Islamic Azad University, P.O. Box 14155/4933, Tehran, Iran
3 Department of Biophysics, Faculty of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Date of Web Publication29-Nov-2010

Correspondence Address:
Mahdi Sadeghi
Agricultural, Medical & Industrial Research School, P.O. Box: 31485-498, Gohardast, Karaj
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.73324

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 > Abstract 

Cancer is a leading cause of morbidity and mortality in the modern world. Treatment modalities comprise radiation therapy, surgery, chemotherapy and hormonal therapy. Radiation therapy can be performed by using external or internal radiation therapy. However, each method has its unique properties which undertakes special role in cancer treatment, this question is brought up that: For cancer treatment, whether external radiation therapy is more efficient or internal radiation therapy one? To answer this question, we need to consider principles and structure of individual methods. In this review, principles and application of each method are considered and finally these two methods are compared with each other.

Keywords: Boron neutron capture therapy, intensity modulated radiation therapy, linac, peptide receptor radionuclide therapy, radioimmunotherapy, targeted radionuclide therapy


How to cite this article:
Sadeghi M, Enferadi M, Shirazi A. External and internal radiation therapy: Past and future directions. J Can Res Ther 2010;6:239-48

How to cite this URL:
Sadeghi M, Enferadi M, Shirazi A. External and internal radiation therapy: Past and future directions. J Can Res Ther [serial online] 2010 [cited 2019 Oct 15];6:239-48. Available from: http://www.cancerjournal.net/text.asp?2010/6/3/239/73324


 > Introduction Top


Cancerous tumors can be treated using the following main methods: surgery, chemotherapy (drugs) and radiation therapy (internal and external beam therapy). [1],[2] Radiation therapy is based on the exposure of malign tumor cells to significant but well localized doses of radiation to destroy the tumor cells. The goal is to maximize the dose at the tumor location while minimizing the exposure of the surrounding body tissue. The damage inflicted by radiation therapy causes the cancerous cells to stop reproducing and thus the tumor shrinks. [1],[2] Radiobiological effect critically depends on the pattern of ionizations at the level of the biomolecule. At low energies, mechanisms other than direct ionization or free radical damage can lead to bond breaks in DNA. [3],[4] DNA damage arise indirectly through non-targeted effects, such as the bystander effect. Unfortunately, healthy cells can also be damaged by the radiation. [3],[4],[5],[6],[7],[8],[9]

Both approaches (external and internal) require careful treatment planning since the radiation therapy is technically difficult and potentially dangerous. [10],[11] The most important parameters for treatment planning and dose calculations are energy loss of radiation, range and scatter of radiation, RBE, [12] dose and isodose of radiation and stopping power of radiation (LET). These parameters need to be carefully studied for planning the radiation treatment to maximize the damage for the tumor while minimizing the potential damage to the normal body tissue. [10],[11],[12],[13] An insufficient amount of radiation dose does not kill the tumor, while too much of a dose may produce serious complications in the normal tissue, may in fact be carcinerous. [9]


 > Materials and Methods Top


Radiation therapy can be performed by using external radiation therapy e.g. charged particle exposure by accelerator beams (e.g. Linac, cyclotron, synchrotron, microtron, betatron), neutron exposure by reactor beams, image guided radiation therapy (IGRT), stereotactic body radiotherapy (SBRT), CyberKnife, intensity modulated radiation therapy (IMRT) and developing methods of IMRT (e.g. tomotherapy and volumetric modulated arc therapy (VMAT)) or by using internal radiation therapy (e.g. long-lived radioactive sources in close vicinity of the tumor (brachytherapy), BNCT and endoradiotherapy (targeted radionuclide therapy): radioimmunotherapy (RIT) and peptide receptor radionuclide therapy (PRRT)).


 > External Radiation Therapy Top


Radiation treatment is based on different kinds of radiation and depends on the different kinds of interaction between the radiation and matter (body tissue) [Figure 1]. [14]
Figure 1: Cancer therapy with various methods of radiation therapy and chemotherapy

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Every treatment using external radiation therapy has to be rigorously planned. The planning process consists of three phases:

  1. Planning: The cancerous tumor has to be located so that its size and position can be analyzed. This information can be obtained from X-rays, positron emission tomography (PET), single photon emission tomography (SPECT), planar gamma camera imaging, CT scans, MRI and MRA scans and ultrasound images. [15]
  2. Simulation: Once the amount of radiation to be given has been accurately calculated, the patient then goes to the simulator to determine what settings are to be selected for the actual treatment using a linear accelerator. The settings are determined by taking a series of X-rays to ensure that the tumor is in the correct position ready to receive the ionizing radiation. [15]
  3. Treatment: Cancerous tumors can be treated using radiotherapy as follows: irradiation using high energy gamma rays or irradiation using high energy X-rays (Linac) and or other methods. [15],[16],[17]


Cyclotron

The cyclotron is a charged particle circular accelerator, mainly used for nuclear physics research. In radiation therapy, these machines have been used as a source of high-energy protons for proton beam therapy. [13] The cyclotron magnetic field causes particles to travel in circular orbits. Ions are produced in an ion source at the center of the machine and are accelerated out from the center. [18] The ions are accelerated by a high frequency electric field through two or more hollow electrodes called dees. The ions are accelerated as they pass from one dee to the next through a gap between the dees. [18] Since the rotational frequency of the particles remains constant as the energy of the particles increases, the diameter of the orbit increases until the particle can be extracted from the outer edge of the machine. Another important use of the cyclotron in medicine is as a particle accelerator for the production of certain radionuclides. [18]

Synchrotron


A synchrotron is a particle circular accelerator that produces very bright light (electromagnetic waves) in the region from infrared through to X-rays [Table 1]. Synchrotrons are useful proton therapy to treat some forms of cancer. [19],[20],[21],[22],[23] The protons and anti-protons at Fermi lab go through a series of accelerators in order to accelerate them to 1 TeV (just 200 miles per hour slower than the speed of light). Synchrotron components are electron gun and Linac (electron gun, Linac, vacuum chamber), Boster ring (magnets, RF cavities), storage ring (insertion devices, RF cavities) and beamline (monochromator, end station). [19],[20],[21],[22],[23]
Table 1: Comparison between linear accelerators and circular accelerators[18,19]

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Linac

Teletherapy is typically carried out in the radiation oncology unit of a hospital using photons or electrons from a linear accelerator. A linear accelerator (Linac) generates high energy electrons and photons (typically 5-25 MeV). The linear accelerator (Linac) is a device that uses high-frequency electromagnetic waves to accelerate charged particles such as electrons to high energies through a linear tube. [13] The high-energy electron beam itself can be used for treating superficial tumors, or it can be made to strike a target to produce X-rays for treating deep-seated tumors. There are several types of linear accelerator designs, but the ones used in radiation therapy accelerate electrons either by traveling or stationary electro-magnetic waves of frequency in the microwave region (3000 megacycles/sec). The difference between traveling wave and stationary wave accelerators is the design of the accelerator structure. [18]

Microtron

The microtron is an electron accelerator that combines the principles of both the linear accelerator and the cyclotron. [13] In the microtron, the electrons are accelerated by the oscillating electric field of one or more microwave cavities. When the beam energy is selected, the deflection tube is automatically moved to the appropriate orbit to extract the beam.The principal advantages of the microtron over a linear accelerator of comparable energy are its simplicity, easy energy selection, and small beam energy spread as well as the smaller size of the machine. [13]

Intensity modulated radiation therapy

Intensity-modulated radiation therapy (IMRT) has been considered as the most exciting development in radiation oncology since the introduction of computed tomography imaging into treatment planning. IMRT is a radiation treatment technique with multiple beams in which at least some of the beams are intensity-modulated and intentionally deliver a non-uniform intensity to the target (e.g. prostate cancer, [24] lung cancer [25] and breast cancer [26] ). IMRT was delivered either with a helical tomotherapy (HTT, n= 54) or with a conventional Linac (Linac-IMRT, n = 37). [27] The desired dose distribution in the target is achieved after superimposing such beams from different directions. The additional degrees of freedom are utilized to achieve a better target dose conformality and or better sparing of critical structures. IMRT provides a higher degree of dose conformity to the tumor and avoid organs at risk. [24],[25],[26],[27],[28],[29]

Cyberknife

Radiosurgery utilizes stereotactic principles of localization and multiple cross-fired beams to deliver a large radiation dose to a well-defined target with little or no fractionation. CyberKnife is an innovative radiosurgery device based on a compact linear accelerator mounted on a robotic arm, and on an X-ray imaging system allowing non-isocentric, frameless operations. [30],[31] The non-isocentric approach is the main characteristic which allows highly conformal isodose shapes; it is possible thanks to a robotic arm with six degrees of freedom. The Linac source is positioned at 80 cm from the virtual isocenter; 100 positions can be assumed by the source on a sphere centeered on this point, and from each position 12 directions can be reached, leading to 1200 different beams in total. [30],[31] Not all these directions will probably be used, but it is, thanks to such a flexibility, and to the different weighting of the beams, that highly conformal shapes can be achieved. The Linac is a compact, 6 MV unit with circular collimators ranging from 5 to 60 mm. Compared to conventional stereotactic radiosurgery systems, the CyberKnife provides enhanced ability to avoid critical structures, thanks to highly conformal dose distribution, dose fractionation (allowed by reliable relocation) and potential to target multiple tumors (e.g. brain [31] ) at different locations during a single treatment. [30],[31]


 > Internal Radiation Therapy Top


Boron neutron capture therapy

Boron neutron capture therapy (BNCT) offers a means of treating individual tumor cells (e.g. multiple pleural tumors [32] multiple liver tumors, [33],[34] spinal tumors, [35] glioblastomas and extracranial tumors, [36] head and neck malignancies [37] and oral cancer [38],[39] ), possibly cells unconnected with a main tumor mass. It is based on the nuclear reaction ( 10 B + n th → [ 11 B*] → α + 7 Li + 2.79 MeV) that alpha and lithium particles have high LET and high RBE. BNCT uses an irradiation beam that is not established for clinical practice and that produces a complex dose distribution with high and low LET components. Furthermore, BNCT needs a boron carrier, which must go through standard clinical testing like all other investigational drugs. In contrast to other anticancer drugs, a compound for BNCT does not have any therapeutic effect by itself but is aimed exclusively to transport 10 B-atoms to tumor cells. [40],[41] The efficacy of BNCT mediated by Boronated phenylalanine (BPA), GB-10 (Na 2 10 B 10 H10 ), (GB-10+BPA) and sodium mercaptoundecahydro-closo-dodecaborane (BSH) [Figure 2] treat tumors with no normal tissue radiotoxicity. [40],[41]
Figure 2: Structure of Na3(B20H17NH3)

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To deal with the increasing number of candidates for BNCT, development of an accelerator-based BNCT (AB-BNCT) system is a prerequisite. The Be(p,n) reaction at low proton energy is widely accepted as the best promising for epi-thermal neutron generation. [34] Shortening of irradiation time makes it possible to finish irradiation while maintaining a high 10 B concentration in the tumor, and to reduce the non-selective background dose. [34] In addition, shortening of irradiation time provides comfort to the patients during irradiation and single or two-fractionated BNCT has economic benefits. Another important feature of the AB-BNCT system is its capability of delivering greater doses to deep-seated tumors than RB-BNCT (reactor-based BNCT). [34],[39]

Brachythrapy

Brachytherapy is a method of treatment in which sealed radioactive sources are used to deliver radiation at a short distance by interstitial, intracavitary, or surface application. With this mode of therapy, a high radiation dose can be delivered locally to the tumor with rapid dose fall-off in the surrounding normal tissue. In the past, brachytherapy was carried out mostly with radium or radon sources. [42],[43],[44],[45],[46],[47],[48],[49] Currently, use of artificially produced radionuclides such as 103 Pd [50] and 125 I [51] is rapidly increasing [Table 2]. This involves placing implants in the form of seeds, wires or pellets directly into the tumor. Such implants may be temporary or permanent depending on the implant and the tumor itself. Brachytherapy is used to treat the following cancers: uterus, cervix, breast, prostate, intraocular, skin, thyroid, bone, brain and other cancers. [42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52]
Table 2: Examples of radionuclides useful in brachytherapy[42-52]

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Endoradiotherapy (targeted radionuclide therapy)

External beam and brachytherapy emissions are composed of photons, whereas radiations of interest in radionuclide therapy are particulate. By labeling the proper transport molecule with a radionuclide that emits ionizing particulate radiation, it is possible to obtain a internal irradiation on the cellular level following the administration of the radiopharmaceuticals. [53],[54],[55],[56],[57],[58],[59],[60],[61] This has been the inspiring factor behind the rapid increase in the research utilizing radioisotopes for internal radiotherapy of cancer diseases, which have lead to a number of potent radiopharmaceuticals currently undergoing clinical trials. [53],[54],[55],[56],[57],[58],[59],[60] Radionuclides that decay by the following three general categories of decay have been studied for therapeutic potential: beta-particle emitters, alpha-particle emitters, and Auger electron-and Coster-Kronig electron emitters following electron capture [Figure 3]. [61] Each type of particle emitted has a different range, effective distance, and relative biologic effectiveness (RBE). The choice of a particular radionuclide for therapy is based on the following: radionuclide physical and chemical properties, production methods and biological behavior (particularly if it suffers in vivo dissociation from the carrier molecule). [53],[54],[55],[56],[57],[58],[59],[60] Recently, antibody or peptide-directed delivery of radionuclides to tumor tissue (endoradiotherapy) has entered clinical testing phase with very promising results. [62],[63],[64],[65] Endoradiotherapy is a versatile nuclear medicine application using ionizing radiation for the treatment of manifold diseases, such as cancer or rheumatoid arthritis. [64],[65],[66] The major advantage of endoradiotherapy compared to other forms of cancer therapy is the possibility to determine the selective accumulation in the targeted tissue by molecular imaging studies via single photon computed tomography (SPECT) or positron emission tomography (PET) using structural identical diagnostic compounds. The targeting of epitopes that are expressed in very low concentrations is feasible. These non-invasive imaging methods also allow dose calculation prior to therapy, staging and monitoring of the efficacy, in particular. [66] The choice of a radionuclide for therapeutic applications is governed by various factors such as the characteristics of radiations emitted (type and energy of radiation), half-life, specific activity, ease of production, natural abundance of target nuclide, radionuclide purity and the feasibility of producing the radionuclide in a suitable form for application. [64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77]
Figure 3: This figure illustrates the spatial ionization patterns associated with α, β and Auger decays. In the vicinity of the Augerdecay site, a very high ionization density is created giving rise to the high-LET effects observed with α-particles.[62]

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Alpha particle emitters

Over the past 35 years, the therapeutic potential of several α-particle emitting radionuclides [Table 3] has been assessed. [58] These particles are positively charged with a mass and charge equal to the helium nucleus, and their emission leads to a daughter nucleus with 2 fewer protons and 2 fewer neutrons. [58] These particles have energies ranging from 5 to 9 MeV with corresponding tissue ranges of 5-10 cell diameters, travel in straight lines, and deposit 80-100 keV/μm along most of their track (rate of energy deposition increases to 300 keV/μm toward the end of the track) [Figure 3]. [58] Consequently, in the case of cell self-irradiation, the following two factors must be considered when evaluating the therapeutic efficacy of α-particle emitters: (a) distance of the decaying atom from the targeted mammalian cell nucleus as it relates to the probability of a nuclear traversal; and (b) contribution of heavy ion recoil of the daughter atom when the α-particle emitter is covalently bound to nuclear DNA. [67],[68],[69],[70]
Table 3: Alpha particle emitting radionuclides with therapeutic potential[67-73]

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β-Particle emitters

Current radionuclide therapy in humans is based almost exclusively on energetic β- particle emitting isotopes [Table 4]. β- Particles are negatively charged electrons that are emitted from the nucleus of a decaying radioactive atom (1 electron/decay) and that have various energies (zero up to a maximum) and, thus, a distribution of ranges. [58] After emission, the daughter nucleus has one more proton and one less neutron. As these β- particles traverse matter, they lose kinetic energy and eventually follow a contorted path and come to a stop. Because of their small mass, the recoil energy of the daughter nucleus is negligible. In addition, the linear energy transfer (LET) of these energetic, light, and negatively charged (-1) particles is very low (0.2 keV/μm) along their up-to-a-centimeter path, except for the few nanometers at the end of the range [Figure 3]. Consequently, their use as therapeutic agents necessitates the presence of high radionuclide concentrations within the targeted tissue. [58]
Table 4: Beta particle emitting radionuclides with therapeutic potential[70-77]

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Auger electron emitters

In recent years, encouraging results have also been shown with radionuclides emitting low-energy electrons e.g. Auger and conversion electrons. Auger electrons are emitted by isotopes that decay by electron capture (EC) or have internal conversion (IC) in their decay [Table 5]. In each decay of these isotopes, a cascade of very low energy electrons is emitted [Figure 3]. [58] The multiplicity and the low energies of these Auger (and Coster-Kronig) electrons with their resulting short ranges in tissue (from a few nm to some μm) give rise to a very high energy density created in the immediate vicinity of the decay site and thus a highly localized absorbed radiation dose to the target region. [78],[79],[80],[81],[82],[83],[84],[85],[86],[87] The high biological toxicity and the considerable therapeutic potential of these low energy electron-emitters are mainly associated with the very high ionization density created in biological tissue (high-LET-like effect) from their decay. [62]
Table 5: Auger electron emitters radionuclides with therapeutic potential[78-87]

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Radioimmunotherapy

Radioimmunotherapy (RIT) is a branch of molecular medicine in which an antibody (e.g. CD20-positive lymphoma, CEA-monoclonal antibody and HER-2 monoclonal antibody) is used to deliver a therapeutic radionuclide to a tumor-associated antigen in order to selectively kill cancer cells. [88],[89],[90] To achieve specific tumor uptake and minimize normal tissue accumulation, the antigenic epitope must be expressed uniquely, or at least preferentially, on cancer cells compared with normal cells. [88],[89],[90] RIT differs from conventional external beam radiation in that RIT is a form of systemically delivered and targeted radiotherapy [Figure 4]. The anti-tumor effect of RIT is primarily due to the radioactivity delivered by the antibody to tumor cells, which provides continuous, exponentially decreasing, low-dose-rate radiation that is sufficient to cause lethal DNA damage in cancer cells. [88],[89],[90] One advantage of RIT is that the antibody itself may also contribute to tumor cell killing by eliciting ADCC and/or CDC. [88],[89],[90] Several factors that are critical in developing an effective RIT regimen include the selection of an optimal radionuclide; identification of a promising tumor-associated antigen; and the design of an antibody radionuclide immunoconjugate with high specificity and low immunogenicity. [84],[85],[86] Radionuclides which may be conjugated to antibodies for RIT of malignancies include alpha (α)-emitters (e.g. 211 At, [91] 212 Pb, 213 Bi and 225 Ac), [92] beta (β- )-emitters (e.g. 131 I (e.g. 131 I-NP-4, 131 I-hMN14, 131 I-CC49, 131 I-ChL6, 131 I- B72.3, 131 Ih-tositumab), 90 Y (e.g. 90 Y-cT84.66, 90 Y-R1549, 90 Y-HMFG-1, 90 Y-MLN591Rl, 90 Y-T84.66, 90 Y-NX-DTPA-BrE-3, 90 Y-ibritumomab), 177 Lu (e.g. 177 Lu-MLN591Rl and 177 Lu-CC49) and 186 Re (e.g. 186 Re-p185HER2)) or low-energy Auger and internal conversion (IC) electron emitters (e.g. 111 In (e.g. 111 In-2IT-BAD-m170), 114m In, 123 I, 125 I, 99m Tc and 67 Ga). [66],[88],[89],[90],[91],[92],[93],[94],[95]
Figure 4: Schematic drawing of Radioimmunotherapy (Nuclear localizing signal (NLS) mediated transport of Auger-electron emitting biomolecule through the nuclear pore complex. (1) Importin-α (IMPα) recognizes and binds to the biomolecule containing an NLS and conjugated to an Auger electron-emitting radionuclide. (2) Importin-β (IMPβ) interacts with the importin-α bound to the NLS and acts as a carrier of the NLS/importin-α/β trimer. (3) The importin/NLS-protein complex is then actively transported into the nucleus through nuclear pores involving the Ran GTPase. (4) The nanometer-to-micrometer range Auger electrons are emitted in close proximity to the nuclear DNA and induce highly cytotoxic DNA double strand breaks).[90,94]

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Peptid receptor radionuclide therapy

Radionuclide therapy using radiolabelled peptides therefore holds great promise for the treatment of cancer, especially when used in conjunction with other therapy modalities or when combinations of, for example, different peptides or radionuclides are used. [96]

On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues is an emerging and convincing treatment modality for patients with unresectable, somatostatin-receptor positive neuroendocrine tumors. Using radiolabelled somatostatin analogues for imaging became the gold standard for staging of neuroendocrine tumors. [97],[98] The somatostatin receptor is strongly over-expressed in most tumors, resulting in high tumor-to-background ratios. Consequently, the next step was to try to treat these patients by increasing the radioactivity of the administered radiolabelled somatostatin analogue in an attempt to bring about tumor cure. [97],[98] Several studies using [ 111 In-DTPA 0 ]octreotide, [ 90 Y-DOTA 0 ,Tyr 3 ]octreotide, [ 90 Y-DOTA]lanreotide, [ 123 I-Tyr 3 ]octreotide, [ 68 Ga-DOTA 0 ,Tyr 3 ]octreotide, [ 99m Tc-Tyr 3 ]octreotide, [ 111 In-DOTA 0 ,Tyr 3 ]octreotide and [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate have been published. [96],[97],[98],[99],[100],[101],[102],[103]

Other Peptides receptors-mediated radionuclide therapy are Cholecystokinin B/Gastrin (CCK-2) kreceptors, Neuropeptide Y (NPY) receptors, Glucagon-like pep tide-1 receptors (GLP-1), Corticotropin-releasing factor (CRF) receptors, α-Melanocyte stimulating hormone (α-MSH) receptors, Substance-P (SP) receptors and Integrin {α}v{β}3 receptors. [56]


 > Future Perspectives and Summary Top


Nowadays, radiation therapy evolves with a surprising growth. By abandoning cobalt-60, linear and circular accelerators, which are able to accelerate particles, are used for cancer treatment. CyberKnife, Vero, VMAT, Tomotherapy and IMRT are among the most advanced methods used to administer radiation therapy to the target volume(s) with substantial sparing of adjacent normal tissues. Today, brachytherapy by increasing production of treatment radioisotopes by cyclotron and reactor is used in the world. Target radionuclide therapy (radioimmunotherapy and peptide-receptor radionuclide therapy) is one considerable method in cancer treatment which is resulted from cooperation and efforts of nuclear medicine, biochemistry, nuclear pharmacology, medical physics, oncology and nuclear engineering specialists in this century. In [Table 6], different types of cancer treatment methods have been compared with each others.
Table 6: Evaluation in various methods of cancer therapy

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Chemotherapy and radiation therapy future may be interrelated. Radionuclide therapy with tracers of chemotherapy medicines such as bleomycin [104] has been done in these days but most often chemotherapy medicines are used as tracers with no significant role in treatment. At the end of this review, some questions are brought up in mind including would it be possible in future to use radionuclide therapy and chemotherapy, simultaneously? Would it be possible to treat cancer completely by radiation therapy? Would it be possible to lower radiation therapy side effects?

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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