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Radiation oncology: physics advances that minimize morbidity

Ron R Allison*,1, Rajen M Patel1 & Robert A McLawhorn1

ABSTRACT Radiation therapy has become an ever more successful treatment for many cancer patients. This is due in large part from advances in physics including the expanded use of imaging protocols combined with ever more precise therapy devices such as linear and particle beam accelerators, all contributing to treatments with far fewer side effects. This paper will review current state-of-the-art physics maneuvers that minimize morbidity, such as intensity-modulated radiation therapy, volummetric arc therapy, image-guided radiation, radiosurgery and particle beam treatment. We will also highlight future physics enhancements on the horizon such as MRI during treatment and intensity-modulated hadron therapy, all with the continued goal of improved clinical outcomes. Virtually since its discovery ionizing radiation has been employed for cancer treatment [1] . While revolutionary in its ability to ablate tumors, it rapidly became evident that normal tissues would also be injured. In particular, the skin would become red and erythematous when exposed to radiation. Skin breakdown was even expected in successful cancer treatments. Despite wide variance in an individual’s baseline skin color, as well as an apparent wide variation in response to radiation exposure, this ‘skin erythema dose’ was state of the art in terms of determining appropriate treatment dose for radiotherapy [2] . Fortunately, far more precise means to determine dose of radiation have been developed, which have allowed radiation therapy to become a standard treatment for cancer patient. Still this serves to remind us that even with current state-of-the-art radiation therapy for cancer, normal tissue is always irradiated during therapy and despite physics and technological advances more often than not, the risk of severe normal tissues injury limits our ability to deliver ablative tumor dose [3] . The current goal of state-of-the-art radiation therapy is, as it has always been, to achieve successful tumor or symptom control without creating permanent or debilitating morbidity from normal tissue (bystander) injury [4] . This paper will describe the clinical application of the physics behind radiation treatments focused on maneuvers and technology that can minimize normal tissue injury. As more than half of all cancer patients undergo radiation therapy, successful therapy without undue morbidity is a worldwide issue.

KEYWORDS 

• advances • image-guided

radiation therapy • intensity-modulated radiation therapy • particle beam • physics • radiation therapy • radiosurgery • volumetric-modulated arc therapy

Radiation therapy Ionizing radiation is a member of the electromagnetic spectrum characterized by highly energetic packets of energy termed photons [5] . As these photons travel, they will interact with matter, which leads to the ionization process [6] . If this ionization is initiated in human tissue, the energetic photons will likely break the bonds of water molecules, the most common component of tissue. This creates reactive oxygen species, the most lethal of which is singlet oxygen, which then inflicts severe 21st Century Oncology, Inc., 801 WH Smith Blvd, Greenville, NC 27858, USA *Author for correspondence: [email protected] 1

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Review  Allison, Patel & McLawhorn tissue damage particularly to DNA [6] . Singlet oxygen creates both ssDNA and dsDNA breaks with the latter generally considered irreparable. These dsDNA breaks will lead to cell death. If enough dsDNA breaks occur within the tumor, then tumor ablation or control may be achieved. However, by identical means, if enough dsDNA breaks occur in normal tissues, then permanent normal tissue damage may occur. Delivering enough ionization to ablate tumors without overdosing normal tissue remains the goal of clinical radiation therapy for cancer patients. As this paper will detail, the physics behind treatment is critical to this goal. Complicating this goal is that, in most instances, while a lethal ionization may take only microseconds, the expression of that lethal event may take days, weeks, months or even years [7] . This is due to the concept that lethal double strand DNA damage will show itself mainly when the cell attempts to reproduce, termed repopulation. Therefore, a tumor may be unable to grow and repopulate due to lethal dsDNA damage, but will not die away until it attempts to repopulate. This may take weeks to accomplish. Clinically, while lethally irradiated, the tumor mass is still present and still appears viable. Similarly, an organ may be permanently injured during radiation therapy, but clinically will not show organ failure until it attempts to repopulate, which, for example, in the spine, may be months to years post radiation therapy. Obviously, both situations have significant c­linical ramifications for treatment and for morbidity. The actual dose of radiation (measured in gray) required to ablate tumors by photon radiation has been worked out to a degree based on clinical and basic science data [8] . Yet the dose that will temporarily or permanently injure a normal organ is less well defined. Clinical guidelines exist, but more than a century of data show a wide variance in what dose and volume of radiation delivered to an organ will lead to acute or chronic injury [9] . While incredibly important, this remains a critical shortcoming of modern treatment [9] . Further as most of these constraints and guidelines are based on outcomes from small daily doses of photon radiation delivered over weeks of therapy (standard external beam therapy), they do not offer much practical help when altered fractionation schedules [10] are used, such as radiosurgery (see next section), or when other types of radiation, such as particles, are employed.

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Treatment concepts A patient who may undergo radiotherapy will be informed of the potential benefits and consequences of treatment, usually with the goal of tumor control and/or palliation of tumorrelated signs and symptoms. They will then sign informed consent for a therapy whose aim is to achieve these goals. A critical point is that treatment should attempt to be as benign as possible in terms of normal tissue damage yet still achieve control of the primary or symptomatic lesions. Since ionizations will occur through the radiation track, normal tissues will always be irradiated. The goal therefore is to place enough ionizations in the tumor for ‘control’ while simultaneously allowing normal tissues to continue to function. Furthermore, both tumor and normal tissue will attempt to repair radiation damage. Again the clinical goal is to allow for the latter, but minimize the chance for tumor survival through overwhelming ionization of the cancerous region. Achieving clinical success without morbidity remains both art and science. A number of physics-based maneuvers will be attempted to achieve this goal. Foremost, the tumor bed will be defined for ablation as will be the surrounding radiosensitive structures that one wishes to avoid during radiation therapy. This is done during treatment planning, which is now mainly image based. The patient will generally undergo computed tomography (CT) scan in the treatment position to better define the tumor bed and normal tissue regions. A treatment plan for this individual is then created. Data obtained from other scans such as MRI or PET/CT will have these images fused into the treatment plan. Once a treatment plan is created, therapy may be a single fraction of radiation or potentially up to 45 daily visits for treatment. In all cases, the goal is to match the treatment plan to the patient’s anatomy and treatment volume to ensure accurate treatment delivery. To allow this, the coordinates in space created during the treatment planning session are transferred to the therapy device. Through rigorous physics-based quality assurance, confidence that the treatment plan matches the delivered treatment is anticipated. Sources of radiation Historically, radiation was delivered by radioactive decay of radioactive sources, which emit γ-rays. These rays behave similarly to x-rays, which are generated by electricity. Both create multiple

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Radiation oncology: physics advances that minimize morbidity  ionizations along their travels (tracks). The interaction of x-rays with matter also depends on the energy of the x-ray. Initially, kilovoltage (KV) x-rays were developed. These interact with matter in a density-dependent fashion. Therefore dense materials, such as bone, would undergo more ionizations. This is also why the usual chest x-ray shows such a striking visual discrepancy between bone (very dense) and lung. Subsequently, megavoltage (MV) x-rays were developed. These more energetic x-rays absorb/ionize nearly equally between different densities of materials (density independent). Clinically, as described below, this was one of the first major advances in physics for cancer patients. The KV (diagnostic) x-rays, available first, were employed to treat superficial and deeper cancers. Yet due to the density dependence of KV x-rays, significantly more ionizations would occur in bone. Therefore many early cancer patients suffered irreparable bone damage and fracture from these unwanted ionizations. This was a very serious side effect of these early treatments. With the introduction of MV treatment in the 1950s, the reduction in permanent bone damage was a remarkable advance. This new physics-based MV technology opened the doors to modern MV radiotherapy, still the most c­ommon form of radiation therapy today. Currently KV x-rays, based on the densitydependent differential interaction of these rays with matter, are mainly used for diagnostic purposes allowing for the generation of stateof-the-art imaging, such as CT scans. Today KV x-rays (and electrons) may be used for very superficially located tumors or treatment of skin cancer. By contrast, MV x-rays still serve mainly for therapy. MV x-rays may also generate CT scans, though contrast between organs is limited (as compared with KV CT). The vast majority of cancer patients worldwide who undergo radiotherapy are treated by MV devices delivering photons. Recently, other forms of radiation are growing in clinical use, including particle-based radiation termed light particles (protons) and heavy particles (Hadrons). The physics behind these innovative sources of radiation appear to offer the potential for clinical benefit. These will be detailed in the section on particle beams. Treatment devices The first x-ray devices were brought into physical contact (contact units) with the tumor bed

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region, or the skin above this anatomy. The doctor would then stay in the room holding or aiming the radiation equipment and watch for the skin reddening (skin erythema) to determine if enough treatment was delivered. Usually, multiple treatment sessions were delivered. Eventually, x-ray devices were made with the doctor and staff behind shielding to minimize radiation exposure. In the 1950s, MV devices were developed. Originally, Cobalt-60 was used as the radioactive source [11] . These more energetic photons allowed both better tissue penetration and sparing of the bone, so this major source of morbidity was rapidly minimized. Of particular note too, was the skin-sparing capabilities of MV treatment, an additional great clinical advance. Patients no longer were guaranteed the severe skin burn or permanent skin damage from KV treatment. An additional advance during this time frame was a cobalt device that allowed multiple angles of treatment delivery. Instead of a fixed head that contained the cobalt, the head was placed on a rotating gantry [12] . Instead of the patient moving to several different positions for treatment (if possible), the machine moved. Not only was this far more comfortable for the patient, but it also created the ability to reliably treat from various angles, thereby better distributing the radiation (see Figure 1A & B). This finally meant that normal tissue routinely received less radiation dose than tumor, so side effects were (again) reduced. Through design advances, by the 1970s, these cobalt units could also deliver arc therapy, another great advance for deep tumors as dose to normal tissue was again minimized (Figure 1C) . As described later in this paper, arc therapy has recently been reborn. What is old is new again. Still, cobalt is a radioactive substance that must be replenished at great cost and with security issues. Cobalt-60 is also a relatively lowenergy MV source of radiation; therefore, to radiate deep-seated tumors such as those in the pelvis and abdomen still allowed more superficial organs of the pelvis, particularly the skin, to potentially be overdosed. Starting in the late 1970s, cobalt units were essentially replaced by linear accelerators (linacs) [13] . As linacs generate MV x-rays from electricity, they can be turned off, which is safer than having a radioactive material, which cannot be turned off. Further, the linacs could be created with higher energy photons to better treat deeper

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A

Single beam

B

Four-field beam technique

Arc therapy

50%

150% Tumor

C

15%

Normal tissue Tumor

100%

Tumor 100%

100%

Normal tissue

Normal tissue

Figure 1. Advances in treatment delivery. (A) Single beam irradiation of tumor results in a higher normal tissue dose than the tumor. (B) Four-field beam irradiation of tumor results in normal tissue receiving a lower dose than the tumor. (C) Arc therapy normal tissue receives a lower dose compared with the tumor and doses in (A & B).

tumors and better spare unwanted radiation dose to more superficial organs such as the skin [14] . An additional physics advance that dramatically improved patient outcome involved the development of collimation [15] . Collimators allow for enhanced direction and precision of radiation beam delivery. Currently, multiple leaves of tungsten are incorporated into the head of the linac to enhance precise delivery of the radiation. These multileaf collimators can be custom shaped depending on the anatomy requiring treatment. This additional collimation of the radiation beam to allow custom field shaping is computer controlled and is now a standard part of modern linac-based radiotherapy [16] . These same finger-like collimators have additional benefits to patients as is discussed in the intensity-modulated radiation therapy (IMRT) section. While the linac is by far the most common treatment device for external beam radiation, other accelerators have been developed [17] . Generally, these were first designed as research tools to better examine other forms of radiation, particularly cosmic radiation. Cosmic rays contain many exotic particle-like forms of radiation. Over time both light particles (protons) and

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heavier particles (Hadrons) have been employed in clinical radiation oncology [18,19] . Based on clinical success, and as will be described, the enhanced physics characteristics of particle beams, these tools are becoming a more common therapeutic intervention. In distinct contrast to linacs, which are self-contained in a treatment room that is comfortable at 500 square feet, all but the newest generation of proton and heavy particle units are massive and require a football field size footprint. These higher energy particles also require hundreds of tons of shielding to prevent scatter of radiation and the costs are in the hundreds of millions of dollars for each of these units [20,21] . As compared with the tens of thousands of linacs worldwide, fewer than a hundred proton units currently exist or are planned. Only a handful of heavy particle units are amenable for patient treatment. The impetus for particle therapy is based on the distinct difference between photons and particles [22,23] . A photon enters and exits tissue, with ionization along the majority of its tract. By contrast, virtually all particle ionizations occur within a specific region termed the Bragg peak. The particle beam enters tissue, ionizes within the Bragg peak and does not exit. The depth

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Radiation oncology: physics advances that minimize morbidity  and location of the Bragg peak can be set by the energy of the entering particle, a very convenient method. As will be discussed in the clinical section, the handful of heavy particle units as compared with light particle (proton) units may offer both a physics and a radiobiological benefit, an important point, particularly in light of the extraordinary costs of these accelerators. Treatment delivery Treatment may be delivered by placing radioactive sources into the tumor bed (brachytherapy) or through external beam devices (teletherapy). ●●Brachytherapy

Radioactive sources may be placed permanently (e.g., prostate) or temporarily (e.g., breast and lung). The radioactive sources provide for high dose rates where treatment is accomplished in minutes or low dose rates where therapy is prolonged for days or weeks [24,25] . In many instances, the radioactive sources are now placed through automated or robotic devices to minimize exposure to staff. Brachytherapy has the great advantage of delivering very high doses of radiation to very small volumes. The physics of radioactive sources is such that the dose of radiation falls off dramatically within a few centimeters of the source. This technique has significant current clinical advantage in that regard, as side effects are expected to be low since little normal tissue should be irradiated [25] . Still, wherever an actual radioactive source is in contact with the tissue, the dose of radiation can be extraordinarily high, potentially leading to tissue breakdown and fistula, an event with high expected morbidity. ●●External beam photon delivery

External beam photon delivery has made dramatic strides based on physics advances. The original contact type of treatment units always delivered therapy that damaged bone and skin.. MV units minimized, but again did not eliminate these effects. Physics advances in the collimation device created further refinement in dose delivery. The early collimators had very limited ability to shape fields, so custom-made ‘cerrobend’ blocks would often be created and physically placed in the beam path to define the radiation field [26] . Subsequently multileaf collimators, with tungsten fingers were refined [27] . Fingers could then be set to create the radiation field, eliminating the need to create

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custom cerrobend blocks, which often weighed as much as 20 lb, a costly and dangerous device if dropped. Additional advances in physics and computing have now allowed for motion of these finger-like projections during the actual radiation delivery [28] . As the fingers move into or out of the radiation field, the radiation is modulated in intensity. Therefore, current state-of-the-art photon delivery is through IMRT [29] . Instead of static radiation treatment fields, the fields are modulated to paint the radiation dose over the target. Additionally, the radiation dose is intentionally minimized over normal tissues, termed dose avoidance or conformal avoidance. The combination of dose painting with conformal avoidance has created the modern age of photon radiation therapy as detailed in the clinical s­ection [30,31] . Various types of IMRT delivery are commercially available including ‘STEP and SHOOT,’ where the collimator moves to its next position before delivering the radiation beam as well as dynamic types of IMRT where the collimation is done with the beam on. IMRT is now evolving further through the use of volumetricmodulated arc therapy [32] . In this case, instead of a limited number of IMRT delivery angles, a 360° arc is used during the IMRT session (see Figure 1C). This arc-type approach allows greater ability to dose paint and for conformed avoidance. Furthermore, the arc delivery is rapid. In comparison with a standard IMRT treatment lasting up to 20 min, arcs can be delivered in less than 2 min. Not only is this more comfortable for the patient, but the rapid throughput is much more economical. This decreased treatment time may also be beneficial in terms of maximizing intrafraction treatment accuracy. Volumetric arc therapy was based upon the original arc therapy employed on cobalt units from the 1950s, but current delivery represents a quantum leap in state-of-the-art therapy because of its ability to dose paint [33] . ●●Radiosurgery

With technological advances, radiosurgery (hypofractionation) has become an option for treatment in a number of clinical instances [34] . Conceptually, radiosurgery is considered surgery without the knife. With this treatment, large doses of radiation are delivered to very small volumes, thereby ablating the lesion. Since the volume treated is so small, normal tissue is somewhat spared [35] . Radiosurgery has a long history

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Review  Allison, Patel & McLawhorn in the treatment of brain tumors due to the pioneering work of Lars Leksell and the Leksell Gamma Knife [36] . Essentially, the Gamma Knife is an array of cobalt sources placed in a helmet-like device. The sources can be collimated to submillimeter precision to allow very precise treatment of brain lesions with sparing of the majority of normal brain [37] . Based in large part of the precision and success of the Gamma Knife, linacs were modified to deliver similar large doses of radiation to very small volumes, again mainly through the use of additional collimator devices [38] . Current stateof-the-art linacs can combine the ultra precision of radiosurgery with volumetric-modulated arc therapy delivery, making radiosurgery treatment a procedure that can be accomplished as an ­outpatient in 10 min or less. A remarkable radiosurgery tool that has found widespread implementation is the CyberKnife [39] . This is a small linac placed upon a robotic arm combined with a robotic table. The combination of robotics with proprietary software allows for a remarkable precision of therapy as well as the versatility to offer reliable radiosurgery to virtually any anatomic site. Unlike other radiosurgery tools, the CyberKnife has a built-in tracking ability whose goal is to follow motion of the tumor and surrounding normal tissues. Ideally, the CyberKnife, as it is tracking and treating the tumor, will deliver the majority of its radiation dose to the tumor and better spare surrounding tissues. ●●Particle delivery

Whereas photons enter and exit tissue with the ionization process tracking from entry to exit, particles do not exit tissue. Virtually all ionizations should occur in the small defined volume termed the ‘Bragg peak’ [40] . While the action of particles in terms of ionization is similar between protons and photons, the actual physical deposition of proton ionization can be far more precise. Therefore, particle accelerators have focused mainly on developing tools to better define the location of the Bragg peak. This is in contrast to linacs where dose painting and conformal avoidance techniques are considered state of the art. Until recently, particle units were with large footprints and multiple treatment rooms connected to a single particle accelerator. Several single room units have now come online. An additional consideration is that heavy particles, in contrast to protons and photons, also densely

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ionize within hypoxic regions. This direct effect of heavy particles offers an additional biologic advantage, particularly since many tumors are felt to contain hypoxic, radioresistant regions. While protons and photons are considered equivalent in terms of ability to damage tumors (although again they have different patterns of ionization), heavy particles are considered far more biologically damaging [41] . Therefore, in addition to the attraction of the Bragg peak for clinical treatment, the enhanced biologic action of heavy particles is also a very attractive property. Essentially then heavy particles may be considered as a different form of particle radiation as compared with protons and also a type of radiation that has advantage over photons (and protons) in their effect on overcoming hypoxia of tumors, currently felt to be a leading cause of treatment failure [42] . Imaging & deformation With treatment delivery now promising millimeter precision, it becomes apparent that geographical miss of the tumor bed in the delivered high-dose radiation treatment volume is a reality. If the tumor, normal tissue or patient moves, the wrong anatomy would undergo high-dose therapy [43] . This motion can be quite dramatic with lesions moving several centimeters, for example, with respiration. Potential for geographic miss is particularly true for particle beams where the ultra precise Bragg peak needs to be accurately placed. Geographic miss leads to poor tumor control and enhanced normal tissue toxicity. Further as tumor bed and normal tissue move, they may deform in shape [44] . For example, a pelvic tumor might change shape based on pressure exerted by a filling rectum or bladder. This deformation may also lead to overdosage or underdosage of tumor and normal tissue. Motion may occur during the fraction of radiation delivery (intrafraction motion) and between fractions (interfraction motion). Therefore, identifying motion extent and correcting for this motion is critical to precise t­reatment delivery and outcome. Imaging prior to therapy to ensure the accuracy of the daily treatment has become a critical component of minimizing morbidity and maximizing outcomes. State-of-the art linacs now contain onboard imaging tools, including CT scans [45] . Onboard KV CTs can be done with the patient in treatment position as part of daily therapy. Similarly, the actual MV radiation

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Radiation oncology: physics advances that minimize morbidity  can be used to create a MV CT. Hybrid tools such as a separate CT scanner on rails can also be placed in the treatment vault along with the linac. A helical CT unit that can image and treat is also commercially available. In each case, the patient is placed into treatment position, but just prior to radiation therapy, is imaged. Discrepancies between anatomic and target location can be adjusted and minimized before the beam is turned on. This is termed image-guided radiation therapy [46] . Image-guided radiation therapy is not a type of treatment delivery, but rather connotates that imaging was done along with therapy delivery. Therapy delivery may be IMRT, 3D treatment, radiosurgery and so on. Relatively few particle beam units are able to CT image in the treatment position. Much more commonly a radio opaque fiducial is placed in or near the tumor [47] . Relatively primitive imaging to ensure the fiducials are within the treatment field is then done. In this situation, little information concerning location of normal tissues is provided, a substantial drawback compared with the daily in-room CT scanning, which is common with linacs. With CT-based imaging, normal tissue conformal avoidance is usually possible as well as also ensuring that the target is within the field. As Gamma Knife patients are imaged and treated based on a secure head frame, ultra precision is possible as long as the frame or lesion has not moved. In contrast, the CyberKnife unit often depends on a combination of radio-opaque fiducial placement in the tumor and motion of the chest/abdomen. While this allows for potential active tracking of the tumor, no information concerning location of normal surrounding t­issue is possible, again a potential drawback [48] . With the exception of the CyberKnife, none of the aforementioned imaging tools provide information on motion during the actual therapy. As both patients and their tumors move, sometimes substantially, additional means of imaging during the actual treatment (intra­ fraction) procedure may be required to minimize geographic miss. This could be done indirectly, via fiducials or software programs similar to CyberKnife technology [49] . An additional means is to use GPS-like technology with a miniature transponder placed in the tumor and monitored to ensure this area is within the radiation field [50] . A more sophisticated approach would also take into account deformations. During radiation

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treatment, normal bodily functions will lead to motion of organs and tumor. Respiration may induce a several cm movement of tumor within the lung and respiration may induce motion in the abdomen from diaphragmatic motion. The bladder and rectum may fill, independently inducing motion in the pelvis. Certainly, the patient may physically move or shift on the treatment table during the actual therapy session. These types of intrafraction motion will also exhibit tumor and normal tissue d­eformations that may induce geographic miss [51] . Ideally not only should motion be accounted for but deformation during treatment should be compensated. Without correction it would be obvious that a high-dose radiation field with 3 mm margin could easily miss the target and lead to overdose of surrounding normal tissue. Yet today even with the state-of-the-art therapy, particularly particle beams, this motion and deformation is only partially compensated for, generally by creating larger than needed high dose volumes for therapy. These larger than needed fields will encompass excess normal tissue, leading to the possibility of side effects. As will be described, an innovative use of magnetic resonance imaging may provide substantial data on deformation and intrafraction motion during the actual therapy session. Fractionation Clinically, radiation delivery has followed two seemingly divergent pathways. In one, historically based on extensive clinical and research outcomes, small daily fractions (1.8–2 Gy) of radiation are delivered over a prolonged multiweek period. Based on decades of peer-reviewed publications, this has allowed for lesion control with acceptable clinical morbidity [52] . The other pathway delivers large doses (10–50 Gy) in one or few fractions (hypofractionation) [53] . This was usually termed radiosurgery. In clinical reality, both standard and hypofractionation treatments can often ablate lesions. However, the morbidity profiles may be quite different with hypofractionated regimens possibly leading to more late side effects (fibrosis) months to years post-therapy. More likely though is that the effects and side effects of these two types of radiation fractionation schemes are based on the volume of normal tissue exposed to high doses [54] . Radiosurgery, by definition, treats limited and small volumes. With this limited high-dose field delivery, side effects may also be limited. By contrast, standard

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Review  Allison, Patel & McLawhorn fractionation may be delivered to far large volumes such as target and regional lymph nodes that are 20 cm away. Any attempt at radiosurgery to these large volumes would induce far more significant morbidity than standard fractionation. Therefore currently radiosurgery technologies and standard fractionation techniques are both an important part of successful radiation therapy. Particle beams are generally employed to smaller volumes that are similar to radiosurgery volumes. Yet in most instances particle beams deliver standard fractionated therapy, perhaps a less than ideal means of treatment [55] . Clinical outcomes of state-of-the-art physics ●●Intensity-modulated radiation therapy

The introduction of MV treatment allowed for a magnitude change in radiation morbidity, particularly skin sparing and diminished bone fracture [56] . MV treatment allowed radiation therapy to become a standard part of successful cancer treatment. In the late 1980s, advances in computing power and imaging (CT scan) again transformed radiation therapy. During this time 3D conformal radiation was developed, which again improved the ability to deliver dose to tumor and minimize dose to normal tissue. Clinical outcomes and side-effect profiles improved. With additional computing power and technological advance, IMRT has become widespread. Here due to dose painting, lesions can achieve even higher doses of radiation while intentionally sparing normal tissues [56] . Clinically tumor control has again improved and side effects dramatically diminished [57] . Now modulated arc therapy shows additional promise for further morbidity reduction with even greater ability to deliver high doses to tumor [58] . IMRT technology has had great impact in the curative treatment of many tumors at many anatomical sites. Solitary tumors of the brain may be better approached through IMRT techniques over conventional radiation therapy as this may spare excessive dose to critical structures such as the optic chiasm. This is particularly true for pituitary lesions [59] . For patients with multiple lesions (brain metastases), IMRT can still be used to spare normal brain in two ways [60,61] . First, if only a handful of brain metastases are detected, IMRT can deliver tumoricidal doses to these lesions and attempt to spare clinically uninvolved brain. Second, with multiple brain

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metastases, IMRT can be delivered as a whole brain radiotherapy but designed to spare stem cell and memory regions of the brain, potentially minimizing acute and chronic morbidity [61] . IMRT is considered a standard technique for tumors of the head and neck region (generally, primary squamous cell tumors arising below the brain but above the clavicles) [62] . Most head and neck tumors are locally aggressive and spread to regional lymph nodes. Cure can often be achieved by surgery, radiation and chemotherapy. This aggressive therapy is highly morbid. IMRT has allowed for both dose escalation to the tumor bed and far more limited dose to normal tissues [63] . This has diminished morbidity extensively. Through IMRT, salivary glands may often be spared so permanent xerostomia, loss of taste and associated tooth decay is minimized. Acute skin morbidity and mucositis are also diminished in intensity, but remain a clinical issue. Similarly IMRT to esophageal and thoracic tumors, particularly mesothelioma allows for diminished toxicity profiles as does IMRT to abdominal tumors such as the pancreas [64–66] . Still the ability to deliver tumoricidal dose without undue normal tissue injury remains to be improved upon. IMRT, however, has allowed for great strides in the treatment of pelvic malignancies, particularly prostate cancer [67] . Compared with 3D treatment, prostate IMRT achieved a 30% reduction in morbidity. In many instances, tumoricidal doses with relatively low, but not negligible side effects, can now be routinely delivered [68] . This is particularly true when radiation is used adjunctively, either for pre-op or post-op treatment of colorectal cancer and as treatment of anal cancer [68] . ●●Radiosurgery

Radiosurgery has revolutionized treatment of early (T1, T2) lung cancers [69] . Outcomes for peripheral lesions are nearly equivalent to surgery without the morbidity/mortality associated with anesthesia and the surgical procedure [70] . This is an important consideration as many patients are elderly and with poor pulmonary function. Radiosurgery to early stage but central lung cancers is substantially more morbid. Still, compared with external beam standard fractionated radiation therapy, radiosurgery offers far higher local control and far less morbidity for early lung cancers [71] . Patients with local recurrence of head and neck tumors may now

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Radiation oncology: physics advances that minimize morbidity  undergo radiosurgery as salvage, which prior to this generally could not be offered through other means [72] . In select early stage lesions, radiosurgery alone may be curative primary therapy [73] . However, the majority of head and neck tumors are with lymphatic spread and therefore IMRT remains the primary treatment of choice for these patients. Radiosurgery has opened the door to new radiation interventions into other tumors considered untreatable mainly due to the inability of prior techniques to avoid normal tissue injury, particularly liver and kidney tumors [74,75] . The precision of this technique makes it ideal for therapy to the spine and spinal cord region [76] . Retreatment of previously irradiated spine is now possible as additional dose to the very radiosensitive spinal cord can be minimized through the precision of radiosurgery techniques. Radiosurgery to the brain for solitary or multiple metastatic lesions can routinely be successfully delivered with minimal normal t­issue injury via Gamma Knife [77] . ●●Particle beams

The Bragg peak makes particle beams extremely attractive as a means to again revolutionize radiation therapy [78] . As these beams do not exit tissue and as the vast majority of ionization occurs in the Bragg peak, this would seem to be a nearly ideal means to treat tumors. As mentioned, heavy particles have an additional benefit of enhanced ablation of hypoxic tumors, currently thought to be a significant cause of treatment failure. However, state-of-the-art imaging still does not allow for exact tumor localization and patients as well as their organs are in motion. Therefore, the ultra precision possible with particles may not yet be exploitable in many clinical situations [79] . Further in clinical situations, the Bragg peak must be enlarged to better cover the volume to be radiated. This modulation of the Bragg peak has clinical consequences as it both diminishes the ionizations in the Bragg peak and increases ionizations prior to the Bragg peak [80] . Still, proton beams have shown outstanding results when very precise and immobile anatomy is treated [81] . This is particularly true for tumors of the eye and spinal cord [82] . Due to the limited ionization in normal tissue, proton beams are also advocated for pediatric radiation where patients may more commonly experience late side effects [83] .

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Proton beams may also show benefit to thoracic and lung tumors as again they may minimize normal tissue consequences [84] . However, the motion of the lung tumor remains a c­hallenge for accurate targeting. Where proton beams have been most commonly employed is for prostate cancers [85] . These localized tumors surrounded by the radiosensitive bladder and rectum would seem ideal for Bragg peak therapy. However, the motion of the prostate is great and most proton centers have very limited image-guided radiation therapy capability [86] . Therefore, the clinical outcomes from proton beams do not appear to be better in terms of local control or morbidity than IMRT [87,88] . However, the cost of a proton therapy is double that of IMRT. Heavy particles have the advantage of both the Bragg peak and a biological advantage of treating hypoxic tumors (far better than protons or photons) [89] . As only a handful of sites offer heavy particle therapy, clinical data are limited [90] . Still these early, nonrandomized outcomes show excellent local control with low morbidity for spine tumors as well as sarcomas, which are often felt to be radioresistant due to high hypoxic fraction. Response of pancreatic tumors is also promising. An additional potential benefit to heavy particles is that as they are biologically more active, fewer fractions of radiation are required for therapy. This is easier on the patient and also allows greater throughput for these incredibly expensive machines. A major current drawback is that while photon and proton dosimetry is well defined, it is still a work in progress for particles. Future Radiation does not discriminate its ionizations, so both tumor and normal tissue are affected. Advances in the physics of treatment delivery will likely continue down the path of enhancing ionization in the malignancy and minimizing ionization to normal tissue. ●●Tumor imaging

A key to accurate dose delivery has been enhanced imaging most recently by the introduction of CT scans both to the treatment planning stages and to the actual delivery of therapy [91] . Further improvement in the quality of the image taken prior to treatment will no doubt enhance this process. Other imaging techniques, particularly MRI, offer more detailed anatomic

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Review  Allison, Patel & McLawhorn definition; therefore, MRI will likely move far further into the planning and treatment process [92] . As magnetic resonance will interfere with generation of linac-based x-rays, innovative approaches to overcome this are required when trying to use MRI to image a tumor during therapy [93] . A novel approach uses cobalt-60 sources for treatment, while MRI imaging is accomplished during the therapy session. Through interlocks treatment is delivered only when the imaged tumor is within the treatment field. Both dosimetric and imaging issues are a work in progress. This concept should open a new door for enhanced intrafraction imaging with compensation of dose based on both motion and deformity possible. A new level of treatment accuracy will then become possible. Protons can be generated that are powerful enough to allow for imaging of their ionizations. This is essentially a type of PET (SPECT) scan without the need for injection of a radioactive tracer. If a proton unit were so designed, it would be quite possible to image the treatment field in real time. This might also allow for prevention of geographic miss, a means to define tumor motion and to also allow for a highly precise radiosurgery type of proton therapy. The imaging could also serve as a means of dosimetry. Current proton units do not routinely allow for this type of enhanced imaging, which is a great loss. Ideally, future units would have this capability built in as it would no doubt improve this therapy on many fronts. In select anatomy, ultrasound offers a nonionizing process for imaging as well [94] . This would be particularly useful as daily diagnostics CT scanning prior to each fraction of therapeutic radiation adds significant dose exposure to ­normal tissues. Tumor imaging can also incorporate biologic activity through PET/CT [95] . Here tumor delineation based on abnormal metabolic profile, particularly hypoxia content, can be more informative and selective than by CT or MRI alone. The biologic activity of the tumor could aid in the amount of radiation dose needed for therapy. Lack of biologic activity post therapy could avoid surgical resection of a residual tumor mass. Future radiation centers will no doubt rely much more heavily on a combination of physical and biologic imaging [96] . Potentially laser-based imaging with the reflection of light may allow for a nonionizing means to define anatomy. Termed optical tomography, this technique may prove to

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be an excellent imaging technique for radiation therapy, particularly during treatment [97] . ●●Tumor deformity correction

As lesions move, they change shape. Currently, little correction for these deformities occurs in the clinically prescribed radiation treatment. This means some of the tumor is underdosed and also due to the deformity of normal tissues, this anatomy may be overdosed. Taking into account these deformities and correcting for them by adding or subtracting subsequent dose will result in a great physics advance. This will likely require far more advancement in imaging, particularly during the actual therapy session. Potentially biologic activity would be added to deformity correction, so that tumor regions that remain biologically active could receive higher doses of radiation, while tumors that respond well biologically may require less therapy [98] . The use of MRI or laser tomography during therapy appears to be a probable means to c­ orrect for deformity [99] . ●●Innovative therapy

Particle units do not now generally offer arc or intensity-modulated therapy. Currently, only select clinical proton units have been developed with spot scanning technology. This allows for modulation of the proton beam. Ideally all future proton units would be able to offer intensity-modulated proton therapy as part of standard operating procedures. Today particle therapy treatment delivery is based on placing the Bragg peak upon the tumor bed. In reality, this is far more complex than it appears. Most particle units produce a very small Bragg peak, far smaller than the lesion or volume needing to be clinically treated. Consequently, the Bragg peak is elongated through the use of modulators. Current modulators diminish the intensity of ionizations within the peak and lead to ionization prior to the peak. These changes mean that far more normal tissue is ionized and the tumor bed is treated with less certainty of dose. Therefore for most patients, multiple particle beams are employed from various angles to ensure tumor coverage. This again, also increases dose to normal tissues in the beam path prior to the Bragg peak. Future proton units will have enhanced modulators of the proton field to better capitalize on the Bragg peak. This will be accomplished through new techniques such as scanning beams and lasers to generate the

future science group

Radiation oncology: physics advances that minimize morbidity  modulation. Of particular note is that current particle units are with a relatively large construction footprint and of high cost to build and operate. Highly innovative technology, such as laserbased generation of a clinically useful particle beam is on the horizon. This holds true promise for far smaller, cost-effective treatment tools. Heavy particle beams have both physical and biologic enhancements that should truly innovate radiation therapy [100] . While not all patients may require this type of treatment, some no doubt would benefit. It is critical then to better identify this cohort. Clearly those with hypoxic tumors might be best served by heavy particles as well as those with immobile tumors within millimeters of other critical structures such as the brain stem or spinal cord. The physics and biology of these heavy particle beams are not as well defined as for photons or protons. This is an exciting open door for the future of radiation physics. Currently, cost and physical size are substantial obstacles to widespread introduction of heavy particle treatment tools. In theory, particles can be generated by very small but powerful laser beam systems, again, an open door for physics and engineering [101] . Ideally the concepts of intensity modulation in combination with advanced image guidance could be brought to the clinic for particle technologies, which no doubt would offer clinical advancement [102] . Additional elegant and innovative approaches would be to enhance techniques such as neutron capture theory. Here the patient is first injected with a compound that is designed to be selectively absorbed in the target tissue and have a high cross-section for neutron capture. Boron is typically employed in the compounds to create the high neutron capture cross-section [103] . The target volume that absorbs the compound is then exposed to slow neutrons, which are captured by the boron. The interaction of the slow neutrons with the boron (10B) produces energetic α-particles and lithium ions (7Li). As previously discussed in the heavy particle therapy section, these particles deliver most of their energy over a small range, enabling very localized and precise dose delivery. While originally developed as a means to treat brain tumors, additional tumors throughout the body have been irradiated with this technique [104] . Results are promising. However, widespread adaptation has been limited by access to neutron sources, development of more tumor selective compounds and limitations in dosimetry methods to determine the delivered

future science group

Review

dose. Future physics studies could address some of these limitations, and studies of processes such as gadolinium-neutron capture theory could c­reate new possibilities for treatment. Localized or targeted α-particle therapy may be similarly revolutionary. Here α-particleemitting radiopharmaceuticals are designed to be selectively absorbed in the target tissue. Once in the selected tissue, the radiopharmaceutical decays release α-particles. The α-particles, being heavy particles as described previously, are extremely destructive to the surrounding tissue. However, due to the rapid rate that they deposit their energy in the surrounding tissue, they have a very short range, thus limiting the dose to areas outside the target. Current limitations in this form of therapy result from the radiopharmaceutical being absorbed in healthy tissue and undergoing decay before being excreted from the body. Additionally, the types of tissue that can selectively absorb these radiopharmaceuticals are limited. Future advances in physics and chemistry might produce α-particle-emitting radiopharmaceuticals for a wider range of target tissues. Other advances could produce compounds that are more rapidly excreted from the body if not absorbed in tissue. Radiation is delivered in such a means as to localize based on cellular receptors. Conceptually tumor receptors specific to α-particle treatment may become widespread. Biologic means to more selectively upregulate tumor death pathways and other cellular functions promoting tumor apoptosis may be possible by exploiting physics techniques to allow for lower, less morbid to normal tissue doses of radiation in combination with tumor-sensitizing agents [105] . A myriad of nanoparticles, modified viruses and natural as well as synthetic chemicals may act as radiation sensitizers [106,107] . When these adjuvants localize in tumors, they may be activated by the energy of the radiation to achieve a more selective tumor destruction with sparing of normal tissues. This no doubt will be another successful future pathway for radiation therapy. Ideally the compounds used for detecting tumors would also act as radiation sensitizers [108] . Some of these agents create destructive singlet oxygen when activated by radiation, so designing a contrast agent that is activated by radiation is a realistic means to first identify tumor and then destroy it through a combination of ionization from the x-rays and the

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Review  Allison, Patel & McLawhorn additional destructive ability of the activated contrast agent. The addition of biologic activity could be measured (similar to agents used in PET/CT) and change in biologic activity might serve as a means of radiation dosimetry to better identify successful therapy or the need for additional intervention.

Conclusion Physics advances have allowed radiation therapy to play a major and successful role in the treatment of many cancers. Within a century, due, in large part, to physics enhancements, radiation treatment has gone from a therapy of last resort to a standard intervention. In the last

EXECUTIVE SUMMARY ●●

Radiation is a packet of energy (photon) that can destroy tumor and normal tissue DNA via ionizations.

●●

Normal tissue and tumor are intertwined, so normal tissue injury can be common.

Photons delivered by standard fractionation ●●

Intensity-modulated radiation therapy allows the dose of radiation to be painted over the tumor and to conformally avoid normal tissues, both diminishing side effects.

●●

Arc therapy (volumetric-modulated arc therapy) allows even better dose painting with therapy sessions of only 2 min.

Photons delivered by radiosurgery ●●

Radiosurgery delivers ablative megavoltage therapy of radiation in only one or a few treatment sessions.

●●

Radiosurgery can only be used for very small volumes as the high doses delivered can easily injure normal tissue.

●●

Currently radiosurgery techniques and intensity-modulated radiation therapy co-exist and complement each other in the clinic.

Particles ●●

All particles deposit their DNA destroying ionizations within a small volume termed ‘The Bragg peak.’

●●

This means particle beams can be extremely precise, with no entry or exit ionizations.

●●

Heavy particles also ionize in hypoxic tumor regions, whereas protons and photons do not.

Image guidance ●●

As treatment delivery can be with submillimeter precision, it may be possible to miss the cancer (geographic miss).

●●

Imaging the tumor bed prior to therapy with linacs that have built-in computed tomography scanners is now common.

●●

Image guidance remains less well defined for particle units.

●●

Biologically active imaging is becoming more common, to better access tumor function.

Deformation ●●

The tumor target may move with respiration, bowel motion and bladder filling.

●●

The target may also deform in shape, which would affect the accuracy of radiation dose delivered.

●●

Strategies to account for both deformation and motion are a current physics effort.

Future ●●

Improved imaging and tracking of tumors even during therapy will allow for more precise dose delivery and to better avoid normal tissues.

●●

Particle units will be commonly equipped with advanced imaging for better accuracy of moving targets.

●●

Particle units will routinely deliver intensity-modulated therapy to better spare normal tissue.

●●

Elegant radiation therapy more precisely delivered by α-particles and boron neutron therapy may become the norm.

●●

The use of nanoparticles, virus’s and other agents to better define tumor and to sensitize tumor to radiation will join the ranks as part of physics advances to better spare normal tissue injury.

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future science group

Radiation oncology: physics advances that minimize morbidity  decade alone, achievements in the field of radiation physics allowed creation of far more precise and far less morbid therapy to become clinically available worldwide. This means many more cancer patients can be treated for cure with an ever decreasing risk of side effects. These physics advances continue to provide hope and benefit to millions of patients around the world. Future perspective Tremendous strides have been made in the physics of radiation therapy, from tumor identification through treatment delivery. Yet the reality remains that tumor and normal tissue are intercalated and often normal tissue morbidity prevents the delivery of tumoricidal doses of radiation. The future of radiation physics will be our increasing ability to overcome this critical issue through more precise treatment that can better exclude normal tissues. This will be achieved through a combination of enhanced imaging of the tumor, likely in Papers of special note have been highlighted as: • of interest 1

Bortfeld T, Jeraj R. The physical basis and future of radiation therapy. Br. J. Radiol. 84(1002), 485–498 (2011).

•

Comprehensive review of current radiation physics.

2

3

4

5

6

Wiernik G. Fractionation in radiotherapy (review). Anticancer Res. 3(4), 283–297 (1983). Chua ML, Rothkamm K. Biomarkers of radiation exposure: can they predict normal tissue radiosensitivity? Clin. Oncol. (R. Coll. Radiol.) 25(10), 610–616 (2013).

combination with advanced particle beams that offer improved precision of dose delivery. No doubt, future radiation physics will also be better able to exploit the different inherent and induced radiosensitivities of tumor and normal tissues to achieve higher tumor control rates without undue morbidity. Ideally a highly tumor-selective radiation-sensitizing agent that also has real-time imaging and dosimetry abilities will be developed allowing a revolution in the field of radiation oncology. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or p­ending, or royalties. No writing assistance was utilized in the production of this manuscript. windows of opportunity in hyper and hypo-fractionated radiation therapy. J. Thorac. Dis. 6(4), 287–302 (2014).

References 9

Marks LB, Yorke ED, Jackson A et al. Use of normal tissue complication probability models in the clinic. Int. J. Radiat. Oncol. Biol. Phys. 76(3 Suppl.), S10–S19 (2010).

10 Kirkpatrick JP, Meyer JJ, Marks LB. The

linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. Semin. Radiat. Oncol. 18(4), 240–243 (2008). 11 McKenzie AL. Cobalt-60 gamma-ray beams.

Br. J. Radiol. 25(Suppl.), 46–61 (1996). 12 Cohen M. Gamma rays: cobalt 60 teletherapy

units. Br. J. Radiol. 11(Suppl. 11), 53–61 (1972).

Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast. Reconstr. Surg. 133(1), e49–e56 (2014).

13 Karzmark CJ. Advances in linear accelerator

Allison RR. The electromagnetic spectrum: current and future applications in oncology. Future Oncol. 9(5), 657–667 (2013).

14 Horwich A. Radiotherapy update.

Kavanagh JN, Redmond KM, Schettino G, Prise KM. DNA double strand break repair: a radiation perspective. Antioxid. Redox Signal. 18(18), 2458–2472 (2013).

7

Brahme A, Lind BK. A systems biology approach to radiation therapy optimization. Radiat. Environ. Biophys. 49(2), 111–124 (2010).

8

Prasanna A, Ahmed MM, Mohiuddin M, Coleman CN. Exploiting sensitization

future science group

Review

design for radiotherapy. Med. Phys. 11(2), 105–128 (1984). BMJ 304(6841), 1554–1557 (1992). 15 Fenwick JD, Riley SW, Scott AJ. Advances in

intensity-modulated radiotherapy delivery. Cancer Treat. Res. 139, 193–214 (2008). 16 Purdy JA. From new frontiers to new

standards of practice: advances in radiotherapy planning and delivery. Front. Radiat. Ther. Oncol. 40, 18–39 (2007). 17 Loeffler JS, Durante M. Charged particle

therapy – optimization, challenges and future directions. Nat. Rev. Clin. Oncol. 10(7), 411–424 (2013).

•

Excellent overview of particle therapy.

18 Combs SE, Kessel K, Habermehl D, Haberer

T, Jakel O, Debus J. Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base. Acta Oncol. 52(7), 1504–1509 (2013). 19 Orth M, Lauber K, Niyazi M et al. Current

concepts in clinical radiation oncology. Radiat. Environ. Biophys. 53(1), 1–29 (2014). 20 Allen BJ, Bezak E, Marcu LG. Quo vadis

radiotherapy? Technological advances and the rising problems in cancer management. Biomed. Res. Int. 2013, 749203 (2013). 21 Sher DJ. Cost-effectiveness studies in

radiation therapy. Expert Rev. Pharmacoecon. Outcomes Res. 10(5), 567–582 (2010). 22 Karger CP, Jakel O, Palmans H, Kanai T.

Dosimetry for ion beam radiotherapy. Phys. Med. Biol. 55(21), R193–R234 (2010). 23 Schulz-Ertner D, Tsujii H. Particle radiation

therapy using proton and heavier ion beams. J. Clin. Oncol. 25(8), 953–964 (2007). 24 Tanderup K, Beddar S, Andersen CE,

Kertzscher G, Cygler JE. In vivo dosimetry in brachytherapy. Med. Phys. 40(7), 070902 (2013). 25 Morton GC, Hoskin PJ. Brachytherapy:

current status and future strategies – can high dose rate replace low dose rate and external beam radiotherapy? Clin. Oncol. (R. Coll. Radiol.) 25(8), 474–482 (2013). 26 Blackwell CR, Amundson KD. Cadmium

free lead alloy for reusable radiotherapy

www.futuremedicine.com

2341

Review  Allison, Patel & McLawhorn shielding. Med. Dosim. 15(3), 127–129 (1990). 27 Prah DE, Kainz K, Peng C, Li XA. The

dosimetric and delivery advantages of a new 160-leaf MLC. Technol. Cancer Res. Treat. 10(3), 219–229 (2011). 28 Purdy JA. Advances in the planning and

delivery of radiotherapy: new expectations, new standards of care. Front. Radiat. Ther. Oncol. 43, 1–28 (2011). •

In-depth publication reviewing the current state of the art in radiation physics.

29 Staffurth J; Radiotherapy Development

Board. A review of the clinical evidence for intensity-modulated radiotherapy. Clin. Oncol. (R. Coll. Radiol.) 22(8), 643–657 (2010). 30 Galvin JM, De Neve W. Intensity modulating

and other radiation therapy devices for dose painting. J. Clin. Oncol. 25(8), 924–930 (2007). 31 Kim Y, Tome WA. On voxel based

iso-tumor control probabilty and isocomplication maps for selective boosting and selective avoidance intensity modulated radiotherapy. Imaging Decis. (Berl.) 12(1), 42–50 (2008). 32 Teoh M, Clark CH, Wood K, Whitaker S,

Nisbet A. Volumetric modulated arc therapy: a review of current literature and clinical use in practice. Br. J. Radiol. 84(1007), 967–996 (2011). 33 Yu CX, Tang G. Intensity-modulated arc

therapy: principles, technologies and clinical implementation. Phys. Med. Biol. 56(5), R31–R54 (2011). 34 Brown JM, Carlson DJ, Brenner DJ. The

tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? Int. J. Radiat. Oncol. Biol. Phys. 88(2), 254–262 (2014). 35 Kirkpatrick JP, Kelsey CR, Palta M et al.

Stereotactic body radiotherapy: a critical review for nonradiation oncologists. Cancer 120(7), 942–954 (2014). 36 Lunsford LD, Levine G, Gumerman LW.

Comparison of computerized tomographic and radionuclide methods in determining intracranial cystic tumor volumes. J. Neurosurg. 63(5), 740–744 (1985). 37 Levivier M, Gevaert T, Negretti L. Gamma

Knife, CyberKnife, TomoTherapy: gadgets or useful tools? Curr. Opin. Neurol. 24(6), 616–625 (2011). 38 Lawson JD, Fox T, Waller AF, Davis L,

Crocker I. Multileaf collimator-based linear accelerator radiosurgery: five-year efficiency analysis. J. Am. Coll. Radiol. 6(3), 190–193 (2009).

2342

39 Dieterich S, Gibbs IC. The CyberKnife in

clinical use: current roles, future expectations. Front. Radiat. Ther. Oncol. 43, 181–194 (2011). 40 DeLaney TF. Proton therapy in the clinic.

Front. Radiat. Ther. Oncol. 43, 465–485 (2011). 41 Wenzl T, Wilkens JJ. Modelling of the oxygen

enhancement ratio for ion beam radiation therapy. Phys. Med. Biol. 56(11), 3251–3268 (2011). 42 Rong Y, Welsh J. Basics of particle therapy II

biologic and dosimetric aspects of clinical hadron therapy. Am. J. Clin. Oncol. 33(6), 646–649 (2010). 43 Li G, Citrin D, Camphausen K et al.

Advances in 4D medical imaging and 4D radiation therapy. Technol. Cancer. Res. Treat. 7(1), 67–81 (2008). 44 Ruan D, Kupelian P, Low DA. Image-guided

positioning and tracking. Cancer J. 17(3), 155–158 (2011). 45 Wang L, Chen X, Lin MH et al. Evaluation

of the cone beam CT for internal target volume localization in lung stereotactic radiotherapy in comparison with 4D MIP images. Med. Phys. 40(11), 111709 (2013). 46 Jadon R, Pembroke CA, Hanna CL et al. A

systematic review of organ motion and image-guided strategies in external beam radiotherapy for cervical cancer. Clin. Oncol. (R. Coll. Radiol.) 26(4), 185–196 (2014). 47 Schippers JM, Lomax AJ. Emerging

technologies in proton therapy. Acta Oncol. 50(6), 838–850 (2011). 48 Nuyttens JJ, van de Pol M. The CyberKnife

radiosurgery system for lung cancer. Expert Rev. Med. Devices 9(5), 465–475 (2012). 49 Preusser T, Gunther M, Hahn HK. Preface:

detection, modeling, and compensation of organ motion and deformation-part I. Crit. Rev. Biomed. Eng. 40(2), 97–98 (2012). 50 Shah AP, Kupelian PA, Willoughby TR,

Meeks SL. Expanding the use of real-time electromagnetic tracking in radiation oncology. J. Appl. Clin. Med. Phys. 12(4), 3590 (2011). 51 Preusser T, Gunther M, Hahn HK. Preface:

detection, modeling, and compensation of organ motion and deformation – part II. Crit. Rev. Biomed. Eng. 40(3), 173 (2012). 52 Hellevik T, Martinez-Zubiaurre I.

Radiotherapy and the tumor stroma: the importance of dose and fractionation. Front. Oncol. 4, 1 (2014). 53 Shibamoto Y, Otsuka S, Iwata H, Sugie C,

Ogino H, Tomita N. Radiobiological

Future Oncol. (2014) 10(15)

evaluation of the radiation dose as used in high-precision radiotherapy: effect of prolonged delivery time and applicability of the linear-quadratic model. J. Radiat. Res. 53(1), 1–9 (2012). 54 Kavanagh BD, Timmerman R, Meyer JL.

The expanding roles of stereotactic body radiation therapy and oligofractionation: toward a new practice of radiotherapy. Front. Radiat. Ther. Oncol. 43, 370–381 (2011). 55 Williams TM, Maier A. Role of stereotactic

body radiation therapy and proton/carbon nuclei therapies. Cancer J. 19(3), 272–281 (2013). 56 Allison RR, Sibata C, Patel R. Future

radiation therapy: photons, protons and particles. Future Oncol. 9(4), 493–504 (2013). 57 Thariat J, Bolle S, Demizu Y et al. New

techniques in radiation therapy for head and neck cancer: IMRT, CyberKnife, protons, and carbon ions. Improved effectiveness and safety? Impact on survival? Anticancer Drugs 22(7), 596–606 (2011). 58 Glide-Hurst CK, Chetty IJ. Improving

radiotherapy planning, delivery accuracy, and normal tissue sparing using cutting edge technologies. J. Thorac. Dis. 6(4), 303–318 (2014). 59 Mackley HB, Reddy CA, Lee SY et al.

Intensity-modulated radiotherapy for pituitary adenomas: the preliminary report of the Cleveland Clinic experience. Int. J. Radiat. Oncol. Biol. Phys. 67(1), 232–239 (2007). 60 Jin JY, Wen N, Ren L, Glide-Hurst C,

Chetty IJ. Advances in treatment techniques: arc-based and other intensity modulated therapies. Cancer J. 17(3), 166–176 (2011). 61 Gondi V, Tolakanahalli R, Mehta MP et al.

Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear acceleratorbased intensity-modulated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 78(4), 1244–1252 (2010). 62 Kessel IL, Blanco A. Update in radiation

therapy for oral and maxillofacial tumors and dose mapping. Oral Maxillofac. Surg. Clin. North Am. 26(2), 223–229 (2014). 63 Gomez-Millan J, Fernandez JR, Medina

Carmona JA. Current status of IMRT in head and neck cancer. Rep. Pract. Oncol. Radiother. 18(6), 371–375 (2013). 64 Bezjak A, Rumble RB, Rodrigues G, Hope A,

Warde P; Members of the IMRT Indications Expert Panel. Intensity-modulated

future science group

Radiation oncology: physics advances that minimize morbidity  radiotherapy in the treatment of lung cancer. Clin. Oncol. (R. Coll. Radiol.) 24(7), 508–520 (2012). 65 Chi A, Liao Z, Nguyen NP et al. Intensity-

modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J. Thorac. Oncol. 6(6), 1132–1141 (2011).

76 Park HK, Chang JC. Review of stereotactic

radiosurgery for intramedullary spinal lesions. Korean J. Spine 10(1), 1–6 (2013). 77 Bowden PJ, See AW, Dally MJ, Bittar RG.

Stereotactic radiosurgery for brain and spine metastases. J. Clin. Neurosci. 21(5), 731–734 (2014). 78 Jiang GL. Particle therapy for cancers: a new

weapon in radiation therapy. Front. Med. 6(2), 165–172 (2012).

66 Tunceroglu A, Park JH, Balasubramanian S

et al. Dose-painted intensity modulated radiation therapy improves local control for locally advanced pancreas cancer. ISRN Oncol. 2012, 572342 (2012). 67 Hummel S, Simpson EL, Hemingway P,

Stevenson MD, Rees A. Intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation. Health Technol. Assess. 14(47), 1–10, iii–iv (2010).

79 Ogino T. Clinical evidence of particle beam

therapy (proton). Int. J. Clin. Oncol. 17(2), 79–84 (2012). 80 Purdy JA. Dose to normal tissues outside the

radiation therapy patient’s treated volume: a review of different radiation therapy techniques. Health Phys. 95(5), 666–676 (2008). 81 Shigematsu N, Shiraishi Y, Seki S, Fukada J,

Ohashi T. Clinical evidence of particle beam therapy. Int. J. Clin. Oncol. 17(2), 75–78 (2012).

68 Samuelian JM, Callister MD, Ashman JB,

Young-Fadok TM, Borad MJ, Gunderson LL. Reduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 82(5), 1981–1987 (2012).

82 Wang Z, Nabhan M, Schild SE et al.

Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int. J. Radiat. Oncol. Biol. Phys. 86(1), 18–26 (2013).

69 Padda SK, Burt BM, Trakul N, Wakelee HA.

Early-stage non-small cell lung cancer: surgery, stereotactic radiosurgery, and individualized adjuvant therapy. Semin. Oncol. 41(1), 40–56 (2014). 70 Nagata Y. Stereotactic body radiotherapy for

early stage lung cancer. Cancer Res. Treat. 45(3), 155–161 (2013). 71 Takahashi W, Yamashita H, Omori M et al.

The feasibility and efficacy of stereotactic body radiotherapy for centrally-located lung tumors. Anticancer Res. 33(11), 4959–4964 (2013). 72 Mantel F, Flentje M, Guckenberger M.

Stereotactic body radiation therapy in the re-irradiation situation – a review. Radiat. Oncol. 8, 7 (2013). 73 Lim CM, Clump DA, Heron DE, Ferris

RL. Stereotactic Body Radiotherapy (SBRT) for primary and recurrent head and neck tumors. Oral Oncol. 49(5), 401–406 (2013). 74 Siva S, Pham D, Gill S, Corcoran NM,

Foroudi F. A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma. BJU Int. 110(11 Pt B), E737–E743 (2012). 75 Klein J, Dawson LA. Hepatocellular

carcinoma radiation therapy: review of evidence and future opportunities. Int. J. Radiat. Oncol. Biol. Phys. 87(1), 22–32 (2013).

future science group

83 De Ruysscher D, Mark Lodge M, Jones B

et al. Charged particles in radiotherapy: a 5-year update of a systematic review. Radiother. Oncol. 103(1), 5–7 (2012). •

Current review of the clinical potential of charged particles.

84 Oshiro Y, Sakurai H. The use of proton-beam

therapy in the treatment of non-small-cell lung cancer. Expert Rev. Med. Devices 10(2), 239–245 (2013). 85 Efstathiou JA, Trofimov AV, Zietman AL.

Life, liberty, and the pursuit of protons: an evidence-based review of the role of particle therapy in the treatment of prostate cancer. Cancer J. 15(4), 312–318 (2009). 86 Bert C, Durante M. Motion in radiotherapy:

particle therapy. Phys. Med. Biol. 56(16), R113–R144 (2011). 87 Yu JB, Soulos PR, Herrin J et al. Proton versus

intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J. Natl Cancer Inst. 105(1), 25–32 (2013). 88 Sheets NC, Goldin GH, Meyer AM et al.

Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307(15), 1611–1620 (2012). 89 Lodge M, Pijls-Johannesma M, Stirk L,

Munro AJ, De Ruysscher D, Jefferson T. A

Review

systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer. Radiother. Oncol. 83(2), 110–122 (2007). 90 Kamada T. Clinical evidence of particle beam

therapy (carbon). Int. J. Clin. Oncol. 17(2), 85–88 (2012). 91 van Elmpt W, Zegers CM, Das M, De

Ruysscher D. Imaging techniques for tumour delineation and heterogeneity quantification of lung cancer: overview of current possibilities. J. Thorac. Dis. 6(4), 319–327 (2014). 92 Orecchia R. MRI for treatment planning: a

necessity. Eur. J. Radiol. 81(Suppl. 1), S110–S111 (2012). 93 Brancaleon L, Moseley H. Laser and

non-laser light sources for photodynamic therapy. Lasers Med. Sci. 17(3), 173–186 (2002). 94 Das S, Liu T, Jani AB et al. Comparison of

image-guided radiotherapy technologies for prostate cancer. Am. J. Clin. Oncol. doi:10.1097/COC.0b013e31827e4eb9 (2013) (Epub ahead of print). 95 Wijsman R, Kaanders JH, Oyen WJ, Bussink

J. Hypoxia and tumor metabolism in radiation oncology: targets visualized by positron emission tomography. Q. J. Nucl. Med. Mol. Imaging 57(3), 244–256 (2013). 96 Partovi S, Robbin MR, Steinbach OC et al.

Initial experience of MR/PET in a clinical cancer center. J. Magn. Reson. Imaging 39(4), 768–780 (2014). 97 Bu L, Ma X, Tu Y, Shen B, Cheng Z. Optical

image-guided cancer therapy. Curr. Pharm. Biotechnol. 14(8), 723–732 (2014). 98 Li G, Citrin D, Camphausen K et al.

Advances in 4D medical imaging and 4D radiation therapy. Technol. Cancer. Res. Treat. 7(1), 67–81 (2008). 99 Baker A, Kanofsky JR. Time-resolved studies

of singlet-oxygen emission from L1210 leukemia cells labeled with 5-(N-hexadecanoyl)amino eosin. A comparison with a one-dimensional model of singlet-oxygen diffusion and quenching. Photochem. Photobiol. 57(4), 720–727 (1993). 100 Welsh JS. Basics of particle therapy:

introduction to hadrons. Am. J. Clin. Oncol. 31(5), 493–495 (2008). 101 Tajima T. Laser acceleration and its future.

Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 86(3), 147–157 (2010). 102 Lomax AJ, Bohringer T, Bolsi A et al. Treatment

planning and verification of proton therapy using spot scanning: initial experiences. Med. Phys. 31(11), 3150–3157 (2004).

www.futuremedicine.com

2343

Review  Allison, Patel & McLawhorn 103 Yinghuai Z, Hosmane NS. Applications and

perspectives of boron-enriched nanocomposites in cancer therapy. Future Med. Chem. 5(6), 705–714 (2013). 104 Moss RL. Critical review, with an optimistic

outlook, on Boron Neutron Capture Therapy (BNCT). Appl. Radiat. Isot. 88, 2–11 (2013).

2344

105 Velikyan I. Prospective of (6)(8)Ga-

radiopharmaceutical development. Theranostics 4(1), 47–80 (2013). 106 Cornelissen B. Imaging the inside of a

tumour: a review of radionuclide imaging and theranostics targeting intracellular epitopes. J. Labelled Comp. Radiopharm. 57(4), 310–316 (2014).

Future Oncol. (2014) 10(15)

107 Waghorn PA. Radiolabelled porphyrins in

nuclear medicine. J. Labelled Comp. Radiopharm. 57(4), 304–309 (2014). 108 Teng FF, Meng X, Sun XD, Yu JM. New

strategy for monitoring targeted therapy: molecular imaging. Int. J. Nanomedicine 8, 3703–3713 (2013).

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