S.R. acknowledges grant funding from the NIH Loan Repayment Program. A.H. has received funding from Bayer, Clovis, Constellation, Agensys, Sotio, Cerulean, and Calithera.&#160;

A.H. has honoraria from Astrazeneca, Bayer, and Novartis. A.H. has consulted with Astrazeneca, Bristol-Myers Squibb, and Bayer and was a speaker for the France Foundation.

Radiation treatment planning and delivery for cancer is a highly customized process personalized to each individual patient and his/her particular cancer. Modern radiation treatment is an image-guided intervention-based CT images obtained during a customized radiation planning simulation. CT imaging is mandatory since it contains 3-dimensional (3D) anatomic information about the patient as well as precise quantification of the tissue densities at different locations within the body that are required for dose calculation. During CT imaging, the patient is positioned on a motorized table. Several mechanical immobilization devices are typically employed to restrict patient movement during imaging and during subsequent RT delivery. Depending on the required precision, these devices range from simple mold-type cushions and plastic meshes, which conform to the patient surface and then harden to restrict motion, to more invasive devices such as rigid skull devices that are drilled in place. Oftentimes, the required precision of the immobilization device is dictated by the proximity of the tumor tissue to nearby critical structures. As an example, the most invasive immobilization device, a head halo drilled into place, is sometimes used when single millimeter precision is needed to treat a tumor near the eyes or optic nerves to minimize the chance of blindness that may occur from the patient moving into an incorrect position during treatment.
CT imaging information is also used to optimize internal normal tissue anatomy. For example, bladder distention is often utilized to minimize bladder and small bowel dose exposure from irradiation of the prostate as noted in the protocol above. Similarly, if the stomach is notably distended with food during simulation for upper abdominal irradiation (for instance, gastric, liver, distal esophagus), then the patient is re-simulated after allowing the food to pass through the stomach and intestinal tract. This will shrink the stomach and reduce the chance of radiation exposure during radiotherapy of upper abdominal tumors. In cases where the stomach or bladder themselves are radiation targets, they may be intentionally distended or emptied to optimize dose distribution.
In some instances, a tumor is not adequately or reliably visualized on CT but may be identified more accurately by an MRI or a PET scan. In such cases, the PET or MRI scans are used to complement CT data since the latter is still required for dose calculation. This is achieved by registering the MRI and PET images to CT images for planning therapy. MRI scans often provide much greater visual contrast and higher resolution than CT, which may be beneficial to identify thin, soft-tissue boundaries of a tumor such as those in the brain or liver. PET provides a functional view of the distribution of radioactive-labeled tracer molecules injected into the patient.
Some tumors arise in areas of the thorax or abdomen where they may move significantly with respiration. In order to account for this motion to ensure radiation accuracy, a 4-dimensional CT, a type of &#34;movie-mode&#34; CT imaging, may be used to capture the 3D patient anatomy as it changes over time during respiration. For some thoracic and abdominal targets, compression belts or other means of motion mitigation may be used during therapy to restrict motion and limit uncertainty regarding tumor location45.
Once the patient is simulated for treatment, a personalized treatment plan is developed with consideration of the cancer histology, tumor location, and anatomic features, which influence the optimal configuration of radiation beams, particle types, energies, and dose levels for each individual patient. For each patient, a number of basic questions are initially considered by the clinical team to develop an optimal treatment plan. As a starting point, the most appropriate form of radiation must be selected. Options include photons, electrons, or protons. This is typically followed by the selection of beam angle(s) for radiation delivery. Most RT machines include a robotic patient positioning table and a rotating gantry that allow RT beams to be directed into the patient by virtually any angle. The decision involves finding the path that most effectively strikes the target with RT and best avoids non-targets that may be in the path of the selected beams. In some cases, beam angles are determined by the planning system itself after inputting in radiation goals for tumors and normal tissues. This process is termed &#34;inverse planning&#34; and is often done in the case of IMRT, which involves modulating the intensity of multiple, incoming radiation beams in a time-dependent manner that provides a uniform target dose but may lead to highly non-uniform dose outside the target. Although both photon or proton therapy may be intensity modulated, inverse planning is utilized largely in photon based IMRT only. If solid radiation beams are to be used, custom metal collimators may be fabricated to match the shape of the radiation beam with the shape of the tumor.
If proton therapy is selected, then a subsequent decision needs to be made regarding the use of passive scatter or PBS techniques. In the case of PBS, an additional decision is required regarding the use of MFO or single-field optimization/single-field uniform dose (SFO/SFUD) strategies. In MFO treatments, multiple beams are required to treat a tumor during every fraction since each beam only targets a portion of the target. In contrast, for SFO plans, every beam covers the entire target. MFO is often favored for tumors near to a critical structure (e.g., brain tumor near the optic nerve) where a variety of beam angles may be advantageous to sculpt radiation dose. MFO strategies also ensure that all the radiation beams/spots do not &#34;end range&#34; into the same area where dose could be unexpectedly high due to the Bragg Peak effect. On the other hand, SFO is favored for targets near areas of anatomic uncertainty, such as the prostate which can move due to differential bladder and rectal filling. SFO provides enhanced robustness against dose changes due to anatomic variances.
Once the basic planning strategy is decided, the next phase of treatment planning typically involves mathematical optimization of the radiation fields. The energy, intensity, and spatial distribution (spatially varying flux) of incoming radiation are typically free parameters in optimization. Along with the large 3D matrix representation of the patient anatomy by CT, these free variables lead to a very large problem size and corresponding large optimization matrices (e.g., thousands of CT values and thousands of possible beam intensities must be considered). These matrices are framed in an Objective Function, which is a mathematical formulation of the &#34;goal of treatment planning&#34;. As mentioned above, treatment goals are prioritized to first achieve the prescribed dose to the target, and secondly to achieve as low of a dose as is possible to normal tissues. To minimize this Objective Function, high computing power is desired to quickly perform RT transport calculations that populate the matrices, and numerical optimization methods, such as gradient-search algorithms, are used to quickly search for local minima in the function. These minima correspond to optimal treatment plans for each unique patient. The role of computers in treatment planning cannot be overstated. Modern radiation treatment and diagnostic radiology would not be possible without the computer advancements of the past three decades.
As a final stage, the optimized treatment plan is reviewed by the medical team (physician, dosimetrist, and physicist). In many cases, the plan may be adapted further or re-optimized with differing objectives to improve overall quality. Once the plan is found to be optimal, the technical parameters of the plan are reviewed by a physicist and transferred to the treatment delivery machine.
In many cases, the patient returns for multiple treatment fractions (sessions), often every weekday for several weeks. Multi-day fractionation can intensify acute radiation-induced side effects but may reduce potential late, more severe side effects of RT compared with single-fraction treatment12. Multi-fraction approaches are optimal for tumors that are rapidly dividing or unable to repair sublethal damage from RT. However, this depends on the exact treatment site and the sensitivity of the nearby normal tissues. Since the goal of radiation treatment delivery is to administer the same treatment during each fraction, even a few millimeters of motion or uncertainty in the patient position may lead to the degradation of the particle therapy treatment plan. For this reason, on-board image guidance systems are of paramount importance during multifraction RT. X-ray imagers, cone beam CT scans, or optical, laser-scanning surface imagers are all available for this purpose. These devices permit image-guided radiotherapy (IGRT) through the imaging of anatomical landmarks, tumor targets, or surrogate radio-opaque fiducial markers. The IGRT images are compared to the original simulation scans and adjusted as necessary prior to each fraction of radiation.
Despite the advantage of the finite range of proton therapy, which limits the exit dose, the precision of range prediction typically seen in treatment planning is on the order of a few millimeters. The exact energy loss in different patient tissues is uncertain, firstly, since the exact molecular components of the tissue are ambiguous, and, secondly, since the patient anatomy changes over time, both over short timescales (e.g., breathing) and longer timescales (e.g., weight loss, tumor shrinkage, normal anatomy changes). To address this uncertainty, a &#34;distal margin&#34; is added to the target volume that is an additional margin of normal tissue just beyond the maximum tumor depth. Such a margin ensures that even with the uncertainties in range prediction, the entire tumor depth will be treated with high confidence. Unfortunately, the normal tissue margin can as a result be exposed to the full RT dose, which can potentially lead to significant RT side effects in that tissue. In contrast, as photons do not stop but rather exit the target, no such distal margin is needed to compensate range uncertainty. A geometric margin is still used in photon therapy to address positional uncertainties of the target, but photons are much less sensitive than protons to the precise status of patient tissues upstream of the target. Therefore, the needed margin can sometimes be smaller for photons than protons. This can be understood by considering that protons undergo continuous energy loss in tissues that greatly affect the position of their range, whereas photons are uncharged and travel freely in the empty space between atoms and their orbitals, except for rare collisions with electrons or nuclei. Large density differences in tissue, e.g., metallic objects or air cavities, however, still influence photon dose as well as proton dose, but to a lower magnitude.
A final and important uncertainty pertains to the radiobiological effectiveness (RBE) of different forms of radiation. The RBE is the ratio of doses, from a reference radiation type and a test radiation type, under the condition that both radiation types produce the same biological effect. The higher the RBE, the more damaging the radiation per unit of energy deposition in tissue. The RBE ratio is defined in reference to photon radiation. Despite this straightforward description, there is actually great uncertainty regarding the RBE values for charged particles as opposed to photons. Differences in the spatial dose distributions between photons and charged particles at the micrometer and nanometer scale lead to differences in biologic effect, even when the macroscopic doses are identical. This can be understood by examining the spatial patterns of DNA damage after exposure to charged particles at different doses and different kinetic energies. Different kinetic energies and different charges of protons (+1) and carbon ions (+6) lead to the differences in energy transfer at different depths in the patient, whereas for photons, the energy transfer is comparably lower and also more homogeneous throughout the patient. While theoretically understood, there is significant debate in the radiation oncology community regarding the ability to accurately predict such biologic effects. For carbon ion therapy, there is a lack of consensus on how best to model these biologic effects, though there is agreement that such effects must be modeled to provide therapy. For protons, most clinical centers currently plan therapy without explicit modeling of RBE effects, except for using a constant correction factor of 1.1, but this is likely to change in the near future as new commercial treatment planning systems are beginning to include biological modeling software tools to model the RBE of proton therapy.
With the completion of randomized trials, including RADCOMP, PARTIQoL and RTOG 1308, we should have more concrete answers as to which forms of radiation may be superior for breast, prostate, and lung cancer, respectively. Similar studies are planned for other disease sites that may help to better identify the best treatment modality for those tumor types. However, there is already sufficient data to suggest the superiority of protons in certain settings, particularly in the pediatric population, where substantial normal tissue sparing can greatly reduce morbidity from toxicities, including secondary malignancies.

It is estimated that 1.7 million individuals in the United States will be diagnosed with cancer in 2018, with over 600,000 succumbing to the disease1. Current treatment options involve mono- or multi-modality therapy using surgery, radiation therapy (RT), and systemic treatments. With respect to RT, one-quarter of newly diagnosed patients will receive it as part of their initial cancer therapy and almost half will ultimately require it during their disease course2,3.
The advent of RT dates back to 1895 when William Conrad Roentgen discovered X-ray while working with a cathode-ray tube in his laboratory at W&#252;rzberg University in Germany4. Not long after, patients with wide ranging diseases such as lupus and cancer were receiving treatments using radium rays. Early complications were quickly realized and were even discussed by Pierre Curie in his Nobel Prize lecture5. Since radiation affects both normal and tumor tissues, carefully controlled doses of radiation must be utilized to maximize the therapeutic ratio, defined as the probability of tumor control versus the probability of unacceptable toxicity. With gradual advancements in technology, as well as better understanding of radiobiology and physics, this therapeutic ratio has greatly improved with time. The use of RT has significantly enhanced outcomes for several cancers, as reflected by its inclusion in national guidelines for cancer therapy6,7,8,9. In some cases, RT may be used as the sole modality for therapy10, whereas in other diseases, it may be used as part of multi-modality therapy for local disease control or the eradication of microscopic disease11. Although often used with a curative intent, many RT patients are treated for palliation of pain or other symptoms that develop from tumor-induced compression, invasion, or destruction of normal tissues in the setting of loco-regional or widespread, metastatic disease.
The basic principles behind RT are straightforward. With the application of radiation, energy is deposited into cells through the ionization of atoms. This energy, though it may raise the temperature of an irradiated region by only a few microkelvin, produces free radicals that can directly damage exposed cells by way of DNA injury12,13. Much of our understanding of high-energy particle radiation and its interaction with matter comes from theoretical and experimental studies of cosmic rays and their interactions in the upper atmosphere carried out in the early 20th century14. High-energy (MeV to GeV) charged particles interact with matter primarily via the electromagnetic force: as these particles pass through matter or tissue, inelastic collisions with orbital electrons lead to ionization and excitation of target matter, and elastic collisions with atomic nuclei lead to scatter or deflection of the particle path. In addition, nuclear collisions and hard collisions with electrons lead to a cascade of secondary radiation that adds to the ionizing effect of particle radiation. High-energy particles traversing matter thus leave behind a wake of ionized atoms, molecules, and free electrons that are chemically reactive and can potentially induce biologic changes or damage to organisms exposed to these ionizing fields.
A major long-term goal of radiotherapy has been to learn how best to harness these ionizing fields in a manner that will effectively treat human disease. Clinically, the ideal form of radiation (such as photon, proton, electron, or heavy ion) should induce sufficient ionization in the disease target to provide therapeutic anti-tumor effect, while at the same time cause minimal ionization in the surrounding normal tissues to minimize deleterious effects. Which type of radiation is selected for RT depends in part on the disease being treated. For tumors that are located deeper within the body and may also be surgically inoperable, megavolt photons, protons, and heavy ions are considered optimal15,16. For superficial cancers, such as those involving the skin, electron therapy may be optimal and even preferable to surgery for cosmesis. On the other hand, the advantage of megavolt photons lies in their ability to penetrate deep in the tissue while limiting damage to the skin. In the case of charged particles, such as electrons, protons, or heavy ions, their primary advantage lies in their &#39;stopping&#39; characteristics; that is, charged particles lose energy continuously via the inelastic collisions described above, and this energy loss is highly predictable on the millimeter scale. Therefore, a charged particle beam can be delivered to a patient with precise energies to desired depths. Further, charged particles produce little to no exit dose17. By contrast, uncharged particles like photons exhibit an exponential falloff (attenuation) with increasing depth, which often leads to a significant exit dose that may compromise healthy tissues distal to the target. These concepts are demonstrated in Figure 1, which shows the radiation dose (ionization) properties of the various types of radiation used clinically. A central motivation for using protons or carbon ions instead of photons for deeper tumor targets is that there is minimal dose entry dose and near zero exit dose beyond target tissues. Table 1 summarizes some of the clinically relevant characteristics of photon and proton beams.
Advances in the field of radiotherapy, including proton therapy, have occurred on two major fronts: 1) the building of efficient particle accelerators capable of producing high-energy (MeV) radiation such as synchrotron and cyclotron accelerators, and 2) the development of sophisticated computational methods that combine disease imaging data and radiation transport calculations to allow computer-simulated &#34;treatment planning.&#34; For treatment planning, patients typically undergo computed tomography (CT) imaging. The CT images contain 3-dimensional anatomic information about the patient as well as precise quantification of the tissue densities. The CT images and density maps are then used in computer simulations to plan the radiation treatment: both the energy and intensity of the radiation field are mathematically optimized for each patient. A magnetic resonance imaging (MRI) scan or a positron-emission tomography (PET) scan may also be used to complement the CT data.
Below, we describe a step-by-step outline of how patients are navigated through their radiation treatment course, followed by the examples of certain tumor types treated with proton therapy.

<table>
	<tbody>
		<tr>
			<td>Proton beam cyclotron and gantry delivery system</td>
			<td>Varian</td>
			<td>N/A</td>
			<td>Allows for generation and delivery of protons for radiotherapy</td>
		</tr>
		<tr>
			<td>kVUE One Proton Couch Top</td>
			<td>Qfix</td>
			<td>RT-4551KV-03</td>
			<td>Permits patient placement for radiotherapy</td>
		</tr>
		<tr>
			<td>CT simulator with 4D scanning capability</td>
			<td>GE</td>
			<td>N/A</td>
			<td>Permits CT simulation for radiation planning</td>
		</tr>
		<tr>
			<td>100&#34; x 70&#34; Qfix VacQfix Cushion</td>
			<td>Qfix</td>
			<td>RT-4517-10070F30</td>
			<td>Immobilizes patient for more precise radiation delivery</td>
		</tr>
		<tr>
			<td>Timo Foam Head Support</td>
			<td>Qfix</td>
			<td>RT-4490-F</td>
			<td>Ensures minimization of head motion during radiotherapy</td>
		</tr>
		<tr>
			<td>3 CT Localizers Localization Markers</td>
			<td>Beekley Medical</td>
			<td>REF 211</td>
			<td>Ensures concordance of external markers and internal patient anatomy from CT simulation</td>
		</tr>
		<tr>
			<td>VacQfix Indexer</td>
			<td>Qfix</td>
			<td>RT-4517-IND01</td>
			<td>Ensures VacQfix cushion placement is reproducible for every radiatiion treatment</td>
		</tr>
		<tr>
			<td>Radiation treatment planning software</td>
			<td>Raystation</td>
			<td>N/A</td>
			<td>Allows for personalized radiation planning for every tumor with robust optimization and multi-criteria optimization</td>
		</tr>
		<tr>
			<td>Proton Range Compensator</td>
			<td>.Decimal</td>
			<td>RC-AC 1018</td>
			<td>Adjusts the range of the proton beam to achieve distal dose conformality</td>
		</tr>
		<tr>
			<td>Proton Beam Aperture</td>
			<td>.Decimal</td>
			<td>AP-BR 1800</td>
			<td>Shapes the proton beam treatment area</td>
		</tr>
		<tr>
			<td>Proton Range Shifter</td>
			<td>.Decimal</td>
			<td>RS-AC 1018</td>
			<td>Adjusts proton beam tissue depth penetration</td>
		</tr>
		<tr>
			<td>Endorectal Balloon</td>
			<td>Radiadyne</td>
			<td>ILG-90F</td>
			<td>Ensures uniform rectal filling and prostate positioning</td>
		</tr>
	</tbody>
</table>

proton therapy delivery and its clinical application in select solid tumor malignancies

Radiation therapy is a frequently used modality for the treatment of solid cancers. Although the mechanisms of cell kill are similar for all forms of radiation, the in vivo properties of photon and proton beams differ greatly and maybe exploited to optimize clinical outcomes. In particular, proton particles lose energy in a predictable manner as they pass through the body. This property is used clinically to control the depth at which the proton beam is terminated, and to limit radiation dose beyond the target region. This strategy can allow for substantial reductions in radiation dose to normal tissues located just beyond a tumor target. However, the degradation of proton energy in the body remains highly sensitive to tissue density. As a consequence, any changes in tissue density during the course of treatment may significantly alter proton dosimetry. Such changes may occur through alterations in body weight, respiration, or bowel filling/gas, and may result in unfavorable dose deposition. In this manuscript, we provide a detailed method for the delivery of proton therapy using both passive scatter and pencil beam scanning techniques for prostate cancer. Although the described procedure directly pertains to prostate cancer patients, the method may be adapted and applied for the treatment of virtually all solid tumors. Our aim is to equip readers with a better understanding of proton therapy delivery and outcomes in order to facilitate the appropriate integration of this modality during cancer therapy.

Available data suggests a substantial benefit with proton therapy for certain cancers20,21. PT may be favored for select pediatric tumors, recurrent cancers in previously irradiated regions, or other cancers where the risk of normal tissue injury is high with photon treatment. Below, we discuss the application and benefit of proton therapy for prostate, breast and medulloblastoma. Our aim is to provide readers with a better understanding of the application of proton therapy for tumors common in men, women, and children.
In the United States, prostate cancer is the most commonly diagnosed malignancy in men and the second most common cause of cancer-related death among men. An estimated 164,690 new cases will be diagnosed in 2018, and over 29,000 men will die of the disease. Non-metastatic prostate cancer patients are eligible for treatment options, including active surveillance, radical prostatectomy, brachytherapy and external beam radiation with photons or protons22. Exact treatment decisions are made depending on patient anatomy, comorbidities, tumor stage, physician judgment and patient preference.
Radiation delivery for early stage prostate cancer is limited to the prostate gland. In the case of intermediate risk prostate cancer, the proximal seminal vesicles are targeted as well. Although partial prostate therapies are being explored, whole gland therapy remains the standard of care. Obturator, pre-sacral, internal iliac, and external iliac nodes are often included for patients with unfavorable intermediate and high-risk disease.
Prior to radiation treatment planning, fiducial markers may be placed to permit image-guided treatment using pre-treatment kilovoltage imaging (i.e., standard X-rays)23. In addition, a hydrogel spacer may also be inserted prior to CT simulation to create a gap between the rectum and prostate to further limit dose to the rectal tissues24,25. During treatment planning, patients should be simulated in the supine position with the pelvis immobilized using a customized cushion device. A rectal balloon may be placed at CT simulation to limit both prostate motion and uncertainty regarding rectal volume and density26. A comfortably full bladder is recommended to limit dose to the small bowel and the anterior portion of the bladder27. MRI simulation is also advised to permit more accurate target volume delineation26.
Treatments should be designed to deliver doses of 75.6 - 79.2 Gy to the prostate, with doses of 45 - 50.4 Gy recommended for elective coverage of nodal or seminal vesicle regions at risk of microscopic disease spread9. All fractions are delivered once daily in 1.8 to 2 Gy per fraction. For intermediate and high-risk patients receiving a brachytherapy boost, the external beam radiation dose should be limited to approximately 45 Gy. Brachytherapy doses of 110 Gy should be used with I-125 low dose rate permanent implants. With high dose rate brachytherapy delivered via catheters, commonly used boost regimens include 13 to 15 Gy x 1 fraction, 8 to 11.5 Gy x 2 fractions, 5.5 to 6.5 Gy x 3 fractions, and 4.0 to 6.0 Gy x 4 fractions9.
Treatment planning dosimetry is optimized to limit dose to the bladder, rectum and bowel. Dosimetric comparisons between photon- versus proton- based therapy (i.e., IMRT versus IMPT techniques) have demonstrated improved sparing of doses to normal tissues with the latter approach28.
Prostate cancer specific mortality is under 2% at 10 years for men with early stage disease22 regardless of the treatment selected. With dose-intensified RT, high risk patients also show a low prostate cancer specific mortality of 5% at 9 years29. Mortality remains low largely due to the availability of systemic therapies that remain effective in the metastatic setting. Results with both IMRT and proton therapy remain excellent30,31. The PARTIQoL (NCT01617161) study is an ongoing, randomized study between proton beam therapy (PBT) and IMRT for low and intermediate risk prostate cancer which will hopefully determine if one modality is superior over the other.
Breast cancer is the most commonly diagnosed malignancy in women and the second most common cause of cancer-related death among U.S. women. An estimated 268,670 new cases will be diagnosed in 2018, and 41,400 women will die of the disease1. Unlike in prostate cancer where most patients receive radiation as monotherapy, breast cancer patients receive radiation postoperatively to reduce the risk of cancer recurrence11. Depending of the extent of surgery required, radiation may be targeted to the remaining breast after tumor lumpectomy or to the chest wall after mastectomy11,32. Regional lymph nodes in the axilla, supraclavicular and internal mammary areas may be targeted if they are deemed at risk for tumor spread.
Treatment schedules for breast patients typically entail once daily treatment, five days per week. Early stage patients are generally treated with conventionally fractionated (1.8-2.0 Gy/fraction; 50 Gy total) or hypofractionated (2.67 Gy/fraction; 40.05-42.56 Gy total) regimens to the whole breast11,33. Patients with more advanced, but localized disease are treated with conventional fractionation to 50 Gy (1.8-2.0 Gy/fraction) to the whole breast or chest wall and regional lymph nodes. These doses are effective for subclinical disease which may be present following surgery.
CT simulation for breast cancer radiotherapy is typically completed in the supine position. In contrast to prostate cancer, both arms are abducted overhead to permit exposure of the chest wall or breast tissue. In addition, a customized cradling device and breast-board are often utilized to immobilize the thorax in a raised position so that the manubrium is parallel to the treatment table. This ensures that the breast tissue does not fall superiorly to the neck area.
Radiation exposure to the heart during breast cancer is associated with an increased risk of future ischemic disease34. As a result, techniques for minimizing heart doses are of paramount importance. One approach is to employ deep-inspiratory breath hold (DIBH) to increase the intrathoracic space and the distance between the heart and anterior chest wall/breast. As the method implies, patients treated with DIBH will suspend their respiratory cycle and receive treatment at the maximum point of inspiration. However, not all patients are able to tolerate breath holds of sufficient duration to permit this technique. In some patients, a prone position may be advantageous and may permit breast tissue to hang away from critical normal tissues, including the heart35. A drawback of this approach is the limitation it places on the ability to target lymphatics regions. Proton therapy can achieve substantial cardiac dose sparing without the need of DIBH and prone techniques36,37.
Proton therapy is employed for breast cancer patients and has been demonstrated to be superior to photon-based techniques with respect to dose sparing effects on critical structures such as the lungs and heart38. A single field pencil beam scanning (PBS) plan with a range shifter may be utilized to administer proton radiation to the chest wall and regional nodes. Passive scatter approaches may also be employed. If multiple fields are required in order to treat the entire chest wall and regional nodes due to field limitations, then field matching techniques must be employed. One strategy is to employ matching supraclavicular and chest wall fields matched with a skin gap of 2-4 mm below the clavicular head39. The field borders are moved over a 1 cm distance at different time points during the radiation course to minimize hot and cold spots.
Clinical results with breast cancer radiation demonstrate an overall survival of 50% for early stage disease11 and 37% for locally advanced patients at 20 years follow-up32. Given the long remission period, minimization of treatment related toxicity is of great concern. Although proton therapy is expected to potentially lower cardiac toxicity risks, this question is being examined in the ongoing RADCOMP Consortium Trial (NCT02603341), which is randomizing women with breast cancer to photon or proton radiotherapy.
Cancer remains the second most common cause of death in children aged 1 - 14 in the United States and is only surpassed by accidents. In 2018, 10,590 children will be diagnosed with cancer, and 1,180 will die of their malignancy1. Among this group, 250-500 patients will be diagnosed with medulloblastoma. The median age at diagnosis of medulloblastoma is 4 - 6 years. Given the high risk for cerebrospinal fluid involvement and dissemination (30-40%), craniospinal irradiation (CSI) is standard of care in these patients, with approximately 80% surviving with appropriate treatment.
Medulloblastoma patients are stratified into standard-risk and high-risk groups based on their age, presence of anaplasia or metastases, and amount of residual tumor after surgical resection. In either case, treatment includes postoperative radiation. RT for medulloblastoma involves initial CSI to a dose of 23.4 - 36 Gy. Additional dose is then given to the tumor bed to achieve a dose of 50.4 - 55.8 Gy to the primary tumor site40. Treatment planning considerations include the limitation of the maximum doses to the brainstem and spinal cord to 54 Gy and 45 Gy, respectively. CSI can be delivered using photon or proton therapy. CT simulation and treatment often require anesthesia to ensure that the patients do not move during treatment41.
Due to the large areas targeted with radiation, photon-based RT techniques result in substantial irradiation exposure to thoracic and abdominal structures anterior to the spinal cord, including the lungs, heart, kidneys bowel, and breast. These regions may be spared from excess radiation with proton therapy (Figure 3)42. PT based CSI requires two slightly oblique lateral fields to irradiate the upper cervical spine and brain, as well as one or more posterior-anterior beams targeted to the lower cervical, thoracic, lumbar, and sacral spine regions. Multiple fields are required since the target CTV for CSI includes the entire cerebrospinal fluid (CSF) space extending from the brain vertex to the spinal canal through the cauda equina at the level of the S2/S3 vertebral junction (Figure 3). The spine length determines the total number of spinal fields required for treatment. The superior border of the uppermost spinal field is matched to the inferior border of the cranial fields. If the spine field cannot cover the entire spine, then a second spinal field is matched to the inferior border of the upper spinal field. This process may be repeated if a third field is required for taller patients. For patients below age 15, the anterior border of the spine fields is extended to include the entire vertebral bodies to ensure a homogeneous dose to bone required to prevent future growth abnormalities in the developing skeleton. For those over age 15, the anterior spine field border is extended 2-3 mm beyond the spinal canal into the spinal column.
Both passive scatter and PBS techniques have been utilized for CSI42,43. Specific goals of CSI therapy include homogeneous radiation dose to the cerebrospinal fluid (CSF) to the lower end of the thecal sac (S2 or S3), full dose to the anterior skull base and cribriform plate, minimization of dose to optic structures, limitation of thyroid to no more than 5% of the prescription dose, and minimization of dose to the esophagus43.
Passive scatter treatment planning typically begins with the creation of cranial fields. Range compensators with manual editing are often required to create a homogeneous dose distribution in the brain while limiting dose to the eyes and cochlea. For spinal fields, compensators are thickened at the thyroid level to minimize dose. Special attention is then paid to field junctions between the cranial and spinal fields and between multiple spinal fields when required. The junction area is defined as the 1.25-1.5 cm length where the fields adjoin. The junction is shifted in the cranial or caudal direction weekly to prevent development of hot or cold dose areas. Ideally, dose variance is kept between 95-108% of the prescription dose. Field weighting, aperture edits, and compensator edits are all employed to achieve this goal43.
Researchers at M.D. Anderson Cancer Center have developed a step-wise strategy for CSI planning42. This approach involves the development of an MFO plan to treat the cranial and lower spine fields followed by the creation of an SFO plan for the thoracic spine. Dose gradients are utilized at junction areas. The SFO plan is then copied into the initial MFO plan to develop a final, composite MFO plan. Spine junctions are shifted once by 2 cm over a 4-week course of treatment. In comparison to passive scatter CSI, PBS based CSI offers substantial reductions in radiation dose to the lenses, cochlea and parotid glands but at the cost of increased thyroid dose42.
Medulloblastoma patients can expect event free survival rates of 60-80% depending on the risk strata44. Given the large area of irradiated tissue with CSI, and the sensitive nature of pediatric patients, long-term side effect risks are considerable and include neurocognitive impairment, secondary malignancies, pituitary dysfunction, hearing loss, heart disease, infertility, hypothyroidism, vasculopathy, dry eyes, cataract formation, vision loss, and radiation necrosis/myelitis. Therefore, proton-based CSI may offer a substantial benefit for many patients.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58372/58372fig1.jpg" /> 
Figure 1: Depth dose curves for radiotherapy. Dose distributions as a function of depth in water shown for various clinical radiation beams. <a href="https://www.jove.com/files/ftp_upload/58372/58372fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/58372/58372fig2.jpg" /> 
Figure 2: Comparison of proton and photon breast radiation. Percent dose distribution for a patient with locally advanced breast cancer receiving radiation therapy with either IMRT (A, B) or Protons (C, D) and demonstrating substantial radiation dose reduction to the heart and lungs with protons. <a href="https://www.jove.com/files/ftp_upload/58372/58372fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/58372/58372fig3.jpg" /> 
Figure 3: Comparison of proton and photon craniospinal radiation. Percent dose distribution for a patient with medulloblastoma receiving craniospinal irradiation using either Protons (A) or IMRT (B) and demonstrating substantial radiation dose reduction to intra-thoracic and intra-abdominal regions with protons. <a href="https://www.jove.com/files/ftp_upload/58372/58372fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td></td>
			<td>Photon</td>
			<td>Proton</td>
		</tr>
		<tr>
			<td>Particle Type</td>
			<td>Boson</td>
			<td>Composite Fermion</td>
		</tr>
		<tr>
			<td>Charge [C]</td>
			<td>0</td>
			<td>+1.602 x 10-19</td>
		</tr>
		<tr>
			<td>Mass [kg]</td>
			<td>0</td>
			<td>1.672 x 10-27</td>
		</tr>
		<tr>
			<td>Spin</td>
			<td>1</td>
			<td>1/2</td>
		</tr>
		<tr>
			<td>Energy&#8224; [MeV]</td>
			<td>0.1 - 25</td>
			<td>10 - 250</td>
		</tr>
		<tr>
			<td>Common Sources</td>
			<td>Linear Accelerator, Co-60 Radioisotopes, X-ray Tube</td>
			<td>Cyclotron or Synchrotron Accelerator</td>
		</tr>
		<tr>
			<td>Delivery Methods</td>
			<td>Collimated Solid Beams, Multileaf Collimators, Intensity Modulation, Arcs</td>
			<td>Passive Scattering, Magnetic Scanning</td>
		</tr>
		<tr>
			<td colspan="2">&#8224; Energy range typically used to treat human cancers</td>
			<td></td>
		</tr>
	</tbody>
</table>
Table 1: Comparison of proton and photon radiation.

Watch this Scientific Journal Video about Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies at JoVE.com

Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies

The fundamentals of radiation planning and delivery for proton therapy using prostate cancer as a model are presented. The application of these principles to other selected disease sites highlights how proton radiotherapy may enhance clinical outcomes for cancer patients.

Radiation therapy is a frequently used modality for the treatment of solid cancers. Although the mechanisms of cell kill are similar for all forms of ...

It is important to understand the potential, and evolving role, of proton radiation therapy for treating certain cancers over the more traditional photon radiation therapy. An important challenge is to identify and understand the cancer disease states that may be particularly suitable for and benefit from proton radiation therapy. As with other forms of external beam radiation therapy, proton therapy is delivered in a non-invasive fashion, using an external robotic device that moves around the patient.The location that the proton therapy beam terminates within the body can be controlled with a high degree of precision. Making it ideal for tumors adjacent to critical healthy organs. Before beginning the simulation, insert the extended table top into the treatment table and insure that it is locked.Place an inflated immobilization cushion over the table top and the indexing bar for the leg mold at that level of the patient's knee. Place a solid head rest at the top of the table and confirm that the patient has completed the full bladder process by drinking 16 to 24 ounces of fluid 45 minutes prior to the scheduled scan time. After registering the patient into the computed tomography, or CT Patient Registration System, select the prostate scanning protocol with a slice thickness of three millimeters.Ask the patient to sit on the table and assist the patient into a supine, headfirst position. Place the patients legs into the inflated immobilization cushion so that the mold will envelope the side of the legs and create a barrier between the legs and position the patient's arms on the chest. Confirm the patient alignment with the laser system and connect the dual vacuum pump to the nozzle of the immobilization cushion.Once the patient is in a maintainable position, use the Qfix dual vacuum pump remove the air from the immobilization cushion to form a solid mold around their legs and feet. Manually adjust the treatment table so that the laser crosshairs are at the level of the hips and at the midline of the hips and abdomen at the level of the hip joint. Use a marking pen to indicate the locations of the crosshairs and place localization markers onto the marks to designate a starting point for the verification simulation during the radiation delivery.Set the appropriate CT scanning parameters to include the pelvic region from the L3 spine to the mid femur. Then scan the patient using the prostate scanning protocol, and export the digital scan file to the treatment planning software before notifying the symmetry. For radiation treatment planning, use the treatment planning system contouring tools to define all of the relevant geometric volumes based on the acquired CT images.Contour the first clinical target volume, or CTV1 to include the prostate, seminal vesicles, and involved lymph nodes. The CTV1 will be prescribed 45 grays and will have the appearance of a U-shaped structure on the axial images. The small bowel, rectum, and bladder normal tissues will reside within the U-shaped target volume.Contour the CTV2 to include the prostate and seminal vesicles. The CTV2 will be prescribed a total dose of 34.2 grays. Select three beams at gantry angles of 90, 180, and 270 degrees for the treatment of the CTV1 volume.And select only the 90 and 270 degree beam angles for the CTV2 treatment. Measure to confirm the accuracy of the planned dose using ionization chamber arrays and to verify the accuracy of the dose calculation using a secondary independent dose calculation software. If the plans and dose distributions meet the accepted dose constraint guidelines and robustness, obtain physician approval before exporting all of the treatment planning data to the treatment delivery system for the patient treatment.On the day of the treatment arrange the treatment room to reproduce the patient setup used during the CT simulation. Insure that the immobilization cushion label matches the patient ID and place the cushion on the treatment table with the correct indexing and with the appropriate headrest at the head of the table. Confirm that the patient has completed the full bladder process and escort the patient into the treatment room.Help the patient into the supine position onto the treatment table with hands clasped across the chest and the legs in the immobilization cushion. Electronically move the treatment table from the load position toward the isocenter to align the patient to the marks that were placed during simulation. Adjusting the table to correct any gross errors in the patient positioning as necessary.Once the patient is properly aligned to the simulation marks, complete the shifts from the start position, to those determined during the dosimetric treatment planning process, to align the patient to the desired treatment isocenter. Perform orthogonal kilovoltage imaging to insure proper internal patient alignment to the pelvic bones and fiducial markers previously placed by urology within the prostate. Overlay the acquired kilovoltage images on digitally reconstructed radiographs from the planning CT simulation scan to determine if positional adjustments are required and apply any necessary shifts to insure alignment.If the kilovolt images demonstrate excessive bowel gas, ask the patient to expel the air while lying on the treatment table if possible and realign and reimage. Once acceptable kilovoltage images are acquired and confirmed, perform a cone beam ct scan to assess bladder and rectal filling applying additional patient positioning adjustments based on the scan as necessary. Then initiate the treatment delivery with audible verification between two therapists of gantry angle, monitor units, number of scanning spots and layers, and snow position for each treatment angle, marking the treatment isocenter for daily alignment and removing the marks after the treatment.Due to the large areas targeted during breast cancer radiation, photon based radiation treatment techniques result in substantial irradiation exposure to thoracic structures, including the lungs, heart, and contralateral breast. These regions may be spared from excess radiation with proton therapy. Multiple irradiation fields are required for photon therapy-based craniospinal irradiation.Since the target CTV for craniospinal irradiation includes the entire cerebrospinal fluid space, extending from the brain vertex, to the spinal canal, through the cauna equida at the level of the S2, S3 vertebral junction. The benefit of using proton therapy for craniospinal treatment, is that the therapy substantially limits the radiation dose to the thoracic abdominal structures anterior to the spinal cord, compared to the area of the dosage experienced with photon based therapy, for the same time of tumor treatment. It is important that every patient is placed in a comfortable position during the CT simulation.So that the same position can be reproduced for every radiation session. Proton therapy can be thoroughly improved by taking advantage of the unique radiobiological properties of protons such as changes in linear energy transfer, or combining protons with other treatment modalities. Challenges include selecting the patients who would most benefit from proton therapy and how to utilize protons to deliver four column more nerve sparing prostate cancer treatment.

Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies

Abstract