Clinical Indications

Proton therapy is an effective treatment choice for many cancers and tumor types. It can be precisely targeted to the tumor, causing less damage to healthy tissue compared with other radiation alternatives, and resulting in fewer short- and long-term side effects.^1-7 The primary tumors treated with protons are listed below. Research continues to report promising results in other tumors.

Proven success in treating^3,8-12:

• Prostate cancer
• Brain tumors
• Pediatric tumors
• Head and neck tumors
• Base-of-skull tumors
• Juxtaspinal cord tumors

• Non-small-cell lung cancer
• Gastrointestinal (GI) cancers
• Paranasal sinus tumors
• Arteriovenous malformations (AVM)
• Ocular (uveal) melanoma

Key criteria used to evaluate patients for proton therapy:

• Solid, localized tumors
• Proximity to critical structures or vital organs
• Intolerance to standard X-ray therapy
• Recurrent malignancy
• Potential for secondary malignancies

Prostate cancer

Proton therapy for prostate cancer offers an alternative to conformal X-ray therapy, surgery, and other treatments, and is as effective as other therapies but with a reduced risk of side effects.⁹ The ability of any radiation treatment to control prostate cancer depends on the dose of radiation delivered to the prostate. The potential for significant damage to nearby critical structures such as the bladder and rectum often limits the dose that can be delivered to the prostate. With proton therapy, higher doses of radiation can be delivered to the tumor while still largely sparing the bladder and rectum.^1,9

Compared with IMRT/X-rays, proton therapy delivers⁹:

• 35% less radiation to the bladder
• 59% less radiation to the rectum

Adapted from Vargas C, et al. Int J Radiat Oncol Biol Phys. 2008;70(3):744-751.
Gy=Gray, the standard measure of absorbed radiation; CGE=Cobalt Gray Equivalent

Vargas, et al treated 10 prostate cancer patients with proton therapy and compared the outcomes with an analysis of IMRT treatment plans for the same group. They found that 59% less radiation was delivered to the rectum than would have been delivered with IMRT.⁹ Additionally, Mendenhall, et al examined rates of GU and GI toxicity in 212 prostate cancer patients treated with proton therapy. They found that GI toxicity was associated with the percentage of the rectal wall receiving doses from 25 Gy to 80 Gy—the more radiation received by the rectal wall, the greater the toxicity. This study also found that patients treated with proton therapy had minimal early grade 3 GU and GI toxicities: <1% and <.5%, respectively.¹³

Source: ProCure Training and Development Center

These treatment plans show that proton therapy can precisely target the cancer and minimize the dose to healthy tissue. This reduces radiation exposure to the bladder and rectum, lowering the risk of side effects.^9,13 With IMRT/X-rays, more healthy tissue around the tumor receives radiation. The colored area in the rightmost image represents the extra dose to healthy tissue that IMRT/X-rays deliver compared to proton therapy.

Recently, a number of researchers studied the effectiveness of using higher doses of radiation for tumors. The 3 trials summarized in the table above all found that using higher doses for prostate cancer resulted in better control of PSA levels. The trial with the best control rate and the lowest toxicity was PROG 95-09—the only one to use proton therapy for the dose escalation.

Brain tumors

Brain tumors may arise from the meninges (the protective covering of the brain underneath the skull), the ependymal cells (the cells that form the fluid which bathes the central nervous system), the nerve sheaths, and the pituitary gland (tumors of the pituitary are technically endocrine tumors, but are managed as brain cancers). In addition to these, other types of tumors can appear in the brain, including lymphomas.

The proper management of brain tumors varies by the type and the location of the cancer. The management can involve surgery, chemo, or radiation therapy. It is fairly common to use more than one of these approaches for brain tumors, and some tumors, such as high-grade gliomas, are often treated with all three.

The fixed anatomy of the brain makes it an ideal site for treatment using proton therapy. Some of the earliest uses of protons in the treatment of cancer were for brain cancers. Doses to the non-target brain—the total brain minus the tumor area—are decreased when using protons versus IMRT/X-rays.¹⁷ This decrease in dose to normal brain tissues may result in better overall function in future years.

A treatment-planning study for small brain legions computed plans for 5 radiation techniques: 3D conformal radiotherapy, stereotactic arc therapy, intensity-modulated radiotherapy, proton therapy with spot scanning, and proton therapy with passive scanning. Proton therapy techniques were shown to be superior to all photon approaches in target dose uniformity and conformity and for sparing organs at risk.¹⁷ The dose that would be delivered to organs at risk was significantly lower for the brainstem, eyes, and the whole brain (brain minus the target and brain stem) with protons than with all other approaches.¹⁷

The brain tumors most appropriate for proton therapy include, but are not limited to¹⁸:

Source: Tarbell, Yock, Loeffler MGH-FBPTC, HMS.

Compared with X-ray/IMRT, proton therapy results in less radiation to normal brain tissue.¹⁷ Less radiation to healthy tissue lowers the risk of side effects.

Pediatric tumors

The use of proton therapy for pediatric patients is one of the most compelling. Often, these patients are treated with radiation therapy as a part of the multi-modality approach to eradicating their cancer. But treating children with radiotherapy presents a unique challenge for physicians: the age of the patients and their susceptibility to developing secondary cancers requires weighing the short-term benefits of the therapy against its long-term implications. One case study assessed the potential influence of dose distribution on the incidence of secondary cancers in a pediatric patient with medulloblastoma. The study estimated that the rate of secondary tumors would be 8 times lower with proton therapy than with IMRT (X-ray) treatment (0.05% vs 0.43%)

Source: ProCure Training and Development Center

In the treatment plans above, the colored areas indicate radiation exposure, the grey and white areas indicate no exposure, and the red area represents the tumor treated. The proton treatment plan shows the eyes, optic nerves, and normal brain are avoided completely, whereas the IMRT treatment plan shows the normal brain, eyes, and optic nerves are exposed to radiation. The colored area in the rightmost image shows the excess radiation that IMRT/X-rays deliver to the eyes and optic nerves as well as to the normal brain.

Source: Tarbell, Yock, Loeffler MGH-FBPTC, HMS.

Proton therapy is generally preferred for treating solid tumors in children because it delivers less radiation to normal tissues, which helps to prevent serious complications and causes fewer short- and long-term side effects.^3,5

The chart above shows data from a study in which Lee and colleagues analyzed treatment plans to compare dose distributions and dose-volume histograms for IMRT and proton therapy in retinoblastomas, medulloblastomas, and pelvic sarcomas of pediatric patients. For each cancer type, protons provided superior target-dose coverage and less radiation to healthy organs at risk. The authors concluded: "As dose-volume parameters are expected to correlate with acute and late toxicity, proton therapy should receive serious consideration as the preferred technique for the treatment of pediatric tumors."⁵

There are numerous adverse effects with X-ray therapy as a result of irradiating healthy tissue. Because of the proximity of the hypothalamus to the site of radiation in pediatric brain tumors, the neurohormones produced in that organ are affected. Hypothyroidism and growth hormone deficiency are often present or may be subclinical conditions.^5,19 The functions regulated by thyroid and growth hormones are particularly important in the growing child.^5,19 Hypothyroidism must be diagnosed and treated (even when subclinical) to achieve normal growth, cognition, and progression to puberty, and timely treatment of growth hormone deficiency is essential for normal linear growth.²⁰

In addition to hypothyroidism and growth hormone deficiency, seizure disorders and auditory and visual impairment after treatment have also been reported.^20,21 One study of children with medulloblastoma treated with X-rays estimated the risk of hearing loss at 13% because of radiation to the inner ear.²⁰

The radiation of healthy and still-developing brain tissue surrounding the tumor can have serious consequences. Studies estimate the average IQ loss with X-rays to be 17 points.²⁰

A treatment-planning study of 10 pediatric patients with craniopharyngioma estimated that treatment with X-rays would lower IQ approximately 10 points more than treatment with proton therapy for patients ages 5 and 9.²²

In a study of patients who had brain tumors in childhood, 18% reported one or more cardiovascular conditions, with an elevated risk of late-onset stroke and angina-like symptoms.²³ Very few late effects were evident among those treated with surgery, but risks were consistently elevated for those treated with both X-ray radiation and surgery.²³ Though surgery results in fewer late effects, used alone it can rarely completely remove the tumor. Radiation therapy is needed to kill the residual tumor cells. Proton therapy is the preferable treatment among all radiation therapy treatment options because it reduces radiation exposure to healthy tissue.

Another primary concern in treating pediatric cancer is the development of secondary malignancies. The potential for secondary malignancies is related to both the initial dose and the initial volume of irradiation used. Pediatric radiation oncologists have become especially mindful of unwanted integral doses. Patients treated with leukemia, retinoblastoma, neuroblastoma, Hodgkin’s disease, central nervous system tumors, and sarcomas are at the highest risk of developing secondary malignancies after treatment.³

Adapted from Miralbell RA, et al. Int J Radiat Oncol Biol Phys. 2002;54(3):824-829.

In a treatment-planning study of medulloblastoma patients, Miralbell, et al estimated that proton therapy lowered the risk of all secondary cancers eightfold compared with IMRT.³

Head and neck tumors

Tumors of the head and neck are treated with surgery, chemotherapy, and radiation therapy. In some instances, a combination of any or all of these treatments is used. Head and neck tumors treated with proton therapy include^2,24,25:

• Nasopharynx
• Nasal cavity and paranasal sinuses
• Tonsil, base of tongue, and other parts of the oropharynx

Depending on the site of treatment, protons may offer substantial reduction in dose-delivery to non-target structures such as the eyes, inner ear, optic nerves, and salivary glands.^2,25,26 Reducing dose to these structures may result in a lower risk of significant side effects such as blindness, hearing deterioration, and dry mouth.^25,27 The risk for secondary malignancies is also reduced.²

Adapted from Taheri-Kadkhoda Z, et al. Radiat Oncol. 2008;3:4.

The images above are from a treatment-planning study of nasopharyngeal cancer. The areas with no radiation are in grey and white; the irradiated areas are in color. In the study, proton therapy significantly reduced exposure to the spinal cord, larynx/esophagus, thyroid, and other at-risk organs.

Adapted from Taheri-Kadkhoda Z, et al. Radiat Oncol. 2008;3:4.
GyE, cobalt Gray equivalent; D. max, the absolute maximal dose in a single voxel; D. mean, mean dose.

In their treatment-planning study, Taheri-Kadkhoda Z, et al compared proton therapy and IMRT/X-rays for 8 nasopharyngeal carcinoma patients. They found that proton therapy significantly improved tumor coverage and conformation and reduced the mean dose to several organs at risk and to non-specific healthy tissue. The table above shows some of their findings.

Base-of-skull tumors

Although often slow-growing, chordomas and chondrosarcomas present complex challenges in clinical management. They often impinge upon the brain stem or spinal cord and can invade central nervous system tissue. In general, it is not possible to completely resect the tumor with adequate margins. The location also often limits the dose of standard X-ray radiation that can be delivered, and the results of conventional treatment are suboptimal. The relative ease of patient immobilization and shallow tumor depths make base-of-skull tumors amenable to treatment with proton therapy. Protons deliver a high dose while avoiding damage to healthy brain or spinal cord tissues.²⁸ The local tumor control rates for proton therapy are reported to be higher than for X-ray radiotherapy in these regions.²⁹

Noël, et al studied 51 patients with intracranial benign meningiomas in the base of the skull who were treated with a combination of photon and proton radiation therapy. Results showed excellent local tumor control and functional outcome with a low risk of treatment-related morbidity. This study demonstrated that the combination of protons and photons is a safe and effective therapeutic option for patients with benign meningioma in the base of skull.³⁰

In addition, a study of 27 patients with intracranial meningiomas concluded that proton therapy is the best choice for controlling large and complex-shaped base-of-skull meningiomas.³¹

Proton therapy has also demonstrated effectiveness in treating vestibular schwannomas with relatively few complications.³²

Source: ProCure Training and Development Center.

In the treatment plans above, the proton therapy plan shows the spinal cord receiving less radiation and the jaw receiving none at all. With the X-ray/IMRT plan, more healthy tissue receives radiation. The colored area in the rightmost image shows the excess radiation that IMRT/X-rays deliver.

Juxtaspinal cord tumors

A complete surgical resection of juxtaspinal cord tumors is generally impossible because of tumor invasion and/or adherence to the vertebrae, spinal cord, or peripheral nerve roots. The spinal cord serves as the main dose-limiting organ for standard X-ray radiotherapy. Proton therapy literally wraps the isodose distribution around the spinal cord using abutting and patched fields and keeps the dose to the spinal cord within tolerance levels while treating the target tissue with a considerably higher dose. Chordomas and blastomas are usually treated using multiple fields to get the dose wrapped around the spine.

Source: ProCure Training and Development Center.

In treating juxtaspinal tumors, proton therapy reduces radiation exposure to the lungs, limiting breathing difficulties and other side effects that commonly result from X-ray therapy. The colored regions in the rightmost image above show the excess radiation delivered by IMRT/X-rays.

Non-small-cell lung cancer

When lung cancer is caught at an early stage, it is curable in more than 50% of cases by surgically removing the tumor and possibly the entire lung. Some patients who are unable to undergo surgery are prescribed radiotherapy, with published results being inferior to those of surgical resection.³³ Several proton centers are studying the use of proton therapy for such patients in an effort to increase the dose delivered to the tumor while reducing exposure to the esophagus, spinal cord, heart, and the normal lungs. Preliminary clinical results suggest that this treatment yields good rates of local tumor control while minimizing lung injury.^34,35

Source: ProCure Training and Development Center.

When used to treat lung cancer, proton therapy reduces the radiation delivered to critical organs compared with X-ray therapy. The colored regions in the rightmost image above show the excess radiation delivered by IMRT/X-rays.

Adapted from Chang JY, et al. Int J Radiat Oncol Biol Phys. 2006:65(4):1087-1096.
Gy=standard measure of absorbed radiation; CGE=cobalt gray equivalent.

In this study by Chang, et al, proton therapy plans showed reduced radiation to the spinal cord of 66% at 66Gy and of 69% when the dose was escalated to 87.5 Gy. Proton therapy showed no radiation to the heart at 66 Gy and when the dose was escalated to 87.5 Gy.

Adapted from Chang JY, et al. Int J Radiat Oncol Biol Phys. 2006:65(4):1087-1096. Gy=standard measure of absorbed radiation; CGE=cobalt gray equivalent.

Proton therapy plans showed reduced radiation to the spinal cord of 45% at 63 Gy and of 27% when the dose was escalated to 74 Gy. Proton therapy also showed 57% less radiation to the heart at 63 Gy and 58% less at 74 Gy.

Gastrointestinal (GI) Cancers

Treatment for GI tract tumors often requires a combination of radiation therapy and either chemotherapy or surgery. The combination of these therapies can be difficult for patients to tolerate. In some cases, standard radiation isn’t a viable treatment option for patients because it would cause too much damage to critical organs adjacent to the tumor. This is not an issue with proton therapy because protons deposit more energy directly in the tumor and significantly reduce the dose to healthy tissues.¹ Patients treated with proton therapy for GI tract tumors often experience fewer side effects.^36,37

While the clinical data is not yet conclusive on the advantages of proton therapy for GI cancers, initial studies show positive results.

Proton Therapy for Esophagus Cancer

Research on the efficacy of proton therapy for esophageal cancer is ongoing, but at present only a few studies have been published. A retrospective study looked at 46 patients treated with proton therapy for locally confined esophageal cancer. The 5-year survival rate for all patient tumor locations was 34%, the 5-year local control rate for T1 patients was 83%, and the 5-year local control rate for T2 to T4 patients was 29%.³⁸ These outcomes are comparable to those seen in patients treated with surgery.³⁸

Source: ProCure Training and Development Center.

Treatment-planning studies for esophageal cancer found that the more precise dose delivered with proton therapy reduced the risk of lung complications.³⁶ The colored regions in the rightmost image above show the excess radiation delivered by IMRT/X-rays.

Proton Therapy for Hepatocellular Carcinoma

Surgery is regarded as the most effective treatment for hepatocellular carcinoma (HCC), and large HCCs are only curable with extensive hepatic resection. However, surgery is often not an option for patients with hepatic dysfunction, multiple tumors, or other illnesses.^37,39

The application of radiotherapy for tumors adjacent to the gastrointestinal tract has been restricted because the dose tolerance of the intestine is extremely low. One recent case study reported a novel two-step treatment with surgical spacer placement that allowed sufficient proton dose delivery to yield a disease-free survival of more than two years. No acute or late treatment-related toxicities of grade 2 or more were observed and liver function was unchanged for up to two years after the proton radiation.³⁸

The 3 studies in the table below looked at survival and control rates for patients with inoperable hepatocellular cancer after treatment with proton therapy.

Survival rates are influenced by the number of tumors, the level of cirrhosis, and presence of vascular invasion. In Chiba’s study, for example, the 50 patients having the least impaired hepatic function had a 5-year survival rate of 53.5%, which is comparable to rates for patients having resection.⁴¹ Fukumitsu, Kawashima, and Chiba each concluded that proton therapy is an effective alternative to previously used treatments, particularly when surgery is not an option.

Rectal and Anal Cancers

Clinical data is limited regarding the efficacy of proton irradiation in rectal and anal cancers. For more than 30 years, the standard of care for this cancer has been radiation therapy to the primary site and draining the lymphatics delivered concurrently with aggressive chemotherapy. While this is a successful regimen, the risk of significant toxicity is high.

A small comparative treatment-planning study of proton and X-ray radiation therapy indicated that proton therapy, used either as the sole modality or as a boost to X-rays, has potential advantages over conventional X-rays used alone in the treatment of inoperable patients with a large rectal cancer. The proton therapy treatment plan is more effective in sparing the small bowel, the bladder, and the femoral heads.⁴² Higher doses are possible with proton therapy and may allow for downstaging and potentially curative resection in patients with locally advanced disease.^42,43

Source: ProCure Training and Development Center.

The treatment plans above show that proton therapy results in less radiation exposure to the pelvic bone and the small bowel compared to standard X-ray therapy.

Paranasal sinus tumors

As a result of a relatively sparse lymphatic drainage system, tumors arising in the paranasal sinus are not as prone to distant metastases as tumors arising in other head and neck sites. Therefore, local control is thought to be closely coupled with survival.⁴⁴ The depth-dose precision and high-radiation-dosage control of proton therapy have a high success rate for tumors in close approximation to the visual system (optic nerves and chiasm).⁴⁵

A study was done on 91 newly diagnosed patients with locally advanced non-metastatic paranasal sinus cancer at stage III to IV based on the American Joint Committee on Cancer classification. Patients were treated with a combination of proton and photon radiotherapy. The disease-free survival rate was 59% at 3 years and 52% at 5 years.²⁴ The actuarial local control rate was 87% at 3 years and 82% at 5 years.²⁴ The overall freedom from distant metastasis was 79% at 3 years and 75% at 5 years. The study concluded that a treatment which combines proton and X-ray radiation results in improved local control for patients with locally advanced paranasal sinus cancer.²⁴

Arteriovenous malformations (AVM)

Arteriovenous malformations of the brain were among the first lesions to be treated with single-dose proton therapy. The results and complications depend on the size of the AVM and on the dose of radiation given. While the Gamma Knife and stereotactic irradiation using a linear accelerator are highly effective for smaller lesions, irregularly shaped and larger AVMs can typically be better treated with stereotactic proton radiosurgery.^12,46 Multi-modality treatment, including embolization and microsurgery, can yield cure rates of 75%, even for some very large AVMs.^47,48

Clinical evidence has shown protons to be associated with improved outcomes (the “obliteration” of the malformation) and reduced side effects when compared with X-rays in the treatment of large and inoperable AVMs.^47,48

Ocular (uveal) melanoma

Uveal melanomas (malignant tumors of the eye) are the most common eye tumor. Historically, these tumors have been treated by completely removing the eye. However, precise forms of radiation treatment have been used to treat these tumors without enucleation and with less damage to the critical structures of the globe (cornea, lens, retina, fovea, optic nerve).⁴⁹ Protons have been used to treat ocular melanoma since the mid-1970s. Clinical study results show control rates greater than 95%, with long-term survival consistent with survival rates for patients who have had their diseased eyes removed.⁴⁹ Most patients treated with proton therapy have retained useful vision in their treated eyes.^49,50 The overall data indicate that proton therapy is effective for treating small, medium, and large tumors of the eye, especially in cases where tumor thickness or location precludes adequate treatment with radioactive plaques.⁴⁹

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