Proton Beam Therapy: The Rolls Royce of Radiation Oncology

All external beam radiation therapy (EBRT) technologies use shaped beams of high-energy radiation to target and kill tumors by either causing irreparable DNA damage within the cancer cells or by disrupting the vascular supply to the growing tumor. The most common radiation technique uses high-energy x-rays, which deposits radiation dose in a path from body surface to the tumor. In most cases, the x-ray beam will continue to travel through the intended target as it deposits the remaining radiation energy in the tissues beyond the tumor.

In contrast to conventional x-ray based EBRT, PBT does not damage healthy tissues beyond the tumor as proton beams stop precisely at the back edge of the tumor due to a unique dose deposition characteristic of protons and other particle-based therapies, called the Bragg peak.  X-ray beams, do not deposit their dose at a sharply defined depth in tissue (Bragg peak), so they pass through the tumor without stopping and continue to deposit ionizing radiation into healthy tissues and organs beyond the intended target.  Dose deposition beyond the intended target is called “exit dose” and is not desired. Unlike x-ray based EBRT, PBT does not exhibit any significant exit dose.

Advances in proton therapy over the last few years have enabled some centers to adopt “pencil beam scanning” (a form of “intensity modulation”) to their proton therapy systems. These allow much higher conformality of the proton beam 3-dimensionally around the target tissues than most of the conventional “scattering” systems in use today. Read a technical discussion about the pros and cons of “scattering” versus “scanning” proton beam therapy here.

A proton beam is generated through 3 steps: 1) through hydrolysis hydrogen atoms (protons) are separated from water molecules, 2) protons are then injected into a cyclotron (a large, 90-200 ton, electromagnetic device) and 3) the protons are accelerated between two electrodes to nearly 2/3 the speed of light.

These high-energy protons are then guided into the treatment rooms through a series of electromagnets. The beams are then shaped and focused to customize the coverage of the target (i.e. tumor) while minimizing radiation dose to the surrounding tissues.

The beam can be rotated around the patient by rotating the gantry (the cylindrical treatment head which delivers the beam into the room) or by adjusting the patient’s position (enabling X-Y-Z movements and pitch, yaw and roll) with a robotic-assisted table-top.

Proton treatment centers are BIG (often 3+ stories high to accommodate the large cylindrical gantries and 4+ treatment rooms) and EXPENSIVE (approximately $200 million). Smaller proton treatment centers (1-2 treatment rooms) with more compact cyclotrons (90 tons versus 200 tons) will be the next evolutionary step for the product developers (expected in the next 5 years). The cost of these smaller facilities will be in the range of $20-40 million.

Complications and side effects rarely occur in unirradiated tissues:

Radiation-related complications rarely occur in unirradiated tissues/organs, which is why radiation oncologists take great care in minimizing high-dose radiation to non-target tissues. (The image to the right demonstrates the substantial differences in the amount of healthy brain tissue that is exposed to the risks of ionizing radiation: Right=PBT, Left=X-rays)

However, even low radiation doses can cause problems in irradiated tissues years-to-decades after completing a course of treatment. The images below shows a child who is receiving treatment for a tumor that can spread to the spinal cord tissues (medulloblastoma). The target tissues in this case are the brain and spinal tissues. In the upper image (x-rays), not only is the target tissue being treated but so is the healthy tissues in the chest (lungs, heart, esophagus), abdomen (stomach, liver, kidneys, bowel) and pelvis (bladder, rectum, reproductive organs). In the lower image (PBT), only the target tissues are being treated–sparing the child from any complications or side effects that could develop in those tissues.

The rarest (and most concerning) complication is the development of a radiation-induced cancer, but a host of other more common complications can also occur: cataracts, coronary artery disease, fibrosis and stenosis of tissues, bone growth impairment in growing children, hormonal and reproductive dysfunction, bowel and bladder functional changes, etc.

The most compelling data regarding the risks of developing a radiation-induced cancer (also known as a “secondary malignancy”) with PBT versus X-ray comes from a historical review of actual patients treated with these two modalities at Harvard. The study authors (Chung et al., International Journal of Radiation Oncology Biology Physics, 2008) reported that there was a 50% lower risk of developing a secondary malignancy among patients treated with PBT versus X-rays.

What tumors and disease sites are currently being treated with PBT?

• Brain, base of skull and spinal cord (arteriovenous malformations, brain metastases, brain tumors, meningiomas, pituitary adenomas, trigeminal neuralgia, vestibular/acoustic schwannomas/neuromas, chordomas, chondrosarcomas, etc.)
• Esophageal cancers
• Eye (uveal melanomas, pediatric orbital and ocular cancers)
• Head and neck cancers
• Liver cancers
• Lung cancers
• Lymphoma
• Pediatric cancers
• Prostate cancer
• Sarcomas

Is PBT more effective than x-ray based radiation therapy?

This remains an area of controversy, as there have been no randomized trials conducted, to date, comparing PBT to x-ray based EBRT. The data clearly indicates that when comparing individual radiation therapy treatment plans for both technologies, PBT wins in most cases. In other words, significantly higher doses can often be delivered to the tumor (using PBT) while still not exceeding the tolerance of the non-target tissues. Nevertheless, as with all new technologies, randomized trials need to be done to prove the technology is in fact an improvement over existing (less expensive) technology. As the cost for PBT becomes more affordable and the treatment facilities are scaled down in their size, there is little doubt that PBT will displace X-rays as the new mainstream technology.

What type of radiation would you rather receive…pictures speak a thousand words (examples):

In summary, the majority of PBT plans demonstrate substantially less non-target tissue radiation dose than can be achieved with X-rays.

The colorized pictures demonstrate the distribution of radiation dose. High-doses are ‘red’ and low-doses are ‘green’ or ‘blue’ (click on the images to enlarge).

Medulloblastoma (Left: X-ray, Right: PBT)

The target area is the posterior fossa (the back of the brain). The excess radiation outside of the posterior fossa is much more extensive with X-ray versus PBT treatment, thereby increasing risks and complications.

Medulloblastoma (Top: X-ray, Bottom: PBT)

Orbital Tumor (Left: X-ray, Right: PBT)

Brain Tumor (Left: PBT, Right: X-ray)

Paraspinal Tumor (Upper: PBT, Lower: X-ray)

Spinal Tumor (Left: PBT, Right, X-ray)

Prostate Cancer (Upper: PBT, Lower: X-ray)

(The dose/volume graph, below, demonstrates the dose to the rectum with prostate radiation; the ‘red’ color illustrates the excess radiation dose deposited in the rectal wall with X-rays versus PBT); University of Florida data: PBT vs. X-ray: (35% less dose to the bladder, 59% less dose to the rectum)

Esophageal Cancer (Left: PBT, Right: X-ray)

Lung Cancer (Left: X-rays, Right: PBT)

Is PBT covered by insurance?

Proton therapy is typically covered by Medicare. Most other insurers will cover proton radiation therapy on a case-by-case basis.

What is the bottom-line with PBT?

Ask your radiation oncology team if proton beam therapy is a reasonable option for you.  There are many conditions for which PBT is currently being used, but may not offer a significant advantage over other technologies that your team is recommending (i.e. brachytherapy, intensity modulated radiation therapy, electron beam therapy, etc.) Based on the details of your cancer and condition, your radiation oncology team will help direct your treatment to the appropriate technology. There are many variables that are weighed in this decision: cancer type, location of the cancer, cancer stage, patient’s overall performance status, published literature suggesting advantages with one technology vs. another, clinical trial eligibility, accessibility of technologies in the community, etc.

Unfortunately, access to proton treatment centers is limited for many patients.  It is therefore quite common for patients to seek out or be referred to proton treatment centers across the country.  The majority of proton treatment facilities have staff that can assist you with coordinating travel arrangements and housing for your appointments and treatments. Financial counselors are typically available to help you better understand the insurance and payment details of this treatment.  This is expensive treatment (i.e. 30-500% more costly than the most advanced x-ray treatment), but the costs will drop over the next few years due to: reductions in construction and machine costs, exciting research demonstrating the efficacy and safety of shorter treatment courses (i.e. 5-day prostate and lung cancer treatment regimens versus 7-9 week conventional regimens, etc.) and decreased insurance reimbursement rates.

It is incumbent on proton therapy researchers and clinicians to demonstrate the superiority of PBT over existing, less costly technologies. Efficacy data will need to prove that PBT is either more effective (i.e. better tumor control), reduces toxicity (complications and side effects) and/or improves patient-reported quality of life.  I am a strong believer that high-quality studies will eventually support these findings for many cancers.

• A multi-institutional, randomized controlled trial (for prostate cancer) is underway to explore these questions.

In December 2012, investigators published their findings of a large retrospective study in which they compared the costs, demographics, access to care and side effect outcomes among men treated with either protons or IMRT for prostate cancer. They found that the patients who received PBT were younger, healthier, and from more affluent areas than patients receiving IMRT (that’s quite typical for most patients who are treated with PBT.) The median Medicare reimbursement was $32,428 for PBT and $18,575 for IMRT. One would hope that the side effect outcomes would be twice as good if the treatment is twice as expensive. The authors found that although there was a slight improvement (3.6%) in urinary side effects 6-months after treatment with PBT versus IMRT, that improvement was no longer evident by 12-months after treatment. There was no significant difference in gastrointestinal or other side effects at 6 months or 12 months after treatment.

• Read the Wall Street Journal‘s take on this study.

Do I believe that PBT is the best radiation treatment technology for all cancers?  No. Having been fortunate enough to train at Harvard, where we had access to PBT and many other technologies, I know the advantages (there are many) and present-day limitations for this incredible modality.  There will always be a role for the less fancy (and less costly) radiation therapy options (i.e. brachytherapy, x-ray and electron-based radiation therapy, etc.), as these alternatives are readily accessible to most patients and they are supported by a long track record of efficacy and safety.

Useful Links:

• ASTRO’s 2014 Policy On The Appropriate Use Of Proton Beam Therapy (Few cancers qualify for proton beam therapy)
• Proton beam therapy and localised prostate cancer: current status and controversies (excellent review article, British Journal of Cancer, March 2013)
• Proton Beam Therapy Sparks Hospital Arms Race (Health News from NPR, May 2013)
• Prostate Cancer Therapy Too Good to Be True Explodes Health Cost (Bloomberg Businessweek, March 2012)
• The National Association For Proton Therapy (http://www.proton-therapy.org)
• Wikipedia (http://www.en.wikipedia.org/wiki/proton_therapy)
• Proton Bob (http://www.protonbob.com)
• IBA Proton Therapy (http://www.iba-protontherapy.com)
• ProCure (http://www.procure.com)
• Proton Therapy Cooperative Group (http://ptcog.web.psi.ch)
• It Costs More, but Is It Worth More? (January 2012, Opinionator, New York Times)