Photons, protons, carbon ions and boron: The pros and cons of external-beam cancer radiotherapy


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Radiotherapy is an important method for treating a variety of cancers, and new approaches in radiation oncology have the potential to provide significant benefits to patients.

In 2020, more than 18 million people were diagnosed with cancer worldwide, and by 2040, the number of new cases annually is expected to surge to 28 million. For the patients who are diagnosed with any form of the disease, access to safe and effective treatment options will define their lives.

Alongside surgery, chemotherapy, immuno-oncology therapies and other modalities, radiation therapy is among the options available.

Radiation oncology holds a special and lasting place in the treatment of cancer, and is delivered to about half of cancer patients globally. Indeed, approximately one-third of cancer survivors in the United States have had some form of radiation during their treatment. And even as the number of therapeutic options increase, radiation oncology is poised to play a prominent role in cancer care in the future.

Given recent approvals and the expansion of radiation modalities, it’s natural to wonder how they compare and what benefits they hold. Like all medicines, there are pros and cons to the different radiotherapy modalities that patients and caregivers need to consider.

Photon Radiotherapy

Photon beam therapy is among the most widely used cancer radiotherapies and is used to treat tumors of the lung, breast and prostate, and others. Radiation oncologists use linear accelerators (LINAC) to deliver X-rays. These beams cause catastrophic damage to the DNA within the cells that they target, leading to cancer cell death.

An attractive feature of photon beam therapy is the relative cost of the hardware. With an average device price tag of $2 million, photon therapy is an affordable option for many hospitals and clinics.

For patients, these weightless packets of elemental energy have two significant downsides. For one, treatment typically requires dozens of sessions, or fractions, sometimes upwards of 40. The numerous visits to hospitals over many weeks are extremely taxing and disruptive to patients, who often must arrange and pay for travel costs and take leave from work. The number of sessions necessary to deliver the required dose also has a negative impact on the efficiency of health care systems to provide dozens of treatments per patient when millions are diagnosed annually with various forms of cancer.

Another drawback of photon beam therapy is that photons don’t discriminate between healthy and cancerous tissue. Photons pass through the body and don’t stop inside the tumor. Doctors can direct photon beams away from healthy tissues and organs with advanced beam targeting, but damage to healthy tissue is nearly unavoidable.

“With photon radiation, we can minimize, but are not always able to eliminate the radiation dose that a neighboring organ receives,” said Dr. Hani Halabi, a radiation oncologist in Atlanta. The negative impacts, Halabi said, “will not be zero.”

Proton Beam Therapy

Unlike photon beams, proton beam therapy (PBT) delivers maximum radiation doses at or near a tumor site. Because proton beams release their energy payload at discrete locations, there is reduced entry dose and no exit dose. This can improve the ability to focus the radiation dose on the tumor, limit damage to surrounding cells and reduce patient side effects.

Unfortunately, PBT shares a negative characteristic with photons in that a typical course regularly involves many fractions — about 30 on average.

Clinically, PBT offers similar outcomes to photon therapy because the biologically effective dose (BED) — the dose that the targeted tissue receives — is the same for both modalities. A 2023 study published in the journal Frontiers in Oncology found no discernible difference between photon radiation therapy and proton radiation therapy in clinical outcomes of notable cancers, including prostate, breast, lung and esophageal. Rather, the biggest advantage of proton beam therapy was a “decrease in certain radiation-induced side effects,” the researchers wrote.

Despite the benefits of PBT, access to the modality in the U.S. is limited. The National Association of Proton Therapy, an advocacy organization, lists just 44 proton therapy centers currently in operation. By comparison, there are more than 3,500 LINACs across the country.

The reason for the mismatch is simple. Some PBT installations can cost up to $40 million, 20-times the cost of a photon delivery machine.

Still, certain indications require the precision offered by proton therapy. These include childhood cancers and tumors adjacent to the spinal cord, eyes and brain.

Carbon Ion Radiation Therapy

The beams in carbon ion radiation therapy (CIRT) differ from the X-rays that are used in photon radiation therapy in several important ways. For one, X-rays release energy as they travel, which can cause significant damage to healthy cells along their path. By contrast, ions are delivered in bursts of energy and can be steered and deposited, reducing risks of collateral damage.

Carbon ion radiation therapy and proton beam therapy are similar in that they deposit their dose at the Bragg peak, which marks the end of a particle’s journey through tissue. The Bragg peak illustrates the energy distribution of ionizing radiation. Notably, there is little to no exit dose with these modalities because their particles eventually come to a stop, sparing normal tissue, says Smith Apisarnthanarax, an associate professor of radiation oncology at the University of Washington, in Seattle.

What separates carbon ion therapy from proton beam therapy, however, is that CIRT has a higher linear energy transfer, or LET, compared to proton PBT. High-LET radiation deposits the energy from a single particle over a shorter path length, compared to radiation with lower LET. This causes damage that is more localized and more complex, for example, in the form of double-strand breaks to DNA that are difficult for cells to repair. The result is that carbon ion radiation therapy has a higher “relative biologic effectiveness,” or RBE, compared to proton beam therapy, meaning that each application of CIRT kills more cancer cells, particularly those that have developed resistance to conventional X-rays.

Carbon ion radiation therapy was developed in the U.S. and pioneered for clinical use in Japan. There are currently 13 CIRT centers worldwide, including in Germany, Austria, Italy, Japan and China. In March 2020, the Mayo Clinic announced plans to build the first carbon ion therapy facility in North America; it expects to start treating patients in 2027.

Despite the promise CIRT has shown in treating stubborn cancers, cost is again an important factor. For instance, it is reported that Mayo Clinic will spend an estimated $233 million for its facility, half of which could be on the CIRT device itself.

Boron Neutron Capture Therapy

Together with carbon ion radiation therapy, boron neutron capture therapy (BNCT) represents the next generation of targeted cancer treatment.

BNCT works by delivering boron medicines, typically by intravenous administration. These medicines are designed to selectively accumulate in tumor cells by targeting receptors that are overexpressed in cancer cells compared to normal cells. When irradiated with epithermal, safe neutrons, the boron in the drug is converted to lithium and releases an alpha particle that only travels the distance of the cell. This results in unparalleled targeting of radiation to cancer cells at the microscopic, rather than macroscopic level. Even diffuse or un-visualized tumors or cancer cells can in principle be treated with BNCT, while sparing nearby sensitive healthy tissues.

There are other key differentiators that set BNCT apart from the other radiation oncology modalities, however. The first is patient comfort and convenience. Unlike most cancer therapies that can require dozens of treatments to see results, BNCT has proven effective in just one or two sessions. Shorter treatment cycles are a benefit to patients and also to the overall healthcare system, as fewer treatments result in overall cost savings.

That said, the investment necessary to develop a BNCT facility remains a challenge for many hospitals and medical centers. Establishing a BNCT facility — either within an existing hospital facility or in a new one built for that purpose — is an investment that typically requires multiple levels of approval within hospital purchasing systems. This reality, combined with the investigational status of BNCT outside Japan, has limited BNCT’s adoption to medical centers with access to significant capital budgets and requires visionary leadership to make the investment in BNCT.

“As an effective cancer modality, BNCT is reaching clinical maturity, and we are seeing growing interest from medical centers in the U.S. and abroad to make this treatment more widely available,” said Aviko CEO Dave Greenwald. Aviko is committed to creating “an ecosystem to advance this promising, lifesaving treatment,” Greenwald said.

Conclusion

There’s no single arrow in the cancer care quiver. As the rate of cancer diagnoses grows, the best option is having a complete set of tools. Indeed, combination is a cornerstone of cancer therapy.

Even similar modalities may have a place in the same treatment plan. As one recent study by scientists at the National Institute of Nuclear Physics in Italy noted, mixing BNCT and CIRT to treat head and neck tumors shows great potential. As the researchers wrote, “combining the advantages of two types of particle therapy may enlarge the pool of patients accessing therapeutic options when no other strategies are available.”

It will take bold vision and collaboration between physicians, medical physicists, hospital administrators, regulators and payors to bring the full suite of radiation oncology tools to patients. We are proud to be a part of this important endeavor.