Radiation’s New Era in Oncology

After more than 125 years of medical use, the most amazing, effective, and precise use of radiation might lie just ahead. Despite radiation’s birth as a rather crude therapeutic tool, it could soon evolve into one of the most accurate forms of cancer treatment. Tomorrow’s—and even some of today’s—medical applications of radiation promise to precisely destroy cancers of many sorts. This is especially true of a class of treatments called radioligand therapies or radiopharmaceuticals that deliver a tiny dose of radiation directly to a tumor.

In the late 1890s, two key discoveries set radiation in motion in medicine. First, in 1895, as German physicist Wilhelm Conrad Röntgen experimented with the fluorescence generated in vacuum tubes, he accidentally discovered X-rays. Just five months later, French physician François-Victor Despeignes used X-rays to treat a man’s stomach cancer. Although the treatment appeared promising, the patient passed away 20 days after the treatment began. A couple years after that, though, two Swedish physicians, Tor Stenbeck and Tage Sjögren, reported curing skin cancer with X-ray therapy. X-rays, though, would not be the only kind of radiation aimed at cancer. Second, in 1898, Marie and Pierre Curie discovered radium, which is a radioactive element that emits a trio of radiation types: alpha particles, which are combinations of two protons and two neutrons; beta particles, which are free electrons or positrons; and electromagnetic gamma radiation. In just a few years, physicians around the world were treating cancer patients with radium, at least when this rare and expensive element could be obtained.

Early in the development of radiation therapies, physicians applied it externally and internally. Externally applied X-rays created challenges in aiming the radiation at the cancer as accurately as possible, and controlling a patient’s dose of radiation proved even more difficult. Early on, some radiologists tested doses on their own arms, adjusting the radiation to create a sunburn-like spot.

In the earliest internal applications of radiation, a physician placed a radioactive source such as radium inside a patient’s body, putting the treatment as close to a tumor as possible, preferably in direct contact with the disease. This became known as curietherapy in honor of Marie and Pierre.

Almost as soon as scientists discovered that radiation could battle cancer, they also learned that it could cause cancer and other diseases. After decades of working with radioactive materials, for example, Marie Curie developed aplastic anemia, which causes low levels of red and white blood cells, as well as platelets.

From the moment scientists realized the yin and yang of radiation—its ability to both heal and injure—they pursued ways to use radiation to eliminate diseased tissue, usually a tumor, as effectively as possible while minimizing the damage to healthy tissue and organs. In a perfect scenario, an oncologist would deliver radiation directly to cancerous cells and only to those cells.

Basics of radiopharmaceuticals

In a way, radiopharmaceuticals resemble laser-guided missiles. To deploy such a missile, a laser paints a target, a guidance system controls the missile’s pathway to the target, and a payload destroys the target. With radiopharmaceuticals, the biology of cancer paints a tumor. To do this, something on, or in some cases near, a tumor must distinguish it from healthy cells. This marker is often a protein on the surface of a cancer cell. The radiopharmaceutical then needs a way to find that marker. Last, the radiation emitted from a radioactive element damages the DNA of nearby cells, which kills them.

Thus, three pieces make up a radiopharmaceutical agent. First, a molecule binds the tumor target. Second, a radioactive payload, like the radioisotope lutetium-177, emits the radiation. Third, a piece connects the targeting molecule with the payload.

Most of today’s payloads, including lutetium-177, are beta-emitters. As these payloads go through the natural process of radioactive decay, they emit beta particles that can travel a few millimeters in a person. This limits the destruction of cells in close proximity to the targeted cancer cells. It’s a precision attack on the disease.

To create an even more precise kill zone, a radiopharmaceutical can be designed to include an alpha-emitter. It’s radiation only extends about 100 micrometers from the target. Consequently, an alpha-emitter’s attack is even more precise than one that relies on beta-emitting radionuclides.

Most of today’s targeted cancer treatments rely on blocking a molecular pathway to damage or kill cancer cells. With such an approach, “you have to worry about whether or not the cancer cell will be susceptible to what you’re delivering,” said Jake Van Naarden, leader of Indianapolis-based Eli Lilly’s oncology business unit. “No forms of life on the planet survive high doses of locally delivered radiation.” So, most targeted cancer therapies depend fundamentally on the biology of a patient’s cancer, but not radiopharmaceuticals. As long as a radionuclide reaches a tumor, the treatment will kill those cells. Crucially, this feature makes radiopharmaceuticals agnostic to a tumor’s type, which promises to make these therapies effective across a wide range of solid cancers.

“The reason that most cancer drugs fail is because it turned out you were wrong about whether or not the disease cared about that thing you were doing—that’s biology,” said Van Naarden. With radiopharmaceuticals, though, “if you can find proteins on the cancer cell or even around the cancer cell that have enough expression and are similarly not expressed in healthy tissues, then you can design a ligand that can get there and stay there long enough to deposit all the radioactive energy.”

In addition to being cancer treatments, radiopharmaceuticals play key roles in a broader application called theranostics, which is a combination of therapy and diagnostics. Before treatment, a patient receives a diagnostic radiopharmaceutical, which is like the therapeutic one, except the radionuclide is replaced with one that produces emissions for imaging, not treatment. Then, an imaging technique—usually positron emission tomography (PET) or single photon emission computed tomography (SPECT)—shows how much of the intended target is in a patient’s tumors. If there’s enough, a patient can receive the therapeutic radiopharmaceutical. A therapeutic radionuclide that destroys tumor cells also emits signals that can be captured with SPECT imaging. This allows a radiopharmaceutical to “be traced in the body as well, so that a scan shortly after the administration of a radiopharmaceutical can confirm if it really reached the target,” said Nathalie Albert, MD, a neuro-oncologist at the University Hospital of the Ludwig-Maximilians-Universität München in Germany.

So, radiopharmaceuticals provide many uses. “You can first select patients who are likely to respond and also monitor whether the radiopharmaceutical indeed reached its target in the tumor in sufficient concentration and how long it stays there,” Albert said. “Further, follow-up scans can reveal changes in a tumor, such as a decrease in radionuclide uptake or tumor size.”

Approved drugs

Even though the devastatingly accurate and effective capabilities of radiopharmaceuticals sound futuristic, some of these treatments are already available. “This field was sort of left on the sidelines for about 20 years, but new technology—more sophisticated designs in the piece of the drug that actually binds the target and in the isotopes that attach to that ligand—revitalized it,” said Van Naarden.

Consequently, these improvements spawned the approval of new radiopharmaceuticals. One of these drugs is Lu-177 dotatate, which targets the somatostatin receptor (SSTR) seen on the surface of various types of cancer cells. In Lu-177 dotatate, an octreotate protein (TATE) binds SSTR and dodecane tetraacetic acid (DOTA) links TATE to the lutetium-177. In 2017, the European Medicines Agency (EMA) approved Lu-177 dotatate for the treatment of SSTR-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETS).

Another recently developed radionuclide, Lu-177-PSMA-617, binds to the prostate-specific membrane antigen (PSMA) on cancerous prostate cells. In 2022, the U.S. Food and Drug Administration (FDA) approved Lu-177-PSMA-617 for the treatment of patients whose prostate cancer resists traditional chemotherapeutic treatments.

As Rahul Aggarwal, MD, a medical oncologist at the University of California San Francisco, noted, “We’re using a lot of radioligand therapy to treat our patients who have metastatic prostate cancer.”

The pretreatment scan reveals whether Lu-177-PSMA-617 is likely to help a patient and even by how much. “There’s good data that the higher the uptake of the drug shown on a scan, the higher odds that a patient is likely to respond,” Aggarwal said. “It’s not a perfect correlation, but it does a pretty good job of selecting patients that are most likely to benefit with the treatment.”

Any treatment involving radioactivity, though, comes with precautions. As Aggarwal pointed out, “Patients have to be given a pretty long list of guidance to follow for a week to 10 days after each dose, in terms of how to safely be at home or around others within the treatment facility.”

Some promising evidence also exists for the use of radiopharmaceuticals against other cancers, especially meningiomas, which are the most common brain cancers in adults. If a meningioma recurs after surgical resection and standard radiation treatments, “these patients have limited treatment options,” said Albert. But these tumors express high levels of a type of SSTR that can be targeted with Lu-177 dotatate. Based on retrospective data, said Albert, such a treatment appears to reduce the odds of a meningioma advancing in more than half of the patients. Nonetheless, Albert is conducting the prospective LUMEN-1 clinical trial to confirm the value of this radionuclide in patients with meningiomas.

Exploring alpha-emitters

To further fine-tune the targeting of radiopharmaceuticals, some pharmaceutical companies are developing alpha-emitting treatments. “Alpha particle–based therapeutics are very promising due to their high cytotoxic effect to kill cancer cells while limiting toxicity to nearby healthy cells,” said Arnaud Lesegretain, CEO at Orano Med, which is headquartered in Paris. “They deliver about 100 times higher energy than beta-emitters, causing complex, often irreparable double-strand DNA breaks in tumor cells, thereby preventing cellular repair mechanisms and the emergence of resistance in tumor cells.”

Based on this mechanism of action, Lesegretain called alpha-emitters “the most powerful payloads to be found for targeted therapies, with fewer than five particles needed to kill a cancer cell versus hundreds of beta-emitting isotopes or thousands of chemotherapy toxins.”

Alpha-emitters also produce lower levels of toxicity. “While beta particles travel more than 50 cell layers, affecting both cancerous and healthy tissues, alpha particles have a very short emission range by traveling only two to five cell layers,” Lesegretain said. “This very short range of emission also makes alpha-emitters particularly suitable for the treatment of micro-metastases, which are difficult to target with other molecules.”

In particular, Lesegretain and his colleagues are developing radioligand therapies with lead-212. This alpha-emitter offers some key benefits. “Its half-life of 11 hours strikes an optimal balance,” Lesegretain said. “That is long enough for effective treatment while allowing outpatient administration and avoiding extended hospitalization.” Plus, decay of lead-212 emits just one alpha particle. As Lesegretain noted, “that limits the circulation of free radioactive isotopes and minimizes toxicity to healthy organs.”

One of Orano Med’s radioligand therapies in development is AlphaMedix, which targets the same cancer cells as Lu-177 dotatate, but with an alpha-emitter rather than a beta-emitter. In a Phase II clinical trial, this radionuclide reduced the size of tumors in more than half of the patients.

Other pharmaceutical companies are also developing treatments based on other alpha emitters. For example, RayzeBio, a Bristol Myers Squibb company based in San Diego, California, is the only company currently studying the actinium-255 isotope in Phase III trials. RayzeBio’s development program includes cancers that express SSTR, like GEP-NETS, small-cell lung cancer, and breast cancer, in addition to a more recent clinical study targeting glypican-3, which is a protein involved in some kidney cancers.

Expanding the options

In the future, radiopharmaceuticals will target cancer in even more ways. For example, Van Naarden mentioned targeting unique molecules like fibroblast activated protein (FAP) that exist at high levels in tissues that surround tumors, but not in other tissues. Eli Lilly scientists have designed an FAP ligand that could be linked to radioactive lutetium to possibly treat any form of solid tumor.

Although an ideal treatment for tumors remains elusive, today’s radiopharmaceuticals are closer than ever. Over the past 15 years or so, “there have been many advances in radioligand therapy, and it’s a highly dynamic field,” said Albert. “I’m absolutely convinced that it’s going to be a very, very important part of precision oncology over the next decade.”

Mike May is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhD in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American, and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.