Radiopharmaceuticals Transforming the Field of Oncology

Would you take a drug, knowing there was a risk of developing secondary cancer, for a chance to beat the cancer you have now? This gamble is a difficult reality thousands of people face each year when they don’t respond favorably to conventional cancer treatments.

Nicole DiCamillo became one of these patients after being diagnosed with a gastroenteropancreatic neuroendocrine tumor (GEP-NET) in 2004. Receiving the news just after the birth of her first son, Nicole was terrified to hear she wouldn’t live past 30, a mere three years away. “I was being told that I wouldn’t see my son lose his first tooth, go to kindergarten, and grow up and graduate,” Nicole lamented in an interview [1].

She tried a long list of standard treatments, but still suffered from debilitating stomach and intestinal issues that greatly reduced her quality of life. Out of options, Nicole was finally given the radioactive drug Lutathera, also known as Lutetium Lu177 Dotatate, through a compassionate use program that granted this experimental drug as a last resort. This therapy is designed to deliver radiation directly to the tumor in order to kill it. For Nicole, however, the drug came with high risks for harmful side effects and lacked FDA approval at the time. Despite the uncertainty, the gamble paid off: the tumors shrank, her chronic pain diminished significantly, and she could return to her everyday life. 

An Old, Yet Innovative Design

The key to Lutathera’s success lies in the drug's unique targeting capabilities. Standard treatments like external radiation target large areas of the body to hit tumors with enough energy to eliminate them. This leads to collateral damage of healthy tissues, however, and an increased risk of secondary cancer from excessive radiation exposure [2]. Furthermore, the cancer could metastasize, or spread to other areas of the body, leaving many small deposits of cancer cells that are even harder to hit precisely. To figure out a better targeting mechanism, scientists looked to existing technology for an answer.

Nuclear imaging techniques, such as positron emission tomography (PET) scans, have been around for decades. They work by tracing signals from weakly radioactive compounds attached to targeting molecules that are introduced into the body. These targeting molecules are chosen for their greater attraction to tumors’ unique characteristics, such as abnormal growth or an increased number of cell surface receptors, in comparison to normal cells. As a result, the weak radioactive compound will accumulate around any tumors and show up during imaging. Researchers then wondered whether these targeting molecules could instead carry radioactive isotopes to kill cancer cells. This inquiry inspired the fundamental design of most radiopharmaceuticals: a radioactive molecule and a targeting molecule specific to one cell type, joined together by a linker [2].

The targeting molecule of a radiopharmaceutical is generally unique to a given cell type. Like a key to a lock, the targeting molecule is created to match to a specific target in tumor cells. For drugs treating GEP-NETs like Nicole’s, the targeting molecule is called dotatate, which binds to receptors expressed only on the surface of neuroendocrine cells [3]. With this mechanism, the drug will only bind to neuroendocrine cells, especially the cancerous ones which typically overexpress cell surface proteins due to rapid tumor growth. 

The real disease fighting component of the drug is the radioactive isotope. Because the isotope is linked to the targeting molecule, the two components travel together to the target tissues. In the case of GEP-NET treatment, dotatate is linked to the radioactive isotope lutetium 177 [3]. The isotope emits radiation as it decays, the released energy disrupting chemical bonds and damaging the DNA in nearby cells. Thus, when the fully constructed radiopharmaceutical compound attaches itself to cancerous cells, the radiation kills the latter [2]. Ideally, the emitted radiation doesn’t travel far outside the cancerous tissue, sparing other healthy tissues in the body. 

This basic template can create many unique radiopharmaceuticals using different sets of the three main components. These can be used to treat a wide range of cancers such as leukemia, melanoma, lung cancer, and colorectal cancer. As long as the tumor has some targetable characteristics along with a good blood supply to deliver the drug, it could be treated with radiopharmaceuticals [2].

The Power of Radioisotopes

Not all radioactive isotopes can be used to make radiopharmaceuticals, however. The radioactive isotope needs to both reach the cancerous cell and remain there long enough to kill an effective number of cells [2]. At the moment, a select few radioactive isotopes that undergo beta decay and emit beta particles are the most well-researched. Their ability to penetrate through surfaces and ionizing energy are intermediate compared to other forms of radiation. This makes it a “goldilocks” treatment with just enough spread and ionizing energy to effectively fight tumors without excessive side effects. 

In fact, the radioactive isotope most commonly used for GEP-NET treatment is the aforementioned beta emitter lutetium-177 in Lutathera. The Food and Drug Administration (FDA) finally approved this drug in 2018 for adult patients with advanced GEP-NETs based on two successful clinical studies. The first compared the efficacy of Lutathera plus octreotide, a clinic standard treatment that Nicole also tried, to octreotide alone. The researchers found that those treated with Lutathera and octreotide experienced significantly longer cancer progression-free survival [3]. The other study measured tumor response to Lutathera and demonstrated complete or partial tumor shrinkage in a favorable 16% of the patients [3]. These results were revolutionary for a cancer with such “limited treatment options after initial therapy fails to keep the cancer from growing,” remarked Richard Pazdur, M.D., who is the director of the FDA’s Oncology Center of Excellence and Office of Hematology and Oncology Products [4].

But this life-saving drug doesn’t come without some drawbacks. In general, any radiation exposure can damage and kill healthy tissue. This can cause a number of symptoms, from lethargy or hair loss to anaphylaxis or extreme hormone imbalances [5]. Additionally, the more radiation delivered to the body in attempts to treat ongoing cancer, the higher the probability of developing another cancer later in life [5]. For Lutathera in particular, the most serious side effects observed are development of blood or bone marrow cancers and permanent damage to organs like the kidney and liver [3]. While adverse effects of this extreme degree are not common, patients must consider all possibilities when weighing risks and benefits.

Luckily, there are radiopharmaceuticals in development that have the potential to outcompete beta-emitters in efficacy and safety. Radioisotopes that undergo alpha decay will emit alpha particles. These particles have higher ionizing power with lower penetrating power, or a shorter range, than beta emitters. This combination would allow for greater ability to kill cancer cells with a lesser degree of harm to nearby healthy tissue. 

Dr. François Bénard, professor of radiology at the University of British Columbia and scientist at the B.C. Cancer Research Institute, compares conventional beta-emitter therapy to “throwing golf balls inside a glass house: they can travel quite a distance and cause various bits of damage along the way.” On the other hand, targeted alpha therapy “is like throwing a bowling ball. So it will cause a lot more damage, but in a much more limited area,” remarked Dr. Bénard [6].

Currently, the use of alpha-emitters in cancer therapy is rare compared to other treatments. The scarcity of emitters and a lack of sufficient research means the FDA has approved very few alpha-emitter radiopharmaceuticals. One notable exception is radium-223 dichloride for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. The general concept of the radiopharmaceutical remains the same. Radium-223 dichloride is designed to mimic calcium, so it is drawn to bone growth in the body [7]. This allows the drug to selectively target and irradiate bone metastases. The landmark study that helped the drug get FDA approval demonstrated radium-223 dichloride significantly increased overall survival and quality of life for patients. Similar promising results are seen in a number of studies across a variety of alpha-particles. More research needs to be done before alpha-emitter therapy can become mainstream, but these early successes just go to show the immense power both alpha and beta-emitters hold. With the countless ways these radioactive compounds can be created and utilized, radiopharmaceuticals might just be the future of oncology.

Future Directions

Nicole’s success story is one of many that sparked strong research interest in radiopharmaceuticals, and a growing number of studies have demonstrated high efficacy and safety with these drugs. Radiopharmaceuticals could be the best solution to treating cancers where long-used treatments like surgery or chemotherapy fail, but a lot of work needs to be done before we reach that point.

There are currently many barriers to radiopharmaceuticals development and access. The research in this field is relatively new, with most studies on drug effectiveness and safety only in the earliest stages. Furthermore, given these drugs’ novelty, many healthcare systems are unprepared for the integration of radioisotope therapy into standard clinical care, in part because they lack professionals trained to administer them [8]. There is also a lack of qualified professionals to create the drug on top of the already extremely high costs of drug production.

Most importantly, many patients may be wary of radiopharmaceuticals because of negative preconceptions around radioactive substances [8]. This is why spreading awareness in the community about radiopharmaceuticals is so important. There is a lot of risk to this gamble, but there is also a lot of hope, hope that many people might not have had otherwise. The remarkable science behind radiopharmaceuticals has potential to beat the toughest cancers, just as it did for Nicole DiCamillo, who survived more than 10 years past her initial projected survival date.

“Lutathera has changed my life. I never take days off work. I coach my son’s soccer team. I watch my kids’ concerts. I spent a whole day enjoying the rides with my family at Universal Studios. I couldn’t even have dreamed of doing these things before Lutathera. It is the best thing that has happened for me and for my family.” -Nicole DiCamillo [1]

About the Author: Lillian Ji

Lillian Ji is a fourth year Biological Sciences major and Sociology minor at UC Davis. She is passionate about healthcare and improving the human experience with medicine. Lillian dedicates her time to volunteering with children as a Outreach, Research, and Education Director for RIVER Club and as an intern for RIVER Pediatric Clinic. In her free time, she enjoys playing Clarinet as part of UC Davis’ Video Game Orchestra Club, reading exciting stories, and supporting local artists.

Author's Note

My first introduction to radiopharmaceuticals through shadowing sparked an ever growing interest in the field’s potential. But with my limited expertise, I found the concepts difficult to understand. When I was assigned a popular science article assignment in my UWP 104E class with Dr. Katie Rodger, I took it as an opportunity to explore the topic at my own pace. Now I hope to share exciting insights into this revolutionary drug with others in an accessible way.

References

1. American Association for Cancer Research. Nicole DiCamillo: Living Family Life to the Full Thanks to Lutathera. AACR Cancer Progress Report; American Association for Cancer Research (AACR). Accessed February 26, 2025. Available from: https://cancerprogressreport.aacr.org/report/survivor-journeys/cpr18-survivors-decamillo/#:~:text=I%20was%20diagnosed%20with%20cancer,better%20than%20I%20ever%20have.
2. National Cancer Institute. 2020. Radiopharmaceuticals: Radiation Therapy Enters the Molecular Age. Accessed February 26, 2025. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2020/radiopharmaceuticals-cancer-radiation-therapy.
3. National Cancer Institute. 2018. FDA Approves New Treatment for Certain Neuroendocrine Tumors. Accessed February 26, 2025. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2018/lutathera-fda-gastrointestinal-nets.
4. United States Food and Drug Administration. 2018. FDA approves new treatment for certain digestive tract cancers. Accessed February 26, 2025. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-certain-digestive-tract-cancers.
5. Centers for Disease Control and Prevention. Facts About Nuclear Medicine. Accessed: February 26, 2025. Available from: https://www.cdc.gov/radiation-health/data-research/facts-stats/nuclear-medicine.html.
6. Crawley M. 2024. Killing cancer cells with alpha particles could be the next frontier in treatment. CBC. Accessed February 26, 2025. Available from: https://www.cbc.ca/news/health/cancer-treatment-research-targeted-alpha-therapy-1.7384434.
7. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O. 2013. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med. 369(3):213–223.
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