By Matt Skoufalos
The study of nuclear pharmacy has been ongoing since the 1970s, and yet in all that time, the promise of partnering radiopharmaceuticals and diagnostic imaging has yet to be fully realized. The field of theranostics involves targeting disease states via molecular imaging and radioisotopes to create a form of personalized medicine. Commonly used for treating various forms of cancer – thyroid, liver, neuroendocrine, prostate – it can deliver a higher degree of precision oncology than chemotherapy can when partnered with molecular imaging.
Despite its continued growth, the practice of theranostics isn’t nearly as widely adopted in the care of as many patients as it could otherwise be. The field is small, expensive to operate within, short-staffed, and needs regulatory and research support to truly deliver on the promise of personalized medicine, of which it has the potential to be a critical component.
Lady Sawoszczyk, who leads the theranostics and collaboration team of the molecular imaging business at Siemens Healthineers in Hoffman Estates, Illinois, spoke about the challenges that professionals in the field face in working to broaden applications of theranostics in the delivery of care. Sawoszczyk, who brings a clinical academic background to her work at Siemens Healthineers, emphasized the importance of cross-industry collaborations among clinical researchers, radiopharmaceutical manufacturers and diagnostic imaging companies.
“We enable a comprehensive patient care solution ranging from targeted development to therapy solutions,” she said. “Molecular imaging enables accurate patient selection and therapy response monitoring; both PET/CT and SPECT/CT scanners are equipped to help effectively and efficiently tailor cancer care.”
Clinical trials are hugely important to the advancement of theranostics because radiopharmaceuticals must demonstrate efficacy and safety in specific applications to clear federal Food and Drug Administration (FDA) approval, and move up in the treatment schema.
For example, Sawoszczyk said, patients battling metastatic, castration-resistant prostate cancer can qualify for a theranostics treatment only after unsuccessful hormone and chemotherapy treatments.
“Researchers are trying to change the treatment paradigm,” Sawoszczyk said. “There are a lot of clinical trials looking at theranostics, some of them first-line and others second-line, and all this data is being assessed by utilizing PET/CT and SPECT/CT quantification. In three years, we had four major FDA approvals, but before that, it was very, very slow; that data is moving a little quicker because of the impact that these patients have shown.”
FDA approval is critical not only for patient safety, but for the Medicare reimbursement that allows for the continued development of proven theranostic approaches. In her four years managing molecular imaging and therapeutics at an Ivy League institution, Sawoszczyk herself worked to advance these causes. She praised the Society of Nuclear Medicine and Molecular Imaging (SNMMI) for its advocacy work in personalized imaging agent reimbursement, which helps patients gain access to theranostics treatments. Even with reimbursement, such treatments are expensive to develop and administer, which means funding for clinical trials is another component of an already complex path to expanding accessibility to theranostic approaches for patients.
Expanding adoption of theranostics requires not only regulatory considerations, but also the broader growth of personalized medicine throughout the health care industry. Sawoszczyk described the challenges of implementing a theranostics program, and how Siemens Healthineers can help institutions establish them.
“I’ve noticed that there’s an opportunity to provide education on what personalized medicine is, and one of the leading questions around it is, ‘How do we get there?’ ” she said. “How do we utilize all our resources and increase theranostics access for patients? It takes a lot of effort, time, and a multidisciplinary approach to provide personalized treatments.”
Self-advocacy and including patients in the calculus of collaborators in care is another critical dimension of personalized medicine that underpins theranostic treatments, Sawoszczyk said. Telemedicine solutions allow physicians to connect with patients to discuss treatment options without delaying care. Virtual meetings enable a collaborative approach to allow a modality expert like Sawoszczyk to evaluate the theranostics program at a given facility, and help customize it for individual patients, and grow it beyond its current capabilities to eventually treat more patients.
“Some health care institutions don’t have resources; some need workflow optimization,” she said. “The idea is to educate, to get the word out; to get us to a point where all patients can have access to these treatments. It’s about ensuring we’re doing it safely and effectively.”
Jill Helmke, a Certified Nuclear Pharmacist and Doctor of Pharmacy, who is also the executive vice-president of clinical development for NuView Life Sciences of Park City, Utah, described some of the inherent difficulties in broadening adoption of theranostics. Chief among them may be the breadth of infrastructure challenges around supporting the creation of the radioisotopes used in the diagnosis and treatment of patient disease states.
To Helmke, the biggest fundamental challenges to radioisotope production involve the scale and scope of the major technologies that underpin them: nuclear cyclotrons and nuclear reactors. She worked on a cyclotron housed in a hospital setting in an earlier phase of her career and spoke about the technical complexities inherent in adding one to any health care approach.
“You need to have a production facility specifically built with those accelerators in your vaults in a separate building, heavily lead-lined so there’s no exposure to people,” Helmke said. “It can be challenging to get different isotopes from a cyclotron versus having the radioisotopes shipped in. You may have to change the targets out daily, make sure the environment is safe to walk into, and then you have to go through and get it to come out of the cyclotron in a liquid form. “
“Then you have to go through quality control testing,” she continued. “When I was working on F-18, we’d start at 2 a.m., prep until 3 a.m.; by 6 a.m., you hope you have the quality control done, and maybe at 6:30 a.m. you’re getting it to a patient. If, at any step along the way, there’s a misstep, or it doesn’t pass a step in the pages on pages of quality control, you have to abort.”
If the manufacturing process fails, a patient who will have been waiting to undergo a potentially life-saving treatment must be turned away, and “to tell them no is devastating,” Helmke said.
“We’ve had to cancel doses if the cyclotron wasn’t producing enough of the radioisotope or not passing quality control testing,” she said. “At any point in time, it’s a day-to-day supply challenge in a production facility like a hospital. But now that there are more generators and reactors, contract distribution with companies that are coming onboard focused on other isotopes, can eliminate those day-to-day challenges.”
Moreover, Helmke said, improvements in the selection, production and delivery of radiopharmaceuticals have made for a more streamlined, patient-friendly atmosphere. In her six years at NuView, Helmke has worked to help develop diagnostic products like a small-molecule peptide that can attach itself to prostate cancer cells shed in urine.
“The trend now is high-precision, targeted therapy,” she said. “We are focusing on a specific biomarker that gives us the opportunity to focus just on cancer cells and prevent toxic side-effects with highly precise targeting. We’re mapping out cancer cells like we mapped out DNA.”
“We would like the FDA to be more aware about what’s coming up the pipeline so that things can be expedited more quickly,” Helmke said. “Some of these products are breakthroughs, and they need to be given to patients. The production supply is so important.”
Gabriela Spilberg, MD, is an assistant professor of radiology and biomedical imaging director at the Yale School of Medicine in New Haven, Connecticut, where she also co-directs theranostics and clinical trials for the section of nuclear medicine at Smilow Cancer Hospital and Yale Cancer Center. Spilberg echoed Helmke’s and Sawoszczyk’s sentiments about the field of theranostics needing support, in terms of collaboration and awareness, to grow.
“We’re still very limited in the scope of clinical practice of where we are, and how little theranostics has advanced since its inception,” Spilberg said. “To develop this field, I think you really need a teamwork approach.”
Dealing with radiation obligates greater regulatory scrutiny; for example, the potential misuse of isotopes and the presence of nuclear technology to create them means theranostics operations are regulated by the Nuclear Regulatory Commission, which is a branch of the U.S. Department of Defense, not the FDA. Health care institutions wishing to study or develop theranostics programs need to retain specialized professionals, like radiation safety officers and their teams.
“There’s a lot of special licenses and handling of material, and dedicated, trained personnel,” Spilberg said. “It’s not something that’s easy, and there’s a big shortage of professionals to start. If you think you’re barely handling your clinical volume, to really move into more research and other things is complicated and expensive.”
The complex infrastructure around the development of theranostic treatments requires visionary leadership as well as deep-pocketed financial support to coordinate, and “that’s not the marriage that happens often and everywhere,” Spilberg pointed out. For precisely such reasons, the field is farther along in countries like Germany and Australia, in her estimation; but even beyond the demands atop the health care industry, there are similar needs in theranostics that extend all the way down its structure, including recruitment of more professionals into the specialty.
“I think it really requires this specific profile of person to be drawn to this field,” Spilberg said, “and then you have to have buy-in from administration, and a lot of times people have not heard about theranostics. It’s such a small field that they just don’t know about it.”
Likewise, although radiopharmaceutical therapies are expensive to develop and administer, Spilberg believes the value of theranostics will only increase as it’s put to broader use delivering real roadmaps of disease expression, in vivo. The issue of how to do so remains a persistent challenge.
“With theranostics, you can really target what’s most expressed and follow it, rather than changing things in a chaotic way,” Spilberg said. “I have a really hard time understanding why this is not the focus of developing drug companies and the FDA. It’s very old-school to still keep looking at treatment response criteria as changes in size and anatomy, when we really know a lot of these treatments have different effects. Just one target won’t ever be enough for any disease.”
As broader adoption of multi-tracer pharmaceuticals can become more common for every patient, AI-driven computer processing can lead to faster interpretation of study results, “and that’s when I think this will be much more leveraged as a technology to move forward into true personalized medicine,” Spilberg said.
“Right now, the way we’re doing things, even though we have these tools, they’re not being optimized,” she said. “I have a lot of patients who are self-referred [for theranostics] because the side effect profile is so much better than chemotherapy. I have patients who come in, and who have been waiting to fail chemotherapy for a year to receive this because they know it’s their preferred modality. There’s this gigantic potential for playing a role in multiple types of disease.”
