Interventional Radiology in the Era of Radiotheranostics: An Update for Interventional Radiologists!

In 2018, the Food and Drug Administration (FDA) approved lutetium-177 ( ¹⁷⁷ Lu) DOTATATE (LUTATHERA, Advanced Accelerator Applications [Novartis]) for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Since then, ¹⁷⁷ Lu DOTATATE has been increasingly used as a treatment option for NETs. Less than 5 years later, in March 2022, ¹⁷⁷ Lu vipivotide tetraxetan (PLUVICTO, Advanced Accelerator Applications) received FDA approval for the treatment of prostate-specific membrane antigen-positive castration-resistant metastatic prostate cancer. Both drugs are excellent examples of viable radiotheranostic therapies. As more radiotheranostic agents and applications get adopted in clinical practice, interventional radiologists are likely to get exposed to this field in a way or another. In this article, we discuss the fundamentals of radiotheranostic therapy and explore the expanding role interventional radiology (IR) is expected to play as an essential partner in modern oncology practice.

The Fundamentals of Radiotheranostics

Detailed discussion of radiotheranostics paradigm is beyond the scope of this article. However, it is noteworthy to discuss the fundamentals of radiotheranostics before digging deep into the emerging role of IR in this exciting field.

In fact, the concept of radiotheranostics has been clinically adopted for more than 70 years. Most radiologists are familiar with the use of radioactive iodine to diagnose and treat thyroid cancer using ¹²³ iodine and ¹³¹ iodine, respectively. ^{1 2} The recent approval of ¹⁷⁷ Lu DOTATATE and ¹⁷⁷ Lu-PSMA-617 gave significant resurgence to this field since both agents were approved to treat advanced stages of NETs and metastatic prostate cancer, respectively. This filled a significant gap in the clinical care of these patients who have limited treatment options in advanced stages of disease, allowing for a quick adoption of these radiopharmaceuticals in the mainstream of cancer therapy.

The structure of most radiotheranostics is almost the same. A ligand–linker–radioisotope frame is used to build up a structurally stable radiopharmaceutical. ³ The ligand, commonly a peptide or an antibody, can precisely target specific receptors overexpressed by particular tumor cells. The linker, usually a macrocyclic chelate, attaches the ligand to a radioisotope establishing a chemically stable radiopharmaceutical. The radioisotope component is the part which switches the radiopharmaceutical from a diagnostic to a therapeutic agent. Prime example to simplify the concept is ¹⁷⁷ Lu DOTATATE. When positron emitting radioisotope such as gallium-68 ( ⁶⁸ Ga) is anchored to DOTATATE (ligand–linker complex), the resultant ⁶⁸ Ga DOTATATE targets somatostatin receptors overexpressed by well-differentiated NETs yielding an exceedingly high-quality PET scan for mapping receptor distribution and density. When ¹⁷⁷ Lu (beta emitting radioisotope) is attached to the same ligand-linker complex (DOTATATE), the resultant ¹⁷⁷ Lu DOTATATE can attach to the same receptors and destroy cancer cells through beta emission.

Most radiotheranostic compounds are currently administrated via an intravenous route. For example, ¹⁷⁷ Lu DOTATATE is administrated intravenously over four cycles, usually 8 weeks apart. A fixed dose, 7.4 GBq (200 millicurie), is infused in each cycle. It is noteworthy to mention that amino acids are infused before and after ¹⁷⁷ Lu DOTATATE administration to provide renal protection. Long- and short-acting octreotide should be discontinued at least 4 weeks and 24 hours prior to ¹⁷⁷ Lu DOTATATE infusion, respectively. Complete blood cell counts renal and liver functions are monitored in between treatment sessions to determine eligibility to receive next cycles. ⁴

IR Role in the Era of Radiotheranostics

Interventional radiologists are increasingly exposed to radiotheranostics in clinical practice and this experience is likely to escalate. It is now essential to understand the concept of radiotheranostics especially when it relates to discussions during multidisciplinary NETs tumor boards. Radiotheranostics have introduced new terminology which is becoming essential knowledge for interventional radiologists. For example, a higher receptor expression on target tumors can predict favorable outcomes of radiotheranostic therapies. For NETs, the degree of somatostatin receptor expression is evaluated with either indium-111 pentetreotide scintigraphy or more commonly nowadays ⁶⁸ Ga-DOTATATE PET/CT scans. The degree of receptor expression is usually described using the “Krenning score” ( Figs. 1 and 2 ). A Krenning score of 3 or 4, which indicates higher radiotracer uptake compared to normal biodistribution of radiotracer in the liver, is one of the main eligibility requirements to consider ¹⁷⁷ Lu DOTATATE therapy. ^{5 6}

Fig. 1.

The use of Krenning score to determine eligibility for ¹⁷⁷ Lu DOTATATE therapy. A 79-year-old woman with metastatic neuroendocrine tumor (NET). ⁶⁸ Ga DOTATATE scan demonstrates multiple metastatic deposits to the spine (arrows— a ) and mediastinal lymph nodes (arrows— b ). These metastatic deposits show low level of radiotracer uptake. ( c ) Maximum intensity projection (MIP) image shows low-level uptake in mediastinal nodes (thick arrow) as well as osseous deposits in the thoracic spine (thin arrows). The uptake is lower than that of the liver. These lesions were given Krenning score of 2; therefore, this patient was not eligible to receive ¹⁷⁷ Lu DOTATATE therapy.

Fig. 2.

The use of Krenning score to determine eligibility for ¹⁷⁷ Lu DOTATATE therapy. A 71-year-old male patient with metastatic neuroendocrine tumor (NET). ⁶⁷ Ga DOTATATE scan shows multiple radiotracer avid metastatic deposits to the liver (arrows— a ) and mesenteric lymph nodes (arrow— b ). ( c ) Maximum intensity projection (MIP) image shows intense radiotracer uptake in mesenteric nodes (thick arrow) as well as hepatic metastatic deposits (thin arrows). The uptake is significantly higher than the liver. These lesions were given Krenning score of 4; therefore, this patient was considered eligible for and received ¹⁷⁷ Lu DOTATATE therapy.

Interventional radiologists should also be prepared for some changes in clinical practice as radiotheranostic therapies become progressively integrated into treatment algorithms. Taking NETs as an example, about 40% of the patients develop distant metastases in the course of the disease, most commonly to the liver. Patients with untreated liver metastases have a 5-year survival rate between 20 and 40%. Surgical resection of liver metastasis is feasible in only 10% of cases. ⁷ This leaves a significant proportion of patients who can benefit from liver-directed therapies (LDTs). ⁸ It is not uncommon to have discussions, sometimes even debates, about whether LDTs or ¹⁷⁷ Lu DOTATATE should be considered and offered as first line of treatment. Ongoing research is investigating what would be the best sequence for treatment of these patients. ⁹ At our institution, we prefer to start with LDTs for liver-dominant disease. However, if there is significant extrahepatic disease, especially if the patient is symptomatic, we may consider treating with ¹⁷⁷ Lu DOTATATE first, followed by LDTs for residual hepatic disease. There will continue to be institutional variability until clear consensus guidelines are developed and interventional radiologists are expected to make decisions based on their clinical judgment and patient presentation.

It is important for interventional radiologists to understand radiotheranostic therapies may result in impairment of liver functions. According to the NETTER-1 trial, ¹⁰ most cases are grade 1 or 2 toxicity and will not exclude patients from receiving LDTs. However, more serious liver injury can occur if there is baseline impairment of liver function. These considerations may then represent contraindications for LDTs and must be trended and communicated by interventional radiologists during discussions with medical oncologists and nuclear medicine physicians. Maintaining excellent communication with nuclear medicine and medical oncology is critical to ensure LDTs are introduced in the correct timing and sequence to achieve the best clinical outcomes.

Radiotheranostics can also provide an excellent platform to guide local thermal ablation. The imaging component of radiotheranostics provides an extremely sensitive tool to detect and localize metastatic disease which can be easily missed by other conventional imaging modalities ( Fig. 3 ). This can help interventional radiologists to target metastatic disease earlier in the course of the disease and potentially achieve better outcomes. Early reports showed that PSMA-PET was used successfully to target cryoablation and stereotactic radiotherapy to oligometastatic prostate cancer deposits. ^{11 12}

Fig. 3.

The increased sensitivity of PSMA-PET/CT scans compared to conventional imaging. A 76-year-old man with castration-resistant prostate cancer. Patient had a rising prostate-specific antigen (PSA) of 24 ng/mL. ( a ) Bone scan shows mild uptake in the thoracic spine (red circle), but no corresponding sclerotic lesion on CT scan. Uptake was favored to represent degenerative changes and follow-up was recommended. Patient continued to have escalating PSA up to 61 ng/mL. ( b ) F-18 PSMA-PET/CT scan performed only 1 month later shows widespread radiotracer intense osseous deposits involving the axial and appendicular skeleton. There was no sclerosis on corresponding CT scan.

Another interesting opportunity for IR involvement is the possibility of intra-arterial administration of radiotheranostic therapies. Currently, there is debate whether intra-arterial injection of ¹⁷⁷ Lu DOTATATE for NETs metastatic liver deposits would achieve a higher tumor-absorbed dose and, consequently, a significantly improved clinical benefit over current IV approach. ¹³ Nevertheless, early reports showed higher mean absorbed dose in metastatic prostate cancer lesions when ¹⁷⁷ Lu PSMA was injected intra-arterially through the internal iliac arteries compared to the intravenous route. ¹⁴ Similar reports showed higher target absorbed dose when intra-arterial ¹⁷⁷ Lu–high-affinity DOTATATE was used to treat refractory meningiomas, which are known to overexpress somatostatin receptors as well. ¹⁵ If intra-arterial administration of radiotheranostic therapies proves significant improvement in clinical outcomes and overall survival in specific clinical scenarios, then the IR role is likely to expand further in the near future.

The future of radiotheranostics is so bright and it is expected that more radiopharmaceuticals will be available clinically during the current decade. ³ Extensive research is currently ongoing to develop new radiotheranostic agents, expand the clinical applications of existing radiotheranostics, refine the administrated dose using personalize dosimetry, investigate potential combination of radiotheranostics and immunotherapy, and even explore the use of radiotheranostics at earlier stages of cancer with potential improvement of clinical outcomes. ³ As the field of radiotheranostics continues to expand, new opportunities for interventional radiologists are likely to evolve.

Training and Certification

The clinical use of radiotheranostics can be challenging and requires deep understating of nuclear and molecular medicine in addition to radiation safety considerations. In view of the expected tremendous growth of this field, a well-trained generation of authorized user physicians who can cross interdisciplinary bridges between nuclear medicine, medical oncology, and IR are needed now than ever before. In majority of treatment centers, radiotheranostic therapies are administrated by authorized nuclear medicine physicians. However, in limited number of treatment centers, these therapies are administrated by interventional radiologists. These interventional radiologists received expanded formal nuclear medicine training and are often board certified in nuclear medicine. Currently, this can be achieved in the United States through one of two pathways: First, a nuclear medicine fellowship in addition to IR training and the second is through the alternate pathway for American Board Certification. ¹⁶ The second pathway is more common among international medical graduates and in many cases includes sufficient nuclear medicine training to allow for American Board of Nuclear Medicine certification.

Conclusion

In conclusion, the IR community needs to be aware of the current challenges and potential opportunities as radiotheranostics are progressively adopted in clinical practice. We need to be proactive to ensure IR maintains an active role as more of these treatments become available. If intra-arterial administration of these medications proves to be more clinically beneficial, then a focused authorized user certification process, like the one currently available for ⁹⁰ Y radioembolization, may be needed in the near future. Meanwhile, interventional radiologists should actively maintain proficiencies and consider implementing radiotheranostics now into their clinical practice, while anticipating the promise of future advances this field provides.