Clinical considerations for pharmacists regarding the use of radiopharmaceuticals in oncology

Abstract

Background

Radiopharmaceutical therapy encompasses the targeted delivery of radioactive atoms to sites of malignancy within the body and represent a rapidly growing area of drug development in oncology. In comparison to cytotoxic chemotherapy, radiopharmaceutical therapy has the potential for fewer adverse effects and is able to produce a strong anti-cancer response in a wide range of malignancies.

Objective

This article reviews radiopharmaceutical therapy mechanisms and discusses four well-established agents that are used in clinical practice, their place in therapy, safety, utilization of concomitant therapies, and contact precautions for each agent.

Sources

Information presented in this article is sourced from the available literature on radiopharmaceutical development, oncology clinical practice guidelines, clinical trial results, and package insert data.

Summary

Radiopharmaceuticals possess significant differences in drug mechanism and design from that of traditional cytotoxic chemotherapy agents. The basic functional and structural variances in combination with isotope selection drive the clinical efficacy of radiopharmaceutical therapy and inform pharmacists of the important considerations of each therapy's distribution, off-target effects, clearance, and toxicities.

Conclusion

The drug and safety information presented in this article pertaining to select radiopharmaceuticals is pertinent to an oncology pharmacist's role in patient care as radioactive therapies continue to expand the complexity of the oncology treatment landscape.

Keywords

Radiopharmaceutical antibody radionuclide conjugate nuclear pharmacy

Introduction

Radiopharmaceutical therapy (RPT) encompasses the targeted delivery of radioactive atoms to sites of malignancy within the body. RPT agents can be used for curative or palliative intent and are utilized for both solid and hematologic malignancies with treatment of localized disease being achieved though locoregional administration or via targeted drug design. Historically, radioactive elements were predominantly used for diagnostic purposes, but RPT has demonstrated significant promise as an effective cancer treatment modality. Hence, the radiopharmaceutical industry is experiencing exponential growth, with total market value estimated to exceed $13 billion by 2032 following this new therapeutic success.¹ Thus, it is essential for oncology pharmacists to familiarize themselves with these agents, their place in therapy, and management of toxicities, as they may provide patient education on RPT agents or post-therapy follow-up in the near future.

RPT is a rapidly growing area of research and FDA approvals within oncology. The use of RPT will always require a collaboration of nuclear medicine experts and oncologists because the preparation, handling, and administration will be completed by specialized team members within nuclear medicine. Despite its growing promise as an efficacious therapy in a variety of malignancies, RPT may not be feasible for eligible patients due to geographic or socioeconomic reasons. This should not deter the use of RPT but may require additional team members such as financial support specialists and social workers to navigate potential barriers to care. During ongoing care coordination, oncology pharmacists may be approached for treatment related questions regarding systemic chemotherapy use for disease temporization while bridging to RPT or if ongoing systemic therapy may be continued throughout RPT. This article will review a selection of RPT that are currently available for clinical use and discuss key pharmacologic considerations pertinent to a pharmacist's role in patient care.

Cytotoxic mechanism of radionuclides

In comparison to cytotoxic chemotherapy, RPT has the potential for fewer adverse effects and is able to produce a strong anti-cancer response in a wide range of malignancies. The clinical and therapeutic role of each RPT is defined predominantly by two factors: emission particle and drug structure ( Table 1 ). RPT with beta-particle emission is the most common mechanism utilized given the wide availability of radionuclides with appropriate pharmacokinetics. High energy alpha-particles are also utilized for their potent therapeutic activity. Although gamma-emission is another radioactive decay product that may be associated with some RPT agents, it does not contribute significantly to clinical efficacy.

Table 1.

Comparison of RPT emission particles.²

	Alpha-particle	Beta-particle
Relative size	Large (x3 beta-particle mass)	Small
Travel distance	∼50–100 μm (1–3 cell lengths)	∼2–12 mm (20–120 cell lengths)
Ideal target	Micrometastases	Large tumors
Linear energy transfer*	50–230 keV/um	0.2 keV/um
Mechanism of cytotoxicity	Causes direct irreparable double-strand DNA breaks	Generates reactive oxygen species (ROS) that causes single strand DNA breaks and other ROS-mediated stress

The energy released by each particle emission is measured over a unit distance.

The second defining factor for RPT is its drug structure ( Figure 1 ). Although the RPT drug class includes free radioisotope products, novel RPT radioisotopes are predominantly chaperoned by a targeting vector such as antibodies, antibody fragments, peptides, or small molecules.³ This drug design is very similar to the concept of an antibody drug conjugate (ADC), where the payload is a radionuclide linked to an antibody structure that targets surface proteins uniquely expressed or overexpressed on malignant tissues. ADCs have several developmental and pharmacokinetic barriers including plasma stability, early payload dissociation, low blood retention time, minimal tumor penetration, immunogenicity, off-target toxicity, and drug resistance.⁴ In contrast, drug resistance and tumor penetration are not an issue for antibody radionuclide conjugates (ARCs) as radiation from the payload is able to target the malignant tissues with close proximity alone. Ultimately, the inherent radiosensitivity of the malignancy will determine the disease response. With respect to toxicities specific to ADCs, ARCs have been carefully designed with a payload-antibody linker that both securely chelates the radionuclide and binds to the organic antibody structure thus avoiding early or unwanted payload dissociation.⁵ Off-tumor toxicities are the consequence the ADC or ARC binding to non-malignant tissues that share surface expression of the target protein. Without a vector-radioisotope paring, localized administration of a radionuclide is preferable to limit systemic distribution and subsequent toxicities of free radioisotope. These structural differences and isotope selection of RPT lead to its clinical efficacy and can inform a pharmacist of important and unique considerations of each agent with respect to the RPT's distribution, off-target effects, clearance, and toxicities.

General pharmacist considerations for RPT

Complications and toxicities of RPT are driven by both the targeting component and the radionuclide present. Antibodies and other organic vectors may carry a risk of hypersensitivity reactions with recommendations for premedications varying by RPT product. Off-target and off-tumor toxicities need to be carefully reviewed for each RPT. Whereas ADCs deliver a potent small molecule chemotherapy agent, ARCs carry high energy radiation emitters, and there are several body tissues that are highly sensitive to radiation injury ( Table 2 ). Underlying organ dysfunction is a significant risk factor for tissue-specific toxicity. Given the diverse tissue toxicities possible with RPTs, some agents may require unique prophylactic supportive care or therapeutic monitoring. Dose reductions may be required in the setting of suspected toxicity for an RPT that requires multiple administrations, since there is generally a low threshold to withhold therapy. Fortunately, when RPTs are dosed and administered appropriately, they are generally safe and well tolerated in contrast to cytotoxic chemotherapy where tolerability can be potentially significant and prohibit treatment intensity.

Table 2.

Tissue-specific radiation injuries.^6,7

Tissue	Symptom Onset	Presentation	Comments
Liver	4–8 weeks	Abdominal pain, hepatomegaly, with possible ascites and jaundice Elevated bilirubin and alkaline phosphatase	Most applicable for localized RPT therapy (i.e., Y-90 microspheres)
Kidneys	1–2 weeks	Increase in serum creatinine Decrease in creatinine clearance and glomerular filtration rate	Predicted renal tissue exposure to RPTs is used to determine the maximumly tolerated doses possible for RPTs that undergo renal elimination
Salivary glands	1–2 weeks	Dry mouth and in severe cases low grade mucositis	Salivary glands readily uptake radionuclides like iodine and selectively bind some protein-bound RPTs
Lungs	4–8 weeks	Nonproductive cough, dyspnea, and new oxygen requirement Bronchoalveolar lymphocytosis and eosinophilia	Most applicable to Y-90 microsphere therapy
Gastrointestinal tract	1–4 weeks	Gastritis, diarrhea, and in severe cases gastric or intestinal ulceration	Most applicable for RPTs that undergo fecal elimination and for Y-90 microsphere therapy
Bone marrow	Variable	Anemia, thrombocytopenia, and neutropenia Bone marrow failure Secondary hematologic malignancy	The risk and degree of hematologic toxicity depends on the distribution of the RPT, absorbed radiation dose by the bone marrow, prior exposure to myelosuppressive chemotherapy, and patient age

There is a risk of secondary malignancy after completion of RPT. It is difficult to define an incidence in adults, since RPT are mostly utilized in the metastatic and relapsed or refractory setting. However, in pediatric neuroblastoma therapy, long-term follow-up of patients who undergo therapy with an RPT called I-131 metaiodobenzyluanidine (MIBG) in addition to cytotoxic chemotherapy, were found to have a 5-year and 10-year incidence of secondary neoplasm of 7.6% and 14.3%, respectively.⁸ Contrasted with peptide-receptor radionuclide therapy (PRRT) in neuroendocrine tumors which has a 20-year incidence of 2.4% for myelodysplastic syndrome (MDS).⁹ Evaluating the risk of secondary malignancy in any patient population is further complicated by pre-treatment history with cytotoxic chemotherapy. The longer a patient is observed after RPT with or without other chemotherapy, the more likely they’ll be diagnosed with a secondary malignancy. The most common secondary hematologic diagnosis includes MDS or acute leukemia. Although secondary malignancy following RPT likely shares a similar incidence to cytotoxic chemotherapy, it remains an important point of consideration and should be discussed during patient counseling as RPT moves further into the upfront setting.

Oncology pharmacists will need to consider drug interactions with RPT in clinical practice. All RPT agents are radioactive and generate oxidative stress. Antioxidants such as vitamin C, vitamin E, beta carotene, and selenium, beyond normal dietary intake, should be avoided while undergoing active RPT treatment. It is possible a patient may be on a drug that can impair the renal or hepatic elimination of the RPT or its components. Specific recommendations for concomitant medications regarding the timing of when to withhold and for how long after administration by be driven by the manufacturer and treating nuclear medicine provider; nevertheless, it is important to review patient medication lists ahead of time to identify the need for any clarifications.

Radiopharmaceutical review

There are 4 well-established agents that demonstrate the unique characteristics of RPT ( Table 3 ). A review of these agents will highlight the important features and considerations an oncology pharmacist should be aware of when encountering these and similar therapies in clinical practice.

Table 3.

Summary of radiopharmaceutical properties, mechanisms, and Indications.^3,10–13

Radiopharmaceutical	Particle Emission	Isotope Half-life	Mechanism of Action	Clinical Indication
Y-90 microspheres (TheraSphere^®; SIR-Spheres ^®)	Beta-particle	64 h	Locoregional arterial injection traps radioactive microspheres in tumor vascular bed	HCC (early to intermediate BCLC stage); Liver metastasis of mCRC
Lu-177 dotatate (Lutathera^®)	Beta-particle	6.4 days	Tumor cell internalization of somatostatin analogue bound radioactive Lu-177	Well-differentiated SSRT-positive GEP-NETs
Lu-177 vipivotide tetraxetan (Pluvicto^®)	Beta-particle	6.4 days	Tumor cell internalization of PSMA ligand bound radioactive Lu-177	PSMA-positive mCRPC who have been treated with an androgen inhibitor and taxane-based chemotherapy
Ra-223 (Xofigo^®)	Alpha-particle	11.4 days	Calcium mimic, localizing radiation to areas of bone metastasis	mCRPC with symptomatic bone metastases

BCLC: Barcelona Clinic Liver Cancer, GEP-NET: gastroenteropancreatic neuroendocrine tumors, HCC: hepatocellular carcinoma, mCRC: metastatic colorectal cancer, mCRPC: metastatic castration-resistant prostate cancer, NHL: non-Hodgkin lymphoma, PSMA: prostate-specific membrane antigen, SSRT: somatostatin receptor.

Yttrium-90 microspheres (TheraSphere^®; SIR-Sphere^®)

Background

Yttrium-90 (Y-90) microspheres are approved for treatment of two solid tumors in the liver. There are a variety of curative treatment options available for early hepatocellular carcinoma (HCC) such as ablation, surgical resection, or liver transplant, with selection being driven by the tumor size and location.¹⁴ Patients with HCC may benefit from Y-90 microspheres during early disease and/or as a bridge to definitive intervention. The Y-90 radionuclide is a constituent of an insoluble microsphere which has a diameter similar to a human cell, and it must be infused intra-arterially to direct the beads to the HCC tumor site.¹⁰ Prior to administration of Y-90 microspheres, hepatic angiography is required to map the tumor blood supply and estimate the off-target radiation dose that will be delivered to the lungs and gastrointestinal tract (referred to as each respective organ's “shunt fraction”). This determines treatment eligibility and limits the severity and incidence of off-target toxicities.

The FDA approved the first Y-90 microspheres product as a medical device in 2021 for treatment of HCC based on the findings of the retrospective, single-arm LEGACY study. Results demonstrated an objective response rate (ORR) of 88.3% and a 3-year overall survival (OS) of 86.6% in patients with solitary HCC of ≤8 cm in diameter, Barcelona Clinic Liver Cancer (BCLC) stage A-C, and Child-Pugh class A cirrhosis.¹⁵ An earlier trial in 2018 prospectively evaluated Y-90 microspheres in patients with BCLC stage A-D HCC and Child-Pugh class A-C cirrhosis with results demonstrating a durable treatment response and improved OS in patients with earlier stage disease and in those with lower Child-Pugh scores.¹⁶ When trialed against sorafenib for first-line therapy in advanced HCC, Y-90 microspheres were not superior to the tyrosine kinase inhibitor.¹⁷ Thus, systemic therapy and Y-90 microspheres are both viable options for locally advanced disease.

The second indication for Y-90 microspheres is in the setting of metastatic colorectal cancer (mCRC) based on the results of a multi-center phase II study where Y-90 microsphere produced an ORR of 24% and a median OS of 12.6 months in patients previously treated with chemotherapy.¹⁸ Although there is mixed evidence regarding the combination of Y-90 and chemotherapy in previously untreated mCRC, there is favorable data supporting the use of Y-90 in patients with chemo-resistant disease who are not eligible for resection.^19,20 Activity in chemo-resistant disease is likely driven by both the direct delivery of the microspheres to the site of active disease and the high energy ionizing radiation given off by the Y-90 radionuclide.

Pharmacist considerations

Safety and utilization

Y-90 microspheres are contraindicated if greater than 70% of the liver is replaced by the tumor or if the patient has baseline pulmonary insufficiency (defined as a baseline oxygen saturation of less than 90%), portal vein thrombosis, or severe liver dysfunction with ascites and hepatic encephalopathy.¹⁰ In clinical practice, a bilirubin of 3 mg/dL or higher is considered a relative contraindication for any arterially directed therapy and a bilirubin of 2 mg/dL or higher has been associated with a high-risk of radiation-induced liver injury following Y-90 therapy.¹⁴ Radiation pneumonitis is a rare complication of Y-90 reported in case studies or series with a symptomatic disease incidence of less than 2%.²¹ Gastritis grade 3 or higher has an incidence of 5%.¹⁵ There is also a risk of gastric and duodenal ulcers following Y-90 administration if beads travel to gastrointestinal vessels. For some patients, a proton pump inhibitor may be indicated starting prior to the procedure and continued for up to 4 weeks to reduce the risk of ulceration. Given the presence of disease within the liver, hyperbilirubinemia and ascites may occur following administration, but these adverse events are rarely grade 3 or higher. Antiemetics should be provided to patients for as needed use.

Concomitant therapy

In clinical practice, Y-90 microspheres continue to be explored in various treatment settings such as frontline therapy, adjuvant, and even neoadjuvant therapy. Concomitant use of Y-90 microspheres with chemotherapy, anti-angiogenesis agents, and targeted therapies is being actively explored. Of note, the VEGF inhibitor bevacizumab is a commonly used agent for the treatment of both mCRC and advanced HCC. Bevacizumab should be held 4 weeks prior to Y-90 microsphere administration and for several weeks after due to the increase the risk of arterial injury.²² Chemotherapy and some oral agents carry less of a risk of tissue injury and more of a concern for overlapping toxicities. Timing considerations may be left to the discretion of the treating physician. For potential dose adjustments to any systemic therapy following Y-90 microspheres, pharmacists should carefully evaluate each patient for any new or worsening hepatic dysfunction.

Contact Precautions

Unlike traditional chemotherapy, Y-90 microspheres remain trapped in the liver capillaries. It does not undergo metabolism and does not leave the body via urine or feces in a meaningful way. It is possible for Y-90 microspheres to be released from the body via open wounds or during a medical procedure, thus patients should disclose the timing of any prior Y-90 microsphere therapy. Generally, administration of Y-90 microspheres is performed outpatient and patients can return home the same day. The manufacturer recommends that patients limit time within 1 meter of other individuals to less than 12 hours per day following administration.¹⁰ Patients may emit radiation for approximately 14 days after administration, which may be detectable at security screenings like those in airports, manufacturing plants, research facilities, or government buildings.

Lutetium-177 dotatate (Lutathera^®)

Background

Lutetium-177 (Lu-177) dotatate is indicated for the treatment of somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of the foregut, midgut, or hindgut, which represent about 70% of all neuroendocrine neoplasms.^11,23 SSTR-positive disease is diagnosed with a SSTR-based MRI or PET/CT scan where SSTR uptake by malignant lesions must be greater than the liver.²³ Most GEP-NET cells express surface somatostatin receptors which when targeted by somatostatin analogs, including octreotide and lanreotide, provide symptomatic relief and inhibition of tumor growth. Although mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, and multiple cytotoxic drugs have been studied for the treatment of GEP-NETs, none have demonstrated improved outcomes over somatostatin agents.

Lu-177 dotatate was approved in 2018 based on the primary analysis results of the NETTER-1 trial, which demonstrated an improved progression and OS benefit of combination Lu-177 dotatate and octreotide to octreotide alone in patients with progressive locally advanced or metastatic SSTR-positive GEP-NET.²⁴ In the 5-year follow up study, the OS did not reach statistical significance between the two arms, likely driven by 36% crossover from the comparator arm, but the 11.7-month improvement in median OS reported nevertheless is clinically significant. Although initial approval was limited to foregut, midgut, or hindgut, the NCCN guidelines do recognize sufficient evidence to support consideration of Lu-177 dotatate in pancreatic NETs, pheochromocytoma/paraganglioma, and lung/thymic NETs.²³

Pharmacist considerations

Safety and utilization

This therapy is administered through a peripheral IV over 30 min every 8 weeks for a total of 4 doses and requires patients to have adequate renal function to clear the medication.¹¹ Lu-177 dotatate is dependent on the kidneys for elimination. The NETTER-1 trial excluded patients with a creatinine clearance below 50 mL/min; however, this therapy may be used in patients with a creatinine clearance of at least 30 mL/min.^11,24 The most clinically significant adverse event for Lu-177 dotatate is renal dysfunction. Any grade renal impairment has an incidence of 13% with grade 3 or higher being noted in 3% of patients. For renal protection during treatment, an amino acid solution of 5% arginine-lysine at a rate of 250 mL/hour is initiated 30 min prior, continued through, and for at least 3 h after the start of the Lu-177 dotatate infusion. Lu-177 dotatate has a high affinity for proteins, so amino acid solution helps decrease renal reabsorption and reduce renal radiation exposure. Dose reductions of Lu-177 dotatate do not affect the dose of amino acid solution required. However, the rate of the amino acid solution administration may be decreased to no less than 150 mL/hour if the patient experiences nausea or vomiting. Administer antiemetic medications prior to starting the amino acid solution with at least ondansetron; supplemental or additional antiemetics may be required for breakthrough nausea.

Carcinoid syndromecan occur following the administration of Lu-177 dotatate due to the subsequent release of vasoactive molecules.²³ Patients may experience flushing, hypotension, and diarrhea. Patients receiving the first dose of therapy for metastatic disease or possess a high tumor burden are at highest risk. Carcinoid syndrome would require symptom-specific supportive care and possible hospital admission if patients become hemodynamically unstable. Pharmacologic agents that may be used include octreotide, steroids, hydralazine, clonidine, albuterol, and vasopressors, if needed.

Concomitant and subsequent therapy

The timing of concomitant somatostatin analogs is critical for this therapy as reduced somatostatin receptor availability on the surface of GEP-NETs may theoretically reduce the efficacy of Lu-177 dotatate. Long acting and short acting somatostatin analogs must be discontinued at least 4 weeks and 24 hours prior to Lu-177 dotatate infusion, respectively.¹¹ During Lu-177 dotatate treatment, long-acting octreotide may be administered between 4 to 24 hours after each infusion and only re-administered every 8 weeks with future Lu-177 dotatate infusions until treatment is complete before returning to an every 4-week schedule. For symptomatic control, short-acting octreotide is permitted between Lu-177 dotatate infusions if not within the timeframe described above.

Options for sequential therapy remain limited for GEP-NET in patients who have received Lu-177 dotatate. Currently, cabozantinib is one of the few recommended therapies to follow Lu-177 dotatate.²³ In the CABINET study, Lu-177 dotatate therapy had to have been completed at least 6 weeks prior to administration of cabozantinib.²⁵ Alternative systemic chemotherapy agents would need to be timed based on consideration of the patient's organ function and recovery from Lu-177 dotatate toxicities.

Contact Precautions

There are three counseling points to share with patients who receive Lu-177 dotatate. Male and female patients should be advised to use effective contraception for up to 4 months and 7 months following the last dose, respectively. Special considerations for handling of body fluids apply for the first few days following administration. Patients should be advised to use the toilet in a seated position (even for men) and flush twice with the lid closed and shower daily. The manufacturer provides treatment cards that patients should receive to present to security officials while undergoing treatment with Lu-177 dotatate.

Lutetium-177 vipivotide tetraxetan (Pluvicto^®)

Background

Lu-177 vipivotide tetraxetan is indicated for patients with metastatic castration-resistant prostate cancer (mCRPC) with prostate-specific membrane antigen (PSMA)-positive disease refractory to first-line androgen receptor inhibition and taxane-based chemotherapy.¹² PSMA is a transmembrane protein found on most prostate cells and in non-prostate tissues such as the liver, spleen, kidneys, and salivary glands.²⁶ Vipivotide is a moiety that binds to PSMA.¹²

Lu-177 vipivotide tetraxetan was approved in 2022 based on the results of the VISION trial. This trial randomized patients to Lu-177 vipivotide tetraxetan with standard of care therapies or to standard of care alone which included abiraterone, enzalutamide, bisphosphonates, denosumab, or glucocorticoids.²⁷ The median OS and progression free survival (PFS) was improved by 4 months and 5 months, respectively. Lu-177 vipivotide tetraxetan is a treatment option for patients with at least one PSMA-positive lesion or metastatic disease that is predominately PSMA-positive.²⁸ Although Lu-177 beta-emission can reach PSMA-negative cells via bystander effect, it should not be used in patients with a dominant PSMA-negative metastatic lesion due to concern for efficacy.

Pharmacist considerations

Safety and utilization

Lu-177 vipivotide tetraxetan is infused IV every 6 weeks for up to 6 doses, or until disease progression, or unacceptable toxicity.¹² The incidence of grade 3 hematologic adverse events for neutropenia, thrombocytopenia, and anemia were 2.5%, 7.9%, and 12.9%, respectively.²⁷ Growth factor support for myelosuppression is not required for this therapy. Renal impairment occurred in 3% of VISION participants, likely due to PSMA expression on renal tissues.¹⁷ Lu-177 vipivotide tetraxetan is dependent on the kidneys for elimination. The VISION trial excluded patients with a creatinine clearance below 50 mL/min; however, this therapy may be used in patients with a creatinine clearance of at least 30 mL/min.^12,27 Patients should be advised to stay well hydrated and urinate frequently starting the day prior to Lu-177 vipivotide tetraxetan administration. Intravenous fluids for renal protection are not required for this therapy but may be considered on a patient-by-patient basis.

There are two prophylactic supportive care considerations for Lu-177 vipivotide tetraxetan. Dry mouth occurred in 39% of patients in the VISION trial due to selective binding of Lu-177 vipivotide tetraxetan by PSMA-positive salivary gland tissue.¹² Although this side effect is transient, patients may find relief with using a sodium bicarbonate mouthwash on days 1 through 3 of each cycle. Some clinics may provide patients with cold compresses to promote vasoconstriction to limit RPT uptake by the salivary glands. Lu-177 vipivotide tetraxetan is associated with a moderate emetogenic risk so at least two prophylactic antiemetics should be administered on the day of infusion.

Concomitant therapy

Patients may have several ongoing supportive care therapies while being treated for prostate cancer. It is safe for patients to continue receiving any ongoing bisphosphonate, hormone, anti-androgen, or steroid therapy while undergoing treatment with Lu-177 vipivotide tetraxetan. Patients with mCRPC likely have heavily pre-treated disease, sometime with other RPT agents. Lu-177 vipivotide tetraxetan should be spaced from radium-223 by at least six months to avoid overlapping hematologic toxicity and concomitant radiation therapies.²⁷ If Lu-177 vipivotide tetraxetan precedes radium-223, patients should demonstrate hematologic recovery prior to receiving the treatment. Localized/targeted external radiation is permitted during ongoing Lu-177 vipivotide tetraxetan treatment in select patients. Patients may return to systemic chemotherapy, immunotherapy, or targeted therapies, for which timing should be based on consideration of the patient's organ function and recovery from Lu-177 vipivotide tetraxetan toxicities.

Contact Precautions

Following administration, there are a few Lu-177 vipivotide tetraxetan specific counseling points for patients once they return home. Patients should refrain from sexual activity for 7 days following administration and use effective contraception during treatment through 14 weeks following the last dose. For a few days following therapy, patients should use the toilet in a seated position and flush twice with the lid closed. It is recommended patients limit close contact within 1 meter with household contacts and sleep in a separate bedroom from others for 2 days following administration. For children or pregnant women, patients should avoid contact for 7 days following administration.

Radium-223 (Xofigo^®)

Background

Radium-223 (Ra-223) is indicated for patients with castration-resistant prostate cancer (mCRPC) with symptomatic bone metastasis and no known visceral metastatic disease.¹³ Bone metastases are prevalent in over 90% of patients with mCRPC and greatly contributes to patient disability, decreases quality of life, increases treatment costs, and is a major cause of death among patients.²⁹ Ra-223 is a dichloride injection of free, unchaperoned alpha-particle emitting isotope. This isotope mimics calcium and complexes with bone minerals at sites of high bone turnover, such as sites of bone metastasis. There is no significant uptake of Ra-223 in other organs such as the heart, liver, kidneys, bladder, and spleen. Ra-223 was approved in 2013 and based on the results of the ALSYMPCA placebo-controlled trial. The median OS and time to first skeletal event was improved by 3 months and 5 months, respectively.²⁹

Pharmacist considerations

Safety and utilization

Ra-223 dosing is weight based, and it is administered as a slow IV injection every 4 weeks for up to 6 injections.¹³ Safety and efficacy beyond 6 injections with Ra-223 have not been studied. Premedications are not required. Ra-223 is an isotope that undergoes decay not metabolism, with fecal excretion being the major route of elimination from the body. By day 7 following administration, 63% of the administered radioactivity is excreted. Therefore, the most common adverse events include nausea (36%), diarrhea (25%), and vomiting (18%).²⁹ Hematologic abnormalities are not as significant of an adverse with grade 3 or higher events being anemia (13%), thrombocytopenia (6%), and neutropenia (3%). The emitted high energy alpha particles cause double-strand DNA brakes within a 10-cell diameter area leading to the cellular death of tumor cells, osteoblasts, and osteoclasts. This arrests bone remodeling within the diseased area and limits hematologic toxicity despite Ra-223 residing predominately in the bone in close proximity to marrow.

Concomitant therapy

Bone protecting agents (BPA) are recommended for patients receiving Ra-223. The ERA trial, evaluated abiraterone plus prednisone with or without Ra-223 and found the addition of Ra-223 to abiraterone was associated with an increased frequency of bone fractures compared with the control in 29% vs 11% of patients, respectively.³⁰ In response to the ERA 223 trial results, BPAs became a crucial supportive care therapy for patients who undergo symptomatic bone mCRPC treatment with Ra-223 while receiving either abiraterone and/or prednisone. If Ra-223 is administered on the same day as a BPA, ALSYMPCA investigators separated the administrations by at least 2 hours without respect to order of infusion.²⁹ While undergoing Ra-223 treatment patients are permitted to take calcium and vitamin D supplements to help support bone health.

There is insufficient evidence to guide the use of concurrent treatment with other systemic chemotherapy or targeted therapy with the exception of androgen deprivation therapy due to concerns of overlapping myelosuppression. Clinical trial participation is highly encouraged for patients with mCRC who are eligible for Ra-223 therapy to better inform dosing, monitoring, and supportive care considerations with concomitant therapy.

Contact Precautions

Following each administration of Ra-223, patients should flush their toilet several times after each use for at least a week. Caregivers should wear gloves when handling body fluids followed by normal hand washing for protection. Clothing soiled with Ra-223 due to fecal matter, urine, or blood should be washed promptly and separately from other clothing. Travel considerations may not be as crucial for this therapy given the short emission distance limiting external detection.

Conclusion

RPTs have proven effectiveness in the treatment of cancer in settings where other efficacious options are limited. The future of oncology will see more RPT treatment options within both solid and hematologic malignancies in the early and metastatic stages of disease. Given the promising results of connecting radionuclides with organic structures like peptide ligands and antibodies and growing interest in combining them with other systemic cancer therapies, RPTs have the potential to significantly change current treatment modality sequencing. Expanding utilization of these therapies in clinical practice will soon introduce a need for specialists with advanced experience in oncology therapeutics, proficiency in evaluation of primary literature, and an adaptive approach to clinical practice. Fortunately, oncology pharmacists are best equipped to help practitioners navigate therapeutic sequencing and management of RPT or combination therapy toxicities. Furthermore, patients may be apprehensive of nuclear medicine, and as patient educators, pharmacists can address this possible barrier to care and can guide patient expectations. RPTs are an exciting and evolving therapeutic development in oncology that will emphasize the valuable knowledge and adaptation skills of oncology pharmacists in the years to come.

Footnotes

Acknowledgments

The authors are thankful to our parent institutions for supporting this work.

Author contributions

HC and JV: co-developed the original article concept; HC: drafted and revised the manuscript;

SP, BH and JV: contributed to the article structure and provided critical revisions.

All authors approved the final version of the article for publication

Data availability

Not applicable.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval and informed consent

Not applicable.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Heather Corello

Stephanie Pang

References

BioSpace. Radiopharmaceuticals market size to surpass USD 13.67 bn by 2032. www.biospace.com/radiopharmaceuticals-market-size-to-surpass-usd-13-67-bn-by-2032 . (2023, accessed 2 August 2024).

Burkett

Bartlett

McGarrah

, et al. A review of theranostics: perspectives on emerging approaches and clinical advancements. Radiol Imaging Cancer 2023; 5: e220157.

Sgouros

Bodei

McDevitt

, et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 2020; 19: 589–608.

Pang

Duong

Siu

, et al. Antibody drug conjugates: design implications for clinicians. J Oncol Pharm Pract 2024; 30: 907–918.

Kitson

Cuccurullo

Moody

, et al. Radionuclide antibody-conjugates, a targeted therapy towards cancer. Curr Radiopharm 2013; 6: 57–71.

Wahl

Sgouros

Iravani

, et al. Normal-Tissue tolerance to radiopharmaceutical therapies, the knowns and the unknowns. J Nucl Med 2021; 62: 23S–35S.

Wright

Werner

Tran

, et al. Radiation pneumonitis following yttrium-90 radioembolization: case report and literature review. J Vasc Interv Radiol 2012; 23: 669–674.

Huibregtse

DuBois

, et al. Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with (131)I-metaiodobenzylguanidine. Eur J Cancer 2016; 66: 144–152.

Chantadisai

Kulkarni

Baum

. Therapy-related myeloid neoplasm after peptide receptor radionuclide therapy (PRRT) in 1631 patients from our 20 years of experiences: prognostic parameters and overall survival. Eur J Nucl Med Mol Imaging 2021; 48: 1390–1398.

10.

Therasphere Y-90 glass microspheres. www.bostonscientific.com (accessed 2 August 2024).

11.

Advanced Accelerator Applications USA Inc. Lutathera (package insert). Millburn, NJ: Advanced Accelerator Applications USA Inc. 2024.

12.

Advanced Accelerator Applications USA Inc. Pluvicto (package insert). Millburn, NJ: Advanced Accelerator Applications USA Inc. 2024.

13.

Bayer HealthCare Pharmaceuticals Inc. Xofigo (package insert). Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc. 2019.

14.

Hepatocellular carcinoma. NCCN guidelines. 2024. (accessed 2 August, 2024).

15.

Salem

Johnson

Kim

, et al. Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: the LEGACY study. Hepatology 2021; 74: 2342–2352.

16.

Salem

Gabr

Riaz

, et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology 2018; 68: 1429–1440.

17.

Vilgrain

Pereira

Assenat

, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol 2017; 18: 1624–1636.

18.

Cosimelli

Golfieri

Cagol

, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer 2010; 103: 324–331.

19.

Wasan

Gibbs

Sharma

, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol 2017; 18: 1159–1171.

20.

Mulcahy

Mahvash

Pracht

, et al. Radioembolization with chemotherapy for colorectal liver metastases: a randomized, open-label, international, multicenter, phase III trial. J Clin Oncol 2021; 39: 3897–3907.

21.

Kim

. Radiation pneumonitis following Yttrium-90 radioembolization: a Korean multicenter study. Front Oncol 2023; 13: 977160.

22.

Boas

Bodei

Sofocleous

. Radioembolization of colorectal liver metastases: indications, technique, and outcomes. J Nucl Med 2017; 58: 104S–111S.

23.

Neuroendocrine and Adrenal Tumors. NCCN Guideline. 2024. (accessed 2 August, 2024).

24.

Strosberg

Caplin

Kunz

, et al. 177Lu-Dotatate Plus long-acting octreotide versus highdose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2021; 22: 1752–1763.

25.

Chan

Geyer

Zemla

, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med 2025; 392: 653–665.

26.

Gaertner

Halabi

Ahmadzadehfar

, et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget 2017; 8: 55094–55103.

27.

Sartor

de Bono

Chi

, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021; 385: 1091–1103.

28.

Prostate Cancer. NCCN Guidelines. 2024. (accessed 2 August, 2024).

29.

Parker

Nilsson

Heinrich

, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–223.

30.

Smith

Parker

Saad

, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 408–419.

Clinical considerations for pharmacists regarding the use of radiopharmaceuticals in oncology

Abstract

Background

Objective

Sources

Summary

Conclusion

Keywords

Introduction

Cytotoxic mechanism of radionuclides

General pharmacist considerations for RPT

Radiopharmaceutical review

Yttrium-90 microspheres (TheraSphere®; SIR-Sphere®)

Background

Pharmacist considerations

Safety and utilization

Concomitant therapy

Contact Precautions

Lutetium-177 dotatate (Lutathera®)

Background

Pharmacist considerations

Safety and utilization

Concomitant and subsequent therapy

Contact Precautions

Lutetium-177 vipivotide tetraxetan (Pluvicto®)

Background

Pharmacist considerations

Safety and utilization

Concomitant therapy

Contact Precautions

Radium-223 (Xofigo®)

Background

Pharmacist considerations

Safety and utilization

Concomitant therapy

Contact Precautions

Conclusion

Footnotes

Acknowledgments

Author contributions

Data availability

Declaration of conflicting interests

Ethical approval and informed consent

Funding

ORCID iDs

References

Yttrium-90 microspheres (TheraSphere^®; SIR-Sphere^®)

Lutetium-177 dotatate (Lutathera^®)

Lutetium-177 vipivotide tetraxetan (Pluvicto^®)

Radium-223 (Xofigo^®)