Rhenium-188 HDD/Lipiodol in Liver Cancer

Summary: Rhenium-188 HDD/Lipiodol represents an innovative and promising radiotherapeutic agent designed for patients with advanced hepatocellular carcinoma (HCC) who are ineligible for surgery or liver transplantation. It combines a complex of radioactive rhenium (¹⁸⁸Re) with iodinated fatty acids of poppy seed oil (Lipiodol™), thereby delivering targeted radiation to tumour sites in the liver. This approach emerges from previous successes with ¹³¹I-Lipiodol, which demonstrated a notable survival benefit in patients with HCC. Its continued development and usage, particularly in Asia, reflects the compound’s therapeutic potential and cost-effectiveness when compared with its iodine-131-based predecessor. Even though the product is still being developed for broader markets, it is already available in India under the name REK-1. This article explores the scientific basis of ¹⁸⁸Re-HDD/Lipiodol, its mechanism of action, clinical utility, current challenges, and future prospects.

Keywords: ¹⁸⁸Re-HDD/Lipiodol; Hepatocellular carcinoma; Radioembolisation; Beta radiation therapy; Lipiodol™; Rhenium-188

Introduction to Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is amongst the most common primary liver malignancies worldwide, ranking as a leading cause of cancer-related mortality. A considerable proportion of HCC cases occur in individuals with underlying cirrhosis, viral hepatitis, or chronic liver disease. The management of HCC can be complex, involving surgical resection, liver transplantation, chemotherapy, loco-regional therapies (including radiofrequency ablation and transcatheter arterial chemoembolisation), and molecularly targeted agents such as sorafenib. However, there remains a subset of patients who cannot undergo surgical removal or transplantation, often because of advanced disease stage, poor hepatic function, or the presence of portal vein thrombosis (PVT).

In such circumstances, targeted radiotherapeutic approaches have drawn extensive interest. Radioembolisation, sometimes referred to as selective internal radiation therapy (SIRT), involves delivering radioactive particles or molecules directly into the hepatic artery that supplies the tumour. This method offers the potential of maximising therapeutic effects locally within the tumour whilst limiting radiation exposure to surrounding healthy tissues. Amongst the radioembolic options for HCC, Lipiodol-based radionuclide therapies have garnered attention for over three decades.

Rhenium-188 HDD/Lipiodol is one such novel and promising therapeutic agent in the Lipiodol-based family. It is composed of ethyl esters of iodinated fatty acids of poppy seed oil (commonly known as Lipiodol™) combined with a complex of radioactive rhenium. This formulation—together with the AHDD-Lipiodol variation that features a diacetylated form of HDD—provides targeted therapy for patients with inoperable HCC, particularly when portal vein thrombosis is also present. This article will provide an overview of Rhenium-188 HDD/Lipiodol, examining its mechanism of action, clinical benefits, and future prospects.

Historical Context: The Foundation of ¹³¹I-Lipiodol

To comprehend the evolution of Rhenium-188 HDD/Lipiodol, one must recognise the groundwork laid by ¹³¹I-Lipiodol, an early example of an intra-arterial radioembolisation agent. Lipiodol, derived from poppy seed oil, has an intrinsic tendency to accumulate in HCC lesions. When labelled with a radioactive isotope, the substance can deliver radiation selectively to cancerous tissue. Clinical investigations of ¹³¹I-Lipiodol revealed that, in cases of advanced HCC, it afforded localised tumouricidal effects, enhancing survival by approximately three years compared to reference groups.

However, in certain regions—particularly in Asia—¹³¹I-Lipiodol has been challenging to procure consistently. Factors such as regulatory constraints, cost, and complexities in supply chains have impeded widespread usage. These barriers fostered a drive within academic groups to develop an alternative radiolabelled compound offering similar or improved therapeutic advantages but with greater availability and affordability. In this setting, the International Atomic Energy Agency (IAEA) lent support to the development of what is known today as Rhenium-188 HDD/Lipiodol.

Composition and Mechanism of Action

Rhenium-188 HDD/Lipiodol is a mixture composed of iodinated fatty acids of poppy seed oil (Lipiodol™) and a radioactive rhenium complex. The “HDD” stands for a compound that contains sulfhydryl groups able to bind rhenium-188, a beta-emitting radionuclide. A variant of HDD, called AHDD, incorporates a diacetylated form, providing additional stability to the sulfhydryl groups within the kit formulation through the presence of acetyl groups.

Lipiodol

Lipiodol, a poppy seed oil derivative, consists largely of ethyl esters of iodinated fatty acids. For several decades, it has been widely utilised for diagnostic imaging (lymphography) and for targeted drug delivery in interventional oncology (transarterial chemoembolisation). The reason Lipiodol is suitable for HCC therapy is its unique property of preferentially accumulating within tumour nodules due to the tumour’s hypervascularity and abnormal vasculature. Consequently, incorporating a therapeutic payload, such as a radionuclide, allows localised radiation to be delivered directly to malignant cells.

Rhenium-188

Rhenium-188 is a beta-emitting radionuclide with a short half-life of approximately 17 hours. It emits beta radiation (β– electrons) capable of delivering high-dose radiation over a short distance, damaging tumour cells whilst minimising exposure to normal tissues. Its relatively short half-life also enables clinicians to deliver therapy without requiring prolonged hospital stays, thereby reducing the overall healthcare burden. Moreover, the short half-life facilitates potential repeated dosing should additional treatments be required.

Target/Mechanism

The primary therapeutic target for Rhenium-188 HDD/Lipiodol is liver tissue containing HCC tumours. When Rhenium-188 HDD/Lipiodol is administered intra-arterially (commonly via the hepatic artery), the Lipiodol fraction preferentially localises within the tumour, drawn by its rich blood supply and unique vascular network. The beta radiation emitted by the rhenium component then delivers cytotoxic effects directly to cancer cells over time.

Compared to conventional chemotherapy, which can be limited by systemic toxicity and drug resistance, Rhenium-188 HDD/Lipiodol targets the site of disease more selectively, sparing non-cancerous regions of the liver to a significant degree. This targeted approach can ultimately improve outcomes and limit adverse effects.

Clinical Applications in Hepatocarcinoma

One of the key areas of development for Rhenium-188 HDD/Lipiodol lies in its potential to treat patients who have advanced HCC accompanied by portal vein thrombosis (PVT). This condition is typically a contraindication or major challenge to many loco-regional and surgical procedures since PVT often indicates extensive vascular involvement and diminished hepatic reserve. Inoperable patients who lack transplant options have limited therapeutic pathways. Notwithstanding this, Rhenium-188 HDD/Lipiodol may offer a solution.

The agent can be selectively delivered via the hepatic artery, bypassing the obstructed portal vein and depositing Lipiodol within the tumour. In this way, localised radiation therapy is achieved, sparing large volumes of healthy liver. This holds particular promise for patients who otherwise have few viable treatment avenues available.

Unresectable and Untransplantable HCC

Another demographic of interest is the wider population of patients with unresectable and untransplantable HCC. Surgery is often the first-line curative treatment, but many individuals either do not qualify for surgical intervention due to tumour burden, comorbidities, or lack of available donor organs. Systemic therapies have improved over the years; yet, these agents may come with significant toxicities or suboptimal long-term outcomes.

Therapeutic radiopharmaceuticals such as Rhenium-188 HDD/Lipiodol fit within a broader strategy of loco-regional treatments designed to reduce tumour burden, maintain liver function, and potentially prolong overall survival. The flexibility of being able to repeat treatment sessions—owing to the short half-life of rhenium-188—adds another advantage for controlling tumour growth long-term.

Current Status and Potential Advantages

A significant motivating factor behind the development of 188Re-HDD/Lipiodol is accessibility and affordability. ¹³¹I-Lipiodol, whilst clinically effective, was often difficult to source reliably in regions where HCC prevalence is high, including several Asian nations. The short half-life of ¹⁸⁸Re (17 hours) facilitates onsite or near-site production, reducing reliance on distant supply chains. The possibility of generator-based production of rhenium-188 is another advantage: a tungsten-188/rhenium-188 generator can yield fresh rhenium-188 for daily or weekly use, providing a cost-effective and convenient supply.

Moreover, academic institutions and research hospitals can adopt local generator-based production, bypassing some of the complexities of nuclear pharmacy distribution that hamper the distribution of certain isotopes. This ensures ¹⁸⁸Re-HDD/Lipiodol can be developed and administered at a fraction of the cost that might be seen with ¹³¹I-labelling or other isotopes requiring centralised production and distribution networks.

Efficacy

Although Rhenium-188 HDD/Lipiodol is categorised as a “generic therapeutic,” its efficacy is largely extrapolated from extensive data on ¹³¹I-Lipiodol, which has shown promising improvements in overall survival and local tumour control in advanced HCC. Early clinical experiences with ¹⁸⁸Re-HDD/Lipiodol have corroborated these findings, demonstrating tumour shrinkage, pain relief, and improved quality of life for many patients. The prospective survival benefit is especially relevant to individuals who have no other curative options.

It should be noted, however, that establishing long-term efficacy and survival outcomes requires large-scale, randomised controlled trials. Additional data collection is essential to confirm its therapeutic benefits comprehensively, particularly in comparison with emerging standards of care such as tyrosine kinase inhibitors and immunotherapies.

Safety Profile

All forms of radioembolisation come with certain risks, including radiation-induced liver disease (RILD) and damage to the lungs if the radioactive material inadvertently shunts to pulmonary circulation. Nonetheless, the short tissue penetration range of beta particles tends to confine radiation to a small area, limiting the exposure of healthy tissue. Furthermore, the short half-life of rhenium-188 helps minimise prolonged radiation doses to non-target tissues. Appropriate dosimetry planning, patient selection, and close monitoring during and after therapy can further reduce risks.

REK-1: Availability in India

In India, Rhenium-188 HDD/Lipiodol is already marketed under the name REK-1. This reflects both the country’s significant burden of HCC and the desire for cost-effective alternatives for patients unable to undergo definitive management strategies. The presence of REK-1 underscores the translational potential of academic research in nuclear medicine to provide real-world therapies.

India’s experience with REK-1 provides a prototype for how generics can be introduced successfully in regions where barriers to established agents are more pronounced. Over time, it may encourage other countries to follow a similar path, ensuring wider global accessibility of targeted radionuclide therapy for HCC.

Ongoing Challenges and Considerations

One of the ongoing hurdles for Rhenium-188 HDD/Lipiodol is regulatory approval across different jurisdictions. The complexity of radiopharmaceutical regulation, coupled with the intricacies of local generator-based production, can sometimes cause delays in authorisation. Each government body requires stringent evaluation of safety, efficacy, and quality control measures.

Standardisation in manufacturing processes, labelling, and dosage calibration is essential to ensure consistent product quality. Industrial-scale production may be complicated by the requirement to maintain good manufacturing practices (GMP) for radioactive products. In some nations, regulatory agencies are still adjusting to the rise of novel radiopharmaceuticals, meaning that the approval pathway may vary significantly.

Physician and Patient Awareness

Relatively few oncologists, interventional radiologists, and patients are aware of Rhenium-188 HDD/Lipiodol therapy. Until recently, radioembolisation research has focused predominantly on yttrium-90 microspheres or ¹³¹I-Lipiodol. As a result, the data pool for ¹⁸⁸Re-HDD/Lipiodol, while growing, is not as robust. Dissemination of clinical trial outcomes, real-world data, and guidelines from professional societies is imperative to raise awareness and encourage uptake.

Additionally, patients often have a limited understanding of radiopharmaceutical therapies. Education and support services are pivotal to demystifying the treatment process and addressing any concerns about radiation safety. Patient advocacy can also play a role in prompting healthcare systems to integrate new options into standard treatment pathways.

Competition and Comparison with Other Radionuclides

Radiopharmaceutical therapies for liver cancer are not limited to ¹³¹I-Lipiodol and 188Re-HDD/Lipiodol. Yttrium-90 (Y-90) microspheres (both resin and glass) have garnered substantial interest, especially in developed markets. These therapies are extensively studied and have a robust commercial presence. On the other hand, ¹⁸⁸Re-HDD/Lipiodol stands out for its potential cost-effectiveness and accessibility advantages.

Further comparative studies would be valuable, examining differences in tumour response, overall survival, toxicity profiles, and cost-effectiveness across Y-90 microspheres, ¹³¹I-Lipiodol, and ¹⁸⁸Re-HDD/Lipiodol. Identifying which subgroup of patients benefits most from each therapy could refine treatment protocols and lead to more personalised care.

Dosimetry and Treatment Planning

Treatment planning for radioembolisation demands careful calculation of activity levels, which in turn ensure adequate tumour coverage whilst minimising damage to healthy liver tissue. Individual patient factors, such as tumour burden, liver function, vascular anatomy, and the presence of PVT, must be assessed thoroughly. Dosimetry software and imaging techniques (e.g., single-photon emission computed tomography or SPECT and positron emission tomography or PET) are crucial for planning and post-procedural evaluation.

Ongoing research aims to refine dosimetry models specifically for rhenium-188, thereby improving safety margins and therapeutic efficacy. Advances in imaging technology, combined with robust patient selection criteria, will contribute to optimal usage and outcomes for Rhenium-188 HDD/Lipiodol.

Potential Future Developments

A promising avenue for enhancing the efficacy of ¹⁸⁸Re-HDD/Lipiodol lies in combining it with other treatments. For instance, the concomitant use of systemic therapies, such as targeted agents (tyrosine kinase inhibitors like sorafenib or lenvatinib) or immune checkpoint inhibitors (e.g., nivolumab or pembrolizumab), may generate synergistic anti-tumour effects. Some preliminary evidence suggests that combining loco-regional radiotherapy with immunotherapy could heighten the immune system’s recognition and destruction of tumour cells.

Additional synergy could be explored by pairing Rhenium-188 HDD/Lipiodol with conventional chemoembolisation or other ablative procedures. These combination regimens might allow for multi-pronged attacks on the tumour, potentially controlling both local and micro-metastatic disease. However, robust clinical trials are needed to define optimal sequencing, dosing, and safety.

Personalised Medicine and Patient Stratification

An essential goal in oncology is the personalisation of therapy. For HCC, the biology of the tumour can vary significantly among patients. Some tumours are highly vascular, while others have heterogeneous vascular patterns. Likewise, the presence of genetic mutations (e.g., in TP53 or WNT/β-catenin pathways) might impact responsiveness to certain treatments. Integrating molecular profiling and advanced imaging could improve the selection of patients for ¹⁸⁸Re-HDD/Lipiodol, thereby maximising treatment benefits.

Moreover, real-time imaging and dosimetry may be used to adapt doses during therapy sessions (intra-procedural dose painting). This “precision radioembolisation” approach would require advanced software, integrated imaging modalities, and robust feedback mechanisms, but could represent the next frontier in personalised loco-regional therapy.

Expanding Indications

Although Rhenium-188 HDD/Lipiodol has been primarily evaluated for HCC, other tumour types might also benefit from Lipiodol-based targeting if they demonstrate a propensity to absorb Lipiodol. Metastatic liver lesions from other primary cancers could, in principle, be treated with rhenium-188-based radioembolisation if further research demonstrates significant tumour uptake. Proof-of-concept studies may assess whether this approach could be generalised beyond HCC, thereby broadening the potential patient population for which ¹⁸⁸Re-HDD/Lipiodol is indicated.

Safety and Toxicology

Given the nature of Rhenium-188 HDD/Lipiodol, radiation exposure is inevitable. Yet the key lies in limiting that exposure to non-target tissues. The relatively short half-life of rhenium-188, combined with the localised uptake of Lipiodol within the liver tumour, substantially reduces off-target radiation. When performed under appropriate safety protocols, radioembolisation with ¹⁸⁸Re-HDD/Lipiodol is generally considered safe.

Common adverse events might include transient fever, fatigue, or mild abdominal pain following administration. Rare but more severe complications can occur if a significant fraction of the injected dose travels to the lungs or non-target organs. To mitigate this risk, pre-therapy imaging using macroaggregated albumin (MAA) labelled with technetium-99m is often performed to assess the degree of lung shunting. Additionally, prophylactic medications, such as proton pump inhibitors, may be prescribed to reduce gastrointestinal complications.

Healthcare providers and nuclear medicine teams are trained to handle radioactive materials safely. Engineering controls (e.g., shielding), administrative controls (e.g., standard operating procedures), and personal protective equipment help protect medical staff during preparation and administration of the therapy. Patients may also need temporary isolation in facilities with adequate shielding, although the short half-life of rhenium-188 generally minimises the duration.

Conclusion

Rhenium-188 HDD/Lipiodol presents a dynamic and potentially cost-effective option for patients with advanced hepatocellular carcinoma, specifically those who cannot be treated by surgical resection or transplantation. Building on the successes and lessons learned from ¹³¹I-Lipiodol, Rhenium-188 HDD/Lipiodol provides a targeted mechanism, delivering therapeutic doses of radiation directly to HCC lesions. Its short half-life, onsite generator-based production, and tumour-specific uptake offer tangible benefits in terms of accessibility, cost-effectiveness, and feasibility.

Although further large-scale studies are necessary to solidify its long-term efficacy and refine patient selection protocols, early clinical evidence is encouraging. REK-1’s introduction in India highlights the real-world potential of this therapy. Moving forward, integrating Rhenium-188 HDD/Lipiodol into emerging combination regimens and leveraging advanced dosimetry will likely enhance outcomes. As knowledge and evidence evolve, the therapy could also find applications in other malignancies that demonstrate Lipiodol affinity.

Rhenium-188 HDD/Lipiodol stands as a testament to the global impetus for innovative, affordable, and effective treatments for one of the most challenging malignancies. In the coming years, multi-institutional collaborations, robust clinical data, and technological improvements will set the stage for the expanded use of this “generic” yet transformative radiotherapeutic agent, ensuring that more patients with advanced liver cancer receive the best possible care.

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