Summary: Yttrium-90 DOTALAN (90Y-Lanreotide, 90Y-Somatulin) is a radiolabelled somatostatin analogue designed to bind specifically to somatostatin receptors in neuroendocrine neoplasms. Lanreotide, the carrier molecule, is linked to the radioactive isotope Yttrium-90, allowing targeted delivery of therapeutic beta electrons (β–) to tumour cells. Although 90Y-Lanreotide showed promise during early-phase clinical trials, it was ultimately overshadowed by other, more advanced radiolabelled somatostatin analogues such as 177Lu-Oxodotreotide. As a result, the development of 90Y-Lanreotide is currently on hold. This article reviews the mechanism of action, clinical development, comparative advantages and drawbacks of 90Y-Lanreotide, and its future outlook in the evolving landscape of neuroendocrine tumour therapy.
Keywords: Yttrium-90; Lanreotide; Neuroendocrine neoplasms; Somatostatin receptors; PRRT (Peptide Receptor Radionuclide Therapy); 177Lu-Oxodotreotide
Introduction to Neuroendocrine neoplasms (NENs)
Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumours originating from specialised neuroendocrine cells in the gastrointestinal tract, pancreas and other organs. These tumours often express high levels of somatostatin receptors, making them prime targets for somatostatin analogues. Over the years, multiple therapies have been developed to address neuroendocrine tumours (NETs). Among these, radiolabelled somatostatin analogues are significant, particularly in patients requiring targeted systemic therapy.
Yttrium-90 DOTALAN also referred to as 90Y-Lanreotide or 90Y-Somatulin, exemplifies a targeted treatment approach that harnesses the specificity of lanreotide for somatostatin receptors and the cytotoxic potential of the beta emitter Yttrium-90. Although this molecule was investigated in clinical trials up to Phase I/II, it failed to demonstrate sufficient advantages over other concurrent therapies, such as 177Lu-Oxodotreotide. Consequently, the development of 90Y-Lanreotide has been placed on hold.
Mechanism of Action and Pharmacokinetics
Central to the value of Yttrium-90 DOTALAN is its ability to exploit the widespread presence of somatostatin receptors in neuroendocrine tumours. Lanreotide, this compound’s carrier or ligand component, is a synthetic octapeptide structurally similar to somatostatin. Somatostatin is a naturally occurring hormone that regulates a range of physiological processes, including inhibiting hormone release from endocrine and exocrine cells. By mimicking somatostatin, lanreotide can bind with high affinity to specific somatostatin receptor subtypes, principally sst2, which tend to be overexpressed in NETs.
After binding, Yttrium-90 DOTALAN enters the tumour cells via receptor-mediated endocytosis. Once internalised, the Yttrium-90 radioisotope delivers its cytotoxic payload through the emission of beta electrons (β–), which causes breakage of DNA strands and subsequent cell death. This targeted delivery mechanism minimises systemic toxicity and off-target effects by directing the radioactive particles specifically to tumour cells that overexpress somatostatin receptors.
From a pharmacokinetic standpoint, 90Y-Lanreotide’s distribution is strongly influenced by the presence of somatostatin receptors. The drug is generally most effective in tumours with a high density of these receptors. However, normal tissues expressing somatostatin receptors (such as the pituitary gland, gastrointestinal tract and pancreas) may also be exposed, potentially leading to subclinical or clinical side effects. Clearance of 90Y-Lanreotide usually occurs through renal excretion. As Yttrium-90 decays, it emits beta radiation with a moderate tissue penetration range, making it suitable for targeting both primary lesions and metastases.
Clinical Development and Efficacy
Lanreotide has a well-documented history of clinical use as a non-radioactive somatostatin analogue for managing symptoms associated with neuroendocrine tumours, such as carcinoid syndrome and acromegaly. The concept of linking lanreotide to a therapeutic isotope like Yttrium-90 emerged as part of an effort to extend the benefits of somatostatin analogue therapy beyond symptom control. By attaching a potent radioactive payload to lanreotide, researchers aimed to create a drug that would alleviate endocrine symptoms and directly induce tumour cell death.
Preclinical studies conducted in vitro and in animal models suggested that 90Y-Lanreotide could be taken up by somatostatin receptor-bearing cells, resulting in significant tumour cell kill. These encouraging data spurred early-phase clinical trials in humans.
Phase I/II Trials
Early clinical studies evaluated the safety, tolerability and preliminary efficacy of 90Y-Lanreotide in patients with advanced neuroendocrine tumours. Although the studies were relatively small, they demonstrated acceptable safety profiles and modest tumour response rates. Various endpoints, including tumour shrinkage and progression-free survival, were investigated.
Nevertheless, the observed efficacy did not surpass that achieved by other radiolabelled somatostatin analogues under development at the time. While 90Y-Lanreotide was shown to be generally well-tolerated, with side effects such as mild haematological toxicity, fatigue and transient gastrointestinal disturbances, its anti-tumour effectiveness was deemed insufficient for a sustained development path. This was exacerbated by growing interest in alternative isotopes, such as Lutetium-177, which has more favourable decay characteristics and a more flexible energy profile for targeting smaller metastases.
Comparison to Other Molecules
During the time 90Y-Lanreotide was in development, other molecules such as 90Y-DOTATOC and 177Lu-DOTATATE (now commonly known as 177Lu-Oxodotreotide) were also being studied. In particular, 177Lu-Oxodotreotide demonstrated compelling benefits, including a longer path length that may be better suited to certain tumour sizes and a more favourable toxicity profile for bone marrow. As evidence mounted for 177Lu-based therapies, the comparative advantages of 90Y-Lanreotide dwindled.
In addition, the high-energy beta emission from Yttrium-90 can be advantageous for targeting bulkier tumours, but it may be less ideal for smaller lesions where crossfire damage can occur to surrounding tissues. On the other hand, the narrower energy spectrum of Lutetium-177 offers a more refined approach in some cases. As a result of these competing radiopharmaceuticals—especially those that reached more advanced stages of development—90Y-Lanreotide found itself in an increasingly narrow market niche.
Comparison with Other Radiolabelled Somatostatin Analogues
Currently, the most prominent alternative to 90Y-Lanreotide is 177Lu-Oxodotreotide, also known as 177Lu-DOTATATE. This therapy has been extensively studied in clinical trials and gained regulatory approval in multiple jurisdictions for the treatment of certain advanced neuroendocrine tumours. Its mechanism is similar to 90Y-Lanreotide, targeting somatostatin receptors on tumour cells. The main distinction lies in the radionuclide attached to the somatostatin analogue: Lutetium-177 vs. Yttrium-90.
177Lu-Oxodotreotide’s energy profile allows for a more controlled radiation dose to tumours, especially when dealing with smaller lesions. It also has the advantage of gamma emission, which can be used for diagnostic imaging, facilitating a personalised dosimetry approach to treatment. This dual therapeutic-diagnostic (theranostic) capability has made 177Lu-Oxodotreotide particularly attractive, granting clinicians a degree of flexibility that 90Y-Lanreotide does not provide.
Efficacy and Safety Profiles
In randomised trials, 177Lu-Oxodotreotide has shown improvement in progression-free survival and, in some cases, overall survival in patients with certain types of NETs. Toxicities, which include mild to moderate bone marrow suppression, renal impairment and transient hormonal imbalances, are typically manageable within the context of monitored treatment protocols. Long-term follow-up studies also suggest that the risk of severe adverse effects can be kept relatively low with careful patient selection and dose-optimisation strategies.
On the other hand, Yttrium-90 DOTALAN, while based on a similar mechanism of action, did not demonstrate an advantage sufficient to gain a robust foothold. Though it showed a reasonable safety profile and some efficacy, it ultimately found it challenging to compete with the more advanced development and widespread adoption of therapies like 177Lu-Oxodotreotide.
Reasoning Behind 90Y-Lanreotide’s Loss of Momentum
The real deciding factor that hindered 90Y-Lanreotide’s progression was the parallel evolution of radiopharmaceuticals that leveraged Lutetium-177. The ability to image with Lutetium-177, combined with promising clinical outcomes from large-scale trials, propelled 177Lu-Oxodotreotide to the forefront of therapy. Furthermore, the narrower emission range of Lutetium-177 can minimise collateral damage to surrounding healthy tissues, offering an overall better risk-benefit balance.
Current Status and Future Outlook
The development of 90Y-Lanreotide has been placed on hold. Researchers concluded that its modest performance did not justify further investment, especially given the momentum behind 177Lu-based therapies. Pharmaceutical companies and academic institutions must operate within limited resources and often choose to advance only the most promising candidates. In the case of 90Y-Lanreotide, the clinical data acquired up to Phase I/II did not provide sufficient evidence to warrant large-scale Phase III trials.
Potential for Revival
It is not impossible that 90Y-Lanreotide could resurface in niche applications where its specific energy profile may offer certain advantages. For example, tumours that are large or have a tendency to be resistant to other isotopes might still benefit from Yttrium-90’s strong beta emission. However, rigorous comparative trials or new approaches to patient selection would be required to justify such a revival.
Additionally, improvements in personalised dosimetry, which involves measuring radiation doses absorbed by specific tissues, may open a window for 90Y-based therapies in certain subsets of patients. By carefully customising the dose to the patient’s tumour characteristics and overall health profile, it might be possible to enhance efficacy and minimise off-target toxicity. Nevertheless, significant hurdles remain, particularly in the abundance of clinically established alternatives.
Broader Implications for PRRT
The story of 90Y-Lanreotide serves as a case study in the evolution of peptide receptor radionuclide therapy. As the field grows, competition among radiopharmaceuticals intensifies, leaving only the most compelling agents to move forward. Although 90Y-Lanreotide did not survive this winnowing, its initial development added to the body of knowledge on how best to deliver targeted radiation to somatostatin receptor-expressing tumours.
Continuing research is now focused on refining existing radiolabelled analogues and developing novel agents with improved tumour affinity, reduced off-target toxicity and the ability to overcome resistance mechanisms. Efforts to combine PRRT with other treatment modalities—such as checkpoint inhibitors, tyrosine kinase inhibitors or targeted therapies—are underway, aiming to produce synergistic effects and broaden the therapeutic spectrum for neuroendocrine neoplasms.
Conclusion
Yttrium-90 DOTALAN (90Y-Lanreotide, 90Y-Somatulin) symbolises an interesting chapter in the development of targeted treatments for neuroendocrine neoplasms. By combining the receptor-binding specificity of lanreotide with the cytotoxic power of Yttrium-90, this radiopharmaceutical was formulated to home in on somatostatin receptors overexpressed on malignant cells. Early clinical trials showed some promise, as patients experienced moderate tumour shrinkage and manageable side effects.
Nevertheless, 90Y-Lanreotide struggled to surpass competing agents, most notably 177Lu-Oxodotreotide, which displayed a more favourable energy profile, strong tumour response data and the additional benefit of imaging capability. As a result, 90Y-Lanreotide did not advance beyond Phase I/II trials and is currently on hold. Although there remains a slim chance that this radiopharmaceutical could find a niche application in the future—particularly for large or otherwise resistant tumours—no immediate plans exist for further clinical development.
For clinicians, patients and researchers, the central lesson gleaned from 90Y-Lanreotide’s journey is the critical role of comparative effectiveness in the crowded domain of PRRT. Each new agent faces the challenge of proving superior efficacy and safety when measured against rapidly evolving standards of care. Developments in personalised dosimetry, patient selection and combination therapy may one day reignite interest in radionuclides like Yttrium-90. However, for the time being, 177Lu-Oxodotreotide stands as the more widely accepted alternative, enabling clinicians to deliver targeted radiotherapy in a safer and more effective manner.
The story of Yttrium-90 DOTALAN highlights both the potential and the challenges inherent in the quest to deliver precise, receptor-directed radiation to neuroendocrine tumours. Although it did not manage to secure a lasting place in the therapeutic arsenal, the knowledge gained throughout its development continues to inform ongoing innovation in radiopharmaceutical science. By building on these lessons and leveraging advances in molecular imaging, synthetic chemistry and precision oncology, the field of PRRT remains poised for further breakthroughs that could transform the management of neuroendocrine neoplasms in the years ahead.
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