Medullary thyroid carcinoma (MTC) represents a rare and particularly challenging malignancy, especially in metastatic stages where therapeutic options remain limited. Recently, the targeted approach of peptide receptor radionuclide therapy (PRRT) using [¹⁷⁷Lu]Lu-DOTA-TATE has revolutionized treatment paradigms in certain neuroendocrine tumors, primarily those originating from the gastroenteropancreatic system. However, its effectiveness and broader clinical applicability in MTC have been subjects of ongoing investigation, as this cancer exhibits unique pathological and molecular characteristics.
A compelling retrospective study has now shed new light on the anatomical and biochemical response patterns in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE. Conducted on a cohort of eighteen patients with somatostatin receptor-positive MTC, this research unfurls crucial insights into treatment efficacy and prognostic factors. The specificity of the somatostatin receptor (SSTR) expression and its implications on therapy decision-making were central to this study, underlining the intricate balance clinicians must navigate when determining personalized treatment strategies.
Among the pivotal findings, the median progression-free survival (PFS) following PRRT was observed to be a substantial 37.0 months. This extended time frame indicates a promising control over disease advancement compared to historical controls. Intriguingly, objective radiologic disease control, assessed through standardized RECIST 1.1 criteria utilizing advanced [⁶⁸Ga]Ga-DOTA-TATE PET/CT imaging, was achieved in nearly 78% of the patients. Such high rates of partial responses and stable disease states highlight the potential robustness of [¹⁷⁷Lu]Lu-DOTA-TATE in restraining tumor growth and dissemination.
Nevertheless, a striking discordance emerged between anatomical imaging and biochemical markers in approximately half of the cases studied. Specifically, only 44% of patients exhibited a biochemical response, defined by a 50% or greater decrease in serum calcitonin—a key tumor marker in MTC. This divergence raises critical questions about the reliance on calcitonin levels alone for monitoring therapeutic response, emphasizing the need for a multimodal assessment approach incorporating both functional imaging and biochemical analysis to capture a more accurate disease status.
Notably, patients harboring bone metastases faced a grimmer prognosis, with a significantly shorter median PFS of 24.6 months compared to 47.0 months in those without osseous involvement. This finding signals the aggressive nature of MTC once it involves the skeletal system, suggesting that bone metastases serve as a crucial prognostic indicator and may necessitate more tailored or intensified therapeutic regimens.
The therapeutic dosage also appeared to influence outcomes, with trends favoring longer PFS in patients receiving higher cumulative [¹⁷⁷Lu]Lu-DOTA-TATE doses. Although these trends did not reach statistical significance in this limited cohort, they pave the way for future dose-optimization studies aiming to maximize efficacy while balancing toxicity. Similarly, patients receiving PRRT as a first-line treatment showed tendencies toward better disease control, indicating that earlier intervention with radionuclide therapy might be advantageous in specific patient subsets.
This study also addressed the challenge posed by variable SSTR expression in MTC tumors. Some patients with low receptor expression were nonetheless candidates for PRRT, decided upon in a multidisciplinary tumor board setting. The tolerability observed across the cohort, including those with diminished SSTR positivity, supports the feasibility of extending PRRT indications beyond strict receptor expression thresholds, provided close monitoring and individual risk-benefit assessments.
The limitations of relying exclusively on biochemical markers for disease monitoring cannot be overstated, given the observed anatomical-biochemical discordance. Calcitonin, while a valuable biomarker, may not fully capture the heterogeneous tumor biology or reflect the therapeutic impact in all cases. Functional imaging with somatostatin analog PET tracers offers a complementary window into receptor dynamics and tumor burden, enabling nuanced treatment response evaluations.
From a mechanistic standpoint, [¹⁷⁷Lu]Lu-DOTA-TATE operates by binding somatostatin receptors on neuroendocrine tumor cells, delivering localized beta radiation, which induces DNA damage and cell death. Its targeted nature ideally spares surrounding healthy tissue, translating to favorable safety profiles observed in neuroendocrine tumor populations and corroborated by this MTC cohort.
Nevertheless, MTC’s biological complexity and relatively lower expression of somatostatin receptors compared to other neuroendocrine tumors present unique challenges. This underscores the imperative for personalized treatment protocols that integrate molecular imaging, genetic profiling, and clinical parameters to optimize patient selection and therapeutic outcomes.
On a broader scale, this emerging data strengthens the case for incorporating PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE into multimodal treatment frameworks for advanced MTC, especially for patients with progressive disease refractory to conventional therapies. The observed disease stabilization and manageable toxicity profile provide a foundation for larger, prospective trials that could redefine standard care practices.
In addition, the notable adverse prognostic role of bone metastases in MTC patients calls for intensified research into novel combinatorial treatments targeting skeletal microenvironments. Adjunctive strategies, such as bone-targeting agents or immunomodulatory therapies, could synergize with PRRT to mitigate metastatic progression and improve survival outcomes.
The evolution of functional imaging techniques, particularly the utilization of [⁶⁸Ga]Ga-DOTA-TATE PET/CT, has markedly enhanced clinicians’ ability to visualize tumor receptor status and distribution non-invasively. This capability not only informs treatment eligibility but also facilitates real-time therapy monitoring and early detection of progression, optimizing patient management.
Emerging therapeutic paradigms in MTC increasingly recognize the necessity of individualized medicine. As the current study illustrates, integration of anatomical, biochemical, and molecular data yields a comprehensive picture of tumor behavior, empowering personalized decision-making and better prognostic stratification.
In conclusion, the study elucidating anatomical-biochemical discordance and prognostic implications of bone metastases in MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE marks a significant advancement in understanding this rare malignancy’s treatment landscape. While challenges remain, especially regarding response assessment and metastasis management, the findings advocate for PRRT’s role as a viable and effective option in select patient populations, charting a hopeful course for future therapeutic innovation.
Subject of Research: Medullary thyroid carcinoma treatment with [¹⁷⁷Lu]Lu-DOTA-TATE peptide receptor radionuclide therapy.
Article Title: Anatomical–biochemical discordance and prognostic role of bone metastases in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE.
Article References:
Bilgic, S., Nazari, A., Sağer, M.S. et al. Anatomical–biochemical discordance and prognostic role of bone metastases in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE. BMC Cancer 25, 1644 (2025). https://doi.org/10.1186/s12885-025-15101-z
Image Credits: Scienmag.com
