New Horizons in Bone Metastasis Treatment
Integrated clinical strategy of preventive radiotherapy and “cold tumor to hot tumor”
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Clinical Challenges of Bone Metastasis
Bone metastasis is a frequent complication in various cancers, particularly breast, prostate, and lung cancers. Statistics indicate that over 70% of advanced breast and prostate cancer patients will develop bone metastases (Ferreira et al., 2022). These metastases can cause severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia. Such skeletal-related events (SREs) not only lead to disability but also significantly increase healthcare burden.
Traditional therapeutic goals have primarily focused on pain relief, structural stabilization, and prevention of complications. However, recent research highlights that bone metastases themselves may serve as an immune breakthrough point, making the combination of prophylactic radiotherapy and cold-to-hot tumor conversion an emerging clinical strategy.
The Role of Prophylactic Radiotherapy
Definition and Application
“Prophylactic radiotherapy” refers to applying localized radiation therapy to high-risk bone lesions before severe complications like fractures or pain occur (Coleman, 2018).
Key Clinical Benefits
- Reduced fracture risk: Stereotactic body radiotherapy (SBRT) delivers focused energy to protect surrounding bone.
- Decreased spinal cord compression risk: Especially relevant for vertebral metastases.
- Pain relief and functional improvement: 70–80% of patients achieve significant pain reduction within 2–4 weeks (Lutz et al., 2017).
Extended Benefit: Immune Activation
Beyond local control, radiotherapy may trigger systemic immune responses, also known as the abscopal effect—a promising avenue in bone metastasis management (Demaria et al., 2004).
Cold-to-Hot Tumor Conversion: Immunological Basis
Characteristics of Cold Tumors
“Cold tumors” lack immune infiltration, show low PD-L1 expression, and insufficient antigen release, making them poorly responsive to immune checkpoint inhibitors (Hegde & Chen, 2020). Bone metastases in breast cancer are frequently cold tumors.
How Radiotherapy “Heats Up” Tumors
Radiotherapy can:
- Induce DNA damage → release tumor antigens.
- Generate danger-associated molecular patterns (DAMPs) → attract dendritic cells.
- Activate interferon signaling → increase CD8⁺ T-cell infiltration.
- Enhance PD-L1 expression → improve checkpoint inhibitor sensitivity (Nabrinsky et al., 2022).
Thus, radiotherapy may serve as an immune “ignition switch,” turning cold tumors into “hot” immunoresponsive tumors.
Oligometastatic Disease (OMD) and Precision Therapy
OMD generally refers to patients with fewer than five metastatic sites. This state is regarded as a therapeutic windowwhere local treatment may still achieve long-term control or even cure (MDPI, 2023).
- SBRT + Immunotherapy: SBRT delays disease progression while immunotherapy enhances systemic surveillance (Palma et al., 2019).
- Clinical Data: A multicenter trial showed that applying SBRT to limited bone metastases improved 2-year progression-free survival to 50%, outperforming systemic therapy alone (Ost et al., 2018).
The Value of Integrative Approaches in Bone Metastasis Care
Immunonutrition
Formulas enriched with arginine, glutamine, and omega-3 fatty acids reduce infection risk, improve treatment tolerance, and support immune function (Arends et al., 2021). When combined with radiotherapy and immunotherapy, they can further facilitate the cold-to-hot conversion.
Dietary Strategies
- Mediterranean diet: Rich in anti-inflammatory and antioxidant compounds, improves tumor microenvironment (De Cicco et al., 2021).
- Polyphenols: Green tea catechins and curcumin modulate immunity and inflammation.
- Protein supplementation: Maintains muscle mass and immune resilience.
Exercise Interventions
Regular exercise strengthens bone health, reduces fatigue, and enhances immune response. RCTs demonstrate that moderate exercise boosts NK cell activity in cancer patients (Campbell et al., 2019).
Psychosocial and Mind-Body Therapies
Anxiety and stress suppress immune function. Mindfulness, music therapy, and acupuncture have clinical evidence for reducing pain and anxiety, thereby improving quality of life (Greenlee et al., 2017).
Future Directions
- Clinical trial design: More prospective randomized studies are needed on “bone metastasis + prophylactic radiotherapy + immunotherapy.”
- Biomarker research: Identifying patients most likely to benefit from cold-to-hot conversion.
- Optimized integrative models: Incorporating nutrition, exercise, and psychological care into multidisciplinary treatment.
Conclusion
Bone metastasis poses a major challenge in cancer progression. However, prophylactic radiotherapy combined with immunomodulatory strategies may open new therapeutic avenues. By reframing bone metastasis from an immunological perspective, cold-to-hot tumor conversion could amplify both local and systemic treatment efficacy. Coupled with immunonutrition, anti-inflammatory diets, exercise, and psychosocial support, this integrative framework offers renewed hope for patients.
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References
- Arends, J., Bachmann, P., Baracos, V., et al. (2021). ESPEN guidelines on nutrition in cancer patients. Clinical Nutrition, 40(5), 2898–2913.
- Campbell, J. P., Fadel, P. J., & Wegner, M. (2019). Exercise and the immune system: clinical benefits. Trends in Immunology, 40(7), 629–641.
- Coleman, R. (2018). Clinical features of metastatic bone disease and risk of skeletal morbidity. Clinical Cancer Research, 24(24), 6248–6256.
- De Cicco, P., Catani, M. V., Gasperi, V., et al. (2021). Nutrition and breast cancer: A literature review on prevention, treatment and recurrence. Nutrients, 13(11), 3889.
- Demaria, S., Ng, B., Devitt, M. L., et al. (2004). Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade. Clinical Cancer Research, 10(2), 531–539.
- Ferreira, B. R., et al. (2022). Bone metastasis: clinical implications and therapeutic advances. Journal of Bone Oncology, 31, 100361.
- Greenlee, H., Balneaves, L. G., Carlson, L. E., et al. (2017). Clinical practice guidelines on integrative therapies for breast cancer patients. Journal of Clinical Oncology, 35(18), 1962–1981.
- Hegde, P. S., & Chen, D. S. (2020). Top 10 challenges in cancer immunotherapy. Immunity, 52(1), 17–35.
- Lutz, S., Balboni, T., Jones, J., et al. (2017). Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology, 7(1), 4–12.
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- Nabrinsky, E., et al. (2022). A review of the abscopal effect in the era of immunotherapy. Cureus, 14(9), e29620.
- Ost, P., et al. (2018). Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. Journal of Clinical Oncology, 36(5), 446–453.
- Palma, D. A., et al. (2019). Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomized, phase 2 trial. The Lancet, 393(10185), 2051–2058.