Compatibility of CyberKnife and PSMA Radioligand Therapy in Treating Prostate Cancer

August 27, 2025August 28, 2025anastasiaNews

We have recently attended the opening of the first CyberKnife Center in Austria, namely in the beautiful city of Salzburg. It was not just a ceremonial occasion. It paved the way to a fruitful cooperation benefiting our patients. These two advanced therapies—CyberKnife radiotherapy and PSMA radioligand therapy (RLT)—can work together to improve outcomes for men with prostate cancer. Far from being alternatives, these two treatments are in fact highly compatible and can complement each other in several meaningful ways.

What Exactly Is CyberKnife?

CyberKnife is a form of robotic stereotactic body radiotherapy (SBRT). In simple terms, it uses a robotic arm and advanced imaging systems to deliver highly focused radiation beams directly to cancerous tissue, while sparing the surrounding healthy organs. Thanks to real-time image guidance and motion tracking, CyberKnife achieves submillimeter precision, even accounting for natural body movements like breathing. Unlike traditional radiation therapy, which can require daily sessions over several weeks, CyberKnife usually involves just one to five sessions, making it far more convenient.

For prostate cancer, CyberKnife is most often used in early-stage disease or for patients with oligometastatic lesions—that is, a few small metastases outside the prostate. It’s particularly appealing because it’s non-invasive, often causes fewer side effects, and has excellent long-term control rates.

What is PSMA Radioligand Therapy?

PSMA radioligand therapy works very differently. Instead of targeting tumors from the outside with external beams, it delivers radiation from the inside out. The treatment involves a radioactive isotope—commonly Lutetium-177 (a beta emitter) or Actinium-225 (an alpha emitter) or Terbium-161 (Auger electrons)—linked to a molecule that binds to PSMA (Prostate-Specific Membrane Antigen), a protein abundant on prostate cancer cells. This allows radiation to go directly where it’s needed, including tiny metastatic deposits in bones and soft tissues that other treatments might miss.

Complementary Roles

Local Control Meets Whole-Body Targeting

The beauty of combining CyberKnife and PSMA RLT lies in their complementary strengths. CyberKnife excels at treating localized tumors—whether that’s the prostate itself or a few large metastatic spots—while PSMA RLT is designed to tackle a wider dispersed disease, including microscopic cancer cells circulating in the body. Used together, they can offer comprehensive disease control, addressing both the macroscopic and microscopic components of prostate cancer.

Typically, CyberKnife is most effective when the prostate gland is relatively small (less than 80–100 cm³). By contrast, PSMA RLT is not limited by tumor size or location, as long as there is sufficient PSMA expression for the therapy to target.

Radiation-Induced PSMA Upregulation

Another way these treatments may work together is through a fascinating biological effect: radiation from CyberKnife can increase PSMA expression on cancer cells, making them more visible and therefore more vulnerable to PSMA radioligand therapy. Laboratory studies and small clinical observations suggest that radiation can upregulate PSMA expression—that is, make prostate cancer cells display even more PSMA on their surface. This occurs through activation of the FOLH1 gene, which encodes PSMA, as part of the tumor’s adaptive response to radiation-induced stress and DNA damage.

Radiation can also alter the tumor microenvironment, such as oxygen levels, inflammation, and blood supply. In particular, hypoxia (low oxygen) has been linked to increased FOLH1 expression in some prostate cancer cell lines, further boosting PSMA expression.

Timing seems to matter: some studies suggest that PSMA expression peaks days to weeks after radiation, though the optimal window for sequencing CyberKnife and PSMA RLT remains under investigation. While this concept—known as radiosensitization—is still being explored, it holds promise for improving outcomes in advanced cases.

Tumor Sink Effect and Personalized Dosing

Another useful synergy relates to the so-called tumor sink effect. When patients have a very large tumor burden, most of the PSMA radioligand goes to the cancer, which actually spares healthy organs like the kidneys and salivary glands from high radiation doses. When the tumor burden is reduced—say, by removing or ablating large lesions with CyberKnife—more radioligand may circulate to normal tissues, slightly increasing their radiation exposure. To manage this, researchers are developing personalized dosimetry approaches, adjusting the administered activity of radionuclides based on tumor volume and organ uptake measured by imaging.

This means that after CyberKnife treatment, a lower dose of PSMA RLT may be administered to keep kidneys and salivary glands safe—without compromising the therapy’s cancer-fighting power. Early studies show that tailoring doses in this way can reduce toxicity while maintaining high response rates.

What Does This Mean for Patients?

The combination of CyberKnife and PSMA RLT is not a one-size-fits-all solution, but it’s an example of how cancer care is becoming more personalized than ever. CyberKnife can eliminate large, visible tumors with precision, while PSMA RLT seeks out and destroys cancer cells throughout the body. Add to this the possibility of radiosensitization and individualized dosing, and the result is a treatment plan that is truly tailored to the patients’ needs.

It’s important to understand that some of these benefits—like radiation-induced PSMA upregulation—are still being studied. Large clinical trials are ongoing to confirm how best to combine these therapies. But the rationale is strong, and the potential for improved outcomes is real.

The Bottom Line

CyberKnife and PSMA radioligand therapy are two cutting-edge approaches that, when thoughtfully combined, can offer a powerful, patient-centered strategy for treating prostate cancer. They complement each other beautifully: one targets the big, visible lesions with surgical precision, the other hunts down microscopic disease hiding elsewhere in the body. Together, they move us closer to truly personalized, effective, and less invasive cancer care.

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