What is the radiobiology of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiosurgery (SRS)?

Radiobiology of SBRT and SRS

SBRT and SRS deliver ablative doses of radiation (typically 8-30 Gy per fraction in 1-5 fractions) that achieve superior tumor control through mechanisms beyond the traditional 4 Rs of radiobiology, primarily by delivering dramatically higher biologically effective doses (BED) that enable direct tumor cell ablation while exploiting steep dose gradients to spare normal tissue. 1, 2

Core Radiobiological Principles

High-Dose Per Fraction Effects

The fundamental mechanism underlying SBRT/SRS success is the delivery of substantially higher BED compared to conventional fractionation, which produces biologically effective doses that directly ablate tumor cells similar to thermal ablation techniques. 3, 1

• Common dose-fractionation schemes include 16-24 Gy in 1 fraction, 24 Gy in 2 fractions, 24-27 Gy in 3 fractions, and 30-35 Gy in 5 fractions for spinal SBRT 3
• For brain metastases, SRS delivers multiple intersecting radiation beams with precision to 1 mm, achieving local control rates of 75-95% 3
• SBRT typically uses 6-18 Gy per fraction delivered in 2-8 sessions, achieving high biological effectiveness 4

Beyond the Traditional 5 Rs

The clinical efficacy of SBRT/SRS exceeds predictions from the linear-quadratic (LQ) model and conventional radiobiological principles (repair, reoxygenation, redistribution, repopulation, and radiosensitivity). 1, 2

• The traditional 4 Rs of radiobiology may no longer fully explain SABR's ablation effects, though they remain relevant 2
• Available preclinical and clinical data suggest that for most tumors, standard radiobiology concepts are sufficient to explain clinical outcomes, with the excellent results primarily attributable to the much larger biologically effective doses delivered 1
• The intrinsic radiosensitivity of tumor cells (the 5th R) correlates with SABR responsiveness 2

Additional Radiobiological Mechanisms

Vascular Endothelial Damage

High-dose radiation induces vascular endothelial cell injury that contributes to tumor control beyond direct tumor cell killing. 1, 2

• Endothelial cell damage has been proposed as an additional biological effect accounting for SBRT/SRS success 1
• SABR-induced vascular endothelial injury plays a crucial role in tumor control 2

Immune System Activation

SBRT/SRS can produce enhanced antitumor immunity, representing a genuine departure from conventional radiobiology. 1, 2

• For some tumors, high doses of irradiation may produce enhanced antitumor immunity, which is the likely exception to relying solely on the classic 5 Rs 1
• Immune activation induced by SABR has been indicated to play a crucial role in tumor control 2

Technical Requirements for Radiobiological Efficacy

Precision and Dose Gradient

The radiobiological advantage of SBRT/SRS depends critically on high-precision stereotactic delivery (≤1 mm accuracy) that creates steep dose gradients outside the target volume. 3, 4

• SRS achieves very rapid decline in radiation dose outside the target volume through stereotactically-based treatment systems 3
• Image guidance and advanced treatment delivery technologies enable dose escalation to tumors while sharply minimizing doses to surrounding normal tissues 5, 6
• SBRT uses focused beams achieving high biological effectiveness while sparing surrounding tissues 4

Tumor Characteristics Affecting Response

Tumors with distinct borders, spherical shape, and radioresistant histology benefit most from the high-BED approach of SBRT/SRS. 3

• Brain metastases are ideal targets because they are often spherical, have distinct borders, and do not contain normal brain within radiographically defined limits 3
• Traditionally radioresistant tumors such as melanoma, renal cell carcinoma, and sarcoma show excellent outcomes with SBRT, with 2-year local control rates of 90% for RCC 3
• Bulky "mass-type" tumors with extraosseous extension that achieve less than 50% control at 1 year with conventional EBRT benefit from higher SBRT doses 3

Clinical Outcomes Supporting Radiobiological Efficacy

Local Control Rates

SBRT achieves approximately 90% local control at 1 year for spinal metastases and 75-95% for brain metastases, substantially exceeding conventional radiotherapy. 3

• For de novo spinal metastases, weighted average reveals 90% 1-year local control rate with SBRT 3
• Conventional low BED irradiation (8 Gy in 1 fraction) achieves 1-year local control rates of less than 50% for bulky tumors 3
• For brain metastases, combination of SRS with WBRT resulted in 82% vs 71% local control rate at 1 year compared to WBRT alone 3

Toxicity Profile Differences

The pattern, timing, and severity of toxicities with SBRT/SRS differ markedly from conventional radiotherapy, reflecting distinct radiobiological mechanisms. 5, 6

• Most common toxicity is vertebral compression fracture (9.4% of cases), with neurologic injury occurring in only 0.2% of cases 3
• The toxicity profile is very different from conventional radiotherapy, posing challenges to understanding radiobiological mechanisms 5

Common Pitfalls

• Avoid applying SBRT/SRS to patients with Child-Pugh C cirrhosis for liver tumors, as safety has not been established in this population with very poor prognosis 3
• Do not use conventional low-dose palliative radiation (8 Gy in 1 fraction) for patients expected to survive long enough to experience local progression, as suboptimal radiation dose is associated with increased spinal adverse events including cord compression 3
• Recognize that Child-Pugh B cirrhosis patients require dose modifications and strict dose constraint adherence when receiving SBRT, though they can be safely treated 3