What is the correlation between the Relative Biological Effectiveness (RBE) of proton versus photon therapy and progression-free survival (PFS)?

RBE of Proton vs Photon Therapy and Correlation with Progression-Free Survival

Proton therapy uses a fixed RBE value of 1.1 relative to photons in clinical practice, but this assumption oversimplifies reality—the actual RBE varies with energy, dose per fraction, tissue type, and biological endpoint, and current evidence shows no consistent correlation between this RBE difference and improved PFS across most cancer types. 1

Understanding RBE in Clinical Context

Fixed vs Variable RBE

• Protons are assigned a constant RBE of 1.1 in all clinical dose calculations, meaning 1 Gy of proton dose is considered biologically equivalent to 1.1 Gy of photon dose 2, 1
• This fixed value is a simplification—actual RBE is complex and depends on proton energy, dose per fraction, tissue/cell type, and biological endpoint 1
• The oversimplification of RBE may limit achievement of proton therapy's true potential and contributes to uncertainties in delivered dose 1
• For comparison, neutrons have dramatically higher RBE values (10-200) than protons, while photons and electrons have RBE of 1.0 2

Dosimetric Advantages vs Clinical Outcomes

• Proton therapy delivers lower integral doses and mean doses to normal tissues compared to photon-based IMRT due to unique depth-dose characteristics 3, 1
• However, these dosimetric advantages have not consistently translated into superior disease control or improved PFS in head-to-head comparisons 3

Disease-Specific PFS Correlations

Prostate Cancer: No PFS Advantage Demonstrated

• The AUA/ASTRO guidelines state that proton therapy has not been shown to be superior to other radiation modalities in terms of cancer outcomes 3
• No prospective study has demonstrated improved disease control with proton beam radiation therapy compared to IMRT for localized prostate cancer 3
• Randomized trials comparing proton vs photon therapy for prostate cancer are ongoing, with primary endpoints focused on toxicity and quality of life rather than PFS 3

Esophageal Cancer: Potential PFS Benefit in Radical Treatment

• Meta-analysis showed photon therapy was associated with worse overall survival (HR 1.31,95% CI 1.07-1.61) compared to proton therapy 4
• In the radical therapy subgroup specifically, photon therapy showed significantly worse PFS (HR 1.48,95% CI 1.06-2.08) compared to proton therapy 4
• Proton therapy achieved 65% PFS at 1 year, 56% at 2 years, 48% at 3 years, and 42% at 5 years 4
• Proton therapy was associated with significantly reduced radiation pneumonitis and pericardial effusion, which may indirectly preserve performance status and treatment continuation 4

Thoracic Esophageal Cancer (T1-3N0): No PFS Difference

• Direct comparison of photon radiotherapy vs proton beam therapy for T1-3N0 thoracic esophageal squamous cell carcinoma showed no significant survival difference 5
• The 5-year PFS was 56.5% overall with no difference between radiation modalities 5
• Extended-field radiotherapy using modern techniques showed satisfactory outcomes regardless of proton vs photon use 5

Low-Grade and Anaplastic Gliomas: No PFS Difference

• Analysis of 99 patients with grade II-III gliomas found no difference in PFS between proton and photon therapy 6
• Pseudoprogression (which was associated with better PFS, HR 0.22, p=0.04) occurred at similar rates between proton (16%) and photon (14.3%) therapy for oligodendrogliomas 6
• However, pseudoprogression occurred significantly earlier after protons (48 days) compared to photons (131 days) in oligodendroglioma patients 6

Chordomas: Comparable Local Control Rates

• Proton therapy for skull base and spine chordomas achieved 5-year local control rates of 62-81% 3
• Carbon ion therapy (which has higher RBE than protons) showed 5-year local control of 77.2% for primary sacral/spine chordomas 3
• The Chordoma Global Consensus Group guidelines present proton and photon-based IMRT data side-by-side without declaring superiority of either modality for PFS outcomes 3

Pediatric Rhabdomyosarcoma: Acceptable PFS with Protons

• Pencil beam scanning proton therapy for pediatric parameningeal rhabdomyosarcomas achieved 5-year PFS of 72% 7
• Delay in initiation of proton therapy (>13 weeks from chemotherapy start) was a significant detrimental factor for PFS on univariate analysis 7
• These results are comparable to combined proton-photon and photon-only series, suggesting no clear PFS advantage attributable to RBE differences 7

Stage III NSCLC: Ongoing Investigation

• Phase I dose-escalation trials with proton therapy showed feasibility of hypofractionated regimens (45-60 Gy RBE in 15 fractions) with acceptable toxicity 3
• No phase III data comparing proton vs photon therapy for PFS in stage III NSCLC are available 3
• The ASCO guidelines for stage III NSCLC do not preferentially recommend proton over photon therapy based on efficacy outcomes 3

Critical Limitations and Pitfalls

Why RBE Doesn't Consistently Correlate with PFS

• The fixed RBE of 1.1 used clinically may not accurately reflect biological effectiveness at the tumor-normal tissue interface where dose gradients are steep 1
• Residual uncertainties in proton dose delivery from inter- and intra-fractional anatomic variations may offset theoretical RBE advantages 1
• The primary benefit of protons appears to be reduced normal tissue toxicity rather than enhanced tumor cell kill, which explains the lack of consistent PFS improvement 3, 4

Avoiding Common Misconceptions

• Do not assume that proton therapy's dosimetric superiority automatically translates to better cancer control—current evidence does not support this for most disease sites 3
• Do not use RBE as the primary justification for choosing proton therapy; instead, focus on normal tissue sparing when critical structures limit photon dose escalation 1
• Do not expect dramatic PFS improvements from proton therapy alone without dose escalation or other treatment intensification 3

When RBE Considerations May Matter Most

• In pediatric cancers where long-term survival is expected and minimizing late effects is paramount, even modest RBE differences may have clinical significance 3
• For tumors immediately adjacent to critical structures (skull base chordomas, parameningeal tumors) where photon dose constraints prevent adequate target coverage 3, 7
• When dose escalation beyond conventional photon limits is feasible with protons, potentially leveraging both physical and biological advantages 1