What evidence shows improvement in progression-free survival (PFS) with proton therapy compared to photon therapy?

Evidence of PFS Improvement with Proton vs Photon Therapy

Direct Answer

Current evidence does NOT demonstrate improvement in progression-free survival (PFS) with proton therapy compared to photon therapy across cancer types. 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. 1

Disease-Specific PFS Evidence

Esophageal Cancer: Favorable PFS Data for Protons

In radical therapy settings for esophageal cancer, proton therapy demonstrated superior PFS compared to photon therapy. 2 A 2023 meta-analysis found:

• Photon therapy was associated with worse PFS in the radical therapy subgroup (HR 1.48; 95% CI 1.06-2.08) 2
• Photon therapy showed worse overall survival (HR 1.42; 95% CI 1.14-1.78) in radical treatment 2
• However, when all treatment settings were combined (including palliative), no significant PFS difference was observed between modalities 2

This represents the strongest evidence for PFS improvement with protons, but applies specifically to radical treatment of esophageal cancer. 2

Pediatric Cancers: Equivalent PFS Outcomes

For pediatric malignancies, proton therapy shows equivalent—not superior—PFS compared to photon therapy:

• Craniopharyngioma: PFS rates after proton therapy are similar to conventional photon therapy 3
• Ependymoma: PFS rates after proton therapy are similar to conventional photon therapy 3
• Ewing Sarcoma: Proton therapy achieved 64% 3-year PFS, comparable to photon therapy 3

Chordoma: No Clear PFS Advantage

The Chordoma Global Consensus Group presents proton and photon-based IMRT data side-by-side without declaring superiority of either modality for PFS outcomes. 1 Proton therapy for skull base and spine chordomas achieved 5-year local control rates of 62-81%, but this was not demonstrated as superior to modern photon techniques. 1

Lung Cancer: No PFS Difference

For limited-stage small cell lung cancer, a 2023 comparative study found:

• 2-year PFS was 35.7% with proton therapy versus 40.8% with photon therapy (p = 0.748) 4
• No significant difference in progression-free survival despite superior dosimetric parameters with protons 4

For early-stage thoracic esophageal cancer without lymph node metastasis:

• 5-year PFS was not significantly different between proton and photon therapy 5
• This held true despite lower radiation exposure to normal tissues with protons 5

Why Protons Don't Improve PFS: Critical Understanding

The RBE Limitation

The fixed RBE value of 1.1 used clinically for protons may not accurately reflect biological effectiveness at the tumor-normal tissue interface where dose gradients are steep. 1 This means:

• Protons deliver equivalent biological tumor cell kill to photons at the same prescribed dose 1
• The advantage is geometric (dose distribution) rather than biological (cell kill) 6
• Residual uncertainties in proton dose delivery may offset theoretical RBE advantages 1

Dosimetric vs Clinical Outcomes Disconnect

Proton therapy delivers lower integral doses and mean doses to normal tissues compared to photon-based IMRT due to unique depth-dose characteristics, which may reduce normal tissue toxicity. 1 However:

• Superior dosimetry does not translate to improved tumor control 7
• The benefit manifests as reduced toxicity and potentially improved quality of life, not disease control 6
• In silico studies consistently show dosimetric superiority, but clinical PFS data remain equivalent 7

Guideline Positions on Proton Therapy Efficacy

Urological Cancers

The American Urological Association and American Society for Radiation Oncology state that proton therapy has not been shown to be superior to other radiation modalities in terms of cancer outcomes for prostate cancer patients. 1

Stage III NSCLC

The American Society of Clinical Oncology guidelines for stage III NSCLC do not preferentially recommend proton over photon therapy based on efficacy outcomes. 3, 1 Phase I trials demonstrated safety and tolerability of dose escalation with protons, but no PFS advantage has been established. 3

Salivary Gland Malignancies

The ASCO guidelines state there are no clear indications for particle therapy over photon or electron therapy for salivary gland malignancies. 3 Without comparative data demonstrating PFS benefit, particle therapy may be used but is not preferentially recommended. 3

Clinical Implications and Pitfalls

When to Consider Proton Therapy

Proton therapy should be selected based on normal tissue sparing potential rather than expectation of improved PFS. 1 Appropriate scenarios include:

• Pediatric cancers where minimizing late effects is paramount, even with equivalent PFS 3
• Tumors adjacent to critical structures where photon dose constraints cannot be met 6
• Situations where reduced integral dose may decrease secondary malignancy risk 7

Critical Pitfall to Avoid

Do not counsel patients that proton therapy will improve their cancer control or survival compared to modern photon techniques. 1 The evidence consistently shows:

• Equivalent local control rates across most tumor types 3
• No consistent OS or PFS advantage except possibly in radical esophageal cancer treatment 2
• Primary benefit is toxicity reduction, not enhanced tumor cell kill 1, 6

The Esophageal Cancer Exception

For patients receiving radical treatment for esophageal cancer, proton therapy may offer PFS benefit and should be strongly considered if available. 2 This represents the single disease site with meta-analytic evidence of PFS improvement, though further validation in randomized trials is warranted. 2