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FoRT Trial: 4 Gy vs 24 Gy Radiotherapy for Follicular and Marginal Zone Lymphoma

Hoskin et al., Lancet Oncology 2021

Introduction & Methods

• Background: Low-dose radiotherapy (4 Gy) has shown efficacy in small studies
• Objective: Compare 4 Gy vs 24 Gy radiotherapy for follicular and marginal zone lymphoma
• Study design: Multicenter, randomized, phase 3, non-inferiority trial
• Key eligibility: Histologically confirmed follicular or marginal zone lymphoma requiring radical or palliative radiotherapy
• Randomization: 1:1 ratio, stratified by histology and treatment intent
• Primary endpoint: Time to local progression

Introduction & Methods

Patient Population

Patient Population

Interventions

• 24 Gy arm: 12 fractions of 2 Gy, treating daily Monday to Friday
• 4 Gy arm: 2 fractions of 2 Gy on consecutive days
• Involved-field radiotherapy based on tumor mass
• Quality assurance program included
• Central histological review performed

Primary Outcome: Local Progression-Free Interval

• Median follow-up: 73.8 months
• 2-year local progression-free rate:
  24 Gy: 94.1% (95% CI 90.6–96.4)
  4 Gy: 79.8% (74.8–83.9)
• 5-year local progression-free rate:
  24 Gy: 89.9% (85.5–93.1)
  4 Gy: 70.4% (64.7–75.4)
• Hazard ratio: 3.46 (95% CI 2.25–5.33; p<0.0001)
• Non-inferiority not achieved: difference at 2 years -13.0% (95% CI -21.7 to -6.9)

Figure: Local Progression-Free Interval

Figure: Local Progression-Free Interval

Secondary Outcomes

• Overall survival: No significant difference
  HR 1.03 (95% CI 0.74–1.43; p=0.86)
• Toxicity at 12 weeks:
  24 Gy: 29 (10%) grade 2 or above events
  4 Gy: 11 (4%) grade 2 or above events
  p=0.0029
• Most common events at 12 weeks: alopecia, dry mouth, fatigue, mucositis, and pain
• No treatment-related deaths reported

Subgroup Analyses

• Curative vs. palliative intent: Both showed significant benefit with 24 Gy
• Follicular vs. marginal zone lymphoma: Similar results in both histologies
• Orbital lymphoma: No progressions in 20 sites treated with 24 Gy, 2 progressions in 13 sites treated with 4 Gy
• No significant interactions found between treatment effect and subgroups

Figure: Subgroup Analyses

Conclusions

• 24 Gy remains the standard of care for durable local control in follicular and marginal zone lymphoma
• 4 Gy is inferior to 24 Gy in terms of local progression-free interval
• No difference in overall survival between the two arms
• 4 Gy may be considered in palliative settings where durable control is not paramount
• Similar results observed in follicular and marginal zone lymphoma subgroups

Strengths and Limitations

• Strengths:
  • Large, multicenter, randomized trial
  • Long-term follow-up (median 73.8 months)
  • Inclusion of both follicular and marginal zone lymphoma

• Limitations:
  • Premature closure (614 of 650 planned sites)
  • Multiple randomizations allowed per patient
  • Central histological confirmation in only 62% of cases

Implications for Practice

• 24 Gy in 12 fractions should remain the standard dose for durable local control
• 4 Gy in 2 fractions may be considered in palliative settings:
  • When durable control is not the primary aim
  • For patients with limited life expectancy
  • In conjunction with systemic treatments
• Treatment decision should balance efficacy, toxicity, and patient factors
• Further research needed on optimal dose for specific subgroups (e.g., orbital lymphoma)

Discussion Points

• How might these results impact current clinical practice?

• Are there specific patient populations where 4 Gy might still be preferred?

• What are the potential benefits and drawbacks of using 4 Gy in a palliative setting?

• How do these findings compare to other studies on low-dose radiotherapy in indolent lymphomas?

• What future research questions arise from this study?