UK IMPORT HIGH Study

Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer

Coles et al., The Lancet 2023

Background

• Tumor-bed boost after whole-breast radiotherapy improves local control
• Sequential boost requires more patient visits and can increase breast hardness
• Simultaneous integrated boost (SIB) may reduce treatment duration
• Previous trials used larger boost volumes, potentially increasing toxicity
• IMPORT HIGH aimed to test SIB with smaller, more targeted boost volumes

Study Objective

To test if SIB reduces treatment duration while maintaining excellent local control and similar or reduced toxicity compared to sequential boost

Study Design

• Phase 3, non-inferiority, open-label, randomized controlled trial
• 2617 patients with pT1-3, N0-3a, M0 breast cancer after BCS
• Three treatment arms:

Note: IMRT was not required (about 50% had inverse planning)

Patient Population

Inclusion Criteria:

• Women aged ≥18 years
• pT1-3pN0-3aM0 invasive carcinoma
• Breast-conserving surgery
• Clear microscopic resection margins

Exclusion Criteria:

• Previous malignancy
• Mastectomy
• Ipsilateral breast implant
• Concurrent chemoradiotherapy

Patient Characteristics

• Median age: 49 years (IQR 44-56)
• Grade: 53% grade 3, 38% grade 2, 9% grade 1
• 30% were node-positive
• About 10% had RT to lymph nodes (~90% to SCV)
• Median tumor size: 2.0 cm

Note: Post-hoc EORTC indications for boost were not required, but characteristics suggest they were mostly met

Methods: Radiotherapy

• Tumor bed localized with titanium clips or gold seeds
• CT-based planning
• Forward or inverse-planned IMRT allowed
• Image-guided radiotherapy (IGRT) used
• Median boost CTV: 13 cm³ (IQR 7-22)

Methods: Radiotherapy Volumes

• PTV 48: tumor bed + 5 mm PTV
• PTV 40 PBI: tumor bed + 1.5 cm + 10 mm PTV
• PTV 36: whole breast + 10 mm PTV

Note: Boost volume smaller than in RTOG 1005

Methods: Dose Constraints

• PTVlow (36 Gy) - PTV PBI V40 Gy < 5%
• PTVhigh (48 Gy) V51.4 Gy < 3%
• PTVhigh (48 Gy) max < 52.8 Gy

Statistical Methods

• Primary endpoint: Ipsilateral breast tumor relapse (IBTR)
• Non-inferiority margin: 3% absolute difference in 5-year IBTR
• Sample size: 856 patients per group (2568 total)
• Kaplan-Meier estimates and Cox proportional hazards models
• Secondary endpoints: Normal tissue effects, quality of life

Results: IBTR

Results: Other Outcomes

• 5-year distant metastasis: 8% in all arms
• 5-year locoregional recurrence: ~5%
• No significant differences in regional recurrence, distant recurrence, or overall survival

Results: Toxicity

Clinician-reported moderate to marked breast induration

Results: Any Breast Adverse Event

Results: Any Breast Adverse Event

5-year rates:

• Control: 33%
• 48 Gy SIB: 30%
• 53 Gy SIB: 35%

Patient-rated: 28% vs. 15% vs. 24%

Results: Other Normal Tissue Effects

• Photographic assessments showed trend towards reduced risk of changes for Test 1 vs Control
• Patient-reported outcomes consistent with clinical assessments
• Severe late adverse events were rare across all groups

Key Findings

• 48 Gy SIB boost is non-inferior to sequential hypofractionation plus boost
• Treatment duration is reduced with SIB
• IBTR is non-inferior with 48 Gy SIB
• 53 Gy SIB and 16 Gy sequential boost worsened cosmesis
• Induration/hardness: Less with 48 Gy SIB

Discussion Points

• IMRT was not required, but about 50% had inverse planning
• Smaller boost volume compared to RTOG 1005
• Option to use 40 Gy to cover the remainder of the breast for those opposed to partial breast irradiation
• Patient characteristics aligned well with typical boost indications
• Lower than anticipated IBTR rates across all groups
• Small boost volumes may contribute to low adverse event rates

Strengths of the Study

• Large sample size (2617 patients)
• Multicenter design (39 radiotherapy centers)
• Use of standardized radiotherapy techniques across all groups
• Comprehensive assessment of normal tissue effects (clinician, patient-reported, photographic)
• Long-term follow-up (median 74 months)

Limitations and Critique

• Open-label design may introduce bias in toxicity reporting
• Lower than expected event rates complicate interpretation of non-inferiority
• Limited data on very long-term outcomes (>10 years)
• Evolving regional node irradiation practices during the study period
• Results may not be generalizable to all boost fractionation schedules
• Limited ethnic diversity in the study population

Clinical Implications

• 48 Gy SIB is a safe and effective alternative to sequential boost
• Reduces treatment duration from 4-5 weeks to 3 weeks
• May improve patient convenience and resource utilization
• No benefit in dose escalation beyond 48 Gy
• Supports the use of smaller, more targeted boost volumes
• May inform future trials of ultra-short course radiotherapy (e.g., 1-week SIB)

Conclusions

• 48 Gy SIB is non-inferior to sequential boost for local control
• Similar or reduced toxicity with 48 Gy SIB compared to sequential boost
• No benefit in dose escalation to 53 Gy
• Results support the use of 48 Gy SIB in early breast cancer
• Reduces treatment duration while maintaining efficacy and safety
• Future research on ultra-short course regimens warranted

UK IMPORT HIGH Study

Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer

Coles et al., The Lancet 2023

Background: EORTC 22881 Trial

• 5318 patients, T1-2, N0-1, microscopically complete excision
• 50 Gy WBRT → no boost vs. 16 Gy boost
• Key findings:
  • ⬇️ 20-yr LR: 16% vs. 12%
  • ⬇️ 10-yr LR age <40: 24% vs. 14%
  • ⬆️ 20-yr severe fibrosis: 1.8% vs. 5.2%
  • No difference in OS

Background: Boost in Breast Cancer

• 16 Gy boost improves local control after whole breast radiation
• Benefit seen across all age groups, greatest in younger patients
• 20-year follow-up MVA: young age and adjacent DCIS are risk factors for IBTR
• TROG BIG trial confirmed boost benefit for DCIS alone
• Debate between 10 Gy vs 16 Gy boost (Lyon vs EORTC trials)

Study Objective

To test if SIB reduces treatment duration while maintaining excellent local control and similar or reduced toxicity compared to sequential boost

Discussion: Context with EORTC 22881

• IMPORT HIGH used 16 Gy boost as control, aligning with EORTC evidence
• No specific eligibility criteria for boost, unlike post-hoc EORTC subgroups
• IMPORT HIGH median age: 49 years (IQR 44-56) - a higher risk group
• Lower IBTR rates in IMPORT HIGH compared to EORTC:
  • IMPORT HIGH 5-year IBTR: ~2% across arms
  • EORTC 5-year LR: 4.3% with boost

Discussion: Boost Considerations

• Balance between local recurrence risk and fibrosis
• Caution against strict age-based recommendations
• Personalization of boost recommendations, similar to RT vs. observation in DCIS
• IMPORT HIGH supports smaller, more targeted boost volumes
• SIB offers potential for reduced treatment duration and toxicity

Implications for Practice

• 48 Gy SIB as an alternative to sequential 16 Gy boost
• Potential for reduced toxicity with similar efficacy
• Consideration of boost for all lumpectomy patients, with personalization based on risk factors
• Importance of long-term follow-up (IMPORT HIGH median follow-up: 74 months)
• Need for studies on ultra-short course RT (e.g., 1-week SIB)