What are the key landmark trials that defined the role of vaginal brachytherapy in the adjuvant treatment of endometrial cancer?

Landmark Trials in Brachytherapy for Endometrial Cancer

PORTEC-2 is the definitive landmark trial establishing vaginal brachytherapy alone as the standard adjuvant treatment for high-intermediate risk endometrial cancer, demonstrating equivalent vaginal and pelvic control to external beam radiotherapy with significantly less toxicity and no difference in overall survival. 1

Key Landmark Trials

PORTEC-2 (2000s) - The Pivotal Brachytherapy Trial

This trial fundamentally changed practice by proving vaginal brachytherapy (VBT) alone is sufficient for most uterine-confined disease. 1

• Randomized patients with high-intermediate risk (HIR) endometrial cancer to external beam pelvic radiotherapy (EBRT) versus vaginal brachytherapy alone 1
• Demonstrated excellent and equivalent vaginal and pelvic control rates with both approaches, with no difference in overall survival 1
• Vaginal brachytherapy was associated with significantly less toxicity than pelvic radiotherapy 1
• Long-term 10-year follow-up confirmed VBT as standard treatment, with 10-year vaginal recurrence of only 3.4% versus 2.4% for EBRT (p=0.55) 2
• The most commonly used regimen from this trial is 21 Gy in three fractions prescribed at 5 mm depth, which remains the standard today 3, 2

Critical limitation: PORTEC-1 and PORTEC-2 specifically excluded patients with 1998 FIGO stage 1C grade 3 endometrial carcinoma (2009 FIGO stage IB grade 3), making the use of brachytherapy alone in this highest-risk subset controversial. 1

GOG 99 (Early 2000s) - Risk Stratification Foundation

This trial defined the high-intermediate risk (HIR) criteria that guide patient selection for adjuvant therapy. 1

• Showed adjuvant pelvic radiotherapy improved locoregional control and progression-free survival without overall survival benefit 1
• Established age-based risk stratification: patients <50 years needed all 3 histologic risk factors (grade 2-3, >50% myometrial invasion, LVSI) to be HIR; ages 50-70 needed 2 of 3 factors; ages ≥70 needed only 1 factor 1
• Revealed that most initial recurrences in uterine-confined tumors were limited to the vagina, prompting increased use of vaginal brachytherapy alone 1

PORTEC-1 (1990s-2000s) - External Beam Radiotherapy Baseline

Established that external beam radiotherapy reduces locoregional recurrence but does not improve overall survival in intermediate-risk disease. 1

• Defined HIR patients as having 2 of 3 risk factors: age >60 years, deep myometrial invasion, or grade 3 histology 1
• Demonstrated external beam pelvic radiotherapy significantly decreased locoregional recurrence but did not increase overall survival 1
• Provided the foundation for PORTEC-2 by questioning whether less toxic approaches could achieve similar outcomes 1

GOG 249 (2010s) - Brachytherapy Plus Chemotherapy Trial

This trial attempted to substitute chemotherapy for external beam radiotherapy in high-risk disease but revealed important limitations. 1

• Compared vaginal cuff brachytherapy plus 3 cycles of carboplatin/paclitaxel versus pelvic EBRT alone in high-risk, uterine-confined endometrial carcinoma (n=601) 1
• Reported significantly increased rates of nodal recurrence (primarily pelvic) in the brachytherapy plus chemotherapy arm compared to pelvic EBRT 1
• More extravaginal pelvic failures occurred in the brachytherapy plus chemotherapy arm 1
• 3-year recurrence-free survival was 82% for both arms; 3-year overall survival was 88% for brachytherapy plus chemotherapy versus 91% for pelvic EBRT 1
• Acute toxicity was more common and severe with brachytherapy plus chemotherapy 1
• Questions were raised whether only 3 cycles of chemotherapy were sufficient to control distant disease 1

Clinical implication: This trial demonstrated that vaginal brachytherapy plus limited chemotherapy cannot adequately replace pelvic EBRT for pelvic control in high-risk disease. 1

Aalders Trial (1980s) - Historical Foundation

The earliest randomized trial showing vaginal brachytherapy reduces vaginal recurrences. 1

• Found that radiotherapy reduced vaginal (locoregional) recurrences but did not reduce distant metastases or improve survival 1
• Long-term follow-up (median 20.5 years) comparing vaginal brachytherapy plus EBRT versus vaginal brachytherapy alone showed no statistical difference in overall survival 1

Clinical Application Algorithm

For High-Intermediate Risk Disease (HIR):

• Vaginal brachytherapy alone is the standard of care 1, 3
• Use 21 Gy in 3 fractions at 5 mm depth (PORTEC-2 regimen) 3, 2
• Expected vaginal recurrence rate: 1.9-3.4% at 3-10 years 4, 2, 5

For Stage IB Grade 3 Disease:

• This remains controversial as PORTEC-1 and PORTEC-2 excluded these patients 1
• Most NCCN panel members recommend adjuvant treatment for deeply invasive grade 3 tumors 1
• Consider pelvic EBRT rather than brachytherapy alone for this highest-risk subset 1, 5

For High-Risk Disease with Unfavorable Molecular Features:

• EBRT provides better pelvic control in patients with L1CAM expression, p53-mutant expression, or substantial lymphovascular space invasion 2
• Do not substitute brachytherapy plus limited chemotherapy for pelvic EBRT in these patients 1

Common Pitfalls

• Applying brachytherapy alone to stage IB grade 3 patients based on PORTEC-2 data, when these patients were specifically excluded from the trial 1
• Using brachytherapy plus chemotherapy as a substitute for pelvic EBRT in high-risk disease, which GOG 249 showed leads to increased pelvic failures 1
• Failing to recognize that 10-year pelvic recurrence was higher with VBT (6.3% vs 0.9%), though mostly combined with distant metastases 2
• Not considering molecular risk factors (L1CAM, p53-mutant, extensive LVSI) that may warrant EBRT over brachytherapy alone 1, 2