GOG 99: Surgery with or without Adjunctive External Pelvic Radiation Therapy in Intermediate Risk Endometrial Adenocarcinoma

Keys HM, Roberts JA, Brunetto VL, et al.
Gynecologic Oncology 2004;92:744-751

Study Design & Methods

• Phase III randomized trial of Gynecologic Oncology Group (GOG)
• Population: Surgically staged endometrial adenocarcinoma with "intermediate risk"
• Initial definition: Any degree of myometrial invasion, no lymph node metastasis
• FIGO stages IB, IC, IIA (occult), and IIB (occult)
• Expected 5-year recurrence rate of 20-25%
• Excluded: Clear cell and papillary serous histologies

Inclusion Criteria & Risk Stratification

Patient Characteristics

• 448 women entered; 392 (88%) determined eligible
• 202 in No Additional Treatment (NAT) arm
• 190 in Radiation Therapy (RT) arm
• Median follow-up: 69 months
• Well-balanced groups for high-risk factors:
• Outer 1/3 myometrial invasion: ~17%
• Grade 3 histology: ~18%
• Lymphovascular space involvement: ~23%
• Age >70 years: ~22%
• Occult cervical involvement: ~9%

Trial Schema

High Intermediate Risk (HIR) Subgroup

• During study, initial definition of intermediate risk needed refinement
• Factors associated with increased recurrence risk were identified:
• Increasing age
• Moderate to poorly differentiated tumor grade
• Presence of lymphovascular invasion
• Outer-third myometrial invasion
• High Intermediate Risk (HIR) subgroup defined as:
• Age ≥70 with any one risk factor OR
• Age ≥50 with any two risk factors OR
• Any age with all three risk factors
• All other patients considered Low Intermediate Risk (LIR)
• About 1/3 of patients (132) were in the HIR subgroup
• This group accounted for ~2/3 of recurrences (28/44) and cancer-related deaths (22/32)

Primary Outcome: Recurrence

• Total recurrences: 44 (31 in NAT arm, 13 in RT arm)
• Radiation reduced recurrence hazard by 58% (RH=0.42, p=0.007)
• 24-month estimated cumulative incidence of recurrence:
• NAT arm: 12% (90% CI=0.09-0.17)
• RT arm: 3% (90% CI=0.02-0.06)
• Most recurrences occurred within 18 months of diagnosis
• Major difference seen in vaginal recurrences:
• NAT arm: 13 vaginal recurrences
• RT arm: 2 vaginal recurrences (both patients refused RT)
• Overall impact on pelvic/vaginal recurrences: 18 in NAT vs 3 in RT

Sites of Recurrence

Outcomes by Risk Group

• High Intermediate Risk (HIR) Subgroup:
• 24-month recurrence rate: 26% in NAT vs 6% in RT
• Treatment showed substantial impact (Relative Hazard = 0.42)
• Absolute reduction of 19% at 24 months
• Low Intermediate Risk (LIR) Subgroup:
• 24-month recurrence rate: ~5% in NAT vs ~2% in RT
• Similar relative effect but small absolute benefit (~4%)
• The benefit was consistent across both local control and distant metastasis
• HIR subgroup showed some survival benefit with RT (not statistically significant)
• No apparent survival benefit in LIR subgroup

Secondary Outcome: Survival

• Total deaths: 66 (36 in NAT arm, 30 in RT arm)
• Cancer/treatment-related deaths: 32 (17 in NAT, 15 in RT)
• 48-month estimated overall survival:
  • NAT arm: 86%
  • RT arm: 92%
• Relative hazard: 0.86 (90% CI=0.57-1.29)
• Not statistically significant (p=0.55)
• About half of deaths due to causes other than endometrial cancer:
  • NAT: 19 of 36 deaths (53%)
  • RT: 15 of 30 deaths (50%)

Treatment-Related Toxicity

• RT group experienced more frequent and more severe toxicities
• Two women in RT arm died from complications involving intestinal injury
• Statistically significant differences (p<0.001) in:
• Hematologic toxicity
• Gastrointestinal toxicity
• Genitourinary toxicity
• Cutaneous toxicity
• No significant difference in bowel obstructions, but higher grade obstructions in RT
• Grade 3-4 obstruction: 6 in RT arm vs 1 in NAT arm

Conclusions

• Adjuvant pelvic RT significantly reduces risk of recurrence in intermediate risk endometrial cancer
• Estimated 58% reduction in recurrence hazard with RT
• Primary benefit seen in reducing vaginal apex recurrences
• Absolute benefit varies dramatically by risk group:
  • High Intermediate Risk: 19% absolute reduction at 24 months
  • Low Intermediate Risk: 4% absolute reduction at 24 months
• Adjuvant RT should be limited to patients whose risk factors fit the High Intermediate Risk definition

High Intermediate Risk (HIR) Definition

Requires ANY ONE of these criteria:

1. Age ≥70 years with ONE additional risk factor
2. Age ≥50 years with ANY TWO additional risk factors
3. Any age with ALL THREE additional risk factors

Additional risk factors:

• Grade 2-3 tumor
• Presence of lymphovascular invasion
• Outer third myometrial invasion

Impact of Stratification

• HIR group: ~1/3 of patients (132)
• 2-year recurrence: 26% in NAT vs 6% in RT
• Accounted for ~2/3 of all recurrences
• Low Intermediate Risk (LIR): remaining patients
• 2-year recurrence: 5% in NAT vs 2% in RT

Conclusions

High Intermediate Risk (HIR) Definition

Requires ANY ONE of these criteria:

1. Age ≥70 years with ONE additional risk factor
2. Age ≥50 years with ANY TWO additional risk factors
3. Any age with ALL THREE additional risk factors

Additional risk factors:

• Grade 2-3 tumor
• Presence of lymphovascular invasion
• Outer third myometrial invasion

Impact of Stratification

• HIR group: ~1/3 of patients (132)
• 2-year recurrence: 26% in NAT vs 6% in RT
• Accounted for ~2/3 of all recurrences
• Low Intermediate Risk (LIR): remaining patients
• 2-year recurrence: 5% in NAT vs 2% in RT