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PORTEC 2

Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial

Pubmed


Hypothesis: Vaginal brachytherapy is equally effective in prevention of vaginal cuff recurrence of endometrial cancer compared to EBRT in high intermediate risk patients.

Standard Arm: EBRT (46 Gy in 2 Gy fractions)

Experimental Arm: Vaginal brachytherapy (21 Gy in 7 Gy fractions spaced 1 week apart for HDR; 30 Gy at 50–70 cGy/h for the low dose rate; and 28 Gy at 100 cGy/h in one session for the medium-dose rate)

Design: Multicenter RCT in 19 Dutch Radiation Hospitals

Inclusion Criteria: Endometrial adenocarcinoma s/p surgery (no routine lymphadenectomy) with:

  • Age > 60 and stage IC grade ½ or IB grade 3
  • Any age, stage IIA
  • (FIGO 1988 staging)

Exclusion Criteria (outside of usual):

  • Serous or clear cell histology
  • Staging lymphadenectomy
  • Interval between surgery and RT >8 weeks
  • History of prior malignancy
  • Previous RT, hormonal therapy or chemotherapy
  • Crohn’s or UC

Primary Endpoint: Vaginal recurrence

Outcomes: 

  • EBRT: 4 vaginal recurrences (1.6%)
  • Vag Brachy: 3 vaginal recurrences (1.8%)
  • Higher rate of pelvic recurrence in Vag Brachy group (0.5% vs 3.8%, HR 8.29, p=0.02)
  • No overall survival difference (82% vs 86%; NS)


Serious Adverse Events: 

  • EBRT: Grade ½ GI toxicities 53.8%
  • VBT: Grade ½ GI toxicities 12.6% (not significant at 2 years follow up); 

Conclusion: Vaginal brachytherapy provides adequate local control to reduce risk of vaginal recurrence in high-intermediate risk endometrial cancer. It has a favorable side effect profile, with no overall survival benefit.

GOG 157

Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study.

Pubmed

Hypothesis: 6 cycles of carboplatin (AUC 7.5) and paclitaxel (175mg/m2) improves survival compared to 3 cycles.

Site: Ovary

Eligibility: Stage IA/IB (Grade 3 or clear cell) or stage II completely resected

Experimental arm: 6 cycles of AUC 7.5 carboplatin and 175 mg/m2 of Paclitaxel

Standard Arm: 3 cycles of AUC 7.5 carboplatin and 175 mg/m2 of Paclitaxel

Primary Outcome:

Results:
n=457 enrolled; 427 final cohort
69% were stage 1
31% were stage 2

Parameter 3 cycles 6 cycles p-value
5-year recurrence rate 25.4% 20.1% ns
Adjusted Recurrence rate 1 ref 0.761 (0.51 – 1.13) 0.18
Neurotoxicity G4 2% 11% ss
Neutropenia G4 52% 66% ss
Anemia 32% 48% ss

ss: statistically significant
ns: not statistically significant

Conclusions:

  • 3 cycles of chemotherapy are non-inferior to 6 cycles after complete surgical staging
  • Post-hoc analysis PubmedSerous tumors 6 cycles improve survival

Limitations:

  • High dose of Carboplatin (AUC 7.5)
  • High proportion of incompletely staged patients (about 30%)
  • Study likely underpowered to show difference between 3 and 6 cycles, so although the null hypothesis is no difference, there may be a difference which would have been seen in a fully powered study

  1. Adjusted for FIGO stage and grade ↩︎

Portec 1

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial

Pubmed

Hypothesis:
Addition of external beam radiation after surgery in early stage endometrial cancer improves survival

Site:
Endometrium

Experimental arm:
Surgery followed by 46 Gy in 2 Gy daily fractions, 3 or 4 field technique (Fields: superior border at L5/S1)

Standard Arm:
Surgery alone

Eligibility Criteria

  • TAH/BSO without routine LND with these criteria
    Invasion Grade
    >50% (deep) 1
    any 2
    <50% superficial 3
  • WHO score of 0-2
  • Histologies allowed:
    • Endometrioid (also including adenocarcinoma with squamous features)
    • Adenocarcinoma not otherwise specified
    • Adenosquamous carcinoma
    • Papillary serous carcinoma
    • Clear-cell carcinoma

Primary Outcome:
Locoregional recurrence and overall survival

Results:

Outcome EBRT Observation p-value
Locoregional Recurrences 4% 14% SS
Overall Survival** 81% 84% NS
Major Toxicity 25% 6% SS
  • 73% recurrences in the vagina. Rate of distal mets same ~7% each arm
  • Prognostic Factors: Age >60, G3, IC predictive for LR; If 2 of 3 criteria, LR 23% vs. 4% (SS)

Conclusions:
Postoperative radiation improves locoregional control, but no survival benefit


See Radiation Oncology WikiBook for more details ↩︎

GOG 99

GOG 99

A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study

Pubmed

Hypothesis:
Addition of external beam radiation to postoperative therapy in intermediate risk endometrial cancer improves recurrence free survival

Site: Endometrium

Study population:
Inclusion: Derived from GOG 33

  • Intermediate Group: Any myometrial invasion with any grade and negative lymph node involvement i.e ([FIGO] stage IB, IC, IIA (occult), and IIB [occult]) – 5-year recurrence rate of 20 – 25%
  • Lymph node – Sampling/debulking if suspicious; Full lymphadenectomy if no enlarged or suspicious nodes
  • Revised during the course of study to enroll only “high intermediate risk” group : Expected 25% recurrence risk:
GOG 99 High Intermediate risk Group. Also used in GOG 249
    -  Age
    -  G2-3 tumor
    -  LVI
    -  Outer 1/3 myometrial invasion

1) >70 yrs old with only 1 other risk factor
2) >50 yrs old with 2 risk factors
3) any age with 3 risk factors

Excluded: High risk pathologies i.e. Clear cell and Papillary Serous, laparoscopic surgery excluded.

Experimental arm:
190 patients: External beam radiation 50.4 Gy given in 28 fractions. No Vag brachytherapy

Standard Arm:
202 patients: No additional therapy after surgery

Outcomes: Experimental arm vs. Standard arm (OR and p-values)

  • Primary Outcome (Recurrence Free @ 24 months) – 3% vs. 12% (OR – 0.42, p=0.007)
  • Secondary Outcome (Overall Survival @ 48 months) – 92% vs. 86% (OR – 0.86, p = 0.557)
  • Local Recurrences – 1.6% vs. 8.9% (p = ss)
  • Significantly Different Toxicity (Grade 2 or greater):
    • Hematologic: 7.4% vs 2.5% (p = ss)
    • GI : 34% vs. 2.5% (p = ss)

Conclusions:

  • Radiation reduced local recurrences but did not improve overall survival
  • Many deaths in the study were not endometrial cancer specific, therefore study underpowered to detect difference in overall survival even if it existed.
  • HIR group (132 total patients) : Defined above
    • Reduction in Hazard of isolated recurrence (RH: 0.37)
    • Reduction in Distant metastatic recurrence related to RT (RH: 0.46)
  • 2/3rd of recurrences and 2/3rd of cancer deaths in this group.
  • HIR – 19% improvement in cumulative recurrence at 24 months compared to no adjuvant therapy group vs LIR group 4% improvement compared to no adjuvant therapy group.

This study was the basis of GOG 249 selection criteria.


PORTEC 3

Pubmed

Study Summary by: Dr. Kevin McCool

Title: Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomized, phase 3 trial

Hypothesis: To investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer.

Standard Arm: EBRT (48.6 Gy in 1.8 Gy fractions)

Experimental Arm: EBRT (48.6 Gy) Chemotherapy (Cisplatin 50 mg/m2 in weeks 1 and 4 during RT followed by 4 cycles of Carboplatin AUC5 and Paclitaxel 175 mg/m2)

Design: Open-label, randomized, multi-center (UK, Australia, Italy, Canada, France)Inclusion Criteria:
– Endometrioid:

  • Stage IA Grade 3 with with LVSI

  • Stage IB Grade 3

  • Any Stage II or  III.

  • Serous or Clear Cell: Stage IA (with invasion), IB, II, III

Exclusion Criteria (outside of usual): Carcinosarcoma, prior malignancy within 10 years, prior radiotherapy, hormonal therapy, chemotherapy, bulky cervical involvement with radical hysterectomy, residual macroscopic disease

Primary Endpoint: Co-primary endpoints were failure-free survival (FFS) and overall survival (OS)

Outcomes: ChemoRT vs. RT alone (HR and p-value)

  • OS: 81.8% vs.76.6% [HR 0.76 (p=0.109)]
  • FFS: 75.5% vs. 68.6%[HR 0.71 (p=0.022) favoring chemotherapy RT]
  • Subgroup analysis: Stage III patients
    • 5 year FFS = 69.3% vs 58.0% (HR=0.66, p=0.031)
    • 5 year OS = 78.7% vs. 69.8% (HR=0.71, p=0.13)

Serious Adverse Events: ChemoRT vs. RT alone (p-value)

  • Any hematologic: 45% vs. 5% (p<0.0001)
  • GI: 14% vs. 5% (p<0.0001)
  • Neuropathy: 7% vs. 0% (p<0.0001)
  • At 12 months no significant difference in any grade 3 toxicity

Conclusions:

  • Improvement in FFS with the addition of chemotherapy. OS unchanged
  • Significant improvement in FFS
  • Most benefit in patients with stage III
  • Age is a significant predictor on risk adjustment. Patients above 70 benefit from chemoradiation (however toxicity discussion is warranted)