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 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)

GOG 218

Incorporation of bevacizumab in the primary treatment of ovarian cancer.

Pubmed

First Author: Burger RA

Hypothesis: Addition of bevacizumab improves progression free interval in previously untreated, incompletely resectable Stage III or any Stage IV EOC, surgery within 12 weeks. (PROTOCOL modification → Patients with Optimal debulking were included later in the trial)

Site: Ovary

Experimental arm – 1 (Bev-initiation): 175 mg/m2 paclitaxel (IV-3hrs) Carboplatin AUC 6 Bev 15 mg/m2 Cycle 2-6 followed by placebo cycle 7-22

Experimental arm – 2 (Bev-maintenance):175 mg/m2 paclitaxel (IV-3hrs) Carboplatin AUC 6 Bev 15 mg/m2 cycle 2-22

Standard Arm: 175 mg/m2 Paclitaxel (IV-3hrs) carboplatin AUC 6 IV x 6 cycle + placebo cycles 2-22

Primary Outcome: Originally planned was overall survival but changed to Progression free survival

Results:

Outcome Standard Bev-Inititation Bev-Maintenance p-value
PFS 10.3 11.2 14.1 SS
OS 39.3 38.7 39.7 NS
G3/4 – % cases
GI* 1.8 2.8 2.6 SS
HTN 7.2 16.5 23 SS
Neutropenia % 57 63 63 NS
VTE 5.8 5.3 6.7 NS
Arterial thrombosis 0.8 0.8 0.7 NS
CNS bleed 0 0 0.3 NS

*perforation, fistula, necrosis, or anastomotic leak

Conclusions: Marginal improvement in PFS, no significant improvement in OS

Important studies:

GOG Ancillary Study: Ascites predicts improved response to bevacizumab

Cost-effectiveness Study: Bevacizumab addition is not cost-effective

Other details

Arm Distribution:

Standard: 625 total - 83% serous,2.2% endometrioid, 3.7% clear cell and 10% other. 33% 1 cm disease, 26% stage IV


Experimental 1 (bev-inititation): 623 total - 84% serous,4% endometrioid, 3.2% clear cell, 1.3% mucinous, 7.5% other. 35%  1 cm disease, 26% stage IV


Experimental 2 (bev-maintenance): 625 total - 87% serous,3.4% endometrioid, 1.9% clear cell, 1% mucinous, 7.5% other. 35%  1 cm disease, 26% stage IV

GOG 152

Secondary surgical cytoreduction for advanced ovarian carcinoma

Pubmed

First Author: Rose PG

Hypothesis: Secondary debulking in sub optimally >1 cm tumor patients after 3 cycles of chemotherapy improves survival

Site: Ovary

Experimental arm: Suboptimal surgery –> 3 cycles of cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 q-24 hr –>Secondary debulking –> 3 further cycles

Standard Arm: Suboptimal surgery –> 6 cycles of cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 q-24 hr

Primary Outcome: OS

Arm Distribution:

Experimental arm (secondary debulking arm): N=208 (Serous 76%, Endometrioid 8%, Measurable disease at 3 cycles 1-2 cm 12%, 2-5 cm 43%, 5-10 cm 33%, > 10 cm 12%)

Standard arm (no secondary debulking): N=216 (Serous 76%, Endometrioid 5%, Measurable disease at 3 cycles 1-2 cm 12%, 2-5 cm 44%, 5-10 cm 38%, > 10 cm 6%)

Results:

Outcome Secondary debulking Chemotherapy only p-value
PFS (Months) 10.5 10.7 NS
OS 33.9 33.7 NS
Neuropathy G2/4 16% 26% SS
GI G2/4 7% 4% SS

Conclusions: If maximum surgical effort up front (by a gynecologic oncologist), no benefit to interval cytoreduction


GOG 172

Intraperitoneal cisplatin and paclitaxel in ovarian cancer

Pubmed

First Author: Armstrong DK

Hypothesis: IP chemotherapy improves overall survival in optimally debulked ovarian cancer

Site: Ovary

Experimental arm: 135 mg/m2 paclitaxel (IV-24hrs) cisplatin 100 mg/m2 IP day 2 60 mg Paclitaxel IP day 8 (All IP meds with 2 L warm saline)

Standard Arm: 135 mg/m2 Paclitaxel (IV-24hrs) cisplatin 75mg/m2 IV on day 2

Primary Outcome: Overall survival

Results:

Outcome IP/IV IV only p-value
PFS 23.8 18 SS
OS 65.6 49.7 SS
Completed all planned cycles 42% 83% SS
G3/G4Toxicity
GI 46% 24% SS
Neutropenia 76% 64% SS
Neuropathy 19% 9% SS
Fatigue 18% 4% SS

Conclusions: Significant improvement in PFS and OS in optimally debulked patients (<1 cm)

Controversies (Select editorials worth reading)

Pro IP chemotherapy

Against IP chemotherapy