Frontline treatment of EOC

Question 1

Which trial established the role of platinum/paclitaxel in ovarian cancer?

Answer 1

GOG 111

[McGuire, W.P., et. al., N. Engl. J. Med; 1996, Jan. 4; 334(1): 1-6]

Question 2

Cisplatin/paclitaxel replaced which prior chemotherapy regimen for treatment of EOC?

Answer 2

cisplatin/cyclophosphamide

Question 3

Which trial demonstrated equivalence between carboplatin/paclitaxel and cisplatin/paclitaxel for treatment of EOC?

Answer 3

GOG 158

[Ozols, R.F., et. al., J. Clin. Oncol. 2003, Sep. 1; 21(17): 3194-3200]

• paclitaxel was given 24 hours in cisplatin group
• pacltaxel was given over 3 hours in carbo group; carbo was a high dose AUC 7.5

Question 4

What are the differences between 3-hour vs 24-hour taxol infusions?

Answer 4

• 24-hour infusion was given to avoid hypersensitivity
• 3-hour infusion of Taxol is safe when given with premedication and is associated with less myelosuppression.
• No difference in response rates

[Eisenhauer EA et al. (1994) JCO 12(12): 2654-2666]

Question 5

What’s the recommended dosing regimen for carboplatin / paclitaxel for EOC treatment?

Answer 5

• 3 hour paclitaxel (175 mg/m2) with carboplatin (AUC ≥ 5) every 21 days

Question 6

What was GOG 182 / ICON5? What were the results?

Answer 6

See picture for trial design

Results: No difference in PFS or OS with doublet or triplet therapy. However, there was more toxicity in the triplet therapy arms

Question 7

Which trials looked at IP chemotherapy in EOC treatment? What were the issues with these trials?

Answer 7

GOG 104 (N = 546)

• IV cyclophosphamide / cisplatin vs IV cyclophosphamide / IP cisplatin
  
  • OS: IV/IV: 41 mos; IV/IP: 49 mos (p=0.02)
• GOG 104 was published around same time GOG 111 published and therefore GOG 104 became obsolete; IV paclitaxel was seen to be more of a benefit than IP.
• IP cyclophosphamide is not given because ?
  
  • needs to be activated by liver vs. big molecule that can’t be absorbed (?)

GOG 114 (N = 462)

• IV paclitaxel / IV cisplatin vs IV carbo then IV paclitaxel + IP cisplatin
  
  • PFS: IV: 22 mos; IP: 28 mos
  • OS: IV: 52 mos; IP Group 2: 63 mos (p=0.05)
• GOG 114: IP group had higher toxicity groups and received 2 extra doses of hig dose carbo (AUC 9) in order to maximally cytoreduce; benefit thought to be due to extra cycles of platinum than due to IP.

GOG 172

• See figure
• OS & PFS improved with best survival outcomes seen.
• Taxol was given over 24 hours in this trial.

Question 8

Which landmark trial confirmed the survival advantage for IP chemotherapy compared to IV chemotherapy for upfront treatment of ovarian cancer?

What was the issue with implementing IP chemotherapy?

Answer 8

GOG 172

[Armstrong D, et al. N Engl J Med 2006:354(1):34-43.]

Issues were that less than half of patients (~42%) completed 6 cycles of IP.

Question 9

1. What proportion of EOC patients will respond to 1st line chemotherapy?
2. What proportion will have a complete response?
3. What proportion with CR will have disease on SLL?

Answer 9

1. ~85%
2. 70%
3. 50%

Question 10

What porportion of HGSOC patients will recur in 2 years?

Answer 10

75%

Question 11

Which trial examined consolidation taxol therapy following carboplatin/paclitaxel therapy?

What were the issues with this trial?

Answer 11

GOG 178

[Markman M, et al. J Clin Oncol 2003;21:2460-65.]

• Median PFS significantly prolonged with 12 cycles (28 months) vs 3 cycles (21 months) of paclitaxel
• Trial closed prematurely due to PFS results but there ended up being no overall survival advantage (thus survival advantage TBD)
• Predominant toxicities were neutropenia and neuropathy

Question 12

Which landmark trial evaluated the use of bevacizumab in the frontline setting and what was the trial design and results?

Answer 12

GOG 218

[Burger et al. N Engl J Med 2011;365:2473-83]

Design: see figure

Results

• mPFS
  
  • control: 10.3 months
  • bev-initiation group: 11.2 months
  • bev-throughout group: 14.1 months
  • Bev maint vs. control
    
    • HR 0.717; 95% CI 0.625 - 0.824; P<0.001
• mOS
  
  • control: 39.3
  • bev-initiation: 38.7
  • bev-throughout group: 39.7 months
  • Bev maint vs. control
    
    • HR, 0.915 95% CI, 0.727 to 1.152; P=0.4

Question 13

What was the ICON7 trial design and the results?

Answer 13

Design/results: see figure.

For the mature OS results:

• Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole.
• However, an overall survival benefit was recorded in poor-prognosis patients (stage IV or suboptimal TRS stage III), which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer.
  
  • This showed that avastin may have a role in suboptimally cytoreduced patients and stage IV disease.

Question 14

Differences between GOG 218 vs ICON7

[summary]

Answer 14

Question 15

What was GOG 157?

Answer 15

RCT

• Carboplatin AUC 6 + paclitaxel 175 mg/m² every 3 weeks x3 cycles vs x6 cycles.
• population: stage IA-B (grade 3 or clear cell), stage IC, and completely resected stage II
• Results: more toxicity (neurotoxicity, anemia, neutropenia) with the 6 cycles than 3 cycles with no difference in survival (RFI)
  
  • However, in exploratory analysis in HGS tumors, sought to determine if patients benefitted from more cycles of chemo; there was improved RFI for 6 cycles compared to 3 cycles chemotherapy

Question 16

Dose dense taxol

• What is the rationale for dose dense taxol?
• Which trial piqued interest in dose dense taxol?
• What was the study design and results?

Answer 16

• Rationale
  
  • Duration of exposure is an important determinant of paclitaxel cytotoxicity
  • Preclinical evidence of anti-angiogenic effect
• JGOG 3016
• Results
  
  • Improved PFS among DD group (28.2 vs 17.5 months; p = 0.004)
  • Improved OS for DD group (100.5 vs 62.2 months)
    
    • There was a difference in OS among patients with residual disease (51.2 vs 33.5 months; p = 0.03) but not among those with optimal disease
  • HGS tumors responded the best but CC not so much.
  • More hematologic toxicity in dose dense (60% vs 43%) with higher discontinuation rates (36% vs 22%)

Question 17

What was the study design and findings of GOG 262?

Answer 17

Study design

• see figure

Findings

• Most patients received avastin (10% did not receive it)
• Overall, there was no difference in findings
  
  • PFS: 14.7 vs 14 mo
  • OS: 40.2 vs 39 mo
• Was avastin the reason for the lack of difference?
  
  • PFS in group w/o avastin: 14.2 vs 10.3; p = 0.03
  • PFS in group w/ avastin: 14.9 vs 14.7

Question 18

What was the study design and findings of ICON8?

Answer 18

Study design

• See figure

Findings

• No significant increase in PFS was observed with either
  
  • a)Weekly treatment: log-rank arm 2v1 p=0.45; arm 3v1 p=0.56

b) Restricted mean survival time: 1=24.4; 2=24.9; 3=25.3 months
c) Median PFS: 1=17.9; 2=20.6; 3=21.1 months
d) HR=0.92 arm 2v1, HR= 0.94 arm 3v1

Question 19

What were the questions that GOG 252 was trying to answer? (hint there were too many)

Answer 19

Question 20

What was the trial design of GOG 252?

What was the difference between the IP cisplatin arm of GOG 252 and arm of GOG 172?

Answer 20

• Dose reduction cisplatin(100 down to 75 mg/m2)
• Infusion time reduction 135 mg/m2 paclitaxel(3 hr instead of 24h)
• All outpatient therapy
• Bevacizumab 15 mg/m2 for all arms on cycles 2-22
• Comparison arm dose dense paclitaxel with carbo IV AUC 6- GOG 262 (JGOG)
• Second experimental Arm IP carbo and dose dense paclitaxel

Question 21

Summary slide for PFS across studies

Answer 21

Question 22

What do you use for treatment? (summary)

Answer 22