Controversies in recurrent ovarian cancer: CA 125, timing, role of surgery and new treatment options of 2-nd line therapy Semir Beslija, MD, PhD Institu t e of oncology Clinical Center of Sarajevo University
I ncidence varies by around 40% across the four regions of Europe, with estimated E U age-standardised rates ranging from 12 per 100,000 women in Southern Europe to 17 per 100,000 in Northern Europe in 2008. 1
The countries with the highest incidence rates are Latvia, Lithuania and Bulgaria (all around 19 per 100,000), and the lowest were Cyprus and Portugal (7 per 100,000).
Balkan area between 7 and 19%
1. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765-81
50% of patients with normal CA-125 level at completion of chemotherapy will have persistent microscopic or macroscopic disease at second-look surgery 
Rising CA-125 level in patients with ovarian cancer whose CA-125 level had previously entered normal range usually indicates disease progression 
Confirmed doubling of CA-125 level is now established as one definition of progression in patients with ovarian cancer
No uniform consensus in the management of post-treatment patients with relation to their CA-125 value
CA-125: Interpreting Significance in Disease-Free Patients (cont ’d) 1. Krebs H-B, et al. Obstet Gynecol. 1986;67:473-477. 2. Markman M. Oncologist. 1997;2:6-9. 3. Goonewardene TI, et al. Lancet Oncol. 2007;8:813-821.
CA-125: Interpreting Significance in Disease-Free Patients
Abnormal CA-125 level correlates to > 95% certainty of residual disease even if second-look surgery fails to confirm disease persistence
Patient/physician preference about instituting chemotherapy is similar (~ 50%)
No evidence that delaying chemotherapy until clinical relapse is detrimental
Evidence that earlier treatment may reduce sequelae such as ascites and intestinal obstruction
Randomized trial in progress in Europe
1. Markman M. Oncologist. 1997;2:6-9. 2. Karavasilis V, et al. ASCO 2008. Abstract 5544.
EORTC 55955-OV05: CA-125 Levels and Therapy in Relapsed Patients
Phase III randomized trial
Primary outcomes: benefit of early chemotherapy, OS, QoL
Findings from this trial still forthcoming
Arm 1: Clinician is informed of CA-125 rise and confirmed by testing; within 4 weeks of the initial CA-125 rise, patients with a second confirmed rise receive treatment for recurrent disease according to standard local practice. Patients with normal CA-125 confirmatory test receive no treatment until clinically indicated Arm 2: Clinician is blinded to the CA-125 results; patients undergo normal monitoring. When clinically indicated, patients commence treatment according to standard local practice Patients with relapsed ovarian epithelial, fallopian tube, or primary peritoneal cancer whose CA-125 levels rise ≥ 2 times the ULN (N = 1400) EORTC. Available at: http://www.eortc.be/protoc/Details.asp?Protocol=55955.
Time From Randomisation to Second-Line Chemotherapy
Role of Secondary Cytoreduction 1. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/ NCT00002568?term=GOG+cytoreduction&rank=1. Accessed February 4, 2008.
Clinical Features for Optimal Secondary Surgical Cytoreduction
258 patients with advanced ovarian cancer reviewed 
40% received chemotherapy within the year
Patients who underwent complete removal of all gross visible cancer (55%) showed superior survival compared with patients who had incomplete cytoreduction (median survival: 45 vs 20 months, respectively)
Factors influencing survival: eligibility for complete surgical resection, absence of ascites, platinum-based chemotherapy after secondary surgery
Complete secondary reduction also associated with a median postrecurrence survival of ~ 50 months in another study of advanced ovarian cancer (N = 55) 
All patients had diagnosis-to-recurrence interval of ≥ 18 months and the presence of only 1-2 recurrence sites on preoperative imaging studies
1. Harter P, et al. ASCO 2005. Abstract 5004. 2. Fader AN, et al. J Clin Oncol. 2007;25:2873-2883.
Effect of PFI on Response Rate Markman M, et al. J Clin Oncol. 1991;9:1801-1805. Months Response Rate (%) 27% 33% 59% 0 10 20 30 40 50 60 5-12 13-24 > 24 The most widely used clinical surrogate for predicting response to chemotherapy and prognosis, as well as for making treatment recommendations in women with recurrent ovarian cancer, is the treatment-free interval, based on the time to progression after chemotherapy.
All patients had completed ≥ 6 months of first-line, platinum-based therapy
Patients stratified by platinum-free interval (6-12 vs ≥ 12 months), first-line therapy (platinum paclitaxel vs other platinum-based therapy), and bidimensionally measurable disease (yes vs no)
Primary endpoint: PFS
*Based on Calvert formula.
Gemcitabine 1000 mg/m 2 on Days 1 and 8 and Carboplatin AUC 4 mg/mL/min on Day 1 every 21 days for 6 cycles (n = 178) Carboplatin (Control) AUC 5 mg/mL/min on Day 1* every 21 days for 6 cycles (n = 178) Patients with recurrent ovarian cancer, measurable/ assessable disease per SWOG criteria, ECOG PS 0/2 (N = 356 ) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
AGO-OVAR 2.5 (GCIG): Progression-Free Survival Carboplatin (n = 178) Gemcitabine/carboplatin (n = 178) Progression-Free Probability 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 42 Months Originally published by the American Society of Clinical Oncology. Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. HR: 0.72 (95% CI: 0.58-0.90; P = .0031) Median: 8.6 months (range: 7.9-9.7) Median: 5.8 months (range: 5.2-7.1) Log-rank P = .0038
Gemcitabine/Carboplatin vs Carboplatin: OS Proportion Surviving Months Log-rank P = .1349* HR: 0.96 (95% CI: 0.75-1.23) 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Median: 18.0 months Median: 17.3 months Carboplatin (n = 178) Gemcitabine/carboplatin (n = 178) *Log-rank, unadjusted. Originally published by the American Society of Clinical Oncology. Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm.
More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm;
M ore hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.
TOXICITY Pujade-Lauraine E et al. JCO 2010;28:3323-3329
Toxicity Comparison of Regimens in Platinum-Sensitive Ovarian Cancer Parmar MK, et al. Lancet. 2003;361:2099-2106. Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707 Pujade-Lauraine E et al. JCO 2010;28:3323-3329 . *Complications of increased myelosuppression manageable.
Less Myelosuppression Less Hand/foot sy and mucositis Gemcitabine/carboplatin * Paclitaxel/carboplatin Pegylated doxorubicin/carboplatin
Conclusions: Platinum-Sensitive Recurrent Ovarian Cancer
Carboplatin is key drug
Carboplatin combinations are superior to single-agent carboplatin
Choice of carboplatin/gemcitabine vs carboplatin/paclitaxel vs Carboplatin + PLD based on toxicity consideration
Phase III Ovarian Cancer Study: PLD Plus Trabectedin vs PLD alone
Opened to accrual April 2005
Closed to accrual May 2007 (N=672)
Primary endpoint: PFS
Secondary endpoints: OS, RR, safety
www.clinicaltrials.gov/ct2/show/NCT00113607 Patients with advanced platinum- sensitive or – resistant recurrent epithelial ovarian cancer and 1 prior platinum-based regimen (planned N = 650, largest trial ever) PLD 30 mg/m 2 plus Trabectedin 1.1 mg/m 2 every 3 weeks PLD 50 mg/m 2 every 4 weeks
(C) Analysis of PFS for patients with platinum-resistant disease.
Study met primary end point, PFS (median: 7.3 vs 5.8 mos for the combination and PLD arms, respectively) and was shown to be significant and clinically meaningful by 3 measures Interim survival data showed positive trend with 15% risk reduction in death for combination arm
Conclusions cont : Platinum-Sensitive Recurrent Ovarian Cancer
Retreat most patients with chemosensitive disease with a platinum-based regimen
Continue treatment until disease progression, unacceptable toxicity, or CR
Expected outcome correlates directly with length of TFI
Retreatment with a platinum-based regimen is appropriate as long as the results of the immediate previous therapy justify categorization of disease as chemosensitive
Trabectedin+PLD (No platinum) valid option but not registered option
Drugs Used for the Treatment of Platinum-Resistant Disease
PLD vs Topotecan: Patients With Platinum-Refractory Disease 100 90 80 70 60 50 40 30 20 10 0 Weeks Since First Dose Overall Survival (%) Pegylated liposomal doxorubicin (n = 130) Topotecan (n = 125) No significant difference in survival HR: 1.069 (95% CI: .823-1.387); P = .618 0 20 40 60 80 100 120 140 160 180 200 220 240 260 Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.
Phase III study
Patients with recurrent platinum sensitive/resistant epithelial ovarian cancer randomly assigned to either
PLD 50 mg/m 2 via an 1-hour infusion every 28 days for 6 cycles (n = 239)
Topotecan 1.5 mg/m 2 via a 30-hour infusion for the first 5 days of a 21-day cycle for 8 cycles (n = 235)
Secondary endpoints: OS, response rate, safety/toxicity, QoL
*Premedication with methylprednisolone 20 mg IV administered 30 minutes before drug infusion.
PLD 40 mg/m 2 via 1-hour infusion every 28 days (n = 76)* Gemcitabine 1000 mg/m 2 via 30-minute infusion on Days 1, 8, and 15 of a 28-day cycle (n = 77) Patients with measurable/ assessable ovarian cancer by RECIST who had recurrence/treatment failure with 1 first-line, platinum- based/paclitaxel-containing chemotherapy (N = 153 ) Ferrandina G, et al. J Clin Oncol. 2008;26:890-896.
No statistically significant difference in time to progression (TTP) curves according to treatment allocation was documented ( P = .411). The trend for more favorable overall survival was documented in the PLD arm compared with the GEM arm, although the P value was of borderline statistical significance (P = .048) Results: TTP and OS