• Save
BALKAN MCO 2011 - S. Beslija - Controversies in recurrent ovarian cancer: role of CA125, timing, role of surgery and new treatment options of 2nd-line therapy
Upcoming SlideShare
Loading in...5
×
 

BALKAN MCO 2011 - S. Beslija - Controversies in recurrent ovarian cancer: role of CA125, timing, role of surgery and new treatment options of 2nd-line therapy

on

  • 1,117 views

 

Statistics

Views

Total Views
1,117
Views on SlideShare
1,117
Embed Views
0

Actions

Likes
2
Downloads
0
Comments
0

0 Embeds 0

No embeds

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Lots of things prior medical history, genetic makeup, and specific char of tumor. Not always static,
  • WHAT KIND OF THE RECURRENCE CA WE SEE AT THE PATIENTS WITH OVARIAN CANCER
  • CA-125, cancer antigen 125; OS, overall survival.
  • CA-125, cancer antigen 125.
  • CA-125, cancer antigen 125EORTC, European Organisation for Research and Treatment of Cancer; ULN, upper limit of normal.
  • EARLY INITIATION OF CHEMOTHERAPY DOES NOT HAVE ANY IMPACT ON SURVIVAL
  • RCT, randomized controlled trial
  • .
  • AUC, area under the curve; ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival; PS, performance score; SWOG, Southwestern Oncology Group.
  • CONSORT diagram. CD, pegylated liposomal doxorubicin plus carboplatin; CP, carboplatin and paclitaxel; ITT, intention to treat; PFS, progression-free survival. (*) Ineligible because of absence of evidence of ovarian cancer.
  • Progression-free survival (PFS). HR, hazard ratio; PLD, pegylated liposomal doxorubicin.
  • 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.[10] OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; RR, response rate. extract from the sea squirt Ecteinascidia turbinata superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis
  • (A) Analysis of progression-free survival (PFS) by independent radiology assessment of all measurable patients (primary end point). (B) Analysis of PFS for patients with platinum-sensitive disease. (C) Analysis of PFS for patients with platinum-resistant disease. (D) Interim analysis of overall survival (OS). HR, hazard ratio; PLD, pegylated liposomal doxorubicin.
  • CR, complete response: TFI, treatment-free interval.
  • PLD, pegylated liposomal doxorubicin.
  • OS, overall survival; PLD, pegylated liposomal doxorubicin; QoL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to progression.
  • GOG, Gynecologic Oncology Group; ORR, overall response rates; SAEs, serious adverse events; TFI, treatment-free interval.
  • CR, complete response; PLD, peglyated liposomal doxorubicin.
  • OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin.
  • GOG, Gynecologic Oncology Group; ORR, overall response rate; SAEs, serious adverse events; TFI, treatment-free interval.
  • CA-125, cancer antigen 125.

BALKAN MCO 2011 - S. Beslija - Controversies in recurrent ovarian cancer: role of CA125, timing, role of surgery and new treatment options of 2nd-line therapy BALKAN MCO 2011 - S. Beslija - Controversies in recurrent ovarian cancer: role of CA125, timing, role of surgery and new treatment options of 2nd-line therapy Presentation Transcript

  • 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
  • Ovarian Cancer: Overview
    • 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
    • Stage I/II
      • Essentially all patients will achieve a clinical CR after surgery and chemotherapy
      • 20% to 25% will relapse
    • Optimal stage III
      • > 90% will achieve a clinical CR
      • 75% will recur
    • Suboptimal stage III and IV ~ 75% of cases [2]
      • No effective early diagnostic tests
      • Requires systemic therapy as the mainstay of treatment
      • 50% will achieve a clinical CR
      • > 90% will recur
    Recurrent Ovarian Cancer: Magnitude of the Clinical Problem
  • Considerations in Recurrence
    • Patient
      • Symptoms
      • Co-morbidities
      • Performance status
      • Prior toxicity :
        • Neuropathy
        • Myelosuppression
        • Allergic reactions
    • Tumor
    • TFI
      • Disease volume
    • Resistance status :
    • Platinum sensitivity/resistance
    • Resistance mechanisms
    • Drug
    • Efficacy
    • Schedule
    • Toxicity
    • Serologic relapse
      • Rising CA-125 only evidence of disease
    • Localized recurrence
    • Disseminated intraperitoneal disease
    • Extraperitoneal metastases
    • Recurrences can be symptomatic or asymptomatic
    Patterns of Recurrence
    • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan / physical examination
    • Role of secondary cytoreduction
    • Maintenance therapy
    • Optimal chemotherapy
      • Platinum-sensitive disease
      • Platinum-resistant disease
      • Determine length of treatment
    • Role of biologic/targeted therapy
    Controversies in Recurrent Ovarian Cancer
    • Rising CA-125 is highly predictive of a clinical relapse
      • Median time of 4-6 m . before symptoms develop and/or a clinical recurrence (physical exam / imaging studies) is documented
    • Serum level of CA-125 demonstrated in multiple clinical trials and standard oncologic practice to be one of the most useful tumor markers in oncology [1]
      • However, it is unclear if the rate of rise of CA-125 carries independent adverse prognostic significance, sufficient to justify therapeutic decision making on this basis alone
    Management of a Rising CA-125 in a Patient Who Is Clinically Disease Free
    • 50% of patients with normal CA-125 level at completion of chemotherapy will have persistent microscopic or macroscopic disease at second-look surgery [1]
    • Rising CA-125 level in patients with ovarian cancer whose CA-125 level had previously entered normal range usually indicates disease progression [2]
      • 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
    • 0.00
    • 0.25
    • 0.50
    • 0.75
    • 1.00
    • Proportion Alive Not Started
    • Second-Line Chemotherapy (%)
    • 264
    • 177
    • 116
    • 91
    • 69
    • 56
    • 49
    • 42
    • 33
    • Delayed
    • 265
    • 23
    • 16
    • 14
    • 11
    • 11
    • 10
    • 10
    • 9
    • Early
    • Number at risk
    • 0
    • 3
    • 6
    • 9
    • 12
    • 15
    • 18
    • 21
    • 24
    • Time (mos since randomisation)
    • Median (mos)
    • Early 0.8
    • Delayed 5.6
    • HR = 0.29 (95% CI 0.24, 0.35) p < .00001
    • Rustin, 2009.
  • Overall Survival
    • HR = 1.00 (95% CI 0.82–1.22) p = .98
    • Early
    • Delayed
    • Abs diff at 2 years = -0.1%
    • (95% CI diff = -6.8, 6.3%)
    • Rustin, 2009.
    • 0.00
    • 0.25
    • 0.50
    • 0.75
    • 1.00
    • Proportion Surviving (%)
    • 264
    • 236
    • 203
    • 167
    • 129
    • 103
    • 69
    • 53
    • 38
    • 31
    • 19
    • Delayed
    • 265
    • 247
    • 211
    • 165
    • 131
    • 94
    • 72
    • 51
    • 38
    • 31
    • 22
    • Early
    • Number at risk
    • 0
    • 6
    • 12
    • 18
    • 24
    • 30
    • 36
    • 42
    • 48
    • 54
    • 60
    • Time (mos since randomisation)
  • CA125 Monitoring: Pro and Con
    • Avoid symptom onset
    • Patient demand
    • “ Active” surveillance strategy
    • Avoid routine radiography
    • Leads to increased toxicity
    • Negative impact on QOL and psychosocial issues
    • Lack of survival advantage
    • Cost
    • Phase III data shows no survival advantage
    • Supporting Rationale
    • Challenging Rationale
    • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan or on physical examination
    • Role of secondary cytoreduction
    • Maintenance therapy
    • Optimal chemotherapy
      • Platinum-sensitive disease
      • Platinum-resistant disease
      • Use of in vitro sensitivity resistance assays
      • Determine length of treatment
    • Role of biologic/targeted therapy
    Controversies in Recurrent Ovarian Cancer
  • Secondary Cytoreduction
    • Epithelial ovarian cancer is moderately chemosensitive
      • Surgical cytoreduction of tumor volume highly correlates with prolongation of patient survival
      • Some patients who develop recurrent disease may be eligible for secondary cytoreduction
    Fader AN, et al. J Clin Oncol. 2007;25:2873-2883.
    • No RCT establishing clinical benefit
      • Gynecologic Oncology Group trial in progress [1]
    • Easier to define patients who should not undergo secondary cytoreduction
      • Short disease-free interval
      • Intraperitoneal carcinomatosis precludes complete resection
      • Ascites
      • Drug-resistant disease
    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 [1]
      • 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) [2]
      • 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.
  • Secondary Debulking: Candidate Selection
    • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan or on physical examination
    • Role of secondary cytoreduction
    • Maintenance therapy
    • Optimal chemotherapy
      • Platinum-sensitive disease
      • Platinum-resistant disease
      • Use of in vitro sensitivity resistance assays
      • Determine length of treatment
    • Role of biologic/targeted therapy
    Controversies in Recurrent Ovarian Cancer
  • Maintenance Therapy in Recurrent Ovarian Cancer
    • Consolidation and maintenance strategies evaluated in clinical trials
      • Consolidation therapies: high-dose chemotherapy with stem cell transplantation, also intraperitoneal administration of antibodies conjugated with various radioisotopes
      • Maintenance therapies: prolonged use of single-agent chemotherapy, intraperitoneal chemotherapy, hormonal therapy, and vaccines
      • To date, none of these interventions has shown an improvement in OS
    Ozols RF. J Clin Oncol. 2003;21:2451-2453.
  • Treating to Progression: Pro and Con
    • Symptom palliation
    • Maintains stable disease
    • Fewer cumulative toxicities with many of the novel agents
    • Limited number of options
    • Survival advantage
    • Cumulative toxicities
    • Negative impact on QOL and psychosocial issues
    • Use of more effective agents delayed
    • Limited documented benefits
    • Supporting Rationale
    • Challenging Rationale
    • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan or on physical examination
    • Role of secondary cytoreduction
    • Maintenance therapy
    • Optimal chemotherapy
      • Platinum-sensitive disease
      • Platinum-resistant disease
      • Determine length of treatment
    • Role of biologic/targeted therapy
    Controversies in Recurrent Ovarian Cancer
  • Concept of Platinum Sensitivity
    • Primary treatment
    • End of front-line therapy
    • 0 mos
    • 6 mos
    • 12 mos
    • Refractory
    • Resistant
    • Platinum sensitive
    • Herzog, 2006.
      • Refractory disease: no response or incomplete response to platinum-based therapy
      • Relapsed disease: progression after clinical complete response
        • Platinum sensitive:  6 month platinum-free interval
        • Platinum resistant:  6 month platinum-free interval
  • 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.
  • Historic Paradigm of Recurrent Disease
    • Increasing evidence suggests the duration of the PFI also influences outcomes of non-platinum chemotherapeutic agents/regimens
    • a Although platinum retreatment was the traditional therapy, emerging evidence suggests non-platinum doublets are effective in treating platinum-sensitive recurrent disease.
    • Monk et al, 2009.
    • Platinum sensitive
    • PFI > 6 mos
    • Platinum a retreatment
    • Platinum
    • refractory/resistant
    • PFI < 6 mos
    • Non-platinum treatment
    • Combinations based on carboplatin shown superior to combinations based on c is platin
    • Combinations shown superior to single-agent carboplatin in RCT
      • Carboplatin + paclitaxel
      • Carboplatin + gemcitabine
      • Carboplatin + PLD
    • Which combination is the best one to use?
    Chemotherapy for Platinum-Sensitive Recurrent Disease
    • ICON-4/AGO-OVAR-2.2
      • Randomization
        • “ Platinum” vs paclitaxel/carboplatin
    • AGO, NCIC-EORTC
      • Randomization
        • Carboplatin vs gemcitabine/carboplatin
    • AGO-OVAR 2.9 (CALYPSO trial)
      • Randomization
        • Carboplatin + PLD vs carboplatin + paclitaxel
    Treatment of Platinum-Sensitive Disease
  • ICON 4/AGO-OVAR 2.2
    • 2 parallel randomized multicenter trials
    Parmar MK, et al. Lancet. 2003;361:2099-2106. Paclitaxel plus Platinum -based chemotherapy (n = 392) Platinum -based chemotherapy (n = 410) Patients with platinum-sensitive recurrent ovarian cancer (N = 802)
  • Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: PFS Parmar MK, et al. Lancet. 2003;361:2099-2106. Paclitaxel plus platinum Conventional treatment Hazard ratio: 0.76; P = .0004 0 20 40 60 80 100 Time From Randomization (yrs) Progression-Free Survival (%) Patients at risk Paclitaxel plus platinum 392 179 52 25 17 Conventional treatment 410 157 45 17 7 1 2 3 4 0
  • Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: OS Parmar MK, et al. Lancet. 2003;361:2099-2106.
    • Paclitaxel plus platinum
    • Conventional treatment
    • Hazard ratio: 0.82; P = .0023
      • Median 2-year survival: 57% vs 50% for paclitaxel/carboplatin (n = 392) and conventional platinum-based treatment (n = 410), respectively
    Proportion Surviving (%) Patients at risk Paclitaxel plus platinum 392 306 167 96 43 18 Conventional treatment 410 295 150 68 33 11 0 20 40 60 80 100 1 2 3 4 0 5 Time From Randomization (yrs)
      • Median follow-up: 42 months
  • AGO-OVAR-2.5: Gemcitabine/Carboplatin
    • International, open-label, phase III trial
    • 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.
    • Pujade-Lauraine E et al. JCO 2010;28:3323-3329
    • ©2010 by American Society of Clinical Oncology
    Pegylated Liposomal Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse
    • Pujade-Lauraine E et al. JCO 2010;28:3323-3329
    • ©2010 by American Society of Clinical Oncology
    PFS
    • 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 Alopecia
      • Less Neuropathy
    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
    • Translational Research
    • Pharmacokinetics
    • Pharmacogenomics
    • Pharmacoeconomics
    • Quality of Life
    • Circulating tumor cells
    • Monk B J et al. JCO 2010;28:3107-3114
    • © 2010 by American Society of Clinical Oncology
    • A) Analysis of progression-free survival (PFS) by independent radiology assessment of all measurable patients (primary end point). (
    • B) Analysis of PFS for patients with platinum-sensitive disease.
    • (D) Interim analysis of overall survival (OS). HR, hazard ratio; PLD, pegylated
    • (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
    • Gemcitabine
    • Topotecan
  • 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)
    • Primary endpoint: PFS, time to progression
  • PLD vs Topotecan: Toxicity
    • PLD
      • Hand-foot syndrome (grade 3 or 4: 23%)
      • Stomatitis (grade 3 or 4: 8%)
    • Topotecan
      • Myelosuppression
      • Neutropenia (grade 3 or 4: 77%)
      • Thrombocytopenia (grade 3 or 4: 34%)
    Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.
  • PLD vs Gemcitabine
    • Phase III, multicenter, comparative study
    • Primary endpoint: TTP
    • 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.
    • Ferrandina G et al. JCO 2008;26:890-896
    • ©2008 by American Society of Clinical Oncology
    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
    • RCT
      • PLD vs topotecan [1]
        • RCT, which included patients with platinum-sensitive and platinum-resistant disease, showed improved OS with PLD
        • Subset analysis showed no difference in OS for platinum-resistant disease
      • PLD vs gemcitabine [2]
        • No difference in PFS or OS in 2 RCTs (improved QoL with PLD in one trial)
    • Toxicity: main consideration in selecting chemotherapy for patients with platinum-resistant disease
      • ORR: 8% to 12%
      • PFS: 3-4 months
      • OS: 11-13 months
    Trial Results in Platinum-Resistant Disease 1. Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. 2. Ferrandina G, et al. J Clin Oncol. 2008;26:890:896.
  • GOG 126 Series: Cytotoxic Agents (1 prior regimen; TFI < 6 months) 1. Rose PG, et al. J Clin Oncol. 1998;16:405-410. 2. Rose PG, et al. Gynecol Oncol. 2003;88:130-135. 3. Markman M, et al. Gynecol Oncol. 2006;101:436-440. 4. Miller DS, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 5524. Study Agent Dose/schedule ORR Common SAEs 126-H [1] Docetaxel 100 mg/m 2 every 3 weeks 22.4% Neutropenia (grade 4, 75%) 126-J [2] Oral etoposide 50 mg/m 2 per day 26.8% Neutropenia (grade 3/4, 45%) 126-N [3] Weekly paclitaxel 80 mg/m 2 per Week 20.9% Neuropathy (grade 2, 21%) 126-Q [4] Pemetrexed 900 mg/m 2 every 3 weeks 21% Neutropenia (grade 3/4, 42%)
    • No evidence that combinations of cytotoxic agents superior to single agents
      • RCT of canfosfamide + carboplatin vs PLD: negative
      • PLD + trabectedin vs PLD negative
    • No RCTs of in vitro sensitivity/resistance assays have shown improvement
    • Biologic agents
      • Bevacizumab single agent or in combination with chemotherapy
      • Imatinib
      • Sorafenib
    Strategies to Improve Outcomes in Platinum-Resistant Disease
  • Current Standards in Recurrent Ovarian Cancer: Conclusions
    • Treat chemoresistant disease with a single nonplatinum agent
      • PLD, topotecan, gemcitabine, oral etoposide, weekly paclitaxel, docetaxel, pemetrexed, bevacizumab, and tamoxifen , trabectedin
      • Give the agent until disease progression, unacceptable toxicity, or clinical CR
      • Once agent is no longer effective, give another single agent
    • Base regimen on clinical trial results, efficacy, toxicity, and patient convenience
    • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan / physical examination
    • Role of secondary cytoreduction
    • Maintenance therapy
    • Optimal chemotherapy
      • Platinum-sensitive disease
      • Platinum-resistant disease
      • Determine length of treatment
    • Role of biologic/targeted therapy
    Controversies in Recurrent Ovarian Cancer
  • How Long to Treat Patients With Recurrent Disease?
    • Only a minority of patients will achieve a clinical CR with chemotherapy
      • In platinum-sensitive disease: 6% to 15%
      • In platinum-resistant disease: 2% to 3%
    • The majority of patients will have residual disease after 6 cycles of chemotherapy
    • What to do?
      • Continue with same chemotherapy if patient is asymptomatic?
      • Stop after 6 cycles ( “drug holiday”) if patient is asymptomatic?
      • Switch to another chemotherapy?
  • Answers
    • No RCTs in recurrent disease directly address this issue
    • In previously untreated patients, RCTs have failed to show any benefit for either continuing with the same chemotherapy or switching to a non – cross-resistant regimen
      • In recurrent disease, the same could be expected
    • Currently, this is a personal choice issue with patient/physician
      • Toxicity is key
      • Some patients will choose more therapy as long as there is evidence they are not in a remission — “psychochemotherapy”
      • Benefit of “drug holidays”
    • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan or on physical examination
    • Role of secondary cytoreduction
    • Maintenance therapy
    • Optimal chemotherapy
      • Platinum-sensitive disease
      • Platinum-resistant disease
      • Use of in vitro sensitivity resistance assays
      • Determine length of treatment
    • Role of biologic/targeted therapy
    Controversies in Recurrent Ovarian Cancer
  • NCCN 2 011 Acceptable Recurrence Therapies
    • NCCN, 2009.
    Agents Cytotoxic Therapy Hormonal Therapy Targeted Therapy Radiation Therapy NCCN preferred Platinum sensitive combinations Carbo/paclitaxel (cat 1) Carbo/docetaxel Carbo/gemcitabine Cisplatin/gemcitabine Platinum sensitive monotherapy Carboplatin Cisplatin Platinum resistant single agents Docetaxel Etoposide (oral) Gemcitabine Liposomal doxorubicin Paclitaxel, weekly Pemetrexed Topotecan Bevacizumab Other acceptable and potential agents Altretamine Capecitabine Cyclophosphamide Ifosfamide Irinotecan Melphalan Oxaliplatin Paclitaxel Vinorelbine Anastrozole Letrozole Leuprolide Megestrol acetate Tamoxifen Palliative localized radiation therapy
  • GOG 160/170 Series: Performance Comparison PFS ≥ 6 (%) RR (%)
    • Bevacizumab
    • Sorafenib
    • Imatinib
    • Gefitinib
    • Trastuzumab
    • Lapatinib
    • Vorinostat
    • US NIH, 2009d
    • Median PFS: 4.4 months
    • Median OS: 10.7 months
    • Phase II trial in patients with platinum-resistant epithelial ovarian cancer or peritoneal serous cancer
      • All patients had progressed during or within 3 months of discontinuing topotecan or PLD therapy
    • Bevacizumab 15 mg/m 2 IV given on Day 1 on each 3-week cycles until unacceptable toxicity or radiographic progression
    • Objectives
      • Primary: evaluate activity of bevacizumab
      • Secondary: PFS, OS, safety
    Bevacizumab in Platinum-Resistant Patients Cannistra SA, et al. J Clin Oncol. 2007;25:5180-5186. Survival PFS 1.0 0.8 0.6 0.4 0.2 0 2 4 6 8 10 12 14 Months Proportion Event Free 16 0
  • GOG 170: Biologic Agents* 1. Schilder RJ, et al. Clin Cancer Res. 2005;11:5539-5548. 2. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. 3. Schilder RJ, et al. J Clin Oncol. 2008;26:3418-3425. 4. Modesitt SC, et al. Gynecol Oncol. 2008;109:182-186. *1-2 previous regimens; TFI < 12 months or 2 previous platinum regimens and TFI > 12 months. Study Agent Dose/Schedule ORR, % Common SAEs 170-C [1] Gefitinib 500 mg PO daily 4.0 Dermatologic, diarrhea 170-D [2] Bevacizumab 15 mg/m 2 21.0 Gastrointestinal, hypertension, venous thromboembolism 170-E [3] Imatinib mesylate 400 mg PO BID 1.8 Neutropenia, dermatologic, gastrointestinal, pain, electrolyte disturbance 170-G [4] Lapatinib 1500 mg PO daily 16.9 Gastrointestinal, hypertension, proteinuria, pulmonary embolus 170-H [4] Vorinostat 400 mg PO daily 4.0 Neutropenia, constitutional, gastrointestinal
  • Issues and Controversies in Recurrent Ovarian Cancer: Summary
    • Despite the many advances in therapeutic options for recurrent ovarian cancer, many controversies remain
    • Research findings continue to resolve many of these issues, including data from trials evaluating the role of secondary cytoreduction, maintenance therapy, and the prognostic significance of CA-125
    • Finding the optimal treatment paradigms for ovarian cancer patients will remain the goal for improving outcomes