Documents
Resources
Learning Center
Upload
Plans & pricing Sign in
Sign Out

GOG IMER Institute for Medical Education Research

VIEWS: 3 PAGES: 71

									                               DISCLAIMER
     This slide deck in its original and unaltered format is a certified educational
activity current as of April 2010. All materials contained herein reflect the views of
      the faculty, and not those of IMER, the CME provider, or the commercial
 supporter. These materials may discuss therapeutic products that have not been
approved by the US Food and Drug Administration and off-label uses of approved
       products. Readers should not rely on this information as a substitute for
 professional medical advice, diagnosis, or treatment. The use of any information
    provided is solely at your own risk, and readers should verify the prescribing
   information and all data before treating patients or employing any therapeutic
                    products described in this educational activity.

                              Usage Rights
  This slide deck is provided for educational purposes and individual slides may
   be used for personal, non-commercial presentations only if the content and
  references remain unchanged. No part of this slide deck may be published in
  print or electronically as a promotional or certified educational activity without
  prior written permission from IMER. Additional terms may apply. See Terms of
                       Service on IMERonline.com for details.
                             DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
    to enhance patient outcomes and their own professional development. The
   information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
     or treatment discussed or suggested in this activity should not be used by
        clinicians without evaluation of their patients’ conditions and possible
   contraindications on dangers in use, review of any applicable manufacturer’s
 product information, and comparison with recommendations of other authorities.


         DISCLOSURE OF UNLABELED USE
         This educational activity may contain discussion of published and
 investigational uses of agents that are not indicated by the FDA. IMER does not
     recommend the use of any agent outside of the labeled indications. The
   opinions expressed in the educational activity are those of the faculty and do
      not necessarily represent the views of IMER. Please refer to the official
  prescribing information for each product for discussion of approved indications,
                          contraindications, and warnings.
Disclosure of Conflicts of Interest
          Bradley J. Monk, MD, FACOG, FACS
Reported a financial interest/relationship or affiliation in the form of:
Speakers' Bureau, Lilly USA, GlaxoSmithKline plc., Merck & Co.,
Inc.; Contracted Research, Johnson & Johnson Services, Inc.,
GlaxoSmithKline plc., sanofi-aventis U.S.
Community Oncology Clinical
  Debates: Ovarian Cancer
                   Learning Objectives
         Upon completion of this program, participants
                  should be better able to:
   Describe the role, rationale, and types of surgical interventions for initial
    and recurrent treatment of ovarian cancer
   Identify evidence-based clinical decisions incorporating standard
    chemotherapeutic and biologic treatment for newly diagnosed and
    recurrent epithelial ovarian cancer
   Outline recent data regarding treatment options between chemo-
    sensitive and chemo-resistant patients with recurrent ovarian cancer
   Analyze recent data evaluating angiogenesis inhibitors alone or in
    combination with chemotherapeutic agents for the treatment of recurrent
    ovarian cancer
   Describe the benefits and risks of therapeutic options when counseling
    patients on treatment planning
   Identify ways to counsel patients on the availability of clinical trial
    participation when warranted
Case Study 1: Front-Line Therapy
   A 52-year-old insurance executive with ascites and
    14-cm pelvic mass on exam and CT scan
    – Omental cake seen on CT as well; CA125 = 899 preoperatively
   Exploratory laparotomy with radical tumor debulking
    including TAH/BSO, omentectomy, appendectomy,
    lymphadenectomy
   Optimally cytoreduced stage IIIC papillary serous
    ovarian cancer
   PS = 0; No significant co-morbidities
                 Question 1

Which treatment would you recommend for
this patient?
1. IV carboplatin and IV paclitaxel
2. IV carboplatin and IV docetaxel
3. IP cisplatin and IV paclitaxel
4. IP cisplatin, IV paclitaxel, and IP paclitaxel
5. IV platinum and taxane plus bevacizumab
                       Disease Burden

            Incidence 21,550 with mortality 14,600
            75% cases present with stage III/IV
            Fifth leading cause of cancer deaths in
             females
            Increased incidence with increasing age
            Nearly 70% of advanced stage cancers
             relapse


ACS, 2009.
             Survival: Increasing Over the Decades

                                         1
                                                                     SEER Data 1973–1997
                                       0.9                               N = 32,845
                                       0.8
                Proportion Surviving




                                                                                 GOG 172
                                       0.7                                        2006
                                       0.6
                                                                                           1973-79
                                       0.5
                                                                                           1980-89
                                       0.4
                                                                                           1990-97
                                       0.3
                                       0.2
                                       0.1
                                         0
                                             0   2        4          6       8       10
                                                     Years After Diagnosis


NCI, 2009; Armstrong et al, 2006.
                        Primary Cytoreduction
            Meta-analysis: 53 studies
            (1989–1998)
              – 81 cohorts (stage III/IV)
              – N = 6,885 patients




                                            Median Survival (mos)
            Results
              – Expert centers have high
                optimal rates
              – Optimal vs not: 11 mos
                (50% increase)
              – Each 10%  in
                cytoreduction = 5.5%  in
                                                                    % Cytoreduction
                survival
              – Platinum intensity = NS
Bristow et al, 2002.
                                     First-Line Therapy



                               Surgery with comprehensive staging
                                    or maximal cytoreduction



                                    Platinum + taxane chemotherapy
                                        (carboplatin + paclitaxel)
                                                 ? ?

                          Maintenance          IP (opt)   Biologics
Herzog et al, 2006, Herzog, 2006.
      GOG 182: Randomized 5-Arm Trial for Epithelial,
         Ovarian, and Primary Peritoneal Cancer
                                 Paclitaxel 175 mg/m2 IV (3H) D1 x 8 cycles (q 21 days)
                            I    Carboplatin AUC 6 IV           D1
     STRATIFICATION

     No gross residual
                                 Paclitaxel 175 mg/m2 IV (3H)        D1 x 8 cycles (q 21 days)
     vs macroscopic Dz
                                 Carboplatin AUC 5 IV                D1
     vs macroscopic Dz
                           II
                                 Gemcitabine 800 mg/m2/d IV          D1, 8
     and intent for
     interval
     cytoreduction               Paclitaxel 175 mg/m2 IV (3H)         D1 x 8 cycles (q 21 days)

                           III   Carboplatin AUC 5 IV                 D1
     RANDOMIZATION
                                 Doxil 30 mg/m2/d IV (every other) D1
     Stage III/IV opt or
     subopt
                                 Carboplatin AUC 5 IV         D3             Paclitaxel 175 mg/m2 IV (3H)
     Primary end points:                                                     Carboplatin AUC 6 IV
     PFS/OS/RR             IV    Topotecan 1.25 mg/m2/d IV D1–3
                                     x 4 cycles (q 21 days)                      x 4 cycles (q 21 days)


                                 Carboplatin AUC 6 IV           D8           Paclitaxel 175 mg/m2 IV (3H)
                                                                             Carboplatin AUC 6 IV
                           V     Gemcitabine 800 mg/m2/d IV D1, 8
                                     x 4 cycles (q 21 days)                       x 4 cycles (q 21 days)


Copeland et al, 2003.
GOG 182-ICON5: Overall Survival




                    Median OS and HR (95% CI)
                    40.0   1.000
                    40.4   0.978   (0.838-1.141)
                    42.8   0.972   (0.832-1.136)
                    39.1   1.068   (0.918-1.244)
                    40.2   1.035   (0.888-1.206)
                                       Key Phase III Studies

                                 1996                            2003       2006


                          GOG 111                         GOG 158       GOG 172

                     Study                              Comparison                    Results
                                                                             first-line paclitaxel ↑ PFS
                                             cisplatin/cyclophosphami
                  GOG 111                                                       and OS in advanced
                                             de vs cisplatin/paclitaxel
                                                                                        disease
                                                                               carboplatin/paclitaxel
                                                     cisplatin/paclitaxel
                  GOG 158                                                          non-inferior to
                                               vs carboplatin/paclitaxel
                                                                                cisplatin/paclitaxel
                                                       paclitaxel + IV
                                               cisplatin vs paclitaxel +     IP arm ↑ OS in optimally
                  GOG 172
                                                   IP cisplatin + IP        debulked stage III disease
                                                       paclitaxel


McGuire et al, 1996; Ozols et al, 2003; Armstrong et al, 2006.
                    Primary Treatment Guidelines

                                      • Grade 1: Observe
                                      • Grade 2: Observe or carboplatin/paclitaxel
                   Stage IA or IB       x 3–6
                                      • Grade 3: Carboplatin/paclitaxel x 3–6



                                      • Grade 1–3: Carboplatin/paclitaxel x 3–6
                         Stage IC


                                      • Intraperitoneal chemotherapya
                      Stage II–IV     • Carboplatin/paclitaxel x 6–8
                                      • Completion surgery




aOptimally
        debulked stage III disease.
NCCN, 2009.
                          Treatment Paradigm


            Diagnosis              Evaluation         Progression Evaluation Progression Death




Symptoms                Chemo #1         +/- Consolidation          Chemo #2   Chemo #3+




                                                             Cure
                Staging                                                           Supportive
                                                                                    Care




Herzog, 2006.
                                      Historic Paradigm of
                                       Recurrent Disease
                       Platinum                                                                          Platinum
                  refractory/resistant                                                                   sensitive

                           PFI < 6 mos                                                               PFI > 6 mos


                         Non-platinum                                                                  Platinuma
                          treatment                                                                   retreatment

           Increasing evidence suggests the duration of the PFI also
            influences outcomes of non-platinum chemotherapeutic
            agents/regimens

aAlthough   platinum retreatment was the traditional therapy, emerging evidence suggests non-platinum doublets are effective
in treating platinum-sensitive recurrent disease.
Monk et al, 2009.
            Controversies in Ovarian Cancer
              Screening                   Maintenance therapy
              Optimal chemotherapy,       CA125 association with
               schedule, courses, and       response and progression
               end points                  Treating to progression
              Role of biologics           Defining and detecting
              IP therapy standard          relapse




Moss et al, 2002.
            Debate 1

  IP Chemotherapy Should Be the
 Standard for Optimally Cytoreduced
Patients in Front-Line Ovarian Cancer
                                           IP Chemotherapy

                                      Median PFS                               Median OS
                                                                     HR                       HR
                                        (mos)                                    (mos)

                                     IV                 IP                     IV      IP

              GOG                                                                             0.76
                                     –                   –            –        41      49
              104                                                                           (p = .02)

              GOG                                                    0.78                     0.81
                                    22                  28                     52      63
              114                                                  (p = .01)                (p = .05)

              GOG                                                    0.80                     0.75
              172                   18                  24                     50      66
                                                                   (p = .05)                (p = .03)




Alberts et al, 1996; Markman et al, 2001; Armstrong et al, 2006.
            Ovarian Cancer: IP Chemotherapy




                 Primary end point: PFS
                 Need 208 events to detect 50% increase in PFS
                 417 randomized; 213 events
US NIH, 2009a.
                 GOG 172 Treatment Regimens
                      Every 21 Days x 6

        Regimen 1                             D1: IV Paclitaxel 135 mg/m2/24h
        IV                                    D2: IV Cisplatin 75 mg/m2
                               D1   D2
                               IV   IV

       Regimen 2                               D1: IV Paclitaxel 135 mg/m2/24h
       IP                                      D2: IP Cisplatin 100 mg/m2
                                               D8: IP Paclitaxel 60 mg/m2
                               D1   D2   D8
                               IV   IP   IP




Armstrong et al, 2006, 2002.
                                                             GOG 172 Survival

                                                             PFS                                                    OS

                                    1.0                                               1.0
                                    0.9                    Rx Group PF Failed Total
                                                           IV       50 160    210     0.9
  Proportion Progression Free (%)




                                    0.8                    IP       63 142    205
                                                                                      0.8
                                    0.7                         IV: 18 mos            0.7
                                    0.6                         IP: 24 mos
                                                                                      0.6
                                                                HR: 0.80, p = .05
                                    0.5                                               0.5       IV: 50 mos
                                    0.4                                                         IP: 66 mos
                                                                                      0.4
                                                                                                HR: 0.75, p = .03
                                    0.3                                               0.3
                                    0.2                                               0.2         Rx Group Alive Dead     Total
                                    0.1                                                           IV       93     117      210
                                                                                      0.1         IP       117    88       205
                                    0.0                                               0.0
                                          0   12     24       36         48   60
                                                                                            0       12     24        36      48   60
                                                   Time (mos on study)                                    Time (mos on study)



Armstrong et al, 2006.
                                 GOG 172
                          Non-Hematologic Toxicity

                           Grade 3/4 AEs       IV (%)   IP (%)

                     Gastrointestinal event     24       46
                               Renal or
                                                 2        7
                         genitourinary event
                              Fatigue            4       18
                                Pain             1       11

                          Metabolic event        7       27

                          Neurologic event       9       19


Armstrong et al, 2006.
                      GOG 172
           Number of IP Courses Completed
                                    100
                                     90       92
                                     80
                                     70            74
                      % Completed




                                     60
                                     50
                                                           59
                                                                     52   47
                                     40                                        42
                                     30
                                     20
                                     10
                                          8
                                     0
                                          0   1    2         3       4    5    6
                                                        IP Courses




Walker et al, 2006.
                       IP: Pro and Con?
     Supporting Rationale             Challenging Rationale
    Three phase III trials show       Toxicity
     improved PFS/OS
                                       High discontinuation rate
    Tolerable in selected patients
                                       Lack of standardized regimen
    Regimen may be modifiable
     to decrease toxicity              Lack of comparison to
                                        contemporary control arm
    GOG 172 with outstanding
     median survival of 66 mos         Majority of studies administered
                                        higher doses in IP arm thus
                                        limited direct comparison to IV




Markman et al, 1999.
            Debate 2

Maintenance Should Be Administered
 to Complete Clinical Responders in
     Front-Line Ovarian Cancer
           Consolidation Therapy: GOG 178

                                        R   Paclitaxel (3-hour)
                                             175 mg/m2 q 28 d x 3
                                        A
               EOC, fallopian, PP       N
               Stage III/IV
               Prior chemo 5–6 cycles   D
               Register 3–8 weeks       O
               CCR
               Neuropathy ≤ grade II    M
                                        I   Paclitaxel (3-hour)
                                        Z    175 mg/m2 q 28 d x 12
                                        E
    N = 450 anticipated
    Accrual closed 9/6/2001
                                                   End points
    N = 277; 222 with follow-up                    • PFS
    54 progression events                          • OS
Markman et al, 2003.
                       GOG 178: Consolidation


                                       Unadjusted Log Rank
                                       p (one-sided) = .0035


                                       Adjusted Log Rank
                                       p (one-sided) = .0023




Markman et al, 2003.
        GCIG Intergroup Protocol: GINECO
                                Paclitaxel (3-hour)
                            R    175 mg/m2 q 21 d x 6
                            A   Carboplatin
      French/German Study        AUC = 5.0 q 21 d x 6
                            N
      Group                 D
      EOC (Stage IIB–IV)
                            O
      All Strata            M
                            I   Paclitaxel (3-hour)
                                 175 mg/m2 q 21 d x 6
      N = 1,308             Z   Carboplatin
                            E    AUC = 5.0 q 21 d x 6




                                Topotecan
                                1.25 mg/m2 q 21 d x 4


Pfisterer, 1999.
           Maintenance Therapy: GOG Trial

                                                R
                                                    Observation
                                                A
     EOC, fallopian, PP                         N
     Stage III/IV                               D
     Prior chemo 5–8 cycles                         Paclitaxel (3-hour)
     Register 3–8 weeks
                                                O     135 mg/m2 q 28 d x 12
     CCR                                        M
     Neuropathy ≤ grade II                      I
                                                Z   PG-Ptx (paclitaxel poliglumex)
                                                E     135 mg/m2 q 28 d x 12


                                                                   End points
                   N = 1,400 anticipated                           • PFS
                Phase III; Superiority Design                      • OS


US NIH, 2008.
                 Ovarian Cancer: First-Line Sorafenib
                    Maintenance (Phase II Study)
                                           Sorafenib 400 mg BID
                                1:1                                           Primary:
         Randomization                                                          PFS
                                                       Placebo
                                                 Continue until progression


        Primary end point: PFS (defined as time from randomization to disease
         progression or death)
        Control median PFS: 20 mos
        1-sided alpha of 0.1
        Power
                 – 90% for 67% increase in PFS
                 – 78% for 50% increase in PFS
           No of events: 101
           No of patients: 217
           Threshold for achieving p < .1 (SoE 0.5): ~ 30% increase in PFS

US NIH, 2009b.
                      Maintenance: Pro and Con?
     Supporting Rationale           Challenging Rationale
   Theoretical basis               Additional toxicity
   Majority will recur without     Lack of proven survival
    treatment                       advantage
   Generally tolerable             Cost
   GOG 178 with PFS                Inconvenience and stress
    improvement                      for patient
   Clinical trials open            GOG 212 under enrolled




Herzog et al, 2006.
            Debate 3

Biologics Should Be Incorporated Into
Front-Line Ovarian Cancer Treatment
                             Biologics as Maintenance:
                                 Anti-VEGF Agents
        Target                                                    Class               Agents
        Ligand
         VEGF-A                                                  Maba             Bevacizumab
         VEGF                                            Soluble decoy receptor    VEGF trap
        Receptor
         VEGFR                                                   TKIb               Cediranib
         VEGFR                                                   TKIb              Pazopanib
         VEGFR + PDGFR + Raf-K                                                      Sorafenib
         VEGFR + PDGFR                                           TKIb               Sunitinib
         VEGFR + PDGFR                                           TKIb              Motesanib
         VEGFR2                                                  Maba             Ramucirumab



aMab.
bTKI.

Presta et al, 1997; Holash et al, 2002; Hu et al, 2005.
                    GOG 218
                     Paclitaxel (3 hours)
                                                     Placebo
                      175 mg/m2 q 21 d x 6           D1 q 21d
                     Carboplatin                     x 15 mos
                      AUC = 6 q 21 d x 6
                R    Placebo D1 x 5, start Cycle 2
                A
     EOC
                N
                     Paclitaxel (3 hours)
   1 periton    D     175 mg/m2 q 21 d x 6           Placebo
    St III/IV        Carboplatin                     D1 q 21d
                O     AUC = 6 q 21 d x 6
    Subopt                                           x 15 mos
                M    Bev D1 x 5, start Cycle 2

                I
                Z    Paclitaxel (3 hours)
                                                     Bev
                      175 mg/m2 q 21 d x 6
                E    Carboplatin                     D1 q 21d
                      AUC = 6 q 21 d x 6             x 15 mos
                     Bev D1 x 5, start Cycle 2


                        Bevacizumab 15 mg/kg IV
Burger, 2007.
                    Front-Line Trial: GCIG
                                  ICON-7
                              EOC, PP cancer



                    Paclitaxel                        Paclitaxel
                   Carboplatin                       Carboplatin
                     Placebo                        Bevacizumab


                 Clinic Assessment              Bevacizumab
                                                 x 12 cycles

                                 N = 500 patients
US NIH, 2009c.
   Biologics Front-Line: Pro and Con
 Supporting Rationale            Challenging Rationale
 Theoretically appealing       Additional overall toxicity
 Different and perhaps less    Some unique severe toxicities
  toxicity
                                Cost
 Generally tolerable
                                Patient selection
 GOG 170-D with proven
  efficacy in recurrent         Lack of proven survival
                                 advantage
 Clinical trials open
                                Lack of understanding of long-
 Combinable with                term effects
  chemotherapy
 Opportunity for PO
  administration
Recurrent Disease
    Case Study 2: Recurrent Disease
   A 68-year-old originally with stage IV ovarian cancer
    with positive small pleural effusion optimally cytoreduced
    who was then treated on GOG 218 (carb/Ptx +/- bev)
   CA125 initially = 456 and nadirs at 11
   She had residual grade 1 neuropathy and has mild
    hypertension; PS = 0
   Optimally cytoreduced stage IIIC papillary serous ovarian
    cancer
   9 mos later her CA125 = 37, with repeat 1 mos
    later = 118; CT with small volume multifocal disease
                 Question 2
Is she plat sensitive or resistant?
Which treatment would you recommend?
1. Carboplatin/paclitaxel
2. Carboplatin/gemcitabine
3. Pegylated liposomal doxorubicin
4. Topotecan
5. Weekly taxane
6. Plat-based doublet plus bevacizumab
7. Pegylated Liposomal doxorubicin and carboplatin
8. Other
 Considerations in Recurrence
 Drug        Patient                  Tumor

Efficacy       Symptoms                  TFI
             Co-morbidities
Schedule                          Resistance status
           Performance status
Toxicity                        Resistance mechanisms
            Disease volume

              Prior toxicity
                         Recurrence Therapy
                                         RR (%)
        Drug            Platinum-Resistant   Platinum-Sensitive
        Docetaxel
        Doxorubicin Hcl liposome injection
        Etoposide
        Gemcitabinea
        Hexamethylmelamine                   10%–20% 20%–35%
        Paclitaxel
        Platinum
        Topotecan
        Vinorelbine
                    FDA approved
aWithcarboplatin.
Herzog, 2006.
                        Recurrence Rx Options
              Liposomal doxorubicin           Novel taxanes (nab-paclitaxel,
              Topotecan                        CT-2103)

              Gemcitabine                     Novel platinum analogs

              Taxane retreatment (bolus,      Combination therapy or
               weekly)                          retreatment

              Docetaxel                       Monoclonals/anti-angiogenics

              VP-16                           Other targeted biologics

              Vinorelbine                     Stem cell, high-dose

              Platinum retreatment            Gene therapy

              Historical agents               Hormones (tamoxifen,
                                                letrozole)
                – Ifosfamide
                – Melphalan
                – Hexamethylmelamine
                – 5-FU/leucovorin
Berek, 2005.
  NCCN Guidelines for Persistent or
 Recurrent Epithelial Ovarian Cancer
Progression or stable disease
on primary chemotherapy or                     Supportive care
Complete remission and relapse                 or
<6 mo after stopping chemotherapy              Recurrence regimen




Stage II, III and IV with partial
response including positive                    Recurrence chemotherapy
reassessment surgical procedure                or
(second look; including microscopic disease)   Observe (category 2B)



                                               Carboplatin/paclitaxel
Complete remission and relapse >6 mo           (category 1)
after stopping chemotherapy                    Or
                                               Gemcitabine/carboplatin
                                               Recurrence regimen



Clinically low-volume or focal recurrence      Consider secondary
after disease-free interval >6 mo              cytoreductive surgery
                                               And/or
                                               Recurrence chemotherapy
                Concept of Platinum Sensitivity
                        0 mos                    6 mos       12 mos


       Primary treatment



           Refractory                Resistant           Platinum sensitive


                          End of
                        front-line
                         therapy




Herzog, 2006.
              Platinum Refractory GOG Trials
                                  Resistant
                 GOG                                                     Treatment                           RR (%)
                                 Population
                126-H                     25                        Topotecan (24H)                            4

                 126-J                    60                             Docetaxela                           22

                126-K                     25                              Oxaliplatin                          4

                 126-L                    57                 Gemcitabine + paclitaxel                         16

                126-M                     50                             Ixabepilone                          14

                126-N                     48                       Weekly paclitaxela                         21

                126-Q                     51                           Pemetrexeda                            20




aAfter
     paclitaxel.
Rose et al, 2003; Markman et al, 2006, 1999; Miller et al, 2009; Fracasso et al, 2003; Brewer et al, 2006.
            Debate 4

  Treatment to Progression Is Best
Practice in Recurrent Ovarian Cancer
                      Value of Stable Disease:
                      Relapsed Ovarian Cancer
                                           N = 392




Cesano et al, 1999.
           Treating to Progression:
                 Pro and Con
 Supporting Rationale         Challenging Rationale
 Symptom palliation          Cumulative toxicities
 Maintains stable disease    Negative impact on QOL
                               and psychosocial issues
 Fewer cumulative
  toxicities with many of     Use of more effective
  the novel agents             agents delayed
 Limited number of           Limited documented
  options                      benefits
 Survival advantage
            Debate 5

Biologics Should Be Incorporated Into
Recurrent Ovarian Cancer Treatment
        NCCN 2009 Acceptable Recurrence Therapies
              Agents                 Cytotoxic Therapy            Hormonal       Targeted     Radiation
                                                                   Therapy       Therapy      Therapy
          NCCN preferred       Platinum sensitive combinations                  Bevacizumab
                                     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
         Other acceptable                Altretamine              Anastrozole                 Palliative
        and potential agents            Capecitabine               Letrozole                  localized
                                      Cyclophosphamide            Leuprolide                  radiation
                                          Ifosfamide               Megestrol                   therapy
                                          Irinotecan                acetate
                                          Melphalan                Tamoxifen
                                          Oxaliplatin
                                           Paclitaxel
                                         Vinorelbine

NCCN, 2009.
                             GOG 160/170 Series:
                           Performance Comparison
                                                          Bevacizumab
                 PFS ≥ 6 (%)




                                          Sorafenib

                               Imatinib
                                            Gefitinib

                               Trastuzumab

                                          Lapatinib
                               Vorinostat




                                                        RR (%)
US NIH, 2009d.
                 GOG 0213 Trial




US NIH, 2009e.
       Phase III Study of Carboplatin + Gemcitabine ±
          Bevacizumab in Patients With Platinum-
           Sensitive Recurrent Ovarian, Primary
           Peritoneal, or Fallopian Tube Cancer

        Oceans                Trial

                           Gemcitabine 1,000 mg/m2 Days 1 + 8            BV                BV
                               Carboplatin AUC 4 Day 1                 (to 51             to PD
                           Bevacizumab 15 mg/kg Day 1 q 21 days x 6a    wks)


             R             Gemcitabine 1,000 mg/m2 Days 1 + 8
                                                                       Placebo
                               Carboplatin AUC 4 Day 1
                                Placebo IV Day 1 q 21 days x 6          (to 51
                                                                         wks)



                                                                                Unblind
aUpto 10 cycles allowed.
US NIH, 2009f.
      Biologics in the Recurrent Setting

   ET-743 (Ecteinascidin)
   Taxanes (ABI-007, CTI-2103)
   Epothilones (patupilone, ixabepilone)
   Karenitecin
   Phenoxodiol
   Folate (pemetrexed, farletuzumab)
   Abagovomab
   Biologics: Multiple addressing VEGFR
    or EGFR pathways
    Biologics Front-Line: Pro and Con
Supporting Rationale          Challenging Rationale
   Theoretically appealing    Additional overall toxicity
   Different toxicities       Some unique severe
                                toxicities
   Generally tolerable
                               Cost
   GOG 170-D with proven
    efficacy in recurrent      How long to continue?
   Clinical trials open       Lack of proven OS
                                advantage
   Need novel agents to
    improve survival
   Ascites palliation
                      Benefits of Participation
               Clinical trials that are well-designed and well-
                executed are the best approach for eligible
                participants to:
                – Play an active role in their own healthcare
                – Gain access to new research treatments before
                  they are widely available
                – Obtain expert medical care at leading health care
                  facilities during the trial
                – Help others by contributing to medical research


US NIH, 2007.
            Debate 6

 CA125 Values Should Be Monitored
Routinely to Detect Recurrent Ovarian
               Cancer
                                                  Trial Profile
                                                             Registered patients
                                                                  N = 1,442

  Non-randomised patients
  N (%)
  421 (29)   CA125 < 2 ULN and no relapse at trial closure
  61 (4)     Simultaneous relapse and CA125 > 2 ULN
  213 (15)   Relapsed without CA125 > 2 ULN
  56 (4)     Died
  133 (9)    Patient withdrawal
  29 (2)     Other/unknown reasons                             Randomized
                                                               N = 529 (37%)




             Early treatment                                                   Delayed treatment
             N = 265                                                           N = 264
             N = 254 (96%) started second-line                                 N = 233 (88%) started second-line
             chemotherapy                                                      chemotherapy




Rustin, 2009.
                 Time From Randomisation to
                 Second-Line Chemotherapy
                                                  1.00
                                                                                          Median (mos)
                  Second-Line Chemotherapy (%)
                   Proportion Alive Not Started




                                                                              Early       0.8
                                                  0.75



                                                                              Delayed     5.6
                                                                                          HR = 0.29 (95% CI 0.24, 0.35) p < .00001
                                                  0.50
                                                  0.25
                                                  0.00




                                                         0     3     6          9       12       15         18      21        24
                                                                           Time (mos since randomisation)

          Number at risk
                   Early                                 265   23    16        14       11       11         10      10        9
                Delayed                                  264   177   116       91       69       56         49      42        33


Rustin, 2009.
                                                            Overall Survival
                                                          HR = 1.00 (95% CI 0.82–1.22) p = .98



                                               1.00
                                                                                        Abs diff at 2 years = -0.1%
                                                                                         (95% CI diff = -6.8, 6.3%)
                    Proportion Surviving (%)
                                               0.75


                                                                                                                       Early
                                                                                                                       Delayed
                                               0.50
                                               0.25
                                               0.00




                                                      0      6      12      18     24       30     36     42     48       54     60
                                                                     Time (mos since randomisation)
           Number at risk
                   Early                              265 247 211 165 131                   94     72     51      38      31     22
                Delayed                                264 236 203 167 129                 103     69     53      38      31     19




Rustin, 2009.
             SGO Statement on Use of CA125
              for Monitoring Ovarian Cancer
            Role of secondary cytoreduction not addressed
            Not stratified for residual disease after
             cytoreduction
            Remission not confirmed by imaging
            Treatment at relapse not standardized
            “Patients and their physicians should still have
             the opportunity to choose [CA125 monitoring]
             as a philosophy of active management that
             includes participation in trials of novel therapies.”
SGO, 2009.
    CA125 Monitoring: Pro and Con
 Supporting Rationale           Challenging Rationale
 Avoid symptom onset            Leads to increased toxicity
 Patient demand                 Negative impact on QOL
                                  and psychosocial issues
 “Active” surveillance
  strategy                       Lack of survival advantage
 Avoid routine radiography      Cost
 Rustin data may not be         Phase III data shows no
  applicable to US population     survival advantage
             Debate 7

 Secondary Cytoreduction Should Be
Routinely Offered to Recurrent Ovarian
           Cancer Patients
                           Secondary Cytoreduction
                                                               Tumor Mass
            Controversial
            Inconsistent definitions
                                                                Vena Cava
            Benefit appears                  Renal Vein
             confined to patients
             like to respond to              Kidney
             additional chemo
             – > 12-mos PFI                      Diaphragm
                                                             Resected Liver
             – Isolated site of recurrence
             – Disease completely
               resectable
                                                  Kidney




PIM & IMPACt Inc., 2009.
                      Secondary Cytoreduction:
                 Survival by Postoperative Residuum




Fader et al, 2007.
Secondary Debulking:
 Candidate Selection
         Secondary Cytoreduction:
              Pro and Con
 Supporting Rationale        Challenging Rationale
 Theoretical appeal         Morbidity
 Survival advantage in      Negative impact on QOL
  selected patients          Lack of clear survival
 “Active” approach           advantage
 Newer tools for patient    Cost
  selection available        Patient selection difficult
                    Key Takeaways
   Front-line surgical therapy should consist of adequate
    and complete staging with optimal cytoreduction as indicated
   Standard front-line chemotherapy should contain a platinum
    and a taxane
   Novel chemotherapeutics and targeted biologics provide
    multiple options for adjuvant therapy
   Treatment selection for relapsed ovarian cancer must be
    based on patient specific variables with the goal of extending
    survival and maximizing QOL

								
To top