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UNANSWERED QUESTIONS IN UPFRONT THERAPY CHEMOTHERAPY ISSUES: WEEKLY DOSING. Andrés Poveda , MD Fundación Instituto Valenciano de Oncología apoveda@fivo.org On behalf of GEICO and GCIG Ovarian Cancer Clinical Trials Planning Meeting Friday, May 29, 2009.

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unanswered questions in upfront therapy chemotherapy issues weekly dosing

UNANSWERED QUESTIONS IN UPFRONT THERAPYCHEMOTHERAPY ISSUES: WEEKLY DOSING

Andrés Poveda, MD

Fundación Instituto Valenciano de Oncología

apoveda@fivo.org

Onbehalf of GEICO and GCIG

Ovarian Cancer Clinical Trials Planning Meeting

Friday, May 29, 2009

slide3

4-A4: Which regimen / kind of regimens can be regarded as standard

  • comparator for future first-line trials?
    • Within a given trial the chemotherapy regimen should be standardized and consistent
    • with respect to drugs, dose, and schedule.
    • The recommended standard comparator for trials on medical treatment in advanced
    • ovarian cancer (FIGO IIB-IV) is carboplatin-paclitaxel
    • The recommended regimen iscarboplatin with a dose of AUC 5 - 7.5 and paclitaxel 175
    • mg/m²/ 3h given every three weeks for 6 courses
    • The recommended standard in early stage ovarian cancer (FIGO I-IIA) patients in whom
    • adjuvant chemotherapy is indicated should contain at least carboplatin AUC 5 -7.5
    • Level of Acceptance: 13 / 13
unanswered questions in upfront therapy weekly dosing rationale
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGRATIONALE
  • AntiangiogenicpropertyofPaclitaxelindependentofitsanti-proliferativeactionLau DH et al. Proc ASCO 17:4141, 1998
  • Antiangiogenicschedulingchemotherapyimprovesefficacyagainst experimental drug-resistantcancerBrowder T, Cancer Res; 2000
  • Norton-Simon hypothesis: a more frequent drug administration would be a more effective way of avoiding the regrowth of cell populations resistant to the agents used (Gomperzian model of tumor growth).
  • Provenactivity in othertumours(BreastCancer,..)
  • Bettertoleranceschedule
mechanisms of paclitaxel induced cell death are concentration dependent
Mechanisms of Paclitaxel-induced cell death are concentration dependent
  • Paclitaxel-mediated cell death may result from two different mechanisms:
    • At low Paclitaxel concentrations (<9 nM), cell death may occur after an aberrant mitosis by Raf-1 independent pathway
    • At higher Paclitaxel concentrations (>9 nM) cell death may be the result of a terminal mitotic arrest occurring by a Raf-1 dependent pathway

Torres R and Horwitz B: Cancer Res 1998, 58:3620

potential advantages of weekly paclitaxel
Potential Advantages of Weekly Paclitaxel
  • Greater dose intensity greater inhibition of mitotic cellular activity
  • Higher frequency of administration Higher cellular exposure in M phase Higher inhibition of mitotic cellular activity
  • Cause of cellular death mediated by other mechanisms (apoptosis)
  • Inhibition of neovascularization
  • Better pharmacodynamic profile
weekly paclitaxel no increase in myelosuppression with dose escalation
WEEKLY PACLITAXEL: NO INCREASE IN MYELOSUPPRESSION WITH DOSE ESCALATION

ANC (1000/µL)

14

12

10

8

6

4

2

0

I

II

III

IV

V

Level

Fennelly et al. JCO 15: 187-92; 1997

slide9
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGPHASE II STUDIES paclitaxelin platinum-resistant ovarian cancer

1) Canada Le. Gyn Oncol 2005: 2) GOG Markman. Gyn Oncol 2006; 3) Japan Kita

Gyn Oncol 2004; 4) Markman at Cleveland. Markman. JCO 2002; 5) Roswell Park.

Ghamande. Int J Gynecol Cancer 2003; * in responders; 6) Royal Mardsden Lynch.

Gyn Oncol 2008 ** including the platinum sensitive patients (1) retrospective;

7) Norwegian Kaern Eur J Gynecol Oncol 2002

slide10
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGPHASE II STUDIES paclitaxelin combination in platinum-resistant ovarian cancer
slide11
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGRANDOMIZED PHASE II STUDIES 3weekly vs weeklypaclitaxel inovarian cancer
slide12
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGPHASE II STUDIES paclitaxel in combinationin front-line ovarian cancer
what else
What else?

AGO Ovarian Cancer Study Group (AGO-OVAR)

slide14

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGRandomized PHASE III TC vs DDT+C in first-line AOC patients: a JGOG StudyIsohishi S et al . ASCO 2008,Abstract-5506

slide15
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGRandomized PHASE III TC vs DDT+C in first-line AOC patients: a JGOG Study
  • Endpoint: PFS
  • n: 637 pts
  • PFS(median follow up 29 m):
    • 17,1m vs 27,9m (p:0.0014) log-rank test
  • OS (at 2 years):
    • 77,7% vs 83,6% (p:0.05)
  • RR: similar
  • Toxicity: Anemia G3-4 in weekly arm more freq

Isohishi S et al . ASCO 2008,Abstract-5506 (Oral)

jgog conventional tc vs dose dense tc in adovca progression free survival
JGOG: Conventional TC vs Dose-Dense TC in ADOVCAProgression-free survival

Isohishi et al, ASCO 2008 (abstract #5506, oral)

unanswered questions in upfront therapy weekly dosing conclusion
UNANSWERED QUESTIONS IN UPFRONT THERAPYWeeklyDosingConclusion
  • Results of trials with impact in FRONT-LINE:
    • TC remains standard since 2003 and after many trials including more than 6000 patients!!!
      • CP vs TC: GOG-111, OV10
      • Carbo T vs Cis T: GOG, AGO, SWOG
    • Weekly T + C (JGOG) : improved PFS (phase III)
    • Ongoing: Triplet: TC + Avastin:
        • ICON-7: (recently closed)
        • GOG-218
        • GOG-213
unanswered questions in upfront therapy weekly dosing open questions
UNANSWERED QUESTIONS IN UPFRONT THERAPYWeeklyDosingOpen Questions
  • Which is the optimal weekly dose?
  • Which drugs should be administered in a weekly schedule
    • Only Taxane?
    • Taxane + carboplatin?
  • How to incorporate weekly dose to
    • i.p strategy?
    • biologic agents combination?
  • How to determine the appropriate duration of weekly dose therapy?