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UNANSWERED QUESTIONS IN UPFRONT THERAPYCHEMOTHERAPY ISSUES:
WEEKLY DOSING
Andrés Poveda, MD
Fundación Instituto Valenciano de Oncología
On behalf of GEICO and GCIG
Ovarian Cancer Clinical Trials Planning Meeting
Friday, May 29, 2009
3rd InternationalOvarian Cancer Consensus Conference
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 is carboplatin 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 THERAPYWEEKLY DOSING
RATIONALE
• Antiangiogenic property of Paclitaxel independent of its anti-proliferative action Lau DH et al. Proc ASCO 17:4141, 1998
• Antiangiogenic scheduling chemotherapy improves efficacy against experimental drug-resistant cancer Browder 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).
• Proven activity in other tumours (Breast Cancer,..)
• Better tolerance schedule
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
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
0
2
4
6
8
10
12
14
I II III IV V
ANC (1000/µL)
Level
Fennelly et al. JCO 15: 187-92; 1997
WEEKLY PACLITAXEL: NO INCREASE IN MYELOSUPPRESSION WITH DOSE ESCALATION
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
PHASE II STUDIES paclitaxel in platinum-resistant ovarian cancer
Schedule (mg/m2) PP N RR PFS OS
1) 60-80 weekly 100% 32 53% 6.1 10.4
2) 80 weekly 100% 48 21% 3.6 -
3) 80 weekly x 3/ 4 ~10% 14 28%
4) 80 weekly 100% 53 25% 24 w 58 w
5) 80 weekly x 6/ 8 96% 28 50% 6* 8*
6) 80-100 weekly (1) 45% 27 70% 4.8** 13.5**
7) 80 weekly 68% 57 56% 5 13.7
1) Canada Le. Gyn Oncol 2005: 2) GOG Markman. Gyn Oncol 2006; 3) Japan KitaGyn 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
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
PHASE II STUDIES paclitaxel in combination in platinum-resistant ovarian cancer
TDose/m2/wk C AUC
AuthorN RR
%
DFS
months
OS
months
T90 C AUC4
d1,8,q 21Cadron Gynecol Oncol 2007
8 38 6.75 8
T80 C AUC2
d1,8,15, q 28Havrilesky, Gynecol Oncol 2003
8 37.5 3.2 11.4
T90 C AUC4
d1,8,15, q 28Van der Burg, Int J Gynecol Cancer, 2005
23 61 11 15
T80 C AUC3
d1,8,15 q28Roxburgh P ESMO 08 A # 668
54 50-63 4.7-7.5 7.5-9
T70 C AUC 3
d1,8,15, q28Sharma R Br J Cancer 2009
20 60 7,9 13,3
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
RANDOMIZED PHASE II STUDIES 3weekly vs weekly paclitaxel in ovarian cancer
Author N Scenario T Doses/m2 Conclusion
Wu, 2001 29 Front-line T175 C AUC6 T60 C AUC 2
Equal RRLess toxicity
Rosenberg, 02 208 Second-line T 200T 67
Equal RR,TTP,
OS Less toxicity
Shen, 05CGOG
125 Front-line TCTwkly C
Equal RR,TTP, OS Less toxicity
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
PHASE II STUDIES paclitaxel in combination in front-line ovarian cancer
Author N Scenario T Doses/m2 Conclusion
Pignata, 2008 (MITO5)
26 Front-line elderly T60 C AUC2 d1,8,15 q28
RR: 38,5% mPFS: 13,6m mOS: 32 m
Sehouli, 2008 (NOGGO)
129 Front-line IIb-IV radical resected
T100 C AUC2 d1,8, q21
RR: 74%mPFS: 21mmOS: 43m
Safra, 2009(Tel Aviv)
64 Front-line Ic-IV T 80 C AUC2 d1,8,15 q28
RR: 92,1%mPFS:25,5mmOS: 52m
AGO Ovarian Cancer Study Group (AGO-OVAR)
What else?What else?
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
Randomized PHASE III TC vs DDT+C in first-line AOC patients: a JGOG Study Isohishi S et al . ASCO 2008,Abstract-5506
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
Randomized 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)
Treatment n Event Median PFS P value HR 95%CI
c-TC 319 200 17.2 mos.
dd-TC 312 160 28.0 mos. 0.0015 0.714 0.581-0.879
Isohishi et al, ASCO 2008 (abstract #5506, oral)
JGOG: Conventional TC vs Dose-Dense TC in ADOVCAProgression-free survival
UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING
ONGOING STUDIES in front-line ovarian cancer
Group Study Design Tmg/m2
n Primary Objetive
Secondary Objetives
Status
Intergroup MO22225 (OCTAVIA)GEICO, GINECO, NSGO, MITO
Phase II T80 d1,8,15 q21 + C AUC 6 q21 + Beva 7.5q21
180 PFS ORRRR DurationOSSafety
Open in June 09
MITO-7Particip:MANGO
Phase III R C AUC6+ T175vsT60 d1,8,15, q21 C AUC 2 q 21
500 QoL ORRPFS,OSSafety
Open
UNANSWERED QUESTIONS IN UPFRONT THERAPYWeekly Dosing
Conclusion
• 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 THERAPYWeekly Dosing
Open 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?