Chemotherapy in Chemotherapy in
Ovarian CancerOvarian Cancer
Dr R JonesDr R Jones
Consultant Medical OncologistConsultant Medical Oncologist
South Wales Gynaecological Oncology GroupSouth Wales Gynaecological Oncology Group
Adjuvant chemotherapy Adjuvant chemotherapy
for early stage EOCfor early stage EOC
�� Fewer than 30% women present with FIGO Fewer than 30% women present with FIGO stage I/II diseasestage I/II disease
�� These patients have 5 yr survival ranging These patients have 5 yr survival ranging from 68 from 68 –– 90%90%
�� Surgery is mainstay of treatmentSurgery is mainstay of treatment
�� Does use of adjuvant chemotherapy prolong Does use of adjuvant chemotherapy prolong recurrencerecurrence--free survival and improve overall free survival and improve overall survival in patients with early stage survival in patients with early stage epithelial ovarian cancer?epithelial ovarian cancer?
Adjuvant chemotherapy Adjuvant chemotherapy
for early stage EOCfor early stage EOC
No difference in No difference in
OS or DFSOS or DFS
HR=1.20HR=1.20
CI 0.46CI 0.46--3.13.1
p=0.71p=0.71
OS 88% vs. 82%OS 88% vs. 82%Cisplatin vs.Cisplatin vs.
delayed Rxdelayed Rx
8585
IAIA--IB, G2IB, G2--33
BolisBolis et alet al
19951995
No difference in No difference in
OS or DFSOS or DFS
Log rank test Log rank test
p=0.43p=0.43
OS 94% vs. 98%OS 94% vs. 98%MelphalanMelphalan vs.vs.
delayed Rxdelayed Rx
9292
FIGO IFIGO I
Young et alYoung et al
19901990
No difference in No difference in
OS or DFSOS or DFS
Log rank test Log rank test
p=0.43p=0.43
OS 86% vs. 85%OS 86% vs. 85%CarboCarbo vs. vs.
delayed delayed
RxRx
162162
I G2I G2--33
Trope et alTrope et al
20002000
Improved 5yr OS Improved 5yr OS
and RFSand RFS
HR=0.69HR=0.69
CI 0.44CI 0.44--1.081.08
p=0.1p=0.1
OS 85% vs. 78%OS 85% vs. 78%Platinum basedPlatinum based
regimen vs.regimen vs.
delayed Rxdelayed Rx
448,448,
Ia/bIa/b G2G2--33
IcIc--IIaIIa G1G1--33
All clear cellAll clear cell
ACTIONACTION
20032003
Improved 5yr OS Improved 5yr OS HR=0.66HR=0.66
CI 0.45CI 0.45--0.970.97
p=0.03p=0.03
OS 79% vs. OS 79% vs.
70%70%
CarboCarbo/CAP/CAP
vs.delayedvs.delayed RxRx
447, 93% FIGO I447, 93% FIGO IICON 1ICON 1
20032003
CommentsCommentsStatisticsStatistics5 yr survival5 yr survivalInterventionInterventionPatientsPatientsTrialTrial
Adjuvant chemotherapy Adjuvant chemotherapy
for early stage EOCfor early stage EOC
�� Cochrane review of above trials concluded:Cochrane review of above trials concluded:
–– Benefit of adjuvant platinum based Benefit of adjuvant platinum based
chemotherapy in prolonging survival (HR 0.71; chemotherapy in prolonging survival (HR 0.71;
95% CI 0.5395% CI 0.53--0.93) and PFS (HR 0.67; 95% CI 0.93) and PFS (HR 0.67; 95% CI
0.530.53--0.84) 0.84)
–– Subgroup analysis: patients who are optimally Subgroup analysis: patients who are optimally
surgically staged may have little to gain from surgically staged may have little to gain from
adjuvant chemotherapyadjuvant chemotherapy
–– Appears safe to withhold adjuvant chemotherapy Appears safe to withhold adjuvant chemotherapy
from optimally staged early EOC with well from optimally staged early EOC with well
differentiated tumours differentiated tumours
Chemotherapy for Chemotherapy for
advanced ovarian canceradvanced ovarian cancer
�� AOCTG metaAOCTG meta--analyses (1998):analyses (1998):–– Included 37 trials, 5667 patients & 4664 deathsIncluded 37 trials, 5667 patients & 4664 deaths
–– No good evidence of any difference between cisplatin and No good evidence of any difference between cisplatin and carboplatin either as single agent or combinationcarboplatin either as single agent or combination
�� ICON 2 (1998): ICON 2 (1998): –– Compared Compared cyclophosphamidecyclophosphamide, doxorubicin and cisplatin vs. , doxorubicin and cisplatin vs. carboplatincarboplatin
–– Survival curves showed no evidence of a difference Survival curves showed no evidence of a difference between carboplatin and CAP (HR=1.0, p=0.98)between carboplatin and CAP (HR=1.0, p=0.98)
–– Single agent carboplatin safe, effective and appropriate as Single agent carboplatin safe, effective and appropriate as standard of care in AOCstandard of care in AOC
Paclitaxel eraPaclitaxel era……..
�� GOG 111GOG 111–– 410 pts, FIGO III/IV, 410 pts, FIGO III/IV,
residual disease >1cmresidual disease >1cm
–– Improved PFS and OS Improved PFS and OS
with taxol combination with taxol combination
�� OV10OV10–– 680 pts, FIGO 680 pts, FIGO IIb/cIIb/c, ,
III/IVIII/IV
–– Optimal or subOptimal or sub--optimal optimal
debulkingdebulking
–– ImprovedImproved PFS and OSPFS and OSMc Guire et al, NEJM. 1996; 334(1):1-6. Piccart et al, JNCI. 2000; 92(9); 699-708
Paclitaxel eraPaclitaxel era……..
�� GOG 132GOG 132–– 614 pts, FIGO III/IV 614 pts, FIGO III/IV residual disease > 1cmresidual disease > 1cm
–– No No diffencediffence in OS in OS between 3 treatment between 3 treatment regimensregimens
�� ICON 3ICON 3–– 2074 pts, all FIGO 2074 pts, all FIGO stagesstages
–– No difference in OS or No difference in OS or PFS between regimensPFS between regimens
Muggia et al. JCO. 2000:18(1); 106-115. ICON group. Lancet. 2002: 360; 505-515
Paclitaxel era..?Paclitaxel era..?
�� Potential explanation for discrepancy Potential explanation for discrepancy
between 4 main trials:between 4 main trials:–– SecondSecond--line therapy and treatment crossoversline therapy and treatment crossovers
–– Cyclophosphamide/cisplatinumCyclophosphamide/cisplatinum combination not combination not
best alternative as standard arm best alternative as standard arm
–– ICON 3 trial 20% pts FIGO stage I/II and extent ICON 3 trial 20% pts FIGO stage I/II and extent
of surgery was not definedof surgery was not defined
Paclitaxel Paclitaxel --
NICE recommendations NICE recommendations
20032003
Paclitaxel Paclitaxel –– the futurethe future
�� DoseDose--dense weekly paclitaxel in dense weekly paclitaxel in
combination with carboplatincombination with carboplatin
�� Recent Japanese study demonstrated Recent Japanese study demonstrated
improved survival compared to 3 improved survival compared to 3
weekly regimen in FIGO IIweekly regimen in FIGO II--IV EOC, IV EOC,
FTC or PPCFTC or PPC
ICON 8 Trial SchemaICON 8 Trial Schema
NeoNeo--adjuvant vs. primary adjuvant vs. primary
surgerysurgery�� Current practice is primary surgical cytoreduction followed by Current practice is primary surgical cytoreduction followed by systemic chemotherapy unless unfeasible:systemic chemotherapy unless unfeasible:
–– Disease bulk, Disease bulk, comorbiditiescomorbidities, poor PS, poor PS
�� Alternative approach is giving primary chemotherapy followed Alternative approach is giving primary chemotherapy followed by surgery in responding patientsby surgery in responding patients
�� Advantages of neoAdvantages of neo--adjuvant approach:adjuvant approach:
–– Avoid surgery in women with aggressive disease, increase Avoid surgery in women with aggressive disease, increase number of pts who obtain optimal debulking and surgery number of pts who obtain optimal debulking and surgery may be less complicatedmay be less complicated
�� However increasing number of chemotherapeutic cycles However increasing number of chemotherapeutic cycles beyond 3 has a potential negative impact on survival beyond 3 has a potential negative impact on survival
Bristow RE, Chi DS. Gynecol Oncol 2006; 103:1070
NeoNeo--adjuvant vs. primary adjuvant vs. primary
surgerysurgery�� Preliminary data from EORTC GCG / NCIC Preliminary data from EORTC GCG / NCIC ––CTG:CTG:
–– No significant difference in PFS or OS between primary No significant difference in PFS or OS between primary and intervaland interval--debulking surgery group (12 and 30 months, debulking surgery group (12 and 30 months, F/U 4.8 yrs)F/U 4.8 yrs)
–– IDS group had significant reduction in postoperative IDS group had significant reduction in postoperative deaths, postoperative fever, haemorrhage and blood clotsdeaths, postoperative fever, haemorrhage and blood clots
–– Multivariate analysis suggested strongest independent Multivariate analysis suggested strongest independent prognostic factor for OS was obtaining optimal debulkingprognostic factor for OS was obtaining optimal debulking
–– But caveat to study, pts with disease less than FIGO IIIC But caveat to study, pts with disease less than FIGO IIIC or small IIIC ovarian cancers were not well representedor small IIIC ovarian cancers were not well represented
Vergote I, Trope CG, Amant F et al. Proceedings of 12th Biennial Meeting of the International Gynecologic Cancer Society, Bangkok 2008
CHORUS trialCHORUS trial
Chemotherapy or Upfront Chemotherapy or Upfront
SurgerySurgery
IntraperitonealIntraperitoneal
ChemotherapyChemotherapy
IP Chemotherapy IP Chemotherapy
GOG 172 trialGOG 172 trial
�� 429 patients with optimally debulked 429 patients with optimally debulked FIGO III EOC: Randomised toFIGO III EOC: Randomised to
–– IV paclitaxel (135mg/mIV paclitaxel (135mg/m22/24 hrs D1), /24 hrs D1), followed by IV cisplatin (75mg/mfollowed by IV cisplatin (75mg/m22 D2)D2)
–– IV paclitaxel (135mg/mIV paclitaxel (135mg/m22/24 hrs D1),IP /24 hrs D1),IP cisplatin (100mg/mcisplatin (100mg/m22 D2) and IP paclitaxel D2) and IP paclitaxel (60mg/m(60mg/m22 D8)D8)
�� Only 42% pts in IP group completed 6 Only 42% pts in IP group completed 6 cyclescycles
IP Chemotherapy IP Chemotherapy
GOG 172 trialGOG 172 trial
�� Median F/U 48 Median F/U 48
monthsmonths
�� IP group associated IP group associated
with improved with improved
median PFS (23.8 median PFS (23.8
vs. 18.3 months) vs. 18.3 months)
and overall survival and overall survival
(65.6 vs. 49.7 (65.6 vs. 49.7
months)months)
IP Chemotherapy IP Chemotherapy
GOG 172 trialGOG 172 trial
�� IP therapy was associated with IP therapy was associated with
significantly more toxicity:significantly more toxicity:
–– CatheterCatheter--related complicationsrelated complications
–– Haematological toxicity (Haematological toxicity (neutropenianeutropenia and and
thrombocytopenia)thrombocytopenia)
–– GI events and abdominal pain GI events and abdominal pain
–– metabolic abnormalitiesmetabolic abnormalities
–– neuropathyneuropathy
Relapsed EOCRelapsed EOC
�� Choice of chemotherapy regimen in Choice of chemotherapy regimen in
relapsed EOC depends on response to relapsed EOC depends on response to
firstfirst--line therapy:line therapy:
–– PlatinumPlatinum--sensitive relapses > 12monthssensitive relapses > 12months
–– Partially platinumPartially platinum--sensitive relapses sensitive relapses
between 6 between 6 –– 12 months12 months
–– PlatinumPlatinum--resistant relapses < 6 monthsresistant relapses < 6 months
–– PlatinumPlatinum--refractoryrefractory
NICE Technology Appraisal 91
Platinum Platinum
Refractory/Resistant Refractory/Resistant
diseasedisease
23%23%7171VinorelbineVinorelbine
23%23%118118OxaliplatinOxaliplatin
18%18%181181GemcitabineGemcitabine
31%31%234234Oral Oral EtoposideEtoposide
22%22%15801580PaclitaxelPaclitaxel
17%17%882882TopotecanTopotecan
18%18%428428Pegylated liposomal Pegylated liposomal
doxorubicindoxorubicin
Response Response
RateRateNo of No of
patientspatientsAgentAgent
Gore ME, 2001. In ASCO Education Book 2001. ASCO, pp 468-476
PlatinumPlatinum--sensitive and sensitive and
partially platinumpartially platinum--sensitive sensitive
diseasedisease�� Combination therapy appears to offer Combination therapy appears to offer
greater benefit in this settinggreater benefit in this setting
�� Increased response to platinum reIncreased response to platinum re--
challenge as time to recurrence challenge as time to recurrence
increasesincreases
–– > 12 months > 12 months –– RR 30 RR 30 –– 60%60%
–– 6 6 --12 months 12 months –– RR 25 RR 25 –– 30%30%
PlatinumPlatinum--sensitive and sensitive and
partially platinumpartially platinum--sensitive sensitive
disease disease �� ICON IV/AGOICON IV/AGO--OVAR 2.2OVAR 2.2
–– 802 pts with treatment802 pts with treatment--free interval at free interval at
least 6least 6--12 months12 months
–– Benefit of paclitaxelBenefit of paclitaxel--platinum regimen platinum regimen
with improved PFS and OSwith improved PFS and OS
–– Higher rate of G2Higher rate of G2--4 neurological toxicity 4 neurological toxicity
and alopecia but lower and alopecia but lower myelosuppressionmyelosuppression
Parmar MK, Ledermann JA, Colombo N et al. Lancet. 2003; 361:2099
PlatinumPlatinum--sensitive and sensitive and
partially platinumpartially platinum--sensitive sensitive
diseasedisease�� CALYPSO trialCALYPSO trial–– 974 pts, stratified by therapy974 pts, stratified by therapy--free intervalfree interval
–– PLD and carboplatin vs. carboplatin/PLD and carboplatin vs. carboplatin/taxoltaxol
–– Results showed PLDResults showed PLD--carboplatin was not inferior carboplatin was not inferior in terms of PFS and was associated with an in terms of PFS and was associated with an decreased risk of recurrencedecreased risk of recurrence
–– Overall survival data immature at presentOverall survival data immature at present
–– Toxicity more severe with Toxicity more severe with taxoltaxol regimen with regimen with hypersensitivity reactions, alopecia and hypersensitivity reactions, alopecia and neuropathyneuropathy
Pujane-Lauraine E et al. J Clin Oncol. 2009;27(15S):Abstract LBA5509
PlatinumPlatinum--sensitive and sensitive and
partially platinumpartially platinum--sensitive sensitive
disease disease -- CONCLUSIONSCONCLUSIONS�� PlatinumPlatinum--based combination superior to based combination superior to platinum platinum monotherapymonotherapy
�� Need to consider:Need to consider:–– Drug activityDrug activity
–– Toxicity profileToxicity profile
–– Quality of lifeQuality of life
–– Nature of prior drug toxicityNature of prior drug toxicity
–– Patient preferencePatient preference
�� Clinical trials: ICON 6, MORAbClinical trials: ICON 6, MORAb--003003--004004
ICON VIICON VI
MORAbMORAb--003003--004 trial004 trial