chemotherapy in ovarian cancer - nhs wales · chemotherapy for advanced ovarian cancer aoctg...

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