chemotherapy in advanced ovarian cancer angiolo gadducci department of gynecology and obstetrics,...

Chemotherapy in advanced ovarian cancer

Angiolo Gadducci

Department of Gynecology and Obstetrics, Unit of

Gynecologic Oncology, University of Pisa

Rome October 5-6 2007

Mediterranean School of Oncology

Highlights in the management of ovarian cancer

Integrated therapies in ovarian cancer (OC)

Early stage: Surgery

Adjuvant therapy

Advanced stage: Surgery: Primary

cytoreduction

Interval surgery

Second-look

Chemotherapy

Consolidation/manteinance

therapy Recurrent disease: Chemotherapy

Surgery

Subjects: 8139 patients (6408 deaths) included in 45 trials.

Conclusions in term of survival

Platinum based treatment was better than non-platinum regimens (RR= 0.93; 95% CI, 0.83-1.05)

Platinum in combination was better single agent

platinum

when used as the same doses (RR= 0.85; 95% CI, 0.72-1.00)

CDDP and CBDCA were equally effective RR= 1.05; 95% CI,

0.94-1.18)

(B.M.J., 1991)

Advanced Ovarian Cancer Trialist Group

49 trials involving 8763 women HR for survival (95% CI) Platinum combination chemotherapy versus single non-platinum 0.93 (0.83-1.05)

CDDP + non-platinum regimen versus non-platinum regimen 0.88 (0.79-0.98) Platinum combination versus single platinum 0.91 (0.79-1.05)

CDDP versus CBDCA 1.02 (0.93-1.12)

Advanced Ovarian Cancer Trialists Group 2000

Chemotherapy for advanced OC

pathologic response 6-y survival rate

PAC 27% 31%

PC 21% 25%

p value 0.01 <0.02

(1991)

Ovarian Cancer Meta-Analysis Project PAC vs PC

Overview of the data from:

Advanced Ovarian Cancer Trialist Group

Ovarian Cancer Metanalysis Project

Impact of DOX on survival in advanced OC

The addition of DOX improves survival (RR= 0.85; 95% CI =

0.76-0.95, p=0.003) and the size of this benefit is of a similar

magnitudo to that of platinum

A’Hern and Gore, 1995

Patient population: 1526 patients from 132 centres in nine countries. CBDCA CAP

360/ 760 368/766

Deaths

Median survival 33 months 33 months

2-year survival 60% 60%

HR= 1.00 (95% CI 0.86-1.16) p=0.98

ICON 2: randomised trial of CBDCA versus CAP

(CTX, DOX, and CDDP)

International Collaborative Ovarian Neoplasm Group Lancet 1998

A prognostic model for survival obtained in the meta-

analysis included residual disease, age, grade and FIGO

stage.

A proportional hazard model, fitted the meta-analysis

data, was used to construct the expected survival

curve for each treatment arm of the ICON 2 trial.

Expected survival curves were compared with

observed survival curves in the ICON 2 trials.

Using the expected survival to explain differences

between the results of randomized trials: a case in advanced OC

Buyse et al, 2003

When this model was applied to the ICON 2 data,

there was no difference between the observed and

expected curves in the CAP arm.

In contrast, the observed survival curve for CBDCA

was superior to the expected survival curve.

The addition of DOX to platinum-based

regimen in OC

Buyse et al, 2003

The difference between the survivals in ICON 2 and in

the meta-analysis may be related to the better results

achieved with CBDCA alone at an optimally tolerated

dose compared with PC at a CDDP dose of 50-60 mg/m2.

The addition of DOX to platinum-based

regimen in OC

Buyse et al, 2003

.

ConclusionsRelationship between dose-intensity (mg/m2/w) of CDDP,

response rate,and survival Bias: analysis performed on trials not designed to assess

value of the dose-intensity concept

Retrospective analysis of 33 published Trials using CDDP in advanced OC

Levin et al, 1989

.High dose arm

CDDP dose CDDP Survival intensity total dose advantage Kaye et al.1992 double double yes

McGuire et al.1992 double identical no Colombo et al. 1992 double identical no

Conte et al. 1996 double double no

Studies designed to explore the dose-response curve of CDDP

Author pts median PFSmedian S n (months) (months)Neijt 2000 208 TAX 175 mg/m2 (3-h) + CBDCA AUC 5 16 32 TAX 175 mg/m2 (3-h) + CDDP 75 mg/m2 16 30 p= ns p=ns Bookman 2003 840 TAX 175 mg/m2 (3-h) + CBDCA AUC 7.5 20.7 56.7 TAX 135 mg/m2 (24-h) + CDDP 75 mg/m2 19.4 48.8 p= ns p=ns Du Bois 2003 798 TAX 185 mg/m2 (3-h) + CBDCA AUC 6 17.2 43.3 TAX 185 mg/m2 (3-h) + CDDP 75 mg/m2 19.1 44.1 p= ns p=ns

First Line Chemotherapy: Randomized trials comparing TAX + CBDCA vs CDDP +

TAX

Vasey P. Proc ASCO 2001;(abstract and oral presentation 804)

SCOTROC ASCO 2002:Progression Free Survival

Time from randomisation (months)

363024181260

Pro

po

rtio

n p

rog

ress

ion

fre

e

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

537537 319

3208090

00

No. of patientsar risk:- PC

DC

Paclitaxel/Carbo

Docetaxel/Carbo


SCOTROC: Overall Survival

Time from randomisation (months)

363024181260

Pro

po

rtio

n a

liv

e

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

537537 454

449183168

00

No. of patientsar risk:- PC

DC

Paclitaxel/Carbo

Docetaxel/Carbo


PC vs DCToxicity

DC PCMyelosuppression NeurotoxicityAllergyStomatitisDiarrheaMyalgia/Arthralgia

Ozols, ASCO 2001

TAX 135 mg/m2 (24-h) +CDDP 75 mg/m2 14.0 26.6

CDDP 100 mg/m2 16.4 30.2

TAX 200 mg/m2 (24-h) 11.2 26.0

Braccio 1+2 versus 3 p< 0.001 p= ns Braccio 1 versus 2 p= ns p =ns

614 evaluable patientsmedian PFS

median S (months) (months)

Muggia, 2000

1st CT: Phase III randomized study of TAX + CDDP vs CDDP vs TAX in stage III-IV

with RD > 1 cm: GOG 132

First Line Chemotherapy: ICON 3 randomized study

2074 randomized patients

Median PFS Median S months months

TAX 175 mg/m2 (3-h) + CBDCA AUC 5-6 17.3 36.1

CBDCA AUC 5-6 or 16.1 35.4 CDDP 50 mg/m2 + DOX 50 mg/m2 + CTX 500 mg/m2

p=ns p=ns

International Collaborative Ovarian Neoplasm Group 2002

Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3

Statistical bias

Different extent of crossover to the taxane-based

treatment in the control arm

The use of CBDCA instead of CDDP in the

experimental arm

Type of treatment used in the control arm

Explanations for different results between

GOG 111 and OV 10 versus GOG 132 and

ICON 3 The large effect seen in GOG 111 which maintained

at 5-years of follow up excludes the possibility of a

type I error.

ICON 3 enrolled 2074 patients and the chance of

missing the effect of TAX as large as seen in GOG 111

is only 1%.



ICON 3

Crossover to taxanes

OV 10 48%

GOG 132 24%

ICON 3 30% (on progression)

6% (before progression)



ICON 3

The experimental arm in ICON 3 differ from that of

the other trials, because CBDCA was used instead of

CDDP and because TAX was given at the dose of 175

mg/m2 3-h infusion. However, recent randomized

studies showed that CBDCA + TAX 3-h infusion can

substitute CDDP + TAX 24-h infusion without

abrogation of activity



ICON 3 Control arm

GOG 111 CTX 750 mg/m2 + CDDP 75 mg/m2

OV 10 CTX 750 mg/m2 + CDDP 75

mg/m2

GOG 132 CDDP 100 mg/m2

ICON 3 CDDP 50 mg/m2 + DOX 50 mg/m2

+ CTX 500 mg/m2 or CBDCA AUC

5-6



ICON 3 The control PC regimen (GOG 111 and OV 10) may be

inferior to the control arm used in ICON 3 (PAC or

CBDCA) and GOG 132 (high-dose CDDP)

The addition of CTX to CDDP may increase the hematologic toxicity of the regimen, causing excessive treatment delay and dose reduction.

Although there is no evidence of an improvement in survival with higher platinum dose-intensity, the addition of CTX to CDDP may have induced a dose reduction below the minimum standard.



ICON 3 The lack of benefit associated to platinum/taxane

combination in ICON 3 may be due to the superiority of

the control arm in this trial compared to the control

arms of the previous trials.

A meta-analysis with individual patient data from the

4 trials revealed a significant benefit for TAX/platinum-

based regimen, which was smaller than that originally

expected on the basis of GOG 111.

• Paclitaxel + Carboplatin (TC)– Accepted standard– “Control Arm” of all recent randomized trials– No other regimen shown to outperform it

– Median TTP: 15-18 months– Median OS: <36-40 months

Advanced Ovarian CancerAdvanced Ovarian Cancer

Current accepted Treatment Current accepted Treatment

Management of Advanced EOCSearch for progress

More active 1st line regimens

Tailored treatments

IP CT

Maintenance/Consolidation therapy

New treatment strategies (IDS, NACT) Novel (targeted) agents

GOG-182 (ICON 5)

OvarianCancerIII/IV

Carboplatin-paclitaxel x 8 OR Carboplatin x 8

Carboplatin-gemcitabine Carboplatin-paclitaxel x 4 x 4

Carboplatin-DoxilTM-paclitaxel x 8

Carboplatin-topotecan Carboplatin-paclitaxel x 4 x 4

Carboplatin-paclitaxel-gemcitabine x 8

Control arm selected by institution

Bookman MA, ASCO 2006

GOG 182- ICON 5 TrialGOG 182- ICON 5 Trial

Phase II trial of the Northeastern German Society of Gynecological Oncology

Study population: 105 pts with stage II-IV EOC.

CT regimen CBDCA AUC 5 every 3 weeks x 4 cycles followed by TAX 80 mg/m2/week x 12 cycles

No grade 3 or 4 neurotoxicity and/or nausea/vomiting

Grade 3-4:thrombocytopenia, 16%; anemia, 3%; leucopenia, 22%

After a median follow-up of 10 months (range 1-27), 20 pts died

Median OS: not yet reached

Median PFS: 19 months (range: 10-23)Oskay-Oezcelik, ASCO Meeting 2007

CBDCA + TAX vs CBDCA + DOXIL in advanced EOC: Preliminary results of phase III MITO-2 trial

RANDOMIZATION

CBDCA AUC 5 + TAX 175 mg/m2 CBDCA AUC 5 + DOXIL 30 mg/m2 every 3 weeks x 6 cycles every 3 weeks x 6 cycles

Preliminary data

Among 137 pts assigned to CBDCA + DOXIL, 87 were not eligible for response assessment by RECIST

Among 50 pts eligible for response assessment, 14 CR and 20 PR were recorded, for a RR of 68%

Among 35 pts with not-target lesions, 9 (26%) CR and 18 (51%) PR were observed

Pignata, ASCO Meeting 2007

ASCO 2007Educational Session

Rare Subtypes of Ovarian Cancer

• Clear Cell Tumors of the Ovary Toru Sugiyama, Iwate University, Japan

• Mucinous Ovarian Cancer Martin Gore, Royal Marsden, UK

Progress in the management of EOC

• Evidence-based optimal care of EOC should include:

- an accurate surgical staging

- a debulking surgery (no macroscopic peritoneal RD, systematic

LY )

- IP CT

• In daily practice, a minority of the pts receive an optimal surgery

and NONE is treated with IP CT

• Tailored treatments should be developed on the basis of clinico-

pathological parameters (histology, tumor grade, stage of

disease, RD after surgery)

• Education and training of health professionals might have a

major impact on survival

Molecular targeted agents able to interfere with

fundamental steps in tumor cell re-growth (i. e.

neoangiogenesis and growth factor signaling pathways)

should be investigated.

CT based on extreme drug resistance (EDR) assay

CT-based on gene-profiling

Conclusions

chemotherapy in advanced ovarian cancer angiolo gadducci department of gynecology and obstetrics,...

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