Treatment of Recurrent Platinum-Refractory Ovarian Cancer

$: Treatment of Recurrent Platinum-Refractory Ovarian Cancer$
© du Bois 2008© du Bois 2008

Treatment of Recurrent Platinum-Refractory Treatment of Recurrent Platinum-Refractory

Ovarian CancerOvarian Cancer

Andreas du BoisAndreas du BoisDept. Gynecology & Gynecologic OncologyDept. Gynecology & Gynecologic Oncology

Wiesbaden, GermanyWiesbaden, Germany


AGO-OVAR Definitions of Platinum Sensitivity*AGO-OVAR Definitions of Platinum Sensitivity*

* A. du Bois et al. 1997

(potentially) platinum-sensitive disease:(potentially) platinum-sensitive disease:

• no prior chemotherapyno prior chemotherapy

• oror response to prior platinum-based Tx or no evidenceresponse to prior platinum-based Tx or no evidence

of disease after prior platinum (CR, PR, NED)of disease after prior platinum (CR, PR, NED)

• andand relapse after treatment free interval > 6 monthsrelapse after treatment free interval > 6 months

platinum-refractory disease:platinum-refractory disease:

• no response to prior platinum-based Tx (NC, PD)no response to prior platinum-based Tx (NC, PD)

• oror PD free interval < 6 months after prior platinum Tx PD free interval < 6 months after prior platinum Tx

Treatment modalities in Platinum-resistentTreatment modalities in Platinum-resistentRecurrent Ovarian Cancer:Recurrent Ovarian Cancer:

SurgerySurgeryfew selected pts. few selected pts.

(e.g. bowel obstruction)(e.g. bowel obstruction)

Endocrine TXEndocrine TXSelected pts.,Selected pts.,

rather 3rd/4th line ?rather 3rd/4th line ?

Supportive careSupportive careevery pt. as neededevery pt. as needed

RadiotherapyRadiotherapyfew selected pts.few selected pts.

Psy-Soc SupportPsy-Soc Supportevery pt. as neededevery pt. as needed

““new drugs“new drugs“only in clinical trialsonly in clinical trials

non-Pt mono-Txnon-Pt mono-Tx

non-Pt non-Pt combination Txcombination Tx

Pt based therapyPt based therapymainly pt-sensitive ROCmainly pt-sensitive ROC

© AdB & JP 2007

What is the Evidence – 9/2008 ?Randomised Studies in Recurrent OC:

Studies Pts.

• mono- vs. mono chemotherapy 10 2.195

• mono: schedule/dose/application 7 1.614

• mono- vs. endocrine therapy 2 303

• endocrine vs. endocrine therapy 2 106

• combination vs. combination 2 107

• mono vs. combination* 14 3.499

all: 37 7.924

* Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensitive relapse

© AdB 2008

TCA Ovarian Cancer Trial

A prospective randomised controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician’s choice in patients with recurrent platinum-resistant ovarian cancer.

Ian A Cree, on behalf of the TCA Ovarian Cancer Trial Group

Methode:ATP-based Tumor ChemosensitivityAssay (ATP-TCA)

Andreotti et al., Cancer Research 1995; 55: 5276-82

© AdB 2008

Patients - tested drugs/combinations

180 randomised

86 assignedPhysician’s choicechemotherapy

94 assignedAssay-directedchemotherapy

28 received >= 6 cycles50 received < 6 cycles8 treatment never began


72 died14 alive at analysis


86 assessed for PFS

94 assessed forPFS

180 randomised

86 assignedPhysician’s choicechemotherapy

94 assignedAssay-directedchemotherapy





86 assessed for PFS

94 assessed forPFS

cisplatincisplatin gemcitabinegemcitabine cisplatin + gemcitabinecisplatin + gemcitabine doxorubicin (Doxil/Caelyx)doxorubicin (Doxil/Caelyx) paclitaxelpaclitaxel mitoxantronemitoxantrone mitoxantrone + paclitaxelmitoxantrone + paclitaxel topotecan topotecan treosulfantreosulfan treosulfan + gemcitabinetreosulfan + gemcitabine treosulfan + epirubicintreosulfan + epirubicin cisplatin (x2) + etoposidecisplatin (x2) + etoposide etoposideetoposide

Physicians choice: mainly single agent therapyPhysicians choice: mainly single agent therapy

© AdB 2008

Results: Chemosensitivity-Assay without any Impact on Outcome

Median PFS: HR: 0.80, 95%CI 0.59 - 1.10Physician’s choice: 93 daysAssay-directed: 104 days

= + 11 days (median)

number at risk

PC 38 22TCA 49 33

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n st

ill ev

ent f

ree

0 100 200 300 400 500 600Event free survival in days

Physician's choice TCA-directed

Progression Free Survival

number at risk

PC 38 22TCA 49 33

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n st

ill ev

ent f

ree

0 100 200 300 400 500 600Event free survival in days

Physician's choice TCA-directed

Progression Free Survival

Median OS:HR: 1.01 95%CI 0.7-1.3Physician’s choice: 260 daysAssay-directed: 261 days

= + 1 day (median)

number at risk

PC 65 51 38 21TCA 74 55 36 26

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n su

rviv

ing

0 100 200 300 400 500 600 700 800 900 1000 1500Survival in days

randcode = Physician's choice randcode = TCA-directed

Overall Survival

number at risk

PC 65 51 38 21TCA 74 55 36 26

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n su

rviv

ing

0 100 200 300 400 500 600 700 800 900 1000 1500Survival in days

randcode = Physician's choice randcode = TCA-directed

Overall Survival

© AdB & JP 2007

mono vs. combination chemotherapy in refractory recurrent OC

R

Melphalan 8 mg/m² d1-4 q28

Melphalan 6 mg/m² d1-4 q28 Hexa-MM 120 mg/kg d1-14 q28

Pater JL 1987, Cancer Treat Rep

103 pts.

102 pts.

results: OR 2% vs 3% (combi), PFS and OS n.a.

R

Paclitaxel 175 mg/m² 3h q28

Paclitaxel 150 mg/m²Epirubicin 120 mg/m² q28

Bolis G 1999, Gynecol Oncol

41 pts.

40 pts.

results: OR 17% vs. 34% (combi), PFS n.a. 2-YSR 10% vs. 18% (n.s.)

© AdB & JP 2007

R

Paclitaxel 175 mg/m² 3h q21

Paclitaxel 175 mg/m²Epirubicin 80 mg/m² q21

Buda A 2004, Br J Cancer

106 pts.

≤ 12 mos.

106 pts.

results: OR 47% vs. 37% (combi), PFS 6 vs. 6 mos. OS 14 vs. 12 mos. (n.s.)

R

Topotecan 1.25 mg/m² d1-5 q21

Topotecan 1.0 mg/m² d1-5 Etoposid 50 mg po d 6-12 q21 Sehouli J 2008, JCO

178 pts.

177 pts.

results: OR 36% (TE) vs. 32% (TG) vs. 28 % (Topo) mean PFS 15 vs. 13 vs. 13 months (n.s.)

mean OS 23 vs. 18 vs. 24 months (n.s.)

Topotecan 0.5 - 0.75 mg/m² d1-5 Gemcitabine 800 mg/m² d1 + 600 mg/m² d8 q21

app. 20% refractory41% > 12 Mon.

147 pts.


© AdB & JP 2007

Trabectedin+PLD4.0 mos

PLD3.7 mos

PFS events: 163HR: 0.95 (0.70-1.30)P = 0.7540 by courtesy of BJ Monk et al (Email: [email protected])


R

Doxil/Caelyx (PLD) 50 mg/m² q28

Trabectedin 1.1 mg/m² q 21 +Doxil/Caelyx (PLD) 30 mg/m² q28

BJ Monk et all , ESMO 2008

118 pts.

113 pts.

results: OR 12,2% vs 13,4% (combi; n.s.), PFS/OS n.s.





Endocrine TxEndocrine TxSelected pts.,Selected pts.,

rather 3rd/4th linerather 3rd/4th line





non-Pt mono-Txnon-Pt mono-Tx

Today, no strong evidence supporting combination Txcombination Tx

outside trials (eg.DOVE)


© AdB & JP 2007

What is the Evidence – 9/2008 ?Randomised Studies in Recurrent OC:

Studies Pts.

• mono- vs. mono chemotherapy 10 2.195

• mono: schedule/dose/application 7 1.614

• mono- vs. endocrine therapy 2 303

• endocrine vs. endocrine therapy 2 106

• combination vs. combination 2 107

• mono vs. combination* 14 3.499

all: 37 7.924

* Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensitive relapse

© AdB & JP 2007

AGO-OVAR 2.3 (Stratum 1, Relapse within 6 mos. after Platinum-Paclitaxel)

R

Treosulfan 7 g/m² iv q21

Topotecan 1,5 mg/m² d1-5 q21

Meier W 2003, ASCO

65 pts.

63 pts.

OR 19.3% (topo) vs 7.0% (p=.0524), OS n.s. (+3,9 mos. for topo),PFS significantly superior after topotecan (median +2 mos.)

Topo (63) median 11.2 Mon.

Treo (65) median 7.3 Mon.

HR = 1.36 [0.93-1.97]

p = 0.1111

0%

25%

50%

75%

100%

0 12 24 36 48 60 72

OS

Topo (63) median 4.2 Mon.

Treo (65) median 2.2 Mon.

HR = 1.44 [1.00-2.07]

p = .0476

0%

25%

50%

75%

100%

0 12 24 36 48 60

PFS

© AdB & JP 2007

R

Paclitaxel 175 mg/m² 3h iv q21

Topotecan 1,5 mg/m² iv d1-5 q21

ten Bokkel Huinink 1997, J Clin Oncol

114 pts.

50% refractory, but „only“ to platinum

112 pts.

results: OR 14% vs. 21% (Topotecan)

median PFS 15 vs. 19 months (n.s.)

median OS 53 vs. 63 months (n.s.)

Cave: patients had no taxans during 1st-line

… but today, most patients had platinum

plus taxan-containing 1st-line therapy!

Therefore, data support mainly Topotecan.

mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs

© AdB & JP 2007

R

Paclitaxel 175 mg/m² 3h iv q21

Caelyx 50 mg/m² iv q28

O’Byrne 2002, ASCO

107 pts.

62% refractory, but „only“ to platinum

106 pts.

results: OR 23% vs 19% (Caelyx; n.s.)

median PFS 4.4 vs. 4.8 months (n.s.)

median OS 13 vs. 11 months (n.s.)

Cave: patients had no taxans during 1st-line

… but today, most patients had platinum

plus taxan-containing 1st-line therapy!

Therefore, data support mainly Caelyx.


© AdB & JP 2007

R

Topotecan 1,5 mg/m² iv d1-5 q21

Caelyx 50 mg/m² iv q28

Gordon 2001, J Clin Oncol 2004, Gynecol Oncol

235 pts.

55% Pt.-refractory, > 70% prior taxans

239 pts.

Results platinum refractory subgroup: Caelyx (130) Topotecan (124) p-value

PFS (weeks, median) 9,1 13,1 0.733

OS (weeks, median) 36 41 0.455

G3/4 toxicity (all pts.;%)

Neutropenia 12 77 < 0.001Anemia 5 28 < 0.001Thrombocytopenia 1 34 < 0.001Leukopenia 10 50 < 0.001Treatment-related sepsis 0 4 < 0.001

Alopecia (all grades) 16 49 0.007Hand-Foot-Syndrom 23 0 < 0.001Stomatitis 8 0.4 < 0.001


© AdB & JP 2007

R

Canfosfamid 1000 mg/m² iv d1 q21

Caelyx 50 mg/m² iv q28 orTopotecan 1.5mg/m² iv d1-5 q21

Vergote 2007, ASCO

232 pts.

3rd-line after platinum-taxan and caelyx or topotecan 2nd-line

229 pts.


N PFS, median (wks)

Canfosfamide 232 10

Control 229 18.8

weeks

N OS, median (wks)

Canfosfamide 232 37

Control 229 58.9

wks

Results: canfosfamide inferior compared to standard arm

© AdB & JP 2007

R

Gemcitabine 1000 mg/m² d1+8 q21

Caelyx 50 mg/m² d1 q28

Mutch, JCO 2007

99 pts.

96 pts.

Results:


66 pts.

64 pts.

ParameterCAELYX(n=96)

Gemcitabine (n=99)

ORR (pts w/ measurable disease)

median PFS

median OS

8%

3.1 mos.

13.5 mos.

6%

3.6 mos.

12.7 mos.

Toxicity

Neutropenia, grade 3/4 Constipation, grade 2-4 N/V, grade 2-4 HFS, grade 2/3 Mucositis, grade 2/3

18%9%

12%19%*15%*

38%*25%*28%*

--3%

*Statistically significant.

© AdB & JP 2007

Results:

OR 16% vs. 18% (Gem), OR duration 18 vs. 17 (Gem) weeks ; n.s.

QoL advantage for caelyx in 2 of 4 time points (p < 0.05)

R

Gemcitabine 1000 mg/m² d1,8, 15 q28

Caelyx 40 mg/m² d1 q28

Mito-3

G Ferrandina et al JCO 2008

77 pts.

100% platinum-taxan, TFI < 12 mos. (57% < 6 mos.)

76 pts.






Endocrine TxEndocrine TxSelected pts.,Selected pts.,

rather 3rd/4th linerather 3rd/4th line





1st choice:1st choice:non-Pt mono-Txnon-Pt mono-Tx• Caelyx Caelyx • Topotecan Topotecan • Gemcitabine

Today, no strong evidence supporting combination Txcombination Tx

outside trials (eg.DOVE)


Treatment of Recurrent Platinum-Refractory Ovarian Cancer

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