gemcitabine/docetaxel association: r e trospective analysis of 133 soft tissue sarcomas

Gemcitabine/Docetaxel association:Gemcitabine/Docetaxel association:RReetrospective analysis of 133 soft trospective analysis of 133 soft

tissue sarcomastissue sarcomas

Gemcitabine/Docetaxel association:Gemcitabine/Docetaxel association:RReetrospective analysis of 133 soft trospective analysis of 133 soft

tissue sarcomastissue sarcomas

J.-O. Bay, for the French Sarcoma Group J.-O. Bay, for the French Sarcoma Group

First line of chemotherapy doxorubicine median OR = 26%

ifosphamide ifosphamide median OR = 26% MAID MAID 47% OR with 10% CR 47% OR with 10% CR (Elias, JCO 1989)(Elias, JCO 1989)

Gemcitabine (Patel et al.)

inhibitor of ribonucleotide reductase and intercalating agent

Docetaxel

stabilization of tubulin, phosphorylation of bcl-2 (apoptotic activity)

BackgroundBackground

Gemcitabine/docetaxel combination (Hensley et al.)

synergistic effect with DNA synthesis arrest and induction of apoptosis

Second line of chemotherapy cisplatine, topotecan, paclitaxel, mitoxantrone, vinorelbine etc …

10 - 20% OR with no standard

Preliminary study for a phase II trial from the French Sarcoma Group evaluating

gemcitabine/docetaxel in soft tissue sarcomas

Analysis of the best response

Objectives of this retrospective studyObjectives of this retrospective study

Survival

Toxicity evaluation

133 patients (75 women / 58 men) treated from 10/2001

to 12/2004

Median age at diagnosis: 51.7 [18-82]

112 patients had already received doxorubicine and/or

ifosphamide

Initial surgery: 115 patients R0 = R0 = 6363 (55 %)(55 %) R1 = R1 = 30 30 (26 %)(26 %) R2 = R2 = 21 21 (19 %)(19 %)

Patient characteristics Patient characteristics (1)(1)

Histological subtypes

Leiomyosarcoma : 76(57.1

%)

Undifferentiated : 17(12.8

%)

Synovialosarcoma : 10(7.5 %)

Liposarcoma : 6(4.5 %)

Angiosarcoma : 5(3.8 %)

Rhabdomyosarcoma : 5(3.8 %)

Epithelioid sarcoma : 5(3.8 %)

Fibrosarcoma : 5(3.8 %)

Others : 4(3.0 %)

Grading (missing information for 10 patients)

Grade I:10

Grade II:43

Grade III:70


Limbs44 (34 %)

Uterine corpus 32 (24 %)

Bone15 (11 %)

Organs23 (14 %)

Retroperitoneal19 (17 %)

Initial localization


Neoadjuvant chemotherapy: 22 patients

115/133 with initial surgery (R0=63; R1=30; R2=22)

36 patients with metastatic surgery at the time of the initial surgery

92 patients with adjuvant chemotherapy before metastatic evolution

90 patients with a first line chemotherapy for metastatic or unresectable disease

Number of anterior lines of chemotherapy

None : 21 patients (17 %)

One : 60 patients (45 %)

Two : 35 patients (26 %)

Three : 9 patients (7 %)

Four : 2 patients (1.5 %)

Five : 5 patients (3.5 %)


Number of metastatic patients: 130

Metastatic localizations Lung: 117 Liver: 42 Bone: 25 Others: 23

Number of metastatic sites One: 72 patients (55 %) Two: 39 (30 %)

• Liver and lung : 23• Lung and bone : 7

More than three: 19 (15 %)


0

1

2

3

Nu

nb

er

of

lin

e

0 1 2 3


Performance Status (PS) before Gemcitabine-Docetaxel

OMS 032 %

OMS 148 %

OMS 214 %

OMS 36 % Correlation between PS and the

number of anterior chemotherapy lines

125 patients available

TreatmentTreatment

J1 J8 J1 J8

21 or 28 days

Gemcitabine 900 mg/m2 over 1h and Docetaxel 100 mg/m2 over 1h

Gemcitabine 900 mg/m2 over 1h Gemcitabine 900 mg/m2 over 1h

Gemcitabine 900 mg/m2 over 1h and Docetaxel 100 mg/m2 over 1h

Number of courses: mean = 4,0 courses and median = 3 courses [1-11]

1 11 8.3 % | ************2 30 22.6 % | *********************************3 27 20.3 % | *****************************4 20 15.0 % | **********************5 11 8.3 % | ************6 14 10.5 % | ***************7 7 5.3 % | *******8 7 5.3 % | *******9 4 3.0 % | ****10 1 0.8 % | *11 1 0.8 % | *

Dose of docetaxel per course and per m² for 528 courses:Mean: 135.3 Standard error: 24,3Median: 141.2 Interquartile interval: [124 ; 179]

Dose of gemcitabine per m² for 519 courses: Mean: 1455 Standard error: 445Median: 1655 Interquartile interval: [1189 ; 1791]

Results Results (1)(1): Treatments received: Treatments received

For 515 courses

Results Results (2)(2): Toxicity: Toxicity

ToxicityToxicitygradegrade

OMS-0 69.90 % 79.61 % 53.79 % 89.60 % 95.76 % 94.99 % 75.10 %

OMS-1 5.83 % 6.99 % 28.54 % 7.90 % 1.93 % 3.47 % 3.47 %

OMS-2 4.66 % 5.05 % 14.76 % 1.54 % 1.16 % 0.77 % 12.16 %

OMS-3 10.29 % 6.02 % 2.52 % 0.58 % 1.16 % 0.58 % 9.07 %

OMS-4 9.32 % 2.33 % 0.39 % 0.39 % 0.19 % 0.19 %

NeutropeniaNeutropenia ThrombopeniaThrombopenia AnemiaAnemiaNausea / Nausea / vomitingvomiting DiarrheaDiarrhea MucosisMucosis AlopeciaAlopecia

Grade-4

Grade-3

Grade-2

Grade-1

Grade-0

Results Results (3)(3): Toxicity: Toxicity

Toxicity over 515 courses of gemcitabine-docetaxel

50%

60%

70%

80%

90%

100%

neutropenia

thro

mbopen

ia

anem

ia

nause

a / v

omiti

ngdi

arrh

eam

ucos

isal

opec

ia

Stable33 patients

(29 %)

Partial response18 patients

(15.8 %)Complete response

3 patients(2.6 %)

Progression60 patients

(52.6 %)

Best response observed

Results Results (4)(4): Best response: Best response

114 patients evaluable for response

Results Results (5)(5): Univariate response analysis: Univariate response analysis

Variables Best response

- Age NS (p = 0.83)

- Sex NS (p = 0.51

- Initial localization NS (p = 0.78)

- Mesastasis localizations (liver-bone-lung) NS (0.07/0.70/0.74)

- Number of metastatic localizations NS (p = 0.18)

- Histological subtypes limite (p = 0.06)

- Grade NS (p = 0.74)

- Number of previous chemotherapy courses NS (p = 0.25)

- OMS Status (0 versus 1, 2 et 3) p = 0.023

- Mean dose of gemcitabine received NS (p = 0.40)

- Mean dose of docetaxel received NS (p = 0.32)

- Number of previous lines of chemotherapy received p < 10-5

OR (CR + PR) rates

Global 18.4 % 21/114 en OR

IC-95% [11.3 ; 25.5]

Leiomyosarcoma 24.2 % 16/66 en OR

Other histological subtypes 10.4 % 5/48 en OR

Uterine localization 18.5 % 5/27 en OR

Other localization 18.4 % 16/87 en OR

Status OMS-0 30.6 % 11/36 en OR

Status OMS-1, 2 et 3 12.5 % 9/72 en OR

Objective response versus stable and progression

CR or PR: mean of 6 courses [5.2-7]non responders: mean of 3.5 course [3.2-4]

OMS-0: 11/36; OMS-1, 2 ou 3: 9/72

leiomyosarcoma

Results Results (6)(6): Multivariate analysis of the response: Multivariate analysis of the response

OMS-0 versus OMS-1, 2 and 3

Only performance status at the time of gemcitabine/docetaxel

treatment was significant, with RR = 3 [1.13-7.7] (p = 0.027)

leiomyosarcomas versus other histological subtypes

Tendency for leiomyosarcoma, with RR = 2.25 [0.74-6.87] (p = 0.09)

Available for 130/133 patients.

23 patients were still under gemcitabine-docetaxel treatment.

Median survival of 12.1 months [1-28]

Rate at 6 months: 76 %, 12 months: 51%, 18 months: 30%, 2 years: 15 %.

Results Results (7)(7): Overall survival: Overall survival

Median of follow-up : 16.2 months [6-45]

months


Covariates Overall survival

- Age NS

- Sex NS

- Initial localization NS

- Metastasis localization NS

- Number of metastatic sites NS

- Histological subtypes p = 0.01

- Grade NS

- Nb previous chemo. courses NS

- OMS status p < 10-4

- Dose of gemcitabine received NS

- Dose of docetaxel received p = 0.008

-Nb of previous lines of chemotherapy p < 10-3

-Response p = 0.016

Survivalat 6 month at 12 months at 18 months at 20 months

Global 76 % 51 % 30 % 15 %

Leiomyosarcoma 87 % 56 % 42 % 21 %

Other histology 60 % 45 %

Uterine localization 74 % 50 % 37 %

Other localization 76 % 52 % 28 % 19 %

OMS-0 100 % 84 % 76 % 51 %

OMS-1, 2 et 3 65 % 39 % 13 %

Results Results (9)(9): Multivariate analysis of survival: Multivariate analysis of survival

OMS-0 versus OMS-1, 2 and 3

Performance status at gemcitabine/docetaxel treatment was

significant, with RR = 3.13 [1.51-6.49] (p = 0.0022)

Quality of the response

Patients in progression versus others: RR = 4.02 [2.16-7.51]

(p = 0.000012)

Histology

Leiomyosarcomas: slightly better overall survival,

with RR = 1.52 [0.86-2.69] (p = 0.15)

monthsmonths

Overall survival according to histology1 : leiomyosarcoma

2 : other

Leiomyosarcoma (range [1-28]): better prognosis than others [1-

16] : (p = 0.01) with median of survival of 13.4 months and 9.1

months respectively

Overall survival according to initial localization1 : cutaneous

2 : soft tissue

3 : retroperitoneal

4 : bone

5 : organ


(p = 0.96) (p = 0.01)

monthsmonths

Overall survival according to PS1 = OMS-0

2 = OMS-1, 2 and 3

Overall survival according to response1 = complete response

2 = partial response

3 = stable

4 = progression

Best response = prognosis factor (p = 0.00087)


100 % 84 % 76 %

51 %

1

2

65 %

39 %13 %

Gemcitabine/docetaxel : leiomyosarcomaGemcitabine/docetaxel : leiomyosarcoma

Patel et al.(J Clin Oncol

2001)

Hensley et al.(J Clin Oncol 2002)

Hensley et al.(abstract 9010 – ASCO

2004)

Look et al.(Gynecol Oncol 2004)

Morgan et al. (abstract 9009 –

ASCO 2004)

Chemotherapy Gemcitabine

J1 – J8

Gemcitabine + Docetaxel

Gemcitabine + Docetaxel

Gemcitabine

J1 – J8 – J15

Gemcitabine + vinorelbine

Number of patients

39 34 52 48 18

Leiomyosarcoma 10 29 uterin

4 others

42 48 uterin 9 uterin

9 others

Response rate 18% [7%-29]

4/10 = prog

53 % [35%-70%]

3 = CR; 15 = prog

35 % [22%-48%]

40 % versus 10 %

20.5 %

1 = CR; 8 = prog

2 = prog

1 stable

ConclusionsConclusions

Better reponse with leiomyosarcoma but without a clear

statistical difference in comparison with other histologies

The initial localization did not influence response or

survival

Performance status was an important prognosis factor

Lower response rate for leimyosarcomas than that

described in literature

• Jérôme Fayette, Jean-Yves Blay, Jérôme Fayette, Jean-Yves Blay, Centre Léon Bérard et CHU E. HerriotCentre Léon Bérard et CHU E. Herriot

• Serge Leyvraz, Serge Leyvraz, CHUV, LausanneCHUV, Lausanne

• Sophie Piperno-Neumann, Sophie Piperno-Neumann, Institut CurieInstitut Curie

• Christine Chevreau, Christine Chevreau, Institut Claudius Regaud, ToulouseInstitut Claudius Regaud, Toulouse

• Axel Lecesne, Axel Lecesne, Institut Gustave Roussy, VillejuifInstitut Gustave Roussy, Villejuif

• Nicolas Isambert, Nicolas Isambert, Centre Georges-François Leclerc, DijonCentre Georges-François Leclerc, Dijon

• Etienne Brain, Etienne Brain, Centre René Huguenin, Saint-CloudCentre René Huguenin, Saint-Cloud

• Nicolas Penel, Nicolas Penel, Centre Oscar Lambret, LilleCentre Oscar Lambret, Lille

• Frédéric Peyrade, Frédéric Peyrade, Centre Antoine Lacassagne, NiceCentre Antoine Lacassagne, Nice

• Pierre Kerbrat, Pierre Kerbrat, Centre Eugène Marquis, RennesCentre Eugène Marquis, Rennes

• Cécile Guillemet, Cécile Guillemet, Centre Henri Becquerel, RouenCentre Henri Becquerel, Rouen

AcknowledgementsAcknowledgements

gemcitabine/docetaxel association: r e trospective analysis of 133 soft tissue sarcomas

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