Ruolo della chemioterapia ad

alte dosi

Paolo Pedrazzoli

Razionale per l’utilizzo delle HDCT in GCTs

• Malattia chemiosensibile

– guaribile anche se malattia in progressione o recidiva

• Effetto dose risposta (etoposide, ifosfamide, carboplatino)

• Pazienti giovani

• Procedura a basso rischio con supporto di cellule staminali del sangue periferico

REFRACTORY

• Postmus PE, et al: Cyclophosphamide and VP 16-213 with autologous bone marrow transplantation: a dose escalation study. Eur J Cancer Clin Oncol 1984; 20:777-782.

• Nichols CR, et al: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a South-Eastern Cancer Study Group and Southwest Oncology Group Protocol. J Clin Oncol 1991; 9:1163-1172.

• Motzer RJ, et al: Phase II trial of high dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst 1993; 85:1828-1835.

• Lotz JP, et al: High dose chemotherapy with ifosfamide, carboplatin and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adult. Cancer 1995; 75: 874-885.

• Kondagunta GV, et al: Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol, 25: 85-90, 2007

CONSOLIDATION

• Bhatia S, et al: High dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 2000; 18:3346-3351.

• Rodenhuis S, Westermann A, Holtkamps MJ, et al: Feasibility of multiple courses of high dose cyclophosphamide, thiotepa and carboplatin for breast cancer or germ cell cancer. J Clin Oncol 1996; 14: 1473-1483

UPFRONT

• Schmoll HJ, Kollmannsberger C, Metzner B, Hartmann JT, Schleucher N, Schoffski P, et al: Long-term results of the first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21: 4083-4091, 2003

• Rosti G, De Giorgi U, Wandt H, Liure B,Leyvraz S, Kolbe K, et al: First-line high-dose chemotherapy for patients with poor prognosis extragonadal germ cell tumors: the experience of the European Group for Blood and Marrow Transplantation (EBMT) Solid Tumors Working Party. Bone Marrow Transplant 34: 1033-1037, 2004

• Bokemeyer C, Schleucher N, Metzner B, Thomas M, Rick O, Schmoll HJ, et al: First-line sequential high-dose VIP chemotherapy with autologous transplantation for patients with primary mediastinal nnseminomatous germ cell tumours: a prospective trial. Br J Cancer 89: 29-35, 2003

HDCT nei GCT: studi di fase I/II

The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

Autotrapianti in Europa per GCT

0

50

100

150

200

250

300

350

1991 1993 1995 1997 1999 2001 2003 2005 2007

** basato sul 75% delle risposte

**

HDCT in GCTs

As Up-front treatment for patients with poor-

prognosis

As Second-line treatment for relapsed/refractory patients

For patients with the poorest outcome (absolute

refractory, third line and further, mediastinal GCTs)

• 219 pts randomized

• DFS improvement from 30% to 50%

• Intermediate or poor-risk GCT

Random: PEB x 4 vs PEB x2 + HD CEC x2

Motzer, R. J. et al. J Clin Oncol; 25:247-256 2007

EFS OS

All patients

Patients with unsatisfactory marker decline

EFS OS

Motzer, R. J. et al. J Clin Oncol; 25:247-256 2007

EORTC 30974 Trial(EORTC, GTCSC, Spanish Group)

R

4 cycles of standard BEP

1 cycle of standard VIP

followed by 3 sequential

HD-VIP

Primary Endpoint:

Failure-free survival (FFS)

Secondary Endpoints:

Response to treatment

Overall Survival (OS)

Toxicity

The protocol was planned to detect a 15% difference in 1-year FFS rate

In June 2007 Executive Committee prematurely closed the trial due to slow recruitment;

Entered/Required patients: 137/222

Inclusion Criteria:

Male patients with Poor

Prognosis NSGCTs

(according to IGCCCG

classification)

Testicular of extragonadal

origin were eligible

EORTC 30974 Trial(EORTC, GTCSC, Spanish Group)

1-yr FFS:

48% Vs 66.1%

P=0.035

2-yr FFS:

44.8% Vs 58.2%

P=0.060

ASCO 2010 abs. n°4512

1-yr OS:

83% Vs 86.1%

2-yr OS:

65.5% Vs 72.9%

HDCT in GCTs

As Up-front treatment for patients with poor-prognosis

As Second-line treatment for relapsed/refractory

patients

For patients with the poorest outcome (absolute

refractory, third line and further, mediastinal GCTs)

HDCT as second line for recurrent/refractory disease

(include consolidation therapy)

Reference Type of trial No Approach OS (%) PFS (%)

Rodenhuis1996

Prospective 35 Conventional

induction CT + 2 cy

of HD-CTC

- 54

Bhatia2000

Prospective 65 1-2 cy of s-VeIP + 2

HD-CE

60 57

Motzer2000

Prospective 37 2 cy of TI + 3 cy of

HD-CE

54 49

Rick2001

Prospective 62 3 cy of s-TIP + 1 cy

of HD-CET

30

(at 3 yr)25

(at 3 yr)

Einhorn2007

Retrospective 135 2 cy of HD-CE - 70

Feldman2010

Prospective 107 2 cy of TI + 3 cy of

HD-CE

52

(at 5 yr)48

(at 5 yr)

Pico2005

Prospective

randomized

280 4 cy of s-VIP or VeIP

Vs 3 cy of s-VIP or

VeIP + 1 cy of HD-

CEC

53 Vs 53

(at 3 yr)

NS

35 Vs 42

(at 3 yr)

NS

The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

July, 2005

280 pts

Incomplete remission or relapse from first-line CT

15% improvement in EFS

The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

Study design

Registration and randomization of eligible pts

2 courses PEI or VeIP

If refractory after 2 courses, OFF

If not

Arm A

1 cycle PEI (or VeIP)

+

1 cycle PEI (or VeIP)

Arm B

1 cycle PEI (or VeIP)

+

CarboPEC + ABMT/ PBPCT

secondary surgery if indicated

The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

EVENT-FREE SURVIVAL Studio IT-94Fase III: PEIx4 vs PEIx3 + carboPEC

PRO

BABIL

ITY

YEARS

4PEI 3PEI+PEC

0 1 2 3 4 5 6

0

.2

.4

.6

.8

1

p=NS

PRO

BABIL

ITY

Am

ong C

R p

atients

YEARS

4PEI (n=51) 3PEI+PEC (n=53)

0 1 2 3 4 5 6

0

.2

.4

.6

.8

1

p=0,04

Pico, Rosti et al. Ann Oncol 2005

All patients Pts achieving CR

0.00

0.25

0.50

0.75

1.00

Pro

bab

ility

95 53 42 34 26 16 8 44PEI+PEC96 36 31 27 19 13 9 14PEI

Number at risk

0 12 24 36 48 60 72 84Months

4PEI 3PEI+PEC

Treatment

p=0.007

HR=0.58 95%CI [0.40-0.86]

Favorable AFP Half-life

Relapse-Free Survival

RFS in patients with favorable AFP decline

according to treatment arm

2-year RFS: 56% vs 36%; HR=0.58; p=0.007

HDT

Conventional-dose chemotherapy

Carbo

Massard et al, ASCO GU 2008

July, 2007

July, 2007

Characteristics of 184 Patients at the Beginning of High-Dose Chemotherapy

Mobilization:

G-CSF

HDCT:

Carboplatin: 2100 mg/m2

Etoposide: 2250 mg/m2

(Tandem)

Stem cell support:

> 1x106 selected CD34+ cells/Kg

Einhorn L et al. N Engl J Med 2007;357:340-348

Disease-free Survival according by the scoring algorythm based on three-variable model

Einhorn L et al. N Engl J Med 2007;357:340-348

Sopravvivenza libera da malattia a 4

anni per sottogruppi

HDCT Seconda linea 70%

HDCT Terza linea o successive 50%

IGCCCG alto rischio 50%

Refrattarietà al Platino 45%

TRM=1,7%

Overall mortality: 2,7%

Toxicity of HDCT

Prognostic factors in relapsed or refractory GCTs

To each variable a score was assigned relative to it’s hazard ratio in

multivariate analysis

A scoring system resulted with scores ranging from 0 to 10

ASCO 2009 abs. n°5030

ASCO 2010 abs. n°4512

HDC more effective in all subgroups

A RANDOMIZED PHASE III TRIAL COMPARING

CONVENTIONAL-DOSE CHEMOTHERAPY USING

PACLITAXEL, IFOSFAMIDE, AND CISPLATIN (TIP)

WITH HIGH-DOSE CHEMOTHERAPY USING

MOBILIZING PACLITAXEL PLUS IFOSFAMIDE

FOLLOWED BY HIGH-DOSE CARBOPLATIN AND

ETOPOSIDE (TI-CE) AS FIRST SALVAGE TREATMENT

IN RELAPSED OR REFRACTORY GERM CELL

TUMORS

Tiger Study

HDCT in GCTs

As Up-front treatment for patients with poor-prognosis

As Second-line treatment for relapsed/refractory patients

For patients with the poorest outcome (absolute

refractory, third line and further, mediastinal GCTs)

Kondagunta, G. V. et al. J Clin Oncol; 23:6549-6555 2005

HDCT as second or third line for patients with refractory or

absolute refractory GCTs

TI-CE is an effective and tolerable dose-intense treatment for patients with

previously treated metastatic GCTs who have a poor predicted outcome to

conventional-dose salvage chemotherapy.

http://www.50states.com/indiana.htm

Einhorn L et al. N Engl J Med 2007;357:340-348

Sopravvivenza libera da malattia a 4

anni per sottogruppi

HDCT Terza linea o successive 50%

Refrattarietà al Platino 45%

HDCT for patients with the poorest outcome (absolute

refractory, third line and further, mediastinal GCTs) [2]

Reference Type of

trial

No. Setting Approach OS (%) PFS (%)

First-line

Bokemeyer2003

Prospective

Phase I/II

28 First-line

PMNSGCTs

HD-VIP 64

(at 5 yr)

56

(at 5 yr)

Rosti

2004

Retrospective 22 First-line

EGCTs poor prognosis

Various 75

(at 5 yr)

67

(at 5 yr)

Banna

2006

Prospective 21 First-line

PMNSGCTs

HD-CEC 41

(at 3 yr)

43

(at 3 yr)

Salvage

Hartmann

2001

Retrospective 142 Salvage

therapy

EGNSGCTs

Various 12 *

(at 3 yr)

11*

(at 3 yr)

De Giorgi

2005

Retrospective 59 Salvage

therapy

EGNSGCTs

Various 14*

(at 3 yr)

14*

(at 3 yr)

* Survival data referred only to primary mediastinal germ-cell tumors

HDCT as First-line treatment in PMNSGCTs

Bokemeyer et al. BJC 2003; 89:129-35

Compared to data of an International database analysis including 253 patients with

PMNSGCTs treated with s-CT, the results may indicate that HDCT results in an

approximately 15% survival improvement

HDCT as salvage treatment in EGGCTs

De Giorgi U et al. Ann Oncol 2005;16:146-151

HDCT has no substantial impact on the outcome of patients with

mediastinal primiry site

● Up-front treatment for poor prognosis patients

● no evidence

● Second-line for relapsed/refractory patients

●consider prognostic factors

●prospective studies

● Third line and further

● Standard when feasible

● Primary mediastinal:

● Option as first-line for responders

● No role as salvage treatment

Conclusions – HDC in germ cell tumors