Oltre la seconda linea NSCLC

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EIS - ESMO International Symposium - Testicular
Cancer Munich, 15-16 May 2008
Salvage Treatment Prognostic Factors
Andrea Necchi, MD Dept of Medical
Oncology Fondazione IRCCS Istituto Nazionale dei
Tumori of Milan
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Background

• Germ-cell tumors are extraordinary
  chemo-sensitive and resemble the clinical and
  biological characteristics of a model for a
  curable neoplasm (Einhorn LH, 1981) 
• Nonetheless a small proportion of patients does
  not achieve durable complete remissions with
  upfront chemotherapy
• Only 20 to 40 of them will be cured with the use
  of platinum-containing standard dose or high-dose
  salvage chemotherapy with autologous stem cell
  support
• Prognostic factors for salvage treatment are
  neither commonly validated nor shared worldwide

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Difficulties in defining prognostic categories

• Paucity of data
• Heterogeneity of data
• Outdated information

? No of studies ? No of patients
? Different histologies (Sem vs Nonsem) ?
Different allocation criteria (MRC,
Indiana, IGCCCG) ? Different regimens
(e.g. not always etoposide in 1st line) ?
Different dose intensities (conventional
vs high-doses) ? Different No of HDCT cycles
(single vs multiple) ? Different settings
(2nd line vs further lines) ? old
regimens ? unproper therapies (delays,
uneffective post-CT surgery)
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Prognosis following Standard-dose salvage
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Prognostic factors for survival after
standard-dose salvage treatment
multivariate significance
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Salvage-chemotherapy in Non-Seminoma Setting up a
Prognostic score

• Patients n164
• Treatment period 1982-1986
• Prior cisplatin-based treatment all cisplatin,
  not all etoposide
• Salvage treatment various regimens (not
  specified)
• Univariate multivariate analysis
• Definition of a Prognostic model
• Data confirmed by an indipendent dataset of 66
  pts

Fosså SD et al, Br J Cancer 1999
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Prognostic Score by Fosså et al. n164
It defines 3 prognostic factors for pts
relapsing/progressing after first-line chemo and
undergoing STANDARD-DOSE salvage
treatment Progression-free interval lt 2 yrs lt CR
to first-line Elevated markers at
relapse-progression (AFP or HCG gt 100) POOR
PROGNOSIS Pts with 3/3 adverse prognostic
factors 2-y OS 7, 3-y OS 0 GOOD
PROGNOSIS Pts with 2 prognostic factors
2-y OS 56, 5-y OS 47
Fosså SD et al, Br J Cancer 1999
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• MSKCC series Prognostic score by Motzer et al.
• Patients who relapsed/progressed after 1st line
  chemo
• extragonadal primary tumor
• relapse after more than six cycles of
  cisplatin-based chemo
• no CR, NED or PRm-
• response duration of less than six months
• no adverse factors "good prognosis"
  conventional-dose chemotherapy with TIP
• at least one adverse factor present "poor
  prognosis" high-dose treament with TI
  plus sequential CE

Adverse prognostic factors were defined as
Motzer RJ. et al, J Clin Oncol 2000 Motzer RJ. et
al, Cancer 1991
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Prognosis following High-dose salvage
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Prognostic factors for survival after high-dose
salvage treatment
multivariate significance
Prospective trial
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Prognostic factors for HDCT of multivariate
significance Prognosis by Beyer score
Hazard
95 CI
p
score
Ratio
lt
0 1-2 ?3 good intermediate poor
Beyer J. et al. J Clin Oncol 1996
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Beyer J. et al. J Clin Oncol 1996
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Beyer model applied to Indiana series 1988-2001
Single Institution, Retrospective
design N80 Eligibility made by any of the
following Platinum refractory Absolutel
y platinum refractory HCG 1000 mUI/ml
prior to HDCT AFP 1000 ng/ml prior to
HDCT Primary mediastinal NSGCT
2-y FFS by Subgroups
Vaena DA et al, J Clin Oncol 2003
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Prognosis according to Indiana Score (1)
N184 Treatment period 1996-2004 Salvage
treatment Mostly Tandem CBDCAVP16 Induction
CT
Einhorn LH. et al. N Engl J Med 2007
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Prognosis according to Indiana Score (2)
Einhorn LH. et al. N Engl J Med 2007
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Prognostic Score by Fosså in High-dose
setting German Series 1988-1999
N 176 Fosså score applied to a revised
population of relapsing pts undergoing Single
HDCT in Germany Differences in PFS and OS
between prognostic groups still
significant Better outcome for poor prognosis
pts Markers remained the only significant
prognostic factors
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Sammler C. et al, Eur J Cancer 2008
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High-dose chemotherapy as FIRST salvage
Prospective trial
Beyer J. et al, J Clin Oncol 1996
Vaena DA. et al, J Clin Oncol 2003
Einhorn LH. et al, N Engl J Med 2007
Motzer RJ. et al, J Clin Oncol 2000
Sammler C. et al, Eur J Cancer 2008
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Prognosis in Extragonadal Mediastinal Primary

• Mediastinal location has been identified as one
  of the most important negative prognostic factors
  for survival in patients receiving salvage HDCT
  (Beyer, JCO 1996 Vaena, JCO 2003)
• Inadequate response to induction treatment is
  associated with a 2-fold higher risk of death
• Only 1/30 patients who had a mediastinal primary
  and an incomplete response to 1st line
  chemotherapy was reported as continously
  disease-free after salvage therapy
• Salvage surgical resection might be beneficial in
  selected pts (Rivoire, J Thorac Cardiovasc Surg
  1996)

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Current practical viewpoint on prognostic
allocation
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How to drive salvage treatment
Patientswith relapse or progression after
chemotherapy

• Indication for salvage
• surgery
• - Growing teratoma syndrome
• Resectable late relapse ( 2
• years)
• - resectable relapse after HDCT

Withoutrisk factors
Withrisk factors
Risk factors - extragonadal primary tumor - no
CR / PRm- after first-line- early relapse -
extrapulmonary visceral metastases- very
high AFP or HCG levels - any second or
subsequent relapse
Conventionaldose treatment
Highdose treatment PMGCTs Excluded (!)
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Conclusions
Salvage treatment is complex best results are
usually achieved in centers with a high
expertise (high-volume centers)
Salvage treatment decision is not yet based on
solid data
Lack of a consensus on a prognostic classification
Attribution of a reproducible prognostic score to
each single pt could lead to better results with
conventional-dose or high-dose treatments
Large database needed to define prognostic
factors andanalyse treatment strategies
Ongoing prospective European (worldwide) registry
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International Prognostic Factors Project 2008
Multicenter retrospective study Identification of
prognostic factors for first salvagechemotherapy
Defined inclusion criteria for all patients
allowing onlymodern "uptodate" regimens and
strategies to be included Chart review of
individual treatments, no register data Aimed to
collect data on more than 1000 patients
worldwide So far, more than 40 collaborating
centers in Europe and US, nearly 980 pts
recorded, 430 pts test-dataset ongoing in
Montpellier, Italy contributed substantially
through INT Milan and IGG
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Fondazione IRCCS Istituto Nazionale dei Tumori of
Milan 1928-2008
Acknowledgements
ACKNOWLEDGEMENTS
Prof. Alessandro Massimo Gianni Chief of Medical
Oncology, University of Milan
Urology
Medical Oncology
Pathology
Massimo Di Nicola
Maurizio Colecchia
Roberto Salvioni Nicola Nicolai Luigi Piva Davide
Biasoni Tullio Torelli Angelo Milani Silvia Stagni
Radiation Oncology
Silvia Tana
(and Thank You for your attention!!)