Embed Size (px)
Citation preview
Optimal use of adjuvant Optimal use of adjuvant chemotherapy for patients with chemotherapy for patients with
stage I, II, or IIIA diseasestage I, II, or IIIA disease
Francesco GrossiFrancesco Grossi
Oncologia Medica AOncologia Medica ADisease Management Team - Lung CancerDisease Management Team - Lung CancerIstituto Nazionale per la Ricerca sul CancroIstituto Nazionale per la Ricerca sul Cancro
GenovaGenova
Highlights in the management of NSCLCRoma, 14 Giugno 2008Roma, 14 Giugno 2008
1995 meta-analysis
Clinical trials post 1995 meta-analysis
2006 LACE meta-analysis
2007 meta-analysis
Trials and meta-analysis with UFT
Adjuvant chemotherapy in NSCLC: Adjuvant chemotherapy in NSCLC: evidence from literatureevidence from literature
1995 Meta-Analysis Results1995 Meta-Analysis Results
15% increase in the risk of death with alky. agents
13% reduction in the risk of death with P-based CT
Absolute benefit for CT of 3% at 2 years and 5% at 5 years (HR:0.87)
Non-small Cell Lung Cancer Collaborative Group, BMJ 1995
LIMITS OF THE 1995 META-ANALYSIS LIMITS OF THE 1995 META-ANALYSIS FOR ADJUVANT CHEMOTHERAPYFOR ADJUVANT CHEMOTHERAPY
Number of patients rather small (1,394 pts in the
cisplatin-treated group)
Patient characteristics often heterogeneous
Difference in survival of borderline statistical
significance
Post 1995 meta-analysis trials: resultsPost 1995 meta-analysis trials: results
Study # Pts Stage CT 5YS gain p
US Interg. 488 II-III PE/RT -6% 0.56
ALPI 1209 Ib-IIIA MVP +1% 0.58
CALGB 344 Ib CT +2% 0.1
IALT 1868 Ib-IIIA PV/PE +4% 0.03
NCIC 482 Ib-II PV +15% 0.02
ANITA 840 Ib-IIIA PV +9% 0.01
LACE Meta-AnalysisLACE Meta-Analysis
Pignon JP, ASCO 2006
OS by trial
UFT meta-analysis UFT meta-analysis
+5%
Hamada C, JCO 2005
2007 meta-analysis2007 meta-analysis
IPD of 8147 patients
15 RCTs with CDDP without UFT, 8 with UFT without CDDP and 7 with both CDDP and UFT
Survival: CT benefit (HR=0.86, p<0.000001); 4% at 5 years (from 60% to 64%)
Stewart LA, ASCO 2007
The benefit of adjuvant treatment The benefit of adjuvant treatment in several other cancers in adultsin several other cancers in adultsCancer Stage Reference 5-years (%) 10-years (%)
BreastEarly
(Chemo)
EBCTCG, Lancet 1992 3.2 6.3
BreastEarly
(Tamoxifen)
EBCTCG, Lancet 1992 3.6 6.2
OvarianEarly (Platinum)
Trimbos JB, JNCI 2003
8 -
ColorectalDukes B,C (5-FU + LV)
IMPACT, Lancet 1995
5 -
LungStage I-IIIA Stewart, ASCO
2007 4 5 (8-yrs)
IALT: OS at 8 yearsIALT: OS at 8 years
Le Chevalier, ASCO 2008
IALT: DFS at 8 yearsIALT: DFS at 8 years
Le Chevalier, ASCO 2008
Cause of deathCause of death
Adjuvant NSCLC chemotherapyAdjuvant NSCLC chemotherapy in Clinical Practice in Clinical Practice
Lynch T et al. ‘‘Early Stage Lung Cancer - New Approaches to Evaluation and Treatment,’’ Cambridge, MA, October 1 - 2, 2004 - Clin Cancer Res 2005
Trial PNX RT Compliance TOX
IALT 35 30 74 ++
NCIC 23 0 65 +++
ANITA 37 25 56 +++
BLT ? 14 64 +++
ALPI 25 43 69 +++
CALGB 10 0 84 +
Post 1995 meta-analysis trials: Post 1995 meta-analysis trials: toxicity and compliancetoxicity and compliance
Now what?Now what?
Should we use adjuvant
chemotherapy in all patients with resected NSCLC?
Post-surgical treatmentPost-surgical treatment
Clinical patient selection
Biological patient selection
Post-surgical treatmentPost-surgical treatment
Clinical patient selection
Biological patient selection
Patient selection criteriaPatient selection criteria
Stage
Good performance status
Rapid postoperative recovery
Few comorbid illnesses
Age < 70 years
Patient selection criteriaPatient selection criteria
Stage
Good performance status
Rapid postoperative recovery
Few comorbid illnesses
Age < 70 years
IA IB II IIIA
ALPI
IALT
NCI-C
CALGB
ANITA
CT effect and stageCT effect and stage
PositiveNegative
Not tested
Cancer Care Ontario and ASCO Cancer Care Ontario and ASCO guidelineguideline
Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA diseaseAlthough there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use
Pisters KMW, JCO 2007
ESMO Clinical RecommendationsESMO Clinical Recommendations
D’Addario G, Ann Oncol 2008
CALGB 9633: OS in patients CALGB 9633: OS in patients with tumor with tumor ≥ 4 cm≥ 4 cm
Japanese clinical practice guidelineJapanese clinical practice guideline
Adjuvant chemotherapy with UFT for patients with stage IB and some IA (tumor size: 2 cm or more)
In Japan, about 70% of patients with stage IB disease receive UFT adjuvant treatment in practice
Tsuboi M, 1° European Lung Cancer Conference – Geneva 2008, abstract 152 O
Efficacy of adjuvant CT in stage IBEfficacy of adjuvant CT in stage IB
UFT studies (and meta-analysis) positive
CALGB study positive for PFS
CALGB subgroup analysis shows survival advantage for T> 4 cm (JBR10 too)
Although not statistically significant LACE meta-analysis shows HR of 0.92 in favour of CT
Number of patients needed to treat to Number of patients needed to treat to detect an OS benefit at 5 yearsdetect an OS benefit at 5 years
Pisters KMW, JCO 2007
Abbreviations: OS, overall survival; HR, hazard ratio; ARR, absolute risk reduction; NNT, number needed to treat to prevent one death;
Estimated absolute risk and benefit for 100 patients Estimated absolute risk and benefit for 100 patients with NSCLC treated with surgery and adjuvant CTwith NSCLC treated with surgery and adjuvant CT
Pisters KMW, JCO 2007
Patient selection criteriaPatient selection criteria
Stage
Good performance status
Rapid postoperative recovery
Few comorbid illnesses
Age < 70 years
Role of PS in the post-surgery Role of PS in the post-surgery treatment decisiontreatment decision
KPS of <70 is an important prognostic factors in Stage I NSCLC. Therefore, KPS assessment is recommended when analyzing the prognostic effects of tumor or treatment-related factors on OS.
Firat S, Int J Radiat Oncol Biol Phys 2002
p=0.001
Patient selection criteriaPatient selection criteria
Stage
Good performance status
Rapid postoperative recovery
Few comorbid illnesses
Age < 70 years
Patient selection criteriaPatient selection criteria
Stage
Good performance status
Rapid postoperative recovery
Few comorbid illnesses
Age < 70 years
Differential prognostic impact of Differential prognostic impact of comorbiditycomorbidity
The highest levels of comorbidity (moderate and severe) were found among the lung cancer patients (38.9%), whereas the least amount was among prostate (13.3%) and breast (18.3%) cancer patients. Comorbidities have little impact on the survival of patients with aggressive tumors
Read WL, JCO 2004
Impact of comorbidity on survival Impact of comorbidity on survival after surgical resection after surgical resection
Comorbidity has a significant impact on survival after surgical resection of patients with stage I NSCLC
These data may help to explain the lower than expected survival results for patients after surgical resection for stage I NSCLC
Battafarano RJ, JTCS 2002
Survival at 3 years for each level of comorbidity (stage I NSCLC):
none, 85.6% mild, 74.8% moderate, 68.8% severe, 70.0% (p <.002)
Patient selection criteriaPatient selection criteria
Stage
Good performance status
Rapid postoperative recovery
Few comorbid illnesses
Age < 70 years
Post-surgical treatmentPost-surgical treatment
Clinical patient selection
Biological patient selection
HypothesisHypothesis
A genomic strategies refines prognosis in early stage non-small cell lung
carcinoma
A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC).Potti A, NEJM 2006
MethodsMethods89 Early stage NSCLC
44 adenocarcinoma
45 squamous cell carcinoma
Age 66 (range 32-83)
Gender 39 female, 52 male
Follow-up 6 years
~ 50% had disease recurrence within 2.5 years
and 50% had disease-free survival of > 5 years
Gene expression using Affymetrix U133-2.0 plus
Potti A, NEJM 2006
Genomic predictor of recurrenceGenomic predictor of recurrenceEarly stage NSCLC Early stage NSCLC (n= 89)(n= 89)
Accuracy ~ 90%Metagene (mgene) 79
Alive Disease recurrence/death
High risk
Low risk
Potti A, NEJM 2006
NSCLC – Recurrence predictorNSCLC – Recurrence predictorGenomic vs Clinical Genomic vs Clinical (n= 89)(n= 89)
Lung Metagene Predictor (LMP) Clinical Model
Accuracy ~ 90% Accuracy ~ 60%Potti A, NEJM 2006
Estimates based on predictions from the Estimates based on predictions from the lung metagene model and clinical modellung metagene model and clinical model
NSCLC Survival LMP
NSCLC Survival – Clinical variables
NSCLC Survival by T alone NSCLC Survival by stage of disease
Potti A, NEJM 2006
Trial Design: Clinical Stage I NSCLCTrial Design: Clinical Stage I NSCLC
Low-Risk; N=150 High-risk; N=300
Adjuvant Chemotherapy
Observation80% 4-year
Total population=500 (450+10% poor RNA)
Observation
Randomize
Signature is prognostic in observation Signature is prognostic in observation but not in CT treated patientsbut not in CT treated patients
Tsao M, ASCO 2008
15-gene signature is prognostic in 15-gene signature is prognostic in stage I and II observation patientsstage I and II observation patients
Tsao M, ASCO 2008
CT benefits JBR.10 high risk but not CT benefits JBR.10 high risk but not low risk patientslow risk patients
Tsao M, ASCO 2008
CALGB 30506CALGB 30506
Stage IA NSCLC patients
Surgery Gene Expression Analysis
Lung Metagene Predictor
Observation Randomize
Observation Chemotherapy
Six gene classifier
Proteomics
ERCC1
RRM1
EGFR FISH or IHC
EGFR TKIFISH+ &/or IHC+
Prognostic tests:
Predictive tests:
Low High
ERCC1 in Early Stage NSCLC & Adjuvant CT
ERCC1 in Early Stage NSCLC & Adjuvant CT
Olaussen KA, NEJM 2006Olaussen KA, NEJM 2006
N= 761; ERCC1 negative= 56%, benefit of adjuvant chemotherapy only in ERCC1 negative tumors (HR for death 0.65, CI95% 0.50-0.86). In surgery alone ERCC1 positive tumors survived longer
4781121161194224355991120163202
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5YearsNo at riskChemotherapy
Control
Control (113 deaths)
Chemotherapy (105 deaths)
Overa
ll Surv
ival
346285121147165336996127149170
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5YearsNo at risk
ChemotherapyControl
Overa
ll Surv
ival
Control (80 deaths)
Chemotherapy (92 deaths)
ERCC1 Positive ERCC1 Negative
HR=1.14 [0.84-1.55], p = 0.40
ERCC1: IALT Bio, n= 761 ptsERCC1: IALT Bio, n= 761 pts
HR=0.65 [.50-.86], p = 0.002
Proposed Adjuvant Trial: NSCLC Proposed Adjuvant Trial: NSCLC Stage II, IIIA Stage II, IIIA
ERCC 1 Expression
Docetaxel+
Vinorelbine
Cisplatin+
Docetaxel
RRM1 Expression
Cisplatin+
Gemcitabine
Simon, Bepler 2007
High Low
High Low
CConclusionsonclusions
For any patient there is a balance between side effects and clinical benefit
It is important to discuss with patients the reality of treatment and the associated risks and benefits
Benefits Risks
