Optimal use of adjuvant chemotherapy for patients with stage I, II, or IIIA disease Francesco Grossi...

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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

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

ColorectalDukes B,C (5-FU + LV)

IMPACT, Lancet 1995

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

Patient selection criteriaPatient selection criteria

Good performance status

Rapid postoperative recovery

Few comorbid illnesses

Age < 70 years

IA IB II IIIA

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

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

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

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)

Age < 70 years

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

EGFR FISH or IHC

EGFR TKIFISH+ &/or IHC+

Prognostic tests:

Predictive tests:

Low High

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 1 2 3 4 5YearsNo at riskChemotherapy

Control

Control (113 deaths)

Chemotherapy (105 deaths)

ll Surv

346285121147165336996127149170

0 1 2 3 4 5YearsNo at risk

ChemotherapyControl

ll Surv

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

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

Thank you for your attention!Thank you for your attention!

francesco.grossi@istge.itfrancesco.grossi@istge.it

Optimal use of adjuvant chemotherapy for patients with stage I, II, or IIIA disease Francesco Grossi...

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