ELSHAMI M. ELAMIN, MDMEDICAL ONCOLOGIST

CENTRAL CARE CANCER CENTERWWW.CCCANCER.COMWICHITA, KS - USA

NSCLC

NSCLC

85% of lung cancers Non-squamous

Adenocarcinoma (subtypes based on gene expression)1. Broncioid (associated with increased survival in

early stage)2. Squamoid (associated with increased survival in

advanced disease) Bronchioloalveolar is subtype of

adenocarcinoma Large-cell

Squamous

Mediastinal L.N. CT scan:

Negative LN by CT 3% +ve by biopsy May proceed with surgery

1-2cm LN by CT 10-20% +ve by biopsy

>2cm LN by CT 60% +ve by biopsy

>4cm LN 90% +ve by biopsy

PET scan: 94% sensit, 86% specif, 88% accuracy

Does not replace Mediastinoscopy

Mediastinoscopy + Biopsy

New TNM Staging

International Association of the Study of lung Cancer (IASLC) staging is adopted by AJCC (7th edition)

Changes To TNM staging

T4 pleural and/or pericardial effusion and/or pleural nodules becomes M1a

Additional nodules in the contralateral lung are subclassified as M1a

Distant metastases are subclassified as M1b

Sub-classify

T1 into T1a and T1ba. T1a < 2 cmb. T1b > 2 cm and < 3 cm

T2 into T2a and T2ba. T2a > 3 cm and < 5 cmb. T2b > 5 cm and < 7 cm

Reclassify

T2 lesions larger than 7 cm as T3 T4 tumors with additional nodules in

the primary lobe as T3 M1 by additional nodules in the

ipsilateral lung (different lobe) as T4

*Red color indicates the changes

AJCC 6th edition AJCC 7th edition

No N1 N2 N3

T1 (< 2 cm) T1a IA IIA IIIA IIIB

T1 (>2-3cm) T1b IA IIA IIIA IIIB

T2 (<5cm) T2a IB IIA IIIA IIIB

T2 (>5-7cm) T2b IIA IIB IIIA IIIB

T2 (>7cm) T3 IIB IIIA IIIA IIIB

T3 invasion T3 IIB IIIA IIIA IIIB

T4 same lobe nodule T3 IIB IIIA IIIA IIIB

T4 extension T4 IIIA IIIA IIIB IIIB

M1 ipsil lung T4 IIIA IIIA IIIB IIIB

T4 p effusion M1a IV IV IV IV

M1 cont lung M1a IV IV IV IV

M1 distant M1b IV IV IV IV

Stages at diagnosis

16% = localized 5YS = 49.5%

25% = regional LN and locally advanced

5YS = 20.6%

51% = metastatic 5YS = 2.8%

8% = unkown 5YS = 8.3%

Prognostic and Predictive Biomarkers

Prognostic: Indicative of survival independent of therapy Indicates innate tumor aggressiveness

ERCC1 (high expression = better prognosis) K-ras mutation = poor prognosis RRM1 (high expression = better prognosis)

Predictive: Indicative of therapeutic efficaciy

EGFR mutation (E19del, L858R) = response to EGFR TKI ERCC1 (high expression = poor response to platinum) K-ras mutation = lack of benefit from EGFR TKI and

platinum/vinorelbine RRM1 (high expression = poor eresponse to Gemzar)

TREATMENT

TREATMENT

1. Surgery Lobectomy is preferred over

pneumonectomy Any surgical resection is preferred over

ablation

2. Radiation Therapy3. Chemotherapy

SURGERY

Surgery

Lobectomy is preferred over pneumonectomy

Any surgical resection is preferred over ablation

Segmentectomy (preferred) or Wedge Resection

1. Not good surgical candidates2. Peripheral nodule < 2cm with at

least one of the following1. Pure BAC histology2. > 50% ground glass appearance on CT3. Doubling time > 400 days

Video-Assisted Thoracotomy (VAT)

Advantages:1. Minimal acute/chronic pain2. Shorter hospitalization3. Low postop morbidity, mortality4. Minimal risk of intraop bleeding5. Minimal locoregional recurrence

Mediastinal LND

ACOSOG Z0030 (ongoing) N0 – N1 disease:

Med LN sampling vs complete Lymphadenctomy Minimum of three N2 stations sampled

Radiation Therapy

Radiation Therapy

1. Adjuvant 2. Primary local treatment

1. Medically inoperable2. Unresectable

3. Palliative

Stereotactic Body RT

Inoperable stage I, N-ve, peripheral lesions <5cm

Provides statistically sig higher 5YS than 3-D RT in stage I

Limited lung mets Brain mets

Radiofrequency Ablation (RFA)

N-ve, isolated peripheral lesion <3cm:

Pt refuse surgery Medically not fit for surgery

Previously irradiated tissue palliation

PCI (25 Gy in 10 factions)

Controversial RTOG 0214 (PCI in stage III):

Brain mets 18% vs 7.7% No survival benefits

ADJUVANT CHEMOTHERAPY

Surgery Chemotherapy

1. International Adj Lung Cancer Trial (IALT):

Resected I, II, III (1867 pts) Adj Cisplatin-based chemo vs

observation 5Y f/u:

44.5 vs 40.4% (p<0.03) DFS 39.4 vs 34.3% (P<0.003)

7.5Y f/u: More death in the chemo arm Chemo benefit is decreasing over time

Surgery Chemotherapy

2. NCIC CTG JBR 10 trail: Stage IB-II (482 pts) Vinorelbine/Cis vs Observation

OS: 94 m vs 73 m RFS: not reached vs 46.7m 5YS: 69 vs 54% (p=0.03)

9Y f/u: Chemo benefits stage II but not IB

Stage II: MS 6.8 vs 3.6 yrs No increase in death rate

Surgery Chemotherapy

3. ANITA (Adj Navelbine International Trialist Association) trial: Stage IB, II, IIIA (840 pts) Vinorelbine/Cis vs Observation

76m f/u: MS 65.7 vs 43.7m Adj chemo improved 5YS in stage II-IIIA No benefit in stage I

Surgery Chemotherapy

4. CALGB 9633 Stage IB (344 pts) Paclitaxel/Carbo vs Observation 3Y OS: 79 vs 70 (P=0.45) 4Y OS: No diff

Subset analysis: Benefit tumor >4cm

Surgery Chemotherapy Summary

Meta-analysis in 4,584 pts (the Lung Adj Cisplatin Evaluation)

Postop Cis-based adj increased survival over 5Y Absolute benefit 5.4% No diff among regimens (Vinorelbine, VP,

others) Benefit greater in stage II-III and good PS

Paclitaxel/Carbo if pt cannot tolerates Cisplatin

ChemoRadiation

Stage IIIA What is the best?!?!?!?

Surgery

RT+/-Chemo

Chemo+/-RT

Unresectable IIIA/IIIB

ChemoRT is superior to RT alone Concurrent chemoRT

Superior to Sequential Higher rate of G3-4 esophagitis Initial concurrent chemoRT:

Cis/VP (preferred) Cis/Vinorelbine (preferred) Taxol/Carbo (category 2B)

Unresectable IIIA/IIIB

Phase II SWOG 9504 (83 pts stage IIIB): Concurrent Cis/VP+RT Doce

MS: 26m 5YS: 29%

Phase III, stage III: Concurrent Cis/VP+RT Doce

No survival benefit Increased toxicity

Randomized trial, IIIA/IIIB (203pts): Induction chemo RT+/-taxol

MS: 18.7 vs 14.1m (P=0.091)

Resected tumor, pN2

NCCN: Negative margins:

Sequential Chemo RT Positive margins:

Postop concurrent ChemoRT +/- chemo

PALLIATIVE CHEMOTHERAPY

Chemotherapy

Stage IV Good PS

Platinum-based 30-40% 1 Yr survival rates Doublets superior to single agents

ROLE of chemotherapy

No chemotherapy: 10% 1YS, 0% 2YS

Active single agent: 15%RR, 20%1YS, 10%2YS

Active 2 drugs: 25%RR, 35%1YS, 20%2YS

Doublets chemo regimens

Cisplatin or Carbo + Taxol

Cisplatin + Vinorelbine Cisplatin + Gemzar Cisplatin + Pemetrexed Cisplatin + docetaxel Phase III studies:

Similar objective responses and Survival

They differ in Toxicities, Convenience, and Cost

Other options: Docetaxel + Gemzar Gemzar +

Vinorelbine Cisplatin + Gemzar Carboplatin +

Pemetrexed Carboplatin +

docetaxel

Abraxane (Albumin-bound Taxol)

For patients with hypersensitivity reaction to: Taxol Docetaxel

Or if premedications are contraindicated

Targeted Therapies

Anti-VEGF Monoclonal antibody: Bevacizumab

(Avastin) Anti-EGFR

Small molecule: Erltinib (Tarceva) Monoclonal antibody: Cetuximab

(Erbitux) Anti-Alk

Small molecule: Crizotinib (Xalkori)

Anti-VEGF

Monoclonal antibody: Bevacizumab (Avastin

Unresectable, recurrent, met NON-SQUAMOUS

ECOG 4599: Avastin + Taxol + Carboplatin

Anti-EGFR (TKIs)

Small molecule: Erltinib (Tarceva) or Gefitinib Locally advanced, met NSCLC

After failure of at least one regimen First-line if EGFR mutation present

Based on Iressa Pan Asia Study (IPASS)

Iressa Pan-Asia Study (IPASS)

First-line gefitinib vs chemotherapy in clinically selected patients with EGFR mutation Sig clinical PFS benefit No sig OS benefit

Because there was a high rate of cross-over

Anti-EGFR

Monoclonal antibody: Cetuximab (Erbitux) Phase III FELX (Cis/Vin +/- Erbitux)

Slight OS benefit (11.3 vs 10.1m) Toxic regimen

Anti-Alk (Anaplastic Lymphoma Kinase)

Small molecule: Crizotinib (Xalkori) Phase II:

Advanced progressive NSCLC >80% RR Improved pain, dyspnea, cough

MAINTENANCE THERAPY

Definition

Treatment beyond 4-6 cycles of 1st line chemotherapy in the absence of disease progression.

Selection of drug depends on histology and pt P.S.

CONCEPT OF MAINTENANCE

1st Line doublet: Platinu

m-based

Diagnosis

Maintenance

Response or

Stable

2nd Line thera

py

Progression

TYPES OF MAINTENANCE THERAPY

Continuation Maintenance: Continuing 1st line cheotherapy

For a limited number of cycles Until progression or toxicity

No randomized trial supporting continuation of cytotoxic drugs

Continuing the non-platinum drug Gemzar Pemetrexed

Non-squamous, EGFR mutation negative or unknown Continuing the same targeted therapy

Bevacizumab (FDA appoved) Cetuximab

Non-squamous, EGFR mutation negative or unknown

TYPES OF MAINTENANCE THERAPY Switch Maintenance:

Switching to a different drug Pemetrexed (FDA approved) Targeted: Erlotinib (FDA approved),

Gefitinib Cytotoxic: Vinorelbine,

Adding a second targeted agent after chemo Erlotinib to Bevacizumab

TARCEVA: maintenanceSATURN (Sequential Tarceva in Unresectable NSCLC)

Have two co primary end points: PFS in the entire intent-to-treat population PFS in pts with EGFR-positive tumors on the basis of IHC

It was large and well powered, It was placebo controlled, following 1st line platinum-

based It met both of its primary end points with:

Significant prolongation of PFS in the intent-to-treat and the EGFR IHC-positive populations. However, the median PFS prolongation for both populations was of

only questionable clinical relevance (despite strong statistical significance) with only 1 month median benefit.

OS also was significantly prolonged in both populations, but once again with only modest absolute improvements.

EGFR mutation status was the most clinically and statistically important marker for PFS benefit in SATURN

SATURN CONCLUSION

First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy

Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled

Study of Erlotinib Maintenace Therapy in Advanced NSCLC

patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy.

Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup

KRAS mutation status was a significant negative prognostic factor for PFS

EGFR IHC–positive KRAS mutations were prognostic for reduced PFS

MAINTENANCE THERAPY

Although maintenance therapy may lead to PFS benefit without meaningful survival benefit: The idea of maintenance therapy is rapidly

gaining acceptance in the cancer community

It is difficult to argue against prolongation of time without cancer progression or time without worsening of symptoms, particularly if this can be achieved without significant toxicity, as is the case with EGFR TKIs

WHO BENEFIT FROM MAINTENANCE THERAPY?

May use the following to identify the patients who are most likely to benefit:

Clinical characteristics molecular markers.

THANK YOU