肺 癌

LUNG CANCER

中山大学肿瘤医院王 思 愚

Lung cancer – China incidence and mortality rates (1990-2009)

– 90 年后肺癌占恶性肿瘤死因第 1 位的省市 :

上 海 : 43.53/10 万 天 津 : 38.86

辽 宁 : 32.07

黑龙江 : 29.06

吉 林 : 28.06

云 南 : 23.07

北 京 : 22.25

内蒙古 : 22.04

Lung cancer - US incidence andmortality rates (1973-1996)

10

50

100

Incidence - malesMortality - malesIncidence - femalesMortality - females

Rate per 100,000 people(log scale)

1974 76 78 80 82 84 86 88 90 92 94 96

Year of diagnosis/death

Ries et al 1999

lung cancer cases diagnosed in Cancer Center of Sun Yat-sen University

0

2

4

6

8

10

12

14

65 75 85 95 2000

lung cancer cases diagnosed in Cancer Center of Sun Yat-sen University

70'S

鼻咽癌 肝 癌 肺 癌

食管癌 乳腺癌 其它

21'S

鼻咽癌 肝 癌 肺 癌

食管癌 乳腺癌 其它

Etiology of Lung Cancer

Cigarette smoking– FHIT gene

• Air pollutions and ionizing radiation• Occupational associations asbestos, uranium( in miners), arsenical fumes, nickel, radon gas Oncogenes and suppressor genes ras,myc,bcl-2,c-erbB-2 p53,RB

Garfinkel L, Silverberg E. CA Cancer J Clin. 1991;41:137-145.

The risk of lung cancer after stoping smoking

Classifications

According to anatomy

Central lung cancer:

mostly is squamous and small cell carcinoma.

Peripheral lung cancer:

mostly is adenous.

According to histologic classification

--SCLC (15-20%)

--NSCLC (80-85%)

includes squamous 、 large cell, adenocarcinoma, adenosquamou

s .

SquamousSquamousNon-squamousNon-squamous

Clinical Manifestations Development and symptoms

– usually asymptomatic :early stage of the lung cancer

– Cough: invasion of small bronchi

– hemoptysis: erosion into vessels

– chest pain: invasion of the pleura, chest wall, or mediastinu

m

– dyspnea and fever :obstruct airway:

– pleural effusion :invasion of the pleura

Other symptoms: inappetence ,weight loss

Clinical Manifestations

Paraneoplasic syndromes

associated with brochogenic carcinoma often stem fro

m release of the following hormones:

    ① ADH (syndrome of inappropriate antidiuretic hormon

e reslease).

    ② ATCH (Cushing’s syndrome).

    ③ Parathormone or PGE (hypercalcemia).

    ④ Calcitionin (hypocalcemia).

Other paraneoplastic syndromes include myopathy, peri

pheral neuropathy, acanthosis nigricans, and hypertrop

hic pulmonary osteoarthropathy (clubbing of fingers).

Diagnosis of lung cancer requires:

A: detecting the tumor.

B: establish the cell type.

C: define the stage of the tumor.

determing cell type is the most important becau

se it influences the treatment !

Lung Cancer diagnosis

Physical examination Detect signs

Visualize and sample mediasturial lymph nodes

Detect position, size, number of tumors

Detect chest wall invasion mediastinallymphodenopathy distant metastases

Lymph node staging

Detect changes in hormone production, and hematological manifestations of lung cancer

Precise location of tumor obtain biopsy

Chest X-ray

CT scan

PET scan

Laboratory analysis

Bronchoscopy

Mediastinoscopy

FNA Cytology

NCCN Guidelines 2000

Physical examinations

Usually in early stage, most of the patients with lung cancer have

no positive physical findings.

General findings include abnormal percussion, breath sounds ch

anges, moist rales (when pneumonia happens)

Digital clubbing, superior vena cava syndrome, horner’s syndrom

e (unilaterally constricted pupil, enophthalmos, narrowed palpebr

al fissure and loss of sweating on the same side of the face.

Physical examinations

Endobronchial obstruction may result in a localiz

ed wheeze

Lobar collapse may result in an area of decreas

ed breath sounds and dullness to percussion.

Chest X-ray

It is the most important method to find lung ca

ncer. If a patient with chronic cough, sputum wit

h few blood, and dyspnea, lower fever he should

adopt a chest X-ray. The most frequent finding is

a mass in the lung field.

chest X-ray

Secondary manifestations include lobar collaps

e, pleural effusion, pneumonitis, elevation of the

hemidiaphragm, hilar and mediastinal adenopath

y, and erosion of ribs or vertebrae due to metasta

ses.

Lung Cancer X-ray

Lung Cancer CT scans

Lung cancer on CT

CT is the most useful in evaluating patients with pulmonar

y and mediastinal masses.

It is also useful for detecting multiple metastases.

CT can show a mass to be located in which lobe of lung fie

ld and the size of the mass. It also shows the nodule in the

mediastinum.

Sometimes, when a mass locate behind the heart, chest X-r

ay can`t detect it .CT can detect some secret sites of lung c

ancer.

Bronchoscopy

It is important both for determining if a tumor is

present and for obtaining tissue for histologic di

agnosis.

Usually, the combination of bronchial brushing a

nd forceps biopsy is positive 90 to 93 percent of t

he tumors located in proximal airway.

Transbronchial lung biopsy

It may be utilized when tumor located

in peripheral airway.

Transthoracic needle with guidance

by CT can be used to detect lesions

located near the chest wall

Lung Cancer diagnosis

Physical examination Detect signs

Visualize and sample mediasturial lymph nodes

Detect position, size, number of tumors

Detect chest wall invasion mediastinallymphodenopathy distant metastases

Lymph node staging

Detect changes in hormone production, and hematological manifestations of lung cancer

Precise location of tumor obtain biopsy

Chest X-ray

CT scan

PET scan

Laboratory analysis

Bronchoscopy

Mediastinoscopy

FNA Cytology

NCCN Guidelines 2000

2008 年 8 月 28 日

Bronchoscopy

Pathology

NSCLC: squamous cell carcinoma

2008 年 11 月 19 日

What should we do before treament ?

Histology classification

– SCLC

– NSCLC

Staging

Treatment based on Evidenced Medicine

Follow up plan

Staging of lung cancer

TNM stage: CTNM, PTNM

– T: Primary Tumor (TX, T0) T1, T2, T3, T4

– N: Nodal Involvement N0, N1, N2, N3

– M: Distant metastasis M0, M1

– The relationship of clinical stage and TNM stage

Staging of small cell lung cancer

– limited stage

– extensive stage.

Stage process

Chest CT (include adrenal gland )

Bone scan

Magnetic resounce imaging (MRI)

PET: positron emission tomogra

py

Bronchoscopic techniques

Video-assisted thoracic surgery

Lung Cancer stages

Stage 0

Stage IA

Stage IIB

Stage IIIB

Stage IV

Lymph nodes

Mainbronchus

Contralaterallymph node

Metastasisto distant

organs

Invasion ofchest wall

SCLC staging

Extensive:Tumor not confined tohemithorax of originDistant metastasis

PDQ Guidelines 2000

Limited:Tumor confined tohemithorax of originand/or themediastinum andsupraclavicular nodes

Stage grouping

T1 T2 T3 T4

N0 IA IB IIB IIIB

N1 IIA IIB IIIA IIIB

N2 IIIA IIIA IIIA IIIB

N3 IIIB IIIB IIIB IIIB

Mountain CF. Chest. 1997;111:1710-1717.

Mountain 1997

NSCLC stages - an overview

Disease

Early

Localized

Advanced

Stage

0IAIB

IIAIIB

IIIA

IIIB

IV

TNM

TIS N0 M0 (carcinoma in situ)T1 N0 M0T2 N0 M0

T1 N1 M0T2 N1 M0T3 N0 M0T3 N1 M0

T1-3 N2 M0

T4, Any N, M0Any T, N3, M0

Any T, Any N, M1

Treatment

Including:

A: Surgery

B: Chemotherapy

C: Radiation therapy

D: Targeted therapy

E: Some other therapy

immunologic therapy

chinese medicine

Surgery

Non-small cell lung cancer:

patients with stage I and II are considered

candidates for surgical resection, with stage III

cancer may be candidates for surgery.

Surgery

More than 90 percent of small cell lung cancer ha

s often metastasized at the time of diagnosis.

So these patients usually adopt radiation therapy

or chemotherapy before surgery.

We must measure pulmonary function before sur

gical therapy.

5-years survival rate after surgery

TNM stage 5 YS（ clinical stage）

5YS（ pathologic stage）

T1 N0 M0 n=687 61% n=511 67%

T2 N0 M0 n=1189 38% n=549 57%

T1 N1 M0 n=29 34% n=76 55%

T2 N1 M0 n=250 24% n=288 39%

T3 N0 M0 n=107 22% n=87 38%

T3 N1 M0 n=40 9% n=55 25%

T1-3 N2 M0 n=471 13% n=344 23%

T4 N0-2 M0 n=458 7% NA

Any T N3 M0 n=572 3% NA

Any T any N M1 n=1427 1% NA

Mountain CF ， Chest 1997.

Radiation therapy

Radiotherapy plays a major role in the

treatment of lung cancer.

It is divided into curative treatment and

palliative treatment.

It is of proven benefit in controlling bone

pain, spinal cord compression, superior vena

cava syndrome and bronchial obstruction.

Chemotherapy

Non-small cell lung cancer

•Adjuvant chem.

•Chem. for stage IV disease

Small-cell lung cancer

it is highly responsive to chemotherapy.

The newest evidence for Adjuvant chemotherapy

2007 update meta-analysis

2007’s ASCO

LACE meta-analysis ： OS

HR=0.8995%CI=0.82-0.96P=0.005

100

80

60

40

20

0 1 2 3 4 5 ≥6

Time From Randomization (years)

Chem.Control

总体

生存

(%

)

Pignon JP, et al. J Clin Oncol 2008; 26:3552-3559

LACE meta-analysis ： DFS

Time From Randomization (years)

100

80

60

40

20

0 1 2 3 4 5 ≥6

Chem.

Control

无病

生存

(%

)

HR=0.8495%CI=0.78-0.91P<0.001

Pignon JP, et al. J Clin Oncol 2008; 26:3552-3559.

LACE meta-analysis ： Survival according to type of death.

Decreases lung cancer–related death (HR=0.83, 95%CI=0.76-0.90, P<0.001)

Increase noncancer-related death (HR=1.36, 95%CI=1.10-1.69, P=0.004)

– 主要出现在前 6 个月 (HR=2.41, 95%CI=1.64-3.55, P<0.001)

100

80

60

40

20

0 1 2 3 4 5 ≥6Time From Randomization (years)

Sur

viva

l (%

) Chem. (noncancer-related death )

Cont (noncancer-related death )化疗 ( 癌症相关死亡 )不化疗 ( 癌症相关死亡 )

Pignon JP, et al. J Clin Oncol 2008; 26:3552-3559.[ 临床肿瘤学杂志中文版 2009; 3(1): 10-17.]

IIIA-N2:Overall survival at 5 years withchemotherapy improved by 12%

31.1% vs 19.1%MS:33m vs 24m

Questions ：

Why the benefits of adjuvant chemotherapy is limited ？ The direction of our following research:

- Do we continue to adopt chemotherapy to all patients just for

the improved 6%-12% total survival rate ？

- Or can we pick out those patients who is sensitive to adjuva

nt chemotherapy ,then the other patients can avoid the unne

cessary toxicity of chemotherapy.

Chemotherapy for advanced stage of lung cancer

BMJ, 1995

NSCLC Meta-analyses

NSCLC Meta-analyses Collaborative Group. JCO 2008; 26:4617-25.[ 临床肿瘤学杂志中文版 2009; 3(2): 45.]

16 项 RCT 2714 例患者 IPD 资料

HR=0.7795%CI=0.71-0.83P≤0.00011YS: 29% vs. 20%

1.0

0.8

0.6

0.4

0.2

0 3 6 9 12 15 18 21 24

时间 ( 月 )

概率

事件数 患者总数

1240

1293

1315

1399

SC+CT

仅 SC

First-line chemotherapy options in NSCLC (E1594): comparable efficacy with platinum doublets

Schiller, et al. NEJM 2002

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25 30Time (months)

Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxel

Pro

bab

ilit

y o

f su

rviv

al

Therapeutic plateau: overall survival <12 months

Overall Survival by Histology

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pemetrexed 15.5 mos Pemetrexed 9.9 mos

Placebo 10.3 mos

Placebo 10.8 mos

Non-squamous (n=481)Non-squamous (n=481) Squamous (n=182)Squamous (n=182)

HR=0.70 (95% CI: 0.56-0.88) P =0.002

HR=1.07 (95% CI: 0.49–0.73) P =0.678

Su

rviv

al P

rob

ab

ilit

y

Time (months) Time (months)

2009 ASCO

Targeted therapy

Such as epidermal growth factor rece

ptor inhibitors, angiogenesis inhibito

rs and apoptosis inducers ects.

晚期非小细胞肺癌 front-line 治疗策略

EGFR 突变者

30 ％

TKIMST ： 20 － 24 月

EGFR 野生者70 ％

腺癌35 ％

鳞癌35 ％

第三代＋铂类10 月

维持治疗13 月

培美曲塞＋铂类：11.8 月

西妥昔单抗或贝伐单抗12 － 16 月

+

ERCC1BRCA1: 选择铂类药物

RRMI ：选择 Gemcitabine

TS ：选择 Pemetrexed

Treatment of Lung Cancer

NSCLC

– Ⅰ, ,N0N1 of a stage: surgery + adjuvant chemotherapyⅡ Ⅲ for those patients who is N0-1 and had radical resection of lung cancer, adjuvant rad

iotherapy is not only inefficacy but do harm to patients.

– N2 of A stage: neoadjuvant chemotherapyⅢ– ⅢB stage: chemotherapy + radiotherapy (surgery when it is

needed.)

– Ⅳstage: chemotherapy and targeted therapy.

SCLC

– limited stage: chemotherapy + surgery / radiotherapy -- chemotherapy

– extensive stage : chiefly chemotherapy

致谢胸科全体家人！