Disorders of the Pleura, Mediastinum, Diaphragm, Chest Wall and

Lung Cancer

Maximino G. Bello III, MD, FPCP, FPSMOExecutive Secretary, Cancer Institute

Take note!

• All exams are Harrison based• Rapid advances in oncology, new findings may

supersede Harrison– Take note if I stressed a particular fact or

statement

• Topics not discussed in today's lecture does NOT mean it would not be included in exams

Pleural diseases

• Pleural effusion– Pleural space from the capillaries in the parietal

pleura removed via lymphatics– Interstitial spaces from the lung via visceral pleura– Peritoneal cavity via diaphragm

• Pneumothorax– Air in the pleural space

Diagnostic approach

• Transudate: systemic factors• Exudate: local factors

• Light’s Criteria– Pleural fluid CHON /serum CHON >0.5– Pleural fluid LDH/serum LDH >0.6– Pleural fluid LDH more than 2/3 normal upper

limit for serum

Light’s Criteria misidentifies ≈25% of transudates as exudates

Light’s Criteria

Transudate• CHF• Cirrhosis• PE• Nephrotic syndrome• Peritoneal dialysis• SVC• Myxedema

Exudate• Infectious• Neoplastic • GI disease• Collagen vascular dse• P CABG• etc

Parapneumonic effusions

• Associated with bacterial infection, lung abscess or bronchiectasis

• Empyema: grossly purulent effusion– Condensed milk

• “significant effusion”– Lateral decubitus view shows 10mm layering of

fluid drainage of effusion

Drainage of effusion

• Need for a more invasive procedure (other than thoracentesis)– Loculated pleural effusion– Pleural fluid pH <7.20– Pleural fluid glucose < 3.3mmol/L– + gram stain or culture of the pleural fluid– empyema

Effusion secondary to malignancy

• Lung and breast carcinoma and lymphoma– 75% of malignant effusion

• Dyspnea is NOT proportionate to the amount of effusion– Lung metastasis

• Treatment– Drainage of the fluid sclerosing agent

treatment of the malignancy

Effusion secondary to mesothelioma

• Primary tumor of the mesothelial cells– Line the pleural cavity

• Significant asbestos exposure• Imaging:

– Effusion, thick pleura, collapse hemithorax• Treatment:

– Surgery– pretexemed

Pneumothorax

• Primary spontaneous pneumothorax– Rupture of apical bleb– It typically occurs in tall, thin boys and men

between the ages of 10 and 30 years– rarely occurs in persons over the age of 40.– Appears almost exclusively in smokers– ½ will have recurrences

• Treatment: aspiration

Pneumothorax

• Secondary spontaneous pneumothorax– COPD– More fatal lesser physiologic reserve

• Treatment– Tube thoracostomy

Pneumothorax

• Traumatic pneumothorax– Penetrating– Non penetrating injuries

• Tension pneumothorax– Medical emergency– During resuscitation

• Cyanosis, hypotension

Diaphragmatic Hernia

Most Diaphragmatic Hernia’s are detected in childhood.

Rare in adults!

Most Diaphragmatic Hernia’s are detected in childhood.

Rare in adults!

Diaphragmatic Hernia

Congenital diaphragmatic hernia • Bochdalek:

– More common– postero-lateral diaphragmatic hernia – majority of Bochdalek hernias (80-85%) occur on

the left side • Morgagni

– Less common– Anterior, right

Mediastinum

• Occupies the central portion of the thoracic cavity

• Boundaries:

1. Lateral- pleural cavity

2. Superior- thoracic inlet

3. Inferior- diaphragm

4. Anterior- sternum

5. Posterior- chest wall

De Vita, et al .Principles & Practice of Oncology 8th ed

De Vita, et al .Principles & Practice of Oncology 8th ed

anterioranterior

posteriorposterior

middlemiddle

Mediastinal tumors:

Feature Thymoma Lymphoma Germ cell tumor

Mesenchymal

Incidence - most common anterior Mediastinal neoplasm

- 20-25% of Mediastinal tumors

- equal in male and female

- ages 30 - 50.

-10-20 % of primary Mediastinal masses

- 2nd most common anterior Mediastinalmass

- Most Mediastinal lymphomas areseen in the anterosuperior mediastinum.

-15% of anterior Mediastinal tumors inadults.(24% in children)

- Rarely, they are found in the posteriormediastinum

- 6% of Mediastinal tumors.

- More than 50% are malignant

Mediastinal tumors:

Feature Thymoma Lymphoma Germ cell tumor

Mesenchymal

Radiographic findings:

•X-ray

-smooth mass in the upper half of the chest.

-Overlying the superior portion of the cardiac shadow.

-The mass projects predominantly into one of the hemithoraces.

- Lobulated with enlargement of hilar and media- stinal lymph nodes.

- well defined mass occasionally containing calcifications.

- Mediastinal widening on CXR

Mediastinal tumors:

Feature Thymoma Lymphoma Germ cell tumor

Mesenchymal

Radiographic findings:

•CT scan

- demonstrates uniform enhancement

- conglomerate of lymph nodes

- discrete enlarged LN with cystic degeneration

-lobulated, asymmetrical, homogenous tumors

- with/ without cystic components

-can determine components of tumor (fat, soft tissue)

- defines the relation of tumor to adjacent tissues.

Mediastinal tumors:

Feature Thymoma Lymphoma Germ cell tumor

Mesenchymal

Signs and symptoms

- 50% asymptomatic

- symptoms due to myasthenia in 35% of patients

- others with substernal pains, dyspnea, cough

- Invasive thymoma cause local compression /svc syndrome

-Majority of are symptomatic at diagnosis.

- Common: fever, weight loss, night sweats

- Compression symptoms: pain, dyspnea, stridor, or superior vena cava syndrome

- Associated pleural effusions are common

-malignant tumors are symptomatic in 85% of patients:-chest pain, -hemoptysis, -cough, -fever, -weight loss.

- Superior vena caval syndrome is occasionally seen

- Compressive sign and symptoms based on adjacent tissues involved.

Lung Cancer

Made Ridiculously simple!

MORTALITY: TEN LEADING (10) LEADING CAUSES Number and rate/100,000 Population Philippines

5-Year Average (2000-2004) & 2005

5 Year Average (2000-2004)

2005* Cause

Number Rate No. Rate 1. Diseases of the Heart 66,412 83.3 77,060 90.4 2. Diseases of the Vascular system 50,886 63.9 54,372 63.8 3. Malignant Neoplasm 38,578 48.4 41,697 48.9 4. Pneumonia 32,989 41.4 36,510 42.8 5. Accidents 33,455 42.0 33,327 39.1 6. Tuberculosis, all forms 27,211 34.2 26,588 31.2 7. Chronic lower respiratory diseases 18,015 22.6 20,951 24.6 8.Diabetes Mellitus 13,584 17.0 18,441 21.6 9. Certain conditions originating in the perinatal period

14,477 18.2 12,368 14.5

10. Nephritis, nephrotic syndrome and nephrosis

9.166 11.5 11,056 3.6

Area Nutritional

Deficiencies

Chronic Lower Resp. Dis.

Pneumonia Cerebro Vascular Diseases

Disorder of the Heart

Transport Accidents

Malignant Neoplasm

of Lung

Philippines 2,607 15,904 32,637 21,705 60,417 5,680 6,395 NCR 220 2,056 4,344 2,840 11,799 653 1,194 CAR 19 167 494 319 642 98 103 Region 1 151 1,309 3,056 2,029 4,345 484 530 Region 2 54 850 1,667 658 1,921 326 266 Region 3 251 2,374 2,652 3,405 7,638 528 966 Region 4 397 2,860 4,060 3,669 10,101 816 1,255 Region 5 228 1,079 2,706 1,359 4,107 366 166 Region 6 369 1,584 4,724 2,057 4,660 438 557 Region 7 264 1,061 2,932 1,416 4,643 335 447 Region 8 155 620 1,978 835 2,764 238 134 Region 9 90 415 671 535 1,404 163 112 Region 10 129 3 59 918 503 1,508 269 150 Region 11 153 587 1,356 1,181 2,727 481 307 Region 12 70 288 416 397 823 203 102 ARMM 9 46 54 48 167 108 12 CARAGA 48 246 609 450 1,141 167 90

Foreign Country

0 3 0 4 27 7 4

Change in the US Death Rates* by Cause, 1950 & 2005

* Age-adjusted to 2000 US standard population.Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.2005 Mortality Data: US Mortality Data 2005, NCHS, Centers for Disease Control and Prevention, 2008.

20.3

180.7

48.1

586.8

193.9

46.6

183.8211.1

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Influenza &Pneumonia

Cancer

1950

2005

Rate Per 100,000

Lung Cancer1975-1977: 13%1984-1986: 13%1996-2003: 16%

World Incidence1 World Mortality1

Lung Cancer

1.5 Mio 90%1. Lung Cancer: Kamangar et al. J Clin Oncol. 2006;24:2137-

2150.

Worldwide Incidence and Mortality for Lung Cancer

• Lung cancer is the most common cancer in the world

• Smoking is the most important risk factor

Host Susecptibility

1. Family Hx

2. Inherited cancer syndrome

3. P53 mutation

4. EGFR mutation

5. Retinoblastoma

6. SNP variation at 15q24–15q25.1

7. susceptibility and risk also increase with reduced DNA repair capacity ERCC1

Host Susecptibility

1. Family Hx

2. Inherited cancer syndrome

3. P53 mutation

4. EGFR mutation

5. Retinoblastoma

6. SNP variation at 15q24–15q25.1

7. susceptibility and risk also increase with reduced DNA repair capacity ERCC1

Clonal Evolution

Changes in certain genes occur in nonmalignant lung tissue of smokers and patients with lung cancer

Early events in the development of NSCLCA include loss of heterozygosity at chromosomal region 3p21.3 , 3p14.2, 9p21 (p16), and 17p13 (p53)

Clonal Evolution

Changes in certain genes occur in nonmalignant lung tissue of smokers and patients with lung cancer

Early events in the development of NSCLCA include loss of heterozygosity at chromosomal region 3p21.3 , 3p14.2, 9p21 (p16), and 17p13 (p53)

Lung Cancer: HistologyThe Clinical Importance

Histological types

NSCLC 80%

Non Small Cell Lung Cancer

SCLC 20 %

Small Cell Lung Cancer

10 %Large Cell Ca.

50 %Adeno-ca.

40 %Squamous-ca.

NSCLC Histological Subtype

non-squamous: 60%

squamous: 40%

Grouping bet. Squamous vs non squamous is an oncologic/clinical classification

Clinical Classification are always clinically useful

Lung Cancer

• NSCLCA• AJCC staging (I to IV)

• Less chemo sensitive• Less radio sensitive• Established role of

surgery

• Small Cell Lung Cancer• Veterans Affairs Staging

(limited vs. extensive)• More chemo sensitive• More radio sensitive• No role for surgery

The difference

• Squamous• Harder to treat• Not susceptible to TKI• Stronger smoking

association

• Males

• TX: gemcitabine

• Non squamous• More “easier to treat”• Sensitive to TKI• Lesser smoking

association: adenocarcinoma

• Females: adenocarcinoma• TX:

– TKI’s bevasizumab & pretexemed

StagingStaging

•

Surgery + chemotherapy

Or chemoRT

Surgery + adjuvant chemo

Surgery Chemoradiotherapy

ChemotherapyChemotherapy

NSCLC treatment

Stage IIIB/IVStage I Stage II Stage IIIA

Platinum = Cisplatin or Carboplatin

1st line

2nd line pemetrexed

platinum + docetaxel

platinum + vinorelbine

docetaxel

3rd line

erlotinib

platinum + paclitaxel

platinum + gemcitabine

gefitinib(Asia)

erlotinib gefitinib(Asia)

The majority

ERBITUX

NSCLC Tumor Stages: IIIB and IV

Stage IIIB Stage IV

Clinical Manifestations

• Tumors in the large airways- cough, wheezing, hemoptysis

• With atelectasis and with pleural space involvement

- pleuritic chest pain• Tumors invading the chest wall

- stabbing or burning radicular pain

Methods to Establish Tissue Diagnosis

• Sputum Cytology-sensitivity is 65% (22%- 98%) -molecular techniques (p53, A2/B1expression,k-ras)

• Percutaneous Fine-Needle Aspiration-fluoroscopic or CT-guided techniques-The positive yield exceeds 95% (even iflesions are less than 1 cm in diameter)

Methods to Establish Tissue Diagnosis

• Bronchoscopy• minimal morbidity,safe• visualization of the tracheobronchial tree to the

2nd or 3rd segmental divisions • cytologic or histologic specimens can be obtained

– -diagnostic yield of FOB with cytologic

– brushings or biopsy of visible lesionsexceeds 90%

Methods to Establish Tissue Diagnosis

• Mediastinoscopy, Mediastinotomy, and Endoscopic Ultrasound-Fine-Needle Aspiration

• most accurate technique to assess paratracheal, proximal peribronchial, and subcarinal lymph nodes in lung cancer patients

• indicated in any patient suspected of having locally advanced disease

• mediastinoscopy before surgical intervention for lung cancer has evolved during recent years

Methods to Establish Tissue Diagnosis

• Thoracentesis• identify inoperable, pleural disease (T4)• unless malignant cells are identified, a bloody pleural effusion

should be considered traumatic• diagnosis of cancer in can be established in 70% of malignant

effusions by thoracentesis

• Thoracoscopy• Video-assisted thoracoscopy is frequently used for the diagnosis,

staging, and resection of lung cancer• valuable for evaluation and palliation of suspected pleural disease,

particularly when thoracentesis has been nondiagnostic

Methods to Establish Tissue Diagnosis

• Thoracotomy• diagnosis often can be obtained via multiple FNAs with

immediate cytologic analysis, or incisional (or preferably excisional) biopsy with frozen section

• intraoperative biopsies of hilar and mediastinal lymph nodes

• resection of the primary lesion and complete mediastinal lymph node dissection

Taxotere 75 mg/m2 over 1 hr day 1Cisplatin 75 mg/m2 day 1q 3 wks

Vinorelbine 25 mg/m2 /wkCisplatin 100 mg/m2 day 1q 4 wks

Paclitaxel 225 mg/m2 over 3 hrs day 1Carboplatin AUC 6 day 1q 3 wks

Gemcitabine 1,000 mg/m2 days 1, 8, 15Cisplatin 100 mg/m2 day 1 q 4 wks

ECOG 1594 (n = 1,207)

SWOG 9509 (n = 408)

Paclitaxel 225 mg/m2 over 3 hrs day 1Carboplatin AUC 6 day 1q 3 wks

Paclitaxel 135 mg/m2 over 24 hrs day 1Cisplatin 75 mg/m2 day 2 q 3 wks

Comparison of First-Line Doublet Trials: Treatments

TAX 326 (n = 1,218)

Taxotere 75 mg/m2 over 1 hr day 1Cisplatin 75 mg/m2 day 1q 3 wks

Vinorelbine 25 mg/m2 days 1, 8, 15, 22Cisplatin 100 mg/m2 day 1q 4 wks

Taxotere 75 mg/m2 over 1 hr day 1Carboplatin AUC 6 day 1q 3 wks

Vinorelbine 25 mg/m2 /wk 12 wks, then every other wkCisplatin 100 mg/m2 day 1q 4 wks

ILCP (n = 612)

Paclitaxel 225 mg/m2 over 3 hrs day 1Carboplatin AUC 6 day 1q 3 wks

Gemcitabine 1,250 mg/m2 days 1, 8Cisplatin 75 mg/m2 day 2q 3 wks

Comparison of First-Line Doublet Trials: Treatments

Comparison of First-Line Doublet Trials:Median Survival Time

0

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Tax 326 ILCP ECOG 1594 SWOG 9509

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1. Pirker et al, JCO 2008; 18S Abstract 3; 2. Scagliotti et al. JTO 2007; 2, 8 (Suppl 4), 308 (Abstr. PRS-03); 3. Fosella et al. JCO 2003; 21: 3016-24; 4. Schiller et al., NEJM 2002; 346: 92–98; 5. Bonomi et al. JCO 2000; 18: 623-31; 6. Kelly et al. JCO 2001; 19:3210–3218; 7. Scagliotti et al. JCO 2002; 21: 4285-4291; 8. Alberola et al. JCO 2003; 9. Wozniak et al. JCO 1998; 16: 2459-65; 10. Cardenal et al. JCO 1999; 17: 12-18; 11. Roszkowiski et al. Lung Cancer 2000; 27: 145-157; 12. Cullen et al. JCO 1999; 17: 3188-94.

Achievements in NSCLCfor patients across all histologies

30 years: step by step increase in median OS ranged from 1-2 months

0 1 2 3 4 5 6 7 8 9 10 11 12

BSC

Cisplatin Monotherapy

Platinum/Etoposide

Platinum/Vinorelbine

Platinum/Gemcitabine

Platinum/Paclitaxel

Platinum/Docetaxel

Cisplatin/Pemetrexed

Chemotherapy + Erbitux

Median OS

Months

1950‘s

1970‘s

1990‘s

1998-

1995

2007

2008

3rd

Ge

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C

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11,12

5, 10

9, 8

9, 3, 6, 7

2, 8, 4, 7

4, 5, 6, 7

3, 4

2

1

BSC2–5 months

Single-agent platinum6–8 months

Platinum-based doublets8–10 months

Median survival (months)

Schiller, et al. NEJM 2002Sandler, et al. NEJM 2006

0 2 4 6 8 10 1214

2000s

1990s

1980s

1970s

Platinum-based doublet + Avastin12.3 months

Longest overall survival achieved in non-squamous metastatic NSCLC patients

with Avastin

BSC = best supportive care

General Conclution about NSCLCA Chemotherapy

• “platinum based doublet”– Platinum: cisplatin or carboplatin

• All are equally effective• None is superior over the other• Toxicity is different• Addition of a biologic agent improves OS

– Cetuximab– bevasizumab

Thank you!

Questions??