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GOOD MORNING! GOOD MORNING! CASE PRESENTATION CASE PRESENTATION & DISCUSSION ON & DISCUSSION ON DIFFICULTY OF DIFFICULTY OF BREATHING BREATHING By: Jeffy G. Guerra, M.D. By: Jeffy G. Guerra, M.D. First year Resident First year Resident Department of Surgery Department of Surgery Ospital ng Maynila Medical Center Ospital ng Maynila Medical Center

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Page 1: CASE PRESENTATION & DISCUSSION ON DIFFICULTY OF …members.tripod.com/j_guerra_gsj/lung_ca_powerpoint.pdf · CASE PRESENTATION & DISCUSSION ON DIFFICULTY OF BREATHING By: Jeffy G

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GOOD MORNING!GOOD MORNING!

CASE PRESENTATION CASE PRESENTATION & DISCUSSION ON & DISCUSSION ON

DIFFICULTY OF DIFFICULTY OF BREATHINGBREATHINGBy: Jeffy G. Guerra, M.D.By: Jeffy G. Guerra, M.D.

First year ResidentFirst year ResidentDepartment of SurgeryDepartment of Surgery

Ospital ng Maynila Medical CenterOspital ng Maynila Medical Center

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General DataGeneral Data

RVHRVH

65 Male65 Male

Chief complaintChief complaintDifficulty of breathingDifficulty of breathing

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History of Present IllnessHistory of Present Illness6 months 6 months cough, generalized body weaknesscough, generalized body weakness

((--) fever, () fever, (--) DOB, () DOB, (--) chills, ) chills, ((--) night sweats) night sweats(+) consult, anti(+) consult, anti--tussivetussiveafforded temporary relief of afforded temporary relief of SSxSSx

2 months 2 months (+) (+) URTI, complicated by URTI, complicated by hemoptysishemoptysis, wt. Loss (10 lbs), wt. Loss (10 lbs)progressive DOBprogressive DOBconsult CXR done (?)consult CXR done (?)lost to followlost to follow--upup

1 week PTA1 week PTA persistence of persistence of SSxSSxworsening shortness of worsening shortness of breathbreath

ConsultConsult

AdmissionAdmission

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Family Medical HistoryFamily Medical HistoryLung Cancer (brother)Lung Cancer (brother)

PSHxPSHx35 pack years smoker35 pack years smoker

Physical ExaminationPhysical ExaminationGeneral Survey: General Survey:

��Conscious, coherent, ambulatoryConscious, coherent, ambulatory��not in not in cardiorespiratorycardiorespiratory distressdistress�� cachecticcachectic, appears older than his , appears older than his

chronological age chronological age

BP110/70mmhgBP110/70mmhg HR 81pmHR 81pm RR 25cpm T 37.1CRR 25cpm T 37.1C�� HEENT: pink HEENT: pink palpebral palpebral conjunctivae, conjunctivae,

supraclavicularsupraclavicular LN, bilateral, no NAD, no TPC, LN, bilateral, no NAD, no TPC, supple necksupple neck

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�� Chest/lung: SCE, no lagging, decreased Chest/lung: SCE, no lagging, decreased breath sounds RLLF, no wheezes, no breath sounds RLLF, no wheezes, no stridorstridor

�� Heart: Heart: Adynamic precordiumAdynamic precordium, normal , normal rate, regular rhythm, no murmur rate, regular rhythm, no murmur

�� Abdomen: flat, Abdomen: flat, normoactivenormoactive bowel bowel sounds, soft, non tender, sounds, soft, non tender, no no organomegalyorganomegaly

�� Extremities: grossly normal, full equal Extremities: grossly normal, full equal pulses, no clubbingpulses, no clubbing

Salient featuresSalient features�� 65 Male65 Male�� Difficulty of breathingDifficulty of breathing�� CoughCough�� HemoptysisHemoptysis�� Weight lossWeight loss�� Generalized body weaknessGeneralized body weakness�� Decreased breath sounds, RLLFDecreased breath sounds, RLLF�� Supraclavicular Supraclavicular LN, bilateralLN, bilateral�� Familial history of Lung Ca, significant smoking Familial history of Lung Ca, significant smoking hxhx

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Difficulty of breathing

cardiac pulmonary others

Circulatory

chemical

central

infectious Non-infectious

URTI LRTI PTB

sinusitis

pharyngitis

pneumonia

bronchitis

Benign Malignant

Obstructive Restrictive

COPD Neuromuscular disease and

chest wall abnemphysema

asthma

∅ √

Primary

Metastatic

MedicalMedical40%40%

COPD COPD probably probably

EmphysemaEmphysema

MedicalMedical60%60%Pulmonary Pulmonary TuberculosisTuberculosis

TreatmentTreatmentCertaintyCertaintyImpressionImpression

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ParaclinicalParaclinical Diagnostic Diagnostic ProcedureProcedure

Do I need Do I need paraclinicalparaclinical procedure?procedure?

Yes. To increase certainty of my diagnosisYes. To increase certainty of my diagnosis

AvailableAvailablePhP PhP 150150

NoneNoneSensitivitySensitivity--80%80%SpecificitySpecificity--90%90%

Sputum Sputum AFBAFB

AvailableAvailablePhP PhP 100100

Radiation Radiation exposureexposure

SensitivitySensitivity--90%90%SpecificitySpecificity--95%95%

CXRCXR--PAPAAVAILABILITYAVAILABILITYCOSTCOSTRISKRISKBENEFITBENEFITOPTIONSOPTIONS

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A PA chest xA PA chest x--ray showing a large mass in the lower right lung. Note ray showing a large mass in the lower right lung. Note that the trachea has been shifted to right (toward the tumor). that the trachea has been shifted to right (toward the tumor).

Medical/SurgicalMedical/Surgical20%20%MetastaticMetastatic

CACA

Medical/SurgicalMedical/Surgical80%80%PrimaryPrimaryCACA

TreatmentTreatmentCertaintyCertaintyImpressionImpression

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BenignMalignant

PULMONARY MASS

DOB

Granuloma

Hamartoma

Others

Primary Metastatic

Do I need further paraclinical procedures?

YES. Primarily to determine treatment options

1. Determine resectability

2. Staging

3. Tissue Diagnosis

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DIAGNOSIS OF SUSPECTED LUNG CADIAGNOSIS OF SUSPECTED LUNG CA

Imaging Studies

CENTRAL TUMOR

PERIPHERAL TUMOR

Options:

1. PFNAB CT guided

2. FiberopticBronchoscopy

3. VATS

4. Thoracotomy

Options:

1. Sputum Cytology

2. FiberopticBronchoscopy

3. PFNAB

4. Thoracotomy

AVAILABILITYAVAILABILITYCOSTCOSTRISKRISKBENEFITSBENEFITSOPTIONSOPTIONS

PhP PhP 6K6K

Negligible Negligible radiationradiationMRIMRI

PhP PhP 8K8K

Bleeding <5%, Bleeding <5%, respi respi distress distress

<10%, <10%, pneumopneumo

thorax 10%thorax 10%

Fiber Optic Fiber Optic BronchoscopyBronchoscopy

PhP PhP 1010--15K15K

PhP PhP 7K7K

Tissue Tissue DXDX

PET PET ScanScan

CT Scan CT Scan with PFNABwith PFNAB

Radiation Radiation contrastcontrast

Radn Radn ex, ex, pneumopneumothorax thorax <10%<10%, ,

hemmoragehemmorage<5%<5%, , embulus embulus

<1%<1%

StagingStagingResectabilityResectability

√ √Sensitivity-85%

Specificity-90%

Sen-85%

Spe-92%Sen-94%

Spe-98%

√ √Sensitivity-80%

Specificity-92%

√ √Sen-85%

Spe-90% �

√ √ √Sensitivity-85%

Specificity-92%

Sen-85%

Spe-92%

√Sensitivity-80%

Specificity-90%

√Sen-80%

Spe-90%

√Sen-94%

Spe-98%

√ √

√ √ √

√ √ √ √

√ √

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Paraclinical Paraclinical Procedure of Procedure of ChoiceChoice

CT with PFNABCT with PFNAB

A CT scan of the lungs showing the large ring enhancing tumor with central necrosis, which is adherent to the chest wall.

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A mediastinal window of the tumor, showing subcarinalinvolvement.

The alcohol-fixed, Papanicolaou-stained smears of the lung aspirate contain cohesive groups of cytologically malignant cells with increased nuclear:cytoplasmic ratios, nuclear pleomorphism, and prominent nucleoli. The vague acinar arrangement of the cell groups and absence of anysquamous features is suggestive of an adenocarcinoma. A mucin stain orimmunohistochemistry could be performed on additional unstained smears or cell block material to confirm the diagnosis.

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Pretreatment diagnosisPretreatment diagnosis

Poorly differentiated Poorly differentiated adenocarcinomaadenocarcinoma, , Stage IIIB (T4N3MO)Stage IIIB (T4N3MO)

PalliativePalliativeTreatment GoalTreatment Goal

AVAILABILITYAVAILABILITYCOSTCOSTRISKRISKBENEFITSBENEFITSOPTIONSOPTIONS

++++++PneumonitisPneumonitis, ,

esophagitisesophagitis,skin ,skin sensitivitiessensitivities5.05.04.04.063.063.0RadiotherapyRadiotherapy

++++++

++++

45.045.020.020.0

39.139.1

1-year survival

(%)

++++++

++++++

Chemoradio Chemoradio AA.. ConcurrentConcurrentB. SequentialB. Sequential

ChemotherapyChemotherapy

combinationcombination15.015.013.313.3

84.084.066.066.0

Bone marrow Bone marrow sup, sup,

hypersensitivity, hypersensitivity, nausea vomitingnausea vomiting

10.010.032.132.1

Median survival (months)

Tumour response

(%)

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Final diagnosisFinal diagnosisPoorly differentiated Adenocarcinoma, Stage IIIB (T4N3M0)

Prevention Prevention amd amd HealthHealthAnticipate complications1. Chemotherapetic effects2. Radiotherapeutic effects

Improving quality of life1. Symptom management2. Pain control3. Self enjoyment

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Lung CancerLung Cancer

EpidemiologyEpidemiology, diagnosis and treatment, diagnosis and treatment

Estimated new cases (incidence) and deaths (mortality) worldwide for the 15 most common cancers, 2000

0 200 400 600 800 1000 1200

IncidenceMortality

Thousands

LungBreastColon/rectumStomachLiverProstateCervix uteriOesophagusBladderNon-Hodgkin’s lymphomaOral cavityLeukaemiaPancreasOvaryKidney

Males Females

1200 1000 800 600 400 200

Parkin et al 2001

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Major presenting symptoms of Major presenting symptoms of lung cancerlung cancer

Baseline major presenting symptoms

0

20

40

60

80

100

HaemoptysisLoss of appetite

PainCoughDyspnoea

Patients(%)

Hollen et al 1999

Syndromes/Symptoms secondary to regional Syndromes/Symptoms secondary to regional metastases:metastases:�� Esophageal compression Esophageal compression �� dysphagiadysphagia�� Laryngeal nerve paralysis Laryngeal nerve paralysis �� hoarsenesshoarseness�� Symptomatic nerve paralysis Symptomatic nerve paralysis �� Horner’s syndromeHorner’s syndrome�� Cervical/thoracic nerve invasion Cervical/thoracic nerve invasion �� Pancoast syndromePancoast syndrome�� Lymphatic obstruction Lymphatic obstruction �� pleural effusionpleural effusion�� Vascular obstruction Vascular obstruction �� SVC syndromeSVC syndrome�� Pericardial/cardiac extension Pericardial/cardiac extension �� effusion, effusion, tamponadetamponade

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Lung Cancer: Metastatic SitesLung Cancer: Metastatic Sites

�� Lymph nodesLymph nodes�� BrainBrain�� BonesBones�� LiverLiver�� Lung/pleuraLung/pleura�� Adrenal glandAdrenal gland

Squamous-cell carcinoma (~30%)• Most commonly found in men

• Closely correlated with smoking (dose dependent)

• Tends to spread locally

• More readily detected in sputum

• Highly expressed genes encoding proteins with detoxification/anti-oxidant properties

Types of lung cancer: non-small-cell lung cancer (NSCLC)

Adenocarcinoma (30-50%)• Most common type of lung cancer

in women and non-smokers• Lesions are usually peripheral• Worldwide incidence increasing• Highly expressed genes encoding

small-airway-associated andimmunologically related proteins

• K-ras mutations frequently reported • Bronchoalveolar carcinoma is a

subtype

Large-cell carcinoma (10-25%)• Very primitive, undifferentiated cells

• Lesions are usually peripheral

• High tendency to metastasise

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Types of lung cancer: smallTypes of lung cancer: small--cell cell lung cancer (SCLC)lung cancer (SCLC)

�� Approximately 20% of all lung cancersApproximately 20% of all lung cancers�� Cellular classificationCellular classification

�� smallsmall--cell carcinomacell carcinoma�� mixed smallmixed small--cell/largecell/large--cell carcinomacell carcinoma�� combined smallcombined small--cell carcinomacell carcinoma

�� Occurs almost exclusively in smokers and is Occurs almost exclusively in smokers and is more prevalent in women than menmore prevalent in women than men

�� Lesions most commonly originate in central part of Lesions most commonly originate in central part of chestchest

�� Tendency to disseminate earlyTendency to disseminate early�� InitiallyInitially chemosensitivechemosensitive, becoming resistant, becoming resistant

Lung cancer diagnosis/stagingLung cancer diagnosis/stagingPhysical examination Detect signs

Visualise and sample mediastinal lymph nodes

Detect position, size, number of tumours

Detect chest wall invasion, mediastinal lymphodenopathy, distant metastases

Lymph node staging

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

Precise location of tumour, obtain biopsy

Chest X-ray

CT scan

PET scan

Laboratory analysis

Bronchoscopy

Mediastinoscopy

FNA Cytology

NCCN Guidelines 2000FNA, fine-needle aspirate; CT, computed tomography;PET, positron emission tomography

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Molecular diagnosisMolecular diagnosis

�� GoalGoal�� to identify distinguishing molecular to identify distinguishing molecular

characteristics of tumours in order to characteristics of tumours in order to develop new diagnostic and therapeutic develop new diagnostic and therapeutic approaches and predict responseapproaches and predict response

�� ProgressProgress�� new molecular biomarkers and new molecular biomarkers and

technologies are being identified and technologies are being identified and evaluated but are not yet routinely used in evaluated but are not yet routinely used in thethe clinicclinic

Gandara et al 2001;Mao 2001; Nacht et al 2001; Niklinski et al 2001

Molecular abnormalities in lung cancer

Commonly observedgenetic changes

Tobaccocarcinogen

Inappropriate response to external signals

Loss of cell cycle controlLoss of apoptosis pathwayLoss of contact inhibition

Ability to metastasiseAngiogenesis

ImmortalityAutocrine growth loops

Atypical alveolarhyperplasia

Premalignantadenomas

Lung cancer

Carcinoma in situDysplasiaBronchial

metaplasia

Normal epithelium

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NSCLC stagesLymph nodes

Main bronchus

Contralateral lymph node

Metastasis to distant

organs

Invasion of chest wall

Stage IV

Stage 0Stage IAStage IIBStage IIIB

5-year survival by TNM status in NSCLC55--year survival by TNM status in NSCLCyear survival by TNM status in NSCLC

Stage

IA

IB

IIA

IIB

IIIA

IIIB

IV

TNM classification

T1N0M0

T2N0M0

T1N1M0

T2N1M0 or T3N0M0

T1-3N2M0 orT3N1M0

T4NanyM0 or TanyN3M0

TanyNanyM1

5-year survival (%)

61

38

34

24

13

5

1

Mountain 1997

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NSCLC: treatment options overview

PDQ Guidelines 2000

Stage I• Lobectomy or segment/wedge

resection• Curative radiotherapy if surgery is

contraindicated• Adjuvant chemotherapy• Adjuvant radiotherapy

Stage II• Lobectomy, pneumonectomy,

segment/wedge resection as appropriate

• Curative radiotherapy if surgery contraindicated

• Adjuvant chemotherapy• Adjuvant radiotherapy

Stage IIIA• Surgery alone• Chemotherapy +

radiotherapy/neoadjuvant therapy• Post-operative radiotherapy• Radiotherapy alone

Stage IIIB• Chemotherapy alone• Chemotherapy + radiotherapy• Radiotherapy alone

Stage IV• Chemotherapy (platinum based),

modest survival benefits• New chemotherapy agents• External beam radiotherapy

(palliative relief)• Endobronchial laser or

brachytherapy for obstruction

The two year survival rate of patients with The two year survival rate of patients with unresectable locally advanced and NSCLL unresectable locally advanced and NSCLL having supportive care is approximately 4%.having supportive care is approximately 4%.

Chemoradiotherapy provides a modest but Chemoradiotherapy provides a modest but significant improvement on survival at one year significant improvement on survival at one year as compared with patients who receive as compared with patients who receive supportive care alone 22% vs. 10%.supportive care alone 22% vs. 10%.

Higgins and Shields, 1990Higgins and Shields, 1990

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Recent studies on concomitant Recent studies on concomitant chemoradiotherapychemoradiotherapyprovides some benefits. The concomitant provides some benefits. The concomitant approach provides the additional benefit of approach provides the additional benefit of increasing increasing locoregional locoregional control through the direct control through the direct interaction of the two modalities. However this is interaction of the two modalities. However this is complicated by increased clinical toxicity such as complicated by increased clinical toxicity such as esophagitisesophagitis, , pneumonitis pneumonitis and bone marrow and bone marrow abnormality. As a result, dosing of radiotherapy abnormality. As a result, dosing of radiotherapy and chemotherapy are carefully scheduled to allow and chemotherapy are carefully scheduled to allow recovery of normal tissues.recovery of normal tissues.

Advanced NSCLC: new chemotherapy agents

� Platinum-based combination therapy gives better response rates than monotherapy and remains the ‘gold standard’ for first-line therapy for advanced disease

� Paclitaxel, vinorelbine, docetaxel, gemcitabine

� In the past 3 decades, median survival in NSCLC patients has only improved by approximately 2 months

Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002

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First-line combination chemotherapy: recent randomised trials in advanced

NSCLC (1)Study

Le Chevalier et al 1994

Bonomi et al 1996

Crino et al 1998

Belani et al 1998

Cardenal et al 1999

Regimens

Vindesine/cisplatinVinorelbine/cisplatin

Etoposide/cisplatinPaclitaxel (135)/cisplatinPaclitaxel (250)/cisplatin/GCSF

Mitomycin/ifosfamide/cisplatinGemcitabine/cisplatin

Etoposide/cisplatinPaclitaxel/carboplatin

Etoposide/cisplatinGemcitabine/cisplatin

Median survival (months)

7.49.2*

7.79.6

10.0

8.88.1

8.3**8.3**

7.28.7

1-year survival

(%)

2836

31.636.939.1

--

35**35**

2632

Tumour response

(%)

19.030.0*

12.026.5*32.1*

2840*

14.021.6

21.940.6*

*p<0.05; **combined population; -, not reported

First-line combination chemotherapy: recent randomised trials in advanced

NSCLC (2)Study

Kelly et al 2001

Schilleret al 2002

Fossella2001

Regimens

Vinorelbine (25)/cisplatin (100)Paclitaxel (225)/carboplatin (AUC 6)

Paclitaxel (135)/cisplatin (75)Gemcitabine (1000)/cisplatin (100)Docetaxel (75)/cisplatin (75)Paclitaxel (225)/carboplatin (AUC 6)

Docetaxel (75)/cisplatin (75)Docetaxel (75)/carboplatin (AUC 6)Vinorelbine (25)/cisplatin (100)

Median survival (months)

88

7.88.17.48.1

10.99.110

1-year survival

(%)

3638

31363134

473842

Tumour response

(%)

2825

21221717

---

Fossella 2001; Kelly et al 2001; Schiller et al 2002 -, not reported

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NSCLC stage IIIA: role ofNSCLC stage IIIA: role ofneoadjuvantneoadjuvant chemotherapychemotherapy

�� Surgical resection alone fails to cure the majority of patients Surgical resection alone fails to cure the majority of patients with NSCLCwith NSCLC

�� NeoadjuvantNeoadjuvant chemotherapy still experimentalchemotherapy still experimental�� 3 randomised trials showed improvement in survival with3 randomised trials showed improvement in survival with

neoadjuvant cisplatinneoadjuvant cisplatin--based chemotherapy (Bunn et al 2000)based chemotherapy (Bunn et al 2000)�� An additional Phase III trial ofAn additional Phase III trial of gemcitabinegemcitabine//cisplatincisplatin has has

demonstrated response in >70% of patients, with tumourdemonstrated response in >70% of patients, with tumourdownstagingdownstaging of nodes in 53% (vanof nodes in 53% (van ZandwijkZandwijk 2000)2000)

�� Neoadjuvant docetaxelNeoadjuvant docetaxel was associated with a trend towards was associated with a trend towards longer median survival in a large Phase III trial (Mattson 2001)longer median survival in a large Phase III trial (Mattson 2001)

NSCLC stage IIIA/IIIB:NSCLC stage IIIA/IIIB:chemotherapy and radiotherapychemotherapy and radiotherapy

Study

Furuse et al 1999, Phase III

Curran et al 2000, Phase III

Gandara et al 2000, Phase II

Response rate (%)

66.084.0

-

-

-

--

Treatment regimens

I) CT with sequential Rx II) CT with concurrent Rx

I) Cis/vinb followed by sequential Rx on Day 50

II) Cis/vinb with concurrent Rx from Day 1

III) Cis/VP-16 with concurrent Rx twice-daily from Day 1

I) Cis/etop/Rx � cis/etopII) Cis/etop/Rx � docetaxel

Median survival (months)

13.316.5

14.6

17.0

15.6

1520

CT, chemotherapy (cisplatin/vindesine/mitomycin); Rx, radiotherapy;cis, cisplatin; vinb, vinblastine; etop, etoposide; -, not reported

No. patients

320

611

-71

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SCLC stagesSCLC stages

ExtensiveTumour not confined to hemithorax of originDistant metastasis

LimitedTumour confined to hemithorax of origin and/or the mediastinum and supraclavicular nodes

PDQ Guidelines 2000

SCLC prognosis*SCLC prognosis*

0

10

20

30

40

50

60

70

Localised Regional Distant Unstaged

Stage distribution5-year relative survival

Limited Extensive

*Based on cases in USA (1992-1997) Ries et al 2001

Patients(%)

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SCLC: treatment options overviewSCLC: treatment options overview

�� LimitedLimited--stage diseasestage disease

�� standard therapystandard therapy

�� surgerysurgery

�� platinumplatinum--based combination chemotherapybased combination chemotherapy

�� thoracic irradiationthoracic irradiation

�� prophylactic cranial irradiation (PCI) [for responders]prophylactic cranial irradiation (PCI) [for responders]

�� new agentsnew agents

�� taxanestaxanes,, eg paclitaxeleg paclitaxel andand docetaxeldocetaxel

�� topoisomerasetopoisomerase I inhibitors,I inhibitors, eg topotecaneg topotecan andand irinotecanirinotecan

�� ExtensiveExtensive--stage diseasestage disease

�� combination chemotherapy +/combination chemotherapy +/-- PCIPCI

�� radiotherapy + combination chemotherapy or vice versaradiotherapy + combination chemotherapy or vice versa

LimitedLimited--stage SCLC: combination stage SCLC: combination chemotherapy plus chest radiotherapychemotherapy plus chest radiotherapy

A metaA meta--analysis of 13 trialsanalysis of 13 trials

Chemotherapy alone n=992Chemotherapy + radiotherapy n=1111

Survival rate (%)

0 1 2 3 4 50

20

40

60

80

100

Years

Pignon et al 1992p=0.001

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LimitedLimited--stage SCLC: PCIstage SCLC: PCI

Without PCI n=149With PCI n=145

Months

Total brain metastasis(%)

0 12 24 36 48 600

20

40

60

80

Arriagada et al 1995

LimitedLimited--stage SCLC: combination stage SCLC: combination chemotherapychemotherapy

�� Commonly used regimensCommonly used regimens�� cisplatincisplatin//etoposideetoposide (PE)(PE)�� cyclophosphamidecyclophosphamide//doxorubicindoxorubicin//vincristinevincristine (CAV)(CAV)�� cyclophosphamidecyclophosphamide//doxorubicindoxorubicin//etoposideetoposide (CAE)(CAE)�� CAV alternating with PECAV alternating with PE

�� PE has become an international standardPE has become an international standard�� CarboplatinCarboplatin//etoposideetoposide active with less toxicity than PEactive with less toxicity than PE

Kelly 2000

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ExtensiveExtensive--stage SCLC:stage SCLC:recent firstrecent first--line Phase III trialsline Phase III trials

�� CisplatinCisplatin//irinotecanirinotecan (CP)(CP) vsvs PE (Noda et al 2002)PE (Noda et al 2002)�� overall response rate (ORR) 84.4% for CP and 67.5% for overall response rate (ORR) 84.4% for CP and 67.5% for

PEPE�� median survival 12.8 months for CP and 9.4 months for median survival 12.8 months for CP and 9.4 months for

PEPE�� 70 deaths in the CP group and 74 in the PE group 70 deaths in the CP group and 74 in the PE group

(p=0.002)(p=0.002)�� a new standard for extensive disease?a new standard for extensive disease?

�� SingleSingle--agentagent topotecantopotecan (Schiller et al 2001)(Schiller et al 2001)�� topotecan vstopotecan vs observation after PE: Phase III Eastern observation after PE: Phase III Eastern

Cooperative Oncology GroupCooperative Oncology Group�� no improvement in overall survival or quality of lifeno improvement in overall survival or quality of life

�� CisplatinCisplatin//etoposideetoposide//cyclophosphamidecyclophosphamide//epidoxorubicin vsepidoxorubicin vs PE PE ((PujolPujol et al 2001)et al 2001)

Phase III trial ofPhase III trial of topotecantopotecan for patients for patients with recurrent SCLCwith recurrent SCLC

No. LRpatients*

107

104

Therapy

Topotecan

CAV

CR

-

1 (1%)

PR

26 (24%)

18 (18%)

Survival(weeks)

25

24.7

Response [no. patients (%)]

*LR, late relapsing: disease progressed >60 days after first-line therapyCR, complete response; PR, partial response

von Pawel et al 1999

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Lung cancer: future developments

� Current treatment remains unsatisfactory

� Earlier diagnosis

� New molecular-based classification

� Improved treatment – novel targeted biological agents, immunological

approaches, gene therapy

– less toxic combinations

� Prevention

Earlier diagnosis� Obstructive lung disease (chronic bronchitis and

emphysema)

� Genetic risk factors

� Sputum cytology

� Molecular tumour markers

� Low-dose spiral computed tomography

� Positron emission tomography

� Laser-induced fluorescence endoscope (LIFE) bronchoscopy

Edell 1997; Hirsch 2001

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Prognostic and predictive factorsPrognostic and predictive factors

�� p53 statusp53 status

�� Other cell cycle components including p27, p15, p16,Other cell cycle components including p27, p15, p16, pRbpRb,,cyclincyclin and CDK and CDK

�� KK--rasras mutationsmutations

�� HER2/HER2/neuneu and epidermal growth factor receptor (EGFR)and epidermal growth factor receptor (EGFR)

�� BetaBeta tubulintubulin

�� Expression of matrixExpression of matrix metalloproteinasemetalloproteinase and inhibitorsand inhibitors

�� DNADNA topoisomerasetopoisomerase IIII�� and IIand II��

�� Single nucleotide polymorphism inSingle nucleotide polymorphism in myeloperoxidasemyeloperoxidase gene gene reduces risk of lung cancerreduces risk of lung cancer

�� HeparinHeparin--binding growth factorbinding growth factor pleiotrophinpleiotrophin

Novel biological approachesNovel biological approaches (1)(1)

�� Inhibitors of the EGFR familyInhibitors of the EGFR family�� small moleculesmall molecule TKIsTKIs of EGFR,of EGFR, eg gefitinibeg gefitinib,,

erlotiniberlotinib�� monoclonal antibodies to EGFR,monoclonal antibodies to EGFR, eg cetuximabeg cetuximab�� monoclonal antibodies to HER2,monoclonal antibodies to HER2, eg trastuzumabeg trastuzumab

�� Farnesyl transferaseFarnesyl transferase inhibitorsinhibitors�� Inducers of apoptosis,Inducers of apoptosis, eg cyclooxygenaseeg cyclooxygenase--2 (COX2 (COX--2) 2)

inhibitors, inhibitors of proteininhibitors, inhibitors of protein kinasekinase C, gene therapy,C, gene therapy,bclbcl--22 antisense oligonucleotideantisense oligonucleotide

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DNA

Mode of action of EGFR inhibitors

Membrane

Extracellular

Intracellular

R

K

R

K EGFR-TKIEGFR-TKI ��

SignallingProliferation Cell survival (anti-apoptosis)

Growth factors

Chemotherapy/radiotherapy sensitivity

Angiogenesis

Metastasis

R, epidermal growth factor receptor

EGF/TGFα

Antibody

Clinical development of anti-EGFR agents in NSCLC

�� Gefitinib Gefitinib

�� Phase II studies of oncePhase II studies of once--daily, oral gefitinib in NSCLC daily, oral gefitinib in NSCLC (Kris et al 2002; Fukuoka et al 2003)(Kris et al 2002; Fukuoka et al 2003)

�� antitumour activity, symptom relief, favourable safety profileantitumour activity, symptom relief, favourable safety profile

�� Phase III firstPhase III first--line combination studies in stage III/IV NSCLC line combination studies in stage III/IV NSCLC (Giaccone et al 2002; Johnson et al 2002)(Giaccone et al 2002; Johnson et al 2002)

�� no added benefit over combination chemotherapy alone no added benefit over combination chemotherapy alone

�� ErlotinibErlotinib

�� Phase II study in EGFRPhase II study in EGFR--positive, previously treated stage IIIB/IV NSCLC (Perezpositive, previously treated stage IIIB/IV NSCLC (Perez--Soler et Soler et al 2001)al 2001)

�� antitumour activity, favourable safety profileantitumour activity, favourable safety profile

�� Phase III firstPhase III first--line combination and thirdline combination and third--line monotherapy studies ongoing in NSCLCline monotherapy studies ongoing in NSCLC

�� Cetuximab Cetuximab

�� Phase I study of cetuximab alone and in combination with cisplatPhase I study of cetuximab alone and in combination with cisplatin in patients with in in patients with EGFREGFR--positive advanced tumourspositive advanced tumours

�� Phase II cetuximab combination studies ongoing in EGFRPhase II cetuximab combination studies ongoing in EGFR--positive NSCLCpositive NSCLC

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Tumour angiogenesisTumour

4. Appearance of newtumour

vasculature

1. Secretion ofangiogenic

factors

3. Endothelial cell proliferation

and migration

2. Proteolyticdestruction of

extracellular matrix

Sprouting capillary

Novel biological approaches (2)Novel biological approaches (2)

�� AntiAnti--angiogenicangiogenic agentsagents�� monoclonal antibodies,monoclonal antibodies, eg bevacizumabeg bevacizumab

((rhuMabrhuMab--VEGF)VEGF)�� VEGF receptorVEGF receptor TKIsTKIs,, egeg ZD6474, PTK787ZD6474, PTK787�� matrixmatrix metalloproteinasemetalloproteinase inhibitors inhibitors �� thalidomidethalidomide

�� Vascular targeting agents,Vascular targeting agents,eg combretastatineg combretastatin A4 phosphate, ZD6126A4 phosphate, ZD6126

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NSCLC stage IIIB and IV:NSCLC stage IIIB and IV:Phase III trials in progress, July 2003 (1)Phase III trials in progress, July 2003 (1)

Sponsor

NCI, NCCTG

NCIC-Clinical Trials Group

Cell Pathways

NCI, NCCTG, NCIC-Clinical Trials Group, SWOG

Ligand Pharmaceuticals

NCI, SWOG

Sanofi-Synthelabo

Investigational regimen

Carboxyamidotriazole

Erlotinib

Docetaxel/exisulind

Cisplatin/etoposide/radiotherapy/

docetaxel/gefitinib

Vinorelbine/cisplatin/bexarotene

Paclitaxel/carboplatin/tirapazamine

Cisplatin/vinorelbine/tirapazamine

Reference regimen

Placebo

Placebo

Docetaxel/placebo

Cisplatin/etoposide/radiotherapy/

docetaxel/placebo

Vinorelbine/cisplatin

Paclitaxel/carboplatin

Cisplatin/vinorelbine

NCI, National Cancer Institute; NCCTG, North Central Cancer Treatment Group; SWOG, Southwest Oncology Group

Sponsor

Genentech

ISIS Pharmaceuticals

NCI, ECOG

Abgenix, Immunex

Roche, Genentech, OSI Pharmaceuticals

Roche, Genentech, OSI Pharmaceuticals

Roche, Genentech, OSI Pharmaceuticals

Investigational regimen

Paclitaxel/carboplatin/erlotinib

Paclitaxel/carboplatin/ISIS 3521

Paclitaxel/carboplatin/radiotherapy/thalidomide

Paclitaxel/carboplatin/ABX-EGF

Gemcitabine/cisplatin/erlotinib

Paclitaxel/carboplatin/erlotinib

Erlotinib

Reference regimen

Paclitaxel/carboplatin

Paclitaxel/carboplatin

Paclitaxel/carboplatin/radiotherapy

Paclitaxel/carboplatin

Gemcitabine/cisplatin/placebo

Paclitaxel/carboplatin/placebo

Placebo

NCI, National Cancer Institute; SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group

NSCLC stage IIIB and IV:NSCLC stage IIIB and IV:Phase III trials in progress, July 2003 (2)Phase III trials in progress, July 2003 (2)

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Sponsor

NCI, ECOG

NCIC-Clinical Trials Group

NCI, Memorial Sloan-Kettering Cancer Center

Investigational regimen

Paclitaxel/carboplatin/bevacizumab

Paclitaxel/carboplatin/BMS-275291

Oblimersen/docetaxel

Referenceregimen

Paclitaxel/carboplatin

Paclitaxel/carboplatin/placebo

Docetaxel

NCI, National Cancer Institute; ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group;

NSCLC stage IIIB and IV:NSCLC stage IIIB and IV:Phase II/III trials in progress, July 2003Phase II/III trials in progress, July 2003

SCLC: SCLC: Phase III trials in progress, July 2003Phase III trials in progress, July 2003

Sponsor

EORTC Lung Cancer Cooperative Group

Vrije Universiteit Medisch Centrum

Investigational regimen

Adjuvant BCG and monoclonal antibody

BEC2

Cyclophosphamide/doxorubicin/

etoposide

Disease stage

Limited

Extensive

Referenceregimen

First-line combined modality treatment

(at least 2-drug chemotherapy and chest

radiotherapy)

Carboplatin/paclitaxel

EORTC, European Organization for Research and Treatment of Cancer; BCG, BacillusCalmette Guerin

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SCLC: SCLC: Phase II trials in progress, July 2003Phase II trials in progress, July 2003

Sponsor

NCI, SWOG

NCI, CALGB

NCI, NCCTG

NCI, ECOG

NCI, Uni of Michigan

Investigational regimen

Gemcitabine/irinotecan

Paclitaxel

Topotecan/paclitaxel

CCI-779

Fenretinide

Disease stage

Untreated, extensive

Extensive

Recurrent, refractory

Extensive

Recurrent

NCI, National Cancer Institute; SWOG, Southwest Oncology Group; CALGB, Cancer and Leukemia Group B; NCCTG, North Central Cancer Treatment Group; ECOG, Eastern Cooperative Oncology Group; FCCC, Fox Chase Cancer Center; Beckman Research Institute

Dyspnea ManagementDyspnea Management�� AssessmentAssessment�� Activity planningActivity planning�� MedicationsMedications

�� CorticosteroidsCorticosteroids�� OpioidsOpioids�� Oxygen therapyOxygen therapy

�� NonNon--traditional/investigational therapiestraditional/investigational therapies�� AcupunctureAcupuncture�� MassageMassage�� ExerciseExercise

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Fatigue ManagementFatigue Management�� AssessmentAssessment�� Activity PlanningActivity Planning�� ExerciseExercise�� Sleep aidsSleep aids�� StimulantsStimulants�� Anemia managementAnemia management

�� Iron supplementsIron supplements�� Epoetin alfaEpoetin alfa

Pain ManagementPain Management�� AssessmentAssessment�� Medications:Medications:

�� OpioidsOpioids�� NSAIDSNSAIDS�� CorticosteroidsCorticosteroids

�� Nonpharmacologic Interventions:Nonpharmacologic Interventions:�� Heat/cold Heat/cold �� Topical agentsTopical agents�� MassageMassage�� Behavioral TherapyBehavioral Therapy

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Prevention� Education and primary prevention

– avoidance of environmental carcinogens, eg tobacco smoke

� Chemoprevention– retinoids

– EGFR inhibitors

– selenium

– COX-2 inhibitors

– green tea

SummarySummary�� Despite improved detection and advances in Despite improved detection and advances in

treatment modalities, only limited progress has treatment modalities, only limited progress has been made in the outcome for patients with lung been made in the outcome for patients with lung cancercancer

�� Targeted molecular therapeutic agents offer new Targeted molecular therapeutic agents offer new hope for the futurehope for the future

�� Through molecular characterisation of a patient’s Through molecular characterisation of a patient’s tumour, it may become possible to offer more tumour, it may become possible to offer more rational, less toxic treatment rational, less toxic treatment

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�� ATS and ERS: Pretreatment evaluation of nonATS and ERS: Pretreatment evaluation of non--smallsmall--cell lung cell lung cancer. The American Thoracic Society and The European cancer. The American Thoracic Society and The European Respiratory Society. Am JRespiratory Society. Am J Respir CritRespir Crit Care Med 1997 Jul; 156(1): Care Med 1997 Jul; 156(1): 320320--3232[Medline][Medline]..

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THANK YOU!THANK YOU!