case presentation & discussion on difficulty of...
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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
3
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
6
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%
�
√ √
√
√ √ √
√ √ √ √
√ √
√
11
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
(%)
14
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
21
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
22
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
23
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
24
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
25
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(%)
26
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
27
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
28
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
29
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
30
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
31
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
32
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
33
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)
34
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
35
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
36
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
37
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
38
�� 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]..
�� BottaBotta DM, Head HD: NonDM, Head HD: Non--small cell lung cancer: an update.small cell lung cancer: an update. Curr Curr SurgSurg 2003 Sep2003 Sep--Oct; 60(5): 492Oct; 60(5): 492--88[Medline][Medline]..
�� BoulikasBoulikas T,T, VougioukaVougiouka M: Recent clinical trials usingM: Recent clinical trials using cisplatincisplatin,,carboplatincarboplatin and their combination chemotherapy drugs (Review).and their combination chemotherapy drugs (Review).OncolOncol Rep 2004 Mar; 11(3): 559Rep 2004 Mar; 11(3): 559--9595[Medline][Medline]. .
�� Dales RE, Stark RM, Raman S: ComputedDales RE, Stark RM, Raman S: Computed tomographytomography to stage to stage lung cancer. Approaching a controversy using metalung cancer. Approaching a controversy using meta--analysis. Am analysis. Am RevRev Respir DisRespir Dis 1990 May; 141(5 Pt 1): 10961990 May; 141(5 Pt 1): 1096--101101[Medline][Medline]. .
�� Hatter J,Hatter J, KohmanKohman LJ,LJ, MoscaMosca RS, et al: Preoperative evaluation of RS, et al: Preoperative evaluation of stage I and stage II nonstage I and stage II non--small cell lung cancer. Annsmall cell lung cancer. Ann Thorac SurgThorac Surg1994 Dec; 58(6): 17381994 Dec; 58(6): 1738--4141[Medline][Medline]..
�� HenschkeHenschke CI,CI, NaidichNaidich DP,DP, YankelevitzYankelevitz DF, et al: Early lung cancer DF, et al: Early lung cancer action project: initial findings on repeat screenings. Cancer 20action project: initial findings on repeat screenings. Cancer 2001 Jul 01 Jul 1; 92(1): 1531; 92(1): 153--99[Medline][Medline]. .
�� Hillers TK,Hillers TK, SauveSauve MD,MD, GuyattGuyatt GH: Analysis of published studies on GH: Analysis of published studies on the detection ofthe detection of extrathoracicextrathoracic metastases in patients presumed to metastases in patients presumed to have operable nonhave operable non--small cell lung cancer. Thorax 1994 Jan; 49(1): small cell lung cancer. Thorax 1994 Jan; 49(1): 1414--99[Medline][Medline]..
�� LababedeLababede O,O, MezianeMeziane MA, Rice TW: TNM staging of lung cancer: a MA, Rice TW: TNM staging of lung cancer: a quick reference chart. Chest 1999 Jan; 115(1): 233quick reference chart. Chest 1999 Jan; 115(1): 233--55[Medline][Medline]. .
�� Landis SH, Murray T, Bolden S,Landis SH, Murray T, Bolden S, WingoWingo PA: Cancer statistics, 1999. PA: Cancer statistics, 1999. CA Cancer JCA Cancer J ClinClin 1999 Jan1999 Jan--Feb; 49(1): 8Feb; 49(1): 8--31, 131, 1[Medline][Medline]. .
�� Lowe VJ,Lowe VJ, NaunheimNaunheim KS: Positron emissionKS: Positron emission tomographytomography in lung in lung cancer. Anncancer. Ann Thorac SurgThorac Surg 1998 Jun; 65(6): 18211998 Jun; 65(6): 1821--99[Medline][Medline]. .
�� Mac Manus MP, Hicks RJ, Ball DL, et al: FMac Manus MP, Hicks RJ, Ball DL, et al: F--1818 fluorodeoxyglucosefluorodeoxyglucosepositron emissionpositron emission tomographytomography staging in radical radiotherapy staging in radical radiotherapy candidates withcandidates with nonsmallnonsmall cell lung carcinoma: powerful correlation cell lung carcinoma: powerful correlation with survival and high impact on treatment. Cancer 2001 Aug 15; with survival and high impact on treatment. Cancer 2001 Aug 15; 92(4): 88692(4): 886--9595[Medline][Medline]. .
�� Martini N,Martini N, BainsBains MS, Burt ME, et al: Incidence of local recurrence MS, Burt ME, et al: Incidence of local recurrence and second primary tumors inand second primary tumors in resectedresected stage I lung cancer. Jstage I lung cancer. JThorac Cardiovasc SurgThorac Cardiovasc Surg 1995 Jan; 109(1): 1201995 Jan; 109(1): 120--99[Medline][Medline]..
�� McLoudMcLoud TC,TC, BourgouinBourgouin PM, Greenberg RW, et al:PM, Greenberg RW, et al: BronchogenicBronchogeniccarcinoma: analysis of staging in thecarcinoma: analysis of staging in the mediastinummediastinum with CT by with CT by correlative lymph node mapping and sampling. Radiology 1992 Feb;correlative lymph node mapping and sampling. Radiology 1992 Feb;182(2): 319182(2): 319--2323[Medline][Medline]. .
39
�� Michel F,Michel F, SolerSoler M,M, ImhofImhof E,E, PerruchoudPerruchoud AP: Initial staging of nonAP: Initial staging of non--small cell lung cancer: value of routine radioisotope bone scannsmall cell lung cancer: value of routine radioisotope bone scanning. ing. Thorax 1991 Jul; 46(7): 469Thorax 1991 Jul; 46(7): 469--7373[Medline][Medline]. .
�� Miller WT: Value of clinical history. AJR Am JMiller WT: Value of clinical history. AJR Am J RoentgenolRoentgenol 1990 Sep; 1990 Sep; 155(3): 653155(3): 653--44[Medline][Medline]. .
Mountain CF: Revisions in the International System for Staging LMountain CF: Revisions in the International System for Staging Lung ung Cancer. Chest 1997 Jun; 111(6): 1710Cancer. Chest 1997 Jun; 111(6): 1710--77[Medline][Medline]..
�� ParkinParkin DM,DM, PisaniPisani P,P, FerlayFerlay J: Estimates of the worldwide incidence J: Estimates of the worldwide incidence of eighteen major cancers in 1985.of eighteen major cancers in 1985. IntInt J Cancer 1993 Jun 19; 54(4): J Cancer 1993 Jun 19; 54(4): 594594--606606[Medline][Medline]..
�� PatzPatz EFEF JrJr, Erasmus JJ, McAdams HP, et al: Lung cancer staging , Erasmus JJ, McAdams HP, et al: Lung cancer staging and management: comparison of contrastand management: comparison of contrast--enhanced andenhanced andnonenhancednonenhanced helical CT of the thorax. Radiology 1999 Jul; 212(1): helical CT of the thorax. Radiology 1999 Jul; 212(1): 5656--6060[Medline][Medline]. .
�� Reilly JJ: Preparing for pulmonary resection: preoperative evaluReilly JJ: Preparing for pulmonary resection: preoperative evaluation ation of patients. Chest 1997 Oct; 112(4of patients. Chest 1997 Oct; 112(4 SupplSuppl): 206S): 206S--208S208S[Medline][Medline]. .
�� Roberts JR, Blum MG,Roberts JR, Blum MG, ArildsenArildsen R, et al: Prospective comparison ofR, et al: Prospective comparison ofradiologicradiologic,, thoracoscopicthoracoscopic, and pathologic staging in patients with , and pathologic staging in patients with early nonearly non--small cell lung cancer. Annsmall cell lung cancer. Ann Thorac SurgThorac Surg 1999 Oct; 68(4): 1999 Oct; 68(4): 11541154--88[Medline][Medline]..
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