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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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
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).
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.
�� 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
�� 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
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
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
�� 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
�� 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
�� 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)
�� 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)
�� 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
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
– 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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