Lung Cancer History Causation Clinical presentation

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Lung CancerHistoryCausation Clinical
presentation
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Alton Ochsner and Evarts Graham
When I was a junior medical student in 1919, the
two senior classes were asked to witness the
autopsy of a man having died of carcinoma of the
lung because the Professor of Medicine thought
that we might never see another such case as long
as we lived. Being young and impressionable this
impressed me very much. It was not until 1936, 17
years later, that I saw my next case of
bronchogenic carcinoma and then, in a period of 6
months, I saw 9 cases . All the patients were
men, heavy smokers and had begun smoking at the
beginning of World War 1.
Alton Ochsner, Chest 1971 59358-9.
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Alton Ochsner and Evarts Graham

• 75th anniversary of the first pneumonectomy for
  lung cancer
• The Surgeon - Evarts Graham went on to be an
  influential researcher
• The operation was performed on a 48 year old
  patient who was an Obsetrician and Gyneacologist

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SMOKING PREVALENCEBritish Doctors - 1951
R Doll, A Bradford Hill BMJ June 1954
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Alton Ochsner and Evarts Graham
Dr Evarts Graham, who performed the first
successful pneumonectomy for cancer of the lung
on a physician in 1933, was my professor of
surgery in my senior year. He was then a young
man so there was not much difference in our ages.
When I first postulated that the increase in
cancer of the lung was due to cigarette smoking
because of the parallel between the sale of
cigarettes and the increasing incidence of cancer
of the lung, I was chided by Dr Graham, who was a
very heavy cigarette smoker.
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Alton Ochsner and Evarts Graham
He (Graham) said, yes there is a parallel
between the sale of cigarettes and the incidence
of cancer of the lung but then there is also a
parallel between the sale of nylon stockings and
the incidence of cancer of the lung," which I
could not refute
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Alton Ochsner and Evarts Graham
He (Graham) said, yes there is a parallel
between the sale of cigarettes and the incidence
of cancer of the lung but then there is also a
parallel between the sale of nylon stockings and
the incidence of cancer of the lung," which I
could not refute Evarts Graham died of lung
cancer in 1957
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Brief history of lung cancer

• It was extraordinarily rare gt100 years ago
• Less than 0.3 of PMs
• Some may have been misclassified metastases
• lt100 cases in 1900 in 1912 estimated 374
• Early in the epidemic, 25-30 of cancers were
  Small Cell Ca (then oat cell)
• Squamous cell carcinoma were most of the rest
• Adenocarcinoma was unusual amongst lung cancers

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Brief history of lung cancer

• Central cancers were much more common than
  peripheral lesions
• This is now reversed likely related to change
  in cigarettes and deeper smoke inhalation
• All these changes over time can be explained by
  changes in smoking, cigarettes and smoking
  practices

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CONTEXT
Smoking kills. If you're killed, you've lost a
very important part of your life." Brooke
Shields, Raleigh News Observer October 21 1997
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Lung cancer and smoking

• Important factors
• Age at Commencement
• Duration of Smoking
• Number of Cigarettes Smoked/day
• Risk per daily cigarette reduces as numbers
  smoked increase
• Cannabis smoking
• 1 joint/day 20 cigarettes/day

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Blame, Stigma Perceived Futility

• If everyone smoked, those (smokers) who developed
  lung cancer would be unlucky
• If some smoke, and many have quit, those who get
  lung cancer are regarded as stupid - non-smokers
  with lung cancer are unlucky
• At an individual level, the major cause of lung
  cancer is bad luck smoking having the effect of
  compromising your luck in a big way
• No one in the world deserves lung cancer

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2003 WCLC QuestionnaireConducted by Global Lung
Cancer Coalition

• Society perceives lung cancer to be a
  self-inflicted disease

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Lung cancerIneffective risk reduction

• Mild/light cigarettes
• No reduction in lung cancer risk
• More tobacco smoke inhaled
• Cancers are more peripherally located
• Reducing number of cigarettes smoked
• More smoke from every cigarette
• No reduction in lung cancer risk

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ETS and lung cancer risk

• ETS is different from mainstream smoke
• Burns at lower temperature
• Some toxic chemical preserved
• Active smokers have most ETS exposure
• The contribution of ETS to lung cancer in active
  smokers may be significant
• Everyone is exposed to some ETS in any community
  where smoking is common
• Assessing the true risk of ETS is statistically
  very difficult when few have no exposure

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Domestic ETS Risks in Hong Kong McGhee at al
BMJ 2005

• Lifetime risk of ETS much greater than previously
  realized
• Lung cancer
• One smoker 1.24
• Two smokers 1.74
• Similar for all cause mortality
• This plugs a gap in lung cancer causation

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Smoking cessation lung cancer risk

• The annual risk of lung cancer rises with every
  year of smoking stops rising after cessation
• Difference between continuing and ex-smoker
  increases every year after cessation
• Exsmoker risk never drops to that of a never
  smoker
• Smoking cessation is always beneficial
• Delays lung cancer development develop at 70
  not 50 or 130 rather than 65
• Quitting before age 30 leaves a very small
  lifetime lung cancer risk
• Cessation improves treatment responses and makes
  some treatment possible(surgery)

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Other factors

• Genetics of cancer causation
• Greatly elevated risk of lung cancer in close
  relatives of those with lung cancer
• Limited to those with ETS or active smoking
• Also increased with other cancers
• Genetics of nicotine dependence
• Increases chance of going from one cigarettes to
  being established smoker
• Higher lung cancer risk
• Same gene(s) two effects?
• Indirect effect of inhaling more smoke?

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Other factors

• COPD increases risk for same smoking
• Risk higher with HN or esophageal cancer
• HIV infection - 3.4 fold increased risk
• Previous radiotherapy
• Breast cancer (on side of DXRT in smokers)
• Lymphoma treatment
• New immunosuppressive agents
• Progression and regression documented on/after
  infliximab
• Rapid progression in grafted/native cancers after
  transplant immunosuppression

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Occupational risks

• In Australia mainly asbestos
• Asbestos at 50 fibre/ml.years doubles risk
• The increased risk from smoking multiplies the
  increased risk from asbestos

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Asbestos ExposureOccupational Causes

• Asbestos Industry
• Miners millers
• Hardies
• Goodyear(adjacent)
• Builders/demolishers
• Wharf labourers
• Power station workers
• Marine Engineers
• Boilermakers
• Minor asbestos exposures are not relevant to lung
  cancer

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The genesis of lung cancer
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Lung cancer genetic change

• Lung cancers are genetically altered - 5-9
  critical genetic changes
• Changes are seen early in life
• Known causal factors and chance
• In smokers there is considerable genetic
  pathology in adjacent normal lung
• Not true of non-smokers!!
• Recognition of genetic changes can lead to
  treatment targets
• VEGF EGFR

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Lung CancerEffects of Genetic Damage

• Inability to repair DNA
• Failure of normal programmed cell death
• Abnormal receptor expression
• Accelerated proliferation
• Stimulation of new blood vessel formation to
  allow growth in news sites
• Invasion
• Metastasis

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The lung cancer genome

• Sequencing of human genome allows comparison of
  tumour and (normal) genome
• 1,000s of single base genetic changes - perhaps
  10,000 or more
• almost all likely unimportant
• some may be potential tumour antigen targets
• True number of critical genetic change is still
  considered to be lower

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Genetic change vs epidemiology

• Genetic changes can occur early - even in teenage
  
• Surveillance abnormalities contribute to later
  critical (or irrelevant) DNA change
• Smoking accelerates risk of genetic errors
• Consistent with observed effect of smoking
  cessation
• Genetic change occurs in a larger field than a
  structural/histological malignancy

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Genetic changes vs clinical course

• The more primitive abnormal genes activated in a
  cancer the worse prognosis
• Therapy will in time be guided by genetic testing
  of tumour tissue
• Rule treatment in
• Rule treatment out
• There are further genetic changes during the
  clinical course of lung cancer
• Some caused by some cytotoxic chemotherapy
• This will influence the treatment sequencing

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Genetics and assumptions

• Even in cancer genetics, good clinical science
  must prevail over assumptions
• Worse genes worse prognosis
• .but may not mean increased utility of
  additional treatment such as adjuvant
  chemotherapy after surgery
• A further example
• Poor DNA error correction increases cancers
• Should we try to enhance residual DNA repair
  mechanisms?

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Symptoms and Presentation
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Symptoms and the course

• By definition lung cancer causes no symptoms for
  most of the time of its development
• Symptoms that are directly related to the cancer
  itself are very often associated with advanced
  disease

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Important symptoms

• Disease contained entirely within lung
• Cough
• Hemoptysis
• Breathlessness (Lobar or lung collapse)
• More extensive disease within the chest cavity
• Breathlessness from pleural effusion
• Obstruction of SVC
• Laryngeal nerve palsy new hoarse voice
• Pain pleural or chest wall

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Important symptoms

• Extensive disease specific symptoms
• Bony pain
• Headache
• Localised pain from any metastatic site
• Extensive disease non-specific symptoms
• Fatigue
• Anemia
• Anorexia
• Weight loss
• Thrombo-embolism
• Psychological effects

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Psychological features

• General effects of malignancy
• Anxiety
• Depression
• Lung cancer specific
• Blame
• Self-blame
• High rates of mental illness in smokers

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Presentation Delays

• Delayed presentation with lung cancer symptoms is
  common
• Earlier presentation date will result in improved
  survival from diagnosis a mix of true and
  apparent benefit
• Delayed presentation with symptoms is also seen
  with breast and colon tumours
• Factors influencing reporting
• More positive view of disease treatment
• Confiding symptoms to a relative or friend

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Awareness early presentation

• Positive awareness
• Knowledge of abnormality of symptoms and
  potential link to lung cancer
• Negative awareness
• Poor outcomes, perceived futility or adverse
  effects of treatment
• Why it is a challenge
• Smokers have self-exempting beliefs
• Non-smokers symptoms (reasonably) not linked
  early to a possible lung cancer

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