Transcript Is there anything wrong with surgery for lung cancer in the UK?

Update on Asbestos
and Lung Cancer
Is There A Basis For A Claim?
Lung Cancer and Asbestos
• Strong epidemiological evidence that
asbestos causes all pathological
types of lung cancer
• Latency between exposure and
increase in risk of lung cancer at
least 10 years for non-small cell
cancer, 5 years for more rapidly
growing small cell cancer
Asbestos and Lung Cancer
• Risk increases with dose
• Much smaller relative risk than for
mesothelioma:
– Heavy exposure eg lagger, 1000 fold risk
for mesothelioma but only 5 fold risk for
lung cancer
– Hence no significant increase in risk of
lung cancer from light exposure which is
more than enough to cause a substantial
increase in risk of mesothelioma
Asbestos Carcinogenesis
• Chromosomal/DNA damage results in mutations
– Caused directly by asbestos
– Caused by chemical mediators produced as a result
of the presence of asbestos fibres
– Caused by asbestos increasing the effects of
tobacco carcinogens
• Asbestos impedes DNA repair and reduces natural
killer cell targeting of malignant cells
• Some mutations promote cancerous behaviour of cells
(oncogenes)
• Others impede the effect of genes which suppress
cancer (tumour suppressor genes)
Does Asbestos Induced
Differ from Smoking Induced Lung Cancer?
• Cancers from asbestos exposed and non-exposed
subjects compared
• Differences in DNA aberration profiles and gene
expression identified
• Implies that increasing the efficacy of tobacco
carcinogens is not the only mechanism of asbestos
lung carcinogenesis
• Raises the possibility that identification of specific
genetic abnormalities might eventually be useful in
identifying which lung cancers were caused by
asbestos
Mechanism of Asbestos Carcinogenesis
• Proliferative model hypothesis (out-dated):
– Asbestos damages epithelial cells lining
airspaces causing proliferation of cells
attempting to repair damage
– Increased proliferation leads to increased
opportunity for mutations leading to cancer
– Increased proliferation is always accompanied
by asbestos induced inflammation which leads
to fibrosis
• This hypothesis was the basis of the proposition
that asbestosis must be present to attribute lung
cancer to asbestos
Asbestos Lung Cancer:
Is Asbestosis Necessary?
• If asbestosis present lung cancer is attributable
to asbestos; no dissent from this view
• Increasingly accepted that asbestosis is not a
necessary precursor of cancer but a marker of
sufficient exposure to have more than doubled
the risk of lung cancer
• Risk increased by asbestos exposure but
probably increased further if asbestosis also
present
Sluis-Cremer GK & Bezuidenhout BN Brit J Ind Med 1990; 47: 215-216
Reid A et al Occup Environ Med 2005;62:885-889
Risk of Lung Cancer from Asbestos and
Smoking
• All studies suggest more than additive,
ie synergistic interaction
• Most suggest multiplicative or near
multiplicative
Doll R, Peto J. Effects on Health of Exposure to Asbestos. HMSO 1985
Risk of Lung Cancer from Asbestos
and Smoking
50
45
40
35
30
Relative Risk 25
20
15
10
5
0
Asbestos
Smoking
Asbestos
and
smoking
Hammond EC et al Ann NY Acad Sci 1979;330:473
Lifetime % Risk Of Lung Cancer
Multiplicative Interaction Means Proportion Of Risk Due
To Asbestos Same In Smokers and Non-Smokers
Practical Implications of Multiplicative
Interaction Between Asbestos and Smoking
• Amount smoked not relevant to establishing causation
of cancer by asbestos; this depends only on
establishing a more than twofold risk from asbestos
• While non-smoking status is a useful ‘jury point’ it is still
necessary to establish a more than twofold risk from
asbestos
• Smoking history may be relevant to contributory
negligence arguments
• Warnings appeared on cigarette packets from 1971
Asbestos Induced Lung Cancer: How
Many Cases?
• Proportional mortality ratios for mesothelioma and
lung cancer calculated for the period 1980 to 2000
• Smoking indicators derived from 3 General
Household Surveys
• Asbestos related lung cancer deaths estimated by
calculating no of deaths expected in each
occupational group if no asbestos exposure and
subtracting from actual number
• Estimated between 0.7 and 1 lung cancer per
mesothelioma, ie ~ around 2000 cases per year
Darnton AJ et al Ann Occup Hyg 2005
Lung Cancer: 2,000 Cases Annually Does
Not Mean 2,000 Viable Claims
• For example, if 40,000 smokers of whom 4,000 would
get lung cancer from smoking were subjected to
enough asbestos exposure to increase their risk of
lung cancer by 50% (1.5-fold) there would be 2,000
extra cases caused by asbestos but in none would it
be possible to establish causation by asbestos on the
basis of the test being more than doubling of the risk
• In reality there is a spectrum of exposures but many
of the cases ‘caused by asbestos’ on the basis of
epidemiology do not have viable claims
Attribution of Lung Cancer to Asbestos:
The Helsinki Criteria
• International expert meeting of 19 participants from 8
countries not producing asbestos
• Report produced in 1998
• Now form the basis for the award of compensation in
several countries
• Any one clinical, pathological or occupational criterion
sufficient for attribution of lung cancer to asbestos
• All criteria imply sufficient exposure to have more than
doubled the risk of lung cancer
Consensus Report Scand J Work Environ Health 1997;23:311
Attribution of Lung Cancer to Asbestos:
The Helsinki Criteria, Occupational
– One year of heavy exposure, eg lagging, or 510 years of moderate exposure, eg
shipbuilding, construction
– Occupational history indicating cumulative
exposure ≥ 25 fibre/ml years
Consensus Report Scand J Work Environ Health 1997;23:311-316
Asbestos Dose Estimation
• Dose measured in fibre ml years
• Represents product of mean airborne fibre
concentration and duration of exposure in
working years (one year taken as 2000 hours,
or sometimes 1920)
• Eg exposure to 5 fibres/ml for 5 years gives a
dose of 25 fibre ml years
Attribution of Lung Cancer to Asbestos:
The Helsinki Criteria: Clinical/ Pathological
• Radiological or pathological diagnosis of asbestosis
• Pathological diagnosis of asbestosis requires diffuse
interstitial fibrosis in association with at least 2 asbestos
bodies per cm2 of routine (5 micron thick) lung tissue
section, averaged over all sections examined
• Fibre count in asbestosis range in same laboratory
• (Specific fibre count numerical criteria quoted not
applicable to data from laboratories other than Helsinki)
Consensus Report Scand J Work Environ Health 1997;23:311-316
Henderson DW Pathology 2004;36:517-550
Roggli VL, et al. Arch Pathol Lab Med 2010;134:462-480.
Attribution of Lung Cancer to Asbestos:
The Helsinki Criteria
• Some criteria more robust than others
• Subsequently criticised for not taking account of
fibre type
• Reviewed and largely reaffirmed in 2004; account
taken of fibre type
Consensus Report Scand J Work Environ Health 1997;23:311
Modified Helsinki Criteria
• Occupational history indicating cumulative exposure ≥ 25
fibre/ml years for exposure to mixed fibre types,
‘predominantly’ (in practice at least 80%) amphiboles
(amosite and /or crocidolite)
• For an equal mix of chrysotile and amphiboles around 40
fibre/ml years needed to double risk of cancer (although
the risk is almost entirely due to the amphibole)
• Dose for exposure to chrysotile only depends upon
industry, eg textile manufacture 100, friction products 1000
fibre/ml years
Consensus Report Scand J Work Environ Health 1997;23:311
Henderson DW et al, Pathology 2004;36:517-550
Hodgson & Darnton Ann Occup Hyg 2000; 66:565-601
The Practical Medical Basis for an
Asbestos Induced Lung Cancer Claim
• At least one of:
– Radiological evidence of asbestosis
– Pathological evidence of asbestosis
– Exposure history assessed by a consultant
engineer/forensic scientist as comfortably
fulfilling modified Helsinki criteria
– A lung fibre count within the asbestosis range
in the same laboratory
Assessing Cumulative Exposure
• Often occupational histories are complex with
different types of exposure in different
employments
• Need to estimate dose received from each
activity in each period of employment
• The more complex the exposure history the
less likely that a dose estimate will be
sufficiently reliable to substantiate a claim
• Small changes in assumptions lead to large
changes in estimated dose
Cumulative Dose Estimation
• Requires detailed explanation and estimation by
the Claimant concerning:
– Circumstances of exposure
– Proximity to source of asbestos dust
– Frequency and duration of episodes of
exposure
– Protective measures, if any
• Expert assessment requires knowledge of
– Fibre levels generated by activities described
– Fibre types associated with different activities
Approximate Asbestos Dust Levels
Process
Mixing lagging
Airborne
Dust (f/ml)
250
Stripping lagging
100
Cutting insulation board power saw
20
Cutting insulation board hand saw
5
Cutting cement sheet hand saw
1
Sanding asbestos plaster eg Artex
0.1
Changing brake linings
<0.1
Health and Safety Executive Guidance Note EH35, 1989
Harries PG Ann Occup Hyg 1971;14:241-254
Fibre Types Usually Involved
• Pipe lagging mostly amphiboles
(amosite and crocidolite)
• Insulation board (soft) amosite
• Cement sheet (hard) chrysotile
• Corrugated roof sheets chrysotile
• Artex chrysotile
• Brake and clutch linings chrysotile
Bystander Exposure
• Frequently exposure was from being in
the vicinity of asbestos use or
disturbance
• Airborne dust levels fall rapidly with
distance
• 20 feet away levels fall by about 90%
• Estimation of distance from source
therefore important
Common Exposures Which Are Unlikely To
Be Important In Lung Cancer Causation
• Brake and clutch linings
• Artex mixing, applying and removing
• Sanding soffits, gutters and downpipes before
painting
• Work with corrugated asbestos cement roofing
sheets
• Stripping asbestos with precautions from 1983
onwards
• It is very uncommon for exposures which
commenced after the early to mid 1970s to have
been sufficient to double the risk of lung cancer
Asbestos Exposure: Indirect Evidence
• Unless employed in a recognised high risk trade, eg
lagger, indirect evidence is seldom a sufficient basis
for a meaningful dose estimate
• Witnesses can describe the circumstances of
exposure but unless they worked alongside the
deceased all the time, or exposure was constant
rather than intermittent, they cannot say what
proportion of the deceased’s working time involved
exposure
• Hence, there is seldom a realistic basis for a claim in
a deceased case without direct witness evidence
unless there is lung tissue available from surgery or
autopsy for fibre analysis
Basis For A Claim From Engineering Evidence
• An estimate based on the Claimant’s evidence which is
‘just enough’, eg 25 fibre ml years of which 80%
amphibole, is not a sound basis for a claim
• Expert would have to concede in cross examination that
there are wide confidence intervals around the estimates
• Defendant will inevitably have an expert whose estimate
on basis of Defendant’s evidence is lower, ie ‘not
enough’
• A Judge who has no basis on which to prefer one expert
is highly likely to find exposure was between the two
estimates, ie ‘not enough’
Basis For A Claim From Engineering Evidence
• If a claim is to be based solely on estimated exposure the
estimate should be high enough for the expert to be able
to acknowledge wide confidence intervals but still be
confident that exposure was ‘enough’,
– eg estimate total dose 80 fibre ml years +/- 40,
– ie 40 – 120 fibre ml years
– Estimate 70% amphibole, +/- 20%, ie 50% - 90%
– So lower end of both ranges is 40 fibre ml years
including at least 50% amphibole, ie ‘enough’
Pathological Quantification of Exposure
• Counting asbestos bodies in lung sections
uninvolved by cancer
– Number of asbestos bodies per cm2 of 5
micron thick section averaged over all
sections examined
• Quantitative analysis of fibre content of lung
tissue; more statistically reliable
– Light microscopy
– Electron microscopy
Quantification of Asbestos Fibres
in Lung Tissue
• A piece of lung is weighed, usually around 0.3g
• Ideally wet fresh lung used but usually lung from
paraffin block used; because of dehydration count
multiplied by 0.7 to convert to wet lung count
• Lung tissue is then digested with chemicals eg
sodium hydroxide, or ashed in a furnace
• Remaining material filtered to collect fibres for
microscopy
• Fibres counted
• Multiplication factor applied to obtain count per gram
of lung tissue
Type of Microscopy
• Light microscopy (LM) can reliably count only coated
fibres, ie asbestos bodies (AB)
– LM cannot identify fibre types
• Electron microscopy (EM) identifies uncoated fibres
– Transmission EM can identify smaller fibres than
scanning EM
– EM can identify fibre types by looking at elemental
composition of the fibre using energy dispersive xray micro-analysis (EDXA)
Fibre Counts: Methodological Issues
• Different laboratories use variations of same
techniques
• Even when ostensibly using exactly the same
technique different laboratories obtain
different values on the same samples
• Therefore necessary to compare result in an
individual case with reference range from
same laboratory
EM Fibre Counts: Methodological Issues
• Non-uniform distribution of fibres in lung
tissue
• Statistical error in counting
• Together lead to variation between results
from different samples of same lung
• Up to 3 fold variation common, up to 10 fold
occasionally
Clearance of Asbestos Fibres
• Fibres cleared over time by natural mechanisms, eg
engulfment by macrophages, expectoration in
sputum, dissolution in situ
• Clearance half time, ie time for count to fall by 50%
varies with fibre type:
– Chrysotile (white asbestos) a few months
– Crocidolite (blue asbestos) 6-7 years
– Amosite (brown asbestos) 20 years
Clearance of Asbestos Fibres
• Difficult to take into account because
published data does not give time since
exposure ceased
• Clearance will have occurred in cases upon
which asbestosis range is defined as well as
in index case
Fibre Counts: Asbestosis Range
• Total retained amphibole asbestos fibre
count in cases of asbestosis, fulfilling current
histological diagnostic criteria
• Lower end of the range is the 5th percentile,
ie the level above which 95% of cases lie
• Chrysotile count excluded because of rapid
clearance and low potency
Fibre Count Criteria To Support Lung
Cancer Causation
• Asbestos bodies in lung sections
– Average of 2 per cm2 of 5 micron thick section
– Or 12 per cm2 of 30 micron thick section
– ie the number needed for a diagnosis of asbestosis if
diffuse interstitial fibrosis present
• Fibre count
– In the asbestosis range in the same laboratory
– Light microscopy usually > 100,000 per gm dried lung
– Electron microscopy (Cardiff) > 3.4 million
amphiboles per gm dried lung (lower 5th centile of 236
cases)
Conflicting Evidence
• If conflict between estimated exposure and a fibre count
usually more weight is accorded to the fibre count, but not
always
• Occupational history accorded more weight if:
– Predominantly chrysotile exposure, because rapid fibre
clearance makes fibre analysis useless for assessing
chrysotile exposure
– Fibre count clearly inconsistent with a simple
occupational history, eg lagger for 20 years
– Technical problem with analysis, eg lung contaminated
by tumour tissue or insufficient tissue available to be
representative
Lung Cancer Claims: Practicalities
• Living Claimant
– Obtain detailed statement specifying for each job
• Dates, employer
• Circumstances of exposure
• Proximity to source of airborne fibres if indirect
exposure
• Frequency and duration of episodes of
exposure
• Precautions, if any
– Warn Claimant and family post-mortem required if
claim not concluded; doctors will not arrange if
they are not thinking of disease as occupational
Lung Cancer Claims: Practicalities
• Living Claimant
– If solicitor is confident statement suggests
sufficient exposure, ask medical opinion as
to whether dose estimate required before
medical report
– If doubtful that sufficient exposure ask
medical opinion, if doctor agrees
insufficient, go no further
– If obviously nowhere near sufficient
exposure, go no further
Lung Cancer Claims: Practicalities
• Deceased Claimant
– If post-mortem done ask pathologist to preserve
lung tissue uninvolved by tumour as well as
tumour
– Do not rely upon the post-mortem examination
report conclusions; many are of abysmal standard
– If PM not done find out if surgery performed; if so
ask hospital to preserve tissues
– Obtain preliminary medical opinion as to whether
review of pathology and/or fibre count required
Lung Cancer Claims: Practicalities
• Deceased Claimant, post-mortem not done and no
surgical tissue available
– Statement by deceased available?
• If confident statement suggests sufficient
exposure: ask medical opinion as to whether
dose estimate required before medical report
• If doubtful that there was sufficient exposure ask
medical opinion; if doctor agrees, go no further
• If obviously nowhere near sufficient exposure go
no further
– No statement by deceased
• unless very obvious probability of heavy
exposure, eg lagger, go no further
Asbestos and Lung Cancer
Could the Test of Causation Change?
• In an obiter dicta in the Supreme Court judgment in
Sienckeiwicz v Grief and Knowsley MBC v Willmore
2011 concrning mesothelioma, Lord Phillips
questioned the conclusion in Shortell v BICAL (2008)
Construction Ltd in which Mackay J based his
assessment of causation of lung cancer on a risk
factor of greater than twofold from asbestos having
been established: “I question whether ……. the
‘doubles the risk’ test is correct in cases where
asbestos and tobacco smoke have combined to
cause lung cancer”.
Shortell v BICAL (2008)
• In Shortell v BICAL Ltd there was little discussion of the
mechanisms of asbestos carcinogenesis
• The Claimant’s case was based upon the dose of
asbestos, estimated by Mr Deary at 99 fibre ml yrs
involving mixed fibre types, having more than doubled the
risk of lung cancer, hence satisfying the ‘but for’ test
• The Defendant accepted that this was the appropriate
test, but relied on Mr Walker who estimated the dose at
only 9.5 fibre ml years, so there was no need to explore
mechanisms in evidence
• This was why Mackay J, who preferred the evidence of
Mr Deary, relied upon doubling of the risk as the test for
establishing causation
Asbestos Carcinogenesis
• It can be demonstrated that there is a synergy
between asbestos and tobacco carcinogens in
causing lung cancer, not only on the basis of the risk
factors but also on the basis of molecular
carcinogenesis
• Asbestos fibres act cumulatively to increase delivery
of tobacco carcinogens to lung epithelial cells, impair
detoxification of some tobacco carcinogens, increase
DNA damage, and impede DNA repair, thus
increasing the frequency of genetic alterations which
lead to cancer
Asbestos Carcinogenesis
• It can thus be argued that in any person who has
developed lung cancer after substantial exposure to
asbestos it is more likely than not that asbestos fibres
have physically contributed to the carcinogenic process,
not just increased the risk that cancer would occur
• It is still necessary to refer to risk factors as determined
from epidemiological studies to quantify the contribution
from asbestos
Phurnacite Litigation (2012)
• The Hon Mrs Justice Swift
– Accepted that coke plant fumes caused lung
cancer (main carcinogen benzo[a]pyrene, also
found in tobacco smoke)
– Relied upon doubling of the risk test
– Rejected an invitation to find that causation could
be established on the basis that tobacco smoke
and occupation involved exposure to the same
carcinogen, even if the risk from the occupational
contribution was less than twofold (Not appealed)
Asbestos and Lung Cancer
Could the Test of Causation Change
• Can the Court be persuaded to follow Lord Phillips to
conclude that a risk of less than twofold from asbestos is
sufficient?
• If so, how much less than twofold? A less than 20%
increase in risk as for mesothelioma in Sienkiewicz?
Asbestos Induced Lung Cancer
Should Damages Be
Apportioned?
Heneghan v Manchester Dry Docks et al (2014)
• Lung cancer attributed to asbestos
• Risk factor from asbestos estimated at 5-fold, risk
from smoking at 4-fold
• Agreed by both sides that, on balance, he would not
have developed lung cancer without asbestos
exposure, ie in legal terms asbestos caused the
cancer
• Available Defendants accounted for only 35.2% of
the total dose, one of them for only 2.5%
• Should damages be apportioned in accordance with
Holtby (in asbestosis)?
Heneghan v Manchester Dry Docks et al 2014
• Claimant argued lung cancer is an indivisible injury,
therefore no apportionment of damages
• Also that, on balance, fibres from all exposures
contributed to carcinogenesis
• Defendants argued causation could be established
only by analogy with Fairchild, ie each Defendant
contributed to the risk since, on the balance of
probabilities, the cancer would have occurred without
any of the Defendants’ exposures, or even without all
of them, since together they accounted for less than
50% of the risk due to asbestos
Heneghan Judgment
• Mr Justice Jay concluded that the Claimant had to rely
on an extension of Fairchild to establish causation
against any of the Defendants, since the conventional
‘but for’ test could not be satisfied against any of them
• Did not accept that consideration of mechanisms of
carcinogenesis established that fibres from each
probably contributed to causation of the disease (did not
explain why not and dismissed evidence about
carcinogenesis, which he referred to as ‘microbiological
processes’ as irrelevant)
Heneghan Judgment
• Damages awarded against the Defendants in
proportion to their contribution to the total risk
resulting from sued and non-sued exposures
• Hence, the Claimant recovered 35.2% of damages
• Mr Justice Jay said if Claimant was right that
damages should not be apportioned for an indivisible
injury, ie cancer, and if the Defendant which
contributed only 2.5% had been the only one
available to be sued that Defendant would have had
to pay 100% of damages which the judge did not
think would have been fair
• The decision has been appealed
Lung Cancer Survival
• 90% of patients inoperable at
presentation
• About half who undergo surgery die of
the disease
• Most with inoperable disease die within
1 year