A study into the urgent
endoscopy referral system for
patients with suspected
gastrointestinal cancer
Christopher Jump
3rd Year Medical Student
Background information
• With the aim of improving the detection of cancers at
an early stage and therefore survival rates the 2week referral system was introduced in 2000 by the
Department of Health and was revised in 2005 by
NICE
• This included a referral form which specified
symptoms that needed to be present in order for the
patient to be urgently referred to a specialist
consultation or directly to endoscopy
Reasons the study was needed
• Many patient’s specimens referred as urgent to the
histopathologist are not diagnosed with malignancy.
This displaces ‘correctly’ referred urgent patients
down the waiting list, potentially causing them a
worse prognosis due to the delay of diagnosis and
subsequent treatment
Reasons the study was needed
• Each colonoscopy costs about £900
• Each oesophagogastroduodenoscopy (OGD) costs about £500600
• Histopathology costs are about:
o £67 per single biopsy site
o £100 for 2 biopsy sites
o £133 for 3 biopsy sites
• The PCT pays for each one they refer for, so if they are not
necessary it is a waste of their limited budget
Reasons the study was needed
• There are significant complications associated with
all types of endoscopy, which patients are being
needlessly exposed to if they are incorrectly referred
• E.g. Perforation, haemorrhage, infection, pain and
discomfort, sedation associated (cardio-pulmonary
events), etc.
Current evidence base
• Limited number of studies investigating urgent
referral for endoscopy in GI cancer patients, most of
which look into therapeutic endoscopy
• Many studies looking into the effectiveness of the
guidelines for urgent referral to a specialist in
secondary care. Have shown mixed results
regarding if the guidelines are specific enough to
detect early cancer presentation and their effect on
the outcome of patients
Main aims of the study
• To investigate:
o The number of patients that are correctly and
incorrectly referred for urgent endoscopies
o The differences in outcome between the patients
who were correctly and incorrectly referred
Method
• 50 patients included in the study, 25 who underwent an upper GI
endoscopy and 25 who had a lower GI endoscopy between the
25th February and 17th March 2009 at Southport and Formby
District General Hospital.
• Patients were identified by urgent histopathology referral forms.
• Medical records were then accessed and data collected.
• Urgent referrals were deemed to be correct or incorrect using
‘NICE referral for suspected cancer guidelines’.
• Outcomes were recorded by assessing their progress since their
endoscopy.
Results
• Mean age of 72.1 years
• 25 males and 25 females in total sample
• When divided:
o 14 females and 11 males in upper GI group
o 11 females and 14 males in lower GI group
Results- Source of referrals
• 43 (86%) of the 50 patients were referred from a GP
• 4 from hospital wards
• 1 from A&E, 1 referred by MDT, 1 surveillance
50
45
Number of patients
40
35
30
25
20
15
10
5
0
GP
Hospital Ward
A&E
Source of referral
MDT
Surveillance
Results- Number of correct and
incorrect referrals
• 18 (36%) of 50 patients were referred in accordance with NICE
guidelines
• When divided:
o Upper GI= 4 correct and 21 incorrect referrals
o Lower GI= 14 correct and 11 incorrect referrals
Figure 3. Number of patients correctly and
incorrectly referred for an urgent lower GI
endoscopy
Figure 2. Number of patients correctly and
incorrectly referred for an urgent OGD
25
Number of patients
Number of patients
25
20
15
10
5
0
20
15
10
5
0
Correct
Incorrect
Referral type
Correct
Incorrect
Referral type
Results- what the upper GI
referrals should have been
• Of the 21 incorrect referrals:
o 12 should have been given an urgent outpatient referral
o 5 should have been considered for an urgent outpatient referral
o 4 should have been routinely referred for an outpatient appointment
Figure 4. Amended referrals for patients incorrectly referred for
urgent OGD
14
Number of patients
12
10
8
6
4
2
0
Urgent outpatient referral
Consider urgent outpatient
referral
Type of amended referral
Routine outpatient referral
Results- Outcomes of correct
referrals
• Upper GI:
o 1 patient with a benign polyp, now on surveillance
o 1 patient with an oesophageal ulcer and gastritis (PPI and
discharged)
o 1 patient with duodenitis, duodenal ulcer, gastritis and 2 gastric
ulcers (PPI and discharged)
o 1 patient with gastritis and duodenitis (PPI and discharged)
• Lower GI:
o 5 cancers; 3 died, 1 is treated palliatively and 1 had surgical
excision and is now under surveillance
o 2 patients with Diverticular Disease discharged
o 2 patients with benign polyps discharged
o 5 patients normal, discharged
Results-Outcome of correct
referrals
Figure 8. Outcomes of correct urgent referrals in total sample
6
Number of patients
5
4
3
2
1
0
Normal
Diverticular Disease
Lower GI polyp
Lower GI malignancy
Upper GI polyp
Diagnosis
Oesophageal ulcer and Duodenitis, duodenal
gastritis
ulcer, gastritis and 2
gastric ulcers.
Gastritis and
duodenitis
Results-Outcome of incorrect
referrals
• Upper GI
o 3 patients died (2 cancers, 1 unknown)
o 13 patients treated for an inflammatory condition (oesophagitis,
gastritis or duodenitis) with a PPI and discharged.
o 2 patients normal
o 2 treated for malignancy (partial gastrectomy, oesophageal stent)
o 1 patient continued on surveillance for Barrett’s oesophagus
Figure 9. Outcomes of incorrect urgent OGD referrals
14
Number of patients
12
10
8
6
4
2
0
Died
Malignancy
treated
PPI, discharged
Outcome
Surveillance
OGD
Normal,
discharged
Results-Outcome of incorrect
referrals
• Lower GI:
o 3 malignancies detected; 2 had successful surgical excisions,
1 treated palliatively
o 3 patients had adenomatous polyps excised, now under
surveillance
o 2 normal patients
o 1 with haemorrhoids, discharged
o 2 treated for ulcerative colitis (both medication, 1 also had a
colectomy)Figure 10. Outcomes of incorrect urgent lower GI endoscopy referrrals
Number of patients
4
3
2
1
0
Ulcerative colitis
treated
Normal, discharged
Polyp excised,
surveillance
Haemorrhoids,
discharged
Outcome
Malignancy treated
Malignancy,
palliative care
What has it shown
• Minority (36%) of urgent referrals comply with guidelines
• Majority (81%) of incorrect referrals are from GPs
• There are considerably more upper GI than lower GI incorrect
urgent referrals for endoscopy (21/25- 11/25)
• Minority of patients who are urgently referred for endoscopy
are diagnosed with cancer (24%)
• The incorrect referrals detected more cancers than the correct
referrals (7-5)
What has it shown
• Correct upper GI referrals detected no cancers, incorrect
detected 4
• Correct lower GI referrals detected 5 cancers, incorrect
detected 3
• Incorrect lower GI referrals had a higher curative treatment
rate for cancer than correct lower GI referrals (66.7%-20%)
• 3 patients out of 50 had life saving surgical resection of their
cancer over the 3 weeks this study observed
• Equates to 52 patients a year saved at an annual cost of
about £718,363 for endoscopy and histopathology only
Conclusions
• The existing guidelines are not effective as originally hoped in
detecting patients with gastrointestinal cancer
• This study suggests that for a cancer to meet the current urgent
referral guidelines it has to be at a late enough stage to exhibit
enough symptoms to fulfil the criteria, with the majority of the time
this being too late to cure the patient
• Guidelines need to be reviewed and amended with the aim of
detecting more cancers at an early stage
• Guidelines need to be made compulsory for all GPs as this is where
the main problem lies
Limitations
• Symptoms in urgent referral form not specified,
which meant many patients may have been eligible
for urgent referral but were deemed not, as form not
filled in extensively enough. E.g. ‘rectal bleeding’ but
duration not specified
• Handwriting on some referral forms illegible so
patient may have met criteria
Limitations
• Some patients had missing histology reports in their
medical files so information had to be taken from
consultants letter to GP, which contains less specific
information
• Sample size in this study is not large enough to
draw significant conclusions, so a possible future
study could expand on these findings with more
patients from a wider region
Thank you for listening
Audit of Lung Biopsies
Received at Whiston Hospital
Histopathology Department in
2009
Dr S Kelly
Dr L Forsyth
Dr S A Melmore
Aim
• To review all lung biopsies received at Whiston
in 2009.
• To assess adequacy.
• Try to further differentiate the non-small cell
carcinomas (NSCC) into adenocarcinoma
(adenoca) and squamous cell carcinoma (SCC)
– on morphology, and
– with the aid of immunohistochemistry.
Background
• Biopsy interpretation limited by
– Sampling error,
– Sample size,
– Tumour heterogeneity.
• BTS guidelines (2001)recommend 90%
adequacy with 5+ biopsies in cases of
suspected malignancy.
• Small cell carcinoma (SMCC) → chemotherapy.
• NSCC → surgery.
• New medical treatments for adenoca
– without squamous differentiation (folate
antimetabolite chemotherapy drugs under
assessment by NICE), and
– with EGFR-TK mutations (EGFR-TK
inhibitors).
• Immunohistochemistry (IHC) may aid further
differentiation.
• Limitations include;
– inadequate sample size,
– crush artefact,
– positive staining of normal lung constituents,
– overlapping immunophenotypes, and
– previous studies conducted on resection
specimens and cytology but not biopsies.
Immunohistochemistry
• Squamous cell carcinoma; CK5, p63 and
34βE12.
• Adenocarcinoma; CK7, CK20 and TTF1.
• P63
– Nuclear, SCC 78-100%, adenoca 1-33%, SMCC
77%.
• CK 5/6
– SCC 100%.
• TTF1
– Nuclear, adenoca 68-85%, SMCC 84%, 5-21%
SCC.
– Poorly differentiated more likely to be negative.
SCC
H&E
TTF -ve
P63 +ve
Adenoca
TTF +ve
H&E
P63 -ve
Method
•
•
•
•
•
Telepath search for all lung biopsies in 2009.
All cases reviewed by 2 consultants and 1 SpR.
Number of biopsy fragments counted.
Morphological diagnosis given.
All carcinoma NOS, 6 adenoca and 6 SCC →
– TTF-1 and p63.
• TTF1 and p63 - ve →
– CK5/6
– Case notes and reports from RLBUHT
reviewed.
Results
• Pieces
1
2
3
4
5
6
• Negative (9) 2
• Suspicious (1) 0
• Malignant (49) 4
4
0
12
2
1
17
0
0
7
1
0
5
0
0
4
• Total (64)
• % of total
16
25
20 7
31.3 11
6
9.4
4
6.3
6
9.4
Number of adequate = 15.7 %
• Total
64
•
•
•
•
•
•
•
•
5
9
1
9
17
11
8
4
Inadequate
Negative
Low grade dysplasia,
Adenocarcinoma
Squamous cell carcinoma,
Carcinoma (NOS)
Small cell carcinoma
Metastatic or other
Not
TTF1+
satisfactory p63+
TTF1+ TTF1 – TTF1p63p63 +
p63 -
TTF1 +
p63 +/-
Adenoc
0
1
(17%)
5
(83%)
0
0
0
sqcc
2
0
0
4
0
(100%)
0
Carcinoma 2
NOS
0
4
(44%)
0
1 (11%)
4
(44%)
• 83% of adenocarcinoma TTF1 + (75-85% in
studies).
• 1 adenocarcinoma TTF1 + p63 + (1-33%
literature).
• 100% of satisfactory biopsies of sqcc p63 +.
• 4 cases of carcinoma NOS TTF1 +, p63 probably adenocarcinoma.
• 1 case p63 +/- , showed a positive internal
control. (Patient with cerebral metastases so no
resection performed).
H&E
CK 5/6 -ve
TTF +ve
P63 +/-ve
• 4 cases TTF1 - ve, p63 – ve,
– all internal controls for p63 + ve, and
– all CK5/6 – ve.
– 1 was small cell marker - ve on biopsy,
• resection showed a squamous cell carcinoma.
– 3 showed possible squamous morphology,
• no resection due to the patient’s co-morbidities,
metastases or locally advanced disease.
Conclusion
• We diagnosed 5/64 cases as inadequate on
H&E.
• Only 10/64 (15.7%) of the remaining cases
contained 5+ fragments of tissue.( vs. 90%).
• We made a morphological diagnosis of
malignancy on 49/64 cases, (9/49 had 5+
biopsies), and
• Differentiated type on H&E in 38/49 cases (6/38
had 5+ biopsies).
• 4/23 cases sent for IHC were inadequate.
– diagnosed on H&E as 2 x SCC, 2 x carcinoma NOS
• Our cases are comparable with the literature for
these robust IHC stains.
• For morphologically classic adenocarcinoma
TTF1 and p63 can be used in combination to
confirm the absence/presence of squamous
differentiation.
• For poorly differentiated NSCC cells the use of
TTF1 and p63 may aid further differentiation.
• Immunohistochemistry should be interpreted
together with morphology and clinical history.
• Sub classification should be avoided if uncertain.
• Limitations include;
– small sample size,
– difficult morphology,
– variable immunohistochemical staining and
interpretation,
– tumour heterogeneity,
– previous studies done on resection
specimens.
The future
• As the prospect of mutational analysis on
more/all of these tumours draws closer, and
• The use of IHC is used increasingly to choose
the tumours that will benefit from treatment,
• Clinicians will need to be aware of
– The need for an adequate sample, and
– The impact on turnaround times will mean
• waiting for a delayed report, or
• receiving preliminary and supplementory reports.
Recommendations
• Use TTF1 and p63;
– to confirm squamous differentiation in
morphologically diagnosed adenocarcinoma,
– in poorly differentiated NSCC but be aware of the
limitations.
•
•
•
•
Cut spare sections on all levels for IHC.
Check results of subsequent resections.
Comment on BTS adequacy in reports.
Disseminate this information to all
histopathologists and relevant clinicians.
Take Home Message
• For clinicians
– An adequate sample is required for accurate
diagnosis, and
– extensive IHC and mutational testing is time
consuming.
• For pathologists
– Immunohistochemistry should ALWAYS be
interpreted together with morphology and
clinical history.
Thank you
Any questions?
Cancer Data for Outcomes
Desperately Seeking
Your Support
‘We can only be sure to improve
what we can actually measure’
– Lord Darzi
NHS North West
Supplier Data
Report 2010/11
Data Supply
Data Quality
Poor Survival
Key Questions?
• Stage at Presentation
– Does my population have a problem with late stage
presentation? (not amenable to healthcare)
– Do I know where and with whom there are delays in
presentation/delays in diagnosis?
– Am I able to make informed investment/disinvestment
decisions?
• Access to Diagnosis and Treatment
– Does the population and sub-populations of my PCT
access the right services at the right time?
March 2011 – Electronic Path
Pipe delimited txt files
PROVIDER
AINTREE UNIVERSITY HOSPITALS NHS
FOUNDATION TRUST
Pathology
GREEN
ALDER HEY CHILDREN'S NHS FOUNDATION
TRUST
GREEN
COUNTESS OF CHESTER HOSPITAL NHS
FOUNDATION TRUST
GREEN
ROYAL LIVERPOOL AND BROADGREEN
UNIVERSITY HOSPITALS NHS TRUST
GREEN
SOUTHPORT AND ORMSKIRK HOSPITAL NHS
TRUST
RED
ST HELENS AND KNOWSLEY HOSPITALS NHS
TRUST
GREEN
WALTON CENTRE FOR NEUROLOGY AND
NEUROSURGERY NHS TRUST
WARRINGTON AND HALTON HOSPITALS NHS
FOUNDATION TRUST
WIRRAL UNIVERSITY TEACHING HOSPITAL
NHS FOUNDATION TRUST
Comment
RED
04/10/2010 First electronic send. Received
a file from Jan 2009 to June 2010.
Receiving monthly sends thereafter
Receipt re-established
Still sending paper
Still sending paper
GREEN
NO DATA RECEIVED SINCE MARCH 2010
RED
Pathology Mark Up
Breast
Size
Laterality
Grade
No of Nodes
Timeliness
• Timeliness of Data Supply
• Timeliness of Data Quality Feedback
– Don’t want to study history
• Timeliness of commentary on services as
they are currently configured and delivered
Summary
• Outcomes Framework a key driver for
regular, high quality, timely cancer data
• Informed service planning depends upon
high quality data – across patient pathway
• Need to achieve full electronic data
supply by March 2011
• Leverage vital for a step change in data
capture and reporting
Emerging technologies and
targeting treatments: EGFR
JR Gosney
Consultant Thoracic Pathologist
Royal Liverpool University Hospital
Epidermal growth factor
receptor (EGFR)
• EGFR (HER-1;
ErbB1)
• HER-2 (neu;
ErbB2)
• HER-3 (ErbB3)
• HER-4 (ErbB4)
EGFR gene mutations
and gefitinib
Sensitising mutations of
EGFR gene
• Classically in
peripheral, well
differentiated, acinar,
non-mucinous
adenocarcinomas with
a bronchioloalveolar
component
• About 60% of nonsmoking, Eastern Asian
women with
adenocarcinoma
• About 10% of Western
subjects with NSCLC
EGFR protein expression
• Immunochemical
detection of EGFR
protein is not
currently a reliable
indicator of
sensitising
mutations nor of
sensitivity to TKIs
EGFR gene amplification
• High EGFR gene
copy number is an
imprecise reflection
of mutational status
and sensitivity to
TKIs and its
detection by in situ
hybridization is time
consuming and
technically
demanding
Detecting mutations
• Mutations are detectable by
screening or targeted detection
– Trials of gefitinib employed an
amplification-refractory mutation
system (ARMS)-based kit that targets
29 mutations in the EGFR gene
– This technique is sensitive and
robust and does not require a high
level of technical expertise
EGFR mutational analysis
In the Merseyside & North
Cheshire Network
• About 750 new cases of NSCLC diagnosed by histoor cytopathology per annum
• Paraffin wax block with accompanying report and
H&E-stained section sent by referring pathologist to
Department of Pathology at RLUH
• Histological assessment with possible
microdissection followed by DNA extraction and
mutational analysis
• Return of report of analysis to managing oncologist
and to referring histopathology laboratory for
integration with histopathology report
• Correlation of histopathology with mutational status
for quality control, audit and development of service
December 2009November 2010
• Phillipe Tanière, University of
Birmingham
• Funded by AstraZeneca
• Non-small cell lung cancer
• Any stage
• 200 cases sent for analysis
December 2009November 2010
• 96 male
• 190 adenocarcinoma, 9 squamous, 1 LCNEC
• 170 tissue biopsies, 15 cytology (10 FNAs (8
EBUS), 4 pleural fluid, 1 washing), 15 from
resections
• 11 sensitizing mutations (5%)
• 2 mutations conferring resistance (1%)
• Mean turnaround time 15 days (8-34)
Eleven sensitizing
mutations
• Six male, five female
• Two of Chinese, one of Pakistani origin
• Eight new diagnoses: three needle cores, two
bronchial biopsies, one lymph node, one bronchial
washings, one from wedge resection
• Three recurrent disease: one original needle biopsy,
one vertebral metastasis, one from previous
resection
• Six point mutations (one 719 exon 18; one 861 exon
21, four 858 exon 21), five deletions (all exon 19)
• Nine adenocarcinoma, two non-small cell carcinoma
not otherwise specified
From December 2010
• Mutational analysis at Royal Liverpool
University Hospital
• Budget for analysis (and gefitinib) held
at Clatterbridge Centre for Oncology
• Locally advanced or metastatic disease
(according to license and NICE
guidance)
• Non-squamous tumours only
Pooja Jain
Consultant Clinical Oncologist
Clatterbridge Centre for Oncology
• EGFR in NSCLC
• Targeting EGFR
– Tyrosine Kinase Inhibitors
• John Gosney
• Key drivers in the
process of
– Cell growth
– Proliferation
• EGFR activating
mutation
– promotion of tumour cell
growth
– blocking of apoptosis
– increasing the production
of angiogenic factors
– facilitating the processes
of metastasis
Tyrosine kinase inhibition
• Initially developed as second line therapy
– BR 21
– Increase in the objective response rate (9%
<1 %)
– Increase in overall survival (6.7 versus 4.7
months)
– Improvement in symptoms & physical
function
• Early indication of selection
• First line therapy
– Platinum doublet
• RR 30%
• 65% of patients would be suitable
• Second line chemotherapy
– 30% of patients would be suitable
• Single agent docetaxel/gemcitabine/vinorelbine
• RR < 10%
• Phase II studies: objective response
rates of 55 to 90%
• IPASS study
• Phase III studies were in Far East
– IPASS
– WJTOG3405
Endpoints
Patients
Primary
•Chemonaïve
•Age
IRESSA
≥18 years
(250 mg daily)
•Adenocarcinoma
histology
•Never
or light
ex-smokers*
1:1 randomisation
•Life
expectancy
≥12 weeks
•PS
0-2
•Measurable stage
IV disease
IIIB /
Carboplatin
(AUC 5 or 6) /
paclitaxel
(200 mg / m2)
3 weekly#
• Progression-free survival (noninferiority)
Secondary
• Objective response rate
• Overall survival
• Quality of life
• Disease-related symptoms
• Safety and tolerability
Exploratory
• Biomarkers
• EGFR mutation
• EGFR-gene-copy number
• EGFR protein expression
* Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack
years; # limited to a maximum of 6 cycles
Carboplatin / paclitaxel was offered to IRESSA patients at progression
PS, performance status; EGFR, epidermal growth factor receptor
Mok et al 2009, Fukuoka 2009
1.0
IRESSA
N
Events
Probability of PFS
IPASS: Progression Free Survival (ITT)
0.8
609
453 (74.4%)
Carboplatin /
paclitaxel
608
497 (81.7%)
HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001
0.6
Median PFS (months)
4 months progression-free
6 months progression-free
12 months progression-free
0.4
5.8
74%
48%
7%
5.7
61%
48%
25%
0.2
0.0
At risk :
IRESSA
Carboplatin /
paclitaxel
•
0
4
8
12
16
20
24 Months
609
608
363
412
212
118
76
22
24
3
5
1
0
0
IPASS exceeded it’s primary endpoint and demonstrated
superiority for IRESSA in PFS compared to doublet
chemotherapy
Mok T, Wu
S et al. N Engl
J Med
2009; consistent
361:947-995
• TL, Thongprasert
PFS effect
was
not
over time
Overall R es pons e R ate %
(IT T P opulation)
IPASS: Overall Response Rate (ITT)
Overall Response Rate, ITT population
50
45
40
35
30
25
20
15
10
5
0
43
32
IR E S S A
C arboplatin/P ac litaxel
Odds ratio = 1.59 (95% CI 1.25, 2.01) p=0.0001
IRESSA produced a greater ORR than doublet chemotherapy in a clinically
selected group of patients
Mok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995
IRESSA EGFR M+ (n=132)
IRESSA EGFR M- (n=91)
1.0
Carboplatin / paclitaxel EGFR M+ (n=129)
Carboplatin / paclitaxel EGFR M- (n=85)
0.8
EGFR M+
HR=0.48, 95% CI 0.36, 0.64, p<0.0001
Probability of PFS
IPASS: Progression Free Survival (EGFR M+)
PFS in the EGFR M+ population
EGFR M-
0.6
HR=2.85, 95% CI 2.05, 3.98, p<0.0001
0.4
0.2
Treatment by subgroup
interaction test,
p<0.0001
0.0
0
•
•
4
8
12
Time from randomisation (months)
16
20
24
IRESSA halved the relative risk of progression compared with
carboplatin/ paclitaxel in EGFR M+ patients1
Median PFS was over 3 months longer with IRESSA in EGFR M+
patients than carboplatin/paclitaxel (9.5 vs 6.3 months)2
Mok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995. Iressa SmPC
80
O verall R es pons e R ate %
IPASS: Overall Response Rate (EGFR M+)
Superior ORR in the EGFR M+ population
71
IRESSA
Carboplatin / paclitaxel
70
60
47
50
EGFR M+ odds ratio (95% CI) = 2.75
(1.65, 4.60), p=0.0001
EGFR M- odds ratio (95% CI) = 0.04
(0.01, 0.27), p=0.0013
40
30
23.5
20
10
(n=132)
(n=129)
(n=91)
(n=85)
1.1
0
E G F R M+
E G F R MMok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995
Iressa SmPC
The NEJ002 and WJTOG3405
studies
Progressionfree survival
(%)
100
HR=0.30,
95% CI 0.22 - 0.41, p<0.001
Median PFS : 10.8 vs 5.4 months
80
60
40
IRESSA
(n=114)
Carboplatin/
20
paclitaxel
(n=110)
0
0
3
6
9
12
15
18
21
24
27
Months since randomization
Maemondo et al 2010
Proportion
without
progression
(%)
100
IRESSA
Cisplatin and
docetaxel
80
n
Median PFS
(95% CI)
60
86
86
9.2 months (8.0-13.0)
6.3 months (5.8-7.8)
HR=0.49, 95% CI 0.34-0.71; p<0.0001
40
20
p<0.0001
0
0
Number at risk
IRESSA
Cisplatin and docetaxel
10
20
30
40
Months since randomization
86
86
PFS: progression-free survival
63
49
22
11
11
7
4
3
3
0
2
0
2
0
0
0
Mitsudomi et al 2010
Line of
Treatmen
t
EGFR M+
(n)
ORR (%)
Median
PFS
(months)
Median
OS
(months)
Sequist et al 2008
1st
31
55%
9.2m
17.5m
Pretreated
10
60%
12.3m
13m
Mixed
24
62%
-
-
1st
55
69%
8m
-
1st
28
75%
11.5m
-
Mixed
17
59%
7.3m
18.9m
Mixed
11
91%
-
-
NON-ASIA
Journal of Clinical Oncology 2008;
26(15): 2442-2449
Cortes-Funes et al
2005
Annals of Oncology 2005; 16:
1081-1086
Cappuzzo et al 2007
Journal of Clinical Oncology 2007;
25(16): 2248-55
Yang et al 2008
Journal of Clinical Oncology 2008;
26(16): 2745-53
ASIA
IRESSA: Efficacy Independent of Ethnicity
STUDY
Tamura et al 2008
British Journal of Cancer 2008;
98(5): 907-14
Sone et al 2007
Cancer 2007; 109(9): 1836-44
Oshita et al 2006
British Journal of Cancer 2006;
• Understanding biology and biomarkers is
key to improve the management of lung
cancer
• Targeting the EGFR pathway represents
a major advance in the management of
NSCLC
• Mutation rates are low in the Western
world (local population is ~ 5%)
th
6
May 2010 –
nd
2
Dec 2010
Andrew Purvis, Clinical Scientist
Cheshire and Merseyside Regional
Molecular Genetics Laboratory
Liverpool Women’s Hospital
KRAS
• KRAS – small GTPase
• Signal transducer downstream of
EGFR (RAS/RAF/MAPK
pathway)
P
EGF
cell
EGFR membrane
P
• Regulator of cell proliferation and
survival
• Somatic mutations in KRAS
abolish GTPase activity =
uncontrolled proliferation
• Pathway isolated from EGFR
• Anti-EGFR therapy ineffective
Cell proliferation and survival
• ~40% of mCRC have a somatic
KRAS
RAF
MEK
MAPK
1
KRAS – sequence and
mutations
ATGACTGAATATAAACTTGTGGTAGTTGGAGCTGGTGGCGTAGGCAAGAGTGCCTTGAC
.-M--T--E--Y--K--L--V--V--V--G--A--G--G--V--G--K--S--A--L--T
60 GATACAGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAGGATTCCTA
20 --I--Q--L--I--Q--N--H--F--V--D--E--Y--D--P--T--I--E--D--S--Y
120 CAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGACACAGCAGG
40 --R--K--Q--V--V--I--D--G--E--T--C--L--L--D--I--L--D--T--A--G
180 TCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGGAGGGCTTTCTTTG
60 --Q--E--E--Y--S--A--M--R--D--Q--Y--M--R--T--G--E--G--F--L--C
240 TGTATTTGCCATAAATAATACTAAATCATTTGAAGATATTCACCATTATAGAGAACAAAT
80 --V--F--A--I--N--N--T--K--S--F--E--D--I--H--H--Y--R--E--Q--I
>90% of mutations in mCRC found in codons 12 and 13
~5% of mutations found in codon 61
detection of KRAS mutations at
LWH
• Why Pyrosequencing?
• Unambiguous detection of ALL possible
mutations in codons 12, 13 and 61
• Sensitive
• Detects 5%-10% mutant depending on the
mutation
• Results obtainable from DNA isolated from
PETs
• DNA of poor quality
• DNA of low quantity
• Proven technology
Example KRAS Pyrosequencing
results
Visible light
Non-mutated patient (normal
sequence)
Gene sequence (codons 12 and 13)
KRAS mutation +ve and –ve
results
c.34G>T,
p.Gly12Cys
No mutation
c.38G>A, p.Gly13Asp
th
6
KRAS testing
May 2010 to
Dec 2010
nd
2
• 28 referrals (cut sections or tissue blocks)
from 5 pathology laboratories:
•
•
•
•
•
Arrowe Park
Chester
Royal Liverpool
Southport
Whiston
6
7
3
8
4
• KRAS results obtained for 28/28 referrals
KRAS testing 6th May 2010 to 2nd
Dec 2010
• Reporting times of 28 referrals
• Mean reporting time 5.5 working days
• 18 (64%) reported within 5 working days
Number of referrals
KRAS reporting times
8
6
4
2
0
2
3
4
5
6
7
9
Working days taken to report results
10
KRAS testing 6th May 2010 to 2nd
Dec 2010
• 16/28 - no detectable KRAS mutation
• 12/28 (43%) - detectable KRAS
34G>T mutation
• 10 in codon 12
• 2 in codon 13
• 0 in codon 61
(Gly12Cys), 2
35G>T
(Gly12Val), 6
Normal, 16
35G>A
(Gly12Asp), 2
38G>A
(Gly13Asp) , 2
Proportion of KRAS mutations
detected
Sensitivity / UKNEQAS (quality
assessment scheme)
• Mutations can be present at low level
• Tumour heterogeneity
• Accompanying normal tissue
• Pyrosequencing detects mutations down
to 5-10% depending on mutation
• Current mutation detection rate is 43%
• Agrees with published data
• Suggests we have not missed any mutations
• Full marks in recent UKNEQAS scheme
• Not all participating labs received full marks
• ? include % neoplastic cells on KRAS reports
12, 13 and 61 have the same effect
on anti-EGFR therapy?
De Roock et al., JAMA. 2010;304(16):1812-1820
BRAF V600E ?
• A proportion of tumours with no KRAS
mutation will not respond to anti-EGFR therapy
• Other biomarkers?
• BRAF V600E detected in 5-12% of mCRC
• Same pathway as KRAS
• V600E increases BRAF activity ~10 fold
• Predicts resistance to anti-EGFR therapy
34G>T
(Gly12Cys), 2
35G>T
(Gly12Val), 6
Normal, 16
35G>A
(Gly12Asp), 2
38G>A
(Gly13Asp) , 2
Colorectal Cancer
Place of K-ras testing
Colorectal Cancer
Stage
Dukes A
Dukes B
Dukes C
Metastatic
Incidence
10%
22%
39%
29%
5yr survival
90+%
60-80%
30-60%
<5%
65% of patients with CRC will eventually
die from advanced disease
19,000pts annually in UK
Systemic therapy for CRC
1957
1994
2005
Best supportive care
5FU
Irinotecan
Capecitabine
30
25
20
15
10
5
0
Oxaliplatin
Bevacizumab
Cetuximab
Median survival - months
Cetuximab - 2003
• Chimeric mouse monoclonal ab
• Targeted against EGFR receptor
• Entry point to signal transduction pathway
– cell proliferation
– cell migration
– cell adhesion
– cell survival
EGFR signaling
Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.
Cetuximab
• active in CTX resistant colorectal xenografts
• synergistic with
– Irinotecan
– radiotherapy
NCI of Canada ph III Cet vs BSC
CO.17
572 pts, egfr expression +ve
Non responders to Ctx
MS
PR
Cetuximab
6.1m
8%
BSC
4.6m
0%
BOND study
Time to progression
Patients free of progression (%)
100
80
60
40
20
0
0
2
4
6
8
10
12
Time to progression (months)
p<0.001
Cunningham et al. N Engl J Med 2004; 351:337-345.
 ERBITUX + irinotecan
 ERBITUX
Cetuximab - Toxicity
• Acneiform rash
– Gd >1 76%
– Gd 3/4 12%
– maximal at wk3 then improves
– ? Rash associated with improved survival
CRYSTAL – Ph III Ist line
• 1198 pts
• FOLFIRI +/- cetuximab
Pfs
RR
OS
8.9m
47%
23.5m
8m
39%
20m ns
COIN – first line 3 arm trial
• FOLFOX/XELOX + cet continuous
• FOLFOX/XELOX
continuous
• FOLFOX/XELOX + cet intermittent
• 1630pts randomised
• No difference in OS or PFS
EGFR expression
• Not a useful predictive factor
– Heterogeneity of EGFR expression
– Variable affinity of EGFR for cetuximab
– Inconsistency in measurement
K-ras oncogene
•
•
•
•
Encode proteins downstream from EGFR
Essential component of EGFR signalling
Can acquire activating mutations in exon 2
Does mutation status of K-ras affect
response to anti-EGFR monoclonals?
CO.17
394/572 samples available for K-ras
analysis
K-ras mutation detected in 40%
CO.17
Cetuximab
BSC
ms
1yr
RR
4.5m
13%
1%
4.6m
19%
0%
Wild Type ms
1yr
RR
9.5m
28%
12%
4.8m
20%
0%
Mutated
CO.17 - Survival
EGFR signaling
Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.
CRYSTAL K-ras WT pts
• Post hoc analysis for NICE (TA176)
• 348pts FOLFIRI + cetuximab
WT
PFS
9.9
MS
24.9m
RR
66%
Surgery 7%
Mutant
8.7m
21 m
43%
3.7%
p=0.0167
ns
p=0.0028
COIN – WT analysis
• 729 WT pts OXFp +/- cetuximab
• PFS ns
• OS ns
• RR 64% vs 57% p=0.049
OPUS – first line Ph II
• 336pts 134 K-ras WT
• FOLFOX +/- cetuximab
WT
PFS
7.7 m
RR
60%
Surgery 11%
Mutant
7.2 m
37%
4.1%
p=0.01
p = 0.011
sig not reported
CELIM – first line
•
•
•
•
•
•
Randomised ph II
114 pts
Initially unresectable liver metastases
folfiri + cetuximab vs folfox + cetuximab
RR 68% vs 57%
Subsequent resection 43 vs 40%
1st line cetuximab + Ctx
• Variable effect on survival
• ? Consistently higher response rates
Liver metastases - down sizing
Operable
liver metastasis
Inoperable
liver metastasis
Chemotherapy
5yr survival< 5%
5yr survival 30-40%
• Systemic therapy may render tumours operable
• 95/701 (13.5%) rendered resectable
– Reason unresectable
•
•
•
•
60% (too large),
49% (ill located),
34% (multinodular),
18% (extrahepatic)
Adam Ann Surg Oncol 2001
Survival after chemotherapy-facilitated
resection of metastases is the same as
that for initially resectable metastases
Proportion surviving
1.0
0.8
54%
0.6
50%
0.4
34%
27%
34%
0.2
29%
19%
0.0
0
1
2
3
4
5
6
7
Survival time (years)
Adam R. Ann Oncol 2003;14:ii13-ii16.
8
9
10
 Resectable (n = 425)
 Initially unresectable (n = 95)
Resection rate correlates with tumor response rate in both
selected and non-selected patients
Studies including selected
patients
(liver metastases only,
no extrahepatic disease)
(r=0.96, p=0.002)
Resection rate
0.6
0.5
0.4
Studies including all
patients with mCRC
(solid line)
(r=0.74, p<0.001)
0.3
0.2
0.1
0.0
0.3
0.4
0.5
0.6
0.7
0.8
Response rate
Folprecht et al. Ann Oncol 2005;16:1311-1319.
0.9
Phase III studies including
all patients in mCRC
(dashed line)
(r=0.67, p=0.024)
NICE guidance TA176
•
Recommended Cetuximab + Chemotherapy for patients
– With inoperable CRC metastases confined to the liver
– Who were fit for surgery
– Who might be downsized to surgery following systemic therapy
CCO – Survival from I-CET
44pts
MS 10m (6 – 13)
CCO – Survival from
CTX
st
1
44pts
MS 36m (32 – 39)
line
Nov 08
Xelox x 12 weeks
Feb 09
May 09
Irinotecan x 12 wks
Oct 09
Jan 10
I-Cetux
Adjuvant Cetuximab
• FOLFOX +/- cetuximab
• NCCTG Intergroup phase III trial NO147
• 1760pts st III colon cancer wild type K-ras
3yr dfs
3yr os
Folfox
74%
87%
Fotfox + cet
73%
82%
Cetuximab 2010
• Downsizing liver metastases to resection
 In combination with oxaliplatin/5FU/Irinotecan
• Third line treatment in pts previously
responding to chemotherapy
 In combination with Irinotecan
 Adjuvant cetuximab not of value
The National Cancer Dataset
Project
- especially pathology!
Di Riley
Director for Clinical Outcomes
CRS, December 2007
.....Better information on cancer services and
outcomes will enhance patient choice, drive up
service quality and underpin stronger commissioning;
.....Collection of defined datasets on all cancer
patients will be mandated through the national model
contract. PCTs will be responsible for ensuring that
this information is collected by MDTs and sent to
cancer registries
CRS, December 2007
.....We particularly need to collect and
use high quality data on:
.....Clinical outcomes, including survival,
with adjustments for co-morbidity and
stage of disease.
60
50
40
Risk-adjusted APE rate
30
20
10
0
100
200
300
400
Number of surgically treated rectal cancer patients
500
Five-year relative survival for colorectal cancer patients (diagnosed 19962002) by stage at diagnosis, England
Number of cases (1996-2006) and five-year relative survival of colorectal
cancer patients (diagnosed 1996-2002) by stage at diagnosis, England
Project Purpose
• To redevelop the National Cancer Dataset for
use as a full operational standard in England
• To review the current business needs for the
collections and make sure that the output is fit
for purpose
NCIN ‘Data Views’
Patient Pathway
Datasets/Sources
Referral
Diagnostics
CWT
MDT
RTDS
HES
NCASP
Ca. Reg
Diag Stage
Rx Rec/Mets Rx
Pall.
Care
Death
SSCRG progress
• Approved mandated datasets
–
–
–
–
Cancer registration – additional review
GFoCW
Radiotherapy
CDS
• 12 SSCRGs identified ‘site specific’ items
– Link to ‘output’ requirements
– Based on existing datasets e.g. NCASP, BAUS
– Period of definitional testing
• Mandated for NHS from October 2012
Challenges....
• Clinical data from MDTs?
• Transport via standard NHS data flows
– SUS, Open Exeter (Cancer Waits)
– Direct Cancer Registries & Nat. Repository
– Direct to NCASP
• Linking activity and ‘care record’ data
– OPCDS + radiotherapy
– CWT + ‘registration’
– NHS number linked data views
• Coded data from path/radiology/etc
Pathology Data
• Patient care & management
– MDT
– Staging
– Ongoing care
• Cancer Outcomes/Registration
– Staging
– Morphology, topography, grade
– Risk adjusted analysis
NCRD – pathology
items -1
Diagnosis
DIAGNOSIS DATE (CANCER)
PRIMARY DIAGNOSIS (ICD)
TUMOUR LATERALITY
BASIS OF DIAGNOSIS (CANCER)
HISTOLOGY (SNOMED)
GRADE OF DIFFERENTIATION (AT DIAGNOSIS)
Staging
T CATEGORY (FINAL PRETREATMENT)
STAGING CERTAINTY FACTOR (T CATEGORY)
N CATEGORY (FINAL PRETREATMENT)
STAGING CERTAINTY FACTOR (N CATEGORY)
M CATEGORY (FINAL PRETREATMENT)
STAGING CERTAINTY FACTOR (M CATEGORY)
TNM CATEGORY (FINAL PRETREATMENT)
STAGING CERTAINTY FACTOR (TNM CATEGORY)
SITE SPECIFIC STAGING CLASSIFICATION
TNM CATEGORY (INTEGRATED)
T CATEGORY (INTEGRATED STAGE)
N CATEGORY (INTEGRATED STAGE)
M CATEGORY (INTEGRATED STAGE)
NCRD – pathology
items -2
Pathology Details
PATHOLOGY INVESTIGATION TYPE
SAMPLE RECEIPT DATE
INVESTIGATION RESULT DATE
CONSULTANT CODE (PATHOLOGIST)
ORGANISATION CODE (OF REPORTING PATHOLOGY)
PRIMARY DIAGNOSIS (ICD)
TUMOUR LATERALITY
INVASIVE LESION SIZE
SYNCHRONOUS TUMOUR INDICATOR
HISTOLOGY (SNOMED)
GRADE OF DIFFERENTIATION
CANCER VASCULAR OR LYMPHATIC INVASION
EXCISION MARGIN
NODES EXAMINED NUMBER
NODES POSITIVE NUMBER
T CATEGORY (PATHOLOGICAL)
N CATEGORY (PATHOLOGICAL)
M CATEGORY (PATHOLOGICAL)
TNM CATEGORY (PATHOLOGICAL)
SERVICE REPORT IDENTIFIER
SERVICE REPORT STATUS
SPECIMEN NATURE
ORGANISATION CODE (REQUESTED BY)
CARE PROFESSIONAL CODE (REQUESTED BY)
T CATEGORY EXTENDED (PATHOLOGICAL)
M CATEGORY EXTENDED (PATHOLOGICAL)
RCPath Datasets
• Guidelines for good clinical reporting
– Specific for different cancer sites
• What proportion of pathologists use
proforma-based reporting tools?
• How to or should we progress to encoded
data?
• Cancer registration & outcomes analysis
would benefit from it?
• Would MDTs also benefit - MDT dataset?
NCIN/RCPath Pathology
Project
• Structured or proforma reporting
• Codify & mandate ‘Core’ items
• Direction of travel too great
– Systems not available
– Change in clinical practice
– Patient management v outcomes analysis
• What is the solution?
– Professional & Clinical Record Standards
Professional Standard Stage 1
• Clarification of content to be provided within
free text reports (RCPAth Core Items)
• Or the use of the RC Path proforma.
• Communication to Pathologists of content
specification and mechanism for
transmission to Registries.
• Both of these aspects covered by RC Path
guidance
Standards - Stage 2
• Professional Standard version 2
– stipulation of proforma to be used for
reporting
– introduction of structured/coded items
• Patient Record Standard version 1
– identification of items which can be
structured and have SNOMED CT codes
Standards - Stage 3
• Professional Standard version 3
– structured data items
• Patient Record Standard version 2
– all items structured with SNOMED CT
coding
– identification of the linkage standards to
allow record to Registry transmission and
use.
Timescales & Process
• Working Group
– RCPath / NCIN / CfH /DH
– National Clinical Content & Requirements Board
(NCCRB)
– Role of RCPath for governance key
– Align with other related initiatives
• Estimated time – 5 years (2015)
–
–
–
–
Content Proposal – approved November 2010
Requirements Statement
Assurance Statement
Then the Information Standards Board
60
50
40
Risk-adjusted APE rate
30
20
10
0
100
200
300
400
Number of surgically treated rectal cancer patients
500