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 2-
week 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 £500-
600
• 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
40
Number of patients
35
30
25
20
15
10
5
0
GP Hospital Ward A&E MDT Surveillance
Source of referral
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
Figure 2. Number of patients correctly and incorrectly referred for an urgent lower GI
incorrectly referred for an urgent OGD endoscopy
25
25
Number of patients 20
20
Number of patients
15
15
10 10
5 5
0 0
Correct Incorrect Correct Incorrect
Referral type 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
12
Number of patients
10
8
6
4
2
0
Urgent outpatient referral Consider urgent outpatient Routine outpatient referral
referral
Type of amended 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
5
4
Number of patients
3
2
1
0
Normal Diverticular Disease Lower GI polyp Lower GI malignancy Upper GI polyp Oesophageal ulcer and Duodenitis, duodenal Gastritis and
gastritis ulcer, gastritis and 2 duodenitis
gastric ulcers.
Diagnosis
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
12
Number of patients
10
8
6
4
2
0
Died Malignancy PPI, discharged Surveillance Normal,
treated OGD discharged
Outcome
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
4
Number of patients
3
2
1
0
Ulcerative colitis Normal, discharged Polyp excised, Haemorrhoids, Malignancy treated Malignancy,
treated surveillance discharged palliative care
Outcome
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 4 2 0 1 0
• Suspicious (1) 0 0 1 0 0 0
• Malignant (49) 4 12 17 7 5 4
• Total (64) 6 16 20 7 6 4
• % of total 9.4 25 31.3 11 9.4 6.3
Number of adequate = 15.7 %
• Total 64
• Inadequate 5
• Negative 9
• Low grade dysplasia, 1
• Adenocarcinoma 9
• Squamous cell carcinoma, 17
• Carcinoma (NOS) 11
• Small cell carcinoma 8
• Metastatic or other 4
Not TTF1+ TTF1+ TTF1 – TTF1- TTF1 +
satisfactory p63+ p63- p63 + p63 - p63 +/-
Adenoc 0 1 5 0 0 0
(17%) (83%)
sqcc 2 0 0 4 0 0
(100%)
Carcinoma 2 0 4 0 4 1 (11%)
NOS (44%) (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 TTF +ve
CK 5/6 -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 NHS North West
Supplier Data
Your Support Report 2010/11
Data Supply
‘We can only be sure to improve
Data Quality
what we can actually measure’
– Lord Darzi
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 Pathology Comment
AINTREE UNIVERSITY HOSPITALS NHS
FOUNDATION TRUST GREEN
ALDER HEY CHILDREN'S NHS FOUNDATION 04/10/2010 First electronic send. Received
TRUST
a file from Jan 2009 to June 2010.
GREEN Receiving monthly sends thereafter
COUNTESS OF CHESTER HOSPITAL NHS
FOUNDATION TRUST GREEN
ROYAL LIVERPOOL AND BROADGREEN Receipt re-established
UNIVERSITY HOSPITALS NHS TRUST GREEN
SOUTHPORT AND ORMSKIRK HOSPITAL NHS Still sending paper
TRUST RED
ST HELENS AND KNOWSLEY HOSPITALS NHS
TRUST GREEN
WALTON CENTRE FOR NEUROLOGY AND Still sending paper
NEUROSURGERY NHS TRUST RED
WARRINGTON AND HALTON HOSPITALS NHS
FOUNDATION TRUST
GREEN
WIRRAL UNIVERSITY TEACHING HOSPITAL NO DATA RECEIVED SINCE MARCH 2010
NHS FOUNDATION TRUST
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 non-
smoking, 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 histo-
or 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 2009-
November 2010
• Phillipe Tanière, University of
Birmingham
• Funded by AstraZeneca
• Non-small cell lung cancer
• Any stage
• 200 cases sent for analysis
December 2009-
November 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%
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
Non-mutated patient (normal
sequence)
Visible light
Gene sequence (codons 12 and 13)
KRAS mutation +ve and –ve
results
c.34G>T,
p.Gly12Cys
No mutation
c.38G>A, p.Gly13Asp
KRAS testing 6th
May 2010 to 2nd
Dec 2010
• 28 referrals (cut sections or tissue blocks)
from 5 pathology laboratories:
• Arrowe Park 6
• Chester 7
• Royal Liverpool 3
• Southport 8
• Whiston 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
KRAS reporting times
Number of referrals
8
6
4
2
0
2 3 4 5 6 7 9 10
Working days taken to report results
KRAS testing 6th May 2010 to 2nd
Dec 2010
• 16/28 - no detectable KRAS mutation
• 12/28 (43%) - detectable KRAS mutation
34G>T
• 10 in codon 12 (Gly12Cys), 2
• 2 in codon 13
35G>T
• 0 in codon 61 (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 Incidence 5yr survival
Dukes A 10% 90+%
Dukes B 22% 60-80%
Dukes C 39% 30-60%
Metastatic 29% 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 8.9m 8m
RR 47% 39%
OS 23.5m 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
Mutated ms 4.5m 4.6m
1yr 13% 19%
RR 1% 0%
Wild Type ms 9.5m 4.8m
1yr 28% 20%
RR 12% 0%
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 Mutant
PFS 9.9 8.7m p=0.0167
MS 24.9m 21 m ns
RR 66% 43% p=0.0028
Surgery 7% 3.7%
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 Mutant
PFS 7.7 m 7.2 m p=0.01
RR 60% 37% p = 0.011
Surgery 11% 4.1% 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
Inoperable Operable
liver metastasis 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% 34%
0.4 27%
34%
0.2 29%
19%
0.0
Resectable (n = 425)
0 1 2 3 4 5 6 7 8 9 10
Survival time (years) Initially unresectable (n = 95)
Adam R. Ann Oncol 2003;14:ii13-ii16.
Resection rate correlates with tumor response rate in both
selected and non-selected patients
Resection rate Studies including selected
patients
0.6
(liver metastases only,
0.5 no extrahepatic disease)
(r=0.96, p=0.002)
0.4
Studies including all
0.3
patients with mCRC
0.2 (solid line)
(r=0.74, p<0.001)
0.1
0.0 Phase III studies including
0.3 0.4 0.5 0.6 0.7 0.8 0.9 all patients in mCRC
Response rate (dashed line)
(r=0.67, p=0.024)
Folprecht et al. Ann Oncol 2005;16:1311-1319.
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 1st line
CTX
44pts
MS 36m (32 – 39)
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
Folfox Fotfox + cet
3yr dfs 74% 73%
3yr os 87% 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
Risk-adjusted APE rate
40
30
20
10
0 100 200 300 400 500
Number of surgically treated rectal cancer patients
Five-year relative survival for colorectal cancer patients (diagnosed 1996-
2002) 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
Refer- Diag Stage Rx Rec/Mets Rx Pall. Death
ral Care
Diagnostics
Datasets/Sources
CWT
MDT
RTDS
HES
NCASP
Ca. Reg
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
Risk-adjusted APE rate
40
30
20
10
0 100 200 300 400 500
Number of surgically treated rectal cancer patients