Every year in the UK, around 7000 people are diagnosed with pancreatic cancer (Office
for National Statistics, 2002), and more than 6500 are recorded as dying from the
disease (Quinn et al, 2001). In contrast to many other cancers, there has been little
improvement in survival prospects in recent decades, and currently, less than 3% of
patients remain alive 5 years after diagnosis (Coleman et al, 1999; Scottish Cancer
Intelligence Unit, 2000). Although this dismal prognosis has led to a nihilistic perspective
by some (Gudjonsson, 1995), others have reported 5-year survival rates following pancreatic
resection in excess of 20% (Yeo et al, 1995). Furthermore, it has recently been suggested
that there may be some scope for improvement in survival figures in the UK (NHS Executive,
2001; Garden, 2001). This guarded optimism is based on accumulating evidence that
the concentration of treatment activity among fewer high volume hospitals and/or surgeons
(as a proxy for specialisation) may lead to improved outcomes for patients with pancreatic
cancer (Edge et al, 1993; Gordon et al, 1995; Lieberman et al, 1995; Neoptolemos et
al, 1997; Gouma et al, 2000; NHS Executive, 2001; Garden, 2001; Rosemurgy et al, 2001;
Teisberg et al, 2001; Halm et al, 2002; Birkmeyer et al, 2002; Bachmann et al, 2003).
Many of the studies report reduced postoperative morbidity and mortality rates, and
shorter postoperative hospital stays following resection of pancreatic cancer, although
few have analysed long-term outcome. Recently, it has also been shown that increased
hospital volume is associated with a decreased hospital mortality rate for palliative
bypass procedures and for stent insertion as treatment for malignant obstructive jaundice
(Sosa et al, 1998). These phenomena have been related to the importance of a multidisciplinary
approach to both curative and palliative procedures available in high volume provider
institutions for patients with pancreatic cancer.
The aim of the present study was to investigate whether there is any evidence of benefit
from specialised care of patients with pancreatic cancer in Scotland, and by inference,
whether there is any scope nationally to improve the outlook of this unfortunate group
of patients.
DATA AND METHODS
The records of residents of Scotland diagnosed with pancreatic cancer (ICD-9157; ICD-10
C25) during the 5-year period 1993–1997 were selected from the Scottish Cancer Registry
(SCR). During this period, the age-standardised incidence rate (world standard population)
per 100 000 was 7.2 in males and 5.3 in females (Parkin et al, 2002). Equivalent mortality
rates for the same period were 6.7 in males and 4.9 in females (World Health Organization,
2001). SCR is a population-based registry that covers the whole of Scotland, with
a catchment population of around 5.1 million. Data quality is believed to be high,
both in terms of reliability (Brewster et al, 2002) and completeness of ascertainment
(Brewster et al, 1997). However, in common with many other countries, a high proportion
of pancreatic cancers are not microscopically verified (Parkin et al, 2002), precise
subsite of origin is often not established or available, and stage of disease at diagnosis
is not collected routinely. Excluded from further analysis were 178 cases registered
on the basis of a death certificate only (DCO), and 67 nonacinar cell pancreatic cancers
(neuroendocrine tumours (n=27), sarcoma (n=4), cholangiocarcinoma (n=8), and other
tumour types rarely associated with pancreas as the primary site of origin (n=28)).
Although mainly not microscopically verified, tumours coded as primary malignant neoplasms,
not otherwise specified (NOS) were included on the basis that they were more likely
than not to be carcinomas.
SCR records were supplemented with information on co-morbidity, metastatic disease
and operative procedures from hospital discharge (SMR01) records, derived from a permanently
linked database of hospital discharges (including day cases), cancer registrations,
and deaths (Kendrick and Clarke, 1993). There is evidence that the coding of hospital
discharge records in Scotland is reliable, at least for the main variables, such as
primary operative procedure (Harley and Jones, 1996). Three indicators of co-morbidity
were calculated for each member of the cohort: two of these – the Charlson score (Charlson
et al, 1987) and the Scottish index (Clinical Outcomes Working Group, 1996) – were
based on selected diagnoses found in any position on SMR01 records within 5 years
of the incidence date on the index cancer registration record. The third co-morbidity
index was based on the number of bed-days of hospitalisation in the 5 years prior
to diagnosis of pancreatic cancer. To avoid confounding due to the often insidious
onset of symptoms and signs of pancreatic cancer, this index was calculated for the
period between 6 months and 5 years prior to diagnosis, and separately for the 6 months
immediately prior to diagnosis.
Operative procedures are coded on SMR01 records according to OPCS4 (Office of Population
Censuses and Surveys, 1990), a widely used UK classification of surgical operations
and procedures. Based on these codes, inpatient and daycase operative procedures were
classified as resection, other surgery (predominantly palliative bypass operations),
or biliary stent. Prior to analysis, and based on local knowledge, consultants were
assigned to three categories: specialist pancreatic surgeons, clinicians with an interest
in the pancreas, or nonspecialists. Specialists were defined as those clinicians who
had a recognised multidisciplinary team with an associated oncologist and pathologist,
who contributed to clinical trials, and who had an established audit system and regularly
reported their results locally and nationally. Clinicians with an interest in the
pancreas were recognised as those who had a broader interest in upper gastrointestinal
conditions but who were known for co-ordinating the assessment and management of patients
with pancreatic cancer. Nonspecialists were defined as those who had a more general
clinical practice or were recognised as having a specific interest in another surgical
subspecialty.
Persons diagnosed with pancreatic cancer during 1993–1997 were assigned to a 1991
census-based Carstairs deprivation quintile according to their postcode sector of
residence at the time of diagnosis (Morris and Carstairs, 1991). The Carstairs deprivation
score is a small area indicator of socioeconomic status based on the prevalence measured
at the decennial census of four characteristics: overcrowding, male unemployment,
social class, and car ownership. Deprivation quintile one represents the least deprived
areas of Scotland and deprivation quintile five the most deprived areas.
Statistical methods
The χ
2-test was used to assess the statistical significance of differences in 30-day postoperative
mortality rates according to age-group, year of diagnosis, hospital caseload, consultant
caseload, and consultant specialisation category. Kaplan–Meier survival analysis was
used to obtain estimates of crude survival at 3 years following diagnosis. The log-rank
test was used to test for equality of survival curves between patients treated by
resection and all other patients. Multivariate Cox's proportional hazards models (Collett,
1994) were used to assess separately the impact of patient-, tumour- and health service-related
factors on survival at 3 years following diagnosis. A final model was based on the
statistically significant factors from the three separate models. The end point for
these analyses was death from any cause.
RESULTS
The final study population included 2794 patients with the characteristics shown in
Table 1
Table 1
Characteristics of the study population
Factor
No. of cases
%
Year of diagnosis
1993
553
19.8
1994
552
19.8
1995
479
17.1
1996
610
21.8
1997
600
21.5
Age groups
0–39
14
0.5
40–49
93
3.3
50–59
312
11.2
60–69
717
25.7
70–79
946
33.9
⩾80
712
25.5
Sex
Male
1330
47.6
Female
1464
52.4
Carstairs deprivation quintile
(Least deprived) 1
510
18.3
2
600
21.5
3
594
21.3
4
527
18.9
(Most deprived) 5
562
20.1
Unknown
1
0.0
Previous cancer
No
2611
93.5
Yes
183
6.6
Charlson co-morbidity index
a
None
2160
77.3
1–2 conditions
95
3.4
⩾3 conditions
539
19.3
Scottish co-morbidity index
a
None
1994
71.4
1 condition
516
18.5
⩾2 conditions
284
10.2
Bed-days co-morbidity index (in 6 months prior to diagnosis)
a
None
334
12
1–4 days
284
10.2
5–10 days
453
16.2
⩾11 days
1723
61.7
Bed-days co-morbidity index (between 6 months and 5 years prior to diagnosis)
a
None
1555
55.7
1–4 days
290
10.4
5–10 days
296
10.6
⩾11 days
653
23.4
Tumour subsite
Head of pancreas
1263
45.2
Body of pancreas
112
4.0
Tail of pancreas
57
2.0
Other
40
1.4
Unspecified
1322
47.3
Tumour morphology
Neoplasm, not otherwise specified
222
8.0
Carcinoma, not otherwise specified
1523
54.5
Adenocarcinoma, not otherwise specified
902
32.3
Mucin-producing adenocarcinoma
51
1.8
Other
96
3.4
Microscopically verified
No
1616
57.8
Yes
1178
42.2
Metastases within 4 weeks of diagnosis
a
No
2023
72.4
Yes
771
27.6
Presence of ascites recorded
a
No
2674
95.7
Yes
120
4.3
Surgical resection
a
No
2663
95.3
Yes
131
4.7
Other surgery
a
No
2102
75.2
Yes
692
24.8
Biliary stent
a
No
2054
73.5
Yes
740
26.5
Chemotherapy
a
No
2646
94.7
Yes
148
5.3
Radiotherapy
a
No
2769
99.1
Yes
25
0.9
Caseload of main treating consultant
a
Unknown
29
1.0
<5 cases
799
28.6
5–9 cases
612
21.9
10–19 cases
460
16.5
⩾20 cases
894
32.0
Caseload of hospital of treatment
a
Unknown
29
1.0
1 case
43
1.6
2–9 cases
113
4.1
10–29 cases
132
4.8
⩾30 cases
2477
89.6
Specialty of main treating consultant
a
Specialist
230
8.2
Clinician with an interest in the pancreas
109
3.9
Nonspecialist
2426
86.8
Unknown
29
1.0
Total
2794
100
a
Information derived from linked hospital discharge records does not include outpatient
diagnostic or procedural information.
. Although the age-standardised incidence of pancreatic cancer is known to be higher
in males than females, the absolute number of cases is higher in females, reflecting
the age and sex structure of the Scottish population. Some of the characteristics
shown are based on information derived from linked hospital discharge records, and
do not include outpatient diagnostic or procedural information. Thus, for example,
the number of patients receiving chemotherapy and radiotherapy may be underestimated.
Table 2
Table 2
30-day postoperative mortality rates for patients undergoing surgery or biliary stenting
by age group, year of diagnosis, hospital workload, workload of main treating consultant,
and specialty of main treating consultant (P-values are shown for statistically significant
differences)
Resectiona
Other surgerya
Biliary stenta
Factor
No. of cases
No. (%) of deaths
No. of cases
No. (%) of deaths
No. of cases
No. (%) of deaths
Age groups
P=0.016
P=0.023
0–39
1
0
6
0
5
0
40–49
14
2 (14%)
24
3 (13%)
19
2 (11%)
50–59
30
1 (3%)
109
9 (8%)
78
7 (9%)
60–69
63
4 (6%)
215
36 (17%)
202
22 (11%)
70–79
21
3 (14%)
239
57 (24%)
261
51 (20%)
⩾80
2
0
99
33 (33%)
175
45 (26%)
Year of diagnosis
P<0.001
P=0.001
1993
21
2 (10%)
158
36 (23%)
119
21 (18%)
1994
23
3 (13%)
153
43 (28%)
116
31 (27%)
1995
24
3 (13%)
129
22 (17%)
148
29 (20%)
1996
32
1 (3%)
144
23 (16%)
183
25 (14%)
1997
31
1 (3%)
108
14 (13%)
174
21 (12%)
Caseload of hospital of treatment
a
1 case
0
N/A
0
N/A
0
N/A
2–9 cases
0
N/A
10
2 (20%)
1
0
10–29 cases
0
N/A
33
12 (36%)
18
4 (22%)
⩾30 cases
131
10 (8%)
649
124 (19%)
721
123 (17%)
Caseload of main treating consultant
a
P=0.014
1 case
7
1 (14%)
102
21 (21%)
88
18 (21%)
2–4 cases
11
3 (27%)
177
37 (21%)
112
24 (21%)
5–9 cases
18
1 (6%)
176
47 (27%)
108
16 (15%)
⩾10 cases
95
5 (5%)
237
33 (14%)
432
69 (16%)
Specialty of main treating consultant
a
P=0.002
Specialist
51
1 (2%)
86
6 (7%)
120
13 (11%)
Clinician with an interest in the pancreas
32
2 (6%)
50
7 (14%)
33
7 (21%)
Nonspecialist
48
7 (15%)
556
125 (23%)
587
107 (18%)
Total
131
10 (8%)
692
138 (20%)
740
127 (17%)
a
Information derived from linked hospital discharge records does not include outpatient
diagnostic or procedural information. Note that patients can appear in more than one
of the treatment groups. N/A: not applicable.
shows the crude 30-day postoperative mortality rates for patients undergoing surgery
or biliary stenting by age-group, year of diagnosis, hospital workload, workload of
main treating consultant, and consultant specialisation category. Only 4.7% of the
entire cohort of patients underwent potentially curative surgical resection and the
relatively small number of events (10 deaths) mitigate against detecting statistically
significant differences between different categories. The overall 30-day postoperative
mortality following pancreatic resection was 8%, with a tendency to be lower in the
two most recent years of diagnosis (3%), although this was not statistically significant.
There was no obvious effect of hospital volume on postoperative mortality, although
very few patients were treated in hospitals dealing with less than 10 cases. Postoperative
mortality was generally lower among patients undergoing potentially curative resection
when treated by consultants with higher caseloads or pancreatic specialists, but these
differences did not achieve statistical significance (P=0.062 and 0.058, respectively).
The overall 30-day postprocedural mortality following palliative pancreatic surgery
and biliary stenting was 20 and 17%, respectively. Mortality was significantly higher
among the elderly, and significantly lower in recent years of diagnosis (Table 2).
Significant differences in postoperative mortality rates were demonstrated in patients
undergoing palliative surgical operations as consultants with higher case loads or
with a specialist pancreatic practice had fewer postoperative deaths (P=0.014 and
0.002, respectively).
Crude survival at 3 years after diagnosis was 19% in those patients undergoing resection,
but only 2% in other patients (P<0.001). Table 3
Table 3
Adjusteda hazard ratios of death (and 95% confidence intervals) within 3 years of
diagnosis
All patients
Surgical patientsb
Factor
HR (95% CI)
P-value
HR (95% CI)
P
-value
Year of diagnosis
No statistically significant differences
1993
1.00
1994
0.98 (0.87, 1.11)
0.779
1995
0.94 (0.83, 1.06)
0.309
1996
0.81 (0.72, 0.92)
0.001
1997
0.88 (0.78, 1.00)
0.043
Age groups
0–49
1.00
1.00
50–59
0.95 (0.75, 1.19)
0.648
1.00 (0.69, 1.46)
0.982
60–69
1.14 (0.92, 1.41)
0.241
1.26 (0.88, 1.78)
0.205
70–79
1.14 (0.92, 1.41)
0.245
1.41 (0.99, 2.02)
0.06
⩾80
1.41 (1.12, 1.76)
0.003
1.83 (1.22, 2.75)
0.003
Sex
No statistically significant differences
Male
1.00
Female
0.92 (0.85, 1.00)
0.042
Scottish co-morbidity index
b
None
1.00
1.00
1 condition
1.24 (1.12, 1.37)
<0.001
1.09 (0.91, 1.32)
0.351
⩾2 conditions
1.25 (1.09, 1.42)
0.001
1.51 (1.12, 2.05)
0.007
Bed-days co-morbidity index (in 6 months prior to diagnosis)
b
No statistically significant differences
None
1.00
1–4 days
1.11 (0.94, 1.30)
0.226
5–10 days
1.20 (1.03, 1.39)
0.017
⩾11 days
1.33 (1.17, 1.50)
<0.001
Tumour subsite
Head of pancreas
1.00
1.00
Body of pancreas
1.01 (0.83, 1.24)
0.918
1.19 (0.78, 1.83)
0.425
Tail of pancreas
0.97 (0.74, 1.28)
0.849
1.18 (0.55, 2.54)
0.665
Other
1.12 (0.81, 1.55)
0.499
0.86 (0.48, 1.52)
0.595
Unspecified
1.20 (1.10, 1.30)
<0.001
1.34 (1.15, 1.56)
<0.001
Tumour morphology
No statistically significant differences
Neoplasm, not otherwise specified
1.00
Carcinoma, not otherwise specified
0.74 (0.51, 1.07)
0.107
Adenocarcinoma, not otherwise specified
0.62 (0.42, 0.93)
0.022
Mucin-producing adenocarcinoma
0.48 (0.27, 0.85)
0.011
Other
0.39 (0.23, 0.66)
<0.001
Microscopically verified
No statistically significant differences
No
1.00
Yes
0.68 (0.55, 0.85)
0.001
Metastases within 4 weeks of diagnosis
b
No
1.00
1.00
Yes
1.92 (1.76, 2.10)
<0.001
1.93 (1.60, 2.33)
<0.001
Surgical resection
b
Not applicable
No
1.00
Yes
0.38 (0.31, 0.46)
<0.001
Other surgery
b
Not applicable
No
1.00
Yes
0.74 (0.67, 0.81)
<0.001
Biliary stent
b
No
1.00
1.00
Yes
0.72 (0.65, 0.79)
<0.001
0.70 (0.57, 0.85)
<0.001
Chemotherapy
b
No statistically significant differences
No
1.00
Yes
0.59 (0.50, 0.71)
<0.001
Caseload of main treating consultant
b
No statistically significant differences
1 case
1.00
2–4 cases
0.87 (0.78, 0.97)
0.013
5–9 cases
0.90 (0.80, 1.02)
0.088
⩾10 cases
0.85 (0.77, 0.95)
0.003
Specialty of main treating consultant
b
No statistically significant differences
Nonspecialist
1.00
Specialist
0.63 (0.50, 0.78)
<0.001
Clinician with an interest in the pancreas
0.63 (0.48, 0.82)
0.001
a
For each model (all patients, surgical patients) the results for the factors shown
are adjusted for all the other statistically significant factors in the table.
b
Information derived from linked hospital discharge records does not include outpatient
diagnostic or procedural information.
summarises the results of multivariate survival analysis, presented as adjusted hazard
ratios, based on the final model derived from Cox's proportional hazard modelling.
For the sake of clarity, only results that achieved (or approached) statistical significance
are shown. For all patients, the adjusted hazard of death was higher in patients diagnosed
in earlier years, older patients, males, patients with co-morbidity (based on two
out of four indices), patients with unspecified subsite of tumour, patients with metastases,
patients who did not undergo any form of surgical procedure or biliary stenting, patients
who did not receive chemotherapy, and patients managed by consultants with a low caseload.
For patients undergoing resection or another surgical procedure, the adjusted hazard
of death was higher in older patients, patients with co-morbidity (based on the Scottish
index), patients with unspecified subsite of tumour, patients with unspecified morphology,
patients without microscopic verification of their disease, patients with metastases,
patients who did not undergo biliary stenting, and patients who were not managed by
a specialist pancreatic surgeon or a clinician with an interest in the field.
DISCUSSION
The results of our study suggest that the risk of death by 3 years after diagnosis
of pancreatic cancer is 37% lower among patients undergoing surgical intervention
who are managed by specialist pancreatic surgeons or clinicians with an interest in
this field. No advantage of specialisation was seen for the total patient population,
but this probably reflects the fact that surgical resection offers the best chance
of survival (Wade et al, 1994; Bramhall et al, 1995; Sener et al, 1999), at least
for localised disease (Wade et al, 1995).
The resection rate of 4.7% in this study was low by international standards (Edge
et al, 1993; Baumel et al, 1994; Nakao and Takagi, 1998), but may reflect the small
number of patients managed by specialist pancreatic surgeons or clinicians with an
interest in this field (12.1% of cohort). However, the resection rate did increase
from 3.8% in 1993 to 5.2% in 1997. The development of regional cancer networks in
the United Kingdom in recent years and the requirement for all patients with cancer
to be discussed at multidisciplinary meetings may result in more patients being considered
for potentially curative surgery. Bachmann et al (2003) suggested that patients referred
to less specialised doctors or hospitals were less likely to be investigated thoroughly,
or to undergo palliative or potentially curative treatment.
Several studies (Edge et al, 1993; Gordon et al, 1995; Lieberman et al, 1995; Neoptolemos
et al, 1997; Gouma et al, 2000; Garden, 2001; NHS Executive, 2001; Rosemurgy et al,
2001; Teisberg et al, 2001; Birkmeyer et al, 2002; Halm et al, 2002; Bachmann et al,
2003) have suggested that specialisation in this field may yield better results in
terms of postoperative mortality, surgical complications, and longer term survival,
although other studies have not found this relationship (Wade et al, 1994, 1996),
and the possibility of publication bias must be considered. Some previous studies
are subject to the criticism that in-hospital mortality was used as an outcome, despite
the fact that length of stay may be lower in patients treated by specialist pancreatic
surgeons or hospitals with higher caseloads (Imperato et al, 1996; Sosa et al, 1998;
Gordon et al, 1999; Simunovic et al, 1999; Rosemurgy et al, 2001). Most of the studies
used hospital or surgeon caseload as a proxy for specialisation, and while this may
be a reasonable assumption, others have argued that there is no proof that repeating
a procedure hundreds of times necessarily guarantees competence (Loefler, 2000). In
our own study, when all patients were considered together, survival was significantly
higher for patients treated by consultants dealing with larger caseloads, but this
factor was not significant in the model concerning only surgical patients. Although
our categorisation of specialist status might be construed as subjective compared
to any definition based on caseload, it was assigned before analysis.
A major strength of our study is the fact that it is population-based and not therefore
subject to some of the potential biases inherent in single institution-based studies.
However, the study is based on data collected routinely and not specifically to fulfil
the aims of the study. Although data quality is believed to be reasonable (Harley
and Jones, 1996; Brewster et al, 1997, 2002), it is unlikely to be as high nor as
detailed as if the data had been collected prospectively. We were obliged to accept
the reality that, in this and many other countries (Parkin et al, 2002), a high proportion
of pancreatic cancers have no information on precise subsite of origin, and are not
verified by microscopy. However, given the very poor survival prospects for patients
registered with pancreatic cancer in Scotland (Scottish Cancer Intelligence Unit,
2000), it seems unlikely that the cancer registry includes many clinically diagnosed
cases of pancreatic cancer that are actually cases of benign pancreatic disease. Restriction
of our analyses to microscopically verified cases only would, in our opinion, have
introduced a substantial risk of bias.
Given the importance of tumour stage as a prognostic variable (Wade et al, 1995),
the absence of this variable is an acknowledged limitation, although its importance
as a discriminating variable may be less among the cohort of patients undergoing surgery.
Although we cannot exclude residual confounding as an explanation for our results,
it seems counter-intuitive that surgical patients with more favourable subsites of
origin, more limited disease, and requiring less technically demanding procedures
would be referred selectively to specialist surgeons. In relation to the variables
available for our study, it is likely that some misclassification exists, although
if this is random with respect to specialist status, it will have attenuated rather
than exaggerated the differences in outcome by this factor. The prognostic impact
of other factors, such as age, presence of metastases at diagnosis and co-morbidity,
is plausible and expected. Although microscopic verification of diagnosis appears
to have no statistically significant effect on the survival of all patients combined,
it is associated with higher survival in surgical patients, presumably because resection
is always likely to result in tissue diagnosis.
It is interesting to note that, although almost 90% of patients were treated in high
volume hospitals, slightly less than half were managed by consultants treating 10
or more cases (Table 1). Thus, any shift in referral patterns towards higher volume
surgeons may not have a substantial impact on patient travel times.
When considering the policy implications of the present study and related studies,
it is important to acknowledge that not everyone is convinced of the merits of specialisation
which does have some theoretical disadvantages (Loefler, 2000). However, the body
of evidence is now such that we would suggest that the onus is on sceptics to provide
evidence that surgical specialisation offers no advantages, or at least that the disadvantages
outweigh the benefits. From a pragmatic point of view, we believe that the individual
faced with a diagnosis of pancreatic cancer would wish to be managed by a multidisciplinary
team including a surgeon with specific training in this area and an annual caseload
above a certain minimum threshold.
In conclusion, we have shown that surgically treated patients with pancreatic cancer
are likely to fare better if they are managed by specialist pancreatic surgeons, or
clinicians with an interest in this field. Although we cannot exclude entirely the
possibility of bias or confounding, our results add to a growing body of evidence
supporting specialisation of surgery for pancreatic malignancy. This has major implications
for the delivery of cancer services in Scotland and the rest of the UK.