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Clinical features of metastatic cancer in primary care; a case-control study using medical
records
William Hamilton, professor of primary care diagnostics1
Jacqueline Barrett, associate research fellow1
Sally Stapley, research fellow1
Debbie Sharp, professor2
Peter Rose, clinical lecturer3
1. University of Exeter Medical School, College House, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU,
United Kingdom
2. Centre for Academic Primary Care, School of Social & Community Medicine, University of Bristol
3. Department of Primary Care Health Sciences, University of Oxford, New Radcliffe House, 2nd Floor,
Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, United Kingdom
Corresponding author: Prof Hamilton, [email protected]
Key words: cancer, diagnosis, primary health care, metastasis
Introduction
There are approximately 2.5 million UK cancer survivors, and this population is increasing by 3% annually.
This population is at risk of recurrence so when a cancer survivor develops a new symptom, one of the key
clinical questions is whether the symptom represents a recurrence. Symptoms of metastases may be sitespecific, as in a pathological fracture causing pain, or systemic, such as fatigue, nausea or anorexia.
Abnormal laboratory tests suggesting possible metastatic spread include anaemia, abnormal liver function
and hypercalcaemia.
After diagnosis and treatment of a primary cancer, hospital follow-up is the norm and a reoccurrence may
be identified at routine follow-up. However, many patients present with new symptoms between outpatient follow-ups, or after follow-up has ceased: these symptoms are usually reported to primary care.
Early identification of progressive disease in cancer patients may not lead to an improvement in survival
but symptom relief can be made more effective with palliative care which can considerably influence
functional outcome and quality of life.
Clinical features of the presentation of metastatic cancer are poorly described. Almost all previous studies
have originated in secondary care, yet the clinical problem of diagnosis resides, in part at least, in primary
care. There are no studies that reflect all aspects of recurrence in a single cohort: timing, site and
symptoms, and no national guidance for primary care in the detection of recurrent disease.
This study sought to fill this gap, by identifying and quantifying the risk of cancer recurrence in
symptomatic primary care patients who had received treatment with curative intent for an earlier cancer.
Design
This was a case-control study using data collected between 2002 and 2009 from the primary care records
of patients ≥ 40 years of age.
Cases were identified from computerised searches for deceased patients with a proven metastatic cancer
and a previous diagnosis of a primary breast, colorectal or prostate cancer, considered curable at the time
of initial diagnosis. The date metastatic disease was first diagnosed in the cases was labelled the index
date. Two types of controls were selected for each case: ‘healthy’ controls, without cancer; and ‘cancer’
controls, diagnosed with the same cancer, but without relapse at the index date. Both had to be alive at
the time of the diagnosis of metastatic cancer in the case and had to have at least one GP consultation in
the year before the index date.
All symptoms, investigations and clinical findings were coded from the notes using an adapted form of the
International Classification of Primary Care-2.
Univariable analyses were performed initially, retaining variables with a p-value of <0.1 to enter
multivariable analyses which used a p-value of 0.05 for retention. Only variables present in more than 2%
of the cases were studied. The cancer controls and healthy controls were used in separate analyses, and
the cancer sites were also analysed separately. Finally, all three cancer sites were merged and a unified
analysis performed. Clinically plausible interaction terms were added to each model, and likelihood ratio
testing applied to test if they improved the models.
Results
A total of 523 potential cases, 208 cancer controls and 177 healthy controls were identified from the
practice searches. Following application of the exclusion criteria 162 cases, 152 cancer controls and 145
healthy controls remained for study.
In total, 207 separate features were recorded in at least 2% of cases. Of these, 50 (43 symptoms and 7
abnormal investigations) were associated with metastatic cancer in the univariable analysis using the
cancer controls and 53 features (46 symptoms and 7 abnormal investigations) were associated using the
healthy controls. These features entered multivariable analyses, with the final models shown in Table 1. A
total of 80% of the cases presented with at least one of the seven features in the final model.
[Table 1]
Only one variable/primary site interaction term was significant.
Low back pain was more strongly
associated with metastases in colorectal cancer using cancer controls: interaction odds-ratio 74.7 (1.8,
3012.2) p=0.02. The time from first presentation to primary care with a relevant feature of possible
metastatic cancer to confirmation was longest in the colorectal cancer patients with a median of 178 days
(interquartile range (IQR) 31-f 269). For the prostate and breast cancer cases the median interval was 176
days (IQR 84-311) days and 120 (IQR 28-270) days respectively.
Discussion
To our knowledge, this is the first paper to describe the clinical features of metastatic cancer in primary
care. The main findings were that vomiting, shoulder pain, low back pain and loss of appetite were
relatively common markers of metastatic spread, but that these features were also experienced by
patients with a previous cancer, but without metastases. Two other less common features had stronger
associations; groin pain, and pleural disease. Abnormalities of liver function were also associated with
metastatic cancer. The time to diagnosis of metastases was surprisingly long, with a median interval
between the first putative symptom and diagnosis exceeding three months. All the features of
disseminated cancer have been reported before in secondary care series, but the relative infrequency of
specific symptoms – such as local pain – and relative commonness of non-specific symptoms, such as
vomiting and loss of appetite is an important finding. This may partially explain the long time to diagnosis
of metastases.
Our methods relied on primary care note keeping, thus unreported or unrecorded symptoms would be
missing from the study. However, because the notes were examined directly, any possible concerns from
data hidden in an inaccessible field, as can happen with studies based on electronic databases, were
avoided. All our cases were deceased so may have had disproportionately severe disease, but this was a
requirement of our ethical permission. On the positive side, we achieved our overall sample size. And,
although the site-specific analysis was slightly underpowered, the main analysis had ample power. As the
main clinical question in a patient with a previous cancer is the possibility of cancer recurrence, rather than
the specific site of the recurrence, the main analysis is the more important one.
Clinical use
Two broad groups of symptoms were associated with metastatic spread in the three cancer sites studied:
generic and specific symptoms. The generic symptoms were common in those with metastases, but were
also more common in patients without – either as cancer controls or healthy controls. Vomiting, low back
pain and loss of appetite nonetheless appear to warrant investigation in patients with a previous cancer.
Abnormal liver function test results were associated with cancer for all three metastatic sites – so also
mandate investigation. The axial skeleton is the commonest site for bone metastases, and our results
support this. Groin pain and shoulder pain were strongly associated with metastatic disease. In an
individual patient, co-morbidities may explain symptoms such as back pain: even so, it is clear that a new
persistent skeletal pain in a cancer survivor also warrants investigation. Primary care X-ray or ultrasound
may uncover sclerotic or lytic bone disease, though more sophisticated imaging may be required. The
rarer, but higher risk, presentation of pleural disease would usually be investigated as a matter of course,
initially by a primary care chest X-ray; though if a pleural effusion is detectable clinically, this would
generally lead to a simultaneous re-referral.
Patients with metastatic cancer present to primary care with common non-specific features of ill-health,
sometimes supplemented by specific features probably representing the anatomical site of the deposit.
These non-specific features make diagnosis more complicated, though the features described in this study
should help clinicians identify cancer spread more rapidly than currently.
Table 1. Features of metastatic cancer and the final models, compared to the two control groups.
Feature
Cases
n
(%)
Cancer
Healthy
Cancer Controls
Healthy Controls
Controls
Controls
Multivariable analysis
Multivariable analysis
n (%)
n
(%)
odds-ratio
p-value
odds-ratio
p-value
Groin pain
16 (10)
1 (1)
5 (4)
10.2 (1.2 to 82)
0.032
n.s.
Pleurisy / pleural
effusion
Shoulder pain
9 (6)
1 (1)
1 (1)
10.2 (1.1 to 92)
0.038
n.s.
27 (17)
8 (5)
21 (15)
5.3 (1.6 to 18)
0.007
n.s.
Loss of appetite
32 (20)
9 (6)
8 (6)
4.0 (1.2 to 13)
0.021
n.s.
Vomiting
40 (25)
13 (9)
9 (6)
3.5 (1.3 to 9.4)
0.011
3.6
(1.3 to 10)
0.016
Low back pain
38 (24)
17 (11)
10 (7)
2.5 (1.1 to 5.6)
0.032
4.2
(1.5 to 12)
0.006
Flank / loin pain
17 (11)
7 (5)
1 (1)
n.s.
19.4 (1.8 to 210)
0.016
Chest pain –
musculo-skeletal
37 (23)
12 (8)
8 (6)
n.s.
5.3
(1.7 to 16)
0.004
Oedema
35 (22)
16 (11)
11 (8)
n.s.
3.4
(1.1 to 10)
0.029
61 (38)
21 (14)
14 (10)
5.1 (1.9 to 14)
0.002
Investigations:
Abnormal liver
function
n.s.= not significant in the final multivariable model.
3.5 (1.6 to 7.5)
0.002