University of Groningen The role of the general practitioner in the care for patients with colorectal cancer Brandenbarg, Daan

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The role of the general practitioner in the care for patients with colorectal cancer

Brandenbarg, Daan

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Rijksuniversiteit Groningen.

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practitioner in the care

for patients with

colorectal cancer

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The role of the general practitioner in the care for patients with colorectal cancer ISBN 978-94-034-0463-9 (printed version)

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in the care for patients with

colorectal cancer

Proefschrift

ter verkrijging van de graad van doctor aan de

Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. E. Sterken

en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 21 maart 2018 om 16.15 uur

door

Daan Brandenbarg

geboren op 21 april 1985

te Hengelo

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Prof. dr. G.H. de Bock

Copromotor

Dr. A.J. Berendsen

Beoordelingscommissie

Prof. dr. J.A. Gietema

Prof. dr. E. Buskens

Prof. dr. J.W.M. Muris

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Chapter 1 General introduction 7

Chapter 2 Diagnosis of colorectal cancer in Dutch primary care: a multi-methods approach 17 Chapter 3 Increased primary health care use in the first year after colorectal cancer diagnosis 35 Chapter 4 Primary health care use during follow-up after curative treatment for 47 colorectal cancer

Chapter 5 Patients’ expectations and preferences about cancer follow-up 65 Chapter 6 Patients’ views on general practitioners’ role during treatment and 85 follow-up of colorectal cancer: a qualitative study

Chapter 7 The effect of physical activity on fatigue among survivors of colorectal 99 cancer: a systematic review and meta-analysis

Chapter 8 General Discussion 121

Summary 133

Nederlandse samenvatting 137

Dankwoord 141

Curriculum vitae 143

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One third of the Dutch population is expected to be diagnosed with cancer in their lifetime. Nowadays people are more likely to live beyond a cancer diagnosis, and make the transition into being a cancer survivor. Main factors contributing to this are advances in earlier detection, better staging and improved treatments. The downside of this great development however, is an increased pressure on the organization of health care. People living with and beyond cancer have specialized health care needs. The organization of cancer care is heavily debated over the recent years, with an increased role for the Dutch general practitioner (GP) being proposed. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, and its incidence is expected to rise due to an ageing population. This make it an interesting example to define the current role of the Dutch GP in this care to assess possibilities for an increased role in the future.

1.1 Epidemiology of colorectal cancer

In Western Europe, CRC is the third most commonly diagnosed cancer in males and the second in females, with an age standardized incidence rate of 39.1 and 24.9 per 100,000 for men and women, respectively (1). In The Netherlands, it was the second most commonly diagnosed cancer for both males and females in 2015, with a total of 15,807 new cases (2). Age is one of the largest risk factors, apart from having a family history, especially having a first-degree relative with CRC (3,4), and having inflammatory bowel disease (5). CRC is diagnosed at a median age of 66 years for males and 70 years for females (6). Due to ageing of the population it is expected that CRC incidence will further increase with 3% per year, up to 17,000 new cases in 2020 in the Netherlands (7). In addition to this, the implementation of a nationwide screening program for people aged 55−75 could lead to an even greater rise in incidence of CRC in the coming years (8). The increase in CRC incidence is also attributed to factors related to a Western lifestyle. These include high consumption of red and processed meat (9), excessive alcohol consumption (10), smoking (11), diabetes (12), and obesity (13).

1.2 Colorectal cancer mortality and early diagnosis

CRC is a well treatable cancer, but survival of CRC is dependent on the stage of the tumor at diagnosis. Five year survival rate is around 90% when CRC is diagnosed at a localized stage, meaning that the cancer has not gone through the outermost layers of the colon/rectum, has not reached nearby organs, and has not spread to lymph nodes. This decreases to roughly 85% when diagnosed at regional stages, meaning there is regional lymph node involvement, and to about 35% when diagnosed at metastasized stages (14-16).

Worldwide, and also in the Netherlands, mortality rates of CRC have decreased over the last two decades, and survival rates have increased (1,17). This is attributed to colorectal cancer screening programs, reduced prevalence of risk factors, improved staging and treatments, and improved access to high quality health care (18-20).

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In the Netherlands, European standardized mortality rates for CRC were 19.0 per 100.000 in 2014 (21). This is favorable compared to countries with comparable health care systems such as the United Kingdom, having a European standardized mortality rate of 27.1 per 100.000 in the same time period (Figure 1) (2,22,23). Interestingly, in the United Kingdom and comparable countries mortality rates fell by more than 30% for both sexes over the past decades. In the Netherlands, a lower decline was achieved of 11.6% and 16.7% for men and women, respectively (24).

45 40 35 30 25 20 15 10 5 0 1990 1995 2000 2005 2010 2013 2014 Year European standardized Mor tality Ra te Netherlands United Kingdom

Figure 1 European standardized mortality rates in the Netherlands and United Kingdom between 1990

and 2014.

Some of the improvements in the UK are most likely the result of improved diagnostics in primary care (25). In the UK much effort has been put into reducing the patient and diagnostic interval, by promoting awareness about cancer symptoms, earlier diagnosis (26,27), and urgent referral pathways which were introduced for suspected cancer in 2000 (28).

The patient interval is the period between the first symptom a patient notices and the first presentation (29), which for CRC is frequently the greatest proportion of the total time to diagnosis (30). This may be due to patients attributing their symptoms to benign conditions in order to remain normality, or do not mention them because of the private nature of the complaints (31).

The diagnostic interval, the period between first presentation of symptoms to a clinician and the diagnosis of cancer, is another challenge in CRC. Several alarm symptoms for CRC have been identified that may guide the diagnostic process in primary care (32,33). The most predictive of these is rectal bleeding. However, the proportion of people presenting this in primary care and being diagnosed with CRC, the positive predictive value, is low: 2.4% (32). Other alarm symptoms such as abdominal pain, constipation, diarrhea, or weight loss show even lower positive predictive values (32,33). The low positive predictive value of alarm symptoms might make a GP reluctant to refer a patient because of the high risk of unnecessary colonoscopy and it’s adverse effects. In contrast, the majority of patients diagnosed with CRC have been shown not to present alarm

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symptoms like rectal bleeding (34). The lack of a clear symptom pattern may preclude a symptom based early diagnosis.

The combination of the patient interval and the diagnostic interval can be considerably lengthy in CRC and lead to unfavourable staging and prognosis at diagnosis (35,36). The efforts to reduce diagnostic delay in the UK may have improved early diagnosis of CRC and therewith mortality rates (25,28). Recent Dutch research suggests that 10−25% of patients with cancer show substantially long diagnostic intervals, and delay appears to be especially long for CRC (37). However, little is known about the diagnostic trajectory for CRC in the Netherlands, and what factors contribute to delays.

In addition, the UK and other surrounding countries have implemented screening programs for CRC since the early 2000’s (38). This may have further lowered mortality rates. In the Netherlands a screening program started in 2014. This implies that in addition to an increasing incidence of early onset CRC in the next few years, a further reduction in CRC specific mortality rates may be expected in the Netherlands. However, despite this screening, it is expected that the majority of patients will still be identified through symptomatic presentation in general practice (39-41). This is due to interval cancers occurring after a negative screening test (39), in patients not in the screening program, and sub-optimal uptake of screening or follow-up diagnostic tests (41,42). It is therefore important to examine what characterizes the diagnostic process in terms of health care use, possible delays, and factors contributing to these delays, in Dutch general practice.

1.3 Rethinking cancer care: substitution to general practice?

The increase in incidence of CRC, combined with better survival, leads to a substantial increase in the number of people being treated for or having survived CRC. It is expected that the 10-years-prevalence of CRC in the Netherlands will rise from roughly 70,000 in 2015 to 92,000 in 2020 (7). In 2011, the costs of cancer care in the Netherlands were € 4,300 million, the majority (73%) being spent on hospital care (43). These costs are expected to rise further in the years to come, not only due to the prevalence of cancer but also to the increased incidence (7). Also, the implementation of screening leads to more diagnostic activity (colonoscopy) in secondary care, further driving hospital costs related to CRC. This has led to a call for effective resource allocation of cancer care, possibly by substituting parts of care from expensive secondary care to cheaper primary care services (44). In 2011 the Dutch Cancer Society (KWF kankerbestrijding) called for coordination of cancer follow-up care by general practice (45). The Dutch Society of General Practitioners (NHG) issued a position paper in 2014, in which substitution of follow-up care is suggested for the 5 most prevalent cancer types – breast, lung, prostate, colorectal and melanoma- provided that evidence-based guidelines are developed (46). This position met resistance from practicing GPs, united in the National Union General Practitioners (Landelijke Huisartsenvereniging – LHV), stating that key conditions had to be met concerning communication between GPs and specialists, and more time for GPs to coordinate this care. Interestingly, the current role played by the GP after CRC diagnosis, is largely unknown.

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1 1.3.1 Treatment for colorectal cancer

After referral due to suspicion of CRC or to a positive screening test, CRC is histologically confirmed by a biopsy taken during colonoscopy in secondary care. Curative treatment of CRC usually consists of surgery, possibly complemented with (neo)adjuvant therapies (47). A colostomy (often temporarily) is frequently required after surgical treatment, especially for patients with rectal cancer (29% versus 12% for patients with colon cancer) (16). Side effects of all therapies are frequently observed among patients. Bowel problems such as incomplete evacuation, flatulence, bloating, fecal incontinence, and chronic diarrhea are frequently reported (48,49), as are urinary problems (50), and sexual dysfunction (51). Given the role of the GP, as a gatekeeper and as a generalist in health care, it might be that the GP is consulted for these problems. Whether that is the case, how often this happens, and for what problems the GP is involved during CRC treatment has never been studied in the Netherlands.

1.3.2 Follow-up of colorectal cancer

After completion of treatment patients enter a follow-up routine, mostly situated in the hospital. The main aim of follow-up is the early detection of recurrent cancer. In Dutch guidelines this follow-up care consists of bi-annual consultation for 2−3 years, and annually up to 5 years after treatment (47). This is complemented by bi-annual ultrasound liver echography or abdominal CT-scan for 1−2 years, and annually up to 5 years after treatment. Moreover, carcinoembryonic antigen (CEA) is tested every 3 to 6 months for 3 years, and bi-annually up to 5 years after treatment. As described earlier, it has been suggested that GPs could coordinate this care, provided that an evidence based protocol is available. Interestingly, the evidence for current hospital based follow-up protocols is being debated as well, with no clear differences in survival between different follow-up routines and tests used for detection of recurrences (52,53). This might provide opportunity to rethink current practices and see whether the GP could fit in. However, it is not known whether the GP is consulted more often, or involved by patients during this phase of their care. Since survivors of CRC show various health care needs related to information about their disease, lifestyle, and psychological support (54). Because most tasks belong to the standard repertoire of GPs, it is likely that they are involved in caring for these patients.

GPs in the Netherlands have been given the responsibility for the care of other chronic diseases, such as diabetes, chronic pulmonary diseases and cardiovascular risk management. One third of all cancer patients are already involved in a disease management program for a chronic disease (55). Possibly, this may lead to an easier enrolment of follow-up care for CRC patients in primary care. Health care use in general practice and reasons for health care use have not been studied thoroughly for patients with CRC during cancer treatment nor follow up.

1.3.3 Preferences and expectations of patients about follow-up

When discussing changes in the organization of health care the patient perspective must be included. By including this perspective future organization of cancer care could be adapted to their views. It is useful to understand whether the expectations of patients correspond with those of doctors and policy makers, and whether their expectations are realistic. This could have

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implications for the organization of care, the role of the GP in this care, or provision of information. There is no coherent review of the (rich) literature on patient expectations and preferences regarding follow-up care in terms of content, frequency, duration, and setting for survivors of cancer. Concerning CRC specifically, the perceptions of survivors of about the current role of their GP have not been examined, nor their preferences and expectations for future CRC care.

1.3.4 Late effects of CRC

Survivors of CRC – persons with CRC post treatment until the end of life − show various health problems which may last up to ten years after treatment, including pain, fatigue, sleep problems, depressive feelings and sexual problems (56,57). Long term health problems are most likely to be presented in general practice. Until recently there has been relatively little attention for these invalidating symptoms, because treatment was aimed at survival. With the increasing prevalence of CRC survivors, long term health problems become more pregnant and need to be dealt with. Especially fatigue has been reported to be very invalidating by survivors of cancer (58), which is reported to be twice as prevalent among survivors of CRC compared with an age- and gender-matched reference population without cancer (59). Moreover, fatigue can persist for a prolonged period, being present up to 10 years after diagnosis (60). One of the possible strategies to counter fatigue that has been suggested is physical activity. However, whether physical activity is advisable for these patients, in the period after treatment, has not been thoroughly studied. Such knowledge contributes to the GPs understanding of how to counter fatigue and thus provide patients with proper advice.

Aim of the thesis

The overall aim of this thesis is to describe aspects of the role of the Dutch GP during all phases of CRC; from early diagnosis, treatment and follow-up care, to care for long term health problems. This will be based on analysis of health care use, qualitative research into perspectives of patients about these roles of the GP, and literature reviews. Research objectives presented in this these are: a) To explore primary health care use and factors contributing to missed diagnostic opportunities

among patients developing CRC in the year prior to diagnosis (Chapter 2).

b) To explore primary health care use during active treatment (Chapter 3), and during follow-up care (Chapter 4).

c) To review patients’ expectations and preferences about follow-up care for cancer (Chapter 5) d) To explore experiences and preferences for the role of the general practitioners among

survivors of CRC (Chapter 6).

e) To review the evidence for the effectiveness of physical activity in order to reduce fatigue after treatment for CRC (Chapter 7).

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Diagnosis of colorectal cancer in

Dutch primary care: a multi-methods approach

Daan Brandenbarg, Feikje Groenhof, Ilse M Siewers, Anna van der Voort,

Fiona M. Walter, Annette J. Berendsen

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18 Abstract

Background Early detection of colorectal cancer (CRC) is important to achieve better survival. Discriminating symptoms suggestive of colorectal cancer from benign conditions is a challenge for general practitioners since most known ‘alarm symptoms’ have low predictive values. Aim To further understand the diagnostic process in general practice in terms of health care use and by analysing factors related to diagnostic intervals.

Design and setting A multi-methods approach comprising a historical prospective registry study and qualitative content analysis.

Method Health care use in the year before referral for colonoscopy was compared between patients diagnosed with colorectal cancer and an age-, gender-, and GP-matched control population. Qualitative content analysis was performed on free texts in electronic patient records from a purposive sample of CRC patients.

Results CRC Patients had 41% (25−29%) more face-to-face contacts and 21% (7−37%) more medication prescriptions than controls. Forty-six percent of CRC patients had 2 or more contacts for digestive reasons, compared to 12.2% of controls. From qualitative analysis two themes emerged; “possible missed diagnostic opportunities” and “improvements in diagnostic process unlikely”. Possible missed diagnostic opportunities were related to patients waiting before presenting symptoms, doctors attributing symptoms to co-morbid conditions or medication use, or doctors sticking to an initial diagnoses.

Conclusion Less missed diagnostic opportunities might occur if GPs are aware of pitfalls in diagnosing CRC: the assumption that symptoms are caused by comorbid conditions or medication, or relating complaints to pre-existing medical conditions. GPs also need to be aware that repeated digestive complaints warrants rethinking earlier diagnoses.

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2 Introduction

Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, with the highest incidence rates occurring in Western countries (1). While screening programs have been implemented in many European countries, including The Netherlands and the United Kingdom, the majority of new cases will present symptomatically and outside screening programs (2-4). In countries where the general practitioner (GP) acts as a gatekeeper referring to specialty care, the GP is challenged to adequately discriminate between symptoms possibly caused by CRC and symptoms caused by benign conditions. This is important since detection of CRC at earlier tumour stages leads to more treatment with curative intent and has been associated with better survival (5,6).

The diagnostic interval, the period between first presentation and diagnosis, can be prolonged in patients with CRC (7,8). ‘Alarm’ symptoms for CRC include rectal blood loss, constipation, diarrhoea, abdominal pain, abdominal tenderness, and weight loss (9-11). However, most of these symptoms are commonly presented in primary care and diagnosing CRC is a relatively rare event for GPs. Therefore, these symptoms have low positive predictive values for CRC (11,12).

Recent Scandinavian studies have analysed routinely collected national health care data for other factors which might improve the diagnostic process. These showed increased contact rates of CRC patients in primary care before CRC diagnosis compared to a reference population; reasons for these contacts were not analysed, neither was prescribed medication (13,14). A recent Danish study also showed increased diagnostic activity in primary care before CRC diagnosis, with patients having more consultations, haemoglobin measurements and more haemorrhoid prescriptions; other reasons for consultations and medication use were not analysed in this study (15).

To help GPs to make timely referrals, potentially leading to more timely diagnosis, we aimed to further unravel the diagnostic process in general practice by performing a multi methods study, combining quantitative and qualitative data from the primary care electronic patient records. Specifically, we aimed to compare annual consultation and medication rates, reasons for these consultations, and type of prescribed medication, between patients developing CRC and a reference population. In addition, we aimed to assess the occurrence of, and factors influencing, diagnostic intervals in the Dutch general practice, and what presenting symptoms patients with CRC consult their GP for.

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20 Methods

Design

A multi methods approach, combining quantitative and qualitative data, was used to study healthcare use and the diagnostic process for CRC in Dutch general practice. Quantitative data from a primary care registry concerning healthcare use of patients in the year preceding a CRC diagnosis was compared to an age- and gender-matched reference population from the same GP. A qualitative content analysis was performed of GPs’ electronic patient records from a purposive sample of these CRC patients.

Participants/Sample

CRC patients and matched controls were identified in the Registration Network Groningen (RNG). This network comprises of three GP group practices in the northern part of The Netherlands and has a dynamic patient population of approximately 30,000 patients. In The Netherlands all inhabitants are registered with a GP. Apart from a slight over-representation of adults aged 25−44 and women, the RNG database is comparable to the Dutch population (16). CRC patients were selected based on the occurrence of ICPC code D75 (colon or rectum malignancy) in their electronic patient record between 1st_{January 1999 and 31}st_{December 2014. Diagnoses of CRC were validated using}

the correspondence with hospital doctors and hospital patient files. Additional information about cancer treatment and stage was also collected. Each CRC patient was individually matched to three controls based on age (± 1 year), gender and GP with a minimum of one control per patient. Patients and controls both had to be registered in the GP’s practice at the time of CRC diagnosis. The date of referral by the GP for colonoscopy was used as the index date for matched controls. When this date was not available, the date of first recording of CRC in the patient record was used. For the qualitative analysis we created a purposive sample of these CRC patients. We sampled purposively on extreme cases in order to obtain as much variation as possible in our sample. Criteria for this sampling procedure were: variation of age, gender, tumour location, tumour stage, and annual number of GP-contacts. These criteria were extracted from the RNG database. Without further knowledge of the content of the patients’ electronic patient record we started selecting two patients from each category; one with a high score on that category, one with a low score. This process was iteratively continued until saturation was reached.

Data collection

The RNG GPs follow a standardized protocol for coding of their data. All patient contacts are coded according to the International Classification of Primary Care (ICPC) version 1 (17) and medication is coded using the Anatomical and Therapeutical Chemical classification (ATC) (18). ICPC codes from 1 to 30 are symptom-codes, while the higher codes, ranging from 70−99, are diagnosis-codes. For example, ICPC-D11 is the code for diarrhoea and ICPC-D75 for colorectal cancer. In two practices these data are stored using the MicroHis (CSC, Virginina, US) electronic health record system, and one practice uses the Medicom (Medicom medical publishers, Baarn, The Netherlands) system. All ICPC and ATC codes and the date of coding are stored in the RNG database, as are patients’

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demographic features. For the purpose of this study we extracted all ICPC codes for face-to-face contacts in the year prior to referral/index date. Face-to-face contacts consisted of consultations in general practice and visits to patients’ homes made by GPs or practice nurses. Furthermore, we extracted all medication prescriptions coded in the RNG database in the year prior to referral/ index date. This includes all new medication prescribed by the GP and also repeated medications for chronic conditions.

ICPC code D75 in patient record between 1998 and 2014 (n = 504)

History of CRC (n = 443) Excluded (n = 61)

● No history of CRC (n = 61)

Excluded (n = 122)

●First diagnosis before 1998 (n = 122)

Included in matching procedure (n = 321)

Excluded (n = 34)

● Unable to be matched (n = 7) ● Not registered at time of diagnosis

(n = 27)

Total included in data analysis (n = 287)

Figure 1 Process of inclusion in database

GPs also register free texts of their consultations in the electronic patient files according to the SOAP-system. A SOAP journal comprises four data fields. The Subjective (S) is used to record, in plain text, what the patient describes, such as complaints, symptoms, or reason for encounter. The Objective (O) is for recording GPs’ findings from clinical examination or measurements. The Analysis (A) is used for coding the diagnosis or most important symptom using the ICPC coding system. GPs mostly use 1 code per consultation. The Plan (P) records GPs’ actions in plain text, e.g. referrals to medical specialists, prescribed medication (ATC codes), or follow-up appointments. For the purposive sample of CRC patients, we downloaded all free text (SOAP) from the year before the referral date. This data was anonymized in general practices and files were stored as Portable Document Format (PDF) files for analysis in Atlas/TI (version 7, Scientific Software Development GmbH, Berlin, Germany).

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22 Quantitative analysis

Calculation of contacts and prescriptions, observation time, and rates

As not all patients were registered during the entire study period, we calculated the observation time between entry in the RNG database and the date of referral/index date. For all CRC patients and controls the number of face-to-face contacts and medication prescriptions were counted in the year prior to referral based on the number of registered dates of contact or start dates of medication, respectively.

Median numbers and interquartile ranges of contacts and prescriptions were then calculated in the year prior to referral. Annual rates were calculated by dividing the total number of contacts and prescriptions by the observation time.

ICPC codes associated with face-to-face contacts and ATC codes for prescriptions in the year before diagnosis were extracted from the RNG database. Rates of ICPC chapters and ATC codes were calculated. ICPC chapters that differed significantly between CRC patients and controls were further analysed. To get an impression whether differences were due to symptoms or diagnoses, we assessed whether differences on these chapters were due to symptom (ICPC 1−30) or diagnostic codes (ICPC 70−99).

Statistical analysis

Due to the overdispersion in the health care data, we fitted a negative binomial regression model with a robust covariance matrix of the exchangeable type. We hereby accounted for clustering in our data due to the matching procedure. Log-transformed observation time was included in the model as an offset-variable to account for differences in observation times. We present annual Incidence Rate Ratios (IRR) and 95% confidence intervals.

Qualitative analysis

Symptoms

Because GPs might have coded only one complaint of patients with CRC, the researchers (DB and IS) extracted and counted descriptively all complaints in the abdominal/pelvic region, and general complaints (e.g. tiredness, fever, feeling ill), from the free-text Subjective (S) data fields.

Qualitative Coding

Coding of the complete SOAP texts was performed by two researchers (DB and IS). First, texts were conscientiously read and re-read by the researchers, potentially interesting text was marked, and descriptive codes were assigned to these segments by researchers independently, e.g. open coding (19). These segments and codes were discussed between the two researchers until consensus was reached. In case researchers did not agree, or were uncertain about contextual interpretation, a third researcher with a background as GP (AJB) was consulted. These codes were then interpreted, categorized, and clustered by three researchers (DB, IS, AJB), thereby creating a thematic map. An iterative process was applied, meaning that the newly formed thematic map was applied to all data, until no new codes or themes emerged, and saturation was reached.

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2 Results

We identified 287 patients with a confirmed diagnosis of CRC (Figure1). The characteristics of these patients (n = 287) and their matched controls (n = 828) are shown in Table 1. Most CRC patients (n = 187; 65.2%) were diagnosed with colon cancer, while 74 (25.8%) were diagnosed with rectal cancer. Almost half were diagnosed with a TNM stage III or IV (44.6%), although staging was unknown for 62 (21.6%).

Table 1 Characteristics of patients with colorectal cancer (CRC) (n = 287) and the reference population

(n = 828) and characteristics of the purposive sample of patients (n = 57) for the qualitative analysis Patients

n = 287 Reference populationn = 828 Purposive Samplen =57 Gender, n(%)

Male 146 (50.9) 423 (51.1) 29 (50.8)

Female 141 (49.1) 405 (48.9) 28 (49.1)

Age at diagnosis, mean (SD), years 68.8 (12.2) 68.3 (12.0) 68.1 (12.5) Tumor location Colon 187 (65.2) 39 (68.4) Rectum 74 (25.8) 16 (28.1) Unknown 26 (9.1) 2 (3.5) TNM stage at diagnosis, n(%) 0/I/II 97 (33.8) 19 (33.3) III/IV 128 (44.6) 27 (47.4) Unknown 62 (21.6) 11 (19.3)

Face-to-face contact, median (IQR) 5.0 (2.0–9.5)

Practice,

n (%) Groningen 18 (31.6)

Sappemeer 21 (36.8)

Hoogeveen 18 (31.6)

Quantitative analysis of healthcare use

In the year prior to the diagnosis, CRC patients had a significantly higher rate of GP contacts (IRR: 1.41, 95% CI: 1.25–1.59) compared to controls; a median of 4.0 (2.0–8.0) versus 3.0 (1.0−6.0), respectively (Table 2). In this period, CRC patients were also prescribed significantly more medication compared to controls (IRR: 1.21, 95% CI: 1.07–1.37).

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Table 2 Comparison of the median number of face-to-face contacts and prescribed medication in the

year prior to referral of CRC between CRC patients (n = 287) and the reference population (n = 828) Median (IQR) RR (95% CI)

Contacts Controls 3.0 (1.0–6.0) 1 CRC Patients 4.0 (2.0–8.0) 1.41 (1.25–1.59) Medication Controls 9.0 (2.0–21.0) 1 CRC Patients 12.0 (4.0–26.0) 1.21 (1.07–1.37)

RR = Rate Ratio, IQR = inter quartile range

CRC patients showed significantly more contacts coded as General and unspecified reasons (ICPC-A, IRR: 1.39, 95% CI: 1.04–1.86), Digestive (ICPC-D, IRR: 3.93, 95% CI: 3.06–5.05), Musculo-skeletal (ICPC-L, IRR: 1.42, 95% CI: 1.10–1.84), Neurological (ICPC-N, IRR: 1.70, 95% CI: 1.03–2.81), Respiratory (ICPC-R, IRR: 1.46, 95% CI: 1.08–1.97), and Endocrine, metabolic, and nutritional reasons (ICPC-T, IRR: 1.56, 95% CI: 1.09–2.23) in the year prior to diagnosis, compared to controls (Table 3). The largest difference was observed for the Digestive system: 46.0% of CRC patients showed two or more contacts for these reasons in the year prior to diagnosis, compared to 12.2% of controls. The most prevalent ICPC-D codes were: unspecified abdominal pain (D06, 13.7% of all ICPC D- codes), constipation (D12, 13.0%), and stomach pain (D02, 7.6%). Further analysis (Figure 2) of the ICPC chapters which differed significantly between CRC patients and their controls, revealed that for ICPC chapters A (General/unspecified), D (Digestive system), L (Musculoskeletal), and N (Neurological) more symptom codes were found (ICPC 1-30). For ICPC chapters R (Respiratory), and T (Endocrine etc.) more diagnoses were coded (ICPC 70-99; Figure 2).

Figure 2 Distribution of proportion of ICPC codes within ICPC chapters for CRC patients and controls

in the year before referral. ICPC codes ranging from 1 to 29 are symptoms whereas codes ranging from 70−99 are diagnoses.

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Table 3 shows differences in prescribed medication between CRC patients and controls. Significantly more medication was prescribed in the year prior to diagnosis for the alimentary tract and metabolism (ATC-A, IRR: 1.25, 95% CI: 1.02–1.54), the cardiovascular system (ATC-C, IRR: 1.24, 95% CI: 1.07–1.43), anti-infectives for systemic use (ATC-J, IRR: 1.25, 95% CI: 1.03–1.51), the musculoskeletal system (ATC-M, IRR: 1.45, 95% CI: 1.05–1.99), and respiratory system (ATC-R, IRR: 1.46, 95% CI: 1.01–2.13).

Table 3 Reasons for primary healthcare use among patients with colorectal cancer (CRC; n = 287) and

patients from the reference population (n = 828) in the year before referral. Reference

population CRC patients IRR (95% CI)* Face-to-face consults by ICPC chapter, Rate a

General and unspecified (A) 0.45 0.60 1.39 (1.04−1.86)

Digestive (D) 0.59 2.22 3.93 (3.06−5.05)

Musculoskeletal (L) 1.24 1.73 1.42 (1.10−1.84)

Neurological (N) 0.20 0.33 1.70 (1.03−2.81)

Respiratory (R) 1.07 1.52 1.46 (1.08−1.97)

Endocrine, metabolic, and nutritional (T) 0.61 0.92 1.56 (1.09−2.23) Rate ratios of prescribed medication by ATC chapter

Alimentary tract and metabolism (A) 1.04 2.87 1.25 (1.02−1.54) Cardiovascular system (C) 4.33 5.45 1.24 (1.07−1.43) Anti-infectives for systemic use (J) 0.99 1.25 1.25 (1.03−1.51)

Musculoskeletal (M) 0.70 1.03 1.45 (1.05−1.99)

Respiratory system (R) 1.10 1.64 1.46 (1.01−2.13)

a _{Crude annual rate (number of contacts per person per year)}

* Ratio of patients with CRC in relation to reference population (1)

Qualitative content analysis of SOAP text

Table 1 also shows the characteristics of the purposive sample of 57 CRC patients and their 25 GPs who were included in the qualitative content analysis of the SOAP texts. Saturation was reached after analysis of 48 electronic patient records; no new information was obtained from 9 subsequent medical records.

Symptoms

We coded 220 presenting symptoms from the Subjective (S) data of the 57 CRC patients during the year prior to referral (Figure 3). The most prevalent symptoms were abdominal pain (n = 28), blood/slime in faeces (n = 21), diarrhoea (n = 19), and change in bowel habits (n = 19). We also frequently coded less specific symptoms such as stomach complaints/vomiting (n = 13), back pain (n = 12), fatigue (n = 10), and flatulence, bloating, or rumbling in the abdominal area (n = 8).

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Figure 3 Complaints (n = 220) mentioned in electronic patient records of the purposive sample (n = 57)

in the year before referral.

Legend: medium gray = alarmsymptoms; light gray = Other complaints abdominal/pelvic region; Dark gray: Other complaints

Themes

Two major themes emerged during the qualitative analysis. The first comprised cases where ‘missed diagnostic opportunities’ may have occurred, leading to less timely diagnoses (n = 35). The second comprised cases where no improvement in the diagnostic process could have been expected (n = 22).

Theme 1: Possible ‘missed diagnostic opportunities’

Possible missed diagnostic opportunities, as derived from the qualitative analysis of electronic patient records, might either be attributed to patient factors or doctor factors.

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Patient factors

Many patients appeared to wait for prolonged periods before presenting themselves with symptoms they experienced. Furthermore, patients who visited their GP frequently did not always mention complaints related to their bowels when they occurred, but only after some time. For example, a patient who had visited the GP for various reasons such as eczema, coughing and diabetes, at one point mentioned he also had defecation problems:

“S-data field, male patient, 70 years: For a prolonged time (+/- one year) increasing

defecation problems, alternating pattern, sometimes slimy and with blood.”

Sometimes patients cancelled appointments when complaints had diminished, which led to longer intervals when complaints returned. One patient, who was scheduled for a colonoscopy, cancelled that appointment because the symptoms were gone. Longer intervals were also due to circumstances in patients’ lives. Patients’ worries about their home situation, problems experienced by their partner, or other situations in their lives, also led to a later presentation with their own health problems. For example, a female patient who had been consulting for diarrhoea and other abdominal complaints, appeared to stop doing that for a couple of months because a situation with her husband interfered.

“S-data field, female patient, 84 years: Panicked, cannot deal with illness of husband and

missing care of children, hyperemotional.”

Doctor factors

In many cases GPs appeared to attribute symptoms to pre-existing conditions. For example, the symptoms of a patient who presented with lower abdominal pain and a history of diverticulitis were at first attributed to that condition. Another patient with persistent abdominal pain was referred to her gynaecologist because of a gynaecological history. Other abdominal or pelvic illnesses also seemed to mask the symptoms. For example, a patients who tested positive for a urinary tract infection (UTI) had a possible missed diagnostic opportunity after receiving test results and subsequent UTI treatment.

The intermittent nature of symptoms also led to longer diagnostic intervals in primary care. Non-persistent pain, and episodes of diarrhoea or obstipation, all made it difficult to pinpoint the exact nature of these complaints. Some GPs did not immediately think of a CRC diagnosis in cases where patients presented with vague complaints, such as ongoing tiredness, or prolonged and unexplained fever.

GPs also seemed susceptible to their patients’ explanations for the reasons for the symptoms. Patients reported symptoms that could be attributed to CRC, but they gave good explanations of other causes. Their GP tended to accept these explanations and did not further investigate the symptoms. For example, a patient reported melena and thought it was caused by his medication.

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In some cases, GPs seemed to attribute possible symptoms of CRC to side-effects of medication. For one patient, consistently (two and a half months and 3 visits) complaining about having “moist flatulence”, referred/ diagnosed 5 months after onset, the GP coded:

“P-data field, male, 64 years, rectum: still problems with metropolol (again moist

flatulence), did not take medication, last ten days little complaints → let’s try enalapril ” Consultation behaviour by patients may also have contributed to prolonged diagnostic intervals. Patients who present themselves frequently to their GP, with a variety of complaints, seemed to get less frequently referred for further investigation. Specialists also appeared to miss diagnostic opportunities, for example:

“O-data field, male, 74, colon: Gastroenterologist: Black defecation with red colouring.

Probably gastro-intestinal bleeding, check Hb again in two month,”

In some cases, GPs stuck to their own preliminary diagnosis and did not re-evaluate their patient during subsequent consultations. This was also the case when one of the colleagues, in case of multiple GP workers, had made a preliminary diagnosis.

Theme 2: Improvements in diagnostic process unlikely

Among the 22 CRC patients in this group, four did not have a GP involved in the diagnostic process. Of these two were diagnosed by the national screening program. Other patients presented themselves at emergency hospital care, or were referred within hospital care.

The remainder mainly had swift referrals, so these notes were markedly shorter.

It frequently appeared that the GP had correctly interpreted symptoms and quickly referred to secondary care for diagnosis.

In many cases it occurred that patients were quickly referred because of the fact that all “red flag symptoms” were presented. These seemed to be patients who had not visited their GP in the last year, and presented with more than one alarm symptom. For example:

“Male, 56, rectum: lost a lot of weight (6 kg) in short period, heavy faecal blood loss. Since

6 weeks tumultuous bowel, no pain. Frequent urgencies. Haemorrhoids around rectum. No deviances with rectal toucher. Decided to refer.”

Discussion

Summary

In the year prior to referral patients diagnosed with CRC had 41% more face-to-face contacts and 21% more medication prescriptions in general practice compared to an age-, gender- and GP-matched reference population. Prior to diagnosis the CRC patients showed significantly more contacts for general reasons, including symptoms relating to the digestive, musculoskeletal,

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neurological, respiratory, and endocrine, metabolic, and nutritional systems; the largest difference was observed for the digestive system. 46% of CRC patients had 2 or more contacts for this reason, compared to 12.2% of controls. Patients diagnosed with CRC were prescribed more medication in the year prior to their referral for the alimentary tract, but also more cardiovascular, musculoskeletal and respiratory medication. Furthermore, CRC patients presented not only with the known “alarm symptoms” but also with a variety of other, less clear symptoms such as back pain, rumbling in the abdominal area, flatulence or general ill feeling.

Our qualitative analysis suggested that patient factors such as prolonged periods before mentioning symptoms or because they had been put at ease after symptoms diminished could lead to missed diagnostic opportunities. Similarly, doctor factors, such as GPs attributing symptoms to co-morbid conditions, medication use, the explanation of their patient about their symptoms, or because they stuck to an initial diagnosis, could also contribute to missed diagnostic opportunities. In other cases, improvements in the diagnostic process within general practice were not possible, mainly because the GP acted swiftly on alarm symptoms.

Strengths and limitations

A strength of this study is the multi-methods approach. Using both quantitative and qualitative data we were able to enrich our quantitative findings to obtain a deeper understanding of the diagnostic process of detecting CRC in primary care. We also used a prospective primary care database where the presentation of health care problems and prescriptions were recorded by GPs using a standardized registration protocol, reducing the risk of recall or non-response bias compared to patient-reported data (20). The likelihood that the data concerning CRC diagnosis was correctly recorded by GPs was increased by revalidating the data with specialist letters in GP practices and hospital records. Moreover, this provided detailed information about type of treatment, tumour location and tumour stage.

Although we enriched our quantitative data with a qualitative analysis of the free texts of the electronic patient records it has to be noted that these records are made by the GP. There are therefore likely to be the GP’s interpretation of symptoms mentioned by the patient, rather than a full representation of the patient perspective or what actually happened in the consultation room.

Comparison with existing literature

In line with our study, earlier research showed an increased consultation rate in general practice for (colorectal) cancer patients prior to their diagnosis (13,15,21). Many CRC patients in our study (46%) had 2 or more contacts for digestive reasons, compared to only 12% of controls. This is in accordance with known ‘alarms symptoms’ such as rectal blood loss, constipation, diarrhoea, abdominal pain or tenderness, and weight loss (9-11). As these ‘alarm symptoms’ as a single symptom do not have a high positive predictive power (22), repeated digestive complaints might warrant further investigation.

Interestingly, patients also had more contacts for Respiratory, and Endocrine, metabolic, and nutritional reasons. The codes in these ICPC chapters were mainly diagnoses. It is known that comorbid conditions such as COPD and diabetes are common among CRC patients (23).

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Moreover, these conditions share lifestyle-related risk factors with CRC (24). This might also explain our finding of higher rates of respiratory, musculoskeletal and cardiovascular drugs among patients.

Moreover, patients do not exclusively present with these ‘alarm symptoms’. These ‘alarm’ symptoms are often the result of a coded interpretation of doctors and researchers of predefined symptoms. Whereas, according to our qualitative analysis, patients seem to present with a variety of vague complaints in the abdominal and pelvic region, and other general complaints symptoms. Vague complaints might explain that patients had more contacts for General and unspecified reasons and Musculoskeletal system.

In an effort to create a standardized set of definitions related to key time points and intervals in the diagnosis of cancer the Aarhus Statement was developed (25). This distinguished the patient interval and doctor, or diagnostic, interval during the diagnostic process. Within these intervals, missed diagnostic opportunities can occur, which could cause delays in the diagnostic process (26). In our study there appeared to be such missed diagnostic opportunities when patients appeared not to mention abdominal problems in such a way that their GP wrote these in the patient records. Earlier research suggested that patients try to attribute their symptoms to benign conditions in order to retain normality, or do not mention them because of the private nature of the complaints (27). We also observed that patients cancelled appointments in secondary care, for example for colonoscopy, when complaints they had diminished. The invasive and private nature of the investigations might lead to this patient decision. In order to improve potential missed diagnostic opportunities, GPs could monitor whether patients attend appointments and investigations after referral.

GPs often appeared to attribute symptoms to other known illnesses, co-morbid conditions or medication use of their patients; this could interfere with a swift referral trajectory. GPs ordered tests (e.g. for urinary infections), changed medication (e.g. in relation to melena), or referred patients to other specialists based on their medical history. This could lead to a ‘restart’ of the diagnostic process, creating the opportunity for new patient factors: patients have to evaluate whether they are feeling better or at what point they need to consult their GP again. Combined with the intermittent nature of some complaints like diarrhoea, this might prolong diagnostic intervals profoundly.

Some GPs also did not appear to reconsider their initial diagnosis during subsequent consultations. They also sometimes seemed to unquestioningly accept explanations and/or diagnoses from colleagues and even from patients.

Implications for research and/or practice

Increased consultation rates for digestive problems, not necessarily ‘alarm symptoms’, might warrant further investigation into possible CRC. While in most cases the diagnostic trajectory in primary care might not be expedited there are pitfalls GPs need to be aware of. These include the assumption that symptoms are caused by comorbid conditions or medication, or relating complaints to pre-existing medical conditions. GPs also need to be aware that repeated complaints warrants rethinking earlier diagnoses.