Risk of cancer and repeated urgent referral after negative investigation for cancer

Risk of cancer and repeated urgent referral after negative investigation for cancer Abstract Introduction Many countries have implemented cancer patient pathways (CPPs) for organ-specific cancers. However, due to high symptom diversity, it can be difficult for the General Practitioner (GP) to decide on the appropriate CPP. Objective The aim of this study was to estimate the proportion of patients who were referred to a second CPP, were diagnosed with cancer or died within 6 months after receiving a negative result from clinical investigation through an initial CPP. Methods We conducted a historical cohort study using routinely collected data with 6 months of follow-up. Data were collected from Danish registries. Results We included 109998 study subjects: 0.6% received a cancer diagnosis, 2.3% died and 6.1% were referred to a second CPP within 6 months. A total of 48.9% of the re-referrals after a first CPP in the gastrointestinal (GI) area were also referred to a second CPP in the GI area. Re-referral to a second CPP corresponded to a positive predictive value (PPV) of 4.4% to be diagnosed with cancer. Conclusion A total of 6% of patients who received a negative result after investigation in an organ-specific CPP were re-referred within 6 months to a new organ-specific CPP; many of these were in the same anatomical area as the first CPP. The PPV of 4.4% to be diagnosed with cancer indicates that some cancers may be missed in the diagnostic investigation through the first CPP. This calls for reconsideration of how CPPs may best support the primary cancer diagnosis. Cancer, early diagnosis, general practice, primary health care, prognostic factors, referral and consultation Introduction Urgent cancer referrals have been implemented in many western countries to ensure better access to timely cancer diagnosis and ultimately to improve survival rates (1–4). In Denmark, 33 organ-specific cancer patient pathways (CPPs) have been introduced, and the General Practitioner (GP) can refer patients to further diagnostic testing on the basis of selected criteria, such as alarm symptoms, for specific types of cancer. It can be a difficult task for the GP to identify the patients who might have cancer. Many alarm symptoms of cancer are highly prevalent among patients seen in general practice and yet have low positive predictive value (PPV) for cancer (5–7). Furthermore, 40–50% of cancer patients present in general practice with vague non-specific symptoms such as fatigue, pain and weight loss (8,9). As non-specific symptoms can be caused by a number of different cancers, it can be challenging for the GP to select the most appropriate organ-specific CPP. Although 88% of the Danish cancer cases are diagnosed through at least one CPP (10), it is unknown to what extent patients undergo multiple CPPs before a final diagnosis of cancer is made. Multiple CPPs could lead to longer diagnostic intervals for the patients, with possible negative prognostic consequences (2). Yet, to our knowledge, no previous study has looked into this. The aim of this study was first to estimate the proportion of patients who were diagnosed with cancer, died or were re-referred for cancer investigation through a second CPP within 6 months after ending an initial CPP with a negative diagnosis. Second, we aimed to investigate potential overlaps between the CPPs referred to. Finally, we aimed to estimate the proportion of cancers detected through referral to a second CPP while considering the time frame and the site of the initial CPP. Method We conducted a historical cohort study using routinely collected data with 6-month follow-up of patients who had completed an initial CPP investigation with no verified cancer diagnosis. Setting The study took place in Denmark, which has ~5.6 million inhabitants and an annual cancer incidence rate of 326 per 100000 (age-standardized world population). All Danish citizens have free access to health care through the publicly funded health care system, and around 98% of Danish citizens are listed with a GP, who acts as a gatekeeper to the rest of the health care system (except for emergencies and private otorhinolaryngologists and ophthalmologists, who can be accessed directly). The Danish CPPs were introduced by national law in October 2007, and the CPPs were sequentially implemented throughout 2008 and 2009. The Danish CPP guidelines state specific criteria for urgent referral and describe well-defined diagnostic entities in the time until treatment, including limited time frames (1). In 2015, ~127000 citizens in Denmark were investigated for cancer through a CPP (10). Population Our study population consisted of all patients completing a first-time CPP with no verified cancer diagnosis between 1 January 2014 and 30 June 2015. Patients were identified through the Danish National Patient Register (NPR) (11) with any code for a CPP (NPR code AFB***) registered in the study period and no CPP registered before 1 January 2014. All patients aged ≥18 years with at least one diagnostic course were assessed for eligibility (n = 166381). Patients were eligible if they ended the CPP either with no diagnosis of cancer (registered with NPR code AFB**X1) or on the patient’s request (registered with NPR code AFB**X2). Patients, who ended a CPP by own request were included under the assumption that these patients did not finalize their diagnostic workup (10). Thus, all patients registered to have started cancer treatment in the CPP (NPR code AFB**F* (n = 39667)) or to have been offered cancer treatment (NPR codes of AFB**C* (n = 16522)) were deemed ineligible. In total, 110192 patients fulfilled the eligibility criteria. We excluded 194 patients due to missing information on gender or age in the registers. Thus, we included 109998 study subjects in the study. Outcomes The primary outcomes were defined as a second CPP, death or a subsequent cancer diagnosis within 6 months after initial CPP conclusion. These outcomes were included regardless of the order in which they occurred. A second CPP was defined as a CPP course registered with both a start date and an end date within 6 months after the end date of the first CPP. A subsequent cancer diagnosis was defined as a cancer diagnosis registered in the Danish Cancer Register (DCR) (12) between 14 days and 6 months after the end date of the initial CPP, regardless of whether the cancer was diagnosed within the CPP framework or not. Information on death was based on the vital status recorded in the Danish Civil Registration System (13) if this was registered in the period between the end date of the initial CPP and 6 months after this end date. Other variables Patients were described by gender, age, comorbidity, educational level, disposable income and marital status. Information on gender and age was retrieved from the Danish Civil Registration System. Based on registrations of diagnoses in the NPR 10 years before the start date of the first CPP, we computed the level of morbidity as measured by the Charlson Comorbidity Index (CCI) (14). We grouped CCI scores into ‘none’ (no recorded disease), ‘moderate’ (index scores of 1 and 2) and ‘high’ (index scores of 3 or more). Information on education, household income and marital status was obtained from Statistics Denmark (15). Level of education was categorized in accordance with the International Standard Classification of Education (ISCED) (16) into ‘low’ (ISCED levels 1 and 2), ‘medium’ (ISCED levels 3 and 4) and ‘high’ (ISCED levels 5 and 6). Level of disposable Organisation for Economic Co-operation and Development (OECD) household income was divided into ‘low’, ‘medium and ‘high’. Marital status was divided into ‘married/partnership’, ‘widowed/divorced’ and ‘single’. Statistical measures First, differences in outcome frequencies across patient characteristics were summarized and compared between subgroups (e.g. men versus women) using Wilcoxon rank sum test, Pearson’s chi-square test or Fischer’s exact test, as appropriate. Second, CPPs were categorized according to the anatomical site of the cancer investigated in the CPP [i.e. the CPP for stomach cancer was categorized as gastrointestinal (GI) cancer], and differences in outcome frequencies across these anatomical groups of CPPs were summarized using frequencies and compared using Pearson’s chi-square or Fischer’s exact test, as appropriate. Sensitivity analyses, excluding patients who were registered to have opted out on own request in the initial CPP, were undertaken to ensure that the inclusion of these patients did not alter the results. Results Of the included 109998 patients, 55.7% were women, and 66.7% were aged 45–74 years. Most patients were married (58.9%), had no comorbidity (62.6%) and had a medium level of education (61.6%). All characteristics varied slightly between men and women (Table 1). Table 1. Characteristics of the 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) aPearson’s chi-square test for difference. View Large Table 1. Characteristics of the 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) aPearson’s chi-square test for difference. View Large The highest proportions of CPPs by anatomical location were found for the GI system (35.9%), breast (14.7%) and lung (11.6%). The first CPP ended for 97.2% of the cases with no cancer diagnosis, whereas the remaining patients opted out (Table 2). Table 2. First cancer patient pathway (CPP) undertaken by anatomical site, specific type of cancer suspected and type of conclusion among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) aPearson’s chi-squared test for difference. bTest for difference without gender-specific cancers (i.e. breast, prostate, gynaecological, penile and testis). View Large Table 2. First cancer patient pathway (CPP) undertaken by anatomical site, specific type of cancer suspected and type of conclusion among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) aPearson’s chi-squared test for difference. bTest for difference without gender-specific cancers (i.e. breast, prostate, gynaecological, penile and testis). View Large In total, 693 (0.6%) of the patients received a new cancer diagnosis during follow-up (irrespective of the patient undergoing a second CPP). Among the patients who opted out on own request, 1.7% (men: 1.3%; women: 2.1%) received a cancer diagnosis (Table 3). The patients who opted out on own request constituted 7.6% of the patients who got a cancer diagnosis (men: 6.6%; women: 8.5%). In total, 295 of the patients (42.6%) received the cancer diagnosis during the second CPP (Table 4); this resulted in a PPV of 4.4% (95% CI: 3.9–4.9) for detecting cancer when undergoing a second CPP and 7.4% (95% CI: 5.4–9.9) when undergoing a third CPP. The proportion of cancers detected within the time frame of the second CPP varied across the sites of the initial CPPs: from 3.8% (initial prostate CPP) to 7.2% (initial malignant melanoma CPP) (Table 4). Table 3. Number of new cancer diagnoses, deaths and referral for second cancer patient pathway (CPP) within 6 months after ending the initial CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) aPercentage of total number of CPP. bPercentage of number of previous CPPs. cTest for difference: Fischer’s exact test. dNumber/percentages not reported due to data protection because of low numbers (anonymity). View Large Table 3. Number of new cancer diagnoses, deaths and referral for second cancer patient pathway (CPP) within 6 months after ending the initial CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) aPercentage of total number of CPP. bPercentage of number of previous CPPs. cTest for difference: Fischer’s exact test. dNumber/percentages not reported due to data protection because of low numbers (anonymity). View Large Table 4. Number and proportions of patients completing a second cancer patient pathway (CPP) within 6 months of follow-up, the most frequently used second CPP, and number and proportion of cancers detected during the time frame of the second CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) aDate of diagnosis falls within the time span of 14 days after the end date of the second CPP. bOf initial CPPs. cOf total second CPPs. dNot reported due to protection of personal data in case of low numbers (anonymity). View Large Table 4. Number and proportions of patients completing a second cancer patient pathway (CPP) within 6 months of follow-up, the most frequently used second CPP, and number and proportion of cancers detected during the time frame of the second CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) aDate of diagnosis falls within the time span of 14 days after the end date of the second CPP. bOf initial CPPs. cOf total second CPPs. dNot reported due to protection of personal data in case of low numbers (anonymity). View Large In total, 2580 patients (2.3%) died during follow-up (men: 2.8%; women: 2.0%). Patients opting out of the first CPP constituted 25.3% of the patients who died during follow-up (Table 3). In total, 6697 patients (6.1%) underwent one or more additional CPPs during follow-up (men: 6.2%; women: 5.2%). Of these patients, 8.5% underwent a third CPP of whom 9.6% underwent a fourth CPP (Table 3). At the anatomical level, 2782 (41.5%) of the second CPPs were related to the GI area, 908 (13.6%) were related to the pulmonary area, 817 (12.2%) were related to the urinary system and 673 (10.0%) were related to the head and neck area (Table 4). In six out of twelve instances, the most frequent second CPP was located in the GI area (Table 4). A total of 1386 (49.8%) of the 2782 individuals who completed a CPP related to the GI area were re-referred to a second CPP that was also related to the GI area (Table 4). At the organ-specific level, 1891 (28.2%) of the second CPPs were related to the colorectal area, 908 (13.6%) were related to the lung area, 817 (12.2%) were related to the urinary area and 747 (11.1%) were related to the oesophagus (Table 4). The proportion of re-referrals to a second CPP ranged from 2.2% among patients who were initially investigated in a breast CPP to 18.7% among patients who were initially investigated in an oesophagus CPP (Table 4). The most frequent second organ-specific CPP overall was the colorectal CPP (Table 4), but the most frequent organ-specific second CPP varied across the sites of the initial CPP. Sensitivity analyses, leaving out cases who opted out from the initial CPP (n = 3, 125) did not alter the results (data not shown). Discussion In this study of almost 110000 patients going through an organ-specific (initial) CPP without receiving a diagnosis of cancer, we found that 0.6% received a cancer diagnosis, 2.3% died and 6.1% were referred to a second CPP within 6 months of follow-up. The most frequent anatomical site of the second CPP was the GI system, and the colorectal area was the most frequent organ-specific site. Many of the second CPPs were in the same anatomical area as the first CPP. For example, nearly half of the re-referred cases with a first CPP in the GI area were re-referred to a CPP in the GI area. Strengths and limitations A major strength of this study was the use of population-based prospective collected data. This minimized the risk of selection bias and ensured a high degree of transferability of findings to real-life settings. Another strength was the use of the Danish national registries (17) to collect data as this minimized the risk of information bias. A limitation of the study was that patients were only eligible for inclusion if an end date was registered for the first CPP. Hence, we might have missed some cases due to a missing end date. We have no information on why some end dates should be missing, but these patients might have been more ill and at higher risk of dying. Our requirement of both a start date and an end date for a CPP infers a risk of misclassifying the number of CPPs undertaken. This could have led us to miss patients terminated in an (initial) CPP with no diagnosis of cancer, which might have lowered the number of included cases. Due to delay in registrations in the DCR, we may have missed some new cancer diagnoses. This could have led to an underestimation of the proportion of cases with a new cancer diagnosis during the follow-up period. Additionally, we may have missed some diagnoses because the date of diagnosis in the DCR is defined as the date of admission, which may be at an earlier point in time than the end date of the first CPP. The opposite might also be the case at the end of the follow-up period. However, such misclassification would not depend on the rejection of a diagnosis in a CPP and would thus be non-differential. A second CPP referral was defined as a CPP course registered with both a start date and an end date within 6 months after the end date of the first CPP. This may have led us to miss some second CPPs, which could have led to an underestimation of the number of second CPPs within 6 months. The relatively high proportions of the outcomes may partly be attributable to the age distribution of the cases, as the risk of dying and of getting cancer increases with age. Yet, our findings regarding the proportions of outcomes occurring during follow-up are still valid. However, due to the competing risk between the outcomes, we cannot account for the risks in the individual patients. Comparison with other findings We have not been able to identify similar studies. Nevertheless, a Danish study showed that cancer patients had an increased number of contacts with a hospital 1–12 months before their diagnosis (18). Although this study is based on data from before the CPP implementation in Denmark, it indicates, as our results, that some patients are prone to multiple diagnostic encounters before a cancer diagnosis. The number of second CPPs within 6 months after an initial CPP, which was found in our study, seems counterintuitive as a rejection of a cancer diagnosis might be seen as reassurance that nothing serious is wrong (19). In line with this, a British study found that an ‘all clear’ diagnosis after investigation of cancer alarm symptoms made the patient less inclined to consult a physician, which could delay help seeking for several months (20). This contrasts our findings that more than 1 in 20 were referred to a new CPP, meaning that these patients did indeed consult a physician. A Norwegian study found that, despite a ‘cancer not likely’ record by the GP, 0.6% of patients were subsequently diagnosed with cancer (21). However, a cancer suspicion that proved to be correct was six times more likely to occur than an erroneous lack of suspicion (21). They concluded that, besides symptoms and patient characteristics, the GP’s gut feeling also influenced the suspicion of cancer. This may also be the case in our study as 6.1% of the patients were re-referred to a second CPP although no cancer diagnosis was given after the first CPP, and only 0.6% of all the patients received a cancer diagnosis within 6 months. The risk of having cancer in Denmark in 2014 was ~800/100000 person-years for people above 20 years of age (22), implying that ~0.4% of the Danish population would be diagnosed with cancer within 6 months. This roughly corresponds to our finding that 0.6% receive a cancer diagnosis. These numbers might give the impression that it is not beneficial to re-refer the patient. However, our finding of a PPV of 4.4% to be diagnosed with cancer after re-referral to a CPP is similar to the PPVs reported for warning signs of cancer (5,23). Therefore, it seems feasible to re-refer the patient if cancer suspicion prevails, even after rejection of cancer after the initial investigation. It has been argued that the referral criteria for urgent referrals are too specific because many cancer patients present with non-specific symptoms (9,24). Part of our findings support this as some patients are referred to multiple consecutive CPPs; many of these concern the same anatomical area. Furthermore, 42.6% of the patients who received a cancer diagnosis got the diagnosis within the time span of the second CPP; this suggests that these cancers were missed in the first CPP, which results in delayed treatment for cancer. This brings into question whether more non-specific referral criteria and/or more broad CPPs, e.g. a gastrointestinal CPP, could be favourable. Conclusion After rejection of cancer in an organ-specific CPP, 6% of investigated patients are re-referred within 6 months to a new organ-specific CPP; many of these concern the same anatomical area as the first CPP. Particularly, patients who are initially referred to a gastrointestinal CPP seem prone to be re-referred. A re-referral to a second CPP has a PPV of 4.4% for finding cancer; this indicates that some cancers may be missed in the first CPP. Acknowledgements We would like to thank data manager Kaare Rud Flarup for his meticulous work preparing the data for analyses. We would also like to thank Statistics Denmark for providing the IT infrastructure of registries, which made this study possible Authors’ contributions NN was involved in the initial conception of the study, participated in its design, participated in the interpretation of the results and drafted the manuscript. HJ performed the statistical analyses. HJ and PV contributed to the conception, development and design of the study, participated in the interpretation of the results and provided critical revision of the intellectual contents of the manuscript. All authors read and approved the final manuscript. Declaration Funding: This study was supported by the Research Centre for Cancer Diagnosis in Primary Care (CaP), which is funded by the Danish Cancer Society. The funders had no influence on the study. Ethical approval: The study was approved by the Danish Data Protection Agency (file no. 2009-41-3471). According to Danish law, the study did not require approval from the Committee on Health Research Ethics of the Central Denmark Region as no biomedical intervention was performed. Conflict of interest: The authors declare that they have no competing interests. References 1. Probst HB , Hussain ZB , Andersen O . Cancer patient pathways in Denmark as a joint effort between bureaucrats, health professionals and politicians—a national Danish project . Health Policy 2012 ; 105 : 65 – 70 . Google Scholar Crossref Search ADS PubMed 2. Tørring ML , Frydenberg M , Hansen RP , et al. Evidence of increasing mortality with longer diagnostic intervals for five common cancers: a cohort study in primary care . Eur J Cancer 2013 ; 49 : 2187 – 98 . Google Scholar Crossref Search ADS PubMed 3. Valentín-López B , Ferrándiz-Santos J , Blasco-Amaro JA , et al. Assessment of a rapid referral pathway for suspected colorectal cancer in Madrid . Fam Pract 2012 ; 29 : 182 – 8 . Google Scholar Crossref Search ADS PubMed 4. Prades J , Espinàs JA , Font R , et al. Implementing a Cancer Fast-track Programme between primary and specialised care in Catalonia (Spain): a mixed methods study . Br J Cancer 2011 ; 105 : 753 – 9 . Google Scholar Crossref Search ADS PubMed 5. Ingebrigtsen SG , Scheel BI , Hart B , et al. Frequency of ‘warning signs of cancer’ in Norwegian general practice, with prospective recording of subsequent cancer . Fam Pract 2013 ; 30 : 153 – 60 . Google Scholar Crossref Search ADS PubMed 6. Hamilton W . The CAPER studies: five case-control studies aimed at identifying and quantifying the risk of cancer in symptomatic primary care patients . Br J Cancer 2009 ; 101 : S80 – 6 . Google Scholar Crossref Search ADS PubMed 7. Svendsen RP , Støvring H , Hansen BL , et al. Prevalence of cancer alarm symptoms: a population-based cross-sectional study . Scand J Prim Health Care 2010 ; 28 : 132 – 7 . Google Scholar Crossref Search ADS PubMed 8. Nielsen TN , Hansen RP , Vedsted P . Symptom presentation in cancer patients in general practice . Ugeskr Laeger 2010 ; 172 : 2827 – 31 . Google Scholar PubMed 9. Jensen H , Tørring ML , Olesen F , et al. Cancer suspicion in general practice, urgent referral and time to diagnosis: a population-based GP survey and registry study . BMC Cancer 2014 ; 14 : 636 . Google Scholar Crossref Search ADS PubMed 10. Sundhedsdatastyrelsen . Årsopgørelse 2015 Monitorering af kræftområdet . Copenhagen, Denmark: Sundhedsdatastyrelsen, 2016 . http://www.esundhed.dk/sundhedsaktivitet/kr%C3%A6ftomr%C3%A5det/%C3%A5rsrapporter/Documents/2015%20%C3%85rsopg%C3%B8relse%20Monitorering%20af%20kr%C3%A6ftomr%C3%A5det%202016%200503.pdf (accessed 4 May 2017). 11. Lynge E , Sandegaard JL , Rebolj M . The Danish National Patient Register . Scand J Public Health 2011 ; 39 : 30 – 3 . Google Scholar Crossref Search ADS PubMed 12. Gjerstorff ML . The Danish Cancer Registry . Scand J Public Health 2011 ; 39 : 42 – 5 . Google Scholar Crossref Search ADS PubMed 13. Pedersen CB . The Danish Civil Registration System . Scand J Public Health 2011 ; 39 : 22 – 5 . Google Scholar Crossref Search ADS PubMed 14. Quan H , Li B , Couris CM , et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries . Am J Epidemiol 2011 ; 173 : 676 – 82 . Google Scholar Crossref Search ADS PubMed 15. Documentation of Statistics . http://dst.dk/en/Statistik/dokumentation.aspx (accessed on 4 May 2017). 16. UNESCO . International Standard Classification of Education: ISCED 2011 . Montreal, Quebec, Canada : UNESCO Institute for Statistics (UIS) , 2012 . 17. Thygesen LC , Daasnes C , Thaulow I , et al. Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving . Scand J Public Health 2011 ; 39 : 12 – 6 . Google Scholar Crossref Search ADS PubMed 18. Christensen KG , Fenger-Grøn M , Flarup KR , et al. Use of general practice, diagnostic investigations and hospital services before and after cancer diagnosis—a population-based nationwide registry study of 127000 incident adult cancer patients . BMC Health Serv Res 2012 ; 12 : 224 . Google Scholar Crossref Search ADS PubMed 19. Solbjor M , Skolbekken JA , Saetnan AR , et al. Could screening participation bias symptom interpretation? An interview study on women’s interpretations of and responses to cancer symptoms between mammography screening rounds . BMJ Open 2012 ; 2: e001508 . 20. Renzi C , Whitaker KL , Winstanley K , et al. Unintended consequences of an ‘all-clear’ diagnosis for potential cancer symptoms: a nested qualitative interview study with primary care patients . Br J Gen Pract 2016 ; 66 : e158 – 70 . Google Scholar Crossref Search ADS PubMed 21. Scheel BI , Ingebrigtsen SG , Thorsen T , et al. Cancer suspicion in general practice: the role of symptoms and patient characteristics, and their association with subsequent cancer . Br J Gen Pract 2013 ; 63 : e627 – 35 . Google Scholar Crossref Search ADS PubMed 22. Engholm G , Ferlay J , Christensen N , et al. NORDCAN—a Nordic tool for cancer information, planning, quality control and research . Acta Oncol 2010 ; 49 : 725 – 36 . Google Scholar Crossref Search ADS PubMed 23. Jones R , Latinovic R , Charlton J , et al. Alarm symptoms in early diagnosis of cancer in primary care: cohort study using General Practice Research Database . BMJ 2007 ; 334 : 1040 . Google Scholar Crossref Search ADS PubMed 24. Vedsted P , Olesen F . A differentiated approach to referrals from general practice to support early cancer diagnosis—the Danish three-legged strategy . Br J Cancer 2015 ; 112 : S65 – 9 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. 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Risk of cancer and repeated urgent referral after negative investigation for cancer

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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0263-2136
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1460-2229
D.O.I.
10.1093/fampra/cmx138
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Abstract

Abstract Introduction Many countries have implemented cancer patient pathways (CPPs) for organ-specific cancers. However, due to high symptom diversity, it can be difficult for the General Practitioner (GP) to decide on the appropriate CPP. Objective The aim of this study was to estimate the proportion of patients who were referred to a second CPP, were diagnosed with cancer or died within 6 months after receiving a negative result from clinical investigation through an initial CPP. Methods We conducted a historical cohort study using routinely collected data with 6 months of follow-up. Data were collected from Danish registries. Results We included 109998 study subjects: 0.6% received a cancer diagnosis, 2.3% died and 6.1% were referred to a second CPP within 6 months. A total of 48.9% of the re-referrals after a first CPP in the gastrointestinal (GI) area were also referred to a second CPP in the GI area. Re-referral to a second CPP corresponded to a positive predictive value (PPV) of 4.4% to be diagnosed with cancer. Conclusion A total of 6% of patients who received a negative result after investigation in an organ-specific CPP were re-referred within 6 months to a new organ-specific CPP; many of these were in the same anatomical area as the first CPP. The PPV of 4.4% to be diagnosed with cancer indicates that some cancers may be missed in the diagnostic investigation through the first CPP. This calls for reconsideration of how CPPs may best support the primary cancer diagnosis. Cancer, early diagnosis, general practice, primary health care, prognostic factors, referral and consultation Introduction Urgent cancer referrals have been implemented in many western countries to ensure better access to timely cancer diagnosis and ultimately to improve survival rates (1–4). In Denmark, 33 organ-specific cancer patient pathways (CPPs) have been introduced, and the General Practitioner (GP) can refer patients to further diagnostic testing on the basis of selected criteria, such as alarm symptoms, for specific types of cancer. It can be a difficult task for the GP to identify the patients who might have cancer. Many alarm symptoms of cancer are highly prevalent among patients seen in general practice and yet have low positive predictive value (PPV) for cancer (5–7). Furthermore, 40–50% of cancer patients present in general practice with vague non-specific symptoms such as fatigue, pain and weight loss (8,9). As non-specific symptoms can be caused by a number of different cancers, it can be challenging for the GP to select the most appropriate organ-specific CPP. Although 88% of the Danish cancer cases are diagnosed through at least one CPP (10), it is unknown to what extent patients undergo multiple CPPs before a final diagnosis of cancer is made. Multiple CPPs could lead to longer diagnostic intervals for the patients, with possible negative prognostic consequences (2). Yet, to our knowledge, no previous study has looked into this. The aim of this study was first to estimate the proportion of patients who were diagnosed with cancer, died or were re-referred for cancer investigation through a second CPP within 6 months after ending an initial CPP with a negative diagnosis. Second, we aimed to investigate potential overlaps between the CPPs referred to. Finally, we aimed to estimate the proportion of cancers detected through referral to a second CPP while considering the time frame and the site of the initial CPP. Method We conducted a historical cohort study using routinely collected data with 6-month follow-up of patients who had completed an initial CPP investigation with no verified cancer diagnosis. Setting The study took place in Denmark, which has ~5.6 million inhabitants and an annual cancer incidence rate of 326 per 100000 (age-standardized world population). All Danish citizens have free access to health care through the publicly funded health care system, and around 98% of Danish citizens are listed with a GP, who acts as a gatekeeper to the rest of the health care system (except for emergencies and private otorhinolaryngologists and ophthalmologists, who can be accessed directly). The Danish CPPs were introduced by national law in October 2007, and the CPPs were sequentially implemented throughout 2008 and 2009. The Danish CPP guidelines state specific criteria for urgent referral and describe well-defined diagnostic entities in the time until treatment, including limited time frames (1). In 2015, ~127000 citizens in Denmark were investigated for cancer through a CPP (10). Population Our study population consisted of all patients completing a first-time CPP with no verified cancer diagnosis between 1 January 2014 and 30 June 2015. Patients were identified through the Danish National Patient Register (NPR) (11) with any code for a CPP (NPR code AFB***) registered in the study period and no CPP registered before 1 January 2014. All patients aged ≥18 years with at least one diagnostic course were assessed for eligibility (n = 166381). Patients were eligible if they ended the CPP either with no diagnosis of cancer (registered with NPR code AFB**X1) or on the patient’s request (registered with NPR code AFB**X2). Patients, who ended a CPP by own request were included under the assumption that these patients did not finalize their diagnostic workup (10). Thus, all patients registered to have started cancer treatment in the CPP (NPR code AFB**F* (n = 39667)) or to have been offered cancer treatment (NPR codes of AFB**C* (n = 16522)) were deemed ineligible. In total, 110192 patients fulfilled the eligibility criteria. We excluded 194 patients due to missing information on gender or age in the registers. Thus, we included 109998 study subjects in the study. Outcomes The primary outcomes were defined as a second CPP, death or a subsequent cancer diagnosis within 6 months after initial CPP conclusion. These outcomes were included regardless of the order in which they occurred. A second CPP was defined as a CPP course registered with both a start date and an end date within 6 months after the end date of the first CPP. A subsequent cancer diagnosis was defined as a cancer diagnosis registered in the Danish Cancer Register (DCR) (12) between 14 days and 6 months after the end date of the initial CPP, regardless of whether the cancer was diagnosed within the CPP framework or not. Information on death was based on the vital status recorded in the Danish Civil Registration System (13) if this was registered in the period between the end date of the initial CPP and 6 months after this end date. Other variables Patients were described by gender, age, comorbidity, educational level, disposable income and marital status. Information on gender and age was retrieved from the Danish Civil Registration System. Based on registrations of diagnoses in the NPR 10 years before the start date of the first CPP, we computed the level of morbidity as measured by the Charlson Comorbidity Index (CCI) (14). We grouped CCI scores into ‘none’ (no recorded disease), ‘moderate’ (index scores of 1 and 2) and ‘high’ (index scores of 3 or more). Information on education, household income and marital status was obtained from Statistics Denmark (15). Level of education was categorized in accordance with the International Standard Classification of Education (ISCED) (16) into ‘low’ (ISCED levels 1 and 2), ‘medium’ (ISCED levels 3 and 4) and ‘high’ (ISCED levels 5 and 6). Level of disposable Organisation for Economic Co-operation and Development (OECD) household income was divided into ‘low’, ‘medium and ‘high’. Marital status was divided into ‘married/partnership’, ‘widowed/divorced’ and ‘single’. Statistical measures First, differences in outcome frequencies across patient characteristics were summarized and compared between subgroups (e.g. men versus women) using Wilcoxon rank sum test, Pearson’s chi-square test or Fischer’s exact test, as appropriate. Second, CPPs were categorized according to the anatomical site of the cancer investigated in the CPP [i.e. the CPP for stomach cancer was categorized as gastrointestinal (GI) cancer], and differences in outcome frequencies across these anatomical groups of CPPs were summarized using frequencies and compared using Pearson’s chi-square or Fischer’s exact test, as appropriate. Sensitivity analyses, excluding patients who were registered to have opted out on own request in the initial CPP, were undertaken to ensure that the inclusion of these patients did not alter the results. Results Of the included 109998 patients, 55.7% were women, and 66.7% were aged 45–74 years. Most patients were married (58.9%), had no comorbidity (62.6%) and had a medium level of education (61.6%). All characteristics varied slightly between men and women (Table 1). Table 1. Characteristics of the 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) aPearson’s chi-square test for difference. View Large Table 1. Characteristics of the 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) Male Female Difference Total n (%) n (%) P valuea n (%) Total 48653 (100) 61345 (100) 109998 (100) Age group (years)  18–44 6961 (14.3) 12865 (21.0) 19826 (18.0)  45–54 8342 (17.1) 13672 (22.3) 22014 (20.0)  55–64 11789 (24.2) 12935 (21.1) 24724 (22.5)  65–74 13512 (27.8) 13111 (21.4) 26623 (24.2)  75–84 6757 (13.9) 7046 (11.5) 13803 (12.5)  ≥85 1292 (2.7) 1716 (2.8) <0.001 3008 (2.7) Marital status  Married/partnership 30810 (63.3) 33930 (55.3) 64740 (58.9)  Widowed/divorced 9371 (19.3) 18123 (29.5) 27494 (25.0)  Single 8472 (17.4) 9292 (15.1) <0.001 17764 (16.1) Comorbidity  None 28742 (59.1) 40117 (65.4) 68859 (62.6)  Moderate 13278 (27.3) 15472 (25.2) 28750 (26.1)  High 6633 (13.6) 5756 (9.4) <0.001 12389 (11.3) Educational level  Low 15616 (32.1) 21430 (34.9) 37046 (33.7)  Medium 30203 (62.1) 37534 (61.2) 67737 (61.6)  High 2834 (5.8) 2381 (3.9) <0.001 5215 (4.7) Household income  Low 15663 (32.2) 20564 (33.5) 36227 (32.9)  Medium 16230 (33.4) 20599 (33.6) 36829 (33.5)  High 16760 (34.4) 20182 (32.9) <0.001 36942 (33.6) aPearson’s chi-square test for difference. View Large The highest proportions of CPPs by anatomical location were found for the GI system (35.9%), breast (14.7%) and lung (11.6%). The first CPP ended for 97.2% of the cases with no cancer diagnosis, whereas the remaining patients opted out (Table 2). Table 2. First cancer patient pathway (CPP) undertaken by anatomical site, specific type of cancer suspected and type of conclusion among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) aPearson’s chi-squared test for difference. bTest for difference without gender-specific cancers (i.e. breast, prostate, gynaecological, penile and testis). View Large Table 2. First cancer patient pathway (CPP) undertaken by anatomical site, specific type of cancer suspected and type of conclusion among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) Male Female Difference Total n (%) n (%) P value n (%) Anatomical site of CPP  Gastrointestinal system 19139 (39.3) 20300 (33.1) 39439 (35.9)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Female cancers 7077 (11.5) 7077 (6.4)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Male cancers 6401 (13.2) 6401 (5.8)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  CNS (brain) 1018 (2.1) 1374 (2.2) 2392 (2.2)  Lymphatic and blood systems 610 (1.3) 516 (0.8) <0.001a 1126 (1.0)  Others 414 (0.9) 424 (0.7) <0.001b 838 (0.8) Organ-specific CPP  Colorectal 16631 (34.2) 17548 (28.6) 34179 (31.1)  Breast 481 (1.0) 15666 (25.5) 16147 (14.7)  Urinary system 8541 (17.6) 4232 (6.9) 12773 (11.6)  Lung 6888 (14.2) 5832 (9.5) 12720 (11.6)  Head and neck 3266 (6.7) 3364 (5.5) 6630 (6.0)  Uterus 5062 (8.3) 5062 (4.6)  Melanoma, malignant 1895 (3.9) 2560 (4.2) 4455 (4.1)  Prostate 4435 (9.1) 4435 (4.0)  Oesophagus, ventricular 1962 (4.0) 2026 (3.3) 3988 (3.6)  Brain 1018 (2.1) 1374 (2.2) 2392 (2.2)  Testicular 1767 (3.6) 1767 (1.6)  Ovarian 1361 (2.2) 1361 (1.2)  Pancreas 370 (0.8) 488 (0.8) 858 (0.8)  Sarcoma, soft tissue 245 (0.5) 241 (0.4) 486 (0.4)  Cervical 467 (0.8) 467 (0.4)  Lymphatic system 224 (0.5) 186 (0.3) 410 (0.4)  Myeloid leukaemia, chronic 189 (0.4) 168 (0.3) 357 (0.3)  Liver, primary 94 (0.2) 133 (0.2) 227 (0.2)  Myeloma 107 (0.2) 104 (0.2) 211 (0.2)  Penile 199 (0.4) 199 (0.2)  Eye and orbit 90 (0.2) 101 (0.2) 191 (0.2)  External female genitals 187 (0.3) 187 (0.2)  Sarcoma, Bone 79 (0.2) 82 (0.1) 161 (0.1)  Leukaemia, acute 90 (0.2) 58 (0.1) 148 (0.1)  Biliary duct 54 (0.1) 80 (0.1) 134 (0.1)  Anal 12 (0.0) 17 (0.0) <0.001a 29 (0.0)  Liver, intestinal metastases 16 (0.0) 8 (0.0) <0.001b 24 (0.0) Result of CPP  Diagnosis dismissed 47072 (96.8) 59801 (97.5) <0.001a 106873 (97.2)  Patient opted out 1581 (3.2) 1544 (2.5) 0.902b 3125 (2.8) aPearson’s chi-squared test for difference. bTest for difference without gender-specific cancers (i.e. breast, prostate, gynaecological, penile and testis). View Large In total, 693 (0.6%) of the patients received a new cancer diagnosis during follow-up (irrespective of the patient undergoing a second CPP). Among the patients who opted out on own request, 1.7% (men: 1.3%; women: 2.1%) received a cancer diagnosis (Table 3). The patients who opted out on own request constituted 7.6% of the patients who got a cancer diagnosis (men: 6.6%; women: 8.5%). In total, 295 of the patients (42.6%) received the cancer diagnosis during the second CPP (Table 4); this resulted in a PPV of 4.4% (95% CI: 3.9–4.9) for detecting cancer when undergoing a second CPP and 7.4% (95% CI: 5.4–9.9) when undergoing a third CPP. The proportion of cancers detected within the time frame of the second CPP varied across the sites of the initial CPPs: from 3.8% (initial prostate CPP) to 7.2% (initial malignant melanoma CPP) (Table 4). Table 3. Number of new cancer diagnoses, deaths and referral for second cancer patient pathway (CPP) within 6 months after ending the initial CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) aPercentage of total number of CPP. bPercentage of number of previous CPPs. cTest for difference: Fischer’s exact test. dNumber/percentages not reported due to data protection because of low numbers (anonymity). View Large Table 3. Number of new cancer diagnoses, deaths and referral for second cancer patient pathway (CPP) within 6 months after ending the initial CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) New cancer diagnosis within 6 months Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a Total 640 (0.6) (92.4) 53 (1.7) (7.6) <0.001 693 (0.6) Men 283 (0.6) (93.4) 20 (1.3) (6.6) 0.002 303 (0.6) Women 357 (0.6) (91.5) 33 (2.1) (8.5) <0.001 390 (0.6) Death within 6 months  Total 1928 (1.8) (74.7) 652 (20.9) (25.3) <0.001 2580 (2.3)  Men 1041 (2.2) (76.2) 326 (20.6) (23.8) <0.001 1367 (2.8)  Women 887 (1.5) (73.1) 326 (21.1) (26.9) <0.001 1213 (2.0) Subsequent CPPs within 6 months Number of CPPs Diagnosis dismissed Patient opted out Total n (%)a (%)b n (%)a (%)b P valuec n (%)a (%)b Total 1 6017 (5.6) 113 (3.6) 6130 (5.6) 2 n/ad (0.5) (8.5) <5d n/ad n/ad 517 (0.5) (8.4) ≥3 n/ad (0.0) (9.6) <5d n/ad n/ad 0.267 50 (0.0) (9.7) Men 1 2913 (6.2) 59 (3.7) 2972 (6.1) 2 n/ad (0.6) (9.2) <5d n/ad n/ad 270 (0.6) (9.1) ≥3 n/ad (0.0) (7.8) <5d n/ad n/ad 0.169 22 (0.0) (8.1) Women 1 3104 (5.2) 54 (3.5) 3158 (5.1) 2 n/ad (0.4) (7.9) <5d n/ad n/ad 247 (0.4) (7.8) ≥3 n/ad (0.0) (11.5) <5d n/ad n/ad 0.873 28 (0.0) (11.3) aPercentage of total number of CPP. bPercentage of number of previous CPPs. cTest for difference: Fischer’s exact test. dNumber/percentages not reported due to data protection because of low numbers (anonymity). View Large Table 4. Number and proportions of patients completing a second cancer patient pathway (CPP) within 6 months of follow-up, the most frequently used second CPP, and number and proportion of cancers detected during the time frame of the second CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) aDate of diagnosis falls within the time span of 14 days after the end date of the second CPP. bOf initial CPPs. cOf total second CPPs. dNot reported due to protection of personal data in case of low numbers (anonymity). View Large Table 4. Number and proportions of patients completing a second cancer patient pathway (CPP) within 6 months of follow-up, the most frequently used second CPP, and number and proportion of cancers detected during the time frame of the second CPP among 109998 patients who concluded an initial CPP with no verified cancer diagnosis from 1 January 2014 to 30 June 2015 Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) Initial CPP Second CPP Total Most frequent New cancer diagnosisa Anatomical site n n (%)b Anatomical site n (%)c n (%)c Gastrointestinal (GI) system 39439 2782 (7.1) GI system 1386 (49.8) 112 (4.0) Breast 16147 352 (2.2) GI system 123 (34.9) 19 (5.4) Urinary system 12773 817 (6.4) Male cancers 348 (42.6) 40 (4.9) Lung 12720 908 (7.1) GI system 357 (39.3) 37 (4.1) Female cancers 7077 521 (7.4) GI system 205 (39.3) 27 (5.2) Head and neck 6630 673 (10.2) Lymphatic and blood systems 262 (38.9) 35 (5.2) Male cancers 6401 249 (3.9) Urinary system 117 (47.0) 8 (3.2) Melanoma, malignant 4455 83 (1.9) GI system 28 (33.7) 6 (7.2) CNS (brain) 2392 113 (4.7) Lung 38 (33.6) <5 n/ad Lymphatic and blood systems 1126 126 (11.2) Lymphatic and blood systems 32 (25.4) 7 (5.6) Others 838 73 (8.7) Lymphatic and blood systems 30 (41.1) <5 n/ad Overall 109988 6697 (6.1) GI system 2782 (41.5) 295 (4.4) Organ-specific site Organ-specific site  Colorectal 34179 1891 (5.5)  Oesophagus, ventricular 588 (31.1) 73 (3.9)  Breast 16147 352 (2.2)  Colorectal 92 (26.1) 19 (5.4)  Urinary system 12773 817 (6.4)  Prostate 333 (40.8) 40 (4.9)  Lung 12720 908 (7.1)  Colorectal 255 (28.1) 37 (4.1)  Head and neck 6630 673 (10.2)  Lymphatic system 250 (37.1) 35 (5.2)  Uterus 5062 291 (5.7)  Colorectal 92 (31.6) 13 (4.5)  Melanoma, malignant 4455 83 (1.9)  Colorectal 24 (28.9) 6 (7.2)  Prostate 4435 184 (4.1)  Urinary system 103 (56.0) 7 (3.8)  Oesophagus, ventricular 3988 747 (18.7)  Colorectal 501 (67.1) 31 (4.1)  Brain 2392 113 (4.7)  Lung 38 (33.6) <5 n/ad  Testicular 1767 58 (3.3)  Prostate 14 (24.1) <5 n/ad  Ovarian 1361 196 (14.4)  Colorectal 80 (40.8) 11 (5.6)  Pancreas 858 91 (10.6)  Colorectal 21 (23.1) <5 n/ad  Sarcoma, soft tissue 486 39 (8.0)  Lymphatic system 14 (35.9) <5 n/ad  Cervical 467 22 (4.7)  Colorectal 8 (36.4) <5 n/ad  Lymphatic system 410 56 (13.7)  Colorectal 13 (23.2) <5 n/ad  Myeloid leukaemia, chronic 357 33 (9.2)  n/ad <5 n/ad <5 n/ad  Liver, primary 227 31 (13.7)  Biliary duct 13 (41.9) <5 n/ad  Myeloma 211 19 (9.0)  n/ad <5 n/ad <5 n/ad  Penile 199 <5 n/ad  n/ad <5 n/ad <5 n/ad  Eye and orbital 191 13 (6.8)  n/ad <5 n/ad <5 n/ad  External female genitals 187 12 (6.4)  n/ad <5 n/ad <5 n/ad  Sarcoma, bone 161 21 (13.0)  n/ad <5 n/ad <5 n/ad  Leukaemia, acute 148 18 (12.2)  n/ad <5 n/ad <5 n/ad  Biliary duct 134 14 (10.4)  n/ad <5 n/ad <5 n/ad  Anal 29 <5 n/ad  n/ad <5 n/ad <5 n/ad  Liver, intestinal metastases 24 <5 n/ad  n/ad <5 n/ad <5 n/ad  Overall 109988 6697 (6.1) Colorectal 1415 (21.1) 295 (4.4) aDate of diagnosis falls within the time span of 14 days after the end date of the second CPP. bOf initial CPPs. cOf total second CPPs. dNot reported due to protection of personal data in case of low numbers (anonymity). View Large In total, 2580 patients (2.3%) died during follow-up (men: 2.8%; women: 2.0%). Patients opting out of the first CPP constituted 25.3% of the patients who died during follow-up (Table 3). In total, 6697 patients (6.1%) underwent one or more additional CPPs during follow-up (men: 6.2%; women: 5.2%). Of these patients, 8.5% underwent a third CPP of whom 9.6% underwent a fourth CPP (Table 3). At the anatomical level, 2782 (41.5%) of the second CPPs were related to the GI area, 908 (13.6%) were related to the pulmonary area, 817 (12.2%) were related to the urinary system and 673 (10.0%) were related to the head and neck area (Table 4). In six out of twelve instances, the most frequent second CPP was located in the GI area (Table 4). A total of 1386 (49.8%) of the 2782 individuals who completed a CPP related to the GI area were re-referred to a second CPP that was also related to the GI area (Table 4). At the organ-specific level, 1891 (28.2%) of the second CPPs were related to the colorectal area, 908 (13.6%) were related to the lung area, 817 (12.2%) were related to the urinary area and 747 (11.1%) were related to the oesophagus (Table 4). The proportion of re-referrals to a second CPP ranged from 2.2% among patients who were initially investigated in a breast CPP to 18.7% among patients who were initially investigated in an oesophagus CPP (Table 4). The most frequent second organ-specific CPP overall was the colorectal CPP (Table 4), but the most frequent organ-specific second CPP varied across the sites of the initial CPP. Sensitivity analyses, leaving out cases who opted out from the initial CPP (n = 3, 125) did not alter the results (data not shown). Discussion In this study of almost 110000 patients going through an organ-specific (initial) CPP without receiving a diagnosis of cancer, we found that 0.6% received a cancer diagnosis, 2.3% died and 6.1% were referred to a second CPP within 6 months of follow-up. The most frequent anatomical site of the second CPP was the GI system, and the colorectal area was the most frequent organ-specific site. Many of the second CPPs were in the same anatomical area as the first CPP. For example, nearly half of the re-referred cases with a first CPP in the GI area were re-referred to a CPP in the GI area. Strengths and limitations A major strength of this study was the use of population-based prospective collected data. This minimized the risk of selection bias and ensured a high degree of transferability of findings to real-life settings. Another strength was the use of the Danish national registries (17) to collect data as this minimized the risk of information bias. A limitation of the study was that patients were only eligible for inclusion if an end date was registered for the first CPP. Hence, we might have missed some cases due to a missing end date. We have no information on why some end dates should be missing, but these patients might have been more ill and at higher risk of dying. Our requirement of both a start date and an end date for a CPP infers a risk of misclassifying the number of CPPs undertaken. This could have led us to miss patients terminated in an (initial) CPP with no diagnosis of cancer, which might have lowered the number of included cases. Due to delay in registrations in the DCR, we may have missed some new cancer diagnoses. This could have led to an underestimation of the proportion of cases with a new cancer diagnosis during the follow-up period. Additionally, we may have missed some diagnoses because the date of diagnosis in the DCR is defined as the date of admission, which may be at an earlier point in time than the end date of the first CPP. The opposite might also be the case at the end of the follow-up period. However, such misclassification would not depend on the rejection of a diagnosis in a CPP and would thus be non-differential. A second CPP referral was defined as a CPP course registered with both a start date and an end date within 6 months after the end date of the first CPP. This may have led us to miss some second CPPs, which could have led to an underestimation of the number of second CPPs within 6 months. The relatively high proportions of the outcomes may partly be attributable to the age distribution of the cases, as the risk of dying and of getting cancer increases with age. Yet, our findings regarding the proportions of outcomes occurring during follow-up are still valid. However, due to the competing risk between the outcomes, we cannot account for the risks in the individual patients. Comparison with other findings We have not been able to identify similar studies. Nevertheless, a Danish study showed that cancer patients had an increased number of contacts with a hospital 1–12 months before their diagnosis (18). Although this study is based on data from before the CPP implementation in Denmark, it indicates, as our results, that some patients are prone to multiple diagnostic encounters before a cancer diagnosis. The number of second CPPs within 6 months after an initial CPP, which was found in our study, seems counterintuitive as a rejection of a cancer diagnosis might be seen as reassurance that nothing serious is wrong (19). In line with this, a British study found that an ‘all clear’ diagnosis after investigation of cancer alarm symptoms made the patient less inclined to consult a physician, which could delay help seeking for several months (20). This contrasts our findings that more than 1 in 20 were referred to a new CPP, meaning that these patients did indeed consult a physician. A Norwegian study found that, despite a ‘cancer not likely’ record by the GP, 0.6% of patients were subsequently diagnosed with cancer (21). However, a cancer suspicion that proved to be correct was six times more likely to occur than an erroneous lack of suspicion (21). They concluded that, besides symptoms and patient characteristics, the GP’s gut feeling also influenced the suspicion of cancer. This may also be the case in our study as 6.1% of the patients were re-referred to a second CPP although no cancer diagnosis was given after the first CPP, and only 0.6% of all the patients received a cancer diagnosis within 6 months. The risk of having cancer in Denmark in 2014 was ~800/100000 person-years for people above 20 years of age (22), implying that ~0.4% of the Danish population would be diagnosed with cancer within 6 months. This roughly corresponds to our finding that 0.6% receive a cancer diagnosis. These numbers might give the impression that it is not beneficial to re-refer the patient. However, our finding of a PPV of 4.4% to be diagnosed with cancer after re-referral to a CPP is similar to the PPVs reported for warning signs of cancer (5,23). Therefore, it seems feasible to re-refer the patient if cancer suspicion prevails, even after rejection of cancer after the initial investigation. It has been argued that the referral criteria for urgent referrals are too specific because many cancer patients present with non-specific symptoms (9,24). Part of our findings support this as some patients are referred to multiple consecutive CPPs; many of these concern the same anatomical area. Furthermore, 42.6% of the patients who received a cancer diagnosis got the diagnosis within the time span of the second CPP; this suggests that these cancers were missed in the first CPP, which results in delayed treatment for cancer. This brings into question whether more non-specific referral criteria and/or more broad CPPs, e.g. a gastrointestinal CPP, could be favourable. Conclusion After rejection of cancer in an organ-specific CPP, 6% of investigated patients are re-referred within 6 months to a new organ-specific CPP; many of these concern the same anatomical area as the first CPP. Particularly, patients who are initially referred to a gastrointestinal CPP seem prone to be re-referred. A re-referral to a second CPP has a PPV of 4.4% for finding cancer; this indicates that some cancers may be missed in the first CPP. Acknowledgements We would like to thank data manager Kaare Rud Flarup for his meticulous work preparing the data for analyses. We would also like to thank Statistics Denmark for providing the IT infrastructure of registries, which made this study possible Authors’ contributions NN was involved in the initial conception of the study, participated in its design, participated in the interpretation of the results and drafted the manuscript. HJ performed the statistical analyses. HJ and PV contributed to the conception, development and design of the study, participated in the interpretation of the results and provided critical revision of the intellectual contents of the manuscript. All authors read and approved the final manuscript. Declaration Funding: This study was supported by the Research Centre for Cancer Diagnosis in Primary Care (CaP), which is funded by the Danish Cancer Society. The funders had no influence on the study. Ethical approval: The study was approved by the Danish Data Protection Agency (file no. 2009-41-3471). According to Danish law, the study did not require approval from the Committee on Health Research Ethics of the Central Denmark Region as no biomedical intervention was performed. Conflict of interest: The authors declare that they have no competing interests. References 1. Probst HB , Hussain ZB , Andersen O . Cancer patient pathways in Denmark as a joint effort between bureaucrats, health professionals and politicians—a national Danish project . Health Policy 2012 ; 105 : 65 – 70 . Google Scholar Crossref Search ADS PubMed 2. Tørring ML , Frydenberg M , Hansen RP , et al. Evidence of increasing mortality with longer diagnostic intervals for five common cancers: a cohort study in primary care . Eur J Cancer 2013 ; 49 : 2187 – 98 . Google Scholar Crossref Search ADS PubMed 3. Valentín-López B , Ferrándiz-Santos J , Blasco-Amaro JA , et al. Assessment of a rapid referral pathway for suspected colorectal cancer in Madrid . Fam Pract 2012 ; 29 : 182 – 8 . Google Scholar Crossref Search ADS PubMed 4. Prades J , Espinàs JA , Font R , et al. Implementing a Cancer Fast-track Programme between primary and specialised care in Catalonia (Spain): a mixed methods study . Br J Cancer 2011 ; 105 : 753 – 9 . Google Scholar Crossref Search ADS PubMed 5. Ingebrigtsen SG , Scheel BI , Hart B , et al. Frequency of ‘warning signs of cancer’ in Norwegian general practice, with prospective recording of subsequent cancer . Fam Pract 2013 ; 30 : 153 – 60 . Google Scholar Crossref Search ADS PubMed 6. Hamilton W . The CAPER studies: five case-control studies aimed at identifying and quantifying the risk of cancer in symptomatic primary care patients . Br J Cancer 2009 ; 101 : S80 – 6 . Google Scholar Crossref Search ADS PubMed 7. Svendsen RP , Støvring H , Hansen BL , et al. Prevalence of cancer alarm symptoms: a population-based cross-sectional study . Scand J Prim Health Care 2010 ; 28 : 132 – 7 . Google Scholar Crossref Search ADS PubMed 8. Nielsen TN , Hansen RP , Vedsted P . Symptom presentation in cancer patients in general practice . Ugeskr Laeger 2010 ; 172 : 2827 – 31 . Google Scholar PubMed 9. Jensen H , Tørring ML , Olesen F , et al. Cancer suspicion in general practice, urgent referral and time to diagnosis: a population-based GP survey and registry study . BMC Cancer 2014 ; 14 : 636 . Google Scholar Crossref Search ADS PubMed 10. Sundhedsdatastyrelsen . Årsopgørelse 2015 Monitorering af kræftområdet . Copenhagen, Denmark: Sundhedsdatastyrelsen, 2016 . http://www.esundhed.dk/sundhedsaktivitet/kr%C3%A6ftomr%C3%A5det/%C3%A5rsrapporter/Documents/2015%20%C3%85rsopg%C3%B8relse%20Monitorering%20af%20kr%C3%A6ftomr%C3%A5det%202016%200503.pdf (accessed 4 May 2017). 11. Lynge E , Sandegaard JL , Rebolj M . The Danish National Patient Register . Scand J Public Health 2011 ; 39 : 30 – 3 . Google Scholar Crossref Search ADS PubMed 12. Gjerstorff ML . The Danish Cancer Registry . Scand J Public Health 2011 ; 39 : 42 – 5 . Google Scholar Crossref Search ADS PubMed 13. Pedersen CB . The Danish Civil Registration System . Scand J Public Health 2011 ; 39 : 22 – 5 . Google Scholar Crossref Search ADS PubMed 14. Quan H , Li B , Couris CM , et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries . Am J Epidemiol 2011 ; 173 : 676 – 82 . Google Scholar Crossref Search ADS PubMed 15. Documentation of Statistics . http://dst.dk/en/Statistik/dokumentation.aspx (accessed on 4 May 2017). 16. UNESCO . International Standard Classification of Education: ISCED 2011 . Montreal, Quebec, Canada : UNESCO Institute for Statistics (UIS) , 2012 . 17. Thygesen LC , Daasnes C , Thaulow I , et al. Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving . Scand J Public Health 2011 ; 39 : 12 – 6 . Google Scholar Crossref Search ADS PubMed 18. Christensen KG , Fenger-Grøn M , Flarup KR , et al. Use of general practice, diagnostic investigations and hospital services before and after cancer diagnosis—a population-based nationwide registry study of 127000 incident adult cancer patients . BMC Health Serv Res 2012 ; 12 : 224 . Google Scholar Crossref Search ADS PubMed 19. Solbjor M , Skolbekken JA , Saetnan AR , et al. Could screening participation bias symptom interpretation? An interview study on women’s interpretations of and responses to cancer symptoms between mammography screening rounds . BMJ Open 2012 ; 2: e001508 . 20. Renzi C , Whitaker KL , Winstanley K , et al. Unintended consequences of an ‘all-clear’ diagnosis for potential cancer symptoms: a nested qualitative interview study with primary care patients . Br J Gen Pract 2016 ; 66 : e158 – 70 . Google Scholar Crossref Search ADS PubMed 21. Scheel BI , Ingebrigtsen SG , Thorsen T , et al. Cancer suspicion in general practice: the role of symptoms and patient characteristics, and their association with subsequent cancer . Br J Gen Pract 2013 ; 63 : e627 – 35 . Google Scholar Crossref Search ADS PubMed 22. Engholm G , Ferlay J , Christensen N , et al. NORDCAN—a Nordic tool for cancer information, planning, quality control and research . Acta Oncol 2010 ; 49 : 725 – 36 . Google Scholar Crossref Search ADS PubMed 23. Jones R , Latinovic R , Charlton J , et al. Alarm symptoms in early diagnosis of cancer in primary care: cohort study using General Practice Research Database . BMJ 2007 ; 334 : 1040 . Google Scholar Crossref Search ADS PubMed 24. Vedsted P , Olesen F . A differentiated approach to referrals from general practice to support early cancer diagnosis—the Danish three-legged strategy . Br J Cancer 2015 ; 112 : S65 – 9 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. 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Family PracticeOxford University Press

Published: Sep 18, 2018

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