The literature search identified a total of 2751 publications which included 1394 duplicate publications for a total of 1357 original identified publications. A PRISMA flow diagram of the search is presented in Fig. 1. When applying the inclusion and exclusion criteria, 1303 publications were excluded, and 53 publications remained for full text assessment. Of these, 42 publications were excluded due to not being a cohort or case control study (n = 26), further duplications (n = 1), being published before 1975 (=2), being wrong setting (=4), wrong outcome (=9). Twelve publications in total were included in the systematic review. Næser published two articles [16, 17] from one study and Moseholm published two articles [25, 26] from another study. These studies were analysed together; thus, the results of these studies are described in this review.
Assessment of the included studies
In the quality synthesis of the nine publications, information for the Newcastle–Ottawa Quality Assessment Scale (NOS) was extracted as shown in Table 2. All studies were cohort studies and were published from 2016 to 2022. The study populations ranged from 290 to 23,934 patients. Analysis of the methodological quality of the included articles was assessed using the NOS methods which categorises studies scoring as low quality (0–5 stars), medium quality, (6–7 stars) and high quality (8–9 stars). All ten studies were considered to be of high quality [10, 12, 16, 17, 21, 24,25,26,27,28,29].
Patient characteristics and patient pathway
Eight included studies provided information about social and mental characteristics of participants [10, 12, 16, 17, 21, 23,24,25,26,27]. One study only included physical characteristics and another included physical characteristics and information about patient pathway [28, 29]. Nine publications held information about physical characteristics [10, 12, 16, 17, 21, 24,25,26,27,28].
Six of the ten included studies were from Denmark [12, 16, 17, 24,25,26,27,28,28] One was from Sweden, Two from UK and one from the Netherlands [10, 21, 23, 29]. The six studies from Denmark, the one from Sweden and the two from UK investigated patients with non-specific symptoms of cancer who were referred to a DC for further examination whereas the study from the Netherlands investigated GPs’ gut feelings regarding cancer possibility [10, 12, 16, 17, 20, 21, 23,24,25,26,27,28, 32]. The studies from Denmark were conducted in specific regions of the country except for the study by Moseholm et al. which was a nationwide study [12, 16, 17, 24,25,26,27,28].
The study population
The study population in the Netherlands study was defined by persons consulting their GP which led to the GP having any kind of gut feeling of cancer independent of clinical signs and symptoms . The study population of the studies from Denmark, the one from Sweden and the two from UK was defined by patients referred to a DC [10, 12, 16, 17, 21, 23,24,25,26,27,28,29].
The population of patients with NSSC were divided into two groups. The first group was made up of all patients referred with NSSC, and the second group was made up of patients diagnosed with cancer after being referred with NSSC.
Patient pathway and characteristics
A. Patients referred with NSSC
Between 11 and 35% of all persons referred to a DC or who triggered GP gut feeling were later diagnosed with a cancer [10, 12, 16, 17, 21, 23,24,25,26,27,28,29].
The median number of days from referral to last visit day in DC was assessed in two studies from Denmark and ranged from 7 to 10 days [12, 16, 17, 24]. The Swedish study found that the median timeframe from patients first contact in primary care to diagnosis after being referred with NSSC was 37 days . It was also revealed that 77% of patients referred with NSSC were investigated in the DC within 22 days . One study found that the median time interval in primary care for patients diagnosed with cancer was 15 days .
Only one study investigated duration of symptoms before patients were referred with NSSC [25, 26]. The median duration of symptoms was 12 days in this study [25, 26]. No studies investigated visits to GP until referral for NSSC. The study from the Netherlands described visits to GP as triggers for referral but no further details were given .
B. the patients diagnosed with cancer after being referred with NSSC
The 1-year mortality was between 28 and 44% for patients with a cancer diagnosed compared to 2–3% for patients who were not diagnosed with cancer after examination at DC [12, 16, 17]. One study showed that the median survival time after cancer diagnosis was 1,4 years .
Two studies examined the stage of cancer and one showed that 47% of patients who attained a cancer diagnose after being referred with NSSC had solid tumors with potential to spread based on TNM-staging [10, 29]. 20% who attained a cancer diagnosis were referred to palliative care . The second study showed how many percent were in the different stages for each cancer diagnose . Four percent of patients with upper Gastrointestinal (GI) cancer, 26% with lung cancer 20% with hematological cancer and 1 % with lower GI cancer were in stage one, 57% of patients with upper Gastrointestinal (GI) cancer, 53% with lung cancer 27% with hematological cancer and 48% with lower GI cancer were in stage one .
A. Patients referred with NSSC
Mean age of the included patients was 62–72 years [10, 12, 16, 17, 21, 24,25,26,27,28,29]. 47–56% of patients referered with NSSC were women and 44–53% were men [10, 12, 16, 17, 23,24,25,26,27, 29]. Four out of seven studies showed hematological cancers as the most frequent cancer diagnosed when referred with NSSC (14–30%) [10, 12, 16, 17, 25, 26, 29]. One study showed that breast cancer (18%) was the most frequent diagnosis while another lung cancer (18%) and a third upper gastrointestinal cancer (22%) as being most frequent [24, 27, 29]. Moreover, the second most prevalent cancers included gastrointestinal cancers (13–23%) in three studies, lung cancers (13–22%) also in three studies and hematological cancers (15%) in one study [10, 12, 16, 17, 24,25,26,27, 29]. The third most prevalent cancers were malignant melanoma and hematological, lung, gastrointestinal and kidney cancers [10, 12, 16, 17, 24,25,26,27, 29]. Four studies included description of non-malignant diseases diagnosed after referral with NSSC, and three of these four studies showed rheumatological diseases or musculoskeletal disorders as the most common non-malignant diseases found with a diagnostic rate of 5–38% [10, 12, 16, 17, 24]. All four studies showed gastrointestinal diseases as the second most common non-cancerous disease with a diagnostic rate of 7–31% [10, 12, 16, 17, 24].
Eight out of ten studies showed the most frequent symptoms for patients referred with NSSC [10, 12, 16, 17, 21, 23, 25,26,27, 29]. Weight loss was distinctively the most common symptom for referral with NSSC in seven out of eight studies and presented in 24–66% of patients [10, 12, 16, 17, 21, 23, 25,26,27, 29]. Fatigue was described as the first, second and third most common symptom and was seen in up to 74% of patients [10, 12, 16, 17, 23, 25,26,27]. Pain and loss of appetite were also some of the most frequent symptoms seen in patients with non-specific symptoms of cancer [10, 12, 16, 17, 21, 23, 25,26,27, 29]. Four studies in this review described known comorbidity; hence cardiovascular diseases, lung diseases, diabetes and previous diagnosed cancer were among the most common comorbidities among patients with NSSC [12, 16, 17, 24, 27]. Two studies showed that previously diagnosed cancer, cardiovascular diseases, cerebrovascular disease and diabetes were among the most common comorbidities for patients with NSSC who received a cancer diagnose [12, 24].
Limited information about mental disorders was described in the studies. One study showed that 7% of the population had a mental illness diagnose when referred with non-specific symptoms of cancer [16, 17]. The same study showed that 2% of the population was diagnosed with a psychiatric disease after being referred with NSSC. Another study showed that 1% of the population was diagnosed with a psychiatric disorder and not cancer after being referred with NSSC . One study showed that 18% of the patientend not diagnosed with cancer had a mental health illness and 13% not diagnosed with cancer had a mental health illness . In one study, 2% of the population had dementia . One study showed that 5% of patients referred with NSSC had mild to moderate mental disorders . None of these patients were diagnosed with cancer. Another study showed that 7% were diagnosed with a mental disorder . No studies reviewed described use of drugs against medical disorders.
Three studies showed that 54–68% of patients referred with NSSC were married/living with a partner and 31–32% were single/widowed/separated [10, 12, 16, 17, 24,25,26]. Two studies found that 28–37% of patients were employed when referred with NSSC, 1–7% were unemployed and 59–68% were retired [24–26].
One study showed that 81% of the population did not consume alcohol on daily basis and another showed that 10% of patients had a weekly consumption of alcohol above national guidelines [12, 16, 17, 33]. Two studies revealed that 34–38% of patients referred with NSSC never smoked while 61–70% were former or current smokers [12, 16, 17, 25, 26].
B. Patients diagnosed with cancer after being referred with NSSC
Four studies showed that 40–58% of patients diagnosed with cancer were women and 42–60% men [12, 21, 24, 28]. Two studies study found that patients diagnosed with cancer had a significant higher age than those not diagnosed with cancer [21, 27].
Ingeman ML et. al . One study found that cancer were more often found in men than women, and another study found that being women were significant associated with getting a cancer [24, 27]. Two studies calculated the odds of getting a cancer diagnose with 1 year increase in age [23, 24]. One found that the odds increased by a factor 1.02% and the other one found that the odds increased by 4% [23, 24].
The percentage of patients who attained a cancer diagnose with medium academic education was 47–52%, with long academic education 6–18% and with short/no education 36–39% [16, 17, 24]. Two studies showed that 56–59% of patients diagnosed with cancer after being referred with NSSC were married patients [16, 17, 24] 17–18% of patients diagnosed with cancer were employed, 0–1% were unemployed and 80–83% were retired [16, 17, 24–26].
One study contained information about the income of the participants [16, 17]. This study showed that 27% of patients who acquired a cancer diagnose were in the lowest income range, 54% in the middle and 19% in the highest [16, 17].
In the Dutch study, 54% of 204 patients with Dutch ethnicity had a cancer diagnose and 50% of 14 patients with another ethnicity . One of the Danish studies showed that 95% of patients with cancer were from Denmark, 3% from another Western country, 1% from Middle East/Asia and 1% from other countries . The English study showed that 56% were white, 6% Black, 4% Asian, and 3% other .
Between 36 to 70% of former/current smokers who were referred with NSSC were later diagnosed with a cancer [12, 21, 23]. 20% drank alcohol within recommendation limit, 13% had an excessive use and 51% did not drink alcohol [12, 21].