Strengths and limitations
To our knowledge, this study is the first to investigate healthcare use preceding a diagnosis of CR and SPC in a nationwide setting on the basis of prospectively collected data from registers with high completeness and accuracy [
25,
32,
33]. Performing epidemiological population-based register studies of patients with CR is a challenging task because remission and CR are not routinely recorded outside of clinical trials [
38]. However, newly developed algorithms allowed us to identify patients with CR in Denmark [
26‐
28]. The study included patients diagnosed with primary cancer over a nine-year period and up to nine years of follow-up; this resulted in as many as 7832 patients with CR and 2703 patients with SPC and enabled us to conduct sex-, age- and comorbidity-stratified analyses with high statistical precision.
The main limitation of the study is that the sensitivity of the algorithms used to identify patients with CR ranged from 85 to 97% and the specificity from 93 to 99% [
26‐
28]. This may have misclassified a minor proportion of CRs as being in continued remission. Such misclassification is likely to have underestimated the differences in healthcare use between patients with CR and patients in remission and thus have lowered the CRR estimates. The agreement between the recurrence dates estimated by the algorithms and the gold standards was high [
27‐
30]. Nevertheless, some recurrence dates were estimated by the algorithm to occur later in time than the true recurrence dates. This may have overestimated the number of pre-diagnostic contacts because contacts related to CR treatment would then be categorised as pre-diagnostic activity. However, this would be counterbalanced by an underestimated number of pre-diagnostic contacts in patients for whom the CR date was estimated to be earlier than the true CR date. Hence, misclassifications of the recurrence dates are not considered to have altered the results.
Changes in contact rates were considered a proxy for symptom presentation of CR and SPC. We included all contacts to general practice and all hospital contacts, and some of these contacts could concern other health problems. Still, we aimed to eliminate confounding by matching on primary cancer disease, age group and CCI score and by adjusting for factors known to affect healthcare use. Finally, we conducted sensitivity analyses excluding some groups of patients, e.g. patients who died within 90 days after the index date (to eliminate activity related to death), patients diagnosed with SPC or CR within 180 days after the index date (to eliminate activity related to a third cancer diagnosis), and patients with an index date of less than 13 months from the final date of treatment for the primary cancer (to eliminate activity originating from the first primary cancer disease). Increased healthcare activity remained for 7 months in general practice and for up to 12 months in hospitals; this was seen even when all four sensitivity analyses were included in one analysis, which suggests that the increase in activity was related to CR and SPC.
More than 65% of the female study population consisted of survivors from colorectal cancer and breast cancer, and almost 50% of the male study population were survivors from colorectal cancer. Although we adjusted for primary cancer disease in the analyses, the patients with breast or colorectal cancers may have dominated the results over smaller populations with bladder or lung cancers. High-definition analyses stratified on primary cancer disease are thus warranted, but these were outside the scope of this study.
Comparison with relevant literature
We found increasing contact frequency in general practice, starting from eleven months before CR and SPC. Other studies have reported similar findings for a first primary cancer diagnosis [
21,
22,
39]. Thus, GPs seem to be as involved in the detection of CR and SPC as in the diagnosis of a first primary cancer.
In the present study, we assessed healthcare activity related to CR and SPC as the increased activity in these patients compared to the activity in patients with no second cancer event, which is illustrated by the contact rates and CRRs in Fig.
2. Augestad et al. [
23] found a 29% probability of CR after initiation of diagnostic work-up based on suspicion of colorectal CR. This increased base consultation rate in patients in remission infers that an elevated activity in patients with a second cancer event is more difficult to detect, why the true onset of elevated activity might be at earlier point in time than illustrated by the contact rates and the CRRs in Fig.
2.
Women tended to have higher CRRs in hospitals prior to CR compared to SPC. This difference was less pronounced in men, which may be explained by the fact that, in this study, 17% of the SPCs in women were breast cancers. Breast cancer is defined as an “easy to diagnose” type of cancer, i.e. a cancer presenting with clear symptoms, which has been associated with fewer contacts prior to diagnosis [
40].
The CRRs were most increased in younger and non-comorbid cancer survivors. Lyratzopoulos et al. [
40] attributed similar findings for first-time primary cancers to a poorer understanding of cancer symptoms in younger patients. Thus, an altered focus on symptom presentation to ensure timely detection in younger patients may be warranted. Patients with comorbidity had more hospital contacts compared to patients with no comorbidity. This group may address both issues related to comorbid disorders and symptoms of subsequent cancer events in a consultation scheduled exclusively for a chronic disorder. This could have caused the lower differences in contact rates in this group compared to the reference population [
41]. Hence, we can neither prove nor reject that patients with comorbid disorders may also have presented CR- and SPC-related symptoms at an earlier point in time. The analyses stratified on age groups and comorbidity revealed a need for increased focus on younger patients, and they indicated that symptom presentation of CR and SPC may occur earlier in time than illustrated by the analyses stratified on sex alone.
Interpretation and implications
We found increased healthcare contacts in both general practice and at hospitals from up to one year before a subsequent cancer diagnosis. This finding indicates a potential to diagnose CR and SPC at an earlier point in time and to improve both the organisation of follow-up and the coordination across sector boundaries.
The data for this study originates from a time when cancer follow-up was organised in specialised hospital departments. Given the median time of 11 months to CR and of 32 months to SPC, patients were most likely actively followed at the time of CR and SPC. We demonstrated increasing activity in general practice prior to a subsequent cancer event, which could indicate that patients found the GP more accessible despite direct access to specialised hospital departments. This is in line with a study by Grunfeld et al. [
17], who reported that most breast cancer recurrences were detected as interval events and that women presented first in general practice despite hospital-based follow-up. Furthermore, studies in gynaecological cancers [
42‐
44], malignant melanoma [
45] and colorectal cancers [
19] found between 42 and 72% of CRs to be diagnosed as interval events outside scheduled follow-up visits and to be symptomatic at diagnosis. Gilbert et al. [
46] found 67% of lung CRs to be detected by the GP. This indicates involvement of general practice and supports that the increased contact rates in general practice found in the present study were related to detection of CR and SPC.
If higher use of healthcare before CR or SPC can be regarded as an indication of increased symptoms caused by the cancer, the findings of this study indicate that prolonged diagnostic pathways prevail in the diagnosis of subsequent cancer events. This is similar to the conclusions made in other studies on first-time primary cancers [
21,
22]. Recent studies exploring frequent vs. less frequent diagnostic testing as part of follow-up found no impact on CR detection, time to CR detection and (overall or cancer-specific) mortality [
3,
47]. Hence, additional approaches to follow-up testing must be considered to ensure more timely detection of CR and SPC. We need a better understanding of the symptom presentation in CR and SPC, and how patients and healthcare professionals react to new symptoms. Furthermore, considerations should be made on the best use of the limited resources in the healthcare system, and risk stratified follow-up pathways should be considered [
48]. Studies have reported a false positive rate of 71% in tests, which all raised suspicion of CR [
23], and a probability of 87% for at least one false positive test within five years of follow-up [
49]. The authors of these studies have suggested risk-tailored surveillance to ensure more cost-effective follow-up, a better balance between harms and benefits from diagnostic investigations and improved pathways for patients.
We found more hospital contacts for patients with CR compared to patients with SPC, primarily for women. This may be due to clearer symptom presentation in SPC and prompt referral to well-organised cancer treatment pathways for primary cancers. Cancer treatment pathways for recurrence do not exist in Denmark, and uniform pathways are challenging to describe as the relevant actions vary according to whether a cancer recurs locally or in a distant site and depending on the state of the patient. However, the increased healthcare activity for up to one year in both general practice and hospitals prior to a diagnosis of CR indicates that optimised diagnostic pathways for CR are warranted. Although some of the increased pre-diagnostic activity could be related to poorer prognosis, the results still indicate that a window of opportunity for earlier diagnosis of CR and SPC exists in both general practice and in hospitals.
Our findings suggest that the current organisation of follow-up is suboptimal as patients with CR and SPC increased their use of both general practice and hospital-based services long before the subsequent CR or SPC was diagnosed. Diagnosing at an earlier point in time requires the patient to present with symptoms earlier, the healthcare provider to react more adequately and faster when patients present with symptoms, and it may also require organisational changes in the healthcare system [
50]. Patient delay, i.e. the time from when the patient assesses a symptom, decides to seek healthcare and schedules an appointment, was not assessed in this study, and the window of opportunity for more timely diagnosis may open at an earlier point in time than illustrated by the increased healthcare contacts. Suboptimal coordination and communication between general practice and hospitals is a well-known challenge in cancer survivorship care [
51]. Difficulties in the transition from hospitals to general practice and unclear responsibility areas remain focal points for healthcare professionals and researchers [
12]. Improved communication between general practice and hospitals is important, irrespective of follow-up model [
16], and pathways for communication should be formalised, clearly defined and easily accessible [
12]. Formal involvement of GPs in cancer follow-up could be a benefit as we found that the GP has regular contact with cancer survivors and seems to be involved in the detection of subsequent cancer events. Additionally, it could be more convenient for the patients [
52]. However, it is important to provide direct access for the GP to relevant diagnostic investigations and to specialist care when conducting GP-led cancer follow-up [
12,
16]. Healthcare professionals and planners should decide on models for cancer survivorship care, define the roles of general practice and hospitals, including areas of responsibility, and advocate for meaningful resource allocation to ensure the best possible future organisation of high-quality follow-up programmes, including well-organised diagnostic pathways for CR and SPC [
1].