Health-related quality of life and functional outcomes of colon cancer patients in the Netherlands: A population-based study.

INTRODUCTION
Over the past few decades, the number of colon cancer survivors has grown due to advances in screening, treatment and perioperative care [1]. Surgical resection is the cornerstone of curative treatment for colon cancer (CC), combined with adjuvant chemotherapy depending on tumour stage [2]. Most treatment‐related morbidity occurs within the first three months, after which health‐related quality of life (HRQoL) improves if there is no recurrence [3, 4]. Research on treatment side effects like low anterior resection syndrome (LARS) and chemotherapy toxicity has mainly focused on rectal cancer, but recent studies show that many CC survivors also face issues such as LARS‐like symptoms, fatigue and neuropathy, which negatively affect quality of life [5, 6, 7, 8].
In order to optimise CC treatment, improve survival and decrease treatment‐related morbidity, new diagnostic and treatment modalities have been introduced [9]. With the introduction and further evolution of enhanced recovery after surgery (ERAS), the perioperative care of CC patients has improved significantly [10]. ERAS aims to optimise perioperative care, both surgical and non‐surgical, and relies on patient education, early oral feeding, mobilisation and optimal pain control [10, 11]. Alongside, minimally invasive surgery (MIS), such as laparoscopy and robotic surgery, was introduced [12]. Another major step was the introduction of population screening for colorectal cancer (CRC) in 2014 in the Netherlands [13, 14]. This led to an increase in the detection of early‐stage CC and, hence, less invasive treatment modalities [15]. Furthermore, the duration of adjuvant chemotherapy regimens was shortened in 2017 from 6 to 3 months CAPOX for all high‐risk stage II and stage III CC patients, based on a pooled analysis of six studies by Grothey et al. [16]. They showed that the absolute benefit of longer treatment was limited, and significantly less grade 2 or higher neuropathy was observed in both patients treated with CAPOX (44.9% vs. 14.2%) and FOLFOX (47.7% vs. 16.6%). Franken et al. confirmed that a short adjuvant regimen did not compromise overall survival and also saw a reduction in long‐term neurotoxicity and improvement in QoL in patients treated after the national guideline change [17].
To date, prospective population‐based data on HRQoL and functional outcomes in CC are limited. Randomised controlled trials, while valuable, often lack generalisability due to a selected population, particularly to the inclusion of younger, healthier patients. Here we use data of the Prospective Dutch ColoRectal Cancer (PLCRC) cohort consisting of clinical data, patient‐reported outcomes and biospecimens from a national CRC population [18].
The aim of this Dutch population‐based study was to evaluate the impact of recent multidisciplinary advancements in colon cancer care (e.g., less invasive surgery, optimized perioperative care and shorter chemotherapy regimens) on HRQoL and functional outcomes. It was hypothesised that patients diagnosed in more recent years scored higher on various HRQoL domains and functional outcomes due to the multidisciplinary advancements that were made in the treatment of CC during the last decade.

METHODS

Study design and data collection
Data for this population‐based study were obtained from the PLCRC cohort. Patients aged 18 years or older, who are legally competent and diagnosed with CRC, can provide informed consent for the collection of long‐term clinical and survival data, the completion of questionnaires on health‐related quality of life, functional outcomes and workability, biobanking of tumour and adjacent normal tissue, the collection of blood samples and participation in studies conducted within the infrastructure of the cohort. Questionnaires are provided at the time of enrolment (baseline) and at 3, 6, 12, 18 and 24 months thereafter. Questionnaires could be completed either digitally or on paper. Clinical information on tumour characteristics and treatment was requested from the Netherlands Cancer Registry (NCR) to complete patient information. Ethics approval for PLCRC was obtained from the Ethics Committee of Utrecht. PLCRC was registered at Clinicaltrials.gov (NCT02070146) [19].
As patients were included at any time during their cancer treatment, a cross‐sectional study design was used for this study. Two separate groups were created based on year of diagnosis (Group A: 2014–2016 and Group B: 2017–2019) and subsequently compared. The outcomes of this study were Health‐Related Quality of Life (HRQoL) and functional outcomes in CC patients at 12‐ and 24‐month post‐diagnosis.

Patient selection
Patients who underwent treatment for stage I–III colon cancer and completed PROMs at either 12 or 24 months (±3 months) post‐diagnosis were selected from the PLCRC cohort. Patients included in 2020 and 2021 were excluded from this study due to the possible effect of the COVID pandemic on overall experienced QoL [20, 21].

Patient‐reported outcomes (EORTC‐C30, CR29 and LARS score)
HRQoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) questionnaires; the EORTC Quality of life questionnaire (QLQ)‐C30 for general HRQoL and the EORTC QLQ‐CR29 for colorectal‐specific assessment. The EORTC QLQ‐C30 consists of five functional scales (physical functioning (PF), role functioning (RF), emotional functioning (EF), cognitive functioning (CF) and social functioning (SF)), a global health status (GHS) scale and nine symptom scales. A HRQoL summary score was calculated based on 13 C30 scale and item scores (excluding global health score and financial difficulties) [22]. EORTC‐C30 values from the general Dutch population were used for comparison [20]. The EORTC QLQ‐CR29 assesses CRC‐specific domains and symptoms, such as bowel function, urogenital function and stoma function. Raw scores for each domain were linearly transformed into a 0–100 outcome. A higher functioning score indicated better functioning, while a higher symptom score indicated increased symptom severity [21]. Bowel function was evaluated using the LAR syndrome (LARS) score in patients without a stoma at the time of assessment. Based on the LARS score, patients were classified as no LARS (0–20), minor LARS (21–29) or major LARS (30–42) [23, 24].

Statistical analysis
Baseline characteristics were reported using basic descriptive statistics. Questionnaires were processed according to their manuals. For analysis, the study population was divided into two groups: Group A included all patients diagnosed between 2014 and 2016, and Group B included all patients diagnosed between 2017 and 2019. To limit bias, propensity score matching (PSM) was applied using covariates: sex, age and tumour stage. A PSM ratio of 1:4 was used with the nearest neighbour matching and a calliper of 0.2. Multivariable analysis was used, corrected for gender, age and tumour stage. In order to assess the clinical relevance of EORTC‐C30 outcomes, a guideline for minimally important differences (MIDs) was used [25]. Analyses were carried out using IBM SPSS version 27 and GraphPad Prism 8.

RESULTS

Study population
In total, 1749 patients were included in this study. Group A (2014–2016) contained 252 patients and Group B (2017–2019) 1497 patients. Mean age was 65.7 (SD 9.1) and 66.3 (SD 10.0), respectively. Both groups had comparable sex (62.3% of patients were male in Group A and 59.2% in Group B) and tumour stage distribution with 43.3% vs. 42.8% being stage III colon cancer for Groups A and B, respectively. The most commonly performed procedure was a hemicolectomy (52.4% vs. 58.4%), followed by sigmoid resection (30.7% vs. 27.0%). A small part of patients underwent endoscopic resection without follow‐up surgery (2.0% vs. 2.3%). In cases where adjuvant therapy was administered, the most commonly used regimen in both groups was capecitabine combined with oxaliplatin (CAPOX) (31.0% vs. 33.7%, p = 0.124). Patients in Group A uniformly received 6 months of chemotherapy, whereas those in Group B predominantly received 3 months. Nearly all patients underwent surgery (97.6% vs. 97.5%, p = 1.000). There was no relevant difference in time to surgery between both groups (40.3 vs. 34.7 days, p = 0.051). Table 1 represents a more detailed overview of baseline characteristics.

Health‐related quality of life EORTC‐C30
After PSM, patients diagnosed between 2017 and 2019 (Group B) did not show any clinically relevant improvement in any EORTC‐QLQ C30 functional or symptom score 1 year after diagnosis compared to patients diagnosed between 2014 and 2016 (Group A) (Table 2). Two years after diagnosis, patients from Group B showed no significant improvement in C30 summary score (+1.3, 95% CI 0.6–1.9) compared to patients in Group A. Looking at functioning scales, Group B reported higher role functioning (+4.3, 95% CI 2.5–6.1) and cognitive functioning (+2.9, 95% CI 1.5–4.4) 2 years after diagnosis. However, no minimal important difference was reached. Patients from Group B, reported less fatigue (−3.5, 95% CI −1.8 to −5.2), nausea and vomiting (−1.5, 95% CI −0.8 to −2.2), appetite loss (−3.7, 95% CI −2.5 to −4.9) and financial difficulties (−2.2, 95% CI −1.3 to −3.1) (Table 2). Again, no minimal important differences were seen. Table 2 shows a complete overview of results.
Compared to the general Dutch population, both groups scored similarly on most domains 2 years after diagnosis, except for the C30 summary score (Group A: 90.6 and Group B: 92.2 vs. 88.6), global health status (Group A: 77.8 and Group B: 80.7 vs. 77.4) and emotional functioning (Group A: 86.7 and Group B: 87.6 vs. 82.3). See Figures 1 and 2 for a schematic overview of outcomes.

Functional outcomes. EORTC‐CR29 and LARS score
Multivariable analyses after PSM of EORTC‐CR29 symptom scales showed no differences 1 year after diagnosis between both groups, except for a trivial improvement in Group B for hair loss (−2.0, 95% CI −1.2 to −2.8) and weight (−3.9, 95% CI −2.0 to −5.8) and a slight deterioration in sore skin (+3.5, 95% CI 1.8–5.2). Both groups reported similar levels of minor (18.0% vs. 17.3%, p = 0.834) and major LARS (14.2 vs. 13.9%, p = 0.909) 1 year after diagnosis (Figure 3).
Two years after diagnosis, only an improvement was seen in taste (−4.1, 95% CI −2.7 to −5.5). Patients in Group B, reported a lower incidence of major LARS complaints 2 years after diagnosis (19.9% vs. 14.6%, p = 0.068), although no significant difference was observed (Figure 3).

DISCUSSION
This Dutch population‐based study compared health‐related quality of life (HRQoL) and functional outcomes in colon cancer patients diagnosed between 2014–2016 and those diagnosed between 2017 and 2019. Despite advances in particular diagnostics and treatment of colon cancer in these timeframes, no clinically relevant differences were observed between the two groups regarding HRQoL according to the EORTC C30 domains. The same applies to the functional outcomes from the EORTC QLQ‐CR29 and LARS scores.
Although not showing a clinical relevant difference between both groups, HRQoL scores in this cohort were high and nearly reached the Dutch population reference scores (26). Two years after diagnosis, the C30 summary score was even 3.6 points higher in Group B compared to normative data from the general Dutch population from the EORTC. This implies that people may have developed strong coping strategies and emotional resilience in response to their diagnosis and treatment [26, 27]. This was well depicted in emotional functioning, where patients from both Groups A and B scored higher than the general population 2 years after diagnosis (86.7 & 87.6 vs. 82.3, respectively). In addition, when comparing with normative C30 summary score data from other countries, Dutch CC patients in Group B scored higher than, e.g., France, Denmark, Germany and Great Britain (92.2 vs. 85.6 vs. 83.0 vs. 81.9 vs. 79.6, respectively) [28]. This shows that in general, Dutch CC patients perform well and experience overall good HRQoL. Nevertheless, it should not be forgotten that the individual CC patient can still suffer from physical or emotional functioning deficits, like fatigue, bowel problems or anxiety. Several recent studies show similar results regarding the high level of HRQoL, however on long term, survivors can still suffer from disease and treatment‐related morbidity [29, 30, 31].
The absence of clinically relevant improvements in HRQoL and functional outcomes over time is noteworthy, particularly in light of the ongoing advancements in colon cancer diagnostics, treatment modalities and survivorship care [7, 8, 31, 32]. These advancements include the increased use of minimally invasive surgery (MIS), optimisation of adjuvant chemotherapy and the introduction of population‐based screening in the Netherlands [10, 11, 12, 13, 15]. One possible explanation for this finding can be the already high standard of colon cancer care in the Netherlands, largely attributed to the implementation of a national, multidisciplinary colorectal cancer guideline in 2008 [2]. This guideline enables healthcare professionals to provide high‐quality, consistent and evidence‐based care to patients with colon cancer. It supports timely and accurate diagnostics, guides treatment decisions based on cancer staging, ensures appropriate follow‐up care and promotes equal access to care for all Dutch patients. As a result of this uniform approach, patients throughout the Netherlands receive standardized care based on the latest clinical insights. Since the guideline was implemented well before 2014, it is plausible that both patient cohorts in this study already benefited from this standard of care, thereby limiting the potential for further measurable improvements in HRQoL and functional outcomes over time. As previously mentioned, several studies have reported a reduction in neurotoxicity when chemotherapy regimens are shortened from 6 to 3 months. Franken et al. also described an additional positive effect on quality of life (QoL) in patients receiving fewer cycles of chemotherapy [16, 17]. The gradual implementation of shortened adjuvant chemotherapy duration resulted in overlap between treatment strategies around the chosen time boundary. However, since adjuvant therapy is only administered to patients with high‐risk stage II or stage III colorectal cancer, and these patients comprise only about one‐third of both groups in this study, this effect may be masked in the overall population.
In recent years, endoscopic local excision by gastroenterologists has gained popularity as a possible treatment modality for early‐stage CC [33]. Notwithstanding the fact that the recommendation pertains exclusively to low‐risk T1 CC or to patients over the age of 80 years who are afflicted with multiple comorbidities, the omission of surgery serves to prevent treatment‐related morbidity [2, 34]. It will be interesting to observe the effects on HRQoL in this specific patient group.
Group B showed a lower proportion of patients with a stoma compared with Group A; however, the absolute numbers were small, rendering this finding sensitive to sampling variation and potential bias. Although stoma formation may affect quality of life, no firm conclusions regarding causality can be drawn from the present data.
At one and 2 years post‐diagnosis, major LARS complaints were reported at similar rates in both groups: 17.1% in Group A and 14.6% in Group B. Although flatulence scores improved in Group B at the two‐year mark, 28.7% of patients continued to experience this symptom, which is included in the LARS score [24]. Heinsbergen et al. reported comparable rates, with 21% of colon cancer patients experiencing major LARS‐like symptoms [5]. Despite the slightly lower rates observed in our study, LARS‐like complaints remain common and have a considerable impact on quality of life—comparable to the effects reported after rectal cancer surgery [5]. The type of resection appears to influence symptom presentation: right hemicolectomy is often associated with loose stools and increased frequency, likely due to removal of the ileocaecal valve, possible small intestinal bacterial overgrowth and bile acid malabsorption. In contrast, left hemicolectomy tends to result in stool fragmentation, prolonged evacuation and a sensation of incomplete emptying, probably due to impaired water absorption [35, 36, 37, 38]. Additionally, resection of the rectosigmoid junction may reduce reservoir function, thereby contributing to faecal incontinence and LARS‐like symptoms [39].
Several limitations must be acknowledged. The PLCRC registry was initiated in 2013, with initial patient inclusion taking place in only a limited number of hospitals in the Netherlands. As a result, early inclusion numbers were low. Over time, more hospitals joined PLCRC, and currently, 66 of 69 Dutch hospitals participate. To avoid comparisons based on small sample sizes, we divided the cohort into two larger time‐based groups. Nevertheless, due to possible differences in early and later participation, differences in baseline characteristics cannot be ruled out [18]. To minimize their impact, we applied PSM. Both groups were sufficiently large to detect statistically significant differences, even in small effect sizes. In addition, as the study focused on population‐level outcomes, it was not powered to reliably assess disease stage–specific effects. To assess the clinical relevance of these findings, we used minimal important differences (MIDs) for EORTC QLQ‐C30 outcomes. For the EORTC‐CR29 and LARS score, no MIDs exist. Furthermore, population‐based studies such as this are prone to selection bias at inclusion due to their sampling design: both severely ill patients and those with few complaints may be less likely to participate. The PLCRC collaborative strives to provide real‐world data (RWD). By prioritising HRQoL, PLCRC facilitates real‐world, population‐based research with high external validity. A recent study showed that, although some differences between the PLCRC cohort and the general Dutch colorectal cancer population exist, these are gradually diminishing over time due to further improvements in recruitment methodologies and the multidisciplinary enrolment of patients [18]. Finally, comparisons between the two time periods reflect differences in overall treatment context rather than discrete treatment strategies, and some overlap in management approaches between groups was inevitable due to the gradual and institution‐dependent implementation of updated guidelines.
In conclusion, this population‐based study demonstrates that colon cancer patients in the Netherlands report good levels of HRQoL and functional outcomes up to 2 years after diagnosis, with no clinically relevant differences between cohorts diagnosed before and after 2017. These findings likely reflect the consistently high standard of care achieved through national guideline implementation and broad access to uniform, evidence‐based treatment. Nevertheless, individual patient burdens should not be overlooked. Future research using updated and longitudinal PLCRC data could further elucidate long‐term trends in colon cancer survivors, identify vulnerable subgroups and evaluate the impact of emerging treatment strategies for this group.

AUTHOR CONTRIBUTIONS

J. Melenhorst: Conceptualization; methodology; writing – review and editing; supervision. A. J. Pennings: Conceptualization; methodology; investigation; formal analysis; writing – original draft; writing – review and editing. S. van Kuijk: Conceptualization; methodology; writing – review and editing. G. R. Vink: Conceptualization; methodology; writing – review and editing; validation. A. M. May: Conceptualization; methodology; writing – review and editing. S. O. Breukink: Supervision; conceptualization; writing – review and editing; methodology. M. Koopman: Writing – review and editing; methodology. G. L. Beets: Writing – review and editing; supervision; conceptualization.

FUNDING INFORMATION
There are no funding sources for this study.

CONFLICT OF INTEREST STATEMENT
The authors state there is no conflict of interest.

ETHICS STATEMENT
Ethical approval for the PLCRC was obtained from the Medical Ethics Committee of Utrecht.

PATIENT CONSENT STATEMENT
Written consent was obtained from all patients involved in the Prospective Dutch ColoRectal Cancer (PLCRC) cohort.

PERMISSION TO REPRODUCE MATERIAL
No material was used from other sources.

CLINICAL TRIAL REGISTRATION
The PLCRC is registered at Clinicaltrials.gov (NCT02070146).