Abstract
Background/Aim: Adjuvant chemotherapy is recommended for a subgroup of colon cancer patients based on patient and tumour characteristics. Population-based data on the adoption of the prevailing guideline recommendations including the assessment of tumour mismatch repair (MMR) status are limited, while variations in treatment strategies may influence patient outcomes. Therefore, the aim of the study was to assess practice variation in adjuvant chemotherapy administration in colon cancer patients. Patients and Methods: We examined the association between patient, demographic and tumour characteristics on the odds of being treated with adjuvant chemotherapy in a random sample of adult stage II-III colon cancer patients from the Dutch National Cancer Registry (2008-2015) and assessed its association with survival. Results: The study population consisted of 2,044 patients of whom 18% (79 out of 450) were high-risk stage II and 65% (645 out of 997) were stage III colon cancer and received adjuvant chemotherapy. Chemotherapy administration differed between individual hospitals (high-risk stage II: 0-39%; p=0.01; stage III: 50-78%; p=0.06). Type of hospital (teaching versus academic) and the presence of a pT4 tumour were positively associated (high-risk stage II), and bowel perforation and examined regional lymph nodes (<10) were negatively associated (stage III) with adjuvant treatment. Higher age was associated with non-administration of adjuvant chemotherapy for both stages. Tumour MMR-status assessment increased from 9% to 23% (p<0.001), but 62% of high-risk stage II and 13% of stage III patients did not undergo guideline-recommended MMR-status testing. Adjuvant chemotherapy was correlated with survival for stage III (HR=0.4; 95%CI=0.3-0.5) but not for high-risk stage II patients (HR=1.2; 95%CI=0.7-2.2). Conclusion: Significant practice variation in the adjuvant treatment of colon cancer on hospital level was demonstrated, predominantly in high-risk stage II patients. The implementation of MMR testing was suboptimal. We recommend continuous monitoring of treatment patterns using population-based data, which should facilitate hospital auditing and improve guideline implementation and quality of care for colon cancer patients.
Clinical guidelines are generated to improve quality of care, but data on the adoption of recommendations including tumour mismatch repair status (MMR-status) assessment in a population-based setting are lacking. The survival of early-stage colon cancer patients has significantly improved since the introduction of adjuvant chemotherapy, and its use has been implemented in guidelines (1). Variation in adjuvant chemotherapy administration may obviously influence patients' outcomes (2-4), but real-life data evaluating practice variation and the implementation of MMR-status assessment are limited.
Adjuvant chemotherapy consisting of fluoropyrimidine-based therapy (5-fluorouracil or capecitabine) in combination with oxaliplatin has been shown to improve survival of patients with stage III colon cancer and is implemented as a standard of care (5). Adjuvant chemotherapy for stage II colon cancer patients is still a matter of debate and results from clinical trials are inconclusive (6, 7). Adjuvant chemotherapy was initially only considered in selected patients with high-risk features for recurrence, however no international consensus exists about the definition of these features (6, 7). The Dutch guideline (2008 and 2014 guideline) recommended to consider adjuvant chemotherapy in each high-risk stage II patient based on the first results of the MOSAIC trial (5).
Practice variation in adjuvant chemotherapy administration rates has been shown in a regional cohort (2). Several determinants are known to influence the administration of adjuvant chemotherapy, among which socioeconomic status (SES), comorbidity and hospital volume (8). Elderly patients are less often exposed to adjuvant chemotherapy although its safety and survival benefit have been demonstrated in this subgroup (2, 9-11). However, the benefit of the addition of oxaliplatin to a fluoropyrimidine to elderly patients remains a matter of debate (12, 13).
Patients with early-stage microsatellite instable (MSI) tumours have a more favourable prognosis compared to patients with microsatellite stable (MSS) tumours. Previous studies demonstrated no or a decreased benefit from adjuvant chemotherapy for stage II and stage III colon cancer patients with MSI tumours compared to patients with MSS tumours (14, 15). These data have resulted in adjustments in the 2014 Dutch colon cancer guidelines (16). The adoption of patients' MMR-status as a factor for decision-making in the adjuvant colon cancer setting has not been assessed to date, and recent population-based studies focusing on these guideline adjustments are lacking.
Therefore, the aim of our population-based study is to evaluate practice variation patterns for adjuvant chemotherapy in stage II and stage III colon cancer patients between 2008 and 2015 and its association with survival.
Patients and Methods
Study design and population. Our observational population-based study consisted of colon cancer patients diagnosed between 2008 and 2015 as registered in the Dutch National Cancer Registry (NCR). This registry has nationwide coverage and includes all patients diagnosed with colorectal cancer and therefore guarantees a reliable reflection of the population. Our source population consisted of 106,998 patients.
The following data-items were routinely registered in the Dutch NCR up to February 2015: hospital, date of diagnosis, gender, date of birth, primary tumour localisation, pathologic features (tumour stage, morphology and differentiation grade) and treatment information including initiation and termination dates (surgery of the primary tumour and first-line systemic treatment regimens). Since February 2015, additional variables including all high-risk stage II features and MMR-status were routinely collected.
An independent collaborator selected a random representative sample of approximately 2,000 patients specified for hospital type (4 academic, 8 teaching, 8 regional), histology (adenocarcinoma or adenocarcinoma-like tumours) and year of diagnosis. Subsequently, we collected the following additional variables from electronic health records from patients diagnosed before February 2015: remaining high-risk stage II features (presence of bowel obstruction or perforation at diagnosis and extramural vascular invasion), MMR-status and comorbidity score (based on comorbid conditions in the following categories: pulmonary disease, cardiovascular disease, digestive disease, genitourinary disease, systemic and rheumatoid disease, neurologic disease, metabolic disease, coagulation disorders and infectious disease).
Dutch colon cancer guidelines. Colon cancer guidelines (2008 and 2014) (16) provided clear recommendations for the use of adjuvant chemotherapy in the Netherlands. Combination treatment of a fluoropyrimidine (5-fluorouracil or capecitabine) combined with oxaliplatin was regarded as standard of care for stage III patients. Patients ineligible for combination treatment may be treated with fluoropyrimidine monotherapy. Adjuvant chemotherapy for stage II patients should be considered if at least one high-risk feature was present: pT4 stage, less than 10 examined regional lymph nodes, poorly or undifferentiated tumours, extramural vascular invasion, and presentation with bowel obstruction and/or perforation. The 2014 guideline included MMR-status in decision-making for adjuvant chemotherapy: stage III patients with MSI tumours should not be treated with fluoropyrimidine monotherapy, and high-risk stage II patients with MSI tumours should not receive adjuvant therapy at all. The 2014 guideline also recommended to initiate adjuvant chemotherapy preferably within 6 to 8 weeks after resection of the primary tumour, but within 12 weeks at the latest.
Outcomes. The primary outcomes of the study are the proportion of stage II and stage III colon cancer patients treated with adjuvant chemotherapy, and practice variation patterns in these patient categories. We evaluated whether patients were treated according to the prevailing colorectal cancer guideline (2008 until March 2014: 2008 guideline; as of April 2014: 2014 guideline), particularly in reference to MMR-status. Secondary outcomes were determinants that may influence adjuvant chemotherapy administration, the underlying reported causes for non-administration of adjuvant treatment and overall survival. Study variables included: hospital, hospital type, period of diagnosis, gender, age, comorbidity, tumour stage, number of examined regional lymph nodes, the presence of bowel obstruction or perforation at diagnosis, extramural vascular invasion and differentiation grade.
Statistical analysis. Descriptive statistics were performed for all study variables. We presented baseline variables using frequency tables and percentages and differentiated between patients treated with surgery alone versus surgery followed by adjuvant chemotherapy. We tested for differences between both categories using χ2 tests or Fisher's exact tests if applicable. Univariable and multivariable logistic regression analysis were performed to determine the unadjusted and adjusted association between demographic, clinical and tumour characteristics on the odds of being treated with adjuvant chemotherapy. We tested for multicollinearity between variables. A Cox proportional hazard regression analysis was performed to study the influence of included co-variables on the risk of death. All statistical analyses were performed using SAS, version 9.4. A p-value below 0.05 was considered as statistically significant.
Results
Study population. Our initial cohort consisted of 2,120 patients, of whom 60 patients did not undergo resection of the primary tumour. We excluded 16 additional patients because of selection errors (patients with metastases at diagnosis and stage I disease), resulting in a study cohort of 2,044 patients (Figure 1). The characteristics of these patients are presented in Table I.
Flowchart of the study population. The risk of recurrence was classified as unknown, if information in the registry about high-risk features was missing (available features were low-risk).
Stage II colon cancer. Our study population included 1,047 patients with stage II disease, of whom 98 patients (9%) received adjuvant chemotherapy. In total, 403 patients had no present high-risk features, while 450 patients had one or more high-risk features for recurrence. Another 194 patients could not be classified for the risk of recurrence, because of missing features in the registry (available features were low-risk) and were classified as unknown risk of recurrence.
In total, 13 low-risk patients (3% of 403 patients) and 6 patients with an unknown risk of recurrence (3% of 194 patients) received adjuvant chemotherapy. A minority of high-risk patients (n=79; 18%) received adjuvant chemotherapy (Figure 1). Chemotherapy administration in this group differed significantly between individual hospitals (range=0%-39%) (p=0.01) (Figure 2), but no differences between different types of hospitals were observed (p=0.09).
Stage III colon cancer. Our study population included 997 patients with stage III disease. The majority of patients (n=645; 65%) received adjuvant chemotherapy (Figure 1). Treatment rates of patients with a pN2 status (≥4 positive regional lymph nodes) did not differ from patients with a pN1 status (<4 positive regional lymph nodes) (p=0.09). Chemotherapy administration ranged from 50% to 78% (Figure 3) (p=0.06) and did not differ per hospital type (p=0.36). In total, 481 patients (75%) received combination chemotherapy, 22 patients received combination chemotherapy followed by single-agent chemotherapy (3%) and 142 patients (22%) received single-agent chemotherapy.
Baseline characteristics of high-risk stage II and stage III colon cancer patients.
Overview of adjuvant therapy administration for high-risk stage II patients differentiated by individual hospital and hospital type.
Implementation of guideline updates. Patients' MMR-status was determined in 319 patients (16%) [MSS: n=242 (76%); MSI: n=77 (24%)] and was more frequently determined upon publication of the 2014 guidelines (9% versus 23%; p<0.001). Forty-two high-risk stage II patients who received adjuvant chemotherapy were treated after publication of the 2014 guideline of whom 11 patients (26%) with an MSS tumour received combination chemotherapy as recommended in the guidelines. The remaining patients (n=31; 74%) had an unknown MMR-status (n=26; 62%), received adjuvant chemotherapy while having an MSI tumour (n=4; 10%) or received single-agent chemotherapy (n=1; 2%).
Overall, 328 stage III patients received chemotherapy after implementation of the updated guidelines. In this patient group, 77 patients (23%) received single-agent chemotherapy, of whom 32 patients (10%) had an MSS tumour, 4 patients (1%) had an MSI tumour and 41 patients (12%) had a tumour with an unknown MMR-status.
In total, 726 patients (98%) received adjuvant chemotherapy within 12 weeks after surgery, although the majority of patients started within 8 weeks (n=639; 86%). Adjuvant chemotherapy was initiated more than 12 weeks after surgery in 17 patients (2%). There was no significant difference in the timing of adjuvant chemotherapy before (median: 5.7 weeks; IQR=4.7-7.1) or after (median: 5.4 weeks; IQR=4.3-6.9) implementation of the 2014 guideline (p=0.07).
Variables associated with adjuvant chemotherapy in high-risk stage II colon cancer. Several factors influenced the administration of adjuvant chemotherapy after adjusting for all co-variables as listed in Table II. Type of hospital (teaching versus academic hospital) (OR=3.6; 95%CI=1.6-8.7) was significantly associated with adjuvant chemotherapy administration in high-risk stage II patients. Of all high-risk stage II features, only the presence of a pT4 tumour (OR=2.6; 95%CI=1.3-5.1) was associated with increased adjuvant chemotherapy administration. Higher age (≥70 years compared to <60 years) was significantly associated with non-administration of adjuvant chemotherapy (70-79 years: OR=0.1; 95%CI=0.1-0.3; >79 years: OR≤0.1; 95%CI≤0.1-0.1). The reason for non-administration of adjuvant therapy as reported in patients' health records for high-risk stage II patients was often unknown (61%), but if reported, it concerned patient or family preference or refusal (10%), poor performance status (7%), higher age (7%), comorbidity (5%) or other (10%).
Variables associated with adjuvant chemotherapy in stage III colon cancer. For stage III colon cancer patients, the presence of a bowel perforation (OR=0.2; 95%CI=0.1-0.4) and less than 10 examined regional lymph nodes (OR=0.5; 95%CI=0.3-0.8) were associated with non-administration of adjuvant chemotherapy. Also, higher age (all age categories ≥60 years compared to <60 years) was significantly associated with non-administration of adjuvant chemotherapy (60-69 years: OR=0.5; 95%CI=0.3-0.9; 70-79 years: OR=0.2; 95%CI=0.1-0.4; >79 years: OR≤0.1; 95%CI≤0.1-0.1). The reasons for non-administration of adjuvant therapy for stage III patients were patient or family preference or refusal (26%), poor performance status (16%), comorbidity (12%), higher age (11%), other (17%) or unknown (18%).
Survival analysis. Female gender (HR=0.7; 95%CI=0.5-0.9) was the only determinant associated with longer survival for high-risk stage II patients, while higher age (>79 years versus <60 years) (HR=2.6; 95%CI=1.2-5.5), presence of bowel obstruction (HR=2.2; 95%CI=1.5-3.3), pT4 stage (HR=2.6; 95%CI=1.8-3.9) and less than 10 examined regional lymph nodes (HR=1.6; 95%CI=1.1-2.5) were associated with higher risk of death after adjusting for all co-variables as listed in Table III. Treatment with adjuvant chemotherapy was not associated with longer survival for high-risk stage II patients (HR=1.2; 95%CI=0.7-2.2).
For stage III patients, higher age (all age categories versus <60 years) (HR=1.8; 95%CI=1.1-2.9; HR=1.8; 95%CI=1.1-2.9; HR=2.0; 95%CI=1.2-3.3), comorbidity (≥2 versus 0) (HR=1.6; 95%CI=1.2-2.2), presence of bowel obstruction (HR=1.7; 95%CI=1.2-2.3) or perforation (HR=1.8; 95%CI=1.1-2.9), pT4 stage (HR=1.9; 95%CI=1.5-2.4), extramural vascular invasion (HR=1.6; 95%CI=1.1-2.2), less than 10 examined regional lymph nodes (HR=1.6; 95%CI=1.1-2.1) and differentiation grade (grade III-IV versus grade I-II) (HR=1.6; 95%CI=1.2-2.1) were associated with higher risk of death (Table III). Treatment with adjuvant chemotherapy was significantly associated with prolonged survival (HR=0.4; 95%CI=0.3-0.5).
Discussion
The results of our population-based study demonstrate practice variation in the adjuvant treatment of colon cancer in the Netherlands, which was predominantly found in high-risk stage II patients. The assessment of patients' tumour MMR-status significantly increased after the implementation of updated guidelines, but still a considerable amount of patients were not tested for MMR-status. Age was strongly inversely correlated with adjuvant treatment in both stages. Adjuvant chemotherapy resulted in longer survival for stage III, but not for high-risk stage II patients.
A previous study showed practice variation on hospital level in adjuvant chemotherapy administration for stage III patients (2). We demonstrated persistence of practice variation in stage III colon cancer, but variation was predominantly found in the treatment of high-risk stage II colon cancer patients (administration rates fluctuated between 0% and 39%). Our results showed that practice variation is particularly present when guidelines leave room for variation, as is the case for the use of adjuvant chemotherapy in high-risk stage II patients (17). It may be considered as undesirable and potentially harmful to individual patients when the choice of treatment is based on individual hospital strategy instead of patient and tumour characteristics.
Overview of adjuvant therapy administration for stage III patients differentiated by individual hospital and hospital type.
Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (95%CI) on adjuvant chemotherapy administration for patients with high-risk stage II and stage III colon cancer.
Age was the strongest predictor of non-administration of adjuvant treatment in both tumour stages, despite demonstrating safety and efficacy in elderly patients in multiple studies (10). Higher age was particularly associated with decreased survival for stage III colon cancer patients. This may be partly explained by the presence of more comorbidity with increasing age, but may also be influenced by non-administration of adjuvant chemotherapy. However, our study did not include cancer-specific survival and we should therefore interpret this finding with caution, but it certainly justifies more awareness on age-based decisions for adjuvant chemotherapy.
The presence of a pT4 tumour was the only high-risk factor that was associated with increased adjuvant chemotherapy administration for stage II patients. The presence of a pT4 tumour was also associated with the highest risk of death (HR=2.6, 95%CI=1.8-3.9), although two other high-risk features showed this association as well [bowel obstruction: HR=2.2 (95%CI=1.5-3.3) and less than 10 examined regional lymph nodes: HR=1.6; 95%CI=1.1-2.5]. Our finding that only the presence of a pT4 tumour is associated with adjuvant chemotherapy administration is remarkable since the 2014 Dutch guideline also defined several other factors as high-risk. Possible explanations are as follows. Firstly, the number of high-risk stage II patients (79 out of 450 patients; 18%) who received adjuvant chemotherapy is rather limited. Secondly, the presence of an obstruction or perforation at time of diagnosis may have resulted in non-administration of adjuvant chemotherapy as these patients may have had a longer or complicated recovery after surgery and passed the time window for adjuvant chemotherapy. Lastly, unawareness of the prevailing guidelines may have contributed to the limited use of adjuvant chemotherapy.
Unadjusted and adjusted hazard ratios (HR) with 95% confidence intervals (95%CI).
Interestingly, longer follow-up of the MOSAIC trial showed no overall survival benefit for adjuvant chemotherapy in high-risk stage II patients (18), and a recent study showed pT4N0 stage as the only positive predictive factor for adjuvant chemotherapy (17, 19). Accordingly, several adjustments in the Dutch guidelines have been made and adjuvant chemotherapy is currently only recommended if a pT4N0 status is present, which is supported by the findings of our study.
This is the first study that evaluated the implementation of MMR-status determination in decision-making for adjuvant chemotherapy for colon cancer patients in daily practice. We found a considerable proportion of both high-risk stage II (62%) and stage III (12%) patients treated with adjuvant chemotherapy (for stage III patients: monotherapy with fluoropyrimidines) who were not tested for MMR-status, which may have led to overtreatment leading to ineffective outcomes which may be harmful to patients with MSI tumours. This is a valuable insight and contributes to more awareness of guideline implementation and adherence. A strength of our study is the large sample size of patients and the use of real-world treatment data instead of patients included in clinical trials. This enlarges the external validity of our study. Although we included a large amount of patients, only a small number of high-risk stage II patients received adjuvant chemotherapy. This probably influenced the findings in this patient group. Unfortunately, information about high-risk features was missing in a considerable amount of stage II patients (n=194). Initiatives that use large nationwide cohorts of colon cancer patients will provide new insights in comparable patient groups (20).
Our data suggest late adoption of guideline updates and warrants new strategies to improve awareness on guideline updates and implementation. The evaluation of guideline implementation can be facilitated by hospital auditing, of which the positive effect on patient outcomes has been demonstrated in previous studies (21, 22). Electronic health records may facilitate hospital auditing by continuous monitoring of real-world treatment data and provide feedback on treatment patterns (20). Moreover, underlying reasons for treatment strategies that are non-adherent to the current guidelines should be reported in patient records. Future studies should focus on analysis of real-world data to evaluate treatment patterns and (survival) outcomes over time, but also compare treatment patterns between providers and hospitals. This may also facilitate international comparison which may ideally lead to future implementation of more data-based tailored treatment of individual patients.
In conclusion, our population-based study demonstrated large hospital and age-dependent treatment variation and suboptimal adoption of updated guidelines that included MMR-status as a decision-making factor in the adjuvant treatment of colon cancer patients. Better strategies for guideline awareness and implementation are still required. We recommend continuous monitoring of treatment patterns using population-based data, which should facilitate hospital auditing and improve guideline implementation and quality of care for colon cancer patients.
Acknowledgements
This study was funded with unrestricted research grants from Amgen, Roche and Merck Serono.
Footnotes
Authors' Contributions
MvO and CP designed the study. Data collection was performed by highly qualified employees of the Dutch National Cancer Registry. LK and MvO participated in the quality assurance of the data. All Authors contributed to data interpretation and the writing and preparing of the final manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
L. Keikes declares that she has no conflict of interest. M. Koopman has acted in advisory boards for Amgen, Bayer, Merck-Serono, Servier, and Roche; and has received unrestricted research funding from Merck-Serono and Roche. V.E.P.P. Lemmens has received unrestricted research funding from Roche. M.G.H. van Oijen has received unrestricted research funding from Amgen, Bayer, Lilly, Merck-Serono, Nordic and Roche. C.J.A. Punt has acted in advisory boards for Bayer, Nordic Pharma and Servier.
- Received June 15, 2020.
- Revision received July 6, 2020.
- Accepted July 7, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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