Challenges in colorectal cancer post-surgical surveillance: A critical evaluation and path forward

Abstract

A recent study by Sala-Miquel et al investigated the diagnostic effectiveness of follow-up strategies in patients with non-metastatic colorectal cancer (CRC) after surgical resection. This research highlighted the significance of using computed tomography (CT), colonoscopy, and tumor markers for the early detection of recurrence or metastasis. The findings indicated that strict adherence to follow-up protocols can contribute to decreased mortality rates among these patients. However, the study has several limitations that must be considered. It was retrospective and conducted at a single center, which may affect the generalizability of the results. Further, the absence of a control group and the exclusion of stage IV patients limit the study's applicability. Methodological issues, including insufficient adjustment for confounding variables, a lack of sensitivity analyses, and limitations in time-dependent covariate analysis, further constrain the conclusions' robustness. Moreover, while the study emphasizes the role of CT scans, it does not adequately address their potential risks and underrepresents the importance of colonoscopy. Future research should focus on multicenter, prospective studies that integrate personalized follow-up approaches and explore innovative technologies to enhance the efficacy of follow-up strategies in CRC management. By addressing these limitations, researchers can improve the applicability and impact of follow-up strategies in the care of CRC patients.

Key Words: Colorectal cancer; Computed tomography; Colonoscopy; Recurrence detection; Patient adherence; Bias; Cost-effectiveness; Real-world evidence; Telemedicine; Artificial intelligence

Core Tip: The study by Sala-Miquel et al evaluated the diagnostic efficacy of follow-up strategies, including computed tomography, colonoscopy, and tumor markers, in detecting recurrences or metastases after surgery for non-metastatic colorectal cancer (CRC). At the same time, the study highlighted the importance of these tools in optimizing post-surgical care; its retrospective, single-center design limits generalizability. Future research should adopt multicenter, prospective designs and include control groups to reduce bias and improve applicability. Addressing confounders like comorbidities and socioeconomic factors, alongside sensitivity analyses, would improve statistical robustness. Integrating emerging technologies such as circulating tumor DNA and patient-centered approaches can enhance diagnostic accuracy and adherence, ultimately refining CRC surveillance outcomes.

TO THE EDITOR

We have read with great interest the recent study by Sala-Miquel et al[1], titled “Diagnostic yield of follow-up in patients undergoing surgery for non-metastatic colorectal cancer”, which has garnered significant interest due to its thorough analysis of the diagnostic performance of various surveillance modalities. These modalities include computed tomography (CT), colonoscopy, and tumor markers (TMs), which are important in detecting recurrence or metastasis following colorectal cancer (CRC) resection. The authors highlighted the critical role of adhering to follow-up recommendations, linking this adherence to reducing mortality rates. However, while the study addresses a vital clinical question, several methodological and analytical concerns and interpretational limitations should be considered to improve the robustness and applicability of the findings. We propose that future research delve into more targeted approaches and consider implementing a tiered management strategy to foster advancement in this field.

Study design and methodological limitations

Retrospective design and single-center bias: The study's retrospective design and single-center structure inherently limit the generalizability of its findings[2]. Retrospective studies are susceptible to selection bias because data collection relies on pre-existing medical records, which may not capture all pertinent variables and can suffer from documentation inconsistencies[3]. For instance, the authors did not account for variations in patient management practices, such as differences in surgical techniques, adjuvant therapies, or follow-up protocols, which could significantly influence outcomes. Additionally, conducting the study at a single center might introduce institutional biases related to patient demographics, socioeconomic status, and access to healthcare, which might not reflect broader clinical practice[4]. Future research should adopt a multicenter, prospective design, as demonstrated in a randomized controlled trial such as the FACS trial[5], which compared intensive vs minimal follow-up strategies. This approach would enhance the generalizability of findings. In addition, we require a well-designed study to improve the external validity of the findings, which would promote standardized data collection and help mitigate bias, allowing researchers to control confounding variables more effectively while ensuring comprehensive data collection.

Lack of a control group: The absence of a control group in the study restricts the ability to assess the effectiveness of intensive follow-up compared to less intensive or alternative surveillance methods[6]. Without a control group, it is challenging to ascertain whether the observed benefits of intensive follow-up are genuinely attributable to the surveillance approaches employed or influenced by confounding factors[7]. For example, patients who adhere to follow-up recommendations may have better health or improved access to healthcare, which could independently affect survival outcomes. Future research should incorporate a control group, including patients who receive less intensive follow-up, to compare the diagnostic yields and survival outcomes associated with various surveillance strategies. This would clarify whether the advantages of intensive follow-up justify the potential risks and costs involved.

Exclusion of stage IV patients: The study's exclusion of stage IV CRC patients limits its applicability to those with advanced disease. Stage IV patients typically have distinct follow-up requirements and may benefit from alternative surveillance strategies, such as more frequent imaging or targeted therapies[8]. An opportunity is lost by excluding these patients from the study to investigate the diagnostic yield of follow-up in a high-risk population for recurrence and metastasis. Future studies should consider including stage IV patients to gain a more comprehensive understanding of the diagnostic yield of follow-up across all stages of CRC. This inclusion would also enable a more nuanced analysis of how follow-up strategies might be tailored according to disease stage and recurrence risk.

Weaknesses in statistical aspects

Ineffective adjustment for confounders: The study incorporated adjustments for several confounding variables in the multivariate analysis, including age, TNM stage, and adherence to follow-up recommendations. However, it failed to consider other significant confounders like comorbidities, socioeconomic status, and access to healthcare. These factors could considerably impact both the observance of follow-up care and overall survival rates[9]. For instance, patients with existing comorbid conditions might struggle to follow through with recommended follow-ups due to competing health issues. At the same time, individuals from lower socioeconomic backgrounds could encounter barriers that hinder their access to healthcare services. It is imperative to include a more comprehensive array of confounders, incorporating variables like comorbidities and socioeconomic indicators to improve the robustness of future analyses. This could involve adding these variables into multivariate models or implementing propensity score matching to create balanced groups for enhanced assessment of the independent effects of follow-up adherence on survival.

Absence of sensitivity analyses: The absence of sensitivity analyses in the study raised concerns about the robustness of the findings[10]. We want to highlight that key aspects, such as missing data effects or follow-up interval variations, were not examined. Missing data could introduce bias, particularly in retrospective studies, and impact the overall validity of the results[11]. Furthermore, differing follow-up intervals, such as delays in scheduling CT scans or colonoscopies, could influence the detection of recurrences and the diagnostic yield overall. Future research should incorporate sensitivity analyses to test the stability of results under various assumptions, addressing potential biases linked to missing data and fluctuations in follow-up protocols. Methods such as data imputation or subgroup analyses based on adherence to recommended follow-up timelines could be considered.

Weaknesses of time-dependent covariate analysis: The existing analysis failed to address the evolving nature of patient characteristics, adherence levels, or disease progression, which was particularly significant considering the well-documented trend that patient adherence to follow-up care tends to diminish as the duration of surveillance extends. By relying on a static analysis, we risk overlooking critical insights regarding how varying surveillance strategies might influence patient outcomes throughout the monitoring period[12]. Implementing a Cox proportional hazards model incorporating time-dependent covariates would allow for a nuanced evaluation of how adherence to surveillance protocols shapes clinical outcomes as time progresses[13]. This dynamic approach would provide a clearer understanding of the relationship between surveillance adherence and patient prognosis over the long term.

Deficiencies in surveillance modalities: Although the study asserts that CT scans demonstrated the highest level of diagnostic accuracy, it lacks rigorous statistical comparisons across different surveillance modalities, including colonoscopies and TM. To comprehensively assess and quantify the differences in diagnostic efficacy among these methods, pairwise comparisons are required to evaluate key metrics such as sensitivity, specificity, and predictive values[14]. Furthermore, these comparisons should be supplemented with appropriate statistical testing to validate the findings robustly. Such an analysis would substantiate the claims made regarding the superiority of CT scans and provide valuable insights into the performance of alternative surveillance strategies in a clinical setting. Nevertheless, CT scans continue to play an important role in monitoring for distant metastases in cases of colon cancer. In the context of rectal cancer, pelvic magnetic resonance imaging (MRI) is more effective than CT in detecting local recurrences following neoadjuvant therapy, particularly due to the presence of fibrotic changes[15]. Integrating CT scans with annual colonoscopy and biennial MRI for rectal cancer, as indicated by recent studies, can enhance the effectiveness of diagnostics while reducing the risk of radiation exposure[15].

Limitations of the results and discussion

Overemphasis on CT as the primary diagnostic tool: The study highlighted the high diagnostic accuracy of CT scans, which successfully identified 88.9% of cancer recurrences or metastases. CT scans are valuable tools for detecting distant recurrences of cancer, but colonoscopy is required for identifying metachronous lesions, especially in high-risk patients. Although TM has sensitivity limitations, it can provide helpful information when used with imaging studies and considered within the broader clinical context. However, the discussion falls short of addressing critical considerations associated with the routine use of CT scans. Frequent exposure to radiation poses potential health risks to patients, which can accumulate over time, increasing the likelihood of secondary malignancies[16]. Repeated CT scans can lead to significant cumulative radiation exposure, which presents a notable risk, particularly for younger patients.

As highlighted in previous research, the timely detection of resectable metastases through early CT scans can decrease long-term healthcare costs by facilitating curative surgical interventions. However, it is important to note that the cost-effectiveness of this approach can differ depending on the specific healthcare environment[17]. Moreover, the economic implications of widespread CT utilization on healthcare systems merit scrutiny, as the costs incurred can strain resources significantly. Research and cost-effectiveness analyses indicated that implementing selective imaging strategies based on risk stratification could enhance the efficient use of healthcare resources[5]. Additionally, the vital role of colonoscopy in identifying metachronous lesions and cancers that develop in the same patient at different times was not sufficiently highlighted, even though it is a key element in the long-term surveillance strategy for CRC patients. Future studies should comprehensively evaluate the various surveillance options available, highlighting the superior diagnostic capabilities of CT scans and the associated radiation risks and financial burdens[18]. Furthermore, a discussion on the indispensable role of colonoscopy in detecting metachronous lesions should be thoroughly developed to provide a more holistic view of patient surveillance.

Limited discussion on TM performance: The findings reveal that TMs demonstrate a sensitivity of only 67.8% for detecting cancer recurrences, with an even less favorable sensitivity of 41% specifically for lung metastases. This noteworthy shortcoming invited a more profound analysis; however, the discussion section did not adequately probe the underlying causes behind this low sensitivity. It also neglected to suggest alternative and potentially more effective biomarkers that could improve diagnostic performance in clinical settings. Future research should focus on exploring the application of emerging biomarkers, mainly circulating tumor DNA (ctDNA), which has shown promise in non-invasive cancer monitoring and could significantly improve sensitivity in detecting recurrences[19]. ctDNA assays offer the advantage of detecting molecular residual disease earlier than traditional imaging methods. By integrating ctDNA testing with CT scans, utilizing imaging only for cases that test positive for ctDNA, unnecessary scans can be reduced by as much as 40%. This approach enhances early detection and minimizes the burden of excessive imaging[20]. A thorough exploration of employing a combination of various biomarkers could also be valuable in improving overall diagnostic accuracy for patients.

Inadequate exploration of adherence barriers: While the study highlighted the issue of low adherence to follow-up recommendations, especially concerning colonoscopy, it did not delve into the intricate reasons behind this non-adherence. Critical factors contributing to this phenomenon include patient anxiety regarding procedures, logistical difficulties related to scheduling, and systemic barriers within the healthcare framework that could impede access to necessary follow-up care[21]. Socioeconomic disparities play a critical role in influencing follow-up adherence. Implementing targeted interventions, like community-based navigation programs, can effectively address these challenges and improve adherence rates[22]. Future studies should incorporate qualitative research methodologies to gain insights into the barriers affecting patient adherence to follow-up protocols. Understanding these patient experiences could inform targeted interventions to bolster compliance with recommended surveillance measures.

Lack of patient-reported outcome considerations: The study addressed adherence from a clinical standpoint but overlooked essential patient-reported barriers that might impede follow-up participation. Factors such as the financial burden associated with surveillance procedures, difficulties in accessing healthcare facilities, and psychological distress induced by ongoing surveillance efforts remain unexamined. Including patient-reported outcome measures could deepen understanding of adherence behaviors and enhance patient-centered care approaches. Telemedicine and remote monitoring can significantly improve adherence to treatment by alleviating travel challenges and offering real-time tracking of symptoms[23]. This innovative approach allows patients to engage with healthcare providers more conveniently, resulting in better management of health conditions.

Oversight of emerging surveillance technologies: Notably, the discussion failed to acknowledge recent advancements in surveillance methodologies, such as the analysis of ctDNA, artificial intelligence-assisted imaging techniques, and telemedicine strategies for follow-up care[24]. These innovative approaches have great potential for improving CRC recurrence detection while reducing patient burden. Future research endeavors should actively explore these cutting-edge technologies and their applicability in enhancing monitoring processes for CRC patients. By integrating such advancements, researchers can potentially alleviate some of the burdens associated with traditional follow-up methods.

Incomplete evaluation of healthcare system barriers: The study neglected how various healthcare system limitations, including insurance coverage discrepancies and geographic disparities in healthcare access, can directly affect patients' adherence to follow-up recommendations[25]. Ignoring these factors limits understanding patients' systemic challenges in receiving adequate surveillance. Policymakers should consider integrating into research discussions to identify structural interventions that can effectively enhance patient compliance with surveillance guidelines. By addressing systemic barriers, researchers could contribute to a more equitable healthcare landscape that promotes improved outcomes for CRC patients.

Unresolved biases

Survivorship bias: The study excluded patients who died within the first year of surgery from the analysis of adherence to follow-up. This exclusion may introduce survivorship bias, as patients who died early may have had more aggressive disease or poorer overall health, which could influence the results[26]. For example, these patients may have been less likely to adhere to follow-up recommendations due to their advanced disease or comorbidities, which could skew the findings on the impact of adherence on survival. Future studies should include all patients in the analysis, regardless of survival time, to avoid survivorship bias and provide a more accurate assessment of follow-up adherence and outcomes. This could involve sensitivity analyses to evaluate the impact of excluding early deaths on the results.

Detection bias: The study relies on CT and colonoscopy as the gold standard for detecting recurrences, but these modalities may not detect all cases, particularly in the early stages[27,28]. This could lead to an underestimation of the true recurrence rate and an overestimation of the diagnostic yield of these modalities. For example, small or early recurrences may not be visible on CT scans, while colonoscopy may miss lesions in areas that are difficult to visualize. Future research should consider incorporating additional diagnostic tools, such as positron emission tomography scans or molecular imaging, to improve the detection of early recurrences. This could also involve using advanced imaging techniques, such as contrast-enhanced CT or MRI, to increase the sensitivity of recurrence detection.

Lead-time bias: While the study highlights CT scans as the most effective tool for recurrence detection, it does not account for lead-time bias, where early detection does not necessarily translate to improved survival[29]. Future research should include survival analyses that adjust for lead-time bias to evaluate whether early detection via CT improves overall survival.

Future direction

Personalized follow-up strategies: Research emphasizes the importance of adherence to follow-up care for improving patient outcomes. However, there is significant potential for developing personalized follow-up strategies that consider individual patient risk profiles. Future studies should focus on creating risk-stratified follow-up protocols tailored to the specific needs of patients. Risk stratification models, like the clinical risk score, can be instrumental in developing personalized surveillance plans[30]. These models help identify high-risk subgroups, allowing for more intensive follow-up where it is most needed. For example, patients identified as high risk, such as those with advanced TNM staging or poorly differentiated tumors, may require a more frequent follow-up regimen involving regular imaging studies and laboratory tests.

On the other hand, lower-risk patients, characterized by favorable histological features and early-stage cancer, could benefit from a less intensive follow-up plan. Artificial intelligence-driven tools and predictive algorithms designed to assess recurrence risk offer the potential to tailor patient follow-up intervals. By personalizing these intervals, these tools can help minimize unnecessary imaging procedures, enhancing patient care efficiency[31]. This personalized approach optimizes the allocation of healthcare resources and can improve survival rates by ensuring that high-risk patients receive the necessary monitoring promptly.

Integration of novel biomarkers: The limitations of traditional TMs, particularly their insufficient sensitivity for detecting recurrences, highlight the urgent need to integrate novel biomarkers, such as ctDNA, into follow-up protocols. Future research should rigorously evaluate the diagnostic effectiveness of these advanced biomarkers relative to conventional methods. Prospective clinical trials focusing on the sensitivity and specificity of ctDNA, when used alongside established TMs and imaging techniques, are needed to assess its role in early recurrence detection. Advancing our understanding of ctDNA's potential in follow-up care could enhance the precision of post-treatment surveillance and ultimately lead to improved patient outcomes.

Patient-centered follow-up models: Given the concerning rates of non-adherence to follow-up recommendations, future research may consider exploring patient-centered models of follow-up care. Innovative solutions, such as telemedicine and remote monitoring, have the potential to significantly improve accessibility and convenience for patients, especially those in isolated or underserved regions. These models should also prioritize comprehensive education and support systems to address psychological barriers to adherence, including anxiety and fear of recurrence. For instance, incorporating telemedicine consultations into follow-up care may allow healthcare providers to offer personalized advice without needing in-person visits. Furthermore, remote monitoring technologies that capture patient-reported symptoms could provide early warnings for potential recurrences, leading to prompt clinical interventions.

Cost-effectiveness analysis: A notable gap in existing research is the assessment of cost-effectiveness associated with various intensive follow-up strategies. Future studies must conduct thorough economic evaluations to shed light on the financial implications of different surveillance approaches. This could involve cost-utility analyses that compare intensive follow-up protocols' economic impact and health benefits against more conservative strategies. By examining quality-adjusted life years and healthcare resource utilization, policymakers can make well-informed decisions that balance high-quality care with economic considerations.

Longitudinal and real-world evidence: Prospective studies incorporating real-world data across various healthcare settings are strongly needed to thoroughly validate follow-up strategies and ensure their relevance to diverse populations. These studies should consider collecting evidence from a broad demographic, reflecting the complexity and variability of patient experiences and outcomes. By integrating real-world evidence into the research framework, we can ensure that follow-up strategies are effective in controlled research environments and practical and beneficial in everyday clinical practice.

CONCLUSION

We appreciate the study's contributions and suggest improving future research with refined methodologies. The present study focused on the effectiveness of various follow-up strategies for patients with non-metastatic CRC. Their study provided valuable insights into how these approaches can impact patient outcomes. However, it has limitations, particularly its methodology and analytical techniques. Addressing these limitations is important for maintaining the credibility and relevance of the findings across various patient populations, and by exploring these promising strategies, we can significantly elevate post-surgical monitoring standards. By doing so, we can ensure that our research resonates meaningfully and effectively with individuals from diverse backgrounds and experiences. The ultimate goal is to improve health outcomes for patients with CRC, ensuring they receive the most effective and appropriate follow-up care.