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INTRODUCTION
Colorectal cancer (CRC) is a major global health concern, ranking as one of the most prevalent cancers worldwide and a leading cause of cancer-related deaths in South Korea and globally [12]. Surgery serves as the primary treatment option for localized CRC, achieving a cure in roughly 50% of cases; however, around 20% of patients are diagnosed with stage IV disease, which is associated with a markedly low 5-year survival rate [34]. Regardless of the possibility of resecting distant metastases, about 10% of patients with stage IV CRC are known to experience obstruction [5]. The presence of obstruction often necessitates immediate intervention to restore bowel continuity and alleviate symptoms, presenting a complex decision-making landscape for clinicians. However, the decision to proceed with primary tumor resection (PTR) in stage IV CRC must be made cautiously, as literature reports mortality rates as high as 15% associated with this procedure, alongside significant complication risks [567]. This highlights the necessity for a thorough evaluation of potential benefits against the high risk of adverse outcomes.
In light of these considerations, self-expanding metallic stents (SEMS) emerge as a compelling alternative for managing obstructive lesions in this patient [8]. SEMS have been shown to not only provide immediate relief from obstruction but also facilitate earlier initiation of chemotherapy, offering a less invasive and potentially more efficient treatment pathway for patients with obstructive stage IV CRC [9]. This advancement signifies a pivotal shift towards less invasive and potentially more patient-friendly interventions in the treatment of CRC [8101112].
Considering the complexities in treating stage IV CRC with obstruction, this study specifically targets the comparative analysis of PTR vs. SEMS, centering on their oncologic outcomes. The aim is to shed light on how these treatment modalities impact cancer progression and patient survival, intending to enhance the management strategies for advanced CRC.
METHODS
Ethics statement
This retrospective cohort study was conducted by reviewing medical records from a single tertiary care center. The study protocol was approved and informed consent was waived by the Institutional Review Board of Chonnam National University Hwasun Hospital (No. CNUHH-2024-073).
Study design and participants
We included patients diagnosed with obstructive, unresectable stage IV CRC between November 2004 and December 2018. Eligibility criteria included adults (aged ≥18 years) with radiologically confirmed obstructive colon cancer, unresectable metastatic disease at diagnosis, and no prior surgical or stenting interventions for obstruction. Unresectable metastatic disease was defined based on multidisciplinary team assessment, including radiologic findings indicating widespread metastases unsuitable for curative resection. All radiologic evaluations were performed using standardized imaging protocols, including contrast-enhanced CT and/or MRI, interpreted by experienced radiologists.
Data collection
Clinical, demographic, and treatment-related data were extracted from electronic health records. This included age, sex, ECOG (Eastern Cooperative Oncology Group) performance status, tumor location, CEA levels at diagnosis, details of chemotherapy, and survival outcomes. Tumor obstruction location was categorized as right-sided or left-sided colon cancer based on the anatomical site.
Self-expanding metallic stent protocol
This approach is consistent with the protocols described in a previous study [13]. In brief, patients underwent diagnostic CT scans within 24 hours of admission. Those with signs of peritoneal irritation or hemodynamic instability were directly recommended for surgery, bypassing stent placement. The SEMS used were primarily nitinol-based covered or uncovered stents, with specific brands (BONASTENT, Standard Sci-Tech Inc.; HANAROSTENT, M.I.Tech Co., Ltd.) selected based on tumor location and degree of obstruction. Obstruction was classified as complete, defined by the absence of gas or stool passage with marked bowel distension, or partial, characterized by reduced passage with bowel distension but no complete blockage on imaging. SEMS placement aimed for technical success, defined by correct stent positioning without adverse events, and clinical success, marked by symptom relief and radiological improvement within 48 hours. In cases of SEMS failure, surgical intervention (e.g., diversion or palliative resection) or re-stenting was performed, depending on the clinical scenario.
Outcome measures
The primary outcome was overall survival, defined as the time from diagnosis to death from any cause. Secondary outcomes included complications related to treatment, need for secondary interventions (e.g., additional stent placement, surgical interventions).
Statistical analysis
Data analysis was performed using the latest version of R statistical software (ver. 4.0.5, The R Foundation). Continuous variables were presented as means ± standard deviations or medians with ranges, depending on their distribution, while categorical variables were expressed as counts and percentages. The chi-square and Fisher exact tests for categorical variables, and the Student t-test or Mann-Whitney U-test for continuous variables, as appropriate. Propensity score matching was conducted to create comparable groups for the primary analysis, using a 1:1 nearest neighbor matching algorithm without replacement.
The primary outcome of overall survival was analyzed using Kaplan-Meier curves, and differences between groups were evaluated using the log-rank test. To investigate the factors influencing overall survival, we applied univariate and multivariate Cox proportional hazards regression models. Variables with a P-value of less than 0.10 in the univariate analysis were included in the multivariate model. Moreover, to explore the impact of chemotherapy on patient outcomes, we utilized multivariate logistic regression analysis. This approach allowed us to adjust for potential confounders and to estimate the odds ratios with 95% confidence intervals (CIs) for the likelihood of receiving chemotherapy. All statistical tests were two-sided, and a P-value of <0.05 was considered statistically significant for all analyses.
RESULTS
Baseline characteristics
Between November 2004 and December 2018, a study analyzed 108 patients with obstructive, unresectable stage IV CRC, who were deemed eligible for this study (Table 1). Of these, 36 patients underwent PTR: right hemicolectomy (n = 14), anterior resection (n = 10), Hartman operation (n = 7), low anterior resection (n = 3), left hemicolectomy (n = 1), and total colectomy (n = 1). While 107 received SEMS to relieve obstruction. Of the SEMS group, 14 patients experienced stent placement failure, leading to 8 patients subsequently undergoing diversion and 6 receiving PTR. Within the successful stent placement subgroup, comprising 93 patients, 21 were later excluded due to undergoing immediate elective palliative surgery following symptomatic improvement. Consequently, the final analysis included 36 patients in the PTR group and 72 patients in the stent placement group, designated as the SEMS group, after accounting for all exclusions and treatment pathways (Fig. 1)
Demographic and clinical parameters
There were no significant differences in age, ECOG performance status, or CEA levels between the groups, indicating a balanced distribution of these key baseline characteristics (Table 1). The average ages of the PTR and SEMS groups were 62.7 and 67.2 years, respectively (P = 0.175), and the administration of chemotherapy was comparable across both groups (P = 0.611). However, significant differences were observed in the location of the tumor obstruction (P = 0.027), sex distribution, and peritoneal metastasis incidence.
Propensity score matching outcomes
Propensity score matching was used to balance these differences, resulting in 36 patients in each group. Pos-tmatching, no significant differences in mean age, sex distribution, ECOG performance status, or CEA levels were observed, effectively addressing initial concerns. The mean age in the PTR group was 62.7 ± 17.7 years, compared to 68.0 ± 13.4 years in the SEMS group, with a P-value of 0.158, indicating no significant difference. Sex distribution also showed no significant bias between the groups, with males representing 50% of the PTR group and 44.4% of the SEMS group (P = 0.813). Further detailed comparisons, including the ECOG performance status and CEA levels, also reflected this balance, with no significant differences observed (P = 0.285 and P = 0.698, respectively). The initial concerns regarding the location of tumor obstruction, sex distribution, and the prevalence of peritoneal metastasis were effectively addressed through the matching process.
Survival analysis outcomes
During the median follow-up of 11.8 months, we conducted both univariate and multivariate Cox regression models to discern factors significantly impacting overall survival among patients subjected to PTR vs. those who received SEMS insertion (Table 2).
In the univariate analysis, age demonstrated a substantial influence, with individuals aged ≥75 years exhibiting a heightened hazard ratio (HR) of 1.586 (95% CI, 1.029–2.444, P = 0.037) relative to their younger counterparts. The ECOG performance status similarly stood out as a critical survival determinant; patients with an ECOG score of 2 showed an augmented mortality risk (HR, 1.8513; 95% CI, 1.0594–3.235; P = 0.031) in comparison to those scoring a 1 on the ECOG scale. Remarkably, not receiving chemotherapy was associated with significantly higher mortality risks in both univariate (HR, 2.175; 95% CI, 1.426–3.317; P < 0.001) and multivariate analyses (HR, 1.963; 95% CI, 1.200–3.211; P = 0.007), highlighting chemotherapy's importance in improving survival outcomes. However, there was no significant difference in survival rates between the PTR and SEMS groups in univariate analysis. (HR, 0.849; 95% CI, 0.555–1.298; P = 0.449).
Impact of treatment modality and chemotherapy
Fig. 2A illustrates Kaplan-Meier survival curves for the PTR and SEMS groups before matching, showing median overall survivals of 9.4 and 13.6 months, respectively, without a significant difference (p = 0.450). Fig. 2B highlights the impact of chemotherapy, with a median survival of 16.5 months for treated patients vs. 7 months for untreated, showcasing a significant benefit (P < 0.001).
After propensity score matching, Fig. 3A shows similar survival for the PTR and SEMS groups, at 9.4 and 15.8 months, respectively, still not significantly different (P = 0.260). Fig. 3B confirms chemotherapy's survival benefit post-matching, with survival nearly the same as before matching (16.7 months with chemotherapy vs. 6.8 months without, P < 0.001).
Factors influencing the adoption of chemotherapy
An analysis of factors influencing chemotherapy adoption revealed that age and ECOG performance status significantly affected the likelihood of receiving chemotherapy, with younger patients and those with better performance statuses more likely to receive it (Table 3). The initial treatment type did not significantly influence chemotherapy administration decisions. The median time to initiation of chemotherapy was 21 days (interquartile range [IQR], 15–28 days) in the SEMS group and 30 days (IQR, 24–36 days) in the PTR group, reflecting recovery time after surgical intervention. The most commonly used chemotherapy regimens included FOLFOX (55%), FOLFIRI (30%), and capecitabine-based therapies (15%). The median number of completed chemotherapy cycles was 8 (IQR, 6–12) in the SEMS group and 7 (IQR, 5–11) in the PTR group, showing no statistically significant difference (P = 0.621).
Analysis of secondary interventions after initial treatment
Following the initial interventions of PTR and SEMS insertion, the secondary interventions necessitated by patient condition progression or complication management were analyzed (Fig. 1). Notably, a significant proportion of the PTR group did not require further interventions (83.3%), contrasting with the SEMS group, where only 56.9% avoided additional treatments. Among the SEMS recipients, re-stent insertion (13.9%), diversion procedures (11.1%), and subsequent PTR (18.1%) were notably prevalent, indicating ongoing management needs or disease progression (Fig. 4). In contrast, the PTR group exhibited a substantially lower incidence of such interventions, underscoring the potential for a more definitive resolution through initial surgical management. Early complications (within 30 days) were categorized using the Clavien-Dindo classification, with grade III or higher complications occurring in 16.7% of the PTR group (16.7% vs. 43.1%, p = 0.012).
DISCUSSION
Our study highlights key outcomes in managing obstructive, unresectable stage IV CRC, focusing on the comparative effectiveness of PTR vs. SEMS and the impact of chemotherapy on survival. It reveals that chemotherapy significantly improves survival outcomes, while the choice between PTR and SEMS shows no substantial difference in overall survival.
In reviewing our findings in the context of existing literature, we affirm the pivotal role of chemotherapy in managing stage IV obstructive CRC, consistent with previous studies. Reports highlight that SEMS can reduce hospital stays and the necessity for stoma formation, besides facilitating an earlier start of chemotherapy compared to surgical options. Nonetheless, our analysis diverges when considering the survival impact of PTR vs. SEMS insertion [679]. Unlike findings from Lee et al. [6], who observed a survival advantage with PTR, indicating that the surgery group had significantly higher 1-year and two-year survival rates compared to the SEMS group, our study's findings are closely aligned with those of Karoui et al. [9], as both investigations did not observe a significant survival difference. This discrepancy brings to the fore the complexity of choosing the most suitable palliative care option for patients with stage IV obstructive CRC. In this regard, to solidify our findings and address the complexities, our study employed propensity score matching. This methodology allowed us to create a more balanced comparison between patients undergoing PTR and those receiving SEMS, minimizing potential biases inherent in retrospective analyses. This approach enhances the robustness of our conclusions, providing a clearer understanding of the comparative effectiveness of PTR vs. SEMS in this challenging patient population. Indeed, despite identifying potential advantages associated with the SEMS group, Lee et al. [6] were unable to account for the higher survival rates observed in the PTR group, nor did they emphasize these outcomes in their report.
There remains considerable debate over the survival benefit of PTR in the treatment of asymptomatic unresectable stage IV CRC, with some literature suggesting a potential advantage while cautioning about the retrospective nature of these studies and the likelihood of bias [14151617]. A randomized controlled trial by Park et al. [18] explored the benefits of PTR followed by chemotherapy in asymptomatic stage IV CRC patients with unresectable metastases. This study, conducted from May 2013 to April 2016 with 48 patients, found that while PTR showed a significant improvement in two-year cancer-specific survival compared to upfront chemotherapy (72.3% vs. 47.1%, P = 0.049), it did not significantly affect 2-year overall survival rates. Despite these insights, the study faced limitations due to early termination from recruitment challenges, highlighting the difficulties in conclusively determining the best treatment approach in such complex cases. The decision-making process intensifies in complexity with the onset of obstructive symptoms. Factors to consider include the patien's expected survival, the possibility of surgically removing the primary tumor, and whether a stoma will be required. SEMS may be advantageous for patients with a limited prognosis by reducing the need for invasive surgery, potentially avoiding stoma, and allowing for quicker commencement of chemotherapy. Nonetheless, the risk of SEMS-related complications is substantial. These can range from procedural failures, such as stent migration or inadequate expansion, to serious complications like perforation, which occurs in up to 12.8% of cases [192021]. Less common issues like migration and bleeding, with incidences up to 5%, may also require urgent surgical intervention, carrying an associated mortality risk of approximately 4% [121921]. Thus, while SEMS has its merits, these must be weighed against the risks of complications when considering the best course of action for a patient.
Adding to this complexity, the study by Frago et al. [7] provides pivotal insights into the management of obstructive, unresectable stage IV CRC with left-sided lesions. Their findings indicate that stenting, while employed to restore bowel patency and facilitate early chemotherapy initiation, may not be as effective as previously believed. Specifically, they observed a high incidence of early and late stenting failures, leading to significant morbidity and necessitating surgical intervention in a notable number of cases. This outcome underscores the potential limitations of relying solely on stenting as a palliative measure. Most strikingly, their analysis revealed a marked contrast in survival rates, with a two-year overall survival of 39.3% in patients who underwent resection compared to just 1% in patients managed with stenting and without resection (P = 0.008). This significant disparity in survival outcomes reinforces the necessity of a nuanced approach to treatment selection, one that carefully balances the immediate benefits of SEMS against its long-term outcomes and the potential survival benefits offered by surgical interventions. Our study corroborates these considerations, revealing notable management needs or disease progression indicators among SEMS recipients, including re-stent insertion (13.9%), diversion procedures (11.1%), and subsequent PTR (18.1%). Particularly, the occurrence of perforation in 6 (8.3%) and obstruction in 6 of the cases (6.9%) necessitating additional PTR interventions aligns with existing research findings. These parallels highlight the imperative to acknowledge the significant complication risks accompanying SEMS, despite its potential benefits.
Despite the insights provided by our study, it is not without limitations. One key limitation is the retrospective nature of the analysis, which could introduce selection bias and limit the generalizability of our findings. Moreover, the small sample size, especially concerning patients experiencing late-stage complications, hampers our ability to draw definitive conclusions about the impact of prolonged chemotherapy on the need for surgical interventions. In addition, the definition of unresectability and the criteria for surgical intervention with curative intent were somewhat ambiguous. For example, there were instances where patients initially deemed to have unresectable metastases underwent surgical resection after systemic therapy, such as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy and liver resection in cases with peritoneal and multiple liver metastases [2223]. This raises questions about the criteria for deeming a patient's condition as surgically convertible. Addressing these gaps in future prospective studies will be essential to enhance our understanding and management of stage IV CRC in the era of advanced systemic therapies. One important consideration is the deliberate exclusion of 21 patients who underwent elective palliative surgery after successful SEMS decompression. These patients, whose surgery was based on proactive surgeon judgment to prevent future complications, followed a markedly different clinical pathway than those managed solely with SEMS. Excluding them allowed us to clearly compare immediate PTR vs. primary SEMS placement, though this exclusion may affect generalizability. Furthermore, our study did not include quality of life (QoL) data, such as stoma-related complications and symptom relief, which are critical aspects of evaluating treatment efficacy, particularly in the palliative setting of stage IV CRC. Addressing these gaps in future prospective studies, including both QoL measures and robust definitions of surgical convertibility, will be essential to enhance our understanding and management of stage IV CRC in the era of advanced systemic therapies.
In conclusion, our study underscores a significant gap in the management of obstructive, unresectable stage IV CRC, particularly in the decision-making between SEMS and PTR. Despite advancements in systemic chemotherapy, standardized clinical guidelines remain insufficient. The elevated complication rates associated with SEMS highlight the necessity for refined patient selection criteria, integrating oncologic outcomes and health-related QoL to optimize comprehensive patient care.
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