Abstract
Objectives:
Surgical resection (SR) is recommended for pT1 colorectal cancer (CRC) with high-risk histological features for lymph node metastasis. However, endoscopic resection (ER) alone without additional SR is sometimes chosen for elderly patients due to surgical tolerance. Comparative studies on outcomes and prognosis between ER and SR remain limited.
Methods:
This retrospective study evaluated the outcomes of ER alone or SR in elderly patients (≥80 years) with high-risk pT1 CRC between 2008 and 2021.
Results:
A total of 59 patients were included, with 23 in the ER group and 36 in the SR group (additional SR after ER: 21, initial SR: 15). In the ER/SR groups, median age was 83 years, and the male ratio was 52%/64%, respectively. Median of Prognostic Nutritional Index (PNI) was 46.9/51.0. Median lesion size was 20 mm in both groups. Pathological findings showed pT1b in 96%/92%, lymphovascular invasion in 35%/33%, and budding grade ≥2 in 22%/28%. Treatment-related complications occurred in 7%/8% in each procedure, with one surgery-related death. Over a median follow-up of 57/63 months, no recurrences or disease-specific deaths were observed. The 5-year survival rates were 90%/81%, with no significant difference in overall survival (P = 0.12). PNI <43.4 was identified as a prognostic risk factor, and in the ER group, patients with low PNI showed significantly worse survival.
Conclusion:
There was no significant difference between the outcomes of ER alone and SR among elderly patients with high-risk pT1 CRC. PNI can be a valuable predictor of prognosis in the ER group.
Keywords: colorectal cancer, elderly, endoscopic resection, surgery, short-term outcome, long-term outcome
INTRODUCTION
Japanese guidelines for the treatment of submucosal invasive (T1) colorectal cancer (CRC) identify deep submucosal invasion (≥1000 μm, T1b), lymphovascular invasion (LVI), histological grade, and tumor budding as risk factors for lymph node metastasis (LNM)[1-4]. Cases with at least one of these factors are considered high-risk T1 CRC due to their significant risk of LNM[5,6]. Consequently, surgical resection (SR) with lymph node dissection is generally recommended for high-risk T1 CRC[7].
SR is generally considered an effective and safe standard treatment option, even in elderly patients[8,9]. Advances in minimally invasive techniques have improved postoperative outcomes, reducing the risks associated with surgery[10,11]. However, endoscopic resection (ER) alone without additional SR is sometimes chosen for elderly patients due to their limited surgical tolerance. Studies have shown that elderly patients undergoing colorectal surgery experienced a higher rate of complications and an increased risk of mortality from other causes[12-14]. This is particularly relevant for patients with frailty or multiple comorbidities, where postoperative overall survival (OS) has been reported to be more influenced by baseline health conditions than by the oncological benefits of SR[14,15]. Given these concerns, as Japan's population ages, reconsidering the selection of treatment options in elderly patients based on their overall health status and remaining life expectancy may be reasonable, balancing the oncological and long-term benefits of treatment against potential risks[16]. However, the evidence remains insufficient to determine which patients truly benefit from SR and which may be better managed with alternative approaches.
In this study, we aimed to clarify the short- and long-term outcomes, including prognosis, of ER and SR among elderly patients (age ≥80 years) with high-risk pT1 CRC.
METHODS
Study design and patients
We conducted a retrospective single-center study among elderly patients (≥80 years) who underwent endoscopic or surgical treatments in Hiroshima University Hospital between 2008 and 2021. Cases which were pathologically diagnosed as high-risk pT1 CRC corresponding to non-curative endoscopic resection were included. Exclusion criteria were cases with positive vertical margin, concurrent CRC (≥T1), other organ cancers, unknown pathological details, inflammatory diseases, or familial polyposis syndromes. Cases were divided into two groups according to final treatment: ER group was those who received ER only and followed up, and SR group was those who received SR as an initial treatment or as an additional treatment after ER.
Baseline patient characteristics
Baseline patient characteristics were assessed by reviewing the following medical records, including medical interviews, physical examinations, peripheral blood sampling, electrocardiography, and chest radiography conducted within two months prior to the initial treatment. The variable examined included age, sex, and possible prognostic factors: Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson comorbidity index (CCI)[17], Onodera's prognostic nutritional index (PNI)[18], and Controlling Nutritional Status (CONUT)[19]. The CCI was calculated by summing the scores assigned to several comorbidities[17]. The PNI was calculated using the formula: PNI = 10 × serum albumin concentration (g/dL) + 0.005 × total lymphocyte count (/mm3)[18]. The CONUT was calculated by summing the scores for serum albumin (g/dL), total lymphocyte count (/mm3), and total cholesterol (mg/dL)[19].
Clinical diagnosis and primary treatment
Lesions were endoscopically assessed before treatment and were checked for location (colon or rectum), size, morphology type, and clinical diagnosis of submucosal invasion depth (cT1a: submucosal invasion <1000 μm, cT1b: submucosal invasion ≥1000 μm)[20]. The morphology type was classified into one of three categories: protruding type, defined as 0-Ip, 0-Is, or 0-Is+IIc; flat type, defined as 0-IIc, 0-IIa, or 0-IIa+IIc; or mixed type, defined as containing both 0-Is and 0-IIa components, following Parris classification[21]. Indication for ER was basically decided based on Japanese guidelines[2]. In accordance with standard recommendations, patients were informed by a surgeon about the indication and details of the SR, with consideration to each patient's general condition and surgical tolerability. If patients refused SR or were deemed unable to tolerate SR, the adaptation of ER was carefully discussed. The final agreement for their treatment plan was reached after the approval of the institution's cancer board.
Histopathological evaluation and additional surgery
Histopathological evaluation was performed according to the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma[20]. ER specimens were sliced into 2-3 mm width, and surgical specimens were sliced into 5-6 mm width. LVI was assessed immunohistochemically in all cases. The definition of high-risk T1 CRC includes any of the following criteria: (1) submucosal invasion depth ≥1000 μm, (2) LVI, (3) tumor budding grade ≥2, or (4) high-grade histology (poorly differentiated adenocarcinoma, mucinous adenocarcinoma, or signet-ring cell carcinoma), according to the criteria of the Japanese Guidelines for the Treatment of Colorectal Cancer[2]. When the pathology of ER case indicated high-risk, patients were informed about the risks of metastatic recurrence and the details of additional SR. Discussions with patients were undertaken, explaining options for additional SR or follow-up without SR, with consideration of their general condition and preferences. Local recurrence was defined as a recurrence that occurred at the ER scar site of the primary lesion, and metastatic recurrence was defined as metastatic recurrence in the lymph nodes or other organs. Follow-up care was performed according to the Japanese guidelines[2].
Short- and long-term outcomes
Treatment-related complications (Clavien-Dindo grade ≥IIIa)[22] and all deaths occurring within 90 days or 1 year after treatment were evaluated as short-term outcomes. Long-term outcomes, including survival data and cause of death, were retrospectively collected from the medical records at our hospital as of October 2024. For patients who had not visited our hospital regularly, data were retrieved by contacting their referring physicians, their families, or by inquiring about statistical data maintained by local government registries.
Statistical analysis
Clinical characteristics and pathological outcomes of the ER and SR groups were assessed by univariate analysis (chi-square test for categorical variables, Wilcoxon rank sum test for continuous variables). OS and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method with a log-rank test. Local and/or distant recurrence was analyzed using cumulative incidence analysis. Prognostic risk factors related to OS were analyzed using univariate and multivariate Cox proportional hazards models (hazard ratio [HR], 95% confidence interval [CI], P value). Values included in the risk factor analyses were patient backgrounds (sex, age, and prognostic factors), pathological factors (pT stage, LVI, and budding grade), and treatment. The cutoff values of age and PNI were determined by the maximum value of Youden's index for the receiver operating characteristic (ROC) curve for 5-year OS. Variables with P <0.2 in the univariate analysis were included in the multivariate analysis. Additionally, stratified OS analysis was performed for the preoperative risk factors using the Kaplan-Meier method and log-rank tests. Statistical significance was set at P <0.05. Analyses were performed using Stata SE version 14.2 for Mac (StataCorp LP, College Station, TX, USA).
Ethical statement
This study was carried out according to the principles of the Declaration of Helsinki. The study was approved by the Hiroshima University Hospital Institutional Review Board Ethics Committee (E2024-0263). Informed consent was obtained by the opt-out method to ensure that patients had the opportunity to make an informed choice about participation.
RESULTS
Patient and lesion characteristics
A flowchart of cases included in this study is presented in Figure 1. There were 78 patients with 80 lesions who were diagnosed as high-risk pT1 CRC older than 80 years old between 2008 and 2021. Among them, 19 patients were excluded, and 59 patients with 59 lesions were analyzed. Of these, 44 initially underwent ER and 15 underwent SR. Among patients with ER, 21 received additional SR whereas 23 selected follow up. Finally, 23 patients who had received ER alone were included in the ER group, and 36 patients who had received initial or additional SR were included in the SR group.
Figure 1.
Flowchart showing the distribution of cases in ER group and SR group.
ER, endoscopic resection; SR, surgical resection; pT1 CRC, submucosal invasive colorectal cancer
Table 1 shows patient and lesion characteristics of each group. Median age was 83 years in both groups, but the proportion of patients older than 90 years was higher in the ER group (ER group 17.4% vs. SR group 2.8%, P = 0.049). Rates of PS ≥2 and CONUT ≥3 were relatively higher in the ER group, but not statistically significant (PS ≥2: 8.7% vs. 2.8%, P = 0.313; CONUT ≥3: 30.4% vs. 19.4%, P = 0.333). The median of PNI was lower in the ER group but was not significant (46.9 vs. 51.0, P = 0.074). The cT stage was also not significantly difference between the two groups (cT1b 52.2% vs. 61.1%, P = 0.498).
Table 1.
Baseline Characteristics.
| ER group n = 23 | SR group n = 36 | P value | ||||
|---|---|---|---|---|---|---|
| Patient characteristics | ||||||
| Age | ||||||
| median (range), years | 83 | (81–95) | 83 | (80–90) | 0.719 | |
| ≥90 years | 4 | (17.4) | 1 | (2.8) | 0.049 | |
| Sex | 0.353 | |||||
| Male | 12 | (52.2) | 23 | (63.9) | ||
| Female | 11 | (47.8) | 13 | (36.1) | ||
| PS ≥2 | 2 | (8.7) | 1 | (2.8) | 0.313 | |
| CCI ≥3 | 3 | (8.3) | 0.961 | |||
| PNI, median (range) | 46.9 | (24.8–57.1) | 51.0 | (39.9–57.3) | 0.074 | |
| CONUT ≥3 | 7 | (30.4) | 7 | (19.4) | 0.333 | |
| Lesion characteristics | ||||||
| Location | 0.887 | |||||
| Colon | 17 | (73.9) | 26 | (72.2) | ||
| Rectum | 6 | (26.1) | 10 | (27.8) | ||
| Size, median (range), mm | 20 | (5–120) | 20 | (6–129) | 0.783 | |
| Morphology | 0.973 | |||||
| Protruding | 11 | (47.8) | 18 | (50.0) | ||
| Flat | 9 | (39.1) | 13 | (36.1) | ||
| Mixed | 3 | (13.0) | 5 | (13.9) | ||
| cT stage | 0.498 | |||||
| cT1a | 11 | (47.8) | 14 | (38.9) | ||
| cT1b | 12 | (52.2) | 22 | (61.1) | ||
Values are presented as n (%) unless otherwise indicated. ER, endoscopic resection; SR, surgical resection; PS, Performance Status; CCI, Carlson Comorbidity Index; PNI, Onodera’s prognostic nutritional index; CONUT, Controlling Nutrition Status; cT1a, submucosal invasive cancer <1000 μm; cT1b, submucosal invasive cancer ≥1000 μm
Shor-term outcomes
Histopathological findings are shown in Table 2. Among the LNM risk factors in the guidelines, pT1b was 95.7% vs. 91.7% (P = 0.553), high grade histology was 0% vs. 2.8% (P = 0.420), LVI was 34.8% vs. 33.3% (P = 0.909), and budding grade ≥2 was 21.7% vs. 27.8% (P = 0.603). The proportion of cases where invasion depth (pT1b) was the sole risk factor of LNM was higher in the ER group but not significant (65.2% vs. 47.2%, P = 0.176).
Table 2.
Histopathological Findings.
| ER group n = 23 | SR group n = 36 | P value | ||||
|---|---|---|---|---|---|---|
| pT stage | 0.553 | |||||
| pT1a | 1 | (4.3) | 3 | (8.3) | ||
| pT1b | 22 | (95.7) | 33 | (91.7) | ||
| Histology | 0.420 | |||||
| tub1/tub2/pap | 23 | (100) | 35 | (97.2) | ||
| por/sig/muc | 0 | (0) | 1 | (2.8) | ||
| LVI (+) | 8 | (34.8) | 12 | (33.3) | 0.909 | |
| Budding grade ≥2 | 5 | (21.7) | 10 | (27.8) | 0.603 | |
| pT1b as a sole LNM risk factor | 15 | (65.2) | 17 | (47.2) | 0.176 | |
| LNM (+) | – | – | 2 | (5.6) | – | |
Values are presented as n (%). ER, endoscopic resection; SR, surgical resection; pT1a, submucosal invasive cancer <1000 μm; pT1b, submucosal invasive cancer ≥1000 μm; LVI, lymphovascular invasion; LNM, lymph node metastasis
Table 3 shows the short-term outcomes. Among 44 ER procedures (ER only and initial ER + additional SR), en-bloc resection rate was 93.2%, with no treatment discontinuation. Three cases with treatment-related complications occurred, all of which were managed without surgical intervention. Among 36 SR procedures (15 initial and 21 additional SR), there were 2 cases of ileus and 1 case of treatment-related death. Supplementary Table 1 summarized mortality within 90 days and 1 year after treatment. The fatal SR case involved a woman in her 80s, who developed respiratory failure and sepsis due to pneumonia following a transverse colectomy and passed away 57 days after the operation. Reasons for not undergoing additional surgery included advanced age (48%), patient refusal (35%), and comorbidities (17%) (Supplementary Table 2). The pathological results of pT1b as the sole LNM risk factor (65%) may have also been considered along with them in treatment decisions.
Table 3.
Short-term Outcomes.
| ER procedure n = 44 | SR procedure n = 36 | ||||
|---|---|---|---|---|---|
| ER en-bloc resection | 41 | (93.2) | – | – | |
| ER discontinuation | 0 | (0) | – | – | |
| Complication | 3 | (6.8) | 3 | (8.3) | |
| Perforation | 1 | (2.3) | – | ||
| Delayed bleeding | 2 | (4.5) | – | ||
| Ileus | 0 | (0) | 2 | (5.6) | |
| Death | 0 | (0) | 1 | (2.8) | |
Values are presented as n (%). ER, endoscopic resection; SR, surgical resection
Long-term outcomes
Figure 2A shows the OS of each treatment groups. During the median follow-up period of 57.2 months for the ER group and 62.8 months for the SR group, the 3-year/5-year survival rates were 90.0%/90.0% for the ER group and 91.5%/81.4% for the SR group, respectively, with no significant difference (P = 0.124). There was no recurrent or metastasis case in either group, as shown in the cumulative recurrence curve (Supplementary Figure 1); therefore, the DSS rates were 100% without any significant difference (Figure 2B).
Figure 2.
Long-term outcomes of the ER group and the SR group among elderly patients with high-risk pT1 CRC. A, Overall survival. B, Disease-specific survival.
ER, endoscopic resection; SR, surgical resection; pT1 CRC, submucosal invasive colorectal cancer
Prognostic risk factors associated with overall survival
Table 4 shows the factors associated with 5-year OS. ROC analyses showed that the areas under the ROC curves of age and PNI for predicting 5-year OS were 0.68 and 0.66, respectively, with optimal cutoff values of 83 and 43.4 (Supplementary Figure 2). Among the factors analyzed, PNI was the only variable that showed a significant relationship. Accordingly, Figure 3 illustrates the OS of the ER and SR groups stratified by PNI. In the ER group, patients with low PNI had significantly poorer OS compared with those with high PNI (P <0.001). In contrast, no significant difference was observed in the SR group according to PNI (P = 0.104).
Table 4.
Clinicopathological Factors Associated with OS.
| Univariate | Multivariate | |||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |||
| Sex | Male | 1.62 | 0.60–4.36 | 0.336 | ||||
| Age | ≥83 years | 2.37 | 0.87–6.49 | 0.093 | 1.57 | 0.52–4.77 | 0.425 | |
| PS | ≥2 | 4.00 | 0.49–33.0 | 0.198 | 1.00 | 0.09–11.0 | 0.999 | |
| CCI | ≥3 | 2.44 | 0.54–11.0 | 0.247 | ||||
| PNI | <43.4 | 17.8 | 3.42–92.8 | 0.001 | 11.3 | 1.56–82.7 | 0.017 | |
| CONUT | ≥3 | 2.15 | 0.80–5.80 | 0.131 | 1.42 | 0.39–5.22 | 0.595 | |
| pT stage | pT1b | 0.43 | 0.96–1.93 | 0.270 | ||||
| LVI | (+) | 1.23 | 0.48–3.20 | 0.664 | ||||
| Budding | Grade ≥2 | 0.65 | 0.21–1.98 | 0.446 | ||||
| Treatment | SR | 2.36 | 0.76–7.32 | 0.136 | 2.15 | 0.64–7.19 | 0.213 | |
OS, overall survival; HR, hazard ratio; CI, confidence interval; PS, Performance Status; CCI, Carlson Comorbidity Index; PNI, Onodera’s prognostic nutritional index; CONUT, Controlling Nutrition Status; pT1b, submucosal invasive cancer ≥1000 μm; LVI, lymphovascular invasion; SR, surgical resection
Figure 3.
Overall survival of the ER group and the SR group among elderly patients with high-risk pT1 CRC stratified by PNI. A, ER group. B, SR group.
ER, endoscopic resection; SR, surgical resection; PNI, Onodera’s prognostic nutritional index; pT1 CRC, submucosal invasive colorectal cancer
DISCUSSION
This study examined the short- and long-term outcomes of ER and SR for high-risk pT1 CRC in elderly patients in a real-world setting. The outcomes, including OS, showed no significant difference between the two groups, despite poorer patient backgrounds in the ER group and worse pathology results in the SR group. Additionally, PNI was identified as a significant prognostic factor in the ER group, with lower PNI associated with worse OS.
Interpretation of these findings requires careful consideration of the substantial baseline differences between the ER and SR groups. Patients in the ER group were generally older and more frail, whereas those in the SR group more frequently exhibited pathological risk factors for LNM. This imbalance reflects real-world clinical decision-making rather than random treatment allocation. In routine practice, ER alone is often selected for frailer or very elderly patients, while SR is reserved for patients considered fit for surgery or at higher oncological risk. Accordingly, the comparable OS observed despite these contrasting baseline profiles should not be interpreted as evidence of treatment equivalence. Rather, it suggests that current clinical judgment in selecting ER versus SR may be functioning appropriately in elderly patients with high-risk pT1 CRC.
This interpretation is particularly relevant in elderly patients, in whom treatment decisions must account for comorbidities, surgical tolerance, and competing risks of mortality. In our cohort, no recurrence or disease-specific death was observed in both ER and SR groups, resulted in favorable long-term outcomes without significant difference in OS. For T1 CRC, patients with risk factors for LNM are generally recommended to undergo additional SR due to the potential risk of recurrence[2,23]. However, the higher incidence of comorbidities in elderly patients highlights the need for careful assessment of surgical tolerance and consideration of less invasive treatment[24]. Furthermore, considering Japan's average life expectancy (81.1 years for male and 87.1 years for female in 2024), even if a residual risk of LNM remains after ER, some patients may not develop recurrence or disease-specific mortality within their remaining lifespan. Indeed, a previous study on patients who underwent surgical R0 resection for CRC has reported that elderly patients had a high risk of non-cancer-specific mortality[12]. The favorable outcomes observed in both groups in our study suggest that while SR should be prioritized as the standard treatment, ER alone can be a viable option for elderly patients when SR is not feasible.
While both the ER and SR groups demonstrated favorable long-term outcomes in our study, patients with low PNI exhibited significantly poorer OS in the ER group. PNI, initially introduced as a nutritional index to predict postoperative complications[18], has since been widely recognized as a prognostic indicator, particularly in elderly populations. For instance, in elderly patients undergoing endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), a lower PNI has been associated with poor OS, necessitating careful determination to perform treatment[25]. Additionally, in elderly males with EGC of relative ER-indication, PNI had a greater impact on OS than treatment (ESD vs. surgery), suggesting that a diagnostic ESD-first approach followed by cautious surgical decision-making may be preferable[26,27]. Although studies on PNI in CRC remain limited, some reports have indicated its prognostic significance across all stages[28,29]. Considering these findings, PNI could be a useful tool for treatment decision-making in elderly patients with high-risk pT1 CRC. In our study, patients with low PNI exhibited significantly poorer OS in the ER group. This suggests that, for patients with low PNI, the necessity of any treatment should be carefully considered. On the other hand, in the SR group, PNI was not significantly associated with OS. This may suggest that PNI has a limited role in prognostic stratification for surgical cases. However, this finding should be interpreted with caution, as the number of cases of low PNI was small and preoperative selection may have led to the exclusion of patients with poor nutritional or general conditions from SR. Notably, the only death in the SR group occurred in a patient with a low PNI(PNI = 39.9), suggesting that PNI may still be relevant for predicting postoperative outcomes. Given these results, although ER alone may be a viable option for elderly patients when SR is not feasible, careful consideration is warranted for those with low PNI, including whether any treatment is appropriate.
Our study has some limitations. First, this was a retrospective study with a limited number of cases due to the single-center study design. Although preoperative factors evaluated in this study are objective, the decision to perform highly invasive procedures, such as SR, is made based on a comprehensive clinical evaluation. Developing indices that can more accurately assess preoperative general condition and conducting a randomized prospective study are considered desirable. Furthermore, our study presents a novel finding, and a subsequent prospective multicenter study is warranted for validation and broader generalizability. Second, the outcomes of cases who did not receive any treatment could not be evaluated because our database includes only those who underwent treatment. However, such cases are very rare, and either ER or SR is usually planned. Therefore, our data largely reflect the real-world situation of elderly patients with high-risk pT1 CRC. Third, since the decision to perform SR is based on a comprehensive clinical and/or pathological assessment, differences in patient backgrounds between the ER and SR groups were inevitable. Patients with a poorer general condition or a lower LNM risk (cases where invasion depth was the only high-risk factor) were more likely to be managed with ER alone, whereas those with a better general condition or a higher LNM risk were more likely to undergo SR. Given these inherent differences, our study provides insights into the real-world outcomes of each treatment strategy. Additional statistical approaches, such as propensity score matching analysis in large-scale cohorts, may further refine our findings.
In conclusion, this study demonstrated that there was no significant difference in short- and long-term outcomes, including OS, between ER alone and SR among elderly patients with high-risk pT1 CRC. Our results suggest that while SR should be prioritized as the standard treatment, ER alone can be a viable option for elderly patients when SR is not feasible. Additionally, for elderly patients with low PNI, careful consideration is warranted even for the appropriateness of ER, given their overall prognosis.
Contributions
YK designed the study, recruited cases, analyzed and interpreted the data, and drafted the article. YK and KY collected the data. TK, TT, AT, HT, KY, YH, HT, YU, MS, HO, and SO contributed to the critical revision of the article for important intellectual content. All authors approved the final version of the manuscript.
Disclaimer
Shiro Oka is one of the Associate Editors of Journal of the Anus, Rectum and Colon and on the journal's Editorial Board. He was not involved in the editorial evaluation or decision to accept this article for publication at all.
Ethics Statement
This study protocol was approved by the Institutional Review Board of Hiroshima University Hospital, Hiroshima, Japan (E2024-0263). Informed consent was obtained by the opt-out method to ensure that patients had the opportunity to make an informed choice about participation.
Conflicts of Interest
The authors declare no conflict of interest for this article.
Data Availability Statement
Data are available from corresponding author upon reasonable request.
Supplementary Files
Supplementary file 1.
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Supplementary file 1.