Introduction

Colorectal cancer is the fourth most common cancer and the second leading cause of cancer death in the world.1 Rectal cancer accounts for approximately 30% of colorectal cancers, and locally advanced rectal cancer (LARC) accounts for 70% of rectal cancers.1,2 Locally advanced rectal cancer, defined here as T3–4 or N-positive disease, generally requires multimodal therapy that includes total mesorectal excision (TME), radiation therapy, and chemotherapy. The previous standard of care for patients with LARC includes neoadjuvant chemoradiotherapy (nCRT) followed by TME.3 With the release of data from randomized controlled trials (RAPIDO, PRODIGE-23, STELLAR), total neoadjuvant therapy (TNT) has moved to the forefront of LARC treatment and is considered a standard option in selected patients.4–7 TNT is a comprehensive approach to cancer treatment that involves the administration of chemotherapy and nCRT prior to surgical resection of the primary tumor. TNT consists of two main Methods: induction chemotherapy, which involves chemotherapy followed by concurrent chemoradiation, and consolidation chemotherapy, which entails systemic chemotherapy following concurrent chemoradiation. This integrated approach aims to reduce tumor size, minimize the risk of metastasis, and optimize the potential for successful surgical removal, ultimately improving patient outcomes.8 Additionally, TNT also promises improved control of systemic diseases, better adherence to treatment, and less time with an ostomy.9

Despite the common occurrence of tumor regression after TNT treatment, approximately 20% of patients demonstrate resistance, presenting with minimal or no tumor regression.5 These individuals do not benefit from additional preoperative chemotherapy cycles during TNT or extended intervals between radiotherapy and surgery. Notably, one study revealed that patients with incomplete tumor regression faced a poorer prognosis than those with complete tumor regression.10 Therefore, early identification of patients who are unlikely to benefit from TNT and adjustment of treatment are imperative to improve prognosis. However, there is a current research gap on the possible risk factors associated with TNT-induced tumor regression in patients with LARC. According to Chapman et al, predictive factors for the complete TNT-induced response in patients with LARC include tumor diameter, p53 and SMAD4 mutations, and cN stage.10 Additionally, Zhang et al identified cN stage, tumor diameter, and CEA level as predictive factors for the TNT-induced response.8

Mounting evidence suggests a link between systemic inflammatory response, malnutrition, and treatment sensitivity, as well as prognosis of various gastrointestinal tumors, such as gastric cancer,11,12 colorectal cancer,8,13 liver cancer,14 pancreatic cancer,15 and gastrointestinal stromal tumor.16 Therefore, surveillance of the correlation between nutritional-inflammatory index and TNT-induced tumor regression can aid in the early identification of patients who are unlikely to derive benefits from TNT. Our study aimed to collect the clinicopathological characteristics of patients with LARC who underwent TNT to explore the potential nutritional inflammatory indices associated with TNT-induced tumor regression.

Materials and Methods Patient Population

This retrospective study analyzed the data of 157 consecutive patients newly diagnosed with LARC, who received TNT at the Gastrointestinal Cancer Center of Chongqing University Cancer Hospital from 1 January 2017 to 30 December 2020.

Patients were included in the study based on the following criteria: 1) diagnosis: confirmed rectal adenocarcinoma diagnosis through preoperative colonoscopy and histology; 2) cancer stage: no distant metastases, with tumors classified as T3, T4 or N+; 3) treatment protocol: receiving the CAPOX-based TNT regimen-; 4) age range: age between 18–75 years; 5) performance status: ECOG PS score of 0–1; 6) previous treatment: no prior tumor-related treatment (except colostomy); 7) laboratory values: white blood cell count (4000 to 10,000 cells/μL), neutrophil percentage (40–60% of total white blood cells), aspartate aminotransferase and alanine aminotransferase levels not exceeding three times the upper limit of normal, and creatinine levels not exceeding 1.5 times the upper limit of normal, all measured within one week before diagnosis; 8) systemic health: absence of serious systemic diseases; 9) treatment tolerance: capability to tolerate radiotherapy and chemotherapy, as assessed in the preoperative evaluation; 10) informed consent: willingness to undergo TNT treatment after understanding the principles and procedures of the treatment.

Exclusion criteria were as follows: 1) highly suspected lateral lymph node metastasis; 2) previous or concurrent malignant tumors, pregnancy, or lactation; 3) severe cardiovascular and cerebrovascular diseases, poor blood sugar control; 4) allergy to fluorouracil or platinum preparations, severe infections; and 5) not having received ≥5 concurrent CapeOX regimen chemotherapy.

After exclusions, the study included 127 patients. A flow diagram depicting the patient selection process is presented in Figure 1. The study adhered to the Declaration of Helsinki and obtained approval from the Ethics Committee of Chongqing University Cancer Hospital (reference number 2023(011)). All patients provided their informed consent in writing before TNT treatment, surgery, or before a watch-and-wait strategies (W&W) strategy.

Figure 1 Study flow chart.

Abbreviations: TNT, total neoadjuvant treatment;TRG, tumor regression grade.

Initial Assessment

The patients underwent a comprehensive evaluation that included medical history, physical examination, digital rectal examination, colonoscopy with biopsy, optional endorectal ultrasound, pelvic magnetic resonance imaging (MRI), computed tomography (CT), and biochemical evaluation. Pelvic MRI served to determine the clinical T stage, identify metastatic lymph nodes, assess circumferential resection margin (CRM) involvement, and evaluate extramural vascular invasion (EMVI). CRM involvement is defined as tumor invasion within 1 mm of the mesorectal surgical margin. EMVI involvement was characterized by intermediate signal intensity within vessels, noticeable irregular vessel contours, or nodular expansion of vessels due to tumor growth. CT scans of the brain, chest, abdomen, and pelvis were performed for the detection of metastatic lesion. All patients were staged according to the UICC TNM classification (8th edition) classification.17

TNT Protocol

We performed consolidation chemotherapy TNT based on the CapeOX regimen. The TNT protocol in this study consisted of 1–2 cycles of CapeOX regimen-based chemotherapy, 2–3 cycles of concurrent chemoradiotherapy (IMRT/VMAT (50–50.4Gy/25-28f. 1.8–2.0Gy/d, 5f/w plus CapeOX regimen), and 3–4 cycles of consolidation chemotherapy (CapeOX regimen) at 7–14 days after completion of radiotherapy. In this study, patients who received ≧5 CapeOX chemotherapy regimens after the start of radiotherapy were identified as TNT mode.18,19 If there was intestinal obstruction before treatment, colostomy was performed first.

Reassessment and Surgical Intervention

Following preoperative therapy, patients underwent reassessment via digital rectal examination, pelvic MRI, colonoscopy, endorectal ultrasound (optional), chest CT, and liver MRI/CT. After TNT, patients willing to and eligible for surgery underwent radical surgery, performed at least three weeks after completion of consolidation chemotherapy. Surgical approaches included TME, with options of Dixon’s procedure, Miles’ procedure, or Hartmann’s procedure, based on tumor distal extension from the anal verge and intraoperative conditions. The protocol allowed for the W&W strategy in cases of clinical complete response (cCR), patient preference for organ preservation, or refusal of radical surgery (nonoperative management).

Follow-Up

Follow-up investigations were scheduled every 3 months during the first 2 years, then every 6 months for the next 3 years, and annually thereafter. Evaluation consisted of physical examination, blood tests, serum carcinoembryonic antigen (CEA) level, chest and abdomen CT, and pelvic MRI. Patients employing a W&W approach were no longer subjected to chemotherapy; instead, a rigorous follow-up observation protocol was advocated. In instances of suspected metastases or recurrent lesions, diagnostic modalities such as PET/CT or needle biopsy were used as deemed suitable Systemic therapy was prescribed according to the guidelines for patients with confirmed metastasis or recurrence. All follow-up data were meticulously documented and patient confidentiality was maintained throughout the process. The follow-up period ended on 30 September 2023.

Safety and Efficacy Analysis

To determine feasibility and toxicity, all patients were clinically and hematologically evaluated weekly to identify adverse events (AEs) before each chemoradiotherapy or chemotherapy cycle throughout the course of TNT. Postoperative complications were defined as those that occurred within the first 30 days after surgery. Adverse events during TNT were reported based on CTCAE version 5.0 criteria.20

Efficacy was assessed using the post-treatment clinical TNM (ycTNM), post-treatment pathological TNM (ypTNM), TRG system, and by progression-free survival (PFS). The tumor stage was determined according to the pathological tumor-node-metastasis (pTNM) classification of the Union for International Cancer Control (UICC), 8th edition.17 TRG system used was recommended by the American Pathologists Tumor Regression Grading System.21 cCR criteria were defined by Maas et al.22 A pathological complete response (pCR) was defined as no residual cancer cells observed in the resection specimen, which was also regarded as TRG0 (ypT0N0M0).23 PFS was defined as the time from the end of TNT to disease progression or death (whichever occurs first).

Data Collection

In this retrospective study, data were collected from patient medical records, which included a comprehensive array of demographic information, laboratory variables, and clinical outcomes. Demographic data included age, sex, and BMI. Laboratory data included serum albumin, white blood cell count, neutrophil count, lymphocyte count, platelet count, hemoglobin level, CEA, CA19-9. Immunological profiles detailing CD4+ T cells, CD8+ T cells, and natural killer (NK) cell counts were also collected. Clinical assessments, including pre- and post-TNT TNM staging, MRI-predicted CRM status, EMVI status, tumor diameter, and tumor distance from anal verge were retrospectively reviewed and collected. For surgical patients, the operative surgical method, operation time, blood loss, stage of pTNM, surgical margin status, tumor regression grade, differentiation grade, perineural invasion, and vascular invasion were documented.

Definition

The hemoglobin and albumin levels and lymphocyte and platelet index (HALP), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and geriatric nutritional risk index (GNRI) were calculated using the following formulas: The HALP = hemoglobin level (g/L) × albumin level (g/L) × lymphocyte count (/L) / platelet count (/L);24 PNI = albumin level (g/L) + 5 × lymphocyte count (n/mm3);25 NLR = neutrophil count (n/mm3) / lymphocyte count (n/mm3);26 PLR = platelet count (n/mm3) / lymphocyte count (n/mm3);27 GNRI = 14.89 × serum albumin level (g/dL) + 41.7 × current body weight (kg)/ideal body weight (kg).28 A good response to TNT is characterized by TRG 0/1 or cCR, while a negative response is indicated by TRG 2/3 or progression during TNT.

Statistical Analysis

Statistical analysis utilized SPSS 25.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). Data presented as numbers (n) and percentages (%) were analyzed with chi-square or Fisher’s exact tests, while means and standard deviations were compared using t-tests or Mann–Whitney U-test. PFS was assessed using the Kaplan-Meier method, and analysis involved the Log rank test and Cox regression model. Statistical significance, for two-tailed tests, was established at p < 0.05. Variables with a significant association (p < 0.05) in univariate analysis were included in a logistic multivariable model. The area under the curve (AUC) summarized the receiver operating characteristics (ROC) curve for discrimination ability.

Results Baseline Characteristics

From January 2017 to January 2021, 127 patients (88 males, 39 females) aged 30–79 (median: 54 years) were analyzed. The average BMI was 23.5 ± 3.0 kg/m2. The anal verge distance ranged from 2–9 cm (average: 4.8 ± 1.4 cm), and tumor diameter ranged 2.5–12.0 cm (average: 5.4 ± 1.7 cm). Pelvic MRI and ultrasonic colonoscopy were used for pre-treatment clinical staging. Eighty patients were in cT3 stage, 42 in cT4 stage, and 116 (89.6%) were N+. Pre-TNT CRM+ was observed in 44 patients (34.6%), while Pre-TNT EMVI+ was present in 45 patients (35.4%). The prevalent AEs included neutropenia (13.4%), thrombocytopenia (11.0%), anemia (11.0%), and diarrhea (4.7%). No grade 4 or severe AEs were observed. Post-TNT, 70 patients (55.1%) exhibited favorable tumor regression response. Among them, 13 achieved cCR and entered the W&W protocol, while 57 were histologically confirmed as TRG 0/1 after surgery. The remaining 57 (44.9%) showed a poor response, 5 progressing to inoperable status, 52 having histologically confirmed TRG 2, and none with TRG 3 (Figure 1). Of the 109 (85.8%) patients undergoing surgery, the median interval between surgery and radiotherapy was 13 weeks (range: 9–16 weeks). Surgical approaches included Dixon’s procedure with a temporary diverting loop ileostomy in 95 cases, Hartmann’s procedure in 4 cases, and Miles’ procedure in 10 cases. Histological findings revealed pCR in 18 (16.5%) patients and R0 resection in 107 (98.2%) patients. Overall, 70 (55.1%) patients achieved a favorable response (cCR + TRG 0/1), while 57 (44.9%) patients exhibited a poor response (TRG2 + progression during treatment). The characteristics of the patients are listed in Table 1 and Table S1. The median follow-up period was 17 months (range: 3–61), with 17 months (range: 3–61) in the good response group and 16 months (range: 7–31) in the poor response group.

Table 1 Clinical and Pathological Characteristics of 127 LARC Patients with TNT

Comparisons of Inflammatory Parameters Between Groups

Table 2 presents the stratification of patients based on TNT-induced tumor regression. No significant variations were observed in demographic and clinical parameters, including age, sex, BMI, cT stage, cN stage, CRM status, EMVI status, albumin, white blood cell count, neutrophil count, platelet count, CEA levels, CD4+ T cell count, CD8+ T cell count, CD4+/CD8+ ratio, or NK/T cell ratio between the response groups. However, patients in the poor response group exhibited larger pretreatment tumor diameters [(6.0 ± 1.8) cm vs (4.9 ± 1.5) cm, p = 0.001], greater distance from the anal verge [(5.2 ± 1.6) cm vs (4.6 ± 1.2) cm, p = 0.017], lower lymphocyte count [(1.63 ± 0.56) × 109/L vs (1.80 ± 0.54) × 109/L, p = 0.015], lower hemoglobin levels [(123.2 ± 25.9) g/L vs (133.4 ± 17.9) g/L, p = 0.027], higher PLR [(162.3 ± 48.5) vs (155.5 ± 96.5), p = 0.030], higher CA19-9 levels [(58.2 ± 97.4) U/mL vs (17.5 ± 16.1) U/mL, p = 0.024], higher PLR [(162.3 ± 48.5) vs (155.5 ± 96.5), p = 0.030], and lower HALP [(35.2 ± 19.0) cm vs (47.1 ± 25.7) cm, p = 0.003].

Table 2 Association Between Pre-TNT Factors and TNT-Induced Tumor Regression

Notably, the PLR was significantly higher in the poor response group, while the HALP was significantly lower in the poor response group. These findings indicate their possible role in predicting tumor regression. Despite these significant findings, NLR, PNI, and GNRI did not differ significantly between the two groups (Table 2). In summary, these Results underscore the importance of the nutritional-inflammatory index and tumor-related parameters in predicting the efficacy of TNT in patients with LARC.

Multivariate Analysis and ROC Curves for Risk Factors That Affect the TNT Response

We incorporated demographic factors and statistically related factors into the regression analysis. Demographic and statistically relevant factors were included in the regression analysis. The cut-off values for CEA and CA19-9 were based on serum reference values. The tumor diameter and distance from anal verge were determined through clinical experience. Cutoff values for PLR and HALP were established using ROC curve analysis.

A univariate logistic regression model using pre-TNT factors identified large tumor diameter, low hemoglobin, and low HALP as unfavorable predictors of the TNT-induced response (Table 3). In the multivariate analysis, large tumor diameter (>5 cm; HR 2.958; 95% CI 1.382–6.335; p = 0.005), and low HALP (≤ 40; HR 0.261; 95% CI 0.111–0.612;p = 0.002) were identified as independent unfavorable predictors of TNT-induced response (Table 3).

Table 3 Univariate and Multivariate Analyses of the Clinicopathological Characteristics for Response

Following multivariate analysis, ROC curves were constructed to evaluate the predictive power of tumor diameter and HALP for TNT response. The ROC curves demonstrated that the tumor diameter and HALP had AUC of 0.678 (95% CI 0.583–0.773) and 0.677 (95% CI 0.583–0.770), respectively. When combined, the AUC for these factors increased to 0.748 (95% CI 0.663–0.833), indicating improved predictive accuracy (Figure 2).

Figure 2 Receiver operating characteristic curve analysis for tumor diameters, HALP, and their combination.

Abbreviation: HALP, combination index of hemoglobin and albumin levels and lymphocyte and platelet.

Association of Predictors of the TNT Response with Recurrence

At the end of the follow-up period, 17/57 (29.8%) patients in the poor response group and 10/70 (14.3%) in the good response group developed local recurrence or distant metastases. The PFS rate of the poor response group in the two groups was significantly poor compared to the good response group (p = 0.006) (Figure 3A). Next, we investigated the correlation of predictive factors and tumor recurrence. Surprisingly, the tumor diameter did not show a significant association with recurrence (p = 0.784) (Figure 3B). Interestingly, low HALP exhibited a nonsignificant trend toward a poor prognosis (p = 0.086; HR 2.008, 95% CI 0.906–4.447) (Figure 3C). This trend suggests that lower HALP may be associated with a higher risk of recurrence, indicating its potential as a prognostic marker.

Figure 3 Progression-free survival after TNT in patients with LARC. (A) Progression-free survival stratified by TNT-induced tumor regression after TNT. (B) Progression-free survival stratified by pre-TNT diameters after TNT. (C) Progression-free survival stratified by HALP after TNT. (D) Progression-free survival stratified by post-TNT TNM stage after TNT.

Abbreviations: HALP, combinational index of hemoglobin and albumin levels and lymphocyte and platelet; TNT, total neoadjuvant treatment.

Finally, we explored the relationship between post-TNT tumor stage and recurrence. As expected, a higher post-TNT TNM stage was significantly associated with a poorer prognosis (p = 0.028) (Figure 3D). This finding reinforces the importance of TNM staging in predicting patient outcomes post-TNT.

Discussion

TNT has been employed as an alternative therapy for patients with LARC, although variable tumor regression responses have been observed.7 This approach has been shown to increase pCR rates and to potentially reduce the risk of distant metastasis by addressing micrometastatic disease earlier in the treatment course.4–6 Despite the advantages of TNT, it is important to acknowledge that the total rate of pCR and sustained cCR in TNT was only 21.8% to 28.0%. Therefore, early identification of unfit patients who may benefit from TNT, coupled with adaptive treatment strategies, shows promise in improving the prognosis. This single-center retrospective study examined the clinical and pathological characteristics of patients with LARC undergoing TNT, exploring their potential as factors that predict tumor regression.

In this study, the total rate of pCR/TRG0 and sustained cCR in TNT was 24.4%, which is consistent with previous findings.4–6 Specifically, 18 patients (16.5%) in our surgical cohort achieved pCR/TRG0, deviating from the rates reported in previous studies.4–6 This discrepancy may be attributed to 10.2% (13/127) of the patients who achieved cCR in our study without undergoing surgery.

The most prevalent grade 3 of hematologic AEs included neutropenia (17/127, 13.4%), thrombocytopenia (14/127, 11.0%), and anemia (14/127, 11.0%). In particular, no grade 4 or severe AEs were documented. In previous studies, the occurrence rates of grade 3–4 of neutropenia, thrombocytopenia, and anemia were 0.7%-16.8%, 1.0%-11.1%, and 0.7%–1.0%, respectively.5,6 The reason for this difference may be the difference in TNT regimens and the frequency of laboratory tests. Consequently, TNT treatment at our center is deemed safe and effective.

In our study, large tumor diameters correlated with a poor TNT-induced response, with logistic multivariate analysis revealing tumor diameter (≥5.0 cm) as an independent risk factor (Table 3). These findings align with the retrospective study conducted by Chapman et al8,10,29 This outcome aligned with our expectations. Larger tumor diameters are inherently more challenging to reduce. Consequently, for patients with larger tumors, transitioning to more intensive chemotherapy regimens, such as FOLFIRINOX, or extending the duration of chemotherapy cycles may enhance tumor regression.

Of note, Zhang reported pre-TNT lymph node-positive tumors as indicative of poor TNT-induced regression.8 In contrast, our study did not observe this phenomenon (Table 2). Discrepancies may have arisen from variations in treatment response Definitions and the limited sample size in our study.

Several studies have investigated the role of nutritional inflammatory factors in predicting the response of tumor regression to nCRT. For example, Novin et al observed that pre-nCRT NLR was unable to predict treatment response in patients with LARC.30 Similarly, our study did not find an association between NLR and TNT-induced tumor regression (p = 0.069) (Table 2). However, we identified a significant association between a low HALP index (≤40) and a lower GNRI index (≤50) with poor TNT-induced regression in patients with LARC (Table 3).

This study also investigated the association between recurrence-free survival and tumor regression effects and their predictors. Patients in the poor response group exhibited worse PFS than those in the good response group (Figure 3A). Similar findings in other studies suggest that TRG 0/pCR is associated with better survival outcomes, indicating that a relatively poor response to TNT is related to worse survival outcomes.31 Furthermore, we revealed that low HALP emerged as adverse prognostic indicators for recurrence in patients with LARC undergoing TNT (Figure 3C). HALP has been reported as predictive factors for tumor prognosis in various studies. Yalav et al demonstrated the independent prognostic significance of HALP in patients undergoing curative resection for colorectal cancer.32 In particular, Zhang and Amano et al highlighted the importance of post-nCRT GNRI in predicting overall survival and PFS for patients with LARC over 60 years of age.33,34 However, our study, with only 39 (30.7%) patients over 60 years of age, did not observe a similar correlation (Table 2).

Although the precise mechanisms underlying systemic inflammation in tumorigenesis, progression, and metastasis remain unclear, some theories propose its role in stimulating angiogenesis, immunosuppression, and the formation of a supportive microenvironment. First, multiple studies have shown that low hemoglobin levels contribute to tumor hypoxia, increasing the risk of local failure and distant metastasis.16,35 Furthermore, a hypoxic tumor environment can inhibit drug accumulation and efficacy.36 Second, serum albumin levels have independently emerged as prognostic factors in various cancers.24 Low albumin levels can increase the concentration of free drugs, increasing the risk of toxic reactions and affecting the patient’s tolerance to chemotherapy, requiring adjustment of treatment doses. Low albumin is often associated with a chronic inflammatory state, which can suppress the immune system and reduce the body’s ability to defend against tumors.37 Third, lymphocytes play a pivotal role in suppressing tumor growth, with higher lymphocyte signatures correlated with improved prognosis in various tumors.38 Finally, platelets can infiltrate the tumor microenvironment and interact with cancer cells, helping circulating tumor cells adhere to endothelial cells and establishing a premetastatic niche.39 Therefore, it is surprising that HALP, which reflects both systemic inflammation and nutritional status, is associated with TNT-induced tumor regression. Consequently, nutritional support can improve the overall condition of patients and their response to treatment.

This study presents several limitations. First, its retrospective nature and single-center design, with a relatively small cohort of patients, did not allow a comprehensive exploration of risk factors or the construction of a regression prediction model for the TNT-induced response. The potential bias in the data collection process was another concern. Second, the exclusive utilization of Capox-based consolidation of TNT in our center raises uncertainty about the generalizability of our findings to other TNT regimens. Third, the absence of genetic test results, such as MSI status, which can affect the biological behavior of tumor cells, is a notable gap in our study. Fourth, due to the limited duration of follow-up, we did not investigate the relationship of TNT-induced tumor regression and its predictors with overall survival of patients. Fifth, we did not collect data on extended treatment intervals or dose reductions resulting from adverse reactions during TNT treatment. Consequently, we were unable to assess the association between HALP and adverse effects. Lastly, our conclusions require further validation through larger prospective studies.

Conclusion

A large tumor diameter (>5 cm) and low HALP (<40) predict poor tumor regression induced by the CAPOX-based TNT regimen in patients with LARC. Large-scale prospective studies are essential to validate and refine our understanding. Whether this subset of patients requires additional in chemotherapy, such as FOLFIRINOX, remains to be verified in a prospective cohort.

Abbreviations

AE, Adverse events; CEA, Carcinoembryonic antigen; CRM, Circumferential resection margin; CT, Computed tomography; EMVI, Extramural vascular invasion; GNRI, geriatric nutritional risk index; HALP, The hemoglobin and albumin levels and lymphocyte and platelet index; LARC, Locally advanced rectal cancer; MRI, Magnetic resonance imaging; NLR, Neutrophil-to-lymphocyte ratio; NK, Natural killer; PFS, Progression-free survival; PLR, Platelet-to-lymphocyte ratio; PNI, Prognostic nutritional index; TME, Total mesorectal excision; TNT, Total neoadjuvant therapy; W&W, Watch-and-wait.

Data Sharing Statement

Data from this study are available from the corresponding author upon request.

Ethics Approval and Informed Consent

The study adhered to the Declaration of Helsinki and obtained approval from the Ethics Committee of Chongqing University Cancer Hospital (reference number 2023(011)). All patients provided their informed consent in writing before TNT treatment, surgery, or before a watch-and-wait strategies (W&W) strategy.

Acknowledgments

The authors declare no specific acknowledgments.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; and all authors took part in drafting, revising or critically reviewing the article, gave final approval of the version to be published, agreed on the journal to which the article has been submitted and agreed to be accountable for all aspects of the work.

Funding

This work was supported by the Research Institutions Performance Incentive Guidance Special Fund of Chongqing, Grant No. cstc2022jxjl0234; and the Project of Technology Innovation and Application Development, Shapingba District, Chongqing, Grant No. 202392.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660

2. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. Ca a Cancer J Clinicians. 2023;73(3):233–254. doi:10.3322/caac.21772

3. Saraf A, Roberts HJ, Wo JY, Parikh AR. Optimal neoadjuvant strategies for locally advanced rectal cancer by risk assessment and tumor location. J Natl Compr Canc Netw. 2022;20(10):1177–1184. doi:10.6004/jnccn.2022.7061

4. Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, Phase 3 trial. Lancet Oncol. 2021;22(1):29–42. doi:10.1016/s1470-2045(20)30555-6

5. Conroy T, Bosset JF, Etienne PL, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702–715. doi:10.1016/s1470-2045(21)00079-6

6. Jin J, Tang Y, Hu C, et al. Multicenter, randomized, Phase III trial of short-term radiotherapy plus chemotherapy versus long-term chemoradiotherapy in locally advanced rectal cancer (STELLAR). J Clin Oncol. 2022;40(15):1681–1692. doi:10.1200/jco.21.01667

7. Benson AB, Venook AP, Al-Hawary MM, et al. Anal carcinoma, version 2.2023, NCCN clinical practice guidelines in oncology. J National Compr Cancer Network. 2023;21(6):653–677.

8. Zhang H, Cao K, Li G, et al. Active surveillance in long period of total neoadjuvant therapy in rectal cancer: early prediction of poor regression response. Front Oncol. 2022;12:1049228. doi:10.3389/fonc.2022.1049228

9. Johnson G, Park J, Helewa RM, Goldenberg BA, Nashed M, Hyun E. Total neoadjuvant therapy for rectal cancer: a guide for surgeons. Can J Surg. 2023;66(2):E196–e201. doi:10.1503/cjs.005822

10. Chapman BC, Lai SH, Friedrich T, et al. Rectal cancer: clinical and molecular predictors of a complete response to total neoadjuvant therapy. Dis Colon Rectum. 2023;66(4):521–530. doi:10.1097/dcr.0000000000002245

11. Sun KX, Xu RQ, Rong H, Pang HY, Xiang TX. Prognostic significance of the Gustave Roussy immune (GRIm) score in cancer patients: a meta-analysis. Ann Med. 2023;55(2):2236640. doi:10.1080/07853890.2023.2236640

12. Ding P, Yang P, Sun C, et al. Predictive effect of systemic immune-inflammation index combined with prognostic nutrition index score on efficacy and prognosis of neoadjuvant intraperitoneal and systemic paclitaxel combined with apatinib conversion therapy in gastric cancer patients with positive peritoneal lavage cytology: a prospective study. Front Oncol. 2021;11:791912. doi:10.3389/fonc.2021.791912

13. Shibutani M, Nagahara H, Fukuoka T, Iseki Y, Hirakawa K, Ohira M. Efficacy of adjuvant chemotherapy according to the classification of recurrence risk based on systemic inflammatory markers in patients with liver metastases of colorectal cancer. Anticancer Res. 2019;39(9):5039–5045. doi:10.21873/anticanres.13695

14. Sprinzl MF, Kirstein MM, Koch S, et al. Improved prediction of survival by a risk factor-integrating inflammatory score in sorafenib-treated hepatocellular carcinoma. Liver Cancer. 2019;8(5):387–402. doi:10.1159/000492628

15. Kiriukova M, de la Iglesia Garcia D, Panic N, et al. Pancreatic cancer malnutrition and pancreatic exocrine insufficiency in the course of chemotherapy in unresectable pancreatic cancer. Front Med Lausanne. 2020;7:495. doi:10.3389/fmed.2020.00495

16. Zhao Z, Yin XN, Wang J, Chen X, Cai ZL, Zhang B. Prognostic significance of hemoglobin, albumin, lymphocyte, platelet in gastrointestinal stromal tumors: a propensity matched retrospective cohort study. World J Gastroenterol. 2022;28(27):3476–3487. doi:10.3748/wjg.v28.i27.3476

17. Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. Vol. 1024. Springer; 2017.

18. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465–1471. doi:10.1200/JCO.2010.33.6297

19. Schmoll HJ, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage iii colon cancer: final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015;33(32):3733–3740. doi:10.1200/JCO.2015.60.9107

20. Health UDo, Services H, Health UDo, Services H. Common Terminology Criteria for Adverse Events. National Institutes of Health, National Cancer Institute; 2017.

21. Chen HY, Feng LL, Li M, et al. College of American pathologists tumor regression grading system for long-term outcome in patients with locally advanced rectal cancer. Oncologist. 2021;26(5):e780–e793. doi:10.1002/onco.13707

22. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29(35):4633–4640. doi:10.1200/jco.2011.37.7176

23. Washington MK, Berlin J, Branton P, et al. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med. 2009;133(10):1539–1551. doi:10.5858/133.10.1539

24. Xu H, Zheng X, Ai J, Yang L. Hemoglobin, albumin, lymphocyte, and platelet (HALP) score and cancer prognosis: a systematic review and meta-analysis of 13,110 patients. Int Immunopharmacol. 2023;114:109496. doi:10.1016/j.intimp.2022.109496

25. Hayashi H, Shimizu A, Kubota K, et al. Combination of sarcopenia and prognostic nutritional index to predict long-term outcomes in patients undergoing initial hepatectomy for hepatocellular carcinoma. Asian J Surg. 2023;46(2):816–823. doi:10.1016/j.asjsur.2022.07.122

26. Fiore M, Ljevar S, Pasquali S, et al. Preoperative neutrophil-to-lymphocyte ratio and a new inflammatory biomarkers prognostic index for primary retroperitoneal sarcomas: retrospective monocentric study. Clin Cancer Res. 2023;29(3):614–620. doi:10.1158/1078-0432.Ccr-22-2897

27. Portale G, Bartolotta P, Azzolina D, Gregori D, Fiscon V. Prognostic role of platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte, and lymphocyte-to-monocyte ratio in operated rectal cancer patients: systematic review and meta-analysis. Langenbecks Arch Surg. 2023;408(1):85. doi:10.1007/s00423-023-02786-8

28. Shiroma K, Tanabe H, Takiguchi Y, et al. A nutritional assessment tool, GNRI, predicts sarcopenia and its components in type 2 diabetes mellitus: a Japanese cross-sectional study. Front Nutr. 2023;10:1087471. doi:10.3389/fnut.2023.1087471

29. Jankowski M, Pietrzak L, Rupiński M, et al. Watch-and-wait strategy in rectal cancer: is there a tumour size limit? Results from two pooled prospective studies. Radiother Oncol. 2021;160:229–235. doi:10.1016/j.radonc.2021.05.014

30. Novin K, Fadavi P, Mortazavi N, et al. Neutrophil-to-Lymphocyte Ratio (NLR) as a poor predictive biomarker for pathological response to neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study. Asian Pac J Cancer Prev. 2023;24(1):61–67. doi:10.31557/apjcp.2023.24.1.61

31. Li JY, Huang XZ, Gao P, et al. Survival landscape of different tumor regression grades and pathologic complete response in rectal cancer after neoadjuvant therapy based on reconstructed individual patient data. BMC Cancer. 2021;21(1):1214. doi:10.1186/s12885-021-08922-1

32. Yalav O, Topal U, Unal AG, Eray IC. Prognostic significance of preoperative hemoglobin and albumin levels and lymphocyte and platelet counts (HALP) in patients undergoing curative resection for colorectal cancer. Ann Ital Chir. 2021;92:283–292.

33. Amano T, Akiyoshi T, Furuta M, et al. Geriatric nutritional risk index after neoadjuvant chemoradiotherapy and survival in older patients with advanced rectal cancer. Int J Colorectal Dis. 2023;38(1):119. doi:10.1007/s00384-023-04425-6

34. Zhang L, Hu C, Li R, et al. The clinical predictive value of geriatric nutritional risk index in elderly rectal cancer patients received surgical treatment after neoadjuvant therapy. Front Nutr. 2023;10:1237047. doi:10.3389/fnut.2023.1237047

35. Rutkowski P, Teterycz P, Klimczak A, Bylina E, Szamotulska K, Lugowska I. Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib. Tumori. 2018;104(6):415–422. doi:10.1177/0300891618765543

36. Hompland I, Bruland ØS, Hølmebakk T, et al. Prediction of long-term survival in patients with metastatic gastrointestinal stromal tumor: analysis of a large, single-institution cohort. Acta Oncol. 2017;56(10):1317–1323. doi:10.1080/0284186x.2017.1330555

37. Daujat-Chavanieu M, Kot M. Albumin is a secret factor involved in multidirectional interactions among the serotoninergic, immune and endocrine systems that supervises the mechanism of CYP1A and CYP3A regulation in the liver. Pharmacol Ther. 2020;215:107616. doi:10.1016/j.pharmthera.2020.107616

38. Ostroumov D, Fekete-Drimusz N, Saborowski M, Kühnel F, Woller N. CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci. 2018;75(4):689–713. doi:10.1007/s00018-017-2686-7

39. Roweth HG, Battinelli EM. Lessons to learn from tumor-educated platelets. Blood. 2021;137(23):3174–3180. doi:10.1182/blood.2019003976