Prognostic Nutritional Index as a Prognostic Indicator for the Occurrence of Postoperative Complications in Patients with Esophageal Squamous Cell Carcinoma Following Neoadjuvant Immunochemotherapy

Introduction

Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in East Asia, with a particularly high incidence in China.¹ Over time, there have been advancements and enhancements in the treatments available for esophageal squamous carcinoma, encompassing surgical procedures, radiation therapy, chemotherapy, and the emerging field of immunotherapy.² In the treatment of locally advanced esophageal squamous cell carcinoma, neoadjuvant chemotherapy followed by surgical intervention has been a well-established approach. Recently, the use of neoadjuvant chemotherapy and immunotherapy has emerged as a hopeful option for individuals diagnosed with advanced esophageal squamous cell carcinoma. Preoperative neoadjuvant therapies are implemented to diminish the size and extent of the tumor, thereby facilitating the execution of surgery.³ Subsequent to neoadjuvant therapy, surgical intervention may enhance the survival rates of certain patients in contrast to immediate surgery; however, it concurrently heightens the likelihood of short-term postoperative complications, including infection, bleeding, and cardiopulmonary complications.⁴ This phenomenon could potentially be attributed to the modified nutritional and immune statuses observed in patients following neoadjuvant therapy.

The Prognostic Nutritional Index (PNI) serves as a valuable instrument for assessing patients’ nutritional and immune health, determined by factors like white blood cell count, lymphocyte ratio, and total protein levels. Originally used in gastrointestinal tumors to predict patient outcomes and post-surgery issues.^5,6 The PNI has been associated with patient survival in the management of esophageal squamous cell carcinoma.^7,8 Nevertheless, there is a lack of adequate research on the use of PNI in predicting short-term postoperative complications in esophageal cancer after neoadjuvant therapy. Thus, this study aims to examine the potential utility of the PNI in predicting short-term complications necessitating reoperation following neoadjuvant therapy for esophageal cancer, thereby offering a more nuanced and targeted approach to the management of this disease.

Materials and Methods

Patients

We retrospectively analyzed the clinical data of patients with esophageal squamous cell carcinoma who underwent neoadjuvant immunotherapy and radical surgery for esophageal cancer at the Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China, between January 2022 and January 2023. In order to qualify for inclusion in this research study, individuals must possess a preoperative diagnosis of esophageal squamous cell carcinoma and have undergone a minimum of two cycles of neoadjuvant immunotherapy in conjunction with chemotherapy. Additionally, patients must have full clinical information, be suitable for surgery, and have no previous cancer diagnoses. The exclusion criteria for this study encompassed several factors: (1) the presence of relevant examinations indicating tumor metastasis, (2) preoperative examinations indicating an infectious condition, (3) the coexistence of severe cardiopulmonary function or metabolic diseases of the immune system, and (4) a previous history of other malignant tumors.

Methods

The study gathered comprehensive patient data, encompassing age, gender, presence of comorbidities, neoadjuvant treatment regimen, and TNM stage prior to treatment. We applied the age-adjusted Charlson Comorbidity Index⁹ to assess patients’ risk of adverse events, and the 8th edition of TNM staging for esophageal cancer published by the American Joint Committee on Cancer was used to assess tumor staging.¹⁰ Additionally, preoperative assessments were conducted, encompassing serum albumin levels, lymphocyte count, lung function test results, and lesion site, among other factors. Surgery-related information included surgical method, duration of surgery, and amount of intraoperative bleeding, and postoperative pathology including pathology type, degree of differentiation, TNM stage, number of days of hospitalization, and number of days of postoperative surgery. We analyzed all complications that occurred within 1 month of surgery. Postoperative complications related data include lung infection, anastomotic fistula, postoperative rebleeding, celiac chest, pulmonary atelectasis, incision infection, venous thrombosis and so on.

Blood samples were obtained at various time points, including pre-surgery, admission day, and the first and third days post-surgery, in order to calculate the PNI for the participants in the study. The PNI was calculated according to the formula PNI = serum albumin (g/L) + 5 × lymphocyte count (10⁹/L).⁷ Furthermore, ROC curves were generated for the subjects using the blood test outcomes. It was observed that the PNI calculated using the pre-surgery blood samples exhibited the largest area under the curve. The ideal threshold for this PNI was established based on the Youden index. The 77 participants were divided into two cohorts based on their PNI levels: a low PNI group (n = 30) and a high PNI group (n = 47), as defined by the ideal PNI threshold. Subsequently, a comparison was made between the two patient groups regarding general information and postoperative complication rates.

Statistical analysis was conducted using SPSS 26.0 software, with group comparisons carried out through the chi-square test. Statistical significance in the results was determined at a significance level of P < 0.05.

Results

The study population consisted of 77 patients with a median age of 62 years (range 41–79), consisting of 62 males and 15 females. All patients received two cycles of a chemotherapy regimen consisting of Paclitaxel (175 mg/m²) and cisplatin (75 mg/m²). Additionally, 70 patients underwent an immunotherapy regimen with intravenous tirilizumab 200 mg every 3 weeks, while the remaining 7 patients received an immunotherapy regimen with pembrolizumab 200 mg every 3 weeks. The clinical stage of esophageal cancer before neoadjuvant therapy was stage 3 in 52 patients and stage 4 in 25 patients. The median age-adjusted Charlson Comorbidity Index was 4 (range 2–7) in this patient cohort. A total of 65 patients underwent McKeown esophagectomy and 12 patients underwent SWEET radical esophagectomy for the treatment of esophageal cancer. Postoperative pathology findings indicated complete pathological remission in 19 patients, accounting for 24.7% of the total cohort. Overall, 68 patients, representing 80.5% of the cohort, achieved pathological remission.

ROC Curves of PNI

The preoperative PNI values demonstrated the highest predictive capacity. Figure 1 illustrates the calculation of corresponding PNI values based on blood check results obtained on the day of admission, the day before surgery, the first and third days after surgery. Complete data on 77 patients were available for each group. ROC curves were created, revealing the highest area under the curve for the PNI values the day prior to surgery at 0.754 (95% CI, 0.632–0.876; P<0.001). The optimal threshold was identified as 47.38, with a sensitivity of 81.3% and specificity of 72.4%.

Figure 1 The ROC curves of PNI: The ROC curve based of PNI on the day before surgery has the maximum area under the curve, with a value of 0.754 (95% confidence interval: 0.632~0.876, P<0.001).

Clinical Characteristics

The study encompassed a cohort of 77 patients, with a mean age of 60.14 ± 7.83 years, ranging from 41 to 79 years. Patients were divided into two categories depending on their PNI levels: a high PNI category (PNI ≥ 47.38, including patients with adequate nutrition or slight malnutrition, n = 47) and a low PNI category (PNI < 47.38, including patients with moderately severe malnutrition, n = 30). Table 1 presents a comparison of fundamental patient data between the low PNI group and the high PNI group. In the high PNI group, 14 patients (29.79%) were aged over 65 years, a proportion that did not significantly differ from the 6 patients (20%) in the low PNI group. The high PNI group consisted of 39 male patients (82.98%), while the low PNI group had 23 male patients (76.67%), with no statistically significant difference between the two groups. Additionally, the tumour T-stage, N-stage, and TNM-stage were found to be more advanced in the low PNI group compared to the high PNI group, with a statistically significant difference (P<0.01). There were no statistically significant differences observed in the incidence of COPD, hypertension, diabetes, coronary artery disease, and hyperlipidemia between the two groups. However, a higher proportion of individuals in the low PNI group (83.33%) had an age-corrected Charlson’s co-morbidity index greater than 4 compared to the high-PNI group (61.70%), with a statistically significant difference noted between the two groups (P=0.042). There was no significant difference in surgical approach and BMI between the two groups. Postoperative pathology indicated complete pathological remission in 20% of patients in the low PNI group and 27.66% in the high PNI group, with no statistically significant variance between the groups.

Table 1 Relationship Between Clinical Characteristics and Prognostic Nutritional Index n (%)

Short-Term Postoperative Complications

The study displays the postoperative complications observed in Table 2. The comprehensive complication rate was approximately 37.66%, with a notably higher prevalence of pulmonary infection (33.77%) and anastomotic fistula (10.39%). The results depicted in Figure 2 indicate that short-term postoperative complications were markedly more prevalent in the low PNI group as opposed to the high PNI group, with occurrence rates of 70% and 17.02% respectively (P < 0.01). Furthermore, a notable discrepancy was observed in the prevalence of lung infections between the low PNI group (70%) and the high PNI group (10.64%). Additionally, anastomotic fistula was detected in 20% of patients in the low PNI group, a significantly higher incidence compared to the 4.26% observed in the high PNI group, indicating statistical significance. There was a lack of statistically significant variation observed in the occurrence of postoperative bleeding, suboptimal incision healing, and thrombosis.

Table 2 Relationship Between Short-Term Postoperative Complications and Prognostic Nutritional Index n (%)

Figure 2 Short-term postoperative complications in patients: Patients in the PNI-low group exhibited significantly higher rates of pulmonary infection and anastomotic fistula compared to those in the PNI-high group. **P<0.01.

Discussion

Despite the current lack of comprehensive data pertaining to the optimal strategy for treating esophageal cancer, the existing findings indicate that the integration of neoadjuvant immunotherapy with chemotherapy holds significant promise.¹¹ The literature reports an average pathological complete response rate (PCR) of 28.3% for the combined use of neoadjuvant immunotherapy and chemotherapy. Notably, certain studies^12–17 have reported PCR rates exceeding 30%. Furthermore, the pairing of neoadjuvant immunotherapy and chemotherapy demonstrated an impressive major pathological response (MPR) rate, averaging 50.3%.¹⁸ Among the 77 patients included in our research, 19 patients (24.7%) achieved complete pathological remission after surgery. This remission rate aligns closely with the findings reported in existing literature. Additionally, 62 patients (80.5%) attained pathological remission, surpassing the rates documented in previous studies. This discrepancy can likely be attributed to our exclusion of patients who experienced disease progression after neoadjuvant therapy, as well as those who did not undergo surgery. These results offer promising evidence supporting the efficacy of combining neoadjuvant immunotherapy with chemotherapy.

Regarding surgical safety, the literature has documented the occurrence of surgical complications in neoadjuvant immunotherapy combined with chemotherapy at rates of 47.1%,¹⁵ 26.3%,¹⁹ and 51.0%.²⁰ Our research revealed a postoperative complication rate of 37.7%, which closely matches the rates documented in previous studies. Despite the existence of multiple studies demonstrating the manageable nature of postoperative complications following the administration of neoadjuvant immunotherapy in conjunction with chemotherapy, and the absence of any reported deaths during the perioperative period,^19,21 it is undeniable that the incidence of complications remains higher compared to patients solely undergoing surgery. This disparity may be attributed to the occurrence of leukopenia and lung injury subsequent to treatment.^16,19 At present, there is a dearth of literature concerning the prediction of postoperative complications following neoadjuvant therapy. Given the elevated rate of complications associated with this treatment, there is an immediate requirement for a dependable predictive index that can effectively evaluate the likelihood of postoperative complications in patients prior to surgery subsequent to neoadjuvant therapy. Such an index would aid in mitigating the occurrence of postoperative complications through timely intervention.

The PNI is determined through the assessment of serum albumin levels and peripheral blood lymphocyte concentrations, integrating data on albumin and absolute lymphocyte counts to provide insight into the patient’s nutritional and inflammatory status. Li²² conducted a meta-analysis comprising nine articles to examine the prognostic implications of esophageal squamous cell carcinoma. The results showed a strong connection between decreased PNI before treatment and both overall survival (OS) and recurrence-free survival (RFS). Consequently, PNI emerges as a dependable prognostic indicator for esophageal carcinoma, with a higher prevalence of low PNI observed in advanced stages of the disease. Our research findings indicate a significant association between low PNI levels and advanced tumor T-stage, N-stage, and clinical stage in individuals with esophageal cancer, underscoring the prognostic value of PNI in this context. However, the utility of PNI in predicting surgical complications remains a subject of debate. A meta-analysis of multiple studies²³ concluded that there is insufficient evidence to support the notion that a low PNI poses a risk for postoperative complications in patients diagnosed with esophageal cancer. Nevertheless, Qi²⁴ identified a significantly greater occurrence of postoperative complications in the low-PNI group as opposed to the high-PNI group (29.69% vs 13.26%, P < 0.001). At present, there is a lack of scholarly investigation into the significance of the Prognostic Nutritional Index in predicting surgical complications among patients with esophageal cancer who have undergone neoadjuvant immunotherapy in combination with chemotherapy. Our research shows that using preoperative PNI is very helpful in evaluating postoperative complications after neoadjuvant treatment. Using the ROC curve, we found a PNI threshold of 47.38, consistent with most previous studies.²⁴ Subsequent analysis based on this threshold revealed a significant difference in the rates of lung infection and anastomotic fistula between the low and high PNI groups. The difference may be due to the reverse relationship between PNI and levels of leukocytes and albumin in patients, suggesting weakened immunity and nutritional status. Furthermore, our study ascertained that PNI serves as an actionable indicator. Due to the retrospective nature of this analysis, our interventions for patients with low PNI after admission were limited to generalized nutritional support and symptomatic treatment. Nonetheless, our findings indicate that preoperative PNI, adjusted for treatment, exhibited a stronger predictive value for postoperative complications compared to PNI upon admission. This suggests the potential for implementing more targeted nutritional support in hospitals, specifically for patients with low PNI, to enhance their preoperative PNI levels and mitigate complications. This assertion, however, necessitates additional clinical trials to validate.

The PNI functions as a dual indicator for nutrition and immunity, influenced by levels of ALB and lymphocyte counts, offering information on the patient’s inflammatory and nutritional condition. Notably, neoadjuvant immunotherapy combined with chemotherapy commonly leads to complications such as leukopenia, granulocytopenia, and hypoproteinemia.¹⁹ Therefore, it is logical to conclude that PNI is a useful indicator of the patient’s nutritional and immune health after treatment, underscoring the importance of assessing and intervening in nutrition before surgery to reduce complications after surgery. Patients with a low PNI necessitate the involvement of dietitians and collaboration with nurses or physicians for clinical management. The initial approach to addressing cancer-related nutritional issues involves nutritional counseling by healthcare professionals, which is regarded as the primary form of nutritional therapy after the identification and categorization of such problems.

Several nutritional and inflammatory markers, such as the mGPS, CONUT score, and GNRI, have been associated with outcomes in esophageal cancer.^25,26 However, additional research is required to explore their utility, as well as their strengths and limitations in comparison to the PNI, in neoadjuvant immunization and chemotherapy patients with esophageal cancer.

This study possesses various limitations, including its retrospective nature and its confinement to a solitary institute, which may introduce selection bias. The limited sample size in this study serves as a constraint, and we anticipate the incorporation of data from additional research centers to bolster our argument. Furthermore, our analysis solely focuses on the correlation between variables, while the underlying mechanism remains indeterminate. In order to validate our results in individuals with esophageal carcinoma, it is crucial to conduct carefully designed prospective studies involving various institutions.

Conclusions

Calculating the PNI is simple and easy, making it a useful tool for predicting short-term postoperative complications in esophageal cancer patients after neoadjuvant therapy. Moreover, implementing nutritional interventions in individuals with moderate-to-severe malnutrition, as indicated by their preoperative evaluation, may potentially help to mitigate the occurrence of postoperative complications.