Abstract
Preoperative Prognostic Nutritional Index (PNI) could be a crucial factor for the prognosis of colorectal cancer (CRC). However, the clinical impact of postoperative PNI is still unclear, and there have been no reports on the significance of postoperative PNI in patients undergoing adjuvant chemotherapy (AC). We retrospectively analysed 227 consecutive patients who underwent AC after radical surgery for high-risk stage II or stage III CRC. PNI value was calculated before radical surgery and before the introduction of AC. In our study, patients with a low PNI value before surgery showed significantly poorer long-term outcomes than those with a high PNI value. Next, we divided the patients into four groups: patients with a high PNI value before surgery and remained after surgery (Group High-High), a high PNI value before surgery but decreased after surgery (Group High-Low), a low PNI value before surgery but recovered after surgery (Group Low-High), and a low PNI value but did not recover after surgery (Group Low-Low). Although the patients in Group Low-Low showed significantly poorer long-term outcomes than those in Group High-High, the prognosis of patients in Group Low-High was the same as that of patients in Group High-High. In addition, in patients with recurrence after AC, those with a high PNI value at the time of recurrence showed a significantly better survival after recurrence than patients with a low PNI value. Postoperative PNI value could be a prognostic biomarker for CRC patients undergoing AC. Even though the PNI value was low before the surgery, recovery of PNI value by the introduction of AC could improve the prognosis of CRC patients.
Keywords: Prognostic nutritional index, colorectal cancer, adjuvant chemotherapy, recurrence
Introduction
Colorectal cancer was the third most frequent malignancy worldwide in 2018. More than 1,800,000 cases occurred worldwide, and nearly 860,000 died from it in 2018 according to GLOBOCAN 2018 [1]. Although the prognosis of colorectal cancer has improved due to the development of multidisciplinary treatment, it is still one of the cancers with a poor prognosis. Surgical treatment is the most curative method for non-metastatic resectable colorectal cancer, but it has been reported that patients with high-risk stage II or stage III colorectal cancer have a high possibility of recurrence after radical surgery [2]. Therefore, postoperative adjuvant chemotherapy is recommended to prevent recurrence in these cases [3,4].
However, the ability of adjuvant chemotherapy to prevent recurrence is limited [2,5,6]. In addition, there are problems with side effects and medical costs [7-9] due to postoperative adjuvant chemotherapy itself. Therefore, a novel method for predicting the effects of adjuvant chemotherapy is warranted in terms of precision medicine.
Prognostic Nutritional Index (PNI) is used as a nutritional and immunological index and has been reported as a prognostic marker for gastrointestinal cancer [10-15]. These previous reports have shown that preoperative PNI value is associated with short and long-term outcomes of patients with gastrointestinal cancer, but few reports have shown a relationship between postoperative PNI value and the outcomes of patients with colorectal cancer.
This study examined the relationship between postoperative PNI value and the outcomes of patients with colorectal cancer, in particular the clinical impact of nutritional status at the time of introduction of adjuvant chemotherapy on the prognosis.
Material and methods
Patients and laboratory data
This study was conducted in accordance with the ethical standards of the Kyoto Prefectural University of Medicine and the Helsinki Declaration. We retrospectively analyzed 227 consecutive patients who underwent adjuvant chemotherapy after radical surgery for high-risk stage II or stage III colorectal cancer at Kyoto Prefectural University of Medicine between 2008 and 2017. In this study, high-risk stage II colorectal cancer was defined as lesions that adhered to or invaded local organs (T4), cases of perforation or obstruction, fewer than 12 analyzed lymph nodes, vascular and perineural invasion, or poorly differentiated histology [2,16]. All patients were pathologically staged according to the 8th edition of the TNM Classification of Malignant Tumors (Union for International Cancer Control). Patients were staged using colonoscopy, barium enema, computed tomography, and positron emission tomography/computed tomography. Patients were followed up every 3 months during the first 3 years and every 6 months thereafter. The treatment plan was decided according to the Japan Colorectal Cancer Guidelines [17]. The regimen of adjuvant chemotherapy was combination therapy consisting of 5-fluorouracil and oxaliplatin or monotherapy of 5-fluorouracil.
Preoperative blood samples were obtained at the first visit to our department almost within one month before the operation. The postoperative blood samples were obtained at the time of introduction of adjuvant chemotherapy and at the point of identifying tumor recurrence. The PNI value was calculated as follows: 10 × serum albumin level (g/dL) +0.005 × TLC (/mm3).
Statistical analysis
Statistical analyses were performed using JMP version 10 (ASA Institute, Cary, NC). Differences in categorical variables were compared using a Chi-squared test and Fisher’s exact probability test. Differences in continuous variables were analyzed with the Student’s t-test and the Mann-Whitney U-test to compare the clinicopathological characteristics between the three groups. Survival curves of the overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method, and statistical differences were examined using the log-rank test. In multiple comparison analysis, significant difference was evaluated by Bonferroni correction. Univariate and multivariate survival analyses were performed using the likelihood ratio test of the stratified Cox’s proportional hazards model. P<0.05 derived from a two-tailed test was considered statistically significant.
Results
Patient characteristics
A total of 227 patients consisted of 40 highrisk stage II patients (17.6%) and 187 stage III patients (82.4%) (Supplementary Table 1). Postoperative complications occurred in 23 cases (10.1%), including anastomotic leakage in 3 cases, anastomotic bleeding in 1 case, intra-abdominal abscess in 4 cases, ileus in 2 cases, surgical site infection in 2 cases and others. The median follow-up period was 52 months (range 9-119 months). Tumor recurrence was identified in 7 patients of high-risk stage II (17.5%) and 48 patients of stage III (25.7%) (Supplementary Figure 1). Among all patients, 89 patients (39.2%) received a combination therapy consisting of 5-fluorouracil and oxaliplatin, such as mFOLFOX6 or CapeOX, and 138 patients (60.8%) received monotherapy of 5-fluorouracil, such as TS-1, UFT/LV, or capecitabine.
Relationships between preoperative PNI value and long-term outcomes
The median preoperative PNI was 49.5 (range 28-64.5). The cut-off value of the PNI was set to 45.6 using a receiver operative characteristic (ROC) curve analysis. The association between preoperative PNI status and clinicopathological features is shown in Table 1. A low preoperative PNI value (PNI≤45.6) was associated with older age (P=0.01), undifferentiated histological type (P<0.01), deeper tumor depth (P=0.01), higher serum level of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) (P=0.01 and P=0.02, respectively), and the occurrence of postoperative complications (P=0.02). Patients with a low-PNI value showed significantly poorer overall survival (OS) and recurrence-free survival (RFS) than those with a high-PNI value (PNI>45.6) (P=0.01, P=0.03, respectively) (Figure 1).
Table 1.
The relationships between preoperative PNI and clinicopathological factors in colorectal cancer patients
| Variables | Preoperative PNI | Univariatea | |
|---|---|---|---|
|
| |||
| lowb (n=57) | highb (n=170) | P-value | |
| Gender | |||
| Female | 26 (46%) | 77 (45%) | 1.00 |
| Male | 31 (54%) | 93 (55%) | |
| Age | |||
| <75 | 42 (74%) | 150 (88%) | 0.01 |
| 75≤ | 15 (26%) | 20 (12%) | |
| BMI | |||
| <18 | 53 (93%) | 160 (94%) | 0.75 |
| 18≤ | 4 (7%) | 10 (6%) | |
| Location | |||
| Colon | 38 (67%) | 102 (60%) | 0.43 |
| Rectum | 19 (33%) | 68 (40%) | |
| Histopathological type | |||
| differentiated | 43 (77%) | 157 (92%) | <0.01 |
| undifferentiated | 13 (23%) | 13 (8%) | |
| Tumor depth | |||
| T1, T2, T3 | 38 (67%) | 138 (83%) | 0.01 |
| T4 | 19 (33%) | 28 (17%) | |
| Lymph node metastasis | |||
| N0, N1 | 44 (77%) | 124 (73%) | 0.60 |
| N2, N3 | 13 (23%) | 46 (27%) | |
| Lymphatic invasion | |||
| Absent | 21 (37%) | 54 (32%) | 0.51 |
| Present | 35 (63%) | 115 (68%) | |
| Venous invasion | |||
| Absent | 21 (37%) | 73 (43%) | 0.53 |
| Present | 35 (63%) | 96 (57%) | |
| CEA (ng/mL) | |||
| <5 | 27 (47%) | 113 (67%) | 0.01 |
| 5≤ | 30 (53%) | 56 (33%) | |
| CA19-9 (U/mL) | |||
| <37 | 46 (81%) | 156 (92%) | 0.02 |
| 37≤ | 11 (19%) | 13 (8%) | |
| Surgical Approach | |||
| Laparoscopic | 50 (88%) | 156 (92%) | 0.42 |
| Open | 7 (12%) | 14 (8%) | |
| Complication (≥CD grade 2) | |||
| Absent | 46 (81%) | 158 (93%) | 0.02 |
| Present | 11 (19%) | 12 (7%) | |
A low preoperative PNI value was associated with older age, undifferentiated histological type, deeper tumor depth, higher serum level of CEA and CA19-9, and the occurrence of postoperative complications.
Univariate analysis was assessed using Chi squared test.
low: PNI<45.6, high: PNI≥45.6.
Figure 1.
Kaplan-Meier survival analysis comparing patients with preoperative low-PNI value (≤45.6) and patients with preoperative high-PNI value (>45.6). The patients with low-PNI value showed significantly poorer overall survival and recurrence-free survival than those with high-PNI value.
Relationships between postoperative PNI value and long-term outcomes
Next, we assessed the clinical impact of PNI value on the introduction of adjuvant chemotherapy. The median postoperative PNI value on the introduction of adjuvant chemotherapy was 50.2 (range 37.1-64.3). The cut-off value was set to 45.6. To investigate whether the recovery of nutritional status in patients with preoperative low PNI value improves long-term outcomes, we divided the patients into four groups: patients with a high-PNI value before radical surgery and remained after surgery (Group High-High), a high-PNI value before surgery but decreased after surgery (Group High-Low), a low-PNI value before surgery but recovered after surgery (Group Low-High), and a low-PNI value but did not recover after surgery (Group Low-Low). Group High-High had 160 patients (70.4%), Group High-Low had 10 patients (4.4%), Group Low-High had 45 patients (19.8%), and Group Low-Low had 12 patients (5.2%). Regarding the long-term outcomes, although the patients in Group Low-Low showed significantly poorer OS and RFS than those in Group High-High (P<0.001, P=0.009, respectively), the prognosis of patients in Group Low-High was the same as that of patients in Group High-High (P=0.426, P=0.263, respectively) (Figure 2). Multivariate analyses using Cox’s proportional hazard model identified that low PNI status at the introduction of adjuvant chemotherapy was an independent prognostic factor (hazard ratio: 4.55) (Table 2). The characteristics of patients in Group Low-Low and Group Low-High are shown in Table 3. There were no significant differences in patients’ background between these two groups. These results suggested that recovery of nutritious status after the introduction of adjuvant chemotherapy would improve long-term outcomes even when the PNI status was low before radical surgery.
Figure 2.
Kaplan-Meier survival analysis comparing patients with high-PNI value (≥45.6) before radical surgery and remained after surgery (Group High-High), those whose PNI value was high and decreased (<45.6) after surgery (Group High-Low), those whose PNI value was low (<45.6) before surgery but recovered after surgery (Group Low-High), and those whose PNI value was low (<45.6) and did not recover after surgery (Group Low-Low). In multiple comparison analysis, significant difference was evaluated by Bonferroni correction. While the patients in Group Low-Low showed significantly poorer OS and RFS than those in Group High-High, the prognosis of patients in Group Low-High was as same as that of patients in Group High-High.
Table 2.
Univariate and multivariate analyses for overall survival of patients with low PNI at the introduction of adjuvant chemotherapy using the Cox’s proportional hazard model
| Variable | n | Univariatea | Multivariateb | |||
|---|---|---|---|---|---|---|
|
| ||||||
| P-value | HRc | 95% CId | P-value | |||
| Gender | male vs female | 31 vs 27 | 0.62 | |||
| Age (75 years old) | 75≤ vs <75 | 15 vs 43 | 0.10 | 7.20 | 1.170-140.7 | 0.03 |
| T stage (TNM classification) | T4 vs T1, 2, 3 | 19 vs 39 | 0.05 | 3.84 | 1.181-13.43 | 0.02 |
| N stage (TNM classification) | N2, 3 vs N0, 1 | 13 vs 45 | 0.55 | |||
| PNI at the introduction of chemotherapy | <45.6 vs 45.6≤ | 12 vs 46 | <0.01 | 4.55 | 1.184-19.65 | 0.02 |
| Charlson Comorbidity Index | 4≤ vs 0-3 | 21 vs 37 | 0.13 | |||
Low PNI status at the introduction of adjuvant chemotherapy was an independent prognostic factor (hazard ratio: 4.55).
Kaplan-Meier method; significance was determined by log-rank test.
Multivariate survival analysis was performed using Cox’s proportional hazard model.
HR: Hazard ratio.
CI: Confidence interval.
Table 3.
The relationships between PNI at the introduction of adjuvant chemotherapy and clinicopathological factors in colorectal cancer patients
| Variables | Group | Univariatea | |
|---|---|---|---|
|
| |||
| Low-Low (n=12) | Low-High (n=45) | P-value | |
| Gender | |||
| Female | 5 (42%) | 21 (47%) | 1.00 |
| Male | 7 (58%) | 24 (53%) | |
| Age | |||
| <75 | 10 (83%) | 32 (71%) | 0.48 |
| 75≤ | 2 (17%) | 13 (29%) | |
| BMI | |||
| <18 | 1 (8%) | 3 (7%) | 1.00 |
| 18≤ | 11 (92%) | 42 (93%) | |
| Location | |||
| Colon | 8 (67%) | 30 (67%) | 1.00 |
| Rectum | 4 (33%) | 15 (33%) | |
| Histopathological type | |||
| differentiated | 8 (73%) | 35 (78%) | 0.70 |
| undifferentiated | 3 (27%) | 10 (22%) | |
| Tumor depth | |||
| T1, T2, T3 | 10 (83%) | 28 (67%) | 0.30 |
| T4 | 2 (17%) | 17 (33%) | |
| Lymph node metastasis | |||
| N0, N1 | 8 (67%) | 36 (80%) | 0.44 |
| N2, N3 | 4 (33%) | 9 (20%) | |
| Lymphatic invasion | |||
| Absent | 4 (33%) | 17 (39%) | 1.00 |
| Present | 8 (67%) | 27 (61%) | |
| Venous invasion | |||
| Absent | 4 (33%) | 17 (39%) | 1.00 |
| Present | 8 (67%) | 27 (61%) | |
| CEA (ng/mL) | |||
| <5 | 6 (50%) | 21 (47%) | 1.00 |
| 5≤ | 6 (50%) | 24 (53%) | |
| CA19-9 (U/mL) | |||
| <37 | 9 (75%) | 37 (82%) | 0.68 |
| 37≤ | 3 (25%) | 8 (18%) | |
| Surgical Approach | |||
| Laparoscopic | 10 (83%) | 40 (89%) | 0.63 |
| Open | 2 (17%) | 5 (11%) | |
| Complication (≥CD grade 2) | |||
| Absent | 9 (75%) | 39 (87%) | 0.38 |
| Present | 3 (25%) | 6 (13%) | |
There were no significant differences in patients’ background between Group Low-Low and Group Low-High.
Univariate analysis was assessed using Chi squared test and Fisher’s exact probability test.
Relationships between PNI value at tumor recurrence and long-term outcomes
The median PNI at tumor recurrence was 50.5 (range 29.1-64.5). The cut-off value was set to 46.1 using an ROC curve analysis. Patients with a low-PNI value (PNI<46.1) at tumor recurrence showed a significantly poorer 5-year survival after tumor recurrence than those with a high-PNI value (PNI≥46.1) (P<0.01) (Figure 3). Similar to the association between PNI status before the introduction of adjuvant chemotherapy and clinicopathological factors, there was no significant association between PNI at tumor recurrence and those factors (Table 4).
Figure 3.
Kaplan-Meier survival analysis comparing patients with low-PNI value (<46.1) at tumor recurrence and patients with high-PNI value (≥46.1) at tumor recurrence. The patients with low-PNI value at tumor recurrence showed significantly poorer overall survival than those with high-PNI value.
Table 4.
The relationships between PNI at tumor recurrence and clinicopathological factors in colorectal cancer patients
| Variables | PNI at tumor recurrence | Univariatea | |
|---|---|---|---|
|
| |||
| lowb (n=11) | highb (n=41) | P-value | |
| Gender | |||
| Female | 4 (36%) | 16 (39%) | 1.00 |
| Male | 7 (64%) | 25 (61%) | |
| Age | |||
| <75 | 8 (73%) | 34 (83%) | 0.42 |
| 75≤ | 3 (27%) | 7 (17%) | |
| BMI | |||
| <25 | 8 (73%) | 27 (66%) | 1.00 |
| 25≤ | 3 (27%) | 14 (34%) | |
| Location | |||
| Colon | 8 (73%) | 20 (49%) | 0.19 |
| Rectum | 3 (27%) | 21 (51%) | |
| Histopathological type | |||
| differentiated | 7 (70%) | 37 (90%) | 0.12 |
| undifferentiated | 3 (30%) | 4 (10%) | |
| Tumor depth | |||
| T1, T2, T3 | 5 (46%) | 25 (61%) | 0.49 |
| T4 | 6 (54%) | 16 (39%) | |
| Lymph node metastasis | |||
| N0, N1 | 7 (64%) | 24 (58%) | 1.00 |
| N2, N3 | 4 (36%) | 17 (42%) | |
| Lymphatic invasion | |||
| Absent | 2 (18%) | 14 (34%) | 0.46 |
| Present | 9 (82%) | 27 (66%) | |
| Venous invasion | |||
| Absent | 5 (46%) | 10 (24%) | 0.26 |
| Present | 6 (54%) | 31 (76%) | |
| CEA (ng/mL) | |||
| <5 | 3 (27%) | 21 (51%) | 0.19 |
| 5≤ | 8 (73%) | 20 (49%) | |
| CA19-9 (U/mL) | |||
| <37 | 8 (73%) | 32 (78%) | 0.70 |
| 37≤ | 3 (27%) | 9 (22%) | |
| Surgical Approach | |||
| Laparoscopic | 6 (60%) | 29 (85%) | 0.17 |
| Open | 4 (40%) | 5 (15%) | |
| Complication (≥CD grade 2) | |||
| Absent | 9 (82%) | 34 (83%) | 1.00 |
| Present | 2 (18%) | 7 (17%) | |
There were no significant differences in patients’ background between patients with low-PNI at tumor recurrence and with high-PNI.
Univariate analysis was assessed using Chi squared test.
low: PNI<46.1, high: PNI≥46.1.
Discussion
Preoperative PNI value is widely used as a nutritional, immunological, and prognostic index for cancer patients. In general, patients with a low preoperative PNI status were reported to show a poor prognosis, so careful treatment is required for those patients. However, the clinical impact of postoperative PNI status is still unclear. In this study, we found that the postoperative PNI value could be a prognostic factor for patients with colorectal cancer who underwent adjuvant chemotherapy after radical surgery. This was true even when the PNI value was low and the nutritional status was poor during radical surgery. Moreover, we showed that PNI value at tumor recurrence also might be a prognostic marker. These results may support the decision-making process for preventing postoperative poor nutritional status in patients with colorectal cancer.
Concerning the association between postoperative nutritional status and long-term outcomes in colorectal cancer, Shibutani et al. reported that a low postoperative PNI value was associated with poor overall survival in stage II/III colorectal cancer patients who had undergone curative surgery [18]. Ihara et al. reported that a low PNI value before adjuvant chemotherapy tended to induce worse disease-free survival [19]. However, no report has evaluated the clinical impact of the change of PNI value between before and after surgery on the prognosis of patients with adjuvant chemotherapy following radical surgery for colorectal cancer. In this study, we focused on the clinical impact of recovery of PNI value, and the recovery by the introduction of adjuvant chemotherapy could improve the prognosis of the patients with adjuvant chemotherapy even if PNI value was low before surgery. In addition, we also found that PNI value at tumor-recurrence was associated with the long-term prognosis after recurrence in CRC patients. The results of our study suggested that perioperative nutritional intervention could improve the postoperative nutritional status resulting in prognostic benefits for patients after adjuvant chemotherapy. Recently, Marian et al. reported the overall positive effect of nutritional interventions during chemo(radio) therapy in the meta-analysis [20]. Prieto et al. also reported that nutrition interventions might improve the outcomes of patients with various cancers [21]. Our data would strongly support these clinical insights.
In this study, patients with a high PNI value at the introduction of adjuvant chemotherapy had better recurrence-free survival than those with a low PNI value. In addition, patients with a high PNI value at recurrence had better long-term outcomes after recurrence than those with a low PNI value. These results suggested that a high level of nutritional status would improve the chemosensitivity and suppress tumor progression. Yoshida et al. reported that low PNI values were significantly correlated with small intratumoral CD8+ cell counts and reflected low tumor immunity in oral squamous cell carcinoma patients [22]. Some kinds of inflammatory cytokines from cancer cells have been reported to activate neutrophil proliferation and activity, suppress lymphocytes, and increase the degradation of proteins including albumin [23]. Given the insights of these reports, there may be a relation between some kinds of immune-oncological responses and the nutritional status of colorectal cancer patients after radical surgery. Mismatch repair deficiency (dMMR) and microsatellite instability (MSI) have recently been focused on as clinical biomarkers reflecting immuno-oncological status [24,25], so it is warranted to clarify the association between these immuno-oncological biomarkers and PNI values.
Our study had some limitations. First, we analysed a limited number of patients from a single institution. Second, we could not evaluate the applied dose of adjuvant chemotherapy because of a lack of data. Moreover, there might have been some biases that influenced PNI status and patients’ prognosis because this study was a retrospective analysis. However, this study is the first report that strongly suggests the clinical benefit of a high postoperative PNI status in colorectal cancer patients with adjuvant chemotherapy. Therefore, our study may be a milestone in the field of perioperative management of colorectal cancer patients with high-risk stage II or stage III lesions. A large prospective study is warranted to confirm these results in a clinical setting.
Conclusions
Postoperative PNI value has potential as a prognostic marker of colorectal cancer patients undergoing adjuvant chemotherapy. Although a low PNI value before surgery is a disadvantageous factor for the prognosis, improvement of nutritional status by the induction of adjuvant chemotherapy would improve the prognosis of the patients. Nutritional intervention may increase the postoperative PNI value resulting in an improvement of prognosis in colorectal cancer patients undergoing adjuvant chemotherapy.
Disclosure of conflict of interest
None.
Supporting Information
References
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