Value of the prognostic nutritional index in advanced gastric cancer treated with preoperative chemotherapy

Accepted Manuscript Value of the Prognostic Nutritional Index in advanced gastric cancer treated with preoperative chemotherapy Jianyi Sun, Donghai Wang, Ying Mei, Hailong Jin, Kankai Zhu, Xiaosun Liu, Qing Zhang, Jiren Yu PII:

S0022-4804(16)30426-7

DOI:

10.1016/j.jss.2016.09.050

Reference:

YJSRE 14011

To appear in:

Journal of Surgical Research

Received Date: 4 June 2016 Revised Date:

16 September 2016

Accepted Date: 27 September 2016

Please cite this article as: Sun J, Wang D, Mei Y, Jin H, Zhu K, Liu X, Zhang Q, Yu J, Value of the Prognostic Nutritional Index in advanced gastric cancer treated with preoperative chemotherapy, Journal of Surgical Research (2016), doi: 10.1016/j.jss.2016.09.050. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Revised Date of revision: 16st, Sep, 2016

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Value of the Prognostic Nutritional Index in advanced gastric cancer treated with preoperative chemotherapy Value of Prognostic Nutritional Index

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Jianyi Sun1, Donghai Wang1, Ying Mei1, Hailong Jin1, Kankai Zhu1, Xiaosun Liu1,

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Qing Zhang1, Jiren Yu1

1Department of Gastrointestinal Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (310003), China Corresponding author

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Jiren Yu, M.D., Department of Gastrointestinal and Thyroid Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79, Qingchun Road, 310003 Zhejiang

Province,

China.

E-mail:[email protected].

Tel:

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Hangzhou,

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0086-0571-87236147. Fax: 0086-0571-87072577.

Jianyi Sun and Donghai Wang designed the study and completed the major part of the manuscript. Ying Mei, Hailong Jin, Kankai Zhu, Xiaosun Liu, Qing Zhang and Jiren Yu also contributed to analysis and revision of the manuscript. Jianyi Sun and Hailong Jin reviewed the medical records and collected the clinical data.

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Abstract Background The Prognostic Nutritional Index (PNI) is a useful parameter indicating the

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immune and nutritional status of cancer patients; this study investigated the prognostic value of the PNI in advanced gastric cancer patients treated with preoperative chemotherapy.

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Materials and methods We retrospectively reviewed 117 advanced gastric cancer

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patients who met the inclusion criteria for preoperative chemotherapy and underwent surgical resection from July 2004 to December 2011. The patients were divided into PNI-high (PNI ≥ 45) and PNI-low (PNI < 45) groups. Clinicopathological features, chemotherapy adverse events and surgical complications were compared between the

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pre-chemotherapy PNI-high and PNI-low groups using the chi-square test. Survival analysis was performed using the Kaplan–Meier method and log-rank test. The Cox

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proportional hazard model was used to identify prognostic factors. Results Overall survival (OS) was better in the pre-chemotherapy PNI-high group than

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in the PNI-low group [hazard ratio (HR) =2.237, 95% confidence interval (CI): 1.271–3.393, p=0.005], while there was no significant difference in OS between the post-chemotherapy PNI-high and PNI-low groups (p>0.05). Cox regression analysis indicated that yield pathological T (ypT), yield pathological N (ypN) stage, and pre-chemotherapy PNI were independent prognostic factors (ypT: HR=2.914, 95%

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CI=1.312–6.470, p=0.009; ypN: HR=4.909, 95% CI=1.764–13.660, p=0.003; pre-chemotherapy PNI: HR=1.963, 95% CI=1.101–3.499, p=0.022).

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Conclusions The pre-chemotherapy PNI is a useful predictor of the long-term outcome of patients with advanced gastric cancer treated with preoperative chemotherapy.

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Key words Gastric cancer; Preoperative chemotherapy; Prognostic nutritional index;

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Introduction

Gastric cancer is the fifth most common cancer and causes the second most cancer-related deaths worldwide (1, 2). Gastrectomy plus D2 lymphadenectomy is the standard treatment for advanced gastric cancer, and for these patients, there is evidence

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that preoperative chemotherapy can induce tumor downstaging and improve the outcome compared with surgery only (3). However, the prognosis of gastric cancer

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remains poor, so indicators that can predict the long-term outcome of patients with gastric cancer have important clinical meaning.

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As a result of malabsorption, obstruction, and tumor consumption, malnutrition

is prevalent in malignant cancer patients, including gastrointestinal cancer patients in China, with an estimated 48% prevalence (4). A perioperative well-nourished status plays an important role in the long-term outcome of malignant tumors, as well as in postoperative complications (5-9) and the effectiveness of antitumor therapy (10, 11). Furthermore, a malnourished status was found to induce increased chemotherapy

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toxicity (12). The Prognostic Nutritional Index (PNI), which was originally used to evaluate the perioperative nutritional and immunological status and surgical risk for

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gastrointestinal surgery (13), has been reported to be associated with the prognosis and postoperative complications of gastric, colorectal, and pancreatic carcinoma (14-22).

This study investigated the prognostic value of the PNI for advanced gastric

Materials and Methods Patients

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cancer patients treated with preoperative chemotherapy followed by surgery.

This study enrolled 117 advanced gastric cancer patients who received preoperative

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chemotherapy and underwent subsequent radical surgery from July 2004 to December 2011 in the Department of Gastrointestinal Surgery, the First Affiliated Hospital, School

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of Medicine, Zhejiang University. All of the patients met the following inclusion criteria: (1) gastric cancer confirmed pathologically by an endoscopic biopsy; (2) serosa

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with tumor involvement with or without regional lymph nodes metastasis on computed tomography (CT); (3) age 18–80 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and (5) no residual tumor (R0 resection). The exclusion criteria included: (1) distant metastases; (2) prior chemotherapy or radiotherapy; (3) prior gastrectomy for any reason; (4) history of another primary malignancy, except cured basal cell carcinoma of the skin or cured carcinoma in-situ of

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the uterine cervix; (5) presence of hematological disorders or inflammatory or autoimmune diseases; (6) blood transfusion within the last 3 months; (7) missing

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laboratory parameters; and (8) lost to follow-up. Peripheral blood samples were obtained within 1 week before initiating chemotherapy and within 1 week before surgery.

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Prognostic Nutritional Index

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The PNI was calculated by the following equation: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (mm–3). The cut-off value of PNI was set at 45, as reported by Onodera (13). The patients were divided into PNI-high (PNI ≥ 45) and PNI-low (PNI < 45) groups.

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Preoperative chemotherapy

The chemotherapy regimens consisted of oxaliplatin plus 5-fluorouracil (5-FU) plus

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leucovorin (FOLFOX), oxaliplatin plus S-1 (SOX), oxaliplatin plus capecitabine (XELOX), paclitaxel plus S-1 (SPA), capecitabine plus oxaliplatin plus epirubicin

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(EOX), or oxaliplatin plus 5-FU plus epirubicin (EOF). Postoperative chemotherapy was begun within 4–6 weeks after surgery. Chemotherapy adverse events and surgical complications We evaluated the chemotherapy adverse events based on post-chemotherapy laboratory parameters according to the Common Terminology Criteria for Adverse Events, ver. 4.03

(23),

including

anemia,

leukopenia,

neutropenia,

lymphocytopenia,

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thrombocytopenia, and increased alanine aminotransferase (ALT) and serum creatinine (SCr) levels. Surgical complications were evaluated according to the Clavien–Dindo

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classification (24). Follow-up

All patients were followed every 3–6 months within 2 years post-surgery, every 6–12

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months for 3–5 years, and then annually. Follow-up included total blood counts,

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albumin level, and tumor markers measured in peripheral blood and endoscopy and radiological examinations, including CT, magnetic resonance imaging, ultrasonography, and positron emission tomography-CT as necessary. Statistical analyses

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The medical records were independently reviewed by two surgeons (H-L.J. and J-Y.S.). Differences in the clinicopathological characteristics of the patients and chemotherapy

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adverse events between the pre-chemotherapy PNI-high and PNI-low groups were analyzed using the chi-square test. Differences in body mass index (BMI) between the

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pre-chemotherapy PNI-high and PNI-low groups were analyzed by the Mann–Whitney U-test. Overall survival (OS) was defined as the time from the date of initiation of preoperative chemotherapy to death due to any cause or last contact. Patients who were alive on February 2016 were censored for OS. Survival analysis was performed using the Kaplan–Meier method and statistical significance was determined by the log-lank test. The Cox proportional hazard model was used for univariate and multivariate

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analyses to determine independent prognostic factors. p<0.05 was considered to indicate statistical significance, and confidence intervals (CI) were calculated at the 95% level.

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All statistical analyses were performed using SPSS ver. 19 (SPSS, Chicago, IL, USA).

Results

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Clinicopathological characteristics

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Table 1 shows the clinicopathological characteristics of the 117 patients [86 (73.5%) males, 31 (26.5%) females; median age 59 (range 34–78) years]. The chemotherapy regime was FOLFOX in 48 (41.0%) patients, SOX in 35 (29.9%), XELOX in 30 (25.6%), EOF in 2 (1.7%) and SPA and EOX in one (0.85%) each. The median number

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of perioperative cycles was 3 (range 1–7). All patients underwent R0 resection with D2 or D2+ lymphadenectomy: 53 (45.3%) and 56 (47.9%) underwent total and subtotal

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gastrectomy, respectively, while 8 (6.8%) patients underwent combined resection, including distal pancreatectomy plus splenectomy in 3, splenectomy in 4, and partial

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transverse colon in 1. After surgery, 98 (85.2%) patients continued chemotherapy and 17 (14.8%) did not receive further chemotherapy. According to the 7th edition of the American Joint Committee on Cancer (25), 10 (9.0%), 26 (23.6%), and 72 (64.5%) patients were categorized as stages I, II, and III, respectively. Seven patients could not be classified: 3 were T0N1M0, 2 were T0N2M0, and 2 were TxN0M0.

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Based on a PNI cut-off value of 45, 95 (81.2%) and 22 (18.8%) patients were divided into the pre-chemotherapy PNI-high and PNI-low groups, respectively. Table 1

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shows the relationship between the pre-chemotherapy PNI and clinicopathological characteristics. There were no significant differences in gender, performance status, BMI, tumor site and differentiation, surgery type, yield pathological T (ypT), yield

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significantly associated with older age (p=0.007).

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pathological (ypN), or ypTNM stage (p>0.05), while a low pre-chemotherapy PNI was

Chemotherapy adverse events and surgical complications

The chemotherapy adverse events included the following: anemia (65/117, 55.5%), leukopenia (36/117, 30.8%), neutropenia (33/117, 28.2%), thrombocytopenia (30/117,

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25.6%), increased ALT (22/117, 18.8%), lymphocytopenia (9/117, 7.7%), and increased SCr (4/117, 3.4%). Grade 3 or 4 chemotherapy adverse events occurred in 25 (21.4%)

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patients. Anemia and lymphocytopenia were significantly associated with a lower pre-chemotherapy PNI (p<0.05, Table 2). However, the incidence of anemia or

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lymphocytopenia was not significantly associated with the chemotherapy regimens or number of cycles (Table 3). The incidence of grade I to IV surgical complications was 17/117 (14.5%), 21/117 (17.9%), 3/117 (2.6%), and 1/117 (0.9%), respectively. Surgical complications were not associated with the pre-chemotherapy PNI (p=0.157).

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Survival analyses By the last follow-up, 60 (50.4%) patients had died, and the 3- and 5-year OS rates were

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61.5% and 49.8%, respectively. The OS of the pre-chemotherapy PNI-high group was longer than that of the pre-chemotherapy PNI-low group [3-year survival rate: 66.0% vs. 43.5%, 5-year survival rate: 55.5% vs. 25.6%, hazard ratio (HR) =2.237, 95% CI

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=1.271–3.393, p=0.005, Figure 1]. However, there was no significant difference in OS

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between the post-chemotherapy PNI-high and PNI-low groups (3-year survival rate 61.5% vs. 61.9%, 5-year survival rate: 49.8% vs. 49.0%, p=0.775, Figure 2). In the univariate analyses, tumor size (HR=1.934, 95% CI=1.124–3.327, p=0.017), ypT stage (HR=3.842, 95% CI=1.741–8.476, p=0.001), ypN stage

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(HR=6.956, 95% CI=2.516–19.227, p<0.001), and pre-chemotherapy PNI (HR=2.213, 95% CI=1.244–3.938, p=0.007) were found to be significant factors (Table 4). The

p=0.009),

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multivariate analysis showed that ypT stage (HR=2.914, 95% CI=1.312–6.470, ypN

stage

(HR=4.909,

95%

CI=1.764–13.660,

p=0.003),

and

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pre-chemotherapy PNI (HR=1.963, 95% CI=1.101–3.499, p=0.022) were independent prognostic factors.

Discussion Some biomarkers that reflect human nutritional and immune status have been reported to be significantly associated with the prognosis of malignant tumors, such as the

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albumin and lymphocyte levels in peripheral blood (5, 26, 27). PNI, which is calculated from the serum albumin level and peripheral lymphocyte count and is easily obtained in

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routine laboratory examinations, was designed to evaluate the perioperative nutritional and immunological statuses (13). In recent years, the PNI has been reported to be associated with the prognoses of various cancers, including digestive tract cancers

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(14-16, 28). The pre-chemotherapy PNI was also found to be a prognostic factor for

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unresectable metastatic colorectal cancer patients receiving chemotherapy (29). In this study, the pre-chemotherapy PNI was an independent prognostic factor for advanced gastric cancer patients treated with preoperative chemotherapy followed by surgery. However, there was no significant difference in survival between the post-chemotherapy

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PNI-high and PNI-low groups. The result may be influenced by factors such as the hematological toxicity of chemotherapy agents, which results in the inhibition of bone

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marrow hematopoietic function and decreases lymphocytes and albumin in peripheral blood (30). Consequently, the post-chemotherapy PNI might not reflect the original

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nutritional or immune status.

We evaluated the association between clinicopathological features and

preoperative PNI and found that a low pre-chemotherapy PNI was significantly associated only with older age, which was in accord with other studies of gastric cancer (15, 31, 32). However, age was not an independent prognostic factor. Unlike those studies, the current study included advanced gastric cancer patients without distant

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metastasis treated with preoperative chemotherapy. There was no significant association between PNI and tumor depth or lymph node metastasis in this study. This result might

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be explained by the downstaging induced by perioperative chemotherapy (3). Malnutrition is a risk factor for chemotherapy adverse events and is involved in reducing tolerance to chemotherapy (33). Malnutrition plays a role in reducing plasma

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protein levels and increases the availability of free plasma agents to exert adverse

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effects(34). Moreover, poor nutritional status potentially plays a role in decreasing oxidative metabolism and reducing renal excretion (34). It was reported that malnourished malignant tumor patients treated with chemotherapy developed more chemotherapy adverse events, including anemia, fatigue, and appetite loss (12). In the

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current study, adverse events based on laboratory parameters were analyzed. The results indicated that patients with low pre-chemotherapy PNI were more likely to develop

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anemia and lymphocytopenia after preoperative chemotherapy. Malnutrition was reported to play important roles in tissue and surgical wound

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healing and immune responses by promoting collagen synthesis, macrophage activation, and granuloma formation (35, 36). Many studies have reported that a low PNI is associated with postoperative complications (15, 16). However, there was no significant correlation between the pre-chemotherapy PNI and surgical complications in this study, which might be ascribed to the perioperative treatment, including nutritional support and chemotherapy. Appropriate nutritional support was reported to improve the

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nutritional status and immunity of malnourished patients who underwent gastric or pancreatic resection (37). Preoperative nutritional supplementation was also found to

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improve the postoperative outcomes of malnourished digestive cancer patients (38, 39). To our knowledge, this is the first study to describe the prognostic value of the PNI in advanced gastric cancer patients without distant metastasis who received

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preoperative chemotherapy followed by surgery. However, this study had some

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limitations. This was a retrospective, single-center study, and further prospective studies are needed to confirm the ability of the pre-chemotherapy PNI to predict long-term outcomes in patients with advanced gastric cancer receiving preoperative chemotherapy

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followed by surgery.

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Acknowledgements Chunhui Shou, Xiaoxiao Shi, Qianyun Shen, Hanliang Yang and Zhicheng

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Zhao provided writing assistance. Disclosure

Conflict of Interest: The authors declare that they have no conflict of interest.

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Review approval: This study was approved by the Institutional Review Board of the First Affiliated Hospital, School of Medicine, Zhejiang University. For this type of

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study formal consent is not required.

Funding: This work was supported by the grant of The Traditional Chinese Medicine Foundation of Zhejiang Province (2014ZZ005) and Zhejiang province key

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Figure captions

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Fig 1. The overall survival of pre-chemotherapy

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The overall survival of pre-chemotherapy PNI-high group was longer than that of the pre-chemotherapy PNI-low group (p =0.005). Fig 2. The overall survival of post-chemotherapy There was no significant difference in OS between the post-chemotherapy PNI-high and PNI-low groups (p =0.775).

ACCEPTED MANUSCRIPT Table 1. Clinicopathological characteristics of the patients and the relationship with pre-chemotherapy PNI Number

Pre-chemotherapy Pre-chemotherapy

p value*

Factor 45

Gender

PNI

45

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PNI

86 (73.5)

16 (13.7)

70 (59.8)

Female

31 (26.5)

6 (5.1)

25 (21.4)

65

36 (30.8)

12 (10.3)

<65

81 (69.2)

10 (8.5)

0-1

102 (87.2)

ECOG

2

15 (12.8)

BMIa (kg/m2)

site

83 (70.9)

3 (2.6)

12 (10.3)

20.7 (15.9-31.5)

21.8 (26.0-30.4)

0.078**

0.796

20 (17.1)

5 (4.3)

15 (12.8)

Middle

27 (23.1)

5 (4.3)

22 (18.8)

Lower

60 (51.3)

11 (9.4)

49 (41.9)

10 (8.5)

1 (0.9)

9 (7.7)

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0.007

71 (60.7)

Upper

More than 2 sites

0.927

19 (16.2)

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Primary tumor

24 (20.5)

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Age (years)

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Male

0.899

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Tumor sizeb (cm) <4

49 (43.8)

7 (6.3)

42 (37.5)

≥4

63 (56.3)

15 (13.4)

48 (42.9)

Well

22 (20.6)

6 (5.6)

16 (15.0)

Poorly

85 (79.4)

16 (15.0)

69 (64.5)

53 (45.3)

11 (9.4)

42 (35.9)

0.208

Differentiationc

0.382

Gastrectomy Total

0.366

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56 (47.9)

11 (9.4)

45 (38.5)

Combine

8 (6.8)

0 (0)

8 (6.8)

0

8 (7.0)

0 (0)

8 (7.0)

1

4 (3.5)

0 (0)

4 (3.5)

2

19 (16.5)

5 (4.3)

14 (12.2)

3

0 (0)

0 (0)

0 (0)

4

84 (73.0)

17 (14.8)

67 (58.3)

Negative

31 (26.5)

5 (4.3)

Positive

86 (73.5)

resectiond yp T stagee

yp TNM stagef

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SC 26 (22.2)

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yp N

17 (14.5)

69 (59.0)

0 (0.9)

3 (2.7)

2 (1.8)

8 (7.3)

5 (4.5)

21 (19.1)

3 (2.7)

I

10 (9.1)

II

26 (23.6)

III

71 (64.5)

15 (13.6)

56 (50.9)

98 (85.2)

17 (14.8)

81 (70.4)

5 (4.3)

12 (10.4)

Absent

EP

Present

TE D

T0N0M0

Post-operation chemotherapyg

17 (14.8)

0.316

0.657

0.846

0.243

AC C

ECOG Eastern Cooperative Oncology Group, BMI Body Mass Index, TNM tumor, node, metastasis; *: χ2 test, except ** Mann–Whitney U test a BMI: Values are median (range), data of 11 patients was not available. b Tumor size: 2 patients found no residual tumor in the resection specimens, while data of 3 patients was not available. c Differentiation: well include well and moderately differentiated adenocarcinoma, poorly include poorly differentiated adenocarcinoma, ring cell carcinoma, squamous carcinoma and mucinous adenocarcinoma. 8 patients found no residual tumor in the resection specimens, while data of 2 patients was not available. d Combine resection: 8 patients received combined resection, including distal pancreatectomy plus splenectomy for three, splenectomy for four, partial transverse colon for one, respectively. e yp Tstage: data of 2 patients was not available because rare tumor cells were residual. f yp TNM stage: 7 patients couldn’t be classified according to the 7th TNM classification,

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AC C

EP

TE D

M AN U

SC

RI PT

namely 3 patients were T0N1M0, 2 patients were T0N2M0 and 2 patients were TxN0M0. g Post-operation chemotherapy: data of 2 patients was not available.

ACCEPTED MANUSCRIPT Table 2. The correlation between pre-chemotherapy PNI with post-chemotherapy adverse events and surgical complications

45

Pre-chemotherapy PNI 45

Anemia

4

48

Grade 1-2

16

45

Grade 3-4

2

2

SC

Grade 0

Leukopenia Grade 0

14

Grade 1-2

7

Grade 3-4

1

2

Grade 0

15

69

Grade 1-2

3

22

Grade 3-4

4

4

17

91

5

4

0

0

Grade 0

15

72

Grade 1-2

6

22

Grade 3-4

1

1

Grade 0

21

74

Grade 1-2

1

20

Grade 3-4

0

1

Lymphocytopenia Grade 0

67

Grade 3-4

0.011

0.718

26

M AN U

EP

Grade 1-2

TE D

Neutropenia

p value

RI PT

Pre-chemotherapy PNI

0.052

0.011

AC C

Thrombocytopenia

0.463

Increased ALT

Increased SCr

0.164

ACCEPTED MANUSCRIPT Grade 0

21

92

Grade 1-2

1

3

Grade 3-4

0

0

Yes

17

58

No

5

37

0.747

Surgical complications

AC C

EP

TE D

M AN U

SC

RI PT

0.157

ACCEPTED MANUSCRIPT Table 3. The correlation between chemotherapy regimen and cycle with post-chemotherapy anemia and lymphocytopenia Anemia

Lymphocytopenia

Grade 0

Grade 1-2

Grade 3-4

p value

Grade 0

XELOX

10

18

2

0.186

27

FOLFOX

28

20

0

45

SOX

12

21

2

32

Others

2

2

0

4

1-2

12

13

0

3-4

35

40

>4

5

8

Grade 1-2

Grade 3-4

p value

0

3

0

3

0

0

0

M AN U

22

3

0

4

75

4

0

0

11

2

0

TE D EP AC C

0.671

3

SC

Cycles

RI PT

Regimen 0.864

0.286

ACCEPTED MANUSCRIPT Table 4. Univariate and multivariate analysis of the prognostic factors for overall survival Univariate analysis HR Gender Male Female Age, years 65

95 % CI

p value

1 1.276

0.733-2.222

0. 388

1.324

0.746-2.351

0.338

1 1.100

0.499-2.422

0.813

1 1.724

0.846-3.512

HR

1

1.124-3.327

TE D

1 1.934 1 3.842

1.741-8.476

1 6.956 2.516-19.227

EP

0-1 2 Differentiation Well Poorly Tumor size <4 ≥4 yp T stage 0-2 3-4 yp N Negative Positive

M AN U

ECOG

95 % CI

p value

SC

<65

Multivariate analysis

RI PT

Variables

0.133

0.017

1 1.340 0.762-2.356

0.309

0.001

1 2.914 1.312-6.470

0.009

<0.001

1 4.909 1.764-13.66 0

0.003

AC C

Pre-chemotherapy PNI 45

1

<45 2.213 Post-chemotherapy

1 1.244-3.938

0.007

0.559-2.180

0.776

PNI 45 <45

1 1.104

HR: Hazard Ratio, CI: Confidence Interval

1.963 1.101-3.499

0.022

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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