Reduced Lymph Node Harvest after Neoadjuvant Chemotherapy in Gastric Cancer

The Journal of International Medical Research 2011; 39: 2086 2095 Reduced Lymph Node Harvest after Neoadjuvant Chemotherapy in Gastric Cancer Z-M WU 1, R-Y TENG 2, J-G SHEN 2, S-D XIE 2, C-Y XU 2,3 AND L-B WANG 2 1 Department of General Surgery, Shaoxing Hospital, China Medical University, Shaoxing, China; 2 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 3 Department of Breast and Thyroid Surgery, Shaoxing People s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China This retrospective study investigated the impact of neoadjuvant chemotherapy on the number of lymph nodes harvested in patients with T 3 /T 4 gastric cancer. Lymph node counts in 58 patients who received preoperative neoadjuvant chemotherapy were compared with those in 168 patients who received surgery alone. Significantly more patients (n = 14, 24.1%) treated with neoadjuvant chemotherapy had < 15 lymph nodes harvested compared with patients (n = 13, 7.7%) treated with surgery alone. A significant correlation between the total number of harvested lymph nodes and the number of metastatic lymph nodes (mlns) existed in both groups. Neoadjuvant chemotherapy was the only factor associated with the retrieval of < 15 lymph nodes. The number of mlns was an independent predictive factor for overall survival. Although neoadjuvant chemotherapy decreased the number of lymph nodes harvested, the number of mlns may still be an acceptable prognostic factor in patients with gastric cancer, following neoadjuvant chemotherapy. KEY WORDS: LEUCOVORIN; 5-FLUOROURACIL; OXALIPLATIN; ANTINEOPLASTIC DRUGS; NEOADJUVANT CHEMOTHERAPY; GASTRIC CANCER; LYMPH NODE HARVEST Introduction Currently, gastric cancer is one of the leading causes of cancer-related death in China. 1 The prognosis for patients with locally advanced gastric cancer who achieve a pathological complete response or downstaging following neoadjuvant chemotherapy is better than that for patients treated with surgery alone. 1 3 The influence of neoadjuvant chemotherapy on gastric cancer patients clinicopathological parameters remains unclear. The number of metastatic lymph nodes (mlns) is currently considered to be the most reliable prognostic indicator for patients with radically resected gastric cancer. 4,5 Many factors impact on the mln count, especially the total number of harvested lymph nodes (tlns). 6 At present 15 lymph nodes need to be harvested to assess the mln stage accurately. 6 Many papers have reported a strong correlation between the number of lymph nodes harvested and the mln count, and even patient prognosis has been found to be positively correlated with the number of lymph nodes harvested. 6,7 Shen et al. 8 analysed data from 1895 patients with T 3 2086

gastric cancer and suggested that increasing the tln count might improve the accuracy of staging in patients who have pt 3 gastric cancer. Furthermore, this publication suggested that harvesting fewer lymph nodes might result in stage migration, which may lead to unnecessary upstaging. 8 Although different staging classifications for gastric cancer exist, the tumour node metastasis (TNM) staging system remains the standard. 9 Since the emergence of neoadjuvant chemotherapy as the optimal treatment approach for advanced gastric cancer, staging classifications based on the number of lymph nodes involved may be inadequate. In fact, some studies have reported a decrease in the number of lymph nodes harvested after neoadjuvant chemotherapy in rectal cancer and breast cancer. 10 12 The number of lymph nodes harvested in gastric cancer and the influence of the number of mlns in gastric cancer after neoadjuvant chemotherapy have not been examined. The present study investigated the impact of neoadjuvant chemotherapy on the number of lymph nodes harvested in patients with gastric cancer. Patients and methods STUDY POPULATION This retrospective analysis included consecutive patients with all stages of gastric cancer who were admitted to the Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine (Hangzhou, China) between 1 July 2005 and 31 July 2009. A proportion of these patients, who were diagnosed as having locally advanced gastric cancer (i.e. stage T 3 or T 4 ) by clinical evaluation, underwent neo - adjuvant chemotherapy with a combination regimen consisting of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) followed by curative surgical resection. Diagnosis and staging of the tumours was done by medical history, physical examination, gastroscopy and biopsy of the tumour, endosonography (EUS), radiographic examination of the chest, ultrasound of the liver and computed tomography (CT). 2 A control group was selected during the same period and included patients with T 3 /T 4 gastric cancer treated with surgery alone. Patient demographics and clinical characteristics were reviewed. The study was approved by the Ethics Committee of Sir Run Run Shaw Hospital. Verbal informed consent under the guidelines of this Ethics Committee was obtained from all patients. NEOADJUVANT CHEMOTHERAPY AND FOLLOW-UP The oxaliplatin, leucovorin and 5-FU combination was administered by a peripheral intravenous catheter as follows: 100 mg/m 2 oxaliplatin on day 1; 200 mg/m 2 leucovorin on day 1; and 400 mg/m 2 5-FU bolus on day 1, with 2.4 g/m 2 5-FU continuous infusion for 46 h. The regimen was repeated every 2 3 weeks. Complete blood cell counts, biochemistry analyses and urinalyses were performed each week. The response to the chemotherapy regimen was evaluated after two courses, by means of subjective signs and by gastroscopy, EUS or a CT scan, in accordance with the World Health Organization criteria. 13 In cases of a partial response or a complete response, two further courses of chemotherapy were given prior to surgery. In all other cases, the patients became eligible for surgery after the second course of chemotherapy. SURGICAL INTERVENTION Surgery was scheduled within 1 week after hospital admission for patients in the surgery alone (control) group, and 1 2 2087

weeks after completion of chemotherapy in the neoadjuvant chemotherapy group. After undergoing laparotomy, the extent of dissection and whether the surgical procedure was likely to be curative (R0) were decided; R1 indicated microscopic evidence of tumour cells at the margin of the resection, whereas R2 indicated macroscopic evidence of tumours beyond the margin of the resection. For patients with R0 resections, total or distal subtotal gastrectomies were performed, depending on the location and macroscopic type of gastric cancer. Splenectomy was only performed if there was a suspicion of direct tumour invasion into the spleen, or accidental injury to the spleen occurred during the operation. 14,15 All resected tissues were examined according to a standardized histopatho - logical protocol, with evaluation of the TNM stage according to the 6th American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC). 9 Depth of invasion was determined by examining the deepest portion of gastric wall invasion. The classification of dissected lymph nodes was verified by surgeons who reviewed the excised specimens after surgery. Tissue sections (4 µm) were prepared from lymph nodes that had been fixed in formalin and paraffin-embedded. All harvested lymph nodes were stained with haematoxylin and eosin, and were examined for metastasis by specialist pathologists. A metastatic lymph node was defined as nodal tissue that included tumour cells. POSTOPERATIVE FOLLOW-UP All patients were followed until death or until the date of last follow-up as of 1 November 2009. Close postoperative followup was undertaken at 3-month intervals for 2 years, then at 6-month intervals for 3 years. The follow-up consisted of a physical examination, full blood count and biochemical analyses. Gastroscopy, CT and positron emission tomography scans were performed if clinically indicated. STATISTICAL ANALYSES All statistical analyses were conducted using the SPSS statistical software program, version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows. The clinicopathological variables were analysed using the two-tailed t-test and the two-tailed χ 2 -test. The relationship between tln count and mln count was assessed by a Pearson s correlation coefficient test and by curvilinear regression. Logistic regression analysis was used to determine the independent risk factors for harvesting < 15 lymph nodes. Univariate analysis of overall patient survival was performed using the Kaplan Meier method. The survival curves were compared using the log-rank test. Multivariate analyses were done using logistic regression and the Cox proportional hazards model. The accepted level of significance was P < 0.05. Results A total of 342 gastric cancer patients were admitted to the Department of Surgical Oncology at Sir Run Run Shaw Hospital. Of these, 58 patients were diagnosed as having locally advanced gastric cancer (T 3 /T 4 ) by clinical evaluation and had undergone neoadjuvant chemotherapy with oxaliplatin, leucovorin and 5-FU, followed by curative surgical resection. The control group comprised 168 patients with T 3 /T 4 gastric cancer who did not receive neoadjuvant chemotherapy prior to surgery. Fifteen patients (25.9%) in the neoadjuvant chemotherapy group and 51 (30.4%) in the surgery alone group died during the follow-up period. The demographic and clinical characteristics of the two groups of patients are shown in Table 1. 2088

TABLE 1: Demographic and clinical data for patients with locally advanced gastric cancer who underwent surgical resection with or without preoperative neoadjuvant chemotherapy with oxaliplatin, leucovorin and 5-fluorouracil Neoadjuvant Surgery only chemotherapy group (control) group Statistical Parameter (n = 58) (n = 168) significance a Age, years 59.8 ± 10.5 60.3 ± 11 Gender Male 47 (81.0) 117 (69.6) Female 11 (19.0) 51 (30.4) Histological type Differentiated 14 (24.1) 61 (36.3) Undifferentiated 41 (70.7) 104 (61.9) Unknown 3 (5.2) 3 (1.8) Location in stomach Upper or whole 25 (43.1) 67 (39.9) Middle or lower 33 (56.9) 101 (60.1) Tumour size (diameter), cm 4.8 ± 2.8 5.9 ± 2.5 P = 0.008 yt stage T 3 53 (91.4) 158 (94.0) T 4 5 (8.6) 10 (6.0) Node involvement P = 0.026 Yes 39 (67.2) 138 (82.1) No 19 (32.8) 30 (17.9) Surgery type R0 48 150 R1/2 10 18 Data presented as mean ± SD or n (%). a Continuous variables were analysed using the two-tailed t-test and categorical variables were analysed by the two-tailed χ 2 -test., not statistically significantly different (P > 0.05). The mean ± SD tlns harvested from the gastric cancer patients (both groups) was 28 ± 12. The mean ± SD tlns harvested after surgery alone (29.6 ± 11.7) was significantly higher than for neoadjuvant chemotherapy (25.3 ± 12.6) (P = 0.022; Table 2); hence treatment with neoadjuvant chemotherapy significantly reduced the tlns harvested compared with surgery alone. A significantly higher proportion of patients who received neoadjuvant chemotherapy had fewer tlns harvested than patients undergoing surgery alone (P < 0.002; (Table 3). Fewer than 15 tlns were harvested in 27/226 (11.9%) patients overall. Less than 15 tlns were harvested in 14/58 (24.1%) patients in the neoadjuvant chemotherapy group, compared with in 13/168 (7.7%) patients in the surgery alone group. A significant direct correlation was observed between the tlns harvested and the number of mlns, both for gastric cancer patients treated with surgery alone (P < 0.001; Fig. 1) and for those who received neoadjuvant chemotherapy prior to surgery (P = 0.021; (Fig. 2). Age, gender, tumour location, tumour stage, extent of differentiation, tumour size, 2089

TABLE 2: Parameters that influenced the total number of lymph nodes harvested in patients with locally advanced gastric cancer who underwent surgical resection with or without preoperative neoadjuvant chemotherapy with oxaliplatin, leucovorin and 5-fluorouracil Total No. of lymph Statistical Parameter n nodes harvested significance a Age 60 years 109 28.6 ± 11.6 > 60 years 117 28.4 ± 12.5 Gender Male 164 27.9 ± 11.5 Female 62 30.1 ± 13.4 Histological type P = 0.009 Differentiated 75 29.7 ± 12.0 Undifferentiated 145 28.4 ± 11.8 Unknown 6 14.2 ± 12.0 Location in stomach Upper or whole 92 28.6 ± 12.2 Middle or lower 134 28.4 ± 12.0 Tumour size (diameter) 5 cm 94 28.2 ± 12.2 > 5 cm 132 28.7 ± 12.0 Serosal invasion Inside 212 28.6 ± 12.3 Outside 14 27.0 ± 8.4 Node stage P = 0.031 ypn 0 1 136 27.1 ± 12.3 ypn 2 3 90 30.6 ± 11.4 Surgery type R0 198 28.6 ± 12.0 R1 28 28.0 ± 12.5 Neoadjuvant chemotherapy P = 0.022 Yes 58 25.3 ± 12.6 No 168 29.6 ± 11.7 Data presented as mean ± SD. a Continuous variables were analysed using the two-tailed t-test;, not statistically significantly different (P > 0.05). surgery type (R0 versus R1/2) and having received neoadjuvant chemotherapy were used in a nominal logistic regression model. The only independent factor that was associated with harvesting < 15 tlns was neoadjuvant chemotherapy (P = 0.014; Table 4). For all patients, the median follow-up and survival times after surgery were 18 months (range 3 43 months) and 31.8 months (95% confidence interval [CI] 27.5, 36.2 months), respectively. In univariate analysis, tumour size (P = 0.005), tumour location (P = 0.044), the number of mlns (ypn 0 1 versus ypn 2 3 ) (P = 0.005) and surgery type (P = 0.035) were significantly associated with overall survival (Table 5). A greater number of mlns had a negative impact on survival: the mean survival times for patients with ypn 0 1 and ypn 2 3 stage nodes were 34.7 2090

TABLE 3: Relationship between the use of neoadjuvant chemotherapy prior to surgery or surgery alone and the total number of lymph nodes (tln) harvested in patients with locally advanced gastric cancer who underwent surgical resection with or without preoperative neoadjuvant chemotherapy with oxaliplatin, leucovorin and 5-fluorouracil Neoadjuvant Surgery only chemotherapy group group Statistical tln (n = 58) (n = 168) significance a 15 44 (75.9) 155 (92.3) < 15 14 (24.1) 13 (7.7) Data presented as n (%) of patients. a Categorical variables were analysed using the two-tailed χ 2 -test. P = 0.002 50 40 P < 0.001 r 2 = 0.089 No. of metastatic lymph nodes 30 20 10 0 0 20 40 No. of lymph nodes harvested 60 FIGURE 1: Correlation between the total number of lymph nodes harvested and the number of metastatic lymph nodes in patients with gastric cancer treated with surgery alone (n = 168) months (95% CI 30.1, 39.2 months) and 22.0 months (95% CI 12.3, 31.7 months), respectively (P = 0.005) (Fig. 3). On multivariate analysis which included all of the variables that were significant in the univariate analysis tumour size and the number of mlns were the two variables that were independent significant predictive factors for overall survival (P = 0.012 and P = 0.020, respectively; Table 5). Discussion The present study evaluated the influence of clinical, pathological and treatment variables on the tlns harvested and the number of mlns after neoadjuvant 2091

50 No. of metastatic lymph nodes 40 30 20 10 P = 0.021 r 2 = 0.091 0 0 20 40 No. of lymph nodes harvested 60 FIGURE 2: Correlation between the total number of lymph nodes harvested and the number of metastatic lymph nodes in the patients with gastric cancer treated with neoadjuvant chemotherapy prior to surgery (n = 58) TABLE 4: Cox proportional hazards model multivariate analysis of the variables influencing the total number of lymph nodes harvested (< 15 versus 15) in patients with locally advanced gastric cancer (n = 58) 95% confidence Statistical Variable Hazard ratio interval significance Neoadjuvant chemotherapy (yes versus no) 3.810 1.314, 11.044 P = 0.014 Age (> 60 versus 60 years) 0.810 0.324, 2.028 Gender (male versus female) 0.981 0.327, 2.984 yt stage (T 3 versus T 4 ) 0.640 0.102, 4.026 Surgery type (R0 versus R1/2) 2.05 0.624, 6.59 Tumour size (diameter; > 5 cm versus 5 cm) 1.343 0.516, 3.495 Differentiated 1.557 0.648, 3.751 Tumour location 0.852 0.321, 2.263, not statistically significantly different (P > 0.05). chemotherapy treatment, in patients with gastric cancer. The results demonstrated that neoadjuvant chemotherapy influenced the tlns harvested. Compared with primary surgery alone, the tlns harvested in the neoadjuvant chemotherapy group was decreased by 14.5%. In addition, the tlns harvested influenced the number of mlns in both the neoadjuvant chemotherapy and surgery groups. Other reports have indicated that neoadjuvant chemotherapy significantly reduced the tlns harvested in patients with rectal cancer and breast cancer. 16 20 2092

TABLE 5: Cox proportional hazards model univariate and multivariate analyses of clinical and pathological factors influencing overall survival in patients with locally advanced gastric cancer who underwent surgical resection with preoperative neoadjuvant chemotherapy with oxaliplatin, leucovorin and 5-fluorouracil (n = 58) Multivariate analysis Univariate Hazard 95% confidence Statistical Variable analysis ratio interval significance No. of metastatic lymph nodes P = 0.005 1.091 1.014, 1.173 P = 0.020 (ypn 0 1 versus ypn 2 3 ) Tumour size (diameter) P = 0.005 1.502 1.095, 2.061 P = 0.012 Surgery type (R0 versus R1/R2) P = 0.035 3.012 0.360, 12.813 Tumour location P = 0.044 1.409 0.288, 6.903 Age (> 60 versus 60 years) Gender (male versus female) yt stage (T 3 versus T 4 ) Differentiated, not statistically significantly different (P > 0.05). 100 80 Overall survival (%) 60 40 ypn 0 1 20 ypn 2 3 0 0 10 20 30 Time after surgery (months) FIGURE 3: Cumulative survival for the overall patient population with locally advanced gastric cancer analysed according to metastatic lymph node stage: ypn 0 1 versus ypn 2 3. Mean survival times for patients with ypn 0 1 and ypn 2 3 stage nodes were 34.7 months and 22.0 months, respectively (P = 0.005) 40 The tlns harvested in gastric cancer patients is of critical clinical significance. A high lymph node yield usually indicates adequate tumour clearance and staging. 6 Compared with gastric cancer patients treated with surgery alone in the present 2093

study, significantly more of the patients treated with neoadjuvant chemotherapy had < 15 lymph nodes harvested. This showed that neoadjuvant chemotherapy for gastric cancer reduced the tln count and increased the number of patients who had < 15 lymph nodes harvested. The number of patients experiencing this situation may increase, because the use of neoadjuvant chemotherapy is also increasing. 21 24 The AJCC/UICC classification 9 that is currently used for gastric cancer is widely accepted because of its strength in prognostic stratification, simplicity, reproducibility and low rate of methodologically related problems. The present study raised the possibility that the number of residual lymph nodes left after neoadjuvant chemotherapy can assist the clinician in making a prognosis. Only 75.9% of the gastric cancer patients treated with neoadjuvant chemotherapy had 15 lymph nodes harvested. With regard to the problems of the AJCC/UICC system, 15 lymph nodes need to be harvested in order to determine adequate tumour staging. 25 Thus, further prospective studies are needed to confirm the validity of the predictive and prognostic role of the number of residual lymph nodes left after neoadjuvant chemotherapy in a more homogeneous group of patients. In conclusion, a decreased tln harvest should be expected in patients undergoing resection after neoadjuvant chemotherapy. The tln harvested was not a predictive factor for overall survival in the present study, which may be because of the relatively small number of patients who had < 15 lymph nodes harvested. The node stage, which was based on the number of mlns, was still predictive of reduced survival in gastric cancer patients following neoadjuvant chemotherapy and surgery, but further analyses involving a larger number of cases may be necessary to confirm the applicability of node stage definition. The problem in the present study was that approximately 25% of the patients treated with neoadjuvant chemotherapy had < 15 lymph nodes harvested, despite adequate surgery and pathological workup. Thus, further studies are needed to confirm the role of the AJCC/UICC classification system of mln counts after neoadjuvant chemotherapy. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 13 April 2011 Accepted subject to revision 1 June 2011 Revised accepted 9 October 2011 Copyright 2011 Field House Publishing LLP References 1 Leung WK, Wu MS, Kakugawa Y, et al: Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol 2008; 9: 279 287. 2 Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11 20. 3 Spizzo G, Öfner D, de Vries A, et al: Preoperative chemotherapy with cisplatin and docetaxel followed by surgery and clip-oriented postoperative chemoradiation in patients with localized gastric or gastroesophageal junction adenocarcinoma: results from a phase II feasibility study. Ann Surg Oncol 2001; 18: 677 683. 4 Wang A, Guo P, Sun Z, et al: Clinicopatho - logical variables associated with lymph node metastasis and prognostic factors in pt2 gastric cancer. J Int Med Res 2009; 37: 359 366. 5 Coimbra FJ, Costa WL Jr, Montagnini AL, et al: The interaction between N-category and N- ratio as a new tool to improve lymph node metastasis staging in gastric cancer: results of a single cancer center in Brazil. Eur J Surg Oncol 2011; 37: 47 54. 6 Liu C, Lu Y, Jun Z, et al: Impact of total retrieved 2094

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