Abstract
Background: The prognosis for advanced gastric cancer with paraaortic lymph node (PALN) metastasis is very poor even after a curative resection. In the present study, induction chemotherapy followed by curative surgery was performed for advanced gastric cancer with PALN metastasis. Patients and Methods: Twenty patients with no non-curative factors except PALN metastasis who showed good clinical response for induction chemotherapy were enrolled in the study. Results: Combined S-1 plus cisplatin chemotherapy was administered to 10 patients; docetaxel, 5-FU plus cisplatin, to 5; S-1 plus paclitaxel to 3; and capecitabine plus cisplatin, to 2 patients. The overall response rate was 80% (16 out of 20 patients responded). All patients underwent curative gastrectomy with extended lymphadenectomy including the PALNs. Out of the 20 patients, 8 survived more than 5 years, and the 3- and 5-year survival rates were 72% and 65%, respectively. Female gender and residual PALN metastasis were significantly associated with worse prognosis and patients with a diffuse-type histology had a tendency to worse prognosis. Conclusion: Induction chemotherapy followed by curative surgery including extended PALN dissection seems a promising strategy for advanced gastric cancer with PALN metastasis as a sole distant metastasis, particularly for male patients and those with intestinal-type histology.
Over the past few decades, the incidence of gastric cancer has decreased worldwide, particularly in Western countries. However, it remains the fourth most common cancer and is the second most common cause of cancer-related death worldwide (1, 2). The prognosis of gastric cancer patients with paraaortic lymph node (PALN) metastasis is very poor, even after curative resection combined with superextended lymph node dissection. Tokunaga et al. reported on the survival curve for 178 advanced gastric cancer patients with PALN metastasis who had curative surgery (3). The three-year, five-year, and ten-year survival rates of patients were 20.9%, 13.0% and 7.9%, respectively. Prophylactic PALN dissection has been the standard of care, since occult metastasis had occasionally been observed in lymph nodes, until a Japanese prospective randomized trial investigating the efficacy of prophylactic PALN dissection showed no survival advantage of PALN dissection for patients with locally advanced gastric cancer and no additional improvement in mortality and morbidity rates after PALN dissection (4, 5). Since then, PALN dissection has not been routinely performed for patients with curative advanced gastric cancer. The appropriate treatment strategy for PALN metastasis has since been controversial, and the Gastric Cancer Treatment Guidelines 2010 do not provide any recommended treatment guidance regarding chemotherapy or surgical resection in gastric cancer patients (6).
Recently, a multi-disciplinary approach has been developed for advanced gastric cancer that includes chemotherapy, radiation, and surgery, and the survival benefit of this approach has been investigated worldwide (7, 8). Several novel chemotherapeutic agents, including taxanes (paclitaxel and docetaxel), irinotecan, oxaliplatin, S-1, and capecitabine, in addition to molecular targeted agents such as trastuzumab, have shown potent effects against gastric cancer (9-14).
Advances in chemotherapy for gastric cancer encouraged us to introduce induction chemotherapy for gastric cancer patients with a poor prognosis, such as those with PALN metastasis. In the present study, we retrospectively investigated the therapeutic effect of induction chemotherapy followed by curative surgery for advanced gastric cancer patients without distant metastasis and with PALN metastasis.
Patients and Methods
Patients. From July 2002 to June 2014, 20 patients with PALN metastasis who underwent curative surgery with extended lymph node dissection at the Osaka University Hospital and Osaka Medical Center for Cancer and Cardiovascular Diseases were enrolled in the study (Table I). Eligibility criteria for this study were as follows: (i) histological confirmation of gastric cancer; (ii) the presence of swollen paraaortic lymph nodes, determined by pre-operative CT and metastasis, confirmed by pathological examination of surgical specimens; additionally, patients whose paraaortic lymph nodes showed pathological complete response to neoadjuvant chemotherapy, were also enrolled in the analysis; (iii) absence of non-curable factors such as distant metastasis to the Virchow lymph nodes, liver, lungs or peritoneum shown by preoperative CT and staging laparoscopy for patients with a serosa invading tumor; (iv) performance status [Eastern Cooperative Oncology Group (ECOG)] less than 2; (v) age of less than 80 years; (vi) no prior treatment; (vii) adequate bone marrow function (a WBC count of more than 3,000/ml and a platelet count of more than 100,000/ml); (viii) adequate liver function (a serum bilirubin level of less than 1.5 mg/dl and a serum transaminase level less than two-times the upper limit of normal); (ix) adequate renal function (serum creatinine level of less than 1.5 mg/dl); (x) no other severe medical conditions such as symptomatic infectious disease, interstitial pneumonia, active hemorrhage/bleeding or obstructive bowel disease; (xi) not pregnancy or lactation; and (xii) provision of written informed consent in accordance to the guidelines of each Institution or Hospital. The study was approved by the ethics committee of each institution.
Induction chemotherapy. Patients with paraaortic lymph node metastasis were first subjected to induction chemotherapy. The chemotherapy regimen consisted of S-1/cisplatin for 10 patients, docetaxel/cisplatin/5-FU (DCF) for 5, S-1/paclitaxel for 3, and capecitabine/cisplatin for 2 patients (Table 1). The S-1/cisplatin protocol was according to the one used in the multicenter phase III “SPIRITS” trial (15). The protocol of triplet chemotherapy with DCF has been reported previously (16). The protocol of combination therapy with S-1 and paclitaxel was in accordance with a previous report (17), as was the protocol for combination therapy with xeloda and oxaliplatin (18). The regimen of chemotherapy has been changed during this study according to the appearance of novel anti-tumor agent especially S-1 in Japan. DCF was introduced between 2002 and 2007. S-1/ paclitaxel was introduced between 2003 and 2007. S-1/cisplatin was used between 2002 and 2014 and capecitabine/cisplatin was used between 2011 and 2014.
Response evaluation of neoadjuvant chemotherapy. Before and after induction chemotherapy, multi-detector row computed-tomography was performed to assess clinical response. The tumor response of the measurable metastatic lymph nodes including PALN was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (19). A complete response (CR) was defined as disappearance of all evidence of cancer for more than 4 weeks. A partial response (PR) was defined as more than a 50% reduction in the sum of the products of the perpendicular diameters of all of lesions without evidence of new regions or progression on any lesions. Stable disease (SD) was defined as less than a 50% reduction or less than a 25% increase in the sum of the products of the perpendicular diameters of all of lesions, without evidence of new lesions. Progressive disease (PD) was defined as more than 25% increase in more than one region or the appearance of new region.
The characteristics of the patients enrolled in this study (n=20)
Statistical analysis. Statistical analysis was performed with JMP® software (JMP version 8.0.2, SAS Institute, Cary, NC, USA). The overall survival (OS) was assessed with the Kaplan–Meier method and compared by the log-rank test. All parameters deemed significant in the univariate analysis using the Cox proportional hazard model were entered into the multivariate survival analysis. p-Values <0.05 were considered significant.
Results
Clinicopathological characteristics of enrolled patients. The characteristics of 20 cases with paraaortic lymph node metastasis are shown in Table I. The average age was 58 (20-74) years. Macroscopic type 3 tumors were dominant, and five patients had type 4 tumors. Diffuse-type histology was dominant in this cohort, especially in female (6 out of 7 cases, 86%), comparded to male patients (7 out of 13 cases, 54%). Twelve out of 20 patients (60%) showed no cancer cells in PALNs with the histological evidence of disappearance of cancer metastasis, such as destruction of normal follicles and/or the presence of fibrous tissue. The remaining 8 patients showed residual cancer metastasis in PALNs. The average number of PALN metastasis in 8 patients was 4.3 (1-17).
Objective response to induction chemotherapy (RECIST criteria).
Effect of induction chemotherapy. Responses to induction chemotherapy, as evaluated by the RECIST criteria targeted for lymph node metastasis including PALN metastasis, are shown in Table II. The total response rate (% of CR+PR) was 80% (16/20). The response rates to docetaxel/5-FU/CDDP, S-1/CDDP, S-1/PTX, and capecitabine /CDDP were 40% (2/5), 100% (10/10), 100% (3/3), and 50% (1/2), respectively.
Surgery. All 20 patients had a curative R0 resection. A distal gastrectomy was performed for 7 patents, a total gastrectomy for 12 patients, and a pancreatico-duodenectomy for one patient. Extended lymphadenectomy was performed for all patients; 16 of the patients had D2 plus paraaortic lymph nodes, and 4 had a D3 lymphadenectomy, which included D2 plus 8p, 12b/p, 13, 14, and 16a2/b1. Ten patients had a total gastrectomy, according to the Japanese Classification of Gastric Carcinoma, 13th Edition (20). Post-operative complications [Grade 3 of the Clavien-Dindo classification (21)] occurred in four patients (20%); among the complications were a pancreatic fistula and abdominal abscess in two cases, anastomotic leakage in one case and lymphorrhea in one case (Table III). No hospital deaths were observed. Among the 20 patients, 16 received post-operative adjuvant chemotherapy with S-1 and the remaining 4 had no adjuvant chemotherapy because of pathological CR in 2 cases and severe adverse events in 2 cases.
Pathological examination. Histopathological examination of the resected specimens revealed the following results: no residual cancer cells were observed in 2 cases; and no tumor cells were detected in the PALNs in 12 cases. A representative case is shown in Figure 1. The metastatic PALNs had decreased after 2 courses of induction chemotherapy with DCF (Figure 1A and B), and the pathological examination showed only a fibrotic change with no viable tumor cells (Figure 1C and D).
Survival analysis. Figure 2A and B shows the overall and disease-free survival rates of the 20 patients from the start of induction chemotherapy. Figure 2C and D show the overall and disease-free survival rates after surgical resection. The three-and five-year survival rates were 72% and 65%, respectively. Thirteen patients suffered cancer recurrence, and the remaining 7 showed no recurrence after surgery. Lymph node recurrence including PALN was observed in 6 patients, and peritoneal recurrence occurred in 5 patients (one patient suffered both). One patient suffered brain metastasis, liver metastasis occurred in one patient, and bone metastasis occurred in one patient. The female patients showed significantly worse survival results than did males (p=0.0169, Figure 3A), and the patients with no residual metastasis in the PALNs after induction chemotherapy showed significantly better survival than those with residual PALN metastasis (p=0.0186, Figure 3B). Patients with diffuse-type histology had a tendency to worse survival (p=0.0741, Figure 3C).
Surgical results.
Discussion
Gastric cancer with PALN metastasis is defined as Stage IV by the Japanese Gastric Cancer Association (JGCA) and the UICC classifications because of a very poor prognosis even after curative resection with extended lymphadenectomy (20, 22). Although treatment results of curative surgery for gastric cancer with positive PALN are not satisfactory, considering the very low CR rate to intense standard chemotherapy treatment, surgical treatment has proven superior to chemotherapy for gastric cancer cure (15). In the present study, we showed that induction chemotherapy and subsequent curative surgery with extended lymphadenectomy increased the 3- and 5-year survival rates up to 72% and 65%, respectively. Out of 20 patients, 8 patients survived more than 5 years, and out of these long-term survivors, only one patient showed residual metastasis in the PALNs. Figure 3B shows that patients with no residual metastasis in the PALNs after induction chemotherapy had significantly better survival results than those with residual PALN metastasis. These results suggest the following treatment strategy for gastric cancer with PALN metastasis and without other distant metastasis: curative surgery with extended lymphadenectomy should be introduced for patients who have shown a clinical response in the PALNs to induction chemotherapy. Additionally, patients with diffuse-type histology had a tendency to worse survival (Figure 3C). In the present study, macroscopic type 4 tumors with diffuse-type histology were dominant in female patients with death from peritoneal metastasis and brain metastasis soon after surgery. Selecting surgery for type 4 tumors in female patients requires caution even in good responders to induction chemotherapy. Patients who have undergone surgery with extended lymphadenectomy after intensive chemotherapy should be carefully assessed for an increase in post-operative morbidity and mortality. This study had a morbidity rate (Clavien-Dindo more than grade III) of 20% (4 of 20) and a mortality rate of 0 %. A pancreatic fistula and intra-abdominal abscess were observed in 2 cases (10%), and anastomotic leakage occurred in one case (5%). The multicenter phase III trial performed in Japan was conducted to compare D2 versus D3 lymphadenectomy (4). That study showed that the morbidity rate of extended lymphadenectomy was 1.9% for an anastomotic leak, 6.2% for a pancreatic fistula, and 5.8% for intra-abdominal abscess and the mortality rate was 0.8% (23). Because the macroscopic lymph node metastasis-negative patients had no preoperative chemotherapy and prophylactic lymphadenectomy, the morbidity rate was lower than in our cohort. Oyama et al. reported a morbidity rate of 33.1% in patients with PALN metastasis who had neoadjuvant chemotherapy with triplet chemotherapy of docetaxel, cisplatin, and S-1. The morbidity rate was higher than that of patients without pre-operative chemotherapy, however, pre-operative chemotherapy was tolerable for routine treatment (24).
A representative case enrolled in the study. A, B: An enhanced computed tomography image shows swollen PALN, which decreased after 2 courses of induction chemotherapy with docetaxel+cisplatin+5-FU. C, D: Histological examination showed that there were no residual cancer cells in the PALNs, and a fibrotic change was observed, which indicated a pathological response to pre-operative chemotherapy.
Survival analyses. A: Kaplan-Meier analyses of overall survival from the start of induction chemotherapy for all 20 patients enrolled in this study. Median survival time (MST) had not been reached. B: Kaplan-Meier analysis of disease-free survival from the start of induction chemotherapy. MST was 24.6 months. C: Kaplan-Meier analyses of overall survival after surgery for all 20 patients enrolled in this study. MST was 62.5 months. D: Kaplan-Meier analysis of disease-free survival after surgery. MST was 22.7 months.
That study presented the results of patients who had responded to induction chemotherapy and undergone surgery; it did not show the results of patients who had shown no response to chemotherapy and had not had a gastrectomy. Recent progress in chemotherapy has enabled the response rate to increase by more than 50%. It is probable that more than half of gastric cancer patients with PALN metastasis might be treated with a combination of induction chemotherapy and surgery. Recently, Tsuburaya et al. reported the results of a Japanese multicenter clinical trial of neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with paraaortic lymph node dissection for advanced gastric cancer with extensive lymph node metastasis. The study enrolled 51 eligible patients, and out of those, 27 cases involved PALN metastasis. The 3- and 5-year overall survival rates were 59% and 53%, respectively. Additionally, the results indicated the advantage of the multidisciplinary approach for treatment of gastric cancer with extensive lymph node metastasis (25).
Induction chemotherapy and subsequent curative surgery including extended PALN dissection constitute a promising multidisciplinary approach for advanced gastric cancer with PALN metastasis, particularly for male patients and those with intestinal-type histology.
Survival analyses. A: Kaplan-Meier survival curves accoding to gender (male/female). B: Kaplan-Meier survival curves according to the results of residual PALN metastasis after induction chemotherapy. C: Kaplan-Meier survival curves according to the results of histological types (intestinal type/diffuse type).
- Received September 12, 2015.
- Revision received October 3, 2015.
- Accepted October 19, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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