Ten-year survival outcomes of patients with potentially resectable gastric cancer: impact of clinicopathologic and treatment-related risk factors

Introduction

Gastric cancer (GC) remains the fifth most frequent cancer and the third cause of cancer-related deaths worldwide [1,2]. In 2012, an estimated 951,600 new cases of GC were diagnosed, while 723,100 deaths due to GC occurred globally [1,2]. Gastric cancer affects twice as many men as women and its incidence presents heterogeneity among different countries: the highest rates are encountered in eastern and western Asia, Latin America, and some former Soviet European countries, and the lowest in Northern America and many parts of Africa [1,2]. In Greece, 1357 deaths from GC were recorded in 2015 (www.statistics.gr). Differences in these rates partly reflect regional discrepancies in several factors, including consumption of fresh products, salt-preserved foods, obesity, alcohol intake, smoking, and incidence of Helicobacter pylori (H. pylori) infection, as well as genetic predisposition such as cadherin 1 gene mutation [2-4]. During the recent decades, the incidence of GC has gradually decreased because of primary prevention programs associated with smoking reduction, H. pylori infection control and reducing reliance on salt-preserved foods [2]. However, despite the additional introduction of specialized multidisciplinary team (MDT) meetings, the optimization of surgical procedures, advances in systemic chemotherapy, targeted treatments and immunotherapies in the metastatic setting, the overall 5-year survival rates remain low at 20-29%, whereas the median survival of patients with metastatic disease is 9-10 months [3,5]. An exception is the improved 5-year survival rate of more than 50% documented in Japan and Korea, due to secondary prevention programs, including endoscopic procedures [5].

Treatment options for patients with GC primarily depend on tumor staging and resectability and derive from a detailed and precise evaluation of imaging and pathology in the context of MDT meetings [6]. Oncologic resection remains the cornerstone of the therapeutic management of GC, but 15-year survival is 21% for the D1 group and 29% for the D2 group (P=0.34) [7]. Aiming to improve these poor results, combination strategies, including chemotherapy, radiotherapy (RT), targeted therapy and immunotherapy, are under intense investigation in the adjuvant, neoadjuvant and metastatic settings. Moreover, following a SWOG-directed Intergroup study, chemoradiation with 5-fluorouracil (5FU) has gained a lot of attention in the United States after curative surgery; nonetheless, concern has been raised about the associated toxicity and benefit of such strategy after optimally performed surgery [8].

The objective of our study was to evaluate the impact of clinical, pathologic and treatment-related risk factors in the survival outcomes of patients with GC from our institution during the period 2006-2010.

Patients and methods

We conducted a retrospective review of patients assessed for potentially resectable GC at Attikon University General Hospital from 2006-2010. All patients were discussed in our institution’s MDT meeting, as per hospital policy, and after thorough clinicopathologic and imaging evaluation, decisions were taken about personalized treatment. As this was a general hospital with two departments of surgery, neither of which was a specialized center for GC, most surgeons had a training background in general surgery. The present study was approved by the institutional review board and written informed consent to the treatment was obtained from all patients, whose data were anonymized and transferred to a dedicated database. The STROBE checklist was applied in this observational study.

Results

Pathology data

T and N stages for all patients are shown in Table 1. Of the 132 patients operated, 92 (70%) had intestinal and 40 (30%) diffuse adenocarcinoma; 33 (25%) had proximal and 99 (75%) distal location; and 52 (39%) had vascular infiltration and 39 (29%) perineural invasion. An R0 resection was identified in 100 patients (75.8%), whereas R1 and R2 resection were recognized in 25 (18.9%) and 7 (5.3%) patients, respectively.

Table 1 Description of clinicopathologic characteristics of patients according to whether surgery was performed or not

Survival outcomes

At the time of analysis, the median follow-up time was 114.8 months (range 4.4-195) and the median survival time was 47.6 months (95% confidence interval [CI] 27.5-70.5). For patients who underwent surgery, the median follow-up and survival times were 114.8 (range 5.1-195.0) and 100.3 (95%CI 54.0-195.0+) months, respectively. In contrast, the median follow-up and survival times in patients who did not undergo surgery were 27 (range 4.4-37.0) and 13 (95%CI 10.0-17.1) months, respectively. The survival time since diagnosis and by surgical margins, plane of nodal dissection and TNM, are shown in Table 2. The Kaplan-Meier survival curve in relation to surgical margin involvement is shown in Fig. 1A. The mean (95%CI) survival rates at 5 years post diagnosis for T3 and T4 were 57.4 (42.1-70.1) and 25.5 (14.2-38.5), whereas for N2, N3a and N3b they were 56.5 (34.3-73.8), 37.0 (19.6-54.6) and 15.4 (4.8-31.5), respectively. The mean (95%CI) survival at 5 years post diagnosis was 85.0 (69.6, 93.0), 81.3 (52.5-93.5), 56.5 (34.3-73.8), 37.0 (19.6-54.6) and 15.4 (4.8-31.5) according to the presence of 0, 1-2, 3-6, 7-15 and >16 infiltrated lymph nodes (Fig. 1B).

Figure 1 Kaplan-Meier survival curves according to: (A) infiltration of surgical margins; (B) number of involved lymph nodes; (C) TNM stages (7th AJCC edition); (D) resection margin (R0, R1, R2) and nodal (N0, N1, N2, N3) infiltration

Table 2 Long-term survival outcomes of patients according to TNM stage, plane of nodal dissection and status of surgical resection margins

The mean (95%CI) survival at 5-years post diagnosis in relation to the absence or presence of vascular infiltration was 61.3 (49.7-70.9) and 48.1 (34.1-60.8), whereas for absence or presence of perineural invasion it was 61.3 (50.6-70.3) and 43.6 (27.9-58.3), respectively. The Kaplan-Meier survival curve according to TNM stage is shown in Fig. 1C.

The association of the surgical margin status with N stage revealed that there was a statistically significant difference (P<0.001) in the mean (95%CI) survival at 2 years post diagnosis between patients in the subgroup including R1/R2 & N0/N1/N2 [11.1 (0.6-38.8)] and those with R0 & N3 [83.3 (64.5-92.7)] disease. The respective Kaplan-Meier survival curves are shown in Fig. 1D.

On univariate Cox regression analysis of patients treated with surgery, T3 and T4 tumors, N2/N3 tumors, perineural infiltration, R1 and R2 resection, chemotherapy and RT were associated adversely with survival to a degree that reached statistical significance (Table 3). Radiotherapy was associated with increased risk of death but this finding was not confirmed in the multivariate analysis. On multivariate Cox regression analysis, patients treated with surgery, T3 and T4 tumors, N3 stage, R1 and R2 resection reached statistical significance and remained independent negative prognostic factors for overall survival (Table 4).

Table 3 Univariate cox regression analysis of prognostic factors in patients treated with surgery

Table 4 Multivariate cox regression analysis of prognostic factors in patients treated with surgery

Discussion

Data on the long-term survival of patients with GC initially considered to be resectable are important and provide a reference point for the evaluation of advanced therapeutic strategies. Our study provides findings concerning the epidemiologic, clinicopathologic and 10-year survival data of patients with potentially resectable GC. This is the first real-world data reporting on patient outcomes from Greece.

Our patients had a male-to-female ratio of 1.87. This is in agreement with a retrospective analysis of 534 patients with stage III GC from Taiwan [11]. The patients’ median age and location rates (proximal vs. distal) were similar to those in previously reported prospective and retrospective studies of patients with resectable GC [12,13].

Adenocarcinoma subtypes were assessed according to the Lauren classification and the intestinal-to-diffuse rate was found to be similar to that in a recent study reporting on 534 patients from Taiwan [11]. Our study was not designed to identify survival benefit in relation to chemotherapy, but a recent report on a GC registry indicated that tumor classification according to Lauren predicted not only survival, but also response to chemotherapy, as docetaxel was associated with improved progression-free survival and overall survival in patients with intestinal adenocarcinoma [14]. The optimal combination and sequence of chemotherapy in the treatment algorithm is under intense investigation, but perioperative chemotherapy is currently gaining ground, particularly for T3/T4a and/or regional lymph node positive tumors [15]. In this context, preoperative FLOT, a docetaxel-based triplet chemotherapy, was compared to ECF/ECX anthracycline-based triplet chemotherapy and was found to be superior, as it was associated with significantly higher proportions of pathologic complete regression [15].

In the univariate analysis of our study, vascular and perineural invasion were found to be associated with an increased risk of death. This effect was not maintained in the multivariate analysis, most probably because of the small numbers of patients, but a previous study including 734 patients who underwent surgery indicated that both vascular and perineural invasion were independent prognostic factors for disease-free and overall survival [16].

Another important pathological aspect influencing the clinical outcome of GC patients was found to be microscopic and macroscopic tumoral infiltration of surgical margins. In the univariate analysis, both R1 and R2 resection were associated with a statistically significantly higher risk of death, an effect also maintained in the multivariate analysis as one of the most important predictors of relapse and death. It is well established that the effectiveness of surgery depends on the adequacy of the surgical procedures and on a cancer-free surgical margin specimen (R0), as patients with R1 or R2 resection have a mean survival of 8.7 months [17]. More importantly, the analysis of patients according to N stage and margin infiltration indicated that patients with margin infiltration had far worse survival when compared to patients with N2 disease. Similarly to our study, achieving R0 resection was also found to be significant in a recent study including 82 patients with gastric cardia cancer and R1/R2 resection was found to be associated with a 5-year survival rate of 13% [18]. Achieving an R0 resection is of the utmost importance, but is not always feasible. Twelve studies included in a systematic review, reporting on a total of 15,008 patients, indicated that intraoperative frozen sections should be performed to achieve a negative margin with intraoperative re-excision and that surgical re-excision of an R1 resection should be considered for patients with fewer than three disease-positive nodes, because survival is more likely to be governed by positive margins than by nodal status [19]. However, although management of the surgical margin seems to be of paramount importance in the early stage, at a later stage of the disease, when additional adverse pathologic characteristics (such as N3 disease) are present and ultimately determine patients’ outcomes, the decision to extend a resection to achieve a cancer-free resection margin should be considered carefully and personalized [20].

The univariate analysis of this study found signs of a possible negative association of RT with survival. This is somewhat misleading, as most patients receiving RT had positive lymph nodes or infiltrated surgical margins and thus a more unfavorable disease prognosis. Despite several clinical studies, the role of RT in resected GC remains controversial [8,9,21]. A previous study from Europe that randomized patients with histologically proven, radically resected GC, stage ≥T3 and ≥N1, to receive 6 cycles of docetaxel with cisplatin, both at 75 mg/m2 every 3 weeks (arm A), or the same treatment with RT (45 Gy; arm B) showed no differences in overall and disease-free survival between the two arms. [9]. Similarly no survival benefit was found in the ARTIST trial from Korea, which randomized patients with resected GC to receive 6 cycles of capecitabine 1000 mg/m2 twice a day on days 1 to 14 and cisplatin 60 mg/m2 on day 1 every 3 weeks (arm A), or two cycles of the same chemotherapy followed by RT 45 Gy concurrently with capecitabine 825 mg/m2 twice a day, followed by two additional cycles of chemotherapy (arm B) [21]. The USA 0116 SWOG-directed intergroup trial randomized patients to surgery alone (arm A) or postoperative chemoradiotherapy, including bolus 5FU 425 mg/m2/d and leucovorin 20 mg/m2/d on days 1 through 5 before, during, and after RT to a total of 45 Gy (1.8 Gy/d 5 d/wk for 5 weeks), targeting common locoregional failure sites such as the tumor bed, regional nodes, and anastomoses [8]. Two major differences between the later study and the previous ones were the administration of 5FU-based chemotherapy and the inclusion of 85% of patients with N1-N3 disease (only 10% of patients had D2 dissection). An important randomized study, which aims to compare TS-1 (40-60 mg b.i.d.; 4 weeks - 2 weeks off; 8 cycles), TS-1 (40-60 mg b.i.d.; 2 weeks - 1 week off) + oxaliplatin (130 mg/m2 q 3 weeks) both for 8 cycles, with or without RT (45 Gy in 5 weeks) in D2 resected GC, is currently underway to shed light on the need for RT in optimally resected patients (ClinicalTrials.gov Identifier: NCT01761461).

Our study has some limitations, as it included only a small number of patients in each subgroup. In our analysis, we identified 34 patients with stage I-II GC who were not treated with nodal dissection. This D0 subgroup had a 10-year survival benefit of 60%, significantly greater than the D1 and D2 survival values achieved. This result is misleading and should be interpreted with caution, as the subgroup of patients with stage I-II and lymph node negative disease had a better natural history and survival [22]. Based on the patient’s performance status and clinical evidence, D1 or D2 resection represents the recommended surgical procedure [23]. Likewise, as our analysis included patients with T1-T2 and node-negative disease who did not receive chemotherapy or RT, overall patient survival was better among those not treated with chemotherapy or RT than in those who were treated, a misleading effect due to the better prognosis of this subgroup of patients.

Notwithstanding the evolution of endoscopic and surgical techniques, improved molecular targeted therapies and chemoradiation, GC remains a leading cause of death worldwide. Multimodal planning of GC management, including surgeons, medical and radiation oncologists, radiologists and pathologists, is imperative and of cardinal importance. Despite improvements in radical resection with tumor-free margins and extended lymph node dissection, patients’ survival prospects remain poor. The prognosis of GC is influenced by a variety of additional tumor-, patient- and therapy-related factors, such as involvement of the surgical margins, lymphovascular invasion, number of lymph nodes involved and molecular signature, regardless of the type of lymphadenectomy [3]. Molecular studies have yielded a vast quantity of new information for the potential exploitation of novel molecules targeting the different GC subtypes [24,25]. Three randomized studies (the Dutch, the FLOT4/AIO and the CRITICS studies) have provided proof of the superiority of perioperative administration of FLOT regimen and gastrectomy with D2 lymphadenectomy over adjuvant postoperative chemoradiotherapy [7,15,26]. These findings offer new therapeutic options expected to supersede the 0116 SWOG trial protocol, the previous standard of care, including adjuvant chemoradiotherapy [8]. Finally, as detailed immune profiling of GC is yielding promising results, early studies with immune checkpoint inhibitors in advanced disease suggest that GC may be amenable to immune modulation [27,28].

Our study provides additional information about the survival of patients with GC, treated in a real-world environment, and confirms the importance of TNM staging for survival, as more advanced tumors (T4, N2 and N3) were found to be associated with worse outcomes on multivariate analysis. Inclusion criteria and analyses of future clinical trials must reevaluate the role of surgery, RT and chemotherapy in relation to tumor location, Lauren histology and the newly developed molecular profiling, as reported in the seminal Cancer Genome Atlas Study.