Abstract
Background/Aim: Elderly patients with pathological stage II/III gastric cancer struggle to complete adjuvant chemotherapy. Neoadjuvant chemotherapy (NAC) for treating locally advanced gastric cancer (LAGC) has drawn attention; however, its indication for elderly patients who are vulnerable to chemotherapy is unclear. This study aimed to investigate the feasibility and efficacy of NAC for elderly patients with gastric cancer. Patients and Methods: In this study, patients aged ≥75 years who underwent curative gastrectomy for LAGC or adenocarcinoma of the esophagogastric junction between April 2013 and November 2021 were included. Vulnerable patients, with poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2-3 were also included. The patients were classified into NAC+ (n=20) and NAC − (n=45) groups. The clinicopathological data of the patients were retrospectively investigated. Results: The NAC+ group showed a higher R0 resection rate than the NAC− group (100% vs. 89.1%, p=0.3) and pathological downstaging was achieved in 12 (60%) cases, including five (25%) pathological complete responses. The incidence of adverse events during postoperative chemotherapy was 35%, and the rate of postoperative complications greater than Clavien–Dindo Grade II was comparable between the two groups (35% vs. 46.7%, p=0.43). The NAC+ group showed a higher three-year overall survival rate (75% vs. 36%, p=0.015). Conclusion: NAC was feasible and effective for elderly patients including vulnerable patients with LAGC or adenocarcinoma of the esophagogastric junction. It can be considered as treatment option, with a high down staging rate and better survival.
Gastric cancer is the fifth most common malignancy worldwide (1). In Japan, the standard treatment for pathological stage (pStage) II/III gastric cancer is gastrectomy with D2 lymph node resection, followed by 12 months of postoperative adjuvant chemotherapy, based on two pivotal clinical trials that investigated the efficacy of postoperative adjuvant chemotherapy after curative resection for gastric cancer (2-4). The efficacy of adjuvant chemotherapy for elderly patients aged >80 years with good physical status has been investigated in a phase III trial (5). However, elderly patients with vulnerability often fail to recover from surgery and to start adjuvant chemotherapy (6). Even if adjuvant chemotherapy could be introduced to this population, Tanahashi T et al. reported that only 44.2% of elderly patients aged >80 years completed S-1 for one year (7); thus, whether annual adjuvant chemotherapy can be introduced as the best treatment option for this population is unclear. There is a strong prediction that the percentage of individuals aged >75 years among all patients with gastric pathologies in Japan will exceed 60% in a decade (8). Thus, devising an effective and continuous perioperative anticancer therapy for gastric cancer in elderly patients is crucial.
In contrast, in Western countries, perioperative chemotherapy with a triplet regimen is the standard treatment for locally advanced gastric cancer (LAGC) and adenocarcinoma of the esophagogastric junction (9, 10). In Japan, although treatment guidelines recommend neoadjuvant chemotherapy (NAC) only for LAGC with extensive lymph node metastases (4, 11), several trials have been vigorously preformed to investigate whether NAC is eligible for other LAGC (12-15). Indeed, these studies have shown the safety and efficacy of NAC with high downstaging and R0 resection rates. Because NAC is administered before surgery for a shorter period than adjuvant chemotherapy, it may have an advantage for elderly patients with vulnerability who cannot tolerate the 12 months chemotherapy. Recently, a phase II clinical trial reported the safety and efficacy of S-1 plus oxaliplatin as NAC for LAGC in patients older than 70 years (16). However, it is unknown whether NAC is safe and effective for elderly patients with vulnerability because this study enrolled patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0-1.
In our hospital, NAC is administered for LAGC in elderly patients who are eligible for surgery, regardless of ECOG-PS. In this study, we investigated the safety of efficacy of NAC for treating LAGC and adenocarcinoma of the gastroesophageal junction in an elderly population including vulnerable patients with ECOG-PS 2-3 compared to the conventional treatment without NAC.
Patients and Methods
Study design. This study included patients aged >75 years who underwent curative gastrectomy with D2 or more extensive lymph node resection for advanced gastric cancer or adenocarcinoma of the esophagogastric junction in Kobe University Hospital between April 2013 and November 2021. The patients were classified into NAC+ and NAC− groups. The NAC+ group received at least one course of NAC, followed by gastrectomy. Both groups received postoperative chemotherapy depending on the pathological stage. Clinicopathological, demographic, perioperative, and follow-up outpatient data were retrospectively collected from a database of our hospital. The study was approved by the Research Ethics Committee of Kobe University Hospital (No.B230023). All patients provided written informed consent for the anonymous use of clinical records.
Neoadjuvant chemotherapy. The indication of NAC was gastric cancer or adenocarcinoma of the gastroesophageal junction (EGJ) that belong to clinical stage II or III (cT3-T4b, cN1-3 for gastric cancer and cT2-T4b, cN0-3 for adenocarcinoma of the EGJ) defined by the seventh edition of the TNM classification (17). Adenocarcinoma of the EGJ was defined as a type II tumor according to the Siewert classification. The patients underwent two courses of either of the following regimens: S-1 or capecitabine plus cisplatin or oxaliplatin (SP/XP/SOX/CapOX) or combination with trastuzumab when human epidermal growth factor receptor 2 was positive. The doses were adjusted to 80%-100% of the standard dose depending on the body surface area, creatine clearance, and physical status of the patients. During each course, the patients in the NAC+ group were admitted to the hospital to receive NAC with nutrition support and preoperative physical rehabilitation. Adverse events were assessed throughout the courses and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0), Japanese edition, Japan Clinical Oncology Group version (18).
Surgical procedure. Distal gastrectomy or total gastrectomy with D2 or more extensive lymph node dissection was performed for gastric cancer, and proximal gastrectomy or plus lower esophagectomy with D2 lymph node dissection was performed for adenocarcinoma of the EGJ based on the Japanese gastric cancer treatment guidelines (4).
Statistical analysis. Patient data were collected from electronically stored medical records using Microsoft Excel (Microsoft, Redmond, WA, USA). Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as medians and ranges. Categorical data were compared using the chi-square test, Fisher’s exact test, and Kruskal–Wallis test, whereas continuous data were analyzed using the t-test and Mann–Whitney U-test. Survival analysis was performed using the Kaplan–Meier method, and the log-rank test was used for statistical comparison. All statistical analyses were performed using EZR (19), which is a modified version of R Commander designed to add statistical functions frequently used in biostatistics. p-Values of <0.05 were used to denote statistical significance.
Results
In this study, 65 patients were included. The NAC+ group comprised 20 patients and the NAC− group included 45 patients. The clinical and surgical characteristics of the patients in each group are presented in Table I. The median age of the NAC+ group was significantly lower than that of NAC− group [77 years (range=75-81 years) vs. 83.5 years (range=75-95 years, p<0.001 years)]. No significant differences were observed between the two groups in terms of sex, performance status, American Society of Anesthesiologists physical status classification, tumor location, and clinical TNM stage. Moreover, no significant differences in the type of surgical procedure, approach, operative time, and amount of intraoperative blood transfusion were observed. Postoperative complications (≥Grade II* based on the Clavien–Dindo classification) were observed in seven (35%) patients in the NAC+ group and 21 patients (46.7%) in the NAC− group (p=0.42). The notable complications were pancreatic fistula (10% vs. 13.3%) and anastomotic failure (0% vs. 8.9%). The R0 resection rate was 100% for the NAC+ group and 89.1% for the NAC− group (p=0.30). The postoperative hospital stay was significantly shorter in the NAC+ group than in the surgery group [16 days (range=10-43 days) vs. 24.5 days (range=9-92 days); p<0.05]. The details of the NAC regimens are presented in Table II. Among the 20 patients in the NAC+ group, 14 (70%) completed the scheduled doses of the treatment. The details of the NAC regimen were as follows: S-1 plus cisplatin: 15%, S-1 plus oxaliplatin: 50%, S-1 plus oxaliplatin plus trastuzumab: 10%, capecitabine plus cisplatin plus trastuzumab: 20%, and others: 5%. The scheduled doses were completed in 14 (70%) cases. The reasons for terminating NAC were as follows, disease progression and adverse events in three patients (50%, respectively). The dose was reduced during the course in 11 patients (55%), including eight (40%) patients whose dose was reduced from the first course. Among these eight patients, three received a reduced dose because of low creatine clearance, whereas the remaining patients received a reduced dose because of their age or low physical status. Fifteen patients (75%) received NAC with hospitalization, including 10 (50%) patients who received physical rehabilitation. Nutritional support was provided in 18 (90%) patients. Adverse events of CTCAE Grade 3 (8) or greater were observed in seven patients (35%), including neutropenia (n=3; 15%), diarrhea (n=2; 10%), anemia (n=2; 10%), and thrombocytopenia (n=1; 5%). The details of the pathological outcomes, adjuvant chemotherapy, and recurrence are presented in Table III. A pathological response greater than Grade 2 (17) was achieved in 12 patients (60%), including five (25%) patients who achieved pathological complete response (pCR). Accordingly, the percentage of pT0 (25% vs. 0%; p=0.0217) and pN0 (55% vs. 21.6%; p=0.00630) was significantly higher in the NAC+ group. Clinical to pathological downstaging was achieved in 12 (60%) cases. The implementation rate of adjuvant chemotherapy for pathological stage II or III disease was significantly higher in the NAC+ group than in the NAC− group (55.5% vs. 11.1%; p<0.001). Among them, four (36.3%) and zero (0%) completed the entire courses of S-1. No significant difference in the total recurrence rate was observed between the two groups. The three-year overall survival (OS) rate was significantly higher in the NAC+ group than in the surgery group (75.0% vs. 36.0%; p=0.0151). The three-year cancer-specific survival (CSS) was also higher in the NAC+ surgery group; however, it did not reach statistical significance (75.0% vs. 50.7%; p=0.0540) (Figure 1A and B).
Demographic and surgical characteristics of patients.
Neoadjuvant chemotherapy (n=20).
Postoperative findings.
Kaplan–Meier curves for survival. A) Three-year overall survival. B) Three-year cancer specific survival.
The perioperative shift of body weight in each group is depicted in Figure 2. The body weight loss rate before and after NAC was as low as 0.9%. Moreover, the weight loss rate one year after surgery was smaller in the NAC+ group than in the NAC− group (10.2% vs. 13%; p=0.33).
The perioperative shift of body weight. The body weight loss rates in each group are shown as Mean±SD. The baseline body weight before neoadjuvant chemotherapy is depicted as the dotted horizontal line.
Discussion
In this study, we showed that NAC was feasible for elderly patients. Although all patients underwent surgery after NAC, the incidence of major Grade 3 or 4 toxicities was 35%, which was higher than that reported in a trial that investigated the safety of NAC for LAGC (19.7%) (14). This is a comparable figure considering that this study included much older patients. Importantly, NAC was discontinued in only three patients (15%) because of adverse events, whereas NAC was discontinued because of adverse events in 57% in the past study (14). In this study, eight (40%) patients started NAC with a reduced dose, of which 87.5% completed the treatment. In contrast, only 58.3% of patients who started with the full dose could continue NAC.
In detail, four patients received a reduced dose because they were regarded as being old, even though their renal or liver functions were normal. Although the standard for dose reduction in elderly patients is unclear, the past study supports the notion that the dose reduction at initial course is important for the safety and efficacy of chemotherapy for elderly patients (20). We considered that reducing the dose at the first course is effective in maintaining a high compliance rate and milder adverse events.
It was concerned that scar formation and edema after NAC could increase the difficulty of surgery and postoperative complications (14). However, in this study, the operative time and laparotomy rate in the NAC+ group were comparable to those in the NAC− group. The incidence of operative morbidities greater than Clavien–Dindo II including pneumonia, a major postoperative complication in elderly patients, was lower in the NAC+ group than in the NAC− group (35.0% vs. 46.7%), although the difference between the two groups did not reach statistical significance. To prevent malnutrition and muscle weakness, which are known to increase postoperative complications (21), we offered nutrition support and preoperative rehabilitation to elderly patients receiving NAC. Although we did not analyze the direct effects of these preoperative interventions by reviewing nutritional state indices, such as the prognostic nutritional index, we considered that this enabled the patients in the NAC+ group to go through the treatment with minimum body weight loss and to regain the weight faster than those in the NAC− group (Figure 2). We also considered that maintaining a good nutritional state in the NAC+ group reduced postoperative complications and allowed the patients to recover faster from the surgical invasion.
In this study, five patients (25%) achieved pCR. This is higher than that reported in a previous study that showed a pCR rate of 10% for cT2-3N+ or cT4Nany resectable gastric cancer with docetaxel, oxaliplatin, and S-1, a more powerful regimen (22). In particular, the proportion of cStage 0/I patients increased from two (10%) to seven (70%). This means that a large proportion of patients who otherwise would have been a candidate for postoperative adjuvant chemotherapy did not need to receive additional postoperative chemotherapy by achieving downstaging after NAC. Moreover, six out of eight patients (75%) with ECOG-PS 2-3 in the NAC+ group, who are considered to be vulnerable to adjuvant chemotherapy completed NAC. Three of them achieved pCR, showing that even patients with poor ECOG-PS maintain a high compliance rate with NAC. Consequently, the shorter duration of NAC provides a significant benefit for patients who require chemotherapy but may be noncompliant or ineligible for adjuvant chemotherapy due to a higher risk of toxicity. As shown in Table III, which was more surprising, the NAC+ group had much higher percentages of pStage II/III patients who received adjuvant chemotherapy than the NAC− group (55.5% vs. 11.1%). Interestingly, based on the questionnaire survey, the most common reason for not recommending or agreeing to adjuvant chemotherapy is that both physicians and patients regarded them as being too old to continue the treatment (7). In the NAC+ group, physicians, patients, and their supporting families would be able to accept or recommend anticancer therapy more easily because they had actually experienced the treatment. In summary, NAC is a more continuable and effective treatment strategy, particularly for elderly patients, which may be a better option than the conventional surgery plus adjuvant chemotherapy regimen.
The significantly better OS rate at three years after surgery came from the downstaging and the higher indication and completion rates of postoperative adjuvant chemotherapy in the NAC+ group. Specifically, histological response has been shown to be associated with better survival in those who received NAC (23). As shown in Table III, 60% of the NAC+ group showed more than Grade2 of a histological response, which contributed to better survival. The much better Kaplan–Meier curve of three-year OS in the NAC+ group could have been emphasized by the younger age of the patients. However, CSS was also better in the group; NAC+ surgery is considered to be useful, from the perspective of oncological outcome, for the elderly population.
Study limitations. First, this study was a retrospective study from a single center. A prospective study including multiple centers is required to validate the efficacy and safety of NAC in elderly patients. Second, the NAC regimen was not fixed. Investigating the efficacy and safety of each considered chemotherapy regimen is desired to determine which regimen is recommended as NAC. Third, because preoperative physical rehabilitation and nutrition were introduced only to patients in the NAC+ group, the results might be influenced by these interventions. Finally, this study included both patients with LAGC and adenocarcinoma of the EGJ. This was because we perform the same treatment strategy for these two cancer types. Moreover, major clinical trials of NAC included both cancer types, and it showed similar efficacy in LAGC and adenocarcinoma of the EGJ (9, 10, 23).
Conclusion
In conclusion, NAC for LAGC or adenocarcinoma of the EGJ is feasible and effective in vulnerable elderly patients with poor ECOG-PS. As the proportion of elderly patients with gastric cancer is increasing, NAC can be considered an option, considering the high curative resection rate and the benefits of preoperative physical rehabilitation and nutritional therapy starting from three months before surgery.
Footnotes
Authors’ Contributions
Study conceptualization: Shingo Kanaji, Naoki Urakawa; Acquisition of data: Ryuichiro Sawada, Hitoshi Harada; Analysis and interpretation of data: Hironobu Goto, Hiroshi Hasegawa; Supervision: Yoshihiro Kakeji; Writing - original draft: Tomosuke Mukoyama; Writing – review and editing: Shingo Kanaji, Kimihiro Yamashita, Takeru Matsuda, Taro Oshikiri. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
Funding
The Authors did not receive any funding for this study.
- Received September 29, 2023.
- Revision received October 25, 2023.
- Accepted October 26, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
