Survival Analysis of Elderly Patients Over 65 Years Old With Stage Ii/iii Gastric Cancer Treated With Adjuvant Chemotherapy After Laparoscopic D2 Gastrectomy: a Retrospective Cohort Study

DOI: https://doi.org/10.21203/rs.3.rs-58754/v1

Abstract

Background: The benefits of adjuvant chemotherapy for elderly patients (age >65) with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. To evaluate the effectiveness and complications of adjuvant chemotherapy in elderly patients (>65 years of age) after laparoscopic D2 gastrectomy.

Methods: This was a retrospective cohort study of elderly patients (>65 years) with stage II/III GC who underwent curative laparoscopic D2 gastrectomy between 2004 and 2018. The patients were divided as surgery alone and surgery plus adjuvant chemotherapy (chemo group). The overall survival (OS), disease-free survival (DFS), circulating tumor cells (CTCs), chemotherapy duration, and toxicity were examined.

Results: There were 270 patients included: 169 and 101 in the surgery and chemo groups, respectively. There were ten (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1-/3-/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P=0.018). For stage III patients, the 1-/3-/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P=0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR=0.568, 95%CI: 0.357-0.903, P=0.017) and DFS (HR=0.511, 95%CI: 0.322-0.811, P=0.004) in stage III patients. CTC >0 had no significant impact on the benefits of adjuvant chemotherapy on OS and DFS.

Conclusions: This study suggested that adjuvant chemotherapy significantly improves OS and DFS for elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.

Background

Gastric cancer (GC), as the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide, was responsible for over 1,000,000 new cases and an estimated 783,000 deaths in 2018[1]. The markedly elevated incidence rates of GC in Eastern Asia (China, Japan, and Korea) indicate that GC is a significant public health threat, especially to the elderly, since over 60% of the GC diagnoses and 70% of GC-related mortality occur in elderly patients (aged 65 years or older)[2, 3]. As the population continues to age, the proportion of the population aged 60 years and over will increase from 12.4% in 2010 to 28% in 2040[4, 5]. Longer life expectancy also results in an increasing number of the elderly (aged 65 years or older) undergoing cancer operation and chemotherapy.

The survival benefits from gastrectomy plus chemotherapy have been confirmed in patients with advanced GC[6-8]. In the United States of America, chemoradiotherapy after gastrectomy has been confirmed to improve overall survival (OS) by the INT-0116 trial[9], while the progression-free survival (PFS) and OS benefits of perioperative chemotherapy have been shown by the MAGIC and FLOT4 trials[10, 11]. The adjuvant chemotherapy following D2 gastrectomy is a standard treatment for stage II/III GC in East Asia[12-14]. Although prior randomized controlled studies (RCTs) indicated that postoperative adjuvant treatment in patients who underwent D2 gastrectomy could improve the 5-year disease-free survival (DFS) and OS, the subgroup analyses showed that the survival benefits decreased with increasing age. Furthermore, the ACTS-GC study showed no statistically significant effects of postoperative chemotherapy on DFS and OS for patients older than 70 years (DFS: hazard ratios (HR)=0.779, 95% confidence interval (CI): 0.527-1.151; OS: HR=0.706, 95% CI: 0.490-1.017)[12]. Similar results for OS were observed in the CLASSIC study for patients older than 65 (HR=0.70, 95% CI: 0.4-1.12)[13]. These results might be due to the considerably higher incidence of comorbidities, higher risk of complications, and shorter life expectancy of elderly patients[15]. Nevertheless, when considering those conflicting results, whether to give or not adjuvant chemotherapy to elderly patients with GC after D2 gastrectomy remains a dilemma for physicians. Therefore, the International Society of Geriatric Oncology suggested that specific trials for older patients with cancer should be conducted[16].

Laparoscopic gastrectomy has gained popularity worldwide for its safety and effectiveness[17, 18]. The Chinese Laparoscopic Gastrointestinal Surgery (CLASS) group recently reported the primary endpoints of the CLASS-01 trial, which suggested that laparoscopic distal gastrectomy for advanced gastric cancer was non-inferior to open surgery in terms of 3-year DFS and safety, with significant minimally invasive benefits[19, 20]. A previous study by our group indicated the potential benefits of laparoscopic gastrectomy for elderly patients with resectable GC[21]. Ushimaru et al.[22] reported that laparoscopic gastrectomy might improve the OS by reducing mortality from respiratory diseases. Still, the benefit of adjuvant chemotherapy after laparoscopic D2 gastrectomy in elderly patients is unknown.

As the elderly patients (over 65 years of age) are underrepresented in most RCTs, the present study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy retrospectively in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy, based on a prospectively registered database in China. Those results could help shed some light on this controversy.

Methods

Study design and patients

This was a retrospective cohort study conducted in the Department of General Surgery of Nanfang Hospital in patients treated between June 2004 and June 2018. This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.

The inclusion criteria were: 1) over 65 years of age; 2) histologically confirmed stage II or III gastric adenocarcinoma, according to American Joint Committee on Cancer (AJCC, 7th Edition); 3) received curative laparoscopic gastrectomy with D2 nodal dissection at Nanfang Hospital; and 4) at least 15 lymph nodes were available to ensure adequate disease classification. The exclusion criteria were: 1) R1 or R2 surgery; 2) palliative surgery; 3) death within 1 month after surgery; 4) a previous history of primary or secondary tumor beside the current GC; 5) neoadjuvant chemotherapy or adjuvant radiotherapy; or 6) incomplete medical record .

The enrolled patients were divided into surgery alone group (surgery group) and the surgery plus adjuvant chemotherapy group (chemo group).

Adjuvant chemotherapy protocols

The adjuvant chemotherapy protocols given during the study period included monotherapy and doublet chemotherapy. The initial dose of each regimen was reduced to 75% of the original regimen to minimized toxic effects in elderly patients. For monotherapy, the patients received oral capecitabine (Capeox). For doublet chemotherapy, the patients received oral capecitabine plus intravenous oxaliplatin (XELOX) or 2-week cycles of intravenous oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX). In all regimens, if grade 4 neutropenia or thrombocytopenia, or grade 3 or above febrile neutropenia was observed, the dose of all drugs was reduced to the next lower dose increment.

Date collection

The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The database includes patient characteristics (age at diagnosis, sex, etc.), clinical variables (postoperative stays, circulating tumor cells (CTCs), etc.), pathological features (tumor size, histological grade, etc.), chemotherapy (regimen, duration, cycles of chemotherapy, and grade 3 or above toxicity events), and follow-up. All data are routinely updated after each routine follow-up visit, either at the outpatient clinic or by phone. For the present study, the last follow-up data were collected on May 30th, 2018.

Outcomes

The observation outcomes of this study were OS and DFS. The OS was calculated from the date of operation to either the date of death or the date of the last follow-up visit. The DFS was calculated from the date of resection to the date of the first recurrence detected, or the last follow-up visit. Recurrence was determined as the appearance of any new lesion either locally, regionally, or distant. All grade 3 or above hematological and non-hematological toxicity events were recorded. Toxicities were graded according to the National Cancer Institute common toxicity criteria version 3.0[23].

Statistical analysis

All statistical analyses were performed using SPSS 24.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Those with a normal distribution were expressed as means ± standard deviations (SD) and were analyzed using Student's t-test; otherwise, they were presented as medians (ranges) and analyzed using the Mann-Whitney U-test. Categorical variables were reported as numbers with percentages and analyzed using the chi-square test with the Yates correction or Fisher’s exact test, as appropriate. The OS and DFS rates were compared between the surgery and chemo groups using unadjusted Kaplan-Meier curves and the log-rank test. The OS and DFS rates of different clinicopathological characteristics and different chemotherapy regimen were compared. HR and 95% CI were used to estimate the role of each independent predictor of survival. Cox regression was used for univariable and multivariable analyses. The level of significance was set at a two-tailed P-value of 0.05.

Results

Patient characteristics

At first, 298 patients were eligible, but 28 were excluded because of the presence of residual tumors, palliative surgery, death within 1 month of surgery, primary or secondary tumor history, neoadjuvant chemotherapy, adjuvant radiotherapy, or incomplete medical record. The remaining 270 patients were included in the analysis; 169 and 101 were classified in the surgery and chemo groups, respectively (Figure 1).

Table 1 presents the characteristics of the patients. The median age in the surgery and chemo groups was 70 years (69-75 years) and 69 years (66-72 years), respectively (P=0.001). The male-to-female ratio was 2.1:1 in the surgery group and 3.2:1 in the chemo group (P=0.152). Most patients in the two groups had an ECOG score and a Charlson comorbidity score of <1 (ECOG: 88.2% and 89.1%; Charlson score: 94.7% and 96.0%; all P>0.05). The number of CTCs in the surgery group was 5 (2-16), while 4 (1-7) in the chemo group (P=0.328). In the surgery group, there were 56 patients with AJCC stage II and 113 with AJCC stage III, while in the chemo group, there were 25 patients with AJCC stage II and 76 with AJCC stage III (P=0.147). In the chemo group, six patients received monotherapy, and 95 patients received platinum-based doublet chemotherapy therapy; 57 patients received adjuvant chemotherapy for less than 3 months, while 44 patients received 3-6 months of adjuvant chemotherapy. The median follow-up in the surgery and chemo groups was 25 (IQR 13-44) months, and 22 (IQR 11-54.5) months, respectively (P=0.452).

Factors associated with OS and DFS in all patients

The univariable and multivariable Cox proportional hazards models for all patients are shown in Table 2. In the multivariable analysis, age >70 years (HR=1.640, 95% CI: 1.119-2.403, P=0.011) and stage III GC (HR=2.738, 95% CI: 1.677-4.471, P<0.001) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR=0.511, 95% CI: 0.322-0.811, P=0.004), surgery performed in 2015-2018 (HR=0.586, 95% CI: 0.376-0.912, P=0.018), and stage III GC (HR=2.345, 95% CI: 1.466-3.751, P<0.001) were independently associated with DFS. Therefore, stage III GC was independently associated with both OS and DFS.

Overall survival

Unadjusted Kaplan-Meier survival curves were constructed for all patients in the two groups. The 1-, 3-, and 5-year OS rates of the surgery group were 72.9%, 51.8%, and 48.3%, compared with 90.1%, 66.4%, and 48.6% for the chemo group, respectively (HR=0.61, 95% CI: 0.42-0.92, P=0.018) (Figure2A). In the stage II cohort, the 1-, 3-, and 5-year OS rates of the surgery group were 96.3%, 80.4%, and 72.7%, compared with 90.5%, 73.8%, and 50.9% for the chemo group, respectively (HR=1.26, 95% CI: 0.483-3.29, P=0.637) (Figure 2B). For stage III patients, the 1-, 3-, and 5-year OS rates of the surgery group were 83.7%, 40.7%, and 28.7%, compared with 89.9%, 61.2%, and 43.6% for the chemo group, respectively (HR=0.58, 95% CI: 0.38-0.90, P=0.015) (Figure 2C).

Disease-free survival

The 1-, 3-, and 5-year DFS rates of the surgery group were 72.9%, 51.8%, and 48.4%, compared with 81.3%, 65.1%, and 53.6% for the chemo group, respectively (HR=0.682, 95% CI: 0.463-1.005, P=0.053) (Figure 2D). In the stage II cohort, the 1-, 3-, and 5-year DFS rates of the surg group were 85.3%, 78.5%, and 74.2%, compared with 91.8%, 64.4%, and 64.4% for the chemo group, respectively (HR=1.02, 95% CI: 0.416-2.54, P=0.9500 (Figure 2E). In stage III patients, the 1-, 3-, and 5-year DFS rates of the surg group were 66.5%, 37.7%, and 34.8%, compared with 77.9%, 60.0%, and 49.0% for the chemo group, respectively (HR=0.55, 95% CI: 0.36-0.83, P=0.007) (Figure 2F). The OS and DFS in the stage III subgroup were significantly different between the surgery and Chemo groups.

Subgroup survival analysis in stage III patients

The univariable and multivariable Cox proportional hazards models in stage III patients are shown in Table 3. Surgery plus adjuvant chemotherapy (HR=0.568, 95% CI: 0.357-0.903, P=0.017) and age >70 years (HR=1.573, 95% CI: 1.029-2.405, P=0.036) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR=0.511, 95% CI: 0.322-0.811, P=0.004) and surgery performed in 2015-2018, HR=0.586, 95% CI: 0.376-0.912, P=0.018) were independently associated with DFS.

Chemotherapy regimens, duration, and toxicity

In stage II patients, platinum-based doublet chemotherapy group had the similar OS and DFS compared to the monotherapy group (P=0.473 and P=0.499) (Supplementary Figure S1A,C). There were no differences in OS and DFS when considering the duration of adjuvant chemotherapy (P=0.531 and P=0.531) (Supplementary Figure S1B,D). In stage III patients, the platinum-based doublet chemotherapy led to better OS and DFS compared with monotherapy (OS: P=0.037; DFS: P=0.013) (Figure 3A,C). No significant differences in OS and DFS were observed in relation to chemotherapy duration (P=0.430 and P=0.418) (Figure 3B,D). There were ten patients with grade 3 or above non-hematological toxicity adverse events, and six with grade 3 hematological toxicity adverse events (neutropenia) (Table 1).

Analysis in patients with available CTC data

An analysis was performed in patients who had a CTC count before surgery. There were 43 patients (13 stage II patients and 30 stage III patients) who were evaluated for CTCs, and 40 were positive. There were no significant differences in OS and DFS between the surgery and chemo groups among CTC-tested patients (OS: P=0.344; DFS: P=0.259) (Figure 4A,C). There were no significant differences in OS and DFS between the surgery and chemo groups among CTC-positive patients (OS: P=0.092; DFS: P=0.095) (Figure 4B,D).

Discussion

The benefits of adjuvant chemotherapy for elderly patients (age over 65) with GC remain unknown because the elderly patients are underrepresented in most clinical trials[16]. Therefore this study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy. The results strongly suggest that adjuvant chemotherapy improves the OS and DFS of elderly patients with stage III GC operated using D2 laparoscopic gastrectomy compared with surgery alone. Platinum-based doublet chemotherapy improves the OS and DFS in elderly patients with stage III GC, compared with monotherapy. No OS and DFS benefits were observed in stage II patients between the chemo and surgery groups.

Previously, there were a few single-center retrospective studies that focused on adjuvant chemotherapy for elderly patients after gastrectomy[24, 25]. Still, those previous studies might not represent the current status of advanced GC treatment since laparoscopic D2 gastrectomy became popular relatively recently[19]. In the present study, only elderly gastric patients who underwent laparoscopic D2 gastrectomy were included. Among them, 41% received adjuvant chemotherapy in the 65-70 age group and only 33% in the >70 age group. This finding is similar to other cancers[26, 27]. This may be due to two reasons. First, there is no solid evidence to prove the efficacy of adjuvant chemotherapy in elderly patients with GC. Second, with a high comorbidity rate, older patients may prefer not to undergo chemotherapy treatment in their relatively limited lifetime[28].

Chemotherapy toxicity is another concern of the elderly who just underwent surgery. In the CLASSIC study, 56% of the patients who received the fluoropyrimidine-platinum chemotherapy regimen experienced grade 3-4 adverse events[13]. In the ACTS-GC study, 22.8% of patients with mono-chemotherapy experienced grade 3-4 adverse events[12]. In the present study, 95 (94.0%) patients in the chemo group received platinum-based doublet chemotherapy, including XELOX and FOLFOX, and 15 (15.6%) patients suffered from grade 3-4 adverse events. In the monotherapy group, one patient suffered from grade 3-4 non-hematological adverse events. The adverse event rate in our cohort is similar to a retrospective study from Korea[25]. Low rates of grade 3-4 adverse events may be due to the low Charlson comorbidity score in the present study since the patients were required to be able to tolerate laparoscopic D2 gastrectomy. The result indicates that adjuvant chemotherapy is tolerable in elderly patients who were suitable for gastrectomy. Still, it is possible that the adverse events were underestimated or not measured strictly in this retrospective study.

In the present study, adjuvant chemotherapy could significantly improve the OS in stage III elderly patients. Jin et al.[24] revealed an OS benefit (P=0.003) of adjuvant chemotherapy in elderly patients in a single-center retrospective study. A single-center retrospective study of elderly patients with GC (over 70 years) in Korea reported a DFS benefit (P=0.03) after adjuvant chemotherapy, but without an OS benefit (P=0.242)[25]. Nevertheless, by analyzing elderly patients with resected GC in the SEER-Medicare database, Hoffman et al.[29] reported that elderly patients might not gain a survival benefit from adjuvant chemotherapy, but most cases in this database underwent D0 or D1 gastrectomy. Up to now, no standard adjuvant chemotherapy regimens were established for the elderly. Some reports suggest that patients might benefit from adjuvant chemotherapy, no matter which chemotherapy regimen is used[30]. The CLASSIC study indicated that the fluoropyrimidine and oxaliplatin combination reduced both locoregional and distant recurrences, but had a smaller effect on peritoneal recurrences[13]. In this study, among the stage III patients, 71 (93.4%) received platinum-based doublet chemotherapy, and five (6.6%) received monotherapy. Better OS and DFS were observed in the platinum-based doublet chemotherapy group, suggesting that elderly patients with resected GC might gain better survival benefit from the fluoropyrimidine plus oxaliplatin chemotherapy regimen than with capecitabine alone, but the number of patients with monotherapy was small, probably biasing the results. When analyzing the influence of duration of platinum-based doublet chemotherapy in stage III patients, no benefits on OS and DFS were observed. Kim et al.[31] reported that there were no significant improvements in OS and RFS when using longer treatments of fluoropyrimidine-based adjuvant chemotherapy in patients with stage II or III GC. Similar results were also observed in stage III colon cancer with 3 vs. 6 months of XELOX[32]. On the other hand, Feng et al.[33] reported that additional oral capecitabine for 6 months after eight cycles of XELOX improved the DFS and OS for stage IIIA GC. Still, those previous studies were not focused on elderly patients with GC. Elderly patients may prefer to undergo fewer treatments or treatments with fewer adverse effects in their relatively limited lifetime[28].

CTCs are cells originating from solid tumors and are related to hematogenous dissemination[34]. Previous studies by our group suggested that CTCs are correlated with chemotherapy response[35, 36]. In the present study, 43 patients were evaluated for CTCs, and 40 were CTC-positive. The CTC-positive patients had a trend toward a benefit from adjuvant chemotherapy, but the numbers of patients were too small to reach any adequate conclusion. In the future, prospective studies regarding the value of CTCs are needed. 

There are several limitations to this study. First, this study was based on retrospective data. Second, the proportion of patients who received monotherapy was small. Third, only 43 patients were evaluated CTCs in the present study, and only three were CTC-negative. Further prospective studies are needed to address those issues.

Conclusion

In this retrospective, single-institution study, the OS and DFS benefited from adjuvant chemotherapy in elderly patients with stage III GC after D2 laparoscopic gastrectomy. Platinum-based doublet chemotherapy might be a better adjuvant therapy regimen compared with monotherapy. The value of chemotherapy in patients with CTCs should be examined more closely. Well-designed prospective studies are needed to confirm these findings. Elderly patients are highly variable in their functional status and comorbidities. Thus, cofactors regarding the functional, social, and mental status should also be considered. Well designed studies are needed to identify the elderly who can tolerate and benefit from adjuvant chemotherapy.

Abbreviations

GC

Gastric cancer

OS

Overall survival

DFS

Disease-free survival

CTCs

Circulating tumor cells

PFS

Progression-free survival

RCTs

Randomized controlled studies

HR

Hazard ratios

CI

Confidence interval

CLASS

The chinese laparoscopic gastrointestinal surgery

AJCC

American Joint Committee on Cancer

SD

Standard deviations

Declarations

CONTRIBUTION TO THE FIELD STATEMENT

The benefits of adjuvant chemotherapy for elderly patients (age >65) with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. A total of 270 patients included for analysis. There were ten (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1-/3-/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P=0.018). For stage III patients, the 1-/3-/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P=0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR=0.568, 95%CI: 0.357-0.903, P=0.017) and DFS (HR=0.511, 95%CI: 0.322-0.811, P=0.004) in stage III patients. CTC >0 had no significant impact on the benefits of adjuvant chemotherapy on OS and DFS. These findings suggested that adjuvant chemotherapy significantly improves OS and DFS for elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.

Consent for publication

Not applicable.

Availability of data and material

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

All authors declare no conflict of interest associated with this manuscript.

Funding

The project was supported by grants from the State's Key Project of Research and Development Plan (2017YFC0108300), the National Natural Science Foundation of China (81672446), the Southern Medical University Clinical Research Start-Up Project (LC2016ZD003), and the Key Clinical Specialty Discipline Construction Program ([2012]121).

Authors’ contributions

Yanrui Liang, Liying Zhao and Hao Chen carried out the studies, participated in collecting data, and drafted the manuscript. Tian Lin, Tao Chen, Mingli Zhao, Yanfeng Hu and Jiang Yu performed the statistical analysis and participated in its design. Hao Liu and Guoxin Li participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors would like to thank all study participants who were enrolled in this study.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018; 68:394-424.
  2. Yancik R, Ries LA. Cancer in older persons. Magnitude of the problem--how do we apply what we know? Cancer. 1994; 74:1995-2003.
  3. Joharatnam-Hogan N, Shiu KK, Khan K. Challenges in the treatment of gastric cancer in the older patient. Cancer treatment reviews. 2020; 85:101980.
  4. Bataillard A, Hebrard A, Gaide-Chevronnay L, Martin C, Durand M, Albaladejo P, Payen JF. Extubation in patients undergoing extracorporeal life support. The International journal of artificial organs. 2017; 40:696-700.
  5. WHO. China country assessment report on ageing and health. . https://wwwwhoint/ageing/publications/china-country-assessment/en/. 2015.
  6. Hu JK, Chen ZX, Zhou ZG, Zhang B, Tian J, Chen JP, Wang L, Wang CH, Chen HY, Li YP. Intravenous chemotherapy for resected gastric cancer: meta-analysis of randomized controlled trials. World journal of gastroenterology. 2002; 8:1023-8.
  7. Wu DM, Wang S, Wen X, Han XR, Wang YJ, Shen M, Fan SH, Zhang ZF, Zhuang J, Shan Q et al. Survival Benefit of Three Different Therapies in Postoperative Patients With Advanced Gastric Cancer: A Network Meta-Analysis. Frontiers in pharmacology. 2018; 9:929.
  8. Bouglé A, Bombled C, Margetis D, Lebreton G, Vidal C, Coroir M, Hajage D, Amour J. Ventilator-associated pneumonia in patients assisted by veno-arterial extracorporeal membrane oxygenation support: Epidemiology and risk factors of treatment failure. PloS one. 2018; 13:e0194976.
  9. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. The New England journal of medicine. 2001; 345:725-30.
  10. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. The New England journal of medicine. 2006; 355:11-20.
  11. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet (London, England). 2019; 393:1948-57.
  12. Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011; 29:4387-93.
  13. Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. The Lancet Oncology. 2014; 15:1389-96.
  14. Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T et al. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019; 37:1296-304.
  15. Saif MW, Makrilia N, Zalonis A, Merikas M, Syrigos K. Gastric cancer in the elderly: an overview. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2010; 36:709-17.
  16. Wildiers H, Mauer M, Pallis A, Hurria A, Mohile SG, Luciani A, Curigliano G, Extermann M, Lichtman SM, Ballman K et al. End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer--Alliance for Clinical Trials in Oncology--International Society Of Geriatric Oncology position article. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013; 31:3711-8.
  17. Wei Y, Yu D, Li Y, Fan C, Li G. Laparoscopic versus open gastrectomy for advanced gastric cancer: A meta-analysis based on high-quality retrospective studies and clinical randomized trials. Clinics and research in hepatology and gastroenterology. 2018; 42:577-90.
  18. Beyer K, Baukloh AK, Kamphues C, Seeliger H, Heidecke CD, Kreis ME, Patrzyk M. Laparoscopic versus open gastrectomy for locally advanced gastric cancer: a systematic review and meta-analysis of randomized controlled studies. World journal of surgical oncology. 2019; 17:68.
  19. Yu J, Huang C, Sun Y, Su X, Cao H, Hu J, Wang K, Suo J, Tao K, He X et al. Effect of Laparoscopic vs Open Distal Gastrectomy on 3-Year Disease-Free Survival in Patients With Locally Advanced Gastric Cancer: The CLASS-01 Randomized Clinical Trial. Jama. 2019; 321:1983-92.
  20. Hu Y, Huang C, Sun Y, Su X, Cao H, Hu J, Xue Y, Suo J, Tao K, He X et al. Morbidity and Mortality of Laparoscopic Versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: A Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016; 34:1350-7.
  21. Yu J, Hu J, Huang C, Ying M, Peng X, Wei H, Jiang Z, Du X, Liu Z, Liu H et al. The impact of age and comorbidity on postoperative complications in patients with advanced gastric cancer after laparoscopic D2 gastrectomy: results from the Chinese laparoscropic gastrointestinal surgery study (CLASS) group. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2013; 39:1144-9.
  22. Ushimaru Y, Kurokawa Y, Takahashi T, Saito T, Yamashita K, Tanaka K, Makino T, Yamasaki M, Nakajima K, Mori M et al. Is Laparoscopic Gastrectomy More Advantageous for Elderly Patients Than for Young Patients with Resectable Advanced Gastric Cancer? World journal of surgery. 2020; 44:2332-9.
  23. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Seminars in radiation oncology. 2003; 13:176-81.
  24. Jin Y, Qiu MZ, Wang DS, Zhang DS, Ren C, Bai L, Luo HY, Wang ZQ, Wang FH, Li YH et al. Adjuvant chemotherapy for elderly patients with gastric cancer after D2 gastrectomy. PloS one. 2013; 8:e53149.
  25. Jo JC, Baek JH, Koh SJ, Kim H, Min YJ, Lee BU, Kim BG, Jeong ID, Cho HR, Kim GY. Adjuvant chemotherapy for elderly patients (aged 70 or older) with gastric cancer after a gastrectomy with D2 dissection: A single center experience in Korea. Asia-Pacific journal of clinical oncology. 2015; 11:282-7.
  26. Merchant SJ, Nanji S, Brennan K, Karim S, Patel SV, Biagi JJ, Booth CM. Management of stage III colon cancer in the elderly: Practice patterns and outcomes in the general population. Cancer. 2017; 123:2840-9.
  27. Samet J, Hunt WC, Key C, Humble CG, Goodwin JS. Choice of cancer therapy varies with age of patient. Jama. 1986; 255:3385-90.
  28. Dudeja V, Habermann EB, Zhong W, Tuttle TM, Vickers SM, Jensen EH, Al-Refaie WB. Guideline recommended gastric cancer care in the elderly: insights into the applicability of cancer trials to real world. Annals of surgical oncology. 2011; 18:26-33.
  29. Hoffman KE, Neville BA, Mamon HJ, Kachnic LA, Katz MS, Earle CC, Punglia RS. Adjuvant therapy for elderly patients with resected gastric adenocarcinoma: population-based practices and treatment effectiveness. Cancer. 2012; 118:248-57.
  30. Liu TS, Wang Y, Chen SY, Sun YH. An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2008; 34:1208-16.
  31. Kim SG, Hwang SH. The association between the duration of fluoropyrimidine-based adjuvant chemotherapy and survival in stage II or III gastric cancer. World journal of surgical oncology. 2016; 14:102.
  32. Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. The New England journal of medicine. 2018; 378:1177-88.
  33. Feng WM, Tang CW, Guo HH, Bao Y, Fei MY. Prolonged adjuvant capecitabine chemotherapy improved survival of stage IIIA gastric cancer after D2 gastrectomy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2015; 72:140-3.
  34. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England journal of medicine. 2004; 351:781-91.
  35. Li TT, Liu H, Yu J, Shi GY, Zhao LY, Li GX. Prognostic and predictive blood biomarkers in gastric cancer and the potential application of circulating tumor cells. World journal of gastroenterology. 2018; 24:2236-46.
  36. Li TT, Liu H, Li FP, Hu YF, Mou TY, Lin T, Yu J, Zheng L, Li GX. Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: Relevance to therapy response. World journal of gastroenterology. 2015; 21:13259-67.

Tables

Table 1. Baseline information of patients

Characteristics

Surgery

N=169

Chemotherapy

N=101

p

Clinical characteristics

 

Age at diagnosis (years), median (IQR)

70 (67-75)

69 (66-72)

0.001

65-70, n (%)

92 (54.4)

64 (63.4)

0.152

>70, n (%)

77 (45.6)

40 (39.6)

Time of diagnosis, n (%)

 

 

0.684

 2005-2014

81 (47.9)

51 (50.5)

 

 2015-2018

88 (52.1)

50 (49.5)

Sex, n (%)

 

 

0.152

Male

115 (68.0)

77 (76.2)

 

 Female

54 (32.0)

24 (23.8)

ECOG score

 

 

0.281

0

78 (46.2)

54 (63.5)

 1

71 (42.0)

36 (35.6)

 2

14 (8.3)

9 (8.9)

 2+

6 (3.5)

2 (2.0)

Charlson score

 

 

0.711

 0

128 (75.7)

74 (73.3)

 

 1

32 (18.9)

23 (22.8)

 2

8 (4.8)

3 (2.9)

 2+

1 (0.6)

1 (1.0)

Tumour location

 

 

0.524

Gastroesophageal junction

58 (34.3)

39 (38.6)

 

Antrum

88 (52.1)

49 (48.5)

Other

23 (13.6)

13 (12.9)

Hospital stays (days), median (IQR)

11 (8-16)

10.0 (8-15)

0.328

CTC (number), median (IQR)

5 (2-16)

4 (1-7)

0.270

Pathological characteristics

 

TMN stage, n (%)

 

 

0.147

II

56 (33.1)

25 (24.8)

 

III

113 (66.9)

76 (75.2)

T stage, n (%)

 

 

0.286

T1-2

13 (7.7)

5 (5.0)

 

T3

35 (20.7)

18 (17.8)

T4

121 (71.6)

78 (77.2)

N stage, n (%)

 

 

0.285

N0

45 (26.6)

17 (16.8)

 

N1

18 (10.7)

17 (16.8)

N2

44 (26.0)

26 (25.8)

N3

62 (36.7)

41 (40.6)

Retrieved lymph nodes (number), median (IQR)

40 (25-55.5)

38 (24-54)

0.516

Grade, n (%)

 

 

0.051

Well or moderately differentiated

123 (72.8)

84 (83.2)

 

Poorly differentiated or undifferentiated

46 (27.2)

17 (16.8)

Lymphatic, blood vessel or perineural invasion, n (%)

100 (59.2)

62 (61.4)

0.720

Tumour size (cm), mean±SD

4.0 (3.0-5.5)

4.5 (3.2-6.0)

0.121

≤5cm

104 (61.5)

51 (50.5)

0.076

>5cm

65 (38.5)

50 (49.5)

Drug delivery and toxicities

 

Adjuvant chemotherapy regimen

 

 

 

 Mono chemotherapy

 

6 (5.9)

 Doublet chemotherapy

 

95 (94.1)

Length of adjuvant chemotherapy

 

 

 

<3 months

 

57 (56.4)

3-6 months

 

44 (43.6)

Toxicities (grade 3 or more)

 

 

 

 Monotherapy

 

1 (1.0)

Non-hematological adverse events

 

1 (1.0)

Hematological adverse events

 

0

 Double therapy

 

15 (14.9)

 Non-hematological adverse events

 

9 (8.9)

Hematological adverse events

 

6 (5.9)

IQR: interquartile range; ECOG: Eastern Cooperative Oncology Group; CTC: circulating tumor cells.

 

Table 2. Association factors of OS and DFS in the total patients

 

Overall survival

Disease-free survival

 

Univariable analysis

Multivariable analysis

Univariable analysis

Multivariable analysis

Factors

HR (95% CI)

p

HR (95% CI)

p

HR (95% CI)

p

HR (95% CI)

p

Treatment

Surgery alone

Surgery/adjuvant chemotherapy

 

1 (Reference)

0.733 (0.486-1.106)

 

-

0.139

 

 

 

 

 

 

 

1 (Reference)

0.673 (0.447-1.012)

 

-

0.057

 

1 (Reference)

0.511 (0.322-0.811)

 

-

0.004

Age of diagnosis

65-70 years

>70 years

 

1 (Reference)

1.560 (1.021-2.385)

 

-

0.028

 

1 (Reference)

1.640 (1.119-2.403)

 

-

0.011

 

1 (Reference)

1.422 (0.978-2.067)

 

-

0.065

 

 

Time of diagnosis

 2004-2014

 2015-2018

 

1 (Reference)

0.967 (0.632-1.478)

 

-

0.876

 

 

 

1 (Reference)

0.713 (0.475-1.069)

 

-

0.102

 

1 (Reference)

0.586 (0.376-0.912)

 

-

0.018

Sex

Male

Female

 

1 (Reference)

0.903 (0.589-1.383)

 

-

0.638

 

 

 

1 (Reference)

0.895 (0.588-1.361)

 

-

0.603

 

 

ECOG score

0

1

2

2+

 

1 (Reference)

1.325 (0.879-1.996)

1.006 (0.504-2.008)

2.016 (0.797-5.100)

 

-

0.179

0.987

0.139

 

 

 

 

 

 

 

1 (Reference)

1.468 (0.982-2.194)

1.105 (0.554-2.202)

2.017 (0.798-5.097)

 

-

0.062

0.777

0.138

 

 

Charlson score

 

1 (Reference)

1.029 (0.631-1.679)

0.992 (0.363-2.710)

1.135 (0.158-8.174)

 

-

0.909

0.988

0.900

 

 

 

1 (Reference)

1.068 (0.661-1.724)

1.182 (0.479-2.961)

1.368 (0.190-9.852)

 

-

0.788

0.716

0.756

 

 

0

1

2

2+

 

 

 

 

Tumor location

 

1 (Reference)

1.304 (0.841-2.023)

1.511 (0.832-2.724)

 

-

0.236

0.175

 

 

 

1 (Reference)

1.321 (0.861-2.027)

1.497 (0.840-2.670)

 

-

0.203

0.171

 

 

Gastroesophageal junction

Antrum

Other

 

 

 

 

Retrieved lymph node

1.002 (0.9931.011)

0.656

 

 

0.999 (0.990-1.008)

0.841

 

 

Hospital stays

1.003 (0.983-1.023)

0.793

 

 

1.006 (0.987-1.025)

0.550

 

 

AJCC stage

II

III

 

1 (Reference)

2.626 (1.610-4.284)

 

-

<0.001

 

1 (Reference)

2.738 (1.677-4.471)

 

-

<0.001

 

1 (Reference)

2.345 (1.466-3.751)

 

-

<0.001

 

1 (Reference)

2.345 (1.466-3.751)

 

-

<0.001

Histologic Grade

Well or moderately differentiated

Poorly differentiated or undifferentiated

 

1 (Reference)

1.293 (0.809-2.068)

 

-

0.283

 

 

 

1 (Reference)

1.247 (0.788-1.975)

 

-

0.346

 

 

Lymphatic, blood vessel or

perineural invasion

Yes

No

 

 

1 (Reference)

0.857 (0.581-1.7266

 

 

-

0.439

 

 

 

 

1 (Reference)

0.740 (0.505-1.083)

 

 

-

0.121

 

 

Tumor size

≤5 cm

>5 cm

 

1 (Reference)

1.610 (1.099-2.356)

 

-

0.014

 

-

-

 

-

-

 

1 (Reference)

1.440 (0.991-2.091)

 

-

0.560

 

 

CTC

0.937 (0.802-1.096)

0.416

 

 

1.007 (0.924-1.088)

0.866

 

 

HR: hazards ratio; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; AJCC: American Joint Cancer Committee; CTC: circulating tumor cells.

Table 3. Association factors of OS and DFS in stage III patients

 

Overall survival

Disease-free survival

 

Univariable analysis

Multivariable analysis

Univariable analysis

Multivariable analysis

Factors

HR (95% CI)

p

HR (95% CI)

p

HR (95% CI)

p

HR (95% CI)

p

Treatment

Surgery alone

Surgery/adjuvant chemotherapy

 

1 (Reference)

0.572 (0.360-0.910)

 

-

0.018

 

1 (Reference)

0.568 (0.357-0.903)

 

-

0.017

 

1 (Reference)

0.542 (0.342-0.859)

 

-

0.009

 

1 (Reference)

0.511 (0.322-0.811)

 

-

0.004

Age of diagnosis

65-70 years

>70 years

 

1 (Reference)

1.560 (1.021-2.385)

 

-

0.040

 

1 (Reference)

1.573 (1.029-2.405)

 

-

0.036

 

1 (Reference)

1.409 (0.926-1.943)

 

-

0.109

 

 

Time of surgery

 2004-2014

 2015-2018

 

1 (Reference)

0.895 (0.565-1.417)

 

-

0.636

 

 

 

1 (Reference)

0.630 (0.405-0.980)

 

-

0.041

 

1 (Reference)

0.586 (0.376-0.912)

 

-

0.018

Sex

Male

Female

 

1 (Reference)

0.987 (0.609-1.602)

 

-

0.959

 

 

 

1 (Reference)

0.957 (0.591-1.55)

 

-

0.860

 

 

ECOG score

0

1

2

2+

 

1 (Reference)

1.345 (0.848-2.132)

1.201 (0.576-2.507)

2.810 (1.098-7.188)

 

-

0.207

0.625

0.031

 

 

-

 

 

-

 

1 (Reference)

1.493 (0.948-2.351)

1.335 (0.643-2.773)

2.715 (1.061-6.950)

 

-

0.083

0.438

0.037

 

 

Charlson score

 

1 (Reference)

1.038 (0.609-1.771)

1.000 (0.364-2.749)

-

 

-

0.890

0.999

-

 

 

 

1 (Reference)

1.119 (0.664-1.885)

1.186 (0.477-2.946)

 

-

0.674

0.713

 

 

 

0

1

2

2+

 

 

 

 

Tumor location

 

1 (Reference)

1.347 (0.838-2.166)

1.862 (0.917-3.780)

 

-

0.219

0.086

 

 

 

1 (Reference)

1.368 (0.858-2.183)

1.521 (0.753-3.073)

 

-

0.188

0.242

 

 

Gastroesophageal junction

Antrum

Other

 

 

 

 

Retrieved lymph node

1.001 (0.991-1.010)

0.853

 

 

0.999 (0.989-1.009)

0.782

 

 

Hospital stays

1.001 (0.980-1.023)

0.905

 

 

1.005 (0.986-1.025)

0.600

 

 

T category

T1-2

T3

T4

 

1 (Reference)

0.596 (0.130-2.729)

0.722 (0.176-2.958)

 

-

0.505

0.651

 

 

 

1 (Reference)

0.464 (0.103-2.098)

0.576 (0.141-2.358)

 

-

0.318

0.443

 

 

N category

N0

N1

N2

N3

 

1 (Reference)

0.223 (0.040-1.231)

0.517 (0.121-2.207)

1.071 (0.261-4.398)

 

-

0.085

0.373

0.924

 

 

 

1 (Reference)

0.234 (0.042-1.288)

0.555 (0.131-2.357)

1.065 (0.259-4.375)

 

-

0.095

0.425

0.930

 

 

Histologic Grade

Well or moderately differentiated

Poorly differentiated or

undifferentiated

 

1 (Reference)

1.035 (0.609-1.759)

 

-

0.899

 

 

 

1 (Reference)

1.043 (0.615-1.769)

 

-

0.877

 

 

Lymphatic, blood vessel or

perineural invasion

Yes

No

 

 

1 (Reference)

0.899 (0.581-1.389)

 

 

-

0.631

 

 

 

 

1 (Reference)

0.741 (0.484-1.134)

 

 

-

0.167

 

 

Tumor size

≤5 cm

>5 cm

 

1 (Reference)

1.209 (0.793-1.843)

 

-

0.377

 

 

 

1 (Reference)

1.147 (0.756-1.738)

 

-

0.519

 

 

HR: hazards ratio; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; AJCC: American Joint Cancer Committee.