Abstract
Background/Aim: The present study evaluated the clinical characteristics and prognostic factors of gastric cancer (GC) patients with synchronous and metachronous other primary cancer who received curative treatment for GC. Patients and Methods: The study included 244 patients who underwent curative treatment for GC between 2005 and 2018. The risk factors for the overall survival (OS) and recurrence-free survival (RFS) were identified. Results: A total of 244 patients were included in this study. Among them, 58 patients were diagnosed with synchronous and metachronous other primary cancer. When comparing the patient background characteristics and clinical course between GC patients without and with synchronous and metachronous other primary cancer, the background, postoperative surgical complications, and details of adjuvant treatment were similar between the two groups. The 3- and 5-year OS rates in GC patients with synchronous and metachronous other primary cancer were 69.7% and 48.0%, respectively, while those in patients without synchronous and metachronous other primary cancer were 80.6% and 74.3%, respectively, showing a statistically significant difference (p<0.001) The synchronous and metachronous other primary cancer status was included in the final multivariate analysis model (hazard ratio=2.201; 95% confidence interval=1.229-3.942; p=0.008). Conclusion: Synchronous and metachronous other primary cancer status is a prognostic factor in GC patients. Therefore, synchronous and metachronous other primary cancer patients need both other primary cancer and GC follow-up to improve their survival.
An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred in 2018 worldwide (1, 2). Recently, the prognosis of cancer patients has been gradually improving due to improvements in the early diagnosis, surgical resection, perioperative care, and perioperative adjuvant treatment. Furthermore, the prognosis of gastric cancer (GC) patients has also been improving due to advances in perioperative adjuvant treatment and chemotherapy (3-5). However, these improvements in GC treatment are expected to increase the chance of detecting synchronous and metachronous other primary cancer (6, 7).
Among a range of cancer types, synchronous and metachronous other primary cancer in GC patients has been reported (8, 9). However, few studies have evaluated the clinical impact of synchronous and metachronous other primary cancer in GC patients who receive curative treatment. If physicians could determine the associated clinical course and prognostic factors of GC patients with synchronous and metachronous other primary cancer, these patients might receive optimal treatment, perioperative care and follow-up care.
The present study therefore explored the clinical characteristics and prognostic factors of GC patients with synchronous and metachronous other primary cancer who received curative treatment for GC.
Patients and Methods
Patients. Consecutive patients who underwent curative resection for GC at Yokohama City University from 2005 and 2018 were selected according to medical records. Patients with histologically proven adenocarcinoma that was classified as clinical stage I–III according to the 15th edition of the general rules for GC published by the Japanese Gastric Cancer Association (10) and who received R0 resection with radical lymph node dissection were included in the study.
Surgery and adjuvant treatment. All patients underwent gastrectomy with D1+ or D2 lymphadenectomy (11). Those with pathological II or III disease received postoperative adjuvant chemotherapy for one year. Generally, pathological stage II disease was treated with S-1 monotherapy, while pathological stage III disease was treated with S-1 plus docetaxel or capecitabine plus oxaliplatin (12-14).
Patient follow-up. At a minimum, patients received physical examination and hematological tests every three months for five years. Tumor marker levels (carcinoembryonic antigen and CA19-9) were also determined every three months for five years. Computed tomography (CT) was performed every 6-12 months for 5 years.
Statistical analyses. Differences between the synchronous and metachronous other primary cancer status and clinicopathological parameters were analyzed by a χ2 test. The overall survival (OS) and recurrence-free survival (RFS) curves were calculated using the Kaplan-Meier method. Univariate and multivariate analyses of the survival were conducted using a Cox proportional hazards model. Statistical significance was defined as p<0.05. All statistical analyses were conducted using the SPSS software program (v27.0 J Win; SPSS, Chicago, IL, USA).
Results
Patients. A total of 244 patients were included in this study. Among them, 58 were diagnosed with synchronous and metachronous other primary cancer. The details of the 58 patients were as follows (There are duplicate cases): 11 patients had colorectal cancer, 9 lung cancer, 6 prostate cancer, 5 breast cancer, 4 parotid tumor, 3 esophageal cancer, 3 bladder cancer, 3 tongue cancer, 2 thyroid cancer, 2 renal cancer, 2 pharyngeal cancer, 2 malignant lymphoma, 2 skin cancer, 2 cervical cancer, 1 eye tumor, 1 ovarian cancer, 1 small intestinal cancer, and 1 liver cancer. When comparing the GC patients without and with synchronous and metachronous other primary cancer, the median age (67 years vs. 72 years, p=0.002), incidence of chronic obstructive pulmonary disease (31% vs. 44.8%, p=0.009) and incidence of a conventional surgical approach (47.5% vs. 67.2%, p=0.008) were significantly higher in the GC patients with synchronous and metachronous other primary cancer than in those without it (Table I and Table II). In contrast, the gender ratio, median body mass index, clinical T and N factor, preoperative laboratory data, surgical details and pathological status were similar between GC patients without and with synchronous and metachronous other primary cancer.
Baseline characteristics of the study patients.
Surgical and pathological findings.
Postoperative clinical course of postoperative surgical complications and adjuvant treatment. When comparing the incidence of postoperative surgical complications between the GC patients without and with synchronous and metachronous other primary cancer, there were no significant differences between the groups (39.0% vs. 34.5%, p=0.533). In addition, the incidence of anastomotic leakage (8.5% vs. 8.6%, p=0.977), pneumonia (6.0% vs. 5.2%, p=0.813), abdominal abscess (3.0% vs. 3.4%, p=0.862), pancreatic fistula (7.5% vs. 5.2%, p=0.540) were similar between the groups. When comparing patients who need adjuvant treatment after surgery, there were no significant differences between the GC patients without and with synchronous and metachronous other primary cancer (40.0% vs. 46.6%, p=0.373). Furthermore, the incidence of the introduction of adjuvant treatment for patients who need adjuvant treatment after surgery was similar between GC patients without and with synchronous and metachronous other primary cancer (62.5% vs. 55.5%, p=0.523).
Survival analyses. The 3- and 5-year OS rates in GC patients with synchronous and metachronous other primary cancer were 69.7% and 48.0%, respectively, while those in GC patients without synchronous and metachronous other primary cancer were 80.6% and 74.3%, respectively, showing statistically significant differences (p<0.001) (Figure 1). The clinicopathological factors were categorized as shown in Table II, and their prognostic significance was analyzed. The univariate analyses of factors associated with OS demonstrated that the synchronous and metachronous other primary cancer status, pathological T status, pathological N status and perioperative surgical complications were significant prognostic factors. Thus, the synchronous and metachronous other primary cancer status was included in the final multivariate analysis model [hazard ratio (HR)=2.201; 95% confidence interval (CI)=1.229-3.942, p=0.008] (Table III).
The overall survival of gastric cancer (GC) patients without and with synchronous and metachronous other primary cancer.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
The 3- and 5-year RFS rates in GC patients with synchronous and metachronous other primary cancer were 69.5% and 45.9%, respectively, while those in GC patients without synchronous and metachronous other primary cancer were 76.7% and 71.4%, respectively (Figure 2), showing statistically significant differences (p<0.001). The univariate analyses of factors associated with the RFS demonstrated that the pathological T status, pathological N status, synchronous and metachronous other primary cancer status and perioperative surgical complications were significant prognostic factors. The synchronous and metachronous other primary cancer status was also selected for inclusion in the final multivariate analysis model (HR=1.814, 95%CI=1.051-3.131, p=0.033).
The recurrence-free survival of gastric cancer (GC) patients without and with synchronous and metachronous other primary cancer.
When comparing the sites of first recurrence between GC patients without and with synchronous and metachronous other primary cancer, there were no significant differences between the two groups (Table IV). However, the incidence of death from other cancers was significantly higher in patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer group (28.6% vs. 6.3%; p=0.039).
Details of recurrence pattern.
Discussion
The present study evaluated the clinical course and prognostic factors of GC patients with synchronous and metachronous other primary cancer who received curative treatment for GC. The major finding was that the synchronous and metachronous other primary cancer status was a prognostic factor for GC patients. In addition, the incidence of death from other cancers was significantly higher in GC patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer. Therefore, synchronous and metachronous other primary cancer patients need both other primary cancer and GC follow-up to improve their survival.
In the present study, colorectal cancer was the most frequent other primary cancer followed by lung cancer, prostate cancer in male patients and breast cancer in female patients. Similar trends were observed in previous studies. For example, Eom et al. evaluated the clinical impact of synchronous and metachronous GC in 4,593 GC patients (15). They found that 159 patients had synchronous and metachronous other primary cancer. They demonstrated that colorectal cancer was the most frequent other primary cancer followed by lung cancer. According to Global Cancer Statistics 2018, the most frequent cancer in males is lung cancer, followed by prostate cancer and colorectal cancer (2), while the most frequent cancer in females is breast cancer, followed by colorectal cancer and lung cancer. The types and frequency of other primary cancers in the present study were similar to general population and previous studies.
When comparing the patient background characteristics between GC patients without and with synchronous and metachronous other primary cancer, the median age was significantly higher in GC patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer. A similar trend was observed in Lee’s and Kato’s previous studies (16, 17). Although the previous studies showed that the incidence of early GC was higher in GC patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer, there was no significant difference in the clinical or pathological GC stage in the present study. The cause of these discrepancies between the present and previous studies is unclear.
In the present study, the prognosis of GC patients with synchronous and metachronous other primary cancer was significantly worse than that of GC patients without synchronous and metachronous other primary cancer. In addition, the synchronous and metachronous other primary cancer status is a prognostic factor for GC patients. There are several possible explanations for this. First, the incidence of postoperative surgical complications might have been higher in GC patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer because those with synchronous and metachronous other primary cancer received other cancer treatment, such as surgery, chemotherapy, and radiation therapy. Especially, chemotherapy and radiation therapy for other primary cancer might be affected by the nutritional and immunological statuses. Recent studies have shown that the nutritional and immunological status affect the occurrence of postoperative surgical complications in GC patients (18, 19). However, the incidence of postoperative surgical complications was not significantly different between the two groups in the present study. Second, the clinical course of the perioperative adjuvant treatment might have been different between these two patient groups. At the present, gastrectomy with D2 lymphadenectomy and perioperative adjuvant treatment is the standard treatment for GC. Previous chemotherapy for other primary cancer might affect the introduction and continuation of adjuvant treatment for GC and associated adverse events. However, the clinical course of adjuvant treatment was similar between the two groups. Third, the rate of the occurrence or recurrence of other primary cancer may have been higher in the GC patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer. In the present study, the incidence of death from other cancers was significantly higher in patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer (28.6% vs. 6.3%; p=0.039). Therefore, GC patients with synchronous and metachronous other primary cancer appear to need follow-up not only for GC but also for other primary cancer. However, the optimal mechanism why the prognosis of GC patients with synchronous and metachronous other primary cancer was significantly worse than GC patients without synchronous and metachronous other primary cancer. Further studies will focus on this issue.
One limitation associated with the present study is that the incidence of synchronous and metachronous other primary cancer in the present study was higher than that in other studies. Although the incidence of synchronous and metachronous other primary cancer in GC patients was almost 20% in the present study, previous studies have reported that this incidence is 1% to 5% (15-17). Notably, the present study was carried out on a case series from a single center. In addition, the GC patients with synchronous and metachronous other primary cancer in the present study were specifically selected and deemed fit for surgery, so generalization might be difficult.
In conclusion, the synchronous and metachronous other primary cancer status was one of the prognostic factors for GC patients. The incidence of death from other cancers was significantly higher in GC patients with synchronous and metachronous other primary cancer than in those without synchronous and metachronous other primary cancer. Therefore, GC patients with synchronous and metachronous other primary cancer need follow-up for both other primary cancer and GC to improve their survival.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number 21K08688.
Footnotes
Authors’ Contributions
TA, MJ, and KK made substantial contributions to the concept and design. TA, MJ, KK, HT, AT, KK2 (Kazuki Kano), IH, YM, HC, KH, TI, SO, TO, NY, TO and YR made substantial contributions to the acquisition of data and their analysis and interpretation. TA, MJ, HT, TO, NY and YR were involved in drafting the article or revising it critically for important intellectual content. TA, MJ, KK and TO gave their final approval of the version to be published.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received June 20, 2022.
- Revision received August 7, 2022.
- Accepted August 8, 2022.
- Copyright © 2022 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
