ABSTRACT
Background
Radical gastrectomy, followed by adjuvant chemotherapy has been a common practice in Japan for peritoneal lavage cytology‐positive (CY1) but peritoneal dissemination‐negative (P0) stage IV gastric cancer. This study aimed to clarify the differences in treatment outcomes between upfront surgery and preoperative chemotherapy, followed by surgery for patients with CY1P0 gastric cancer using data from Japanese patients recruited for the CONVO‐GC‐1 study.
Methods
This study used data from Japanese patients with CY1P0 gastric cancer recruited for the international retrospective observational CONVO‐GC‐1 study. Gastrectomy was performed between January 1, 2001, and December 31, 2014. CY1 was cytologically confirmed. The patients were divided into two groups: upfront surgery (Sx) and preoperative chemotherapy, followed by surgery (CSx). Patient background and survival outcomes were compared between the groups.
Results
Four hundred and thirty‐three patients treated at 45 Japanese institutions were analyzed. There were 306 and 127 patients in the Sx and CSx groups, respectively. The 5‐year overall survival (OS) rates were 19.2% in the Sx group and 35.9% in the CSx group, with a significant difference. When stratifying OS of the two groups by residual tumor status, the 5‐year OS rates were 43.0% in the CSx‐R0 group, 14.9% in the CSx‐R1 group, 20.7% in the Sx‐R1 group, and 0.0% in the CSx‐R2 and Sx‐R2 groups.
Conclusions
In CY1P0 gastric cancer, survival was better with preoperative chemotherapy, followed by surgery than with upfront surgery. Survival was particularly favorable in patients who underwent R0 resection.
Keywords: chemotherapy, cytology, gastrectomy, stomach neoplasms, survival
Short abstract
A subgroup analysis of Japanese patients was conducted in the CONVO‐GC‐1 trial. For CY1P0 gastric cancer, survival was better with preoperative chemotherapy, followed by surgery than with upfront surgery. Survival was particularly favorable in patients who underwent R0 resection.
1. Introduction
Gastric cancer is the sixth most common cancer and fifth leading cause of cancer‐related deaths worldwide [1]. Peritoneal lavage cytology‐positive (CY1) gastric cancer is classified as stage IV even if peritoneal dissemination is negative (P0) [2, 3]. Systemic chemotherapy is widely accepted as the standard treatment for stage IV advanced gastric cancer. However, similar to locally advanced gastric cancer, radical gastrectomy with lymph node dissection, followed by adjuvant chemotherapy has been a common practice in Japan for CY1P0 gastric cancer. In fact, the 5‐year overall survival (OS) rate for CY1P0 gastric cancer patients who underwent surgery, followed by adjuvant S‐1 chemotherapy was reported to be 26%–30.2%, which is relatively favorable [4, 5]. Treatment outcomes may improve if chemotherapy can convert CY1P0 to CY0P0 [6]. However, no reports have compared the treatment outcomes of upfront surgery, followed by adjuvant chemotherapy and preoperative chemotherapy, followed by surgery for CY1P0 gastric cancer.
The CONVO‐GC‐1 study, an international retrospective cohort study involving 55 institutions in Japan, Korea, and China, reported the survival outcomes of 1206 patients with stage IV gastric cancer who underwent surgery after preoperative chemotherapy [7]. Data on patients with CY1P0 gastric cancer who underwent upfront surgery were also collected outside the main cohort of the CONVO‐GC‐1 study, but were excluded from the original analysis. Therefore, the impact of upfront surgery versus preoperative chemotherapy, followed by surgery on the survival of patients with CY1P0 gastric cancer remains unclear.
This study aimed to clarify the differences in treatment outcomes between upfront surgery and preoperative chemotherapy, followed by surgery for patients with CY1P0 gastric cancer using data from Japanese patients recruited for the CONVO‐GC‐1 study. To ensure ethical and practical feasibility in terms of data governance, we focused our analysis on the patient data registered in Japanese institutions.
2. Methods
2.1. Participants
This study utilized data from Japanese patients with CY1P0 gastric cancer recruited for the international retrospective observational CONVO‐GC‐1 study [7].
Patients were histologically confirmed to have primary gastric cancer and staged according to the UICC classification (7th edition) and the Japanese classification of gastric carcinoma (3rd English edition) [3, 8]. Gastrectomy was performed between January 1, 2001 and December 31, 2014. CY1 was histologically confirmed through peritoneal lavage cytology performed during staging laparoscopy or gastrectomy. Staging laparoscopy was generally performed for patients with a type 4 or large type 3 tumor or suspected peritoneal dissemination based on an imaging examination. Peritoneal lavage cytology was routinely performed during surgery for advanced gastric cancer.
2.2. Treatment
Treatment for CY1P0 gastric cancer, including surgical procedures (gastrectomy and lymphadenectomy), the administration of preoperative chemotherapy (either as treatment for unresectable disease or as neoadjuvant therapy), perioperative chemotherapy regimens, and the use of restaging laparoscopy varied according to the policy of each institution. During the study period, laparoscopic gastrectomy and robotic gastrectomy were not common or recommended; thus, open surgery was the primary option. Immune checkpoint inhibitors had not yet been approved at the time of registration and were therefore not in use. Therefore, mainly cytotoxic agents were administered as systemic chemotherapies. Only a limited number of institutions administer intraperitoneal chemotherapy. The histological response to chemotherapy was evaluated according to the Japanese Classification of Gastric Carcinoma (3rd English edition) [3].
2.3. Study Design
The patients were divided into two groups: upfront surgery (Sx) and preoperative chemotherapy, followed by surgery (CSx). In the Sx group, patients were diagnosed with CY1 before or during surgery, but were treated with upfront surgery, or patients whose peritoneal lavage fluid collected during surgery were found to be CY1 after surgery. In the CSx group, patients initially received systemic chemotherapy after being diagnosed with CY1 through staging laparoscopy, and subsequently underwent gastrectomy. Patient background and survival outcomes were compared between the groups.
To evaluate the effect of postoperative chemotherapy on survival, survival outcomes were compared between patients with and without postoperative chemotherapy in both the Sx and CSx groups. Patients in the Sx group who underwent R2 resection and those who underwent R1 resection due to positive margins were excluded. In the CSx group, only patients with ypStage II or III disease who underwent R0 resection were analyzed. Furthermore, because the study dataset could not strictly distinguish between adjuvant chemotherapy and chemotherapy following recurrence, chemotherapy initiated within 60 days postoperatively is presumed to be predominantly adjuvant chemotherapy.
2.4. Statistical Analysis
The Wilcoxon rank‐sum test was used for continuous variables and Fisher's exact test was used for categorical variables. OS was defined as the time from the diagnosis to death due to any cause and was censored on the date of last contact for surviving patients. OS was calculated using the Kaplan–Meier method. The log‐rank test was used to determine the significance of the OS in each group. Two‐sided p values of < 0.05 were considered statistically significant. All statistical analyses were performed using R Statistics (ver. 4.5.0, R Foundation for Statistical Computing, Vienna, Austria).
3. Results
3.1. Patient Characteristics
Among the 47 Japanese institutions participating in the CONVO‐GC‐1 study, two institutions declined to participate. Of the 433 patients analyzed in the present study, 306 underwent upfront surgery (Sx group), whereas 127 received preoperative chemotherapy, followed by surgery (CSx group). The patient characteristics at the time of the diagnosis are shown in Table 1. In the CSx group, patients were younger and tended to have more type 4 tumors and tumors with undifferentiated histology in comparison to the Sx group.
TABLE 1.
Patient characteristics.
| Characteristics | Sx group (n = 306) | CSx group (n = 127) | p |
|---|---|---|---|
| Age (years) | 69 (61–76) | 63 (54–69) | < 0.001 |
| Sex | 0.129 | ||
| Male | 196 (64.1%) | 71 (55.9%) | |
| Female | 110 (35.9%) | 56 (44.1%) | |
| BMI (kg/m 2) | 21.3 (19.1–23.3) | 21.1 (19.5–23.5) | 0.749 b |
| ECOG‐PS | 0.828 | ||
| 0 | 260 (85.0%) | 109 (85.8%) | |
| 1 | 42 (13.7%) | 16 (12.6%) | |
| 2 | 3 (1.0%) | 2 (1.6%) | |
| 3 | 1 (0.3%) | 0 (0.0%) | |
| Macroscopic type | < 0.001 c | ||
| Type 0 | 11 (3.6%) | 1 (0.8%) | |
| Type 1 | 5 (1.6%) | 0 (0.0%) | |
| Type 2 | 51 (16.7%) | 9 (7.1%) | |
| Type 3 | 160 (52.3%) | 39 (30.7%) | |
| Type 4 | 76 (24.8%) | 72 (56.7%) | |
| Type 5 | 3 (1.0%) | 5 (3.9%) | |
| Unknown | 0 (0.0%) | 1 (0.8%) | |
| Histology | 0.007 c | ||
| Differentiated | 112 (36.6%) | 29 (22.8%) | |
| Undifferentiated | 190 (62.1%) | 97 (76.4%) | |
| Other | 2 (0.7%) | 0 (0.0%) | |
| Unknown | 2 (0.7%) | 1 (0.8%) | |
| Clinical depth of tumor invasion a | 0.435 | ||
| cT1 | 3 (1.0%) | 0 (0.0%) | |
| cT2 | 9 (2.9%) | 3 (2.4%) | |
| cT3 | 40 (13.1%) | 19 (15.0%) | |
| cT4a | 248 (81.0%) | 99 (78.0%) | |
| cT4b | 6 (2.0%) | 6 (4.7%) | |
| Clinical lymph node metastasis a | 0.007 c | ||
| cN0 | 122 (39.9%) | 43 (33.9%) | |
| cN1 | 66 (21.6%) | 38 (29.9%) | |
| cN2 | 83 (27.1%) | 31 (24.4%) | |
| cN3a | 35 (11.4%) | 9 (7.1%) | |
| cN3b | 0 (0.0%) | 4 (3.1%) | |
| Unknown | 0 (0.0%) | 2 (1.6%) |
Note: Data are shown as n (%) or median (interquartile range).
Abbreviations: BMI, body mass index; ECOG‐PS, Eastern Cooperative Oncology Group Performance Status.
Japanese Classification of Gastric Carcinoma, 3rd English Edition.
There were 24 patients with missing data.
Patients with missing data were excluded.
3.2. Preoperative Chemotherapy in the CSx Group
The preoperative chemotherapy and clinical responses to chemotherapy in the CSx group are shown in Table 2. Most of the patients (92.9%) underwent surgery after first‐line chemotherapy. Frequently used chemotherapy regimens in first‐line treatment were S‐1 plus cisplatin (SP), docetaxel plus cisplatin (DS), docetaxel, cisplatin, and S‐1 (DCS). The median preoperative chemotherapy period (from first chemotherapy to surgery) was 2.7 months (interquartile range; 2.3–3.5). Whether a staging laparoscopy was performed after preoperative chemotherapy and before surgery in the CSx group remains unknown because we did not collect such data.
TABLE 2.
Preoperative chemotherapy (in the CSx group).
| Characteristics | CSx group (n = 127) |
|---|---|
| Treatment line before surgery | |
| 1st line | 118 (92.9%) |
| 2nd line | 9 (7.1%) |
| 1st line regimen | |
| SP | 67 (52.8%) |
| DS | 18 (14.2%) |
| DCS | 12 (9.4%) |
| XP | 2 (1.6%) |
| S‐1 | 1 (0.8%) |
| FP | 1 (0.8%) |
| Others | 26 (20.5%) |
| 2nd line regimen (n = 9) | |
| S‐1 | 2 (22.2%) |
| SP | 2 (22.2%) |
| CPT11 + CDDP | 1 (11.1%) |
| Others | 4 (44.4%) |
| Chemotherapy period (months) | 2.7 (2.3–3.5) |
| Clinical response of chemotherapy before surgery a | |
| CR | 1 (0.8%) |
| PR | 26 (20.5%) |
| SD | 32 (25.2%) |
| Non‐CR/non‐PD | 35 (27.6%) |
| PD | 5 (3.9%) |
| Unknown | 28 (22.0%) |
Note: Data are shown as n (%) or median (interquartile range).
Abbreviations: CPT11 + CDDP, Irinotecan plus cisplatin; CR, Complete Response; DCS, Docetaxel, cisplatin, and S‐1; DS, Docetaxel plus S‐1; FP, Fluorouracil plus cisplatin; Non‐CR/non‐PD, Non‐Complete Response/Non‐Progressive Disease; PD, Progressive DiseasePR, Partial Response; S‐1, Tegafur/gimeracil/oteracil; SD, Stable Disease; SP, S‐1 plus cisplatin; XP, Capecitabine plus cisplatin.
Response Evaluation Criteria in Solid Tumor (RECIST) version1.1.
3.3. Surgical Outcomes and Postoperative Chemotherapy
The details of the surgery and histological results are presented in Table 3. In the CSx group, patients tended to have more total gastrectomy, more D2 or more lymphadenectomy, and longer operation time. In the CSx group, R0 resection was possible in 76.4% of the patients.
TABLE 3.
Surgical and pathological results and postoperative chemotherapy.
| Characteristics | Sx group (n = 306) | CSx group (n = 127) | p |
|---|---|---|---|
| Type of gastrectomy | < 0.001 | ||
| Total | 183 (59.8%) | 109 (85.8%) | |
| Distal | 121 (39.5%) | 18 (14.2%) | |
| Proximal | 2 (0.7%) | 0 (0.0%) | |
| Lymphadenectomy a | 0.007 d | ||
| D0 | 1 (0.3%) | 2 (1.6%) | |
| D1 | 92 (30.1%) | 24 (18.9%) | |
| D2 | 208 (68.0%) | 95 (74.8%) | |
| D2 + PAND | 4 (1.3%) | 6 (4.7%) | |
| Unknown | 1 (0.3%) | 0 (0.0%) | |
| Operation time (min) | 237 (200–273) | 266 (226–354) | < 0.001 e |
| Blood loss (mL) | 405 (238–620) | 357 (222–669) | 0.814 f |
| Residual tumor b | < 0.001 | ||
| R0 | 0 (0.0%) | 97 (76.4%) | |
| R1 | 284 (92.8%) | 25 (19.7%) | |
| R2 | 22 (7.2%) | 5 (3.9%) | |
| Histological response b | — | ||
| Grade 0 | — | 7 (5.5%) | |
| Grade 1a | — | 35 (27.6%) | |
| Grade 1b | — | 25 (19.7%) | |
| Grade 2 | — | 34 (26.8%) | |
| Grade 3 | — | 5 (3.9%) | |
| Unknown | — | 21 (16.5%) | |
| Pathological depth of tumor invasion b | < 0.001 d | ||
| pT1/ypT1 | 2 (0.7%) | 4 (3.1%) | |
| pT2/ypT2 | 0 (0.0%) | 6 (4.7%) | |
| pT3/ypT3 | 30 (9.8%) | 40 (31.5%) | |
| pT4a/ypT4a | 241 (78.8%) | 62 (48.8%) | |
| pT4b/ypT4b | 32 (10.5%) | 10 (7.9%) | |
| pTX/ypTX | 0 (0.0%) | 1 (0.8%) | |
| Unknown | 1 (0.3%) | 4 (3.1%) | |
| Pathological lymph node metastasis b | < 0.001 | ||
| pN0/ypN0 | 17 (5.6%) | 34 (26.8%) | |
| pN1/ypN1 | 22 (7.2%) | 21 (16.5%) | |
| pN2/ypN2 | 32 (10.5%) | 21 (16.5%) | |
| pN3a/ypN3a | 95 (31.0%) | 32 (25.2%) | |
| cN3b/ypN3b | 140 (45.8%) | 19 (15.0%) | |
| Postoperative chemotherapy | 0.430 | ||
| Administrated | 242 (79.1%) | 105 (82.7%) | |
| Not administrated | 64 (20.9%) | 22 (17.3%) | |
| Postoperative chemotherapy regimen c | < 0.001 d | ||
| S‐1 | 201 (83.1%) | 68 (64.8%) | |
| SP | 16 (6.6%) | 4 (3.8%) | |
| DS | 4 (1.7%) | 5 (4.8%) | |
| Paclitaxel | 3 (1.2%) | 8 (7.6%) | |
| Other | 17 (7.0%) | 19 (18.1%) | |
| NA | 1 (0.4%) | 1 (1.0%) | |
| Postoperative chemotherapy start date (days postoperatively) c | 40 (31–51) | 39 (26–60) | 0.820 |
Note: Data are shown as n (%) or median (interquartile range).
Abbreviation: PAND, Para‐aortic lymph node dissection.
Japanese gastric cancer guidelines 2018 (5th edition).
Japanese Classification of Gastric Carcinoma, 3rd English Edition.
Patients who did not administered postoperative chemotherapy (n = 86) were excluded.
Patients with missing data were excluded.
There were 19 patients with missing data.
There were 22 patients with missing data.
Among the 106 patients for whom data were available for the histological response to chemotherapy, grade 1b or higher was observed in 64 patients (60.4%).
Postoperative complications are shown in Table 4. Grade ≥ 3 complications were observed in 11.5% of the patients in the Sx group and 11.8% of the patients in the CSx group. The rates and severity of the complications were similar. Postoperative chemotherapy was administered to approximately 80% of the patients in both groups (Table 3).
TABLE 4.
Postoperative complication.
| Complication | G1 | G2 | G3 | G4 | G5 |
|---|---|---|---|---|---|
| Sx group (n = 306) | |||||
| Anastomotic leakage | 0 (0.0) | 0 (0.0) | 6 (2.0) | 0 (0.0) | 0 (0.0) |
| Pancreatic fistula | 8 (2.6) | 7 (2.3) | 17 (5.6) | 0 (0.0) | 0 (0.0) |
| Abdominal abscess | 0 (0.0) | 4 (1.3) | 12 (3.9) | 1 (0.3) | 0 (0.0) |
| Pneumonia | 1 (0.3) | 11 (3.6) | 1 (0.3) | 0 (0.0) | 0 (0.0) |
| Others a | 8 (2.6) | 15 (4.9) | 12 (3.9) | 1 (0.3) | 0 (0.0) |
| Total a | 15 (4.9) | 29 (9.5) | 33 (10.8) | 2 (0.7) | 0 (0.0) |
| CSx group (n = 127) | |||||
| Anastomotic leakage | 0 (0.0) | 1 (0.8) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
| Pancreatic fistula | 0 (0.0) | 2 (1.6) | 6 (4.7) | 0 (0.0) | 0 (0.0) |
| Abdominal abscess | 0 (0.0) | 3 (2.4) | 4 (3.1) | 0 (0.0) | 0 (0.0) |
| Pneumonia | 0 (0.0) | 1 (0.8) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
| Others a | 4 (3.1) | 6 (4.7) | 6 (4.7) | 1 (0.8) | 0 (0.0) |
| Total a | 3 (2.4) | 10 (7.9) | 14 (11.0) | 1 (0.8) | 0 (0.0) |
Note: Data are shown as n (%). Clavien‐Dindo classification.
Most severe complication.
3.4. Survival Outcomes
The OS of the two groups is shown in Figure 1. The median OS and 5‐year survival rate were 21.9 months (95% CI; 19.9–27.4) and 19.2%, respectively, in the Sx group, and 38.4 months (95% CI; 30.5–47.6) and 35.9% in the CSx group, which amounted to a significant difference. Multivariate analyses of baseline factors associated with overall survival shows initial treatment as independent prognostic factor (Table 5). The OS according to preoperative chemotherapy regimen is shown in Figure S1. Survival among patients receiving SP was comparable to that of patients receiving other regimens. The OS of Sx group patients (excluding patients who underwent R2 resection and those who underwent R1 resection due to positive margins) according to the administration of postoperative chemotherapy is shown in Figure S2. The median OS and 5‐year survival rate were 29.8 months (95% CI: 27.1–36.0) and 26.1%, respectively, in patients who received any postoperative chemotherapy, and 13.1 months (95% CI: 10.7–17.0) and 5.7% in patients did not, which amounted to a significant difference. The clinicopathological characteristics of the patients are presented in Table S1. If postoperative chemotherapy was limited to that which started within 60 days after surgery, the result was similar; the median OS and 5‐year survival rate were 30.5 months (95% CI; 26.5–41.8) and 28.7%, respectively, in patients who received postoperative chemotherapy, and 16.9 months (95% CI; 15.1–19.9) and 7.3% in patients who did not, which amounted to a significant difference.
FIGURE 1.
Kaplan–Meier curves. Overall survival curves according to initial treatment. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio; Sx, upfront surgery.
TABLE 5.
Univariate and multivariate analyses of baseline factors associated with overall survival using Cox proportional hazards models.
| Characteristics | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| Age (≤ 75 vs. > 75 years) | 0.414 | 0.319–0.538 | < 0.001 | 0.472 | 0.360–0.619 | < 0.001 |
| Sex (Male vs. Female) | 1.134 | 0.899–1.430 | 0.300 | |||
| BMI (≤ 21 vs. > 21/Unknown kg/m2) | 1.194 | 0.953–1.494 | 0.100 | 1.121 | 0.894–1.406 | 0.323 |
| ECOG‐PS (0 vs. ≥ 1) | 0.558 | 0.412–0.756 | < 0.001 | 0.683 | 0.501–0.932 | 0.016 |
| Macroscopic type (Type 4 vs. Others) | 1.111 | 0.879–1.405 | 0.400 | |||
| Histology (Undifferentiated type vs. Others) | 1.062 | 0.838–1.347 | 0.600 | |||
| Clinical depth of tumor invasion a (≤ T3 vs. T4) | 1.104 | 0.823–1.482 | 0.500 | |||
| Clinical lymph node metastasis a (N0 vs. N+/Unknown) | 0.831 | 0.657–1.050 | 0.100 | 0.793 | 0.627–1.003 | 0.052 |
| Initial treatment (Chemotherapy vs. Surgery) | 0.553 | 0.421–0.725 | < 0.001 | 0.626 | 0.479–0.818 | < 0.001 |
Abbreviations: BMI, body mass index; CI, confidence interval; ECOG‐PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.
Japanese Classification of Gastric Carcinoma, 3rd English edition.
The OS of the two groups stratified by the residual tumor status is shown in Figure 2. The median OS and 5‐year survival rate were 42.4 months (95% CI; 35.7—not‐reached: NR) and 43.0%, respectively, in the CSx group patients with R0 resection, 27.9 months (95% CI; 23.7–44.0) and 14.9% in CSx group patients with R1, 23.5 months (95% CI; 20.3–28.8) and 20.7% in Sx group patients with R1, 18.1 months (95% CI; 8.9—NR) and 0.0% in the CSx group patients with R2, and 11.7 months (95% CI; 8.9–27.0) and 0.0% in the Sx group patients with R2. The CSx‐R0 group, in which peritoneal lavage cytology was negative by chemotherapy, showed the highest rate of survival. The survival outcomes of patients whose peritoneal lavage cytology did not become negative were similar to those of patients who underwent upfront surgery (CSx‐R1 vs. Sx‐R1). For R2 resection, the 5‐year survival rate was 0% in both groups. The OS according to macroscopic tumor type is shown in Figure S3. In the CSx‐R0 and CSx‐R1 groups, survival did not differ significantly between type 4 and non‐type 4 tumors. However, among Sx‐R1 patients, type 4 tumors were associated with significantly poor survival. The OS of the CSx group patients with ypStage II or III who underwent R0 resection according to postoperative chemotherapy is shown in Figure S4. The clinicopathological characteristics of the patients are shown in Table S2. Unlike the Sx group, patients who underwent any postoperative chemotherapy or chemotherapy started within 60 days postoperatively had comparable survival outcomes to those who did not receive postoperative chemotherapy.
FIGURE 2.
Kaplan–Meier curves. Overall survival curves according to initial treatment and residual tumor. CSx, preoperative chemotherapy, followed by surgery; R0, no residual tumor; R1, microscopic residual tumor; R2, macroscopic residual tumor; Sx, upfront surgery.
4. Discussion
The present study focused on CY1P0 gastric cancer and clarified the survival outcomes of patients treated with upfront surgery or preoperative chemotherapy, followed by surgery, using data obtained from a large number of facilities in Japan. Despite more unfavorable oncological factors such as type 4 tumor and undifferentiated histological type, the OS of the CSx group was significantly better than that of the Sx group. Additionally, preoperative chemotherapy remained an independent favorable prognostic factor after adjustment.
One interesting finding is that the OS of the CSx and Sx groups was comparable based on residual tumor status. The 5‐year OS rate of the CSx group with R0 resection was 43.0%, which is favorable and corresponds to that of patients with stage IIIB disease in a nationwide survey by the Japanese Gastric Cancer Association based on registry data from patients who underwent surgery during the same period [9]. Therefore, administering preoperative chemotherapy to initially CY1P0 gastric cancer patients helps in selecting patients who can benefit from surgery. These results indicate that, to further improve the outcomes of CY1P0 gastric cancer, aggressive preoperative chemotherapy should be used to convert CY1P0 to CY0P0 and achieve R0 resection. Furthermore, even if CY failed to convert to negative, there would be no disadvantage to preoperative chemotherapy unless obvious tumor progression occurred, since survival after R1 resection was similar in the two groups. No studies have compared the survival outcomes between continuing chemotherapy and radical gastrectomy in patients in whom CY does not convert to negative after chemotherapy. Therefore, it remains unclear whether surgery should be performed in such cases. Randomized controlled trials comparing surgical treatment with continued chemotherapy in patients in whom CY does not become negative after chemotherapy are needed to resolve this question.
The rate of conversion from CY1P0 to CY0P0 through chemotherapy was reported to be 43.7% (45/103) by Yamaguchi et al. [6]. Conversely, for patients whose cancer progressed despite chemotherapy, 26.6% (40/150) of the patients in the Initial‐Cx group did not undergo surgery. However, the reasons for not undergoing surgery have not been specified. Iwasaki et al. evaluated the efficacy of neoadjuvant chemotherapy (NAC) using S‐1 plus cisplatin for type 4 or large type 3 gastric cancers in a randomized controlled trial (JCOG0501) [10]. They reported that the CY1 rate in the neoadjuvant chemotherapy (NAC) group (Arm B) decreased from 21.2% (32/151) before NAC to 13.7% (19/139) at the time of surgery after NAC. In this study, 3.3% (5/151) of patients did not undergo gastrectomy due to tumor progression. However, the study included a small number of patients with P1a/1b, and it did not mention patients in whom CY0 changed to CY1 after NAC. Therefore, caution should be exercised when interpreting the results. In a single‐institution retrospective study, Yasufuku et al. [11] reported that the conversion rate following NAC for type 4 and large type 3 gastric cancers was 40.6%. These results were obtained in an era when mainly cytotoxic agents were used, as in this study. In the future, if more effective molecularly targeted drugs are developed, especially for undifferentiated and diffuse types, the conversion rate from CY1P0 to CY0P0 through chemotherapy can be expected to improve [12, 13, 14].
Few studies have compared treatment outcomes between patients treated with upfront surgery and those who received preoperative chemotherapy, followed by surgery for initial CY1P0 gastric cancer. Yamaguchi et al. [6] retrospectively collected data from 824 patients with CY1 and/or P1a gastric cancer from multiple institutions in Japan and divided them into two groups: those who underwent upfront surgery (Initial‐Sx) and those who underwent chemotherapy as the initial treatment (Initial‐Cx). Approximately 70% of the patients in both groups had CY1P0. OS and progression‐free survival (PFS) were comparable between the two groups, and a subgroup analysis showed that patients who converted to P0CY0 in the Initial‐Cx group had favorable survival outcomes, with a median OS of 32.0 months. However, the study also included patients with P1a gastric cancer, and a detailed subgroup analysis of patients with CY1P0 was not conducted. Therefore, for the first time, we revealed a detailed comparison of treatment outcomes between patients who received upfront surgery and those who received preoperative chemotherapy, followed by surgery for CY1P0 advanced gastric cancer.
The duration of preoperative chemotherapy is also important when radical surgery is performed. The median duration of preoperative chemotherapy in the present cohort was 2.7 months, which was similar to that of general neoadjuvant chemotherapy. Additionally, it is generally comparable to the duration of preoperative chemotherapy for CY1 and/or P1a gastric cancer, as reported by Yamaguchi et al. [6]. At that time in Japan, chemotherapy for CY1P0 gastric cancer was administered as treatment for unresectable disease. In such cases, surgery was considered for patients who showed a sufficient response to chemotherapy, such as conversion from CY1P0 to CY0P0. Conversely, at some institutions, chemotherapy was used as neoadjuvant treatment, and radical gastrectomy was performed even when cytology remains positive, as long as there was no obvious tumor progression. There are currently no detailed reports on the optimal duration of preoperative chemotherapy for CY1P0 gastric cancer. The median time to maximum tumor shrinkage by chemotherapy in patients with unresectable or recurrent gastric cancer is reported to be 2.4–5 months [15, 16, 17, 18]. Hence, further comparative studies with longer preoperative chemotherapy durations are required.
Regarding postoperative chemotherapy, the results of the present study suggest that it may improve survival in the Sx group, consistent with the established benefit of adjuvant chemotherapy for locally advanced gastric cancer [19, 20]. However, because the clinical background differed substantially between patients who received postoperative chemotherapy and those who did not, this result should be interpreted with caution. Although this study cannot strictly distinguish between adjuvant chemotherapy and chemotherapy after recurrence, chemotherapy initiated within 60 days postoperatively is presumed to be predominantly adjuvant chemotherapy. The survival outcomes of these patients were consistent with those previously reported [4, 5]. In contrast, in patients with CY1P0 gastric cancer who underwent preoperative chemotherapy, followed by radical gastrectomy, the efficacy of adjuvant chemotherapy was not demonstrated in the present study. Further research is needed to determine the efficacy of adjuvant chemotherapy in patients who receive R0 resection.
This study had several limitations. First, because this was a retrospective study, there were biases between the two groups in terms of both background factors and facilities. Treatment decisions, including surgical indications and the diagnostic methods used to determine them, were determined individually by each institution. Ideally, a randomized controlled trial is necessary to overcome this bias. However, given the current trend toward multidisciplinary treatment development, it is difficult to include an upfront surgery group. Second, the CSx group in the present study consisted only of patients who underwent surgery, and did not include patients who did not undergo surgery. Therefore, this study did not provide a comprehensive overview of patients who received initial chemotherapy for CY1P0 gastric cancer, and more reports are needed. Finally, the cohort used in the present study consisted of patients who underwent surgery between 2001 and 2014; therefore, the available drugs, postoperative adjuvant chemotherapy, and minimally invasive surgery differed from the current situation.
In conclusion, survival was better with preoperative chemotherapy, followed by surgery than with upfront surgery for CY1P0 gastric cancer. Survival was particularly favorable in patients who underwent R0 resection.
Author Contributions
Kenichiro Furukawa: conceptualization, methodology, data curation, formal analysis, writing – original draft, writing – review and editing, investigation. Itaru Yasufuku: conceptualization, methodology, data curation, formal analysis, project administration, writing – original draft, writing – review and editing, investigation. Hironori Ishigami: data curation, writing – original draft, writing – review and editing. Masahiro Yura: writing – original draft, writing – review and editing, data curation. Takanobu Yamada: data curation, writing – original draft, writing – review and editing. Shigeaki Baba: data curation, writing – original draft, writing – review and editing. Takeshi Kubota: data curation, writing – original draft, writing – review and editing. Erina Nagai: data curation, writing – original draft, writing – review and editing. Seito Fujibayashi: data curation, writing – original draft, writing – review and editing. Mitsumasa Yoshida: writing – original draft, writing – review and editing, conceptualization, data curation. Takahiro Kinoshita: conceptualization, data curation, writing – original draft, writing – review and editing. Nobuhisa Matsuhashi: conceptualization, writing – original draft, writing – review and editing. Masanori Terashima: conceptualization, methodology, data curation, formal analysis, writing – original draft, writing – review and editing, supervision.
Funding
The authors have nothing to report.
Disclosure
Study Group Affiliations: Gifu University, Tochigi Cancer Center, Keiyukai Sapporo Hospital, Kanagawa Cancer Center, Gunma Prefectural Cancer Center, Kyoto Prefectural University of Medicine, Hakodate Goryoukaku Hospital, Shizuoka Cancer Center, Dokkyo Medical University, Ishikawa Prefectural Central Hospital, Osaka General Medical Center, Medical Research Institute Kitano Hospital, NHO Osaka National Hospital, Nagoya University Graduate School of Medicine, Hiroshima City Hiroshima Citizens Hospital, Kochi Medical School, Hamamatsu University School of Medicine, Osaka Metropolitan University Hospital, Kobe University Graduate School of Medicine, Hyogo Medical University, Kanazawa Medical University, Hiroshima University, Institute of Science Tokyo Hospital, The University of Tokyo Hospital, Kitasato University School of Medicine, Gifu Municipal Hospital, Iwate Medical University, Kyushu University, Chiba Cancer Center, Okayama University Hospital, Cancer Institute Hospital, Kumamoto University, Mie University Graduate School of Medicine, Shizuoka General Hospital, Kagoshima University Graduate School of Medical and Dental Sciences, National Cancer Center Hospital East, National Cancer Center Hospital, The Jikei University School of Medicine, Keio University School of Medicine, Kyoto University, Saitama Medical University International Medical Center, Osaka University, Fukushima Medical University Hospital.
Ethics Statement
All procedures were conducted in accordance with the ethical standards of the corresponding committees on human experimentation (institutional and national) and the Helsinki Declaration of 1964 and its later versions. The Gifu University Review Board (approval number: 2024‐183) or review boards of the participating institutions approved all aspects of this study.
Consent
Each participating facility posted the study information on its website or other platforms and provided patients with the opportunity to opt out.
Conflicts of Interest
N.M. received research grants from Asahi Kasei Pharma, Chugai Pharm, Covidien Japan, Daiichi Sankyo, Eisai, e‐NA Biotec, EP‐CRSU, EPS Corporation, JMS, Johnson & Johnson, Kaken Pharm., Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharm., ShiftZero K.K., Taiho Pharm., TERUMO, and Toray Medical, and received honoraria from Abbott, Alfresa Pharma, AMCO Inc., Asahi Kasei Pharma, Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Bristol‐Myers Squibb, Chugai Pharm., Covidien Japan, Daiichi Sankyo, EA Pharma, Eisai, Eli Lilly Japan, Guardant Health Japan Corp, Gunze Medical Limited, Intuitive Surgical, Johnson & Johnson, Kaken Pharm., Kyowa Kirin, MC Medical, Merck Biopharma Japan, Miyarisan Pharm., MSD, Novartis, Olympus Marketing Inc., Ono Pharm., Stryker, Taiho Pharm., TAKATA Pharm, Takeda Pharm., TERUMO, Tsumura, Viatris, Yakult Honsha, and ZERIA Pharm. M.T. received honoraria from Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Bristol Myers Squib Japan K.K., Yakult Honsha Co. Ltd., Astra Zeneca Co. Ltd., Eli Lilly Japan K.K., Astellas Pharm. Inc., Daiichi Sankyo Ltd., Johnson and Johnson K.K., Medtronic Japan Co. Ltd., Intuitive Japan Inc., and Olympus Co. Ltd.
Supporting information
Table S1: Patient clinicopathological characteristics for all postoperative chemotherapy in the Sx group (patients with R2 resection and those with R1 resection due to positive margins were excluded).
Table S2: Patient clinicopathological characteristics for all postoperative chemotherapy in CSx group patients with ypStage II or III who underwent R0 resection.
Figure S1: Kaplan–Meier curves. Overall survival curves according to preoperative chemotherapy regimen in the CSx group. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio; S‐1, Tegafur/gimeracil/oteracil.
Figure S2: Kaplan–Meier curves. Overall survival curves according to any postoperative chemotherapy (A), and chemotherapy started within 60 days after surgery (B) in the Sx group. Sx, upfront surgery; CI, confidence interval; HR, hazard ratio.
Figure S3: Kaplan–Meier curves. Overall survival curves according to macroscopic tumor type in CSx‐R0 (A), CSx‐R1 (B), and Sx‐R1 (C) groups. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio; R0, no residual tumor; R1, microscopic residual tumor; R2, macroscopic residual tumor; Sx, upfront surgery.
Figure S4: Kaplan–Meier curves. Overall survival curves according to any postoperative chemotherapy (A), and chemotherapy started within 60 days after surgery (B) in the CSx group with ypStage were II or III who underwent R0 resection. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Patient clinicopathological characteristics for all postoperative chemotherapy in the Sx group (patients with R2 resection and those with R1 resection due to positive margins were excluded).
Table S2: Patient clinicopathological characteristics for all postoperative chemotherapy in CSx group patients with ypStage II or III who underwent R0 resection.
Figure S1: Kaplan–Meier curves. Overall survival curves according to preoperative chemotherapy regimen in the CSx group. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio; S‐1, Tegafur/gimeracil/oteracil.
Figure S2: Kaplan–Meier curves. Overall survival curves according to any postoperative chemotherapy (A), and chemotherapy started within 60 days after surgery (B) in the Sx group. Sx, upfront surgery; CI, confidence interval; HR, hazard ratio.
Figure S3: Kaplan–Meier curves. Overall survival curves according to macroscopic tumor type in CSx‐R0 (A), CSx‐R1 (B), and Sx‐R1 (C) groups. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio; R0, no residual tumor; R1, microscopic residual tumor; R2, macroscopic residual tumor; Sx, upfront surgery.
Figure S4: Kaplan–Meier curves. Overall survival curves according to any postoperative chemotherapy (A), and chemotherapy started within 60 days after surgery (B) in the CSx group with ypStage were II or III who underwent R0 resection. CI, confidence interval; CSx, preoperative chemotherapy, followed by surgery; HR, hazard ratio.