Edited by: Alberto Biondi, Catholic University of the Sacred Heart, Italy
Reviewed by: Chukwuemeka Ihemelandu, MedStar Washington Hospital Center, United States; Qiuming He, University of Texas MD Anderson Cancer Center, United States
*Correspondence: Hong-Feng Gou,
†These authors have contributed equally to this work
This article was submitted to Surgical Oncology, a section of the journal Frontiers in Oncology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Signet ring cell containing gastric cancer (SRCGC) is a rare subtype of gastric cancer, and its adjuvant therapy is based on general gastric cancer. However, the effectiveness of radiotherapy for those SRCGC patients remains unknown.
The purpose of the study was to analyze whether the addition of radiotherapy to adjuvant chemotherapy (CT) can benefit survival in resected SRCGC patients.
Patients with SRCGC, who underwent D2 gastrectomy followed by adjuvant chemotherapy or chemoradiotherapy (CRT), were retrospectively collected. According to the proportion of signet ring cells, patients were histologically classified as pure SRCGC (pSRCGC) containing 100% of signet ring cells, mixed SRCGC (mSRCGC) containing >50% of signet ring cells, and contaminated SRCGC (cSRCGC) containing <50% of signet ring cells. Among the 272 patients, 156 were treated by CT alone and 116 by CRT. The primary endpoint was 3-year overall survival rate (3-year OS rate).
With a median follow-up of 80.5 months, the 3-year OS rate was significantly higher in the CT group (70.5% vs. 58.6%, HR = 0.633,
Adjuvant chemoradiotherapy was associated with poor survival compared with adjuvant chemotherapy in SRCGC patients with D2 gastrectomy.
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide, with an estimated 783,000 deaths in GLOBOCAN 2018 (
Perioperative chemotherapy became a standard treatment for local advanced resectable gastric cancer in Western countries (
The purpose of this retrospective study was to confirm whether the addition of radiotherapy to adjuvant chemotherapy could benefit survival in patients with radically resected SRCGCs. We analyzed the overall survival for SRCGC patients in correlation with adjuvant CT and CRT. We also explored the characteristics related to poor prognosis and the pattern of recurrence in the SRCGC population. We hypothesized that SRC status may serve as a potential indicator for adjuvant treatment, therefore a tailored adjuvant treatment should be considered for patients with SRCGC.
The medical records of patients were retrospectively collected in a central teaching hospital (West China Hospital, Sichuan University) between August 2007 and December 2014. This study was based on the Surgical Gastric Cancer Patient Registry of West China Hospital (id: WCH-SGCPR-2019-01) (
All the patients underwent operations at West China Hospital. Distal or total gastrectomy was performed based on the location of the tumor, and a standard D2 or D2+ lymphadenectomy was generally performed according to the Japanese Gastric Cancer Treatment Guidelines (
Tumor staging was assessed according to the American Joint Committee on Cancer/Union International Control Center TNM Staging Manual, 7th edition (
Criteria for patients receiving adjuvant therapy are based on the NCCN Guidelines, including stage IB with high-risk factors, stages II and stage III. Patients were administered adjuvant treatment postoperative 3–8 weeks. The following primary chemotherapy schemes were accepted in our study: (1) S-1mono-regimen [body-surface area (BSA) <1.25 m2, 80 mg daily; BSA ≥1.25 m2 but <1.5 m2, 100 mg daily; BSA≥1.5 m2, 120 mg daily, d1-28, every 6 weeks]; (2) mFOLFOX6 (oxaliplatin 85 mg/m2, d1; CF 400 mg/m2, 2h, d1; 5-fluorouracil 400 mg/m2, iv, d1, and 2400 mg/m2, civ 48 h, every 2 weeks); (3) SOX (S-1 40 mg/m2/day, d1-14; oxaliplatin 130 mg/m2, d1, every 3 weeks). A less common regimen DCF (docetaxel 75 mg/m2, d1, cisplatin 20 mg/m2, d1, CF 200mg/m2, d1, 5-Fu 400 mg/m2, iv, d1 and 600 mg/m2, civ 48h, every 3 weeks) was also included. Among them, 29 patients received a single regimen, 235 patients received a double-agent combination, and 8 patients received triple-drug chemotherapy.
For postoperative chemoradiotherapy, patients received one cycle of adjuvant FOLFOX, SOX, S-1 mono-regimen, or DCF before starting radiotherapy. The 3D-CRT or IMRT technique was selected by the physician according to the complexity of the target volume and the organs at risk (OAR). Patients received CT simulation using helical CT scan and were treated in a supine position. The criterion of clinical target volume (CTV) was the gastric bed, anastomoses and stumps, and the draining lymph nodes. The planning target volume (PTV) comprised a 1.0 cm margin around the CTV. A total irradiation dose of 50.4 Gy was administered in 28 fractions of 1.8 Gy, 5 days per week. Dose constraints of critical organs were as follows: spinal cord Dmax < 40 Gy; liver V30 < 30%; two-thirds of one kidney less than 18 Gy or 30% of each kidney volume of each kidney less than 25 Gy. During the process of radiotherapy, S-1 (40 mg/m2/day) was orally given twice daily from day 1 to 5 per week. Two or four weeks after the completion of radiotherapy, additional cycles of regimen were given.
Follow-up lasted until June 30, 2018. The toxicity, survival status, follow-up duration, and loss were recorded. The primary endpoint was 3-year overall survival rate (3-year OS rate), referred to as the proportion of resected SRCGC patients who were alive 3 years after the primary surgery date. Treatment toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) (
The collection of medical information for the surgical gastric cancer patients was approved by the Biomedical Ethical Committee of West China Hospital, Sichuan University. The participants were not required to sign written informed consent in this retrospective study. However, the records were anonymized and de-identified before analyses. The study complied with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research involving human subjects.
Statistical analysis was performed using the Statistical Package for Social Science (SPSS), version 23.0. In the baseline comparisons, the ranked variables were compared by the Mann-Whitney U test, while continuous variables were compared by the Mann-Whitney U test or one-way ANOVA test, where applicable. Categorical variables were compared by Pearson’s chi-square test or Fisher’s exact test. The survival rates were calculated by the Kaplan-Meier method, median survival times (MST) were not reached, and the 3-year OS rate was expressed. Univariate survival analyses were performed by the log-rank test. Multivariable analysis of prognostic factors was conducted by the Cox proportional hazards model. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. Cox models in multivariate analyses were adjusted for clinicopathologic features, and surgical and adjuvant treatment, without selection procedure.
A total of 272 patients met the inclusion criteria between August 2007 and December 2014 (
Flow chart. SRCGC, Signet ring cell containing gastric cancer; CT, chemotherapy; CRT, chemoradiotherapy.
Patient characteristics (
Variables | Total |
CT group |
CRT group |
|
---|---|---|---|---|
Gender | 0.710 | |||
Male | 163 (59.9) | 92 (59.0) | 71 (61.2) | |
Female | 109 (40.1) | 64 (41.0) | 45 (38.8) | |
Age | 0.347 | |||
<60 | 213(78.3) | 119 (76.3) | 94 (81.0) | |
≥60 | 59 (21.7) | 37 (23.7) | 22 (19.0) | |
Tumor location | 0.321 | |||
Cardia/GEJ | 25 (9.2) | 12 (7.7) | 13 (11.2) | |
Non-cardia/GEJ | 247 (90.8) | 144 (92.3) | 103 (88.8) | |
Gastrectomy | 0.283 | |||
Subtotal | 174 (64.0) | 104 (66.7) | 70 (60.3) | |
Total | 98 (36.0) | 52 (33.3) | 46 (40.0) | |
Tumor size | 0.208 | |||
<5 cm | 141 (51.8) | 86 (55.1) | 55 (47.4) | |
≥5 cm | 131 (48.2) | 70 (44.9) | 61 (52.6) | |
Vessel invasion | 0.396 | |||
No | 204 (75) | 114 (73.1) | 90 (77.6) | |
Yes | 68 (25) | 42 (26.9) | 26 (22.4) | |
Perineural invasion | 0.748 | |||
No | 202 (74.3) | 117 (75.0) | 85(73.2) | |
Yes | 70 (25.7) | 39 (25.0) | 31(26.7) | |
TNM stage | 0.066 | |||
I | 20 (7.4) | 15 (9.6) | 5 (4.3) | |
II | 65 (23.9) | 42 (26.9) | 23 (19.8) | |
III | 187 (68.8) | 99 (63.5) | 88 (75.9) | |
T category | 0.552 | |||
T1 | 27 (9.9) | 19 (12.2) | 8 (6.9) | |
T2 | 41 (15.1) | 23 (14.7) | 18 (15.5) | |
T3 | 76 (27.9) | 43 (27.6) | 33 (28.4) | |
T4 | 128 (47.1) | 71 (45.5) | 57 (49.1) | |
N category | 0.001 | |||
N0 | 25 (8.8) | 23 (14.7) | 2 (1.7) | |
N1 | 45 (16.5) | 27 (7.3) | 18 (15.5) | |
N2 | 66 (24.2) | 35 (22.4) | 31 (26.7) | |
N3 | 136 (50.4) | 71 (45.5) | 65 (56.0) | |
SRC status | 0.573 | |||
cSRCGC | 123 (45.2) | 69 (44.2) | 54 (46.6) | |
mSRCGC | 99 (36.4) | 55 (35.3) | 44 (37.9) | |
pSRCGC | 50 (18.4) | 32 (20.5) | 18 (15.5) |
CT, chemotherapy; CRT, chemoradiotherapy; cSRCGC, contaminated signet ring cell containing gastric cancer; mSRCGC, mixed signet ring cell containing gastric cancer; pSRCGC, pure signet ring cell containing gastric cancer.
By the end of the follow-up date (June 30, 2018), 165 (60.7%) patients had recorded disease free survival (DFS), and 88 (53.3%) of them had local recurrence and metastases. To compare the pattern of recurrence more accurately in the different groups, we calculated the rates and sites of recurrence in those patients who had known DFS (
Pattern of recurrence (
Variables | Total |
pSRCGC |
mSRCGC |
cSRCGC |
|
---|---|---|---|---|---|
Recurrence | 0.9671 | ||||
No | 77 (46.7) | 15 (45.5) | 29 (46.0) | 33 (47.8) | |
Yes | 88 (53.3) | 18 (54.5) | 34 (54.0) | 36 (52.2) | |
Sites of recurrence | 0.0690 | ||||
Peritoneal | 37 (22.4) | 8 (24.2) | 14 (22.2) | 15 (21.7) | |
Lymph nodes# | 35 (21.2) | 9 (27.3) | 15 (23.8) | 11 (15.9) | |
Liver | 9 (5.5) | 0 | 1 (1.6) | 8 (11.6) | |
Other sites* | 19 (11.5) | 3 (9.1) | 10 (15.9) | 6 (8.7) | |
Median time to recurrence (months) | 19.0 | 21.8 | 17.5 | 19.0 | 0.6724 |
[range min–max] | [1–117.5] | [3–108.5] | [2–97.5] | [1–117.5] |
#Some patients had both nodal and extranodal sites of recurrence.
*Other sites including remnant stomach, lung, gallbladder, ovary, and bone.
The hematologic toxicities were gathered and are shown in
Hematologic toxicity (NCI-CTCAE v3.0)* (
CT group ( |
CRT group ( |
|
||||
---|---|---|---|---|---|---|
Toxicity | All grades |
Grade III/IV |
All grades |
Grade III/IV |
All grades | Grade III/IV |
Leukopenia | 90 (57.7) | 15 (9.6) | 86 (74.1) | 22 (19.0) | 0.005 | 0.026 |
Anemia | 118 (75.6) | 20 (12.8) | 86 (74.1) | 12 (10.3) | 0.777 | 0.531 |
Thrombocytopenia | 71 (45.5) | 12 (7.7) | 60 (51.7) | 14 (12.1) | 0.311 | 0.225 |
Neutropenia | 80 (51.3) | 13 (8.3) | 76 (65.5) | 13 (11.2) | 0.019 | 0.425 |
Elevated AST or ALT level | 69 (44.2) | 6 (3.8) | 54 (46.6) | 5 (4.3) | 0.704 | 0.848 |
*All adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
The median follow-up duration was 85.0 months (range 5.0–121.0 months), except for 8 patients with inadequate follow-up (3 in the CRT group and 5 in the CT group). A total of 108 (39.7%) of the 272 participants had died by the end of data accumulation on June 30, 2018. The 3-year OS was higher in the CT group than in the CRT group (70.5% vs. 58.6%, HR = 0.633,
Overall survival curves for patients grouped according to
In univariate analyses, several factors were statistically associated with poor survival: advanced TNM stage (
Variables with
Survival prediction by multivariate analysis of variables for patients with gastric SRC.
Variables | Total | No. events | Hazard ratio | 95%CI |
|
---|---|---|---|---|---|
Gender | |||||
Male | 163 | 68 | |||
Female | 109 | 49 | 0.946 | 0.638–1.405 | 0.784 |
Age | |||||
<60 | 213 | 88 | |||
≥60 | 59 | 29 | 1.245 | 0.783–1.979 | 0.354 |
Tumor location | |||||
Cardia/GEJ | 25 | 11 | |||
Non-cardia/GEJ | 247 | 106 | 0.670 | 0.340–1.320 | 0.247 |
Gastrectomy | |||||
Subtotal | 174 | 65 | |||
Total | 98 | 52 | 0.364 | 0.555–1.241 | 0.830 |
Tumor size | |||||
<5 cm | 141 | 39 | |||
≥5 cm | 131 | 78 | 2.281 | 1.487–3.499 | <0.001 |
Vessel invasion | |||||
No | 204 | 81 | |||
Yes | 68 | 36 | 1.740 | 1.148–2.639 | 0.009 |
T category | |||||
T1,T2 | 68 | 15 | |||
T3,T4 | 204 | 102 | 0.564 | 0.301–1.056 | 0.074 |
N category | |||||
N0,N1 | 70 | 20 | |||
N2,N3 | 202 | 97 | 0.932 | 0.547–1.591 | 0.797 |
SRC status | |||||
cSRCGC | 123 | 48 | |||
mSRCGC | 99 | 48 | 1.243 | 0.721–2.142 | 0.434 |
pSRCGC | 50 | 21 | 1.446 | 0.959–2.181 | 0.078 |
Treatment | |||||
CT | 156 | 57 | |||
CRT | 116 | 60 | 1.574 | 1.079–2.295 | 0.019 |
Subgroup analyses were performed to identify patients who may benefit from chemotherapy (
Forest plot for survival hazard ratios and CIs for treatment within subsets of the selected variables.
Despite considerable advances in treatment, the prognosis in GC patients is still poor, especially in cases of diffuse subtype or SRC adenocarcinoma. Adjuvant chemotherapy is a recommendable treatment for resectable GC, with the potential of improving survival outcome (
The ARTIST trial compared the adjuvant capecitabine and cisplatin (XP) regimen to chemoradiotherapy (XP plus radiotherapy with capecitabine) in patients with D2 gastrectomy, while the addition of radiotherapy did not improve the DFS and OS significantly (
Together with our and previous research results, adjuvant chemoradiotherapy might not benefit patients with SRCGC. It may be due to the fact that diffuse gastric cancer appears to have decreased intracellular adhesion as a result of E-cadherin mutation and/or hypermethylation (
Not only is the benefit of additional radiotherapy for SRCGCs still controversial, but there is no currently recognized standard regimen for SRCGCs in adjuvant setting due to poor tumor differentiation and lower chemosensitivity (
Our study has several limitations. First, the nature of retrospective design without randomized allocation made selection bias unable to be avoided. Patients in the CT group tended to have earlier N category than those in the CRT group. However, the differences between the number of N0 and N3 categories in the CT and CRT groups were not obvious. In multivariate analyses, the N category was not proven to be an independent factor of poor survival, which may have little effect on the final results. Second, similarly due to the retrospective nature, the variation of regimens might introduce potential performance bias. Third, the definite SRCGC only contains pSRCGC (100%) and mSRCGC (>50%) according to WHO classification, thus cSRCGC (≤50%) may partially function as a negative control. In our study, 44.3% of patients were cSRCGC, which may lead to the lower power of definite SRCGC (pSRCGC and mSRCGC) subgroup to gain robust conclusion. Finally, it must be considered that the classification of SRCGC subtypes may differ among pathologists. Nevertheless, there are some advantages we have to mention. To our knowledge, it might be the first data of SRCGC patients comparing adjuvant chemotherapy with chemoradiotherapy.
In conclusion, our study might be the first data of SRCGC patients comparing adjuvant chemotherapy with chemoradiotherapy. Adjuvant chemoradiotherapy may not bring additional survival benefits compared to adjuvant chemotherapy in SRCGC patients with D2 gastrectomy. Specially, chemoradiotherapy should be considered with caution in patients with signet ring cell proportion less than 50%, lower-middle site tumor, partial gastrectomy, male, <60 years old, and have no vessel invasion. Therefore, adjuvant chemoradiotherapy shouldn’t be performed routinely for SRCGC patients in general practice. We suggest that a tailored adjuvant scheme could be further investigated based on SRC status, and high-qualified prospective trials are required to obtain more robust evidence.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
H-FG, XW, and DC participated in the study design. Y-TZ, X-ZC, and YC participated in manuscript preparation. D-YL, MQ, and QL designed the methodology. YY, Y-LS, and Z-PL participated in data analysis and prepared figures. Y-TZ, Y-WZ, and L-ST collected the detailed information of patients. FB and J-YL reviewed and revised manuscript. All authors contributed to the article and approved the submitted version.
The authors disclosed receipt of the following financial support for the research, authorship, and publication of this article: This work was supported by the National Natural Science Foundation of China (Grant No. 81672397).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.