Addition of Taxanes to Platinum and Fluoropyrimidines in Adjuvant Setting Did Not Improve Survival in Patients with Gastric Cancer after Curative Gastrectomy

Background To evaluate whether the addition of taxane to platinum and fluoropyrimidines in adjuvant chemotherapy would result in longer survival than platinum plus fluoropyrimidines in patients who underwent curative gastrectomy. This study retrospectively analyzed survival for patients with stage Ⅱ-Ⅲ gastric adenocarcinoma who received curative gastrectomy and adjuvant chemotherapy with platinum plus fluoropyrimidines (PF group) or taxanes and platinum plus fluoropyrimidines (TPF group). Survival curves were estimated using the Kaplan-Meier method, and the differences were compared using the log-rank test. Baseline characteristics were balanced between the PF group and TPF group. The median disease-free survival (DFS) was 14.9 months ( 95% CI : 11.0-18.8) in the PF group and 13.8 months ( 95% CI : 9.3-18.3) in the TPF group ( HR =0.90, 95% CI : 0.63-1.29, log-rank test , P =0.560). The median overall survival (OS) was 30.0 months for patients in the PF group ( 95% CI : 24.5-35.5) and 25.6 months ( 95% CI : 22.3-28.9) for those in the TPF group ( HR =0.93, 95% CI : 0.64-1.35, log-rank test , P =0.705).


Background
To evaluate whether the addition of taxane to platinum and fluoropyrimidines in adjuvant chemotherapy would result in longer survival than platinum plus fluoropyrimidines in patients who underwent curative gastrectomy.

Methods
This study retrospectively analyzed survival for patients with stage Ⅱ-Ⅲ gastric adenocarcinoma who received curative gastrectomy and adjuvant chemotherapy with platinum plus fluoropyrimidines (PF group) or taxanes and platinum plus fluoropyrimidines (TPF group). Survival curves were estimated using the Kaplan-Meier method, and the differences were compared using the log-rank test.

Results
Baseline characteristics were balanced between the PF group and TPF group. The

Conclusion
For stage Ⅱ-Ⅲ gastric adenocarcinoma, the adjuvant triple combination of TPF regimen after curative gastrectomy did not demonstrate survival benefit compared to the PF regimen. Background 4 It was estimated that there are more than 1 million incident gastric cancer cases worldwide every year, of which 44% were diagnosed in China [1]. For resectable cases, surgery is the only curative approach, either alone or in combination with perioperative treatment. Radical gastrectomy with D2 lymphadenectomy followed by adjuvant chemotherapy is now considered as standard of care for most gastric cancers in Asian countries [2]. Monotherapy or doublet regimens were frequently used in adjuvant settings. According to results of randomized clinical trials, oxalipatin plus capecitabine or S1 monotherapy were recommended adjuvant regimens [3,4]. In fact, in actual clinical practice, varied doublet combinations of platinum (oxalipatin, cisplatin, or lobaplatin) with fluoropyrimidines (5-fluorouracil, capecitabine or S1) were all universally acceptable adjuvant regimens. Taxanes, which mainly consist of docetaxel or paclitaxel, are effective in gastric cancer treatment and were also tested in adjuvant settings. In the Stomach Cancer Adjuvant Multi-Institutional Group Trial (SAMIT), sequential paclitaxel followed by oral fluoropyrimidines as adjuvant chemotherapy for T4a/b gastric cancer did not improve disease-free survival (DFS) compared to oral fluoropyrimidines [5].
However, recently, docetaxel plus S1 was demonstrated to be superior to S1 monotherapy in stage Ⅲ gastric cancer treatment [6]. Triple combination chemotherapeutic regimens added with taxanes are usually used in perioperative or palliative settings for patients with good performance status [7,8]. Whether the addition of docetaxel or paclitaxel to the traditional combination of platinum and fluoropyrimidines as adjuvant regimen could improve survival for gastric cancer had not been explored in clinical trials. This retrospective study used real-world data from clinical practice and attempted to investigate the value of the triple combination regimen with taxanes in the adjuvant chemotherapy of patients with resectable stage Ⅱ-Ⅲ gastric cancer.

Patients
This retrospective study consisted of 156 patients diagnosed with gastric adenocarcinoma in the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China, from 2008 to 2016. All patients included in the study met the following criteria: underwent curative gastrectomy followed by adjuvant chemotherapy; with detailed postoperative pathological report and with stage Ⅱ or Ⅲ disease according to the American Joint Committee on Cancer (AJCC) seventh For platinum drugs, it could be cisplatin, oxaliplatin, or lobaplatin; for fluoropyrimidine compounds, intravenous 5-fluorouracil injection, oral capecitabine tablets, or tegafur-gimeracil-oteracil potassium capsules were all acceptable; taxanes could either be docetaxel or paclitaxel. In consideration of tolerance to toxicity, drug accessibility, etc., patients whose adjuvant chemotherapeutic drugs were switched from one platinum drug to another, or one fluoropyrimidine compound to another, or docetaxel to paclitaxel (vice versa) in different cycles were considered eligible. Patients who met any of following criteria were excluded from the study: did not receive curative surgery; diagnosed as having a very early phase of disease (stage Ⅰ); with no adjuvant chemotherapy apart from the abovementioned regimens; with missing information on surgery, pathology, adjuvant treatment, or recurrence and metastasis.

Data collection and follow-up
We retrieved the medical records of the patients from the Hospital Information System (HIS), and reviewed all related medical files. The following variables were collected: demographic variables including age and sex as well as pathological variables including tumor location, subtype, grade, tumor infiltration (T category), regional lymph node involvement (N category), vascular or perineuronal invasion by tumors in pathological specimens, and perigastric tumor deposits. Treatment information, including laparotomic approaches, scope of gastrectomy, type of lymphadenectomy, adjuvant chemotherapeutic drugs, date of the first and last dose of chemotherapeutic drug, and cycles of adjuvant chemotherapy, was obtained.
Staging groups were derived from the T and N categories according to the AJCC seventh staging system. The time to chemotherapy after surgery was defined as interval days from primary surgery to the first dose of adjuvant chemotherapy. The duration of adjuvant chemotherapy was defined as interval days from the first to the last dose of chemotherapeutic drug. Recurrence and metastasis were defined as tumor recurrence in situ (anastomotic stoma or gastric remnant) or metastasis to distant organs, lymph node(s), or intraperitoneal implantation after gastrectomy, with evidence of either imaging, cytology, or histopathology. Survival status was obtained from death records in the HIS or telephone follow-up on the patients or their relatives.

Statistical analysis
DFS was defined as interval months between gastrectomy and first evidence of recurrence and metastasis. Overall survival (OS) was defined as interval months between gastrectomy and death date or last follow-up date. For categorical variables, the Chi-square test was used to examine the differences between the two groups; for numerical variables and nonparametric independent samples the Mann-Whitney U test was used. Survival curves were calculated using the Kaplan-Meier method, and differences were compared using the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) and two-sided P values were reported. HRs in subgroups according to baseline characteristics and two-tailed 95% CIs were calculated using the Cox proportional hazards model. All statistical analyses were performed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA). Two-sided P < 0.05 was considered to be statistically significant. GraphPad Prism 5.01 software (GraphPad Software Inc., San Diego, CA, USA) was used to draw survival curves and forest maps of the subgroup analysis.  Table 1. The demographic characteristics, pathological factors, and surgical details of the patients were balanced between the PF group and TPF group.

Details of adjuvant chemotherapy in the two groups
The details of adjuvant chemotherapy are shown in Table 2. With regard to chemotherapeutic drugs, in both groups, approximately 60% of patients were treated with intravenous 5-fluorouracil in adjuvant settings (55.4% in the PF group and 68.2% in the TPF group, 2 test, P=0.143); the frequencies of capecitabine and S1 use were also similar, at 29.5% and 23.2% for capecitabine and S1 in the PF group compared to 25.0% and 25.0%, respectively, in the TPF group (P > 0.05).
More patients in the TPF group were treated with cisplatin than those in the PF group (56.8% vs. 2.7%, P=0.000); accordingly, more patients in the PF group were treated with oxaliplatin than those in the TPF group (93.8% vs. 56.8%, P=0.000).
The proportions of lobaplatin use were comparable between the two groups (7.1% in the PF group vs. 9.1% in the TPF group, P > 0.05). In the TPF group, 50% of patients

Disease-free survival
The median DFS was 14.9 months (95% CI: 11.0-18.8) in the PF group and 13.8 months (95% CI: 9.3-18.3) in the TPF group (HR=0.90, 95% CI: 0.63-1.29, log-rank test, P=0.560). Survival curves for DFS are shown in Figure 1a. Figure 2 shows a plot of Cox-adjusted DFS HRs (with 95% CIs) for the subgroups with respect to baseline characteristics. There were no differences in the effect of the TPF regimen on DFS relative to the PF regimen across all subgroups according to baseline characteristics.

Overall survival
As shown in Figure 1b, the median OS was 30.0 months for patients in the PF group (95% CI: 24.5-35.5) and 25.6 months (95% CI: 22.3-28.9) in the TPF group (HR=0.93, 95% CI: 0.64-1.35, log-rank test, P=0.705). Figure 3 shows that the effect of adjuvant PF regimen on survival relative to TPF regimen was different according to the Borrmann subtype; the PF regimen in patients with Borrmann Ⅰ/Ⅱ cancers resulted in marginally significantly better survival than the TPF regimen (HR=1.93, 95% CI: 1.03-3.62, P=0.041). The adjuvant TPF regimen did not show any survival benefit in comparison to the PF regimen in any gastric cancer subgroups.

Discussion
In Asian countries, the survival for stage Ⅱ-Ⅲ gastric cancer patients was improved  [12]. In the CALGB 80101 study, after curative resection of gastric or gastroesophageal junction adenocarcinoma, adjuvant chemoradiotherapy using the three-drug regimen of epirubicin, cisplatin, and infusional FU (ECF) did not improve survival compared with chemoradiotherapy with bolus fluorouracil and leucovorin [13]. A multicenter randomized phase Ⅱ trial (NCT02931890) of neoadjuvant docetaxel, oxaliplatin, plus capecitabine chemotherapy with or without radiotherapy in resectable gastric cancer had been initiated, and the results were as expected [14]. To our knowledge, our study is the first attempt to evaluate the triple-drug combination with taxanes as adjuvant chemotherapy for patients who underwent curative gastrectomy.
In this study, extended lymphadenectomy, also known as D2 gastrectomy, was carried out in only 47% of patients, similar to that of the MAGIC study, whereas in the CLASSIC and ACTS-GC trials, all patients underwent gastrectomy plus D2 gastrectomy. In fact, in the actual clinical practice, D1 lymphadenectomy is still performed by some surgeons. According to the INT-0116 study [15], of which D2 surgery was performed in only 10% of patients with gastric or gastroesophageal adenocarcinoma, postoperative chemoradiotherapy should be considered. However, our patients received adjuvant chemotherapy alone, but not radiation. In view of this fact and taking into account that postoperative chemoradiotherapy using the triple ECF regimen did not provide survival benefit in the CALGB 80101 study [13], we postulated that the omission of postoperative radiation may partially explain the overlap of survival curves for the two groups.
Due to the limitations in terms of data acquisition and the retrospective design of the study, treatment-related toxicity could not be detected in our study; as typically known, patients undergoing intensive chemotherapy may experience greater toxicities, and this could influence the efficacy of the adjuvant chemotherapy. In addition, some important information cannot be obtained in our study, for example, nutritional status after surgery, comorbidity, and postoperative complications et al. [16][17][18][19][20], These factors were considered to have an influence on the survival of the patients.

Conclusions
We concluded that adjuvant chemotherapy with taxanes, platinum and fluoropyrimidines for stage Ⅱ-Ⅲ gastric adenocarcinoma after curative gastrectomy

Consent for publication: Not applicable.
Availability of data and materials: The data that support the findings of this study are available from the corresponding author on reasonable request.

Competing interests:
The authors declare that they have no competing interests.  a Continuity correction 2; b Patients with either microscopic residues, or vessel invasion, or perineuronal invasion or tumor node in postoperative samples.  Overall survival hazard ratios (taxanes, platinum plus fluoropyrimidines over platinum plus fl