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Effect of apatinib plus neoadjuvant chemotherapy followed by resection on pathologic response in patients with locally advanced gastric adenocarcinoma: A single-arm, open-label, phase II trial
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Department of Gastrointestinal Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China
Treatment-naïve patients received S-1, oxaliplatin and apatinib before surgery.
•
Pathologic response rate was used as a primary end-point.
•
The pathologic response rate was 89.7%, with acceptable safety.
•
The pathologic complete response rate was 13.8%.
•
Neoadjuvant chemotherapy + apatinib was feasible for locally advanced gastric cancer.
Abstract
Background
The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma.
Methods
Treatment-naïve patients received three preoperative cycles of S-1 (80–120 mg/day on days 1–14) and oxaliplatin (130 mg/m2 on day 1) and two cycles of apatinib (500 mg/day for 21 days) at 3-week intervals, followed by surgery. The primary end-point was pathologic response rate (pRR). This trial is registered at ChiCTR.gov.cn: ChiCTR-OPC-16010061.
Results
Of 29 patients included, median age was 60 (range, 43–73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%–97.8%; 26 of 29 patients; P < 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%–92.0%) and a disease control rate of 96.6% (95% CI, 82.2%–99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%–99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%–26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients.
Conclusion
SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).
Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy--Japan Clinical Oncology Group study 9501.
]. Neoadjuvant chemotherapy may offer benefits for these patients. Combination chemotherapy with S-1 plus oxaliplatin (SOX) for advanced gastric cancer has shown promising efficacy with acceptable toxicity [
]. Nevertheless, there are still some patients who cannot benefit from the SOX regimen because of the heterogeneity of their gastric carcinoma or the homogenous insensitivity of tumour to chemotherapy. Molecular targeted therapy might be a better add-on option for those patients than conventional chemotherapeutic agents [
]. Antiangiogenic agents including anti-vascular endothelial growth factor (VEGF) antibodies and VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have shown potent anti-tumour activity in many human cancers [
Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.
Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
]. As reported in a phase III trial, apatinib treatment significantly improved overall survival and progression-free survival with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy [
Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
]. Given the current evidence of apatinib in advanced gastric cancer, we designed this study to preliminarily observe the efficacy and safety of the SOX regimen combined with apatinib (SOXA) as neoadjuvant therapy (NAT) for patients with locally advanced gastric adenocarcinoma in China.
2. Methods
2.1 Study design and patients
This was a single-arm, open-label phase II trial (ChiCTR-OPC-16010061) of treatment-naïve patients with resectable locally advanced gastric adenocarcinoma conducted at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between December 2016 and August 2018. This study was approved by the Ethics Committee of Ruijin Hospital. All patients provided written informed consent. The protocol is available in Supplement 1.
Eligibility criteria included age at 18–75 years, histologically and/or cytologically proven, previously untreated, clinical diagnosis of locally advanced gastric adenocarcinoma, cT3/4aN + M0 evaluated by computed tomography (CT) and laparoscopy, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and adequate bone marrow, hepatic and renal functions. Patients with at least one measurable lesion (in accordance with the Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1 [
]) were eligible. Pregnant and lactating women were excluded, as were patients with history of prior or concurrent malignancies (except skin basal cell carcinoma and in situ carcinoma of the cervix), known allergies to apatinib or any of the study drugs, a definite gastrointestinal bleeding tendency and/or coagulation disorders (international normalised ratio >1.5), uncontrolled blood pressure and prior myocardial infarction within 6 months.
2.2 Procedures
Patients received NAT for three cycles (3 weeks/cycle). Apatinib was given orally (500 mg/day) for continuous two cycles, followed by a one-cycle rest. S-1 was given orally twice daily for 2 weeks, followed by a 1-week break. The dose of S-1 was determined based on the body surface area (BSA) as follows: BSA <1.25 m2, 80 mg/day; BSA ≥1.25 to <1.50 m2, 100 mg/day and BSA ≥1.50 m2, 120 mg/day. Oxaliplatin was administered at 130 mg/m2 intravenously on day 1. Four weeks after completing NAT, tumour resectability was assessed by CT, and gastrectomy with standard D2 lymphadenectomy was performed. The assessment of tumour resectability and surgeries were performed by three surgeons with at least 10-year experiences in surgery for gastric cancer and according to the criteria set by the Japanese Gastric Cancer Association. Patients underwent three cycles of adjuvant chemotherapy with the SOX regimen after surgery.
Dose adjustments including interruptions and reductions were allowed for the management of treatment-related adverse events (AEs). Details are available in Supplement 1.
2.3 Assessments
The primary end-point was pathologic response rate (pRR). Secondary end-points included preoperative objective response rate (ORR), preoperative disease control rate (DCR), margin-free (R0) resection rate, downstaging and safety. Pathologic response was evaluated and graded using post-SOXA resection materials, according to the Japanese Classification of Gastric Carcinoma (JCGC), 3rd English edition [
]. Pathologic response was defined as viable tumour cells remained in less than 2/3 of the tumourous area (grade Ib or greater). Major pathologic response (MPR) was defined as <10% residual tumour cells. Tumour response was evaluated in accordance with the RECIST 1.1 [
], by the investigators. Complete response (CR) and partial response (PR) were regarded as objective response, and CR, PR and stable disease (SD) were regarded as disease control. Tumour staging (cTNM and ypTNM) was performed according to the seventh American Joint Committee on Cancer/Union for International Cancer Control TNM classification of gastric cancer. Surgical safety was assessed by the incidence of surgery-related complications. AEs during the NAT period were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The relationship between treatment and AEs was assessed by the investigators.
2.4 Statistical analysis
Based on the assumption that the pRR for standard SOX regimen was 50%, we set the pRR for SOXA regimen at 75%. With a one-sided α of 5% and a power of 80%, a sample size of 23 patients was necessary. Assuming a 15% dropout rate, the calculation yielded 28 patients.
Patients’ baseline characteristics were summarised for the intention-to-treat (ITT) population, defined as all enrolled patients. The pRR, ORR, DCR, R0 resection rate and downstaging analyses were performed on ITT population. Descriptive statistics of baseline and clinicopathological characteristics were performed. The 95% confidence intervals (CIs) of pRR, ORR, DCR and R0 resection rate were estimated using the Clopper-Pearson exact method. The exact binomial P value was calculated for pRR compared with 50% (the pRR for standard SOX regimen). If the lower limit of 90% CI of pRR is greater than 50%, the SOXA regimen would be considered superior to SOX regimen. Non-surgical AEs and serious AEs were analysed in the safety population, defined as patients who received at least one dose of study drugs. Surgery-related complications were analysed in the per-protocol (PP) population, defined as patients who were compliant with the protocol and proceeded to surgery.
3. Results
3.1 Patient characteristics
From December 2016 to August 2018, 31 patients were accrued and assessed for eligibility. Two patients were excluded because of pathological diagnosis of neuroendocrine carcinoma or ECOG performance status of >1 (Supplementary Fig. 1). The baseline characteristics of the remaining 29 patients (ITT population) are presented in Table 1. The median age was 60 years (range, 43–73 years), and 20 (69%) patients were male.
Table 1Baseline characteristics.
Variable
Patients (N = 29)
Age (years), median (range)
60 (43–73)
Sex, N (%)
Male
20 (69.0)
Female
9 (31.0)
ECOG performance status, N (%)
0
19 (65.5)
1
10 (34.5)
Primary tumour location, N (%)
Upper
16 (55.2)
Middle
9 (31.0)
Lower
4 (13.8)
Histology, N (%)
Adenocarcinoma (not evaluated)
9 (31.0)
Poorly differentiated adenocarcinoma
15 (51.7)
Moderately differentiated adenocarcinoma
2 (6.9)
Moderately and poorly differentiated adenocarcinoma
The median duration of apatinib treatment was 41 days (range, 31–45 days). During treatment, one patient had two dose interruptions, and seven had one dose interruption. The main reasons for dose interruption included thrombocytopaenia (two patients), hypertension (one patient), proteinuria (one patient), epistaxis (one patient), headache (one patient), menstruation (one patient) and fatigue accompanied by sore gums (one patient). Only one patient experienced dose reduction (500–250 mg) because of granulocytopaenia.
3.3 Tumour response to neoadjuvant therapy
Of the 29 patients, four (13.8%) achieved CR, 19 (65.5%) achieved PR, five (17.2%) achieved SD, and one had progressive disease (PD), with an ORR of 79.3% (95% CI, 60.3%–92.0%; 23 of 29 patients) and a DCR of 96.6% (95% CI, 82.2%–99.9%; 28 of 29 patients).
3.4 Surgical treatment
Twenty-eight patients (PP population) who received neoadjuvant SOXA proceeded to surgery: 25 patients received total gastrectomy with D2 lymphadenectomy, and three patients received distal gastrectomy with D2 lymphadenectomy. The R0 resection rate was 96.6% (95% CI, 82.2%–99.9%; 28 of 29 patients). The median intraoperative blood loss was 100 mL (range, 10–1500 mL). The median operative time was 177.5 min (range, 125–255 min). The median length of stay was 11.5 days (range, 8–46 days).
One patient had a benign liver lesion (evaluated by the investigator) before enrolment, which was confirmed to be malignant after the initiation of NAT. He was evaluated as PD and did not undergo surgery because of multiple unresectable metastatic liver lesions. He was treated with another regimen, and rapid progression of tumour was observed after 2 months of treatment.
3.5 Pathologic response and downstaging
As shown in Table 2, all 28 patients who received neoadjuvant SOXA and surgery had pathologically confirmed gastric adenocarcinoma, and most of them were poorly differentiated (18 [64.3%]). Most patients were free of vascular (20 [71.4%]) and nerve (19 [67.9%]) invasion. There were 26 patients with grade Ib or greater pathologic response, with a pRR of 89.7% (95% CI, 72.7%–97.8%; 26 of 29 patients, P < 0.001). The pathologic CR rate was 13.8% (95% CI, 1.2%–26.3%; 4 of 29 patients). The proportion of patients with MPR (<10% residual tumour cells) was 37.9%, whereas six other patients achieved 90% tumour shrinkage. A waterfall plot representing the best ranked tumour shrinkage after surgery is shown in Fig. 1. The median tumour shrinkage was 89.7%. Twenty of 28 (71.4%) patients had a decrease of at least one level in their T stage, and 11 (39.3%) with N+ disease had post-NAT N0 disease. Downstaging of overall TNM stage was observed in 16 of 29 (55.2%) patients (Table 3).
Table 2Pathological results after neoadjuvant therapy.
Pathologic response was assessed in intention-to-treat population (N = 29). One patient did not undergo surgery, with unknown result of pathologic response.
No viable tumour cells remain in the sections where tumour cells are likely to remain.
4 (14.3)
Vascular invasion (N = 28)
8 (28.6)
Nerve invasion (N = 28)
9 (32.1)
TNM, tumour-node-metastasis.
a Pathologic response was assessed in intention-to-treat population (N = 29). One patient did not undergo surgery, with unknown result of pathologic response.
b No viable tumour cells remain in the sections where tumour cells are likely to remain.
Post-neoadjuvant therapy overall stage information was available for all 29 patients. Post-neoadjuvant therapy T and N information was missing for one patient, who were not explored surgically.
Post-neoadjuvant therapy overall stage information was available for all 29 patients. Post-neoadjuvant therapy T and N information was missing for one patient, who were not explored surgically.
Post-neoadjuvant therapy overall stage information was available for all 29 patients. Post-neoadjuvant therapy T and N information was missing for one patient, who were not explored surgically.
Post-neoadjuvant therapy overall stage information was available for all 29 patients. Post-neoadjuvant therapy T and N information was missing for one patient, who were not explored surgically.
Downstaged
16 (55.2)
Upstaged
0
No change
13 (44.8)
a Post-neoadjuvant therapy overall stage information was available for all 29 patients. Post-neoadjuvant therapy T and N information was missing for one patient, who were not explored surgically.
During the NAT period, all 29 (100%) patients had any grade AEs, and 10 (34.5%) patients had grade ≥III AEs. The NAT-related AEs are listed in Table 4. No treatment-related death occurred. The most common NAT-related AEs were hypertension (19 [65.5%]), leucopenia (18 [62.1%]), hematuresis (18 [62.1%]), decreased haemoglobin (16 [55.2%]) and proteinuria (15 [51.7%]). Treatment-related grade ≥III AEs included hypertension (2 [6.9%]), thrombocytopaenia (2 [6.9%]), diarrhoea (2 [6.9%]), leucopenia (2 [6.9%]), oral mucositis (2 [6.9%]), granulocytopaenia (1 [3.4%]), neutrocytopenia (1 [3.4%]) and upper gastrointestinal haemorrhage (1 [3.4%]).
Surgery-related complications were observed in 12 of 28 (42.9%) patients including fever (9 [32.1%]), anastomotic leakage (1 [3.6%]), fat liquefaction of post-surgical incision (1 [3.6%]) and gastroparesis (1 [3.6%]). Additionally, one patient had pulmonary infection, and one patient had pleural effusion after surgery. No patient underwent reoperation. No intensive care unit stay or re-admission occurred.
4. Discussion
In this single-arm phase II study, we evaluated the efficacy and safety of neoadjuvant SOXA followed by surgery for patients with locally advanced gastric adenocarcinoma. The pRR was 89.7%. To our knowledge, this is the first study evaluating the efficacy and safety of VEGFR-TKI add-on to conventional chemotherapy as NAT in patients with locally advanced gastric adenocarcinoma.
Previous clinical trials have suggested a dose of 500–850 mg/day of apatinib in patients with several solid tumours [
Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study.
]. Considering the toxicity of SOX, we used 500 mg/day as the initial dose of apatinib in this study. Antiangiogenic therapy is associated with potentially serious toxic effects such as gastrointestinal perforation, thromboembolism, haemorrhage, delayed wound-healing and rarely fistula formation, bringing additional challenges for NAT. Therefore, apatinib was given for two continuous cycles, followed by a one-cycle rest, and surgery was scheduled 4 weeks after the completion of NAT.
pRR is a commonly used end-point in the preoperative settings of gastric cancer without measurable lesions. Kurokawa et al. [
] demonstrated that response assessment validity was higher with pRR than with RECIST, and pRR might be a better surrogate end-point for overall survival than radiologic response rate in studies of NAT for gastric cancer. Many phase II trials have adopted pRR as the primary end-point [
Preoperative capecitabine, oxaliplatin, and irinotecan in resectable gastric or gastroesophageal junction cancer: pathological response as primary endpoint and FDG-PET predictions.
A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker.
Phase II study of preoperative chemotherapy with S-1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancers (JCOG0210).
A phase II study of preoperative chemotherapy with S-1 plus cisplatin followed by D2/D3 gastrectomy for clinically serosa-positive gastric cancer (JACCRO GC-01 study).
In the present study, the efficacy outcomes demonstrated that patients had favourable response and tumour shrinkage following neoadjuvant SOXA and surgery. A phase II study of neoadjuvant SOX in Japanese patients with locally advanced gastric and oesophago-gastric cancer showed the pRR of 53.2% in ITT population [
]. The pRR of 89.7% in the present study is higher than that of the SOX regimen previously reported in Japan and previous Chinese results. This improvement may be attributed to the addition of apatinib to chemotherapy. The pathologic CR rate was 13.8%, which is higher than the 8% and 8.5% observed in another Chinese trial and a Japanese trial with neoadjuvant SOX [
Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.
Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.
Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.
]. The median tumour shrinkage was 89.7%, also higher than expectation. The commendable downstaging of overall TNM stage was noted (55.2%). As described previously, the fewer residual tumours of the primary lesion that remain, the longer the gastric cancer patients tend to survive [
Determination of the optimal cutoff percentage of residual tumors to define the pathological response rate for gastric cancer treated with preoperative therapy (JCOG1004-A).
Regarding safety, all patients completed the neoadjuvant SOXA therapy despite the dose adjustment. The incidence of grade ≥III AEs was 34.5%. No treatment-related death occurred. All AEs during the NAT period were tolerable and manageable, demonstrating that apatinib can be safely added to SOX chemotherapy before surgery. Although the prevalence of surgery-related complications was 42.9%, the most common complication was fever (32.1%). Only one patient had duodenal anastomotic leakage, which was managed with drainage and antibiotics. Fever and other complications were controlled with high proficiency. Fortunately, no patient underwent reoperation. Postoperative haemorrhage, thrombosis, ileus, pancreatic fistula or renal dysfunction was not observed. The interval between the NAT and surgery decreased the negative impact of SOXA regimen on surgery.
There were several limitations to this study. First, this was a single-arm trial, without control group or randomisation, thus selection bias could not be ruled out. Second, pRR was adopted as the primary end-point. MPR has been recommended as a global standard to determine pathologic response in NAT setting [
Determination of the optimal cutoff percentage of residual tumors to define the pathological response rate for gastric cancer treated with preoperative therapy (JCOG1004-A).
]. A randomised controlled trial comparing three intervention groups (SOXA plus camrelizumab, SOXA and SOX) with MPR as the primary end-point in previously untreated patients with locally advanced gastric or oesophagogastric junction adenocarcinoma (NCT04208347) is ongoing. Third, survival data were not obtained because of the short follow-up. Nevertheless, this study exhibited high clinical and pathologic response rates; therefore, improvement in patient survival should be expected after neoadjuvant SOXA.
In conclusion, these preliminary results suggested that neoadjuvant SOXA followed by surgery can be performed safely with a high pRR in patients with locally advanced gastric adenocarcinoma. Our ongoing randomised controlled trial (NCT04208347) of this neoadjuvant approach in patients with gastric or oesophagogastric cancer will provide more evidence.
Funding
None.
Conflict of interest statement
All authors declare that they have no conflict of interest.
Acknowledgements
None.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy--Japan Clinical Oncology Group study 9501.
Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.
Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study.
Preoperative capecitabine, oxaliplatin, and irinotecan in resectable gastric or gastroesophageal junction cancer: pathological response as primary endpoint and FDG-PET predictions.
A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker.
Phase II study of preoperative chemotherapy with S-1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancers (JCOG0210).
A phase II study of preoperative chemotherapy with S-1 plus cisplatin followed by D2/D3 gastrectomy for clinically serosa-positive gastric cancer (JACCRO GC-01 study).
Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.
Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.
Determination of the optimal cutoff percentage of residual tumors to define the pathological response rate for gastric cancer treated with preoperative therapy (JCOG1004-A).
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