The primary outcome is the rate of nutrition and immune-related complications up to 30 days after surgery. These include gastrointestinal complications (anastomotic leakage, gastrointestinal dysfunction), metabolic complications (electrolyte disturbances, liver or renal dysfunction) and infectious complications (wound infection, catheter-related infection, pneumonia, sepsis, or other infections requiring antibiotics).
The secondary endpoints include the following outcomes:
Neoadjuvant therapy measures: completion rate of neoadjuvant chemoradiation, adverse events during neoadjuvant chemoradiation, rate of pathological complete response (pCR).
Peri-operative measures: blood loss, operation time, rate of surgery-related complications (conversion to open surgery, recurrent nerve injury, cardiac and cerebrovascular accident), length of hospital stay, hospitalization costs.
Nutrition and immune-related changes measured from the beginning of neoadjuvant chemoradiation to 6 months after surgery: weight loss, Scored Patient-Generated Subjective Global Assessment (PG-SGA score), white blood cells, hemoglobin, albumin, C-reactive protein, TNF-α, interleukins, IgA, IgG, IgM, fasting blood-glucose.
Survival and recurrence: 30-day and 90-day mortality, overall survival (OS) (time from the date of randomization to the day of death or last follow-up), progression-free survival (PFS) (time from the date of randomization to the day of tumor progression, tumor recurrence, death or last follow-up).
Quality of life (QoL): European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and Oesophageal-18 (QLQ-OES18) scored at randomization, before surgery, 1, 3, 6 month(s) and 1, 3, 5 year(s) after surgery.
Power and sample size calculation
The power and sample size calculation was based on the hypothesis that pre-operative immunonutrition during the neoadjuvant therapy can reduce postoperative nutrition and immune-related complications after esophagectomy. According to the previously published articles  and our own experience, the related complication rates were estimated at 50% in the control group and 30% in the interventional group. The required sample size of interventional and control arm (ratio = 2:1) was therefore calculated as 137 cases and 69 cases to detect the reduction in related complications from 50 to 30% based on a bilateral significance level (α) of 0.05 and a power of test (1-β) of 0.80. Considering an estimated drop rate of 15%, the minimum sample size of this study is 244 patients, 162 cases in the interventional group and 82 in the control group.
All the esophageal cancer patients in the outpatient and inpatient service are screened for eligibility. Recruiting announcements are also published on the website of the participating center to promote recruitment.
After signing the informed consent, every eligible participant is randomized into nutritional therapy group or control group (ratio 2:1) based on a computer-generated random number stratified by institution. Sequentially numbered, opaque, sealed envelopes are distributed to all the study sites by the sponsor to conceal the sequence until interventions are assigned. The allocation sequence is generated by a statistician (JL). The enrollment and assignment of participants are implemented by each study site.
This is an open-labeled study, so trial participants and care providers are not blinded. However, outcome assessors will be masked with assignment to interventions.
Assessment and follow-up
The time schedule of enrolment, interventions, assessments and follow-ups is summarized in Additional file 1.
For the sake of eligibility screen, medical history, physical examination, demographic information, upper gastrointestinal endoscopy with tissue biopsy, thoracic and abdominal computed tomography (CT), and ultrasonography of abdominal organs as well as superficial lymph nodes (LNs) are routinely assessed before any treatment. After enrolment, nutritional assessments (including PG-SGA score, body weight and oral intake recording) are performed prior to neoadjuvant chemoradiation along with QoL evaluation (EORTC QLQ-C30 and QLQ-OES18 questionnaires) and laboratory tests (blood routine, biochemistry, immunoglobulin, cytokine and tumor marker).
After 4–6 weeks of neoadjuvant chemoradiation, participants are reevaluated for the clinical response and any contraindications to esophagectomy. Physical examination, thoracic and abdominal CT scan, ultrasonography of abdomen and superficial LNs, nutritional assessments, laboratory tests and QoL evaluations are recorded.
The first 3 follow-ups are performed 1 month, 3 months and 6 months after surgery, including physical examination, nutritional assessments, laboratory tests, CT scan and QoL evaluations. Long-term follow-ups are performed 1 year, 3 years and 5 years after surgery, including physical examination, nutritional and QoL assessments as well as CT scan and other examinations for detecting recurrence. Telephone interview will be supplied to promote completion of follow-up.
All the adverse events (AE) and complications will be recorded through the study period, whether caused by neoadjuvant chemoradiation, nutritional intervention or surgery. Serious adverse events (SAE) should be reported to the principal investigator and sponsor within 24 h. Clinical trial insurance is purchased for every participant to compensate those who suffer harm from trial participation.
Peripheral blood and tissue samples are collected for future translational research. Blood samples are collected in two 5 ml EDTA tubes before the start of neoadjuvant treatment and at the time of pre-operative evaluation, respectively. Tissue samples are collected before treatment (if available) and during the radical surgery, respectively.
Data collection and monitoring
All data collected by the participating sites will be recorded in an electronic data capture (EDC) system (https://h6world.cn). To protect confidentiality, only authorized and trained investigators will have access to the data of enrolled patients. Any protocol amendments will be reviewed by the ethical committee and communicated to the participating centers after approval. Auditing will be performed every 6 months until the end of the trial.
Data will be analyzed according to the ‘intention to treat’ principle. The statistical analyses will be conducted by using R software (version 4.1.2, R Foundation for Statistical Computing, Vienna, Austria). For the primary endpoint, Pearson’s Chi-squared test or Fisher’s exact test will be used to compare the complication rate between the two groups. Regarding secondary outcomes, categorical variables will be presented as number (percentage) and analyzed as the primary endpoint. Normally distributed continuous variables will be presented as mean ± standard deviation (SD) and compared using Student’s t-test. In case of non-normal distribution, continuous variables will be presented as median (interquartile range [IQR]) and compared using Wilcoxon rank-sum test. Time-to-event data will be estimated by Kaplan–Meier method and analyzed by log-rank test as well as Cox proportional hazard model.
Subgroup analyses will be performed by stratifying sex, age, BMI, region, ECOG PS, tumor stage, histology and surgical procedure. P < 0.05 is considered to be statistically significant. Interim analysis will be conducted when 50% of the estimated patients are recruited. Missing data will be dealt with pairwise deletion.
This study was approved by the Ethics Committee of Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (RJ 2019–198) on 24 September 2019 and registered on ClinicalTrials.gov (NCT04513418) before recruitment. The current protocol version is Version 2.0 (November 2020). The recruitment was started on 10 November 2020. The POINT trial is still at the stage of recruiting as 36 patients have been recruited until 14 March 2022. The results of primary and secondary outcomes will be published after the recruitment and follow-up.