ABSTRACT
Over half of patients with advanced or recurrent esophageal cancer experience malnutrition, psychological distress, and cancer-related pain, which impair immune function, diminish quality of life, and attenuate responses to immunotherapy. Whether a precision palliative care (PC) model that integrates nutritional, psychological, and symptomatic support can improve survival and quality of life in these patients undergoing anti-PD-1/PD-L1 immunotherapy remains unknown. We are conducting a multicenter randomized trial to evaluate the superiority of a precision PC model compared with standard oncology care in improving patients’ overall survival (OS). All patients will be randomly assigned to either the Standard Arm (standard oncology care)or the Precision Arm (standard oncology care + precision PC). Patients in the Standard Arm receive anti-PD-1/PD-L1 immunotherapy-based standard oncology care. Patients assigned to the Precision Arm receive anti-PD-1/PD-L1 immunotherapy-based standard oncologic care and precision PC, in which patients meeting any of the following criteria are stepped up to meet with the precision PC clinicians every 4 weeks: (1) malnutrition (NRS2002 ≥ 3 or meeting GLIM criteria), (2) psychological distress (GAD-7 ≥ 5 or PHQ-9 ≥ 5), or (3) moderate-to-severe symptoms (any MDASI symptom score ≥4). The primary endpoint is overall survival (OS). The secondary endpoints are quality of life and progression-free survival (PFS).Clinical trial registration: NCT06787313 (clinicaltrials.gov)
KEYWORDS: Esophageal cancer, interdisciplinary precision palliative care, anti-PD-1/PD-L1 immunotherapy, advanced/recurrent cancer, standard oncology care
Plain Language Summary
Immunotherapy is the standard treatment for people with advanced esophageal cancer. But many patients also face other problems during treatment – like not getting enough nutrition, feeling very anxious or sad, or dealing with physical pain. These issues can hurt their overall health and may even make the immunotherapy work less well. We know that giving extra support early can help. But there are not enough trained experts to provide this kind of care to every patient who needs it. To solve this problem, we created a new study to test a program called “precision palliative care.” The goal is to see if this program can help patients live longer and feel better. The study will have 624 patients. There are two groups: one group will get standard cancer treatment only and the other group will get standard treatment plus the new support program. In the second group, a team of specialists – including doctors, dietitians, and psychologists – will regularly check how each patient is doing. They will look at nutrition, emotions, and symptoms like pain. If a patient is struggling in any of these areas, they will get help right away. The main goal is to find out if this personalized support helps patients live longer than those who only get standard treatment. The results will help doctors understand the best way to support people going through immunotherapy for esophageal cancer.
1. Introduction
Approximately 200,000 new cases of esophageal cancer are diagnosed in China each year, accounting for about half of all global cases [1]. Notably, 40% of patients are diagnosed at an advanced stage, and nearly 70% will develop metastasis or recurrence [2,3]. Currently, the first-line standard treatment regimen for advanced or recurrent esophageal squamous cell carcinoma is immunotherapy combined with chemotherapy [4–7]. But, the impact of palliative care for esophageal cancer patients receiving immunotherapy has not been explored.
About 52.9–62.5% of the patients with esophageal cancer suffer from malnutrition, which is an independent unfavorable prognostic factor for patients receiving immunotherapy [8–11]. Nutritional risk screening and intervention can improve the quality of life and survival of esophageal cancer patients receiving chemotherapy [12–14]. However, there are no prospective clinical trial data on the effect of nutritional intervention on immunotherapy outcomes.
Approximately half of the esophageal cancer patients experience abnormal psychological states, which can amplify the systemic inflammation induced by tumors and mediate a series of symptoms [15,16]. Depressive or anxious state can lead to local and systemic immunosuppression of tumors and lead to poorer immunotherapy outcomes in non-small cell lung cancer and melanoma [17–19]. Therefore, screening and treating psychological disorders may improve the quality of life and survival of advanced cancer patients.
National Comprehensive Cancer Network guidelines recommend that all patients with advanced cancer receive early palliative care (PC), within 8 weeks of diagnosis [20], on the basis of evidence that concurrent care improves patient symptoms, mood and quality of life (QOL), caregiver distress, and survival [21]. While integrating early palliative care offers significant benefits, there is a mismatch between the supply of medical resources and the patient demand [22,23]. A shift from uniform early palliative care to palliative care models, is justified to better align interventions with individual patient needs. Evidence indicates that such tailored approaches can maintain clinical effectiveness – as demonstrated in advanced lung cancer, where stepped care preserved quality of life comparable to early palliative care, while using resources more efficiently [24,25].
In China, the implementation of PC is still in its early stages, and the treatment of advanced cancer patients is usually managed by oncologists. Considering the current situation of PC in China, it is theoretically and technically feasible for us to conduct a study comparing precision PC based on patient needs with standard oncologic care of recurrent or metastatic esophageal cancer.
2. Methods
2.1. Trial design
This is a multicenter open-label RCT comparing precision PC to standard oncologic care in 624 patients with recurrent or metastatic esophageal cancer. The trial start date was 31 December 2024. The Consolidated Standards of Reporting Trials flow diagram is illustrated in Figure 1. The Fudan University Shanghai Cancer Center (FUSCC) Institutional Review Board approved the study prior to initiation.
Figure 1.
Design of the ESO-Shanghai 25 trial. Standard oncology care is anti-PD-1/PD-L1 immunotherapy-based treatment, with or without chemotherapy. Precision palliative care is provided by the precision PC team and is initiated once a patient’s assessment score reaches (1) NRS 2002 ≥ 3 or malnutrition (GLIM), or (2) PHQ-9 ≥ 5 or GAD-7 ≥ 5, or (3) any symptom in MDASI ≥4. Abbreviation: NRS 2002, Nutritional Risk Screening 2002; GLIM, Global Leadership Initiative on Malnutrition; PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder-7; MDASI, The MD Anderson Symptom Inventory; QOL, quality of life.
2.2. Randomization
Within 2 weeks of providing informed consent, patients were randomly assigned in a 1:1 ratio to either Standard arm (standard oncology care) or Supportive arm (standard oncology care + precision palliative care). Patients complete baseline demographic and study questionnaires. Randomization was stratified by age (＜70 vs ≥70)，ECOG (0–1 VS 2), metastatic status (local recurrent or oligometastatic cancer vs polymetastatic cancer), and centers (FUSCC vs other centers). The SAS was used to generate a random permutation sequence and produce patient randomization numbers. The data center receives the enrollment, assigns a unique identification number to every participant, and notifies the respective investigators.
3. Objectives
3.1. Primary objective
To explore whether precision palliative care (PC) improves the overall survival (OS) of patients with recurrent or advanced esophageal cancer receiving anti-PD-1/PD-L1 immunotherapy.
3.2. Secondary objectives
To evaluate the impact of precision PC on improving quality of life (QOL) at 24 weeks and 48 weeks.
To evaluate the impact of precision PC on the progression-free survival (PFS) of esophageal cancer patients receiving anti-PD-1/PD-L1 immunotherapy.
3.3. Exploratory objectives
To investigate the effects of precision PC on the immune system of esophageal cancer patients receiving anti-PD-1/PD-L1 immunotherapy.
To explore peripheral blood and fecal biomarkers predictive of efficacy outcome.
4. Participant selection
To be eligible for this study, patient must fulfill all of the following criteria;
Patients are ≥18 years old.
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
Histologically confirmed esophageal squamous cell carcinoma, esophageal adenocarcinoma, or esophageal small cell carcinoma and informed of advanced or recurrent disease within the prior 12 weeks.
Clinical stages IV (AJCC 8th) or recurrent esophageal cancer ineligible for radical surgery or radical chemoradiotherapy.
Patients must be either anti-PD-1/PD-L1 immunotherapy-naïve or without resistance to anti-PD-1/PD-L1 immunotherapy (previously received anti-PD-1/PD-L1 immunotherapy without discontinuation due to toxicity or disease progression, and be anti-PD-1/PD-L1 immunotherapy-free for more than 12 weeks).
No contraindications to PD-1/PD-L1 immunotherapy. Adequate organ functions for chemoradiation therapy: (1) white cell count ≥ 3 × 109⁄L; (2) absolute neutrophil counts ≥ 1.5 × 109⁄L; (3) hemoglobin ≥ 10 g⁄dL; (4) platelet ≥ 100 × 109⁄L; (5) total bilirubin < 1.5 upper limit of normal (ULN); (6) aspartate transaminase ≤ 2.5 ULN; (7) alanine aminotransferase ≤ 2.5 ULN and (8) creatinine ≤ 1.5 ULN.
Written informed consent.
Patients fulfilling any of the following criteria are ineligible for this study:
Esophageal perforation or hematemesis.
Synchronous or metachronous malignancies (except for cutaneous (non-melanomas) carcinoma, thyroid papillary carcinoma, phase I seminoma or cervical carcinoma in situ curatively treated and disease free for a minimum of 3 months).
Patients who require long-term oral, intravenous, or intramuscular administration of systemic corticosteroids.
Has not fully recovered from toxicity and/or complications caused by any intervention before starting treatment (i.e., ≤grade 1 or baseline, excluding weakness or hair loss).
History of active autoimmune disease or autoimmune disease with a potential for recurrence. Controlled type 1 diabetes, hypothyroidism requiring only hormone replacement therapy, well-controlled celiac disease, skin conditions that do not require systemic treatment (such as vitiligo, psoriasis, or alopecia) or diseases expected not to relapse without external factors are allowed.
Unstable angina and/or congestive heart failure requiring hospitalization within 6 months.
Known history of HIV infection (i.e., HIV 1/2 antibody positive). Untreated active hepatitis B (defined as HBsAg positive and HBV-DNA copy number detected greater than the ULN value in the laboratory of the study center). Active HCV-infected subjects (HCV antibody positive and HCV-RNA levels above the lower limit of detection).
Received immunomodulatory drugs (e.g., thymosin, interferon, interleukin) within 2 weeks before the first administration.
Received a live vaccine within 30 days before the first dose, including but not limited to mumps, rubella, measles, varicella/zoster (chickenpox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine (inactivated viral vaccines are allowed).
Pregnancy, lactation, or unwillingness to adopt contraception.
Severe psychiatric disease.
Already receiving PC or hospice services since diagnosis of esophageal cancer.
Inability to complete questionnaires.
Other ineligible conditions according to the researchers.
5. Intervention delivery
5.1. Standard arm (standard oncology care)
Standard oncology care is based on anti-PD-1/PD-L1 immunotherapy, determined by the medical oncologists. Treatment involves 4–6 cycles of anti-PD-1/PD-L1 immunotherapy with or without chemotherapy every 21 days, followed by anti-PD-1/PD-L1 maintenance immunotherapy every 21 days for up to 2 years. Patients must receive at least one cycle of anti-PD-1/PD-L1 immunotherapy. When clinically indicated, local treatments (e.g., palliative surgery, radiotherapy, or radiofrequency ablation) or anti-angiogenic targeted therapy should be considered. We will not deny patients the opportunity to meet with the PC clinicians at any time.
5.1.1. Anti-PD-1/PD-L1 immunotherapy
The selected anti-PD-1/PD-L1 agents include Pembrolizumab, Nivolumab, Camrelizumab, Tislelizumab, Sintilimab, Toripalimab, Serplulimab, and any other anti-PD-1/PD-L1 agents approved by China’s National Medical Products Administration (NMPA). All agents must be administered in accordance with their approved prescribing information. Oncologists will decide whether to stop the medicine depending on the seriousness of any side effects according to NCI CTCAE V5.0.
5.1.2. Chemotherapy
Patients with esophageal squamous cell carcinoma will receive fluoropyrimidine plus cisplatin, paclitaxel plus cisplatin, or paclitaxel for first-line chemotherapy. Patients with esophageal adenocarcinoma will receive paclitaxel, fluoropyrimidine plus cisplatin/oxaliplatin, fluoropyrimidine plus paclitaxel, or fluoropyrimidine plus paclitaxel plus oxaliplatin for first-line chemotherapy. Patients with esophageal small cell carcinoma will receive etoposide plus cisplatin for first-line chemotherapy. The duration of first-line chemotherapy is 4–6 cycles.
Post-first-line chemotherapy will be determined by the medical oncologist.
The dose of chemotherapy drugs will be adjusted based on the severity of adverse events according to NCI CTCAE V5.0.
5.1.3. Local therapy
Other treatments will be determined by the medical oncologist. Local therapies, including palliative surgery, radiotherapy, or ablation, may be utilized based on the patient’s clinical condition.
5.1.4. Side effect treatment
Antiemetics, sedatives, antibiotics, analgesics, antihistamines, steroids, granulocyte colony-stimulating factor, and transfusion of red blood cell, platelet transfusion, or fresh frozen plasma may be administered to manage pain, infection, other comorbidities, and treatment-related toxicities during the study.
5.2. Supportive arm (standard oncology care + precision palliative care)
All patients randomized to the Supportive arm will receive anti-PD-1/PD-L1 immunotherapy-based standard oncology care, combined with nutritional, psychological, and symptom assessments, followed by precision palliative care for those with identified abnormalities.
5.2.1. Standard oncology care
Standard oncology care is primarily based on anti-PD-1/PD-L1 immunotherapy, the same as the patients in Standard Arm.
5.2.2. Nutritional, psychological, and symptom assessments
Precision PC team includes esophageal medical oncologist, nurse, dietitian, psychologist, and palliative medicine physician. After enrollment, patients in this group will undergo a scale assessment by the interdisciplinary precision palliative care (PC) team within 4 weeks of enrollment. Patients complete the NRS2002, GLIM, PHQ-9, GAD-7, MDASI every 3 weeks during first 12 weeks and then every 6 weeks from week 12 to week 48 after enrollment, with a time window at ±1 week (see Table 1). Precision palliative care (PC) is initiated based on the following assessment results: (1) NRS 2002 ≥ 3 or malnutrition (GLIM), or (2) PHQ-9 ≥ 5 or GAD-7 ≥ 5, or (3) any symptom in MDASI ≥4. In first 12 months, patients under precision PC meet with precision PC clinical at least every 4 weeks either in-hospital or online. If a patient misses a scheduled visit or is unable to be scheduled for a PC visit, the PC clinical attempts to contact them by telephone and reschedules the visit as soon as possible. Patients in the Supportive arm surviving greater than 12 months from enrollment are permitted to decrease the frequency of PC visits as per their preference and the discretion of their PC and oncology clinicians.
Table 1.
Timepoints of trial.
| Questionnaires | Baseline | q3w for up to 12 week | q6w from 12 week to 48 week |
|---|---|---|---|
| Demographic questionnaire | X | ||
| NRS2002 | X | X | X |
| GLIM | X | X | X |
| PHQ-9 | X | X | X |
| GAD-7 | X | X | X |
| DT | X | X | X |
| MDASI | X | X | X |
| EORTC QLQ-C30 | X | X | X |
| EORTC QLQ-OES18 | X | X | X |
Abbreviation: NRS 2002, Nutritional Risk Screening 2002; GLIM, Global Leadership Initiative on Malnutrition; PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder-7; DT, Distress Thermometer; MDASI, The MD Anderson Symptom Inventory; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EORTC QLQ-OES18, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Esophageal 18.
All participating sites will receive standardized training based on a detailed study manual, including assessment scales, intervention protocols, and step-by-step guidance for nutritional, psychological, and symptom management. Concrete intervention options will be provided for each supportive care site to reduce variation in practice. All supportive care interventions are tracked in real time and systematically reviewed by palliative care specialists for protocol adherence. Identified deviations from the prescribed plan are documented, analyzed, and addressed through retraining or procedural refinement to maintain consistency across sites.
5.2.3. Precision palliative care
5.2.3.1. Nutritional support program
The nutritional risk screening and nutritional assessment are performed by a nutrition nurse or a doctor from the nutrition department, including the Nutritional Risk Screening 2002 (NRS 2002), the Global Leadership Initiative on Malnutrition (GLIM), and the types of diet (general diet, semi-liquid diet, liquid diet). Patients with an NRS 2002 ≥ 3 or diagnosed with malnutrition, according to GLIM, receive nutritional intervention within 3 days.
The calculation of the energy intake of the daily diet is based on the “Guidelines for Nutritional Therapy of Subjects with Malignant Tumors of the Chinese Society of Clinical Oncology (CSCO) 2024.” The daily target nutritional intake (including the daily diet and parenteral nutrition support) is an energy intake of 25–30 kcal/kg of the standard body weight and a daily protein intake of 1.5-2 g/kg of the standard body weight. Enteral nutrition (EN) is the preferred nutritional method. If 60% of the target energy intake cannot be achieved within 7 days, parenteral nutrition (PN) will be added. Patients with contraindications to enteral nutrition support (intestinal obstruction, intestinal perforation, gastrointestinal bleeding, abdominal infection) should receive total parenteral nutrition. When the total amount of the diet reaches an appropriate level (reaching 60% or more of the target), the parenteral and enteral nutrition support can be gradually reduced or stopped.
The available EN preparations include: 1. Standard whole protein formula: suitable for most patients with normal digestive and absorptive functions. Homemade diets are not routinely recommended due to risks of unclear nutrient composition, tube blockage, and contamination. 2. Short peptide formula: This formulation is indicated for patients with impaired digestion or absorption. It may be considered as the initial choice for those with inflammatory bowel disease, severe malabsorption, or fiber intolerance presenting with diarrhea, as well as for conditions such as severe pancreatitis, short bowel syndrome, and radiation enteritis. 3. Diabetic formula: Specially designed for patients with diabetes to help attenuate postprandial blood glucose fluctuations.
Enteral nutrition (EN) support should be discontinued when any of the following criteria are met: 1) manifestations of severe enteral nutrition complications or emergence of a contraindication to EN; 2) adequate oral intake is resumed and meets nutritional requirements; 3) patient experiences clinical deterioration, such as hemodynamic instability or other conditions that contraindicate EN administration
For patients on a liquid diet who cannot reach 60% of the nutritional target, placement of a nasojejunal or post-pyloric feeding tube should be considered. Tube feeding should generally not be continued beyond 4 weeks; if longer-term nutritional support is required, percutaneous endoscopic gastrostomy (PEG) or radiologically inserted gastrostomy (RIG) is indicated.
Parenteral nutrition (PN) is recommended under the following conditions: (1) for patients with an NRS 2002 score ≥5, and EN fails to provide ≥60% of energy and protein requirements within 72 h; (2) for severely malnourished patients with significant gastrointestinal dysfunction where EN is not feasible, PN should be initiated promptly. For patients with an NRS 2002 score of 3 to <5, PN is indicated if they still cannot achieve ≥60% of their nutritional targets after 7 days of EN.
5.2.3.2. Psychological intervention
Psychological assessment is conducted by a psychologist or a psychiatric nurse, using the Generalized Anxiety Disorder-7 (GAD-7) scale, the Patient Health Questionnaire-9 (PHQ-9), and the Distress Thermometer (DT).
A score of PHQ-9 ≥ 5 or GAD-7 ≥ 5 triggers the initiation of psychological intervention within 1 week. A total of four sessions are delivered over 6 months, with each session lasting 45–60 min. If an in-person hospital visit is not feasible, the psychologist will schedule the session at the nearest available time or conduct the intervention via telephone. After every session, the psychologist coordinates with the oncology team and the family. This communication aims to facilitate the resolution of patient-raised issues, such as queries about treatment cycles, therapeutic outcomes, intra-family communication, and the handling of emerging adverse symptoms.
There are two forms of psychological intervention: group psychological intervention and individual psychological intervention. Group sessions involve 3–10 patients, with flexible group size and focus on four thematic modules: “Group Art Therapy – Painting,” “Group Art Therapy – Music,” “Group Art Therapy – Family Dance,” and “Mindfulness Meditation,” targeting emotional distress, sleep, family dynamics, and self-awareness. This involves one-on-one sessions following the Managing Cancer and Living Meaningfully (CALM) therapy model. Delivery is guided by the Chinese Clinical Practice Guidelines for Psychosocial Oncology (2020) to ensure the provision of high-quality, integrated palliative care.
Patients are permitted to request additional sessions or to extend the duration of individual interventions based on their clinical needs and personal preference. If the consulting psychologist determines that pharmacotherapy is indicated, the patient will be referred to the psychiatric outpatient clinic for pharmacological treatment.
Psychological intervention should be temporarily withheld in cases of acute clinical changes, such as tracheostomy, intensive care unit (ICU) admission, or impaired consciousness.
5.2.3.3. Principle of symptom management
Symptom screening and assessment are conducted by oncologists or the palliative care (PC) clinic using the MD Anderson Symptom Inventory (MDASI), which evaluates the severity of 13 common symptoms. A score of ≥4 on any single MDASI symptom triggers the precision PC team to provide symptom management in accordance with the NCCN Guidelines for Adult Cancer Pain (2024, Version 2.1).
6. Study questionnaires
The questionnaires and their administration schedule are summarized in Table 1.
► At baseline, patients self-report demographic and clinical characteristics, including gender, smoking and alcohol history, living situation, comorbidities, occupation, education, and insurance type.
► To measure quality of life, patients complete the EORTC QLQ-C30 and EORTC QLQ-OES18.
► We assess patients’ nutritional risk using the NRS 2002 (Nutritional Risk Screening 2002) and GLIM (Global Leadership Initiative on Malnutrition) scales.
► We evaluate patient distress via the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item scale (GAD-7) and (DT).
► The MD Anderson Symptom Inventory (MDASI) to assess symptom severity, where items are rated from 0 (no symptom/interference) to 10 (the most severe imaginable).
Study staff administer study questionnaires at baseline prior to randomization and then at 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 weeks (with a ± 1-week window). As noted above, patients in step 1 complete the NRS 2002, GLIM, PHQ-9, GAD-7, DT, MDASI every 3 weeks for first 12 weeks, and then every 6 weeks thereafter. Patients may complete questionnaires either in-clinic, on paper at home, via telephone, Tencent’s online survey tool or videoconference.
7. Sample collection
Upon obtaining informed consent, peripheral blood (including serum and peripheral blood mononuclear cells) and fecal samples will be collected at baseline and upon first efficacy assessment. Fecal samples will be stored in fecal DNA storage tubes at −80°C.
8. Statistical analysis
The primary efficacy analysis was conducted within the intention-to-treat population, encompassing all randomly assigned participants. Safety evaluation was performed exclusively on randomized subjects who received a minimum of one dose of the investigational treatment. All statistical analyses will be performed using SPSS V.29.0. Survival analysis will be conducted using the Kaplan–Meier method and log-rank test analysis.
9. Sample size
Based on data from the Chinese population in the RATIONALE-306 study, the OS of the standard oncologic care in this study is assumed to be 16.6 months, while the OS of precision PC group is 21.6 months. The sample size is required to obtain 80% power with a one-sided significance level of 0.025 (alpha). The hazard ratio (HR) is 0.76. With the assumption of a 5% dropout rate, the planned sample size is 624 (312 patients in each arm).
10. EHR data
We are collecting the following information from the EHR: date of birth; cancer type; past medical history; date of diagnosis of esophageal cancer; smoking pack years; ECOG Performance Status; date and location of death. We are also collecting cancer treatment regimens (e.g., chemotherapy, anti-PD-1/PD-L1 immunotherapy, targeted therapy, radiation), adverse events, response evaluation, CT or MRI or PET-CT images.
11. Safety and adverse events
PC members review the PHQ-9 and GAD-7 on completion to evaluate for suicidal ideation. If a patient endorses suicidal ideation, the PI and/or PC members are notified and contact the patient to conduct a safety assessment. Given that this study is a supportive oncology PC intervention trial, we do not anticipate any study-related serious adverse events. Anti-tumor treatment-emergent adverse events will be assessed and categorized using the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0).
12. Discussion
The first-line treatment for advanced or recurrent esophageal cancer is chemotherapy and immunotherapy. While squamous cell carcinoma constitutes approximately 90% of esophageal cancer cases in China, the primary focus of this study is not on pathological type and anti-tumor therapy but on evaluating the impact of precision palliative care on patient outcomes. Consequently, patients with all pathological subtypes of esophageal cancer are eligible for enrollment in this study.
This trial aims to evaluate the superiority of precision palliative care versus standard care. The selected stratification variables – age, ECOG status, metastatic status, and study center – were chosen because ECOG status and metastatic status have been consistently demonstrated as independent factors affecting survival in esophageal cancer. First-line immunotherapy plus chemotherapy was administered to all study participants in line with current clinical guidelines. Additionally, the precision palliative care (nutritional, psychological, and symptom management) is independent of the first-line anticancer regimen. Although combination with chemotherapy is an important clinical factor, we believe that its potential influence on prognosis and outcome complexity can be effectively balanced through large-sample randomization. With a planned sample size of 624 participants, a centralized 1:1 randomization system is expected to achieve probabilistic balance across key prognostic factors, including the use of combination chemotherapy. Given these considerations, combining immune checkpoint inhibitors with chemotherapy was not included as a stratification variable.
Although important, health economic evaluation was precluded by practical constraints. The fragmentation of care across institutions and provinces, coupled with the lack of a unified national health information network in China, makes it impossible to accurately capture complete cost and utilization data, thereby preventing a formal analysis in this trial.
13. Conclusion
ESO-Shanghai 25 is a prospective, multicenter, randomized phase III trial that enrolls 624 advanced/recurrent esophageal cancer patients randomized 1:1 to either a Standard Arm (anti-PD-1/PD-L1 immunotherapy based-standard oncology care)or the Precision Arm (anti-PD-1/PD-L1 immunotherapy based-standard oncology care + precision palliative care). The primary endpoint is overall survival (OS). The secondary endpoints include: (1) the progression-free survival (PFS), (2) the impact of precision PC on improving quality of life (QOL) at 24 weeks and 48 weeks. This study will provide the first randomized data evaluating the superiority of a precision palliative care model compared with standard oncology care in patients with advanced or recurrent esophageal cancer receiving anti-PD-1/PD-L1 immunotherapy.
Supplementary Material
Funding Statement
This manuscript was funded by the National Natural Science Foundation of China [U22A20326]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Article highlights
Background and rationale
Anti-PD-1/PD-L1 immunotherapy with or without chemotherapy represents the current standard first-line regimen for advanced or recurrent esophageal cancer.
Over half of patients with advanced or recurrent esophageal cancer suffer from malnutrition, psychological distress, cancer-related symptom, and treatment-related symptom. Malnutrition, depressive and anxious state lead to poorer immunotherapy outcomes.
Currently, the application and study of palliative care remain limited to the context of chemotherapy and have not yet been robustly evaluated alongside immunotherapy.
There is a shortage of specialty-trained palliative care clinicians and resources are lacking to care for all patients diagnosed with advanced cancer. Therefore, there is an urgent need to optimize the palliative care model.
ESO-Shanghai 25 study
This study is the first phase III randomized multicentered study comparing precision palliative care and standard oncology care in newly diagnosed advanced or recurrent esophageal cancer receiving anti-PD-1/PD-L1 immunotherapy.
In the randomization session, patients were stratified by age (＜70 vs ≥70)，ECOG (0–1 VS 2), metastatic status (local recurrent or oligometastatic cancer vs polymetastatic cancer), and centers (FUSCC vs other centers).
Patients were randomly assigned in a 1:1 ratio to either Standard arm (standard oncology care) or Supportive arm (standard oncology care + precision palliative care). The planned sample size is 624 (312 patients in each arm).
The primary endpoint is overall survival (OS). The secondary endpoints are quality of life and progression-free survival (PFS).
All patients will receive anti-PD-1/PD-L1 immunotherapy. All patients randomized to the Supportive arm will receive nutritional, psychological, and symptom assessments, followed by precision palliative care for those with identified abnormalities.
This study will provide the first randomized data evaluating the superiority of a precision palliative care model compared with standard oncology care in patients with advanced or recurrent esophageal cancer receiving anti-PD-1/PD-L1 immunotherapy.
Author contributions
Shengnan Hao and Xiaomin Wang were responsible for writing original draft, data curation, investigation, and formal analysis. Huiping Ding, Yun Chen, Qi Liu, Junhua Zhang, Xingwen Fan, Ying Lin, Xiaofang Xu, Guangmin Mao, Dashan Ai, Jiaying Deng, Jinjun Ye, Zhihuang Hu, Huijie Wang，Hongcheng Zhu, Yufen Xu, and Zhenhua Wu were responsible for investigation and data curation. Shengnan Hao and Miao Mo were responsible for software. Wenwu Cheng, Wei Feng, Yiqun Ling, Jialei Wang, and Shisuo Du were responsible for methodology and conceptualization. Kuaile Zhao was responsible for conceptualization, supervision, and funding acquisition. All authors were responsible for review and editing.
Disclosure statement
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Ethical declaration
This trial has been approved by all participating centers, including Fudan University Shanghai Cancer Center Institutional Review Board (Ethics Committee of Fudan University Shanghai Cancer Center: No. 2412311-8). Written informed consent will be obtained from all participants. The trial results will be disseminated through publications in peer-reviewed scientific journals and presentations at relevant academic conferences.
Neither patients nor the public will be involved in the design, recruitment, outcome measures, and conduct of the study.
Data availability statement
The datasets produced and/or analyzed during the present study are not currently publicly accessible as the study remains ongoing and the data has not yet been published. Nevertheless, interested parties may request access to the data from the corresponding author, subject to reasonable conditions.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2026.2637738
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets produced and/or analyzed during the present study are not currently publicly accessible as the study remains ongoing and the data has not yet been published. Nevertheless, interested parties may request access to the data from the corresponding author, subject to reasonable conditions.