Camrelizumab in combination with chemotherapy versus concurrent chemoradiotherapy for the conversion of locally advanced unresectable oesophageal squamous carcinoma: protocol for a two-arm, open-label phase II trial

Abstract

Introduction

Oesophageal cancer (OC) has higher morbidity and mortality rate than most other malignancies. The standard treatment for unresectable locally advanced oesophageal squamous cell carcinoma (OSCC) is concurrent chemoradiotherapy, with tumour regression observed in a proportion of patients after treatment, but prognostic improvement remains limited. Immunotherapy in combination with chemotherapy (CT) has been shown to be efficacious as the first-line treatment of advanced OC and neoadjuvant therapy. Therefore, we conducted a prospective, two-arm, randomised, unblinded phase II study to explore the efficacy of camrelizumab in combination with CT versus chemoradiotherapy for the conversion of unresectable advanced OSCC.

Methods and analysis

All participants meeting the inclusion criteria will be enrolled after signing an informed consent form. Patients with clinically cT4b or spread to at least one group of lymph nodes with possible invasion of surrounding organs and unresectable locally advanced squamous carcinoma of the thoracic segment of the oesophagus will be included in the study. Patients with suspected distant metastases on the preoperative examination will be excluded from this study. Patients eligible for enrolment will be grouped by centre randomisation according to the study plan. Patients will undergo radical surgery after completion of two cycles of chemotherapy (CT) combined with camrelizumab induction therapy or concurrent chemoradiotherapy if assessed to be operable. Patients evaluated as inoperable will be scheduled for a multidisciplinary consultation to determine the next treatment option. The primary endpoint is the R0 resection rate in patients undergoing surgery after treatment. Secondary endpoints are the rate of major pathological remission, pathological complete response rate, overall survival, progression-free survival and adverse events for all patients.

Ethics and dissemination

Ethical approval was obtained from the ethics committees of Fujian Medical University Union Hospital (No. 2022YF039-02). The findings will be disseminated in peer-reviewed publications.

Trial registration number

NCT05821452.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a two-arm, open-label, prospective phase II exploratory clinical trial.

• Sample size is large enough to give some conclusive results.

• The lack of blinding of interventions is a limitation of the study design.

• Another limitation of this trial is that it does not have a multicentre design.

Introduction

Oesophageal cancer (OC) is the seventh most common cancer and the sixth leading cause of cancer-related mortality worldwide.¹ Oesophageal squamous cell carcinoma (OSCC) accounts for more than 90% of all OC cases worldwide, and China is among the regions with the highest incidence of OSCC.² The lack of a serosa layer in the oesophagus and its close encirclement by respiratory and cardiovascular organs means that locally progressive squamous cell carcinoma of the thoracic oesophagus has a strong tendency to invade adjacent organs, including the trachea, heart and aorta.³ Radical resection is considered infeasible in patients with locally advanced OSCC, especially in patients with T4b in which adjacent organs are directly invaded to the point of being initially unresectable. The standard of therapy for such patients involves radical chemoradiotherapy or consideration of CT alone in cases of invasion of the trachea, large vessels, vertebrae or heart. However, the survival of such patients with OC remains limited even after chemoradiotherapy, with a reported median survival of only 14 months and a 5-year overall survival (OS) of 26%.^{4 5}

Chemoradiotherapy is preferred for neoadjuvant treatment of OC and advanced first-line treatment. According to van Hagen et al, surgery following radiotherapy is more beneficial than surgery alone for locally advanced OC.⁶ Day et al have reported a tumour remission rate of up to 50% (33% complete and 17% partial remission) in unresectable, non-metastatic patients with locally advanced OC after chemoradiotherapy.⁷ Clinical studies have shown that conversion therapy based on CT or chemoradiotherapy is expected to achieve tumour regression for patients with stage T4b OC, thus, providing an opportunity for surgery. Furthermore, patients with T4b OC who underwent R0 resection after induction therapy had higher local control rates and survival rates.^{8 9} However, the R0 resection rates of the induction regimens reported in the current study still do not meet expectations. Some studies have revealed that oesophagectomy for T4b OC after induction approach treatment is associated with higher mortality.^10–12 The explanation for this result is that patients receiving concurrent chemoradiotherapy cause a reduction in lymphatic vessels and microvascular beds at the irradiation site, increasing the formation of postoperative anastomotic fistulae, and the infiltration of body fluids into adjacent organs through anastomotic leakage may be the cause of treatment-related deaths.¹³ In addition, chemoradiotherapy (CRT)-related mucosal damage may aggravate dysphagia, leading to a situation where patients struggle to intake sufficient nutrients. This can result in substantial weight loss and malnutrition, rendering them unfit for surgery and being shunted towards palliative care.⁹ Therefore, a better induction regimen is yet to be determined to improve the conversion rate while reducing treatment-related adverse effects.

The utilisation of immunotherapy in combination with CT in the treatment of OC has been promisingly demonstrated through the available clinical data on immune checkpoint inhibitors.¹⁴ The KEYNOTE-590 study has provided compelling evidence of the enhanced survival benefits associated with chemoimmunotherapy compared with CT alone for patients facing unresectable, locally advanced or metastatic OC.¹⁵ Some literature states that immunotherapy combined with CT shows relatively high pathological complete remission (pCR) rates and safety in neoadjuvant therapy for locally advanced resectable OC.^16–18 The RICE-Retro study has analysed the efficacy of conversion surgery (CS) after induction of immune-combination CT in patients with initially unresectable locally advanced OSCC and reported that a total of 116 patients among 155 underwent oesophagectomy, leading to a conversion rate of 74.8%. Furthermore, 109 of the afore-mentioned patients could achieve R0 resection, with an overall R0 resection rate of 70.3%.¹⁹ In addition, a retrospective study by Fan et al has revealed that CT combined with immunotherapy had a more favourable conversion outcome in patients with unresectable OC compared with CT alone.²⁰ However, there is currently no conclusive evidence to support the effectiveness of immunotherapy combined with CT for induction therapy in patients with advanced OSCC.

Therefore, we conduct a phase II prospective, two-arm, randomised, unblinded clinical study to explore the efficacy of camrelizumab in combination with CT versus chemoradiotherapy for the conversion of unresectable advanced OSCC.

Methods and analysis

Study design and setting

This study is an open-label, phase II prospective, two-arm clinical study designed to evaluate the safety and efficacy of camrelizumab in combination with CT versus concurrent radiotherapy for the conversion of potentially resectable advanced OSCC. In the study, all subjects meeting the enrolment criteria will be enrolled with a signed enrolment informed consent form and undergo radical surgery within 4–8 weeks after completion of the conversion therapy. The need for postoperative adjuvant therapy and the specific adjuvant regimen will be determined jointly by two chief physicians of the study committee, and all subjects will be required to complete the follow-up plan developed by the study after surgery. The study pathway is illustrated in figure 1. The trial protocol has been registered on the NIH ClinicalTrials database (www.clinicaltrials.gov/, NCT05821452).

Figure 1.

Flow chart of the study. OSCC, oesophageal squamous cell carcinoma.

Recruitment

All participants will be recruited from the department of thoracic surgery, Fujian Medical University, from March 2023 to March 2026. Patient selection is based on the following inclusion and exclusion criteria.

Inclusion criteria

1. Men or women aged 18–75 years.

2. Diagnosis of OSCC confirmed by pathological histological examination of the primary focus biopsy.

3. Patients who have not received any previous antineoplastic therapy.

4. Patients with unresectable locally advanced squamous carcinoma of the thoracic segment of the oesophagus judged by imaging and oesophagoscopy to be at clinical stage cT4b according to the Union for International Cancer Control (UICC) tumour-node-metastasis (TNM) staging system or at least one group of lymph nodes that may invade surrounding organs.

5. At least one imaging measurable lesion according to the solid tumour efficacy evaluation criteria (Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1).

6. The Eastern Cooperative Oncology Group (ECOG) Performance Status Scale score of 0–1.

7. Major organ function is tolerant to immunotherapy combined with CT. Adequate organ function in accordance with the following:

   1. Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction>50%.

   2. Adequate respiratory function with forced expiratory volume in 1 second (FEV1)≥1.2 L, FEV1%≥50% and lung diffusing capacity for carbon monoxide≥50% shown in pulmonary function tests.

   3. Adequate bone marrow function (white blood cells>4×10⁹/L, neutrophil>2.0×10⁹/L, haemoglobin>90 g/L, platelets>100×10⁹/L).

   4. Adequate liver function (total bilirubin<1.5× upper level of normal (ULN), aspartate aminotransferase and alanine aminotransferase<1.5× ULN).

   5. Adequate renal function (glomerular filtration rate>60 mL/min, serum creatinine≤120 µmol/L).

8. Patients and their families agreed to participate in this study and signed a written informed consent form.

Exclusion criteria

1. Combined diagnosis of other untreated malignant tumours.

2. Persons with known hypersensitivity to the active ingredient or excipients of camrelizumab.

3. The possibility of tracheo-oesophageal or aorto-oesophageal fistula.

4. The patient has participated in other clinical trials within the past 4 weeks.

5. The patient has received systemic therapy with drugs with immunomodulatory effects for antitumor indications within the past 2 weeks.

6. Active autoimmune disease requiring systemic therapy that occurred within 2 years prior to the first dose.

7. Known allogeneic organ transplants (except corneal transplants) or allogeneic hematopoietic stem cell transplants.

8. Presence of any serious or uncontrollable systemic disease.

9. Medical history or evidence of disease that may interfere with the results of the trial, prevent the subject from participating in the study in its entirety, abnormal treatment or laboratory test values, or other potential risks deemed by the investigator to be inappropriate for participation in this study.

Sample size calculation

This study is a two-arm, randomised, non-controlled clinical trial. According to the results of the literature, we anticipate achieving an R0 resection rate of 80% in the experimental group (immunotherapy combined with CT group) and a 50% R0 resection rate in the control group (CT alone group). We will employ a one-sided alpha level of 0.05 with a statistical power of 80%. To achieve this, we will require 33 participants in both the immunotherapy combined with CT group and the CT alone group, for a total of 66 participants.

Randomisation

After obtaining informed consent, participants will undergo unstratified randomisation. Enrolled patients will be randomly allocated in a 1:1 ratio to either the camrelizumab combined with CT group or the chemoradiotherapy group. Randomisation lists were generated by a blinded statistician and managed by a blinded secretary using sequentially numbered, sealed, opaque envelopes. Patient randomisation occurred following the completion of relevant tests and assessments during hospitalisation. The assignment envelopes were opened by the physician responsible for patient care in the unit.

Study interventions

Subjects will receive camrelizumab in combination with CT or concurrent radiotherapy as induction therapy according to the study plan and will undergo surgical evaluation after completion of two cycles of conversion therapy, with radical surgical treatment for those whose evaluation suggests operability and camrelizumab in combination with paclitaxel and platinum or radical chemoradiotherapy for those who are inoperable. All subjects will be required to complete the follow-up schedule established by the study. Details are provided as follows.

Camrelizumab combined with CT group

Paclitaxel: 175 mg/m², administered by intravenous infusion on day 1 of each cycle and every 3 weeks for two cycles (Q3W).

Cisplatin: 75 mg/m², administered by intravenous infusion on day 1 of each cycle and every 3 weeks for two cycles (Q3W).

Camrelizumab: 200 mg, administered by intravenous infusion on day 1 of each cycle and every 3 weeks for one cycle (Q3W), for a total of two cycles.

Chemoradiotherapy group

Paclitaxel: 175 mg/m², administered by intravenous infusion on day 1 of each cycle, one cycle every 3 weeks (Q3W), two cycles in total.

Cisplatin: 75 mg/m², administered by intravenous infusion on day 1 of each cycle, one cycle every 3 weeks (Q3W), two cycles in total.

Radiotherapy: irradiation mode and irradiation dose: 3D conformal or intensity-modulated radiotherapy techniques are used, giving 41.4 Gy at 1.8 Gy each time, five times a week. Target area: the clinical target volume (CTV) includes 3 cm above and below the preoperative primary lesion and the regional lymphatic drainage area; then, the lymphatic drainage area where the metastatic lymph nodes are located, and the planning target volume (PTV) is extensively expanded by 5 mm on the basis of CTV.

Conversion surgical treatment

After two cycles of induction therapy, patients will be re-evaluated by the investigators according to RECIST V.1.1. If the evaluation results suggest operability and there is no evidence of metastatic disease, oesophagectomy will be performed. Patients will undergo robotic minimally invasive oesophagectomy, minimally invasive oesophagectomy or right-sided open oesophagectomy with two-field or three-field lymph node dissection. Transhiatal or left-sided open oesophagectomy is not acceptable due to the limited ability of upper mediastinal lymph node dissection. Surgery-related complications will be documented on a case report form within 90 days after the surgery.

Outcomes

The primary endpoint is the R0 resection rate in patients undergoing surgery after treatment. Secondary endpoints are the rate of major pathological remission (MPR), pCR, OS, progression-free survival (PFS) and adverse events (AEs) for all patients. MPR is defined as having ≤10% remaining viable tumour cells on postoperative pathology, while pCR is defined as the primary tumour being free of residual viable tumour cells as assessed by H&E staining. All AEs during conversion therapy, surgical morbidity and mortality are also recorded.

Side effect documentation and safety assessment

AEs will be recorded and graded according to the Common Terminology Criteria for Adverse Events V.5.0. Throughout the trial, all potential AEs will be conducted under the supervision of the ethics review committee of Fujian Medical University Union Hospital. Patients could withdraw from the trial at any time if they could not tolerate the treatment.

Statistical analysis

On the basis of written informed consent, participants’ medical data will be reviewed and examined by the study staff at all times, and relevant data will be collected and recorded. All statistical analyses will be conducted using SPSS V.22.0 (or a later version) statistical analysis software programming. Statistical tests will be performed as one-sided 0.05 hypothesis of superiority tests, and 95% CIs and p values will be reported for group comparisons. Statistical measures will be described statistically using either mean±SD or median (minimum, maximum), unless otherwise specified. Count data will be presented as frequency (percentage). For the analysis of OS and PFS, the Kaplan-Meier survival analysis method will be employed. The log-rank test will be used to compare survival curves between different treatment groups. Additionally, Cox proportional hazards regression models will be applied to assess the impact of various factors on OS and PFS.

Data collection and management

Experienced and trained study coordinators will be dedicated to data acquisition, coding, security and storage, under the responsibility of investigators. Data will be recorded in paper case report forms at the time of each patient contact. All written form data will be stored in cabinets with lock, permitting access for only investigators. All study procedures were developed to ensure data protection and confidentiality.

Patient and public involvement

None.

Ethics and dissemination

The study protocol is approved by the ethics committees of Fujian Medical University Union Hospital, (No. 2022YF039-02) and will be conducted in agreement with the Helsinki Declaration.

The results of this study will be presented at national or international conferences and will be published in a peer-reviewed journal.

Discussion

Clinical screening and diagnostic techniques for OSCC have seen significant improvements, but more than half of patients are still diagnosed with unresectable tumours or metastases.²¹ Clinical evidence has confirmed that this subset of locally advanced cancer patients can demonstrate tumour downstaging after induction therapy, opening the possibility for surgical resection. Simultaneous radiotherapy is the standard of care for patients with unresectable OC and has been shown to increase the R0 resection rate in patients with advanced potentially resectable cancer, thereby improving outcomes and survival.²² Immune-combination CT has generated considerable interest as an induction treatment option due to its strong efficacy in neoadjuvant therapy and first-line treatment; yet, solid evidence of its effectiveness in conversion therapy is still lacking.

Studies have confirmed that conversion therapy appears to provide a significant OS benefit in the case of locally advanced unresectable OC.^22–25 The COSMOS study is a prospective, phase II clinical trial that aimed to evaluate the efficacy of docetaxel plus cisplatin and 5-fluorouracil induction CT, followed by conversion surgery (CS), for initially unresectable OSCC. The results of this study have revealed that R0 resection was achieved in 19 out of 48 cases, leading to an overall R0 resection rate of 39.6% and a point estimate of 1-year survival of 67.7%. However, 66.7% of patients experienced grade III or higher neutropenia due to concomitant CT.⁹ In another multicentre prospective trial, CRT with CT as initial induction therapy for CS in clinical T4b OC, 69% and 14% of patients underwent CS after initial and supplemental adjuvant therapy, respectively, with 40% achieving complete histological remission of the primary tumour.²² Despite this, due to the lack of relevant comparative studies, there is yet to be a consensus on the optimal induction treatment modality for locally advanced unresectable OC.

A combination of immunotherapy and CT shows encouraging antitumor activity in multiple tumour types.^{26 27} The ESCORT-1st study has demonstrated significant improvement in OS in late-stage OSCC with the addition of camrelizumab to CT compared with CT alone.²⁸ Yang et al have shown that camrelizumab combined with CT as a preoperative neoadjuvant therapy for OC achieved an impressive objective remission rate of 90.5%.²⁹ Given the promising outcomes observed with the combination of camrelizumab and CT in managing locally advanced or advanced OSCC, camrelizumab was chosen as the immunotherapeutic agent for this study. However, there is still an absence of more conclusive evidence to ascertain the effectiveness of immunotherapy combined with CT induction therapy; thus, further prospective studies are needed to evaluate its benefit in terms of the R0 resection rate of the CS and long-term survival.

This is the first reported prospective clinical study exploring the potential of camrelizumab in combination with CT versus radiotherapy for conversion treatment of potentially resectable advanced OSCC. It is hypothesised that CT can stimulate the immune system by activating antigens to attenuate the immune escape of cancer cells, potentially improving the response to immunotherapy and magnifying the benefits while minimising potential adverse effects.³⁰ Thus, in the current study, we will experimentally combine two systemic therapies, immunotherapy and CT, in the preliminary induction treatment of OC with the goal of reducing tumour volume and creating conditions for conversion surgery.

Ethics statements

Patient consent for publication

Not applicable.