CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer

The CRITICS-II study is a multicentre, non-comparative randomised phase II trial. The study is currently recruiting in several centres in The Netherlands. Randomisation is computer generated and will be performed and registered by the data managers. Stratification factors include Lauren classification (intestinal, diffuse, unclassifiable) and centre. The primary objective is to assess 1 year event-free survival in patients treated with preoperative CT, preoperative CT followed by CRT, or preoperative CRT (Fig. 1).

Event-free survival (EFS) is defined as interval between randomisation and local and/or regional recurrence or progression, distant recurrence or death from any cause.

Secondary endpoints are: toxicity, percentage radical (R0) resections, pathological tumour response, disease recurrence, overall survival and health related quality of life (HRQOL). Exploratory endpoints include translational studies into the relationship between classical histological and clinical parameters, the identification of new biomarkers that predict clinical outcome and response, genomic changes in circulating tumour-derived DNA for diagnosis of different molecular subtypes of gastric cancer, and as biomarkers for response to treatment.

Patients will be informed and treated by their treating physician. Patients with histologically proven, stage IB-IIIC (TNM 8th edition), resectable gastric adenocarcinoma are eligible for this study. Patients with tumours at the gastro-oesophageal junction (GOJ) may be included, but the tumour bulk has to be in the stomach. Patients should be ≥18 years old and should have WHO performance status < 2. Patients must have adequate haematological, renal and liver function. A staging laparoscopy is mandatory for all patients. At staging laparoscopy, biopsies from suspicious peritoneal lesions and/or free peritoneal fluid if any, should be pathologically proven tumour negative. Patients should have caloric intake ≥1500 kcal/day, verified by a dietician before registration. If caloric intake is < 1500 kcal/day or if bodyweight has decreased > 10% over the last 6 months or > 5% over the last month, dietary intervention such as oral nutritional support or via an enteral feeding tube is mandatory.

Exclusion criteria include: T1 N0 disease (assessed by endoscopic ultrasound), distant metastasis, inoperable/irresectable patients, previous malignancy, solitary functioning kidney within the potential radiation field and gastro-oesophageal stent within the radiation field. Required baseline investigations prior to randomisation consist of blood tests, dietician visit, oesophagoduodenoscopy with representative tumour biopsy samples, computed tomography of the chest and abdomen, staging laparoscopy, renography if there are signs on computed tomography abdomen and/or biochemically signs of impaired renal function. Endoscopic ultrasound (for >T1 N0 disease) and performing a FDG-PET/ computed tomography scan are optional per centre.

All treatment arms will start within 15 working days after randomisation. Patients in arm 1 receive four cycles of docetaxel+oxaliplatin+capecitabine (DOC) at a three-weekly interval preoperatively. Patients in arm 2 receive two cycles of DOC at a three-weekly interval, followed by CRT (weekly paclitaxel and carboplatin concurrent with radiotherapy). Chemoradiotherapy starts 3 weeks after start of the second DOC cycle. Patients in arm 3 receive CRT. Prior to surgery, a computed tomography will be performed to exclude progressive disease.

Patients can withdraw their informed consent at any time for any reason if they wish so without any consequences. The investigator can decide to withdraw a patient from the study for urgent medical reasons.

Chemotherapeutic treatment consists of docetaxel 50 mg/m² on day 1, followed by oxaliplatin 100 mg/m² on day one, followed by capecitabine 850 mg/m² b.i.d. orally on days 1–14. All drugs are administered in a cycle of 21 days. For capecitabine, drug tablet return and a diary are provided. Dose could be discontinued/reduced in case of severe toxicities.

Concurrent with radiotherapy, weekly CT is administered. Paclitaxel at a dose of 50 mg/m² and carboplatin Area Under the Curve (AUC) = 2 are given by intravenous infusion on days 1, 8, 15, 22 and 29. Radiotherapy starts at the first day of the first cycle of CT. Radiotherapy and/or chemotherapy dose could be discontinued/reduced in case of severe toxicities.

Surgery is planned 3–4 weeks after preoperative treatment in arm 1 and 6–8 weeks after preoperative treatment in arms 2 and 3. The standard surgical procedure is a (sub)total gastrectomy with a D2 lymph node dissection. A minimum of 15 lymph nodes should be removed. Lymph nodes will be submitted in separate pots, or alternatively, will be clearly marked at the resection specimen. Surgical technique is either open or laparoscopic.

The pathology report includes at least the following items: tumour type, localisation, size of tumour, surgical margins, response to neo-adjuvant therapy in the primary tumour and the lymph nodes (by nodal station), presence of lymphatic invasion, presence of venous invasion, surgical stage, number of (positive) lymph nodes.

All tumours are classified using the Lauren classification (intestinal, diffuse and unclassifiable). For staging, the TNM 8th edition is used. Biopsies, photographs, resection specimen and when performed fresh frozen specimen will be sent for central pathological review. Pathological response according to the Becker scoring system [18] and the Mandard scoring system [19] will be investigated in central pathological review.

Health related quality of life will be carried out in cooperation with the Prospective Observational Cohort study of Oesophagogastric cancer Patients (POCOP), which is a prospective nationwide study to investigate HRQL in oesophagogastric cancer of all stages [20]. Health related quality of life will be assessed at baseline (before start preoperative treatment), pre-surgery and from surgery every 3 months in the first year, every 6 months in the second year and yearly thereafter until 5 years.

Patients can optionally participate in this part of the protocol. All patients participating in this part of the protocol need to have signed informed consent specifically for this optional side study of the trial. Blood will be collected at baseline before start of any of the preoperative treatment modalities, after every preoperative treatment modality, after surgery and at every follow-up visit until 5 years after surgery or until recurrence. Material processing and storage will be done centrally at the VU University Medical Center.

Toxicity during this trial is scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Serious adverse events are defined according to the rules of good clinical practice and must be reported within one working day and are reported once yearly in the annual safety report. The Clavien-Dindo grading system is used for the classification of surgical complications [21].

After treatment, patients are followed by all treating medical specialists. The follow-up moments in the first year are, counted from surgery, at 1, 3, 6 and 12 months. From the second year, follow-up will occur every 6 months until 5 years after surgery. To enable evaluation of the primary endpoint, one-year EFS, CT chest and abdomen will be performed 1 year after randomisation.

Future protocol modifications will be submitted as amendment at the central medical ethics committee. After obtaining approval, this will be communicated to the participating sites by the study coordinator or project manager.

The central data management, data processing and statistical analysis of this study are performed at the Biometric Department of the sponsor. The study coordinators are responsible, in cooperation with the Data Centre, for writing the protocol, reviewing all case report forms, reporting and correctness of SAE. They are also responsible for answering clinical questions, treatment and evaluation of the patients and for publishing study results. Authors on the key-publication includes at least the protocol writing committee and additional a maximum of three authors per centre. The key-publication will be submitted to a major, peer-reviewed journal. Data is entered by data managers into a coded electronic case-report form. The study will be considered as a medium risk according Dutch Federation of University Medical Centres guidelines. Site monitoring will be performed by an independent Clinical Research Monitor or the person to whom the monitoring tasks have been delegated. The monitor will judge: compliance with the protocol, all applicable regulatory requirements, informed consent, source data verification, investigator study file, SAE/Serious Unexpected Serious Adverse Reactions. If necessary, active feedback will be provided to the participating sites. The study will be monitored and an auditing trail will not be performed routinely. The study coordinators will have access to the final dataset. Queries will be sent in case of missing data.

The primary endpoint of this trial is EFS at 1 year. Statistical analysis will be performed on basis of intention to treat analysis. For each treatment arm, a 1-year EFS of 60% is considered insufficient and a 1-year EFS of 75% is active enough to further explore in a phase III study, taking other endpoints in consideration. The 1-year EFS of 60% is based on results of the MAGIC [22] and the CRITICS trial [11]. The design calculations assume Weibull distributions (shape = 1), which is equivalent to an exponential distribution. Scale parameters were chosen such that 1 year EFS would be 60% and 75% respectively. The type I (α) error is fixed at 10% (one-sided) and power is set at 90%.The R package OptInterim minimising the expected sample size was used for calculating the sample size for each stage as well as the time of interim and final analyses. We used exact binomial correction adjusting all sample size and analysis times.

The trial is designed as a two-stage trial with one interim analysis at which futile arms are discontinued. Because the primary endpoint is evaluated at 1 year, the commonly used Simon’s two stage design would imply up to 1 year in which the trial would be put on hold. To improve the efficiency, we will use the two stage design for survival endpoints as proposed by Case and Morgan [23].

The expected accrual is 30 patients per arm per year. After accruing 42 patients in each arm, the interim analysis will be performed. Futile arms will be discontinued and the remaining arms will accrue 27 more patients each (to a total of 69 patients in each arm). Final analysis will be performed 1 year after accrual of last patient. In both stages the null hypothesis will be evaluated using Lin’s statistics [24]. If in the final analysis more than one arm will reject the null hypothesis, the decision about which arm should continue to the phase III trial will be made based on the Kaplan Meier point estimates of the 1-year EFS in combination with other factors such as toxicity, cost, convenience and quality of life.

The aim of this study is to select the most promising preoperative treatment regimen among three experimental arms in patients with resectable gastric adenocarcinoma. This treatment regimen will subsequently be compared with the current standard therapy in a phase III trial.