Study setting {9}
The randomized controlled trial will be multicenter, two-armed, and blinded (both patient- and observer-blinded) to assess the efficacy of RAMPS versus SRPS for the treatment of resectable pancreatic adenocarcinoma of the pancreatic body and tail. A superiority trial will be used to test the hypothesis that RAMPS is superior to SRPS in improving survival outcomes. The full protocol was prepared in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations. Figure 1 shows the flow chart of the study. The complete protocol is attached in supplementary file.
The trial will be conducted in CSPAC-associated hepatobiliary-pancreatic units or pancreatic cancer centers with high volumes of suitable cases. It will be a multicenter trial. Suitable sites will be selected based on their case volumes, surgical expertise, and surgical oncological experience according to the standards of the protocol. In terms of case volumes, the surgical cases treated should comprise at least 50 and be mostly distal pancreatectomies. A multi-disciplinary team will evaluate the patient regimens.
Eligibility criteria {10}
Inclusion criteria
Treatment-naïve PDAC diagnosed either histologically or cytologically.
Adenocarcinoma of the pancreatic body and tail duct, together with an absence of distant metastases (e.g., liver, peritoneum, lung) and periadrenal infiltration as shown by radiological assessment (enhanced computed tomography [CT], enhanced magnetic resonance imaging [MRI], or positron emission tomography-computed tomography [PET-CT]) and surgery.
The presence of a standard resectable ductal adenocarcinoma in the body and tail of the pancreas, evaluated both preoperatively and intraoperatively (refer to NCCN guideline 2021 of Pancreatic Cancer and ISGPS consensus 2014 of standard distal pancreatectomy)
No indications for neoadjuvant therapy (chemotherapy or radiation).
No previous systemic therapy for advanced disease.
No contra-indications for curative surgery.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Aged between 19 and 80 years.
Laboratory findings four weeks before randomization: Adequate bone marrow function (Hb ≥6.0 mmol/L, absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x 109/L), renal function (serum creatinine ≤ 1.5 x ULN and creatinine clearance, Cockroft formula, ≥30ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN).
Expectation of adequate follow-up
Written informed consent
Exclusion criteria
Pregnancy, lactation.
Primary tumor deemed unresectable due to e.g., neurovascular encasement, significant ingrowth in the pancreatic head.
Conditions precluding safe or feasible resection of the primary tumor e.g., massive ascites.
Intraoperative exclusion criteria including evidence of metastasis, non-pancreatic primary disease, unresectable tumor, Gerota fascia invasion.
Postoperative exclusion criterion of lack of pathological confirmation of pancreatic ductal adenocarcinoma.
History of a different primary tumor five years before randomization, excluding basal cell carcinoma of the skin or an adequately treated in situ carcinoma in any organ.
Any medical condition precluding the safe administration of systemic treatment.
The presence of cardiopulmonary dysfunction affecting tolerance of surgery.
Requirements for neoadjuvant therapy (chemotherapy or radiation).
No informed consent, either due to refusal or withdrawal of consent
Who will take informed consent? {26a}
The study coordinator will obtain consent from the eligible patients, which will ask for permission for the research team to share relevant data and notice that there is neither anticipated harm nor compensation for trial participation
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable, no samples collected
Interventions
Explanation for the choice of comparators {6b}
The use of RAMPS has increased over the past decade. It is reported that RAMPS is superior to SRPS in improving both the rate of R0 resection and lymph node yield. Despite these advantages, however, there is little high-level documentation of the superiority of RAMPS in terms of survival and this needs to be investigated. To address this issue, CSPAC has instigated the first prospective, randomized phase III control trials, aiming to explore the optimal surgical strategy for improving the prognosis and OS of patients with left-sided pancreatic cancer.
Intervention description {11a}
Surgery
Key element
|
SRPS
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RAMPS
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Aim of retroperitoneal dissection
|
Margin-negative resection with the posterior plane of
dissection deep to the gross tumor; can be in front of the
anterior renal fascia
|
Margin-negative resection with the posterior plane of
dissection deep to the anterior renal fascia
|
Extent of lymphadenectomy
|
Regional lymph nodes, which included stations 9, 10, 11, and 18. Additionally, Ln station 9 should be removed, particularly when the tumor is close to the celiac axis in the body of the pancreas.
|
Regional lymph nodes, which include stations 8, 10, 11, 18, 7, 9, 12, 14. Additionally,
nodes around the hepatic artery, celiac trunk, and superior
mesenteric artery
|
Examination after surgery
The following laboratory examination should be performed after treatment (may overlap the examination prior to next treatment)
• Blood routine, urine routine, stool routine+occult blood tests
• Liver function (AST, ALT, γ-GT, TBil, albumin, pre-albumin), renal function (creatinine), electrolytes, blood glucose, blood amylase
• Coagulation function (PT)
• Quantitative measurement of CA19-9, CA125, CEA and other tumor markers
Chemotherapy regimen
The adjuvant chemotherapy regimen is to the discretion of the local investigator, who may choose from the following schedules:
Modified FOLFIRINOX: Every 2 weeks: 2-hour infusion LV 400 mg/m2 followed by an FU 46-hour infusion of 2,400 mg/m2 every 2 weeks, with irinotecan 150 mg/m2 as a 2-hour infusion and oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, administer up to 24 weeks.
Gemcitabine + capecitabine: Every 4 weeks: capecitabine 1660 mg/m2 orally b.i.d. on day 1-21, with GEM 1000 mg/m2 intravenously on days 1, 8 and 15, 6 cycles, 6 cycles.
Gemcitabine: Every 4 weeks: GEM 1000 mg/m2 intravenously on days 1, 8 and 15, 6 cycles.
S-1: Every 6 weeks: S-1 80-120 mg/d orally b.i.d. on day 1-28, administered up to 6 months.
5-FU + leucovorin: Every 2 weeks: 2-hour infusion of LV (200mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, administered up to 6 months.
Criteria for discontinuing or modifying allocated interventions {11b}
Subjects may early discontinue treatment or withdraw from the study before the end of the study. Possible causes of the discontinuation/withdrawal may be as below:
• Clinical symptoms and signs, laboratory test results in consistent with the appearance of pregnancy
• Subjects receive unallowed concomitant treatment which may significantly affect the assessment of the effect.
• Intercurrent diseases or other events that may significantly affect the clinical condition and endpoint.
• Poor compliance which may interfere the analysis of effect.
• Announcement of withdrawal by the subject or their legal representative.
• Loss to follow up
• Death
• Decision made by the organizer of the study
The follow up will be continued if a treatment discontinuation is judged by the investigator as an event different from withdrawal, the data of the subject will still be included in the study analysis.
Strategies to improve adherence to interventions {11c}
After surgery, telephone visit will be performed once 1 month for every subject till the end of the study.
Relevant concomitant care permitted or prohibited during the trial {11d}
Any operation if deviates the study plan should not be performed without permission. The study organizer should be informed as quickly as possible of any accidental or deliberate deviation (e.g., inclusion/exclusion criteria, dosage, treatment cycle omission)
Provisions for post-trial care {30}
Other unforeseen or even serious adverse effects may occur with any treatment or medication. The doctor will closely monitor your condition, and if you have an adverse reaction, you must notify your doctor promptly, and your doctor will determine if you have an adverse reaction and will use other drugs to treat you to reduce the adverse reaction or discomfort. In the unlikely event that you develop an unexpected adverse reaction, we will manage it in accordance with clinical study regulations, excluding common expected adverse reactions or chemotherapy-related comorbidities, and medical issues not related to this clinical study.
Outcomes {12}
Primary outcome:
The primary outcome is OS (interval between randomization and all-cause death) in all randomly assigned patients.
Secondary outcomes:
Secondary outcomes included Quality of Life (QoL), RFS, the number of dissected lymph nodes, R0 resection rate and post-operative complications.
QoL is assessed among patients by using the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30). Patients will be invited to finish the two questionnaires at the day of recruitment, the day of charge and 1th,12th, 24th and 36th month after randomization.
RFS is defined as the time from the date of randomization to the day of tumor recurrence, tumor progression, or patients’ death assessed up to 36 months.
Participant timeline {13}
Parameter
|
Pre-study screening
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Randomization
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Follow-up
|
|
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Baseline screening
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RAMPS arm
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SRPS arm
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Examination after surgery
|
|
Written informed consent
|
✔
|
|
|
|
|
|
ECOG scoring
|
✔
|
✔
|
✔
|
✔
|
✔
|
✔
|
Abdominal CT/MRI scanning (plain+enhanced)
|
✔
|
✔
|
|
|
|
✔
|
Chest CT plain scanning
|
✔
|
✔
|
|
|
|
✔
|
Quantitative measurement of CA19-9, CA125, CEA
|
✔
|
✔
|
✔
|
✔
|
✔
|
✔
|
Demographic data
|
✔
|
|
|
|
|
|
History and physical examination
|
✔
|
✔
|
|
|
|
|
Blood routine, biochemical and coagulation function tests
|
✔
|
✔
|
✔
|
✔
|
✔
|
✔
|
Blood, urine, stool samples for lab test
|
|
✔
|
|
|
|
|
EKG
|
|
✔
|
|
|
|
|
QoL scoring
|
|
✔
|
✔
|
✔
|
✔
|
✔
|
Concomitant treatment
|
|
|
✔
|
✔
|
|
|
Adverse events
|
|
✔
|
✔
|
✔
|
✔
|
✔
|
Inclusion criteria
|
|
✔
|
|
|
|
|
Randomization
|
|
✔
|
|
|
|
|
Urine pregnancy test
|
|
✔
|
|
|
|
|
Operation method
|
|
|
✔
|
✔
|
|
|
Adjuvant chemotherapy and dosage
|
|
|
✔
|
✔
|
|
|
Recurrence/metastasis/progress of tumor
|
|
|
|
|
✔
|
✔
|
Sample size {14}
Based on the former small sample study results (the expected median survivals were 24.6 months and 15.5 months in the operation group and control arm, respectively), and the assumption that the enrollment requires 24 months, the last patient should be followed at least 12 months, a total of 266 patients (133 vs 133) is needed according to PASS 15.0 software (two-sided Log-Rank test, significance 0.05; power 80%). Considering 10% drop-off, 296 patients is needed. Therefore, we plan to enroll 300 patients (150 each group) that will be sufficient to meet the needs of sample size.
Recruitment {15}
In principle, all eligible patient (according to inclusion/exclusion criteria) will be enrolled. The enrollment and its completion in each surgery group will be summarized with a list of drop-off. The comparison of different data set size, case distribution, total drop-off rate, and cause of termination in each group will be listed in detail. The demography characteristics (age, height, vital signs, etc.), history, as well as medication history will be described, and comparison of age, height, and weight, etc., between the groups will be performed to assess the comparability of the two groups
Assignment of interventions: allocation
Sequence generation {16a}
Patients will be enrolled based on inclusion/exclusion criteria, baseline examination, imaging, and pathological examination (reviewed by third party). The general information (initial, age, gender, screening number), which is obtained via IVRS/IWRS system, and stratification variable of the subjects will be used to get random number. The date when random number is generated will be defined as day 0 to count study date. A copy of ID card will be filed for every enrolled patient.
Concealment mechanism {16b}
Allocation concealment will be ensured using sequentially numbered opaque envelopes prepared previously by a person independent from recruitment or allocation of participants to groups.
Implementation {16c}
The allocation sequence was generated by the study statistician and tested in the online randomization system. The principal investigators and enrolling study staff are unaware of the sequence.
Assignment of interventions: Blinding
Who will be blinded {17a}
Trial participants, care providers, outcome assessors, and data analysts will be blinded to the assignment of intervention. The only research personnel who will be unblinded are the surgeons performing the RAMPS or SRPS. The surgery records and surgery videos will be strictly kept confidential, they will not be distinguishable to the trial participants, care providers, or outcome assessors to maintain their blinding. Data analysis will occur outside of the unit with the type of intervention received by each patient concealed until the completion of analysis.
Procedure for unblinding if needed {17b}
If needed, all trial staff (trial participants, care providers, outcome assessors, data analysts, and surgeons) can get access to the subject randomization list and the total dispensing unit number list, and perform the unblinding procedure. Unblinding can be performed under the following circumstances: treatment of a participant in a medical emergency that requires knowledge of treatment allocation; treatment of a participant for an adverse event (AE); in the event of a suspected unexpected serious adverse reaction (SUSAR); for the submission of trial data to the Data Monitoring and Safety Committee for the monitoring of safety and/or efficacy.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Evaluation of outcomes
Efficacy variables
• Major parameter: OS
• Minor parameters: RFS, the rate of R0 resection, the number of lymph node dissection, post-operative complications and QoL scores.
Procedure
Primary efficacy analysis
Primary efficacy analysis is to determine the overall survival (OS): Log-Rank test will be performed to compare the differences between the RAMPS group and the SRPS group. Kaplan-Meier curve will be used to plot the difference in OS.
Secondary efficacy analysis
Recurrence-free survival (RFS) will be analyzed using the same method as that for OS. Descriptive analysis using covariance analysis (ANCOVA) model will be performed for the changes in QoL when compared with baseline. Baseline serves as a covariant in the model, and the effects of assessors are considered as a random effect. The value of difference (D-value) in each group before and after treatment, the LSmeans of the difference in D-values and the 95% confidential interval of the difference between the two groups are calculated based on the model.
The incidence and severity of hematological, non-hematological and overall toxicity and complications will be assessed. The incidence of any Grade 3 or 4 toxicities will be compared across treatment groups using Pearson’s chi-square test with continuity correction or Fishers Exact test where appropriate.
For the rate of R0 resection and number of harvested lymph nodes outcome, two-sided tests will be performed for all statistical tests, and p-value <0.05 will be considered statistical difference. Mean value, standard deviation (SD), median, minimum, maximum, upper and lower quartiles will be calculated for quantitative index description, while number of cases and percentage will be used to describe classification index. Comparison of general condition of the two groups will be performed by corresponding analytic method according to the type of the index: paired-t-test or Wilcoxon rank-sum test will be used for comparison of quantitative data between the groups, Chi-square test or Fisher's exact probability test will be used for classification index, and Wilcoxon rank-sum test and CMH test for ranked data.
For the QoL outcome, characteristics of RAMPS group and SRPS group will be compared, and potential biases assessed. Quality of life will be assessed over time and surgery groups compared using longitudinal analysis with appropriate recognition for informative dropout. Joint modelling or quality-adjusted survival analysis will be undertaken to allow a simultaneous assessment of quality of life and survival. The changes in QoL before and after surgery in each group are compared using paired-sample t-test.
Analyses will be done in eligible patients according to the intention-to-treat principle.
End of trial (EOT) assessment
EOT assessment will be performed for every subject who has completed the study at the end of the trial, including:
• Physical examination, weight, vital signs, ECOG scoring, QoL scoring
• Blood routine, liver, and renal function tests
• Imaging examination (according to the length of follow up duration)
• CA19-9, CA125, CEA and other tumor markers
• Assessment of adverse events.
Plans to promote participant retention and complete follow-up {18b}
A regular telephone follow-up will be performed every 2 months in the participating centers.
Data management {19}
Treatment of the data
The data of enrolled subjects must be recorded by the investigator in the CRF after randomization, data of those fail to pass the screening is not required to be filled in. The accuracy and completion of the data must be ensured, and the original records must be well kept. The CRF for every enrolled patient must be completed right in time. The completed CRF will be reviewed and then turned over to the data administrators for data entry and management.
Data entry
Data entry and management are performed by appointed data administrator unit. Data administrators compile data entry procedure by computer software to perform data entry and management. Transcribed data must be proofread by another person to ensure the accuracy of the data.
Medical information coding
The coding of medical information will be performed by using:
• MedDRA 11.0 (patient history and adverse event)
• WHO Drug 2008.03 (concomitant medications)
• NCI-CTCAE 3.0 (toxic reaction)
Data review
The established database will be reviewed by the principal investigator, organizer, data administrators, statisticians, and the locking of the database will be performed when the study data set and the statistical analysis plan have been confirmed.
Confidentiality {27}
Any observed results and examination results during the study must be completely and accurately recorded in a standard manner in the medical record and CRF by the investigator right in time. At will modification of the records is not allowed. Correction of wrong-filled items must keep the original record legible, and the correction must be dated along with the signature of modifier’s name. The original data/file must be carefully stored in the research center according to the ICH GCP guidelines as well as local laws and regulations.
The superior competent department and the regulatory authorities have the right to supervise and inspect the implementation process of the clinical study as well as the original data/source file but have no right to modify the original data/source file. Once a mistake is found, the investigator must be informed because s/he is the only one who has the right to modify the record.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Standard operating procedure for sample collection
Samples from the subjects is collected strictly according to our center’s standard operating procedure (SOP) for blood and tumor tissue sample collection.
Sample storage
The principal investigator will be responsible for the storage of samples. Informed content is obtained prior to the enrollment. Both paraffin-embedded and frozen specimens of tumor tissues will be regularly kept after surgery in the operation group; the paraffin-embedded will be used to make tissue chip after completion of enrollment. The blood samples will be centrifuged to separate serum and blood cells for storage.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Statistical methods
The study statistical analysis plan is made by professional statistician with the principal investigator when the study plan is determined. SPSS 25.0 software will be used for statistical analysis. Two-sided tests will be performed for all statistical tests, and p-value <0.05 will be considered statistical difference. Mean value, standard deviation (SD), median, minimum, maximum, upper and lower quartiles will be calculated for quantitative index description, while number of cases and percentage will be used to describe classification index. Comparison of general condition of the two groups will be performed by corresponding analytic method according to the type of the index: paired-t-test or Wilcoxon rank-sum test will be used for comparison of quantitative data between the groups, Chi-square test or Fisher's exact probability test will be used for classification index, and Wilcoxon rank-sum test and CMH test for ranked data. RFS serves as first minor efficacy variable, which is tested only when a significant difference in OS (the major efficacy variable) is found.
Primary efficacy analysis
Primary efficacy analysis is to determine the overall survival (OS): Log-Rank test will be performed to compare the differences between the RAMPS group and the SRPS arm. Kaplan-Meier curve will be used to plot the difference in OS.
Secondary efficacy analysis
Recurrence-free survival (RFS) will be analyzed using the same method as that for OS. Descriptive analysis using covariance analysis (ANCOVA) model will be performed for the changes in QoL when compared with baseline. Baseline serves as a covariant in the model, and the effects of assessors are considered as a random effect. The value of difference (D-value) in each group before and after treatment, the LSmeans of the difference in D-values and the 95% confidential interval of the difference between the two groups are calculated based on the model. The changes in QoL before and after treatment in each group are compared using paired-sample t-test.
Interim analyses {21b}
No interim analyses are planned.
Methods for additional analyses (e.g. subgroup analyses) {20b}
The safety analysis includes all AEs and SAEs (including the number and the occurrence rate of the events), complications and mortality during the perioperative period, routine blood and biochemical data, weight, vital signs, physical examinations, and all treatments and simultaneous medication. Safety indexes include: weight, vital signs, clinical laboratory indexes, AE, etc. The laboratory indexes will be listed according to treatment group, actual value at each assessment, change in value than baseline, and comparison with the reference range (lower than, within or higher than the reference range); the weight and vital signs will be listed according to treatment group, actual value at each assessment, and change in value than baseline.
The number of subjects who experiences AE to the number of all patients with assessable safety data is used to represent the occurrence rate of AE. The AE rate in each group will be summarized using the organ classification and standard terminology listed in MedDRA. An AE during the study is defined as an event occurs during the period from first dose to the last dose or within 30 days after the last dose or the day when the treatment is discontinued. The severity of the toxic reaction is classified according to NCI- CTCAE 3.0. For an individual subject, the same adverse event if occurs more than once will be counted only once, the event of the worst CTCAE grade is to be counted.
The type, grade, frequency, severity, lasting duration, as well as its relationship to the intervening agent, its treatment and outcome will be listed and described in detail for all AEs.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
In case of missing data, an intention-to-treat analysis will be performed. For primary outcomes, for patients who are lost to follow-up, censored data will be the date of last follow-up. For secondary outcomes, we may consider multiple imputation or other strategies in place of imputed missing values.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
In the current document, the full protocol is outlined. Non-identifiable data may be made available upon reasonable and well-motivated request. A data sharing agreement must be signed in addition to privacy regulations and informed consent. Data cannot be made freely available to the public.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The coordinating center is the Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. In each participating center, a lead investigator (surgeons) will be identified, to be responsible for identification, recruitment, data collection, and completion of CRFs, along with follow-up of study patients and adherence to study protocol. To ensure optimal quality control regarding GCP-compliant data management, monitoring, and biometry, the Institutional Review Board/Ethics Committee (IRB/EC) is part of the trial. Prior to the initiation of the study, the study plan, informed content, and any potentially wanted or required document, should be submitted to the IRB/EC with an enclosed cover or form, listing the names and publication date of the documents submitted, as well as the research center waiting to be permitted. The documents will also be submitted to the regulatory authority according to local laws and regulations.
Composition of the data monitoring committee, its role and reporting structure {21a}
A data monitoring committee (DMC) has been established parallel to the finish of study protocol. The data monitoring committee consists of the key persons for conducting this trial (Jialin Li, Si Shi, and Wei Wang) and will maintain monthly meetings to discuss the progress and possible harms of this trial. The DMC should consider essential parts of study conduct such as protocol adherence, safety monitoring, and patient withdrawal. In addition, a DMC should consider potential recommendations to the sponsor if major problems with study conduct are observed.
Adverse event reporting and harms {22}
Adverse event will closely be monitored. Any AE (reported by the subject or observed by health-care providers) from randomization to end of the study or withdrawal, must be recorded in medical record and CRF. A record of an AE includes: name of AE, time of occurrence and end, severity, treatment, outcome, relationship with intervening agent, etc.
Changes in vital signs, physical examination results, clinical manifestation and laboratory tests must be assessed during the study. Any medical record about AE must be recorded in original document, including laboratory test and auxiliary examination results. Reported AE and its severity must be assessed according to NCI-CTCAE 3.0.
Relevant researcher’s name and telephone number must be offered to subjects at the time of signing informed content, so that they can contact the researcher in case of an emergency, or report any medical symptom or adverse event.
Toxic reaction or AE exists prior to the study, will be recorded as an AE only when it significantly elevates to a higher level. In this study, the worsening of tumor symptom than the baseline is also recorded as an AE.
Frequency and plans for auditing trial conduct {23}
There will be constant audits of the data and the conduct of the study by the study coordinator, but there is no external auditing planned.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
The revision of the study plan is allowed during the study if necessary. The revision must be made by the investigator and the organizer according to relevant GCP requirement. The approval of the Ethics Committee must be obtained before the implementation of the revised plan. The revision opinion approved by the EC must be included in the revised plan.
Dissemination plans {31a}
The results of the study may be published in medical journals or used in teaching. In addition, the study and its results can be registered in the health research institutes and published at the website of the health care registration authority (e.g. ClinicalTrials.gov), according to the requirements of local health care authority. The selection of first author is based on several considerations, including but not limited to below items: participate in the study, has contribution to the development of study plan, and contribute to manuscript, abstract, description and analysis.