Study setting {9}
All patients with isolated local PDAC recurrence, who participate in the PACAP-cohort and have provided informed consent to receive quality of life questionnaires and to be randomized according to the TwiCs design, are eligible to be included in the ARCADE trial.
Eligibility criteria {10}
Patients are eligible for randomization if they meet all the following criteria:
- Participation in the PACAP-cohort with written informed consent for quality of life questionnaires (patient reported outcome measures; PROMs) and broad consent for future randomization (TwiCs)
- Histologically proven local recurrence after primary resection. Regional lymph node metastases are also considered local recurrence. In case histological confirmation cannot be obtained (because the first attempt fails or since it is technically impossible), consensus on presence of isolated local recurrence may be obtained in a multidisciplinary meeting (e.g., based on imaging, elevated cancer antigen 19-9 (CA 19-9) and clinical situation)
- Eastern Cooperative Oncology Group (ECOG) performance score 0-2
Exclusion criteria are as follows:
- Distant metastases at recurrence diagnosis. Regional lymph nodes are not considered distant metastases.
- Expected lifespan < 3 months
- Previous radiotherapy precluding SBRT
- Highly selective cases eligible for re-resection without induction therapy, according to the expert panel
- Age < 18 years
- Pregnancy
Who will take informed consent? {26a}
According to the TwiCs design, only patients randomized for the intervention group are approached by the radiation oncologist from one of the three participating radiation centers to obtain additional informed consent.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Participants included in the ARCADE trial have provided informed consent to collect their data in a standardized fashion in context of PACAP. According to the TwiCs design, only patients randomized for the intervention group are asked to provide informed consent for participation in the ARCADE trial.
Interventions
Explanation for the choice of comparators {6b}
All patients (in both study groups) will receive standard of care. In most cases this comprises standard chemotherapy, either consisting of 12 cycles of (modified) leucovorin, 5-fluorouracil (5-FU), irinotecan and oxaliplatin combination therapy (FOLFIRINOX), consisting of a 5-FU bolus 400 mg/m2 on day 1 and continued infusion of 2400 mg/m2 during 46 hours; Oxaliplatin 85 mg/m2 on day 1; Irinotecan 180 mg/m2 on day 1 and Leucovorin 400 mg/m2 on day 1, or 6 cycles of Gemcitabine (1000 mg/m2) and Nab-Paclitaxel (125 mg/m2) on day 1, 8 and 15 of a 4-week cycle. If patients refrain from chemotherapy, out of choice or because of impaired physical condition, patients will receive best supportive care (BSC).
Intervention description {11a}
Additional SBRT will be administered to patients in the intervention group following an image-guided, hypo-fractionated scheme of 5 fractions of 8 Gray (Gy), prescribed to 95% of the planning target volume. The gross tumor volume is the local recurrent PDAC as defined on either CT or MRI. SBRT is delivered in one of the three participating centers. In the UMC Utrecht and Amsterdam UMC, SBRT is applied using MR-guidance. In the Erasmus MC, CT-guided imaging is used and therefore three radiopaque markers (fiducials) are placed in or near the tumor.56 Treatment is delivered on alternate days 2 or 3 times a week with a maximum overall treatment time of 21 days in one of the participating centers. Treatment preparation and delivery procedures will be determined in accordance with the protocols of the treating center. However, the irradiation dose constraints for all organs at risk will be the same for all institutions.
Concurrent treatment
Patients randomized for SBRT can receive the intervention in addition to standard of care, which mostly comprises systemic chemotherapy. There is no preset order in which both treatments are applied. However, they cannot be received simultaneously. SBRT will be given as early as possibly after diagnosing isolated local recurrence. Hence, if systemic chemotherapy treatment has already started, SBRT can be delivered between two cycles of systemic therapy.
Criteria for discontinuing or modifying allocated interventions {11b}
Patients can leave the study at any time for any reason if they wish to do so without any consequences. The steering committee may withdraw a patient from the study for one or more of the following reasons: 1. Incorrect randomization, meaning that the eligibility criteria were not followed correctly, 2. continuing participation could be harmful to the patient, 3. the study is stopped early. An individual patients will not be replaced by another patient after withdrawal, but they will be followed-up by a medical doctor until death.
Strategies to improve adherence to interventions {11c}
To improve adherence to the intervention protocol, patients can freely choose in which of the three participating radiotherapy centers they want to undergo the intervention. After SBRT and corresponding follow-up appointments, patients can go back to their referring hospital to receive further treatment and/or follow-up.
Relevant concomitant care permitted or prohibited during the trial {11d}
Other experimental treatment is only prohibited during the radiotherapy intervention of patients.
Provisions for post-trial care {30}
Participants will remain enrolled in the ARCADE trial for a maximum of 18 months or until patient withdrawal. After their participation in the ARCADE trial, participants will be referred to their treating medical oncologist or general practitioner.
Outcomes {12}
The primary study endpoint is survival after recurrence by intention-to-treat, defined as the time between the date of recurrence diagnosis and the date of death from any cause or date of last follow-up. The date of histological evidence of disease recurrence will be used as the date of recurrence diagnosis. In case histological evidence could not be obtained, the date of the multidisciplinary meeting in which isolated local recurrence was diagnosed will be used.
Secondary endpoints are:
- Patient-reported quality of life, as standardly measured by assessing PROMs as a part of the current PACAP of the Dutch Pancreatic Cancer Group (DPCG).52
- Treatment response, assessed by CT-imaging according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST).57
- Acute and late toxicity, as assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 during regular follow-up moments.58 In the intervention arm acute toxicity will be monitored by the treating radiation oncologist. Acute toxicity will be defined as toxicity within 90 days from the end of SBRT treatment and will be assessed in week 1, 3, 6 and 12. Late toxicity is defined as toxicity occurring > 90 days from SBRT.
- Overall survival, defined as the interval between the date of primary resection and the date of death from any cause.
- Progression-free interval, defined as the interval between the date of disease recurrence and the date that local and/or distant progression of disease occurs.
- Local progression-free interval, defined as the interval between the date of disease recurrence and the date that locoregional progression of disease occurs.
- Distant metastasis-free interval, defined as the interval between the date of disease recurrence and the date that distant progression of disease occurs.
- To assess patients’ acceptability of SBRT
Participant timeline {13}
Table 1: schedule of enrolment, intervention, and assessments according to the SPIRIT guidelines
|
STUDY PERIOD
|
|
Identification
|
Allocation
|
Post-allocation
|
TIMEPOINT
|
Recurrence diagnosis
|
pre-SBRT
|
SBRT
|
After completing therapy%
|
PACAP registry, TwiCs & PROMs informed consent
|
X
|
|
|
|
|
Histological confirmation PDAC recurrence
|
X
|
|
|
|
|
Informed consent for additional SBRT (investigational arm)
|
|
X
|
|
|
|
SBRT 5x8 Gy
|
|
|
|
X
|
|
History & physical examination
|
|
|
X
|
|
Every 3 months
|
Laboratory investigation including tumor markers
|
|
|
X
|
|
Every 3 months
|
MRI-scan chest and abdomen
|
|
|
X$
|
|
|
CT-scan chest and abdomen
|
|
|
X
|
|
At 3, 6 and every subsequent 6 months
|
Fiducial marker-placing
|
|
|
X#
|
|
|
QoL questionnaires*
|
X
|
|
|
|
At 3, 6, 9, 12 and 18 months after recurrence diagnosis
|
* The following questionnaires are used: general questions, questions on exocrine pancreas insufficiency (EPI), non-disease specific health-related quality-of-life (HRQL) (EQ-5D-5L), cancer-specific HRQL (EORTC QLQ-C30), tumor-specific HRQL (EORTC QLQ-PAN26), neuropathy (EORTC QLQ-CIPN20), happiness, hospital anxiety and depression scale (HADS), worry of progression of cancer scale (WOPS; modified from ways of coping scale (WOCS); $ Only for patients treated at the UMC Utrecht or Amsterdam UMC; # Only for patients treated at the Erasmus MC; % For patients receiving chemotherapy, this will be after their chemotherapy. During chemotherapy they will be treated according to standard of care. For patients receiving best supportive care, this will be after radiotherapy.
|
Sample size {14}
The pooled median survival in patients with isolated local PDAC recurrence is 9 months from the time of recurrence; the pooled median survival of patients additionally treated with SBRT is 16 months.10,19,23,48,49,59,60
As we expect 80% of patients to accept the experimental intervention offered in the intervention group, an estimated refusal rate of 20% needs to be taken into account. This dilutes the overall survival rate to 14.6 months (80% x 16 months + 20% x 9 months) for all patients in the intervention group. The clinically relevant survival difference of 14.6 months vs. 9 months for respectively the intervention and control group corresponds to a relative hazard (RH) of survival of 1.62, which was used to calculate the sample size of the study.
To detect a 62% improvement (RH of survival of 1.62) in overall survival for patients in the intervention group, as compared with the control group, with a statistical power of 80% and a 0.05 two-sided significance level, a sample size of 174 patients is required. This calculation was based on the assumption of an exponential model, a median overall survival of 9 months in the control group, a follow-up duration of 18 months, a censoring rate of 1% and a baseline event rate of 7.7%. Following this calculation, we plan to include 174 patients in total: 87 patients in the control group and 87 patients in the intervention group.61
Recruitment {15}
Nationwide collaboration within the DPCG will enhance patient enrolment. In the Netherlands, treatment of patients with isolated PDAC recurrence takes place in centers affiliated with the DPCG. Our goal is to include all 15 DPCG-affiliated centers in this study.
In 2019, 360 patients underwent macroscopically radical (R0-R1) resection of a PDAC in the Netherlands. All pancreatic resections in the Netherlands are performed in centers affiliated with the DPCG. An earlier study showed that 21% of these patients develop isolated local recurrence.62 However, previous trials conducting a trial-specific, standardized surveillance strategy showed that with standardized surveillance, isolated local recurrence can be found in 26% of patients (Table 2). As the RADAR-PANC trial on the additional value of a three-monthly standardized surveillance with imaging and tumor marker testing will be conducted simultaneously within the Netherlands (NCT04875325), isolated local recurrence is expected in about 25% of patients (n = 90). Based on the current successful enrolment progress, we anticipate that 90% (n = 81) of all patients will be registered yearly in the PACAP-cohort, and that 83% (n = 67) of these patients will provide informed consent for the TwiCs design, based on the current PACAP participation rate. Fifty percent of these patients (n = 33) will be randomized to the intervention arm of the trial. The expected time needed for inclusion of a total of 174 patients (87 patients in each arm) will be 4.5 years, including a start-up period of 1.5 years in which the trail is initiated in all DPCG centers. Besides, during this start-up phase of the trial, isolated local recurrence rates will be lower due to the fact that the standardized follow-up protocol initiated by the RADAR-PANC trial is not yet rolled out in all centers. The final analysis will be performed 18 months after the last patient is enrolled.
Table 2: Incidence of isolated local recurrence after resection for pancreatic cancer in selected randomized controlled trials on adjuvant therapy
Reference and name of the study
|
N
|
Incidence of ILR
|
Neoptolemos et al. (2004); ESPAC-1 4
|
289
|
35%
|
Smeenk et al. (2007) EORTC 40891 (long-term results) 22
|
218
|
21%
|
Regine et al. (2008); RTOG 97-04 15
|
451
|
26%
|
Ueno et al. (2009); JSAP-02 16
|
118
|
28%
|
van Laethem et al. (2010); EORTC-40013-22012/FFCD-9203/GERCOR 17
|
90
|
18%
|
Uesaka et al. (2016); JASPAC 01 18
|
377
|
23%
|
Pooled incidence
|
|
26%
|
National recurrence database 62
|
|
21%
|
Assignment of interventions: allocation
Sequence generation {16a}
Participants are randomly allocated by a computer-generated program, following 2-4-6 block randomization. Randomization will be stratified by institute and surveillance strategy. This can be symptomatic, according to current clinical practice, or standardized, for example when a patient is participating in the RADAR-PANC trial (TwiCs to investigate the impact of a standardized surveillance strategy using imaging and serum tumor marker testing on survival and quality of life in patients who underwent resection of PDAC; NCT04875325).
Concealment mechanism {16b}
According to the TwiCs design, only participants randomized for the intervention will be informed about their randomization. Directly after randomization, these patients will be contacted by the radiation oncologist to inform them that they have been randomized for the intervention. Patients randomized for the control group will not be informed. Therefore, there is no need to conceal participants’ allocation.
Implementation {16c}
Participants are randomized as soon as they meet all of the inclusion criteria. The central study coordinator performs the randomization and allocates participants to the intervention. The pros and cons of SBRT will be explained and additional informed consent will be asked. Patients not giving informed consent for SBRT will be followed and analyzed according to the intervention arm (ITT). When a participant is randomized for the intervention arm, the radiation oncologist from one of the three radiation centers (based on patient preference) will be informed. The radiation oncologist will contact the patient to schedule an appointment to inform them about the intervention.
Assignment of interventions: Blinding
Who will be blinded {17a}
Blinding is not applicable to studies that are designed according to the TwiCs design. However, as inherent to the design, participants randomized to the control group will not be informed explicitly.
Procedure for unblinding if needed {17b}
Not applicable since blinding will not be performed.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Baseline characteristics of all trial participants are standardly collected as part of the PACAP-cohort of the DPCG. Also, quality of life is assessed at standard time points in all PACAP-participants by the PROMs. Additional data is collected from the patients’ electronic files. Local clinicians in the participating centers are responsible for data collection. They can, however, transfer this responsibility to the study team. The study team will appoint appropriate personnel for data collection.
Plans to promote participant retention and complete follow-up {18b}
The treating radiation oncologist will schedule follow-up appointments conform protocol to retain participants randomized for the intervention in the trial and complete their follow-up. Additionally, the central study coordinator will closely follow all trial participants during their follow-up.
Data management {19}
Data management will be carried out in accordance with the UMC Utrecht data management policy in accordance with the predefined data management plan. Data will be collected using a predefined electronic case report form in Castor EDC, containing only coded data.
Confidentiality {27}
The handling of personal data will comply with the Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons regarding the processing of personal data and on the free movement of such data (General Data Protection Regulation). A subject identification code list will be used to link the data to the subject. These codes will not be based on the patient initials and birth date. The local investigator will safeguard the key to this code.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Baseline data will be analyzed and reported using standard descriptive statistics. Randomization success will be evaluated by comparing baseline data of the intervention group to the control group. Analyses will be performed according to the intention-to-treat principle. The primary endpoint is survival after recurrence, defined as the time between the date of recurrence diagnosis and the date of either death from any cause or last follow-up. Survival after recurrence, as well as the secondary endpoints overall survival, progression-free interval, local progression-free interval, and distant metastases-free interval will be reported as median with 95% confidence interval (CI) and will be calculated using the Kaplan-Meier survival curve method. Log-rank test will be used to compare groups. In addition, a sensitivity analysis will be conducted on survival after recurrence, whereby this will be defined as the time between the date of randomization and the date of death from any cause or last follow-up. Univariate cox-proportional hazard analysis will be performed to determine the crude effect of SBRT on survival after recurrence. Multivariable analysis will be performed to determine adjusted effect estimates. The adjusted analysis will be corrected for several baseline confounding factors, such as age, sex, preoperative CA 19-9 level, tumor size, number of positive lymph nodes, tumor differentiation, resection margin status, adjuvant chemotherapy, and treatment for disease recurrence. Results will be presented as HRs with corresponding 95% CIs. A two-tailed probability value (P-value) of < 0.05 is considered statistically significant. Treatment response, acute and late toxicity and reasons for non-eligibility or exclusion will be reported using descriptive statistics. Chi-square or Fisher’s exact test are used to compare categorical variables as appropriate. Parametric continuous variables are presented as mean with standard deviation (SD) and are compared using the Student’s T-test. Non-parametric continuous variables are presented as median with interquartile range (IQR) and are compared using the Mann-Whitney-U test. Acute and late toxicity will also be evaluated by a mixed model, to account for both within-person and across-person variability and to take repeated toxicity measurements into account. Baseline quality of life will be compared to all other time points during follow-up. A change of 10% of the scale width will be considered a clinically relevant change of quality of life.63 The data will be presented as stable, worsened (≥10% decrease in quality of life) or improved (≥10% increase in quality of life). These time point will be compared using a Chi-square test with a P-value of ≤0.05. We will also evaluate the pattern of quality of life as continuous outcome over time during follow-up with repeated measurement analysis using the mixed-models approach.
The latest version of R Studio will be used for statistical analysis.
Interim analyses {21b}
Interim analysis on efficacy will be conducted when 50% of the required patient number (87 patients) is included, and of which the patients randomized for the intervention have received SBRT. Results will be shared with the Medical Research Ethics Committee (MREC), which can decide to prematurely end the study. Stopping guidelines are a twofold increase in the primary endpoint (survival after recurrence) of the intervention group compared to the control group, or more than 20% refusal of the intervention. A P-value of < 0.01 will be considered statistically significant.
Methods for additional analyses (e.g. subgroup analyses) {20b}
When sufficient number of patients are available within the following subgroups, comparisons will be made between patients who received SBRT + chemotherapy, SBRT alone, chemotherapy alone and BSC alone, and the impact on survival outcomes and quality of life within these specific subgroups will be assessed. Assuming a 0.,50 minimum relevant effect size, statistical power of 80% and a 0.05 two-sided significance level, a subgroup should contain at least 33 patients to detect the effect size.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Since some patients will deny the intervention after being randomized (according to the TwiCs design), a refusal rate was taken into account when calculating the sample size. Analyses will be performed according to the intention-to-treat principle, which means that participants who are randomized for the intervention group but deny this intervention will therefore be analyzed as if they did receive the intervention. Missing baseline data will be imputed using multiple imputation techniques. Both complete case analysis and analysis after multiple imputation will be performed to check for inconsistencies.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The study protocol, derived data and statistical analysis code will be made available upon request.
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
At the coordinating center, a Doctor of Philosophy (PhD) student is responsible for running the trial on a day-to-day basis, supervised by two principal investigators and a postdoctoral researcher. At least once a week, trial progress is being evaluated and during the week supervisors can be consulted for additional deliberation. Also, (potential) trial participants are identified and discussed during weekly multidisciplinary team meetings.
At all three participating radiation centers, the local principal investigators (radiation oncologists) are responsible for the on-site logistics. The Trial Steering Committee contains members of the DPCG, who can easily be updated on the progress of the trial during the four yearly meetings but can be additionally updated upon request. Data management by the trial team is supported by data managers from the coordinating.
Composition of the data monitoring committee, its role and reporting structure {21a}
The quality of the study is monitored by Julius Clinical, an independent science contract research organization, which will control the safety of trial subjects. The assigned monitor will check inclusion and drop-out rates, completeness of study documents and informed consents, information on serious adverse event (SAE) procedures, in- and exclusion criteria, study procedures, and personnel certification and training, Initiation visits will be scheduled before commencing including in each participating center. Following monitoring visits will be scheduled after the first five inclusions, and consequently at least two times a year per center (depending on patient enrolment). In the end, a close-out visit will be scheduled in each participating center.
Adverse event reporting and harms {22}
All grade 3 or higher (S)AEs (either expected or unexpected) reported spontaneously by the subject or observed by the site investigator, or his staff will be recorded up to 3 months after SBRT in the corresponding section of the electronic case report form. SAEs will be reported by the local principal investigator or his staff within 24 hours of becoming aware of the SAE to the UMC Utrecht principal investigator in encrypted form by means of the SAE form. The sponsor will then report the SAEs through the web portal ToetsingOnline to the accredited MREC that approved the protocol, within 7 days of first knowledge for SAEs that result in death or are life threatening followed by a period of maximum of 8 days to complete the initial preliminary report. All other SAEs will be reported within a period of maximum 15 days after the sponsor has first knowledge of the SAE. After the first 3 months after treatment, only the treatment induced grade 3 or higher (S)AEs will be recorded up to the end of the study. The principal investigator or an authorized delegate will decide whether an (S)AE is related to the SBRT. As PDAC patients have a very poor prognosis, we expect that many patients suffer from follow-up radiotherapy unrelated SAEs within the two-year study period. These SAEs will be recorded, although not reported.
Frequency and plans for auditing trial conduct {23}
At any given point during the study, the trial can be selected for audit. There is no predefined schedule for audits and inspections.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
During the trial, the sponsor might want to make changes to the protocol or other trial documents which require a new favorable opinion by the competent authority and MREC. If necessary, trial participants will be informed about these amendments and updated Informed Consent might be obtained. All amendments will be communicated to the participating trial centers.
Dissemination plans {31a}
Trial results will be fully disclosed by means of publication in peer-reviewed journal and by presentations at national and international scientific meetings. Both positive and negative findings will be disclosed.