Objectives
The primary aim is to assess whether there are differences in PERITONEAL RECURRENCE in patients with limited-volume colon cancer PM treated with complete surgical resection and systemic chemotherapy, with or without HIPEC with MMC.
Secondary Objectives are:
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Evaluate whether there are differences in global disease recurrence (at any location) between both groups (disease free survival-DFS).
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Assess the toxicity of the treatments and compare the postoperative complications between both groups.
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Determine prognostic factors for peritoneal relapse and recurrence at other sites.
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Compare overall survival between both groups.
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Study of the quality of life in both groups using EORTC (European Organisation for Research and Treatment of Cancer) validated questionnaires.
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Correlation between surgical and pathological PCI, comparing their respective prognostic values (ancillary study).
Design
This will be a multicenter, prospective, open-label, randomized (1:1) phase IV clinical trial in patients undergoing CRS for PM from colon cancer, with (Arm 1) or without (Arm 2) HIPEC with high-dose MMC (Fig. 1). This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. The protocol adheres to SPIRIT guidelines for reporting clinical trial study protocols.
It is called phase IV since, after the results of PRODIGE-7, both treatments (CRS + HIPEC vs a procedure based exclusively on CRS, eliminating HIPEC as a component of treatment) could be considered standard.
Study population (eligible patients)
Patients with colon cancer PM who are considered for CRS by a Multidisciplinary Tumour Board (MTB), and can present in various clinical scenarios:
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a)
Synchronous PM: patients with primary colon tumours “in situ” with synchronous peritoneal disease and presumable possibility of complete CRS (Primary Surgery).
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b)
Persistence of synchronous PM: patients with resected primary colon tumours in whom synchronous peritoneal disease is discovered but not completely removed at the time of initial surgery, considering that complete CRS is possible (Rescue Surgery).
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c)
Metachronous PM: patients with resected primary colon tumours that relapse in the peritoneum, in whom a complete CRS seems possible (Secondary Surgery).
The inclusion criteria are:
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1)
Histologically confirmed colon adenocarcinoma, except signet ring cell carcinomas (those with > 50% of the tumour composed of these cells, which comprise only 1% of all colon adenocarcinomas).
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2)
Absence of previously treated or current extraperitoneal metastases, including distant lymphadenopathy (retroperitoneal, mediastinal, etc), liver metastases, or lung metastases (ruled out by PET-scan in case of doubt).
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3)
Synchronous or metachronous peritoneal metastasis of mild to moderate volume, with a PCI ≤ 20 (intraoperative confirmation).
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4)
Macroscopically complete surgical cytoreduction: CCS = 0 (intraoperative confirmation).
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5)
Treatment with perioperative SCT, before and/or after the surgical procedure.
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6)
Age > 18 years.
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7)
Acceptable anaesthetic/surgical risk: ASA 1–3, ECOG 0–1. No severe alterations in hematological, renal, cardiac, pulmonary or hepatic function (operable patients).
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8)
Information to the patient and signing of a study-specific informed consent.
And the exclusion criteria are:
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1)
Peritoneal Carcinomatosis of any other origin, particularly rectal cancer or appendiceal adenocarcinoma, or signet ring cell colon cancer on histology.
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2)
No intraoperative confirmation of peritoneal disease (PCI 0). Likewise, cases of perianastomotic (local) or lymph node (locoregional) recurrences will be excluded.
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3)
High volume peritoneal disease with a PCI > 20 (intraoperative confirmation).
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4)
Concurrent or previously-treated extraperitoneal disease.
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5)
Disease progression during preoperative SCT, if received.
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6)
Patients previously treated with HIPEC.
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7)
History of other cancers (except cutaneous basal cell carcinoma or cervix carcinoma in situ) in the 5 years prior to entry into the study.
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8)
Patients included in another first-line clinical trial for the studied disease.
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9)
Pregnancy (or suspicion of it) or lactation period.
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10)
Emergency surgical intervention for obstruction or perforation of a primary tumour with synchronous PM (although rescue and secondary CRS ± HIPEC after emergency surgery of the primary tumour are acceptable if inclusion criteria are fulfilled)
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11)
Persons deprived of liberty or under legal or administrative supervision.
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12)
Inability to understand the nature of the intervention, the risks, benefits, expected evolution and the need to undergo periodic medical examinations, either for geographical, social or psychological reasons.
The exclusion of patients with PM from rectal cancer must be ensured. Likewise, metastasis that are exclusively extraperitoneal, whether perianastomotic (local) or lymphatic (locoregional or distant, including retroperitoneal), must be excluded. Cases with preoperative suspicion of peritoneal disease, in which its extra-peritoneal location is confirmed intraoperatively, should be excluded from randomization.
Patients will be randomized intraoperatively only when it is confirmed that intraoperative PCI is ≤20 and a complete CRS (CCS-0) has been achieved.
Patients previously treated, even radically, for extraperitoneal metastases (liver or lung) will be excluded, since although the main objective of the study is peritoneal recurrence, the inclusion of these cases could predictably affect OS.
There is no upper limit for chronological age in this study. The limit is imposed by the functional situation (ASA, ECOG), so that results can be extrapolated as best as possible to the “real” population.
Preoperative work-up
The following assessments should be performed to check the inclusion and exclusion criteria:
All cases will be evaluated individually in the MTB, proposing entry into the study to those who meet all the presurgical requirements. All these patients are metastatic and candidates for perioperative SCT for at least 6 months, although the sequence (pre or postoperative or both) will be individualized in each case. The SCT regimen will be chosen by the medical oncologist according to information on response (if any) to prior SCT, and should be one of the currently accepted regimens for metastatic colorectal cancer. If patients receive preoperative SCT, they should be reassessed after a short course of treatment (3–4 cycles) and surgery should be avoided if there is tumour progression. SCT should be stopped at least 4 weeks before the intervention, or 6 weeks if bevacizumab is included in the neoadjuvant treatment.
Likewise, indication for laparoscopy and sequence of re-evaluation tests following neoadjuvant SCT will be decided in the MTB, in order to make subsequent decisions.
Recruitment, informed consent, and registration in the trial
Recruitment will be carried out at the outpatient clinic, once the indication of CRS ± HIPEC (PM of apparently limited volume without metastases at other sites) has been established after presenting the case in the MTB, checking that eligible patients meet the presurgical inclusion criteria (although some criteria have to be confirmed during surgery for randomization). At that time, eligible patients will complete the basal health-related quality of life questionnaires; they will sign a specific Informed Consent, and they will be registered in the trial. Women in childbearing age will be informed that they should avoid pregnancy for at least 1–2 years after finishing treatment.
Nevertheless, during surgery patients could be withdrawn from the trial if they do not meet the intraoperative inclusion criteria (confirmation of peritoneal disease, low to moderate volume PM with PCI ≤ 20, absence of extraperitoneal disease, and complete CRS-CCS 0 achieved), and it is not until then when randomization is performed.
Treatment and randomization
Patients must undergo OPEN SURGERY, through a midline laparotomy, to avoid bias of PCI underestimation if the laparoscopic approach is admitted. The first step is to confirm definitively that peritoneal tumour volume is not excessive (PCI ≤ 20) and that complete cytoreduction is possible without prohibitive sequelae, otherwise the surgical procedure is aborted. Patients with PCI > 20, or those in whom there is no confirmation of peritoneal disease, are withdrawn from the study intraoperatively. Cases with preoperative suspicion of peritoneal disease, in which during surgery it is noted that the disease is not peritoneal but extraperitoneal, should also be rejected from randomization, same as those in which unexpected systemic disease (eg, liver metastases) is discovered. The goal is to resect all visible disease, without residual tumour nodules, so that HIPEC, if used, is effective. Those cases in which a complete CRS (CCS 0) is not achieved are withdrawn intraoperatively from the study.
In all cases, the greater omentum and cecal appendix (target organs) are resected, if they have not been previously excised. In postmenopausal women the adnexa are also removed even if they are not affected.
Once complete CRS is achieved, patients are randomized 1:1 to receive HIPEC with MMC (Arm 1) or not (Arm 2). Intestinal anastomoses can be performed before or after HIPEC if the patient is randomized to the control arm (Arm 1). Randomization will be done through a computer program (computer-generated random numbers) generated by the Clinical Research Organization (CRO), and will be stratified by surgical PCI: 1–10; 11–15; 16–20.
Any HIPEC modality can be used (open, closed or closed with CO2). HIPEC will be performed with MMC, at an average intraperitoneal temperature of 42 °C, and a dose of 35 mg/m2 in peritoneal dialysis solution (PHYSIONEAL 35 Glucose 1.36% w/v / 13.6 mg/dl, or equivalent) for 90 minutes (with dose fractionation: 50% at minute 0, 25% at 30 minutes, and 25% at 60 minutes of perfusion). The MMC will be reconstituted in 3 syringes with the corresponding fractions. The volume of solution will be 2 L/m2, adapting it to the capacity of the individual abdominal cavity.
Postoperative phase
The most common intraoperative and early postoperative adverse effects (hemoperitoneum, gastrointestinal bleeding, anastomotic leak, digestive fistula, urinary fistula, seroma, surgical site infection, evisceration, urinary infection, atelectasis, pneumonia, renal failure, central catheter infection, thromboembolism, hematological toxicity if HIPEC is administered) are detected during hospital admission, and will be collected in the electronic Case Report Form. They will be classified according to the CTCAE system (Common Terminology Criteria for Adverse Events) v5.0 [27]. Any other deviation from the normal postoperative course (including minor complications such as vomiting, diarrhea, pain, etc.), red blood cells transfusion if it occurs, and length of stay (discharge date) will also be recorded. All complications will be recorded up to the 90th postoperative day, whether those occurred during hospital admission or those that present later, in readmissions (if they occur), or after discharge not requiring readmission, which will be recorded in follow-up visits.
Upon final discharge, patients will be scheduled for the first postoperative visit. They will also be presented again in the MTB for subsequent management, and an appointment in Medical Oncology will be made to complete SCT.
Follow up
Patients will return to standardized follow-up visits every 4 months for the first two years, and every 6 months during the third year, at the end of which the last trial visit occurs. Subsequently, visits will continue outside the trial according to the protocol of each centre, normally every 6 months during the 4th and 5th year, and annually thereafter until the 10th year. At each revision, contrast-enhanced thoraco-abdomino-pelvic CT scan and regular laboratory blood test with tumour markers (CEA, CA 19.9) will be requested. A complete colonoscopy is recommended at the 1st postoperative year (and later on according to the standard surveillance protocols in CRC). The tests can be ordered before the scheduled dates and/or other complementary tests can be added depending on the clinical situation.
Quality of life
Given the importance of assessing not only the strict biomedical results of treatments, but also the patient’s personal perception of their impact, patients will complete the health-related quality of life questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) Core 30 (QLQ-C30) and Colorectal Cancer Module (QLQ-CR29). These tests will be completed at the time of recruitment (before randomization), at the end of SCT (average 4 moths), and during follow-up visits at 12 and 24 months. The QLQ-CR29 is a supplementary questionnaire module to be employed in conjunction with the QLQ-C30. In fact, their numbering is consecutive (the last item of QLQ-C30 is number 30, being the first item of QLQ-CR29 number 31). Both have function and symptom scales/single-items. All of the scales and single-item measures range in score from 0 to 100. A high score for the functional scale and functional single-items represents a high level of functioning, whereas a high score for the symptom scales and symptom single-items represents a high level of symptomatology or problems.
Endpoints of the study
The primary endpoint of the study is Peritoneal Recurrence Free Survival (RFS) at 3-years.
The secondary endpoints are:
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Global recurrence rate (DFS) at 3-years.
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Locoregional and distant recurrence rate (isolated or coincident, with or without simultaneous peritoneal recurrence) at 3-years.
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Postoperative complications using the CTCAE v5.0 adverse event classification system up to the 90th postoperative day, including those related to HIPEC.
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Prognostic factors for peritoneal and global recurrence: synchronous/metachronous PM, perioperative SCT, use of biological agents or immunotherapy, stratified PCI (1–10, 11–15, 16–20), postoperative complications, right/left colon, degree of tumor differentiation, vascular/lymphatic/perineural invasion, RAS/RAF status, microsatellite instability, and degree of peritoneal tumour regression (if applicable).
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Overall survival rate (OS) at 3-years.
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Study of the Quality of Life in both groups using the EORTC questionnaires QLQ-C30 and QLQ-CR29 at the mentioned time spots.
Ancillary study
Once the pathology report has been obtained, the surgical PCI will be recalculated, corroborating or invalidating the involvement of the scored lesions, thus obtaining the pathological PCI. Correlation between surgical and pathological PCI will be analysed, comparing their respective prognostic values.
Sample size calculation
Although median OS of patients with limited PM-CRC treated with CRS + HIPEC (40 months) is much higher than that estimated if they received only SCT (16 months), relapse after CRS + HIPEC is very common. It is difficult to ascertain the actual incidence of recurrence in the literature, with very variable published figures. Van Oudheusden et al. in a systematic review on the item [28] point out that the global recurrence after CRS + HIPEC ranges between 22.5–82%, the local one ranging between 6 and 42.5%, the systemic one between 10.4–43%, and the combined (local + systemic) between 5.8–21.5%, with a median time to recurrence of 9–23 months and a 3-year RFS of 14–41.5%. However, it is estimated that only 16% are cured (5-year RFS rate) and therefore the majority (> 80%) of patients relapse, almost all of them in the first two years, and a high percentage (30–50%) do it at the peritoneum (either isolated or with metastases at other sites).
Sample size was calculated with a bilateral hypothesis, a statistical power of 80% and an alpha level of 0.05. In order to verify a reduction in peritoneal recurrence at 3 years of 20% in the group treated with HIPEC (assuming a probability of 3-year peritoneal relapse of 50% in the group without HIPEC and 30% in the group with HIPEC), 103 patients are needed in each arm (206 in total). Corrected for a 5% of possible losses, 108 participants will be needed in each arm, requiring 216 patients.
Data analysis
Data will be collected in an ad-hoc electronic Case Report Form (eCRF) already designed in REDCap (Research Electronic Data Capture). Descriptive analysis of the data will be carried out. Qualitative variables will be presented by their frequency distribution (proportions) and quantitative variables will be measured by indicators of central tendency (mean or median) and dispersion (standard deviation or interquartile range respectively).
Hypothesis contrast tests will be performed, with comparison of proportions when both variables are qualitative (Chi square test for normal distribution, Fisher exact test for non-normal distribution) and comparisons of means for independent samples when one of them is quantitative (Student t-test if normal distribution or Mann-Whitney U-test for variables that do not comply with normality).
Survival will be estimated with the Kaplan-Meier method and survival curves will be compared using the Log-Rank test to analyse the effect of the different factors that can influence survival.
A Cox proportional hazard model will be performed to evaluate the effect of representative covariates on RFS. For this, those that are significant in the univariate analysis (p < 0.2) or clinically relevant will be included.
A p value < 0.05 will be considered statistically significant.
Study results will be analyzed by intention to treat. A second analysis will be conducted according to the treatment actually administered (per protocol analysis). After the recruitment of half of the patients, an interim data analysis of toxicity will be performed, in which severe adverse events with their accountability will be described. The final analysis will be carried out in two phases, one on the morbidity and mortality results at the end of recruitment, and another one at the end of the study with the definitive data on peritoneal disease control and survival. The coordinating investigator will be in charge of writing and publishing the results, complying with international CONSORT (Consolidated Standards of Reporting Trials) recommendations, and with the collaboration of the entire research team.
Stopping guidelines: Study participation by individual sites or the entire study may be prematurely terminated, if in the opinion of the Coordination Centre there is sufficient reasonable cause. Any investigator who wants to discontinue his/her participation to the study must immediately inform the Coordination Centre of this decision. Written notification documenting the reason for study termination will be provided to the Coordinating Investigator by the terminating party.
Ethics, Regulatory & Legal Considerations
The study is carried out under the ethical principles that appear in the revised version of the Declaration of Helsinki (Fortaleza, Brazil 2013), the Convention on Human Rights and Biomedicine (Oviedo 1997), the Law 41/2002 on Patient Autonomy, the ICH (International Conference on Harmonization) guidelines on “Standards of Good Clinical Practice” (CPMP/ICH/135/95), and complying with the current European (EU Regulation 536/2014) and Spanish (Royal Decree 1090/2015) legislation on clinical trials.
Similarly, the research team undertakes to ensure the privacy of patient data in accordance with the new legislation in the European Union on personal data, specifically the General Data Protection Regulation (GDPR) of the European Parliament and of the Council of April 27, 2016 (2016/679; https://www.boe.es/doue/2016/119/L00001-00088.pdf), fully applicable throughout the European Union since May 25, 2018.
The trial (protocol version 11) obtained authorization both from the Clinical Research and Ethics Committee (CREC) of the IdiPAZ (Hospital La Paz Research Institute) on April 7, 2021 (Code 5814), and from the Spanish Agency for Medicines and Sanitary Products (AEMPS) on April 21, 2021. The mentioned CREC also approved an amendment (protocol version 12) on February 10, 2022. Any other major changes in the study protocol must be documented in protocol amendments that must be submitted to and approved by the CREC, prior to their implementation.
The contracts between the Coordination Centre and each of the participating centres are in process since mid-February 2021 and most of them completed, which is an essential condition to start recruitment.
Monitoring/audit/safety
The Clinical Research and Clinical Trials Unit (UICEC: Unidad de Investigación Clínica y Ensayos Clínicos) of Hospital Universitario La Paz (UICEC-HULP), independent from the Sponsor/Coordinating Centre (Hospital Universitario Fuenlabrada) and with no competing interests, will carry out the monitoring and pharmacovigilance of the trial, acting as CRO. Representatives of the CRO will visit the investigators from each centre periodically to monitor the progress of the study in accordance with Good Clinical Practice regulations. It is the responsibility the Investigators to be present or available for consultation during such scheduled monitoring visits. During these routine visits, all data pertaining to a patient’s participation in this clinical investigation must be available to the monitor. On-site review of the eCRF for completeness and clarity, cross checking with documental sources, and reconciliation and clarification of administrative matters will be performed.
In addition, a representative of the regulatory agency (AEMPS) may choose to inspect a study centre at any time prior to, during, or after completion of the clinical study. A Coordination Centre representative or designee will be available to assist in the preparation for such an inspection. All pertinent study data should be made available as requested to the regulatory authority for verification, audit, or inspection purposes.
All adverse effects that occur during the intervention, in the postoperative period (both the most serious and the mildest), or in the course of patient follow-up will be collected in the clinical records. The eCRF will record all adverse events that occur in the postoperative phase, up to the 90th postoperative day. All Serious Adverse Events (SAE), regardless of treatment group or suspected relationship with study treatment, should be reported to the Responsible of Pharmacovigilance at UICEC-HULP within 24 hours of knowledge of the episode.
Patient participation and withdrawal
Participation of patients is completely voluntary, and they have the right to withdraw from the trial at any time without causing them any harm. If a patient withdraws from the study, the reason will be recorded. Among these reasons it is worth highlighting:
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At the request of the patient, without causing him/her any harm.
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During surgery, if the intraoperative inclusion criteria are not met (PCI ≤ 20 and CCS 0).
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Loss to follow-up.
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Major protocol deviation.
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If the researchers consider it appropriate from a clinical point of view.
When a patient decides to withdraw from the study, he/she should always be contacted in order to obtain information about the reason for withdrawal, and requested to return for a follow up visit, if applicable, and posterior follow-up regarding any potential adverse even and subject outcome, if possible. A patient is considered lost to follow-up if no information has been obtained when the last patient has completed the clinical phase of the study. During this time there must be documented attempts to contact the patient either by phone or letter.