Appendiceal Neoplasms, Colorectal Neoplasms, Peritoneal Carcinomatosis, Peritoneal Neoplasms
Conditions
Keywords
Colorectal Neoplasms, Peritoneal Neoplasms, Intraperitoneal Injections, Laparoscopy, Aerosols, Chemotherapy, Cancer, Regional Perfusion, Antineoplastic Agents, Leucovorin, Fluorouracil, Platinum, Intraoperative Complications, Postoperative Complications, Drug-Related Side Effects and Adverse Reactions, Disease-free survival, Survival, Mortality, Quality of Life, Costs and Cost Analysis, Translational Medical Research, Clinical Trials, Phase II as topic, PIPAC, Pressurized Intraperitoneal Aerosol Chemotherapy, Pressurised Intraperitoneal Aerosol Chemotherapy, Peritoneum, Cecal Neoplasms, Oxaliplatin
Brief summary
This is multicentre, open-label, single-arm phase II study that investigates the feasibility, safety, tolerability, preliminary efficacy, costs, and pharmacokinetics or repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC-OX) as a palliative monotherapy for patients with isolated unresectable colorectal peritoneal metastases.
Detailed description
Rationale: repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs, and pharmacokinetics in this setting. Objectives: to prospectively explore the feasibility, safety, tolerability, preliminary efficacy, costs, and pharmacokinetic profile of repetitive ePIPAC-OX as a palliative monotherapy for isolated unresectable colorectal PM under controlled circumstances. Study design: multicentre, open-label, single-arm, phase II study. Setting: two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM. Study population: adults who have a World Health Organisation (WHO) performance status of 0 or 1, adequate organ functions, histologically or cytologically confirmed unresectable PM of a colorectal or appendiceal carcinoma, no systemic metastases, no symptoms of gastrointestinal obstruction, no contraindications for the planned intervention, and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Intervention: instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled ePIPAC-OX (92 mg/m2 body-surface area \[BSA\]) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every six weeks. Four weeks after each procedure, patients undergo clinical, radiological, and biochemical evaluation. ePIPAC-OX is repeated until clinical, radiological, or macroscopic disease progression, after which standard palliative treatment is (re)introduced. Outcomes: the primary outcome is the number of patients with major toxicity (grade ≥3 according to the Common Terminology Criteria for Adverse Events v4.0) up to four weeks after the last procedure. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, the number of procedures in each patient and reasons for discontinuation, minor toxicity, organ-specific toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical, and macroscopic tumour response. Atomic absorption spectrophotometry is used to measure concentrations of oxaliplatin in plasma, plasma ultrafiltrate, urine, ascites, PM, and normal peritoneum during and after ePIPAC-OX.
Interventions
COMBINATION_PRODUCTrepetitive ePIPAC-OX
Instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) (92 mg/m2 body-surface area \[BSA\]) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every six weeks. Four weeks after each procedure, patients undergo clinical, radiological, and biochemical evaluation. ePIPAC-OX is repeated until clinical, radiological, or macroscopic disease progression, after which standard palliative treatment is (re)considered.
Sponsors
Koen Rovers
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Eligible patients are adults who have: * a World Health Organisation (WHO) performance status of ≤1; * histological or cytological proof of PM of a colorectal or appendiceal carcinoma; * unresectable disease determined by abdominal computed tomography (CT) and a diagnostic laparoscopy or laparotomy; * adequate organ functions (haemoglobin ≥5.0 mmol/L, neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L, serum creatinine \<1.5 x ULN, creatinine clearance ≥30 ml/min, and liver transaminases \<5 x ULN); * no symptoms of gastrointestinal obstruction; * no radiological evidence of systemic metastases; * no contraindications for oxaliplatin or 5-fluorouracil/leucovorin; * no contraindications for a laparoscopy; * no previous PIPAC-procedures. Enrolled patients are excluded from the analyses in case they did not receive a first ePIPAC-OX, e.g.: * due to systemic metastases on baseline thoracoabdominal CT, or; * due to non-access during first ePIPAC-OX, or; * due to resectable disease during first ePIPAC-OX. Importantly, enrolment is allowed for patients with an unresected primary tumour (if asymptomatic) and for patients in various lines of palliative treatment, including patients who refuse, have not had, or do not qualify for first-line palliative systemic therapy. All potentially eligible patients are discussed by a multidisciplinary team. Enrolled patients are informed about the potential consequences of postponing or discontinuing standard palliative treatment by a medical oncologist prior to enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major toxicity | Expected (in case of three ePIPAC-OX): 16 weeks | Number of patients with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade III-V, up to 4 weeks after the last ePIPAC-OX |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Organ-specific toxicity | Expected (in case of three ePIPAC-OX): 16 weeks | Number of patients that develops bone marrow, kidney, or liver function disorders, up to four weeks after the last ePIPAC-OX |
| Major postoperative complications | Expected (in case of three ePIPAC-OX): 16 weeks | Number of patients with Clavien-Dindo grade III-V postoperative complications, up to four weeks after the last ePIPAC |
| Minor postoperative complications | Expected (in case of three ePIPAC-OX): 16 weeks | Number of patients with Clavien-Dindo grade II postoperative complications, up to four weeks after the last ePIPAC-OX |
| Hospital stay | Expected (in case of three ePIPAC-OX): 16 weeks | Number of days between ePIPAC-OX and initial discharge, up to four weeks after the last ePIPAC-OX |
| Readmissions | Expected (in case of three ePIPAC-OX): 16 weeks | Number of hospital admissions after initial discharge after ePIPAC-OX, up to four weeks after the last ePIPAC-OX |
| Radiological tumour response | Expected (in case of three ePIPAC-OX): 16 weeks | Number of patients with radiological response/stable disease/progression, based on central review of thoracoabdominal CT and diffusion-weighted MRI at baseline and four weeks after each ePIPAC-OX, performed by two independent radiologists blinded to clinical outcomes (classification not defined a priori) |
| Histopathological tumour response | Expected (in case of three ePIPAC-OX): 12 weeks | Peritoneal Regression Grading Score (PRGS), based on central review of collected peritoneal biopsies during each ePIPAC-OX, performed by two independent pathologists blinded to clinical outcomes |
| Cytological tumour response | Expected (in case of three ePIPAC-OX): 12 weeks | Number of patients with positive/negative cytology, based on collected ascites or peritoneal washing cytology during each ePIPAC-OX |
| Macroscopic tumour response | Expected (in case of three ePIPAC-OX): 12 weeks | Peritoneal Cancer Index and ascites volume during each ePIPAC-OX |
| Biochemical tumour response | Expected (in case of three ePIPAC-OX): 16 weeks | Tumour marker value measured at baseline, each postoperative day, and four weeks after each ePIPAC-OX |
| Quality of life: EQ-5D-5L | Expected (in case of three ePIPAC-OX): 16 weeks | EQ-5D-5L at baseline and one and four weeks after each ePIPAC-OX |
| Minor toxicity | Expected (in case of three ePIPAC-OX): 16 weeks | Number of patients with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade II, up to 4 weeks after the last ePIPAC-OX |
| Quality of life: QLQ-CR29 | Expected (in case of three ePIPAC-OX): 16 weeks | QLQ-CR29 at baseline and one and four weeks after each ePIPAC-OX |
| Costs | Expected (in case of three ePIPAC-OX): 16 weeks | Costs of treatment, based on questionnaires (iMTA PCQ, iMTA MCQ) four weeks after each ePIPAC-OX, derived from the Dutch costing guidelines for health care research at the time of analysis |
| Progression-free survival | 24 months | Time between enrolment and clinical, radiological, or macroscopic progression, or death |
| Overall survival | 24 months | Time between enrolment and death |
| Environmental safety of ePIPAC-OX | 1 week (measured only during the first three procedures in the study) | Platinum concentrations in the air of the operating room and on the surface of the operating room during ePIPAC-OX |
| Pharmacokinetics | Expected (in case of three ePIPAC-OX): 13 weeks | Platinum concentrations in plasma and plasma ultrafiltrate (collected before ePIPAC-OX and 5, 10, 20, 30, 60, 120, 240, 360, and 1080 minutes after oxaliplatin injection), urine (collected before ePIPAC-OX and on postoperative days 1, 3, 5, and 7), and two pieces of normal peritoneum and two peritoneal metastases collected during each ePIPAC-OX. |
| Procedure-related characteristics: intraoperative complications | Expected (in case of three ePIPAC-OX): 12 weeks | Number of procedures with intraoperative complications determined during each ePIPAC-OX |
| Procedure-related characteristics: adhesions | Expected (in case of three ePIPAC-OX): 12 weeks | Zühlke score determined during each ePIPAC-OX |
| Procedure-related characteristics: operating time | Expected (in case of three ePIPAC-OX): 12 weeks | Operating time in minutes determined during each ePIPAC-OX |
| Procedure-related characteristics: blood loss | Expected (in case of three ePIPAC-OX): 12 weeks | Blood loss in minutes determined during each ePIPAC-OX |
| Quality of life: QLQ-C30 | Expected (in case of three ePIPAC-OX): 16 weeks | QLQ-C30 at baseline and one and four weeks after each ePIPAC-OX |
Countries
Netherlands
Outcome results
None listed