Clinical trial NCT02758951: Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases
Official title: Perioperative Systemic Therapy and Cytoreductive Surgery with HIPEC Versus Upfront Cytoreductive Surgery with HIPEC Alone for Isolated Resectable Colorectal Peritoneal Metastases: a Multicentre, Open-label, Parallel-group, Phase II-III, Randomised Superiority Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Colorectal Neoplasm
Colorectal Cancer
Colorectal Neoplasms Malignant
Colorectal Carcinoma
Colorectal Adenocarcinoma
Peritoneal Neoplasms
Peritoneal Carcinomatosis
Peritoneal Cancer
Peritoneal Metastases
Peritoneal Neoplasm Malignant Secondary Carcinomatosis
Peritoneal Neoplasm Malignant Secondary
Keywords: Colorectal Neoplasms
Peritoneal Neoplasms
Cytoreduction Surgical Procedures
Hyperthermia, Induced
Neoadjuvant Therapy
Adjuvant Chemotherapy
Bevacizumab
Randomized Controlled Trial
Mortality
Progression-Free Survival
Lead sponsor: Catharina Ziekenhuis Eindhoven
Sponsor class: OTHER
Collaborators: name: Dutch Cancer Society
name: Comprehensive Cancer Centre The Netherlands
name: Hoffmann-La Roche
First posted: 2016-05-03
Enrollment: 358
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicentre, open-label, parallel-group, phase II-III, superiority study that randomises patients with isolated resectable colorectal peritoneal metastases in a 1:1 ratio to receive either perioperative systemic therapy and cytoreductive surgery with HIPEC (experimental arm) or upfront cytoreductive surgery with HIPEC alone (control arm).

Detailed description: Rationale: cytoreductive surgery with HIPEC (CRS-HIPEC) is a curative intent treatment for patients with isolated resectable colorectal peritoneal metastases (PM). Upfront CRS-HIPEC alone is the standard treatment in the Netherlands. The addition of neoadjuvant and adjuvant systemic therapy (together: perioperative systemic therapy) to CRS-HIPEC could have benefits and drawbacks. Potential benefits are eradication of systemic micrometastases, preoperative intraperitoneal tumour downstaging, elimination of post-surgical residual cancer cells, and improved patient selection for CRS-HIPEC. Potential drawbacks are preoperative disease progression and secondary unresectability for CRS-HIPEC, systemic therapy related toxicity, increased postoperative morbidity, decreased quality of life, and higher costs. Currently, there is a complete lack of randomised studies that prospectively compare the oncological efficacy of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone. Notwithstanding this lack of evidence, perioperative systemic therapy is widely administered to patients with isolated resectable colorectal PM. However, administration and timing of perioperative systemic therapy vary substantially between countries, hospitals, and guidelines. More importantly, it remains unknown whether perioperative systemic therapy has an intention-to-treat benefit in this setting. Therefore, this study randomises patients with isolated resectable colorectal PM to receive either perioperative systemic therapy (experimental arm) or upfront CRS-HIPEC alone (control arm).

Study design: a multicentre, open-label, parallel-group, phase II-III, superiority study that randomises eligible patients in a 1:1 ratio.

Objectives: objectives of the phase II study (80 patients) are to explore the feasibility of accrual, the feasibility, safety, and tolerance of perioperative systemic therapy, and the radiological and pathological response of colorectal PM to neoadjuvant systemic therapy. The primary objective of the phase III study (358 patients) is to compare overall survival between both arms. Secondary objectives are to assess progression-free and disease-free survival, surgical characteristics, major postoperative morbidity, patient-reported outcomes, and costs in both arms. Other objectives are to assess major systemic therapy related toxicity and the objective radiological and pathological response of colorectal PM to neoadjuvant systemic therapy.

Study population: adults who have a good performance status, histological or cytological proof of PM of a colorectal adenocarcinoma, resectable disease, no systemic colorectal metastases within three months prior to enrolment, no systemic therapy for colorectal cancer within six months prior to enrolment, no previous CRS-HIPEC, no contraindications for the planned systemic treatment or CRS-HIPEC, and no relevant concurrent malignancies.

Intervention: at the discretion of the treating medical oncologist, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by either four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles.

Endpoints: primary endpoints of the phase II study are to explore the feasibility and safety of perioperative systemic therapy by comparing proportions of patients undergoing complete CRS-HIPEC and proportions of patients with major postoperative morbidity between both arms. The primary comparative endpoint of the phase III study is overall survival. Major secondary endpoints assessed in both arms are proportions of major postoperative morbidity, progression-free survival, disease-free survival, patient-reported outcomes (PROs), and costs. Major secondary endpoints assessed in the experimental arm are the proportion of patients with major systemic therapy related toxicity and the proportions of patients with objective radiological and pathological responses of colorectal PM to neoadjuvant systemic therapy.

Statistical analysis: the study is powered to detect an increase in 3-year overall survival from 50% in the control arm to 65% in the experimental arm (corresponding hazard ratio 0.62), which is considered to be a clinically relevant difference by the investigators. A total number of 358 patients (179 in each arm) is needed to detect this hypothesized difference with 5% drop-out, 80% power, and a two-sided log-rank test of p\<0.05. In August 2024, when several patients in the experimental arm were still receiving trial treatment, a regular follow-up update revealed that 156 events for the primary outcome (i.e. deaths) had occurred. The study then had 85% power to detect the hypothesized hazard ratio of 0.62 for overall survival in the analysis of superiority of the experimental arm relative to the control arm at a two-sided alpha of 0.05. After discussing these data with the Data Monitoring Committee and the medical ethics committee, it was decided to schedule data cut-off for a first analysis of the primary outcome at the time the last patient in the experimental arm (enrolled April 2024) finishes trial treatment, which is expected 1 November 2024 at an estimated number of +/- 172 events (+/- 88% power).

Eligibility criteria: Eligible patients are adults who have:

* a World Health Organisation (WHO) performance status of ≤1;
* histological or cytological proof of PM of a non-appendiceal colorectal adenocarcinoma with ≤50% of the tumour cells being signet ring cells;
* resectable disease determined by a diagnostic laparoscopy/laparotomy in combination with abdominal computed tomography and/or magnetic resonance imaging (MRI); only in patients in whom diagnostic laparoscopy or laparotomy is considered not feasible or valuable (e.g. due to known adhesions impeding adequate PCI scoring), it is also allowed to determine resectability by CT or MRI only (provided that the colorectal PM are histologically or cytologically proven);
* no evidence of systemic colorectal metastases within three months prior to enrolment;
* no systemic therapy for colorectal cancer within six months prior to enrolment;
* no contraindications for CRS-HIPEC;
* no previous CRS-HIPEC;
* no concurrent malignancies that interfere with the planned study treatment or the prognosis of resected colorectal PM.

Importantly, enrolment is allowed for patients with radiologically non-measurable disease. Enrolment is also allowed for patients who are referred to a study centre after a macroscopically complete resection of colorectal PM in a referring centre, since it is assumed that microscopic (and often macroscopic) colorectal PM are still present. The diagnostic laparoscopy/laparotomy may be performed in a referring centre, provided that the peritoneal cancer index (PCI) is appropriately scored and documented before enrolment.

Patients are excluded in case of any comorbidity or condition that prevents safe administration of the planned perioperative systemic therapy, determined by the treating medical oncologist, e.g.:

* Inadequate bone marrow, renal, or liver functions (e.g. haemoglobin \<6.0 mmol/L, neutrophils \<1.5 x 109/L, platelets \<100 x 109/L, serum creatinine \>1.5 x ULN, creatinine clearance \<30 ml/min, bilirubin \>2 x ULN, serum liver transaminases \>5 x ULN);
* Previous intolerance of fluoropyrimidines or both oxaliplatin and irinotecan;
* Dehydropyrimidine dehydrogenase deficiency;
* Serious active infections;
* Severe diarrhoea;
* Stomatitis or ulceration in the mouth or gastrointestinal tract;
* Recent major cardiovascular events;
* Unstable or uncompensated respiratory or cardiac disease;
* Bleeding diathesis or coagulopathy;
* Pregnancy or lactation.

The aforementioned laboratory values and tests are to be determined at the discretion of the physician, e.g. only if the patient is suspect for abnormal conditions tests will be conducted.

Primary outcomes:
measure: Overall survival
timeFrame: From enrolment up to five years thereafter
Secondary outcomes:
measure: Progression-free survival
timeFrame: From enrolment up to five years thereafter
measure: Disease-free survival
timeFrame: From enrolment up to five years thereafter
measure: Macroscopic complete CRS-HIPEC
timeFrame: From enrolment up to approximately six weeks (control arm) or five months (experimental arm) thereafter
measure: Surgical characteristics: peritoneal cancer index
timeFrame: During CRS-HIPEC, one to five months after enrolment
measure: Surgical characteristics: bowel anastomoses
timeFrame: During CRS-HIPEC, , one to five months after enrolment
measure: Surgical characteristics: ostomy formations
timeFrame: During CRS-HIPEC, one to five months after enrolment
measure: Surgical characteristics: operating time
timeFrame: During CRS-HIPEC, one to five months after enrolment
measure: Major postoperative morbidity
timeFrame: From (intended) CRS-HIPEC up to three months postoperatively
measure: Postoperative hospital stay
timeFrame: During the postoperative course of CRS-HIPEC, up to 90 days postoperatively
measure: Postoperative readmissions
timeFrame: From CRS-HIPEC to 90 days postoperatively
measure: Patient-reported outcomes: EQ-5D-5L
timeFrame: From enrolment up to five years thereafter
measure: Patient-reported outcomes: QLQ-C30
timeFrame: From enrolment up to five years thereafter
measure: Patient-reported outcomes: QLQ-CR29
timeFrame: From enrolment up to five years thereafter
measure: Costs
timeFrame: From enrolment up to five years thereafter
Other outcomes:
measure: Major systemic therapy-related toxicity (experimental arm)
timeFrame: From the first administration of systemic therapy up to 30 days after the last administration
measure: Radiological response to neoadjuvante treatment (experimental arm)
timeFrame: After radiological restaging during neoadjuvant treatment, approximately three months after randomisation
measure: Pathological response to neoadjuvant treatment (experimental arm)
timeFrame: After (intended) CRS-HIPEC, approximately five months after randomisation
Locations:
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
state: Vlaanderen
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre, Location VUMC
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Nieuwegein
country: Netherlands
facility: St. Antonius Hospital
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Centre
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
Study officials:
affiliation: Catharina Hospital, Eindhoven, Netherlands
name: Ignace H de Hingh, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Surgery, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands
name: Pieter J Tanis, MD, PhD
role: STUDY_DIRECTOR
affiliation: Department of Medical Oncology, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands
name: Cornelis J Punt, MD, PhD
role: STUDY_DIRECTOR
affiliation: Department of Surgery, Erasmuc University Medical Centre, Rotterdam, Netherlands
name: Alexandra R Brandt-Kerkhof, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, Amsterdam University Medical Centre, Location VUMC, Amsterdam, Netherlands
name: Jurriaan B Tuynman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands
name: Arend G Aalbers, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, St. Antonius Hospital, Nieuwegein, Netherlands
name: Marinus J Wiezer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, University Medical Centre Groningen, Groningen, Netherlands
name: Patrick H Hemmer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands
name: Sandra A Radema, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, University Medical Centre Utrecht, Utrecht, Netherlands
name: Wilhemina M van Grevenstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, Medisch Spectrum Twente, Enschede, Netherlands
name: Eino B van Duyn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, Catharina Hospital, Eindhoven, Netherlands
name: Ignace H de Hingh, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rovers KP, Bakkers C, Nienhuijs SW, Burger JWA, Creemers GM, Thijs AMJ, Brandt-Kerkhof ARM, Madsen EVE, van Meerten E, Tuynman JB, Kusters M, Versteeg KS, Aalbers AGJ, Kok NFM, Buffart TE, Wiezer MJ, Boerma D, Los M, de Reuver PR, Bremers AJA, Verheul HMW, Kruijff S, de Groot DJA, Witkamp AJ, van Grevenstein WMU, Koopman M, Nederend J, Lahaye MJ, Kranenburg O, Fijneman RJA, van 't Erve I, Snaebjornsson P, Hemmer PHJ, Dijkgraaf MGW, Punt CJA, Tanis PJ, de Hingh IHJT; Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group. Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial. JAMA Surg. 2021 Aug 1;156(8):710-720. doi: 10.1001/jamasurg.2021.1642.
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