Clinical Trial on HIPEC With Mitomycin C in Colon Cancer Peritoneal Metastases (GECOP-MMC)

Sponsor

Hospital Universitario de Fuenlabrada (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05250648

Collaborator

Instituto de Investigación Hospital Universitario La Paz (Other)

216

Enrollment

Locations

Arms

Anticipated Duration (Months)

7.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this study is to assess whether there are differences in PERITONEAL RECURRENCE in patients with Colon Cancer Peritoneal Metastases treated with complete surgical resection and systemic chemotherapy, with (Group 1) or without (Group 2) HIPEC with Mitomycin-C.

Condition or Disease	Intervention/Treatment	Phase
Peritoneal Carcinomatosis Colon Cancer	Drug: complete cytoreductive surgery plus HIPEC with Mytomicin C for 90 minutes Procedure: complete cytoreductive surgery without HIPEC	Phase 4

Detailed Description

CytoReductive Surgery (CRS) + Hyperthermic IntraPEritoneal Chemotherapy (HIPEC), especially from the year 2000 onwards, has obtained unprecedented results in patients with low to moderate volume peritoneal metastases (PM) of colorectal cancer (CRC), so that it has gradually been accepted, even being considered the best treatment for these patients. However, the actual role of HIPEC as a necessary component of treatment is unknown, despite its proven experimental basis. The French PRODIGE 7 study, presented at ASCO in 2018 and published on January 2021, has raised doubts about the survival benefit of HIPEC. In this study, there was no difference in overall survival (OS) with or without HIPEC (with Oxaliplatin 30 minutes) after resection of PM-CRC. However, since its presentation, several methodological flaws have been identified: a short exposure time to Oxaliplatin, an overestimation of the effect of HIPEC on OS (18 months) considered for the sample calculation, or the choice of OS as the main endpoint (since HIPEC can reduce peritoneal relapses, while OS is also influenced by the systemic treatment received by all patients). Due to these shortcomings and some others, the results have not been assumed to be definitive. Therefore, the majority of units specialized in peritoneal surface malignancy, continue to consider HIPEC in these patients as a recommended option, usually changing Oxaliplatin for Mitomycin-C (MMC). With these premises we propose this multicenter Clinical Trial, correcting the retrospective defects of PRODIGE 7. To do this, the cytostatic used in HIPEC will be changed (MMC instead of oxaliplatin), the infusion time will be increased (from 30 to 90 minutes), rectal cancers are ruled out (only colon cancers will be included), cases with high peritoneal extension (PCI> 20) will be avoided, those cases in which a complete CRS (CCS 0) is not achieved will be excluded, and the main objective will be the Peritoneal Recurrence Free Survival (RFS) instead of the OS.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

216 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Recruitment will be carried out at the outpatient clinic, once the indication of CRS ± HIPEC (CC-PM of apparently limited volume without metastasis at other sites) has been established after presenting the case in the Multidisciplinary Tumour Board. Eligible patients need to meet the presurgical inclusion criteria (even though some criteria have to be confirmed during surgery for randomization), and sign the informed consent. Randomization occurs intraoperatively, once the extension of peritoneal disease is found to be truly limited (PCI ≤ 20) after complete surgical exploration, and only after radical surgery (CCS 0) has been possible. At this time, patients are randomized to receive HIPEC with MMC for 90 minutes (Arm 1), or no HIPEC and therefore surgery is finished (Arm 2).Recruitment will be carried out at the outpatient clinic, once the indication of CRS ± HIPEC (CC-PM of apparently limited volume without metastasis at other sites) has been established after presenting the case in the Multidisciplinary Tumour Board. Eligible patients need to meet the presurgical inclusion criteria (even though some criteria have to be confirmed during surgery for randomization), and sign the informed consent. Randomization occurs intraoperatively, once the extension of peritoneal disease is found to be truly limited (PCI ≤ 20) after complete surgical exploration, and only after radical surgery (CCS 0) has been possible. At this time, patients are randomized to receive HIPEC with MMC for 90 minutes (Arm 1), or no HIPEC and therefore surgery is finished (Arm 2).

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase IV Multicentric Clinical Trial to Evaluate the Efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) With Mytomicin-C After Complete Surgical Cytoreduction in Patients With Colon Cancer Peritoneal Metastases

Anticipated Study Start Date :

Feb 1, 2022

Anticipated Primary Completion Date :

Jan 1, 2027

Anticipated Study Completion Date :

Jan 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: complete cytoreductive surgery plus HIPEC with Mytomicin C for 90 minutes	Drug: complete cytoreductive surgery plus HIPEC with Mytomicin C for 90 minutes In the arm with HIPEC, this will be performed with Mytomicin C, at a dose of 35 mg/m2 in peritoneal dialysis solution (2 liter/m2) for 90 minutes, with dose fractionation: 50% min 0, 25% min 30, 25% min 60
Experimental: complete cytoreductive surgery without HIPEC	Procedure: complete cytoreductive surgery without HIPEC in the arm without HIPEC, only complete cytoreductive surgery will be performed

Arm

Intervention/Treatment

Active Comparator: complete cytoreductive surgery plus HIPEC with Mytomicin C for 90 minutes

Drug: complete cytoreductive surgery plus HIPEC with Mytomicin C for 90 minutes

In the arm with HIPEC, this will be performed with Mytomicin C, at a dose of 35 mg/m2 in peritoneal dialysis solution (2 liter/m2) for 90 minutes, with dose fractionation: 50% min 0, 25% min 30, 25% min 60

Experimental: complete cytoreductive surgery without HIPEC

Procedure: complete cytoreductive surgery without HIPEC

in the arm without HIPEC, only complete cytoreductive surgery will be performed

Outcome Measures

Primary Outcome Measures

Peritoneal Recurrence Free Survival [3 years]
From the date of surgery to the date of peritoneal recurrence or death, or to the end of follow-up

Secondary Outcome Measures

Global recurrence at any location (Disease Free Survival) [3 years]
From the date of surgery to the date of recurrence at any site or death
Locoregional and distant recurrence rate (isolated or coincident, with or without simultaneous peritoneal recurrence) [3 years]
From the date of surgery to the date of locoregional and/or distant recurrence
Postoperative complications (rate and severity grade) [days 1-90 after surgery]
Using the CTCAE v5.0 adverse event classification system, including those related to HIPEC.
Peritoneal and global recurrence rate according to stratified PCI [3 years]
Rate of peritoneal and global recurrence in 3 subgroups of PCI ((1-10, 11-15, 16-20)
Overall survival [3 years]
Months from from the day of treatment initiation (either neoadjuvant SCT or upfront CRS) to the date of death or to the end of follow-up.
Quality of Life with EORTC validated questionnaire Core 30 (QLQ-C30) [pre-surgery, at the end of postoperative SCT (an average 4-6 months), at 12 months and at 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.
Quality of Life with EORTC validated questionnaire Colorectal Cancer Module (QLQ-CR29). [pre-surgery, at the end of postoperative SCT (an average 4-6 months), at 12 months and at 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed colon adenocarcinoma, except signet ring cell carcinomas (those with > 50% of the tumor composed of these cells, which comprise only 1% of all colon adenocarcinomas).
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).
Synchronous or metachronous peritoneal metastasis of mild to moderate volume, with a PCI ≤ 20 (Appendix 2) (intraoperative confirmation).
Macroscopically complete surgical cytoreduction CCS-0 (intraoperative confirmation).
Treatment with perioperative systemic chemotherapy (SCT), before and/or after surgical procedure.
Age> 18 years.
Acceptable anesthetic/surgical risk: ASA 1-3 (Appendix 3), ECOG 0-1 (Appendix 4). No severe alterations in hematological, renal, cardiac, pulmonary or hepatic function (operable patients).
Information to the patient and signing of a study-specific informed consent.

Exclusion Criteria:

Peritoneal carcinomatosis of any other origin, particularly rectal cancer or appendicular adenocarcinoma, or signet ring cell colon cancer on histology.
No intraoperative confirmation of peritoneal disease (PCI 0). Likewise, cases of perianastomotic (local) or lymph node (locoregional) recurrences will be excluded.
High volume peritoneal disease with a PCI> 20 (intraoperative evaluation).
Concurrent or previously treated extraperitoneal disease.
Disease progression during preoperative chemotherapy, if received.
Patients previously treated with HIPEC.
History of other cancers (except cutaneous basal cell carcinoma or cervix carcinoma in situ) in the 5 years prior to entry into the study.
Patients included in another first-line clinical trial for the studied disease.
Pregnancy (or suspicion of it) or lactation period.
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).
Persons deprived of liberty or under legal or administrative supervision.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital General Universitario de Elche	Elche	Alicante	Spain	03203
2	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33011
3	Hospital Sant Joan Despi Moises Broggi	Sant Joan Despí	Barcelona	Spain	08970
4	Hospital General Universitario de Castellón	Castelló de la Plana	Castellón	Spain	12004
5	Consorcio Hospitalario Provincial de Castellón	Castellón De La Plana	Castellón	Spain	12006
6	Hospital Universitario Donostia	San Sebastián	Gipuzkoa	Spain	20014
7	Hospital Universitario de Gran Canaria Doctor Negrín	Las Palmas De Gran Canaria	Gran Canaria	Spain	35010
8	Hospital Universitario Principe de Asturias	Alcalá de Henares	Madrid	Spain	28805
9	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid	Spain	28922
10	HOSPITAL UNIVERSITARIO DE FUENLABRADA (Coordinating Centre)	Fuenlabrada	Madrid	Spain	28942
11	Hospital Universitario Infanta Elena	Valdemoro	Madrid	Spain	28340
12	Hospital Universitario Son Espases	Palma De Mallorca	Mallorca	Spain	07210
13	Hospital Universitario Virgen de La Arrixaca	El Palmar	Murcia	Spain	30120
14	Hospital Universitario Torrecárdenas	Almería		Spain	04009
15	Complejo Hospitalario Universitario de Badajoz	Badajoz		Spain	6080
16	Hospital General Universitario de Ciudad Real	Ciudad Real		Spain	13005
17	Hospital Universitario Reina Sofía	Córdoba		Spain	14004
18	Hospital General Universitario Gregorio Marañón	Madrid		Spain	28007
19	Md Anderson Cancer Center	Madrid		Spain	28033
20	Hospital Universitario Ramón Y Cajal	Madrid		Spain	28034
21	Fundación Jiménez Díaz	Madrid		Spain	28040
22	Hospital Universitario La Paz	Madrid		Spain	28046
23	Hospital General Universitario Reina Sofía	Murcia		Spain	30003
24	Hospital Quirónsalud Málaga	Málaga		Spain	29004
25	Hospital Universitario Virgen Del Rocío	Sevilla		Spain	41013
26	Instituto Valenciano de Oncología	Valencia		Spain	46009
27	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
28	Hospital Universitario Y Politécnico La Fe	Valencia		Spain	46026
29	Hospital Universitario Río Hortega	Valladolid		Spain	47012
30	Hospital Clínico Universitario "Lozano Blesa"	Zaragoza		Spain	50009