Proactive Management of Endoperitoneal Spread in Colonic Cancer

NCT ID: NCT02974556

Last Updated: 2023-05-06

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-01
• Study Completion Date: 2025-09-30

Brief Summary

This study aims to determine the oncological effectiveness, compared to standard surgical treatment, of proactive management including target organs for peritoneal spread resection (omentectomy, bilateral adnexectomy, appendectomy, hepatic round ligament resection) and preventive HIPEC (intraperitoneal oxaliplatin with concomitant i.v. 5-fluorouracil/leucovorin) following a curative resection of high-risk ( >/= 5 mm tumor invasion beyond the muscularis propria) T3 and T4 colon cancer in preventing the development of peritoneal metastases. Adjuvant systemic chemotherapy will be reserved in both groups for patients with poor prognostic factors according to Folinic acid/Fluorouracil/Oxaliplatin (FOLFOX) or to Capecitabine/Oxaliplatin (CAPOX) regimens.

Hypothesis:

The hypothesis is that compared to the standard treatment proactive management following curative resection of high-risk T3 and T4 colon cancer will reduce the development of endoperitoneal metastases

Detailed Description

Colorectal cancer is one of the leading causes of cancer death in developed countries. Despite recent advances in understanding the molecular pathogenesis and improvements in diagnosis and treatment, more than 1,2 million new cases and 600,000 deaths occur annually worldwide and cure rates remain low for patients with metastatic or recurrent disease. According to reports from the National Cancer Institute, cancer of the colon is a highly treatable and often curable disease when confined to the bowel. Surgery is the primary treatment and results in a cure rate of approximately 50% of the patients; however, recurrence following surgery is a major problem and is often the ultimate cause of death. In colon cancer locoregional recurrence (local recurrence and metachronous peritoneal spread), as the main site of recurrence, is less common (up to 10% of all recurrences) and generally occurs within 3 years of resection. An important concept is the origin of local recurrences and peritoneal metastases that have a common natural history. Specific features of the primary tumor like size and depth of bowel wall invasion (pT3-pT4), which determine a specific clinical evolution (obstruction, perforation with exfoliation of cancer cells) are responsible for endoperitoneal recurrence. Cytoreductive Surgery (CRS) defined as removal of macroscopic abdominal and peritoneal disease combined with Hyperthermic Perioperative Chemotherapy (HIPEC) is the treatment considered standard of care for selected patients with moderate to small volume peritoneal metastases secondary to colorectal cancer. Nevertheless treatment of locoregional recurrence and peritoneal metastases in colon cancer are disappointing first because only 30% of patients can be surgically treated and second because of this 30% only 15- 30% survive 5 years, leaving only 10% of patients with a chance of being cured. Furthermore the economic burden of metastatic colorectal cancer treatment is considerable including the common adverse events associated that increase healthcare resource utilization and considering the addition of biological drugs to standard treatment. An evaluation of CRS combined with HIPEC for peritoneal metastases of colorectal origin in the era of value-based medicine, showed an incremental cost respect to modern chemotherapy regimens of 44,217 US$ for life-year saved, making investment in prevention even more attractive. Despite screening for colorectal cancer in average-risk patients using colonoscopy was associated with a substantially reduced risk of diagnosis with new-onset primary late-stage tumors, colorectal cancer screening remains underused. Analyzing the recent surgical published series, the majority (around 70%), of patients with a diagnosis of colonic cancer operated with curative intent, have a pT3-4 tumor, which is exactly the high-risk class of patients for local recurrence and peritoneal metastases. In this scenario the most effective strategy to combat endoperitoneal recurrence seems prevention. Two previous studies performed in our Institution investigated how a proactive management of peritoneal metastases in colon cancer patients considered at high-risk for peritoneal recurrence according to depth of bowel wall invasion and specific histopathologic features (pT3, pT4 any N, M0, mucinous or signet ring cell pathology) influence outcome. A group of 25 patients for whom inclusion criteria were verified by intraoperative pathologic assessment, were submitted to a "proactive" treatment that included in addition to the standard surgical treatment, a greater omentectomy, appendectomy, exeresis of the liver round ligament and, in post-menopausal women, a bilateral oophorectomy. At the end of the operation, in these patients a HIPEC was performed with oxaliplatin and simultaneous iv infusion of 5-fluorouracil (FU) + leucovorin (LV). Short and long-term results showed that when compared to a control group (50 cases) of similar patients treated only by standard treatment in the same Institution, this group of patients had a statistically significant decreased incidence of peritoneal recurrence (4 vs. 28%) and an increase in overall and disease-free survival rates. These results should obviously validated by larger controlled studies, and this is the aim of the PROMENADE protocol, to verify if the treatment criteria applied in colorectal peritoneal metastases (Surgery combined with HIPEC) could represent a mean of tertiary prevention of endoperitoneal recurrence in high-risk colon cancer. However, simpler application criteria were needed for a large-scale study. For this reason histological typing have not been yet considered an inclusion criteria and will only represent a secondary outcome measure. Furthermore, also considering other experiences, the protocol will use an imaging technique (MDCT) for preoperative selection of high-risk T3 (>/= 5 mm tumor invasion beyond the muscularis propria) and T4 colon cancers, combined in patients with suspected systemic disease after MDCT with functional positron-emission tomography (PET), avoiding the need for an intraoperative frozen-sections pathologic assessment. The results of this study will hopefully confirm the therapeutic rationale that makes microscopic local seeding as the main reason for endoperitoneal recurrence. It will be also important to verify if, as demonstrated in our pilot study, a better loco-regional control of the disease will carry better long-term survival.

Conditions

Colon Cancer; Intraperitoneal Rectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Standard surgical treatment group

Colon cancer patients (high-risk T3 and T4) without peritoneal or systemic metastases are resected for cure.

Standard adjuvant systemic chemotherapy (FOLFOX or CAPOX regimens for 6 months) will be reserved in pT3 tumors with poor prognostic factors, pT4 tumor and if lymph-nodes metastases are present. Presence or absence of peritoneal recurrence will be evaluated by MDCT.

Group Type: ACTIVE_COMPARATOR

Standard surgical treatment

Intervention Type: PROCEDURE

Standard surgical treatment (open or laparoscopic techniques) containing at least 12 lymph-nodes for accurate pN staging.

Standard adjuvant systemic chemotherapy

Intervention Type: DRUG

Adjuvant systemic chemotherapy (according CAPOX or FOLFOX regimens for a total of 6 months) will be reserved in patients with pT3 tumors with poor prognostic factors, in patients with pT4 tumors and when lymph-nodes metastases are present. Presence or absence of peritoneal recurrence will be evaluated by MDCT every six months for the first 24 months and later every year for the next three years in both study arms.

Proactive management group

Colon cancer patients (high-risk T3 and T4) without peritoneal or systemic metastases are resected for cure. Simultaneously patients will undergo infracolic omentectomy, appendectomy, exeresis of the liver round ligament and, in women, a bilateral oophorectomy. At the end of surgical procedure HIPEC will be performed with oxaliplatin 460 mg/m2 and before the beginning of HIPEC an intravenous infusion of 400 mg/m2 of 5-FU and 20 mg/m2 of leucovorin will be administered.

Standard adjuvant systemic chemotherapy (FOLFOX or CAPOX regimens for 6 months) will be reserved in pT3 tumors with poor prognostic factors, pT4 tumor and if lymph-nodes metastases are present. Presence or absence of peritoneal recurrence will be evaluated by MDCT.

Group Type: EXPERIMENTAL

Proactive management

Intervention Type: PROCEDURE

Colon cancer patients (high-risk T3 and T4) without peritoneal or systemic metastases are resected for cure. Simultaneously patients will undergo infracolic omentectomy, appendectomy, exeresis of the liver round ligament and, in women, a bilateral oophorectomy. After positioning three in- and outflow catheters HIPEC perfusion starts with a minimum of 2 L isotonic dialysis fluid at a flow-rate of 1-2 l min and an inflow temperature of 42-43° C with a total of 30 minutes perfusion time. Before the beginning of HIPEC 5-fluouracil and leucovorin will be administrated intravenously to potentiate oxaliplatin activity.

Standard adjuvant systemic chemotherapy

Intervention Type: DRUG

Adjuvant systemic chemotherapy (according CAPOX or FOLFOX regimens for a total of 6 months) will be reserved in patients with pT3 tumors with poor prognostic factors, in patients with pT4 tumors and when lymph-nodes metastases are present. Presence or absence of peritoneal recurrence will be evaluated by MDCT every six months for the first 24 months and later every year for the next three years in both study arms.

Interventions

Standard surgical treatment

Standard surgical treatment (open or laparoscopic techniques) containing at least 12 lymph-nodes for accurate pN staging.

Intervention Type: PROCEDURE

Proactive management

Colon cancer patients (high-risk T3 and T4) without peritoneal or systemic metastases are resected for cure. Simultaneously patients will undergo infracolic omentectomy, appendectomy, exeresis of the liver round ligament and, in women, a bilateral oophorectomy. After positioning three in- and outflow catheters HIPEC perfusion starts with a minimum of 2 L isotonic dialysis fluid at a flow-rate of 1-2 l min and an inflow temperature of 42-43° C with a total of 30 minutes perfusion time. Before the beginning of HIPEC 5-fluouracil and leucovorin will be administrated intravenously to potentiate oxaliplatin activity.

Intervention Type: PROCEDURE

Standard adjuvant systemic chemotherapy

Adjuvant systemic chemotherapy (according CAPOX or FOLFOX regimens for a total of 6 months) will be reserved in patients with pT3 tumors with poor prognostic factors, in patients with pT4 tumors and when lymph-nodes metastases are present. Presence or absence of peritoneal recurrence will be evaluated by MDCT every six months for the first 24 months and later every year for the next three years in both study arms.

Intervention Type: DRUG

Other Intervention Names

adjuvant capecitabine and oxaliplatin (CAPOX); adjuvant 5-FU and oxaliplatin (FOLFOX)

Eligibility Criteria

Inclusion Criteria

• Patients with colon cancer or intraperitoneal rectosigmoid cancer with clinical (by CT) high-risk(> 5mm) T3, T4 tumors, any N, M0
• Performance Status (ECOG) 0, 1 or 2
• Signed informed consent

Exclusion Criteria

• BMI> 30
• Impossibility of an adequate follow-up
• Intra and extraabdominal metastatic disease, multiple colorectal cancer or other malignancies
• Active infections or severe associated medical conditions (ASA IV or V)
• Abnormal bone marrow or renal and liver function indices

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Roma La Sapienza

OTHER

Sponsor Role: lead

Responsible Party

Tommaso Cornali

Prof. Paolo Sammartino, MD Phd

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Paolo Sammartino, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Roma La Sapienza

Locations

ASST Nord Milano P.O. Città di Sesto S. Giovanni

Milan, PD, Italy

ASO S. Croce e Carle

Cuneo, , Italy

Azienda Ospedaliera dei Colli

Napoli, , Italy

Istituto Nazionale Tumori IRCCS Fondazione Pascale di Napoli

Napoli, , Italy

Ospedale di Rimini

Rimini, , Italy

University of Rome Sapienza

Roma, , Italy

Ospedale Sant'Eugenio

Rome, , Italy

Azienda Ospedaliera Universitaria Integrata di Verona

Verona, , Italy

Countries

Italy

Central Contacts

Paolo Sammartino, MD PhD

Role: CONTACT

paolo.sammartino@uniroma1.it

336615632 ext. +39

Tommaso Cornali, MD

Role: CONTACT

tommaso.cornali@uniroma1.it

Facility Contacts

Gianandrea Baldazzi, MD

Role: primary

gbaldazzi@hotmail.com

Felice Borghi, MD

Role: primary

borghi.f@ospedale.cuneo.it

Gianluca Garulli, MD

Role: primary

lucagarulli@gmail.com

Paolo Sammartino, MD PhD

Role: primary

paolo.sammartino@uniroma1.it

336615632 ext. +39

Tommaso Cornali, MD

Role: backup

tommaso.cornali@uniroma1.it

Massimo Carlini, MD FACS

Role: primary

maxcarlini@tiscali.it

References

Sammartino P, Biacchi D, Cornali T, Cardi M, Accarpio F, Impagnatiello A, Sollazzo BM, Di Giorgio A. Proactive Management for Gastric, Colorectal and Appendiceal Malignancies: Preventing Peritoneal Metastases with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Indian J Surg Oncol. 2016 Jun;7(2):215-24. doi: 10.1007/s13193-016-0497-1. Epub 2016 Jan 26.

Reference Type: BACKGROUND

PMID: 27065712 (View on PubMed)

Sammartino P, Sibio S, Biacchi D, Cardi M, Mingazzini P, Rosati MS, Cornali T, Sollazzo B, Atta JM, Di Giorgio A. Long-term results after proactive management for locoregional control in patients with colonic cancer at high risk of peritoneal metastases. Int J Colorectal Dis. 2014 Sep;29(9):1081-9. doi: 10.1007/s00384-014-1929-4. Epub 2014 Jul 1.

Reference Type: BACKGROUND

PMID: 24980687 (View on PubMed)

Sammartino P, Sibio S, Accarpio F, Di Giorgio A. Prevention of peritoneal carcinomatosis from colorectal cancer: a critical issue. Ann Surg. 2014 Mar;259(3):e51. doi: 10.1097/SLA.0000000000000372. No abstract available.

Reference Type: BACKGROUND

PMID: 24263309 (View on PubMed)

Sammartino P, Sibio S, Biacchi D, Cardi M, Accarpio F, Mingazzini P, Rosati MS, Cornali T, Di Giorgio A. Prevention of Peritoneal Metastases from Colon Cancer in High-Risk Patients: Preliminary Results of Surgery plus Prophylactic HIPEC. Gastroenterol Res Pract. 2012;2012:141585. doi: 10.1155/2012/141585. Epub 2012 May 8.

Reference Type: BACKGROUND

PMID: 22645605 (View on PubMed)

Other Identifiers

PROMENADE v1.0

Identifier Type: -

Identifier Source: org_study_id