Proactive Management of Endoperitoneal Spread in Colonic Cancer (PROMENADE)

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

Study Overview

• Status: Not yet recruiting
• Conditions: Colon Cancer; Intraperitoneal Rectal Cancer
• Intervention / Treatment: Procedure: Standard surgical treatment; Drug: Standard adjuvant systemic chemotherapy; Procedure: Proactive management

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.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Paolo Sammartino, MD PhD; Phone Number: +39 336615632; Email: paolo.sammartino@uniroma1.it
• Study Contact Backup: Name: Tommaso Cornali, MD; Email: tommaso.cornali@uniroma1.it

Study Locations

• Italy
  • Cuneo, Italy, 12100
    • ASO S. Croce e Carle
    • Contact: Felice Borghi, MD; Email: borghi.f@ospedale.cuneo.it
    • Principal Investigator: Felice Borghi, MD
    • Sub-Investigator: Maria Carmela Giuffrida, MD
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Dei Colli
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori IRCCS Fondazione Pascale di Napoli
  • Rimini, Italy, 47923
    • Ospedale di Rimini
    • Principal Investigator: Gialuca Garulli, MD
    • Sub-Investigator: Basilio Pirrera, MD
  • Roma, Italy, 00161
    • University of Rome Sapienza
    • Contact: Paolo Sammartino, MD PhD; Phone Number: +39 336615632; Email: paolo.sammartino@uniroma1.it
    • Principal Investigator: Paolo Sammartino, MD PhD
    • Sub-Investigator: Tommaso Cornali, MD
    • Sub-Investigator: Fabio Accarpio, MD PhD
    • Sub-Investigator: Daniele Biacchi, MD Phd
    • Contact: Tommaso Cornali, MD; Email: tommaso.cornali@uniroma1.it
  • Rome, Italy, 00144
    • Ospedale Sant'Eugenio
    • Contact: Massimo Carlini, MD FACS; Email: maxcarlini@tiscali.it
    • Principal Investigator: Massimo Carlini, MD
    • Sub-Investigator: Domenico Spoletini, MD
    • Sub-Investigator: Daniela Apa, MD
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria Integrata di Verona
  • PD
    • Milano, PD, Italy, 35031
      • ASST Nord Milano P.O. Città di Sesto S. Giovanni
      • Contact: Gianandrea Baldazzi, MD; Email: gbaldazzi@hotmail.com
      • Principal Investigator: Gianandrea Baldazzi, MD
      • Sub-Investigator: Diletta Cassini, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Procedure: Standard surgical treatment; Standard surgical treatment (open or laparoscopic techniques) containing at least 12 lymph-nodes for accurate pN staging.; Drug: 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.; Other Names: adjuvant capecitabine and oxaliplatin (CAPOX); adjuvant 5-FU and oxaliplatin (FOLFOX)
Experimental: 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.	Drug: 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.; Other Names: adjuvant capecitabine and oxaliplatin (CAPOX); adjuvant 5-FU and oxaliplatin (FOLFOX); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of endoperitoneal recurrence at 36 months	The primary endpoint is the incidence of endoperitoneal recurrence at 36 months defined as the proportion of subjects with peritoneal metastases at 36 months from randomization.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIPEC toxicity rate		1 month
HIPEC toxicity rate		6 month
overall survival (OS)		3 years
disease-free survival (DFS)		3 years
disease-free survival (DFS)		5 years
overall survival (OS)		5 years
extraperitoneal (systemic) or liver recurrence rate		3 years
morbidity rate		1 month
morbidity rate		6 months
EORTC QLQ-C30 Summary Score	The EORTC QLQ-C30 Summary Score range from 0 to 100 and is calculated from the mean of 13 of the 15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact scale are not included). Prior to calculating the mean, the symptom scales need to be reversed to obtain a uniform direction of all scales. QLQ-C30 Summary Score = (Physical Functioning+ Role Functioning+ Social Functioning+ Emotional Functioning+ Cognitive Functioning+ 100-Fatigue+ 100-Pain+ 100-Nausea_Vomiting+ 100-Dyspnoea+ 100-Sleeping Disturbances+ 100-Appetite Loss+ 100-Constipation+ 100-Diarrhoea)/13	6 months
EORTC QLQ-C30 Summary Score	The EORTC QLQ-C30 Summary Score range from 0 to 100 and is calculated from the mean of 13 of the 15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact scale are not included). Prior to calculating the mean, the symptom scales need to be reversed to obtain a uniform direction of all scales. QLQ-C30 Summary Score = (Physical Functioning+ Role Functioning+ Social Functioning+ Emotional Functioning+ Cognitive Functioning+ 100-Fatigue+ 100-Pain+ 100-Nausea_Vomiting+ 100-Dyspnoea+ 100-Sleeping Disturbances+ 100-Appetite Loss+ 100-Constipation+ 100-Diarrhoea)/13	1 year

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2024
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): September 1, 2025

Study Registration Dates

• First Submitted: November 9, 2016
• First Submitted That Met QC Criteria: November 22, 2016
• First Posted (Estimate): November 28, 2016

Study Record Updates

• Last Update Posted (Estimate): May 8, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Oxaliplatin
• Other Study ID Numbers: PROMENADE v1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No