<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02974556</url>
  </required_header>
  <id_info>
    <org_study_id>PROMENADE v1.0</org_study_id>
    <nct_id>NCT02974556</nct_id>
  </id_info>
  <brief_title>Proactive Management of Endoperitoneal Spread in Colonic Cancer</brief_title>
  <acronym>PROMENADE</acronym>
  <official_title>Proactive Management of Endoperitoneal Spread in Colonic Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Roma La Sapienza</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Roma La Sapienza</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to determine the oncological effectiveness, compared to standard surgical&#xD;
      treatment, of proactive management including target organs for peritoneal spread resection&#xD;
      (omentectomy, bilateral adnexectomy, appendectomy, hepatic round ligament resection) and&#xD;
      preventive HIPEC (intraperitoneal oxaliplatin with concomitant i.v.&#xD;
      5-fluorouracil/leucovorin) following a curative resection of high-risk ( &gt;/= 5 mm tumor&#xD;
      invasion beyond the muscularis propria) T3 and T4 colon cancer in preventing the development&#xD;
      of peritoneal metastases. Adjuvant systemic chemotherapy will be reserved in both groups for&#xD;
      patients with poor prognostic factors according to Folinic acid/Fluorouracil/Oxaliplatin&#xD;
      (FOLFOX) or to Capecitabine/Oxaliplatin (CAPOX) regimens.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The hypothesis is that compared to the standard treatment proactive management following&#xD;
      curative resection of high-risk T3 and T4 colon cancer will reduce the development of&#xD;
      endoperitoneal metastases&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Colorectal cancer is one of the leading causes of cancer death in developed countries.&#xD;
      Despite recent advances in understanding the molecular pathogenesis and improvements in&#xD;
      diagnosis and treatment, more than 1,2 million new cases and 600,000 deaths occur annually&#xD;
      worldwide and cure rates remain low for patients with metastatic or recurrent disease.&#xD;
      According to reports from the National Cancer Institute, cancer of the colon is a highly&#xD;
      treatable and often curable disease when confined to the bowel. Surgery is the primary&#xD;
      treatment and results in a cure rate of approximately 50% of the patients; however,&#xD;
      recurrence following surgery is a major problem and is often the ultimate cause of death. In&#xD;
      colon cancer locoregional recurrence (local recurrence and metachronous peritoneal spread),&#xD;
      as the main site of recurrence, is less common (up to 10% of all recurrences) and generally&#xD;
      occurs within 3 years of resection. An important concept is the origin of local recurrences&#xD;
      and peritoneal metastases that have a common natural history. Specific features of the&#xD;
      primary tumor like size and depth of bowel wall invasion (pT3-pT4), which determine a&#xD;
      specific clinical evolution (obstruction, perforation with exfoliation of cancer cells) are&#xD;
      responsible for endoperitoneal recurrence. Cytoreductive Surgery (CRS) defined as removal of&#xD;
      macroscopic abdominal and peritoneal disease combined with Hyperthermic Perioperative&#xD;
      Chemotherapy (HIPEC) is the treatment considered standard of care for selected patients with&#xD;
      moderate to small volume peritoneal metastases secondary to colorectal cancer. Nevertheless&#xD;
      treatment of locoregional recurrence and peritoneal metastases in colon cancer are&#xD;
      disappointing first because only 30% of patients can be surgically treated and second because&#xD;
      of this 30% only 15- 30% survive 5 years, leaving only 10% of patients with a chance of being&#xD;
      cured. Furthermore the economic burden of metastatic colorectal cancer treatment is&#xD;
      considerable including the common adverse events associated that increase healthcare resource&#xD;
      utilization and considering the addition of biological drugs to standard treatment. An&#xD;
      evaluation of CRS combined with HIPEC for peritoneal metastases of colorectal origin in the&#xD;
      era of value-based medicine, showed an incremental cost respect to modern chemotherapy&#xD;
      regimens of 44,217 US$ for life-year saved, making investment in prevention even more&#xD;
      attractive. Despite screening for colorectal cancer in average-risk patients using&#xD;
      colonoscopy was associated with a substantially reduced risk of diagnosis with new-onset&#xD;
      primary late-stage tumors, colorectal cancer screening remains underused. Analyzing the&#xD;
      recent surgical published series, the majority (around 70%), of patients with a diagnosis of&#xD;
      colonic cancer operated with curative intent, have a pT3-4 tumor, which is exactly the&#xD;
      high-risk class of patients for local recurrence and peritoneal metastases. In this scenario&#xD;
      the most effective strategy to combat endoperitoneal recurrence seems prevention. Two&#xD;
      previous studies performed in our Institution investigated how a proactive management of&#xD;
      peritoneal metastases in colon cancer patients considered at high-risk for peritoneal&#xD;
      recurrence according to depth of bowel wall invasion and specific histopathologic features&#xD;
      (pT3, pT4 any N, M0, mucinous or signet ring cell pathology) influence outcome. A group of 25&#xD;
      patients for whom inclusion criteria were verified by intraoperative pathologic assessment,&#xD;
      were submitted to a &quot;proactive&quot; treatment that included in addition to the standard surgical&#xD;
      treatment, a greater omentectomy, appendectomy, exeresis of the liver round ligament and, in&#xD;
      post-menopausal women, a bilateral oophorectomy. At the end of the operation, in these&#xD;
      patients a HIPEC was performed with oxaliplatin and simultaneous iv infusion of&#xD;
      5-fluorouracil (FU) + leucovorin (LV). Short and long-term results showed that when compared&#xD;
      to a control group (50 cases) of similar patients treated only by standard treatment in the&#xD;
      same Institution, this group of patients had a statistically significant decreased incidence&#xD;
      of peritoneal recurrence (4 vs. 28%) and an increase in overall and disease-free survival&#xD;
      rates. These results should obviously validated by larger controlled studies, and this is the&#xD;
      aim of the PROMENADE protocol, to verify if the treatment criteria applied in colorectal&#xD;
      peritoneal metastases (Surgery combined with HIPEC) could represent a mean of tertiary&#xD;
      prevention of endoperitoneal recurrence in high-risk colon cancer. However, simpler&#xD;
      application criteria were needed for a large-scale study. For this reason histological typing&#xD;
      have not been yet considered an inclusion criteria and will only represent a secondary&#xD;
      outcome measure. Furthermore, also considering other experiences, the protocol will use an&#xD;
      imaging technique (MDCT) for preoperative selection of high-risk T3 (&gt;/= 5 mm tumor invasion&#xD;
      beyond the muscularis propria) and T4 colon cancers, combined in patients with suspected&#xD;
      systemic disease after MDCT with functional positron-emission tomography (PET), avoiding the&#xD;
      need for an intraoperative frozen-sections pathologic assessment. The results of this study&#xD;
      will hopefully confirm the therapeutic rationale that makes microscopic local seeding as the&#xD;
      main reason for endoperitoneal recurrence. It will be also important to verify if, as&#xD;
      demonstrated in our pilot study, a better loco-regional control of the disease will carry&#xD;
      better long-term survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">March 1, 2024</start_date>
  <completion_date type="Anticipated">September 2025</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of endoperitoneal recurrence at 36 months</measure>
    <time_frame>36 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>disease-free survival (DFS)</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>disease-free survival (DFS)</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OS)</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OS)</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>extraperitoneal (systemic) or liver recurrence rate</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>morbidity rate</measure>
    <time_frame>1 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>morbidity rate</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIPEC toxicity rate</measure>
    <time_frame>1 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIPEC toxicity rate</measure>
    <time_frame>6 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EORTC QLQ-C30 Summary Score</measure>
    <time_frame>6 months</time_frame>
    <description>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.&#xD;
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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EORTC QLQ-C30 Summary Score</measure>
    <time_frame>1 year</time_frame>
    <description>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.&#xD;
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</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">140</enrollment>
  <condition>Colon Cancer</condition>
  <condition>Intraperitoneal Rectal Cancer</condition>
  <arm_group>
    <arm_group_label>Standard surgical treatment group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Colon cancer patients (high-risk T3 and T4) without peritoneal or systemic metastases are resected for cure.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Proactive management group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Standard surgical treatment</intervention_name>
    <description>Standard surgical treatment (open or laparoscopic techniques) containing at least 12 lymph-nodes for accurate pN staging.</description>
    <arm_group_label>Standard surgical treatment group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Proactive management</intervention_name>
    <description>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.</description>
    <arm_group_label>Proactive management group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard adjuvant systemic chemotherapy</intervention_name>
    <description>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.</description>
    <arm_group_label>Proactive management group</arm_group_label>
    <arm_group_label>Standard surgical treatment group</arm_group_label>
    <other_name>adjuvant capecitabine and oxaliplatin (CAPOX)</other_name>
    <other_name>adjuvant 5-FU and oxaliplatin (FOLFOX)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with colon cancer or intraperitoneal rectosigmoid cancer with clinical (by&#xD;
             CT) high-risk(&gt; 5mm) T3, T4 tumors, any N, M0&#xD;
&#xD;
          -  Performance Status (ECOG) 0, 1 or 2&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  BMI&gt; 30&#xD;
&#xD;
          -  Impossibility of an adequate follow-up&#xD;
&#xD;
          -  Intra and extraabdominal metastatic disease, multiple colorectal cancer or other&#xD;
             malignancies&#xD;
&#xD;
          -  Active infections or severe associated medical conditions (ASA IV or V)&#xD;
&#xD;
          -  Abnormal bone marrow or renal and liver function indices&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paolo Sammartino, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Roma La Sapienza</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Paolo Sammartino, MD PhD</last_name>
    <phone>336615632</phone>
    <phone_ext>+39</phone_ext>
    <email>paolo.sammartino@uniroma1.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tommaso Cornali, MD</last_name>
    <phone_ext>+39</phone_ext>
    <email>tommaso.cornali@uniroma1.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>ASST Nord Milano P.O. Città di Sesto S. Giovanni</name>
      <address>
        <city>Milano</city>
        <state>PD</state>
        <zip>35031</zip>
        <country>Italy</country>
      </address>
    </facility>
    <contact>
      <last_name>Gianandrea Baldazzi, MD</last_name>
      <email>gbaldazzi@hotmail.com</email>
    </contact>
    <investigator>
      <last_name>Gianandrea Baldazzi, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Diletta Cassini, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>ASO S. Croce e Carle</name>
      <address>
        <city>Cuneo</city>
        <zip>12100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <contact>
      <last_name>Felice Borghi, MD</last_name>
      <email>borghi.f@ospedale.cuneo.it</email>
    </contact>
    <investigator>
      <last_name>Felice Borghi, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Maria Carmela Giuffrida, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera dei Colli</name>
      <address>
        <city>Napoli</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori IRCCS Fondazione Pascale di Napoli</name>
      <address>
        <city>Napoli</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale di Rimini</name>
      <address>
        <city>Rimini</city>
        <zip>47923</zip>
        <country>Italy</country>
      </address>
    </facility>
    <contact>
      <last_name>Gianluca Garulli, MD</last_name>
      <email>lucagarulli@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Gialuca Garulli, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Basilio Pirrera, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Rome Sapienza</name>
      <address>
        <city>Roma</city>
        <zip>00161</zip>
        <country>Italy</country>
      </address>
    </facility>
    <contact>
      <last_name>Paolo Sammartino, MD PhD</last_name>
      <phone>336615632</phone>
      <phone_ext>+39</phone_ext>
      <email>paolo.sammartino@uniroma1.it</email>
    </contact>
    <contact_backup>
      <last_name>Tommaso Cornali, MD</last_name>
      <phone_ext>+39</phone_ext>
      <email>tommaso.cornali@uniroma1.it</email>
    </contact_backup>
    <investigator>
      <last_name>Paolo Sammartino, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tommaso Cornali, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Fabio Accarpio, MD PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Daniele Biacchi, MD Phd</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ospedale Sant'Eugenio</name>
      <address>
        <city>Rome</city>
        <zip>00144</zip>
        <country>Italy</country>
      </address>
    </facility>
    <contact>
      <last_name>Massimo Carlini, MD FACS</last_name>
      <email>maxcarlini@tiscali.it</email>
    </contact>
    <investigator>
      <last_name>Massimo Carlini, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Domenico Spoletini, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Daniela Apa, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Universitaria Integrata di Verona</name>
      <address>
        <city>Verona</city>
        <zip>37126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>27065712</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24980687</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24263309</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22645605</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>November 9, 2016</study_first_submitted>
  <study_first_submitted_qc>November 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Roma La Sapienza</investigator_affiliation>
    <investigator_full_name>Tommaso Cornali</investigator_full_name>
    <investigator_title>Prof. Paolo Sammartino, MD Phd</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colonic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02974556
org study id: PROMENADE v1.0
nct id: NCT02974556
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Outcomes Assessor)
measure: Incidence of endoperitoneal recurrence at 36 months
time frame: 36 months
description: 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.
measure: disease-free survival (DFS)
time frame: 3 years
measure: disease-free survival (DFS)
time frame: 5 years
measure: overall survival (OS)
time frame: 3 years
measure: overall survival (OS)
time frame: 5 years
measure: extraperitoneal (systemic) or liver recurrence rate
time frame: 3 years
measure: morbidity rate
time frame: 1 month
measure: morbidity rate
time frame: 6 months
measure: HIPEC toxicity rate
time frame: 1 month
measure: HIPEC toxicity rate
time frame: 6 month
measure: EORTC QLQ-C30 Summary Score
time frame: 6 months
description: 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
measure: EORTC QLQ-C30 Summary Score
time frame: 1 year
description: 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
arm group label: Standard surgical treatment group
arm group type: Active Comparator
description: 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.
arm group label: Proactive management group
arm group type: Experimental
description: 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.
intervention type: Procedure
intervention name: Standard surgical treatment
description: Standard surgical treatment (open or laparoscopic techniques) containing at least 12 lymph-nodes for accurate pN staging.
arm group label: Standard surgical treatment group
intervention type: Procedure
intervention name: Proactive management
description: 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.
arm group label: Proactive management group
intervention type: Drug
intervention name: Standard adjuvant systemic chemotherapy
description: 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.
arm group label: Proactive management group
arm group label: Standard surgical treatment group
other name: adjuvant capecitabine and oxaliplatin (CAPOX)
other name: adjuvant 5-FU and oxaliplatin (FOLFOX)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Paolo Sammartino, MD PhD
role: Principal Investigator
affiliation: University of Roma La Sapienza
last name: Paolo Sammartino, MD PhD
phone: 336615632
phone ext: +39
email: paolo.sammartino@uniroma1.it
last name: Tommaso Cornali, MD
phone ext: +39
email: tommaso.cornali@uniroma1.it
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country: Italy
citation: 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.
PMID: 27065712
citation: 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.
PMID: 24980687
citation: 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.
PMID: 24263309
citation: 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.
PMID: 22645605
responsible party type: Principal Investigator
investigator affiliation: University of Roma La Sapienza
investigator full name: Tommaso Cornali
investigator title: Prof. Paolo Sammartino, MD Phd
mesh term: Colonic Neoplasms
mesh term: Capecitabine
mesh term: Oxaliplatin
sharing ipd: No