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Cola

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.

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.

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

Standard surgical treatment

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.

Proactive management

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.

Standard adjuvant systemic chemotherapy

Paolo Sammartino, MD PhD

Tommaso Cornali, MD

Gianandrea Baldazzi, MD

Diletta Cassini, MD

Felice Borghi, MD

Maria Carmela Giuffrida, MD

Gianluca Garulli, MD

Gialuca Garulli, MD

Basilio Pirrera, MD

Fabio Accarpio, MD PhD

Daniele Biacchi, MD Phd

Massimo Carlini, MD FACS

Massimo Carlini, MD

Domenico Spoletini, MD

Daniela Apa, MD

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.

Proactive Management of Endoperitoneal Spread in Colonic Cancer

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.

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

University of Roma La Sapienza

Prof. Paolo Sammartino, MD Phd

Symptoms and General Pathology

Wounds and Injuries

Behaviors and Mental Disorders

Hyperthermia

Fever

Rectal Diseases

Body Temperature Changes

Stress Disorders, Traumatic

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Bone Density Conservation Agents

Vitamins

Levoleucovorin

Raltitrexed

Calcium

Calcium, Dietary

Hormones

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folic Acid Antagonists

Enzyme Inhibitors

Folinic Acid

Folate

Vitamin B9

Patients undergo radical resection of colorectal cancer (open/laparoscopic) and receive standard adjuvant systemic chemotherapy comprising mFOLFOX6/CapeOx/sLV5FU2/Cape. Systemic chemotherapy will continue for 6 months.

Patients undergo radical resection of colorectal cancer (open/laparoscopic) and receive standard adjuvant systemic chemotherapy comprising mFOLFOX6/CapeOx/sLV5FU2/Cape. Systemic chemotherapy will continue for 6 months. Patients also undergo HIPEC with raltitrexed (3mg/m2) intraperitoneally for 60 minutes during surgery or within 10 days after the operation.

Patients undergo radical resection of colorectal cancer (open/laparoscopic) and receive standard adjuvant systemic chemotherapy comprising mFOLFOX6/CapeOx/sLV5FU2/Cape. Systemic chemotherapy will continue for 6 months. Patients also undergo HIPEC comprising oxaliplatin (130mg/m2) intraperitoneally during surgery and hyperthermia for 30 minutes, following leucovorin calcium (20mg/m2 intravenously) and 5-FU (400 mg/m2 intravenously)

Patients undergo radical surgery with standard adjuvant systemic chemotherapy (mFOLFOX6/CapeOx/sLV5FU2/Cape).

mFOLFOX6: oxaliplatin 85 mg/m2 IV d1 + leucovorin calcium 400 mg/m2 IV d1 + 5-FU 400 mg/m2 IV bolus d1 + 5-FU 2400 mg/m2 continuous IV over 46-48 hours d1-2. Repeat every two weeks for twelve cycles.

CapeOx: oxaliplatin 130 mg/m2 IV d1 + capecitabine 1000mg/m2 po bid d1-14. Repeat every three weeks for eight cycles.

sLV5FU2: leucovorin calcium 400 mg/m2 IV d1 + 5-FU 400 mg/m2 IV bolus d1 + 5-FU 2400 mg/m2 IV over 46-48 hours d1-2. Repeat every two weeks for twelve cycles.

Cape: capecitabine 1000mg/m2 po bid d1-14. Repeat every three weeks for eight cycles.

Raltitrexed (3 mg/m2) is added to the perfusate after attaining 42 degrees of inflow temperature and last for 60 minutes.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with raltitrexed

Before the beginning of HIPEC, 5-FU 400 mg/m2 and leucovorin calcium 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (130 mg/m2) is added to the perfusate after attaining 42 degrees inflow temperature with a total of 30 minutes perfusion time.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin

Guoxiang Cai, M.D. Ph.D.

This study is designed to evaluate the efficacy and safety of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) with raltitrexed or oxaliplatin versus no HIPEC in locally advanced colorectal cancer

Peritoneum is one of the common sites of metastasis in advanced stage colorectal cancer patients, resulting in a poor prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) is effective to colorectal peritoneal metastasis and may play a significant role in reducing the risk of metachronous peritoneal metastasis among patients with locally advanced colorectal cancer. Oxaliplatin is routinely used for HIPEC in the Europe and Raltitrexed may be another ideal drug for HIPEC. The present phase II multicenter, randomized controlled trial is designed to evaluate the efficacy and safety of adjuvant HIPEC with raltitrexed or oxaliplatin versus no HIPEC in locally advanced colorectal cancer.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Versus no HIPEC in Locally Advanced Colorectal Cancer (APEC Study)

Multicenter, Randomized Controlled Trial Designed to Evaluate the Efficacy and Safety of Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) With Raltitrexed or Oxaliplatin Versus no HIPEC in Locally Advanced Colorectal Cancer (APEC Study)

Fudan University

Associate Professor

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Proactive Management of Endoperitoneal Spread in Colonic Cancer	NCT02974556	Colon Cancer Intraperitoneal...	Standard surgic... Proactive manag... Standard adjuva...	18 Years - 70 Years	University of Roma La Sapienza
Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Versus no HIPEC in Locally Advanced Colorectal Cancer (APEC Study)	NCT02965248	Locally Advance...	Standard adjuva... Hyperthermic in... Hyperthermic in...	18 Years - 75 Years	Fudan University

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