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Gastrointestinal Diseases

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Pancreatic Cancer

Sönke Detlefsen, MD, PhD

Michael B Mortensen, MD, PhD

Pancreatic cancer (PC) is a deadly disease and surgical resection of the tumor is the only hope of cure. Approximately 20-25% of the PC patients are candidates for intended curative resection, but despite microscopically radical resection the majority of patients will have recurrent disease within 2 years. This indicates that most patients will harbour non-detected (i.e. occult) cancer cells at the time of resection. Studies suggest that free tumor cells in the peritoneum and in the blood are part of this occult disease burden, and that patients with such findings should not be operated but treated as having metastatic disease. However, the exact incidence of these tumor cells in an unselected cohort of patients undergoing pancreatic resection is unknown, and the potential impact on postoperative survival is also uncertain. In recent years, molecular biomarkers are increasingly being regarded as both predictive and prognostic tools for cancer patients. This study will use the most optimal available methods to investigate the incidence of biomarkers for tumor cells in the peritoneum and blood in PC patients, and to relate these findings to the final outcome of the resected patients. This project has become highly relevant since new treatment methods (i.e. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)) may be used to eradicate free tumor cells.

A recent systematic review and meta-analysis demonstrated that PC patients with positive peritoneal cytology (Cy+) had a significant poorer survival than patients with negative peritoneal cytology (Cy-) (HR 3.18), and the authors concluded that Cy+ patients should not undergo surgery. This conclusion was supported by a significant lower overall survival and a higher peritoneal recurrence rate after resection of Cy+ patients when compared to Cy- patients. Agreement that Cy+ in resectable PDAC is a negative predictor of prognosis came from another recent meta-analysis and systematic review. However, this study also indicated that the median OS was worse in patients without than in those with resection among patients with Cy+, thereby emphasizing need of further careful assessment of indications for radical resection in Cy+ patients.

KRAS mutations have been detected in circulating tumor DNA (ctDNA) in the blood (liquid biopsies) from patients with metastatic PC, and ctDNA is considered a marker of poor prognosis. Similar, KRAS mutations were found in the plasma of one-third of patients with a resectable tumor, and ctDNA positive (ctDNA+) patients had a significantly poorer overall survival (13.6 months vs 27.6 months, p\<0.0001). Similar conclusions were drawn in recent systematic reviews and meta-analyses, while one study failed to confirm these results. The detection of KRAS mutations in cell-free DNA has also been identified as a prognostic biomarker in PC patients. If looking at studies including all stages of PC patients, the prevalence of KRAS mutations in liquid biopsies was 40.8%, and these mutations had a negative impact on overall survival with a HR of 3.16. Different ctDNA detection methods have been used, however the recent introduction of digital droplet PCR (ddPCR), a new robust PCR method for quantifying low-abundance point mutations in cell-free circulating DNA, shows promising results and offers increased sensitivity and reproducibility relative to quantitative PCR (qPCR).

The treatment of resectable, locally advanced and metastatic PC has changed significantly over the past few years. New chemotherapy regimens have improved survival in metastatic PC, and these regimens (+/- radiation therapy) are presently being tested in both resectable and locally advanced PC with promising preliminary results. In theory, these new regimens may be potentially effective against ctDNA in PC patients, whereas the effect on peritoneal lavage positive (PLF+) PC patients is more speculative due to the low intraperitoneal concentrations of systemic chemotherapy. However, the latter problem may be solved by using Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) which allows better intraperitoneal distribution, concentration and accumulation of chemotherapy, without the systemic side effects. It may be speculated that the highly sensitive ddPCR of KRAS may be a better tool for PLF+ detection when focusing on PC patients, as up to 95% of these harbour mutations in this gene. So far, only very few studies used PCR to evaluate KRAS mutations in PLF in PC patients.

Main study aims are:

1. We aim to investigate the incidence of PLF+ and KRAS ctDNA in the blood from an unselected cohort of PC patients scheduled for attempted curative surgery.
2. Secondly, we will study the prognostic impact of PLF+ and KRAS ctDNA positivity in PC patients.

Surgical specimens, peritoneal lavage and peripheral blood

Liquid Biopsy for ctDNA in Peritoneal Lavage and Blood in Pancreatic Cancer

Pre- and Postoperative Incidence and Prognostic Implication of Positive Peritoneal Lavage and Circulating Tumor DNA in Patients With Pancreatic Cancer

Martin-Luther-Universität Halle-Wittenberg

University Hospital Schleswig-Holstein

Karolinska Institutet

Sonke Detlefsen

Professor

Symptoms and General Pathology

Wounds and Injuries

Colorectal Neoplasms

Neoplasm Metastasis

Hyperthermia

Fever

Neoplastic Processes

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Herbal and Botanical

Cisplatin

Mitomycins

Mitomycin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Alkylating Agents

Enzyme Inhibitors

Cola

Adjuvant HIPEC will be performed simultaneously with primary tumor resection in patients undergoing curative surgery for primary colorectal cancer associated with risk factors for the development of metachronous peritoneal metastases.

Comparable controls will be retrospectively selected from patients undergoing curative surgery for colorectal cancer at the National Cancer Institute (Milan, Italy) during the same period.

Every single control patient will be matched with a.patient in HIPEC group according to the following criteria: i) risk-factor for metachronous PM (minimal synchronous PM vs. ovarian metastases vs. pathological tumor \[pT\] stage (pT4a/b); ii) pathological node (pN) stage (pN0 vs. pN1/2); iii) grading (well/moderately vs. poorly differentiated); iv) histological subtype (adenocarcinoma vs. mucinous/signet ring cell carcinoma); v) sex; vi) age (+/-5 years). The investigators will be blinded to patient outcomes during the process.

Closed-abdomen HIPEC with cisplatin (25 mg/m2/l of perfusate) and mitomycin-C (3•3 mg/m2/l of perfusate) at 42•5°C for 60 minutes. Perfusate volume: 4-6 l.

adjuvant HIPEC

Colon resections for primary tumors were performed according to the oncologic principles of adequate lymph-adenectomy. Complete adhesiolysis, resection of falciform hepatic ligament, greater and lesser omentectomy were performed in all patients to ensure optimal perfusion during the HIPEC. Tumor deposits on visceral and parietal surfaces were surgically removed by formal peritonectomy procedures and/or organ resections, as needed.

surgery

Marcello Deraco, MD

The prognosis of peritoneal metastases from colorectal cancer has recently improved with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Although outcomes are further improved when early stage peritoneal metastases are treated, adjuvant HIPEC has not yet been thoroughly addressed. This prospective pilot study assessed feasibility, safety and efficacy of HIPEC performed simultaneously with primary curative surgery in colorectal cancer patients with primary tumor-related risk-factors for the development of metachronous peritoneal metastases.

BACKGROUND Peritoneal surfaces are the second most common site of disease progression for colorectal cancer (CRC), following liver metastases. Historically, prognosis of CRC peritoneal metastases (PM) was only about 6 months with palliative systemic chemotherapy or supportive care. Survival improvements have been reported with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). However, CRS/HIPEC is more effective and safe when early-stage CRC-PM are treated and most patients are not suitable for CRS/HIPEC, due to extensive peritoneal and/or systemic disease. Also, in the palliative setting, modern systemic therapies appear to be less effective for PM, than non-PM metastatic CRC and absence of symptoms and current limitations of imaging hamper early diagnosis and treatment of PM. These points would support the use of adjuvant HIPEC to prevent the outgrowth of occult peritoneal seeding into macroscopic disease.

STUDY DESIGN This tudy to assesses feasibility and safety of an integrated approach of curative surgery and adjuvant HIPEC performed at the same time as primary surgery in patients with primary CRC at high risk for the development of metachronous PM. Patients are prospectively selected on the base of preoperative clinical and radiological work-up. At surgery, careful exploration of all peritoneal the cavity, and intra-operative pathological examination are carried out to confirm clinical-pathological risk-factors for PM development Standard adjuvant systemic chemotherapy is intended in the postoperative setting. A matched control group will be selected among patients with colorectal cancer undergoing curative surgery and standard adjuvant systemic chemotherapy at the same institution and during the same period.

STUDY POPULATION Patients with colorectal cancer undergoing intentionally curative resection for primary tumors infiltrating the visceral serosa (T4a) or directly invading adjacent organs (T4b), with positive peritoneal washing cytology or resected ovarian or minimal peritoneal metastases.

INTERVENTION Adjuvant HIPEC procedure is performed under general anaesthesia after the completion of the surgical procedures. Colon resections for primary tumors are performed according to the oncologic principles of adequate lymph-adenectomy.Greater and lesser omentectomy and adhesiolysis (if necessary) are performed routinely to ensure optimal perfusion during the HIPEC. Tumor deposits on visceral and parietal surfaces are surgically removed by formal peritonectomy procedures and/or organ resections, as needed. HIPEC is performed with cisplatin (25 mg/m2/l of perfusate) and mitomycin-C (3•3 mg/m2/l of perfusate) at 42•5°C for 60 minutes according to the closed-abdomen .technique.

OUTCOMES Primary end-point is the sensitivity and false positive rate of preoperative/intraoperative assessment of primary tumor-related risk-factors for the development of peritoneal metastases in patients with colorectal cancer undergoing curative surgery..Secondary endpoints are number of participants with adverse events as a measure of safety and tolerability, Cumulative incidence of PM, overall and progression-free survival are assessed in comparison with matched controls.

Adjuvant HIPEC to Prevent Colorectal Peritoneal Metastases in High-risk Patients

Pilot Study of Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients With Colorectal Cancer at High Risk for the Development of Metachronous Peritoneal Metastases

Overall survival is dated from the day of surgery with HIPEC to the time of death for any cause.

Progression-free survival is dated from the day of surgery with HIPEC to the time of postoperative disease progression involving any site, including peritoneal surfaces

The presence versus absence of primary tumor-related risk-factors for the development of metachronous peritoneal metastases, as assessed during the preoperative/intraoperative phase, is compared with the findings of the pathological examination of surgical specimens.

All-type adverse events occurring within 60 days from surgery and adjuvant HIPEC (including surgical complications and systemic toxicities) will be recorded and graded according to the Common Terminology Criteria for Adverse Events of the National Institute of Health (version 4.0).

Peritoneal progression-free survival is calculated from the day of surgery and HIPEC to the date of death for any cause, or first recurrence involving the peritoneum..

Azienda Usl di Bologna

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Liquid Biopsy for ctDNA in Peritoneal Lavage and Blood in Pancreatic Cancer	NCT05400681	Pancreatic Canc... Pancreatic Aden...		20 Years - 100 Years	Odense University Hospital
Liquid Biopsy for ctDNA in Peritoneal Lavage and Blood in Pancreatic Cancer	NCT05400681	Pancreatic Canc... Pancreatic Aden...		20 Years - 100 Years	Odense University Hospital
Liquid Biopsy for ctDNA in Peritoneal Lavage and Blood in Pancreatic Cancer	NCT05400681	Pancreatic Canc... Pancreatic Aden...		20 Years - 100 Years	Odense University Hospital
Adjuvant HIPEC to Prevent Colorectal Peritoneal Metastases in High-risk Patients	NCT02575859	Colorectal Neop... Metastasis	adjuvant HIPEC surgery	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Adjuvant HIPEC to Prevent Colorectal Peritoneal Metastases in High-risk Patients	NCT02575859	Colorectal Neop... Metastasis	adjuvant HIPEC surgery	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Adjuvant HIPEC to Prevent Colorectal Peritoneal Metastases in High-risk Patients	NCT02575859	Colorectal Neop... Metastasis	adjuvant HIPEC surgery	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for peritoneal lavage