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

NCT05400681 | Unknown

• 1 other identifier: S-20190140
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

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. 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. 2.Secondly, we will study the prognostic impact of PLF+ and KRAS ctDNA positivity in PC patients.

Conditions

Pancreatic Cancer; Pancreatic Adenocarcinoma

Keywords

peritoneal lavage; peripheral blood; circulating tumor DNA

Outcome Measures

Primary Outcomes (1)

• Relative frequency of ctDNA in peritoneal lavage and peripheral blood

  Percentage

  2 years

Secondary Outcomes (1)

• Prognostic value of ctDNA in peritoneal lavage and peripheral blood

  2 years

Eligibility Criteria

• Age: 20 Years - 100 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients scheduled for surgery of pancreatic cancer

You may qualify if:

• Patients diagnosed with pancreatic cancer (adenocarcinoma) on a pancreatic resection specimen Age \> 18 years

You may not qualify if:

• Duodenal carcinoma, ampullary carcinoma, bile duct cancer
• Benign surgical diagnosis
• Pregnancy

Sponsors & Collaborators

• Sonke Detlefsen: lead
• Martin-Luther-Universität Halle-Wittenberg: collaborator
• University Hospital Schleswig-Holstein: collaborator
• Karolinska Institutet: collaborator

Study Sites (1)

Odense University Hospital

Odense, 5000, Denmark

RECRUITING

Related Publications (34)

• Hruban, R.H., et al., Digestive System Tumours. 2019, World Health Organization: Lyon (France). p. 322-332.

  BACKGROUND

• Graversen M, Detlefsen S, Bjerregaard JK, Pfeiffer P, Mortensen MB. Peritoneal metastasis from pancreatic cancer treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Clin Exp Metastasis. 2017 Jun;34(5):309-314. doi: 10.1007/s10585-017-9849-7. Epub 2017 May 17.

  PMID: 28516306 BACKGROUND

• Sergeant G, Roskams T, van Pelt J, Houtmeyers F, Aerts R, Topal B. Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma. BMC Cancer. 2011 Jan 31;11:47. doi: 10.1186/1471-2407-11-47.

  PMID: 21281486 BACKGROUND

• Steen W, Blom R, Busch O, Gerhards M, Besselink M, Dijk F, Festen S. Prognostic value of occult tumor cells obtained by peritoneal lavage in patients with resectable pancreatic cancer and no ascites: A systematic review. J Surg Oncol. 2016 Nov;114(6):743-751. doi: 10.1002/jso.24402. Epub 2016 Sep 19.

  PMID: 27642007 BACKGROUND

• Graversen M, Fristrup C, Kristensen TK, Larsen TR, Pfeiffer P, Mortensen MB, Detlefsen S. Detection of free intraperitoneal tumour cells in peritoneal lavage fluid from patients with peritoneal metastasis before and after treatment with pressurised intraperitoneal aerosol chemotherapy (PIPAC). J Clin Pathol. 2019 May;72(5):368-372. doi: 10.1136/jclinpath-2018-205683. Epub 2019 Feb 12.

  PMID: 30755498 BACKGROUND

• Crepaldi-Filho R, Palma RT, Giusti MF, Bueno Mde A, Silva PS, Waisberg J. Levels of carcinoembryonic antigen and CA 19-9 in the sera and peritoneal washing of patients undergoing surgical treatment for gastric carcinoma. Arq Gastroenterol. 2008 Jul-Sep;45(3):219-24. doi: 10.1590/s0004-28032008000300010.

  PMID: 18852950 BACKGROUND

• Hoskovec D, Varga J, Konecna E, Antos F. Levels of CEA and Ca 19 - 9 in the sera and peritoneal cavity in patients with gastric and pancreatic cancers. Acta Cir Bras. 2012 Jun;27(6):410-6. doi: 10.1590/s0102-86502012000600009.

  PMID: 22666759 BACKGROUND

• Nomoto S, Nakao A, Kasai Y, Inoue S, Harada A, Nonami T, Takagi H. Peritoneal washing cytology combined with immunocytochemical staining and detecting mutant K-ras in pancreatic cancer: comparison of the sensitivity and availability of various methods. Pancreas. 1997 Mar;14(2):126-32. doi: 10.1097/00006676-199703000-00004.

  PMID: 9057184 BACKGROUND

• Yamashita K, Kuba T, Shinoda H, Takahashi E, Okayasu I. Detection of K-ras point mutations in the supernatants of peritoneal and pleural effusions for diagnosis complementary to cytologic examination. Am J Clin Pathol. 1998 Jun;109(6):704-11. doi: 10.1093/ajcp/109.6.704.

  PMID: 9620027 BACKGROUND

• Rall CJ, Rivera JA, Centeno BA, Fernandez-del Castillo C, Rattner DW, Warshaw AL, Rustgi AK. Peritoneal exfoliative cytology and Ki-ras mutational analysis in patients with pancreatic adenocarcinoma. Cancer Lett. 1995 Nov 6;97(2):203-11. doi: 10.1016/0304-3835(95)03978-6.

  PMID: 7497464 BACKGROUND

• Kristensen AT, Wiig JN, Larsen SG, Giercksky KE, Ekstrom PO. Molecular detection (k-ras) of exfoliated tumour cells in the pelvis is a prognostic factor after resection of rectal cancer? BMC Cancer. 2008 Jul 27;8:213. doi: 10.1186/1471-2407-8-213.

  PMID: 18655729 BACKGROUND

• Cao F, Li J, Li A, Li F. Prognostic significance of positive peritoneal cytology in resectable pancreatic cancer: a systemic review and meta-analysis. Oncotarget. 2017 Feb 28;8(9):15004-15013. doi: 10.18632/oncotarget.14745.

  PMID: 28122342 BACKGROUND

• Satoi S, Murakami Y, Motoi F, Uemura K, Kawai M, Kurata M, Sho M, Matsumoto I, Yanagimoto H, Yamamoto T, Mizuma M, Unno M, Hashimoto Y, Hirono S, Yamaue H, Honda G, Nagai M, Nakajima Y, Shinzeki M, Fukumoto T, Kwon AH. Reappraisal of peritoneal washing cytology in 984 patients with pancreatic ductal adenocarcinoma who underwent margin-negative resection. J Gastrointest Surg. 2015 Jan;19(1):6-14; discussion 14. doi: 10.1007/s11605-014-2637-7. Epub 2014 Oct 15.

  PMID: 25316482 BACKGROUND

• Yin Z, Ma T, Chen S. Intraoperative Peritoneal Washing Cytology on Survival in Pancreatic Ductal Adenocarcinoma With Resectable, Locally Advanced, and Metastatic Disease. Pancreas. 2019 Apr;48(4):519-525. doi: 10.1097/MPA.0000000000001266.

  PMID: 30946232 BACKGROUND

• Schlitter AM, Segler A, Steiger K, Michalski CW, Jager C, Konukiewitz B, Pfarr N, Endris V, Bettstetter M, Kong B, Regel I, Kleeff J, Kloppel G, Esposito I. Molecular, morphological and survival analysis of 177 resected pancreatic ductal adenocarcinomas (PDACs): Identification of prognostic subtypes. Sci Rep. 2017 Feb 1;7:41064. doi: 10.1038/srep41064.

  PMID: 28145465 BACKGROUND

• Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, Choti MA, Yeo CJ, McCue P, White MA, Knudsen ES. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015 Apr 9;6:6744. doi: 10.1038/ncomms7744.

  PMID: 25855536 BACKGROUND

• Perets R, Greenberg O, Shentzer T, Semenisty V, Epelbaum R, Bick T, Sarji S, Ben-Izhak O, Sabo E, Hershkovitz D. Mutant KRAS Circulating Tumor DNA Is an Accurate Tool for Pancreatic Cancer Monitoring. Oncologist. 2018 May;23(5):566-572. doi: 10.1634/theoncologist.2017-0467. Epub 2018 Jan 25.

  PMID: 29371474 BACKGROUND

• Hadano N, Murakami Y, Uemura K, Hashimoto Y, Kondo N, Nakagawa N, Sueda T, Hiyama E. Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer. Br J Cancer. 2016 Jun 28;115(1):59-65. doi: 10.1038/bjc.2016.175. Epub 2016 Jun 9.

  PMID: 27280632 BACKGROUND

• Li T, Zheng Y, Sun H, Zhuang R, Liu J, Liu T, Cai W. K-Ras mutation detection in liquid biopsy and tumor tissue as prognostic biomarker in patients with pancreatic cancer: a systematic review with meta-analysis. Med Oncol. 2016 Jul;33(7):61. doi: 10.1007/s12032-016-0777-1. Epub 2016 May 25.

  PMID: 27225938 BACKGROUND

• Creemers A, Krausz S, Strijker M, van der Wel MJ, Soer EC, Reinten RJ, Besselink MG, Wilmink JW, van de Vijver MJ, van Noesel CJM, Verheij J, Meijer SL, Dijk F, Bijlsma MF, van Oijen MGH, van Laarhoven HWM. Clinical value of ctDNA in upper-GI cancers: A systematic review and meta-analysis. Biochim Biophys Acta Rev Cancer. 2017 Dec;1868(2):394-403. doi: 10.1016/j.bbcan.2017.08.002. Epub 2017 Aug 8.

  PMID: 28801248 BACKGROUND

• Zhuang R, Li S, Li Q, Guo X, Shen F, Sun H, Liu T. The prognostic value of KRAS mutation by cell-free DNA in cancer patients: A systematic review and meta-analysis. PLoS One. 2017 Aug 10;12(8):e0182562. doi: 10.1371/journal.pone.0182562. eCollection 2017.

  PMID: 28796802 BACKGROUND

• Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, Kitano TK, Hodel MR, Petersen JF, Wyatt PW, Steenblock ER, Shah PH, Bousse LJ, Troup CB, Mellen JC, Wittmann DK, Erndt NG, Cauley TH, Koehler RT, So AP, Dube S, Rose KA, Montesclaros L, Wang S, Stumbo DP, Hodges SP, Romine S, Milanovich FP, White HE, Regan JF, Karlin-Neumann GA, Hindson CM, Saxonov S, Colston BW. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem. 2011 Nov 15;83(22):8604-10. doi: 10.1021/ac202028g. Epub 2011 Oct 28.

  PMID: 22035192 BACKGROUND

• Groot VP, Mosier S, Javed AA, Teinor JA, Gemenetzis G, Ding D, Haley LM, Yu J, Burkhart RA, Hasanain A, Debeljak M, Kamiyama H, Narang A, Laheru DA, Zheng L, Lin MT, Gocke CD, Fishman EK, Hruban RH, Goggins MG, Molenaar IQ, Cameron JL, Weiss MJ, Velculescu VE, He J, Wolfgang CL, Eshleman JR. Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer. Clin Cancer Res. 2019 Aug 15;25(16):4973-4984. doi: 10.1158/1078-0432.CCR-19-0197. Epub 2019 May 29.

  PMID: 31142500 BACKGROUND

• Mulcahy HE, Lyautey J, Lederrey C, qi Chen X, Anker P, Alstead EM, Ballinger A, Farthing MJ, Stroun M. A prospective study of K-ras mutations in the plasma of pancreatic cancer patients. Clin Cancer Res. 1998 Feb;4(2):271-5.

  PMID: 9516910 BACKGROUND

• Yamada T, Nakamori S, Ohzato H, Oshima S, Aoki T, Higaki N, Sugimoto K, Akagi K, Fujiwara Y, Nishisho I, Sakon M, Gotoh M, Monden M. Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features. Clin Cancer Res. 1998 Jun;4(6):1527-32.

  PMID: 9626473 BACKGROUND

• Zambon C, Navaglia F, Basso D, Gallo N, Greco E, Piva MG, Fogar P, Pasquali C, Pedrazzoli S, Plebani M. ME-PCR for the identification of mutated K-ras in serum and bile of pancreatic cancer patients: an unsatisfactory technique for clinical applications. Clin Chim Acta. 2000 Dec;302(1-2):35-48. doi: 10.1016/s0009-8981(00)00351-x.

  PMID: 11074062 BACKGROUND

• Uemura T, Hibi K, Kaneko T, Takeda S, Inoue S, Okochi O, Nagasaka T, Nakao A. Detection of K-ras mutations in the plasma DNA of pancreatic cancer patients. J Gastroenterol. 2004 Jan;39(1):56-60. doi: 10.1007/s00535-003-1245-1.

  PMID: 14767735 BACKGROUND

• Takai E, Totoki Y, Nakamura H, Morizane C, Nara S, Hama N, Suzuki M, Furukawa E, Kato M, Hayashi H, Kohno T, Ueno H, Shimada K, Okusaka T, Nakagama H, Shibata T, Yachida S. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Sci Rep. 2015 Dec 16;5:18425. doi: 10.1038/srep18425.

  PMID: 26669280 BACKGROUND

• Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. doi: 10.1056/NEJMoa1011923.

  PMID: 21561347 BACKGROUND

• Gemenetzis G, Groot VP, Blair AB, Laheru DA, Zheng L, Narang AK, Fishman EK, Hruban RH, Yu J, Burkhart RA, Cameron JL, Weiss MJ, Wolfgang CL, He J. Survival in Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy and Surgical Resection. Ann Surg. 2019 Aug;270(2):340-347. doi: 10.1097/SLA.0000000000002753.

  PMID: 29596120 BACKGROUND

• Grass F, Vuagniaux A, Teixeira-Farinha H, Lehmann K, Demartines N, Hubner M. Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg. 2017 May;104(6):669-678. doi: 10.1002/bjs.10521.

  PMID: 28407227 BACKGROUND

• Graversen M, Detlefsen S, Bjerregaard JK, Fristrup CW, Pfeiffer P, Mortensen MB. Prospective, single-center implementation and response evaluation of pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal metastasis. Ther Adv Med Oncol. 2018 Jun 1;10:1758835918777036. doi: 10.1177/1758835918777036. eCollection 2018.

  PMID: 29899763 BACKGROUND

• Graversen M, Detlefsen S, Fristrup C, Pfeiffer P, Mortensen MB. Adjuvant Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in resected high-risk colon cancer patients - study protocol for the PIPAC-OPC3 Trial. A prospective, controlled phase 2 Study. Pleura Peritoneum. 2018 Jun 12;3(2):20180107. doi: 10.1515/pp-2018-0107. eCollection 2018 Jun 1.

  PMID: 30911655 BACKGROUND

• Harris M, Chung F. Complications of general anesthesia. Clin Plast Surg. 2013 Oct;40(4):503-13. doi: 10.1016/j.cps.2013.07.001. Epub 2013 Aug 1.

  PMID: 24093647 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Surgical specimens, peritoneal lavage and peripheral blood

MeSH Terms

Conditions

Pancreatic Neoplasms

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Sönke Detlefsen, MD, PhD

  Odense University Hospital

  STUDY DIRECTOR

Central Study Contacts

Sönke Detlefsen, MD, PhD

CONTACT

+45 65414806; Sonke.Detlefsen@rsyd.dk

Michael B Mortensen, MD, PhD

CONTACT

+45 29694638; Michael.Bau.Mortensen@rsyd.dk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 26, 2022
• First Posted: June 1, 2022
• Study Start: August 1, 2020
• Primary Completion: June 30, 2023
• Study Completion: December 31, 2024
• Last Updated: June 8, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)