The Role of the Tumor Microenvironment of Pancreatic Cancer to Predict Treatment Outcome

NCT01989000 | Completed

• 1 other identifier: NL45913.018.13
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 2

Brief Summary

Pancreatic cancer is a highly lethal disease. Patients with resectable or borderline resectable disease may benefit from preoperative radiochemotherapy. However, only a subset of patients will respond to this potentially toxic and expensive treatment. Therefore, novel predictive markers are needed to determine treatment efficacy at an early stage. Preferably, these markers could be determined non-invasively and provide insight into the biology of pancreatic cancer. Pancreatic cancers are heterogeneous tumors. The tumor microenvironment is often characterized by large amounts of stroma, hypovascularization, and hypoxia. As these three factors can all contribute to treatment resistance, a quantitative assessment of these markers may aid in the prediction of response to preoperative radiochemotherapy. Moreover, these assessments may have prognostic value. Finally, further insight into the interrelation of these aspects of the tumor microenvironment can contribute to the evaluation of new targeted treatment options. Tumor cellularity and extracellular matrix composition can be assessed non-invasively in vivo by diffusion weighted magnetic resonance imaging (DWI) and tumor vascularity can be assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Finally, tumor hypoxia can be evaluated by T2\* MRI and PET-CT, using the 18F-labeled hypoxic marker HX4. Objective of the study: The primary aim of the study is to assess whether DWI, DCE-MRI, T2\*, and 18F-HX4-PET/CT predict overall survival in patients with pancreatic cancer treated with surgery and adjuvant chemotherapy or with neoadjuvant radiochemotherapy, surgery and adjuvant chemotherapy. Secondary aims of the study include the assessment of the predictive value of DWI, DCE-MRI, T2\*, and 18F-HX4-PET/CT for pathological response to neoadjuvant chemoradiation, the correlation of DWI, DCE-MRI, T2\*, and 18F-HX4-PET/CT with histopathological assessment of tumor stroma, vascularization, and hypoxia, and the assessment of the predictive value of these histopathological markers for overall survival.

Conditions

Pancreatic Cancer

Keywords

Pancreatic cancer; Hypoxia; Vasculature; Stroma

Outcome Measures

Primary Outcomes (1)

• Predictive value of pretreatment DWI, DCE-MRI, T2*, and 18F-HX4-PET/CT on overall survival in patients with pancreatic cancer treated with surgery and adjuvant chemotherapy or with neoadjuvant radiochemotherapy, surgery and adjuvant chemotherapy.

  DWI: mean ADC of the whole tumor. DCE: mean Ktrans of the whole tumor. T2\*: average value of the whole tumor. 18F-HX4-PET/CT: SUVmean of the whole tumor.

  Within two weeks before start radiochemotherapy or within two weeks before surgery

Secondary Outcomes (6)

• Predictive value of pretreatment DWI, DCE-MRI, T2*, and 18F-HX4-PET/CT on recurrence free survival in patients with pancreatic cancer treated with surgery and adjuvant chemotherapy or with neoadjuvant radiochemotherapy, surgery and adjuvant chemotherapy.

  Within two weeks before start radiochemotherapy or within two weeks before surgery

• Predictive value of pretreatment DWI, DCE-MRI, T2*, and 18F-HX4-PET/CT on pathological response in patients with pancreatic cancer treated with neoadjuvant radiochemotherapy

  Within two weeks before start radiochemotherapy

• Predictive value of changes in DWI, DCE-MRI, T2*, and 18F-HX4-PET/CT parameters after radiochemotherapy on pathological response in patients with pancreatic cancer treated with neoadjuvant radiochemotherapy

  Within two weeks before start radiochemotherapy and within two weeks before surgery

• Predictive value of changes in DWI, DCE-MRI, T2*, and 18F-HX4-PET/CT parameters after radiochemotherapy on recurrence-free survival in patients with pancreatic cancer treated with neoadjuvant radiochemotherapy, surgery and adjuvant chemotherapy

  Within two weeks before start radiochemotherapy and within two weeks before surgery

• Immunohistochemically determined parameters of the tumor microenvironment assessed after resection of the pancreatic tumor to predict overall and recurrence-free survival

  Within 1h after surgery

Other Outcomes (2)

• DWI, DCE-MRI, T2*, and 18F-HX4-PET/CT parameters obtained just before surgery correlate with immunohistochemically determined parameters of the tumor microenvironment assessed in tumor tissue obtained at surgery

  Within two week before surgery and within 1h after surgery

• Immunohistochemically determined parameters of the tumor microenvironment assessed in pretreatment tumor biopsies and post-surgery resection material correlate

  Within 4 weeks before start treatment and within 1h after surgery

Study Arms (2)

Neoadjuvant radiochemotherapy

ACTIVE COMPARATOR

Patients elected for neoadjuvant radiochemotherapy undergo DWI-MRI, DCE-MRI (Gadobutrol),T2\*-MRI and \[F-18\]HX4 PET/CT imaging within two weeks before start of the chemoradiation and again after radiochemotherapy (Gemcitabine/Radiotherapy), within two weeks before surgery (Pancreaticoduodenectomy).

Drug: Gadobutrol; Drug: [F-18]HX4; Drug: Gemcitabine; Radiation: Radiotherapy; Procedure: Pancreaticoduodenectomy

Primary Surgery

ACTIVE COMPARATOR

Patients elected for primary surgery undergo DWI-MRI, DCE-MRI (Gadobutrol),T2\*-MRI and \[F-18\]HX4 PET/CT imaging within two weeks before surgery (Pancreaticoduodenectomy).

Drug: Gadobutrol; Drug: [F-18]HX4; Procedure: Pancreaticoduodenectomy

Interventions

Gadobutrol DRUG

0.1 ml/kg Gadovist is administered at 5 ml/s followed by a 15 ml saline flush

Also known as: Gadovist

Neoadjuvant radiochemotherapy; Primary Surgery

[F-18]HX4 DRUG

400 MBq \[F-18\]HX4, is administered in a single intravenous bolus injection, followed by a saline flush.

Also known as: [18 F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-, 1H-1,2,3-triazol-1-yl)propan-1-ol

Neoadjuvant radiochemotherapy; Primary Surgery

Gemcitabine DRUG

1000 mg/m2/dose on day 1 and 8 in 2 cycles of 21 days (three weeks) each, one cycle before and one cycle after radiochemotherapy. During radiotherapy gemcitabine is administered at 1000 mg/m2/dose on day 1, 8 and 15.

Also known as: Gemzar

Neoadjuvant radiochemotherapy

Radiotherapy RADIATION

A hypofractionated scheme of 15 fractions of 2.4 Gy in three weeks will be applied, combined with the second course of gemcitabine.

Neoadjuvant radiochemotherapy

Pancreaticoduodenectomy PROCEDURE

Also known as: PPPD, Whiple

Neoadjuvant radiochemotherapy; Primary Surgery

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with pancreatic tumors, with histological or cytological proof of adenocarcinoma or a high suspicion on CT imaging.
• Tumor size ≥ 1cm.
• WHO-performance score 0-2.
• Scheduled for surgery or neo-adjuvant chemotherapy/radiation followed by surgery. For the reproducibility part of the study, patients who will not undergo surgery, may be included, too.
• Written informed consent.

You may not qualify if:

• Any psychological, familial, sociological or geographical condition potentially hampering adequate informed consent or compliance with the study protocol.
• Contra-indications for MR scanning, including patients with a pacemaker, cochlear implant or neurostimulator; patients with non-MR compatible metallic implants in their eye, spine, thorax or abdomen; or a non-MR compatible aneurysm clip in their brain; patients with severe claustrophobia.
• Renal failure (GFR \< 30 ml/min) hampering safe administration of Gadolinium containing MR contrast agent.
• For the reproducibility part of the protocol: surgery, radiation and/or chemotherapy foreseen within the timeframe needed for MR scanning.

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Erasmus Medical Center: collaborator
• Dutch Cancer Society: collaborator

Study Sites (2)

Academic Medical Center

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Erasmus MC

Rotterdam, South Holland, 3000CA, Netherlands

Location

MeSH Terms

Conditions

Pancreatic Neoplasms; Hypoxia

Interventions

gadobutrol; 3-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol; Gemcitabine; Radiotherapy; Pancreaticoduodenectomy

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Therapeutics; Digestive System Surgical Procedures; Surgical Procedures, Operative

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D., Ph.D.

Study Record Dates

• First Submitted: November 8, 2013
• First Posted: November 20, 2013
• Study Start: November 1, 2013
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: June 27, 2018

Record last verified: 2018-06

Locations

NL (2)