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

NCT ID: NCT01989000

Last Updated: 2018-06-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2017-12-31

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.

Detailed Description

Background of the study:

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.

Study design:

The target population will be recruited from the the Academic Medical Centre (AMC) and Erasmus MC. First, to assess reproducibility, patients with pancreatic cancer will undergo MRI twice, once in the AMC and once in the EMC. Next, 40 consecutive patients that will undergo surgery+adjuvant treatment will have MRI and 18F-HX4-PET/CT measurements once to assess the value of the techniques to predict outcome of standard treatment. 40 patients who will undergo preoperative radiochemotherapy will have MRI and 18F-HX4-PET/CT at baseline, and 1 week before surgery. We will assess the relative contribution of each imaging method as well as the integrated use of these methods as predictive markers for survival and pathological response to treatment. Tumor tissue from resected patients will be analyzed for markers of tumor vascularization (CD31, VEGF), hypoxia (HIF1alfa, GLUT1, CA9), and stromal activation (smooth muscle actin, markers for Hedgehog pathway activity). Results will be correlated with imaging parameters, as well as patient outcome.

Conditions

Pancreatic Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Neoadjuvant radiochemotherapy

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).

Group Type: ACTIVE_COMPARATOR

Gadobutrol

Intervention Type: DRUG

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

[F-18]HX4

Intervention Type: DRUG

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

Gemcitabine

Intervention Type: 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.

Radiotherapy

Intervention Type: RADIATION

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

Pancreaticoduodenectomy

Intervention Type: PROCEDURE

Primary Surgery

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).

Group Type: ACTIVE_COMPARATOR

Gadobutrol

Intervention Type: DRUG

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

[F-18]HX4

Intervention Type: DRUG

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

Pancreaticoduodenectomy

Intervention Type: PROCEDURE

Interventions

Gadobutrol

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

Intervention Type: DRUG

[F-18]HX4

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

Intervention Type: DRUG

Gemcitabine

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.

Intervention Type: DRUG

Radiotherapy

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

Intervention Type: RADIATION

Pancreaticoduodenectomy

Intervention Type: PROCEDURE

Other Intervention Names

Gadovist; [18 F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-; 1H-1,2,3-triazol-1-yl)propan-1-ol; Gemzar; PPPD; Whiple

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Erasmus Medical Center

OTHER

Sponsor Role: collaborator

Dutch Cancer Society

OTHER

Sponsor Role: collaborator

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

OTHER

Sponsor Role: lead

Responsible Party

H.W.M. van Laarhoven

M.D., Ph.D.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Academic Medical Center

Amsterdam, North Holland, Netherlands

Erasmus MC

Rotterdam, South Holland, Netherlands

Countries

Netherlands

Other Identifiers

NL45913.018.13

Identifier Type: -

Identifier Source: org_study_id