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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01989000
Recruitment Status : Completed
First Posted : November 20, 2013
Last Update Posted : June 27, 2018
Sponsor:
Collaborators:
Erasmus Medical Center
Dutch Cancer Society
Information provided by (Responsible Party):
H.W.M. van Laarhoven, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description
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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.


Condition or disease Intervention/treatment Phase
Pancreatic Cancer Drug: Gadobutrol Drug: [F-18]HX4 Drug: Gemcitabine Radiation: Radiotherapy Procedure: Pancreaticoduodenectomy Not Applicable

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 47 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: The Role of the Tumor Microenvironment of Pancreatic Cancer to Predict Treatment Outcome
Study Start Date : November 2013
Actual Primary Completion Date : December 2017
Actual Study Completion Date : December 2017

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: 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).
 Drug: Gadobutrol
0.1 ml/kg Gadovist is administered at 5 ml/s followed by a 15 ml saline flush
Other Name: Gadovist

Drug: [F-18]HX4
400 MBq [F-18]HX4, is administered in a single intravenous bolus injection, followed by a saline flush.
Other Names:
  • [18 F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-
  • 1H-1,2,3-triazol-1-yl)propan-1-ol

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.
Other Name: Gemzar

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

Procedure: Pancreaticoduodenectomy
Other Names:
  • PPPD
  • Whiple
Active Comparator: 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).
 Drug: Gadobutrol
0.1 ml/kg Gadovist is administered at 5 ml/s followed by a 15 ml saline flush
Other Name: Gadovist

Drug: [F-18]HX4
400 MBq [F-18]HX4, is administered in a single intravenous bolus injection, followed by a saline flush.
Other Names:
  • [18 F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-
  • 1H-1,2,3-triazol-1-yl)propan-1-ol

Procedure: Pancreaticoduodenectomy
Other Names:
  • PPPD
  • Whiple


Outcome Measures
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Primary Outcome Measures :
  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. [ Time Frame: Within two weeks before start radiochemotherapy or within two weeks before surgery ]
    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.


Secondary Outcome Measures :
  1. 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. [ Time Frame: Within two weeks before start radiochemotherapy or within two weeks before surgery ]
    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.

  2. 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 [ Time Frame: Within two weeks before start radiochemotherapy ]
    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.

  3. 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 [ Time Frame: Within two weeks before start radiochemotherapy and within two weeks before surgery ]
    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.

  4. 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 [ Time Frame: Within two weeks before start radiochemotherapy and within two weeks before surgery ]
    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.

  5. Immunohistochemically determined parameters of the tumor microenvironment assessed after resection of the pancreatic tumor to predict overall and recurrence-free survival [ Time Frame: Within 1h after surgery ]

    Tumor stroma: SMA (DAKO M0851, 1:800); collagen (picro-sirius red), SHH (H160 anti-SHH, 1:500).

    Tumor angiogenesis: VEGF (VEGF RB-9031, 1:200) and CD34 (Immunotech 0787, 1:600).

    Tumor hypoxia: HIF-1α (Abcam 2185, 1:750), GLUT1 (NeoMarkers RB-90522,1:500), and CA-IX (Mo-anti-CA-IX m75, 1:25).

    Measure: Percentage of staining of the total tumor area


  6. Immunohistochemically determined parameters of the tumor microenvironment assessed in a pretreatment tumor biopsy to predict overall and recurrence-free survival [ Time Frame: Within 1h after surgery ]

    Tumor stroma: SMA (DAKO M0851, 1:800); collagen (picro-sirius red), SHH (H160 anti-SHH, 1:500).

    Tumor angiogenesis: VEGF (VEGF RB-9031, 1:200) and CD34 (Immunotech 0787, 1:600).

    Tumor hypoxia: HIF-1α (Abcam 2185, 1:750), GLUT1 (NeoMarkers RB-90522,1:500), and CA-IX (Mo-anti-CA-IX m75, 1:25).



Other Outcome Measures:
  1. 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 [ Time Frame: Within two week before surgery and within 1h after surgery ]
    See before

  2. Immunohistochemically determined parameters of the tumor microenvironment assessed in pretreatment tumor biopsies and post-surgery resection material correlate [ Time Frame: Within 4 weeks before start treatment and within 1h after surgery ]
    See before


Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01989000


Locations
Layout table for location information
Netherlands
Academic Medical Center
Amsterdam, Noord Holland, Netherlands, 1105AZ
Erasmus MC
Rotterdam, Zuid Holland, Netherlands, 3000CA
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Erasmus Medical Center
Dutch Cancer Society
More Information
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Layout table for additonal information
Responsible Party: H.W.M. van Laarhoven, M.D., Ph.D., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01989000    
Other Study ID Numbers: NL45913.018.13
First Posted: November 20, 2013    Key Record Dates
Last Update Posted: June 27, 2018
Last Verified: June 2018
Keywords provided by H.W.M. van Laarhoven, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Pancreatic cancer
Hypoxia
Vasculature
Stroma
Additional relevant MeSH terms:
Layout table for MeSH terms
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Pancreatic Diseases
Digestive System Diseases
Endocrine System Diseases
 Gemcitabine
Imidazole
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors