Correlation of FAZA PET Hypoxia Imaging To 3D Histology in Oral Tongue Cancer (FAITH)

Cancer of the Tongue Clinical Trial

— FAITH  

Official title:

Defining a Personalized Hypoxic Radiation Target Through Correlation of Functional F18-FAZA PET Imaging to Pimonidazole-stained 3D Whole-mounted Histological Specimen

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02519959
• Other study ID #: 253-2015
• Status: Not yet recruiting
• Phase: Phase 1
• First received: August 6, 2015
• Last updated: March 14, 2016
• Start date: December 2016
• Est. completion date: December 2018

Study information

• Verified date: March 2016
• Source: Sunnybrook Health Sciences Centre
• Contact: Ian Poon, M.D., FRCPC
• Phone: (416) 480-6100
• Email: ian.poon[@]sunnybrook.ca
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial Summary

In head and neck cancer, areas of tumours with low oxygen supply (called tumour hypoxia) harbour cells that are resistant to radiation and are prone to metastasize. Modern radiotherapy techniques are precise enough to deliver radiation to these small areas and could be used to target these areas to receive higher doses of radiation than the rest of the tumour to overcome resistance. Hypoxia can be "seen" in the body using special imaging such as [F-18]-FAZA-PET ([F-18]-Fluoroazomycin arabinoside positron emission tomography) but it has not been tested as a method for creating radiation treatment targets. As part of regular pathology tumour tissue is sliced extremely thinly (<1/100th of a millimeter) and stained so that individual cells can be seen under a microscope. Immunohistochemistry (IHC) is a special type of "stain" that can specifically highlight hypoxic areas. This method is considered the most accurate way to inspect for the presence of hypoxia. There is not a specific staining target for hypoxia ordinarily, but when patients ingest a substance called pimonidazole-HCl it builds up specifically in hypoxic areas and can be targeted for IHC staining. In this study participants with oral tongue cancer will have a [F-18]-FAZA-PET scan and take a single dose of oral pimonidazole-HCl before having surgery to remove their cancer. The whole tumour will be used to create microscope slides using very thin slices of the tumour. The slices will be stained using IHC to show where the pimonidazole has built up. Digital scans of the slides will be made using a laser scanner. The hypoxia seen on their FAZA-PET scan will be "matched" with hypoxia on the electronic slides to see if the FAZA truly shows where hypoxia is in tumours and if it could be used as a way to plan radiation treatments to deliver more radiation to just those areas.

Description:

Modern radiotherapy (RT) now possesses a high level of technical and physical precision that allows for dose escalation to levels previously considered unsafe (e.g. lung stereotactic RT). Due to safety concerns, there is considerable interest in the concept of 'dose painting', where a non-uniform dose is delivered to a biologic target volume where radioresistance is expected. The hypoxic target volume is likely a major source of cancer recurrence and can be defined on functional imaging (FAZA-PET). However, the accuracy of FAZA-PET in defining a hypoxic volume for radiation targeting is not known. Finding a good correlation between pathology (as a reference standard) to a hypoxic PET target would provide the foundation for a feasible dose escalation clinical trial in high risk head and neck cancer that can finally take advantage of all the technical improvements in radiation delivery.

This study aims to assess the degree to which hypoxia measured by [F-18]-FAZA-PET imaging is correlated with a reference standard of hypoxia confirmed by pimonidazole targeted immunohistochemistry using a 3D whole-mount histopathologic approach.

This is a pilot study in the form of a prospective, Phase II, single arm, trial to investigate the use of IHC methods to validate functional medical imaging on the sub-tumour level.

Ten patients with biopsy confirmed oral tongue squamous cell carcinoma where surgery is the intended form of definitive treatment will be approached to participate in the study. Participants will have received pre-study testing that is standard of care (e.g. biopsy, complete blood count, serum electrolytes, urinalysis, liver function tests, beta-hCG testing, etc.) with no incremental testing. Patients will receive a routine MRI and CT. In addition they will receive a [F-18]-FAZA-PET scan 2-3 days prior to surgery. Within 1 week of surgery patients will be seen in the pre-anaesthesia clinic for repeat bloodwork and routine peri-operative assessments. On the day before surgery, in addition to typical peri-operative activities (e.g. 24 hour solid fast, only consuming clear fluids) the patient will be instructed to take the prescribed dose of oral pimonidazole-HCl 16-20 hours before surgery. The patient will be admitted for same day surgery which will be carried out in a routine fashion, e.g. total removal of tumour plus appropriate margins. For research purposes, the specimen will be processed differently than routine pathology. Once the specimen has been completely removed have several external markers applied to its surface to guide orientation. The specimen will then be embedded in 3.5% agar and placed on ice for 1 hour. The embedded specimen will undergo an MRI (ex-vivo) noting the position of the specimen in the block using the external markers. The MRI will be a single 5 minute T1 sequence. The specimen is cut from front to back in 3 mm slices and stained for pimonidazole to show hypoxia as well as typical hematoxylin and eosin staining that will be used for clinical pathologic assessment. Histology slides will be digitized with a laser scanner at a resolution of 0.5µm/pixel. The gross tumour and areas of macroscopic hypoxia will be defined by a pathologist. The histology images will be reconstructed using the external markers and internal landmarks as well as the ex-vivo MRI and matched (co-registered) to the in vivo FAZA-PET/CT/MRI tumour volumes.

Despite the available high technical precision of radiation treatment machines, limited clinical progress has been made in the last 15 years in sub-volume (i.e. less than whole tumour) targeting because of target uncertainty. With a multidisciplinary, multi-institutional collaboration, our group will correlate FAZA-PET imaging to a 3D histological reference to validate (i.e. evaluate accuracy) functional imaging at a unprecedented level. This invaluable understanding of the biological underpinnings of commonly used functional imaging could help form the basis of future clinical trials.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: December 2018
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female patients = 18 years old

• Biopsy proven Stage II-III oral tongue squamous cell carcinoma

• Patients must be naïve to treatment for resectable disease

• Surgical resection as definitive treatment modality

• Ability to participate and willingness to give written informed consent prior to performance of any study-related procedures and to comply with the study protocol

• Adequate hematologic, renal and liver function as defined by the following laboratory values (upper limit of normal, ULN, as per Sunnybrook Reference Test Manual) performed prior to admission to the Odette Cancer Centre:

• Absolute neutrophil count (ANC) = 1.5 x 109/L

• Platelet count = 50 ×109/L

• Hemoglobin = 9 g/dL

• Bilirubin = 1.5 × the upper limit of normal ULN (20.0 µmol)

• AST, ALT, and alkaline phosphatase = 2.5 × the ULN (37 U/L, 40 U/L, 120 U/L)

• Serum creatinine = 1.5 × the ULN (106 µmol/L) or creatinine clearance = 50 mL/min on the basis of the Cockroft-Gault glomerular filtration rate estimation: [(140-age) × (weight in kg × (0.85 if female)]/[72 × (serum creatinine in mg/dL)]

• Prothrombin time (PT), international normalized ratio (INR), partial thromboblastin time (PTT) = 1.5 × the ULN (respectively 1.1, 14 sec, 35 sec)

• Negative serum pregnancy test within 14 days prior to commencement of dosing in women of childbearing potential. Women of non-childbearing potential need not undergo pregnancy testing.

Exclusion Criteria:

• Patients who have received prior chemotherapy or radiation therapy for their oral tongue carcinoma

• Stage I, Stage III T1/N1/M0, and Stage IV disease

• Pregnancy or breastfeeding at the time of consent

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Cancer of the Tongue

Intervention

Drug:
• (F18)-FAZA injection
Participants will have received pre-study testing that is standard of care (e.g. biopsy, complete blood count, serum electrolytes, urinalysis, liver function tests, beta-hCG testing, etc.) with no incremental testing. Patients will receive a routine MRI and CT. In addition they will receive a FAZA-PET scan 2-3 days prior to surgery.
• Pimonidazole-HCl
Two to three days prior to surgery participants will be dispensed oral pimonidazole-HCl. On the day before surgery, in addition to typical peri-operative activities (e.g. 24 hour solid fast, only consuming clear fluids) the patient will be instructed to take the prescribed dose of oral pimonidazole-HCl 16-20 hours before surgery. The patient will be admitted for same day surgery which will be carried out in a routine fashion.

Locations

Country	Name	City	State
n/a

Sponsors (6)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre	Cancer Care Ontario, Princess Margaret Hospital, Canada, Sunnybrook Research Institute, University of Toronto, University of Western Ontario, Canada

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Defining an hypoxic radiation target	To define a reference standard hypoxic radiation target through the correlation of functional F18-FAZA PET imaging to a pimonidazole-stained 3D whole mounted histological specimen.	2-3 years from study initiation	No
Primary	Correlation of FAZA-PET hypoxia to pimonidazole stained histology	To determine the degree to which hypoxic signal measured by FAZA-PET imaging is correlated with true cellular hypoxia confirmed by immunohistochemical staining of pimonidazole using a 3D whole-mount approach.	2-3 years from study initiation	No
Secondary	Quality of co-registration techniques	To assess quality of registration through measuring registration error of various automatic and semi-automatic co-registration techniques.	1-3 years from study initiation	No
Secondary	Correlation of textural features	To evaluate potential relationships between textural features of MRI, PET-CT, and immunohistochemistry.	2-3 years from study initiation	No

External Links

•   MedlinePlus: Cancer
•   MedlinePlus: Oral Cancer