Patient Selection for Hypoxia Modifying Treatments in Larynx Carcinomas

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT00160095

Collaborator

Dutch Cancer Society (Other)

Enrollment

Locations

140

Duration (Months)

15.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to identify in a prospective manner microregional profiles of oxygenation and proliferation based on exogenous and endogenous markers that are predictive for outcome of radiotherapy in squamous cell carcinoma of the larynx and to investigate if these profiles can identify patients that are most likely to benefit from hypoxia modifying treatment strategies like ARCON (Accelerated radiotherapy combined with carbogen breathing and nicotinamide).

Condition or Disease	Intervention/Treatment	Phase
Larynx Cancer

Detailed Description

Purpose

Prognostic indicators discriminate patients with good and bad prognosis. Predictive assays are tools that select patients for specific treatments or treatment modifications such that outcome will be improved relative to conventional treatment. In oncology, many prognostic indicators based on clinical or biological tumor characteristics have been described but only very few have proven to be useful as predictive assays. We have developed an imaging modality for coregistration of tumor oxygenation and proliferation at the microregional level with preservation of the tumor anatomy and the microenvironmental structure. We have strong indications that this functional imaging can be a powerful tool for identifying those patients that will profit from hypoxia modifying treatments.

Tumor oxygenation and proliferation are recognized as important determinants of the outcome of radiotherapy and possibly also of other treatment modalities in a number of tumor types and in particular in squamous cell carcinomas. Various exogenous and endogenous markers for hypoxia and proliferation are currently available which can be studied in relation to each other, the tumor architecture and the tumor microenvironment using immunohistochemistry and advanced image analysis techniques.

The purpose of this project is to identify microregional profiles of oxygenation and proliferation based on exogenous and endogenous markers that:

Are predictive for outcome of radiotherapy in squamous cell carcinoma of the larynx.
Can identify the patients that are most likely to benefit from hypoxia modifying treatment strategies.

And to:

Validate these marker profiles in a prospective manner and in a sufficiently large group of patients.

Plan of investigation

In 2001 a multicenter randomized trial was initiated comparing accelerated radiotherapy with carbogen and nicotinamide as hypoxic modifiers against accelerated radiotherapy alone in patients with carcinoma of the larynx. This trial is approved and supported by the Dutch Cancer Society and currently 6 Dutch and 1 British center are participating. This trial provides a unique opportunity to prospectively test oxygenation and proliferation related marker profiles in a large homogeneous patient population and to assess the predictive capacity in a comparative setting with one group of patients receiving a hypoxia modifying treatment and the other group not.

Paraffin-embedded biopsy specimens will be collected from all patients entered in this trial. In part of the patients, biopsies will be taken after injection of the hypoxic marker pimonidazole and the S-phase marker iododeoxyuridine (IdUrd). Sections will be immunohistochemically processed and stained for various combinations of vascular markers, endogenous hypoxia and proliferation markers and, if applicable, for pimonidazole and IdUrd. The sections will be analyzed by computerized image processing. Apart from overall single parameter values that will be obtained, the interrelationship of the various parameters will be studied and the microregional phenotype of the tumors will be characterized by quantification and integration of the marker profiles. The information thus obtained will be related to treatment outcome in terms of both local control and survival and results from the two treatment groups will be compared.

Possible results

This investigation can identify oxygenation and proliferation related parameters and profiles that are predictive for outcome of radiotherapy in squamous cell carcinoma of the larynx and provide a selection tool for hypoxia modifying treatments. The principle of characterization of the tumor phenotype at the microregional level using functional imaging may also be applied to other tumor types and treatment strategies.

Study Design

Study Type:

Observational

Actual Enrollment :

79 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Patient Selection for Hypoxia Modifying Treatments Based on Functional Microregional Imaging of Tumor Vasculature, Oxygenation and Proliferation in Squamous Cell Carcinoma of the Larynx

Study Start Date :

Jul 1, 2001

Actual Primary Completion Date :

Mar 1, 2010

Actual Study Completion Date :

Mar 1, 2013

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Pathological confirmed squamous cell carcinoma of the larynx.
TNM-classification (UICC 1997, appendix I):
T3-4 glottic or supraglottic carcinoma
T2 glottic carcinoma with impaired cord mobility or subglottic extension
T2 supraglottic carcinoma with invasion of mucosa of base of tongue or vallecula or invasion of the medial wall of the piriform sinus.
any N-stage, M0.
WHO performance status 0 or 1.
Age > 18 years.
Written informed consent.
Treatment in the ARCON phase III trial

Exclusion Criteria:

Prior or concurrent treatment for this tumour.
Severe stridor and adequate debulking of airway not possible.
Impaired renal function: serum creatinine above upper normal limit.
Use of nephrotoxic medication (including ACE-inhibitors) that cannot be discontinued for the duration of the radiation treatment.
Impaired hepatic function: ASAT and ALAT more than 1.5 times the upper normal limit.
Use of anti-convulsants that cannot be discontinued for the duration of the radiation treatment.
History of malignancy during the previous 5 years except basal cell carcinoma of skin, carcinoma in situ of the cervix, or superficial bladder neoplasm (pTa).

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Free University Medical Centre Amsterdam	Amsterdam	Netherlands	po 7057 1007 MB
2	Rijnstate Ziekenhuis Arnhem	Arnhem	Netherlands	po 9555 6800 TA
3	Academic Hospital Maastricht	Maastricht	Netherlands	po 5800 6202 AZ
4	Radboud University Nijmegen Medical Centre	Nijmegen	Netherlands	6500 HB
5	Universitair Medisch Centrum Utrecht	Utrecht	Netherlands	po 85500 3508 GA