Version of 3 March 2003

 

 

 

Role of hyperbaric oxygen in enhancing radiosensitivity on glioblastoma multiforme.

 

 

A randomised controlled prospective study

 

 

 

 

                       

 

COST action B14

 

 

                       

 

 

This protocol has been adopted by the Working Group Oncology of COST action B14.

 

 


Protocol coordinator:    

 

GERMANY                                                                              FEHLAUER  Fabian

 

 

 

Writing committee:

 

1.       F. Fehlauer, M.D.

2.       U.M. Carl M.D. Ph. D

3.       P. Sminia, Ph. D

 

 

 

1.       Dept. Radiation Oncology, University of Hamburg,  Martinistr. 52, 20246 Hamburg, Germany.  Phone:+ 49-40-42803-2525, Fax:+ 49-40-42803-8119, e-mail: fehlauer@uke.uni-hamburg.de

2.       Dept. Radiation Oncology and Nuclear Medicine, Diakoniekrankenhaus Rotenburg, Elise-Averdieck Strasse 17, 27356 Rotenburg (Wümme), Germany. Phone:+ 49 -4261/77-2741; Fax: 04261/77-2148 e-mail: UMCARL@diako-online.de

3.       Dept. Radiation Oncology, section Radiobiology, VU Universtity medical center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands, Phone: + 31 20 4448355,, Fax:+ 31 20 4448285, E-mail: p.sminial@vumc.nl

 

 

“This protocol has been considered in detail, and accepted by COSTB14. This is a multi-national group of experts in the field of Hyperbaric Medicine, appointed nationally in each individual case, and organised and supported by the European Commission. Thus, the work described has been subjected to extensive peer review and amendment, and may be regarded as consistent with best practice in the field of Hyperbaric Medicine”

 

 

COST B14 Working Group Oncology:

 

CARL Ulrich M                                              GERMANY

GRANSTRÖM Gösta                                      SWEDEN       

HAMILTON-FARRELL Martin                      UNITED KINGDOM

            HARTMANN Axel                                         GERMANY

JANSEN Erik C                                              DENMARK

MAYER Ramona                                            AUSTRIA

MELAMED Yehuda                                        ISRAEL

            SCHMUTZ Jorg                                              SWITZERLAND

SICKO Zdzislaw                                             POLAND

SMINIA Peter                                                THE NETHERLANDS

VAN DER KLEIJ Adrian                                THE NETHERLANDS

                                                                                                         

 

                       


1.      Background

Malignant gliomas, such as glioblastoma multiforme, are the most common type of primary brain tumours of the central nervous system and remain incurable. The efficacy of surgical resection, radiotherapy and chemotherapy seems to have reached a plateau. In spite of the benefit of postoperative radiotherapy, the mean survival is less than 12 months.

One of the major factors of the poor response to therapy is the tumour cell heterogeneity containing oxygen deprived tumour areas (Vaupel 1991, Denekamp 1996). It has been long recognised that oxygenation influences the response of tumours to radiation and may led to radioresistance. For sterilisation of hypoxic tumour cells, a three times higher radiation dose is required than for cells at normal oxygen tension. Recently, Collingridge et al. (1999) quantified the spatial distribution of the oxygen pressure (pO2) in glioma by polarographic measurements. The study showed regions with oxygen tension less than 2.5 mm Hg. Hence, hyperbaric oxygenation (HBO) is a promising approach to cope with the phenomenon of hypoxia and to increase the cellular radiation sensitivity (Nordmarks 1996, Overgaard 1996).

The theoretical basis for the use of HBO as an adjunct to radiotherapy is as follows:

 

·        Hypoxic regions are present in malignant gliomas.

·        Non-proliferating, quiescent hypoxic cells are radioresistant compared to their well-oxygenated counterparts. Following irradiation, well-oxygenated cells will be lethally damaged. As a result, hypoxic cells will be reoxygenated, enter the proliferative tumour cell compartment and repopulate the tumour.

·        The larger the number of cells that lose their reproductive capacity, the greater the probability of palliation.

 

Several experimental studies indicated that the radiation response can be enhanced under HBO (Johnson 1978, Brizel 1997, Hartmann 1997). Hyperbaric oxygen exposure was used in combination with radiotherapy to treat malignant gliomas (Kohshi 1999). Fifteen patients (10 glioblastoma, 5 anaplastic astrocytoma) were irradiated within 15 minutes after HBO. The median survivals in patients with and without HBO were 24 and 12 months, respectively, and were significant different. No serious side effects were observed in HBO patients. However, a major drawback of this promising non-randomised study presents the concurrence of patients with two pognostically different tumours.

 

 

2. Objectives

 

Main endpoint:

·        Efficiency on median survival of HBO prior to conventional radiation

 

Secondary endpoints:

·        Efficiency on recurrent free survival of HBO before conventional radiation

·        PET study to assess metabolic changes before and after therapy (optional)

·        Influence on quality of life

 

 

3.      Study population

 

Inclusion criteria:

·        Pathologically verified glioblastoma multiforme

·        Complete or partial macroscopic surgical resection, or biopsy only

·        Karnofsky status ³ 70%

·        Leucocytes ³ 3000

·        Thrombocytes ³ 100.000

·        Hemoglobin ³ 10 g/dl

·        HBO fitness

·        Informed consent

 

Exclusion criteria before therapy:

·        Age < 18 years

·        Karnofsky status < 70%

·        Prior chemotherapy

·        Prior brain irradiation

·        Pregnancy

·        Secondary malignancies, except squamous cell carcinoma of the skin.

·        Severe internal or neurological disease

·        Contraindications to HBO: as assessed by the medical direction of the HBO facility.

 

Breaking off criteria / exclusion criteria during therapy:

·        Severe side effects (WHO III-IV)

·        Lacking concordance

In these cases, patients will be treated following the conventional radiotherapy protocol.

 

 

4.      Sample size assumptions and estimates

 

Phase III trial: - prospective, randomised, unblinded

·        Sample size: 40 patients each group

 

 

5.      Enrolment of participants

 

5.a. Baseline examinations

 

Clinical examination:

General clinical examination, including neurological status and Karnofsky performance status. CTC status (common toxicity criteria).

 

HBO fitness examination:

According to the regulations of the medical director.

 

Laboratory investigations:

Blood cell count, Hematocrit, Na, K, Cl, Creatinin.

 

Preclinical examination:

Contrast-enhanced computerised tomography (CT) or magnetic resonance imaging (MRI) scan. Optional: PET scan (FDG uptake).

These methods are used to evaluate the tumour volume before and after treatment.

 

 

5.b.Personal data:

Age, date of diagnosis, tumour localisation, operation status (complete macroscopical resection, partial resection, or biopsy only).

 

Subjective evaluation: Quality of life questionnaire.

 

 

6.      Randomisation (Phase III)

 

After informed consent, patients will be randomised into two arms (A: with or B: without HBO; the irradiation treatment is identical in both groups) using a blinded envelope technique, consisting of a choice of 1 to 10 envelopes (5 containing a piece of paper indicating `HBO`). Every patient will be presented 10 envelopes, in order to give every patient a 50% probability of HBO.

 

 

7.      Intervention

 

Radiotherapy must begin within three weeks after surgery.

 

Procedure: Three-dimensional treatment planning aiming for application of 60 Gy tumour dose in daily fractions of max. 2 Gy. Overall treatment time: 6-7 weeks.

 

Arm A patients will receive HBO before irradiation. At least 80% of the irradiation fractions should be preceded by HBO.

 

·        each irradiation must be given within 20 min. of HBO treatment.

·        all irradiation fractions should be preceded by HBO treatment at 2.5 (2.4-2.6) (to be specified exactly) ATA for 60 min. without air breaks.

 

Transcutaneous oxygen measurements will be done to confirm hyperoxygenation.

 

Patients should be transported from the HBO facility to the X-ray machine without excersion. The time interval between HBO treatment and radiotherapy must be recorded.

Arm B patients will not be submitted to (sham) compression.

 

 

8.      Blinding

 

Presence of complications and side effects will independently be recorded be a clinician treating the patient, and analysed by a researcher unaware of the nature of the treatment given.

 

 

9.      Evaluation criteria

 

Evaluation of the patients will be performed on coded evaluation record, devoid of any possible identification of the patient.

 

Evaluation will be done on Day 0 (before start of the treatment, during radiation planning), Week 1 – 6 (once a week during treatment period), Day X (end of treatment), Months 3 (3 month after start of the treatment).

 

Each set of evaluation will be documented on standardised tables, which allow analysis for comparison and will comprise:

 

Day 0: Clinical examination (general clinical examination, including neurological status and Karnofsky performance status; CTC status)

 

Week 1 – 6: Clinical examination, laboratory investigations (blood cell count, hematocrit, Na, K, Cl, creatinin)

 

Day X: Clinical examination, laboratory investigations, quality of live questionnaire (Phase III)

 

Months 3: Clinical examination, laboratory investigations, contrast-enhanced computerised tomography (CT) or magnetic resonance imaging (MRI) scan, quality of live questionnaire (Phase III)

 

 

10. Data and statistical analysis

 

Patients' recurrence free survival will be assessed by clinical monitoring. The individual survival time will be evaluated by contacting treating clinician, general practicians and local registry office.

Statistical tests will be performed two years after the last patient has entered the study:

The differences in patients characteristics and treatment parameters between the treated group with or without HBO will be investigated using the student`s t-test or chi-square-test. Survival curves will be calculated using the Kaplan-Meyer method. Differences in survival curves will be determined using the log-rang test. The Cox proportional hazard model will be used to calculate the relative risk on each variable for survival. Results will be considered significant for p-values <0.05.

 

The time interval between HBO treatment and radiotherapy will be recorded.

 

11. References

 

Brizel DM, Hage WD, Dodge RK, Munley MT, Piantadosi CA, Dewhirst MW: Hyperbaric oxygen improves tumour radiation response significantly more than carbogen/nicotinamide. Rad Res 1997;147:715-720

 

Collingridge DR, Piepmeier JM, Rockwell S, Knisely JP: Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother Oncol. 1999;53(2):127-31.

 

Denekamp J, Waites A: The potential for improving radiotherapy outcome by improving the oxygen supply to solid tumours. Strahlenther Onkol 1996;172(S2):22-23

 

Hartmann KA, vd Kleij AJ, Schneider CJ, Sminia P: Is hyperbaric oxygen more effective than carbigen/nicotinamide in tumour radiation response? Rad Res 1997;148:523-524

 

Johnson R, Philips TL, Wassermann TH, Gomer CJ, Lawrence GA, Levine ML, Sadee W, Pentra JS, Rubin DJ: The hypoxic cell sensetizer program in the United States. Br J Cancer 1978;37:276

 

Kohshi K, Kinoshita Y, Imada H, Kunugita N, Abe H, Terashima, Tokui N, Uemura S: Effects of radiotherapy after hyperbaric oxygenation on maligant gliomas. Br J Cancer 1999;80:236-241

 

Nordmarks M, Overgaard M, Overgaard J: Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of head and neck. Radiother Oncol 1996;41:31-39

 

Overgaard J, Horsman MR: Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and senzitisers. Sem Radiat Oncol 1996;6:10-21

 

Patient report protocol 01 (this space for study centre only)

 

Centre code                          Patient code                               Date