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:

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

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:



“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

GRANSTRΦM Gφsta                                      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          




Informed consent


Role of hyperbaric oxygen in enhancing radiosensitivity on glioblastoma multiforme


Dear patient,


you may wish to participate in a study which is being conducted to evaluate if hyperbaric oxygen delivered before conventional radiotherapy affects the outcome.


Oxygen has in experimental studies been shown to enhance radiotherapy efficiency.


If you accept to participate in the study, you will be selected to participate either in a group of patients who will be given hyperbaric oxygen therapy before radiotherapy or in a group of patients will have no special treatment before each irradiation.


Hyperbaric oxygen treatment will mean 30 treatments in a chamber compressed with air. Each treatment takes approximately two hours and will be conducted at the hyperbaric chamber nearest to where you live.


If you accept to participate, and if you are selected for hyperbaric oxygen treatment, you will called to the hyperbaric chamber for practical information of how the treatment will be conducted, and an individual treatment plan for you will be put forward.


Participation in the study is voluntary and can be stopped whenever you wish without giving any reason.



I have read the above information, understood the content and accept to participate in the study.










01.08 Short-Form-36 (SF-36) Health Survey



The Short-Form-36 (SF-36) Health Survey was developed by Dr John Ware and was derived from the Rand Corporation's Medical Outcomes Study (MOS). It is used as a general survey of health status and an outcome measure in clinical practice. It can also be used together with disease-specific instruments for patient evaluation. The survey may be self-administered or may be completed by an interviewer.


Instructions for self-administration

This survey asks for your views about your health. This information will help keep track of how you feel and how well you are able to do your usual activities. Answer every question by marking the answer as indicated. If you are unsure about how to answer a question, please give the best answer you can.


1. In general would you say your health is:

   • excellent [1]

   • very good [2]

   • good [3]

   • fair [4]

   • poor [5]


2. Compared to one year ago, how would you rate your health in general now?

   • much better now than one year ago [1]

   • somewhat better now than one year ago [2]

   • about the same now as one year ago [3]

   • somewhat worse now than one year ago [4]

   • much worse now than one year ago [5]


3. The following items are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how


   a. Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports.

   b. Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf.

   c. Lifting or carrying groceries.

   d. Climbing several flights of stairs.

   e. Climbing one flight of stairs.

   f. Bending, kneeling, or stooping.

   g. Walking more than one mile.

   h. Walking several blocks.

   i. Bathing or dressing yourself.



   • Yes, limited a lot [1]

   • Yes, limited a little [2]

   • No, not limited at all [3]


4. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of your  physical health?

   a. Cut down on the amount of time you spent on work or other activities.

   b. Accomplished less than you would like.

   c. Were limited in the kind of work or other activities.

   d. Had difficulty performing the work or other activities (for example, it took extra effort).



   • Yes [1]

   • No [2]


5. During the past 4 weeks, have you had any of the following problems with your work or other regular activities as a result of any emotional problems (such as feeling depressed or anxious)?


   a. Cut down on the amount of time you spent on work or other activities.

   b. Accomplished less than you would like.

   c. Didn't do work or other activities as carefully as usual.



   • Yes [1]

   • No [2]


6. During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your normal social activities with family, friends, neighbours, or groups?

   • not at all [1]

   • slightly [2]

   • moderately [3]

   • quite a bit [4]

   • extremely [5]


7. How much bodily pain have you had during the past 4 weeks?

   • none [1]

   • very mild [2]

   • mild [3]

   • moderate [4]

   • severe [5]

   • very severe [6]


8. During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)?

   • not at all [1]

   • a little bit [2]

   • moderately [3]

   • quite a bit [4]

   • extremely [5]


9. These questions are about how you feel and how things have been with you during the past 4 weeks. For each question, please give the one answer that comes closest to the way you have been feeling. How much of the time during the past 4 weeks:

   a. Did you feel full of pep?

   b. Have you been a very nervous person?

   c. Have you felt so down in the dumps that nothing could cheer you up?

   d. Have you felt calm and peaceful?

   e. Did you have a lot of energy?

   f. Have you felt downhearted and blue?

   g. Did you feel worn out?

   h. Have you been a happy person?

   i. Did you feel tired?



   • all of the time [1]

   • most of the time [2]

   • a good bit of the time [3]

   • some of the time [4]

   • a little of the time [5]

   • none of the time [6]


10. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting with friends, relatives, etc.)?

   • all of the time [1]

   • most of the time [2]

   • some of the time [3]

   • a little of the time [4]

   • none of the time [5]


11. How TRUE or FALSE is each of the following statements for you?

   a. I seem to get sick a little easier than other people.

   b. I am as healthy as anybody I know.

   c. I expect my health to get worse.

   d. My health is excellent.



   • definitely true [1]

   • mostly true [2]

   • don't know [3]

   • mostly false [4]

   • definitely false [5]




Responses to 35 of the questions are divided into 8 "dimensions", while the response to question 2 indicates the change in health over the past year. A more favorable response is assigned a higher score.



           Dimensions                           No                   Items


Physical functioning             10                   3a, 3b, 3c, 3d, 3e, 3f, 3g ,3h, 3i, 3j


Role limitations                    4                  4a, 4b, 4c, 4d


Bodily pain                           2                  7, 8


Social functioning                2                  6, 10


General mental health         5                  9b, 9c, 9d, 9f, 9h


Role limitations due to

emotional problems             3                   5a, 5b, 5c


Vitality, energy or fatigue     4                   9a, 9e, 9g, 9i


General health perceptions  5                  1, 11a, 11b, 11c, 11d


Rand approach to scoring

• each response to a question converted to a 0-100 value, with a higher score indicating a more favorable state

• the responses in each dimension are averaged to generate a response from 0 to 100

• 3 response scale: 0, 50, 100

• 5 response scale: 0, 25, 50, 75, 100

• 6 response scale: 0, 20, 40, 60, 80, 100

• if a question is not answered, then it is ignored

Recommended scoring

• described in the SF-36 manual

• somewhat complex

• computer-based scoring available from Response Technologies, Inc (see below)


                                                   Supplemental Information


Variant forms available

• acute version referenced to the past week

• knee replacement version


Addresses for additional information

(1) printed forms: The Medical Outcomes Trust, PO Box 1917, Boston, MA. 02205

(2) technical information: SF-36 Health Survey, The Health Institute, New England Medical Center Hospitals, Box 345, 750 Washington Street, Boston, MA, 02111

(3) computerized scoring system: Response Technologies, Inc., 3399 South County Trail, East Greenwich, RI, 02818



Lanksy D, Butler JBV, Waller FT. Using health status measures in the hospital setting. 1992; 30: MS57-MS73.

McDowell I, Newell C. Measuring Health - A Guide to Rating Scales and Questionnaires, Second Edition. Oxford Press. 1996. pages


Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). Medical Care. 1992; 30: 473-483.


Patients report protocol                Instiution:                               date:

Please tick:   before O                    during O                     after O            radiotherapy



first name






HBO fitness:

yes O , no O                      date of examination:

operation status:

R1 O             R2 O             biopsy only O


O HBO+radiation              O radiation allone

Karnofsky status


neurological status


laboratory investigation

yes O             non O                      date:

medication (dose)




additive remarks:







no O; before O, after O overall treatment

second operation:

histology:                      date:              resection status:





breaking off:


after therapy:

total number of HBO sessions:







Radiotherapy evaluation protocol                Instiution:                   date:


To be filled out by clinician after overall treatment

1)     Personal data

Name:                                               First name:                            birth:                                      

Tumour localisation:                                                              

2)     Radiation treatment

Start of radiotherapy:                                  End of radiotherapy:                                   

Dose per faction:                             Total dose:                total number of fraction:      

Tumour:                                             Gy                               Gy                               Gy

Radiotherapy break or break off :              (yes =1, no=2)


Clinical target volume (gross tumour volume + 2.0 cm margin):           (yes=1, no=2)

Linear accelerator (energy):                       MV                              Co-60                        

Clinical target volume             cm3

CT-planning:              number of field          technique:                  field shaping:           


Taget volume dose/ICRU reference doset:                                             Gy

Dose maximum:                   % ; Minimum:            %

Dose to organs at risk:

Brain steam:              Gy, Chiasma opticum:         Gy, Eye lens ri:                     le:       


Radiotherapy evaluation protocol           page 2

Name:                                               First name:                            birth:                          


3)     Acute treatment toxicity (highest acute reaktion, CTC modification):


Headache:                 (0 no, 1 minimal, 2 intermittent, 3 intense)

Nausea:                     (0 no, 1 minimal, 2 persistent)

Seizures:                               (0 no, 1 oral medication controlled, 2 i.v. medication)


Skin:               (0 no reaktion, 1 mild erythema, 2 marked erythema, 3 ulcer)


Other treatment toxicity :                                                                                       



Clinician :                                          signature:                                          date:              

HBO evaluation protocol

Name:                                               First name:                            birth:                          



Treatment number

and date

HBO time (from -to)   duration      ATA HBO    T C Oxygen         beginn radiotherapy





























































Patients sometimes report that they have the following symptoms. Please indicate the extent
to which you have experienced these symptoms or problems during the past week.



During the past week:                                                           Not at          A        Quite      Very

                                                                                                           All          Little      a Bit     Much


31.     Did you feel uncertain about the future?                                        1               2             3            4


32.     Did you feel you had setbacks in your condition?                            1               2             3            4


33.     Were you concerned about disruption of family life?                       1               2             3            4


34.     Did you have headaches?                                                             1               2             3            4


35.     Did your outlook on the future worsen?                                         1               2             3            4


36.     Did you have double vision?                                                          1               2             3            4


37.     Was your vision blurred?                                                              1               2             3            4


38.     Did you have difficulty reading because of your vision?                  1               2             3            4


39.     Did you have seizures?                                                                 1               2             3            4


40.     Did you have weakness on one side of your body?                         1               2             3            4


41.     Did you have trouble finding the right words to

          express yourself?                                                                         1               2             3            4


42.     Did you have difficulty speaking?                                                  1               2             3            4


43.     Did you have trouble communicating your thoughts?                       1               2             3            4


44.     Did you feel drowsy during the daytime?                                       1               2             3            4


45.     Did you have trouble with your coordination?                                 1               2             3            4


46.     Did hair loss bother you?                                                              1               2             3            4


47.     Did itching of your skin bother you?                                              1               2             3            4


48.     Did you have weakness of both legs?                                            1               2             3            4


49.     Did you feel unsteady on your feet?                                              1               2             3            4


50.     Did you have trouble controlling your bladder?                               1               2             3            4




© Copyright 1994 EORTC Study Group on Quality of Life.   (phase III module)