Writing
committee:
1. PD Dr. K.A.
Hartmann, PD Dr. U.M. Carl, Dr. S. Lentrodt, Prof. Dr. G. Schmitt
2. Dr. K.A.
Becker, Prof.Dr. J. Dunst
1. Dept. Radiation Oncology, University
Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany, Tel: 0211-811-7990, FAX:
0211-811-8051
2.
Dept.
Radiation Oncology, Martin-Luther-University, Dryanderstr. 4-7, 061110 Halle,
Germany, Tel.: 0345-5774319, FAX: -557-4333
This protocol has been
adopted by the Working Group Oncology of COST action B14.
“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 consitent with best
practice in the field of Hyperbaric Medicine”
COST B14 Working Group Oncology:
DENMARK JANSEN
Erik C
POLAND SICKO
Zdzislaw
PORTUGAL
SIMAO
Antonio
SWEDEN GRANSTRÖM
Gösta
SWITZERLAND SCHMUTZ
Jorg
SMINIA Peter
UNITED
KINGDOM HAMILTON-FARRELL
Martin H
It is
generally accepted that hypoxic clonogenic tumour cells are an important factor
of radioresistance. The assumption that hypoxic clonogenic tumours cells are an
important factor of radioresitance in solid human tumours is based on oxygen
measurements and clinical studies with various hypoxic modifiers. There is
clear evidence that the oxygenation status as evaluated by computerized
polarographic needle measurements is a predictor of radiation-tumour response
in cancer of the head and neck [i]
[ii]
[iii]
uterine cervix[iv] and other
tumour sites [v]. It was
shown that hyperbaric oxygenation improves the oxygenation status both in
experimental tumours [vi]
[vii]
[viii]
and human tumours in situ [ix].
Further
evidence comes from a meta-analysis published by Overgaard and Horsman which
comprises 83 randomized clinical studies with various hypoxic modifiers such as
chemical radiosensitizers, hyperbaric oxygen, normobaric carbogen breathing,
artificial oxygen carriers and blood transfusions. The most widely used
treatment modality were chemical sensitizers (52 trials) followed by hyperbaric
oxygen (28 trials). The modification of tumour hypoxia improved local tumour
control and overall survival by 4.7% and 2.7%, respectively (p=0.00004 and
0.004). The largest benefit was demonstrated for tumours of the head and neck
region. When the chemical sensitizer and hyperbaric oxygen trials were
separately analyzed HBO was still significantly superior to treatment under
normobaric air breathing conditions. One of the conclusions from this
meta-analysis was that hyperbaric oxygen might have been given up prematurely.
Due to the positive meta-analysis HBO has regained interest both by preclinical
and clinical investigators[x][xi].
One center in the U.S. with a profound expertise in hyperbaric oxygenation is
preparing remote afterloading treatments in combination with HBO[xii]
[xiii].
Recurrent head
and neck tumours after radio-(chemotherapy)-therapy pose a therapeutic problem.
When the recurrent tumour is unresectable the prognosis for this group is
patients is very poor. Depending on the performance status, the preceding
radiation dose, tumour localisation and tumour extent, treatment options are
“best supportive care” or re-irradiation in combination with chemotherapy
and/or hyperthermia. At the present time no standard treatment exists for this
group of patients. Polarographic oxygen measurements in SCCHN have demonstrated
that oxygen tension is one predictive factor for the outcome of
radio-(chemotherapy)-therapy and it can therefore be assumed that recurrencies
represent the “hypoxic variants”. For that reason this subgroup was chosen for
the modulation of tumour hypoxia with hyperbaric oxygen.
The objective
of this study is to evaluate whether HBO enhances tumour radiosensitivity in
recurrent previously irradiated head and neck cancers using a conventionally
fractionated treatment schedule.
The following
criteria must be fulfilled:
1. Histologically
proven recurrent SCC of the head and neck region
2. Age
> 18 years
3. Preceding
radiotherapy > 6 months
4. Unresectable
disease
5. WHO-index
<3
6. No
distant metastases
The following
criteria exclude a patient from the study:
1. Severe
complication from the first course of radiotherapy (e.g. osteoradionecrosis)
2. Contraindications
for hyperbaric oxygenation (see appendix)
3. Serious
medical risk factors involving any of the major organ systems may prevent
adherence to the treatment schedule
This
investigation is intended as phase I/II trial. After 20 patients it will be
decided whether it is worthwhile to run a randomized study.
NMR/CT of the
head and neck
Clinical
examination by a head and neck surgeon
Clinical
examination by a specialist in hyperbaric medicine
Blood count
and blood chemistry
At this very
early stage no randomisation procedure is intended.
Radiation
treatment planning
Treatment
planning is based on NMR and/or CT-scans. Treatment portals encompass the
primary recurrrent tumour and nodal disease with a safety margin of 1-2cm. The
guideline is to reduce the volume of normal tissues to a minimum. This can be
achieved by conformal radiotherapy techniques, 3D-treatment planning and the
application of brachytherapy for a part of the treatment. Maximum doses to
critical organs such as spinal cord and lens is based on individual decisions
weighing the risk of local tumour growth against the risk of radiation damage.
To estimate the risk of late normal tissue damage the LQ model is used.
Radiobiologic investigations revealed that there is long term recovery from
radiotherapy with an increased re-treatment tolerance in some tissues [xiv].
This is especially true for the spinal cord [xv].
It seems therefore to be justified to re-irradiate the spinal cord above 50Gy
when this is urgently needed.
Safety guidelines according hyperbaric medicine practice have to be fulfilled. The number of HBO sessions is dependent on patients tolerance and acute normal tissue reactions. The aim is to give HBO with each radiation fraction.
The total dose
of re-irradiation is determined by the preceding radiation schedule. It is
common practice to go up to cumulative doses of approximately 100-120Gy with
fraction doses in the range of 1.8-2.0Gy. The intention is to keep to this
schedule and add hyperbaric oxygen. Assuming an oxygen-enhancement ratio of
1.5, re-treatment doses of 40-50Gy are likely to be curative. The pilot study is
performed with conventionally fractionated radiotherapy with fraction sizes of
1.8-2.0Gy given five times per week.
All
irradiation fractions should be preceeded by HBO treatment, 2.5 ATA (2.4-2.6)
for 60 minutes without air breaks. Each irradiation fraction must be given
within 10-20 minutes after HBO treatment. At least 80% of the irradiations
should be preceeded by HBO.
Hemoglobin
concentration
The hemoglobin
concentration should be > 10 mg/dl during the whole course of treatment.
If Hb
<10mg/dl, patients receive blood transfusions or recombinant human
erythropoietin.
No blinding
Primary
endpoint: progression-free interval
Secondary
endpoints: overall survival, feasibility, acute and late toxicity
Transcutaneous
oxygen measurements will be done to confirm hyperoxygenation.
The hyperbaric
unit must be close enough to the radiation facilities to allow irradiation
within 10-20 minutes after hyperbaric oxygen treatment.
[i] Brizel, DM, Sibley, GS, Prosnitz, LR,
Scher, RL, Dewhirst, MW. Tumor hypoxia adversely affects the prognosis of
carcinoma of the head and neck (1997)
Int. J. Radiat. Oncol. Biol. Phys. 38,
285-289.
[ii] Gatenby, RA, Kessler, HB, Rosenblum,
JS, Coia, LR, Moldofsky, PJ, Hartz, WH, Broder, GJ (1988) Oxygen distribution
in squamous cell carcinoma metastases an its relationship to outcome of
radiation therapy. Int. J. Radiat. Oncol.
Biol. Phys. 14, 831-838.
[iii] Nordsmark, M. Overgaard, M, Overgaard,
J (1996) Pretreatment oxygenation predicts radiation response in advanced
squamous cell carcinoma of the head and neck. Radiother. Oncol. 41,
31-39.
[iv] Höckel, M, Schlenger, K, Mitze, M, Schäffer,
U, Vaupel, P (1996) Hypoxia and radiation response in human tumors. Sem. Radiat. Oncol. 6, 3-9.
[v] Brizel, DM, Scully, SP, Harrelson, JM,
Layfield, LJ, Dodge, RK, Charles, HC, Samulski, TV, Prosnitz, LR, Dewhirst, MW
(1996) Radiation therapy and hyperthermia improve the oxygenation of human soft
tissue sarcomas. Cancer Res. 56, 5347-5350.
[vi] Mueller-Klieser, W, Vaupel, P. Manz, R
(1983) Tumour oxygenation under normobaric and hyperbaric conditions. Br. J. Radiol. 56, 559-564.
[vii] D.M. Brizel, S. Lin, J.L. Johnson, J.
Brooks, M.W. Dewhirst C.A. Piantadosi. The mechanisms by which hyperbaric
oxygen and carbogen improve tumor oxygenation. Br. J. Cancer 72,
(1995), 1120-1124.
[viii] Thews, O, Kelleher, DK, Vaupel, P.
(1996) Hyperbaric oxygenation of experimental tumors. Strahlenther. Onkol. 172,
Suppl. II, 24-25.
[ix] Jamieson, D, Van den Brenk, HAS (1964)
Oxygen tension in human malignant disease under hyperbaric conditions. Br. J. Cancer 19, 139-150.
[x] Brizel, DM, Hage, WD, Dodge, RK,
Munley, MT, Piantadosi, CA, Dewhirst, MK. (1997a) Hyperbaric oxygen improves
tumor radiation response significantly more than carbogen/nicotinamide. Radiat. Res. 147, 715-720.
[xi] Brizel, DM, Lin, S, Johnson, JL,
Brooks, J, Dewhirst, MW, Piantadosi, CA (1995). The mechanisms by which
hyperbaric oxygen and carbogen improve tumor oxygenation. Br. J. Cancer 72,
1120-1124.
[xii] Feldmeier, JJ, Alecu, R, Court, WS,
Davolt, DA, Porter, AT (1996) Does high dose brachytherapy offer us the
opportunity to revisit hyperbaric oxygen radiation sensitization? Radiother. Oncol. 40, Suppl. 1, 534.
[xiii] Feldmeier, JJ, Alecu, R, Court, WS,
Onada, JM, Davolt, DA (1997) Should we re-explore the issue of hyperbaric
oxygen radiosensitization in the setting of high dose rate brachytherapy? Strahlenther. Onkol. 173, P108.
[xiv] Stewart, FA (1997) Re-treatment
tolerance of normal tissues. In Steel, GG (ed) Basic clinic radiobiology,
Edward Arnold London, pp 203-211.
[xv] Ang, KK, Price, RE, Stephens, LC et
al. (1993) The tolerance of primate spinal cord to re-irradiation. Int. J. Radiat. Oncol. Biol. Phys. 25, 459-464.
E : Toxizitäts score
Toxizitäten
nach NCI
|
|
0 |
1 |
2 |
3 |
4 |
|
Allergien |
|||||
|
Allergien |
keine |
vorübergehender Ausschlag, Fieber < 38° C |
Urtikaria, Fieber ³ 38° C, leichter Bronchospasmus |
Serumkrankheit, Bronchospasmus, parenterale Medikation erforderlich |
Anaphylaxie |
|
Andere |
keine Symptome |
geringe Symptome |
mäßige Symptome |
schwere Symptome |
lebensbedrohliche Symptome |
|
Blut/Knochenmark |
|||||
|
Leukozyten (109/L) |
³ 4x109/L |
3,0-3,9 x 109/L |
2,0-2,9 x 109/L |
1,0-1,9 x 109/L |
< 1,0 x 109/L |
|
Thrombozyten (109/L) |
Normal (> 100,0x109/L) |
75,0-100,0 x 109/L |
50,0-74,9 x 109/L |
25,0-49,9 x 109/L |
< 25,0 x 109/L |
|
Hämoglobin (g/L) |
Normal (> 110 g/L) |
100-110 g/L |
80-99 g/L |
65-79 g/L |
< 65 g/L |
|
Granulozyten (109/L) |
³ 2x109/L |
1,5-1,9 x 109/L |
1,0-1,4 x 109/L |
0,5-0,9 x 109/L |
< 0,5 x 109/L |
|
Lymphozyten (109/L) |
³ 2,0 109/L |
1,5-1,9 109/L |
1,0-1,4 109/L |
0,5-0,9 109/L |
< 0,5 109/L |
|
Hämorrhagie (aufgrund von Thrombozytopenie) |
keine Hämorrhagie |
leichte Hämorrhagie, keine Transfusion (inkl. Quetschung, Hämatom, Petechien) |
starke Hämorrhagie, 1-2 Transfusionsein-heiten pro Vorfall |
starke Hämorrhagie, 3-4 Transfusionsein-heiten pro Vorfall |
massive Hämorrhagie, > 4 Transfusionseinheiten pro Vorfall |
|
Andere |
keine Symptome |
geringe Symptome |
mäßige Symptome |
schwere Symptome |
lebensbedrohliche Symptome |
|
Krebs-assoziierte Symptome |
|||||
|
Schmerzen aufgrund | |||||