Conference
Preview: Joint Cancer Conference 2000
Clinical
Research
Role of Carbogen in the Treatment of Head and Neck Cancer
Dietmar
W. Siemann, PhD, and William M. Mendenhall, MD
From the Department of Radiation Oncology,
University of Florida Shands Cancer Center College of Medicine,
Gainesville, Fla.
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Because
of rapid and uncontrolled neoplastic cell proliferation, solid tumor masses
typically exhibit abnormal blood vessel networks that fail to provide
adequate and homogeneous nutritional support to the tumor cells. Such
spatial and temporal heterogeneity of the microcirculation within a tumor
can result in an expansion of intercapillary space and a decrease in vessel
density. These factors may consequently lead to increased oxygen-diffusion
distances and oxygen-deficient or hypoxic regions in tumors. Areas of
low oxygen tensions (pO2) have been well documented using oxygen
electrodes in both rodent and human tumors. Most critically, pO2
distributions measured in malignancies generally have been found to be
far lower than those in the surrounding normal tissues.1
The
importance of oxygen in modifying radiation response has been appreciated
for more than 90 years. Cells irradiated in the presence of oxygen are
approximately 2.5 to 3 times more sensitive than cells irradiated under
conditions of severe hypoxia. As the level of oxygen increases, the sensitivity
of cells rises rapidly to near maximal levels at a pO2 of approximately
25 mm Hg, well below the value of 40 mm Hg that is typical of venous blood.
Half-maximum sensitization is obtained with pO2 values of approximately
3 to 4 mm Hg. Based on such observations, it was postulated that
one possible cause for failure of radiation therapy was the existence
within tumors of viable hypoxic cells of reduced radiosensitivity.2
Indeed, a growing body of evidence strongly supports the hypothesis that
hypoxic cells influence radiation response in at least some human tumors.
Support for this notion has come primarily from two sources: (1) retrospective
clinical studies in which pathophysiologic parameters were related to
tumor control or patient survival and (2) prospective studies that employed
regimens aimed at targeting hypoxic cells. For example, it has been well
documented that in certain disease sites, patients with anemia do poorer
when treated with radiation, and the outcome for such patients may be
improved by transfusion.3
Improvement
of survival and/ or local control rates in some trials of hypoxic cell
radiation sensitizers and hyperbaric oxygen also is taken as evidence
that radioresistant hypoxic cells in some solid tumors can influence outcome.
Meta-analysis of the randomized, prospective clinical trials of electron-affinic
radiosensitizers has revealed the efficacy of this approach to be more
significant than originally appreciated.4 Finally, several
recent papers have shown excellent correlation between tumor therapy outcome
and the distribution of intratumor oxygen concentration measured with
the Eppendorf oxygen electrode histograph.5 Evidence for a
detrimental role of hypoxia is particularly strong in tumors of the head
and neck.4,5
Since
normal tissues are presumed to be sufficiently well oxygenated to show
maximum radiation sensitivity, numerous strategies are aimed at improving
treatment outcome by increasing tumor oxygenation overcoming radio resistance
and, hence, improving the likelihood of cure. One method being investigated
is high-oxygen-content inhalation (specifically, carbogen: 95% O2
plus 5% CO2) during radiation therapy. Data indicate that carbogen
alone or in combination with nicotinamide may improve the likelihood of
local-regional control.6-9
Beginning
in November 1996, a prospective, randomized trial of carbogen breathing
during hyperfractionated radiation therapy for head and neck cancer was
initiated at the University of Florida. The primary endpoints of the study
were local control and cause-specific survival. Secondary endpoints were
toxicity and indentification of parameters that might predict a benefit
from carbogen breathing.
The
volume of the primary tumor was calculated on pretreatment computed tomography
(CT) or magnetic resonance imaging (MRI) in all patients. Hyperfractioned
radiation therapy was employed because it may improve the likelihood of
tumor control by decreasing overall treatment time, thus offsetting (to
some degree) tumor repopulation during treatment.10 Patients
eligible for the trial had previously untreated T2, T3, and T4 squamous
cell carcinomas of the oropharynx, hypopharynx, and larynx (excluding
T2 glottic larynx). Exclusion criteria included age under 18 years, pregnancy,
nonsquamous histology, distant metastases, resection of the primary cancer
as part of the treatment plan, and inability to tolerate carbogen breathing.
After
signing an informed consent, patients underwent a carbogen breathing test
for 10 minutes. If this was well tolerated, they were stratified according
to site and T stage and were randomized to either radiation therapy alone
or radiation therapy with carbogen breathing. Before beginning treatment,
the patients were asked to fill out a questionnaire pertaining to their
smoking history. Blood was obtained for arterial blood gases before and
after carbogen breathing. Patients underwent CT simulation, and time-dose-volume
data were prospectively calculated to correlate these parameters with
the likelihood of late complications. The radiation therapy treatment
schedule was 1.2 Gy per fraction twice daily, with a minimum 6-hour interfraction
interval, to total doses ranging from 74.4 Gy to 79.2 Gy. The radiation
therapy schedule was identical in both arms with the exception that field
size was reduced to exclude the spinal cord after 40.8 Gy in 34 fractions
in the carbogen arm as opposed to 45.6 Gy in 38 fractions in the radiation
therapy alone arm. Carbogen breathing was administered 6 to 8 minutes
before and during each treatment to those patients receiving carbogen.
Early in the study, patients who received induction adjuvant chemotherapy
as a means of treatment selection (radiation therapy vs surgery plus postoperative
radiation therapy) were included. After approximately 1 year, it was decided
to limit the trial to patients treated with radiation therapy alone.
Between
November 1996 and August 1999, 55 patients were entered into the trial.
Breathing carbogen increased the median arterial oxygen tensions from
approximately 85 mm Hg to approximately 375 mm Hg. The data on toxicity,
tumor control, and survival were analyzed in January 1999. There was no
difference in any of the end results between the two groups. Specifically,
acute toxicity was comparable. Although there are no obvious differences
in the rates of tumor control and survival, the number of patients treated
is relatively small and the follow-up is short. The trial is ongoing.
References
1. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient
supply, and metabolic microenvironment of human tumors: a review. Cancer
Res. 1989;49: 6449-6465.
2. Thomlinson RH, Gray LH. The histological structure of some human lung
cancers and the possible implications for radiotherapy. Br J Cancer.
1955;9:539-549.
3. Bush RS, Jenkins RD, Allt WE, et al. Definitive evidence of hypoxic
cells influencing cure in cancer therapy. Br J Cancer. 1978;37:302-306.
4. Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance
in tumors by the use of oxygen and radiosensitizers. Semin Radiat Oncol.
1996;6:10-21.
5. Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts
radiation response in advanced squamous cell carcinoma of the head and
neck. Radiother Oncol. 1996;41:31-39.
6. Kaanders JH, Pop LA, Marres HA, et al. Accelerated radiotherapy with
carbogen and nicotinamide (ARCON) for laryngeal cancer. Radiother Oncol.
1998;48:115-122.
7. Siemann DW. The tumor microenvironment: a double-edged sword. Int
J Radiat Oncol Biol Phys. 1998;42:697-699.
8. Stuben G, Stuschke M, Knuhmann K, et al. The effect of combined nicotinamide
and carbogen treatments in human tumour xenographs: oxygenation and tumour
control studies. Radiother Oncol. 1998;48:143-148.
9. Powell ME, Collingridge DR, Saunders MI, et al. Improvement in human
tumour oxygenation with carbogen of varying carbon dioxide concentrations.
Radiother Oncol. 1999;50:167-171.
10. Mendenhall WM, Parsons JT. Altered fractionation in radiation therapy
for squamous-cell carcinoma of the head and neck. Cancer Invest.
1998;16:594-603.
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