Is Hyperbaric Oxygen More Effective than Carbogen/Nicotinamide in Tumor Radiation Response?

Abstract

radiosensitizers. They demonstrated tumor growth delay to be significantly longer after irradiation combined with hyperbaric oxygen ? nicotinamide than in combination with carbogen + nicotinamide. In the last decades, different methods to overcome tumor hypoxia have been used in the clinic. A meta-analysis (2) demonstrated the efficacy of hyperbaric oxygen in improving local tumor control and overall survival. Both physiological and radiobiological aspects of hyperbaric oxygen were discussed recently (3). One of the conclusions of the workshop was that more experimental data, particularly the comparison of hyperbaric oxygen with other treatment modalities, are warranted. At our institution we are engaged in both experimental (4) and clinical studies (5) with hyperbaric oxygen. We would therefore like to make some remarks. First, we want to discuss the authors' conclusion that hyperbaric oxygen is a more effective radiosensitizer than carbogen, since this is based on data for tumor growth delay after irradiation with large single-dose fractions. In their experiments, tumor vasculature might be damaged by the polarographic pO02 needle as well as by the thermocouple probe insertions, and animals were under anesthesia while being irradiated. Suit et al. (6) demonstrated in a TCD,0 study with hyperbaric oxygen an increase in the oxygen enhancement ratio (OER) from 1.25 without to 2.01 with pentobarbital anesthesia. Measurements of hemodynamic parameters in a previous study do not rule out the possibility that tumor oxygenation and tumor response are influenced by the use of pentobarbital in their model (7). Furthermore, the apparent inefficiency of carbogen for radiosensitizing the R3230Ac carcinoma has to be considered, since in most experimental studies, carbogen breathing alone did result in an increased tumor response (for overview see ref. 8). Randomized clinical trials with adequate preirradiation breathing times and sufficient numbers of patients are lacking. However, a few phase II studies indicate favorable results with carbogen breathing alone (9). The authors suggest that hyperbaric oxygen may improve the radiation response by additional mechanisms of cell killing. Indeed, exposure to hyperbaric oxygen alone was found to increase DNA damage in human leukocytes (10). Interestingly, DNA damage was evident after the first treatment but not after repeated exposures. To our knowledge there are no such data for tumor tissue. It is questionable, however, whether the supposed additional cell-killing effect can be extrapolated to multifraction experiments. Recently, a local control assay was performed with unanesthetized Wag/Rij rats at our institution.' R1H rhabdomyosarcomas transplanted in the flank were irradiated with 30 fractions of 2 Gy of X rays for an overall treatment time of 41 days. Ten animals per group were assigned randomly to treatment in air, normobaric carbogen or high-pressure oxygen (240 kPa). One animal treated in air, two treated in hyperbaric oxygen and four treated in carbogen developed lung metastases (log rank test P = 0.3). Carbogen and hyperbaric oxygen yielded the same local control probability. The local control for both groups was significantly higher compared to the air-breathing control group (Table I). Model calculations presented by Wouters and Brown in this journal (11) showed that tumor response in fractionated studies is highly dependent upon the cells at oxygen levels intermediate (oxygen partial pressure from 0.5 to 20 mm Hg) between the radiobiologically hypoxic and welloxygenated fractions. Figure 2 of their article shows the hypothetical tumor cell survival after single-dose irradiation of a well-oxygenated tumor and of a tumor in which a hypoxic fraction of 20% was assumed. At high doses (>10 Gy),