Published data for this review were identified by a search of PubMed with the search terms “ARCON”, “carbogen and radiotherapy”, “nicotinamide and radiotherapy”, and “accelerated radiotherapy”. References from relevant articles were also included. Additional papers were identified from the personal collections of the authors.
ReviewARCON: a novel biology-based approach in radiotherapy
Section snippets
Tumour-cell repopulation and accelerated radiotherapy
The probability of local tumour control decreases as the overall treatment time of radiotherapy increases without a change in the radiation dose, particularly in squamous-cell carcinomas.2, 3 This relation is explained by an increase in the net production of clonogenic tumour cells during radiotherapy. Although during a course of radiotherapy the number of tumour cells with clonogenic potential is greatly reduced, cells that survive are triggered to repopulate more effectively.3 Reducing the
Tumour oxygenation
Tumour-cell hypoxia is another well-recognised cause of resistance to radiation. Oxygen mediates the biological effects of ionising radiation, and the response of cells to radiation depends strongly on the availability of oxygen. The importance of the “oxygen effect” in radiotherapy was recognised by Mottram7 in 1936 and later studied in greater detail in mammalian tissues by Gray and colleagues.8 Typically, hypoxic cells are 2·5–3·0 times more radioresistant than well-oxygenated cells. In
Carbogen
Currently, raising arterial partial pressure of oxygen (pO2) by inhalation of hyperoxic gases is the most effective way to decrease diffusion-limited hypoxia. Carbogen is effective in a large number of tumour models and in patients as shown by use of various different measures of tissue oxygenation12, 13, 14, 15, 16, 17, 18, 19 Most studies found a significant decrease in hypoxia irrespective of the tumour type or method used. However, a few studies found no effect or even a worsening of the
Nicotinamide
Nicotinamide is the amide derivative of vitamin B3 and has been extensively studied for its radiosensitising properties.27, 28, 29 The mechanism of action originally proposed was the inhibition of repair of radiation-induced DNA damage.30 Nicotinamide inhibits the chromatin-bound enzyme adenosine diphosphoribosyl transferase, which is known to participate in DNA-excision repair after exposure of cells to radiation. Later, evidence was found that this mechanism could not fully explain the
Preclinical studies
Rojas and colleagues studied the effects of the individual components of ARCON alone and in combination in the mouse mammary tumour CaNT.2 They observed an enhancement ratio of 1·19 for accelerated radiotherapy compared with conventional radiotherapy. Thus, for a 50% tumour control rate with the accelerated schedule, a 1·19 times lower radiation dose than that of conventional radiotherapy was needed. When carbogen was added to the accelerated schedule, an enhancement ratio of 1·71 was seen
ARCON clinical studies
In the early 1990s, phase 1 and 2 trials of ARCON were initiated on the basis of evidence from clinically relevant experiments, which showed effective radiosensitisation in murine tumours. During this time, clinical evidence was accumulating that accelerated fractionation could improve tumour control which has since been confirmed by several randomised trials.1, 5 The principle that inhalation of hyperoxic gas can counteract hypoxic radioresistance was established 25 years ago by randomised
Selection of patients
So far, selection of patients for studies of ARCON has been mainly based on clinical and histopathological tumour characteristics and by identification of tumour categories in which repopulation and hypoxia were thought to be major causes of radiation resistance. There is, however, much heterogeneity in biological characteristics between tumours of a same site and histology. A more sophisticated approach would be to select candidates individually by assessment of the proliferative activity and
Conclusion
In this review we have described the development of ARCON from hypothesis to animal experiments leading to phase 1 and 2 clinical trials and current phase 3 trials. This is an excellent example of how translational research should work. This novel biology-based approach exploits known mechanisms of radiation resistance and uses previous clinical experience to refine the treatment strategy. Phase 1 and 2 trials have shown the feasibility and tolerability of ARCON in several tumour types. Phase 2
Search strategy and selection criteria
References (75)
- et al.
Carbogen and nicotinamide as radiosensitizers in a murine mammary carcinoma using conventional and accelerated radiotherapy
Int J Radiat Oncol Biol Phys
(1996) - et al.
Repopulation of FaDu human squamous cell carcinoma during fractionated radiotherapy correlates with reoxygenation
Int J Radiat Oncol Biol Phys
(2001) - et al.
Altered fractionation: limited by mucosal reactions?
Radiother Oncol
(1999) - et al.
Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial
Lancet
(1997) - et al.
The importance of the pre-irradiation breathing times of O and carbogen (5% CO2: 95% O2) on the in vivo radiation response of a murine sarcoma
Int J Radiat Oncol Biol Phys
(1977) - et al.
Dynamics of tumor oxygenation and red blood cell flux in response to inspiratory hyperoxia combined with different levels of inspiratory hypercapnia
Radiother Oncol
(2002) - et al.
Changes in tumor hypoxia measured with a double hypoxic marker technique
Int J Radiat Oncol Biol Phys
(2000) - et al.
Effects of nicotinamide and carbogen on oxygenation in human tumor xenografts measured with luminescence-based fiber optic probes
Radiother Oncol
(2000) - et al.
Tumour radiosensitization by high-oxygen-content gases: influence of the carbon dioxide content of the inspired gas on pO2, microcirculatory function and radiosensitivity
Int J Radiat Oncol Biol Phys
(1998) - et al.
Effects of carbogen breathing on oxygenation and vascularity of head and neck tumors as measured by MRI
Int J Radiat Oncol Biol Phys
(2002)