Elsevier

The Lancet Oncology

Volume 3, Issue 12, December 2002, Pages 728-737
The Lancet Oncology

Review
ARCON: a novel biology-based approach in radiotherapy

https://doi.org/10.1016/S1470-2045(02)00929-4Get rights and content

Summary

Two mechanisms of radiotherapy resistance which are of major importance in various tumour types are tumour-cell repopulation and hypoxia. ARCON (accelerated radiotherapy with carbogen and nicotinamide) is a new therapeutic strategy that combines radiation treatment modifications, with the aim of counteracting these resistance mechanisms. To limit clonogenic repopulation during therapy, the overall duration of the radiotherapy is reduced, generally by delivering several fractions per day. This accelerated radiotherapy is combined with inhalation of hyperoxic gas to decrease diffusion-limited hypoxia, and nicotinamide, a vasoactive agent, to decrease perfusion-limited hypoxia. Preclinical studies have been done to test the enhancing effects of these three components of ARCON, individually and in combination, in several experimentally induced tumours and normal tissues. In a mouse mammary carcinoma, the tumour-control rate obtained with ARCON was the same as that with conventional treatment, but with a radiation dose almost 50% lower. Phase 1 and 2 clinical trials have shown the feasibility and tolerability of ARCON, and have produced promising results in terms of tumour control. In particular in cancers of the head and neck and bladder, the local tumour-control rates are higher than in other studies, and phase 3 trials for these tumour types are underway. In conjunction with these trials, hypoxia markers detectable by immunohistochemistry are being tested for their potential use in predictive assays to select patients for ARCON and other hypoxia-modifying therapies.

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

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.

References (75)

  • MEB Powell et al.

    Improvement in human tumour oxygenation with carbogen of varying carbon dioxide concentrations

    Radiother Oncol

    (1999)
  • C Aquino-Parsons et al.

    Oxygen tension in primary gynaecological tumours: the influence of carbon dioxide concentration

    Radiother Oncol

    (2000)
  • JHAM Kaanders et al.

    Radiotherapy with carbogen breathing and nicotinamide in head and neck cancer: feasibility and toxicity

    Radiother Oncol

    (1995)
  • JHAM Kaanders et al.

    Accelerated radiotherapy with carbogen and nicotinamide (ARCON) for laryngeal cancer

    Radiother Oncol

    (1998)
  • PJ Hoskin et al.

    Inspired and expired gas concentrations in man during carbogen breathing

    Radiother Oncol

    (1999)
  • JHAM Kaanders et al.

    ARCON: experience in 215 patients with advanced head-and-neck cancer

    Int J Radiat Oncol Biol Phys

    (2002)
  • DK Kelleher et al.

    Nicotinamide exerts different acute effects on microcirculatory function and tissue oxygenation in rat tumors

    Int J Radiat Oncol Biol Phys

    (1993)
  • DJ Honess et al.

    Effects of the radiosensitising agent nicotinamide on relative tissue perfusion and kidney function in C3H mice

    Radiother Oncol

    (1993)
  • DK Kelleher et al.

    Possible mechanisms involved in tumor radiosensitization following nicotinamide administration

    Radiother Oncol

    (1994)
  • MR Horsman et al.

    Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy

    Radiother Oncol

    (1993)
  • JHAM Kaanders et al.

    Administration of nicotinamide during a five to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance

    Radiother Oncol

    (1997)
  • PJ Hoskin et al.

    Administration of nicotinamide during CHART: pharmacokinetics, dose escalation, and clinical toxicity

    Int J Radiat Oncol Biol Phys

    (1995)
  • J Bussink et al.

    Pharmacology and toxicity of nicotinamide combined with domperidone during fractionated radiotherapy

    Radiother Oncol

    (2002)
  • MW Ruddock et al.

    The effect of nicotinamide on spontaneous and induced activity in smooth and skeletal muscle

    Radiother Oncol

    (2000)
  • MJ Dorie et al.

    Comparison of the enhancement of tumor responses to fractionated irradiation by SR 4233 (tirapazamine) and by nicotinamide with carbogen

    Int J Radiat Oncol Biol Phys

    (1994)
  • JM Simon et al.

    Nicotinamide and carbogen: major effect on the radiosensitivity of EMT6 and HRT18 tumours

    Radiother Oncol

    (1993)
  • E Kjellen et al.

    A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments

    Radiother Oncol

    (1991)
  • MR Horsman et al.

    Nicotinamide as a radiosensitizer in tumours and normal tissues: the importance of drug dose and timing

    Radiother Oncol

    (1997)
  • K Haustermans et al.

    Influence of combined use of nicotinamide and carbogen on rat spinal cord radiation tolerance

    Radiother Oncol

    (1994)
  • S Dische

    What have we learnt from hyperbaric oxygen?

    Radiother Oncol

    (1991)
  • P Rubin et al.

    Carbogen breathing during radiation therapy: the Radiation Therapy Oncology Group Study

    Int J Radiat Oncol Biol Phys

    (1979)
  • L Martin et al.

    Changes in the oxygenation of head and neck tumors during carbogen breathing

    Radiother Oncol

    (1993)
  • M Nordsmark et al.

    A confirmatory prognostic study on oxygenation status and locoregional control in advanced head and neck squamous cell carcinoma treated by radiation therapy

    Radiother Oncol

    (2000)
  • MI Saunders et al.

    Accelerated radiotherapy, carbogen and nicotinamide (ARCON) in locally advanced head and neck cancer: a feasibility study

    Radiother Oncol

    (1997)
  • J Bernier et al.

    ARCON; accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas: the experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer (EORTC)

    Radiother Oncol

    (2000)
  • B Fertil et al.

    Intrinsic radiosensitivity of human cell lines is correlated with radio responsiveness of human tumors: analysis of 101 published survival curves

    Int J Radiat Oncol Biol Phys

    (1985)
  • R Rampling et al.

    Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors

    Int J Radiat Oncol Biol Phys

    (1994)
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