The Four R of Radiotherapy

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• The Four R of Radiotherapy
• Reoxygenation
• Repopulation
• Reassortment
• Repair

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• Oxygen Effect
• The OER typically ranges between values of
  2.5-3.0.
• Half maximal sensitivity occurs at oxygen
  tensions of 3 mm Hg.
• Above pO2 values of 20 mm Hg near maximal
  oxygen effects are seen.

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• Oxygen Effect
• For sparsely ionizing radiation 2/3 of the
  damage produced is mediated by free radicals
  which may be fixed by oxygen.
• Hall, 1998

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• Oxygen Effect
• Impact of oxygen diffusion on radiation survival
  curve.

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Tumor Vasculature
Brown Giaccia, 1994
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Tumor Hypoxia

• Preclinical Observations
• Most animal tumor models contain significant
  proportions of hypoxic cells.
• Hypoxic cells in tumors dominate their response
  to large single doses of radiation.

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• Effect of hemoglobin level on local regional
  control in Head and Neck Cancer.
• Overgaard et al, 1989

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• Effect of hemoglobin level on survival in Head
  and Neck Cancer.
• Lee et al, 1998

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Hb - Head Neck Cancer

• Fein, D.A. et al - JCO 132077-2085, 1995

Local Control () Survival ()
Hb lt 13 g/dL
66 46
T1 - T2 Glottic Ca N 109
p .0018 p lt .001
95 88
Hb gt 13 g/dL
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• Influence of smoking during treatment on outcome
  of radiotherapy in Head and Neck Cancer.
• Overgaard and Horsman, 1996

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• Oxygen tensions (pO2 frequency distributions) in
  normal breast and breast cancers.
• Vaupel and Hoeckel, 1999

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• Overall and disease-free survival probabilities
  for patients with advanced cancers of the uterine
  cervix treated with curative intent.
• Hoeckel et al, 1996

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• Soft tissue sarcoma survival as a function of
  tumor oxygenation.
• Brizel, 1999

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Hypoxia in Tumors

• Aggressiveness of Disease
• Hypoxia may provide a mutant p53 growth advantage
  (Graeber et al., 1996).
• In carcinoma of the cervix, patients with hypoxic
  tumors treated with surgery had a significantly
  worse disease-free and overall survival compared
  to patients with non-hypoxic tumors (Hoeckel et
  al., 1996).

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• Influence of tumor hypoxia on malignant
  progression. Giaccia et al., 1999

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Hypoxia in Tumors

• Aggressiveness of Disease
• Hypoxia may provide a mutant p53 growth advantage
  (Graeber et al., 1996).
• In carcinoma of the cervix, patients with hypoxic
  tumors treated with surgery had a significantly
  worse disease-free and overall survival compared
  to patients with non-hypoxic tumors (Hoeckel et
  al., 1996).

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• Overall and disease-free survival probabilities
  in patients with advanced cancers of the uterine
  cervix treated with primary surgery.
• Hoeckel et al., 1996

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Hypoxia in Tumors

• Metastatic Spread
• Hypoxic exposure of tumor cells in vitro can
  increase metastases in mice (Young et al., 1988).
• Increased metastases can occur in mice with
  primary hypoxic tumors (De Jaeger et al., 2001).
• The probability of distant metastases in soft
  tissue sarcoma was twice as great for tumors with
  median pO2 values lt 10 mm Hg than for those with
  median pO2 values gt 10 mm Hg (Brizel et al.,
  1996).

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Tumor Oxygenation

• If hypoxia has a detrimental impact on treatment
  outcome, what approaches should be taken to
  minimize its impact?

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Strategies

• Correct factors known to be associated with poor
  oxygenation.
• Increase oxygenation above normal.
• Directly target hypoxic tumor cells.

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Reoxygenation

• Process by which surviving hypoxic cells may gain
  access to oxygen after a dose of radiation.
• Theoretically will reduce the relevance of
  hypoxic cells and result in an increase in the
  sensitivity of tumors during fractionated
  radiotherapy.

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Reoxygenation

• Pre-clinical Studies
• Tumors vary greatly in their reoxygenation
  patterns.
• Many tumors reoxygenate poorly -
• the hypoxic fraction in the surviving cell
  population often is greater after irradiation.

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• Reoxygenation patterns observed in preclinical
  tumor models treated with radiation.
• Tannock and Hill, 1998.

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Hypoxia in Head Neck Cancer

• Observation
• The oxygenation of tumors during the course of
  radiotherapy could improve, worsen or remain the
  same.

• Authors
• Gabalski et al., 1998
• Stadler et al., 1998
• Brizel et al., 1999
• Jund et al., 1999
• Lyng et al., 1999

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Hypoxia in Tumors

• Reoxygenation
• Current studies do not support the notion that
  continuous improvements of the oxygenation status
  of tumors are achieved during fractionated
  radiotherapy.