Is acute mucositis dose limiting for altered fractionated radiotherapy?

Abstract

There is nowa substantial number of studies on radiotherapy for head and neck cancer using altered fractionation schedules.

Accumulated dose/week (AD) vs incidence and severity of acute mucositis

In conventional radiotherapy given in 1.6–2.0 Gy fractions up to total dose of about 70 Gy, confluent mucositis (CM) is generally reached at day 22. The threshold for the CM appears to be around 20 Gy and the CM usually develops about 9 days after delivering that dose. However, some studies suggest that the onset of CM may depend on accumulated dose/week and the larger AD is the sooner CM is reached. All these observations suggest that the intensity of acute epithelial reactions, and likely other H-type-like tissues reflects the balance between the rate of cell killing by irradiation and the rate of regeneration of surviving stem cells. Once a critical level ot survival cells has been attained, a certain type of clinical damage will develop at a rate only determined by the cellular kinetics ot the tissue. When a peak in the CM is reached, further stem cell killing can not produce an increase in intensity of acute reactions, but could be manifest as prolonged time to heal the reactions.

Accelerated and hyperfractionated schedules

Analysis of the sets of data of accelerated, predominantly accelerated and hyperfractionated radiation treatments shows that, except with hyperfractionation and short single course accelerated regimens, the AD is not constant in consecutive weeks of treatment. High AD, above 25 Gy is typical for accelerated treatments when the dose is condensed into a single course in a short overall treatment time.

Conclusions

• 1.

  When fractionation regimens are altered to achieve a therapeutic gain through an increased tumour response relative to late normal tissue response, acute mucosal reactions become dose limiting in radiotherapy for head and cancer.

• 2.

  Acceptable risk of acute mucositis can be expected when the Dose-Time Ratio (DTR) is lower than 2.5 Gy × day -2 and accumulated dose per week (AD) is less than 12 Gy. Higher AC can only be considered if it is administered in no more than 2 consecutive weeks of 5–6 week treatment or 2-3 week split is given between series of high AD (or DTR).

• 3.

  High constant value of the AD (>14 Gy) during 5–6 weeks of treatment or the AD above 20 Gy and DTR above 10 Gy × day-2 lead to high risk of persistent confluent mucositis and consequential late necrosis which may occur within 4–8 months after treatment.