The effect of fractionation on the response of normal tissues to irradiation was already investigated in the 1930s. Reisner (Reisner, A. Hauterythem und Röntgenstrahlung. Erg. Med. Strahlenforsch, 6: 1-60, 1933) measured the time course of skin erythema on thighs of humans by applying different doses per fraction while keeping constant total dose and overall treatment time. The results showed that acute skin damage was reduced with small doses per fraction. Two years later Miescher (Miescher, G. Tierexperimentelle Untersuchungen über den Einfluss der Fraktionierung auf den Späteffekt. Acta Radiol, 16: 25-38, 1935) published his results on late radiation effects in rabbit skin. He also reported that the main influencing factor for tissue tolerance was dose per fraction. In addition, he found indications that there was no impact of overall treatment time on the development of late reactions. Strandqvist in his famous monograph on the time factor in treatment of skin cancer (Strandqvist, M. Studien über die kumulative Wirkung der Röntgenstrahlen bei Fraktionierung. Erfahrungen aus dem Radiumhemmet an 280 Haut -und Lippenkarzinomen. Acta Radiol. (Suppl.) 55: 1-300, 1944), however, postulated that total dose and overall treatment time were the main determinants of local control as well as of normal tissue damage, apparently omitting to consider the findings of Reisner and Miescher in his own analysis. It is our impression that mainly due to the large influence of Strandqvist's work on radiobiological thinking the early findings on the normal tissue sparing effect of small fraction size have been forgotten and had to be rediscovered about 40 years later.
