Summary Conventional fractionation in radiotherapy may not be the most optimal with respect to the cellular kinetics and radiosensitivity of the proliferating tumour cells. Some biological experiments suggest that if the interval between treatments is reduced to 3 to 8 h and irradiation given 2 to 3 times/day then the therapeutic ratio can be improved because o (a) repair will be completed in normal well oxygenated cells but not in hypoxic cells of tumour which will suffer greater damage from subsequent doses of radiation, (b) repopulation of tumour cells between fractions of radiation can be minimized, (c) redistribution of cells into more sensitive phase of division cycle can occur, (d) reoxygenation may be completed. The interpretation of some of the experiments is controversial and there is an ever existing problem as to how well will in vitro findings apply in vivo. Yet, there is a suggestion that small doses per fraction (about 100 rad) can exploit minor differences in radiation response between normal cells and tumour cells and decrease or eliminate the problem of relative resistance of hypoxic tumour cells. If therapy is given 2 or 3 times/day, a full or almost full usual daily dose (150–300 rad) can be given in each session, thus doubling or tripling the usual daily dose and in this way the overall treatment time will be substantially reduced (1–3 weeks). It is proposed to call this method “hyperfractionation”. Another approach is to use smaller doses per fraction (50–150 rad), 2 to 4 times/day, which together would amount to or exceed somewhat the usual daily dose of conventional radiotherapy. The term “superfractionation” is proposed by the reviewer (Table 1). There is some experimental and theoretical evidence that this second approach could be more advantageous. Clinical studies reporting on the treatment of 713 patients were published by 14 groups of clinical investigators and these suggest that both methods using multiple daily fractions are feasible. In no case was this new fractionation found to be inferior to conventional treatment. The treatment results are at least as good and usually better than conventional radiotherapy in the treatment of Burkitt's lymphomas, skin carcinomas, anaplastic carcinoma of the thryoid, carcinoma of the head and neck, bladder, cervix and inflammatory carcinoma of the breast (Table 2). The use of multiple daily fractions was found to be safe in a wide range of dose and time factors with the regimes characterized by Cumulative Radiation Effect (CRE) up to 1900 reu. Acute reactions were usually the same or less severe than with similar conventional therapy. In situations where more severe reactions were observed, the regime was slightly modified and reactions became acceptable (Table 3). Late complications were not frequent and usually could be related to higher dose/shorter time regimes than that used in other patients but more observations are needed concerning the effect of multiple daily fractions on tissues such as the spinal cord and lung (Table 4). Only 3 of the clinical studies, discussed in this review, were randomized, with a control group treated by conventional fractionation. In other studies authors used historical control groups, sometimes not well defined. Some authors indicating superiority of multiple daily fraction therapy refer only to their general past experience to support their conclusion. The follow-up period of many studies was short and further limited by deaths from distant metastases, because most patients had very advanced malignant disease. Future studies also need to incorporate the state of art treatment planning and pay full attention to the best selection of treatment volumes, beam energy and adjuvant chemotherapy if the advantage of any particular fractionation is to be convincingly demonstrated. CRE formalism, applied to regimes with three daily fractions, underestimates the effect on skin by 5 to 10% but after such correction it could have good predictive value. Mathematical modelling can be also a useful tool for design of more effective unconventional fractionation regimes. There is need of further experimental work to evaluate the effect of various fractionation regimes on both the tumour and the normal tissues and to estimate the therapeutic ratio. In some clinical situations (e.g. very advanced cancer of the head and neck) locoregional control with conventional radiotherapy is so poor and accumulated experience with multiple daily doses so promising, that the superfractionation may fast become the treatment of choice. In several other malignant diseases, prospective controlled clinical trials comparing the best conventional fractionation with multiple daily fractionation, are urgently required.
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Aug 1, 1988
William M Saunders + 7
Open Access