A rationale for fractionation for slowly proliferating tumors such as prostatic adenocarcinoma

The incidence of carcinoma of the prostate has recently begun to exceed that of carcinoma of the lung in males in the United States. Although survival and local tumor control after treatment are good for early stages, improvements are being sought for more locally advanced stages. Dose escalation might be of benefit and might be accomplished using "three-dimensional" conformal radiotherapy or hyperfractionation. Because carcinoma of the prostate is known to be a generally slowly growing tumor, there may be more scope for extreme hyperfractionation, even with prolongation to allow for the extra number of very small fractions. This article explores only the hyperfractionation approach, and only theoretically, to investigate when treatments might become too hyperfractionated.

The major problem was what to assume for proliferation rates in human adenocarcinomas. A literature search yielded labeling indices (S-phase proportions) often averaging about 1%, but spreading up to 6% or more in individual cases. These data are reviewed, and three bands of rate of loss of local control were chosen for the subsequent calculations: 0.5%, 1%, and 2% loss of local control per week of prolongation. Calculations were done using the linear-quadratic model for a series of doses per fraction of 1.2, 1.0, 0.8, and 0.6 Gy, given twice a day (b.i.d.) in 7, 9, 12, and 17 weeks, respectively. They were compared with a "standard" 36 fractions of 2 Gy = 72 Gy in 7 weeks. Total doses for equal late effects were calculated assuming a late alpha/beta of 3 Gy; the tumor Biologically Effective Doses were calculated assuming tumor alpha/beta values of 30, 10, and 5 Gy. The possible increases of local tumor control were estimated assuming a gamma-37 slope of 2% (per percent increase in total tumor dose).

Graphs are presented of the estimated local control as a function of dose per fraction (and overall time), for advanced tumors (starting at 30% LC) and for less advanced tumors (starting at 70%). The largest increase is always for the change from 2 Gy once a day (q.d.) to 1.2 Gy b.i.d. Further changes of local control with hyperfractionation depend upon tumor proliferation rate and on the shape of the tumor cell survival curve. The largest gains are for the more advanced tumors.

There is no great encouragement to proceed to more hyperfractionated and prolonged schedules than 1.2-1.0 Gy b.i.d. in 7-9 weeks. We await developments that might more reliably enable potential doubling time and cell survival curve shapes to be routinely determined for individual tumors, before further hyperfractionation might be considered. In the absence of tumor kinetic measurements, we might consider low grade tumors to be the ones to select for prolonged fractionation, whereas high grade tumors would be more suitable for 1.2 Gy b.i.d. with no prolongation, or for dose escalation using conventional fraction sizes and conformal radiotherapy.