Impact of tumor repopulation on radiotherapy planning

Biologic/functional imaging (e.g., fluorodeoxyglucose/3'-deoxy-3'-fluorothymidine-positron emission tomography) is promising to provide information on tumor cell repopulation. Such information is important in the design of biologically conformal radiotherapy for cancer. The questions remaining unclear are whether it is necessary to escalate the dose to the regions with rapid cell repopulation in the tumor target and, if so, by how much. The purpose of this work was to address these questions using radiobiologic modeling.

The generalized linear-quadratic model, extended to account for the effect of clonogenic cell repopulation, was used to calculate the cell-killing efficiency of radiotherapy. The standard Poisson tumor control probability (TCP) model was used to bridge cell killing to treatment outcome. Prostate cancer was chosen as the example for this study. In situ measurements of prostate cancer patients have shown that the potential doubling time of tumor cells has a large variation, ranging from 15 to 170 days. On the basis of the linear-quadratic and TCP parameters (alpha = 0.14 Gy(-1), alpha/beta = 3.1 Gy, and the number of clonogens K = 10(6)-10(7) cells) determined in earlier studies, we evaluated the influence of tumor cell repopulation during protracted treatment courses on treatment outcome. The dose escalations, which can be used to combat aggressive cell repopulation in regions with different doubling times (15-170 days) and sizes (5, 10, 15, and 40 cm(3) of a 40-cm(3) tumor), were calculated for commonly practiced radiotherapy modalities. The influence of linear-quadratic parameters on this calculation was also considered.

The impact of tumor cell repopulation on TCP and the corresponding dose escalation required to account for this impact were investigated for both external beam radiotherapy and permanent implantation. The results indicated that for regions with aggressive tumor cell growth, dose escalation is necessary to compensate for the repopulation effect. For example, for tumors with an effective doubling time changing from 42 days to 15 days, the prescription dose of external beam radiotherapy needs to be increased from 75.6 to 81 Gy to maintain a target TCP of 80% for intermediate-risk prostate cancer. For (125)I implants, dose escalation from 152 to 160 Gy is required for the same target TCP. These data were calculated on the basis of an alpha/beta ratio of 3.1 Gy. Greater dose escalations are required if the alpha/beta ratio is 1.5 Gy (e.g., 88 Gy for external beam radiotherapy or 180 Gy for (125)I implantation for the same treatment outcome). Our study results showed that it is important to cover the entire tumor volume, including all aggressive spots, with the desired prescription dose, especially for low-dose-rate brachytherapy.

Dose escalation is necessary to offset the accelerated tumor cell repopulation during prolonged treatment courses. This study provides a preliminary estimate of the dose escalation for prostate cancer based on the in situ measurements of potential doubling time and radiobiologic models. The proposed dose prescriptions are technically feasible for clinical trials.