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Purpose: To investigate the effect of heterogeneity in tumor cell kinetics on radiation dose-response curves for a population of patients., Materials and Methods: A series of exploratory calculations have been performed using an improved geometric-stochastic model of tumor cure., Results: Radiation therapy dose-response curves may plateau, or nearly so, at tumor control levels well below 100%, if a proportion of tumors would grow sufficiently fast to counterbalance the effect of fractionated radiotherapy. If the model assumptions of doubling time heterogeneity are correct, the difference between a short and protracted radiation regimen would be not only in the position and steepness of the radiation dose-response curve, but also in the level of the predicted plateau., Conclusions: For a given rate of dose accumulation, the one-sided flattening in dose-response curves at high doses is predicted from the modeling, and determined by the proportion of most radioresistant and rapidly growing tumors. This shows that empirical models of tumor control probability which assume a symmetric sigmoid relationship from 0 to 100% have apparent limitations, seemingly not well acknowledged in the literature.

Repopulation in mouse tongue epithelium was determined during unconventional fractionation schedules, i.e., hyperfractionation (2 x 1.5 and 2 x 1.75 Gy/day) and accelerated treatment (2 x 3 Gy/day). The residual tolerance of the epithelium at defined days of the fractionated treatment was tested by graded single test doses (top-up design). The dose required to induce complete epithelial denudation in 50% of the animals (ED50) was used to calculate the number of fractions repopulated during the preceding treatment. After the first week of hyperfractionation, tolerance was reduced compared to untreated epithelium. However, subsequently no further change was observed, indicating complete compensation of the weekly dose with all doses per fraction used. Epithelial cell density, defined by histological examination in additional experiments, in all fractionation arms decreased similarly by approximately 40% during the first week and remained constant at 60-80% in the subsequent 2 weeks. During accelerated fractionation, the residual mucosal tolerance decreased continuously with treatment time and resulted in epithelial denudation after 12 fractions. However, a substantial repopulation effect was observed, compensating 1.5 fractions by day 2, and 5 fractions by day 5, respectively. After cessation of the therapy the repopulation rate clearly decelerated to compensate a dose equivalent to about 0.5 fractions per day. Cell density decreased linearly during the treatment with 5, 10 or 12 fractions at a rate close to normal cell loss. Marked cell production, dependent on the total fractionated dose, was seen from one day after the last fraction in each experimental arm. These results indicate that maximum stem cell repopulation occurs predominantly during treatment, while major production of differentiating cells take place in treatment splits.

Experiments were performed to establish the extent and kinetics of tumor cell repopulation in a murine sarcoma, designated SA-NH, treated with cyclophosphamide (CY). Mice bearing 8-mm leg tumors were treated with 200 mg/kg CY which caused a transient tumor regression. Changes in the absolute clonogen content of tumors was determined by the change in TCD50 values (50% tumor control) obtained under hypoxic conditions of local tumor irradiation at different times after CY treatment until tumors regrew to the pretreatment size. For comparison, hypoxic TCD50 values were determined during the growth of tumors not treated with CY. CY greatly depleted tumors of clonogenic cells as manifested by the reduction in the control TCD50 value of 64.5 Gy to 32.8 Gy 1 day after CY treatment. The reduced TCD50 value remained unchanged for 2 weeks after treatment with CY, at which time the TCD50 began to rapidly increase, continuing until the end of the observation period of 21 days when tumors reached the pretreatment size. In contrast, there was a constant but slower increase in TCD50 values during the growth of tumors not treated with CY. The daily increase in TCD50 was more than twice as high in CY-treated than in CY-untreated tumors: 4.5 Gy/day versus 2.1 Gy/day. This implies that the rate of clonogen production in CY-treated tumors was twice as high as that of unperturbed tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

A major purpose of total body irradiation (TBI) for bone marrow transplantation in leukemia patients is to help eradicate all leukemia cells; the ideal regimen has not yet been determined. To answer basic questions regarding leukemic cell survival kinetics, a human acute lymphoblastic leukemia (ALL) cell line (Reh), with the common ALL antigen (CALLA-positive), has been used to assess in vitro the efficacy of one widely used hyperfractionated TBI (HTBI) regimen versus single dose TBI (SDTBI). The regimen studied in this model was 1.2-1.25 Gy/fraction, 3 fractions/day, 5 h apart each day, for 5 days (11-12 fractions) for a total dose of 13.2-15.0 Gy. It was found that: (i) cell survival was consistent with the linear-quadratic model for early responding tissues (alpha/beta = 7.0 Gy). (ii) The change in shape of the 'effective' cell survival curve for three fractions/day was consistent with the hypothesis that there was complete repair between fractions. (iii) Cell regrowth between fractions was minimal (< or = 5%). (iv) Division delay between fractions (2.9 h/Gy) could explain the small contribution to the survival curve of regrowth between fractions. (v) For a full HTBI course to 15 Gy, cell survival was predicted to be approximately 5 x 10(-5), compared with approximately 10(-3) for a low dose rate (0.04-0.07 Gy/min) SDTBI to 10 Gy; the latter projected from the initial slope of the high dose rate, single dose survival curve.

10-16-Week-old female BALB/c mice received low dose total body irradiation (LDTBI) in one fraction immediately before the beginning of treatment with recombinant human interleukin-2 (rIL-2). LDTBI prevented in a dose-dependent manner the weight increase of the spleen, liver and lungs induced by fluid extravasation provoked by rIL-2 injections. It also limited the increase of the number of mononuclear cells in the spleen induced after in vivo treatment with rIL-2. Immunofluorescence analysis of spleen cells revealed that LDTBI decreased the relative sIgM+ cell number in spleen, while the relative numbers of Lyt-1+, Thy-1+ and L3T4+ cells were increased, indicating that a T and/or NK population, radioresistant to LDTBI, could still proliferate under rIL-2 stimulation in vivo. Such lymphocytes were capable of in vitro lysis of YAC cells in a 4-hour 51Cr release assay, as well as lymphokine-activated killer (LAK) cells obtained in mice treated with rIL-2 alone. Thus, LDTBI given prior to rIL-2, yet preserving the cytotoxic capacity of the LAK cells activated by rIL-2, could prevent the vascular leak syndrome toxicity induced by rIL-2 injection.

The radiosensitivity of four human ovarian cancer cell lines was investigated in vitro by a clonogenic assay and analyzed using the linear-quadratic model. Two cell lines were found to be highly radiosensitive (mean inactivation dose (D) 0.82-0.92 Gy; surviving fraction 2 Gy (SF2) less than or equal to 0.13). Two other cell lines were less sensitive to radiation (D 1.31-1.94 Gy; SF2 0.22-0.38). Although the use of external radiotherapy in ovarian cancer has been limited due to the pattern of metastatic spread of this cancer, the present data support the view that ovarian carcinomas are radiosensitive tumors. Investigations on the effects of new approaches, such as delivering radiation more specifically to intraperitoneal ovarian cancer cells, are warranted.