Heterogeneity In Radiosensitivity Research Articles

The clinical significance of ratios of radiobiological parameters

Purpose : Interindividual heterogeneity of the radiobiological characteristics of malignant and normal tissues hampers the derivation of radiobiological parameters from clinical data. Focusing on the ratio Dprolif, i.e., the dose to compensate 1 day of treatment interruption, this article onvestigates the hypothesis that ratios of parameters might be less sensitive to interpatient heterogeneity and may cnstitute a more reliable description of the radiobiological properties of tissues than the parameters themselves. Methods and Materials : Analytic calculations were performed in an idealized example in which the only source of heterogeneity was the number of clonogeniccells. Computer simulations were used to assess the effects of heterogeneity in radiosensitivity and in proliferative capcity. Treatment utcome was simulated in pseudopatients with increasing dose-time correlation. Results : Interindividual heterogeneity in clonogenic cell number, radiosensitivity, or proliferative ability results in marked underestimation of the response parameters describing these processes. In contrast, the estimates of the ratio Dprolif were more stable. The coefficients of variation increased with increasing heterogeneity. However, this only became unacceptable when heterogeneity in radiosensitivity was marked, or when total dose and trratment time were closely correlated. Conclusions : Parameter ratios may provide more robust radiobiological information than single parameters estimated frm clinical data except when interindividual heterogeneity is very large or when the treatment modalities are too highly correlated. As usual, caution is advised in the presence of patient selection, a correlation between treatment prescription and expected outcome, or limited ranges of dose-time treatment patterns.

Does tumor control decrease by prolonging overall treatment time or interrupting treatment in laryngeal cancer?

Purpose: To evaluate treatment results of radiotherapy in laryngeal cancer and to retrospectively investigate the influence of treatment interruptions on local control rates. A multivariate analysis was performed to investigate the role of overall treatment time on local control rates. Material and methods: From 1962 to end 1986, 864 patients with cancer of the larynx were treated with primary radiotherapy, with a variation of doses and treatment times. In 352 patients a systematic interruption of 2 weeks was done after 50 Gy (split-course). Local control rates were calculated by the actuarial method. A multivariate analysis was subsequently performed in order to identify independent variables influencing local control rates. Results: The univariate analysis showed that in patients treated with a split-course schedule, local control rates were significantly lower in glottic cancer ( p < 0.001), with differences of 7% in T 1 ( p = 0.05) and 11% in T 2 ( p = 0.11). in node-negative supraglottic cancer a difference of 10% ( p = 0.16) was observed. The multivariate analysis showed the following factors to significantly influence local control: site, total dose, total treatment time, T and N stage. Split-course treatment was not an independently significant factor, probably caused by time being a stronger factor. In subgroup analysis, the effect of total treatment time remained statistically significant in T 2 glottic cancer. Conclusion: A significant negative influence of treatment interruption was seen in glottic cancer, and a trend toward significance in node-negative supraglottic cancer in univariate analysis. A multivariate analysis showed a negative influence of prolonging treatment time in the total patient group. The effect remained significant in T 2 glottic cancer in subsequent subgroup analysis, possibly due to the fact that there is little variation in tumour volume in this group. in larger tumours, where there is substantial variation in tumour volume and a higher probability of heterogeneity in radiosensitivity, the effect of dose-time variations could be more difficult to discern.

Radiosensitivity of Human Cell Lines to Small Doses. Are There Some Clinical Implications?

The concept of intrinsic radiosensitivity is now strongly associated with the linear-quadratic (LQ) model which is currently the best and the most reliable method to fit the first three decades of a survival curve for both human fibroblast and human tumor cell lines. This approach has led to the major conclusions that it is the initial part, and not the distal part, of the survival curve which truly characterizes intrinsic cellular radiosensitivity and there is a correlation between the parameters describing mainly the initial part of the survival curve (alpha, SF2, D) and the clinical radioresponsiveness. More accurate analysis with flow cytometry or a dynamic microscopic image processing scanner (DMIPS) has allowed further study of the survival curve which has shown two sorts of substructure. On one hand, the overall survival curve of exponentially growing cells is described by two or more sets of alpha, beta parameters (heterogeneity in radiosensitivity due to the cell cycle). On the other hand, hypersensitivity at very low doses (< 0.5 Gy) followed by an increase of the radioresistance of the whole population at higher doses has also been observed. This phenomenon is not described by the conventional LQ model and has been interpreted as an induced radioresistance which seems to be negatively correlated with intrinsic radiosensitivity. In clinical radiotherapy, there are two sorts of response of normal tissues: (1) the early and late damage and (2) the carcinogenesis. Concerning the first point, the clinically detectable radiation damage appears at doses usually around 20 Gy (in 2-Gy fractions) with the exception of the hemopoietic and the lymphatic tissues. Therefore, the small doses delivered at the edges or in the penumbrae of treatment fields in routine radiotherapy cannot create detectable damage, despite a potentially much higher effect per unit dose, because the total doses are still very small. However, it may be important to bear in mind the possible extra effect of low doses outside the target volume if regions in the vicinity are subsequently retreated. Concerning clinical radiation-induced carcinogenesis, three studies described a higher relative risk associated with small doses per fraction or very low dose rate. The results and the interpretation of these studies are discussed.

Heterogeneity of radiosensitivity in a human glioma cell line

Sixteen clones were isolated from an early-passage human glioma cell line (IN859) and have been found to show variation in several biological characteristics including DNA content, modal chromosome number, and morphology. In addition, heterogeneity of radiosensitivity was detected: the doses that gave a surviving fraction of 0.01 varied by a factor of approximately 1.5. The most sensitive (clone 6) and the most resistant (clone 9) clones were selected for further study; their surviving fractions at 2Gy (SF2) were 0.37 and 0.64, respectively. When compared at a fixed radiation dose the sensitive clone surprisingly demonstrated greater split-dose recovery than the resistant clone; it also showed greater low dose-rate sparing.

Eradication of leukaemic marrow and prevention of leukaemia relapse with total body irradiation and bone marrow transplantation

A series of studies was carried out to determine the effect of allogeneic bone marrow transplantation (BMT) on leukaemia. The study aimed at two different, but strictly linked issues: (1) identification of the eradication capability of BMT, and (2) evaluation of the effect of BMT, both in preventing relapse and in producing long-term disease-free survival. Fifty-four patients allografted for leukaemia were evaluated at various intervals, after bone marrow transplantation, for the presence of host haemopoiesis using red-blood-cell and cytogenetic markers. Among 40 patients in remission, 10 showed functional host and donor haemopoiesis (mixed chimerism), while in 30, host haemopoiesis was never detected (complete chimerism). Seven of the 14 evaluable patients who relapsed showed the reappearance of host haemopoiesis at the time of relapse. The records of received doses of TBI indicate that patients who achieved mixed chimerism, either relapsing or not, received significantly lower doses than complete chimeras. However, some patients with complete chimerism received a TBI dose equivalent to the dose received by those with mixed chimerism, suggesting that the TBI dose is not the only factor determining the reappearance of host haemopoiesis. The data on chimerism and relapse suggest that there is heterogeneity in radiosensitivity between normal marrow cells and leukaemic cells, and further, within the different types of leukaemia. The incidence/severity of acute and chronic graft-vs-host disease (GvHD) was significantly higher in complete chimeras than in mixed chimeras suggesting that mixed chimerism may play a role in the development of tolerance; however, it could be the tolerance (i.e. absence of GvHD) which is responsible for the persistence of host haemopoietic cells. One-hundred-and-sixty-eight patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) and chronic myeloid leukaemia were analyzed for risk factor associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) of 330 cGy on days -3, -2, -1. There was a difference of +/- 18% between the nominal total dose of 990 cGy and the actual received dose as indicated by dosimetric recordings. While interstitial pneumonitis had minimal impact on survival there was a considerable difference in the incidence of relapses. The incidence of relapse was higher in patients receiving less, than in patients receiving more than 1000 cGy respectively and this had a major impact on survival. However, transplant-related mortality was slightly higher in the group of patients receiving higher doses of TBI.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for the re-establishment of a heterogeneity in radiosensitivity among spermatogonial stem cells repopulating the mouse testis following depletion by X-rays

Earlier studies have shown that the spermatogonial stem cells of the mouse testis recovering from previous radiation or chemical mutagen exposure give subnormal yields of genetic damage with subsequent X-irradiation. This response has been investigated further: (a) with a high, 9-Gy X-ray dose given 4, 12 or 21 days after a 1-Gy conditioning dose (Expt. 1), and (b) with a 1 + 7-Gy, 24-h fractionation regime given 4 or 14 days after a 1-Gy conditioning dose (Expt. 2). In Expt. 1 the 1 + 9-Gy, 4-day interval regime gave a very low response, lower than obtained previously with an equivalent 1 + 5-Gy treatment. This suggests that a heterogenity in radiosensitivity, such as exists in unirradiated stem cell populations and absent 24–48 h after radiation depletion, is quickly re-established among the stem cells repopulating the testis. By contrast, the 1 + 7-Gy, 24-h fractionation when given 4 days after the 1-Gy conditioning dose (Expt. 2) gave a very high yield of genetic damage, almost as high as that given by he fractionated (1 + 7 Gy) dose applied to previously unirradiated stem cells. This suggests that the newly established heterogeneity is removed by the second 1-Gy conditioning dose. With longer intervals between treatments, genetic yields consistent with additivity were obtained in Expt. 1; less clear results were obtained Expt. 2. Comparison with earlier data generally suggested that the duration of the repopulating period is dose-dependent. In a third experiment evidence was obtained that genetic damage induced by X-irradiation can be reduced by a subsequent treatment with triethylenemelamine (TEM) during the repopulating phase. This confirmed an earlier finding. Such an interaction could not be demonstrated with two X-ray treatments. An explanation for the X-ray/TEM interaction is offered.

Translocation yield from mouse spermatogonial stem cells following unequal-sized X-ray fractionations: Evidence of radiation-induced loss of heterogeneity

Previous work has shown that a high yield of genetic damage can be recovered from stem spermatogonia exposed to a high (900 R) X-ray dose, despite extensive cell killing, when this follows 24 h after a smaller (100 R) radiation exposure. This differs from the response of the normal stem-cell population and has been interpreted to mean that the more radio-resistant cells surviving the first exposure become sensitive both to radiation-induced killing and genetic damage after this time interval and, as a consequence, lose the heterogeneity in radio-sensitivity that typifies a normal stem-cell population. Similar results have now been obtained with doses of 600 and 800 R given in fractions of 100 + 500 R and 100 + 700 R 24 h apart. Yields of translocations among spermatocytes were higher than obtained with the single doses and responses consistent with the fractions acting additively were obtained when the fractions were given in reverse order. Further analyses of the data provided support for the concept that 24 h after a radiation exposure there is a loss of heterogeneity in radio-sensitivity in the surviving stem-cell population.