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Biomedical subjects

H D Thames

Publications and source records attributed to H D Thames.

At least 73 records · Page 4Linked to original sources
PubMed1993

Hypofractionation in retinoblastoma: an increased risk of retinopathy.

Forty-four eyes in 38 children were treated between 1963 and 1991 by external radiotherapy for retinoblastoma. Treatment modalities varied widely during this period; in addition to radiotherapy there was chemotherapy (16/44), photocoagulation (14/44), and laser therapy or cryotherapy (14/44). Treatment technique and dose fractionation also varied widely; lateral beam technique (39/44) versus anterior or anterior/lateral beam; doses per fraction ranged from 1 to 4.5 Gy, total doses from 30 to 61.5 Gy, and overall times from 22 to 49 days. Patients were followed at 3-month intervals, and actuarial survival at 10 years was 88%, with 62% local control. Ten eyes showed clinical evidence of retinopathy. A multivariate analysis of factors associated with increased risk of retinopathy was carried out using the Cox proportional hazards model and the mixture model of Farewell. The estimated latent time was 17 months (95% confidence interval, 14-20 months). The only factors found to be significantly associated with retinopathy were total dose multiplied by dose per fraction, or total dose normalized to the equivalent total dose in 2-Gy fractions as estimated from the LQ model, and these gave equivalent descriptions. There were trends (not significant) for increased risk of retinopathy when treatments included chemotherapy or photocoagulation, and for decreased risk (also not significant) when cryotherapy was used in conjunction with radiotherapy. No significance could be attached to any of the following: number of sites per eye, Reese-Ellsworth stage, and family history. We conclude that hypofractionation carries a significant risk for retinopathy in the treatment of retinoblastoma.

Child, Preschool↗
PubMed1993

Early and late injuries in mouse rectum after fractionated X-ray and neutron irradiation.

PURPOSE: to assess mouse rectum tolerance to fractionated X-ray and neutron irradiation. MATERIALS AND METHODS: doses per fraction ranged between 0.25 and 35 Gy for X-rays, 0.05 and 12 Gy for neutrons. Neutron top-up doses were added when the fractionated irradiation was given in fractions less than 2 Gy of X-rays or 0.35 Gy of neutrons in order to bring the damage into the detectable range. The early endpoints were the nadir of weight loss occurring within the first 2-3 weeks following irradiation and lethality by 2 months. The late endpoints were the peak of weight reached at maturity of the mice, the proportion of short feces in the daily fecal output at 10 months and lethality by 12 months. The linear-quadratic (LQ) model was fitted to the data (direct "one-step" analysis) and the estimated parameters were used to calculate relative biological effectiveness (RBE) values. RESULTS: alpha/beta ratio estimates were for X-rays: 19.9 Gy [95% confidence limits: 15.2, 27.0] for weight nadir. 13.4 Gy [9.3, 19.5] for early lethality, 6.4 Gy [3.6, 11.0] for peak weight, and 6.9 Gy [4.2, 10.8] for late lethality, for neutrons 19.9 Gy [9.5, 61.0] for peak weight. The fecal-deformity data were poorly fitted by the LQ model. The RBE was slightly higher for acute endpoints than for the late ones when X-ray fraction sizes were equal to or larger than 10 Gy. However, the change in RBE with decreasing X-ray dose per fraction was much steeper for the late endpoints, so that it became equal to or even higher than for acute reactions at doses per fraction of 5 Gy or less. CONCLUSION: Our results were consistent with those obtained from previously published studies using the same experimental system but larger doses per fraction.

Animals↗
PubMed1993

Is reseeding from the primary a plausible cause of node failure?

In a previous analysis of node failures in 1251 consecutive patients with node positive oropharyngeal and pharyngolaryngeal squamous cell carcinomas treated by external radiotherapy alone at the Institut Curie, the main reasons for patient exclusion were node recurrence associated with primary failure (N+T failures) and doses less than 55 Gy. These exclusions reduced the number of node failures from 399/1251 (32%) to 77/798 (10%). Multivariate analysis of node recurrence indicated that node size and fixity, treatment duration, and T stage of primary were significant (higher probability of isolated node failure for the T1-T2 primaries). In the present analysis, it is noted that 60% of the N+T failures were observed less than 1 month after the completion of the irradiation and, therefore, were not likely the result of reseeding from the primary tumor. When all 1251 patients were included in the analysis, the probability of nodal failure increased for larger nodes, T4 primaries, lower nodal doses, presence of contralateral node metastases, and nodal fixation to the surrounding structures. No influence of the primary site was found. Treatment duration was closely associated with total dose to the nodes. The best description of the data was obtained with a model including total dose and not treatment time. However, as in the previous analysis, the exclusion of low-dose (less than 55 Gy) treatments resulted in the loss of a significant dose-control relationship. We conclude that the majority of node failures is unlikely to result from reseeding from the primary tumor, and therefore should not be excluded from local-control analyses. From a more radiobiological point of view, the exclusion of palliative treatments is questionable when studying the effect of dose on local control.

Adult↗
PubMed1993

Radiation dose-fractionation and dose-rate relationships for long-term repopulating hemopoietic stem cells in a murine bone marrow transplant model.

Fractionated and low-dose-rate total-body irradiation (TBI) were compared with single-dose high-dose-rate TBI for induction of long-term hemopoietic chimerism in a murine syngeneic bone marrow transplantation model. At 5 months after TBI and bone marrow transplantation, the degree of stable blood chimerism was determined from the proportion of stem cell-derived donor (B6-Gpi-1a) and host (B6-Gpi-1b) blood erythrocytes. This end point was used to construct radiation dose-response curves for long-term donor marrow engraftment corresponding to ablation of primitive bone marrow stem cells of the host. Increasing dose fractionation and decreasing dose rate had the effect of restoring host hemopoiesis and required higher TBI doses for equal donor engraftment. Most of the dose recovery occurred within the first 6 h between fractions, consistent with the kinetics of sublethal damage repair. The late chimerism data were fitted to the linear-quadratic model using indirect and direct analysis for a fixed threshold response. Both analyses gave relatively low alpha/beta ratios (below 2 Gy), within the range normally seen in late-responding tissues. The dose-rate data gave a repair half-time of 2 h as estimated by the incomplete-repair model. These estimates contrast with the much higher alpha/beta values and lower repair half-times derived from acute hemopoietic failure as indicated by LD50/30, with the implication that separate target cell populations with differing radiosensitivities are involved in these two bone marrow end points.

Animals↗
PubMed1993

Recovery from radiation damage in mouse lung: interpretation in terms of two rates of repair.

A reanalysis was performed of the extensive data set obtained with fractionated irradiations of mouse lung reported by Travis et al. (Int. J. Radiat. Biol. 52, 903-919, 1987). The possibility was investigated that the poor fit of these data to the linear-quadratic model might have been the result of the presence of two rates of repair of sublethal damage instead of one. Therefore, the incomplete-repair linear-quadratic model was adapted to incorporate two independent rates of repair and the data were analyzed using this two-component incomplete-repair model. The results which are subjected to certain qualifications with respect to the assessment of the validity of the confidence limits indicated the presence of two significantly different repair rates, corresponding to a fast-repair half-time (t1/2) of 0.40 h (0.28, 0.53) and a slow t1/2 of 4.01 h (1.55, 6.57). A weight factor determined simultaneously indicated that the fast component has approximately four times more weight than the slow component. The alpha/beta value calculated for the entire data set using the same model was 3.8 Gy (3.0, 4.6), which is not significantly different from the alpha/beta of 3.6 Gy (2.8, 4.5) calculated for the 8- and 12-h data only, using the complete-repair linear-quadratic model. An experiment specifically designed to test the significance of the fast-repair component was performed in which mouse lungs were irradiated with two equal dose fractions, separated by intervals ranging from 10 min to 6 h. Data obtained from this experiment allowed only one repair rate to be determined, corresponding to a t1/2 of only 0.4 h. This finding confirms the presence of a very fast repair rate in mouse lung.

Animals↗
PubMed1992

Time factors in breast carcinoma: influence of delay between external irradiation and brachytherapy.

From 1971 to 1983, 398 (33 T1, 309 T2, 56 T3) biopsy-proven breast adenocarcinomas were treated conservatively at Hôpital Henri Mondor by an initial course of external irradiation (45 Gy, 25 fractions, 5 weeks) followed by interstitial iridium-192 implant for a further 37 Gy to the tumor. The mean interval between external irradiation and brachytherapy was 5.9 weeks (S.D. 1.7, range 1-18). Seventy-seven local failures were observed at 10-148 months (median 34.5). The actuarial probabilities (S.E.) of local control at 5 and 10 years were 0.86 (0.02) and 0.74 (0.03), respectively. The follow-up for patients free of local recurrence was 4-205 months (median 95). Multivariate analysis showed an increasing probability of local failure with longer interval between external irradiation and brachytherapy (Relative Risk [R.R.] 1.23 [95% confidence limits: 1.07, 1.41] per week, p = 0.005), and a lower risk of failure in case of complete tumor regression after external irradiation (R.R. 0.47 [0.25, 0.90], p = 0.022), and higher brachytherapy dose rate (R.R. 0.13 [0.02, 1.02] per Gy/h, p = 0.053). No influence of tumor size and total dose (possibly because only limited variations in total dose were observed), or histological grading (not performed in 140 [35%] patients) was found. Because of the lack of dose-control relationship, quantification of the effects of delay between external irradiation and brachytherapy (in terms of compensatory dose) and of dose rate (Incomplete Repair Model) was not possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1992

Is the experience with CHART compatible with experimental data? A new model of repair kinetics and computer simulations.

A new incomplete repair model is introduced that differs from previous models of this type by not assuming that repair is complete during long intervals, e.g. "overnight" intervals of 12-24 h. The model was used to assess the risk of myelopathy resulting from continuous hyperfractionated accelerated radiotherapy treatment (CHART) in light of recent experimental data on the rat spinal cord. Model calculations employing biexponential repair kinetics showed that CHART treatments might result in a higher myelopathy risk than an equal dose given in conventional 2-Gy fractions if the parameters obtained from the animal data hold. The probability of observing what has been reported for CHART was determined in computer simulations for different variance scenarios. The chance to observe four myelopathies in the 74 cervical cord patients was estimated to range between 25 and 62%, while the probability to see 0 in 68 thoracic cord patients ranged from 48 to 27%. These numbers were derived from reasonable assumptions about the repair kinetics (e.g. 60% of damage repaired with a half-time of 8 h) so that the over-all probability to observe 4/74 and 0/68 was maximized, and depending on the scenario fell in the range 12-17%. Finally, from these simulations a myelopathy risk of approximately 0.3-1.2% is predicted for the currently employed maximal CHART dose to the spinal cord, i.e. 42 Gy. We conclude that the CHART experience is not compatible with the new experimental data (p < 5%). Incomplete repair is unlikely to be the sole reason for the unexpected toxicity of CHART (p < or = 17%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Impact of spinal cord repair kinetics on the practice of altered fractionation schedules.

The kinetics of repair of sublethal lesions in the spinal cord was assessed in detail using a rodent model. Experiments were designed to obtain the fractionation sensitivity, alpha/beta, and to quantify the kinetics of repair after a clinically relevant fraction size. Pairs of 2-Gy fractions at intervals ranging from 0 to 24 h were given from Monday through Friday, to cumulative doses of 40-84 Gy. In addition, two groups of animals received 1.5 or 1.2 Gy twice a day at 8-h intervals, 5 days a week, to total doses of 66-90 Gy and 67.2-98.4 Gy, respectively. All irradiations were followed by a top-up dose of 16 Gy. Analysis of the experimental data revealed that a bi-exponential repair model fit the experimental data significantly better than did the mono-exponential model (p = 0.002). The repair half times obtained were 0.7 (0.2-1.3) h and 3.8 (2.6-4.9) h, respectively. The proportion of injury repaired by the longer half time was estimated to be 0.62 (0.37-0.86). The data showed that delivering 2 fractions per day at 6- or 8-h intervals instead of one per day led to a 16.5% (11.8-21.1%) and 13.5% (9.1-17.8%) reduction in the tolerance, respectively. Finally, the results indicated that when incomplete repair between fractions was accounted for, the linear-quadratic (LQ) model was valid in describing fractionation response down to 1.2 Gy per fraction.

Animals↗
PubMed1992

Fractionation response and repair kinetics of radiation-induced heart failure in the rat.

Local heart irradiation with single or fractionated doses leads to heart failure after dose-dependent latency times. Clinical symptoms of heart failure are dyspnoea at rest, apathy and subcutaneous oedema. Animals autopsied when they presented with these symptoms, have a congested liver and occasional pleural effusions. The left ventricle is dilated, showing a reduction in wall thickness by 15-17% of control values. Histological examination reveals a focal degeneration and necrosis of about 23% of the total myocardial volume. Loss of alkaline phosphatase activity from myocardial capillaries, which is known to precede myocardial degeneration, involves 77% of the myocardium. These findings at the time of manifest heart failure are constant, independent on whether injury to the heart was inflicted by single-dose or fractionated irradiation or whether heart failure developed within a relatively short time after high total doses or within many months after low total doses. The latent time of heart failure therefore can be considered an appropriate endpoint for comparison of treatment groups. From experiments giving 1, 2, 4, or 10 dose fractions, a low alpha/beta ratio of 3.7 Gy (95% confidence interval 1.8-5.6 Gy) can be calculated. When the time interval between dose fractions is varied in a split-dose experiment, time intervals of up to 3 h do not increase the survival time significantly. This appears to indicate very slow repair of sublethal damage. On the other hand, it cannot be excluded that pathogenetic mechanisms independent of cell death in the renewing cell population contribute to this effect, making an interpretation of the alpha/beta ratio in terms of cell survival parameters of a defined target cell population difficult.

Animals↗
PubMed1992

Post-irradiation hyperamylasemia as a biological dosimeter.

Serum alpha-amylase was measured before and 24 h after either total body (31 patients) or localized irradiation including the salivary glands (40 patients) or the pancreatic area (22 patients). A significant increase in amylasemia was observed for doses to the parotid glands larger than 0.5 Gy. A sigmoid function of dose was fitted to the data and predicted a maximum amylasemia level for doses larger than 4 Gy and smaller than 10 Gy. The raw data from other published series were adequately described by the same model. However, the confidence limits of the parameters remained wide, because of a considerable interindividual variability. Post-irradiation hyperamylasemia appears to provide a good criterion for triage of accidentally irradiated patients: 24 h after a dose larger than 2 Gy to the parotid glands, 91% of the patients had an amylasemia level higher than 2.5-fold the upper normal value (sensitivity). Conversely, 96% had their serum amylasemia lower than 2.5-fold the upper normal value when dose was smaller than 2 Gy (specificity). However, a retrospective estimation of the absorbed dose (dosimetry) is not likely to be very precise because of the large interindividual variability.

Adult↗
PubMed1992

Can modest escalations of dose be detected as increased tumor control?

Clinically defined groups of tumors are usually characterized by shallow dose-response curves, and this results from heterogeneity among individual dose-response curves, each of which is very likely quite steep. A review of published results for human tumors indicates that a 10% escalation of dose to tumors controlled at the 50% level, where changes in outcome are most likely to be detected, will be detectable in a population of unselected patients only in sizable clinical trials (130-300 patients per dose level). With a few exceptions, a dose escalation of 20% will be detectable in much smaller trials (50-130 patients per dose level). Therefore, clinical trials of improved treatment modalities will be confounded by patient heterogeneity, and modest improvements may go undetected in all but the largest trials. Mathematical modeling was used to study the effect on the steepness of the dose-response curve of selecting patients on the basis of the radiosensitivity measure SF2 (surviving fraction at 2 Gy). If SF2 is a faithful predictor of response in a group of tumors, then heterogeneity could be reduced by excluding the patients with the most sensitive (controlled with near certainty) and most resistant (recurring with near certainty) tumors. The resulting "stochastic fraction" (tumors for which treatment outcome is probabilistic) would be characterized by a steep dose response, and the number of patients required to demonstrate the effect of dose escalation would be substantially reduced (by about 50%).

Dose-Response Relationship, Radiation↗
PubMed1992

Evidence for individual differences in the radiosensitivity of human skin.

Previously published clinical data have been re-analysed to investigate individual differences in the radiosensitivity of human skin. In the clinical studies, acute and late skin reactions were recorded for 254 breast cancer patients receiving radiotherapy to the internal mammary nodes following simple or modified radical mastectomy. Each patient was treated bilaterally with different fractionation schedules to the right and left fields. Patients were assigned prospectively to 10 different treatment groups of 11-35 patients each, with all patients in a group receiving the same pair of fractionation schedules to the right and left fields. In the present study, correlations between the skin reactions in the two treatment fields per patient were investigated. For each of three different endpoints--peak reflectance measure of erythema, peak acute skin reaction score, and a ranking measure of the progression rate of telangiectasia--significant correlations were found between the levels of skin injury to the right and left treatment fields of the patients in most treatment groups. Although there were correlations between the absorbed doses in the right and left fields, statistical analyses indicated that dose effects were not sufficient to explain fully the patient-to-patient differences in skin response. Thus, these data provide evidence for the existence of individual differences in the radiation response of human skin, both for early and late effects. Whether these differences are dominated by heterogeneity in intrinsic cell radiosensitivity or by other factors has yet to be determined. However, there was no clear evidence of a correlation between the acute and late endpoints, suggesting that the individual differences in radiosensitivity are not dominated by a common genetic component expressed equally in all cells.

Breast Neoplasms↗
PubMed1991

Syngeneic and allogeneic bone marrow engraftment after total body irradiation: dependence on dose, dose rate, and fractionation.

Murine bone marrow chimera models were used to assess the efficacy of host total body irradiation (TBI) given at different doses, dose rates, and fractionation schemes in providing for engraftment of syngeneic and allogeneic bone marrow. B6-Hbbd congenic and LP mice, respectively, were used as donors (10(7) bone marrow cells) for syngeneic and allogenic (H-2 compatible) transplantation in standard B6 recipients. Stable marrow chimerism was determined from host and donor stem cell-derived hemoglobin phenotypes (Hbbs and Hbbd) on gel electrophoresis at 3 months posttransplant. Partial engraftment of syngeneic marrow was seen at single doses as low as 2 Gy, with the donor component increasing steadily with increasing TBI dose to a level of 100% at 7 Gy. Immunologic resistance of the host appeared to prevent allogeneic engraftment until 5.5 Gy. A very steep radiation dose response was then observed so that the level of chimerism with 6 Gy and above became comparable with syngeneic engraftment. Low dose rate (5 cGy minute-1) and fractionated TBI required higher total doses for equivalent engraftment (radiation dose-sparing) in both syngeneic and allogenic bone marrow transplantation. This displacement in the dose-response curve on fractionation was seen with interfraction intervals of 3 and 6 hours. A further dose-sparing effect was observed on extending the interval to 18 and 24 hours, but only for allogeneic transplantation, and may therefore be related to recovery of immune-mediated graft resistance. The involvement of multiple target cell populations in determining allogenic engraftment rendered the application of the linear-quadratic model for radiation cell survival problematic in this case. The recovery in dose when low dose rate and 6-hour interfraction intervals were applied in either syngeneic or allogeneic BMT is consistent with appreciable sub-lethal damage repair in the primitive self-renewing stem cell population of the host marrow. These results contrast with the poor repair capacity of the 11-day spleen colony-forming units (CFUs) population after fractionated irradiation and support the notion that ablation of early stem cells in the pre-CFUs compartment is essential for long-term marrow engraftment.

Animals↗
PubMed1991

Clinical evidence for tumor clonogen regeneration: interpretations of the data.

A therapeutic gain is expected from accelerated fractionation in radiotherapy because of reduced times for proliferation of tumor clonogens and the likelihood that the late effects of radiation are unaffected by changes in overall time. While there can be no dispute over the existence of the phenomenon, there are questions about the ways clinical data have been interpreted to adduce the influence of proliferation. Moreover, recent clinical and experimental evidence throw some doubt on the assumption that late effects are independent of overall treatment time. It is concluded that some of the issues remain in doubt, and that rather large-sized phase-III trials may be required to show any benefit from reductions in the overall time, especially if this is accompanied by substantial reductions in the total dose.

Carcinoma, Squamous Cell↗
PubMed1991

Clinical radiobiology of squamous cell carcinoma of the oropharynx.

Local tumor control is analyzed in a series of 181 patients treated with definitive megavoltage radiotherapy (RT) for histologically proven squamous cell carcinoma of the oropharynx. Considerable variation in treatment time stemmed from the general use of a split-course technique in 49 patients treated from 1978 to 1985. Incomplete follow-up, in those patients alive and well at the termination of the study or who have died from metastases or intercurrent disease before developing a local recurrence, was allowed for by using a multi-variate mixture model. The tumor control probability (TCP) after radiotherapy showed a significant dependence on the following tumor and treatment characteristics: (a) tumor size: the number of tumor target cells increases approximately as the fourth root of estimated tumor volume; (b) sex: the estimated TCP in males is lower than in females with the same characteristics; (c) histopathological differentiation: well-differentiated tumors have a lower TCP than poorly and intermediately differentiated; (d) hemoglobin concentration: patients in the upper normal range have a significantly higher TCP than others; (e) total dose: there is a significant dose-response relationship; and (f) overall treatment time: TCP decreased with increasing overall time, the dose equivalent of proliferation with 2 Gy per fraction was 0.68 Gy/day with 95% confidence limits [0.05, 1.3] Gy/day. The TCP did not depend significantly on subsite within the oropharynx or nodal disease at presentation. The data were consistent with an alpha/beta ratio of the linear-quadratic model of 10 Gy.

Carcinoma, Squamous Cell↗