Time-dose Relationships Research Articles

Carcinoma of the larynx: Results of treatment and time-dose relationships

Carcinoma of the larynx: Results of treatment and time-dose relationships

Dose response relationships in radiotherapy: Applications of a logistic regression model

A logistic regression method has been developed to analyze time-dose relationships in clinical data. The method determines the form for the time-dose isoeffect curve; it provides confidence limits for its estimates and is sufficiently flexible to include additional co-variates such as tumor size. The method is applied to an example of clinical data, and to simulated data designed to test its ability to detect non-linear, non-monotonic, non-parallel iso-effect lines.

Dose-time relationships for post-irradiation cutaneous telangiectasia

Seventy-five patients who had received electron beam radiation a year or more previously were studied. The irradiated skin portals were photographed and late reactions graded in terms of the number and severity of telangiectatic lesions observed. The skin dose, number of fractions, overall treatment time and irradiated volume were recorded in each case. A Strandqvist-type iso-effect line was derived for this response. A multi-probit search program also was used to derive best-fitting cell population kinetic parameters for the same data. From these parameters a comprehensive iso-effect table could be computed for a wide range of treatment schedules including daily treatment as well as fractionation at shorter and longer intervals; this provided a useful set of normal tissue tolerance limits for late effects.

The response of experimental animal tumors to neutron radiation therapy

Several transplantable rodent neoplasms have been treated with photons and 142-15 MeV D-T or cyclotron produced neutrons, using single doses as well as a variety of fractionation schemes and total treatment times which approach the time-dose relationships utilized in radiotherapy of human tumors. Several endpoints of response have been studied, including tumor growth delay, local tumor control and clonogenic cell survival. Responses of normal tissue, particularly skin and lung, have been used to calculate therapeutic gain factors (TGF = neutron RBE tumor/neutron RBE normal tissue). The initial single fraction studies emphasized determinations of RBE and OER and corroborated the existence of an hypoxic fraction of cells in most solid tumors which limited the effectiveness of photon treatment. TGF's were found to be considerably larger than 1.0, due to neutron RBE's as high as 3.8 for tumor damage, based principally on existence of these hypoxic cells. Extensive fractionation scheme studies have been done with a few tumor lines, including C3H mouse mammary carcinomas and R-1 rhabdomyosarcomas. The importance of hypoxia, reoxygenation, and tumor cell repopulation changes have been most thoroughly studied. However, neutron KBE's for different endpoints in the same tumor system as well as RBE and TGF for various fractionation schemes vary in a manner not easily predicted. This variability is due mostly to fluctuation in response to photons; tumor damage by neutrons varies much less as a function of fractionation scheme. This complexity of tumor response to radiation has made it difficult to select criteria which would indicate which tumors are good candidates for neutron therapy. The studies of reoxygenation in C3H mammary tumors have done much to clarify the basis of low TGF for many fractionated neutron regimes used with those tumors. Other aspects of tumor radiobiology and dose limitation by different normal tissues need to be examined using fractionated radiation.

Time-dose relationships for the cure of an experimental rat tumor with fractionated radiation

A detailed analysis has been carried out of tumor cure doses for three fractions per week X-ray treatments of an experimental rhabdomyosarcoma in rats. The tumor cure doses rise sharply between 1 and 5 days, have a slight dip at 10 days, and then rise steadily from 10 to 50 days. The 10–50 day portion of the time-dose relationship appears to be linear when plotted on a linear coordinate plot of tumor cure dose versus time; the time-dose relationship is not linear when plotted on log-log coordinates. Because a constant number of fractions/week were used in all fractionation schemes, the relative importance of time and fraction number could not be assessed directly. An analysis of the tumor cure time-dose relationship and the known in vivo and in vitro characteristics of the tumor cells suggests that there is effective reoxygenation in fractionation schemes longer than 10 days, and that repair of sublethal damage is a more important factor in the increases of the tumor cure dose with fractionation than is repopulation between treatments. A comparison of these tumor cure time-dose relationships with previously published normal tissue tolerance time-dose relationships shows that three fraction/week treatments lasting 5–33 days give no better and often worse results than single doses, but that a three fraction/week treatment lasting 50 days gives dramatically better “therapeutic results”.

Proceedings: Time-dose relationships for spinal cord damage.

Proceedings: Time-dose relationships for spinal cord damage.

Radiation-related pericardial effusions in patients with Hodgkin's disease.

Pericardial effusions following radiotherapy for Hodgkins Disease have previously been described as infrequent and related to the total dose of radiation received. Analysis of all chest x-rays on 81 patients who received upper-mantle radiotherapy for Hodgkins Disease at the Baltimore Cancer Research Center between 1968 and 1972 disclosed an incidence of pericardial effusions of 30.9% (25 of 81), with 13.6% (11 of 81) requiring limitation of activity (5) or pericardiectomy (6). Clinical presentation of radiation-related percardial effusions was subtle, with signs and symptoms a late finding if they occurred. Radiotherapy data was reviewed and no difference in total dose (rads) or time-dose relationships (rets) was found between the groups who did or did not develop effusions. Analysis of multiple pre-treatment clinical and pathological characteristics disclosed four parameters that were felt to be related to the development of pericardial effusions; elevated ESR, normal absolute lymphocyte count, initial presence of extensive mediastinal adenopathy and the addition of adjuvant chemotherapy. The presence of increasing combinations of these pretreatment 'risk factors' led to an increasing likelihood of developing a radiation-related pericardial effusion such that six of seven patients with all four 'risk factors' developed a pericardial effusion. Nine of 13 clinically significant effusions were associated with the addition of adjuvant chemotherapy. Possible pathogenetic mechanisms that include factors other than radiation dosage and the clinical management of radiation-related pericardial effusions are discussed.

Dose-time relationships for skin reactions and structural damage in rat feet exposed to 250-kVp x rays.

The effects of fractionated irradiation on the feet of rats were the subjects of a time-dose study. The doses required to produce various levels of early skin damage, late skin damage, and late structural damage were determined for single doses and for treatments employing three fractions per week and lasting up to 50 days. The data did not follow the relationship first proposed by strandqvist, in which dose is proportional to time-n; rather, when the normal-tissue reactions were plotted on a linear-coordinate graph, they formed parallel time-dose isoeffect curves with distinct positive curvatures.

Brain tumors in children: analysis of 136 cases.

Between 1960 and 1971, 137 children with inoperable or partially resectable brain tumors were treated in the Division of Therapeutic Radiology at Duke University. The treatment approach to each major type of tumor is discussed, including radiotherapy techniques and time-dose relationships. Results are presented with regard to survival time, complications of radiation, symptomatic relief and quality of survival. Particular emphasis is placed on the question of retreatment and tolerance of the brain to irradiation.

The results of split-course radiation therapy in cancer of the lung.

T HE primary role of radiotherapy in the patient with advanced carcinoma of the lung is to offer palliation of distressing symptoms. This palliation may be expressed in terms of prolongation of survival, if relief of symptoms is also obtamed. Occasionally, aggressive palliative therapy may result in a cure or a long term survival. Since most carcinomas of the lung have limited radiosensitivity, for effective palliation the dosage has to be of a moderately high level. Various time-dose relationships with standard daily fractionation and splitcourse radiotherapy have been employed.”35’7 The aim of palliation for the patient with lung cancer is to achieve effective relief of symptoms with minimal morbidity from the treatment, and limitation of the time and cost involved for an individual who is probably incurable. At the same time it is felt valid not to jeopardize his chances for cure if a cure is possible. If survival is the objective, then it is important that relief of symptoms are also obtained and that a significantly greater survival is achieved than with no therapy at all. Radiotherapists utilizing split-course treatment for lung carcinomas have reported variable results. A high order of palliation has been achieved with improved survival’ and on the other hand the palliation and survival have been at least as good as with conventional irradiation.4’5’7Certain advantages, however, are inherent in the split-course approach: a planned rest period allows reactions to improve and a positive attitude on the patient’s behalf to further treatment; persistent severe reactions or a poor response after the rest period may determine a less aggressive policy or a radical approach may be adopted if the tumor response appears to warrant it. The present report deals with a series of patients treated by the split-course technique and compares results with a similar group who were treated by a standard daily fractionation regimen. The results have proved satisfactory and it has been possible to draw certain conclusions as to the reason for the variable results reported in the literature. Variations of the splitcourse technique will be discussed and their rationale elaborated upon. Finally, the complications of treatment and methods to avert these are described.

Achievements to be expected from new developments in tumour radiotherapy

A number of possibilities for future improvements of radiotherapeutical tumour treatments are evaluated, with a view of indicating areas where integration of experimental and clinical research might be most fruitful. Such areas are the combinations of radiotherapy with surgery and with chemotherapy, to be based on improved insights into various factors which determine the radioresistance of tumours, e.g. intrinsic cellular radiosensitivity, cell proliferation kinetics, repair of potentially lethal damage, and the presence of anoxic cells. Finally some aspects of time-dose relationships are discussed.

Letter: Comments on the use of a separation coefficient in the analysis of clinical data.

Recently Kagan et al. (1973) proposed a modified approach to the analysis of time-dose relationships in radiation therapy. According to these authors, the Strandqvist and Ellis type of formulae could be interpreted as curves (straight lines in log-log coordinates) which best separate points of successful outcome from points representing failure on time-dose plots of clinical data.

Medulloblastoma: an analysis of time-dose relationships and recurrence patterns.

Forty-three cases of medulloblastoma were retro spectively evaluated. Patients who initially received irradiation to the entire central nervous system had a better survival than those receiving limited irradiation. Patient survival was improved with a dose of 4500 to 5500 rads to the posterior fossa, 3500 rads to the remainder of the brain, and 3000 rads to the spinal cord. There was a 27% complication incidence in 11 patients who received supplemental intrathecal radiogold and their survival has not been significantly better than those who received only external beam therapy to the spinal cord. Reirradiation of intracranial recurrences improved survival, while reirradiation of spinal core recurrences did little to improve survival. Proven intracranial recurrences were all anterior to the posterior fossa. We have concluded that the entire brain should receive 5000 rads, the spine should receive 3500 rads, and recurrences should be accurately localized and retreated by irradiation.

Early changes in the functional vasculature of Walker carcinoma 256 following irradiation.

Early vascular changes in Walker carcinoma 256 of rats were studied following x-irradiation with doses of 250–2,000 rads and at intervals of 6 to 36 hours. It was found that 250 rads produced only a transient decrease in vascular volume and increased permeability. As the dose was increased, vascular volume continued to decrease, accompanied by significantly elevated levels of plasma protein extravasation which were interpreted as a sign of severe endothelial damage. Monitoring vascular changes to indicate loss of endothelial integrity may be helpful in establishing new time-dose relationships.

Radiographic appearance of the chest following extended field radiation therapy for Hodgkin's disease. A consideration of time-dose relationships.

Radiation change in the thorax following extended field radiation therapy for Hodgkin's disease was reviewed retrospectively. All patients were treated with cobalt-60. Strict criteria were established to exclude patients with previous radiation therapy, chemotherapy, evidence of pulmonary parenchymal disease, or inadequate radiogrophic follow-up. Nineteen of 20 patients showed changes; 13 showed evidence of radiation pneumonitis. Nineteen showed evidence of radiation fibrosis or loss of volume. Radiation pneumonitis appeared more frequently at 8-12 weeks following the completion of therapy. Radiation fibrosis was generally established by the ninth to twelth month following the completion of therapy. Two cases of radiation pericarditis were seen. There is a time-dose relationship of the pulmonary parenchymal radiation changes that needs to be further defined.

Time-dose and tumor volume relationships in the irradiation of squamous cell carcinoma of the tonsillar fossa.

Megavoltage irradiation was used in treating 129 patients with squamous cell carcinoma of the tonsillar fossa. The data were analyzed with time-dose scattergrams and by using the nominal standard dose (NSD) to correlate the probability of control of the primary lesion with dose and stage (tumor volume). All early lesions (T1) were controlled with 6,500 rads given in 6.5 weeks. For more advanced disease (T2), 7,000 rads in 7 weeks (or its equivalent) was required in order to obtain a high probability of local control. The largest lesions (T3 and T4) have been most effectively treated with doses of 7,500 rads in 8 weeks (or its equivalent). Complications have been correlated with dose and volume irradiated.

An examination of some dose-time relationships in therapeutic radiology.

Abstract We have compared three representations of dose-time (or fraction number) relations in radiation therapy on published data for cancer of the breast, Hodgkin's disease, squamous cell carcinoma of the aerodigestive tract, and pericardial effusion. The comparison was on the basis of how well each representation separated the two groups of outcomes, success or failure, in each clinical series. As a measure of separation we have used a dimensionless coefficient and calculated its value as a function of the choice of recovery coefficient in the Strandqvist relations and for the Ellis formula. In general, the Strandqvist relations with an optimal value of the recovery coefficient—defined as that value which produces the maximum separation of the two groups of outcomes—give a better separation than the Ellis formula. Our method of analysis provides a unique procedure for estimating the best value for the recovery coefficient. More importantly, it shows whether the separation is sensitive to the choice of ...

Determination of an optimal treatment plan for rat rhabdomyosarcomas.

Experiments with rat rhabdomyosarcomas were conducted to determine time-dose relationships for tumor cures and normal tissue responses. The frequently stated dose α timen relationships were not demonstrated, and no clearly optimal fractionation period can be established for this tumor system at this time. The eventual optimum may depend upon which tissue tolerance isoeffect is considered most important.

Time-dose relationships in combined bleomycin treatment and radiotherapy

The biological effect of bleomycin resembles that of X-ray irradiation indicating that the combination of bleomycin and radiotherapy may have a synergistic effect. In cyclic bleomycin treatment of a murine carcinoma it was found that intermittent bleomycin treatment and radiotherapy results in a simple addition of the therapeutic effects of the two different treatments. Simultaneous treatment, however, results in a synergistic intensifying of the therapeutic effect. The toxicity of bleomycin was found to be unaltered by the regional application of X-ray irradiation.

The determination of time-dose relationships from clinical data.

The problem of determining tumour time-dose isoeffect (Strandqvist, 1944) curves from clinical data has been examined. Initially a detailed discussion of the basic factors underlying the observed results is presented, making use of current radiobiologic concepts. A multiple probit analysis technique is then described for clinical data, and when applied to published results from Hodgkin's disease indicates that the time-dose curve may really be flat. A mathematical model is developed which allows prediction by use of the Monte Carlo technique of the outcome of clinical trials for any given actual time-dose response characteristics and any pattern of choosing treatment conditions. The pitfalls in the traditional methods of analysis of such data can then be shown explicitly and the power of the multi-probit curve method demonstrated. The importance of accurate time-dose data is stressed and the suggestion made that a complete re-evaluation of current concepts may be the most promising approach to improve clinical results in radiation therapy.