Biological Effective Dose for Treatment of a Heterogeneous Population of Cells with a Spread-Out Bragg Peak of Particle Radiation.

Calculation of the biological effective dose (BED) of a fractionated course of hadron particle radiation (e.g., protons or carbon ions) administered via a spread-out Bragg peak (SOBP) to a population of cells with heterogeneous radiosensitivity is described. The calculated BED has the important property that, if equal to that of a course of photon radiation, the particle course will result in the same fraction of cells of the exposed population that survive and can be expected to have the same clinical effect. The calculated BED provides a way to relate the effect of a planned treatment course with particle radiation to clinical experience of the effects of treatment with low-LET photon radiation.

A Microdosimetric-Kinetic Model of Cell Killing by Irradiation from Permanently Incorporated Radionuclides.

An expression for the surviving fraction of a replicating population of cells exposed to permanently incorporated radionuclide is derived from the microdosimetric-kinetic model. It includes dependency on total implant dose, linear energy transfer (LET), decay rate of the radionuclide, the repair rate of potentially lethal lesions in DNA and the volume doubling time of the target population. This is used to obtain an expression for the biologically effective dose ( BEDα/ß) based on the minimum survival achieved by the implant that is equivalent to, and can be compared and combined with, the BEDα/ß calculated for a fractionated course of radiation treatment. Approximate relationships are presented that are useful in the calculation of BEDα/ß for alpha- or beta-emitting radionuclides with half-life significantly greater than, or nearly equal to, the approximately 1-h repair half-life of radiation-induced potentially lethal lesions.

A comparison of mechanism-inspired models for particle relative biological effectiveness (RBE).

BACKGROUND AND SIGNIFICANCE: The application of heavy ion beams in cancer therapy must account for the increasing relative biological effectiveness (RBE) with increasing penetration depth when determining dose prescriptions and organ at risk (OAR) constraints in treatment planning. Because RBE depends in a complex manner on factors such as the ion type, energy, cell and tissue radiosensitivity, physical dose, biological endpoint, and position within and outside treatment fields, biophysical models reflecting these dependencies are required for the personalization and optimization of treatment plans. AIM: To review and compare three mechanism-inspired models which predict the complexities of particle RBE for various ion types, energies, linear energy transfer (LET) values and tissue radiation sensitivities. METHODS: The review of models and mechanisms focuses on the Local Effect Model (LEM), the Microdosimetric-Kinetic (MK) model, and the Repair-Misrepair-Fixation (RMF) model in combination with the Monte Carlo Damage Simulation (MCDS). These models relate the induction of potentially lethal double strand breaks (DSBs) to the subsequent interactions and biological processing of DSB into more lethal forms of damage. A key element to explain the increased biological effectiveness of high LET ions compared to MV x rays is the characterization of the number and local complexity (clustering) of the initial DSB produced within a cell. For high LET ions, the spatial density of DSB induction along an ion's trajectory is much greater than along the path of a low LET electron, such as the secondary electrons produced by the megavoltage (MV) x rays used in conventional radiation therapy. The main aspects of the three models are introduced and the conceptual similarities and differences are critiqued and highlighted. Model predictions are compared in terms of the RBE for DSB induction and for reproductive cell survival. RESULTS AND CONCLUSIONS: Comparisons of the RBE for DSB induction and for cell survival are presented for proton (1 H), helium (4 He), and carbon (12 C) ions for the therapeutically most relevant range of ion beam energies. The reviewed models embody mechanisms of action acting over the spatial scales underlying the biological processing of potentially lethal DSB into more lethal forms of damage. Differences among the number and types of input parameters, relevant biological targets, and the computational approaches among the LEM, MK and RMF models are summarized and critiqued. Potential experiments to test some of the seemingly contradictory aspects of the models are discussed.

Mammalian cell killing by ultrasoft X rays and high-energy radiation: an extension of the MK model.

An alternate formulation of the microdosimetric-kinetic (MK) model is presented that applies to irradiation of mammalian cells with ultrasoft X rays as well as high-energy radiations of variable linear energy transfer (LET). Survival and DNA double-strand break measurements for V79 cells from the literature are examined to illustrate application of the model. It is demonstrated that the linear component of the linear-quadratic survival relationship (alpha) is enhanced because repairable potentially lethal lesions formed from a single ultrasoft X-ray energy deposition event, when closer on average than for a single high-energy radiation event, are more likely to combine to form a lethal lesion. The quadratic component (beta) of the linear-quadratic survival relationship is increased because the potentially lethal lesions formed by ultrasoft X rays are created with greater efficiency than those of high-energy radiation. In addition, potentially lethal lesions from very low-energy carbon K-shell X rays may be enriched in structural forms that favor combination to form lethal lesions instead of repair. These features account for the increased effectiveness of killing of V79 cells by ultrasoft X rays compared to cobalt-60 gamma radiation. The importance of pairwise combination of potentially lethal lesions to form exchange chromosome aberrations that become lethal lesions is discussed. The extended MK model explains and reconciles differences between the MK model and the theory of dual radiation action on the one hand, and on the other, the view that variation in the RBE with radiation quality is explained by differences in energy deposition in nanometer- rather than micrometer-size volumes.

Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: efficacy and associations with chromosomal abnormalities.

PURPOSE: The purpose of this article is to determine the response rate and toxicity of PCV administered before radiation therapy in patients with newly diagnosed LGO/LGOA and to explore correlations between response with 1p/19q deletions and aberrant p53 expression. BACKGROUND: Despite prolonged survival of patients with low-grade oligodendroglioma (LGO) and oligoastrocytoma (LGOA), the majority will succumb to progressive disease. Because procarbazine, lomustine (CCNU), and vincristine (PCV) is active in patients with recurrent LGO/LGOA, we hypothesized that it would be beneficial as primary therapy. METHODS: Adult patients with residual tumor on magnetic resonance imaging scan following biopsy or subtotal resection of LGO/LGOA received up to six cycles of PCV. Radiation therapy (59.4 or 54.0 Gy) began within 10 weeks of completing chemotherapy or immediately if there was evidence of tumor progression on PCV. Tumor tissue was analyzed by fluorescent in situ hybridization for 1p and 19q deletion and by immunohistochemistry for p53 expression. RESULTS: Eight of 28 (29%) and 13 of 25 (52%) eligible patients demonstrated tumor regression as assessed by the treating physician and a blinded central neuroradiology reviewer, respectively. Myelosuppression was the predominant toxicity. Loss of 1p and 19q were associated with LGO but not LGOA (P =.009), were inversely associated with p53 detection, and were not associated with response to PCV (possibly because of the small sample size). CONCLUSION: PCV produces tumor regressions in a meaningful proportion of patients with LGO/LGOA. Toxicity, especially myelosuppression, is significant. Loss of 1p and 19q seems limited to patients with pure LGO and is inversely related to p53 alterations.

The influence of concentration of DNA on the radiosensitivity of mammalian cells.

PURPOSE: To develop relations that explicitly show the dependence of the linear-quadratic survival parameters alpha and beta on the nuclear volume, average DNA concentration, and degree to which the chromatin is condensed in zones of the nucleus. METHODS AND MATERIALS: The microdosimetric-kinetic model of mammalian cell killing is used. RESULTS: The relations indicate an increased tendency for lethal lesions to form by pairwise combination of potentially lethal lesions in regions of relatively greater local DNA concentration. In particular, the value of beta is proportional to the average nuclear concentration of DNA and to a parameter that reflects the condensation of DNA into a relatively concentrated phase, such as occurs in mitotic chromosomes and heterochromatin. These relations indicate local DNA concentration in the nucleus is a significant determinant of three magnitude of beta. Because alpha is composed of a term that is proportional to beta, it is also affected by DNA concentration, generally to equal or less degree. CONCLUSION: It may be possible to establish a correlation between nuclear size and morphology, as determined from microscope slides prepared from biopsy specimens, with radiation sensitivity and the alpha/beta ratio that could be useful in radiation treatment planning.

A microdosimetric-kinetic model for the effect of non-Poisson distribution of lethal lesions on the variation of RBE with LET.

The microdosimetric-kinetic (MK) model for cell killing by ionizing radiation is summarized. An equation based on the MK model is presented which gives the dependence of the relative biological effectiveness in the limit of zero dose (RBE1) on the linear energy transfer (LET). The relationship coincides with the linear relationship of RBE1 and LET observed for low LET, which is characteristic of a Poisson distribution of lethal lesions among the irradiated cells. It incorporates the effect of deviation from the Poisson distribution at higher LET. This causes RBE1 to be less than indicated by extrapolation of the linear relationship to higher LET, and to pass through a maximum in the range of LET of 50 to 200 keV per micrometer. The relationship is compared with several experimental studies from the literature. It is shown to approximately fit their results with a reasonable choice for the value of a cross-sectional area related to the morphology and ultrastructure of the cell nucleus. The model and the experiments examined indicate that the more sensitive cells are to radiation at low LET, the lower will be the maximum in RBE they attain as LET increases. An equation that portrays the ratio of the sensitivity of a pair of cell types as a function of LET is presented. Implications for radiotherapy with high-LET radiation are discussed.

A microdosimetric-kinetic model for cell killing by protracted continuous irradiation II: brachytherapy and biologic effective dose.

Relationships based on the microdosimetric-kinetic model are presented that calculate the average number of lethal lesions, and the associated cell survival, produced in mammalian cells by exposure to protracted continuous irradiation by temporary and permanent implantation of radioactive sources. The influence of cell parameters of linear-quadratic survival, repair function and proliferation rate, as well as the influence of dose rate, isotopic decay rate and linear energy transfer (LET) quality on cell killing are displayed and discussed. An expression for biologic effective dose (BED) is presented that facilitates comparison of the effects of protracted low-dose-rate irradiation and with a course of multiple instantaneously administered radiation treatments (fractions).

A microdosimetric-kinetic model for cell killing by protracted continuous irradiation including dependence on LET I: repair in cultured mammalian cells.

Relations based on the microdosimetric-kinetic (MK) model are presented that describe killing of mammalian cells by protracted continuous exposure to ionizing radiation of varying linear energy transfer quality (LET) at constant dose rate. The consequences of continuous irradiation exposure actually consisting of a discontinuous sequence of events corresponding to passage of each high-energy particle through or near the cell are incorporated into the model. The derived relations are applied to protracted irradiation experiments of Amdur and Bedford to determine the rate of repair of potentially lethal lesions. It is found that as the dose rate becomes less than about 5 Gy per hour the repair rate decreases significantly with decreasing dose rate. This suggests that repair function in these cells is induced and maintained in response to the intensity of irradiation. Clinical and radiation protection implications of this finding are noted.

Effects of dose-delivery time structure on biological effectiveness for therapeutic carbon-ion beams evaluated with microdosimetric kinetic model.

Treatment plans of carbon-ion radiotherapy have been made on the assumption that the beams are delivered instantaneously irrespective to the dose delivery time as well as the interruption time. The advanced therapeutic techniques such as a hypofractionation and a respiratory gating usually require more time to deliver a fractioned dose than conventional techniques. The purpose of this study was to investigate the effects of dose-delivery time structure on biological effectiveness in carbon-ion radiotherapy. The rate equations defined in the microdosimetric kinetic model (MKM) for primary lesions caused in the DNA were reanalyzed and applied to continuous or interrupted irradiation with therapeutic carbon-ion beams. The rate constants characterizing the time of the primary nonlethal lesions to repair or to convert to lethal lesion were experimentally determined for human salivary gland (HSG) tumor cells. Treatment plans were made for a patient case on the assumption that the beam is delivered instantaneously. The RBE weighted absorbed doses of 2.65, 3.45 and 6.86 Gy (RBE) was prescribed to the target. These plans were recalculated by varying the dose delivery time and the interruption time ranging from 1-60 min based on the MKM with the determined parameters. The sum of rate constants for nonlethal lesion to repair a and to convert to lethal lesion c, (a + c), is 2.19 ± 0.40 h⁻¹. The biological effectiveness in the target decreases with the dose delivery time T in continuous irradiation compared to the planned one due to the repair of nonlethal lesions during the irradiation. The biological effectiveness in terms of equivalent acute dose decreases to 99.7% and 96.4% for T = 3 and 60 min in 2.65 Gy (RBE), 99.5% and 94.3% in 4.35 Gy (RBE), and 99.4% and 91.7% in 6.86 Gy (RBE), respectively. For all the cases, the decrease of biological effectiveness is larger at the proximal side with low-LET than the distal side with high-LET. Similar reductions of biological effectiveness with comparable amounts are observed in the interrupted irradiations with prolonged interruption time τ. For the fraction time, i.e., T and/or τ, shorter than 3 min, the decrease of the biological effectiveness with respect to the planned one is less than 1.0%. However, if the fraction time prolongs to 30 min or longer, the biological effectiveness is significantly influenced in carbon-ion radiotherapy, especially with high-prescribed doses. These effects, if confirmed by clinical studies, should be considered in designing the carbon-ion treatment planning.

CHOD/BVAM chemotherapy and whole-brain radiotherapy for newly diagnosed primary central nervous system lymphoma.

PURPOSE: To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL). METHODS AND MATERIALS: Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival. RESULTS: Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity. CONCLUSIONS: This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.

The relationship between the sensitivity of cells to high-energy photons and the RBE of particle radiation used in radiotherapy.

The relationship between relative biological effectiveness in the limit of zero dose (RBE(1)) and the LET of radiation is examined and compared for several cell lines, including cells from patients with ataxia telangiectasia, in the context of a microdosimetric-kinetic (MK) model of cell killing by radiation. Evidence is presented that the sensitivity of a cell to low-LET photon radiation, as measured by the linear parameter of the linear-quadratic cell survival relationship (alpha), is largely determined by its vulnerability to formation of a lethal lesion from transformation of a single potentially lethal lesion (PLL) in DNA, as opposed to formation by combination of two PLL. As a result, the RBE(1) of cells that are relatively less sensitive to low-LET photon radiation increases more with increasing LET than the RBE(1) of cells that are more sensitive to low-LET radiation. As a consequence, a pair of cells that have clearly different sensitivity to low-LET radiation tend to have more nearly the same sensitivity as the LET increases into the range of 100 to 200 keV microm(-1). Cells with the same, or nearly the same, sensitivity to low-LET photon radiation continue to have nearly the same sensitivity as the LET is similarly increased. Thus there may be a radiobiological advantage to treatment with high-LET particle radiation for situations in which the target tumor cells are less radiosensitive than the cells that determine the tolerance of the normal tissue at risk. This may be the case for treatment of many of the common malignancies that occur in adults. This general principle may be helpful in selection of patients for treatment with particle radiation, such as carbon ions, and in the design of clinical trials to determine the optimal dose and fractionation schedules for such treatment.

Phase III trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials.

PURPOSE: In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT). PATIENTS AND METHODS: After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART). RESULTS: Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33). CONCLUSION: Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.

Adjuvant and neoadjuvant treatment of resectable, locally advanced, rectal carcinoma with radiation therapy and chemotherapy.

Patients who undergo apparently curative low anterior or abdominal-perineal resection of locally advanced carcinoma of the rectum have a significant rate of local pelvic recurrence and death from cancer in the years following surgery. Pre- and postoperative irradiation and chemotherapy in various combinations and schedules have been recommended to improve the outcome for these patients. Several randomized trials have evaluated the effectiveness of adjuvant and neoadjuvant treatments in improving survival and reducing the rate of pelvic recurrence with a combination of radiation and chemotherapy. There is some evidence that preoperative treatment with radiation is more effective than postoperative treatment. The treatment program preferred at Ochsner is described.