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.

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.

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 ( BED) based on the minimum survival achieved by the implant that is equivalent to, and can be compared and combined with, the BED calculated for a fractionated course of radiation treatment.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.