Point dose variations with time during traditional brachytherapy for cervical carcinoma.

In traditional brachytherapy for carcinoma of the cervix, doses are often prescribed to specifically chosen points (A and B) and the normal tissue tolerance calculated at specific reference points in the bladder and rectum. These tolerance doses are often used to modify the brachytherapy treatment plan. It is inherently assumed that the position of the brachytherapy applicator does not change in relation to the relevant anatomical structures over the time-course of an implant. To assess the accuracy of this assumption, 2 sets of localization films were obtained for each implant in 28 patients, 1 prior to loading and another after the removal of the radioactive sources. Significant applicator movement and, consequently, significant dose variations were ob: served. Therefore, isolated one-time dose measurements to normal critical structures should not be used as the sole basis for making therapeutic decisions. The magnitude of dose variations and their clinical significant are discussed.

Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation.

To determine whether intratracheal (IT) lung protective manganese superoxide-plasmid/liposomes (MnSOD-PL) complex provided 'bystander' protection of thoracic tumors, mice with orthotopic Lewis lung carcinoma-bacterial beta-galactosidase gene (3LL-LacZ) were studied. There was no significant difference in irradiation survival of 3LL-LacZ cells irradiated, then cocultured with MnSOD-PL-treated compared with control lung cells (D0 2.022 and 2.153, respectively), or when irradiation was delivered 24 h after coculture (D0 0.934 and 0.907, respectively). Tumor-bearing control mice showed 50% survival at 18 days and 10% survival at 21 days. Mice receiving liposomes with no insert or LacZ-PL complex plus 18 Gy had 50% survival at 22 days, and a 20% and 30% survival at day 50, respectively. Mice receiving MnSOD-PL complex followed by 18 Gy showed prolonged survival of 45% at 50 days after irradiation (P < 0.001). Nested RT-PCR assay for the human MnSOD transgene demonstrated expression at 24 h in normal lung, but not in orthotopic tumors. Decreased irradiation induction of TGF-beta1, TGF-beta2, TGF-beta3, MIF, TNF-alpha, and IL-1 at 24 h was detected in lungs, but not orthotopic tumors from MnSOD-PL-injected mice (P < 0.001). Thus, pulmonary radioprotective MnSOD-PL therapy does not provide detectable 'bystander' protection to thoracic tumors.

Inhibition of peridural fibrosis after laminectomy using low-dose external beam radiation in a dog model.

OBJECTIVE: Clinical studies have demonstrated a significant association between the presence of extensive postlumbar discectomy peridural scar formation and the recurrence of low back and radicular pain. Low-dose perioperative radiation therapy has previously been demonstrated to inhibit peridural fibrosis after laminectomy in a rat model. The current study was designed to measure the effect of low-dose radiation on postlaminectomy peridural fibrosis development in a larger animal model. METHODS: Three dogs underwent a total of 12 lumbar hemilaminectomies. For each animal, two levels received 1) external beam radiation 24 hours before surgery, 2) surgery alone, or 3) radiation alone. Radiation was administered in a single fraction of 700 cGy using computed tomographic guidance for dosimetry planning. The isodose distribution was such that the dose conformed to the posterior epidural space with minimal exit dose to normal tissue. Port films were used to confirm the correct levels. Gadolinium-enhanced magnetic resonance imaging (MRI) of the lumbar spines was obtained before the animals were killed 12 weeks after surgery. The spines were harvested, and axial sections through the laminectomy defect were stained with hematoxylin and eosin and Masson's trichrome. All specimens were evaluated for extent of fibrosis along the dura, density of fibrosis, nerve root entrapment, and sublaminar fibrosis. RESULTS: There were no complications from the surgery, and no new neurological deficits were noted. There was a statistically significant difference between the irradiated and nonirradiated groups regarding the extent of fibrosis (P = 0.001) and the density of fibroblasts (P = 0.001). There was also a marked difference in nerve root entrapment (P = 0.182) and the presence of sublaminar fibrosis (P = 0.061) between the treatment and control groups. MRI revealed less gadolinium enhancement at the irradiated levels compared with the nonirradiated levels, confirming the usefulness of MRI in predicting the degree of epidural fibrosis. CONCLUSION: Low-dose external beam radiation therapy administered 24 hours before laminectomy in a dog model significantly decreased the extent and density of peridural fibrosis as well as nerve root entrapment and sublaminar fibrosis. This treatment strategy may be efficacious in patients with recurrent radicular pain after lumbar discectomy that is thought to be secondary to peridural fibrosis on the basis of gadolinium-enhanced MRI studies, and who might benefit from reoperation for nerve root decompression.

Results of multifield conformal radiation therapy of nonsmall-cell lung carcinoma using multileaf collimation beams.

A five-field conformal technique with three-dimensional radiation therapy treatment planning (3-DRTP) has been shown to permit better definition of the target volume for lung cancer, while minimizing the normal tissue volume receiving greater than 50% of the target dose. In an initial study to confirm the safety of conventional doses, we used the five-field conformal 3-DRTP technique. We then used the technique in a second study, enhancing the therapeutic index in a series of 42 patients, as well as to evaluate feasibility, survival outcome, and treatment toxicity. Forty-two consecutive patients with nonsmall-cell lung carcinoma (NSCLC) were evaluated during the years 1993-1997. The median age was 60 years (range 34-80). The median radiation therapy (RT) dose to the gross tumor volume was 6,300 cGy (range 5,000-6,840 cGy) delivered over 6 to 6.5 weeks in 180-275 cGy daily fractions, 5 days per week. There were three patients who received a split course treatment of 5,500 cGy in 20 fractions, delivering 275 cGy daily with a 2-week break built into the treatment course after 10 fractions. The stages of disease were II in 2%, IIIA in 40%, IIIB in 42.9%, and recurrent disease in 14.3% of the patients. The mean tumor volume was 324.14 cc (range 88.3-773.7 cc); 57.1% of the patients received combined chemoradiotherapy, while the others were treated with radiation therapy alone. Of the 42 patients, 7 were excluded from the final analysis because of diagnosis of distant metastasis during treatment. Two of the patients had their histology reinterpreted as being other than NSCLC, 2 patients did not complete RT at the time of analysis, and 1 patient voluntarily discontinued treatment because of progressive deterioration. Median follow-up was 11.2 months (range 3-32.5 months). Survival for patients with Stage III disease was 70.2% at 1 year and 51.5% at 2 years, with median survival not yet reached. Local control for the entire series was 23.3+/-11.4% at 2 years. However, for Stage III patients, local control was 50% at 1 year and 30% at 2 years. Patients who received concurrent chemotherapy had significantly improved survival (P = 0.002) and local control (P = 0.004), compared with RT alone. Late esophageal toxicity of > or =Grade 3 occurred in 14.1+/-9.3% of patients (3 of 20) receiving combined chemoradiotherapy, but in none of the 15 patients treated with RT alone. Pulmonary toxicity limited to Grades 1-2 occurred in 6.8% of the patients, and none developed > or =Grade 3 pulmonary toxicity. Patients with locally advanced NSCLC, who commonly have tumor volumes in excess of 200 cc, presenta challenge for adequate dose delivery without significant toxicity. Our five-field conformal 3-DRTP technique, which incorporates treatment planning by dose/volume histogram (DVH) was associated with minimal toxicity and may facilitate dose escalation to the gross tumor.

Inhibition of peridural fibrosis after laminectomy using low-dose external beam radiation in a rat model.

OBJECTIVE: Clinical studies have revealed a significant association between the presence of extensive postlumbar discectomy peridural scar formation and the reoccurrence of low back and radicular pain. Low-dose perioperative radiation therapy has been shown to inhibit scar formation. Its effect on peridural fibrosis, however, has not been studied. METHODS: Thirty male Sprague-Dawley rats underwent L5 laminectomies. Ten rats each received a single fraction of 700-cGy external beam radiation to the lumbar spine 24 hours before surgery; 10 rats each received 700 cGy 24 hours after surgery. The remaining 10 rats served as a control group. All of the rats were killed 30 days after surgery. The spines were harvested, and axial histological sections through the laminectomy defect were evaluated. Each specimen was scored for extent, density, and arachnoidal involvement by fibrosis. RESULTS: There was a statistically significant difference between the treatment and control groups regarding the extent of fibrosis along the dura (P < 0.001), the density of fibroblasts (P < 0.005), and the arachnoid involvement (P < 0.01). There was no difference in fibrosis reduction between the groups receiving pre- and postlaminectomy radiation. CONCLUSION: Low-dose external beam radiation therapy administered before or after laminectomy in a rat model significantly decreases the extent, density, and arachnoidal involvement of peridural fibrosis. This technique may improve the outcome of patients who undergo reoperations for recurrent radicular and/or low back pain after successful lumbar discectomy in whom there is a significant amount of peridural fibrosis.

Considerations in optimizing radiation therapy for non-small cell lung cancer.

Irradiation therapy for lung cancer is mostly restricted to conventional methods. To improve therapeutic ratio, we have combined a treatment planning and a gene therapy approach. Three-dimensional conformal radiotherapy is described as carried out by methods of gene therapy for radiation protection using the manganese-superoxide-dismutase transgene delivered by inhalation gene transfer. These methods may improve therapeutic outcomes in lung cancer.

Dosimetric consequences of 10B(n, alpha)7Li reaction occurring at the cellular membrane.

PURPOSE: Microdosimetric expectations of Boron contents are extracted from a CRAY-Monte Carlo simulation of the nuclear reaction 10B(n, alpha)7Li as it occurs on a boronated membrane of a model cell and as the reaction fragments (alpha and Li) traverse into the cellular nucleus. METHODS AND MATERIALS: The present microdosimetry calculation is based upon the assumption that the therapeutic advantage of boron neutron capture therapy (BNCT), while depending upon the RBE and LET of the reaction particles, is equally dependent on the boron carrier preferential localization to tumor tissue, and the boron selectivity to cancerous cells and its specificity within subcellular compartments. In particular, boron fixes to cell membrane as it ought to, using monoclonal antibodies. The present Monte Carlo simulation computes stochastic expectations of alpha/Li energy depositions to the nucleus in a uniformly boronated membrane shell of a spherical cell. Differential energy gain was deduced from the stochastic energy depositions in events of neutron reactions with membrane boron compared against those with natural elements (O, H, N) in the cell. RESULTS: Microdosimetry data are presented in terms of specific energy (keV/micron3) and lineal energy (keV/micron) functions of the nucleus-to-cell volume ratios (NCVR). When folded with the geometric boron content and accounting for background reaction energies, the distributions yield effective energy gain to the cell nucleus per neutron capture event. Boron amount required to yield these energy gains are found to be of the order of picograms of boron per gram of cell mass. CONCLUSION: The boron content as inferred by the present Monte Carlo microdosimetry compares well with that deliverable by present pharmacokinetic means, but are orders of magnitude (mu-grams) less than those deduced previously from anthropomorphic macrodosimetry.

Transmission block technique for the treatment of the pelvis and perineum including the inguinal lymph nodes: dosimetric considerations.

Radical radiotherapy of pelvic malignancies (e.g., vulva, anus) includes therapeutic dosage to the inguinal nodes. To minimize the dosage to the femoral head, the transmission block technique has been developed to fully irradiate the central pelvis midplane and inguinal nodes. Originally, this technique compensated for dose inhomogeneity in the transverse plane only. In some patients, however, we have observed a significant dose variation along the sagittal plane. The authors have developed a lead compensation technique to homogenize the sagittal dose variations due to the longitudinal sloping in the patient, along with further refinements in this technique. Dosimetric and technical details are also discussed.

Predicted dose-volume isoeffect curves for stereotactic radiosurgery with the 60Co gamma unit.

Mathematical models were developed to predict tolerance of brain tissue to stereotactic radiosurgery. The use of these formulas for predicting symptomatic brain necrosis from stereotactic radiosurgery with the 60Co gamma unit is discussed. Predicted dose-response curves for different collimator sizes were calculated. Dose-volume isoeffect curves for a 3% risk of brain necrosis from a single fraction radiosurgery were then derived. Dose-volume isoeffect curves for combinations of fractionated whole brain irradiation with radiosurgery boosts were also calculated. The predicted dose-volume isoeffect curves provide useful tolerance guidelines for the practice of stereotactic radiosurgery.

Treatment volume shaping with selective beam blocking using the Leksell gamma unit.

The Leksell gamma unit at the University of Pittsburgh uses 201 highly focused 60Co beams arranged in a hemispherical array. Selective beam blocking can be used to modify the treatment volume into ellipsoid shapes oriented in different directions to match better the shape of the target volume. Dose distributions for different blocking patterns were calculated using specially developed computerized 3-D treatment planning software. The changes in dose distribution with different blocking patterns predicted by computer were verified by film densitometry. Techniques for using selective beam blocking to match more closely the treatment volume to the intended target volume have the potential of reducing the likelihood of complications for radiosurgery with the Leksell gamma unit and need to be further developed.

Clinical use of a wing field with transmission block for the treatment of the pelvis including the inguinal node.

Treatment planning of photon and electron beams to include the pelvis and the groin poses a technical difficulty of positioning beams, and a dosimetric problem of abutting fields at the groin. We have analyzed a simpler AP/PA method using a central transmission block. The posterior portal is smaller and opposes only the pelvic portion of the anterior portal under the transmission block, while the anterior extended portion (hence the wing) is unattenuated to treat the inguinal region. By calculating the attenuation thickness according to the patient's separation and the beam quality, the dose distribution is tailored to yield the proper dose to the pelvic mid-plane and the inguinal nodes while minimizing the dose to the femora. Measured dose distribution (6MV) using film dosimetry in a tissue-equivalent phantom indicates that a 30% hot spot is created by the posterior portal diverging into the wings of the anterior field. Therefore, the pelvic attenuator is tapered at its lateral edges, thereby significantly reduced the dose inhomogeneity (5%) at the groin. Clinical methods are outlined for the verification of the patient portal films against possible mismatch in beam divergence.

Separation of dose-gradient effect from beam-hardening effect on wedge factors in photon fields.

It is known experimentally that a wedge transmission factor depends upon the field size and depth of measurement in particular. Dependence of the transmission upon depth has been attributed to a hardening of the incident beam through the filter, which preferentially absorbs the low-energy photon of the bremsstrahlung component of that beam. We have attempted to separate this hardening effect from that of increased phantom scatter due to dose gradient induced by the wedge filter. Using an experimental wedge machined from cerrobend, the filter transmission at depth is measured and redefined relative to an "equally hardened" beam, obtained by filtering through a flat slab of equal thickness at the center of the wedge. Results of the Co-60, 4-, and 8-MV wedged beams indicate that nearly half of the increase in the transmission at depth is due to the effect of dose-gradient scatter in polystyrene phantom. Based on a simple relationship between primary and scattering radiation, an algebraic presentation is indeed in support of the dose gradient resulting in apparent increase in the wedge factors, at depth.

Treatment planning for gamma knife radiosurgery with multiple isocenters.

Many arteriovenous malformations and tumors suitable for radiosurgical treatment have non-spherical or irregular shapes. Forty-eight percent of the first 156 patients treated with the gamma unit at the University of Pittsburgh required treatment with two or more isocenters to optimize dose distributions. Dose distributions for combining gamma knife treatments to two or more isocenters were systematically investigated. High speed computerized dosimetry was performed using specially developed software and dose distributions were confirmed with film densitometry. We have developed guidelines for treatment to two or more isocenters which help reduce treatment planning time, and facilitate selection of treatment doses and optimum dose distributions. These guidelines include maintaining an account of the distances between all isocenters, using a catalogue of sample two-isocenter isodose plans, comparing dose volume histograms, and calculating complication probabilities using the integrated logistic formula.

Use of normalized total dose to represent the biological effect of fractionated radiotherapy.

There are currently a number of radiobiological models to account for the effects of dose fractionation and time. Normalized total dose (NTD) is not another new model but is a previously reported, clinically useful form in which to represent the biological effect, determined by any specific radiobiological dose-fractionation model, of a course of radiation using a single set of standardized, easily understood terminology. The generalized form of NTD reviewed in this paper describes the effect of a course of radiotherapy administered with nonstandard fractionation as the total dose of radiation in Gy that could be administered with a given reference fractionation such as 2 Gy per fraction, 5 fractions per week that would produce an equivalent biological effect (probability of complications or tumor control) as predicted by a given dose-fractionation formula. The use of normalized total dose with several different exponential and linear-quadratic dose-fraction formulas is presented.

Physics of gamma knife approach on convergent beams in stereotactic radiosurgery.

The Presbyterian-University Hospital of Pittsburgh installed the first clinically designated Leksell gamma knife in the U.S. in August 1987. Gamma knife radiosurgery involves stereotactic target localization with the Leksell frame and subsequent closed-skull single-treatment session irradiation of a lesion with multiple highly focused gamma ray beams produced from 60Co sources. The hemispherical array of sources, the large number of small-diameter beams, and the steep dose gradients surrounding a targeted lesion make physical characterization of the radiation field complex. This paper describes the physical features and the operation of the gamma knife as well as the calibration procedures of the very small, well-collimated beams. The results of studies using in-phantom ion chamber, diode, film, and lithium fluoride thermoluminescent dosimetry were all in close agreement. Both single-beam and multiple-beam dose profiles were measured and reported for the interchangeable helmets, which have 4-, 8-, 14-, and 18-mm-diameter collimators. We also describe the dose calculation and treatment planning algorithm in the treatment planning system. Measurements of the accuracy of mechanical and radiation alignment are also performed and discussed.

Local stem cell depletion model for radiation myelitis.

We propose a model for normal tissue damage based on the assumption that adult mammalian stem cells have limited mobility and, consequently, for each organ, there is a maximum volume (the "critical volume," Vc), that can be repopulated and repaired by a single surviving stem cell. This concept is applied to a simple, 1-dimensional model of the spinal cord, where the critical volume is a "slice" of "thickness," t, assumed to be small compared to lengths of spinal cord usually irradiated clinically. The probability of myelitis is explicitly obtained as a function of the dose, dose per fraction, length of cord irradiated, slice thickness, number of stem cells per slice and parameters alpha and beta of the stem cell survival curve. The complication probability is expressed as a triple negative exponential function of dose analogous to the double negative exponential function for tumor control, resulting in a steep dose-response curve with short tails in both the high dose and low dose regions. We show that the model predictions are compatible with the experimental data for radiation myelitis in the rat. We discuss how this concept can be applied to other organs such as skin and to organs composed of structurally and functionally distinct subunits, such as the kidney.