The efficacy of calcitriol therapy in the management of bone loss and fractures: a qualitative review.

UNLABELLED: Osteoporosis, a skeletal disorder characterized by a reduction in bone strength, increases fracture risk. Primary osteoporosis is usually a result of reduced bone mineral density as a consequence of natural aging. Secondary osteoporosis is usually a result of a disease, such as cystic fibrosis, or medical treatment, such as corticosteroids or cancer treatment. INTRODUCTION: Currently, ten million Americans are osteoporotic and an additional 34 million have the precursor condition, osteopenia. Osteoporosis leads to 1.5 million fractures and 500,000 hospitalizations annually. Osteoporosis-related fractures increase mortality and reduce quality of life. Calcitriol, the active form of vitamin D, regulates intestinal calcium absorption, among other actions. During the past four decades, many clinical trials investigating the effect of calcitriol on bone loss have been performed. METHODS: We conducted a systematic qualitative review of clinical trials that assessed calcitriol for the treatment of osteoporosis and bone loss. In these clinical trials, calcitriol was used as a monotherapy and in combination with other therapeutic bone agents. RESULTS AND CONCLUSION: Studies using calcitriol monotherapy, although not conclusive, found that calcitriol slowed the rate of bone loss in a variety of populations. Calcitriol in combination with other therapeutic bone agents was shown to have additional bone-preserving effects when compared to the use of therapeutic bone agents alone. A common side-effect of calcitriol therapy was hypercalcemia and hypercalciuria, but the degree of hypercalcemia was mild. Recent research found that intermittent dosing can reduce hypercalcemia rates. Calcitriol, alone or in combination with other agents, should be considered for the therapy of osteoporosis.

A non-invasive immobilization system and related quality assurance for dynamic intensity modulated radiation therapy of intracranial and head and neck disease.

PURPOSE: To develop and implement a non-invasive immobilization system guided by a dedicated quality assurance (QA) program for dynamic intensity-modulated radiotherapy (IMRT) of intracranial and head and neck disease, with IMRT delivered using the NOMOS Corporation's Peacock System and MIMiC collimator. METHODS AND MATERIALS: Thermoplastic face masks are combined with cradle-shaped polyurethane foaming agents and a dedicated quality assurance program to create a customized headholder system (CHS). Plastic shrinkage was studied to understand its effect on immobilization. Fiducial points for computerized tomography (CT) are obtained by placing multiple dabs of barium paste on mask surfaces at intersections of laser projections used for patient positioning. Fiducial lines are drawn on the cradle along laser projections aligned with nasal surfaces. Lateral CT topograms are annotated with a crosshair indicating the origin of the treatment planning and delivery coordinate system, and with lines delineating the projections of superior-inferior field borders of the linear accelerator's secondary collimators, or with those of the fully open MIMiC. Port films exposed with and without the MIMIC are compared to annotated topograms to measure positional variance (PV) in superior-inferior (SI), right-left (RL), and anterior posterior (AP) directions. MIMiC vane patterns superposed on port films are applied to verify planned patterns. A 12-patient study of PV was performed by analyzing positions of 10 anatomic points on repeat CT topograms, plotting histograms of PV, and determining average PV. RESULTS AND DISCUSSION: A 1.5+/-0.3 mm SD shrinkage per 70 cm of thermoplastic was observed over 24 h. Average PV of 1.0+/-0.8, 1.2+/-1.1, and 1.3+/-0.8 mm were measured in SI, AP, and RL directions, respectively. Lateral port films exposed with and without the MIMiC showed PV of 0.2+/-1.3 and 0.8+/-2.2 mm in AP and SI directions. Vane patterns superimposed on port films consistently verified the planned patterns. CONCLUSION: The CHS provided adequately reproducible immobilization for dynamic IMRT, and may be applicable to decrease PV for other cranial and head and neck external beam radiation therapy.

Dosimetric verification of the dynamic intensity-modulated radiation therapy of 92 patients.

PURPOSE: To verify that optimized dose distributions provided by an intensity-modulated radiation therapy (IMRT) system are delivered accurately to human patients. METHODS AND MATERIALS: Anthropomorphic phantoms are used to measure IMRT doses. Four types of verification are developed for: I) system commissioning with beams optimized to irradiate simulated targets in phantoms, II) plans with patient-optimized beams directed to phantoms simulating the patient, III) patient-phantom hybrid plans with patient-optimized beams calculated in phantom without further optimization, and IV) in vivo measurements. Phantoms containing dosimeters are irradiated with patient-optimized beams. Films are scanned and data were analyzed with software. Percent difference between verified and planned maximum target doses is defined as "dose discrepancy" (deltavp). The frequency distribution of type II deltavp from 204 verification films of 92 IMRT patients is fit to a Gaussian. Measurements made in vivo yield discrepancies specified as deltaivp, also fit to a Gaussian. RESULTS AND DISCUSSION: Verification methods revealed three systematic errors in plans that were corrected prior to treatment. Values of [deltavp] for verification type I are <2%. Type II verification discrepancies are characterized by a Gaussian fit with a peak 0.2% from the centroid, and 158 [deltavp] <5%. The 46 values of [deltavp] >5% arise from differences between phantom and patient geometry, and from simulation, calculation, and other errors. Values of [deltavp] for verification III are less than half of the values of [deltavp] for verification II. A Gaussian fit of deltaivp from verification IV shows more discrepancy than the fit of deltavp, attributed to dose gradients in detectors, and exacerbated by immobilization uncertainty. CONCLUSIONS: Dosimetric verification is a critical step in the quality assurance (QA) of IMRT. Hybrid Verification III is suggested as a preliminary quality standard for IMRT.

Dosimetric comparison of stereotactic radiosurgery to intensity modulated radiotherapy.

To compare the dosimetry achievable with an intensity modulated radiotherapy (IMR) system to that of stereotactic radiosurgery (SRS) for an irregularly shaped moderate size target. A treatment plan was selected from 109 single fraction SRS cases having had multiple non-coplanar arc therapy using a 6 MV linear accelerator fitted with circular tertiary collimators 1.00 to 4.00 cm in diameter at isocenter. The CT scan with delineated regions of interest was then entered into an IMR treatment planning system and optimized dose distributions, using a back projection technique for dynamic multileaf collimator delivery, were generated with a stimulated annealing algorithm. Dose volume histograms (DVH), homogeneity indices (HI), conformity indices (CI), minimum and maximum doses to surrounding highly sensitive intracranial structures, as well as the volume of tissue treated to > 80, 50, and 20% of the prescription dose from the IMR plan were then compared to those from the single isocenter SRS plan used and a hypothetical three isocenter SRS plan. For an irregularly shaped target, the IMR plan produced a HI of 1.08 and CI of 1.50 compared to 1.75 and 4.41, respectively, for the single isocenter SRS plan (SRS1) and 3.33 and 3.43 for the triple isocenter SRS plan (SRS3). The maximum and minimum doses to surrounding critical structures were less with the IMR plan in comparison to both SRS plans. However, the volume of non-target tissue treated to > 80, 50, and 20% of the prescription dose with the IMR plan was 137, 170, and 163%, respectively, of that treated with the SRS1 plan and 85, 100, and 123% of the volume when compared to SRS3 plan. The IMR system provided more conformal target doses than were provided by the single isocenter or three isocenter SRS plans. IMR delivered less dose to critical normal tissues and provided increased homogeneity within the target volume for a moderate size irregularly shaped target, at the cost of a larger penumbra.

A technique for accurate planning of stereotactic brain implants prior to head ring fixation.

PURPOSE: A two-step procedure is described for accurate planning of stereotactic brain implants prior to head-ring fixation. METHODS AND MATERIALS: Approximately 2 weeks prior to implant a CT scan without the head ring is performed for treatment-planning purposes. An entry point and a reference point, both marked with barium and later tattooed, facilitate planning and permit correlation of the images with a later CT scan. A plan is generated using a conventional treatment-planning system to determine the number and activity of I-125 seeds required and the position of each catheter. I-125 seed anisotropy is taken into account by means of a modification to the treatment planning program. On the day of the implant a second CT scan is performed with the head ring affixed to the skull and with the same points marked as in the previous scan. The planned catheter coordinates are then mapped into the coordinate system of the second CT scan by means of a manual translational correction and a computer-calculated rotational correction derived from the reference point coordinates in the two scans. RESULTS: The rotational correction algorithm was verified experimentally in a Rando phantom before it was used clinically. For analysis of the results with individual patients a third CT scan is performed 1 day following the implant and is used for calculating the final dosimetry. CONCLUSION: The technique that is described has two important advantages: 1) the number and activity of seeds required can be accurately determined in advance; and 2) sufficient time is allowed to derive the best possible plan.

Response of intracranial melanoma metastases to stereotactic radiosurgery.

We analyzed our recent stereotactic radiosurgery (SRS) experience to determine the radiographic response of intracranial metastatic melanomas to SRS. Twelve patients with 21 intracranial melanoma metastases treated with SRS were evaluated. Fifteen (72%) metastases were hemispheric, 3 (14%) were cerebellar, and 3 (14%) were in the basal ganglion or thalamus. All lesions were 2.5 cm or less in maximum diameter. Eleven patients also had whole brain external beam radiotherapy. Mean SRS dosage was 1,800 cGy to the 85% isodose surface and median dose was 1,800 cGy to the 80% isodose surface (range 1,100-3, 100 cGy at the 80-95% isodose surface). Overall, 12 (57%) lesions showed decrease or stabilization of tumor volume (i.e., local control), while 9 (43%) showed enlargement. Division of metastases into small (< or = 1.0 cm diameter) and large (> 1.0 cm diameter) tumors showed that the small tumors were more likely to regress than the large tumors (chi-square test; P < 0.03). Only 1 of 9 (11%) large lesions regressed as opposed to 7 of 12 (58%) small lesions regressed with SRS. We conclude that SRS is suited for small melanoma brain metastases, but lesions between 1.0 and 2.5 cm in diameter, while still generally considered appropriate for SRS, may not be as responsive to SRS at currently employed dosages.

Radiation therapy of external iliac lymph nodes with lateral pelvic portals: identification of patients at risk for inadequate regional coverage.

PURPOSE: To determine whether "standard" lateral pelvic radiation therapy portals provide adequate margins for treating the external iliac lymph nodes (EILNs). MATERIALS AND METHODS: With computed tomographic (CT) data and a computerized algorithm, the course of the EILN chain was reconstructed in 48 patients. The marginal distance between a consistently localized portion of the EILNs and the anterior field border that was placed at the front of the pubic symphysis was recorded for each patient. RESULTS: The EILNs were covered adequately in only 50% of both men and women. More adequate EILN margins were observed in (a) women older than 68 years, (b) women with small anteroposterior separations, (c) men older than 70 years, and (d) men and women with a low central obesity index. Less adequate margins were observed in men who were obese or men with large anteroposterior separations. In the study population, no correlation was observed for sex, race, or tumor site. CONCLUSION: The authors recommend portals that are designed specifically for patients rather than standard portals that may inadequately cover the intended targets.

A model system that predicts effective half-life for radiolabeled antibody therapy.

Radiolabeled antibodies to tumor associated proteins localize in both experimental and clinical cancers. In the therapeutic applications of radiolabeled antibody, tumor effective half-life (composite of biological and physical half-lives), along with the concentration of isotope deposited and energies of the isotope used, determine the tumor dose. Antibodies directed against the same antigenic specificity but derived from different species have varied tumor and whole body effective half-lives and as a result, achieve different tumor doses. In vitro testing does not evaluate the in vivo differences in effective half-life that affect tumor dose. We have developed an animal model to evaluate the effective half-life and biodistribution of radiolabeled immunoglobulin (IgG) from diverse species. To determine the relevance of such a model, the effective half-lives and tissue distributions of the different immunoglobulins in the model were compared to those obtained from the clinical program using the same radiolabeled antibody preparations. In both the experimental model and in the clinical trials, radiolabeled immunospecific and normal IgG derived from monkey, rabbit, and porcine sources had the longest effective half-lives, goat and sheep had intermediate effective half-lives, and chicken and turkey had the shortest effective half-lives. Prescreening of bovine and baboon normal IgG predict long half-lives and similar organ distributions. These species have been immunized for clinical use. Bovine IgG has a long clinical half-life and has been added to our other successful antibodies. Baboon IgG is now ready for clinical testing. The value of this model system is that it appears to be an effective in vivo preclinical screen for tumor effective half-life of antibodies and IgG from diverse species, thus guiding potential clinical use.