Robert D. Zwicker

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases

PURPOSE Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was

INTERNAL MAMMARY NODE COVERAGE: AN INVESTIGATION OF PRESENTLY ACCEPTED TECHNIQUES

4119 less costly than SRS. CONCLUSION HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.

The biological effectiveness of intermittent irradiation as a function of overall treatment time: Development of correction factors for linac-based stereotactic radiotherapy

PURPOSE Recent publications have generated a renewed interest in regional nodal treatment to include the ipsilateral supraclavicular and internal mammary nodes (IMN). The purpose of this study is to evaluate three presently accepted treatment techniques for coverage of the intact breast and ipsilateral lymph node regions and to construct recommendations regarding the utilization of these techniques. METHODS AND MATERIALS Anatomic data were obtained from five randomly selected patients with computerized tomography (CT) in treatment position. Three patients presented with cancer of the left breast and two with cancer of the right. Using the Pinnacle 3-D planning system, normal tissue volumes of breast, ipsilateral lung, heart, sternum, and the IMN target were delineated for each patient. Three accepted techniques used to treat ipsilateral breast, internal mammary and supraclavicular nodes (extended tangents, 5-field, partly wide tangents) were configured and compared to a supraclavicular field matched to standard tangential fields. A dosage of 50 Gy in 25 fractions was prescribed to the target volume. Dose-volume histograms (DVH) were generated and analyzed with regard to target volume coverage and lung/heart volumes treated. RESULTS All of the treatment techniques covering IMN include at least 10% more lung and heart volume than that covered by standard tangential fields. The relative lung and heart volumes treated with each technique were consistent from patient to patient. The 5-field technique clearly treats the largest volume of normal tissue; however, most of this volume receives less than 50% of the dose prescribed. The percent of heart and ipsilateral lung treated to 20 Gy, 30 Gy, and 40 Gy have been calculated and compared. Due to the increase in chest wall thickness and depth of IMN superiorly, complete coverage was not achieved with any technique if the IMN target extended superiorly into the medial supraclavicular field where dose fall-off resulted in a significant underdosing at depth. For the same anatomic reasons, the 5-field technique underdosed 10-15% of the IMN target volume in 4 of the 5 cases. This technique also yielded a greater dose heterogeneity, which was not seen with the other techniques evaluated and correlated with the change of anterior chest wall thickness. CONCLUSIONS Anatomic variation in chest wall thickness and IMN depth strongly suggests the routine use of multislice CT planning to ensure complete coverage of the target volume and optimal sparing of normal tissue. All of the techniques can be constructed to look acceptable at central axis. To cover the superior most aspect of the IMN chain either high tangential fields, a supraclavicular field photon beam of energy >6 MV, or an AP/PA supraclavicular setup should be considered. The 5-field technique has the most difficulty in compensating for the increased depth of the IMN in the superior aspect of the tangent fields with up to +/-40% variation of the dose noted in isolated areas within the target volume. Based on our evaluation, the partly wide tangent technique offers many advantages. It provides optimal coverage of the target volume, reduces coverage of normal tissue volumes to an acceptable level, and is easily reproducible with a high degree of dose homogeneity throughout the target.

Comparison of dose homogeneity effects due to electron equilibrium loss in lung for 6 MV and 18 MV photons

PURPOSE Continuous irradiation of relatively short duration as administered in gamma-ray stereotactic radiosurgery (SRS) is biologically not equivalent to the more protracted intermittent exposures during accelerator-based radiosurgery with multiple arcs. Accelerator-based SRS and fractionated stereotactic radiotherapy (SRT) is currently performed with a high degree of variability in equipment and techniques resulting in highly variable treatment delivery times. The present work is designed to quantify the effects of radiation delivery times on biological effectiveness. For this, the intermittent radiation delivery schemes, typical for linac-based SRS/SRT, have been simulated in vitro to derive biological correction factors. METHODS AND MATERIALS The experiments were carried out using U-87MG human glioma cells in suspension at 37 degrees C irradiated with 6 MV X-rays to clinically relevant doses ranging from 6 to 18 Gy, delivered over total irradiation times from 16 min to 3 h. The resulting cell survival data was used to calculate dose correction factors to compensate for wide variations in dose delivery times. RESULTS At each total dose level, cell survival increased with increasing total irradiation time. The increase in survival was more pronounced at higher dose levels. At a total dose of 12 Gy, cell survival increased by a factor of 4.7 when irradiation time was increased from 16 to 112 min. Dose correction factors were calculated to allow biologically equivalent irradiations over the range of exposure times. Cells irradiated with corrected total doses of 11.5 Gy delivered incrementally in 16 min up to 13.3 Gy in 112 min were found to exhibit the same survival within the experimental limits of accuracy. CONCLUSIONS For a given total dose, variations in dose delivery time typical of SRS/SRT techniques will result in significant changes in cell survival. In the dose range studied, an isoeffect dose correction factor of 2 to 3 cGy/min was shown to compensate for the change in delivery time for U-87 MG human gloma cells in vitro.

Radiation-induced light in optical fibers and plastic scintillators: application to brachytherapy dosimetry

PURPOSE Loss of electronic equilibrium within and adjacent to low density materials can result in a dose reduction along the central axis and near the beam edge for megavoltage photon beams. In this context, Radiation Therapy Oncology Group (RTOG) protocol #91-05 recommends the use of photon beams of energy 12 MV or less for nonsmall cell lung cancer therapy. This work presents data to support the use of higher energy photons for some clinical lung field setups. METHODS AND MATERIALS Beam profiles were obtained from films inserted into homogeneous (polystyrene) and heterogeneous (polystyrene and lung-equivalent material) phantoms and irradiated in both single-field and parallel-opposed setups with 6 and 18 MV photon beams. Depth-dose curves were obtained with a parallel-plate ion chamber in the heterogeneous phantom to determine the range of field sizes over which the dose reduction at the lung/polystyrene interface becomes clinically significant. RESULTS Opposed field profiles show less degradation in the penumbra (50-90% width) at the lung/polystyrene interface than single-field profiles. The difference between 6 and 18 MV penumbra widths at the interface also reduced when an opposed field is added. The central axis dose reduction at the interface was negligible for single fields of a width of 8 cm or more. CONCLUSION Our results show that for opposed fields, the difference in penumbra degradation of the 6 and 18 MV photon beams is clinically insignificant compared to daily setup errors and patient motion. The central axis dose reduction is also shown to be small. Our data support the use of higher energy beams to obtain lower peripheral dose maxima in small clinical geometries.

Interstitial high-dose-rate brachytherapy boost: The feasibility and cosmetic outcome of a fractionated outpatient delivery scheme

A small plastic scintillator bonded to an optical fiber has several characteristics that make it promising as a brachytherapy dosimeter. In these dosimeters, scintillation light represents signal, whereas Cerenkov and luminescence light from the optical fiber stem is noise that must be subtracted. The dosimeter accuracy can be improved by optically filtering part of the fiber stem light. Spectral measurements were performed to guide the choice of scintillator, fiber, and filter. Spectral signatures and total luminescence of three scintillators and five different silica optical fibers, excited by a 8 Ci /sup 192/Ir source, were measured. The total radiation-induced light from the various optical fibers differed by up to a factor of 5.6. The percentage of fiber-produced light due to luminescence varied between 15 and 79%. A fiber with weak emission was used in the dosimeter with BC408S, a scintillator with minimum emission wavelength of 400 mm. A 400-nm cutoff UV filter gave a factor of two increase in signal-to-noise. The dosimeter response was linear for dose rates varying by at least three orders of magnitude, representing source-to-probe distances of 0.2-10 cm. Measurement errors of the dosimeter compare favorably with other brachytherapy dosimeters.

Dose uniformity in a planar interstitial implant system

PURPOSE To evaluate the feasibility, potential toxicity, and cosmetic outcome of fractionated interstitial high dose rate (HDR) brachytherapy boost for the management of patients with breast cancer at increased risk for local recurrence. METHODS AND MATERIALS From 1994 to 1996, 18 women with early stage breast cancer underwent conventionally fractionated whole breast radiotherapy (50-50.4 Gy) followed by interstitial HDR brachytherapy boost. All were considered to be at high risk for local failure. Seventeen had pathologically confirmed final surgical margins of less than 2 mm or focally positive. Brachytherapy catheter placement and treatment delivery were conducted on an outpatient basis. Preplanning was used to determine optimal catheter positions to enhance dose homogeneity of dose delivery. The total HDR boost dose was 15 Gy delivered in 6 fractions of 2.5 Gy over 3 days. Local control, survival, late toxicities (LENT-SOMA), and cosmetic outcome were recorded in follow-up. In addition, factors potentially influencing cosmesis were analyzed by logistic regression analysis. RESULTS The minimum follow-up is 40 months with a median 50 months. Sixteen patients were alive without disease at last follow-up. There have been no in-breast failures observed. One patient died with brain metastases, and another died of unrelated causes without evidence of disease. Grade 1-2 late toxicities included 39% with hyperpigmentation, 56% with detectable fibrosis, 28% with occasional discomfort, and 11% with visible telangiectasias. Grade 3 toxicity was reported in one patient as persistent discomfort. Sixty-seven percent of patients were considered to have experienced good/excellent cosmetic outcomes. Factors with a direct relationship to adverse cosmetic outcome were extent of surgical defect (p = 0.00001), primary excision volume (p = 0.017), and total excision volume (p = 0.015). CONCLUSIONS For high risk patients who may benefit from increased doses, interstitial HDR brachytherapy provides a convenient outpatient method for boosting the lumpectomy cavity following conventional whole breast irradiation without overdosing normal tissues. The fractionation scheme of 15 Gy in 6 fractions over 3 days is well tolerated. The volume of tissue removed from the breast at lumpectomy appears to dominate cosmetic outcome in this group of patients.

BIOLOGIC TREATMENT PLANNING FOR HIGH-DOSE-RATE BRACHYTHERAPY

PURPOSE This work makes use of a volume-ratio technique to examine dose uniformity in a planar interstitial implant system based entirely on geometrical constraints. The rationale for determining an upper limit for acceptable dose variation is examined and discussed. Variation of ribbon spacing and interplanar separation is evaluated in terms of its effect on dose homogeneity. METHODS AND MATERIALS Volume-dose curves were generated for a range of planar implant dimensions. The volume inside the target region and enclosed between the reference isodose and a higher isodose surface was calculated as a measure of dose uniformity. Studies of homogeneity, target coverage, and external tissue irradiation were carried out to evaluate the importance of flexible interplanar spacing in optimizing implants. New dose tables were generated to accommodate the frequent clinical need to minimize the number of catheter insertions. RESULTS Implants carried out in accordance with specified geometric constraints were found also to provide optimal dose homogeneity as determined using the volume ratio method with a flexible high dose limit. For two-plane implants, the interplanar spacing should be determined specifically in each case to ensure accurate target coverage. Calculations for specific cases showed that the tissue volume treated to unnecessarily high dose levels can be reduced by a large factor by careful positioning of the implant planes. A smaller ribbon and seed spacing will, in general, lead to better dose uniformity when this is evaluated in terms of the volumes treated to very high dose levels. CONCLUSIONS Our studies showed that implants carried out using simple and useful geometric guidelines will also provide an acceptably uniform dose distribution. For double plane implants, the separation of the implant planes should be optimized for each target thickness.

Optimization of planar high-dose-rate implants

PURPOSE Interstitial brachytherapy treatment plans are conventionally optimized with respect to total target dose and dose homogeneity, which does not account for the biologic effects of dose rate. In an HDR implant, with a stepping source, the dose rate dramatically changes during the course of treatment, depending on location, as the source moves from dwell position to dwell position. These widely varying dose rates, together with the related sequencing of the dwell positions, may impart different biologic effects at points receiving the same total dose. This study applies radiobiologic principles to account for the potential biologic impact of dose delivery at varying dose rates within an HDR implant. METHODS AND MATERIALS The model under study uses a generalized version of the linear-quadratic (LQ) cell kill formula to calculate the surviving fraction of cells subjected to HDR irradiation. Using a planar interstitial HDR implant with the dwell times optimized to produce a homogeneous dose distribution along a reference plane parallel to the implant plane, surviving fractions were compared at selected reference points subjected to the same total dose. Biologic effect homogeneity was compared to dose homogeneity by plotting the effects at the reference points. The effects were examined with LQ parameters alpha, beta, and sublethal repair time T(1) varied over a range typical of human cells. RESULTS In a region in which dose is relatively uniform, surviving fraction for some values of the model parameters are found to vary by as much as an order of magnitude due to differences in the HDR irradiation profiles at different dose points. This effect is more pronounced for shorter repair times and smaller alpha/beta ratios, and increases with increasing total irradiation time. CONCLUSION Conventional HDR treatment planning currently considers dose distribution as the primary indicator of clinical effect. Our results demonstrate that plans optimized to maximize homogeneity within a target volume may not reflect the effect of the sequential nature of HDR dose delivery on cell kill. Biologic effect modeling may improve our understanding and ability to predict the adverse effects of our treatment, such as fat necrosis and fibrosis. Accounting for irradiation history and repair kinetics in the evaluation of HDR brachytherapy plans may add an important new dimension to our planning capabilities.

A pilot study of concomitant boost accelerated superfractionated radiotherapy for stage III cancer of the uterine cervix

PURPOSE Brachytherapy has long been used to deliver localized radiation to the breast and other cancer sites. For interstitial implants, proper source positioning is critical in obtaining satisfactory dose distributions. The present work examines techniques for optimizing source guide placement in high-dose-rate (HDR) biplanar implants, and examines the effects of suboptimal catheter placement. METHODS AND MATERIALS Control of individual dwell times in HDR implants allows a high degree of dose uniformity in planes parallel to the implant planes. Biplanar HDR implants can be considered optimized when the dose at the implant center is equal to the dose at the symmetric target boundaries. It is shown that this optimal dose uniformity is achieved when the interplanar separation is related to the target thickness T through the direct proportionality, s = T/square root2. To quantify the significance of source positioning, the average dose and a related quantity, equivalent uniform dose (EUD), were calculated inside the treatment volume for two conditions of suboptimal catheter geometry. In one case, the interplanar spacing was varied from 1 cm up to the target thickness T, while a second study examined the effects of off-center placement of the implant planes. RESULTS Both the average dose and EUD were minimized when the interplanar spacing satisfied the relationship s = T/square root2. EUD, however, was significantly smaller than the average dose, indicating a reduced relative cell killing in the high dose regions near the dwell points. It was also noted that in contrast to the average dose, the EUD is a relatively weak function of catheter misplacement, suggesting that the biological consequences of suboptimal implant geometry may be less significant than is indicated by the increase in average dose. CONCLUSION A concise formula can be used to determine the interplanar separation needed for optimal dose uniformity in Manchester-type implants. Deviations from optimal source geometry result in an increase in the average dose inside the treatment volume, but the weaker dependence of the EUD suggests that the surviving fraction of cells may not be not strongly affected by suboptimal source geometry.