Synergistic antitumor activity of cisplatin and interleukin 1 in sensitive and resistant solid tumors.

The antitumor activity of cis-diamminedichloroplatinum(II) (cP) and human recombinant interleukin-1 alpha (IL-1 alpha) was studied in RIF-1 and SC VII solid tumor models and in a cP-resistant subline of RIF-1 designated RIF-R1cP. In RIF-1 tumors, clonogenic cell survival after cP plus IL-1 alpha combinations was highly schedule and IL-1 alpha dose dependent. More than additive clonogenic cell kill was seen when cP was given 6 h before, but not 8 h before or at 2-6 h after IL-1 alpha. Time course studies indicated that maximal clonogenic cell killing was achieved within 4-6 h after the cP plus IL-1 alpha combination, with little or no recovery for up to 24 h. In vivo dose-response studies indicated that cP plus IL-1 alpha combinations induced more clonogenic cell kill than cP alone in all three tumor models, and analysis by the median effect principle indicated highly synergistic antitumor activity. Dexamethasone but not indomethacin inhibited the synergistic interaction. IL-1 alpha had no effect on the cytotoxicity of cP in SCC VII cells in vitro, and neither in vitro hypoxia nor in vivo ischemia, induced by clamping tumor blood supply, significantly affected cP clonogenic cell killing. Increased clonogenic cell killing was seen, however, after removal of the clamp, implicating reperfusion events, such as oxyradical stress, as a potential mechanism for increased cP cytotoxicity in SCC VII solid tumors. The data from our model systems provide a rationale for additional work to define the mechanisms of the synergistic antitumor activity of the cP plus IL-1 alpha combination and indicate that IL-1 alpha might be a useful adjunct to increase the clinical efficacy of cP-containing strategies for both sensitive and cP-resistant cancers.

Scattered radiation from linear accelerator and cobalt-60 collimator jaws.

PURPOSE: Solid state diodes and/or thermoluminescent dosimeters (TLDs) are often used to measure scattered radiation doses to critical organs immediately adjacent to radiation field sites. The energy-dependent response of these commonly used in vivo dosimeters sometimes makes the interpretation of measured values uncertain. This study investigates scattered radiation arising from the collimator jaws of linear accelerators and the treatment head of a cobalt-60 teletherapy unit. METHODS AND MATERIALS: A thin window Markus-type parallel-plate ionization chamber placed in a polystyrene phantom was employed to document the magnitude, energy composition, and sources of scattered radiation at surfaces near radiation fields. Measurements were taken both with and without additional phantom material covering the ionization chamber, as well as with various distances between the ionization chamber and edges of the radiation fields tested. RESULTS: Data was collected, analyzed and compared for treatment units produced by different manufacturers. It was found that the magnitude of scattered radiation to surfaces immediately adjacent to radiation fields ranged from 1% to 15% of the maximum dose along the beam central axis. These values showed a strong dependence upon distance from the edge of the radiation field, beam energy, collimator setting (field size), and the presence of externally mounted accessories. Teletherapy unit differences due to manufacturing firm origins were found to only slightly affect scattered radiation magnitude, while the orientation of upper and lower collimator jaws had absolutely no effect. CONCLUSIONS: Percent depth dose curves of scattered radiation were obtained and analyzed. The shapes of these depth dose curves suggest the presence of complex energy spectra from secondary electrons and scattered x-rays. Because of the presence of these complex energy spectra in areas immediately adjacent to radiation fields, caution should be observed when interpreting patient doses near radiation fields, if dose values have been measured in vivo using thermoluminescent dosimeters (TLDs) or solid state diodes. Many of these on-patient dosimetry devices are strongly energy dependent and may demonstrate large over- or under-responses in areas dominated by scattered radiation. The results of this study, thus, suggest that ionization chambers are preferred for determination of scattered radiation doses in such regions.

Improved linac dose distributions for radiosurgery with elliptically shaped fields.

Stereotactic radiosurgery techniques for a linear accelerator typically use circular radiation fields to produce an essentially spherical radiation distribution with a steep dose gradient. Target volumes are frequently irregular in shape, and circular distributions may irradiate normal tissues to high dose as well as the target volume. Improvements to the dose distribution have been made using multiple target points and optimizing the dose per arc to the target. A retrospective review of 20 radiosurgery patients has suggested that the use of elliptically shaped fields may further improve the match of the radiation distribution to the intended target volume. This hypothesis has been verified with film measurements of the radiation distribution obtained using elliptical radiation beam in a head phantom. Reductions of 40% of the high dose volume have been obtained with elliptical fields compared to circular fields without compromising the dose to the target volume.

Stereotactic target point verification of an X ray and CT localizer.

Stereotactic radiosurgery with a linear accelerator requires the accurate determination of a target volume and an accurate match of the therapeutic radiation dose distribution to the target volume. X ray and CT localizers have been described that are used to define the target volume or target point from angiographic or CT data. To verify the accuracy of these localizers, measurements were made with a target point simulator and an anthropomorphic head phantom. The accuracy of determining a known, high contrast, target point with these localizers was found to be a maximum of +/- 0.5 mm and +/- 1.0 mm for the X ray and CT localizer, respectively. A technique using portal X rays taken with a linear accelerator to verify the target point is also described.

MR characterization of brain and brain tumor response to radiotherapy.

This paper describes our experience in using the T1 and T2 relaxation times for quantitative evaluation of brain and brain tumor response to radiation therapy. Twenty-two computed T1 and 22 computed T2 images were obtained from 66 routine inversion-recovery and spin-echo magnetic resonance (MR) brain scans. The relaxation times of the brain tissues, determined from the computed images, were examined as a function of the absorbed dose. Statistical evaluation of the results showed no significant difference between the relaxation times of irradiated and not irradiated tissues, including tumor and normal white matter. Influence of the magnetic field strength and imaging techniques on the computed T1 and T2 values was confirmed. We conclude that the relaxation time values, as obtained today using conventional MR scanner and standard software, are not specific enough to warrant a correct assessment of the acute radiation effect on the brain tissues.

Radiosurgery target point alignment errors detected with portal film verification.

Stereotactic radiosurgery with a linear accelerator requires an accurate match of the therapeutic radiation distribution to the localized target volume. Techniques for localization of the target volume using CT scans and/or angiograms have been described. Alignment of the therapeutic radiation distribution to the intended point in stereotactic space is usually accomplished using precision mechanical scales which attach to the head ring. The present work describes a technique used to verify that the stereotactic coordinates of the center of the intended radiation distribution are in agreement with the localized target point coordinates. This technique uses anterior/posterior and lateral accelerator portal verification films to localize the stereotactic coordinates of the center of the radiation distribution with the patient in the treatment position. The results of 26 cases have been analyzed. Alignment errors of the therapeutic radiation distribution in excess of 1 mm have been found using the portal film verification procedure.

Optimization of high dose-rate cervix brachytherapy; Part I: Dose distribution.

Computer controlled high dose-rate (HDR) brachytherapy afterloading machines are equipped with a single, miniaturized, high activity Ir-192 source that can be rapidly moved in fine increments among several channels. Consequently, by appropriate programming of source dwell positions and times, the dose distribution can be optimized as desired. We have explored the optimization potential of this new technology for two applications: (a) cervix brachytherapy, and (b) transvaginal irradiation. Cervix brachytherapy with a gynecologic ring applicator was simulated by 48 sources of relative activities ranging from 0.17 to 1.00 that were equally distributed between the tandem and the ring. The results confirmed that the optimized distribution of physical doses are superior to those achievable with standard brachytherapy sources and applicators. For example, with five-point optimization, the relative dose-rate in the rectum was only 47% of that in point A; for standard application the dose rate was 47% higher. For transvaginal application 27 sources of relative activities between 0.07-0.79 were placed in the ring and a single source of unit strength in the tandem. Using dose distribution homogeneity as an optimization criterion, the results (+/- 2.5%) were again superior to those obtained for commonly used double ovoid (+/- 15%), linear cylinder (+/- 27%), or a "T" source (31%).

Dose determination in high dose-rate brachytherapy.

Although high dose-rate brachytherapy with a single, rapidly moving radiation source is becoming a common treatment modality, a suitable formalism for determination of the dose delivered by a moving radiation source has not yet been developed. At present, brachytherapy software simulates high dose-rate treatments using only a series of stationary sources, and consequently fails to account for the dose component delivered while the source is in motion. We now describe a practical model for determination of the true, total dose administered. The algorithm calculates both the dose delivered while the source is in motion within and outside of the implanted volume (dynamic component), and the dose delivered while the source is stationary at a series of fixed dwell points. It is shown that the dynamic dose element cannot be ignored because it always increases the dose at the prescription points and, in addition, distorts the dose distribution within and outside of the irradiated volume. Failure to account for the dynamic dose component results in dosimetric errors that range from significant (> 10%) to negligible (< 1%), depending on the prescribed dose, source activity, and source speed as defined by the implant geometry.

Computer controlled stereotaxic radiotherapy system.

A computer-controlled stereotaxic radiotherapy system based on a low-frequency magnetic field technology integrated with a single fixation point stereotaxic guide has been designed and instituted. The magnetic field, generated in space by a special field source located in the accelerator gantry, is digitized in real time by a field sensor that is six degree-of-freedom measurement device. As this sensor is an integral part of the patient stereotaxic halo, the patient position (x, y, z) and orientation (azimuth, elevation, roll) within the accelerator frame of reference are always known. Six parameters--three coordinates and three Euler space angles--are continuously transmitted to a computer where they are analyzed and compared with the stereotaxic parameters of the target point. Hence, the system facilitates rapid and accurate patient set-up for stereotaxic treatment as well as monitoring of patient during the subsequent irradiation session. The stereotaxic system has been developed to promote the integration of diagnostic and therapeutic procedures, with the specific aim of integrating CT and/or MR aided tumor localization and long term (4- to 7-week) fractionated radiotherapy of small intracranial and ocular lesions.

MR technique for localization and verification procedures in episcleral brachytherapy.

Spatial definition of an intraocular tumor and subsequent determination of the actual position of an implanted eye plaque are essential for adequate ocular brachytherapy treatment planning. However, a method for verification of the plaque placement which would provide required 3-dimensional information is not available at present. In addition, tumor localization procedures, including ultrasonography and CT techniques, cannot always offer the precision needed for 3-dimensional definition of an intraocular target. This communication describes a magnetic resonance imaging technique specifically developed for both localization and verification procedures. A 1.5 Tesla magnetic resonance scanner, spin-echo pulse sequence (echo time 30 msec, repetition time 700 msec), and commercially available surface coil were used to obtain a series of transverse, coronal, and sagittal images of a slice thickness of 3 mm. Usually, eight scans in each of the three planes were needed for adequate coverage of the orbit. The required patient set-up and data acquisition time did not exceed 40 minutes. With a data matrix size of 256 X 256 pixels and 13 cm field of view, localization and verification were accomplished with a precision of 0.5 mm. Our results suggest that the magnetic resonance imaging technique permits precise integration of diagnostic and therapeutic procedures, and in addition provides adequate data for accurate treatment planning. We conclude that magnetic resonance imaging is the preferred diagnostic technique for episcleral brachytherapy.

Orally given indomethacin and blood flow response to UVL.

Blood flow in normal skin and skin treated with ultraviolet light (UVL) has been determined by measuring the clearance of epicutaneously applied xenon 133 gas. Mean blood flow in UVL-irradiated skin was 25.7 ml/100 gm/min, which is about twice that found in normal skin (12.2 ml/100 gm/min). Orally administered indomethacin reduced by one third the increase in blood flow produced by UVL irradiation.

Dosimetry of small radiation fields for 10-MV x rays.

Dosimetry for 10-MV x rays has been extended to radiation fields smaller than 4 X 4 cm which may be suitable for radiation therapy of small lesions, e.g., intracranial tumors, benign or malignant. Special consideration in this study was given to (i) the variation of dose with field size (collimator and phantom scatter), (ii) the central axis percentage depth doses, and (iii) the moving-beam therapy dose distribution. We conclude that simple dosimetric techniques can provide adequate physics background for stereotaxic radiosurgery with small radiation fields and high-energy x rays.

Stereotaxic radiotherapy technique for small intracranial lesions.

A stereotaxic radiotherapy technique that permits accurate delivery of highly localized dose to a small intracranial target has been developed. The technique facilitates precise integration of the diagnostic and therapeutic procedures including target localization, treatment planning, simulation, repetitive patient irradiation, and daily treatment verification. A conventional linear accelerator and computed tomography scanner as well as special diagnostic and therapeutic guides are used. A suitable dosimetric distribution is achieved using arc therapy with small radiation fields and 10-MV x rays.

A rapid method for electron beam energy check.

Assessment of electron beam energy and its long term stability is part of standard quality assurance practice in radiation oncology. Conventional depth-ionization or depth-film density measurements are time consuming both in terms of data acquisition and analysis. A procedure is described utilizing ionization measurements at two energy specific depths. It is based on a linear relationship between electron beam energy and its practical range. Energy shifts within the range covered by the two measurement depths are easily resolved. Within a range of +/- 0.50 MeV (+/- 1.30 MeV) around the established mean incident energy of 5.48 MeV (20.39 MeV), the method accuracy is better than 0.10 MeV.

Stereotactic radiosurgery: dose-volume analysis of linear accelerator techniques.

Stereotactic radiosurgery of the brain may be accomplished with a linear accelerator by performing several noncoplanar arcs of a highly collimated beam focused at a point. The shape of the radiation distribution produced by this technique is affected by the beam energy, field size, and the number and size of the arcs. The influence of these parameters on the resulting radiation distributions was analyzed by computing dose volume histograms for a typical brain. Dose volume functions were computed for: (a) the energy range of 4-24 MV x rays; (b) target sizes of 1-4 cm; and (c) 1-11 arcs and dynamic rotation. The dose volume histograms were found to be dependent on the number of arcs for target sizes of 1-4 cm. However, these differences were minimal for techniques with 4 arcs or more. The influence of beam energy on the dose volume histogram was also found to be minimal.

Scattering effects on the dosimetry of iridium-192.

Dosimetry calculations for iridium-192 sources generally assume that a sufficient medium surrounds both the iridium source(s) and the point of calculation so that full scattering conditions exist. In several clinical applications the iridium sources may be anatomically located so that the full scattering requirement is not satisfied. To assess the magnitude of this problem, relative measurements were made with a small ionization chamber in phantoms near air and lung-equivalent interfaces. Dose reduction caused by decreasing the volume of scattering material near these interfaces was then evaluated for a few clinical applications. The results show that reductions on the order of 8% may be expected at the interface with minimal dose reduction within the volume of the implant itself. In addition, the results indicate the verification of source strength of iridium sources in phantom require phantom dimensions determined by the source-chamber separation distance.

A comparison of calculated and measured data for total body irradiation by 10 MV x-rays.

This paper describes the rationale for using computed rather than measured data as a reference in the dosimetry of total body irradiation. The proof of this statement rests on a comparison of measured dosimetric values for large fields at extended distances with those derived by simple recalculation from the data measured at the isocentre. The depth doses and dose rates were experimentally obtained for 10 MV x-rays at distances of 100, 200 and 300 cm for collimated square fields with sides ranging from 5 to 30 cm. Phantoms of different volumes and shapes, including a RANDO phantom, and a large (50 cm x 50 cm x 50 cm), intermediate (25 cm x 25 cm x 25 cm), and 'mini-phantom' (build-up cap, 4.6 cm diameter) were used. Comparison of the measured and computed data for the largest collimated field shows that (i) calculated dose rates do not differ by more than +1% from the measured data, phantom size and shape having no effect on the results, (ii) depth doses measured in a patient-like RANDO phantom are a maximum of 2% higher than the calculated data but are also 2% lower than the depth doses measured in a standard water tank. For the radiation fields and treatment distances commonly employed in total body irradiation, we conclude that the calculated data can serve as reference values for dosimetry because they have the same inherent uncertainty as the data measured in non-patient-like phantoms.

Tissue maximum ratios (and other parameters) of small circular 4, 6, 10, 15 and 24 MV x-ray beams for radiosurgery.

Small, circular, x-ray beams are commonly used for radiosurgery applications. Dosimetric characteristics of 4, 6, 10, 15 and 24 MV circular x-ray beams ranging in size from 10 to 40 mm are reported. These characteristics include the measurement of TMR, beam profiles and relative output factors. Measurements of these parameters were performed in a solid water phantom using film, a small diode, small parallel-plate and cylindrical ionization chambers and TLD. Comparison of relative dose measurements of small, circular beams performed using these detectors showed that the small diode, film and TLD results consistently agreed for circular beams as small as 10 mm diameter. Beam profiles were measured using film dosimetry. Comparison of TMR values of a 10 mm diameter beam measured using film and a small parallel-plate ionization chamber showed no significant differences. Tertiary collimators designed with tapered, divergence-matching holes, and straight-drilled holes have been used for radiosurgery applications. Measurement of beam penumbra produced with either of these types of tertiary collimators showed minimal differences between them.

Hyperfractionated radiation therapy and concurrent 5-fluorouracil, cisplatin and mitomycin-C in head and neck carcinoma. A pilot study.

Seventeen patients were entered into a Phase I/II trial of concurrent hyperfractionated radiation therapy (7,440 cGy total dose; 120 cGy b.i.d.) combined with constant infusion of 5-fluorouracil (5-FU) (1,000 mg/m2/24 hours for 72 hours) and cisplatin (DDP) (50 mg/m2) for a total of three cycles. Thirteen patients had Stage IV disease; three, Stage III disease; and one, Stage II hypopharyngeal disease. Thirteen of 17 patients had positive cervical lymph nodes, and the mean size of the largest lymph node was 5.5 x 5.1 cm. The patients were not treated with planned adjunctive surgery except for one patient who had a radical neck dissection for massive, rapidly growing cervical adenopathy, which recurred promptly within 1 month before the initiation of protocol therapy. After the initial six patients were entered, mitomycin-C (Mito 8 mg/m2) was added during the second cycle. All the patients completed the planned course of radiotherapy with a median dose of 7,440 cGy and a mean dose of 7,248 cGy except for two patients who died--one from toxicity and the other, suicide. The predominant toxicity was mucositis, which was grade 3/4 in 11 of 15 patients, resulting in an average interruption of radiation therapy of 12 days. Weight loss was significant and was on the average 12% of baseline weight. Hematological toxicity was mild in the 5-FU/DDP group (only one grade 3 toxicity of six) and severe in the 5-FU/DDP/Mito-treated patients (five of eight patients having grade 3/4 toxicity including one leukopenic pneumonitis death). Additional toxicity included one parapharyngeal cellulitis, which responded to antibiotics. Noncompliance with the complex regimen was only seen in three patients. One patient refused b.i.d. radiation therapy, and one patient refused further chemotherapy after the first cycle. Additionally, one patient who had a severe ethanol withdrawal reaction during the first cycle of 5-FU/DDP did not receive further chemotherapy. The complete response rate of both primary site and neck by the protocol regimen alone was 71%. However, two patients, one from each group, did undergo salvage neck dissection, and the locoregional control is currently 73%, with a mean follow-up time of 18.4 months. The feasibility of combining hyperfractionated radiation therapy with aggressive concurrent chemotherapy was demonstrated. The response and local control rate justifies the added toxicity of concurrent chemotherapy and radiation therapy.

The role of steroids in the management of metastatic carcinoma to the brain. A pilot prospective trial.

This prospective study attempted to evaluate the indications for glucocorticoids which are commonly given to patients with brain metastases. Twelve patients with histologically confirmed malignancies and radiographically documented brain metastases were enrolled. Patients were scored for general performance status and neurologic function class. All subjects were given high-dose dexamethasone (HDD) for 48 hours and then randomized to receive either intermediate-dose dexamethasone (IDD) or no steroids with cranial radiotherapy. Of these 12 study patients, 3 achieved a complete response, 1 partial response, and 8 nonresponses to HDD. Seven patients had IDD, while five received no IDD. Although a small sample size prevented any statistical analysis, this study does suggest that the place for using glucocorticoids in treating patients with metastatic carcinoma to the brain remains uncertain and should be evaluated in a cooperative prospective trial.