Dosimetric validation for multileaf collimator-based intensity-modulated radiotherapy: a review.

The creation of intricate dose distributions produced by intensity-modulated radiotherapy (IMRT) depends on complex planning systems and specialized mechanical devices. The many possible sources of inaccuracy and the complexity of the dose maps themselves require that a substantial effort be made to ensure that calculated and delivered dose distributions agree. This review provides an overview of the current status of the validation of dose predictions of IMRT planning systems by comparisons with measurements. Emphasis is placed on multileaf collimator- (MLC) based IMRT. Discrepancies between calculations and measurements may be due to any of 3 causes: errors and uncertainties in the dose calculation algorithm, in measurements, or in beam delivery by the accelerator/MLC combination. Some of the factors affecting dosimetry include: the technique employed for modulating the fluence, the dose calculation algorithm and other aspects of the planning system, mechanical limitations of the MLC hardware, dosimetric characteristics of the MLC, such as MLC leakage and rounded leaf ends, the choice of dosimeter, and the measurement geometry and technique. The advantages and drawbacks of various dosimeters including film, ion chambers, thermoluminescent dosimetry, and electronic portal imaging devices are discussed. The steps involved in validating dosimetrically a planning system are outlined, including the various fields that need to be measured, the phantoms that may be used, and measurement techniques. The achievable accuracy of dosimetry for IMRT is discussed.

A Monte Carlo study of radiation transport through multileaf collimators.

Due to the significant increase in the number of monitor units used to deliver a dynamic IMRT treatment, the total MLC leakage (transmission plus scatter) can exceed 10% of the maximum in-field dose. To avoid dosimetric errors, this leakage must be accurately accounted for in the dose calculation and conversion of optimized intensity patterns to MLC trajectories used for treatment delivery. In this study, we characterized the leaf end transmission and leakage radiation for Varian 80- and 120-leaf MLCs using Monte Carlo simulations. The complex geometry of the MLC, including the rounded leaf end, leaf edges (tongue-and-groove and offset notch), mounting slots, and holes was modeled using MCNP4b. Studies were undertaken to determine the leakage as a function of field size, components of the leakage, electron contamination, beam hardening and leaf tip effects. The leakage radiation with the MLC configured to fully block the field was determined. Dose for 6 and 18 MV beams was calculated at 5 cm depth in a water phantom located at 95 cm SSD, and normalized to the dose for an open field. Dose components were scored separately for radiation transmitted through and scattered from the MLC. For the 80-leaf MLC at 6 MV, the average leakage dose is 1.6%, 1.7%, 1.8%, and 1.9% for 5 x 5, 10 x 10, 15 x 15, and 20 x 20cm2 fields, respectively. For the 120-leaf MLC at 6 MV, the average leakage dose is 1.6%, 1.6%, 1.7%, and 1.9% for the same field sizes. Measured leakage values for the 120-leaf MLC agreed with calculated values to within 0.1% of the open field dose. The increased leakage with field size is attributed to MLC scattered radiation. The fractional electron contamination for a blocked MLC field is greater than that for an open field. The MLC attenuation significantly affects the photon spectrum, resulting in an increase in percent depth dose at 6 MV, however, little effect is observed at 18 MV. Both phantom scatter and the finite source size contribute to the leaf tip profile observed in phantom. The results of this paper can be applied to fluence-to-trajectory and trajectory-to-fluence calculations for IMRT.

A method for determining multileaf collimator transmission and scatter for dynamic intensity modulated radiotherapy.

The main purpose of this work is to demonstrate a practical means of determining the leaf transmission and scatter characteristics of a multileaf collimator (MLC) pertinent to the commissioning of dynamic intensity modulated radiotherapy, especially for the sweeping window technique. The data are necessary for the conversion of intensity distributions produced by intensity-modulated radiotherapy optimization systems into trajectories of MLC leaves for dynamic delivery. Measurements are described for two, tungsten alloy MLCs: a Mark II 80-leaf MLC on a Varian 2100C accelerator and a Millenium 120-leaf MLC on a Varian 2100EX accelerator. MLC leakage was measured by film for a series of field sizes. Measured MLC leakage was 1.68% for a 10 x 10 cm2 field for both 6 and 18 MV for the 80-leaf MLC. For the 6 MV field, the 1.68% leakage consisted of 1.48% direct transmission and 0.20% leaf scatter. Direct transmission through the 80-leaf MLC, including the rounded leaf tip, was calculated analytically taking into account the detailed leaf geometry and a Monte Carlo-generated energy spectrum of the accelerator. The integrated fluence under the leaf tip was equivalent to an inward shift of 0.06 cm of a hypothetical leaf with a flat, focused tip. Monte Carlo calculations of the dose to phantom beyond a closed 80-leaf MLC showed excellent agreement with the analytic results. The transmission depends on the density of the MLC alloy, which may differ among individual MLCs. Thus, it is important to measure the transmission of any particular MLC. Calculated doses for a series of uniform fields produced by dynamic sweeping windows of various widths agree with measurements within 2%.

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

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.

Internal mammary node coverage: an investigation of presently accepted techniques.

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.

The impact of electron transport on the accuracy of computed dose.

The aim of this work was to investigate the accuracy of dose predicted by a Batho power law correction, and two models which account for electron range: A superposition/convolution algorithm and a Monte Carlo algorithm. The results of these models were compared in phantoms with cavities and low-density inhomogeneities. An idealized geometry was considered with inhomogeneities represented by regions of air and lung equivalent material. Measurements were performed with a parallel plate ionization chamber, thin TLDs (thermoluminescent dosimeters) and film. Dose calculations were done with a generalized Batho model, the Pinnacle collapsed cone convolution model (CCC), and the Peregrine Monte Carlo dose calculation algorithm. Absolute central axis and off axis dose data at various depths relative to interfaces of inhomogeneities were compared. Our results confirm that for a Batho correction, dose errors in the calculated depth dose arise from the neglect of electron transport. This effect increases as the field size decreases, as the density of the inhomogeneity decreases, and with the energy of incident photons. The CCC calculations were closer to measurements than the Batho model, but significant discrepancies remain. Monte Carlo results agree with measurements within the measurement and computational uncertainties.

Clinical use of a digital simulator for rapid setup verification in high dose rate brachytherapy.

PURPOSE: Fractionated high dose rate (HDR) brachytherapy provides a number of technical advantages over conventional implant therapy in that (a) it can be carried out on an outpatient basis, (b) personnel exposure is reduced to insignificant levels, and (c) patient motion during irradiation is minimized, resulting in a more accurate delivery of the planned radiation dose distribution to the target and critical structures. The patient discomfort associated with the repeated applicator insertions and/or treatment setups can be alleviated to the extent that the setup time is held to a minimum. This work describes the use of a prototype digital simulator to obtain fast, high-quality digital images for rapid setup verification. METHODS AND MATERIALS: The digital imaging system of the prototype simulator consists of a charge-coupled device (CCD) camera, which views the x-ray image optically transmitted from a conventional phosphor screen. Treatment is carried out with a remote afterloading HDR unit immediately after setup verification with the patient on the simulator stretcher. The high-resolution digital images are processed and displayed in about 5 s, as opposed to a minimum of approximately 2 min for film. RESULTS: The imaging system has been evaluated for a variety of implant types, both intracavitary and interstitial. The digital radiographs provided permanent high-resolution images as required in most cases for precise applicator positioning. The gray scale manipulation capabilities were found to be useful for imaging in regions of different density, such as lung and soft tissue, in the same radiograph. The advantages of short image acquisition and display times were observed in all cases, but were most evident in the intraluminal procedures, which sometimes involved several pretreatment applicator adjustments at a time of considerable patient discomfort. CONCLUSION: Pretreatment imaging is necessary to fully exploit the technical advantages of HDR brachytherapy. High-quality digital radiography offers unique advantages in HDR setup and verification by providing fast high-resolution, undistorted images with software manipulation capabilities and permanent storage of images.

Optical properties of experimental prostate tumors in vivo.

The optical properties of tumor tissue provide important information for optimizing treatment plans in photodynamic therapy, especially when interstitial application by multiple fibers is planned. Near infrared light, required to activate novel photosensitizers, should facilitate improved light penetrance of tumor tissue compared with 630 nm light used for activating Photofrin II. We have measured light energy fluence rates for 630 and 789 nm light along radial tracks from a single laterally diffusing optical fiber centrally implanted into Dunning R3327-AT and R3327-H rat prostate tumors in anesthetized rats. A total of 20 R3327-AT and 10 R3327-H tumors were used in this study with volumes from 2.6 to 13.3 cm3. Light track data were analyzed by an empirical model that described light attenuation. At 630 nm, light attenuation coefficients (LAC) were approximately 1.9 x higher than those at 789 nm for both tumors with the well-differentiated, well-perfused tumor (R3327-H) attenuating to a greater extent than did the rapidly growing anaplastic tumor (R3327-AT). The intertumor variation of LAC was greater than the spatial variations observed within individual tumors. LAC were a function of tumor volume for only 630 nm light in the R3327-AT tumors.

Analysis of tissue optical coefficients using an approximate equation valid for comparable absorption and scattering.

New photosensitizers activated by longer wavelengths than 630 nm light used with Photofrin II are under evaluation by various groups for the treatment of malignancies. Any increase in tumour volume destroyed by these agents as compared to Photofrin II will be partly determined by tissue penetrance at the longer wavelengths. Attenuation coefficients were measured for various tissues at 630 nm and the more penetrative near infrared wavelength of 789 nm. A new model of light propagation in tissue is shown to be accurate for arbitrary ratios of absorption and scattering, by comparison with a rigorous solution to the transport equation. Absorption and transport scattering coefficients of tissues at 630 and 789 nm were obtained by fitting this model to optical attenuation measurements. In vitro tissues included bovine heart, kidney and tongue, pig liver and fat, and chicken muscle; in vivo tissues included Dunning R3327-AT and R3327-H tumours. The penetration depth was found to be 1.35-2.25 times greater at 789 than 630 nm, depending on tissue type. The greatest differences in penetration between the two wavelengths were in the highly pigmented tissues. These substantial increases in penetration in the infrared may be important in future applications of photodynamic therapy.

Non-invasive monitoring of photodynamic therapy with 99technetium HMPAO scintigraphy.

The effect of photodynamic therapy (PDT) on tumour perfusion in both anaplastic (R3327-AT) and well differentiated (R3327-H) Dunning prostatic tumours was studied using the radiopharmaceutical 99Technetium hexamethylpropyleneamine oxime (99mTc-HMPAO). Tumours in the left flanks of rats (Copenhage x Fischer, F1 hybrids) were treated with interstitial PDT when their volumes reached 2-3 cm3. Qualitative and quantitative data from pre- and post-PDT scintigraphy revealed a light-dose-dependent shut-down of tumour perfusion which was also time-dependent. Maximal shut-down, following a 1,600 J light-dose, occurred about 8 h post-PDT. Light exposure 2 h after the intravenous administration of the photosensitiser (Photofrin II) produced a greater vascular shut-down than did light exposure 24 h after the administration of the drug. Regional differences in perfusion within treated and non-treated tumours were measured by tomographic procedures. Light-dose-dependent volumes of perfusion shut-down were demonstrated in addition to the naturally occurring regional differences in tumour perfusion. This radiopharmaceutical may have future utility for monitoring the clinical treatment of solid tumours with PDT.

The effectiveness of short-term versus long-term exposures to Photofrin II in killing light-activated tumor cells.

Asynchronous populations of mouse EMT-6 tumor cells were exposed to various doses of 630-nm light in slowly stirred aerobic suspensions after both short-term and long-term exposures to Photofrin II. All survival curves are characterized by a "threshold" light dose below which no cell inactivation occurs followed by a steep light-dose response. Both the shoulder widths and the inactivation curve slopes are functions of Photofrin II concentration. After high doses of light where survival levels are 0.003 and lower, "resistant tails" are observed on some survival curves. Light doses required to inactivate 50% of tumor cell populations were obtained from whole survival curves and their reciprocals (1/D50% survival) used as inactivation "rates". The amount of Photofrin II within cells was measured by a fluorescence assay. Per unit of fluorescence, this photosensitizer is at least 10 times more effective after long-term than after short-term exposures. After long-term exposures, both fluorescence activity and photosensitizing effectiveness are retained in washed cells for several hours. After short-term exposures, a majority of both the fluorescence and photosensitizing activity is lost by multiple washings or stirring in tissue culture medium without drug. These data suggest that the cellular compartments associated with photosensitization after short-term exposures to Photofrin II are probably different from the cellular compartments associated with photosensitization after long-term exposures to the drug. The data are consistent with known properties of the monomeric and oligomeric components of Photofrin II.

Oxygen dependency of tumor cell killing in vitro by light-activated Photofrin II.

Asynchronous populations of mouse EMT-6 tumor cells were treated with Photofrin II and exposed to various doses of 630 nm light in slowly stirred suspensions which had been equilibrated with various concentrations of oxygen. Survival curves were generated with cells exposed to 20 micrograms/ml Photofrin II in tissue culture medium for 1 h, a procedure which made it possible to remove more than 50% of the drug by washing. It is expected that under these conditions the drug would be loosely bound to cell surface and plasma membranes and in the cellular cytosol. Survival curves were also generated with cells exposed to 5 micrograms/ml Photofrin II for 20-24 h, a procedure which resulted in greater than 90% of the drug being tightly bound within cells, presumably to cellular lipids and membranes. Oxygen was obligatory for killing cells which had been exposed for both "short term" and "long term" to Photofrin II. After 30-40 min of pregassing cells with nitrogen gas which contained precise levels of oxygen, the concentration required to reduce rates of cell killing to 50% of maximum was approximately 0.5% O2 (gas phase) for short-term drug exposures and less than or equal to 0.05% O2 for long-term drug exposures. Even after pregassing times of 90-120 min prior to light administration, a Km of approximately equal to 0.1% O2 was observed for cells exposed to the drug for the longer time. When the same cells were exposed to 137Cs gamma rays in this irradiation chamber, no change in radiation sensitivity was observed after 30 min of pregassing cells with all oxygen concentrations studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Photodynamic therapy dosimetry in postmortem and in vivo rat tumors and an optical phantom.

Dosimetry in photodynamic therapy as currently practiced is empirical in that it does not account for optical properties of the target lesion. However, since light attenuation in tissue is unpredictable, measurements of optical properties are needed to ensure optimal light dose delivery. Further improvements in the uniformity of light dose distribution in tumors can be afforded by implanting multiple light sources. A technique is described in which the use of multiple cylindrical sources was combined with measurements of light energy fluence rate in the tumor. Six sources were placed within translucent plastic needles, which were inserted into tumors in a parallel array. Tumor attenuation characteristics were measured by placing a miniature light detector in one needle, while illuminating a cylindrical source in another, nearby, needle. This process was repeated for different needle pairs. In one postmortem and two in vivo tumors the absorption coefficient, transport scattering coefficient and penetration depth ranged from 0.56-0.81 cm-1, 9.4-15.2 cm-1 and 1.7-2.3 mm, respectively. Apparent penetration depths for in vivo tumors changed with time, during experiments. Predictions of dosimetry were generally consistent with direct measurements of light in tumors. Somewhat better agreement was observed in an optical phantom.

Optical dosimetry for interstitial photodynamic therapy.

An approach to photodynamic treatment of tumors is the interstitial implantation of fiber optic light sources. Dosimetry is critical in identifying regions of low light intensity in the tumor which may prevent tumor cure. We describe a numerical technique for calculating light distributions within tumors, from multiple fiber optic sources. The method was tested using four translucent plastic needles, which were placed in a 0.94 X 0.94 cm grid pattern within excised Dunning R3327-AT rat prostate tumors. A cylindrical diffusing fiber tip, illuminated by 630 nm dye laser light was placed within one needle and a miniature light detector was placed within another. The average penetration depth in the tumor region between the two needles was calculated from the optical power measured by the detector, using a modified diffusion theory. Repeating the procedure for each pair of needles revealed significant variations in penetration depth within individual tumors. Average values of penetration depth, absorption coefficient, scattering coefficient, and mean scattering cosine were 0.282 cm, 0.469 cm-1, 250 cm-1 and 0.964, respectively. Calculated light distributions from four cylindrical sources in tumors gave reasonable agreement with direct light measurements using fiber optic probes.

Neodymium:YAG laser therapy for infiltrating bladder cancer.

There were 32 high risk patients with stages T2 to T4 bladder cancer treated with neodymium:YAG laser irradiation to the tumor base after cautery resection between July 1981 and October 1986. All 12 patients with stage T2 disease followed for 6 to 78 months had no recurrence locally although 4 had stage T1 recurrences elsewhere in the bladder. Of 14 stage T3 cancer patients 8 demonstrated tumor persistence locally but 3 were well 4 to 24 months later without local recurrence (all stage T3a) and 3 were alive 14 to 24 months later with stage T1 recurrences. Of 6 stage T4 cancer patients 4 obtained reasonable hemorrhagic control with laser irradiation used for palliation purposes. A 90-year-old man with stage T3b disease died 5 days postoperatively of a myocardial infarct but no bladder or bowel perforation was documented. We believe that neodymium:YAG laser irradiation is a safe alternative for the treatment of bladder cancer in selected patients.

Treatment of Dunning R3327-AT rat prostate tumors with photodynamic therapy in combination with misonidazole.

Fischer X Copenhagen rats bearing Dunning R3327-AT tumors were treated with hematoporphyrin derivative and red light (630 nm from an argon-driven dye laser) alone or in combination with the hypoxic cell radiosensitizer, misonidazole (MISO). In vitro studies had suggested that hypoxia might significantly decrease the cytotoxicity of photodynamic therapy (PDT) and labeling with [14C]MISO had revealed a significant fraction of viable hypoxic cells in this tumor. PDT alone resulted in a growth delay of 8.8 days but no tumor cures were observed. The administration of MISO (i.p. at 0.5 mg/g) 33 min prior to PDT resulted in an average growth delay of 15.2 days and tumor cures (local control at 33 days) in 20% of animals treated. If MISO at a similar dosage was administered 30 min after PDT an average growth delay of 16.3 days was measured and tumor cure was observed in 70% of the animals treated. These results suggest that the hypoxic cell fraction in R3327-AT tumors might be a limitation to their curability by PDT. The addition of MISO and/or other hypoxic cell cytotoxic agents to PDT procedures may provide an effective means of treating PDT-resistant hypoxic cells in solid tumors.