Sui Shen

TUMOR CONTROL PROBABILITY FOR SELECTIVE BOOSTING OF HYPOXIC SUBVOLUMES, INCLUDING THE EFFECT OF REOXYGENATION

PURPOSE To study the effect on tumor control probability of selectively boosting the dose to hypoxic subvolumes. METHODS AND MATERIALS A Monte Carlo model was developed that separates the tumor into two compartments, one of which receives a primary dose, and one of which receives a higher boost dose. During radiation delivery, each compartment consists of three clonogen subpopulations: those that are well oxygenated, those that are temporarily hypoxic (geometrically transient hypoxia), and those that are permanently hypoxic (geometrically stable hypoxia). The spatial location of temporary hypoxia within the tumor volume varies over time, whereas, the spatial location of permanent hypoxia does not. The effect of reoxygenation was included. Clonogen proliferation was not included in the model. RESULTS A modest boost dose (120%-150% of the primary dose) increases tumor control probability to that found in the absence of permanent hypoxia. The entire hypoxic subvolume need not be included to obtain a significant benefit. However, only tumors with a geometrically stable hypoxic volume will have an improved control rate. CONCLUSIONS Tumors with an identifiable geometrically stable hypoxic volume will have an improved control rate if the dose to the hypoxic volume is escalated. Further work is required to determine the spatiotemporal evolution of the hypoxic volumes before and during the course of radiotherapy.

MIRD Dose Estimate Report No. 20: Radiation Absorbed-Dose Estimates for 111In- and 90Y-Ibritumomab Tiuxetan

Absorbed-dose calculations provide a scientific basis for evaluating the biologic effects associated with administered radiopharmaceuticals. In cancer therapy, radiation dosimetry supports treatment planning, dose-response analyses, predictions of therapy effectiveness, and completeness of patient medical records. In this study, we evaluated the organ radiation absorbed doses from intravenously administered 111In- and 90Y-ibritumomab tiuxetan. Methods: Ten patients (6 men and 4 women) with non-Hodgkin lymphoma, cared for at 3 different medical centers, were administered the tracer 111In-ibritumomab tiuxetan and assessed using planar scintillation camera imaging at 5 time points and CT–organ volumetrics to determine patient-specific organ biokinetics and dosimetry. Explicit attenuation correction based on the transmission scan or transmission measurements provided the fraction of 111In-administered activity in 7 major organs, the whole body, and remainder tissues over time through complete decay. Time–activity curves were constructed, and radiation doses were calculated using MIRD methods and implementing software. Results: Mean radiation absorbed doses for 111In- and for 90Y-ibritumomab tiuxetan administered to 10 cancer patients are reported for 24 organs and the whole body. Biologic uptake and retention data are given for 7 major source organs, remainder tissues, and the whole body. Median absorbed dose values calculated by this method were compared with previously published dosimetry for ibritumomab tiuxetan and the product package insert. Conclusion: In high-dose radioimmunotherapy, the importance of patient-specific dosimetry becomes obvious when the objective of treatment planning is to achieve disease cures, safely, by limiting radiation dose to any critical normal organ to its maximum tolerable value. Compared with the current package insert, we found differences in median absorbed dose by multiples of 24 in the kidneys, 1.8 in the red marrow, 0.65 in the liver, 0.077 in the intestinal wall, 0.30 in the lungs, 0.46 in the spleen, and 0.34 in the heart wall.

ING-1, a Monoclonal Antibody Targeting Ep-CAM in Patients with Advanced Adenocarcinomas

Purpose: To determine the feasibility of administration, safety, toxicity, immunogenicity, pharmacokinetics, maximum tolerated dose, and biodistribution of ING-1, a high-affinity, Human-Engineered monoclonal antibody (heMAb) to the Mr 40,000 epithelial cell adhesion molecule Ep-CAM, in patients with advanced adenocarcinomas. Experimental Design: ING-1 was initially administered to patients as a 1-hour intravenous infusion every 3 weeks. Toxicity and pharmacokinetic data led to the evaluation of a weekly schedule. The distribution of iodine-131 (131I)-labeled ING-1 was studied. Results: Twenty-five patients received 82 courses of ING-1. Minimal toxicity was initially observed at the 0.03-, 0.10-, and 0.30-mg/kg dose levels. A patient dosed at 1.0 mg/kg developed acute pancreatitis with severe abdominal pain, nausea, and vomiting. A patient dosed at 0.3 mg/kg had an asymptomatic amylase and lipase elevation to 502 units/L and 1,627 units/L, respectively. Both patients made uncomplicated recoveries. No other dose-limiting toxicities were observed. Regardless of dose, the volume of distribution (mean ± SEM) was 46.6 ± 1.6 mL/kg. ING-1 clearance decreased with increasing dose. To minimize toxicity and increase dose intensity, we then administered ING-1 weekly. No significant toxicity was observed in 7 patients dosed at 0.1 mg/kg. Studies of 131I-labeled ING-1 biodistribution showed radiolocalization to colorectal and prostate cancers. A patient with colorectal cancer had an 80% decrement in the levels of carcinoembryonic antigen. Conclusion: The recommended dose for ING-1 is 0.10 mg/kg by intravenous infusion weekly. The absence of severe toxicity at this dose, low immunogenicity, and preliminary evidence of ING-1 tumor localization and antitumor efficacy support the further clinical development of this antibody to treat Ep-CAM–positive malignant diseases.

Dosimetric and radiobiological impact of dose fractionation on respiratory motion induced IMRT delivery errors: A volumetric dose measurement study

Respiratory motion can introduce substantial dose errors during IMRT delivery. These errors are difficult to predict because of the nonsynchronous interplay between radiation beams and tissues. The present study investigates the impact of dose fractionation on respiratory motion induced dosimetric errors during IMRT delivery and their radiobiological implications by using measured 3D dose. We focused on IMRT delivery with dynamic multileaf collimation (DMLC-IMRT). IMRT plans using several beam arrangements were optimized for and delivered to a polystyrene phantom containing a simulated target and critical organs. The phantom was set in linear sinusoidal motion at a frequency of 15 cycles/min (0.25 Hz). The amplitude of the motion was +/- 0.75 cm in the longitudinal direction and +/- 0.25 cm in the lateral direction. Absolute doses were measured with a 0.125 cc ionization chamber while dose distributions were measured with transverse films spaced 6 mm apart. Measurements were performed for varying number of fractions with motion, with respiratory-gated motion, and without motion. A tumor control probability (TCP) model for an inhomogeneously irradiated tumor was used to calculate and compare TCPs for the measurements and the treatment plans. Equivalent uniform doses (EUD) were also computed. For individual fields, point measurements using an ionization chamber showed substantial dose deviations (-11.7% to 47.8%) for the moving phantom as compared to the stationary phantom. However, much smaller deviations (-1.7% to 3.5%) were observed for the composite dose of all fields. The dose distributions and DVHs of stationary and gated deliveries were in good agreement with those of treatment plans, while those of the nongated moving phantom showed substantial differences. Compared to the stationary phantom, the largest differences observed for the minimum and maximum target doses were -18.8% and +19.7%, respectively. Due to their random nature, these dose errors tended to average out over fractionated treatments. The results of five-fraction measurements showed significantly improved agreement between the moving and stationary phantom. The changes in TCP were less than 4.3% for a single fraction, and less than 2.3% for two or more fractions. Variation of average EUD per fraction was small (< 3.1 cGy for a fraction size of 200 cGy), even when the DVHs were noticeably different from that of the stationary tumor. In conclusion, IMRT treatment of sites affected by respiratory motion can introduce significant dose errors in individual field doses; however, these errors tend to cancel out between fields and average out over dose fractionation. 3D dose distributions, DVHs, TCPs, and EUDs for stationary and moving cases showed good agreement after two or more fractions, suggesting that tumors affected by respiration motion may be treated using IMRT without significant dosimetric and biological consequences.

Validation of target volume and position in respiratory gated CT planning and treatment

The capability of a commercial respiratory gating system based on video tracking of reflective markers to reduce motion-induced CT planning and treatment errors was evaluated. Spherical plastic shells (2.8-82 cm3), simulating the gross target volume (GTV), were placed in a water-filled body phantom that was moved sinusoidally along the longitudinal axis of the CT scanner and the accelerator for +/- 1 cm at 15-30 cycle/min. During gated CT imaging, the x-ray exposure was initiated by the gating system shortly before the end of expiration (so that the imaging time would be centered at the end of expiration); it was terminated by the scanner after completion of each slice. In nongated CT images, the target appeared distorted and often broken up. GTVs volume errors ranged 16%-110% in axial scans, and 7%-36% in spiral scans. In gated CT images, the spheres appeared 3 and 5 mm longer than their actual diameters (volume errors 2%-16%), at the respective respiration rates of 15 and 20 cycles/min. At 30 cycles/min the target appeared 1 cm longer, and volume error ranged 25%-53%. During treatment, gating kept the beam on for a duration equal to the CT acquisition time of 1 s/slice. The difference in positional errors between gated CT and portal films was 1 mm, regardless the size of residual motion errors. Because of the potential of suboptimal placement of the gating window between CT imaging and treatment, an extra 1.5-2.5 mm safety margin can be added regardless of the size of residual motion error. For respiratory rates > or = 30 cycles/min, the effectiveness of gating is limited by large residual motion in the 1 s CT acquisition time.

Comprehensive evaluation of a commercial macro Monte Carlo electron dose calculation implementation using a standard verification data set.

A commercial electron dose calculation software implementation based on the macro Monte Carlo algorithm has recently been introduced. We have evaluated the performance of the system using a standard verification data set comprised of two-dimensional (2D) dose distributions in the transverse plane of a 15 X 15 cm2 field. The standard data set was comprised of measurements performed for combinations of 9-MeV and 20-MeV beam energies and five phantom geometries. The phantom geometries included bone and air heterogeneities, and irregular surface contours. The standard verification data included a subset of the data needed to commission the dose calculation. Additional required data were obtained from a dosimetrically equivalent machine. In addition, we performed 2D dose measurements in a water phantom for the standard field sizes, a 4 cm X 4 cm field, a 3 cm diameter circle, and a 5 cm X 13 cm triangle for the 6-, 9-, 12-, 15-, and 18-MeV energies of a Clinac 21EX. Output factors were also measured. Synthetic CT images and structure contours duplicating the measurement configurations were generated and transferred to the treatment planning system. Calculations for the standard verification data set were performed over the range of each of the algorithm parameters: statistical precision, grid-spacing, and smoothing. Dose difference and distance-to-agreement were computed for the calculation points. We found that the best results were obtained for the highest statistical precision, for the smallest grid spacing, and for smoothed dose distributions. Calculations for the 21EX data were performed using parameters that the evaluation of the standard verification data suggested would produce clinically acceptable results. The dose difference and distance-to-agreement were similar to that observed for the standard verification data set except for the portion of the triangle field narrower than 3 cm for the 6- and 9-MeV electron beams. The output agreed with measurements to within 2%, with the exception of the 3-cm diameter circle and the triangle for 6 MeV, which were within 5%. We conclude that clinically acceptable results may be obtained using a grid spacing that is no larger than approximately one-tenth of the distal falloff distance of the electron depth dose curve (depth from 80% to 20% of the maximum dose) and small relative to the size of heterogeneities. For judicious choices of parameters, dose calculations agree with measurements to better than 3% dose difference and 3-mm distance-to-agreement for fields with dimensions no less than about 3 cm.

Dosimetric effect of respiration-gated beam on IMRT delivery.

Intensity modulated radiation therapy (IMRT) with a dynamic multileaf collimator (DMLC) requires synchronization of DMLC leaf motion with dose delivery. A delay in DMLC communication is known to cause leaf lag and lead to dosimetric errors. The errors may be exacerbated by gated operation. The purpose of this study was to investigate the effect of leaf lag on the accuracy of doses delivered in gated IMRT. We first determined the effective leaf delay time by measuring the dose in a stationary phantom delivered by wedge-shaped fields. The wedge fields were generated by a DMLC at various dose rates. The so determined delay varied from 88.3 to 90.5 ms. The dosimetric effect of this delay on gated IMRT was studied by delivering wedge-shaped and clinical IMRT fields to moving and stationary phantoms at dose rates ranging from 100 to 600 MU/min, with and without gating. Respiratory motion was simulated by a linear sinusoidal motion of the phantom. An ionization chamber and films were employed for absolute dose and 2-D dose distribution measurements. Discrepancies between gated and nongated delivery to the stationary phantom were observed in both absolute dose and 2-D dose distribution measurements. These discrepancies increased monotonically with dose rate and frequency of beam interruptions, and could reach 3.7% of the total dose delivered to a 0.6 cm3 ion chamber. Isodose lines could be shifted by as much as 3 mm. The results are consistent with the explanation that beam hold-offs in gated delivery allowed the lagging leaves to catch up with the delivered monitor units each time that the beam was interrupted. Low dose rates, slow leaf speeds and low frequencies of beam interruptions reduce the effect of this delay-and-catch-up cycle. For gated IMRT it is therefore important to find a good balance between the conflicting requirements of rapid dose delivery and delivery accuracy.

Dose Escalation and Dosimetry of First-in-Human α Radioimmunotherapy with 212Pb-TCMC-Trastuzumab

Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity, and tumor response of intraperitoneal 212Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2)–expressing malignancy. Methods: In a standard 3 + 3 phase 1 design for dose escalation, 212Pb-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies. Results: Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m2) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n = 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time). Non–decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5μSv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative. Conclusion: Five dose levels of intraperitoneal 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.

Image-Based 3D Treatment Planning for Vaginal Cylinder Brachytherapy: Dosimetric Effects of Bladder Filling on Organs at Risk

PURPOSE To investigate the dosimetric effects of bladder filling on organs at risk (OARs) using three-dimensional image-based treatment planning for vaginal cylinder brachytherapy. METHODS AND MATERIALS Twelve patients with endometrial or cervical cancer underwent postoperative high-dose rate vaginal cylinder brachytherapy. For three-dimensional planning, patients were simulated by computed tomography with an indwelling catheter in place (empty bladder) and with 180 mL of sterile water instilled into the bladder (full bladder). The bladder, rectum, sigmoid, and small bowel (OARs) were contoured, and a prescription dose was generated for 10 to 35 Gy in 2 to 5 fractions at the surface or at 5 mm depth. For each OAR, the volume dose was defined by use of two different criteria: the minimum dose value in a 2.0-cc volume receiving the highest dose (D(2cc)) and the dose received by 50% of the OAR volume (D(50%)). International Commission on Radiation Units & Measurements (ICRU) bladder and rectum point doses were calculated for comparison. The cylinder-to-bowel distance was measured using the shortest distance from the cylinder apex to the contoured sigmoid or small bowel. Statistical analyses were performed with paired t tests. RESULTS Mean bladder and rectum D(2cc) values were lower than their respective ICRU doses. However, differences between D(2cc) and ICRU doses were small. Empty vs. full bladder did not significantly affect the mean cylinder-to-bowel distance (0.72 vs. 0.92 cm, p = 0.08). In contrast, bladder distention had appreciable effects on bladder and small bowel volume dosimetry. With a full bladder, the mean small bowel D(2cc) significantly decreased from 677 to 408 cGy (p = 0.004); the mean bladder D(2cc) did not increase significantly (1,179 cGy vs. 1,246 cGy, p = 0.11). Bladder distention decreased the mean D(50%) for both the bladder (441 vs. 279 cGy, p = 0.001) and the small bowel (168 vs. 132 cGy, p = 0.001). Rectum and sigmoid volume doses were not affected by bladder filling. CONCLUSIONS In high-dose rate vaginal cylinder brachytherapy, treatment with a distended bladder preferentially reduces high dose to the small bowel around the vaginal cuff without a significant change in dose to the bladder, rectum, or sigmoid.

Model prediction of treatment planning for dose-fractionated radioimmunotherapy

Clinical trials of radioimmunotherapy (RIT) often use dose fractionation to reduce marrow toxicity. The dosing scheme can be optimized if marrow and tumor cell kinetics following radiation exposure are known.