J McDonough

Cell Cycle–Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation

The antineoplastic drug sorafenib (BAY 43-9006) is a multikinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G2-M. In synchronized cells, sorafenib causes a reversible G1 delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies.

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer

PURPOSE An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. METHODS AND MATERIALS The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the targets distal surface. RESULTS The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. CONCLUSIONS A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

The effect of independent collimator misalignment on the dosimetry of abutted half-beam blocked fields for the treatment of head and neck cancer

BACKGROUND AND PURPOSE Independent collimation conveniently allows for the junctioning of abutting fields with non-diverging beam edges. When this technique is used at the junction of multiple fields, e.g. lateral and low anterior fields in three-field head and neck set-ups, there should be a dosimetric match with no overdose or underdose at the matchline. We set out to evaluate the actual dosimetry at the central match plane. MATERIALS AND METHODS Independent jaws were used to mimic two half-beam blocked fields abutting at the central axis. X-Ray verification film was exposed in a water-equivalent phantom and the dose at the matchline was evaluated with laser densitometry. Collimators were then programmed to force a gap or overlap of the radiation fields to evaluate the effect of jaw misalignment within the tolerance of the manufacturers specification. Diode measurements of the field edges were also performed. Four beam energies from four different linear accelerators were evaluated. RESULTS Small systematic inhomogeneities were found along the matchline in all linear accelerators tested. The maximum dose on the central axis varied linearly with small programmed jaw misalignments. For a gap or overlap of 2 mm between the jaws, the matchline dose increased or decreased by 30-40%. The region of overdose or underdose around the matchline is 3-4 mm wide. The discrepancy between the width of jaw separation and the width of the region of altered dose is explained by a penumbra effect. CONCLUSION We recommend that independent jaw alignment be evaluated routinely and provide a simple method to estimate dose inhomogeneity at the match plane. If there is a field gap or overlap resulting in a clinically significant change in dosimetry, jaw misalignment should be corrected. If it cannot be corrected, part of the benefit of asymmetric collimation is lost and other methods of field junctioning may have to be considered. We routinely use a small block over the spinal cord at the mono-isocenter set-up plane for three-field head and neck treatments to prevent an overdose.

Design study of an in situ PET scanner for use in proton beam therapy

Proton beam therapy can deliver a high radiation dose to a tumor without significant damage to surrounding healthy tissue or organs. One way of verifying the delivered dose distribution is to image the short-lived positron emitters produced by the proton beam as it travels through the patient. A potential solution to the limitations of PET imaging in proton beam therapy is the development of a high sensitivity, in situ PET scanner that starts PET imaging almost immediately after patient irradiation while the patient is still lying on the treatment bed. A partial ring PET design is needed for this application in order to avoid interference between the PET detectors and the proton beam, as well as restrictions on patient positioning on the couch. A partial ring also allows us to optimize the detector separation (and hence the sensitivity) for different patient sizes. Our goal in this investigation is to evaluate an in situ PET scanner design for use in proton therapy that provides tomographic imaging in a partial ring scanner design using time-of-flight (TOF) information and an iterative reconstruction algorithm. GEANT4 simulation of an incident proton beam was used to produce a positron emitter distribution, which was parameterized and then used as the source distribution inside a water-filled cylinder for EGS4 simulations of a PET system. Design optimization studies were performed as a function of crystal type and size, system timing resolution, scanner angular coverage and number of positron emitter decays. Data analysis was performed to measure the accuracy of the reconstructed positron emitter distribution as well as the range of the positron emitter distribution. We simulated scanners with varying crystal sizes (2-4 mm) and type (LYSO and LaBr(3)) and our results indicate that 4 mm wide LYSO or LaBr(3) crystals (resulting in 4-5 mm spatial resolution) are adequate; for a full-ring, non-TOF scanner we predict a low bias (<0.6 mm) and a good precision (<1 mm) in the estimated range relative to the simulated positron distribution. We then varied the angular acceptance of the scanner ranging from 1/2 to 2/3 of 2π; a partial ring TOF imaging with good timing resolution (≤600 ps) is necessary to produce accurate tomographic images. A two-third ring scanner with 300 ps timing resolution leads to a bias of 1.0 mm and a precision of 1.4 mm in the range estimate. With a timing resolution of 600 ps, the bias increases to 2.0 mm while the precision in the range estimate is similar. For a half-ring scanner design, more distortions are present in the image, which is characterized by the increased error in the profile difference estimate. We varied the number of positron decays imaged by the PET scanner by an order of magnitude and we observe some decrease in the precision of the range estimate for lower number of decays, but all partial ring scanner designs studied have a precision ≤1.5 mm. The largest number tested, 150 M total positron decays, is considered realistic for a clinical fraction of delivered dose, while the range of positron decays investigated in this work covers a variable number of situations corresponding to delays in scan start time and the total scan time. Thus, we conclude that for partial ring systems, an angular acceptance of at least 1/2 (of 2π) together with timing resolution of 300 ps is needed to achieve accurate and precise range estimates. With 600 ps timing resolution an angular acceptance of 2/3 (of 2π) is required to achieve satisfactory range estimates. These results indicate that it would be feasible to develop a partial-ring dedicated PET scanner based on either LaBr(3) or LYSO to accurately characterize the proton dose for therapy planning.

PREDICTED RATES OF SECONDARY MALIGNANCIES FROM PROTON VERSUS PHOTON RADIATION THERAPY FOR STAGE I SEMINOMA

PURPOSE Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities. METHODS AND MATERIAL Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors. RESULTS Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22-5.01), large bowel (0.81; 95% CI, 0.39-1.01), and bladder (0.03; 95% CI, 0.01-0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, -0.01-0.06). CONCLUSIONS For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined and warrants further study for patients with seminoma, to decrease radiation-induced toxicity.

Experimental characterization of two-dimensional pencil beam scanning proton spot profiles

Dose calculations of pencil beam scanning treatment plans rely on the accuracy of proton spot profiles; not only the primary component but also the broad tail components. Four films are placed at several locations in air and multiple depths in Solidwater® for six selected energies. The films used for the primary components are exposed to 50-200 MU to avoid saturation; the films used for the tail components are exposed to 800, 8000 and 80,000 MU. By applying a pair/magnification method and merging these data, dose kernels down to 10(-4) of the central spot dose can be generated. From these kernels one can calculate the dose-per-MU for different field sizes and shapes. Measurements agree within 1% of dose-kernel-based calculations for output versus field size comparisons. Asymmetric, comet-shaped profile tails have a bigger impact at superficial depths and low energies: the output difference between two orientations at the surface of a rectangular field of 40 mm×200 mm is about 2% at the isocentre at 100 MeV. Integration of these dose kernels from 0 to 40 mm radius shows that the charge deficit in the Bragg peak chamber varies <2% from entrance to the end of range for energies <180 MeV, but exceeds 5% at 225 MeV.

Experimental characterization of two-dimensional spot profiles for two proton pencil beam scanning nozzles.

Dose calculation for pencil beam scanning proton therapy requires accurate measurement of the broad tails of the proton spot profiles for every nozzle in clinical use. By applying a pair/magnification method and merging film data, 200 mm × 240 mm dose kernels extending to 10(-4) of the central spot dose are generated for six selected energies of the IBA dedicated and universal nozzles (DN and UN). One-dimensional, circular profiles up to 100 mm in radius are generated from the asymmetric profiles to facilitate spot profile comparison. For the highest energy, 225 MeV, the output of both the DN and the UN for field sizes from 40 to 200 mm increases in parallel, slowest at the surface (∼1%) and fastest at a depth of 150 mm (∼9%). In contrast, at the lowest energy, 100 MeV, the output of the DN across the same range of field sizes increases 3-4% versus 6-7% for the UN throughout all the depths. The charge deficits in the measured depth-dose of Bragg peaks are similar between the UN and the DN. At 100 MeV, the field size factor difference at the surface between two orientations of a rectangular 40 mm × 200 mm field is 1.4% at isocentre for the DN versus 2% for the UN. Though the one-dimensional distributions are similar for the primary and tail components at different positions, the primary components of the DN spots are more elliptical 270 mm upstream than at isocentre.

Proton beam irradiation in pediatric oncology: an overview.

The greatest challenge for the treatment of children with cancer is to attain the highest probability of cure with the least morbidity. This has stimulated advances in radiotherapy technology. In recent literature published regarding proton radiation therapy (PRT) for pediatric cancer patients, PRT has been shown to have a distinct advantage over conventional photon therapy because of the ability to confine the high-dose treatment area to the tumor volume and minimize the radiation dose to the surrounding tissue. This is particularly important in children, in whom late effects of radiation to normal tissue can include developmental delay and increased risk of second malignant neoplasms. Several proton facilities are operating world-wide, and several medical centers in the United States and Europe are in the midst of planning and constructing new proton facilities. This may enlarge the role of radiation therapy in the multimodal management of children with cancer.

Potential of 3D printing technologies for fabrication of electron bolus and proton compensators

In electron and proton radiotherapy, applications of patient‐specific electron bolus or proton compensators during radiation treatments are often necessary to accommodate patient body surface irregularities, tissue inhomogeneity, and variations in PTV depths to achieve desired dose distributions. Emerging 3D printing technologies provide alternative fabrication methods for these bolus and compensators. This study investigated the potential of utilizing 3D printing technologies for the fabrication of the electron bolus and proton compensators. Two printing technologies, fused deposition modeling (FDM) and selective laser sintering (SLS), and two printing materials, PLA and polyamide, were investigated. Samples were printed and characterized with CT scan and under electron and proton beams. In addition, a software package was developed to convert electron bolus and proton compensator designs to printable Standard Tessellation Language file format. A phantom scalp electron bolus was printed with FDM technology with PLA material. The HU of the printed electron bolus was 106.5±15.2. A prostate patient proton compensator was printed with SLS technology and polyamide material with −70.1±8.1 HU. The profiles of the electron bolus and proton compensator were compared with the original designs. The average over all the CT slices of the largest Euclidean distance between the design and the fabricated bolus on each CT slice was found to be 0.84±0.45 mm and for the compensator to be 0.40±0.42 mm. It is recommended that the properties of specific 3D printed objects are understood before being applied to radiotherapy treatments. PACS number: 81.40

Comparative treatment planning between proton and X-ray therapy in pancreatic cancer.

With the utilization of new biologic agents and experimental chemotherapy in the treatment of pancreatic cancer, the issue of local-regional control will become increasingly important. This study was undertaken to determine the feasibility of dose escalation using proton therapy, as compared to conventional 3-dimensional conformal radiation, by minimizing the dose to normal tissues. The photon treatment plans of 4 patients with unresectable pancreatic cancer treated on a biologic therapy trial were utilized. Each patient was treated using a 3- or 4-field photon plan with 45 Gy to the clinical target volume (CTV), followed by a boost of 14.4 Gy to the gross target volume (GTV). Using a Helax treatment planning system, proton plans were generated to encompass the same CTV and GTV to the same prescribed dose. Dose-volume histograms (DVHs) were generated for the GTV, CTV, spinal cord, liver, and right and left kidneys. Each DVH was compared between the photon and proton plans. Proton plans utilized either a 2- or 3-field technique. Available energies included 130 or 180 MeV. Range modulators and bolus were used as needed to conform to the target volume. With the CTV and GTV receiving the same dose from the proton and photon plans, all individual proton plans were superior to the photon plans in reduction of normal tissue dose. For the 4 patients, the average dose reduction to 50% of the organ at risk was 78% to spinal cord (p = 0.003), 73% to left kidney (p = 0.025), 43% to right kidney (p = 0.059), and 55% to liver (p = 0.061). These comparative treatment plans show proton therapy results in significant reductions of dose to normal tissue compared to conventional photons while treating the same target volumes. This allows for the design of dose-escalation protocols using protons in combination with new biologic therapies and chemotherapy.