Xing-Qi Lu

A Critical Examination of the Results from the Harvard-MIT NCT Program Phase I Clinical Trial of Neutron Capture Therapy for Intracranial Disease

SummaryA phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase 1 trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The10B carrier,l-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg−1 over 1 h (10 subjects), 300 mg kg−1 over 1.5 h (two subjects), or 350 mg kg−1 over 1.5–2 h (10 subjects). The pharmacokinetic profile of10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

Bevacizumab Reverses Cerebral Radiation Necrosis

A 43-year-old Chinese woman, with a 6-month history of hearing loss, was diagnosed with biopsy-proven T3, N1, M0, stage III undifferentiated nasopharyngeal carcinoma. Her initial head magnetic resonance imaging (MRI) scan showed a mass in the nasopharynx (Fig 1A, asterisk) extending into the left sphenoid sinus (Fig 1B, arrow), and there was fluid accumulation in the left mastoid process. She received cisplatin and involved-field intensity-modulated radiotherapy (IMRT) to 70 Gy, followed by an additional three cycles of cisplatin and fluorouracil. Her inferior temporal lobes received up to 68.5 Gy of radiation (Fig 1C, red isodose line). Two years later, she experienced verbal memory loss, together with fatigue and mild imbalance. Her neurological examination was notable for psychomotor slowing and deficit in immediate recall. She also had a mini–mental status examination score of 26 (from a total of 30), suggesting moderate cognitive dysfunction. A gadolinium-enhanced head MRI, taken for evaluation of her neurocognitive deficits, showed enhancement in the inferior left temporal lobe with increased fluid-attenuated inversion recovery signals in the surrounding brain parenchyma (Figs 2A and 2B). She underwent [F]fluorodeoxyglucose (FDG)–positron emission tomography and thallium–single photon emission computed tomography, and revealed no uptake of either radionuclide in the corresponding region of gadolinium enhancement. The inferior left temporal lobe did not have increased blood flow, as measured by arterial spin labeling. Because the findings suggest radiation necrosis of the brain, she was treated with 5 mg/kg of bevacizumab every other week. After four doses, the enhancement on MRI was nearly gone (Fig 3A & 3B) and her mini–mental status examination score increased to 30. Her imbalance and fatigue disappeared. These neurocognitive improvements persisted at the time of follow-up 6 months later. Temporal lobe radiation necrosis was common before the adoption of IMRT for head and neck cancer. The spectrum of this disorder ranged from edema noted as hyperintense fluid-attenuated inversion recovery, T2 signals in the temporal lobes, and hemorrhagic transformation, to necrotic cysts causing mass effect. The development of cerebral radiation necrosis from fractionated radiotherapy is a function of total dose, dose per fraction, and time from completion of radiation. The higher the total dose or dose per fraction, the sooner cerebral radiation necrosis would appear in patients. The mechanism appears to be a result of radiation damage to vascular endothelial cells, causing endothelial cell proliferation, telangiectatic vessels, and fibrinoid necrosis with accompanying perivascular exudation and edema. In experimental settings, microhemorrhages was noted in the brains of rabbits when they were treated with proton stereotaxic radiosurgery. Similarly, in the gastrointestinal tract of mice treated with 15 Gy of whole-body irradiation, radiation-induced endothelial cell apoptosis was the primary mechanism leading to stem-cell dysfunction, crypts damage, and death. The secondary stem-cell dysfunction was probably a result of damage to the vascular niche where the stem cells reside. Although the kinetics of this damage is unknown in experimental animals, patients who received radiation at 62.5 Gy or more have greater than 25% probability of radiation necrosis within 5 years. Our patient received a dose of up to 68.5 Gy in the inferior temporal lobe, making her high risk for developing radiation necrosis despite the tight conformality of IMRT-limiting scattered radiation to the temporal lobes. The gadolinium-enhancing abnormality was not FDG or thallium avid, suggesting that it was unlikely to be tumor or infection. A diagnosis of cerebral radiation necrosis was also supported by more than 2 years of delayed development of her temporal abnormality. Conventional treatment consisted of corticosteroid to limit the extent of cerebral edema and, if necessary, drainage of compressive cysts. Unfortunately, due to the unrelenting process of necrosis, patients in the past typically succumbed to complications of

A miniature MOSFET radiation dosimeter probe

Prototype miniature dosimeter probes have been designed, built, and characterized employing a small, radiation sensitive metal oxide semiconductor field effect transistor (MOSFET) chip to measure, in vivo, the total accumulated dose and dose rate as a function of time after internal administration of long range beta particle radiolabeled antibodies and in external high energy photon and electron beams. The MOSFET detector is mounted on a long narrow alumina substrate to facilitate electrical connection. The MOSFET, alumina substrate, and lead wires are inserted into a 16 gauge flexineedle, which, in turn, may be inserted into tissue. The radiation dosimeter probe has overall dimensions of 1.6 mm diam and 3.5 cm length. The MOSFET probe signals are read, stored, and analyzed using an automated data collection and analysis system. Initially, we have characterized the probes response to long range beta particle emission from 90Y sources in solution and to high energy photon and electron beams from linear accelerators. Since the prototype has a finite substrate thickness, the angular dependence has been studied using beta particle emission from a 90Sr source. Temperature dependence and signal drift have been characterized and may be corrected for. Measurements made in spherical volumes containing 90Y with diameters less than the maximum electron range, to simulate anticipated geometries in animal models, agree well with Berger point kernel and EGS4 Monte Carlo calculations. The results from the prototype probes lead to design requirements for detection of shorter range beta particles used in radioimmunotherapy and lower photon energies used in brachytherapy.

Use of a realistic breathing lung phantom to evaluate dose delivery errors

PURPOSE To compare the effect of respiration-induced motion on delivered dose (the interplay effect) for different treatment techniques under realistic clinical conditions. METHODS A flexible resin tumor model was created using rapid prototyping techniques based on a computed tomography (CT) image of an actual tumor. Twenty micro-MOSFETs were inserted into the tumor model and the tumor model was inserted into an anthropomorphic breathing phantom. Phantom motion was programed using the motion trajectory of an actual patient. A four-dimensional CT image was obtained and several treatment plans were created using different treatment techniques and planning systems: Conformal (Eclipse), step-and-shoot intensity-modulated radiation therapy (IMRT) (Pinnacle), step-and-shoot IMRT (XiO), dynamic IMRT (Eclipse), complex dynamic IMRT (Eclipse), hybrid IMRT [60% conformal, 40% dynamic IMRT (Eclipse)], volume-modulated arc therapy (VMAT) [single-arc (Eclipse)], VMAT [double-arc (Eclipse)], and complex VMAT (Eclipse). The complex plans were created by artificially pushing the optimizer to give complex multileaf collimator sequences. Each IMRT field was irradiated five times and each VMAT field was irradiated ten times, with each irradiation starting at a random point in the respiratory cycle. The effect of fractionation was calculated by randomly summing the measured doses. The maximum deviation for each measurement point per fraction and the probability that 95% of the model tumor had dose deviations less than 2% and 5% were calculated as a function of the number of fractions. Tumor control probabilities for each treatment plan were calculated and compared. RESULTS After five fractions, measured dose deviations were less than 2% for more than 95% of measurement points within the tumor model for all plans, except the complex dynamic IMRT, step-and-shoot IMRT (XiO), complex VMAT, and single-arc VMAT plans. Reducing the dose rate of the complex IMRT plans from 600 to 200 MU/min reduced the dose deviations to less than 2%. Dose deviations were less than 5% after five fractions for all plans, except the complex single-arc VMAT plan. CONCLUSIONS Rapid prototyping techniques can be used to create realistic tumor models. For most treatment techniques, the dose deviations averaged out after several fractions. Treatments with unusually complicated multileaf collimator sequences had larger dose deviations. For IMRT treat-ments, dose deviations can be reduced by reducing the dose rate. For VMAT treatments, using two arcs instead of one is effective for reducing dose deviations.

Lung Dose-Volume Parameters and the Risk of Pneumonitis for Patients Treated With Accelerated Partial-Breast Irradiation Using Three-Dimensional Conformal Radiotherapy

PURPOSE There are no data on how complication rates after accelerated partial-breast irradiation delivered by three-dimensional conformal radiotherapy are affected by treatment technique. We therefore examined the risk of pneumonitis in relation to lung dose-volume parameters. PATIENTS AND METHODS Our prospective dose-escalation trial enrolled 198 treated patients from 2003 to 2007. Patients received 32 or 36 Gy in 4-Gy fractions, given twice daily: 29 (14%) were treated with pure photons; 149 (77%) with mixed photons and electrons; and 20 (10%) with protons. RESULTS There were four cases of pneumonitis at 4, 4, 7, and 9 months after treatment. All were in the 36-Gy cohort and were treated with pure photons. The risk of pneumonitis for the two cohorts combined was: 17% (four of 24) for an ipsilateral lung volume (ILV) receiving 20 Gy or higher (ILV, 20 Gy) of 3% or higher (P = .0002 for comparison to ILV 20 Gy < 3%, Fishers exact test); 20% (four of 20) for an ILV 10 Gy of 10% or higher (P = .0001); and 15% (four of 26) for an ILV 5 Gy of 20% or higher (P = .0002). CONCLUSION The risk of pneumonitis appeared related to the ILV treated. This volume can be reduced by using mixed photons and electron when possible. We recommend that the ILV 20 Gy should be lower than 3%, the ILV 10 Gy lower than 10%, and the ILV 5 Gy lower than 20% when purely coplanar techniques are used.

Organ Deformation and Dose Coverage in Robotic Respiratory-Tracking Radiotherapy

PURPOSE Respiratory motion presents a significant challenge in stereotactic body radiosurgery. Respiratory tracking that follows the translational movement of the internal fiducials minimizes the uncertainties in dose delivery. However, the effect of deformation, defined as any changes in the body and organs relative to the center of fiducials, remains unanswered. This study investigated this problem and a possible solution. METHODS AND MATERIALS Dose delivery using a robotic respiratory-tracking system was studied with clinical data. Each treatment plan was designed with the computed tomography scan in the end-expiration phase. The planned beams were applied to the computed tomography scan in end-inspiration following the shift of the fiducials. The dose coverage was compared with the initial plan, and the uncertainty due to the deformation was estimated. A necessary margin from the clinical target volume to the planning target volume was determined to account for this and other sources of uncertainty. RESULTS We studied 12 lung and 5 upper abdomen lesions. Our results demonstrated that for lung patients with properly implanted fiducials a 3-mm margin is required to compensate for the deformation and a 5-mm margin is required to compensate for all uncertainties. Our results for the upper abdomen tumors were still preliminary but indicated a similar result, although a larger margin might be required. CONCLUSION The effect of body deformation was studied. We found that adequate dose coverage for lung tumors can be ensured with proper fiducial placement and a 5-mm planning target volume margin. This approach is more practical and effective than a recent proposal to combine four-dimensional planning with respiratory tracking.

Sampling techniques for the evaluation of treatment plans

Sampling techniques using randomly distributed points and regular Cartesian grids were compared for the evaluation of volume, dose-volume histogram, tumor control, and normal tissue complication probabilities in radiation treatments. Particularly, the uncertainties associated with each sampling technique in estimating the dose-volume histograms for several dose distributions are analyzed in detail. It is found that the estimation of these parameters using sampling points on a regular Cartesian grid is, in general, significantly more efficient than using random points. This finding is different from other published results. The choice of grid size for sampling was analyzed according to the AAPM recommended uncertainty on the dose delivered to the patient. It was concluded that when grid sampling is used, a grid size of 0.5 cm is adequate for most plans to meet the guidelines.

The spatial accuracy of cellular dose estimates obtained from 3D reconstructed serial tissue autoradiographs

In order to better predict and understand the effects of radiopharmaceuticals used for therapy, it is necessary to determine more accurately the radiation absorbed dose to cells in tissue. Using thin-section autoradiography, the spatial distribution of sources relative to the cells can be obtained from a single section with micrometre resolution. By collecting and analysing serial sections, the 3D microscopic distribution of radionuclide relative to the cellular histology, and therefore the dose rate distribution, can be established. In this paper, a method of 3D reconstruction of serial sections is proposed, and measurements are reported of (i) the accuracy and reproducibility of quantitative autoradiography and (ii) the spatial precision with which tissue features from one section can be related to adjacent sections. Uncertainties in the activity determination for the specimen result from activity losses during tissue processing (4-11%), and the variation of grain count per unit activity between batches of serial sections (6-25%). Correlation of the section activity to grain count densities showed deviations ranging from 6-34%. The spatial alignment uncertainties were assessed using nylon fibre fiduciary markers incorporated into the tissue block, and compared to those for alignment based on internal tissue landmarks. The standard deviation for the variation in nylon fibre fiduciary alignment was measured to be 41 microns cm-1, compared to 69 microns cm-1 when internal tissue histology landmarks were used. In addition, tissue shrinkage during histological processing of up to 10% was observed. The implications of these measured activity and spatial distribution uncertainties upon the estimate of cellular dose rate distribution depends upon the range of the radiation emissions. For long-range beta particles, uncertainties in both the activity and spatial distribution translate linearly to the uncertainty in dose rate of < 15%. For short-range emitters (< 100 microns), such as alpha particle sources, the magnitude of the uncertainty in serial section alignment is comparable with the particle track length. Under these circumstances, dosimetric errors are introduced in proportion to the serial section alignment inaccuracy.

Design of an ultrasonic therapy system for breast cancer treatment

This paper describes the design of a novel ultrasonic therapy system dedicated to the breast cancer treatment and the theoretical investigation of the heating characteristics of the system. The applicator is a cylinder comprised of a stack of rings. Each ring has up to 48 transducers mounted on the inside of the ring and directed towards the centre. The transducers operate in one of two frequency bands (1.8-2.8 MHz and 4.3-40.8 MHz), arranged alternately in each ring. During treatment the patient is positioned in prone position, with the breast immersed in water and surrounded by this array. This design was modelled and optimized by 3-D simulations for a variety of treatment conditions. The simulated results demonstrate that the system has an excellent capability to achieve and maintain a temperature distribution (41.5-44 degrees C) in a quadrant to a whole breast. Initial experiments using a single ring of transducers has been performed to verify the power deposition calculation.

Cyberknife Radiosurgery for Basal Skull Plasmacytoma

The Cyberknife delivers frameless image‐guided stereotactic radiosurgery to intracranial and extracranial tumors. We report our use of Cyberknife radiosurgery on a medullary plasmacytoma in the clivus extending into the foramen magnum. No acute toxicity was seen during or within 24 hours of treatment, and the subject had a complete and durable radiographic response on MRI 12+ months after treatment. To our knowledge, this is a first case of successful Cyberknife radiosurgery of a medullary plasmacytoma.