Colleen DesRosiers

Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer

PURPOSE Surgical resection is standard therapy in stage I non-small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. PATIENTS AND METHODS Eligible patients included clinically staged T1 or T2 (< or = 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. RESULTS All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have died as a result of cancer (n = 5), treatment (n = 6), or comorbid illnesses (n = 17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in a total of 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors. CONCLUSION High rates of local control are achieved with this SBRT regimen in medically inoperable patients with stage I NSCLC. Both local recurrence and toxicity occur late after this treatment. This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.

Extracranial Stereotactic Radioablation Physical Principles

Extracranial stereotactic radioablation (ESR) involves treating well-demarcated targeted tissues (e.g. tumor with minimal margin for set-up uncertainties) with very large doses of radiation in single or a few fractions with the intent of causing profound late tissue damage within the targeted volume. In such circumstances, considerable effort must be taken to reduce non-target tissue exposure to the high dose levels in order to prevent late complications to involved organs. Consequently, the following conditions for effective delivery of the ESR techniques have to be satisfied: 1) delivery of a high dose per fraction, i.e. 10–24 Gy; 2) delivery of only a few fractions per course of treatment (e.g. 1–4); 3) shaping of the prescription isodose surface conformally to the target surface; 4) delivery of a non-uniform dose distribution within the target with the highest dose in centrally located regions of hypoxia; 5) rapid fall-off of dose from the target volume to healthy tissue in all directions. In this paper it is shown that high doses per fraction in few fractions can be delivered to a variety of locations with both efficacy and acceptable toxicity (conditions 1 and 2). Conformal shaping of the high isodose surfaces is best accomplished by employing many beams (5–10) each with carefully milled apertures precisely coincident with the target projection (condition 3). Beam intensity modulation creating parabolic beam entrance fluence profiles both concentrates the highest dose in central regions of tumor hypoxia and increases fall-off gradients outside of the target (conditions 4 and 5). It is also shown that isotropic, highly non-coplanar beam arrangements avoiding oppositional fields allow more optimal fall-off gradients to normal tissue as opposed to coplanar treatments (condition 5).

Monte Carlo simulation of the Leksell Gamma Knife®: II. Effects of heterogeneous versus homogeneous media for stereotactic radiosurgery

The absence of electronic equilibrium in the vicinity of bone-tissue or air-tissue heterogeneity in the head can misrepresent deposited dose with treatment planning algorithms that assume all treatment volume as homogeneous media. In this paper, Monte Carlo simulation (PENELOPE) and measurements with a specially designed heterogeneous phantom were applied to investigate the effect of air-tissue and bone-tissue heterogeneity on dose perturbation with the Leksell Gamma Knife. The dose fall-off near the air-tissue interface caused by secondary electron disequilibrium leads to overestimation of dose by the vendor supplied treatment planning software (GammaPlan) at up to 4 mm from an interface. The dose delivered to the target area away from an air-tissue interface may be underestimated by up to 7% by GammaPlan due to overestimation of attenuation of photon beams passing through air cavities. While the underdosing near the air-tissue interface cannot be eliminated with any plug pattern, the overdosage due to under-attenuation of the photon beams in air cavities can be eliminated by plugging the sources whose beams intersect the air cavity. Little perturbation was observed next to bone-tissue interfaces. Monte Carlo results were confirmed by measurements. This study shows that the employed Monte Carlo treatment planning is more accurate for precise dosimetry of stereotactic radiosurgery with the Leksell Gamma Knife for targets in the vicinity of air-filled cavities.

150-250 MeV electron beams in radiation therapy

High-energy electron beams in the range 150-250 MeV are studied to evaluate the feasibility for radiotherapy. Monte Carlo simulation results from the PENELOPE code are presented and used to determine lateral spread and penetration of these beams. It is shown that the penumbra is comparable to photon beams at depths less than 10 cm and the practical range (Rp) of these beams is greater than 40 cm. The depth dose distribution of electron beams compares favourably with photon beams. Effects caused by nuclear reactions are evaluated, including increased dose due to neutron production and induced radioactivity resulting in an increased relative biological effectiveness (RBE) factor of < 1.03.

Monte Carlo simulation of the Leksell Gamma Knife?: I. Source modelling and calculations in homogeneous media

The Monte Carlo code PENELOPE has been used to simulate photon flux from the Leksell Gamma Knife, a precision method for treating intracranial lesions. Radiation from a single 6OCo assembly traversing the collimator system was simulated, and phase space distributions at the output surface of the helmet for photons and electrons were calculated. The characteristics describing the emitted final beam were used to build a two-stage Monte Carlo simulation of irradiation of a target. A dose field inside a standard spherical polystyrene phantom, usually used for Gamma Knife dosimetry, has been computed and compared with experimental results, with calculations performed by other authors with the use of the EGS4 Monte Carlo code, and data provided by the treatment planning system Gamma Plan. Good agreement was found between these data and results of simulations in homogeneous media. Owing to this established accuracy, PENELOPE is suitable for simulating problems relevant to stereotactic radiosurgery.

Use of the Leksell Gamma Knife for localized small field lens irradiation in rodents.

For most basic radiobiological research applications involving irradiation of small animals, it is difficult to achieve the same high precision dose distribution realized with human radiotherapy. The precision for irradiations performed with standard radiotherapy equipment is ±2 mm in each dimension, and is adequate for most human treatment applications. For small animals such as rodents, whose organs and tissue structures may be an order of magnitude smaller than those of humans, the corresponding precision required is closer to ±0.2 mm, if comparisons or extrapolations are to be made to human data. The Leksell Gamma Knife is a high precision radiosurgery irradiator, with precision in each dimension not exceeding 0.5 mm, and overall precision of 0.7 mm. It has recently been utilized to treat ocular melanoma and induce targeted lesions in the brains of small animals. This paper describes the dosimetry and a technique for performing irradiation of a single rat eye and lens with the Gamma Knife while allowing the contralateral eye and lens of the same rat to serve as the “control”. The dosimetry was performed with a phantom in vitro utilizing a pinpoint ion chamber and thermoluminescent dosimeters, and verified by Monte Carlo simulations. We found that the contralateral eye received less than 5% of the administered dose for a 15 Gy exposure to the targeted eye. In addition, after 15 Gy irradiation 15 out of 16 animals developed cataracts in the irradiated target eyes, while 0 out of 16 contralateral eyes developed cataracts over a 6-month period of observation. Experiments at 5 and 10 Gy also confirmed the lack of cataractogenesis in the contralateral eye. Our results validate the use of the Gamma Knife for cataract studies in rodents, and confirmed the precision and utility of the instrument as a small animal irradiator for translational radiobiology experiments.

Development of a Porcine Delayed Wound-Healing Model and Its Use in Testing a Novel Cell-Based Therapy

PURPOSE A delayed full-thickness wound-healing model was developed and used for examining the capacity of adipose-derived stem cells (ASCs), either alone or in platelet-rich fibrin gels, to promote healing. METHODS AND MATERIALS Four pigs received electron beam radiation to the dorsal skin surface. Five weeks after radiation, subcutaneous fat was harvested from nonirradiated areas and processed to yield ASCs. Two weeks later, 28 to 30 full-thickness 1.5-cm(2) wounds were made in irradiated and nonirradiated skin. Wounds were treated with either saline solution, ASCs in saline solution, platelet-rich plasma (PRP) fibrin gel, ASCs in PRP, or non-autologous green fluorescence protein-labeled ASCs. RESULTS The single radiation dose produced a significant loss of dermal microvasculature density (75%) by 7 weeks. There was a significant difference in the rate of healing between irradiated and nonirradiated skin treated with saline solution. The ASCs in PRP-treated wounds exhibited a significant 11.2% improvement in wound healing compared with saline solution. Enhancement was dependent on the combination of ASCs and PRP, because neither ASCs nor PRP alone had an effect. CONCLUSIONS We have created a model that simulates the clinically relevant late radiation effects of delayed wound healing. Using this model, we showed that a combination of ASCs and PRP improves the healing rates of perfusion-depleted tissues, possibly through enhancing local levels of growth factors.

Phosphorus-32 therapy for cystic craniopharyngiomas

BACKGROUND AND PURPOSE To examine control rates for predominantly cystic craniopharyngiomas treated with intracavitary phosphorus-32 (P-32). MATERIAL AND METHODS 22 patients with predominantly cystic craniopharyngiomas were treated at Indiana University between October 1997 and December 2006. Nineteen patients with follow-up of at least 6 months were evaluated. The median patient age was 11 years, median cyst volume was 9 ml, a median dose of 300 Gy was prescribed to the cyst wall, and median follow-up was 62 months. RESULTS Overall cyst control rate after the initial P-32 treatment was 67%. Complete tumor control after P-32 was 42%. Kaplan-Meier 1-, 3-, and 5-year initial freedom-from-progression rates were 68%, 49%, and 31%, respectively. Following salvage therapy, the Kaplan-Meier 1-, 3-, and 5-year ultimate freedom-from-progression rates were 95%, 95%, and 86%, respectively. All patients were alive at the last follow-up. Visual function was stable or improved in 81% when compared prior to P-32 therapy. Pituitary function remained stable in 74% of patients following P-32 therapy. CONCLUSIONS Intracystic P-32 can be an effective and tolerable treatment for controlling cystic components of craniopharyngiomas as a primary treatment or after prior therapies, but frequently allows for progression of solid tumor components. Disease progression in the form of solid tumor progression, re-accumulation of cystic fluid, or development of new cysts may require further radiotherapy or surgical intervention for optimal long-term disease control.

Estrogen Protects against Radiation-Induced Cataractogenesis

Abstract Dynlacht, J. R., Valluri, S., Lopez, J., Greer, F., DesRosiers, C., Caperell-Grant, A., Mendonca, M. S. and Bigsby, R. M. Estrogen Protects against Radiation-Induced Cataractogenesis. Radiat. Res. 170, 758–764 (2008). Cataractogenesis is a complication of radiotherapy when the eye is included in the treatment field. Low doses of densely ionizing space radiation may also result in an increased risk of cataracts in astronauts. We previously reported that estrogen (17-β-estradiol), when administered to ovariectomized rats commencing 1 week before γ irradiation of the eye and continuously thereafter, results in a significant increase in the rate and incidence of cataract formation and a decreased latent period compared to an ovariectomized control group. We therefore concluded that estrogen accelerates progression of radiation-induced opacification. We now show that estrogen, if administered continuously, but commencing after irradiation, protects against radiation cataractogenesis. Both the rate of progression and incidence of cataracts were greatly reduced in ovariectomized rats that received estrogen treatment after irradiation compared to ovariectomized rats. As in our previous study, estradiol administered 1 week prior to irradiation at the time of ovariectomy and throughout the period of observation produced an enhanced rate of cataract progression. Estrogen administered for only 1 week prior to irradiation had no effect on the rate of progression but resulted in a slight reduction in the incidence. We conclude that estrogen may enhance or protect against radiation cataractogenesis, depending on when it is administered relative to the time of irradiation, and may differentially modulate the initiation and progression phases of cataractogenesis. These data have important implications for astronauts and radiotherapy patients.

Effect of Estrogen on Radiation-Induced Cataractogenesis

Abstract Dynlacht, J. R., Tyree, C., Valluri, S., DesRosiers, C., Caperell-Grant, A., Mendonca, M. S., Timmerman, R. and Bigsby, R. M. Effect of Estrogen on Radiation-Induced Cataractogenesis. Radiat. Res. 165, 9–15 (2006). Cataractogenesis is a widely reported late effect that is observed in patients receiving total-body irradiation (TBI) prior to bone marrow transplantation or radiotherapy for ocular or head and neck cancers. Recent studies indicate that estrogens may protect against age-related and drug-induced cataracts. Moreover, other reports suggest that estrogen possesses antioxidant properties. Since the effect of estrogen on radiation cataractogenesis is unknown, we wished to determine whether estrogen modulates radiation-induced opacification of the lens. Intact or ovariectomized Sprague-Dawley rats were treated with either 17-β-estradiol or an empty silastic capsule. The right orbit was then irradiated with either 10 or 15 Gy of 60Co γ rays using a Leksell Gamma Knife, and lenses were examined at various times postirradiation with a slit lamp or evaluated for light transmission. We found that for ovariectomized rats irradiated with 15 Gy, the lens opacity and the incidence of cataract formation in the estradiol-treated group were significantly increased compared to the control group at the end of the 25-week period of observation. Cataract incidence was also high in irradiated eyes of ovary-intact animals at 25 weeks postirradiation but was greatly reduced in the ovariectomized control group, with less than half of irradiated eyes showing evidence of cataractogenesis. Thus, after irradiation with 15 Gy of γ rays, estrogen increased the incidence of cataract formation. We also observed that although the incidence of cataract formation in rats irradiated with 10 Gy and receiving continuous estrogen treatment was not altered compared to rats in the control group that did not receive estrogen, the latent period for posterior subcapsular cataract formation decreased and the severity of the anterior cataract increased. Taken together, our data suggest that estrogen accelerates progression of radiation-induced opacification.