A phase I/II study piloting accelerated partial breast irradiation using CT-guided intensity modulated radiation therapy in the prone position.

BACKGROUND AND PURPOSE: External beam accelerated partial breast irradiation (EB-aPBI) is noninvasive with broader potential applicability than aPBI using brachytherapy. However, it has inherent challenges in daily reproducibility. Image-guide radiotherapy (IGRT) can improve daily reproducibility, allowing smaller treatment margins. Our institution proposed IG-IMRT in the prone position to evaluate dose homogeneity, conformality, normal tissue avoidance, and reliable targeting for EB-aPBI. We report preliminary results and toxicity from a phase I/II study evaluating the feasibility of EB-aPBI in the prone position using IG-IMRT. MATERIALS AND METHODS: Twenty post-menopausal women with node-negative breast cancer, excised tumors <3.0 cm, negative sentinel lymph node biopsy, and surgical clips demarcating the lumpectomy cavity underwent prone EB-aPBI using IG-IMRT on an IRB-approved phase I/II study. All patients underwent CT planning in the prone position. The lumpectomy cavity PTV represented a 2.0 cm expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered >99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. RESULTS: The median patient age was 61.5. Mean tumor size was 1.0 cm. 35% of patients had DCIS. Median PTV was 243 cc (108-530) and median breast reference volume was 1698 cc (647-3627). Average daily shifts for IGRT were (0.6, -4.6, 1.7 mm) with standard deviations of (6.3, 6.5, 6.4mm). Acute toxicity was G1 erythema in 80%, and G2 erythema, G2 fatigue, and G2 breast pain each occurred in 1 patient. With a median follow-up of 18.9 months (12-35), 40% of patients have G1 fibrosis and 30% have G1 hyperpigmentation. 95% of patients have good to excellent cosmesis. There have been no recurrences. CONCLUSIONS: These data demonstrate that EB-aPBI in the prone position using IG-IMRT is well tolerated, yields good dosimetric conformality, and results in promising early toxicity profiles.

Impact of computed tomography image quality on image-guided radiation therapy based on soft tissue registration.

PURPOSE: In image-guided radiation therapy (IGRT), different computed tomography (CT) modalities with varying image quality are being used to correct for interfractional variations in patient set-up and anatomy changes, thereby reducing clinical target volume to the planning target volume (CTV-to-PTV) margins. We explore how CT image quality affects patient repositioning and CTV-to-PTV margins in soft tissue registration-based IGRT for prostate cancer patients. METHODS AND MATERIALS: Four CT-based IGRT modalities used for prostate RT were considered in this study: MV fan beam CT (MVFBCT) (Tomotherapy), MV cone beam CT (MVCBCT) (MVision; Siemens), kV fan beam CT (kVFBCT) (CTVision, Siemens), and kV cone beam CT (kVCBCT) (Synergy; Elekta). Daily shifts were determined by manual registration to achieve the best soft tissue agreement. Effect of image quality on patient repositioning was determined by statistical analysis of daily shifts for 136 patients (34 per modality). Inter- and intraobserver variability of soft tissue registration was evaluated based on the registration of a representative scan for each CT modality with its corresponding planning scan. RESULTS: Superior image quality with the kVFBCT resulted in reduced uncertainty in soft tissue registration during IGRT compared with other image modalities for IGRT. The largest interobserver variations of soft tissue registration were 1.1 mm, 2.5 mm, 2.6 mm, and 3.2 mm for kVFBCT, kVCBCT, MVFBCT, and MVCBCT, respectively. CONCLUSIONS: Image quality adversely affects the reproducibility of soft tissue-based registration for IGRT and necessitates a careful consideration of residual uncertainties in determining different CTV-to-PTV margins for IGRT using different image modalities.

Cellular inflammatory infiltrate in pneumonitis induced by a single moderate dose of thoracic x radiation in rats.

The goal of these studies was to characterize the infiltrating inflammatory cells during pneumonitis caused by moderate doses of radiation. Two groups of male rats (WAG/RijCmcr, 8 weeks old) were treated with single 10- or 15-Gy doses of thoracic X radiation; a third group of age-matched animals served as controls. Only 25% rats survived the 15-Gy dose. Bronchoalveolar lavage fluid and whole lung mounts were subjected to cytological and histological evaluation after 8 weeks for distribution of resident macrophages, neutrophils, lymphocytes and mast cells. There was a modest increase in airway and airspace-associated neutrophils in lungs from rats receiving 15 Gy. Mast cells (detected by immunohistochemistry for tryptase) increased over 70% with 10 Gy and over 13-fold after 15 Gy, with considerable leakage of tryptase into blood vessels and airways. Circulating levels of eight inflammatory cytokines were not altered after 10 Gy but appeared to decrease after 15 Gy. In summary, there were only modest increases in cellular inflammatory infiltrate during pneumonitis after a non-lethal dose of 10 Gy, but there was a dramatic rise in mast cell infiltration after 15 Gy, suggesting that circulating levels of mast cell products may be useful markers of severe pneumonitis.

Structural and functional alterations in the rat lung following whole thoracic irradiation with moderate doses: injury and recovery.

PURPOSE: To characterize structural and functional injuries following a single dose of whole-thorax irradiation that might be survivable after a nuclear attack/accident. METHODS: Rats were exposed to 5 or 10 Gy of X-rays to the whole thorax with other organs shielded. Non-invasive measurements of breathing rate and arterial oxygen saturation, and invasive evaluations of bronchoalveolar lavage fluid, (for total protein, Clara cell secretory protein), vascular reactivity and histology were conducted for at least 6 time points up to 52 weeks after irradiation. RESULTS: Irradiation with 10 Gy resulted in increased breathing rate, a reduction in oxygen saturation, an increase in bronchoalveolar lavage fluid protein and attenuation of vascular reactivity between 4-12 weeks after irradiation. These changes were not observed with the lower dose of 5 Gy. Histological examination revealed perivascular edema at 4-8 weeks after exposure to both doses, and mild fibrosis beyond 20 weeks after 10 Gy. CONCLUSIONS: Single-dose exposure of rat thorax to 10 but not 5 Gy X-irradiation resulted in a decrease in oxygen uptake and vasoreactivity and an increase in respiratory rate, which paralleled early pulmonary vascular pathology. Vascular edema resolved and was replaced by mild fibrosis beyond 20 weeks after exposure, while lung function recovered.

Irradiation of varying volumes of rat lung to same mean lung dose: a little to a lot or a lot to a little?

PURPOSE: To investigate whether irradiating small lung volumes with a large dose or irradiating large lung volumes with a small dose, given the same mean lung dose (MLD), has a different effect on pulmonary function in laboratory animals. METHODS AND MATERIALS: WAG/Rij/MCW male rats were exposed to single fractions of 300 kVp X-rays. Four treatments, in decreasing order of irradiated lung volume, were administered: (1) whole lung irradiation, (2) right lung irradiation, (3) left lung irradiation, and (4) irradiation of a small lung volume with four narrow beams. The irradiation times were chosen to accumulate the same MLD of 10, 12.5, or 15 Gy with each irradiated lung volume. The development of radiation-induced lung injury for < or =20 weeks was evaluated as increased breathing frequency, mortality, and histopathologic changes in the irradiated and control rats. RESULTS: A significant elevation of respiratory rate, which correlated with the lung volume exposed to single small doses (> or =5 Gy), but not with the MLD, was observed. The survival of the rats in the whole-lung-irradiated group was MLD dependent, with all events occurring between 4.5 and 9 weeks after irradiation. No mortality was observed in the partial-volume irradiated rats. CONCLUSIONS: The lung volume irradiated to small doses might be the dominant factor influencing the loss of pulmonary function in the rat model of radiation-induced lung injury. Caution should be used when new radiotherapy techniques that result in irradiation of large volumes of normal tissue are used for the treatment of lung cancer and other tumors in the thorax.

Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.

PURPOSE: Intra- and interfractional errors for breast cancer patients undergoing breast irradiation in the prone position were analyzed. METHODS AND MATERIALS: To assess intrafractional error resulting from respiratory motion, four-dimensional computed tomography scans were acquired for 3 prone and 3 supine patients, and the respiratory motion was compared for the two positions. To assess the interfractional error caused by daily set-up variations, daily electronic portal images of one of the treatment beams were taken for 15 prone-positioned patients. Portal images were then overlaid with images from the planning system that included the breast contour and the isocenter, treatment beam portal, and isocenter. The shift between the planned and actual isocenter was recorded for each portal image, and descriptive statistics were collected for each patient. The margins were calculated using the 2Sigma + 0.7sigma recipe, as well as 95% confidence interval based on the pooled standard deviation of the datasets. RESULTS: Respiratory motion of the chest wall is drastically reduced from 2.3 +/- 0.9 mm in supine position to -0.1 +/- 0.4 mm in prone position. The daily set-up errors vary in magnitude from 0.0 cm to 1.65 cm and are patient dependent. The margins were defined by considering only the standard deviation to be 1.1 cm, and 2.0 cm when the systematic errors were considered using the 2Sigma + 0.7sigma recipe. CONCLUSIONS: Prone positioning of patients for breast irradiation significantly reduces the uncertainty introduced by intrafractional respiratory motion. The presence of large systematic error in the interfractional variations necessitates a large clinical target volume-to-planning target volume margin and indicates the importance of image guidance for partial breast irradiation in the prone position, particularly using imaging modality capable of identifying the lumpectomy cavity.