Natalya Morrow

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.

Prone Whole-Breast Irradiation Using Three-Dimensional Conformal Radiotherapy in Women Undergoing Breast Conservation for Early Disease Yields High Rates of Excellent to Good Cosmetic Outcomes in Patients With Large and/or Pendulous Breasts

PURPOSE To report our institutions experience using prone positioning for three-dimensional conformal radiotherapy (3D-CRT) to deliver post-lumpectomy whole breast irradiation (WBI) in a cohort of women with large and/or pendulous breasts, to determine the rate of acute and late toxicities and, more specifically, cosmetic outcomes. We hypothesized that using 3D-CRT for WBI in the prone position would reduce or eliminate patient and breast size as negative prognostic indicators for toxicities associated with WBI. METHODS AND MATERIALS From 1998 to 2006, 110 cases were treated with prone WBI using 3D-CRT. The lumpectomy, breast target volumes, heart, and lung were contoured on all computed tomography scans. A dose of 45-50 Gy was prescribed to the breast volume using standard fractionation schemes. The planning goals were ≥95% of prescription to 95% of the breast volume, and 100% of boost dose to 95% of lumpectomy planning target volume. Toxicities and cosmesis were prospectively scored using the Common Terminology Criteria for Adverse Effects Version 3.0 and the Harvard Scale. The median follow-up was 40 months. RESULTS The median body mass index (BMI) was 33.6 kg/m(2), and median breast volume was 1396 cm(3). The worst toxicity encountered during radiation was Grade 3 dermatitis in 5% of our patient population. Moist desquamation occurred in 16% of patients, with only 2% of patients with moist desquamation outside the inframammary/axillary folds. Eleven percent of patients had Grade ≥2 late toxicities, including Grade 3 induration/fibrosis in 2%. Excellent to good cosmesis was achieved in 89%. Higher BMI was associated with moist desquamation and breast pain, but BMI and breast volume did not impact fibrosis or excellent to good cosmesis. CONCLUSION In patients with higher BMI and/or large-pendulous breasts, delivering prone WBI using 3D-CRT results in favorable toxicity profiles and high excellent to good cosmesis rates. Higher BMI was associated with moist desquamation, but prone positioning removed BMI and breast size as factors for poorer cosmetic outcomes. This series adds to the growing literature demonstrating that prone WBI may be advantageous in select patients.

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

Abstract 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.

Laminin 332 Deposition is Diminished in Irradiated Skin in an Animal Model of Combined Radiation and Wound Skin Injury

Skin exposure to ionizing radiation affects the normal wound healing process and greatly impacts the prognosis of affected individuals. We investigated the effect of ionizing radiation on wound healing in a rat model of combined radiation and wound skin injury. Using a soft X-ray beam, a single dose of ionizing radiation (10–40 Gy) was delivered to the skin without significant exposure to internal organs. At 1 h postirradiation, two skin wounds were made on the back of each rat. Control and experimental animals were euthanized at 3, 7, 14, 21 and 30 days postirradiation. The wound areas were measured, and tissue samples were evaluated for laminin 332 and matrix metalloproteinase (MMP) 2 expression. Our results clearly demonstrate that radiation exposure significantly delayed wound healing in a dose-related manner. Evaluation of irradiated and wounded skin showed decreased deposition of laminin 332 protein in the epidermal basement membrane together with an elevated expression of all three laminin 332 genes within 3 days postirradiation. The elevated laminin 332 gene expression was paralleled by an elevated gene and protein expression of MMP2, suggesting that the reduced amount of laminin 332 in irradiated skin is due to an imbalance between laminin 332 secretion and its accelerated processing by elevated tissue metalloproteinases. Western blot analysis of cultured rat keratinocytes showed decreased laminin 332 deposition by irradiated cells, and incubation of irradiated keratinocytes with MMP inhibitor significantly increased the amount of deposited laminin 332. Furthermore, irradiated keratinocytes exhibited a longer time to close an artificial wound, and this delay was partially corrected by seeding keratinocytes on laminin 332-coated plates. These data strongly suggest that laminin 332 deposition is inhibited by ionizing radiation and, in combination with slower keratinocyte migration, can contribute to the delayed wound healing of irradiated skin.

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.

WE‐E‐AUD C‐02: Impact of Image Quality On CT Guided Prostate Radiotherapy

Purpose: Different CT modalities with varying image quality are being used to correct for interfractional variations in patient setup and anatomy changes, thereby reducing CTV‐to‐PTV margins, for prostate radiotherapy (RT). We explore how CTimage quality affects patient repositioning and CTV‐to‐PTV margin. Method and Materials: Three CT‐based IGRT modalities routinely used in our institute for prostate RT are considered in this study: MV fan beam CT (Tomotherapy), MV cone beam CT (MVision, Siemens) and kV fan beam CT (CTVision, Siemens). Daily shifts are 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 65 prostate cancer patients (34 Tomotherapy, 21 CTVision,10 MVision) treated in our clinics. The impact of soft tissue contrast on organ interface identification was evaluated by analyzing contours drawn by 7 users on the scans from each imaging modality. In addition, variability of soft tissue registration between 10 users was evaluated based on the registration of representative scan for each CT modality with its corresponding planning scan. CTV‐to‐PTV margin was defined as 1.96σ. Results: Inferior image quality with MV CT based IGRT leads to increased variations in daily shifts (3, 4, 5 mm for CTVision, Tomotherapy and MVision) and in prostate delineation (6, 3, 10 mm for CTVision, Tomotherapy and MVision). Superior image quality with the kV CT results in reduced variation between 10 users in soft tissue registration. Uniform margin introduced to account for the uncertainty in the identification of prostate edge are determined to be 2, 6 and 5 mm for CTVision, Tomotherapy and MVision. Conclusion:Image quality adversely affects the reproducibility of the manual registration for IGRT and necessitates a margin of 2 mm for kV CT and 6 mm for MV CT to ensure adequate coverage.

Abstract P1-15-17: Sustained acceptable cosmetic outcomes and local control following accelerated partial breast irradiation using CT-guided IMRT in the prone position: Results from a phase I/II feasibility study

Objective/Purpose External beam accelerated partial breast irradiation (EB-aPBI) can have potential challenges in daily reproducibility, although it has broader potential use than aPBI using brachytherapy. Image-guide radiotherapy (IGRT) can improve daily reproducibility and allow smaller treatment margins. Our institution utilized IG-IMRT to administer EB-aPBI in the prone position in a Phase I/II study to increase dose homogeneity, conformality, normal tissue avoidance, and reliable targeting. Our preliminary results and toxicity were promising. Here we report final physician- and patient-reported cosmetic outcomes from this prospective trial. Materials and Methods Women with node-negative invasive breast cancer or DCIS, tumors less than 3.0 cm, a 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. The lumpectomy PTV represented a 2.0 cm lumpectomy cavity expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered greater than 99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. Results Twenty patients were enrolled, with a median patient age of 61.5 and a mean tumor size of 1.0 cm. 35% of patients had DCIS. At a median follow-up of 18.9 months, 40% and 10% of patients had G1 and G2 fibrosis, respectively, and 95% of patients had good to excellent physician-assessed cosmesis. At a median follow-up of 60.0 months (range 54-79 months), physician-assessed cosmetic outcome was good to excellent in 80%, with 30% and 20% of patients experiencing G1 and G2 fibrosis. Patient-reported outcomes at one year yielded 90% of patients with good to excellent cosmetic outcomes. At 3 years, 75% of patients reported good to excellent cosmesis. Eighty-eight percent of patients were completely satisfied with the treatment and results, and 94% of patients would choose aPBI again. With one local recurrence, the actuarial five year rate of local control was 95%. Conclusions These data demonstrate that EB-aPBI in the prone position using IG-IMRT continues to yield acceptable cosmetic outcomes at longer term follow-up, and a very high percentage of patients would choose this treatment again. (Supported by Komen Grant: BCTR0504070). Citation Format: Carmen Bergom, Phillip Prior, Kristofer Kainz, Natalya V Morrow, Ergun E Ahunbay, Alonzo Walker, X Allen Li, Tracy Kelly, Adam D Currey, Julia White. Sustained acceptable cosmetic outcomes and local control following accelerated partial breast irradiation using CT-guided IMRT in the prone position: Results from a phase I/II feasibility study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-17.

SU‐E‐J‐129: Dosimetric Impact of Interfractional Anatomy Changes On Breast Radiotherapy Based On Accumulative Dose: IMRT Versus 3DCRT

Purpose: Interfractional anatomy changes (e.g., changes in breast shape and volume) in breast radiotherapy (RT) can be significant and cannot be fully accounted for by the current IGRT repositioning practice. This work aims to quantify dosimetric impact of these changes based on accumulative dose for IMRT and 3DCRT. Methods: Daily CT data acquired using a CT‐on‐Rails (CTVision, Siemens) during IGRT for 5 representative breast cancer patients treated in prone position were analyzed. Each daily CT was registered with corresponding planning CT by aligning the lumpectomy cavity, mimicking the IGRT repositioning. Contours of breast, lumpectomy PTV and critical structures on daily CTs were generated using an auto‐segmentation tool (ABAS, Elekta) based on deformable image registration. For each patient, plans for IMRT and 3DCRT with wedge were developed, and were applied to each registered daily CT set to reconstruct the daily doses with the deformation fields from ABAS which were used to compute the accumulative dose. Results: Daily variations in D95 (dose received by 95% of treated breast volume) and D50 were not significantly different between 3DCRT and IMRT plans (within 0.5–2%). Variation of daily dose maximum for IMRT was statistically significantly higher than that for the 3DCRT plans, with some fractions increased by up to 15–20%. However, the variations of the accumulated doses from the original plans for both 3DCRT and IMRT plans are comparable. Conclusion: Although daily doses from IMRT are more sensitive to the interfractional anatomy changes than those from 3DCRT, the variations of the accumulated doses from the original plans are comparable, as the higher variation in the hot spots for IMRT were “washed out” due to the random interfractional changes.