Association between cumulative radiation dose, adverse skin reactions, and changes in surface hemoglobin among women undergoing breast conserving therapy.

INTRODUCTION: Radiation therapy is crucial to effective cancer treatment. Modern treatment strategies have reduced possible skin injury, but few clinical studies have addressed the dose relationship between radiation exposure and skin reaction. This prospective clinical study analyzes skin oxygenation/perfusion in patients undergoing fractionated breast conserving therapy via hyperspectral imaging (HSI). METHODS: Forty-three women undergoing breast conserving therapy were enrolled in this study. Optically stimulated luminescent dosimeters (OSLDs) measured radiation exposure in four sites: treatment breast, lumpectomy scar, medial tattoo and the control breast. The oxygenation/perfusion states of these sites were prospectively imaged before and after each treatment fraction with HSI. Visual skin reactions were classified according to the RTOG system. RESULTS: 2753 observations were obtained and indicated a dose-response relationship between radiation exposure and oxygenated hemoglobin (OxyHb) after a 600 cGy cumulative dose threshold. There was a relatively weak association between DeoxyHb and radiation exposure. Results suggest strong correlations between changes in mean OxyHb and skin reaction as well as between radiation exposure and changes in skin reaction. CONCLUSION: HSI demonstrates promise in the assessment of skin dose as well as an objective measure of skin reaction. The ability to easily identify adverse skin reactions and to modify the treatment plan may circumvent the need for detrimental treatment breaks.

External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site.

BACKGROUND: External volume expansion prepares recipient sites to improve outcomes of fat grafting. For patients receiving radiotherapy after mastectomy, results with external volume expansion vary, and the relationship between radiotherapy and expansion remains unexplored. Thus, the authors developed a new translational model to investigate the effects in chronic skin fibrosis after radiation exposure. METHODS: Twenty-four SKH1-E mice received 50 Gy of ß-radiation to each flank and were monitored until fibrosis developed (8 weeks). External volume expansion was then applied at -25 mmHg to one side for 6 hours for 5 days. The opposite side served as the control. Perfusion changes were assessed with hyperspectral imaging. Mice were euthanized at 5 (n = 12) and 15 days (n = 12) after the last expansion application. Tissue samples were analyzed with immunohistochemistry for CD31 and Ki67, Masson trichrome for skin thickness, and picrosirius red to analyze collagen composition. RESULTS: All animals developed skin fibrosis 8 weeks after radiotherapy and became hypoperfused based on hyperspectral imaging. Expansion induced edema on treated sides after stimulation. Perfusion was decreased by 13 percent on the expansion side (p < 0.001) compared with the control side for 5 days after stimulation. Perfusion returned to control-side levels by day 15. Dermal vasculature increased 38 percent by day 15 (p < 0.01) in expansion versus control. No difference was found in collagen composition. CONCLUSIONS: External volume expansion temporarily reduces perfusion, likely because of transient ischemia or edema. Together with mechanotransduction, these effects encourage a proangiogenic and proliferative environment in fibrotic tissue after radiotherapy in the authors' mouse model. Further studies are needed to assess these changes in fat graft retention.

Hyperspectral Imaging as an Early Biomarker for Radiation Exposure and Microcirculatory Damage.

BACKGROUND: Radiation exposure can lead to detrimental effects in skin microcirculation. The precise relationship between radiation dose received and its effect on cutaneous perfusion still remains controversial. Previously, we have shown that hyperspectral imaging (HSI) is able to demonstrate long-term reductions in cutaneous perfusion secondary to chronic microvascular injury. This study characterizes the changes in skin microcirculation in response to varying doses of ionizing radiation and investigates these microcirculatory changes as a possible early non-invasive biomarker that may correlate with the extent of long-term microvascular damage. METHODS: Immunocompetent hairless mice (n = 66) were exposed to single fractions of superficial beta-irradiation in doses of 0, 5, 10, 20, 35, or 50 Gy. A HSI device was utilized to measure deoxygenated hemoglobin levels in irradiated and control areas. HSI measurements were performed at baseline before radiation exposure and for the first 3 days post-irradiation. Maximum macroscopic skin reactions were graded, and histological assessment of cutaneous microvascular densities at 4 weeks post-irradiation was performed in harvested tissue by CD31 immunohistochemistry. RESULTS: CD31 immunohistochemistry demonstrated a significant correlation (r = 0.90, p < 0.0001) between dose and vessel density reduction at 4 weeks. Using HSI analysis, early changes in deoxygenated hemoglobin levels were observed during the first 3 days post-irradiation in all groups. These deoxygenated hemoglobin changes varied proportionally with dose (r = 0.98, p < 0.0001) and skin reactions (r = 0.98, p < 0.0001). There was a highly significant correlation (r = 0.91, p < 0.0001) between these early changes in deoxygenated hemoglobin and late vascular injury severity assessed at the end of 4 weeks. CONCLUSION: Radiation dose is directly correlated with cutaneous microvascular injury severity at 4 weeks in our model. Early post-exposure measurement of cutaneous deoxygenated hemoglobin levels may be a useful biomarker for radiation dose reconstruction and predictor for chronic microvascular injury.

Dosimetric impact of the AeroForm tissue expander in postmastectomy radiation therapy: an ex vivo analysis.

PURPOSE: To evaluate the effect of the AeroForm (AirXpanders Inc, Palo Alto, CA) tissue expander on the dose distribution in a phantom from a simulated postmastectomy radiation treatment for breast cancer. METHODS AND MATERIALS: Experiments were conducted to determine the effect on the dose distribution with the metallic reservoir irradiated independently and with the entire AeroForm tissue expander placed on a RANDO phantom (The Phantom Laboratory, Salem, NY). The metallic reservoir was irradiated on a block of solid water with film at various depths ranging from 0 to 8.2 cm from the surface. The intact 400 cc AeroForm was inflated to full capacity and irradiated while positioned on a RANDO phantom, with 12 optically stimulated luminescent dosimeters (OSLDs) placed at clinically relevant expander-tissue interface points. RESULTS: Film dosimetry with the reservoir perpendicular to film reveals 40% transmission at a depth of 0.7 cm, which increases to 60% at a depth of 8.2 cm. In the parallel position, the results vary depending on which area under the reservoir is examined, indicating that the reservoir is not a uniformly dense object. Testing of the intact expander on the phantom revealed that the average percent difference (measured vs expected dose) was 2.7%, σ = 6.2% with heterogeneity correction and 3.7%, σ = 2.4% without heterogeneity correction. The only position where the OSLD readings were consistently higher than the calculated dose by >5% was at position 1, just deep to the canister at the expander-phantom interface. At this position, the readings varied from 5.2% to 14.5%, regardless of heterogeneity correction. CONCLUSIONS: Film dosimetry demonstrated beam attenuation in the shadow of the metallic reservoir in the expander. This decrease in dose was not reproduced on the intact expander on the phantom designed to replicate a clinical setup.

Skin perfusion and oxygenation changes in radiation fibrosis.

BACKGROUND: Ionizing radiation is known to have deleterious chronic effects on skin, including fibrosis and poor wound healing, hypothesized as mediated by ischemia and hypoxia. Past studies have been unable to simultaneously investigate changes in perfusion and oxygenation as separate parameters. Hyperspectral imaging has emerged as a tool with which to concurrently measure skin perfusion and oxygenation. The authors investigated the use of hyperspectral imaging in a novel murine model of chronic radiation injury. METHODS: Areas of flank skin (n = 20) on hairless mice were exposed to a 50-Gy dose of beta-radiation. Hyperspectral imaging acquisition was performed at select points through 8 weeks. Immunohistochemical staining and gene expression analysis were performed to evaluate cutaneous vascular density, epidermal cell hypoxia, and angiogenic factors. RESULTS: All irradiated areas developed a chronic-phase wound by day 28. Hyperspectral imaging demonstrated a 21 percent decline in perfusion on day 56 (p < 0.001), whereas oxygenation levels were unchanged. A 1.7-fold reduction in blood vessel density was measured in irradiated skin compared with control tissue (p < 0.001), but no difference in epidermal cell hypoxia was observed. Vascular endothelial growth factor and related receptor expression were significantly lower in irradiated tissue. CONCLUSIONS: The authors' analysis does not support the presence of hypoxia in chronic-phase irradiated skin but suggests that hypoperfusion may be a predominant characteristic. The concurrent states of hypoperfusion and normoxia may be explained by the lower metabolic demands of fibrosed tissue.

Volume Modulated Arc Therapy (VMAT) for pulmonary Stereotactic Body Radiotherapy (SBRT) in patients with lesions in close approximation to the chest wall.

PURPOSE: Chest wall pain and discomfort has been recognized as a significant late effect of radiation therapy in historical and modern treatment models. Stereotactic Body Radiotherapy (SBRT) is becoming an important treatment tool in oncology care for patients with intrathoracic lesions. For lesions in close approximation to the chest wall with motion management, SBRT techniques can deliver high dose to the chest wall. As an unintended target of consequence, there is possibility of imposing significant chest wall pain and discomfort as a late effect of therapy. The purpose of this paper is to evaluate the potential role of Volume Modulated Arc Therapy (VMAT) technologies in decreasing chest wall dose in SBRT treatment of pulmonary lesions in close approximation to the chest wall. MATERIALS AND METHODS: Ten patients with pulmonary lesions of various sizes and tomography in close approximation to the chest wall were selected for retrospective review. All volumes including tumor target, chest wall, ribs, and lung were contoured with maximal intensity projection maps and four-dimensional computer tomography planning. Radiation therapy planning consisted of static techniques including Intensity Modulated Radiation Therapy compared to VMAT therapy to a dose of 60 Gy in 12 Gy fraction dose. Dose volume histogram to rib, chest wall, and lung were compared between plans with statistical analysis. RESULTS: In all patients, dose and volume were improved to ribs and chest wall using VMAT technologies compared to static field techniques. On average, volume receiving 30 Gy to the chest wall was improved by 74%; the ribs by 60%. In only one patient did the VMAT treatment technique increase pulmonary volume receiving 20 Gy (V20). CONCLUSIONS: VMAT technology has potential of limiting radiation dose to sensitive chest wall regions in patients with lesions in close approximation to this structure. This would also have potential value to lesions treated with SBRT in other body regions where targets abut critical structures.

Hyperspectral imaging for early detection of oxygenation and perfusion changes in irradiated skin.

Studies examining acute oxygenation and perfusion changes in irradiated skin are limited. Hyperspectral imaging (HSI), a method of wide-field, diffuse reflectance spectroscopy, provides noninvasive, quantified measurements of cutaneous oxygenation and perfusion. This study examines whether HSI can assess acute changes in oxygenation and perfusion following irradiation. Skin on both flanks of nude mice (n=20) was exposed to 50 Gy of beta radiation from a strontium-90 source. Hyperspectral images were obtained before irradiation and on selected days for three weeks. Skin reaction assessment was performed concurrently with HSI. Desquamative injury formed in all irradiated areas. Skin reactions were first seen on day 7, with peak formation on day 14, and resolution beginning by day 21. HSI demonstrated increased tissue oxygenation on day 1 before cutaneous changes were observed (p<0.001). Further increases over baseline were seen on day 14, but returned to baseline levels by day 21. For perfusion, similar increases were seen on days 1 and 14. Unlike tissue oxygenation, perfusion was decreased below baseline on day 21 (p<0.002). HSI allows for complete visualization and quantification of tissue oxygenation and perfusion changes in irradiated skin, and may also allow prediction of acute skin reactions based on early changes seen after irradiation.

Hybrid IMRT for treatment of cancers of the lung and esophagus.

PURPOSE: To report on a hybrid intensity-modulated radiation therapy (IMRT; static plus IMRT beams treated concurrently) technique for lung and esophageal patients to reduce the volume of lung treated to low doses while delivering a conformal dose distribution. METHODS: Treatment plans were analyzed for 18 patients (12 lung and 6 esophageal). Patients were treated with a hybrid technique that concurrently combines static (approximately two-thirds dose) and IMRT (approximately one-third dose) beams. These plans were compared with conventional three-dimensional (3D; non-IMRT) plans and all IMRT plans using custom four- and five-field arrangements and nine equally spaced coplanar beams. Plans were optimized to reduce V13 and V5 values. Dose-volume histograms were calculated for the planning target volume, heart, and the ipsilateral, contralateral, and total lung. Lung volumes V5, V13, V20, V30; mean lung dose (MLD); and the generalized equivalent uniform dose (gEUD) were calculated for each plan. RESULTS: Hybrid plans treated significantly smaller total and contralateral lung volumes with low doses than nine-field IMRT plans. Largest reductions were for contralateral lung V5, V13, and V20 values for lung (-11%, -15%, -7%) and esophageal (-16%, -20%, -7%) patients. Smaller reductions were found also for 3D and four- and five-field IMRT plans. MLD and gEUDs were similar for all plan types. The 3D plans treated much larger extra planning target volumes to prescribed dose levels. CONCLUSIONS: Hybrid IMRT demonstrated advantages for reduction of low-dose lung volumes in the thorax for reducing low dose to lung while also reducing the potential magnitude of dose deviations due to intrafraction motion and small field calculation accuracy.