Continuous Positive Airway Pressure-Assisted Breathing With Supine Tangential Left Breast Radiation Therapy When Deep Inspiration Breath-Hold Radiation Therapy Was Ineffective or Unsuitable: Clinical Implications for an Affordable Heart-Sparing Breast Radiation Therapy to Reduce the Health Care Disparities in Low-Resource Settings.

Purpose: To report continuous positive airway pressure (CPAP)-assisted breathing with supine tangential left breast radiation therapy (CPAP-RT) when deep inspiration breath-hold RT (DIBH-RT) was ineffective or unsuitable. Methods and Materials: Ten patients with left breast cancer underwent computed tomography simulation scan (CT-sim) under DIBH followed by CPAP-assisted breathing (15 cm H2O) to create CPAP-RT plans in authors' institute. Reasons for CPAP-RT include inability to reproduce DIBH (n = 5), DIBH-RT plan exceeded dose limits to the heart (n = 2), and unable to proceed with planned DIBH-RT due to mechanical issues (n = 3). Radiation target volumes and organs at risk were contoured according to published atlas data. For dosimetric comparison, supine tangential fields for breast only RT (Breast-RT) and wide-tangential fields for breast + internal mammary nodal RT (Breast + IMN-RT) were used with prescription of 40 Gy in 15 fractions on each patients' CT-sim with free-breathing (FB), DIBH, and CPAP-assisted breathing, respectively. Results: Planning target volume (PTV) coverage was acceptable and comparable in all RT plans. Compared with FB, both DIBH and CPAP-assisted breathing inflated the thorax and increased left lung volume on average by 46% and 51%, respectively (FB: 1230 vs DIBH: 1802 vs CPAP-assisted breathing:1860 cc, P < .01), and increased the shortest distance between PTVeval-Breast to the heart by 5.6 ± 3.0 and 11.9 ± 3.6 mm (P < .01) and to LAD by 4.9 ± 2.9 and 10.8 ± 4.3 mm, respectively (P < .01). Compared with FB, both DIBH and CPAP significantly reduced radiation dose to the heart and LAD. A mean dose to the heart (HeartDmean) was FB: 2.3 ± 0.9, DIBH: 1.2 ± 0.7, and CPAP: 0.9 ± 0.4 Gy in Breast-RT (P < .01); FB: 3.2 ± 1.7, DIBH: 1.7 ± 0.8, and CPAP: 1.3 ± 0.5 Gy in Breast + IMN-RT (P < .01). LADDmean was FB: 11 ± 4.5, DIBH: 5.4 ± 3.2, and CPAP: 2.4 ± 0.9 Gy in Breast-RT (P < .01); FB: 15.5 ± 7.8, DIBH: 7.4 ± 4.1, and CPAP: 3.5 ± 1.4 Gy in Breast + IMN-RT (P < .01). A maximum dose to LAD (LADDmax) was FB: 35.8 ± 8.7, DIBH: 22.4 ± 15.4, and CPAP: 7.8 ± 5.3 Gy in Breast-RT (P < .01); FB: 38.7 ± 5.0, DIBH: 25.3 ± 15.2, and CPAP: 10.2 ± 6.8 Gy in Breast + IMN-RT (P < .01). All patients successfully completed CPAP-RT. Conclusions: CPAP-RT provides efficient and practical heart and LAD sparing RT using simple supine tangential fields for Breast-RT or wide-tangential fields for Breast + IMN-RT when DIBH-RT was ineffective or unsuitable. With its easy accessibility and low infrastructural requirement, CPAP-RT can provide affordable heart-sparing left breast RT to reduce the health care disparities in low-resource settings.

Pharyngeal Constrictor-Sparing Salvage Stereotactic Body Radiation Therapy With Tongue-Out for In-Field Recurrence After Definitive Radiation Therapy for Head and Neck Cancer: Guide to Tongue-Out Radiation Therapy.

This report details a pharyngeal constrictor muscle (PCM)-sparing stereotactic body radiation therapy (SBRT) using our institutional technique of "tongue-out" radiation therapy (TORT) for treating a local recurrent cancer in the uvula (GTVuvula) in a patient with history of a definitive chemotherapy with radiation therapy (70 Gy with weekly cisplatin) for a locally advanced laryngeal cancer 4 years ago. TORT includes optimizing the patients' reproducible tongue-out position using readily available medicine cup (30 cc) followed by sculping the thermoplastic mask with tongue-out, and real-time visual monitoring of the tongue position during the computed tomography simulation scan, cone beam computed tomography acquisition, and treatment. Between arcs during volumetric modulated arc therapy, time for tongue relaxation and saliva swallowing can be given to the patient. Without TORT, the patient's GTVuvula abutted the medial aspect of superior PCM (medial-sPCM) and a substantial volume of the previously irradiated superior PCM (sPCM) would have received high radiation dose from this salvage SBRT (32.5 Gy in 5 fractions). Comparing without TORT, the shortest distance between medial-sPCM-to-GTVuvula was increased by 13 mm with TORT, which reduced radiation dose to sPCM in the salvage SBRT plan. The mean dose to sPCM was decreased from 20.5 Gy without TORT to 12.7 Gy with TORT. With TORT, minimal sPCM volumes fell within higher isodose line: volume receiving ≥ 60% prescription dose (V60%Rx), V80%Rx, and V100%Rx to sPCM was, 4.8 versus 0.7 cc (without vs with TORT, respectively), 2.9 versus 0.19 cc, and 1.6 versus 0.04 cc, respectively. Maximum dose (Dmax) to medial-sPCM was 34.6 Gy without TORT versus 22.7 Gy with TORT. These high doses to the sPCM and intrafractional swallowing-related geographic misses of GTVuvula were avoided through the application of TORT in this salvage reirradiation setting. The patient successfully finished salvage SBRT with TORT resulting in no dysphagia or mucositis and maintained complete response at 12 months after treatment.

Hypofractionated passively scattered proton radiotherapy for low- and intermediate-risk prostate cancer is not associated with post-treatment testosterone suppression.

BACKGROUND: To investigate post-treatment changes in serum testosterone in low- and intermediate-risk prostate cancer patients treated with hypofractionated passively scattered proton radiotherapy. MATERIAL AND METHODS: Between April 2008 and October 2011, 228 patients with low- and intermediate-risk prostate cancer were enrolled into an institutional review board-approved prospective protocol. Patients received doses ranging from 70 Cobalt Gray Equivalent (CGE) to 72.5 CGE at 2.5 CGE per fraction using passively scattered protons. Three patients were excluded for receiving androgen deprivation therapy (n = 2) or testosterone supplementation (n = 1) before radiation. Of the remaining 226 patients, pretreatment serum testosterone levels were available for 217. Of these patients, post-treatment serum testosterone levels were available for 207 in the final week of treatment, 165 at the six-month follow-up, and 116 at the 12-month follow-up. The post-treatment testosterone levels were compared with the pretreatment levels using Wilcoxon's signed-rank test for matched pairs. RESULTS: The median pretreatment serum testosterone level was 367.7 ng/dl (12.8 nmol/l). The median changes in post-treatment testosterone value were as follows: +3.0 ng/dl (+0.1 nmol/l) at treatment completion; +6.0 ng/dl (+0.2 nmol/l) at six months after treatment; and +5.0 ng/dl (0.2 nmol/l) at 12 months after treatment. None of these changes were statistically significant. CONCLUSION: Patients with low- and intermediate-risk prostate cancer treated with hypofractionated passively scattered proton radiotherapy do not experience testosterone suppression. Our findings are consistent with physical measurements demonstrating that proton radiotherapy is associated with less scatter radiation exposure to tissues beyond the beam paths compared with intensity-modulated photon radiotherapy.

Rapid and Durable Symptom Palliation With Quad Shot Radiation Therapy to Nonosseous Metastatic/Recurrent Cancer in Elderly or Frail Patients in a Rural Community Clinic.

More than half of patients with cancer receiving radiation therapy (RT) are treated in a palliative setting. Elderly or frail patients with metastatic/recurrent cancer require palliative RT that can provide a rapid cancer-related symptom response with low toxicity and short overall treatment time. Cyclical hypofractionated RT (quad shot: 14-14.8 Gy/4 fractions, twice-daily treatments with 6-hour intervals on 2 consecutive days monthly to a total of 42-44.4 Gy) can be a practical palliative RT regimen for patients with poor performance status. In this report, we present palliative symptom response and objective tumor response after quad shot for elderly or frail patients with nonosseous metastatic/recurrent cancers in various sites with varying histology.

The Radiosensitizing Effect of AZD0530 in Glioblastoma and Glioblastoma Stem-Like Cells.

AZD0530, a potent small-molecule inhibitor of the Src kinase family, is an anticancer drug used in the treatment of various cancers. In the case of glioblastoma (GBM), where resistance to radiotherapy frequently occurs, Src kinase is known as one of the molecules responsible for imparting radioresistance to GBM. Thus, we evaluated the effect of AZD0530 on the radiosensitivity of human GBM cells and human glioblastoma stem-like cells (GSCs). We show that Src activity of GBM and GSC is increased by radiation and inhibited by AZD0530, and using clonogenic assays, AZD0530 enhances the radiosensitivity of GBM and GSCs. Also, AZD0530 induced a prolongation of radiation-induced γH2AX without specific cell cycle and mitotic index changes, suggesting that AZD0530-induced radiosensitization in GBM cells and GSCs results from the inhibition of DNA repair. In addition, AZD0530 was shown to inhibit the radiation-induced EGFR/PI3K/AKT pathway, which is known to promote and regulate radioresistance and survival of GBM cells by radiation. Finally, mice bearing orthotopic xenografts initiated from GBM cells were then used to evaluate the in vivo response to AZD0530 and radiation. The combination of AZD0530 and radiation showed the longest median survival compared with any single modality. Thus, these results show that AZD0530 enhances the radiosensitivity of GBM cells and GSCs and suggest the possibility of AZD0530 as a clinical radiosensitizer for treatment of GBM.

In vitro and in vivo radiosensitization induced by the DNA methylating agent temozolomide.

PURPOSE: Temozolomide, a DNA methylating agent, is currently undergoing clinical evaluation for cancer therapy. Because temozolomide has been shown to increase survival rates of patients with malignant gliomas when given combined with radiation, and there is conflicting preclinical data concerning the radiosensitizing effects of temozolomide, we further investigated the possible temozolomide-induced enhancement of radiosensitivity. EXPERIMENTAL DESIGN: The effects of temozolomide on the in vitro radiosensitivity of U251 (a human glioma) and MDA-MB231BR (a brain-seeking variant of a human breast tumor) cell lines was evaluated using clonogenic assay. DNA damage and repair were evaluated using phosphorylated histone H2AX (gammaH2AX), and mitotic catastrophe was measured using nuclear fragmentation. Growth delay was used to evaluate the effects of temozolomide on in vivo (U251) tumor radiosensitivity. RESULTS: Exposure of each cell line to temozolomide for 1 h before irradiation resulted in an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 ranging from 1.30 to 1.32. Temozolomide had no effect on radiation-induced apoptosis or on the activation of the G(2) cell cycle checkpoint. As a measure of DNA double strand breaks, gammaH2AX foci were determined as a function of time after the temozolomide + irradiation combination. The number of gammaH2AX foci per cell was significantly greater at 24 h after the combined modality compared with the individual treatments. Mitotic catastrophe, measured at 72 h, was also significantly increased in cells receiving the temozolomide + irradiation combination compared with the single treatments. In vivo studies revealed that temozolomide administration to mice bearing U251 tumor xenografts resulted in a greater than additive increase in radiation-induced tumor growth delay with a dose enhancement factor of 2.8. CONCLUSIONS: These results indicate that temozolomide can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair leading to an increase in mitotic catastrophe.

Bronchoalveolar lavage findings of radiation induced lung damage in rats.

Radiation induced lung damage is a main dose limiting factor when irradiating the thorax. Although Bronchoalveolar lavage (BAL) is a valuable tool for studying the mechanisms in pulmonary disorders, there are only a few studies about the BAL findings of radiation-induced lung damage. We evaluate the BAL findings for the evaluation of radiation-induced lung damage. Sprague-Dawley rats received 20 Gy of radiation to the right lung and control group were sham irradiated. BAL was performed for the right and left lungs separately 3, 7, 14, 28, and 56 days after radiation. The cells in the BAL fluid were counted and the concentrations of protein, NO, and TGF-beta in the BAL fluid were measured. Lung tissues were removed after BAL and stained with hematoxylin-eosin (H-E) and trichrome. From 2 weeks, histological findings showed definite lung damage. The protein level and TGF-beta in BAL fluid from the irradiated lung peaked at 4 and 8 weeks, respectively, after radiation. Total cell count in BAL fluid from both sides of lungs was increased from 2 weeks and continued to increase at 8 weeks after irradiation. NO in BAL fluid from both sides of lungs peaked at 4 weeks after irradiation. The protein level and TGF-beta were increased in BAL fluid from irradiated lungs. However, alveolar cells and NO increased in BAL fluid from both irradiated and non-irradiated lungs. BAL is a valuable tool for the evaluation of radiation induced lung damage.

Clinical and radiobiological consideration of cyclical hypofractionated radiation therapy also known as QUAD Shot for neglected skin cancer disfiguring the face of a non-compliant patient who was refusing surgery and protracted radiation therapy: case report.

Although surgery is the mainstay of local treatment for skin cancer, definitive radiation therapy (RT) has been also applied for patients who are unable to tolerate surgery. Definitive RT regimens usually consist of daily treatment for 4-7 weeks. Such protracted daily RT regimens, however, would not be feasible for non-compliant patients or patients who are unable to make multiple daily trips for weeks. Without treatment, however, skin cancers can continuously progress and cause distressing symptoms. A cyclical hypofractionated RT (QUAD Shot: 14 Gy in 4 fractions, twice-daily treatments with 6 hours interval on 2 consecutive days) can be a practical RT regimen for those patients. In this report, we present the successful treatment course of repeated QUAD Shots in a 79-year-old patient with neglected skin cancer that was disfiguring his face yet declined definitive surgery and protracted RT. We also evaluated and compared biologically equivalent doses between QUAD Shots and conventionally fractionated protracted RT regimens.

Practical Heart Sparing Breast Cancer Radiation Therapy Using Continuous Positive Airway Pressure (CPAP) in Resource-Limited Radiation Oncology Clinics.

PURPOSE: The purpose of this study was to report experiences of practical heart sparing breast radiation therapy (RT) using continuous positive airway pressure (CPAP) in resource-limited radiation oncology clinics. PATIENTS AND METHODS: Twelve patients underwent computed tomography-simulations with both free-breathing (FB) and CPAP under the individual maximum tolerable air pressure. For each patient, left-sided breast RT plans (9 with breast only, 3 with breast and regional nodal stations) with FB and CPAP were created using 3-dimensional conformal RT (supine tangential or wide tangential RT fields) according to RTOG 1304. For daily RT, patients started CPAP in the patients waiting area for 15 minutes before entering the treatment room and continued CPAP during RT. Treatment setup times between breast RT with and without CPAP were compared. RESULTS: All patients tolerated CPAP well with 8 to 15 cm H2O of air pressure. Compared with FB, CPAP inflated the thorax and increased total lung volume by 35±16% (CPAP: 3136±751 vs. FB: 2354±657 cm, P<0.01); caudally displaced the heart by 1.8 cm (P<0.01); and decreased heart volume within tangential RT fields on computed tomography-simulation scans by 96±4% (1.4±2.5 vs. 21±17 cm, P=0.02) in all patients. Planning target volume coverage was acceptable in all RT plans. CPAP lowered mean dose (Dmean) to heart by 47±22% (2.5±1.5 vs. 5.4±3.3 Gy, P<0.01); heart volume receiving ≥25 Gy (V25) by 82±18% (2.2±2.6 vs. 9.1±7.1%, P<0.01); Dmean to left anterior descending coronary artery by 68±8% (4.7±1.9 vs. 14.8±3.3 Gy, P<0.01). CPAP decreased radiation dose to ipsilateral lung compared with FB: 9.1±5.8 versus 11.2±8 Gy (20% reduction, P=0.03) of Dmean; 15.7±12.5 vs. 20.5±17.5% (25% reduction, P=0.03) of V20. RT with CPAP did not increase treatment setup time compared with FB (week 1: 362±63 vs. 352±77 s; week 2 to 5: 217±13 vs. 201±14 s, all P>0.25). CONCLUSION: Novel use of CPAP allowed efficient and practical heart sparing breast RT without increasing infrastructural requirements in resource-limited radiation oncology clinics.

The impact of continuous positive airway pressure on radiation dose to heart and lung during left-sided postmastectomy radiotherapy when deep inspiration breath hold technique is not applicable: a case report.

Deep inspiration breathing hold (DIBH) compared to free-breathing (FB) during radiotherapy (RT) has significantly decreased radiation dose to heart and has been one of the techniques adopted for patients with breast cancer. However, patients who are unable to make suitable deep inspiration breath may not be eligible for DIBH, yet still need to spare the heart and lung during breast cancer RT (left-sided RT in particular). Continuous positive airway pressure (CPAP) is a positive airway pressure ventilator, which keeps the airways continuously open and subsequently inflates the thorax resembling thoracic changes from DIBH. In this report, authors applied CPAP instead of FB during left-sided breast cancer RT including internal mammary node in a patient who was unable to tolerate DIBH, and substantially decreased radiation dose the heart and lung with CPAP compared to FB.

Cyclical hypofractionated radiotherapy also known as "QUAD Shot" alone using intensity-modulated radiotherapy for squamous cell carcinoma of the parotid gland in an 85-year-old patient with multiple comorbidities.

BACKGROUND: Palliative radiotherapy (RT) is not commonly offered to patients with head and neck cancer because of the belief that toxicity from the RT would not provide great palliative benefits. The purpose of this study was for us to report the advantages of cyclical hypofractionated RT (QUAD Shot) using intensity-modulated RT (IMRT) for an elderly comorbid patient with head and neck cancer. METHODS: An 85-year-old multiple comorbid man with squamous cell carcinoma in the left parotid gland with left facial pain received the IMRT-QUAD Shot (14 Gy/4 fractions, twice-daily treatment with 6 hours interval, on 2 consecutive days) to lesions, which were repeated every 4 weeks 3 times. RESULTS: With the IMRT-QUAD Shot, he achieved complete left facial pain relief without acute toxicity. At 12 months after the first IMRT-QUAD Shot, he remained without left facial pain, late toxicity, or disease recurrence impacting positively on his quality of life. CONCLUSION: The IMRT-QUAD shot is reasonable and safe to apply for symptom palliation in elderly multiple comorbid patients with head and neck cancer. 2017 Wiley Periodicals, Inc. Head Neck 39: E55-E60, 2017.

Tongue-out versus tongue-in position during intensity-modulated radiotherapy for base of tongue cancer: Clinical implications for minimizing post-radiotherapy swallowing dysfunction.

BACKGROUND: The purpose of this study was to assess whether different tongue positions change the radiation doses to swallowing organs at risks: the pharyngeal constrictor, oral cavity, and larynx during intensity-modulated radiotherapy (IMRT) for base of tongue (BOT) cancer. METHODS: IMRT plans with Tongue-out (IMRT-TO) and tongue-in position (IMRT-TI) was compared in 3 cases. RESULTS: Distance from BOT to pharyngeal constrictor was increased to 1.8 ± 0.8 cm with IMRT-TO from 0.9 ± 0.6 cm with IMRT-TI (P < .01). Compared to IMRT-TI, IMRT-TO significantly decreased the radiation dose to the anterior oral cavity, oral tongue, superior pharyngeal constrictor, middle pharyngeal constrictor, and supraglottic larynx (all P ≤ .04). IMRT-TO also had a smaller volume irradiated than IMRT-TI to the anterior oral cavity and the oral tongue receiving ≥30 Gy (V30) and V35, and superior pharyngeal constrictor and middle pharyngeal constrictor for V55 and V65 (all P ≤ .04). CONCLUSION: Dosimetric advantage with IMRT-TO over IMRT-TI may potentially reduce post-IMRT swallowing dysfunction in selected patients with BOT cancer.

Geometric shifting of the porta hepatis during posthepatectomy radiotherapy for biliary tract cancer.

PURPOSE: To evaluate geometric shifting of the porta hepatis induced by liver regeneration during radiotherapy (RT) after partial hepatectomy for biliary tract cancer. METHODS AND MATERIALS: Between August 2004 and August 2005, the study enrolled 10 biliary tract cancer patients who underwent hemihepatectomy or more extensive surgery and were scheduled to receive postoperative RT. All patients received 4500 cGy RT in 25 fractions with concurrent 5-fluorouracil. Before RT and in the third and fifth weeks during RT, the liver volume was determined using CT, and geometric location of the porta hepatis was determined using a conventional simulator. RESULTS: The liver volume increase during RT was 246.6 +/- 118.2 cm(3). The overall actual shifting length of the porta hepatis was 9.8 +/- 2.5 mm, with right and left hepatectomy causing a 10.1 +/- 1.7 mm shift to the right or 9.2 +/- 4.3 mm shift to the left, respectively. The actual shifting length of the porta hepatis was proportional to the increase in liver volume during RT (r = 0.742, p = 0.014). CONCLUSION: The results of this study have demonstrated that the porta hepatis can be shifted by liver regeneration after partial hepatectomy. We recommend an additional RT margin or adaptive RT (repeat planning at several intervals during the treatment course) to avoid exclusion of the porta hepatis from the RT target volume after partial hepatectomy for biliary tract cancer.

Decreased radiation doses to tongue with "stick-out" tongue position over neutral tongue position in head and neck cancer patients who refused or could not tolerate an intraoral device (bite-block, tongue blade, or mouthpiece) due to trismus, gag reflex, or discomfort during intensity-modulated radiation therapy.

PURPOSE: To assess changes in oral cavity (OC) shapes and radiation doses to tongue with different tongue positions during intensity-modulated radiation therapy (IMRT) in patients with head and neck squamous cell carcinoma (HNSCC) but who refused or did not tolerate an intraoral device (IOD), such as bite block, tongue blade, or mouthpiece. RESULTS: Tongue volume outside of OC was 7.1 ± 3.8 cm3 (5.4 ± 2.6% of entire OC and 7.8 ± 3.1% of oral tongue) in IMRT-S. Dmean of OC was 34.9 ± 8.0 Gy and 31.4 ± 8.7 Gy with IMRT-N and IMRT-S, respectively (p < 0.001). OC volume receiving ≥ 36 Gy (V36) was 40.6 ± 16.9% with IMRT-N and 33.0 ± 17.0% with IMRT-S (p < 0.001). Dmean of tongue was 38.1 ± 7.9 Gy and 32.8 ± 8.8 Gy in IMRT-N and IMRT-S, respectively (p < 0.001). V15, V30, and V45 of tongue were significantly lower in IMRT-S (85.3 ± 15.0%, 50.6 ± 16.2%, 24.3 ± 16.0%, respectively) than IMRT-N (94.4 ± 10.6%, 64.7 ± 16.2%, 34.0 ± 18.6%, respectively) (all p < 0.001). Positional offsets of tongue during the course of IMRT-S was -0.1 ± 0.2 cm, 0.01 ± 0.1 cm, and -0.1 ± 0.2 cm (vertical, longitudinal, and lateral, respectively). MATERIALS AND METHODS: 13 patients with HNSCC underwent CT-simulations both with a neutral tongue position and a stick-out tongue for IMRT planning (IMRT-N and IMRT-S, respectively). Planning objectives were to deliver 70 Gy, 63 Gy, and 56 Gy in 35 fractions to 95% of PTVs. Radiation Therapy Oncology Group (RTOG) recommended dose constraints were applied. Data are presented as mean ± standard deviation and compared using the student t-test. CONCLUSIONS: IMRT-S for patients with HNSCC who refused or could not tolerate an IOD has significant decreased radiation dose to the tongue than IMRT-N, which may potentially reduce RT related toxicity in tongue in selected patients.