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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Proton therapy versus photon radiation therapy for the management of a recurrent desmoid tumor of the right flank: a case report.

Desmoid tumors are benign mesenchymal tumors with a strong tendency for local recurrence after surgery. Radiotherapy improves local control following incomplete resection, but nearby organs at risk may limit the dose to the target volume. The patient in this report presented with a recurrent desmoid tumor of the right flank and underwent surgery with microscopically positive margins. Particular problems presented in this case included that the tumor bed was situated in close proximity to the liver and the right kidney and that the right kidney was responsible for 65% of the patient's renal function. Intensity-modulated radiation therapy plans delivering 54 Gy necessarily exposed the right kidney to a V18 of 98% and the liver to a V30 of 55%. Proton therapy plans significantly reduced the right kidney V18 to 32% and the liver V30 to 28%. In light of this, the proton plan was utilized for treatment of this patient. Proton therapy was tolerated without gastrointestinal discomfort or other complaints. Twenty-four months after initiation of proton therapy, the patient is without clinical or radiographic evidence of disease recurrence. In this setting, the improved dose distribution associated with proton therapy allowed for curative treatment of a patient who arguably could not have been safely treated with intensity-modulated radiation therapy or other methods of conventional radiotherapy.

Post-radiation increase in VEGF enhances glioma cell motility in vitro.

BACKGROUND: Glioblastoma multiforme (GBM) is among the most lethal of all human tumors, with frequent local recurrences after radiation therapy (RT). The mechanism accounting for such a recurrence pattern is unclear. It has classically been attributed to local recurrence of treatment-resistant cells. However, accumulating evidence suggests that additional mechanisms exist that involve the migration of tumor or tumor stem cells from other brain regions to tumor bed. VEGFs are well-known mitogens and can be up-regulated after RT. Here, we examine the effect of irradiation-induced VEGF on glioma cell motility. MATERIALS AND METHODS: U251 and LN18 cell lines were used to generate irradiated-conditioned medium (IR-CM). At 72 h after irradiation, the supernatants were harvested. VEGF level in IR-CM was quantified by ELISA, and expression levels for VEGF mRNA were detected by RT-PCR. In vitro cancer cell motility was measured in chambers coated with/without Matrigel and IR-CM as a cell motility enhancer and a VEGF antibody as a neutralizer of VEGF bioactivity. Immunoblots were performed to evaluate the activity of cell motility-related kinases. Proliferation of GBM cells after treatment was measured by flow cytometry. RESULTS: Irradiation increased the level of VEGF mRNA that was mitigated by pre-RT exposure to Actinomycin D. U251 glioma cell motility (migration and invasion) was enhanced by adding IR-CM to un-irradiated cells (174.9 ± 11.4% and 334.2 ± 46% of control, respectively). When we added VEGF antibody to IR-CM, this enhanced cell motility was negated (110.3 ± 12.0% and 105.7 ± 14.0% of control, respectively). Immunoblot analysis revealed that IR-CM increased phosphorylation of VEGF receptor-2 (VEGFR2) secondary to an increase in VEGF, with a concomitant increase of phosphorylation of the downstream targets (Src and FAK). Increased phosphorylation was mitigated by adding VEGF antibody to IR-CM. There was no difference in the mitotic index of GBM cells treated with and without IR-CM and VEGF. CONCLUSIONS: These results indicate that cell motility can be enhanced by conditioned medium from irradiated cells in vitro through stimulation of VEGFR2 signaling pathways and suggest that this effect involves the secretion of radiation-induced VEGF, leading to an increase in glioma cell motility.

High throughput evaluation of gamma-H2AX.

The DNA double-strand break (DSB) is the primary lethal lesion after therapeutic radiation. Thus, the development of assays to detect and to quantitate these lesions could have broad preclinical and clinical impact. Phosphorylation of histone H2AX to form gamma-H2AX is a known marker for irradiation-induced DNA DSBs. However, the first generation assay involves the use of immunofluorescent staining of gamma-H2AX foci. This assay is time consuming, operator dependent and is not scalable for high throughput assay development. Thus, we sought to develop a new assay using a high throughput electrochemiluminescent platform from Mesoscale Discovery Systems to quantify gamma-H2AX levels. The results show that our assay utilizes significantly less time and labor, has greater intra-assay reproducibility and has a greater dynamic range of gamma-H2AX versus irradiation dose.