Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression.

Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-ß1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

High-dose-rate interstitial brachytherapy with hypoxic radiosensitizer KORTUC II for unresectable pelvic sidewall recurrence of uterine cervical cancer: a case report.

In order to improve oncologic outcomes in radiotherapy treatments of patients with unresectable pelvic sidewall recurrences of uterine cervical cancer, we combined high-dose-rate interstitial brachytherapy (HDR-ISBT) with newly tested hypoxic radiosensitizer Kochi oxydol-radiation therapy for unresectable carcinomas (KORTUC II), an enzyme-targeting radiosensitization treatment involving intra-tumoral injection of sodium hyaluronate mixed with hydrogen peroxide. We report on a 63-year-old patient referred to our department with an extensive pelvic sidewall recurrence of uterine cervical cancer after initial hysterectomy. The tumor size was 55 × 25 × 80 mm, with a calculated volume of 89.7 cc. Whole pelvic irradiation of 50 Gy in 25 fractions was administered, combined with weekly cisplatin injections. KORTUC II injections were given two times: at day 21 (42 Gy) and at day 24 (48 Gy). After finishing whole pelvic irradiation, HDR-ISBT of 25 Gy in 5 fractions b.i.d. over 3 days was administered. KORTUC II was also injected at the time of implantation. Dose-volume histogram (DVH) values for clinical target volume were D90, D98, and D100 of 6.0, 5.0, and 3.5 Gy per fraction, respectively. D2cc values were 2.1, 4.1, 3.2, and 2.0 Gy per fraction for the bladder, rectum, sigmoid colon, and small bowel, respectively. No acute adverse events ≥ grade 3 were observed. Repeated grade 3 pyelonephritis occurred as a late complication at 11, 24, and 26 months after the treatment, and was successfully resolved with antibiotics. Moreover, grade 2 late toxicity was documented, including sciatic neuralgia, lower limb lymphedema, and urinary incontinence. At present, 32 months after HDR-ISBT, the patient remains free of disease, with no toxicity-related deterioration in physical condition.

A new implant device to prevent edema-associated underdosage in high-dose-rate interstitial brachytherapy of mobile tongue cancer.

PURPOSE: Tongue edema is a potential cause of treatment target underdosage in high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. To prevent such edema-associated alteration of dosimetry, we developed a special silicon device. In this report we communicate our initial experience with two mobile tongue cancer patients whom we treated using this new device. MATERIAL AND METHODS: The device consists of silicone tubes with a fixed width and scalable length depending on tongue size. These tubes are lined and fixed like a palisade, allowing the device to be used also as a template. The device is placed next to the lateral border of the tongue and on the floor of the mouth. In addition, a vinyl template can be placed on the dorsal tongue surface with both devices combined for implantation guidance. Between June and August 2012, two patients with locally confined tongue cancer were treated. RESULTS: Between June and August 2012, two mobile tongue cancer patients classified as cT2N0M0 were treated with HDR-ISBT using the silicone device. They underwent ISBT as monotherapy with fractional doses of 6.0 Gy up to a total physical dose of 54.0 Gy. The D90 (CTV) values of both patients were 6.3 Gy and 6.6 Gy and the D2cc (mandible) values were 3.4 Gy and 2.6 Gy, respectively. At present, both patients remain without local disease recurrence at 60 and 56 months after ISBT, respectively. CONCLUSIONS: The described silicone device has the potential to prevent underdosage to the treatment target related to tongue edema. It has been shown to be safe and easy to implement.

Edema worsens target coverage in high-dose-rate interstitial brachytherapy of mobile tongue cancer: a report of two cases.

PURPOSE: We report our study on two patients to highlight the risk of underdosage of the clinical target volume (CTV) due to edema during high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. MATERIAL AND METHODS: To treat the lateral side of the CTV, flexible applicator tubes were implanted on the mouth floor. Two-dimensional planning was performed using X-ray images for Case 1, and three-dimensional (3D) planning was performed using computed tomography (CT) for Case 2. Prescribed doses for both cases were 54 Gy in nine fractions. CASE REPORTS: Case 1 was treated for cancer of the right lateral border of the tongue in 2005. Tongue edema occurred after implantation, and part of the lateral border of the tongue protruded between the applicator tubes. Acute mucosal reaction abated in the protruded area earlier than in the other parts of the CTV. In this case, the tumor recurred in this area 5 months after the treatment. Case 2 was treated for cancer of the left lateral border of the tongue. Because tongue edema occurred in this case also, plastic splints were inserted between the applicator tubes to push the edematous region into the irradiated area. The mucosal surface of the CTV was covered by the 70% isodose, and 100% isodose line for before and after splint insertion. Local control of the tumor was achieved 4 years after treatment. DISCUSSION AND CONCLUSIONS: To ensure sufficient target coverage, 3D image-based planning using CT should be performed, followed by re-planning using repeated CT as needed. Also, the development of devices to prevent protrusion of the edematous tissue outside the target area will help to ensure the full dosing of CTV.

Nationwide multi-institutional retrospective analysis of high-dose-rate brachytherapy combined with external beam radiotherapy for localized prostate cancer: An Asian Prostate HDR-BT Consortium.

PURPOSE: To report outcomes and risk factors of high-dose-rate (HDR) brachytherapy combined with external beam radiotherapy with or without androgen deprivation therapy (ADT) in prostate cancer patients. MATERIALS AND METHODS: This multi-institutional retrospective analysis comprised 3424 patients with localized prostate cancer at 16 Asian hospitals. One-thirds (27.7%) of patients received only neoadjuvant ADT, whereas almost half (49.5%) of patients received both neoadjuvant and adjuvant ADT. Mean duration of neoadjuvant and adjuvant ADT were 8.6 months and 27.9 months, respectively. Biochemical failure was defined by Phoenix ASTRO consensus. Biochemical control rate, clinical disease-free survival (cDFS), cause-specific survival, and overall survival (OS) were calculated. RESULTS: Median followup was 66 months. Ten-year biochemical control, cDFS, cause-specific survival, and OS rate were 81.4%, 81.0%, 97.2%, and 85.6%, respectively. Receiving both neoadjuvant and adjuvant ADT was detected as a favorable factor for biochemical control, cDFS, and OS, but pelvic irradiation was detected as an adverse factor for cause-specific survival, and OS. Ten-year cumulative rates of late Grade ≥2 genitourinary and gastrointestinal toxicities were 26.8% and 4.1%, respectively; receiving both neoadjuvant and adjuvant ADT was detected as a favorable factor for preventing both toxicities. CONCLUSIONS: HDR combined with external beam radiotherapy was an effective and safe treatment for localized prostate cancer. Combination of long-term ADT was suggested to be necessary, even for HDR brachytherapy, and was useful in suppressing late toxicities. Meanwhile, pelvic irradiation was suggested to have an adverse effect on OS of our study population.

Treatment Results of Radiotherapy Combined with Balloon-occluded Arterial Infusion Chemotherapy for Invasive Bladder Cancer.

AIM: We present preliminary results from our clinical study evaluating the effectiveness of combination of radiotherapy with balloon-occluded arterial infusion (BOAI) and hemodialysis (HD) for bladder cancer. PATIENTS AND METHODS: We investigated 134 patients with a median age of 67 years (range=38-88 years) and a median follow-up time of 31 months. According to the UICC classification, 89 patients were at clinical stage T2, 40 at T3, and 5 at T4. All patients received external-beam radiation therapy (EBRT) of 50 Gy to the whole pelvis with 10 Gy to the bladder as a boost. During EBRT, BOAI of cisplatin (CDDP) (100 mg/body) was administered from bilateral internal iliac arteries with simultaneous HD to prevent back-flow of CDDP into the systemic circulation. RESULTS: Three-year local control and overall survival (OS) rates were 68% and 80%, respectively, and 3-year bladder preservation rate was 90%. Univariate and multivariate analysis showed that T stage and primary effect were significant prognostic factors for OS. In addition, primary effect was a significant prognostic factor for bladder preservation. None of the patients had grade 2 or more severe hematological toxicity. Late grade ≥3 genitourinary (GU) and gastrointestinal (GI) complications were observed in 6% and 2% of the patients, respectively. CONCLUSION: Combination of radiotherapy with BOAI and HD, associated with reduced hematological toxicity, may be regarded as a curative therapy for patients with bladder cancer. Late GU and GI complications were within acceptable limits. T stage is an important predictive factor for the outcome of this therapy.

Simulation analysis of optimized brachytherapy for uterine cervical cancer: Can we select the best brachytherapy modality depending on tumor size?

PURPOSE: To choose the optimal brachytherapeutic modality for uterine cervical cancer, we performed simulation analysis. METHODS AND MATERIALS: For each high-risk clinical target volume (HR CTV), we compared four modalities [classical conventional intracavitary brachytherapy (ConvICBT), Image-guided ICBT (IGICBT), intracavitary/interstitial brachytherapy (ICISBT), and interstitial brachytherapy (ISBT) with perineal approach] using dose-volume histograms using eight sizes of HR CTV (2 × 2 × 2 cm to 7 × 4 × 4 cm) and organs at risk model. RESULTS: In ConvICBT, the doses covered 90% of the HR CTV [D90(HR CTV)] decreased from 197% prescribed dose (PD) for the HR CTV size (2 × 2 × 2 cm) to 73% PD for 5 × 4 × 4 cm, whereas the other three modalities could achieve 100% PD for all HR CTV sizes. The minimum doses received by the maximally irradiated 2-cm(3) volumes for organs at risks of IGICBT demonstrated lower values than those of ConvICBT for the HR CTV size of 4 × 3 × 3 cm or smaller. ICISBT demonstrated lower values than those of IGICBT for 4 × 3 × 3 cm or larger. ISBT demonstrated lowest values for 5 × 4 × 4 cm or larger. CONCLUSIONS: HR CTV size of 4 × 3 × 3 cm seems to be a threshold volume in this simulation analysis, and IGICBT is a better choice for smaller HR CTV than the threshold volume. On larger HR CTV, ICISBT or ISBT is the better choice.

Role of vaginal pallor reaction in predicting late vaginal stenosis after high-dose-rate brachytherapy in treatment-naive patients with cervical cancer.

OBJECTIVE: To assess actual rates of late vaginal stenosis and identify predisposing factors for complications among patients with previously untreated cervical cancer following high-dose-rate brachytherapy. METHODS: We performed longitudinal analyses of 57 patients using the modified Dische score at 6, 12, 18, 24, 36, and 60 months after treatment, which consisted of 15 interstitial brachytherapys and 42 conventional intracavitary brachytherapys, with a median follow-up time of 36 months (range, 6 to 144 months). RESULTS: More than half of the patients developed grade 1 (mild) vaginal stenosis within the first year of follow-up, and grade 2 (97.5%, moderate) to grade 3 (severe) stenosis gradually increased with time. Actual stenosis rates for grade 1, 2, and 3 were 97.5% (95% confidence interval [CI], 92.7 to 97.5), 60.7% (95% CI, 42.2 to 79.3), and 7.4% (95% CI, 0 to 18.4) at 3 years after treatment. Pallor reaction grade 2-3 at 6 months was only a statistically significant predisposing factor for grade 2-3 late vaginal stenosis 3 years or later with a hazard ratio of 3.48 (95% CI, 1.32 to 9.19; p=0.018) by a multivariate Cox proportional hazard model. Patients with grade 0-1 pallor reaction at 6 months showed a grade ≥2 vaginal stenosis rate of 53%, whereas the grade 2-3 pallor reaction group achieved a grade ≥2 vaginal stenosis rate at 3 years at 100% (p=0.001). CONCLUSION: High-dose-rate brachytherapy was associated with high incidence of late vaginal stenosis. Pallor reaction grade 2-3 at 6 months was predictive of late grade 2-3 vaginal stenosis at 3 years after treatment. These findings should prove helpful for patient counseling and preventive intervention.

Novel Radiobiological Gamma Index for Evaluation of 3-Dimensional Predicted Dose Distribution.

PURPOSE: To propose a gamma index-based dose evaluation index that integrates the radiobiological parameters of tumor control (TCP) and normal tissue complication probabilities (NTCP). METHODS AND MATERIALS: Fifteen prostate and head and neck (H&N) cancer patients received intensity modulated radiation therapy. Before treatment, patient-specific quality assurance was conducted via beam-by-beam analysis, and beam-specific dose error distributions were generated. The predicted 3-dimensional (3D) dose distribution was calculated by back-projection of relative dose error distribution per beam. A 3D gamma analysis of different organs (prostate: clinical [CTV] and planned target volumes [PTV], rectum, bladder, femoral heads; H&N: gross tumor volume [GTV], CTV, spinal cord, brain stem, both parotids) was performed using predicted and planned dose distributions under 2%/2 mm tolerance and physical gamma passing rate was calculated. TCP and NTCP values were calculated for voxels with physical gamma indices (PGI) >1. We propose a new radiobiological gamma index (RGI) to quantify the radiobiological effects of TCP and NTCP and calculate radiobiological gamma passing rates. RESULTS: The mean RGI gamma passing rates for prostate cases were significantly different compared with those of PGI (P<.03-.001). The mean RGI gamma passing rates for H&N cases (except for GTV) were significantly different compared with those of PGI (P<.001). Differences in gamma passing rates between PGI and RGI were due to dose differences between the planned and predicted dose distributions. Radiobiological gamma distribution was visualized to identify areas where the dose was radiobiologically important. CONCLUSIONS: RGI was proposed to integrate radiobiological effects into PGI. This index would assist physicians and medical physicists not only in physical evaluations of treatment delivery accuracy, but also in clinical evaluations of predicted dose distribution.

Treatment results of image-guided high-dose-rate interstitial brachytherapy for pelvic recurrence of uterine cancer.

PURPOSE: We analyzed clinical data to evaluate the effectiveness of image-guided high-dose-rate interstitial brachytherapy (HDR-ISBT) for pelvic recurrence of uterine cancer. METHODS AND MATERIALS: Between 2003 and 2011, 56 patients were treated with HDR-ISBT with or without external beam radiotherapy (EBRT). The median followup time was 33 months (range, 1-109 months). Pre-ISBT treatments included radical hysterectomy for 35 patients (Group A), radical hysterectomy with postoperative radiotherapy for 8 patients (Group B), and radical radiotherapy for 13 patients (Group C). We initiated MRI-assisted CT-based planning for the last 49 patients. The median ISBT single fraction dose was 6 Gy. The median total doses were 30 and 54 Gy with and without EBRT (range, 30-50 Gy) for Group A, respectively and 48 Gy without EBRT for Groups B and C. RESULTS: The 3-year local control (LC) rates were 85%, 75%, and 46% for Groups A, B, and C, respectively (p = 0.017). The 3-year LC rates were 84%, 73%, and 33% for clinical target volume at the time of HDR-ISBT of <10, 10-29, and ≥30 cc, respectively (p = 0.005). The 3-year LC results tended to be higher for patients whose D100 (clinical target volume) was equal or higher than 67.1 Gy (p = 0.098). A total of 13 late complications of Grades 3-5 occurred in 11 patients (20%). CONCLUSIONS: Our image-guided HDR-ISBT for pelvic recurrence of uterine cancer provided good treatment outcomes. The treatment results for patients who underwent radical surgery with or without postoperative radiotherapy are better than those for patients who underwent radical radiotherapy.

Preliminary results of MRI-assisted high-dose-rate interstitial brachytherapy for uterine cervical cancer.

PURPOSE: To investigate the effectiveness of our novel MRI-assisted high-dose-rate interstitial brachytherapy for uterine cervical cancer. METHODS AND MATERIALS: Between June 2005 and June 2009, 29 previously untreated patients with cervical cancer were enrolled (2 T2b, 2 T3a, 19 T3b, and 6 T4 tumors). We implanted MRI-compatible plastic catheters using our unique ambulatory technique. The total treatment doses were 30-36 Gy (6 Gy per fraction) combined with external beam radiotherapy. RESULTS: The median D90 (high-risk clinical target volume), D(2 cc) (bladder), and D(2 cc) (rectum) per fraction were 6.9, 5, and 4.6 Gy, respectively. The 3-year local control rates were 100%, 95%, and 83% for T2, T3, and T4 tumors, respectively. Grade 3 or 4 late complications occurred in 4 patients. CONCLUSIONS: Our preliminary evaluation of image-based high-dose-rate interstitial brachytherapy showed favorable local treatment results with an acceptable complication rate.

Three-dimensional image-based high-dose-rate interstitial brachytherapy for mobile tongue cancer.

To investigate the influence of a 3D image-based treatment-planning method for high-dose-rate interstitial brachytherapy (HDR-ISBT) for mobile tongue cancer, we analyzed dose-volume histogram results for the clinical target volume (CTV) and the mandible. Between October 2010 and November 2011, one and four patients having T2 and T3 tumors, respectively, were treated with HDR-ISBT. Multiplane implantation using 9-15 treatment applicators was performed. Lugol's iodine staining, metal markers, ultrasonography, and magnetic resonance imaging were used to identify the contours of the gross tumor volume (defined as the CTV). The results of the image-based treatment plan were compared with those of the conventional simulated plan on the basis of a reference point 5 mm from the applicator position. The mean D90(CTV) and V100(CTV) were 112% of the prescribed dose (PD) and 98.1%PD, respectively, for the image-based plan, and 113%PD and 97.2%PD, respectively, for the conventional plan. The median CTVref/Vref was 0.23 for the image-based plan and 0.16 for the conventional plan (P = 0.01). The mean D0.1 cm(3) (mandible), D1 cm(3) (mandible), and D2 cm(3) (mandible) were 80.1%PD, 62.5%PD, and 55.7%PD, respectively, for the image-based plan, and 109.1%PD (P = 0.02), 82.4%PD (P = 0.005), and 74%PD (P = 0.004), respectively, for the conventional plan). Image-based treatment planning may achieve high-conformity radiotherapy for the CTV and decrease irradiated doses to the mandible.

Appropriate evaluation of and risk factors for radiation dermatitis in breast cancer patients receiving hypofractionated whole-breast irradiation after breast-conserving surgery.

BACKGROUND: In grading radiation-induced dermatitis (RID), there are not only inter-evaluator differences but also intra-evaluator variations. We retrospectively analyzed the advantages of establishing a more precise evaluation method using photographs to minimize intra-evaluator variations and RID risk factors. METHODS: We analyzed 301 breasts, including those of 3 patients with bilateral breast cancer who underwent hypofractionated whole-breast irradiation (WBI) after breast-conserving surgery. Four radiation oncologists (A, B, C and D) evaluated photographs taken before, during and after radiation therapy and graded RID using two methods. RESULTS: The percentages of maximum grades between the two methods varied widely. Kappa statistics revealed that the inter- and intra-evaluator agreements were mostly fair. In multivariate analysis, age (≤60 years old), boost irradiation, concurrent hormonal therapy and chemotherapy prior to WBI are statistically significant risk factors for ≥ grade 2 RID according to two evaluators (B and D), two evaluators (A and B), one evaluator (B) and one evaluator (D), respectively. CONCLUSIONS: The assessment of serial skin change in photographs is useful for judging RID. No risk factor was statistically significant for all evaluators because of wide intra-evaluator variations and large inter-evaluator differences. More objective criteria are needed for appropriate evaluation of RID.

Sivelestat sodium hydrate reduces radiation-induced lung injury in mice by inhibiting neutrophil elastase.

The aim of this study was to investigate whether sivelestat, a neutrophil elastase (NE) inhibitor, mitigates radiation-induced lung injury in mice. C57BL/6J mice were administered a dose of 20 Gy to the bilateral whole lungs. Sivelestat was administered immediately before and 1 h after irradiation in group RE2, and immediately before and 1, 3 and 6 h after irradiation in group RE4. Group R received irradiation without sivelestat injection. Mice that did not receive sivelestat injection or irradiation were used as controls. NE activity was measured 24 and 48 h after irradiation, and the mice were sacrificed 24 h, 48 h and 15 weeks after irradiation for histopathological examination. In groups RE2 and RE4, NE activity was significantly suppressed until 48 h after irradiation compared to group R. The degree of lung damage in each group was scored during histopathological examination. Results showed that the scores of groups RE2 and RE4 were significantly lower compared to those of group R 15 weeks after irradiation. In conclusion, sivelestat reduced radiation­induced lung injury in the mice by suppressing NE activity and excessive inflammatory reactions.

Extra-nodal natural killer/T cell lymphoma, nasal-type, treated by concurrent chemoradiotherapy.

The present study reports on a case of extra-nodal natural killer/T cell lymphoma, nasal-type (ENKL), stage IIEA, in a 50-year-old woman who presented with a white tumor on a refractory ulcer on the gum. Concurrent chemoradiotherapy was administered, and effected a partial response. However, tumor recurrence was observed 5 months after the final diagnosis, and the patient succumbed 1 month after recurrence. Although a definitive treatment for ENKL has yet to be established due to its rarity, radiation therapy (RT) is crucial to therapy, as ENKL is very sensitive to RT. However, treatment with radiation levels above 50 Gy with an extended RT field are required for a favorable outcome. The development of novel chemotherapy regimens may therefore be useful. Additionally, autologous or allogenic hematopoietic stem-cell transplantation may prove to be a promising approach.

Photocatalytic degradation of nonionic surfactants with immobilized TiO2 in an airlift reactor.

The photocatalytic degradation of a nonionic surfactant, Sanonic SS-90 (polyoxyethylene alkyl ether) which is one of polyoxyethylene nonionic surfactants, in water has been investigated using immobilized titanium dioxide (TiO2) photocatalyst. An external UV irradiation type airlift reactor was used as a photoreactor. The effects of initial nonionic surfactant concentration, intensity of UV light, and concentrations of TiO2 photocatalyst on degradation rate of Sanonic SS-90 were examined. The photocatalytic decomposition of Sanonic SS-90 was assumed to be approximately described by the Langmuir-Hinshelwood kinetics. The rate constant of photocatalytic degradation was found to be proportional to TiO2 surface area and the square root of UV light intensity and independent on the initial concentration of Sanonic SS-90. The evaluated average UV light intensity in the airlift photoreactor was used to determine the rate constants in the Langmuir-Hinshelwood kinetics. It was found that the kinetic model for the degradation by immobilized TiO2 photocatalyst can simulate the experimental results reasonably.