Definitive radiotherapy consisting of external beam radiotherapy without central shielding and 3D image-guided brachytherapy for patients with cervical cancer: feasibility for Japanese patients and dose-response analyses for local control in the low-dose range.

OBJECTIVE: To assess the feasibility of external beam radiotherapy without central shielding in definitive radiotherapy for Japanese patients with cervical cancer. METHODS: We retrospectively analysed the data of cervical cancer patients treated with definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy. RESULTS: The study included 167 patients (T1 + 2 = 108, T3 + 4 = 59) from eight Japanese institutions. For three-dimensional-image-guided brachytherapy, intra-cavitary and interstitial brachytherapy was utilized in 33 patients (20%). The median follow-up was 26.6 months (interquartile range, 20-43.2). The maximum rectal D2 (75 Gy)/bladder D2 (90 Gy) constraints were deviated by 6%/10% and 10%/5% for T1 + 2 and T3 + 4, respectively. The 2-year incidence of ≥grade 3 proctitis/cystitis was 4%/1% for T1 + 2 and 10%/2% for T3 + 4. The 2-year local progression-free survival was 89% for T1 + 2 and 82% for T3 + 4. For T1 + 2, the 2-year local progression-free survival for the high-risk clinical target volume D90 ≥ 68 Gy (indicated by receiver operating characteristic analysis; area under the curve = 0.711) was 92% versus 67% for <68 Gy (log-rank; P = 0.019). Cox multivariate analysis indicated that the high-risk clinical target volume D90 was one of independent predictors of local failure (P = 0.0006). For T3 + 4, the 2-year local progression-free survival was 87% for the high-risk clinical target volume <82 cm3 (area under the curve = 0.67) and 43% for ≥82 cm3 (P = 0.0004). Only the high-risk clinical target volume was an independent predictor of local failure (P = 0.0024). CONCLUSIONS: Definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy was feasible for Japanese patients with cervical cancer. Dose de-escalation from the current global standards is suggested for patients with T1 + 2 disease.

Cumulative Incidence and Clinical Risk Factors of Radiation Cystitis after Radiotherapy for Prostate Cancer.

OBJECTIVES: This study aimed to evaluate the cumulative incidence of overall and severe radiation cystitis following external beam radiation therapy for prostate cancer and investigate the clinical factors predictive of radiation cystitis. METHODS: This retrospective study comprised 246 patients who received external beam radiation therapy for localized or locally advanced prostate cancer between 2013 and 2016 in our institution. Of these, 189 received primary radiation therapy and 57 received adjuvant/salvage radiation therapy. Radiation cystitis was recorded using the Common Terminology Criteria for Adverse Events version 5.0 definition, and severe radiation cystitis was defined as grade 3 or higher. All medical records were reviewed to calculate the cumulative incidence of radiation cystitis. Univariate and multivariate Cox regression analyses were used to evaluate its association with clinicopathologic features. RESULTS: The median follow-up period after radiation therapy was 56 months (range 5-81). The 5-year cumulative incidence of radiation cystitis and severe radiation cystitis was 16.2% and 3.0%, respectively. Multivariate analyses identified radiation therapy in the adjuvant/salvage setting was the sole risk factor associated with the development of radiation cystitis (hazard ratio: 2.75, p = 0.02). CONCLUSIONS: Radiation therapy in the post-prostatectomy setting was associated with increased risk of radiation cystitis compared with radiotherapy as the primary treatment.

History of whole pelvis plus para-aortic radiation is a risk factor associated with febrile neutropenia during chemotherapy for recurrent cervical cancer.

BACKGROUND: Radiation-based therapy is widely used for advanced cervical cancer. Prior radiation-based therapy is a potential risk factor for febrile neutropenia (FN). However, the effect of irradiation field size on the incidence of FN during recurrent cervical cancer treatment is unclear. This study aimed to investigate the relationship between prior irradiation field size and FN development during recurrent chemotherapy. METHODS: This retrospective, observational study included cervical cancer patients who received recurrent chemotherapy between November 2006 and June 2020. The patients were classified into two groups based on the area of irradiation fields. The first group included patients with a history of whole pelvis (WP) irradiation (WP group). The second group had patients who underwent WP plus para-aortic lymph node (PAN) irradiation (WP + PAN group). The incidences of hematological toxicities and FN during the recurrent chemoradiotherapy were compared between the two groups. RESULTS: The FN incidence was significantly higher in the WP + PAN group than in the WP group (32.1% vs. 0%, P < 0.001). The incidence of Grade 4 neutropenia was not significantly different between the WP + PAN and WP groups. The nadir absolute neutrophil counts were significantly lower and the dose reduction or discontinuation rate of chemotherapy was significantly higher in the WP + PAN group than in the WP group. CONCLUSION: History of WP plus PAN radiation is a risk factor for developing FN during recurrent cervical cancer chemotherapy.

Injection of hydrogel spacer increased maximal intrafractional prostate motion in anterior and superior directions during volumetric modulated arc therapy-stereotactic body radiation therapy for prostate cancer.

BACKGROUND: The aim of this study was to clarify the association between intrafractional prostate shift and hydrogel spacer. METHODS: Thirty-eight patients who received definitive volumetric modulated arc therapy (VMAT)-stereotactic body radiation therapy (SBRT) for prostate cancer with prostate motion monitoring in our institution in 2018-2019 were retrospectively evaluated. In order to move the rectum away from the prostate, hydrogel spacer (SpaceOAR system, Boston Scientific, Marlborough, the United States) injection was proposed to the patients as an option in case of meeting the indication of use. We monitored intrafractional prostate motion by using a 4-dimensional (4D) transperineal ultrasound device: the Clarity 4D ultrasound system (Elekta AB). The deviation of the prostate was monitored in each direction: superior-inferior, left-right, and anterior-posterior. We also calculated the vector length. The maximum intrafractional displacement (MID) per fraction for each direction was detected and mean of MIDs was calculated per patient. The MIDs in the non-spacer group and the spacer group were compared using the unpaired t-test. RESULTS: We reviewed 33 fractions in eight patients as the spacer group and 148 fractions in 30 patients as the non-spacer group. The superior MID was 0.47 ± 0.07 (mean ± SE) mm versus 0.97 ± 0.24 mm (P = 0.014), the inferior MID was 1.07 ± 0.11 mm versus 1.03 ± 0.25 mm (P = 0.88), the left MID was 0.74 ± 0.08 mm versus 0.87 ± 0.27 mm (P = 0.55), the right MID was 0.67 ± 0.08 mm versus 0.92 ± 0.21 mm (P = 0.17), the anterior MID was 0.45 ± 0.06 mm versus 1.16 ± 0.35 mm (P = 0.0023), and the posterior MID was 1.57 ± 0.17 mm versus 1.37 ± 0.22 mm (P = 0.56) in the non-spacer group and the spacer group, respectively. The max of VL was 2.24 ± 0.19 mm versus 2.89 ± 0.62 mm (P = 0.19), respectively. CONCLUSIONS: Our findings suggest that maximum intrafractional prostate motion during VMAT-SBRT was larger in patients with hydrogel spacer injection in the superior and anterior directions. Since this difference seemed not to disturb the dosimetric advantage of the hydrogel spacer, we do not recommend routine avoidance of the hydrogel spacer use.

Establishment of a Prediction Model for Overall Survival after Stereotactic Body Radiation Therapy for Primary Non-Small Cell Lung Cancer Using Radiomics Analysis.

Stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) leads to recurrence in approximately 18% of patients. We aimed to extract the radiomic features, with which we predicted clinical outcomes and to establish predictive models. Patients with primary non-metastatic NSCLC who were treated with SBRT between 2002 and 2022 were retrospectively reviewed. The 358 primary tumors were randomly divided into a training cohort of 250 tumors and a validation cohort of 108 tumors. Clinical features and 744 radiomic features derived from primary tumor delineation on pre-treatment computed tomography were examined as prognostic factors of survival outcomes by univariate and multivariate analyses in the training cohort. Predictive models of survival outcomes were established from the results of the multivariate analysis in the training cohort. The selected radiomic features and prediction models were tested in a validation cohort. We found that one radiomic feature showed a significant difference in overall survival (OS) in the validation cohort (p = 0.044) and one predicting model could estimate OS time (mean: 37.8 months) similar to the real OS time (33.7 months). In this study, we identified one radiomic factor and one prediction model that can be widely used.

Helical Skin Radiation Therapy Including Total Skin Radiation Therapy Using Tomotherapy for Primary Cutaneous Lymphoma With Bone Marrow Suppression as a Related Adverse Event.

PURPOSE: Total skin electron beam therapy (TSEBT) is useful for primary cutaneous lymphoma. However, helical skin radiation therapy (HSRT) using tomotherapy may avoid the complexity and uncertainty of TSEBT. METHODS AND MATERIALS: All patients with primary cutaneous lymphoma who underwent HSRT at our hospital between June 2015 and July 2019 were investigated, including 7 patients registered in a clinical trial approved by an institutional review board (ID UMIN000022142). HSRT was performed in 3 partitioned skin areas: head and neck, trunk and arms, and legs. RESULTS: A total of 24 patients with 53 skin areas (including 8 patients with 24 skin areas who had undergone sequential total skin irradiation), with a median follow-up time of 13 months (range, 2-50), were investigated. Twenty patients (83.3%) had mycosis fungoides (MF). For 41 of 53 (77.4%) cases, a dose of 20 Gy in 10 fractions was used. The overall response rate in the treated fields of each HSRT in patients with MF was 100%, including 38 (80.9%) complete response, 4 (8.5%) good partial response, and 5 (10.6%) partial response. Eight patients with MF who underwent sequential total skin irradiation showed a 100% complete response. For patients with MF, the median survival time after a first round of HSRT was 22 months (95% confidence interval [CI], 13.6-30.4 months), the median response duration of each HSRT was 5 months (95% CI, 3.67-6.32 months), and the median time to in-field reirradiation for each HSRT was 15 months (95% CI, 9.76-20.24 months). Bone marrow suppression (grade ≥3) often occurred (94.1%) with HSRT on trunk and arm skin. An early patient died of HSRT-caused grade 5 leukopenia. CONCLUSIONS: HSRT targeting trunk and arm skin induced severe bone marrow suppression that led to a temporary palliative effect. TSEBT should still be considered standard treatment for primary cutaneous lymphoma covering the total body surface area.

Improvement of the robustness to set up error by a virtual bolus in total scalp irradiation with Helical TomoTherapy.

Intensity-modulated radiation therapy has recently been used for total scalp irradiation. In inverse planning, the treatment planning system increases the fluence of tangential beam near the skin surface to counter the build-up region. Consequently, the dose to the skin surface increases even with small setup errors. Replacing the electron density of the surrounding air of some thickness with a virtual bolus during optimization could suppress the extremely high fluence near the skin. We confirmed the usefulness of a virtual bolus in total scalp irradiation. For each patient, two beams were planned, one with and the other without a virtual bolus. The dose distribution was calculated using computed tomography images that were shifted to simulate setup errors. The hot spot dose was suppressed in the plans using a virtual bolus. In conclusion, using a virtual bolus improved the robustness to setup errors.

Adequate target volume in total-body irradiation by intensity-modulated radiation therapy using helical tomotherapy: a simulation study.

Recently, intensity-modulated radiation therapy (IMRT) has been used for total-body irradiation (TBI). Since the planning target volume (PTV) for TBI includes the surrounding air, a dose prescription to the PTV provides high fluence to the body surface. Thus with just a small set-up error, the body might be exposed to a high-fluence beam. This study aims to assess which target volume should be prescribed the dose, such as a clinical target volume (CTV) with a margin, or a CTV that excludes the surface area of the skin. Three treatment plans were created for each patient: the 5-mm clipped plan (Plan A), the 0-mm margin plan (Plan B) and the 5-mm margin plan (Plan C). The CTV was the whole body. PTVs were the CTV with the exception of 5 mm from the skin surface in Plan A, equal to the CTV in Plan B, and the CTV with a 5 mm margin in Plan C. The prescribed dose was 12 Gy in six fractions. To assess the influence of the set-up error, dose distributions were simulated on computed tomography (CT) images shifted 2 pixels (= 4.296 mm), 5 pixels (= 10.74 mm) and 10 pixels (= 21.48 mm) in the lateral direction from the original CT. With a set-up error of 10.74 mm, V110% was 8.8%, 11.1% and 23.3% in Plans A, B and C, respectively. The prescription to the PTV containing the surrounding air can be paradoxically vulnerable to a high-dose as a consequence of a small set-up error.

Distinct modulatory effects of 5-HT on excitatory synaptic transmissions in the nucleus tractus solitarius of the rat.

The second-order relay neurons in the nucleus tractus solitarius (NTS) receive numerous peripheral afferent inputs mainly from the vagus nerve. Their activity is modified by several neuromodulators and hence autonomic responses are properly regulated. Serotonin (5-HT) is an important candidate for such neuromodulators, since serotonergic inputs and distribution of 5-HT receptors are provided in the NTS. However, its mechanism of action remains unclear. To evaluate the serotonergic modulation of synaptic transmission, we examined the effects of 5-HT (1.0-10.0 µM) on the solitary tract-evoked excitatory postsynaptic currents (eEPSCs) and spontaneously occurring EPSCs (sEPSCs) in the preselected second-order neurons of the rat NTS. 5-HT concentration-dependently decreased the amplitude of eEPSCs, which was accompanied by an increase in paired-pulse ratio. The inhibitory effect of 5-HT was mimicked by α-methylserotonin and blocked by ketanserin. 5-HT had no effect on the inward current induced in the NTS neurons by topically applied α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). On the other hand, 5-HT increased the frequency of sEPCSs without effect on their amplitude. This excitatory effect of 5-HT was mimicked by 2-methylserotonin and antagonized by ondansetron. The results suggest a dual modulation of the excitatory synaptic transmission by 5-HT in the NTS; presynaptic inhibition of the peripheral inputs synapsing to the relay neurons via 5-HT(2) receptors and presynaptic excitation of inputs from the intrinsic local network via 5-HT(3) receptors. These effects of 5-HT may provide important means of optimizing the autonomic responses mediated by the NTS network.