Late genitourinary toxicity in salvage radiotherapy for prostate cancer after radical prostatectomy: impact of daily fraction doses.

OBJECTIVE: To evaluate the impact of daily fraction doses on late genitourinary (GU) toxicity after salvage radiotherapy (SRT) for prostate cancer. METHODS: This multi-institutional retrospective study included 212 patients who underwent SRT between 2008 and 2018. All patients received image-guided intensity-modulated SRT at a median dose of 67.2 Gy in 1.8-2.3 Gy/fraction. The cumulative rates of late grade ≥2 GU and gastrointestinal (GI) toxicities were compared using Gray test, stratified by the ≤2.0 Gy/fraction (n = 137) and ≥2.1 Gy/fraction groups (n = 75), followed by multivariate analyses. The total dose was represented as an equivalent dose in 2-Gy fractions (EQD2) with α/ß = 3 Gy. RESULTS: After a median follow-up of 63 months, the cumulative rates of 5-year late grade ≥2 GU and GI toxicities were 14% and 2.5%, respectively. The cumulative rates of 5-year late grade ≥2 GU toxicity in the ≥2.1 Gy/fraction and ≤2.0 Gy/fraction groups were 22% and 10%, respectively (P = .020). In the multivariate analysis, ≥2.1 Gy/fraction was still associated with an increased risk of late grade ≥2 GU toxicity (hazard ratio, 2.37; 95% confidence interval, 1.12-4.99; P = .023), while the total dose was not significant. CONCLUSION: The present results showed that ≥2.1 Gy/fraction resulted in a higher incidence of late grade ≥2 GU toxicity in SRT. ADVANCES IN KNOWLEDGE: The impact of fraction doses on late GU toxicity after SRT remains unknown. The results suggest that higher fraction doses may increase the risk of late GU toxicity in SRT.

Impact of radiation doses on clinical relapse of biochemically recurrent prostate cancer after prostatectomy.

The relationship between radiation doses and clinical relapse in patients receiving salvage radiotherapy (SRT) for biochemical recurrence (BCR) after radical prostatectomy (RP) remains unclear. We identified 292 eligible patients treated with SRT between 2005 and 2018 at 15 institutions. Clinical relapse-free survival (cRFS) between the ≥ 66 Gy (n = 226) and < 66 Gy groups (n = 66) were compared using the Log-rank test, followed by univariate and multivariate analyses and a subgroup analysis. After a median follow-up of 73 months, 6-year biochemical relapse-free survival, cRFS, cancer-specific survival, and overall survival rates were 58, 92, 98, and 94%, respectively. Six-year cRFS rates in the ≥ 66 Gy and < 66 Gy groups were 94 and 87%, respectively (p = 0.022). The multivariate analysis revealed that Gleason score ≥ 8, seminal vesicle involvement, PSA at BCR after RP ≥ 0.5 ng/ml, and a dose < 66 Gy correlated with clinical relapse (p = 0.015, 0.012, 0.024, and 0.0018, respectively). The subgroup analysis showed the consistent benefit of a dose ≥ 66 Gy in patients across most subgroups. Doses ≥ 66 Gy were found to significantly, albeit borderline, increase the risk of late grade ≥ 2 GU toxicity compared to doses < 66 Gy (14% vs. 3.2%, p = 0.055). This large multi-institutional retrospective study demonstrated that a higher SRT dose (≥ 66 Gy) resulted in superior cRFS.

Biological effects of prostaglandin E2-EP4 antagonist (AAT-008) in murine colon cancer in vivo: enhancement of immune response to radiotherapy and potential as a radiosensitizer.

Background: Prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four receptors (EP1-4). We investigated the radiosensitizing effects of a newly developed antagonist of PGE2-EP4 (AAT-008) in mouse colon cancer cells in vivo and explored the mechanism using flow cytometry (FCM). Methods: CT26WT cells grown in Balb/c mice were used. AAT-008 at doses of 0, 3, 10, and 30 mg/kg/day was orally administered once or twice daily for up to 19 days. On day 3, the tumors were irradiated at 9 Gy in the radiotherapy (RT) group. Tumor sizes were measured every other day. For the first FCM series, AAT-008 (10 mg/kg/day) was administered from day 0 to 18 and RT (9 Gy) was given on day 3. The population of effector T cells (Teff), defined as CD45+CD8+CD69+, in the tumors was investigated on day 19. For the second FCM series, AAT-008 (30 mg/kg/day) was administered from day 0 to 12. The populations of Teff and regulatory T cells (Treg), and the ratio of Teff/Treg were investigated on day 13. Results: The growth delay effect of AAT-008 administered alone (3-30 mg/kg/day) appeared minimal. In the first growth delay experiment where AAT-008 was administered once daily, the combined effect of AAT-008 (30 mg/kg/day) and RT appeared additive. In the second growth delay experiment where AAT-008 was administered twice daily, the combined effect appeared additive at 3 and 10 mg/kg/day and supra-additive at 30 mg/kg/day. In the first FCM series, the mean Teff proportions in the tumors were 43% and 31% in the 10 mg + RT and 0 mg + RT groups, respectively. Notably, 67% Teff was observed in responsive mice in the 10 mg + RT group. In the second FCM series, the mean Treg proportion and Teff/Treg ratio in the 0 mg + RT and 30 mg + RT groups were 4.0% and 1.5%, respectively (P=0.04) and 10 and 22, respectively (P=0.04). Conclusions: AAT-008 potentially enhances the radiosensitivity of colon cancer cells, apparently by stimulating the immune system against the cancer cells.

Comparison of intensity-modulated radiotherapy with the 5-field technique, helical tomotherapy and volumetric modulated arc therapy for localized prostate cancer.

The outcomes of three methods of intensity-modulated radiation therapy (IMRT) for localized prostate cancer were evaluated. Between 2010 and 2018, 308 D'Amico intermediate- or high-risk patients were treated with 2.2 Gy daily fractions to a total dose of 74.8 Gy in combination with hormonal therapy. Overall, 165 patients were treated with 5-field IMRT using a sliding window technique, 66 were then treated with helical tomotherapy and 77 were treated with volumetric modulated arc therapy (VMAT). The median age of patients was 71 years. The median follow-up period was 75 months. Five-year overall survival (OS) and biochemical or clinical failure-free survival (FFS) rates were 95.5 and 91.6% in the 5-field IMRT group, 95.1 and 90.3% in the tomotherapy group and 93.0 and 88.6% in the VMAT group, respectively, with no significant differences among the three groups. The 5-year cumulative incidence of late grade ≥2 genitourinary and gastrointestinal toxicities were 7.3 and 6.2%, respectively, for all patients. Late grade ≥2 gastrointestinal toxicities were less frequent in patients undergoing VMAT (0%) than in patients undergoing 5-field IMRT (7.3%) and those undergoing tomotherapy (11%) (P = 0.025), and this finding appeared to be correlated with the better rectal DVH parameters in patients undergoing VMAT. Other toxicities did not differ significantly among the three groups, although bladder dose-volume parameters were slightly worse in the tomotherapy group than in the other groups. Despite differences in the IMRT delivery methods, X-ray energies and daily registration methods, all modalities may be used as IMRT for localized prostate cancer.

Stereotactic body radiotherapy using a hydrogel spacer for localized prostate cancer: A dosimetric comparison between tomotherapy with the newly-developed tumor-tracking system and cyberknife.

PURPOSE: With a new tumor-tracking system (Synchrony®) for tomotherapy (Radixact®), the internal and set-up margins can be tightened, like cyberknife (CyberKnife®), in the planning of stereotactic body radiotherapy (SBRT) for prostate cancer. Recently, the usefulness of placing a hydrogel spacer between the prostate and rectum has been established in prostate radiotherapy. We evaluated the characteristics of tomotherapy plans with the tumor-tracking system and compared them with cyberknife SBRT plans for localized prostate cancer using a hydrogel spacer. METHODS: In 20 patients, two plans were created and compared using tomotherapy and cyberknife. All patients underwent hydrogel spacer injection behind the prostate before simulation CT and MRI for fusion. For all plans, 36.25 Gy in 7.25-Gy fractions for a minimum coverage dose of 95% of planning target volume (PTV) (D95%) was prescribed. The D99% of PTV and D0.1 ml of the PTV, urethra, bladder, and rectum were intended to be > 90%, 110-130%, 100-110%, <110%, and <100%, respectively, of the prescribed doses. RESULTS: All plans using tomotherapy and cyberknife achieved the intended dose constraints. The cyberknife plans yielded better median PTV-V110% (volume of PTV covered by 110% isodose line, 54.8%), maintaining lower median D0.1 ml of the urethra (37.5 Gy) and V80% of the bladder (11.0 ml) compared to the tomotherapy plans (39.0%; p < 0.0001, 38.2 Gy; p < 0.0001, and 18.3 ml; p < 0.0001, respectively). The tomotherapy plans were superior to the cyberknife plans for the rectum (V80% = 0.4 vs. 1.0 ml, p < 0.001; D1ml = 26.4 vs. 29.0 Gy, p = 0.013). CONCLUSIONS: Our results suggested that tomotherapy with the tumor-tracking system has reasonable potential for SBRT for localized prostate cancer using a hydrogel spacer.

Effects of a combined treatment regimen consisting of Hsp90 inhibitor DS-2248 and radiation in vitro and in a tumor mouse model.

BACKGROUND: Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the conformational maintenance of several client proteins that play important roles in DNA damage repair, apoptosis following radiation, and resistance to radiation therapy. DS-2248 (tricyclic pyrazolopyrimidine derivative) is a newly-developed, orally available inhibitor of HSP90 with low adverse effects. We investigated the combined effects of radiation and DS-2248 in vitro and in vivo. METHODS: SCCVII squamous cell carcinoma cells and tumors transplanted in C3H/HeN mice were used. In vitro combined effects of X-ray radiation and DS-2248 were investigated using a colony assay. Phosphorylated histone H2AX (γH2AX) was quantified after 2-Gy irradiation with or without 24-hour pretreatment with DS-2248. The mice bearing SCCVII tumors received oral DS-2248 10 times over 2 weeks and received local irradiation with doses of 1, 2, 3, and 4 Gy delivered 6 times over 2 weeks. Then, tumor volumes were measured. RESULTS: Radiation plus pretreatment with 50 nM DS-2248 for 24 hours produced synergistic effects on SCCVII cells. γH2AX foci persisted after radiation for longer periods (6 and 24 hours) in DS-2248-treated cells than in control cells. In vivo, the combined effects appeared to be additive when 5 or 10 mg/kg DS-2248 was combined with total radiation doses of 6-18 Gy, but the effect was considered supra-additive when 15 mg/kg of DS-2248 was combined with a total dose of 24 Gy. CONCLUSIONS: The combined effects of DS-2248 and radiation were additive at low drug and radiation doses, but may have been supra-additive at higher doses. Inhibition of slow repair of DNA double strand breaks (i.e., homologous recombination) was considered to contribute to this combined effect.

Stereotactic body radiotherapy using the forward-planned static-port tomotherapy for lung cancer: a novel planning technique with the newly-developed mode.

With the newly-developed static-port forward-planning (FP) mode of tomotherapy, the ratio of the dose of the planning target volume (PTV) periphery to the maximum dose can be easily adjusted by modifying leaf margins when planning stereotactic body radiotherapy (SBRT). The purpose of this study was to evaluate the characteristics of FP plans compared to helical intensity-modulated radiotherapy (IMRT) and helical 3D conformal radiotherapy (3DCRT) plans of SBRT for lung tumors. The three plans were created for 14 tumors in 11 patients. For 13 tumors, 60 Gy in 7.5-Gy fractions was prescribed for a minimum coverage dose of 95% of the PTV (D95). The prescribed isodose line (PIL) was intended to be 60-80% of the maximum dose. Nine angles were used for the FP plans. The median D98 and D50 of the internal target volume for FP, helical-IMRT and helical-3DCRT plans were 70.4, 71.4 and 60.5 Gy, respectively (P < 0.001), and 77.7, 75.7 and 62.3 Gy, respectively (P < 0.0001). The median PIL and the lung volume receiving ≥20 Gy (V20) were 73.4, 73.4 and 94.3%, respectively (P < 0.0001), and 4.7, 4.0 and 5.7%, respectively (P < 0.0001). These parameters were not significantly different between the FP and helical-IMRT plans. The median beam-on times were 238.6, 418.9 and 197.1 s, respectively (P < 0.0001). The FP plans reduced the beam-on time by 43% compared to the helical-IMRT plans. The dose distribution of the FP plans was comparable to that of the helical-IMRT plans. The helical-3DCRT plans could not adjust PIL to be 60-80%.

Factors related to primary cancer death and non-primary cancer death in patients treated with stereotactic body radiotherapy for pulmonary oligometastases.

Cancer-specific death (CSD) and non-cancer-specific death (non-CSD) after stereotactic body radiotherapy (SBRT) for pulmonary oligometastases have not been studied in detail. The aim of this study was to determine the cumulative incidences of CSD and non-CSD and to reveal prognostic factors. Data from a large survey of SBRT for pulmonary oligometastases were used for analyses, and patients with unknown cause of death were excluded from current analyses. CSD was primary cancer death and non-CSD was non-primary cancer death including a series of cancer treatment-related deaths. Cumulative incidences were calculated using the Kaplan-Meier method and a stratified Cox regression model was used for multivariate analyses (MVA). Fifty-two patients with an unknown death were excluded and a total of 1326 patients was selected. CSD and non-CSD occurred in 375 and 109 patients, respectively. The median OS period was 53.2 months and the cumulative incidences of 1-, 3-, and 5-year CSD vs. non-CSD rates were 6.5% vs. 2.3%, 29.5% vs. 8.6%, and 41.2% vs. 11.0%, respectively. In MVA, the incidence of CSD was related to performance status (1 vs. 0; p < 0.001, 2-3 vs. 0; p = 0.011), oligometastatic state (sync-oligometastases vs. oligo-recurrence, p = 0.026) and maximum tumor diameter (p = 0.009), and the incidence of non-CSD was related to age (p = 0.001), sex (p = 0.030), performance status (2-3 vs. 0; p = 0.002), and irradiated tumor-located lung lobe (left lower lobe vs. other lobes, p = 0.036). CSD was main cause of death, but non-CSD was not rare after SBRT. Prognostic factors for CSD and non-CSD were different, and an understanding of the factors would help in treatment.

Analyses of the local control of pulmonary Oligometastases after stereotactic body radiotherapy and the impact of local control on survival.

BACKGROUND: Successful local therapy for oligometastases may lead to longer survival. The purpose of this multicentre retrospective study was to investigate factors affecting the local control (LC) of pulmonary oligometastases treated by stereotactic body radiotherapy (SBRT) and to investigate the impact of LC on survival. METHODS: The inclusion criteria included 1 to 5 metastases, the primary lesion and other extrathoracic metastases were controlled before SBRT, and the biological effective dose (BED10) of the SBRT was 75 Gy or more. The Cox proportional hazards model was used for analyses. RESULTS: Data of 1378 patients with 1547 tumours from 68 institutions were analysed. The median follow-up period was 24.2 months. The one-year, 3-year and 5-year LC rates were 92.1, 81.3 and 78.6%, respectively, and the 1-year, 3-year and 5-year overall survival rates were 90.1, 60.3 and 45.5%, respectively. Multivariate analysis for LC showed that increased maximum tumour diameter (p = 0.011), type A dose calculation algorithm (p = 0.005), shorter overall treatment time of SBRT (p = 0.035) and colorectal primary origin (p < 0.001 excluding oesophagus origin) were significantly associated with a lower LC rate. In the survival analysis, local failure (p < 0.001), worse performance status (1 vs. 0, p = 0.013; 2-3 vs. 0, p < 0.001), oesophageal primary origin (vs. colorectal origin, p = 0.038), squamous cell carcinoma (vs. adenocarcinoma, p = 0.006) and increased maximum tumour diameter (p < 0.001) showed significant relationships with shorter survival. CONCLUSIONS: Several factors of oligometastases and SBRT affected LC. LC of pulmonary oligometastases by SBRT showed a significant survival benefit compared to patients with local failure.

Analyses of local control and survival after stereotactic body radiotherapy for pulmonary oligometastases from colorectal adenocarcinoma.

This study is a subset analysis of a retrospective multicenter study performed in Japan and its purpose was to investigate the effectiveness of stereotactic body radiotherapy (SBRT) for pulmonary oligometastases from colorectal cancer. Local control (LC), freedom from further metastases, relapse-free survival and overall survival (OS) after SBRT were retrospectively analyzed. The Kaplan-Meier method was used to estimate lifetime data and the log-rank test was performed as univariate analyses. The Cox proportional hazards model was applied in multivariate analyses. Data for 330 patients with 371 tumors were used for analyses. The median follow-up period was 25.0 months. The 3-year LC, freedom from further metastases, relapse-free survival and OS rates were 64.9, 34.9, 24.9 and 63.4%, respectively. The results of multivariate analyses showed that a higher LC rate was associated with no history of local therapy for oligometastases (P = 0.01), SBRT without concurrent chemotherapy (P < 0.01), type B calculation algorithm (P < 0.01) and higher biological effective radiation doses (≥115 Gy, P = 0.04). A longer OS was associated with no history of local therapy for oligometastases (P = 0.04), a more recent period of SBRT (2010-15, P = 0.02), tumor located in the upper or middle lobe (P < 0.01) and higher biological effective radiation doses (≥115 Gy, P = 0.01). In conclusion, OS after SBRT was good, but LC rate was relatively low. The use of high biological effective radiation doses can improve both LC and OS outcomes.

Early salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy: Its impact and optimal candidate.

AIM: We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level < 0.50) and BCR after SRT was tested in each subgroup according to our own risk stratification. RESULTS: The median follow-up time was 51 months. By multivariate analysis, pT3b, Gleason score ≥ 8, negative surgical margins, PSA doubling time < 6 months, and non-early SRT were associated with BCR after SRT. Patients were stratified by four risk factors other than non-early SRT: (1) low risk (0 risk factor), (2) intermediate risk (1 risk factor), and (3) high risk (≥2 risk factors). The BCR-free survival was higher in the early SRT group than the nonearly SRT group in the high-risk subgroup (P = 0.020), whereas that was similar between two groups in the low-risk and intermediate-risk subgroups (P = .79 and .18, respectively). Multivariate analysis revealed that early SRT was beneficial for the high-risk subgroup (P = .032), whereas early SRT was not associated with improved outcomes in the low-risk and intermediate-risk subgroups (P = .92 and 1.0, respectively). CONCLUSIONS: This study suggested that early SRT seemed to contribute to better biochemical control for patients with more adverse features, whereas no benefit was observed in men with no adverse features.

Significant reduction of oncologic pulmonary death by local control for pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: The rate of oncologic pulmonary death after stereotactic body radiotherapy for pulmonary oligometastases has never been reported. The purpose of current study was to investigate the rate of freedom from oncologic pulmonary death (FOPD) and to analyze factors affecting for FOPD. MATERIALS AND METHODS: The inclusion criteria for this retrospective study were that SBRT was performed between 2004 and 2015, the number of metastases was 5 or less, the primary lesion and extrathoracic metastases needed to be controlled before SBRT and a biological effective dose (BED10) of 75 Gy or more was needed. The Kaplan-Meier estimator and the log-rank test were used to calculate and compare the stratified rates of FOPD. The Cox proportional hazards model was used for multivariate analyses (MVA). Primary disease death from a non-oncologic pulmonary cause was censored in model 1 and was excluded in model 2. RESULTS: A total of 1172 patients with 1315 tumors were enrolled. During a median follow-up period of 24.5 months, oncologic pulmonary deaths accounted for 101 of 221 primary disease deaths. The 1-year, 3-year and 5-year FOPD rates in model 1 were 98.2%, 89.4% and 84.0%, respectively. MVA for FOPD revealed that local failure of the irradiated tumor, squamous cell carcinoma pathology, and chemotherapy after SBRT had significant relationships with lower FOPD rates in both model 1 and model 2. CONCLUSIONS: Successful local control of pulmonary oligometastases by SBRT contributed to a higher FOPD rate.

Intensity-modulated radiation therapy for multiple targets with tomotherapy using multiple sets of static ports from different angles.

BACKGROUND: To treat multiple targets separated in the craniocaudal direction within a short time, we invented a new technique using multiple static-port tomotherapy with the dynamic-jaw mode and named it the pseudo-DJDC (pDJDC) technique. We compared the pDJDC plans and helical tomotherapy plans using the dynamic-jaw mode (HDJ) for multiple targets. In the pDJDC plans, we used a beam set with 2-7 ports to the targets at the same level in the craniocaudal direction, and employed another beam set for other targets using different port angles (9-12 angles in total). METHODS: In seven patients, two plans using the pDJDC and HDJ techniques were compared. For multiple targets (n = 2-6), 20-60 Gy in 2- to 7.5-Gy fractions were prescribed for the planning target volumes at D50%. The conformity index, uniformity index (D5%/D95%), dose distribution in the lung, and treatment time were evaluated. RESULTS: The median conformity index of all seven patients was 3.0 for the pDJDC plans and 2.4 for the HDJ plans (P = 0.031). The median uniformity indices of the planning target volume (n = 25) for the two plans were 1.048 and 1.057, respectively (P = 0.10). For five patients with thoracic targets, the median mean lung doses were 2.6 Gy and 2.4 Gy, respectively (P = 0.63). The median V5Gy and V20Gy of the lungs in the five patients were 11.8% and 8.5% (P = 0.63), and 1.6% and 2.1% (P = 0.31), respectively. The pDJDC plans reduced the treatment time by 48% compared to the HDJ plans (median: 462 and 884 sec, respectively, P = 0.031). CONCLUSION: The pDJDC technique allows treatment of multiple targets in almost half the time of the HDJ technique. The pDJDC plans were comparable to the HDJ plans in dose distribution, although the conformity index deteriorated.

Pulmonary Oligometastases Treated by Stereotactic Body Radiation Therapy: A Nationwide Survey of 1,378 Patients.

AIM: This study was performed to confirm the superior overall survival (OS) after pulmonary oligo-recurrence compared to pulmonary sync-oligometastases in a large nationwide study. PATIENTS AND METHODS: Patients that met the following criteria were included: 1 to 5 lung-only metastases at the beginning of stereotactic body radiation therapy (SBRT) was performed between January 2004 and June 2015, and the biological effective dose (BED) of SBRT was 75 Gy or more. The parameters included in the analyses were age, gender, ECOG PS, primary lesion, pathology, oligoetastatic state, SBRT date, chemotherapy before SBRT, chemotherapy concurrent SBRT, chemotherapy after SBRT, maximum tumor diameter, number of metastases, field coplanarity, dose prescription, BED10, OTT of SBRT. RESULTS: In total, 1,378 patients with 1,547 tumors were enrolled. Oligo-recurrence occurred in 1,016 patients, sync-oligometastases in 118, and unclassified oligometastases in 121. The three-year OS was 64.0% for oligo-recurrence and 47.5% for sync-oligometastasis (p<0.001). In the multivariate analysis, the hazard ratio (HR) for sync-oligometastases versus oligo-recurrence was 1.601 (p=0.014). Adverse events of Grade 5 were occurred in 3 patients. CONCLUSION: This is the first nationwide to indicate that the OS of patients with pulmonary oligo-recurrence is better than that of patients with sync-oligometastases.

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy.

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8-5.4, p < 0.001) and use of whole-pelvic radiotherapy (HR 7.6, CI 1.0-56, p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3-7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

Clinical Evaluation of Onrad, A New Low-cost Version of TomoTherapy that Uses Only Static Beams.

OBJECTIVE: This study evaluated the clinical feasibility of a new low-cost TomoTherapy system (OnradTM) and compared it with low-cost linear accelerator models (linacs). METHODS: Various aspects of treatment and cost were compared between Onrad and linacs for 3-dimensional radiotherapy (3DCRT). Dosimetric comparisons of 10 patients each with breast, stage III lung, prostate, head and neck, and cervical cancers were carried out (total 100 plans). RESULTS: Onrad had advantages in terms of availability of long treatment fields and a smaller mechanical footprint. For breast cancers and lung cancers, target dose homogeneity in Onrad plans was better than that in 3DCRT. In the prostate plans, Onrad plans provided superior D95, conformity and homogeneity. The rectum doses of Onrad plans were lower than those with 3DCRT. Onrad plans provided superior homogeneity and D95 in head and neck cancer. The mean dose and V10-40 Gy of the parotid glands was lower using Onrad. In the cervical cancer plans, target doses were similar with both systems. Normal tissue doses were equal. CONCLUSIONS: Onrad is useful in the clinical setting. Onrad can achieve favorable or comparable dose distributions compared with those of 3DCRT in actual clinical treatment of breast, lung, prostate, head and neck, and cervical cancers.

Efficacy of herbal medicine TJ-14 for acute radiation-induced enteritis: a multi-institutional prospective Phase II trial.

The purpose of this multi-institutional Phase II trial study was to prospectively investigate the efficacy of the herbal medicine TJ-14 for acute radiation-induced enteritis (ARE). TJ-14 was administered orally as a first-line treatment for ARE. The primary end point was efficacy at 1 week. The secondary end points were: (i) the efficacy of TJ-14 at 2 and 3 weeks after its administration, (ii) the quality of life score (FACT-G) at 1, 2 and 3 weeks after its administration, and (iii) adverse events. If the efficacy of TJ-14 was observed in eight patients or fewer, its efficacy was rejected. Results: Forty patients receiving pelvic radiotherapy were enrolled. Of these, 22 developed ARE and received TJ-14. Among these, 19 had cervical cancer and 9 received chemoradiotherapy. TJ-14 efficacy was shown in 19 out of the 22 patients (86%). Stool frequency per day at 1 week significantly decreased (mean ± SD: 4.9 ± 2.1 vs 3.7 ± 1.9, P = 0.02). This effect continued at 2 (2.2 ± 1.4, P = 0.004) and 3 weeks (2.1 ± 0.9, P = 0.05). Thirteen out of the 22 patients (59%) continued TJ-14 until the end of radiotherapy. FACT-G score deterioration was not observed after the administration of TJ-14. Grade 1 hypokalemia was observed in 4 patients, and Grade 1 constipation in 3. We concluded that TJ-14 is sufficiently promising to be examined in a Phase III trial. A randomized controlled trial is currently being planned.

Helical tomotherapy for chemo-refractory multiple liver metastases.

BACKGROUND: Despite advances in chemotherapy, curing multiple liver metastases is quite rare. Even when response is obtained, regrowth of the tumors is almost inevitable. We aimed to evaluate the efficacy and adverse events of helical tomotherapy for chemo-refractory multiple liver metastases. METHODS: Forty-five patients with chemo-refractory multiple (3-10) liver metastases after standard systemic chemotherapy entered the single-institutional prospective study. Liver metastases were the major disease; however, 31 also had uncontrolled primary lesions and/or other metastases. The prescribed dose was 55 Gy in 25 fractions. The median planning target volume (PTV) and normal liver volume (NLV) of first treatment were 128 cm3 and 1175 cm3 , respectively. The median of V15Gy , V30Gy , and mean dose to NLV were 45%, 23%, and 19.4 Gy, respectively. RESULTS: Forty-two patients (93%) completed the planned treatment. Median survival time (MST) for all patients was 8 months, and the 1-year survival rate was 29%. The median local control (LC) period was 5 months and the 6-month control rate of irradiated tumors was 33%. A ≥30% decrease in tumor markers was observed in 31%. The most common grade 3 toxicity was lymphocytopenia (40%), followed by fatigue (6%). Radiation-induced liver disease (RILD) was not observed. Pancreatic cancer as the primary tumor, distant metastases outside the liver, low pretreatment neutrophil-to-lymphocyte ratio (NLR), and low pretreatment monocyte-to-lymphocyte ratio (MLR) were associated with poorer prognoses. CONCLUSIONS: Helical tomotherapy for chemo-refractory multiple liver metastases is a feasible and potentially effective treatment. Incorporating tomotherapy into the first-line treatment in combination with systemic chemotherapy should be considered. TRIAL REGISTRATION NUMBER: CROG 12005.

Differentiation between malignant and benign musculoskeletal tumors using diffusion kurtosis imaging.

OBJECTIVE: The purpose of this study was to evaluate differences in parameters of diffusion kurtosis imaging (DKI) and minimum apparent diffusion coefficient (ADCmin) between benign and malignant musculoskeletal tumors. MATERIALS AND METHODS: In this prospective study, 43 patients were scanned using a DKI protocol on a 3-T MR scanner. Eligibility criteria were: non-fatty, non-cystic soft tissue or osteolytic tumors; > 2 cm; location in the retroperitoneum, pelvis, leg, or neck; and no prior treatment. They were clinically or histologically diagnosed as benign (n = 27) or malignant (n = 16). In the DKI protocol, diffusion-weighted imaging was performed using four b values (0-2000 s/mm2) and 21 diffusion directions. Mean kurtosis (MK) values were calculated on the MR console. A recently developed software application enabling reliable calculation was used for DKI analysis. RESULTS: MK showed a strong correction with ADCmin (Spearman's rs = 0.95). Both MK and ADCmin values differed between benign and malignant tumors (p < 0.01). For benign and malignant tumors, the mean MK values (± SD) were 0.49 ± 0.17 and 1.14 ± 0.30, respectively, and ADCmin values were 1.54 ± 0.47 and 0.49 ± 0.17 × 10-3 mm2/s, respectively. At cutoffs of MK = 0.81 and ADCmin = 0.77 × 10-3 mm2/s, the specificity and sensitivity for diagnosis of malignant tumors were 96.3 and 93.8% for MK and 96.3 and 93.8% for ADCmin, respectively. The areas under the curve were 0.97 and 0.99 for MK and ADCmin, respectively (p = 0.31). CONCLUSIONS: MK and ADCmin showed high diagnostic accuracy and strong correlation, reflecting the accuracy of MK. However, no clear added value of DKI could be demonstrated in differentiating musculoskeletal tumors.

Radiation-induced dermatitis after administration of mogamulizumab for adult T-cell leukaemia/lymphoma: a multi-institutional retrospective study.

BACKGROUND: Cutaneous adverse reactions are frequently induced by mogamulizumab. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and severe photosensitivity related to mogamulizumab have been reported. This study investigated whether severe radiation-induced dermatitis occurred in patients undergoing radiotherapy after the administration of mogamulizumab for adult T-cell leukaemia/lymphoma. METHODS: We retrospectively reviewed 46 courses of radiotherapy administered to 15 consecutive patients with adult T-cell leukaemia/lymphoma (acute, n = 7; lymphoma, n = 7; smouldering, n = 1) who received mogamulizumab before or during radiotherapy at three institutions between 2012 and 2017. RESULTS: During 43 of the 46 radiotherapy courses, patients developed Grade ≤1 radiation-induced dermatitis. No patient developed Grade ≥3 radiation-induced dermatitis. No patient was prescribed ointments as prophylactic treatment for radiation-induced dermatitis. Development of radiation-induced dermatitis was not significantly associated with the number of days since the administration of mogamulizumab prior to radiotherapy (P = 0.85), frequency of administration of mogamulizumab before/during radiotherapy (P = 0.33), administration of mogamulizumab during radiotherapy (P = 0.41) or types of lesions in adult T-cell leukaemia/lymphoma cases (cutaneous vs. non-cutaneous, P = 0.74). Development of radiation-induced dermatitis was significantly related to the total cutaneous dose (mean, 31.9 Gy [95% confidence interval: 26.6-37.1 Gy] vs. 19.7 Gy [95% confidence interval: 16.2-23.2 Gy], P = 0.0004) and total prescribed dose (mean, 31.5 Gy [95% confidence interval: 26.2-36.8 Gy] vs. 18.5 Gy [95% confidence interval: 15.0-22.0 Gy], P = 0.0002). CONCLUSION: None of the 15 patients who received moderate-dose radiotherapy developed severe radiation-induced dermatitis during the 46 courses of radiotherapy after mogamulizumab administration.