Short diameter may be a useful simple indicator of the tumor response in skull base meningiomas after conventionally fractionated stereotactic radiotherapy.

OBJECTIVES: The purpose of this study was to assess the radiological change patterns in skull base meningiomas after conventionally fractionated stereotactic radiotherapy (CFSRT) to determine a simple and valid method to assess the tumor response. MATERIALS AND METHODS: Forty-one patients with a benign skull base meningioma treated by CFSRT from March 2007 to August 2015 were retrospectively evaluated. We measured tumor volume (TV), long-axis diameter (LD), and short-axis diameter (SD) on both pre-treatment images and follow-up images of 1, 3, and 5 years after CFSRT, respectively. The paired t test was used to detect differences in the LD and SD change rates. Spearman's correlation coefficients were calculated to evaluate relationships between the TV and the diameters changes. RESULTS: The number of available follow-up MRIs that was performed at 1, 3, and 5 years after the CFSRT was 41 (100%), 34 (83%), and 23 (56%), respectively. The change rates of SD were significantly higher than those of LD at every time point and more strongly correlated with the change rates of tumor volume at 3 and 5 years after CFSRT. CONCLUSIONS: SD may be useful as a simple indicator of the tumor response for skull base meningioma after CFSRT. KEY POINTS: • The change rate in short-axis diameter is a useful and simple indicator of the response of skull base meningioma to conventionally fractionated stereotactic radiotherapy. • Conventionally fractionated stereotactic radiotherapy for skull base meningioma achieved excellent 5-year local control.

Pathological responses to low-dose irradiation and Pepleomycin in Oral squamous cell carcinoma are predictive of Locoregional control.

BACKGROUND: The prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence. METHODS: We retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3-4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato. RESULTS: Eight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100 and 56.6% in patients with favorable and unfavorable pathological responses, respectively. CONCLUSIONS: The present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Recurrence-free survival and prognosis after adjuvant therapy with radioactive iodine-131 in patients with differentiated thyroid carcinoma.

This study aimed to assess recurrence-free survival (RFS) rates and recurrence-related factors of patients who received adjuvant therapy (AT) with radioactive iodine (RAI) for differentiated thyroid cancer (DTC) following thyroidectomy. We evaluated 284 patients who underwent AT between January 2011 and July 2020 at our hospital. Recurrence was defined as visible recurrent lesions on image analysis or need for repeat surgery with pathologically confirmed recurrent lesions. RFS rate and prognostic factors were statistically evaluated. The median observation period was 30.2 months (range, 5.7-294 months). Overall, 192 patients were female and 92 were male, and the median age was 54 years (range, 9-85 years). Initial assessment revealed 39 recurrence cases. The 3-year RFS rate was 85.8% (95% confidence interval: 81.1-90.9%). Univariate analysis revealed that histology (except for papillary carcinoma), Tg level > 4 ng/dL before AT, and AT result significantly exacerbated the RFS rate. In multivariate analysis, histology and AT result were also important contributors to the worsening RFS rate. Results of AT can be determined relatively early and are important in predicting future recurrence in patients with DTC. Increasing the success rate of AT may lead to an improved prognosis.

Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer.

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.

Comparison between planar and single-photon computed tomography images for radiation intensity quantification in iodine-131 scintigraphy.

This study aimed to evaluate the feasibility of quantifying iodine-131 (131I) accumulation in scintigraphy images and compare planar and single-photon emission computed tomography (SPECT) images to estimate 131I radioactivity in patients receiving radioactive iodine therapy for thyroid cancer. We evaluated 72 sets of planar and SPECT images acquired between February 2017 and December 2018. Simultaneously, we placed a reference 131I capsule next to the patient during image acquisition. We evaluated the correlation between the intensity of the capsule in the images and the capsule dose and estimated the radiation dose at the thyroid bed. The mean capsule dose was 2.14 MBq (range, 0.63-4.31 MBq). The correlation coefficients (p-value) between capsule dose and maximum and mean intensities in both planar and SPECT images were 0.93 (p < 0.01), 0.96 (p < 0.01), 0.60 (p < 0.01), and 0.47 (p < 0.01), respectively. The mean intensities of planar images show the highest correlation coefficients. Based on a regression equation, the average radiation dose in the thyroid bed was 5.9 MBq. In conclusion, planar images reflected the radiation dose more accurately than SPECT images. The regression equation allows to determine the dose in other regions, such as the thyroid bed or sites of distant metastasis.

Interfractional target changes in brain metastases during 13-fraction stereotactic radiotherapy.

BACKGROUND: The risk for radiation necrosis is lower in fractionated stereotactic radiotherapy (SRT) than in conventional radiotherapy, and 13-fraction SRT is our method of choice for the treatment of brain metastases ≥ around 2 cm or patients who are expected to have a good prognosis. As 13-fraction SRT lasts for at least 17 days, adaptive radiotherapy based on contrast-enhanced mid-treatment magnetic resonance imaging (MRI) is often necessary for patients undergoing 13-fraction SRT. In this study, we retrospectively analyzed interfractional target changes in patients with brain metastases treated with 13-fraction SRT. METHODS: Our analyses included data from 23 patients and 27 metastatic brain lesions treated with 13-fraction SRT with dynamic conformal arc therapy. The peripheral dose prescribed to the planning target volume (PTV) was 39-44.2 Gy in 13-fractions. The gross tumor volume (GTV) of the initial SRT plan (initial GTV), initial PTV, and modified GTV based on the mid-treatment MRI scan (mid-treatment GTV) were assessed. RESULTS: The median initial GTV was 3.8 cm3 and the median time from SRT initiation to the mid-treatment MRI scan was 6 days. Compared to the initial GTV, the mid-treatment GTV increased by more than 20% in five lesions and decreased by more than 20% in five lesions. Interfractional GTV volume changes of more than 20% were not significantly associated with primary disease or the presence of cystic components/necrosis. The mid-treatment GTV did not overlap perfectly with the initial PTV in more than half of the lesions. CONCLUSIONS: Compared to the initial GTV, the mid-treatment GTV changed by more than 20% in almost one-third of lesions treated with 13-fraction SRT. As SRT usually generates a steep dose gradient as well as increasing the maximum dose of PTV compared to conventional radiotherapy, assessment of the volume and locational target changes and adaptive radiotherapy should be considered as the number of fractions increases.

Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.

INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors. MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP. RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007). CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.

Comparison of thyroid hormone withdrawal and recombinant human thyroid-stimulating hormone administration for adjuvant therapy in patients with intermediate- to high-risk differentiated thyroid cancer.

OBJECTIVE: To compare the clinical outcome in patients who received adjuvant therapy with radioactive iodine (RAI) using different preparation methods, namely, thyroid hormone withdrawal (THW) and recombinant human thyroid-stimulating hormone (rhTSH), after undergoing thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma (DTC) according to the American Thyroid Association criteria. METHODS: Between May 2012 and October 2018, 136 patients who underwent adjuvant therapy with high-dose (3700 MBq) RAI for DTC without any metastatic lesions or macroscopic residual lesions after surgical resection were retrospectively selected. Patients were excluded if distant metastasis was confirmed during adjuvant therapy or if the outcome could not be confirmed; thus, 112 patients were finally evaluated. Patients underwent either a 3-week I restriction with thyroxine withdrawal or a 2-week I restriction with rhTSH administration. The serum thyroglobulin (Tg) concentration was measured, and 131I scintigraphy (370 MBq) was performed 6-12 months after adjuvant therapy. The definition of the initial achievement of adjuvant therapy was the disappearance of the uptake of 131I at the thyroid bed and serum Tg concentration < 2.0 ng/mL. The results of the adjuvant therapy between the groups were compared using the Fisher's exact test, and the TSH levels and estimated glomerular filtration rate (eGFR) were compared using the Welch's t test. RESULTS: The THW and rhTSH groups included 47 and 65 patients, respectively, and the intermediate- and high-risk groups included 63 and 49 patients, respectively. No patient was assigned to the low-risk group. In the THW and rhTSH groups, the initial RAI adjuvant therapy goal was achieved in 30/47 (63.8%) and 46/65 patients (70.8%), respectively (p = 0.54); mean ± standard deviation of the TSH levels was 123.8 ± 46.4 µIU/mL and 274.5 ± 97.7 µIU/mL, respectively (p < 0.01), and eGFR (treatment/pre-treatment) was 0.81 and 0.99, respectively (p < 0.01). In the intermediate- and high-risk groups, the initial RAI adjuvant therapy goal was achieved in 43/63 patients (68.3%) and 33/49 (67.3%), respectively (p = 1.0). CONCLUSION: No significant differences were observed between the preparation methods in the initial achievement of RAI adjuvant therapy. However, patients in the rhTSH group demonstrated higher TSH levels and retained eGFR.

Comparison between the different doses of radioactive iodine ablation prescribed in patients with intermediate-to-high-risk differentiated thyroid cancer.

OBJECTIVE: This study aimed to compare the clinical outcomes of patients who received radioactive iodine (RAI) ablation after undergoing thyroidectomy for intermediate-to-high-risk differentiated thyroid carcinoma (DTC) according to the American Thyroid Association (ATA) criteria. METHODS: We retrospectively examined patients who underwent RAI ablation for DTC after surgical resection without macroscopic residual lesions or metastatic lesions between December 2011 and August 2016. Among 147 patients who underwent RAI ablation, those whose initial pathological stages or RAI ablation results were unknown and whose distant metastases were confirmed during RAI ablation were excluded. Low-dose therapy was defined as administration of 1110 MBq of 131iodine (131I), while high-dose therapy referred to administration of 2960-3700 MBq of 131I. We defined initial success of RAI ablation as a serum thyroglobulin concentration of < 2.0 ng/mL without thyroid-stimulating hormone stimulation and disappearance of 131I uptake in the thyroid bed on 131I scintigraphy 6-12 months after RAI ablation. RAI ablation success rates were compared between the low-dose and high-dose groups using Fisher's exact test, and inverse probability of treatment weighting (IPTW) analysis was performed for adjusting potential biases. RESULTS: Among the 119 patients examined in this study (39 men and 80 women), 79 were classified as having intermediate risk, while 40 were classified as having high risk based on the ATA guideline. Initial RAI ablation success was achieved in 50/68 (73.5%) patients from the low-dose group and in 36/51 patients (70.6%) from the high-dose group (p = 0.84). Moreover, IPTW analysis showed no significant difference between the low-dose and high-dose groups. However, the success rate tended to be superior in high-risk patients who received high-dose therapy (86.2%) than in those who received low-dose therapy (72.7%) (p = 0.37). CONCLUSION: There was no significant difference in the RAI ablation success rate between the low-dose and high-dose groups involving patients with intermediate-to-high-risk DTC. However, high-dose RAI ablation may be recommended in high-risk patients.

Single-isocenter volumetric-modulated Dynamic WaveArc therapy for two brain metastases.

PURPOSE: A new irradiation technique, volumetric-modulated Dynamic WaveArc therapy (VMDWAT), based on sequential non-coplanar trajectories, can be performed using the Vero4DRT. This planning study compared the dose distribution and treatment time between single-isocenter volumetric-modulated arc therapy (VMAT) with multiple straight non-coplanar arcs and single-isocenter VMDWAT in patients with two brain metastases. MATERIALS AND METHODS: Twenty patients with two planning target volumes exceeding 2.0 cm3 were included. Both VMAT and VMDWAT plans were created with single isocenter and a prescribed dose of 28 Gy delivered in five fractions. Target conformity was evaluated using indices modified from the RTOG-CI (mRTOG-CI) and IP-CI (mIP-CI). RESULTS: VMDWAT significantly improved both mRTOG-CI and mIP-CI and reduced the volume of normal brain tissue receiving 25 and 28 Gy compared to VMAT. The two modalities did not significantly differ in terms of the volume of normal brain tissue receiving 5, 10, 12, 15, and 20 Gy. The mean treatment time was significantly shorter in the VMDWAT group. CONCLUSION: VMDWAT significantly improved dose distribution in a shorter treatment time compared to VMAT in patients treated for two brain metastases. Single-isocenter VMDWAT may thus be a promising treatment for two brain metastases.

HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog.

Hypoxic and stroma-rich microenvironments, characteristic features of pancreatic cancers, are strongly associated with a poor prognosis. However, whether and how hypoxia increases stromal compartments remain largely unknown. Here, we investigated the potential importance of a master regulator of the cellular adaptive response to hypoxia, hypoxia-inducible factor-1 (HIF-1), in the formation of stroma-rich microenvironments of pancreatic tumors. We found that pancreatic cancer cells secreted more Sonic hedgehog protein (SHH) under hypoxia by upregulating its expression and efficiency of secretion in a HIF-1-dependent manner. Recombinant SHH, which was confirmed to activate the hedgehog signaling pathway, accelerated the growth of fibroblasts in a dose-dependent manner. The SHH protein secreted from pancreatic cancer cells under hypoxic conditions promoted the growth of fibroblasts by stimulating their Sonic hedgehog signaling pathway. These results suggest that the increased secretion of SHH by HIF-1 is potentially responsible for the formation of detrimental and stroma-rich microenvironments in pancreatic cancers, therefore providing a rational basis to target it in cancer therapy.

Dosimetric comparison between dual-isocentric dynamic conformal arc therapy and mono-isocentric volumetric-modulated arc therapy for two large brain metastases.

Mono-isocentric volumetric-modulated arc therapy (VMAT) can be used to treat multiple brain metastases. It remains unknown whether mono-isocentric VMAT can improve the dose distribution compared with dual-isocentric dynamic conformal arc therapy (DCAT), especially for two brain metastases. We compared the dose distribution between dual-isocentric DCAT and mono-isocentric VMAT for two large brain metastases, and analyzed the relationship between the distance between the two targets and the difference in dose distribution. A total of 19 patients, each with two large brain metastases, were enrolled. The dose prescribed for each planning target volume (PTV) was 28 Gy in five fractions (D99.8 = 100%). We created new indices derived from conformity indices suggested by the Radiation Therapy Oncology Group (RTOG; mRTOG-CI) and Paddick et al. (mIP-CI), using the dosimetric parameters of the sum of the two PTVs. The median PTV was 5.05 cm3 (range, 2.10-28.47). VMAT significantly improved mRTOG-CI and mIP-CI compared with DCAT. In all cases, VMAT was able to improve mRTOG-CI and mIP-CI compared with DCAT. Whereas the normal brain volume receiving 5 Gy was similar between the two modalities, the normal brain receiving 10, 12, 15, 20, 25 and 28 Gy (V10-V28) was significantly smaller in VMAT. The mean beam-on times were 213.3 s and 121.9 s in DCAT and VMAT, respectively (P < 0.001). Mono-isocentric VMAT improved the target conformity and reduced the beam-on time and V10-V28 of the normal brain for not only two close metastases but also two distant metastases. Mono-isocentric VMAT seems to be a promising treatment technique for two large brain metastases.