Large volume was associated with increased risk of acute non-hematologic adverse events in the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer: preliminary results of prospective phase I/II clinical trial.

OBJECTIVE: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer. METHODS: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%. RESULTS: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036). CONCLUSION: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial.

Stereotactic body radiation therapy for Japanese patients with localized prostate cancer: 2-year results and predictive factors for acute genitourinary toxicities.

OBJECTIVE: We aimed to report the 2-year results of stereotactic body radiation therapy for prostate cancer and identify the clinical and dosimetric factors that predict acute genitourinary toxicities. METHODS: We retrospectively reviewed the medical records of patients with non-metastatic prostate cancer treated at Toyota Memorial Hospital between 2017 and 2020. The patients were treated with stereotactic body radiation therapy with a total dose of 36.25 Gy in five fractions on consecutive weekdays. While low-risk patients received radiotherapy alone, intermediate- to high-risk patients also received androgen deprivation therapy. RESULTS: We analysed a total of 104 patients, including 10, 60 and 34 low-, intermediate- and high-risk patients, respectively. The median follow-up duration was 2 years. We did not observe biochemical/clinical recurrence, distant metastasis or death from prostate cancer. One patient died of another cause. Grade 2 acute genitourinary toxicity was observed in 40 (38%) patients. Age (P = 0.021), genitourinary toxicity of grade ≥1 at baseline (P = 0.023) and bladder mean dose (P = 0.047) were significantly associated with the incidence of grade 2 acute genitourinary toxicity. The cut-off value of 65 years for age and 10.3 Gy for the bladder mean dose were considered the most appropriate. Grade 2 acute gastrointestinal toxicity was observed in five (5%) patients. None of the patients experienced grade ≥3 acute or late toxicity. CONCLUSIONS: Stereotactic body radiation therapy is feasible for Japanese patients with prostate cancer, with acceptable acute toxicity. Age, genitourinary toxicity at baseline and bladder mean dose predict grade 2 acute genitourinary toxicity.

Role of high-dose salvage radiotherapy for oligometastases of the localised abdominal/pelvic lymph nodes: a retrospective study.

BACKGROUND: Abdominal/pelvic lymph node (LN) oligometastasis, a pattern of treatment failure, is observed occasionally, and radiotherapy may work as salvage therapy. The optimal prescription dose, however, is yet to be determined. This study assessed the efficacy of high-dose radiotherapy. METHODS: The medical records of 113 patients at 4 institutes were retrospectively analysed who had 1 to 5 abdominal/pelvic LN oligometastases and were treated with definitive radiotherapy between 2008 and 2018. The exclusion criteria included non-epithelial tumours, uncontrolled primary lesions, palliative intent, and re-irradiation. The prescription dose was evaluated by using the equivalent dose in 2 Gy fractions (EQD2). Patients receiving EQD2 ≥ 60 Gy were placed into the high-dose group, and the remaining others the low-dose group. Kaplan-Meier analyses were performed to evaluate overall survival (OS), local control (LC), and progression-free survival (PFS). Univariate log-rank and multivariate Cox proportional hazards model analyses were performed to explore predictive factors. Adverse events were compared between the high-dose and low-dose groups. RESULTS: The primary tumour sites included the colorectum (n = 28), uterine cervix (n = 27), endometrium (n = 15), and ovaries (n = 10). The rate of 2-year OS was 63.1%, that of LC 59.7%, and that of PFS 19.4%. On multivariate analyses, OS were significantly associated with solitary oligometastasis (hazard ratio [HR]: 0.48, p = 0.02), LC with high-dose radiotherapy (HR: 0.93, p < 0.001), and PFS with long disease-free interval (HR: 0.59, p = 0.01). Whereas high-dose radiotherapy did not significantly improve 2-year OS in the entire cohort (74.8% in the high-dose vs. 52.7% in the low-dose; p = 0.08), it did in the subgroup of solitary oligometastasis (88.8% in the high-dose vs. 56.3% in the low-dose; p = 0.009). As for Late grade ≥ 3 adverse event, ileus was observed in 7 patients (6%) and gastrointestinal bleeding in 4 (4%). No significant association between the irradiation dose and adverse event incidence was found. CONCLUSIONS: As salvage therapy, high-dose radiotherapy was recommendable for oligometastasis in the abdominal/pelvic LNs. For solitary oligometastasis, LC and OS were significantly better in the high-dose group.

Clinical usefulness of MLCs in robotic radiosurgery systems for prostate SBRT.

Stereotactic body radiation therapy (SBRT) using recently introduced multileaf collimators (MLC) is preferred over circular collimators in the treatment of localized prostate cancer. The objective of this study was to assess the clinical usefulness of MLCs in prostate SBRT by comparing the effectiveness of treatment plans using fixed collimators, variable collimators, and MLCs and by ensuring delivery quality assurance (DQA) for each. For each patient who underwent conventional radiation therapy for localized prostate cancer, mock SBRT plans were created using a fixed collimator, a variable collimator, and an MLC. The total MUs, treatment times, and dose-volume histograms of the planning target volumes and organs at risk for each treatment plan were compared. For DQA, a phantom with a radiochromic film or an ionization chamber was irradiated in each plan. We performed gamma-index analysis to evaluate the consistency between the measured and calculated doses. The MLC-based plans had an ~27% lower average total MU than the plans involving other collimators. Moreover, the average estimated treatment time for the MLC plan was 31% and 20% shorter than that for the fixed and variable collimator plans respectively. The gamma-index passing rate in the DQA using film measurements was slightly lower for the MLC than for the other collimators. The DQA results acquired using the ionization chamber showed that the discrepancies between the measured and calculated doses were within 3% in all cases. The results reinforce the usefulness of MLCs in robotic radiosurgery for prostrate SBRT treatment planning; most notably, the total MU and treatment time were both reduced compared to the cases using other types of collimators. Moreover, although the DQA results based on film dosimetry yielded a slightly lower gamma-index passing rate for the MLC than for the other collimators, the MLC accuracy was determined to be sufficient for clinical use.

Retrospective case series of 15 patients treated with chemoradiation using 5-FU and nedaplatin for gynecological malignancy: with regard to hemotoxicity.

We conducted a retrospective comparison of the hemotoxicity of the sequential administration of 5-Fluorouracil (5-FU) prior to Nedaplatin (NDP) (FN therapy) and that of its reverse sequence (NF therapy) for gynecological malignancy. From February 2002 to November 2004, a total of 15 gynecological malignancy patients were treated with radiation therapy combined with NDP and 5-FU. Of these 15 patients, 5 were treated with NF therapy, and 10 were treated with FN therapy. No significant differences were detected between the FN and NF groups with regard to white blood cell count (WBC), hemoglobin level (Hb), and platelet count. The results of this study do not show that the FN group has a lesser degree of hemotoxicity than the NF group.

Solid tumours showing oligoprogression to immune checkpoint inhibitors have the potential for abscopal effects.

PURPOSE: Given the uncertainty surrounding the abscopal effect (AE), it is imperative to identify promising treatment targets. In this study, we aimed to explore the incidence of AE when administering radiotherapy to patients with oligoprogressive solid tumours while they are undergoing treatment with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: In this multicentre prospective observational study, oligoprogressive disease was defined as a < 20% increase in lesions compared to > 2 months before enrolment. We enrolled patients who requested radiotherapy during the ICI rest period between 2020 and 2023. AE was considered present if ≥ 1 non-irradiated lesion decreased by ≥ 30% before the next line of systemic therapy started. RESULTS: Twelve patients were included in this study; the common primary lesions were in the lungs (four patients) and kidneys (three patients). AEs were observed in six (50%) patients, with a median time to onset of 4 (range 2-9) months after radiotherapy. No significant predictors of AEs were identified. Patients in the AE group had a significantly better 1-year progression-free survival (PFS) rate than those in the non-AE group (p = 0.008). Two patients from the AE group were untreated and progression-free at the last follow-up. Four (33%) patients experienced grade 2 toxicity, with two cases attributed to radiotherapy and the other two to ICI treatment. No grade 3 or higher toxicities were observed in any category. CONCLUSION: Patients with oligoprogressive disease may be promising targets with potential for AEs. AEs can lead to improved PFS and, in rare cases, to a certain progression-free period without treatment. Irradiating solid tumours in patients with oligoprogressive disease during immune checkpoint inhibitor therapy may be a promising target with the potential for abscopal effects (AEs). AEs can lead to improved progression-free survival and, in rare cases, to a certain progression-free period without treatment.

Stereotactic body radiation therapy for prostate cancer: a study comparing 3-year genitourinary toxicity between CyberKnife and volumetric-modulated arc therapy by propensity score analysis.

BACKGROUND: To investigate whether the rate of stereotactic body radiation therapy-related (SBRT-related) genitourinary (GU) toxicity is lower in patients with prostate cancer treated with CyberKnife. METHODS: We retrospectively reviewed the medical records of patients with nonmetastatic prostate cancer at two institutions between 2017 and 2020. We analyzed 70 patients who were extracted by propensity score matching based on age, pre-treatment International Prostate Symptom Score (IPSS), and prostate volume. The patients were treated with SBRT, with a total dose of 36.25 Gy in five fractions over five consecutive weekdays, using CyberKnife or volumetric-modulated arc therapy (VMAT). RESULTS: The low-, medium-, and high-risk patients were 2, 19, and 14, respectively, in the CyberKnife group and 4, 17, and 14, respectively, in the VMAT group. The median follow-up time in both groups was 3 years. One patient with CyberKnife died of unrelated causes. No biochemical or clinical recurrence, distant metastases, or death from prostate cancer was observed. The peak values of IPSS in the acute phase (< 3 months) were significantly lower in the CyberKnife than in the VMAT group (CyberKnife:16.2 vs VMAT:20.2, p = 0.025). In multiple regression analyses, the treatment modality (p = 0.03), age (p = 0.01), bladder medication pre-irradiation (p = 0.03), and neoadjuvant androgen deprivation therapy (p = 0.04) contributed to the peak value of the acute-phase IPSS. The incidence of treatment-related grade 2 acute GU toxicity tended to be lower in the CyberKnife than the VMAT group (CyberKnife: 22.9% vs. VMAT: 45.7%, p = 0.077). No difference was noted between the groups with regard to late IPSS or GU toxicity and gastrointestinal toxicity in all phases. Toxicities of grade ≥ 3 have not been observed to date. CONCLUSIONS: Regardless of treatment modality, SBRT is effective in treating prostate cancer without serious toxicity. However, CyberKnife has an advantage over VMAT in terms of acute prostate symptoms.

Treatment planning comparison of high-dose-rate brachytherapy vs. robotic and conventional stereotactic body radiotherapy for ultrahypofractionated treatment of prostate cancer.

Background and purpose: Ultrahypofractionated radiation therapy is increasingly used in the treatment of prostate cancer. High-dose-rate brachytherapy (HDR-BT) and stereotactic body radiotherapy (SBRT) are representative methods of ultrahypofractionation. This study was performed to compare clinically applied treatment plans for patients who had been treated using HDR-BT vs. conventional or robotic SBRT. Materials and methods: Calculated dose-volume indices between HDR-BT without a perirectal spacer (n = 20), robotic SBRT without a spacer (n = 40), and conventional (non-robotic) SBRT with a spacer (n = 40) were compared. Percentages against the prescription dose regarding the planning target volume (PTV), bladder, rectum, and urethra were statistically compared. Results: The D50% of the PTV with HDR-BT (140.5% ± 4.9%) was significantly higher than that with robotic or conventional SBRT (116.2% ± 1.6%, 101.0% ± 0.4%, p < 0.01). The D2cm3 of the bladder with HDR-BT (65.6% ± 6.4%) was significantly lower than those with SBRT (105.3% ± 2.9%, 98.0% ± 1.3%, p < 0.01). The D2cm3 of the rectum with HDR-BT (60.6% ± 6.2%) was also significantly lower than those with SBRT (85.1% ± 8.8%, 70.4% ± 9.6%, p < 0.01). By contrast, the D0.1cm3 of the urethra with HDR-BT (117.1% ± 3.6%) was significantly higher than those with SBRT (100.2% ± 0.7%, 104.5% ± 0.6%, p < 0.01). Conclusions: HDR-BT could administer a higher dose to the PTV and a lower dose to the bladder and rectum, at the cost of a slightly higher dose to the urethra compared with SBRT.

Phase I/II prospective clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer.

OBJECTIVE: The purposes of this trial were to demonstrate the feasibility and effectiveness of the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients in the phase I/II prospective clinical trial. METHODS: Patients with FIGO stage IB2-IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by magnetic resonance imaging were eligible for this clinical trial. The protocol therapy included 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of HBT and pelvic radiotherapy with a central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase II part was 2-year pelvic progression-free survival (PPFS) rate higher than historical control of 64%. RESULTS: Between October 2015 and October 2019, 73 patients were enrolled in the initial registration and 52 patients proceeded to the secondary registration. With the median follow-up period of 37.3 months (range, 13.9-52.9 months), the 2- PPFS was 80.7% (90% confidence interval [CI]=69.7%-88%). Because the lower range of 90% CI of 2-year PPFS was 69.7%, which was higher than the historical control ICBT data of 64%, therefore, the primary endpoint of this study was met. CONCLUSION: The effectiveness of HBT were demonstrated by a prospective clinical study. Because the dose goal determined in the protocol was lower than 85 Gy, there is room in improvement for local control. A higher dose might have been needed for tumors with poor responses.

Comparison of Physician-recorded Toxicities and Patient-reported Outcomes of Five Different Radiotherapy Methods for Prostate Cancer.

BACKGROUND/AIM: To compare five radiotherapy methods for prostate cancer. PATIENTS AND METHODS: During 2005-2018, the data of patients with non-metastatic prostate cancer were retrospectively analysed. Patients were treated with high-dose-rate brachytherapy (HDR-BT); low-dose-rate brachytherapy (LDR-BT); or external-beam radiotherapy (EBRT), including conventionally fractionated radiotherapy (CFRT), moderate-hypofractionated radiotherapy (MHRT), and ultra-hypofractionated radiotherapy (UHRT). RESULTS: In total, 496 patients (149, HDR-BT; 100, LDR-BT; 100, CFRT; 97, MHRT, and 50, UHRT) with a median follow-up of 4.3 years were enrolled. The incidence of grade ≥2 acute genitourinary toxicities was significantly lower with HDR-BT (p<0.001) than with any other radiotherapy. The cumulative incidence of late grade ≥2 genitourinary toxicities was the highest with UHRT and significantly higher (p=0.005) with UHRT than with HDR-BT. Higher symptom score peaks were noted 4 weeks after therapy for LDR-BT than for EBRT. CONCLUSION: Physician-recorded toxicities were slightly lower with HDR-BT and patient-reported outcomes tended to be worse with LDR-BT.

Inter-individual Comparison of Gadobutrol and Gadoteridol Tissue Time-intensity Profiles for Dynamic Susceptibility Contrast Perfusion MR Imaging.

PURPOSE: Gadobutrol is a gadolinium-based contrast material (GBCM) with a high concentration of gadolinium and high relaxivity. Our purpose was to evaluate the signal intensity profiles in brain tissue for the bolus width and degree of signal change after bolus injection using an echo planar dynamic susceptibility contrast (DSC) sequence. We compared gadobutrol to gadoteridol using various injection speeds and saline flush volumes. METHODS: We studied 97 patients who underwent brain MRI. Datasets for perfusion studies were acquired using a 3T scanner with an echo planar imaging (EPI) sequence. The injection protocols were set up with combinations of injection speed and saline flush volume for both gadobutrol and gadoteridol. The full width at half maximum (FWHM) and the maximum signal change ratio (SCRmax) of the time intensity curves were measured. RESULTS: The FWHM did not show a statistically significant difference according to injection speed, flush volume, or type of GBCM. The SCRmax showed a greater change with a faster injection speed, larger saline flush, and gadobutrol administration. The difference between gadobutrol and gadoteridol became smaller with a faster injection speed and a larger saline flush. CONCLUSION: The maximum signal drop was larger with gadobutrol when the injection speed was slow and the saline flush was small. Thus, gadobutrol may be useful to obtain a better profile for DSC perfusion MRI in conditions requiring a slower injection speed and/or a smaller volume of saline flush.

[Chemoradiation using 5-fluorouracil (5-FU) and nedaplatin (NDP) for gynecological malignancy--the relation between hemotoxicity and sequence of 5-FU and NDP].

We compared sequence-dependent schedules of 5-fluorouracil (5-FU) and nedaplatin (NDP) for hemotoxicity in genecological malignancy (GM). The safety of schedules using 5-FU before/after NDP combined radiotherapy in 8 patients with GM was evaluated. They received either 5-FU 700 mg/m2 i.v. continuous infusion on days (D) 1-4 + NDP 100 mg/m2 i.v. bolus on D1 (group A: 5 pts), or NDP on D4, 5-FU on D1-4 (group B: pts). In group A, 4 patients received a reduced dose of NDP because of less than 60 ml/min of creatinine clearance. In group A, WBC (2 pts), hemoglobin (3 pts), and platelet (1 pts) were grade 3 or higher. In group B, grade 3 or higher in hemotoxicity was not seen. A higher percentage of hemotoxicity was seen in group A compared with group B.

Intraarterial cisplatin/nedaplatin and intravenous 5-fluorouracil with concurrent radiation therapy for patients with high-risk uterine cervical cancer.

OBJECTIVE: The purpose of this study was to determine the effectiveness of the combination of intraarterial and intravenous concurrent chemoradiation therapy (CIAIV-CCRT) for the treatment of high-risk uterine cervical cancer. METHODS: Between January 2000 and November 2004, we reviewed 45 cervical cancer patients treated by CIAIV-CCRT. The numbers of patients with stage IB2, IIA, IIB, IIIA, IIIB, and IVA were 3, 6, 14, 1, 17, and 4, respectively. Patients with stage III and IVA or patients with tumors >3 cm in diameter were enrolled in this study. Two sessions of CCRT were administered every 3 weeks using a combination of 70 mg/m2 x h(-1) cisplatin or 50 mg/m2 x h(-1) nedaplatin via the bilateral uterine artery and 2800 mg/m2 x 96 h(-1) 5-fluorouracil intravenously. Patients concurrently received external beam radiation therapy and brachytherapy. A nonrandomized control group of 47 patients who underwent radiation therapy alone between 1993 and 2000 was used for comparison. RESULTS: Of the 45 patients, 28 (62%) exhibited complete response and 16 (36%) exhibited partial response. One IIIB patient (2%) did not show any response. The 5-year overall survival (OAS) rates in the CCRT group and control group were 80.6% and 54.9%, respectively. With regard to late toxicities, no statistically significant differences were observed between the two groups. In uni- and multivariate analyses, positive pelvic lymph node showed a statistically significant influence on the OAS in the CIAIV-CCRT group (P = 0.049). CONCLUSION: These preliminary results suggest that CIAIV-CCRT can improve the prognosis of patients with high-risk cervical cancer.

Long-term result of high dose-rate afterloading brachytherapy in squamous cell carcinoma of the cervix: relationship between facility structure and outcome.

OBJECTIVE: To compare outcome results for squamous cell carcinoma of the uterine cervix between patients treated in a single facility [single facility therapy: (SFT)] and others combined with external beam irradiation (EBRT) in a small facility and intracavitary brachytherapy in a central facility (combined facilities therapy: CFT). METHODS: This is a retrospective analysis of 155 patients with histologically proven squamous cell carcinoma of the cervix radically treated by EBRT and high dose-rate (HDR) intracavitary brachytherapy from August 1995 to May 2000. The overall survival and cause-specific survival rates were calculated by using the Kaplan-Meier method. The endpoint was defined as death due to cervical cancer for the cause-specific survival. The log-rank test and the generalized Wilcoxon test were used to compare the survival curves between the two treatment groups. RESULTS: Nine patients were lost, so 146 patients were retrospectively analyzed. There were 22 patients (15%) in stage I, 21 (14%) stage IIA, 51 (35%) stage IIB, 41 (28%) stage III, 11 (8%) stage IVA. The median age was 72 years (range, 30-89 years). The median follow-up time was 58 months. The proportion of patients treated with SFT was 23% (33/146) and CFT 77% (113/146). The overall survival rate was 62.3% and the cause-specific survival rate was 71.3%. The cause-specific survival rates for SFT and CFT were 87.9% and 66.4%, respectively; the difference between these two treatments was statistically significant (P = 0.024). The difference in the survival rate between these two treatments for stage III and IVA patients was also statistically significant (P = 0.021). However, no significant difference between these treatments was seen in the cause-specific survival rate for each stage. There was a significant difference between SFT and CFT in the incidence rate of severe late complications (grade 3-5) (P = 0.038). There was no significant difference in overall treatment times and total dose between the two groups; the applied photon beam energy showed a significant difference. CONCLUSION: Our results suggest that the survival outcome will be aggravated by CFT. If the treatment process of using a lower photon beam energy were to be improved by the installation of a high-energy linear accelerator, CFT can be applied to patients with cervical cancer.