Dose-intensified stereotactic body radiotherapy for painful vertebral metastases: A randomized phase 3 trial.

BACKGROUND: The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment. METHODS: This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis. RESULTS: Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p = .02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups. CONCLUSIONS: Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months.

Utility of molecular markers in predicting local control specific to lung cancer spine metastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: We report outcomes following spine stereotactic body radiotherapy (SBRT) in metastatic non-small cell lung cancer (NSCLC) and the significance of programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR) mutation and timing of immune check point inhibitors (ICI) on local failure (LF). MATERIALS AND METHODS: 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary, overall survival (OS) and vertebral compression fracture (VCF). Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. RESULTS: The median follow-up and OS were: 13.0 months (range, 0.5-95.3 months) and 18.4 months (95% CI 11.4-24.6). 52.1% were male and 76.4% had adenocarcinoma. Of the 389 segments, 30.3% harboured an EGFR mutation and 17.0% were PD-L1 ≥ 50%. The 24 months LF rate in PD-L1 ≥ 50% vs PD-L1 < 50% was 10.7% vs. 38.0%, and in EGFR-positive vs. negative was 18.1% vs. 30.0%. On MVA, PD-L1 status of ≥ 50% (HR 0.32, 95% CI 0.15-0.69, p = 0.004) significantly predicted for lower LF compared to PD-L1 < 50%. Lower LF trend was seen with ICI administration peri and post SBRT (HR 0.41, 95% CI 0.16-1.05, p = 0.062). On MVA, polymetastatic disease (HR 3.28, 95% CI 1.84-5.85, p < 0.0001) and ECOG ≥ 2 (HR 1.87, 95% CI 1.16-3.02, p = 0.011) significantly predicted for worse OS and absence of baseline VCF predicted for lower VCF rate (HR 0.20, 95% CI 0.10-0.39, p < 0.0001). CONCLUSION: We report a significant association of PD-L1 ≥ 50% status on improved LC rates from spine SBRT in NSCLC patients.

Stereotactic Body Radiotherapy: is less fractionation more effective in adrenal and renal malignant lesions?

PURPOSE: Stereotactic body radiotherapy (SBRT) has become an excellent non-invasive alternative for many patients with primary renal cell carcinoma (RCC) and adrenal malignancies (AM). The aims of this study were to analyse how tumor-, patient- and treatment-related factors may influence the outcomes and side effects of SBRT and to assess its benefits as an alternative to surgery. METHODS: This retrospective, multicenter study included 25 lesions in 23 patients treated with SBRT using different devices (LINAC, CyberKnife® and Tomotherapy®). A multivariate linear regression was used for the statistical study. RESULTS: Local control time was higher than six months in more than 87% of patients and treatment response was complete for 73.68%. There was an overall 2-year survival of 40% and none of the deaths were secondary to renal or adrenal local progression. Patients treated with lower total radiation dose (mean [m] = 55 Gy) but less fractions with more dose per fraction (> 8.5 Gy) showed better outcome. Patients with previous chemotherapy and surgery treatments also showed higher complete response and disease-free survival (> 6 months). CONCLUSIONS: This study highlights the importance of ultra-hypofractionated regimens with higher doses per session. Thus, the referral of patients with RCC and AM to Radiotherapy and Oncology departments should be encouraged supporting the role of SBRT as a minimally invasive and outpatient treatment.

Two-institution results of Stereotactic Body Radiation Therapy (SBRT) for treating adrenal gland metastases from liver cancer.

OBJECTIVE: Stereotactic Body Radiation Therapy (SBRT) has been found beneficial for adrenal gland metastases (AGMs) with a high local control rate and low toxicity. The role of SBRT for AGMs in patients with liver cancer has not been well-discussed before. We, therefore, report our two-institution experience to further elaborate on the feasibility and effectiveness of SBRT in the treatment of AGMs from liver cancer. METHODS: A total of 23 liver cancer patients (19 males, 4 females) with 24 AGMs treated by SBRT from July 2006 to April 2021 were retrospectively included in this study. Toxicity was assessed based on clinical adverse events using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The effectiveness was assessed based on local control (LC), progression-free survival (PFS), and overall survival (OS), which were calculated using the Kaplan-Meier method. Univariate analyses were compared by log-rank test. The relevant covariates were evaluated using Cox proportional hazards models. RESULTS: The median dose was 40 Gy in 5 fractions, with the corresponding median biological effective dose (BED10, α/ß = 10 Gy) of 72 Gy. The median overall follow-up time was 15.4 months (range: 4.2-70.6 months). The complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) rates were 25.0%, 20.8%, 33.3%, and 20.8%, respectively. All 6 patients with AGMs accompanying symptoms had varying degrees of alleviation after SBRT. The 0.5-, 1-year and 2-year LC rates were 87.5%, 77.8%, and 77.8%, respectively. The 0.5-, 1-year and 2-year OS rates were 95.5%, 66.8%, and 41.1%, respectively. The treatments were all tolerated with only one patient reporting a grade-3 hepatic injury. The univariate analysis concluded that only gross tumor volume (GTV) < 34.5 ml (p = 0.039) was associated with a favorable LC rate. After multivariate analysis, favorable predictors correlated with OS were GTV < 34.5 ml (p = 0.043), systemic therapy (p = 0.017), and without additional organ metastasis after SBRT (p = 0.009). CONCLUSION: Our results suggest that SBRT is a safe and effective technique to treat AGM from liver cancer, especially for small GTV (< 34.5ml). Moreover, the small metastatic lesion volume, fewer metastatic lesions, and intervention of systemic therapy are more likely to improve OS.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT).

BACKGROUND: Ultra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT-utilizing potentially fewer treatments-is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment. METHODS/DESIGN: A total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10-14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7-10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score. DISCUSSION: FORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04984343 . Date of registration: July 30, 2021. PROTOCOL VERSION: 4.0, Nov 8, 2022.

Post radiation mucosal ulcer risk after a hypofractionated stereotactic boost and conventional fractionated radiotherapy for oropharyngeal carcinoma.

BACKGROUND/PURPOSE: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. MATERIAL AND METHODS: We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. RESULTS: All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. CONCLUSION: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Stereotactic body radiotherapy for recurrent and oligometastatic soft tissue sarcoma.

BACKGROUND: Soft tissue sarcoma (STS) is a malignant tumor of highly heterogeneous mesenchymal origin. STS has a biological pattern and clinical transformation with localized invasive growth and is susceptible to hematogenous metastasis. Local therapeutic strategies may treat recurrent and oligometastatic STS, including surgery and radiation therapy. This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for recurrent and oligometastatic STS. METHODS: We retrospectively analyzed 37 recurrent and oligometastatic STS patients with 58 lesions treated with SBRT from 2009 to 2019 at our institution. Oligometastatic is defined as metastatic lesions less than or equal to 3. The primary endpoint was local control (LC); secondary endpoints were survival and toxicity. RESULTS: The median follow-up was 21.0 months (3.0 to 125.0 months). Among 37 patients, 18 were recurrent patients, and 19 were oligometastatic patients. Median LC was 25.0 months (95% CI 20.0-45.0). The 1-, 2-, and 3-year LC rates were 80.2%, 58.3%, and 46.6%, respectively. Median overall survival (OS) was 24.0 months (95% CI 13.0-28.0), and the survival rates after SBRT were 71.5%, 40.0%, and 29.1% at 1, 2, and 3-year, respectively. Median progression-free survival (PFS) was 10.0 months (95% CI 8.0-15.0 months), PFS rate after SBRT was 43.6%, 26.8%, and 18.4% at 1, 2, and 3 years, respectively. Late grade 3 radiation dermatitis was observed in one patient (2.7%). Using univariate and multivariate COX analysis, better OS, PFS, and LC were obtained in the histologic grade 1(G1) group, and tumor size and a number of lesions influenced LC. CONCLUSIONS: SBRT is a safe and effective treatment for patients with recurrent and oligometastatic STS. Histological grade influences local control and survival. SBRT may be a promising treatment option for recurrent and oligometastatic STS.

Treatment plan comparison of volumetric-modulated arc therapy to intensity-modulated radiotherapy in lung stereotactic body radiotherapy using either 6- or 10-MV photon energies.

PURPOSE: The aim of this study was to dosimetrically compare volumetric-modulated arc therapy (VMAT) with intensity-modulated radiotherapy (IMRT) techniques using either 6- or 10-MV photon beam energies in lung stereotactic body radiation therapy (SBRT) plans. METHODS: Thirty patients with primary or metastatic lung tumors eligible for SBRT were randomly selected. VMAT and IMRT treatment plans using either 6- or 10-MV photon energies were generated through automatic SBRT planning software in the RayStation treatment planning system. RESULTS: For planning target volume, there was no difference in D95% for all plans, whereas D2% and D50% were significantly increased by 5.22%-5.98% and 2.47%-2.59%, respectively, using VMAT6/10-MV plans compared to IMRT6/10-MV plans. When comparing the Dmax of organs at risk (OARs), VMAT6/10-MV was 18.32%-47.95% lower than IMRT6/10-MV for almost all OARs. VMAT6/10-MV obviously decreased Dmean , V5Gy , V10Gy , and V20Gy of whole lung by 9.68%-20.92% than IMRT6/10-MV . Similar results were found when comparing VMAT6-MV with IMRT10-MV or VMAT10-MV with IMRT6-MV . The differences in the D2% , heterogeneity index, and conformity index between 6- and 10-MV plans are not statistically significant. Plans using 6-MV performed 4.68%-8.91% lower levels of Dmax of spinal cord, esophagus, great vessels, and trachea and proximal bronchial tree than those using 10-MV plans. Similarly, Dmean , V5Gy , V10Gy , and V20Gy of whole lung were also reduced by 2.79%-5.25% using 6-MV. For dose fall-off analysis, the D2cm and R50% of VMAT6/10-MV were lower than those of IMRT6/10-MV . Dose fall-off curve based on 10 rings was steeper for VMAT plans than IMRT plans regardless of the energy used. CONCLUSIONS: For lung SBRT plans, VMAT-based plans significantly reduced OARs dose and steepened dose fall-off curves compared to IMRT-based plans. A 6-MV energy level was a better choice than 10-MV for lung SBRT. In addition, the dose differences between different techniques were more obvious than those between different energy levels.

Magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer (mirage): a phase iii randomized trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is becoming increasingly used in treating localized prostate cancer (PCa), with evidence showing similar toxicity and efficacy profiles when compared with longer courses of definitive radiation. Magnetic resonance imaging (MRI)-guided radiotherapy has multiple potential advantages over standard computed tomography (CT)-guided radiotherapy, including enhanced prostate visualization (abrogating the need for fiducials and MRI fusion), enhanced identification of the urethra, the ability to track the prostate in real-time, and the capacity to perform online adaptive planning. However, it is unknown whether these potential advantages translate into improved outcomes. This phase III randomized superiority trial is designed to prospectively evaluate whether toxicity is lower after MRI-guided versus CT-guided SBRT. METHODS: Three hundred men with localized PCa will be randomized in a 1:1 ratio to SBRT using CT or MRI guidance. Randomization will be stratified by baseline International Prostate Symptom Score (IPSS) (≤15 or > 15) and prostate gland volume (≤50 cc or > 50 cc). Five fractions of 8 Gy will be delivered to the prostate over the course of fourteen days, with or without hormonal therapy and elective nodal radiotherapy (to a dose of 5 Gy per fraction) as per the investigator's discretion. The primary endpoint is the incidence of physician-reported acute grade ≥ 2 genitourinary (GU) toxicity (during the first 90 days after SBRT), as assessed by the CTCAE version 4.03 scale. Secondary clinical endpoints include incidence of acute grade ≥ 2 gastrointestinal (GI) toxicity, 5-year cumulative incidences of physician-reported late grade ≥ 2 GU and GI toxicity, temporal changes in patient-reported quality of life (QOL) outcomes, 5-year biochemical recurrence-free survival and the proportion of fractions of MRI-guided SBRT in which online adaptive radiotherapy is used. DISCUSSION: The MIRAGE trial is the first randomized trial comparing MRI-guided with standard CT-guided SBRT for localized PCa. The primary hypothesis is that MRI-guided SBRT will lead to an improvement in the cumulative incidence of acute grade ≥ 2 GU toxicity when compared to CT-guided SBRT. The pragmatic superiority design focused on an acute toxicity endpoint will allow an early comparison of the two technologies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04384770. Date of registration: May 12, 2020. https://clinicaltrials.gov/ct2/show/NCT04384770 PROTOCOL VERSION: Version 2.1, Aug 28, 2020.

Controversies in radiotherapy for pancreas cancer.

The management of pancreatic adenocarcinoma remains an area of controversy and ongoing discovery. Despite advances in surgical and radiation techniques, as well as chemotherapeutic agents, outcomes of patients diagnosed with this devastating malignancy remain poor. This article aims to review the available literature evaluating the efficacy of adjuvant, neoadjuvant, and definitive radiation therapy. We will also highlight areas of ongoing research efforts being carried out to improve outcomes in this patient population.

Transmission study of the Abdominal Compression plate (BodyFIX Diaphragm Control) for abdominal and stereotactic body radiotherapy.

PURPOSE: Abdominal Compression is one of the methods available to minimize breathing motion during stereotactic body radiotherapy (SBRT), particularly for abdominal malignancies. It might be necessary to treat some tumors with radiation entering through the compression device. One clinically available compression plate device (Elekta BodyFIX Diaphragm Control) was evaluated to understand its impact on dosimetry during clinical treatments. METHODS: The BodyFIX compression device was CT scanned following departmental stereo scanning protocols. Treatment planning system (TPS) calculations were used to determine attenuation ratios through each section of the compression device: the outer frame, compression plate, and higher density couch fixation points and compression screw. TPS calculated skin doses where the compression plate will come in contact with the skin were recorded. All attenuation ratio fields were measured on an Elekta Versa HD linear accelerator. Where differences in attenuation were observed, TPS density overrides were found to bring calculated doses into agreement with measurement. RESULTS: The compression plate and frame showed low dose attenuation (3%-4%). Only minor density overrides for the frame were required due to artefacts from the limited CT field-of-view. The high-density materials in the couch fixation points resulted in higher attenuation (14%-20%). Similarly, the compression screw recorded very high attenuation (44%-65%), depending on the length of screw used. Skin doses assessed from the TPS calculations showed dose build-up under the compression plate that would result in skin receiving the maximum dose. CONCLUSION: Compression devices can cause significant dose attenuation. Density overrides for TPS calculations are recommended for correcting attenuation in some sections of the device. High-density structures like the fixation screw and frame fixation points create high levels of dosimetric uncertainty, and beam entry through those areas has been disallowed.

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.

A multicenter prospective phase II study of postoperative hypofractionated stereotactic body radiotherapy (SBRT) in the treatment of early-stage oropharyngeal and oral cavity cancers with high risk margins: the STEREO POSTOP GORTEC 2017-03 trial.

BACKGROUND: Primary surgery is usually the mainstay treatment in early-stage oropharyngeal and oral cavity cancer. Typically, neck surgery is performed. Negative tumor margins are recommended (> 5 mm). If feasible, re-resection of any positive margin is preferred. Otherwise, postoperative radiotherapy is required. Adjuvant postoperative radiotherapy can be limited to the primary site for patients with pT1-T2 tumors and negative neck exploration. Currently, both fractionated external beam radiotherapy and brachytherapy can have a role in the postoperative management of early-stage oropharyngeal and oral cavity cancer with high risk margins. Another possible alternative could be postoperative stereotactic body radiotherapy (SBRT). The aim of this study is to evaluate postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancer with high risk margins. METHODS: The STEREO POSTOP study is a national, open-label, non-randomized phase II trial within the GORTEC network. Patients with early-stage oropharyngeal and oral cavity cancers with high risk margins indicating the need for postoperative radiation are eligible for enrollment. SBRT consists of a total dose of 36 Gy in 6 fractions over 2 weeks. The primary endpoint is severe late toxicity defined as 2-year toxicity of grade ≥ 3 according to CTCAE V4.03 classification. The secondary endpoints include acute toxicity (≤ 3 months), local and locoregional control, disease-free and overall survival, quality of life of patients, nutritional impact and predictive factors of toxicity. The experimental design chosen is a one-step Fleming plan design without interim analysis as the primary endpoint will be evaluated at a 2-year follow-up. Ninety patients will be recruited. The study was started in January 2018 with a 4-year enrollment period and an estimated completion in January 2024. DISCUSSION: This study is the first prospective trial to evaluate head and neck cancer postoperative SBRT in the setting of early-stage oropharyngeal and oral cavity cancers with high risk margins. SBRT is an attractive option because it delivers a highly conformal dose of radiation in a limited number of fractions (like brachytherapy but with less contraindication), with steep dose gradients resulting in reduced normal tissue irradiation and with a short overall treatment time. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03401840 , registered on 17-1-2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID - RCB 2017-A02058-45, registered on July 2017. Protocol version: Version 3 dated from 25th November 2019.

Radiopharmaceuticals for Treatment of Osteosarcoma.

Although trace amounts of radioactivity are routinely used to detect osteosarcoma, the use of larger therapeutic amounts of radiation is often an unrecognized opportunity to treat metastatic osteosarcoma. This chapter will review a number of approaches to use ionizing radiation in the form of injectable radiopharmaceuticals. Since bone metastases are a common pattern of metastatic spread of cancer in general, a number of bone-seeking radiopharmaceuticals have been developed and FDA approved for treatment of bone metastases. Although osteosarcoma, a bone-forming cancer, would seem ideally suited to be treated with bone seekers, patterns of relapse involving non-ossifying metastases remain a major problem to be overcome. Thus, this review will not only describe experience using a number of bone-seeking radiopharmaceuticals such as 153-samarium-EDTMP, 153-samarium-DOTMP, and 223-radium against osteosarcoma, but also approaches to identify patients who may benefit as well as some means to the improve overall efficacy including combination therapy with routine agents and using nuclear imaging to develop best strategy for use. These include imaging with not only 99mTc-MDP standard bone scans, but also 99mTc-MDP bone scans with SPECT CT, bone-specific sodium fluoride PET-CT (Na18F), and 18FDG-PET-CT. Accurate knowledge of oligometastatic active disease can facilitate more effective use of combination therapy, including radiosensitizers and local control measures, for example, stereotactic body radiotherapy (SBRT) and/or cryoablation to reduce disease burden as well as manage and prevent micrometastatic disease from growing and metastasizing. Finally, a new tumor-specific radiopharmaceutical, CLR 131, may also provide another radiopharmaceutical to treat both osteoblastic and non-ossifying areas of osteosarcoma.

Relapsed Osteosarcoma Trial Concepts to Match the Complexity of the Disease.

Osteosarcoma relapses not only herald a very poor prognosis but also opportunities to treat this genetically diverse complex cancer in new ways. This review will attempt to show that the field is a rapidly evolving one in which not only cytotoxic agents but also local control strategies and the immune system can be harnessed to improve the prognosis of relapsed patients. The molecular heterogeneity and the difficulty of effectively treating most common patterns of relapse with surgery and/or radiation (lung and/or bone metastases) have been responsible for a wide variety of approaches to learning whether agents are active against osteosarcoma. This chapter will highlight past, current, and potential future approaches to provide more effective systemic therapy for the problem of recurrent metastases of osteosarcoma. These include single-agent trials with a wide variety of agents, radiopharmaceuticals, and immune therapies. Finally, how such efforts are integrated into more effective local control strategies is also discussed.

Correlation of clinical outcome, radiobiological modeling of tumor control, normal tissue complication probability in lung cancer patients treated with SBRT using Monte Carlo calculation algorithm.

PURPOSE/BACKGROUND: We analyzed the predictive value of non-x-ray voxel Monte Carlo (XVMC)-based modeling of tumor control probability (TCP) and normal tissue complication probability (NTCP) in patients treated with stereotactic body radiotherapy (SBRT) using the XVMC dose calculation algorithm. MATERIALS/METHODS: We conducted an IRB-approved retrospective analysis in patients with lung tumors treated with XVMC-based lung SBRT. For TCP, we utilized tumor size-adjusted biological effective dose (s-BED) TCP modeling validated in non-MC dose calculated SBRT to: (1) verify modeling as a function of s-BED in patients treated with XVMC-based SBRT; and (2) evaluate the predictive potential of different PTV dosimetric parameters (mean dose, minimum dose, max dose, prescription dose, D95, D98, and D99) for incorporation into the TCP model. Correlation between observed local control and TCPs was assessed by Pearson's correlation coefficient. For NTCP, Lyman NTCP Model was utilized to predict grade 2 pneumonitis and rib fracture. RESULTS: Eighty-four patients with 109 lung tumors were treated with XVMC-based SBRT to total doses of 40 to 60 Gy in 3 to 5 fractions. Median follow-up was 17 months. The 2-year local and local-regional control rates were 91% and and 78%, respectievly. All estimated TCPs correlated significantly with 2-year actuarial local control rates (P < 0.05). Significant corelations between TCPs and tumor control rate according to PTV dosimetric parameters were observed. D99 parameterization demonstrated the most robust correlation between observed and predicted tumor control. The incidences of grade 2 pneumonitis and rib fracture vs. predicted were 1% vs. 3% and 10% vs. 13%, respectively. CONCLUSION: Our TCP results using a XVMC-based dose calculation algorithm are encouraging and yield validation to previously described TCP models using non-XVMC dose methods. Furthermore, D99 as potential predictive parameter in the TCP model demonstrated better correlation with clinical outcome.

The effect of stereotactic body radiotherapy (SBRT) using flattening filter-free beams on cardiac implantable electronic devices (CIEDs) in clinical situations.

PURPOSE: This study focused on determining risks from stereotactic radiotherapy using flattening filter-free (FFF) beams for patients with cardiac implantable electronic device (CIEDs). Two strategies were employed: a) a retrospective analysis of patients with CIEDs who underwent stereotactic radiosurgery (SRS)/SBRT at the Peter MacCallum Cancer Centre between 2014 and 2018 and b) an experimental study on the impact of FFF beams on CIEDs. METHODS: A retrospective review was performed. Subsequently, a phantom study was performed using 30 fully functional explanted CIEDs from two different manufacturers. Irradiation was carried out in a slab phantom with 6-MV and 10-MV FFF beams. First, a repetition-rate test (RRT) with a range of beam pulse frequencies was conducted. Then, multifraction SBRT (48 Gy/4 Fx) and single-fraction SBRT (28 Gy/1 Fx) treatment plans were used for lung tumors delivered to the phantom. RESULTS: Between 2014 and 2018, 13 cases were treated with an FFF beam (6 MV, 1400 MU/min or 10 MV, 2400 MU/min), and 15 cases were treated with a flattening filter (FF) beam (6 MV, 600 MU/min). All the devices were positioned outside the treatment field at a distance of more than 5 cm, except for one case, and no failures were reported due to SBRT/SRS. In the phantom rep-rate tests, inappropriate sensing occurred, starting at a rep-rate of 1200 MU/min. Cardiac implantable electronic device anomalies during and after delivering VMAT-SBRT with a 10-MV FFF beam were observed. CONCLUSIONS: The study showed that caution should be paid to managing CIED patients when they undergo SBRT using FFF beams, as it is recommended by AAPM TG-203. Correspondingly, it was found that for FFF beams although there is small risk from dose-rate effects, delivering high dose of radiation with beam energy greater than 6 MV and high-dose rate to CIEDs positioned in close vicinity of the PTV may present issues.

Travel distance and stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND: Definitive stereotactic body radiotherapy (SBRT) represents an emerging and debated treatment option for patients with prostate cancer, with potential economic savings and reports of short-term efficacy since 2006. The current study sought to define national trends in definitive prostate SBRT use and determine whether patterns vary by travel distance for treatment. METHODS: The National Cancer Data Base identified 181,544 men with localized prostate cancer who were treated with definitive external beam radiotherapy from 2004 through 2012. Joinpoint regression analyzed definitive prostate SBRT trends over time, whereas multivariable logistic regression defined the odds for its receipt by travel distance for treatment. RESULTS: Definitive prostate SBRT use increased from 1.8% in 2004 to 5.9% in 2012 (P for trend <.0001), with a joinpoint for increased use noted in 2006 (P<.0001). Higher SBRT use was found to be associated with longer travel distance for treatment, younger age, white race, more affluent zip code of residence, academic treatment center, favorable disease characteristics, and fewer comorbidities (all P<.0001). Compared with travel distances <25 miles for treatment, travel distances of 25 to 50 miles and >50 miles were associated with increasing adjusted odds of receipt of definitive prostate SBRT (1.63 [95% confidence interval, 1.51-1.76] and 2.35 [95% confidence interval, 2.14-2.57], respectively; both P < .0001). CONCLUSIONS: Definitive prostate SBRT use increased more than 3-fold since 2004, with a significant increase in use coinciding with early reports of short-term efficacy. Long-distance travel for treatment was associated with greater than twice the odds of receipt of definitive prostate SBRT compared with short-distance travel, suggesting that treatment decisions with unknown long-term clinical implications may be strongly driven by sociodemographic factors. Cancer 2018;124:1141-9. © 2017 American Cancer Society.

Using max standardized uptake value from positron emission tomography to assess tumor responses after lung stereotactic body radiotherapy for different prescriptions.

PURPOSE: To retrospectively investigate tumor responses of lung SBRT patients for different prescriptions. To analyze the relation between optimal biologically equivalent dose (BED) and tumor responses. METHODS AND MATERIALS: Tumor responses after lung SBRT were compared by examining 48 treatments used four prescriptions. This study used simplified tumor response criteria: (a) Complete Response (CR) - post max SUV (SUVpost ) after SBRT in the treated tumor region was almost the same as the SUVs in the surrounding regions; (b) Partial Response (PR) - SUVpost was smaller than previous max SUV (SUVpre ), but was greater than the SUVs in the surrounding regions; (c) No Response (NR) - SUVpost was the same as or greater than SUVpre . Some SUVpost reported as mild or favorable responses were classified as CR/PR. BED calculated using α/ß of 10 Gy were analyzed with assessments of tumor responses for SBRT prescriptions. RESULTS: For the prescriptions (9 Gy × 5, 10 Gy × 5, 11 Gy × 5, and 12 Gy × 4) historically recommended by RTOG, we observed that higher BED10 and lower tumor volume would achieve a higher complete response rate. The highest complete response rate was observed for smallest tumor volume (PTVave  = 6.8 cc) with higher BED10 (105.6) of 12 Gy × 4 prescription. For 11 Gy × 5 prescription, the BED10 (115.5) was the highest, but its complete response rate (58%) was lower than 79% of 12 Gy × 4 prescription. We observed the PTVave of 11 Gy × 5 prescription was more than double of the PTVave of 12 Gy × 4 prescription. For the same lung SBRT prescription (BED10  > 100) earlier staging tumor had more favorable local control. CONCLUSION: We demonstrated post max SUV read from PET/CT could efficiently and accurately assess tumor response after lung SBRT. Although SBRT with prescriptions resulting in a BED10  > 100 experienced favorable tumor responses for early staging cancer, escalation of BED10 to higher levels would be beneficial for lung cancer patients with later staging and larger volume tumors.