Initial Radiotherapy Research Articles

Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy

BackgroundThe immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and MethodsPatients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.ResultsOf 143 patients identified, the median age was 66 (range, 19–90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13–25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/µL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.ConclusionGrade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.

Cumulative dose, toxicity, and outcomes of spinal metastases re-irradiation

The aim of this study was to identify patient-, tumor-, or treatment-related factors which may affect disease-related outcomes of re-irradiation (reRT) in patients with previously irradiated vertebral metastases. A computerized search of the literature was performed by searching for terms related to reRT and spinal metastases in MEDLINE, EMBASE, OVID, and the Cochrane database from 1995 to 2019. Studies including at least 10patients who had received reRT at the same site of initial radiotherapy for vertebral metastases with localized external beam radiotherapy were included. To determine the pooled ≥G3 acute and late toxicity rate, pain relief, local control, and overall survival, ameta-analysis technique of single-arm studies was performed. Nineteen studies including 1373patients met the inclusion criteria for this systematic review. The pooled pain relief, neurological improvement, 1‑year local control, and 1‑year overall survival rates were 74.3%, 73.8%, 78.8%, and 54.6%, respectively, with moderate to high heterogeneity among studies. No difference in heterogeneity was evidenced for pain relief or local control after omitting studies not using stereotactic body radiotherapy (SBRT) or studies delivering biologically effective dose (BED) < 45 Gy10, whereas heterogeneity for 1‑year OS was lower after omitting studies not using SBRT and delivering BED < 45 Gy10. The pooled results of grade ≥ 3 acute and late toxicity were 0.4% (95% confidence interval: 0.1-1.2%) and 2.2% (95% confidence interval: 1.2-37%), respectively, with low heterogeneity among studies. While this systematic review confirmed that reRT is both safe and effective for treating patients with recurrent spinal metastases, it could not identify factors which may affect outcomes of reRT in this patient population.

Diagnostic utility of (18)f-fluciclovine positron emission tomography (FACBC) in biochemically recurrent (BCR) prostate cancer (PCa) based on prior primary treatment modality for localized disease and the impact of FACBC findings on treatment selection.

34 Background: Management of BCR PCa requires accurate assessment of location and extent of recurrent disease. FACBC has been shown to be a sensitive modality for detection and localization of recurrent disease but treatment guidelines are based on the findings of conventional (conv) imaging, including computed tomography, magnetic resonance imaging, or bone scintigraphy, and little is known about how prior treatment impacts FACBC findings and concordance with conv scans. Methods: This single-center retrospective study included 137 patients (pts) who had FACBC for BCR at the University of Wisconsin-Madison from 10/2017-10/2019. Clinical, pathological, imaging, and treatment data were collected by chart review. Pts were classified by type of primary treatment for localized PCa, either radical prostatectomy (RP) or radiation therapy (RT). Findings of conv scans performed within 4 weeks prior or any time after FACBC were collected. Results: 105 pts had RP and 32 pts had RT as their primary PCa treatment. Gleason score and PSA at diagnosis were similar between groups. Median PSA at time of FACBC was higher in the RT compared to RP group (3.3 vs 0.7 ng/dL) and median time from initial diagnosis to FACBC was longer (70 vs 55 months). Frequency of (+) FACBC findings was higher in the RT group (66% vs 47%); only 3% of pts in the RT group had a (-) FACBC compared to 29% in the RP group. The rate of (+) lesions in the prostate/prostate bed was higher in the RT group (41% vs 22%), while the rate of (+) lesions in pelvic nodes and distant sites was similar between groups. Of 69 pts who also had conv imaging, 61% had concordant conv imaging findings. In the RT group, conv and FACBC findings were similar in 47% of pts and not similar in 28%. In the RP group, conv and FACBC findings were similar in 26% of pts and not similar in 17%. Management after FACBC is listed in table. Median time from FACBC to first (+) conv scans was 6 (range: 0-18) and 5 (range: 0-17) months for RT and RP groups, respectively. Conclusions: In this large retrospective cohort, pts treated with initial RT had a longer median time from diagnosis to FACBC and higher median PSA at the time of FACBC compared to the RP group. RT patients had a higher rate of (+) FACBC findings but were more likely to continue on observation. The median time from FACBC to first (+) conv scan was 5-6 months, supporting the role of FACBC in earlier detection of recurrent disease in both groups of patients. Further analysis of concordance between FACBC and conv imaging is in process. [Table: see text]

Neoadjuvant versus concurrent androgen deprivation therapy plus radiotherapy for unfavorable intermediate-risk and high-risk prostate cancer with low PSA.

243 Background: Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment for localized prostate cancer (LPCa), but the optimal sequencing of hormone therapy with RT is unclear, with most patients treated with neoadjuvant ADT. Clinical trials addressing this question have not yielded definitive results. During COVID-19, there has been greater interest in neoadjuvant ADT as a way to delay initiation of RT to reduce risk of COVID transmission from daily RT visits with recent analysis from the NCDB showing that RT can be delayed for up to 6 months after neoadjuvant ADT. It is unclear if neoadjuvant ADT is appropriate for all patients or if select cohorts may benefit from concurrent ADT and upfront RT, such as patients with higher grade disease and low PSA who may have less hormone-responsive disease. Methods: Using the NCDB, we identified men diagnosed from 2004 to 2015 with NCCN unfavorable intermediate risk or high-risk adenocarcinoma of the prostate with a presenting PSA ≤ 5 ng/mL treated with definitive RT and either ADT initiated 2-4 months prior to RT (neoadjuvant ADT) or ADT started within 7 days of RT (concurrent ADT). OS was the primary endpoint. OS was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards analyses was performed using age, facility type, Charlson-Deyo comorbidity score, clinical T stage, and Gleason score. Results: 2393 patients were identified, with 2103 receiving neoadjuvant ADT and 290 receiving concurrent ADT. Multivariable analysis (MVA) showed that concurrent ADT was associated with a lower risk of death relative to patients receiving neoadjuvant ADT {hazard ratio (HR): 0.58 [95% confidence interval: 0.36-0.94], p = 0.02}. The number of days from diagnosis to the start of RT was not associated with worse OS (HR:[0.99-1.01], p = 0.61) on MVA. Age (HR = 1.03 [1.01-1.05], p = 0.002) and treatment at an academic center (HR: 0.71 [0.53-0.94], p = 0.02) were also significantly associated with OS on MVA. The benefit of concurrent ADT relative to neoadjuvant ADT was greatest in patients with Gleason 4 and Gleason 5 disease (HR: 0.31 [0.14-0.71], p = 0.005). Conclusions: For patients with unfavorable intermediate-risk or high-risk prostate cancer and a PSA ≤ 5 ng/mL, concurrent ADT and upfront RT was associated with improved OS compared to neoadjuvant ADT and RT. The associated benefit appeared to be more pronounced for Gleason Score ≥ 8. Results are hypothesis generating and require validation in a randomized trial.

TraceIT: A prospective pilot study of a temporary intravesical fiducial marker for bladder cancer radiation therapy.

457 Background: Precision image-guided radiotherapy (RT) for patients (pts) with muscle-invasive bladder cancer (MIBC) is limited by daily anatomic variation and difficulty visualizing the tumor bed. We hypothesized that TraceIT, a radiopaque resorbable hydrogel, can be injected around the tumor bed to improve image guidance. We present the results of our pilot trial (NCT03125226) evaluating safety/feasibility of TraceIT in pts undergoing definitive RT. Methods: Eligibility included MIBC with plan to receive definitive RT +/- chemo. Fifteen patients were available for analysis (11 enrolled on trial from 2017-2018, plus an additional 4 received TraceIT off study). TraceIT was injected around the circumference of the tumor bed during pre-radiation maximal re-transurethral resection of bladder tumor (TURBT) for all pts, and again during the mid-radiation TURBT to improve visibility in n = 8 pts. The primary endpoint was assessment of interfraction motion on daily cone-beam CT (CBCTs) based on alignment to fiducial vs standard-of-care pelvic bone anatomy. Van Herk (VH) margin equation was used to determine the planning target volume margin optimized for the clinical target volume receiving at least 95%-prescription dose in 90% of pts. Recurrence rates and survival were estimated by Kaplan Meier. Toxicity was measured by CTCAE v4.03. Results: Patients underwent RT to a median total dose of 63.5 Gy (range 35.75-66.6), typically to an initial small pelvis field follow by a tumor boost. 14/15 received chemo with RT. Median TraceIT volume was 0.5cc (range 0.3-0.75) per injection site for 4 (range 4-6) sites per patient for total volume of 2cc (range 2-3). All pts demonstrated 100% visibility of TraceIT on initial simulation CT and day 1 CBCT. TraceIT visibility declined slightly over time, with 91.5% of patients having visible TraceIT by the end of the initial RT phase (usually week 5) and 82.5% by end of the boost phase. For the initial phase, alignment to fiducials over bone anatomy allowed for reduced VH margins (0.67cm vs 1.56cm). For the boost phase, the VH margin was similar between fiducial and bone alignment (1.01cm vs 0.96cm). There have been no acute or late complications from TraceIT placement. There were no grade grade (G) 4/5 toxicities; three pts had acute G 3 events, and three pts experienced late G 3 toxicity: two related to hematuria and one from ureteral stenosis. There were no late G≥2 GI toxicities. No patients have undergone cystectomy. At a median follow-up of 22 months, 2-yr OS was 79.1% and 2-yr PFS was 75.4%. Conclusions: TraceIT is safe and feasible for use in image-guided RT. TraceIT can increase the precision of RT by facilitating accurate target delineation of the bladder tumor bed and daily motion management which may allow for smaller radiation treatment margins to be used to reduce toxicity and to potentially facilitate safe dose escalation to tumor, which can improve tumor control. Clinical trial information: NCT03125226.

Abstract SS2-07: Predictors for fear of cancer recurrence in breast cancer patients referred for radiation therapy during the COVID-19 pandemic: A multi-center cross-section survey

Abstract Background The outbreak of COVID-19 pandemic in China has greatly impacted the radiotherapy (RT) strategy for breast cancer (BC) patients, which might lead to an increased distressing psychological symptom. Thus, we perform a multi-center cross-section survey aiming to investigate the prevalence of fears of cancer recurrence (FCR) and explore predictors for FCR in BC patients referred for RT during pandemic. Methods: 542 BC patients who referred for RT between 24th Jan and 30th April 2020 during pandemic were consecutively enrolled from 14 hospitals around China including Yangtze Delta River Region, Guangdong and Shanxi province. Patients’ sociodemographic, treatment information as well as psychological characteristics were collected using an information sheet, Fear of progression questionnaire-short form (FoP-Q-SF), Hospital Anxiety and Depression Scale (HADS) and EORTC QLQ-C30. The influence of pandemic on RT schedule was divided into four categories: “delay” was defined as &amp;gt;12 weeks from surgery to RT in patients without chemotherapy or &amp;gt;8 weeks from last time of anti-tumor therapy (including chemotherapy and surgery) to RT in patients with chemotherapy; “Special normal” was defined that patients themselves believed to have delayed RT initiation but actually not; “Interruption” was defined as any unplanned gaps in original RT regime and all other would be classified into “normal”. Another type of influence on RT strategy was that patients had to shift planned RT hospital from Grade-A tertiary hospital to local hospitals. Univariable analyses of FCR were performed in a one-way analysis of variance (ANOVA) or student t-test or Pearson correlation analyses and candidate variables with P&amp;lt;0.2 were included Hierarchical multiple regression models to investigate predictors for FCR. Guangdong province was chosen as reference in models. Results 488 patients with complete data were eligible for the present analysis and none of patients and their family members had been diagnosed as COVID-19. The RT strategy was affected in 265 (54.3%) patients, including 143 with delayed RT initiation, 66 with “special normal” schedule, 24 (4.9%) with RT interruptions, 19 shifting to local hospitals for RT, and the remaining 13 being influenced on both RT schedule and planned RT hospitals. Most of patients with affected RT strategy occurred in late January and February, when was peak of COVID-19 pandemic in China. The mean FCR scores was 24.83 (SD=8.554) and 84 patients (17.3%) were classified as dysfunctional level of FCR (sum score ≥34). In univariable analyses, FCR were significantly higher in patients who received RT in Guangdong province and in hospitals with &amp;lt; 100 BC cases per year. In term of during pandemic, a significant difference in FCR was observed in terms of influence on RT schedule (p&amp;lt;0.001). and changes of hospital levels(p=0.009). There were significant correlations between FCR and anxiety/depressive in HADS or all five function scales (physical, role, emotional, cognitive and social) and global QoL in QLQ-C30 (p&amp;lt;0.001). Finally, the model explained 59.7% of observed variances in FCR and showed that influence of RT strategy during pandemic had significantly impacted on FCR (ΔR2=0.01, ΔF=2.966, p=0.019). Hospitals in Shanxi province (β=-0.117, p=0.001), emotional function (β=-0.19, p&amp;lt;0.001), social function (β=-0.111, p=0.006), anxiety (β=0.434, p&amp;lt;0.001) and RT interruption (β=0.071, p=0.035) were independent predictors for FCR. Conclusions RT strategy for BC patients was greatly influenced during pandemic. RT interruption is an independent predictor for high FCR. Our findings emphasize the necessity to ensure the continuum of RT in BC patients, and efforts should be taken to alleviate the FCR through psychological interventions. Citation Format: Jinrong Xie, Weixiang Qi, Lu Cao, Yuting Tan, Jin Huang, Xiaodong Gu, Bingguang Chen, Peipei Shen, Ying Zhang, Qingwen Zhao, Hecheng Huang, Yubin Wang, Haicheng Fang, Zhenjun Jin, Hui Li, Xuehong Zhao, Xiaofang Qian, Feifei Xu, Dan Ou, Shubei Wang, Cheng Xu, Min Li, Zefei Jiang, Yu Wang, Xiaobo Huang, Jiayi Chen. Predictors for fear of cancer recurrence in breast cancer patients referred for radiation therapy during the COVID-19 pandemic: A multi-center cross-section survey [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS2-07.

Cytokine Profiles of Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy with Regards to Radiation Pneumonitis Severity.

The immunologic aspects of radiation pneumonitis (RP) are unclear. We analyzed variations in cytokine profiles between patients with grade (Gr) 0–1 and Gr ≥ 2 RP. Fifteen patients undergoing concurrent chemoradiotherapy for non-small cell lung cancer were included. Blood samples of 9 patients with Gr 0–1 and 6 with Gr ≥ 2 RP were obtained from the Biobank. Cytokine levels were evaluated using an enzyme linked immunosorbent assay at before radiotherapy (RT) initiation, 1, 3, and 6 weeks post-RT initiation, and 1 month post-RT completion. Concentrations of granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-10, IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β were analyzed; none were related to the occurrence of Gr ≥ 2 RP at pre-RT initiation. At 3 weeks, relative changes in the G-CSF, IL-6, and IFN-γ levels differed significantly between the groups (p = 0.026, 0.05 and 0.026, respectively). One month post-RT completion, relative changes of IL-17 showed significant differences (p = 0.045); however, relative changes in TNF-α, IL-10, IL-13, and TGF-β, did not differ significantly. Evaluation of changes in IL-6, G-CSF, and IFN-γ at 3 weeks after RT initiation can identify patients pre-disposed to severe RP. The mechanism of variation in cytokine levels in relation to RP severity warrants further investigation.

Timing of Urgent Inpatient Palliative Radiation Therapy

PurposeUrgent indications for palliative radiation therapy (RT) include malignant spinal cord compression, symptomatic brain metastases, pain, airway obstruction, and bleeding. Data on the timing of palliative RT in the inpatient setting are limited. We report our experience with inpatient palliative RT at a tertiary academic center and evaluate the effect of a dedicated inpatient palliative RT nurse practitioner (NP) on treatment timelines. Methods and MaterialsWe performed a retrospective, single-institution review of 219 inpatients consulted for RT to sites of metastatic disease between May 2012 and May 2018. We compared time-to-treatment intervals before and after integrating an NP for palliative RT in August 2017. ResultsThe median age of the 219 patients receiving RT was 61 years (interquartile range [IQR], 51-69 years). The most frequent indications were symptomatic brain metastases (73 patients [33%]), pain (61 patients [28%]), and cord/cauda compression (48 patients [22%]). The median time from consultation request to consult was 1 day (IQR, 0-2 days), and the median time from consultation request to first RT fraction was 3 days (IQR, 2-6 days). The median time from consultation request to RT was shorter for cord compression (2 [IQR, 1-4] days) than for pain (5 [IQR, 2-7] days) (P = .001) or symptomatic brain metastases (3 [IQR, 1-6] days; P = .037). With an NP, patients were more likely to undergo same-day consultation and simulation (75% vs 60%; P = .045), which was associated with shorter median duration from consultation to initiation of RT (1 [IQR, 0-3] days vs 4 [IQR, 2-7] days; P <.001). After the integration of an NP for palliative RT, patients had a higher median Karnofsky Performance Score (70 [IQR, 60-80] vs 50 [IQR, 40-60]; P < .001) and were more likely to complete their prescribed RT course (93% vs 82%; P = .05) ConclusionsTime from consultation request to RT is necessarily short for urgent inpatient palliative RT. Advanced practice providers may facilitate and potentially expedite treatment, with significantly shorter times to treatment among patients who undergo same-day consultation and simulation.

Determinants of delay in the head and neck oncology care pathway: The next step in value-based health care.

ObjectiveHead and neck squamous cell carcinomas (HNSCC) are relatively fast‐growing tumours, and delay of treatment is associated with tumour progression and adverse outcomes. The aim of this study is to identify determinants of delay in a head and neck oncology centre.MethodsThis cohort study with prospectively collected data investigated associations between patient (including geriatric assessment at first consultation), tumour and treatment characteristics and treatment delay. Two quality indicator intervals assessing value‐based healthcare were studied: care pathway interval (CPI, interval between first visit in an HNOC and treatment initiation) and time‐to‐treatment initiation (TTI, interval between histopathological confirmation of HNSCC and treatment initiation), using regression analyses.ResultsStage‐IV tumours and initial radiotherapy were independent predictors of delay in CPI. Initial radiotherapy was associated with delay in TTI. Overall, 37% of the patients started treatment within 30 days after first consultation (67% in case of initial surgical treatment and 11.5% if treated with (chemo)radiation, p < 0.001). Geriatric assessment outcomes were not associated with delay. Indicators for delay in initial surgery patients were stage‐IV tumours (CPI).ConclusionThe majority of HNSCC patients encounter delay in treatment initiation, specifically in patients with advanced‐stage tumours or when radiotherapy is indicated.

Patient-Provider Communication, Decision-Making, and Psychosocial Burdens in Palliative Radiotherapy: A Qualitative Study on Patients’ Perspectives

ContextPatient-provider communication impacts how patients with cancer make decisions about treatment. ObjectivesTo examine patient perceptions of discussions, decision-making, and psychosocial burdens related to receiving palliative radiotherapy (RT), in order to inform best practices for communication about palliative RT. MethodsWe conducted an exploratory qualitative study using oral questionnaires and semi-structured interviews. Seventeen patients receiving their first course of palliative RT for lung or bone metastases at a comprehensive cancer center were interviewed. Patient interviews were transcribed verbatim and thematically analyzed using NVivo software. ResultsThemes that impacted patients’ decisions to initiate RT included a desire to minimize pain, optimism about what RT could provide for the future, perception of having “no other choice,” disappointment about cancer progression, and unfamiliarity with RT. Most patients preferred shared decision-making regarding RT initiation and reported patient empowerment, effective communication, and team collaboration as contributing to shared decision-making. Most patients preferred their physicians to make decisions about RT treatment intensity and described trust in their physicians, institutional reputation, and RT expertise as motivators for this preference. Patients who possessed a proactive decisional mindset about initiating RT as opposed to having “no other choice” were less likely to report experiencing psychosocial burdens. ConclusionMost patients prefer shared decision-making regarding RT initiation but prefer their radiation oncologists to make decisions regarding treatment intensity. Communication that empowers patients in their desired level of engagement for RT decision-making may help patients make informed decisions, contribute toward a proactive decisional mindset, and reduce their perception of psychosocial burdens.

Use of radiotherapy in breast cancer patients with brain metastases: a retrospective 11-year single center study

AimTo analyse the use of radiotherapy (RT) and factors affecting overall survival (OS) after RT in breast cancer patients with brain metastases. MethodsBreast cancer patients treated from 2008 to 2018 with whole brain RT (WBRT) or stereotactic radiosurgery (SRS) at a large regional cancer referral center were identified from the hospital's RT register. Clinical variables were extracted from medical records. OS was calculated from date of first RT until death or last follow up. Potential factors affecting OS were analyzed. Results255 females with WBRT (n = 206) or SRS (n = 49) as first RT were included. An increased use of initial SRS was observed in the second half of the study period. The most common WBRT fractionation regimen was 3 Gy × 10. SRS was most often single fractions; 18 or 25 Gy between 2009 and 2016, while fractionated SRS was mostly used in 2017 and 2018. Median OS in the WBRT group was 6 months (CI 1–73) relative to 23 (CI 0–78) in the SRS group. Age, performance status, initial RT technique, extracranial disease, brain metastasis surgery, number of brain metastases and DS-GPA score had significant impact on OS. Only ECOG 0 and brain metastasis surgery were associated with superior OS in multivariate analysis. ConclusionWBRT was the most frequent primary RT. An increased use of initial SRS was observed in the second half of the study period. Only ECOG 0 and brain metastasis surgery were associated with superior OS in multivariate analysis.

Disease Control and Patterns of Failure After Proton Beam Therapy for Rhabdomyosarcoma

Pediatric patients with rhabdomyosarcoma (RMS) are treated with multimodal therapy, often with radiation therapy (RT) as part of local therapy. We report on the efficacy and patterns of failure after proton beam therapy (PBT) for RMS. Between January 2006 and February 2017, patients with RMS were enrolled in a prospective institutional review board-approved registry protocol for pediatric patients undergoing PBT. Demographics, clinical characteristics, and treatment related outcomes were reviewed. Ninety-four RMS patients were treated with a combination of chemotherapy (CT) and PBT. The majority of patients had head and neck (49%) and genitourinary (30%) primaries. Median tumor size was 4.1 cm (range, 1.0-16.5 cm); 33 patients (35%) had primary tumors >5 cm. Median cyclophosphamide equivalent dose was 14.4 g/m2 (range, 0-30.8 g/m2). Median time from CT initiation to RT initiation was 13 weeks (range, 1-58 weeks). With median follow-up of 4 years, 4-year overall survival (OS) was 71%, and 4-year progression-free survival (PFS) was 63%. Thirty patients (32%) experienced relapse (13% with local failure [LF]). Four-year local control (LC) was 85% overall; 4-year LC rates were 100% for low-risk, 85% for intermediate-risk, and 55% for high-risk patients (P = .02). Tumor size predicted LC (P = .007), with 7% versus 33% LF rate by tumor size (≤5 cm vs >5 cm). Delayed RT delivery (≥13 weeks from initiation of CT) predicted worse LC (P = .01). Increased tumor size predicted both inferior PFS (P = .02) and OS (P = .01). Delayed RT delivery predicted both inferior PFS (P = .04) and OS (P = .03). PBT provides LC comparable to prior studies using photon RT. Inferior LC, PFS, and OS rates were observed for patients with larger tumors and those treated with delayed RT. This finding supports ongoing prospective efforts to dose-escalate treatment of tumors >5 cm; however, these data call into question the optimal timing of local therapy, particularly for patients treated with reduced-dose cyclophosphamide.

Clinical outcomes and radiation pneumonitis after concurrent EGFR-tyrosine kinase inhibitors and radiotherapy for unresectable stage III non-small cell lung cancer.

BackgroundConcurrent epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) with radiotherapy in patients with EGFR‐mutant unresectable stage III non‐small cell lung cancer (NSCLC) might improve survival. However, both treatments carry a potential risk of pneumonitis.MethodsBetween May 2012 and December 2017, patients with unresectable stage III NSCLC treated with concurrent radiotherapy and EGFR‐TKI were enrolled in this retrospective study. The baseline characteristics were evaluated to determine correlations with toxicity development.ResultsAmong 45 eligible patients, 20 (44.4%) had an EGFR mutation and 44 (97.8%) received 50–66 Gy of radiotherapy. The median follow‐up was 62.7 months. The median progression free survival (PFS) and overall survival (OS) for patients with EGFR‐mutations were 27.9 (95% CI: 18.7–37.2) and 49.7 (95% CI: 27.7–71.8) months, and 13.8 (95% CI: 8.8–18.9) and 31.1 (95% CI: 9.8–52.4) months for EGFR wild‐type/unknown patients. A total of 17 patients (37.7%) developed radiation pneumonitis/pneumonitis (14 grade 2, 3 grade 3). In 16 patients, pneumonitis occurred within the radiation field and one patient had bilateral pneumonitis. The median time from the initial radiotherapy to pneumonitis was 74 days. Logistic regression analysis revealed a trend between the time of EGFR‐TKI and the development of G2+ pneumonitis. For late toxicity, only two patients had G2+ fibrosis. The daily dyspnea symptoms of patients with G2+ pneumonitis recovered significantly after the phase of pneumonitis (P = 0.007).ConclusionsCombined EGFR‐TKI and radiotherapy showed favorable survival in EGFR‐mutant patients with inoperable stage III NSCLC, with a 6.7% incidence of grade 3 radiation pneumonitis/pneumonitis, despite a higher incidence of mild‐to‐moderate radiation pneumonitis.Key pointsSignificant findings of the studyWe evaluated the outcomes and radiation pneumonitis after EGFR‐TKI during interval radiotherapy. EGFR‐TKI plus radiotherapy increased survival in patients with EGFR‐mutant inoperable stage III NSCLC. The mild‐to‐moderate radiation pneumonitis incidence increased but no grade 4–‐5 adverse events occurred.What this study addsThe combination of EGFR‐TKI and radiotherapy might carry a risk of pneumonitis; however, there are limited data concerning dose constraints. Our results showed a slightly higher incidence of mild or moderate radiation pneumonitis by strict dose limitation.

New brain metastases after whole-brain radiotherapy of initial brain metastases in breast cancer patients: the significance of molecular subtypes (KROG 16-12).

To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC). In this multi-institutional study, 538BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149). In 37.4% of patients, new BM emerged at a median of 10.5months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2-, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1year, p < 0.001) according to molecular subtype (HR+/HER2-, 42% reduction at 1year, p < 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis revealed an increased risk of new BM for the following factors: shorter intervals between primary BC diagnoses and BM (p = 0.031); TNBC (relative to HR+/HER2-) (p = 0.016); presence of extracranial metastases (p = 0.019); number of BM (>4) (p < 0.001); and BM in both tentorial regions (p = 0.045). Anti-HER2 therapy in HER2+ patients (p = 0.013) and initial use of WBRT (p < 0.001) significantly lowered new BM development. Tumor molecular subtypes were associated with both rates of new BM development and the effectiveness of initial WBRT. Anti-HER2 therapy in HER2+ patients significantly lowered new BM occurrence.

Psychosomatic symptoms affect radiotherapy setup errors in early breast cancer patients.

ObjectiveTo examine the trajectory of psychosomatic symptoms and to explore the impact of psychosomatic symptoms on setup error in patients undergoing breast cancer radiotherapy.MethodsA total of 102 patients with early breast cancer who received initial radiotherapy were consecutively recruited. The M.D. Anderson Symptom Inventory (MDASI) and three different anxiety scales, i.e., the Self-Rating Anxiety Scale (SAS), State-Trait Anxiety Inventory (STAI), and Anxiety Sensitivity Index (ASI), were used in this study. The radiotherapy setup errors were measured in millimetres by comparing the real-time isocratic verification film during radiotherapy with the digitally reconstructed radiograph (DRR). Patients completed the assessment at three time points: before the initial radiotherapy (T1), before the middle radiotherapy (T2), and before the last radiotherapy (T3).ResultsThe SAS and STAI-State scores of breast cancer patients at T1 were significantly higher than those at T2 and T3 (F=24.44, P<0.001; F=30.25, P<0.001). The core symptoms of MDASI were positively correlated with anxiety severity. The setup errors of patients with high SAS scores were greater than those of patients with low anxiety levels at T1 (Z=−2.01, P=0.044). We also found that higher SAS scores were associated with a higher risk of radiotherapy setup errors at T1 (B=0.458, P<0.05).ConclusionsThis study seeks to identify treatment-related psychosomatic symptoms and mitigate their impact on patients and treatment. Patients with early breast cancer experienced the highest level of anxiety before the initial radiotherapy, and then, anxiety levels declined. Patients with high somatic symptoms of anxiety may have a higher risk of radiotherapy setup errors.

Optimal Timing of Radiotherapy after Incomplete Transarterial Chemoembolization for Barcelona Clinic Liver Cancer Stage B Hepatocellular Carcinoma.

PurposeThe optimal timing for radiotherapy (RT) after incomplete transarterial chemoembolization (TACE) remains unclear. This study investigated the optimal timing to initiate RT after incomplete TACE in patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma.Materials and MethodsThis study included 116 lesions in 104 patients who were treated with RT after TACE between 2001 and 2016. The time interval between the last TACE session and RT initiation was retrospectively analyzed. The optimal cut-off time interval that maximized the difference in local failure-free rates (LFFRs) was determined using maximally selected rank statistics.ResultsThe median time interval was 26 days (range: 2–165 days). At a median follow-up of 18 months (range: 3–160 months), the median overall survival was 18 months. The optimal cut-off time interval appeared to be 5 weeks; using this cut-off, 65 and 39 patients were classified into early and late RT groups, respectively. Early RT group had a significantly poorer Child-Pugh class and higher alpha-fetoprotein levels compared to late RT group. Other characteristics, including tumor size (7 cm vs. 6 cm; p=0.144), were not significantly different between the groups. The 1-year LFFR was significantly higher in the early RT group than in the late RT group (94.6% vs. 70.8%; p=0.005). On multivariate analysis, early RT was identified as an independent predictor of favorable local failure-free survival (hazard ratio: 3.30, 95% confidence interval: 1.50–7.29; p=0.003).ConclusionThe optimal timing for administering RT after incomplete TACE is within 5 weeks. Early administration of RT is associated with better local control.

Phase II Trial Investigating Definitive Radiation Therapy in Lieu of Systemic Therapy for Oligometastatic Renal Cell Carcinoma

Background: The role of definitive radiation therapy (RT) in metastatic renal cell carcinoma (RCC) is controversial. We prospectively tested the feasibility, efficacy, and safety of definitive RT to defer systemic therapy for patients with oligometastatic RCC. Methods: This single-arm phase 2 study (NCT03575611) enrolled patients with histologically confirmed RCC, ≤5 metastatic lesions, and ≤1 prior systemic therapy. Patients were treated with definitive RT to all lesions and maintained off systemic therapy. Additional rounds of RT were allowed to treat new sites of progression. The co-primary endpoints were progression-free survival (PFS) and feasibility. Criteria for initiating systemic therapy were progression in >3 lesions, toxicity, local progression, or patient/provider preference. Findings: Thirty patients were enrolled in July 2018–September 2020 (median follow-up time 17.5 months). All patients had clear cell histology and had undergone nephrectomy before enrollment. Nine patients (30%) had received one prior systemic therapy. All patients completed initial RT and 13 (43%) received a second round. Median PFS was 22·7 months (1-year PFS rate 64%). All patients were alive at last follow-up, and one local failure was observed. The 1-year systemic therapy–free survival was 82%, with 7 patients (23%) initiating systemic therapy at a median 8.1 months from enrollment. Adverse events were grade ≥2 in six patients and ≥3 in three patients. At first follow-up, no viable tumor cells were detected in 5 of 14 biopsy samples obtained after RT (36%). For patients in whom viable tumor was present, the Ki-67 labeling index was significantly reduced (P =0·0068). Interpretation: Sequential definitive RT is a feasible and effective strategy for patients with oligometastatic RCC seeking to defer systemic therapy. Clinical Trial Registration: This study is registered with ClinicalTrials.gov as NCT03575611. Funding: Grant support from the Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Center, National Institutes of Health (P30 CA016672, PI P. Pisters). Declaration of Interest: PM has received honoraria for service on scientific advisory boards for Mirati Therapeutics, Bristol- Myers Squibb, and Exelixis; consulting for Axiom Healthcare Strategies; non-branded educational programs supported by Exelixis and Pfizer; and research funding for clinical trials from Takeda, Bristol- Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research, and UT MD Anderson Cancer Center. INCOMPLETE Ethical Approval: This protocol underwent full approval by the Institutional Review Board at MD Anderson. All patients provided written informed consent to participate.

ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation.

Simple SummaryProstate cancer is the most frequently diagnosed cancer in men. Despite the importance of radical radiotherapy for the management of this disease, recurrence remains a challenge. PTEN is a tumour suppressor that is frequently inactivated in advanced prostate cancer and has been associated with relapse following radiotherapy. The present study shows that the role of PTEN in response to ionizing radiation is complex. Furthermore, it demonstrates that in the absence of PTEN, an increased response to combined treatment using radiotherapy and the ATM inhibitor KU-60019 can be observed. Our findings provide a strong rationale for evaluating loss of PTEN in prostate cancer as a therapeutic target for ATM inhibitor in combination with radiotherapy in the clinical setting.Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer

To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.

DIPG-01. REIRRADIATION PRACTICES FOR DIFFUSE INTRINSIC PONTINE GLIOMA

INTRODUCTIONDiffuse intrinsic pontine gliomas (DIPG) are a leading cause of brain tumor deaths in children. Current standard of care includes focal radiation therapy (RT). Despite clinical improvement in the majority of patients, the effect is temporary and median survival is less than one year. The use of reirradiation and possible benefit has been reported in progressive DIPG, yet standardized approaches are lacking. We conducted an internet-based survey to assess physicians’ practices in pediatric DIPG.METHODSA 14-question REDCap survey regarding re-irradiation practices was emailed to 396 physicians identified through an International Pediatric Neuro-Oncology and Radiation-Oncology database.RESULTSResponse rate was 35% overall (radiation-oncologists, 28%; pediatric oncologists, 57%). Two participants were excluded (did not treat DIPG). Participants included radiation-oncologists (62%), pediatric oncologists (7%), and pediatric neuro-oncologists (29%). Most physicians (62%) treated 1–5 DIPG patients per year, with 10% treating >10/year. Reirradiation was considered a treatment option in 88%. Progressive disease or worsening clinical status were the most common reasons to consider reirradiation. The majority (84%) considered reirradiation a minimum of 6 months following initial RT. Doses varied, with median total dose 24Gy (range 12–60); 2Gy/fraction (range 1–9). Concurrent use of systemic agents with reirradiation was considered in 46%, mainly with targeted agents (37%), biologics (34%), or immunotherapy (25%). One-time reirradiation was the most common practice (71%). Interestingly, 9% of respondents would not consider reirradiation.CONCLUSIONAlthough, the vast majority of physicians agree with re-irradiation as a treatment option for DIPG the total doses varied, and further clinical trials are needed.