Brain Metastasis Incidence and Patterns of Presentation After Definitive Treatment of Locally Advanced Non-Small Cell Lung Cancer: A Potential Argument for Brain Magnetic Resonance Imaging Surveillance.

Purpose: Brain metastases (BMs) are a common source of morbidity and mortality. Guidelines do not advise brain surveillance for locally advanced non-small cell lung cancer (LA-NSCLC). We describe the incidence, time to development, presentation, and management of BMs after definitive chemoradiotherapy (CRT). Methods and Materials: We reviewed records of patients with LA-NSCLC treated with CRT within the period from 2013 to 2020. Descriptive statistics were used to characterize the population and the Kaplan-Meier method was used to estimate time to BM. Fisher exact tests and Wilcoxon rank-sum tests were used to compare outcomes between symptomatic and asymptomatic patients. Results: A total of 219 patients were reviewed including 96 with squamous cell carcinoma, 88 with adenocarcinoma, and 35 with large cell/not otherwise specified (LC/NOS). Thirty-nine patients (17.8%) developed BMs: 35 (90%) symptomatic and 4 (10%) asymptomatic. The rate of BM was highest in LC/NOS (34.3%) and adenocarcinoma (23.9%). Ninety percent of BMs occurred within 2 years. All asymptomatic patients underwent stereotactic radiosurgery alone, compared with 40% of symptomatic patients (P = .04). Symptomatic patients were more likely to require hospitalization (65.7% vs 0%, P = .02), craniotomy (25.7% vs 0%, not significant), and steroids (91.4% vs 0%, P < .001). Cumulative BM volume was higher for symptomatic patients (4 vs 0.24 cm3, P < .001) as was median greatest axial dimension (2.18 vs 0.52 cm, P < .001). Conclusions: We identified a high rate of BMs, particularly in LC/NOS and adenocarcinoma histology NSCLC. The majority were symptomatic. These results provide rationale for post-CRT magnetic resonance imaging brain surveillance for patients at high risk of BM.

Association of Unilateral Radiotherapy With Contralateral Lymph Node Failure Among Patients With Squamous Cell Carcinoma of the Tonsil: A Systematic Review and Meta-analysis.

Importance: Ipsilateral neck radiotherapy (RT) is controversial in some patients with tonsil cancer due to concern for nodal failure within the contralateral nonirradiated neck (hereinafter referred to as contralateral neck failure [CNF]). Objective: To determine the rate of CNF following ipsilateral neck RT in patients with tonsil cancer. Data Sources: Databases including PubMed, Embase, Web of Science, and Cochrane Library were queried for peer-reviewed, English language articles published between January 1, 1980, and December 31, 2021. Study Selection: Studies reporting rates of CNF from at least 20 patients treated with ipsilateral neck RT. Studies were excluded if they lacked full text, reported results from databases or systematic reviews, or did not provide RT details. Data Extraction and Synthesis: Data were extracted following the PRISMA reporting guideline. Study quality was assessed using criteria from a methodological index for nonrandomized studies. Pooled outcomes were estimated using random-effects models. Main Outcomes and Measures: Primary outcome was the pooled rate of CNF following ipsilateral neck RT. Secondary outcomes were the pooled rates of CNF by tumor and nodal staging categories from the 7th edition of the AJCC Cancer Staging Manual and rates of toxic effects. Results: A total of 17 studies (16 retrospective and 1 prospective) including 1487 unique patients were identified. The pooled risk of CNF was 1.9% (95% CI, 1.2%-2.6%). The rate of CNF by tumor (T) category was as follows: 1.3% (95% CI, 0.3%-2.3%) for T1; 3.0% (95% CI, 1.6%-4.4%) for T2; 11.3% (95% CI, 3.3%-19.2%) for T3; and 16.0% (95% CI, -7.8% to 39.8%) for T4. Patients with T3 to T4 tumors had a significantly higher rate of CNF than those with T1 to T2 tumors (11.5% [95% CI, 3.9%-19.1%] vs 1.8% [95% CI, 1.0%-2.6%]; P < .001). The rate of CNF by nodal (N) category was 1.2% (95% CI, 0.1%-2.2%) for N0; 4.8% (95% CI, 2.4%-7.2%) for N1; 3.1% (95% CI, 0.4%-5.8%) for N2a; 3.1% (95% CI, 1.2%-4.9%) for N2b; and 0 (95% CI, not applicable) for N3. Rates of CNF were similar for patients with N2b to N3 and N0 to N2a disease (3.0% [95% CI, 1.2%-4.7%] vs 1.7% [95% CI, 0.6%-2.8%], respectively; P = .07). Compared with bilateral RT, ipsilateral RT was associated with increased risk of CNF (log odds ratio, 1.29 [95% CI, 0.09-2.48]; P = .04). The crude rates of xerostomia of grade 3 or greater and feeding tube use were 0.9% (95% CI, -0.2% to 1.9%) and 13.3% (95% CI, 8.3%-18.3%), respectively. Conclusions and Relevance: In this systematic review and meta-analysis, ipsilateral neck RT was associated with a low rate of CNF in patients with small, lateralized tonsil cancers. Bilateral neck RT was associated with lower risk of CNF compared with ipsilateral neck RT. Patients with tumors of a higher T category were at increased risk for CNF following ipsilateral neck RT, and advanced nodal stage was not associated with CNF. Rates of toxic effects appeared favorable in patients treated with ipsilateral neck RT.

Bridging the Communication Gaps: A Prospective Single-Arm Pilot Study Testing the Feasibility of Interdisciplinary Radiotherapy Planning in Locally Advanced Lung Cancer.

RATIONALE AND OBJECTIVES: The treatment of locally advanced lung cancer (LALC) with radiotherapy (RT) can be challenging. Multidisciplinary collaboration between radiologists and radiation oncologists (ROs) may optimize RT planning, reduce uncertainty in follow-up imaging interpretation, and improve outcomes. MATERIALS AND METHODS: In this prospective clinical treatment trial (clinicaltrials.gov NCT04844736), 37 patients receiving definitive RT for LALC, six attending ROs, and three thoracic radiologists were consented and enrolled across four treatment centers. Prior to RT plan finalization, representative computed tomography (CT) slices with overlaid outlines of preliminary irradiation targets were shared with the team of radiologists. The primary endpoint was to assess feasibility of receiving feedback no later than 4 business days of RT simulation on at least 50% of plans. RESULTS: Thirty-seven patients with lung cancer were enrolled, and 35 of 37 RT plans were reviewed. Of the 35 patients reviewed, mean age was 69 years. For 27 of 37 plans (73%), feedback was received within 4 or fewer days (interquartile range 3-4 days). Thirteen of 35 cases (37%) received feedback that the delineated target potentially did not include all sites suspicious for tumor involvement. In total, changes to the RT plan were recommended for over- or undercoverage in 16 of 35 cases (46%) and implemented in all cases. Radiology review resulted in no treatment delays and substantial changes to irradiated volumes: gross tumor volume, -1.9 to +96.1%; planning target volume, -37.5 to +116.5%. CONCLUSION: Interdisciplinary collaborative RT planning using a simplified workflow was feasible, produced no treatment delays, and prompted substantial changes in RT targets.

Intensity-modulated radiotherapy with planned Gamma Knife radiosurgery boost for head and neck cancer with extensive disease in proximity to critical structures.

BACKGROUND: To describe intensity-modulated radiotherapy (IMRT) with Gamma Knife Radiosurgery (GKRS) boost for locally advanced head and neck cancer (HNC) with disease near dose-limiting structures. METHODS: Patients with HNC treated with IMRT/GKRS as part of a combined modality approach between 2011 and 2021 were reviewed. Local control, overall survival and disease-specific survival were estimated using the Kaplan Meier method. RESULTS: Twenty patients were included. Nineteen patients had T3-4 tumors. Median follow-up was 26.3 months. GKRS site control was 95%. Two patients progressed at the treated primary site, one patient failed at the edge of the GKRS treatment volume, with no perineural or intracranial failure. 2-year OS was 94.7% (95% CI: 85.2%-100%). Concurrent chemotherapy was given in nine patients (45%). One patient (5%) received induction/concurrent chemotherapy. Brain radionecrosis occurred in three patients, one of which was biopsy-proven. CONCLUSIONS: IMRT plus GKRS boost results in excellent disease control near critical structures with minimal toxicity.

Discordance Between Oncology Clinician-Perceived and Radiologist-Intended Meaning of the Postradiotherapy Positron Emission Tomography/Computed Tomography Freeform Report for Head and Neck Cancer.

Importance: Assessment of response after radiotherapy (RT) using 18F-fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT) is routine in managing head and neck squamous cell carcinoma (HNSCC). Freeform reporting may contribute to a clinician's misunderstanding of the nuclear medicine (NM) physician's image interpretation, with important clinical implications. Objective: To assess clinician-perceived freeform report meaning and discordance with NM interpretation using the modified Deauville score (MDS). Design, Setting, and Participants: In this retrospective cohort study that was conducted at an academic referral center and National Cancer Institute-designated Comprehensive Cancer Center and included patients with HNSCC treated with RT between January 2014 and December 2019 with a posttreatment PET/CT and 1 year or longer of follow-up, 4 masked clinicians independently reviewed freeform PET/CT reports and assigned perceived MDS responses. Interrater reliability was determined. Clinician consensus-perceived MDS was then compared with the criterion standard NM MDS response derived from image review. Data analysis was conducted between December 2021 and February 2022. Exposures: Patients were treated with RT in either the definitive or adjuvant setting, with or without concurrent chemotherapy. They then underwent posttreatment PET/CT response assessment. Main Outcomes and Measures: Clinician-perceived (based on the freeform PET/CT report) and NM-defined response categories were assigned according to MDS. Clinical outcomes included locoregional control, progression-free survival, and overall survival. Results: A total of 171 patients were included (45 women [26.3%]; median [IQR] age, 61 [54-65] years), with 149 (87%) with stage III to IV disease. Of these patients, 52 (30%) received postoperative RT and 153 (89%) received concurrent chemotherapy. Interrater reliability was moderate (κ = 0.68) among oncology clinicians and minimal (κ = 0.36) between clinician consensus and NM. Exact agreement between clinician consensus and the NM was 64%. The NM-rated MDS was significantly associated with locoregional control, progression-free survival, and overall survival. Conclusions and Relevance: The results of this cohort study suggest that considerable variation in perceived meaning exists among oncology clinicians reading freeform HNSCC post-RT PET/CT reports, with only minimal agreement between MDS derived from clinician perception and NM image interpretation. The NM use of a standardized reporting system, such as MDS, may improve clinician-NM communication and increase the value of HNSCC post-RT PET/CT reports.

Timing of radiotherapy and chemotherapy start for patients treated with definitive concurrent chemoradiation for head and neck cancer.

BACKGROUND: The ideal timing for the initiation of chemotherapy and radiation therapy (RT) in the use of definitive chemoradiation (CRT) for patients with head and neck cancer is not well established. We sought to evaluate the impact of the timing of initiating these two modalities on clinical outcomes. MATERIALS AND METHODS: Patients with squamous cell carcinoma of the head and neck who were treated using definitive chemoradiation from 2012 to 2018 were identified. Patients undergoing re-irradiation, post-op CRT, had recurrent or second primaries, or ECOG 3-4 were excluded. Outcomes including locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated and compared between subgroups of the cohort based on the timing in which chemotherapy or RT were initiated: chemotherapy first, same day start, within 24 h, or start on Monday/Tuesday/Wednesday. RESULTS: A total of 131 patients were included for analysis consisting of oropharynx (64%), larynx (22.9%), nasopharynx (6.9%), hypopharynx (3.1%), oral cavity (1.5%), and unknown primary (1.5%). Chemotherapy was administered as bolus cisplatin every 3 weeks in 40% of patients and weekly cisplatin in 60% with a median cumulative dose of 240 mg/m2. In the multivariable analysis (MVA), starting chemotherapy before RT was associated with improved LRC (HR 0.33, 95% CI: 0.11-0.99). Three-year LRC for patients starting chemotherapy first was 90.9% compared to 78.2% in those starting RT first. In the MVA, cisplatin regimen and cumulative cisplatin dose were associated with improved OS, while no factors were significantly associated with DC or PFS. CONCLUSION: Starting chemotherapy prior to radiation therapy improves LRC, but did not impact DC, PFS, or OS. Clinical outcomes were not different when stratifying by the other differences in the timing of initiating chemotherapy or RT.

Rapid Development of Clinically Symptomatic Radiation Recall Pneumonitis Immediately Following COVID-19 Vaccination.

In this report, we present the case of a 66-year-old man who received local consolidation radiotherapy to the right lung and mediastinum for oligometastatic non-small cell lung cancer (NSCLC) following partial response to upfront chemoimmunotherapy. He continued with maintenance immunotherapy and was asymptomatic for eight months after completing radiation therapy. He then developed symptoms consistent with pneumonitis within three to five days of his first administration of the coronavirus disease 2019 (COVID-19) vaccine injection. He reported that these symptoms significantly intensified within three to five days of receiving his second dose of the vaccine. The clinical time frame and radiographic evidence raised suspicion for radiation recall pneumonitis (RRP). Patients undergoing maintenance immunotherapy after prior irradiation may be at increased risk of this phenomenon that may be triggered by the administration of the COVID-19 vaccine.

Long-Term Outcomes From a Phase 2 Trial of Radiofrequency Ablation Combined With External Beam Radiation Therapy for Patients With Inoperable Non-Small Cell Lung Cancer.

PURPOSE: Long-term outcomes after external beam radiation therapy (EBRT) and radiofrequency ablation (RFA) for medically inoperable early-stage non-small cell lung cancer (NSCLC) are not well known. METHODS AND MATERIALS: Patients with medically inoperable early-stage NSCLC were enrolled in a prospective single-arm, phase 2 study between June 2007 and October 2008 and were treated with RFA followed by EBRT. Radiation was delivered using hypofractionated radiation therapy (HFRT; 70.2 Gy in 26 fractions) or stereotactic body radiation therapy (54 Gy in 3 fractions). RESULTS: Twelve patients were evaluable; 10 patients were treated with HFRT. The cumulative incidence of local progression at 5 years was 16.7% (95% confidence interval [CI], 0-37.8). Median progression-free survival was 37.8 months (95% CI, 11.1 to not reached) and median overall survival was 53.6 months (95% CI, 21.0 to not reached). There were no mortalities within 30 days after RFA and no grade ≥4 toxicity. CONCLUSIONS: The combination of RFA with EBRT appears feasible with favorable long-term local control. However, because SBRT alone has similar or better rates of control, we do not recommend routine combined RFA and EBRT.

Stereotactic body radiotherapy for synchronous early stage non-small cell lung cancer.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC) who present with multiple pulmonary nodules, it is often difficult to distinguish metastatic disease from synchronous primary lung cancers (SPLC). We sought to evaluate clinical outcomes after stereotactic body radiotherapy (SBRT) alone to synchronous primary lesions. MATERIAL AND METHODS: Patients with synchronous AJCC 8th Edition Stage IA-IIA NSCLC and treated with stereotactic body radiation therapy (SBRT) to all lesions between 2009-2018 were reviewed. SPLC was defined as patients having received two courses of SBRT within 180 days for treatment of separate early stage tumors. In total, 36 patients with 73 lesions were included. Overall survival (OS), progression-free survival (PFS), cumulative incidence of local failure (LF), and regional/distant failure (R/DF) were estimated and compared with a control cohort of solitary early stage NSCLC patients. RESULTS: Median PFS was 38.8 months (95% CI 14.3-not reached [NR]); 3-year PFS rates were 50.6% (35.6-72.1). Median OS was 45.9 months (95% CI: 35.9-NR); 3-year OS was 63.0% (47.4-83.8). Three-year cumulative incidence of LF and R/DF was 6.6% (3.7-13.9) and 35.7% (19.3-52.1), respectively. Patients with SPLC were compared to a control group (n = 272) of patients treated for a solitary early stage NSCLC. There was no statistically significant difference in PFS (p = .91) or OS (p = .43). Evaluation of the patterns of failure showed a trend for worse cumulative incidence of R/DF in SPLC patients as compared to solitary early stage NSCLC (p = .06). CONCLUSION: SBRT alone to multiple lung tumors with SPLC results in comparable PFS, OS, and LF rates to a cohort of patients treated for solitary early stage NSCLC. Those with SPLC had non-significantly higher R/DF. Patients with SPLC should be followed closely for failure and possible salvage therapy.

Perineural Invasion As the Sole Pathologic Risk Factor After Surgical Resection for Head and Neck Squamous Cell Carcinoma.

Introduction Postoperative radiotherapy (PORT) is routinely recommended for patients with head and neck squamous cell carcinoma (HNSCC) based on pathologic risk factors (pRFs) such as perineural invasion (PNI). Patients with PNI as the sole pRF after resection of HNSCC are uncommon and their prognosis is less clear. The aim of this study is to assess the role of PNI as a sole risk factor in patients with otherwise pathologically low-risk HNSCC. Methods Patients with HNSCC of the oral cavity, pharynx, or larynx treated with primary surgical resection from 2013 to 2018 were identified from an institutional cancer registry. Those with pRFs (pathologic T3-4 disease, lymphovascular space invasion [LVSI], multiple positive lymph nodes, close [within 2 mm] or positive margins, extranodal extension [ENE], or recurrent disease) were excluded, yielding an otherwise pathologically low-risk cohort with or without incidental, pathologic PNI. Locoregional control (LRC), overall survival (OS) and disease-specific survival (DSS) were estimated and compared between PNI groups and by adjuvant therapy. Results A total of 1,058 patients were identified as having undergone surgical resection. Exclusion of patients with other pRFs, those with unknown PNI, and oral cavity patients with depth of invasion > 10 mm yielded a study cohort of 85 patients. Eight patients (10% of study group, <1% of all patients) had PNI as the sole pRF, none of which had clinical signs or symptoms of perineural tumor spread. The remaining 77 were negative for PNI and thus pathologically low risk. Patients with PNI were more likely to have oral cavity cancer, to be younger, and to have received PORT than those without PNI; no patient received concurrent chemotherapy. At a median follow-up of 46.4 months, two- and five-year LRC rates were 81.4% and 78.5%, respectively. No differences were noted between PNI-positive and PNI-negative groups (p=0.73) or PORT v. no-PORT groups (p=0.39). While the utility of PORT is not possible to assess given limited sample size, four patients with PNI who did not receive PORT did not experience locoregional failure. Seventeen patients overall experienced locoregional failure and 14 were ultimately salvaged. Five-year OS and DSS were 77.4% and 90.8%, respectively. Conclusion Patients with pathologically low-risk HNSCC after surgical resection experience high rates of LRC. In this large institutional cohort, PNI as the sole pRF was exceedingly rare, and the benefit of adjuvant therapies is difficult to assess. Within this limitation, PORT remains the standard of care for patients with PNI to reduce the risk of locoregional failure. Further collaborative studies are required to adequately assess the prognostic impact of PNI alone in resected HNSCC.

Impact of dose to lung outside the planning target volume on distant metastasis or progression after SBRT for early-stage non-small cell lung cancer.

Mean dose (EQD2) to 3-cm shell of lung surrounding the PTV was evaluated for association with distant metastasis and PFS after SBRT for stage I NSCLC. Dose was uniformly above previously determined threshold and metastasis was uncommon. An association between outcomes and mean EQD2 could not be confirmed or refuted.

Cisplatin/5-Fluorouracil (5-FU) Versus Carboplatin/Paclitaxel Chemoradiotherapy as Definitive or Pre-Operative Treatment of Esophageal Cancer.

Purpose To determine the efficacy and toxicity of two standard chemotherapy regimens used concurrent with radiation for the treatment of esophageal cancer: cisplatin/5-fluorouracil (5-FU) and carboplatin/paclitaxel. Materials and methods We prospectively reviewed records of 364 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy (CRT) with or without resection. All patients received surgical evaluation and imaging at presentation as well as following completion of their course of CRT. Treatment and prognostic variables were compared across the two chemotherapy regimens. Results We identified 261 patients treated with concurrent carboplatin/paclitaxel (n = 133) or cisplatin/5-FU (n = 128). Weight loss during CRT was lower in patients receiving carboplatin/paclitaxel (median: 7.0 pounds; 4.1% body weight) vs. cisplatin/5-FU (median: 11.0 pounds; 6.5% body weight) (p < 0.01). In 117 patients receiving trimodality therapy, post-operative death rates within one month of resection were similar. Pathologic complete response was better with carboplatin/paclitaxel vs. cisplatin/5-FU, 29.6% vs. 21.8% (p = 0.03), respectively. In the multivariable analysis, there was no association between chemotherapy regimen and overall survival (OS) or progression-free survival (PFS), though there was a trend toward improved OS with carboplatin/paclitaxel with a HR = 0.75 (p = 0.08). Further analysis revealed that trimodality therapy and stage were predictors for improved OS and PFS while female gender and grade predicted for improved PFS. Conclusions Carboplatin/paclitaxel was associated with decreased weight loss and improved pathologic response for trimodality patients when compared to cisplatin/5-FU. We observed no differences in OS, PFS, or post-operative death by chemotherapy regimen for both the entire cohort and trimodality patients.

Five- Versus Ten-Fraction Regimens of Stereotactic Body Radiation Therapy for Primary and Metastatic NSCLC.

INTRODUCTION: At our institution, stereotactic body radiotherapy (SBRT) has commonly been prescribed with 50 Gy in 5 fractions and in select cases, 50 Gy in 10 fractions. We sought to evaluate the impact of these 2 fractionation schedules on local control and survival outcomes. METHODS: We reviewed patients treated with SBRT with 50 Gy/5 fraction or 50 Gy/10 fraction for early-stage non-small cell lung cancer (NSCLC) and metastatic NSCLC. Cumulative incidence of local failure (LF) was estimated using competing risk methodology. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method only for patients with stage I disease. RESULTS: Of the 353 lesions, 300 (85%) were treated with 50 Gy in 5 fractions and 53 (15%) with 10 fractions. LFs at 3 years were 6.5% and 23.9% and Kaplan-Meier estimate of median time to LF was 17.5 months and 26.2 months, respectively. Multivariable analysis revealed increasing planning target volume (hazard ratio 1.01, P = .04) as an independent predictor of increased LF, but tumor size, ultracentral location, and 10 fractions were not. Among patients with stage I NSCLC (n = 298), overall median PFS was 35.6 months and median OS was 42.4 months. There was no difference in PFS or OS between the 2 treatment regimens for patients with stage I NSCLC. Low rates of grade 3+ toxicity were observed, with 1 patient experiencing grade 3 pneumonitis after a 5-fraction regimen of SBRT. CONCLUSION: Dose-fractionation schemes with BED10 ≥ 100 Gy provide superior local control and should be offered when meeting commonly accepted constraints. If those regimens appear unsafe, 50 Gy in 10 fractions may provide acceptable compromise between tumor control and safety with relatively durable control, and minimal negative impact on long-term survival.

Multi-Contrast Super-Resolution MRI Through a Progressive Network.

Magnetic resonance imaging (MRI) is widely used for screening, diagnosis, image-guided therapy, and scientific research. A significant advantage of MRI over other imaging modalities such as computed tomography (CT) and nuclear imaging is that it clearly shows soft tissues in multi-contrasts. Compared with other medical image super-resolution methods that are in a single contrast, multi-contrast super-resolution studies can synergize multiple contrast images to achieve better super-resolution results. In this paper, we propose a one-level non-progressive neural network for low up-sampling multi-contrast super-resolution and a two-level progressive network for high up-sampling multi-contrast super-resolution. The proposed networks integrate multi-contrast information in a high-level feature space and optimize the imaging performance by minimizing a composite loss function, which includes mean-squared-error, adversarial loss, perceptual loss, and textural loss. Our experimental results demonstrate that 1) the proposed networks can produce MRI super-resolution images with good image quality and outperform other multi-contrast super-resolution methods in terms of structural similarity and peak signal-to-noise ratio; 2) combining multi-contrast information in a high-level feature space leads to a significantly improved result than a combination in the low-level pixel space; and 3) the progressive network produces a better super-resolution image quality than the non-progressive network, even if the original low-resolution images were highly down-sampled.

Reirradiation Using Permanent Interstitial Brachytherapy: A Potentially Durable Technique for Salvaging Recurrent Pelvic Malignancies.

PURPOSE: To present a time-to-failure (TTF) analysis for all patients treated with permanent interstitial brachytherapy (PIB) at our institution, with additional analyses to correlate successful reirradiation and to identify the frequency of severe grade 3 to 4 toxicity. METHODS AND MATERIALS: Forty-two previously irradiated patients received curative or palliative intent PIB for a recurrent pelvic malignancy between January 2009 and August 2016. Minimum follow-up was 6 months after the PIB procedure. All patients had a biopsy-proven recurrence and were treated using PIB alone (n=32) or in combination with a short course of additional radiation therapy (n=10). Competing risk analyses were performed to assess the risk of failures in the presence of death without failure. Exploratory analyses were performed for factors related to failure using competing risk analyses and the Gray statistic. RESULTS: A total of 61 PIB implants were performed among 42 patients with a median follow-up of 16.3 months. Fifty-two implants were performed as the first salvage reirradiation to a solitary recurrence (8 patients had more than 1 lesion); the success rate for initial reirradiation using PIB was 73% (38 cases out of 52), and the median TTF was not reached. Nine patients underwent a second repeat PIB to the same recurrence as a form of salvage; 3 (33%) remain without evidence of recurrence. The median TTF after second salvage was 7.7 months. Even with the limited sample size, prolonged TTF was marginally associated with definitive intent (P=.07) and the extent of disease at the time of PIB (P=.08). Grade 3+ toxicities were seen in 8 patients (16.7%). CONCLUSIONS: Permanent interstitial brachytherapy is a feasible and potentially durable treatment modality that can be used to curatively salvage selected recurrent pelvic malignancies in a previously irradiated field.

Host mediated inflammatory influence on glioblastoma multiforme recurrence following high-dose ionizing radiation.

Despite optimal clinical treatment, glioblastoma multiforme (GBM) inevitably recurs. Standard treatment of GBM, exposes patients to radiation which kills tumor cells, but also modulates the molecular fingerprint of any surviving tumor cells and the cross-talk between those cells and the host. Considerable investigation of short-term (hours to days) post-irradiation tumor cell response has been undertaken, yet long-term responses (weeks to months) which are potentially even more informative of recurrence, have been largely overlooked. To better understand the potential of these processes to reshape tumor regrowth, molecular studies in conjunction with in silico modeling were used to examine short- and long-term growth dynamics. Despite survival of 2.55% and 0.009% following 8 or 16Gy, GBM cell populations in vitro showed a robust escape from cellular extinction and a return to pre-irradiated growth rates with no changes in long-term population doublings. In contrast, these same irradiated GBM cell populations injected in vivo elicited tumors which displayed significantly suppressed growth rates compared to their pre-irradiated counterparts. Transcriptome analysis days to weeks after irradiation revealed, 281 differentially expressed genes with a robust increase for cytokines, histones and C-C or C-X-C motif chemokines in irradiated cells. Strikingly, this same inflammatory signature in vivo for IL1A, CXCL1, IL6 and IL8 was increased in xenografts months after irradiation. Computational modeling of tumor cell dynamics indicated a host-mediated negative pressure on the surviving cells was a source of inhibition consistent with the findings resulting in suppressed tumor growth. Thus, tumor cells surviving irradiation may shift the landscape of population doubling through inflammatory mediators interacting with the host in a way that impacts tumor recurrence and affects the efficacy of subsequent therapies. Clues to more effective therapies may lie in the development and use of pre-clinical models of post-treatment response to target the source of inflammatory mediators that significantly alter cellular dynamics and molecular pathways in the early stages of tumor recurrence.

Outpatient template-guided permanent interstitial brachytherapy using 131Cs in gynecologic malignancies: Initial report.

PURPOSE: Optimal curative intent brachytherapy for certain gynecologic cancers requires interstitial brachytherapy, often using template-guided techniques such as a Syed-Neblett implant. Whether high or low dose rate (LDR), these procedures pose significant risks to patients, partly attributable to the prolonged period of bed rest. Published results of free-handed permanent interstitial brachytherapy (PIB) with 131Cs demonstrate it to be an effective modality for the management of small volume gynecologic cancers. This report is the first to describe a permanent template-guided interstitial technique using 131Cs for gynecologic cancers, performed as an LDR outpatient procedure. METHODS AND MATERIALS: Five sequential patients with recurrent or primary gynecologic malignancies underwent template-guided PIB using 131Cs. A posttreatment planning CT was obtained immediately after the procedure and again 3-4 weeks later. Both CT data sets were fused and the relative positions compared to assess for migration in the x, y, and z planes. Seed positions as well as dosimetric parameters including D90, D100, V100, and the dose to 2 cc of rectum and bladder were compared to quantify migration of sources and the resulting effect, if any, on the treatment. RESULTS: The median age was 69 years (range 64-85). All patients received a template-guided 131Cs PIB implant to treat gross disease. All 5 patients had significant medical comorbidities that limited treatment options. Considering all 5 patients, a total of 40 interstitial needles were placed. Ten needles carried only Vicryl-stranded sources, and 30 needles carried a combination of stranded 131Cs seeds and free seeds. Needle count was between 6 and 10 needles per patient, with active lengths of 4-10 cm. The median dose was 30 Gy (range 25-55 Gy) to permanent decay, enabling a cumulative median biological effective dose 91.5 Gy (range 60.9-92.1 Gy) and equivalent dose at 2 Gy per fraction 75.9 Gy (range 50.7-76.8 Gy). All implants were performed as outpatient procedures with only the first patient admitted for 23-hour observation. All calculated median migration distances were less than 1 cm in the axial, sagittal, or coronal planes. In 69.2% cases, the individual seed migration was <5 mm. Strand migration appeared directly related to peripheral placement and the use of stranded sources. The median D90, D100, and V100 were compared between study sets, and no significant differences were identified. No Grade 3 or higher complications occurred. CONCLUSIONS: Permanent LDR template-guided PIB using 131Cs can be safely performed on an outpatient basis. Compared to currently used template-guided techniques, the use of 131Cs avoids prolonged bed rest and hospitalization, significantly lowers cost, and enables a higher cumulative dose. Seed migration is minimal with this technique. Early experience suggests that the technique is safe and merits further study.