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INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009–2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm(3) and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

PURPOSE IDH wild-type (WT) glioblastoma (GBM) is an aggressive tumor with poor survival despite current therapies. The aim of this study was to characterize its genomic profile and determine whether a particular molecular signature is associated with improved survival outcomes. PATIENTS AND METHODS Tumor samples from 232 patients with IDH-WT GBM were sequenced, and the landscape of genomic alterations was fully delineated. Genomics data from The Cancer Genome Atlas (TCGA) cohort were analyzed for confirmation. Association of alterations with survival was evaluated in both univariable and multivariable approaches. RESULTS The genomic landscape of IDH-WT GBM revealed a high frequency of CDKN2A/B loss, TERT promoter mutations, PTEN loss, EGFR alteration, and TP53 mutations. Novel variants or gene mutations, such as ARID1B and MLL2, were identified. To better understand synergistic effects and facilitate decision making for precision medicine, we identified 11 pairs of gene alterations that tended to co-occur or were mutually exclusive, which were confirmed in the TCGA cohort. Survival analysis showed that genomic alterations in TP53 were associated with worse overall survival (OS). However, alterations in PI3K class I genes were associated with significantly better OS (univariable analysis: P = .002; multivariable analysis: hazard ratio [HR], 0.5785; P = .00162) and longer progression-free survival (univariable analysis: P = .0043; multivariable analysis: HR, 0.6228; P = .00913). CONCLUSION Genomic alterations in PI3K class I are a favorable prognostic factor in IDH-WT GBM. This new prognostic biomarker may facilitate risk stratification of patients, assist in clinical trial enrollment, and provide potential therapeutic targets

Tumor samples from 232 patients withThe genomic landscape ofGenomic alterations in PI3K class I are a favorable prognostic factor in

Multisession staged stereotactic radiosurgery (SRS) represents an alternative approach for management of large brain metastases (LBMs), with potential advantages over fractionated SRS. This study investigated clinical efficacy and safety of 2-stage stereotactic radiosurgery (2-SSRS) in patients with LBMs.Patients with LBMs treated with 2-SSRS between 2014 and 2020 were evaluated. Demographic, clinical, and radiologic data were obtained. Volumetric measurements at first SRS session, second SRS session, and follow-up imaging studies were obtained. Characteristics that might predict response to 2-SSRS were evaluated through Fisher exact or Mann-Whitney U test.The study included 24 patients with 26 LBMs. Median (range) marginal doses for first and second SRS sessions were 15 Gy (14-18 Gy) and 15 Gy (12-16 Gy), respectively. Median (range) tumor volumes at first SRS session, second SRS session, and 3-month follow-up were 8.1 cmOur study supports the effectiveness and safety of 2-SSRS as a treatment modality for patients with LBMs, especially in poor surgical candidates. The local failure rate and low occurrence of adverse effects are comparable to other staged radiosurgery studies.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Nuclear protein in testis (NUT) carcinoma is a rare, highly aggressive, undifferentiated carcinoma that harbors a characteristic rearrangement of the NUTM1 gene. The majority arise in adolescents and young adults especially from the midline structures of the thorax, head, and neck. Until the present, there have only been three reported cases of NUT carcinoma of the submandibular gland, two of which were reported in children and another one in an adult from Korea. Here, we report the first case of NUT carcinoma arising in the submandibular gland of an adult female in the United States, representing the fourth case worldwide. A fine needle aspiration and biopsy was performed, and the diagnosis was confirmed by NUT immunohistochemical staining and fusion of the BRD4 (19p13.12) and NUTM1 (15q14) gene loci by fluorescence in-situ hybridization on the resection specimen. Salivary gland is an unusual site for NUT carcinoma and is rarely described in submandibular gland. We reviewed the clinicopathologic features of this entity at this site along with role of NUTM1 gene rearrangements in NUT tumorigenesis.

Background Prior retrospective and prospective studies suggest improved survival with the use of stereotactic radiosurgery (SRS) and bevacizumab in the treatment of limited-volume glioblastoma (GBM) recurrences. Methods We retrospectively reviewed our experience with gamma knife SRS in combination with bevacizumab for the treatment of focal GBM recurrence during 2009–2015. Outcomes include overall survival, progression free survival (PFS), and radiation-related adverse events. Kaplan–Meier methods and multivariable Cox proportional hazards models were performed for survival analysis. Results Within a median of 13.7 months after diagnosis, a total of 45 patients with GBM underwent gamma knife SRS and bevacizumab treatment. Median age was 57 years (range: 20–78 years) and 63.3% were women. The median Karnofsky Performance Score (KPS) at recurrence was 80 (range: 40–100). Sixty-four percent of patients had single radiosurgery target (range: 1–4) and median target volume and margin dose were 2.2 cm3 (range: 0.1–25.2 cm3) and 17.0 gray (Gy) (range: 13–24 Gy), respectively. Median PFS and overall survival were 9.3, 31.0 months following diagnosis, and 5.2, 13.3 months after SRS, respectively. Factors associated with poor outcomes were KPS ≤70, SRS dose Conclusions SRS in combination with bevacizumab can be safely used to treat focal GBM recurrence. KPS, radiation dose, and multi-agent chemotherapy usage prior to SRS demonstrated significant impact on PFS. Bevacizumab may provide clinically relevant radioprotection.

BACKGROUND Recurrent glioblastoma (rGBM) treatment is not well defined and multiple therapeutic approaches have been proposed, none of which has shown to prolong survival in randomized trials. The role of reoperation for rGBM is still unclear. While most studies demonstrate improve overall survival (OS) and post-progression survival (PPS), recent studies employing time-dependent analysis appear to undermine the OS benefit in reoperated patients. Moreover, the relevance of rGBM molecular subtypes that benefit from reoperation is an important question that may guide clinical decision-making. METHODS A retrospective review of rGBM demographics, clinical, molecular, and outcome characteristics was performed for all cases managed by us between 01/2005 to 10/2019 at our institution. IDH1/IDH2 status was determined by immunohistochemistry and/or next-generation sequencing (NGS). A genetic subanalysis was conducted for most rGBM IDH-wildtype (IDH-WT) by NGS. The primary outcome was PPS. Kaplan-Meier method, multivariable Cox proportional-hazards model, and accelerated failure time model were performed in survival analysis. Random survival forest was applied to identify variable importance. RESULTS 284 rGBM patients fulfill inclusion criteria, 145 (51.1%) had reoperation at their 1st recurrence. Reoperated patients were significantly younger, had better performance status, and had a higher extent of resection at initial surgery; meanwhile, they were less likely to receive bevacizumab. Patients undergoing reoperation experienced superior PPS (11.5 vs. 7.4, months, log-rank test: p= 0.002), which kept consistent in multivariable Cox model (HR: 0.62, p= 0.001). Moreover, reoperated rGBM IDH-WT (N= 238) had 37% reduced risk of post-progression death compared to non-reoperated patients. A subanalysis of rGBM IDH-WT molecular subtypes identified that EGFR mutant, NF1 wildtype, and TP53 wildtype subgroups could benefit from reoperation (all p< 0.008). CONCLUSIONS Maximal safe re-resection improved the PPS of rGBM regardless of their IDH status. Reoperation for 1st recurrence was especially beneficial for GBM IDH-WT harboring EGFR alteration, TP53 WT, and NF1-WT.

OBJECTIVES To investigate the impact of biopsy preceding resection compared to upfront resection in glioblastoma overall survival (OS) and post-operative outcomes using the National Cancer Database (NCDB). METHODS A total of 17,334 GBM patients diagnosed between 2010 and 2014 were derived from the NCDB. Patients were categorized into two groups: “upfront resection” versus “biopsy followed by resection”. Primary outcome was OS. Post-operative outcomes including 30-day readmission/mortality, 90-day mortality, and prolonged length of inpatient hospital stay (LOS) were secondary endpoints. Kaplan-Meier methods and accelerated failure time (AFT) models with gamma distribution were applied for survival analysis. Multivariable binary logistic regression models were performed to compare differences in the post-operative outcomes between these groups. RESULTS Patients undergoing “upfront resection” experienced superior survival compared to those undergoing “biopsy followed by resection” (median OS: 12.4 versus 11.1 months, log-rank test: P=0.001). In multivariable AFT models, significant survival benefits were observed among patients undergoing “upfront resection” (time ratio [TR]: 0.83, 95% CI: 0.75–0.93, P=0.001). Patients undergoing upfront GTR had the longest survival compared to upfront STR, GTR following STR, or GTR and STR following an initial biopsy (14.4 vs. 10.3, 13.5, 13.3, and 9.1, months), respectively (TR: 1.00 [Ref.], 0.75, 0.82, 0.88, and 0.67). Recent years of diagnosis, higher income and treatment at academic facilities were significantly associated with the likelihood of undergoing upfront resection after adjusting the covariates. Multivariable logistic regression revealed that 30-day mortality and 90-day mortality were decreased by 73% and 44% for patients undergoing “upfront resection” over “biopsy followed by resection”, respectively (both p < 0.001). CONCLUSIONS Pre-operative biopsies for surgically accessible tumors with characteristic imaging features of Glioblastoma lead to worse survival despite subsequent resection compared to patients undergoing upfront resection.

INTRODUCTION Resection is a well-established treatment for BM ≥ 2 cm, albeit with potential for perioperative complications and delays in systemic treatment. Staged stereotactic radiosurgery (S-SRS) may improve outcomes versus traditional SRS, representing an alternative to surgery in responders. We reviewed institutional outcomes using 2-session S-SRS, focusing on lesion volume kinetics. METHODS 25 patients with 27 lesions underwent S-SRS at our institution between 2014 and 2020. Tumor volumes (TV) were measured at both S-SRS sessions and on follow-up MRI studies. RESULTS Median age at S-SRS was 61 years (range (r:) 31–84). Nine patients (10 BM) were lost to follow-up. Two patients failed to receive their second S-SRS due to local progression. The median margin tumor doses at first and second S-SRS were 15 Gy (r: 12–18 Gy) and 15 Gy (r: 12–16 Gy). The median interval between stages was 32 days (r: 8–63), and median TV at the first and second stages were 9.3 cm3 (r: 1.5–34.7 cm3) and 3.3 cm3 (r: 0.76–26.1 cm3), respectively. The median absolute and relative decrement between S-SRS sessions was 3.7 cm3 (r: 2.8-16.5 cm3) and 49.5% (r: 17.1-87.1%), respectively. [1-2]-month, [3-5]-month, and [6-12]-month MRI scans were available for 17, 10, and 15 lesions. The median decrease in TV compared to baseline was 50.2%, 78.2%, 74.9%. Two of 17 lesions (12%) had initial control but subsequently experienced volumetric progression and required resection. There were no G3+ adverse events (AE). Crude tumor control was achieved in 14 of 17 individual lesions (82%). CONCLUSION Two-session S-SRS is an effective treatment modality for treating patients with large BM, which is feasible in over 80% of patients with sustained tumor control and early volumetric regression.

Previous studies have demonstrated possible differences in glioblastoma (GBM) survival attributable to ethnicity. The goal of this study was to quantify oncogenic differences and evaluate the overall survival (OS) and progression-free survival (PFS) differences in GBM patients across race/ethnicity using both population-based surveillance and institutional data sets from the United States (US) and Mexico.Retrospective cohort study comprising the Texas Cancer Registry (TCR, n = 4134) and referral institutions located in US (n = 254) and Mexico (n = 47) were evaluated. Primary outcomes include OS and PFS. Oncogenic differences attributable to ethnicity were assessed. IDH1/IDH2 status was evaluated by sequencing in US and Mexico samples. Kaplan-Meier and Cox proportional hazards regression for survival analysis.A total of 4134 GBM patients were identified from the TCR data set, ethnicity comparison demonstrated that Hispanic patients were diagnosed at a significantly younger age compared to non-Hispanic white patients (NHW) (median: 58 vs. 62, P0.001) and had improved OS (hazard ratio: 0.82, P0.001). In the oncogenic analysis, we observed a significant enrichment of IDH1/IDH2 mutations in Mexican Hispanic patients compared to US Hispanic patients (29.8% vs. 7.9%, P = 0.012); IDH2 mutations drove this difference. Post-progression survival was significantly shorter in patients from Mexico than US (3.0 vs. 11.4 months; P0.001), while OS remained similar.IDH2 mutations are more prevalent in Mexican Hispanic individuals compared to US individuals and may be a crucial contributor to the previously reported survival benefit of Hispanic individuals in large population databases. These findings are critical for both screening of IDH2 mutations and targeted interventions in GBM.

Objective To determine the feasibility of a Gamma Knife boost after intensity-modulated radiation therapy in combination with multimodal therapy in patients with nasopharyngeal carcinoma and sinonasal malignancies with skull base or cavernous sinus involvement. Methods Nine patients were treated with intensity-modulated radiation therapy followed by a Gamma Knife boost. In one case Gamma Knife was given as salvage treatment after resection. Five patients had sinonasal malignancies and 4 had nasopharyngeal carcinoma. The mean radiation therapy dose was 64.3 Gy (range, 54–70 Gy) at 2 Gy per fraction. The median interval from completion of radiation therapy to Gamma Knife boost was 2.2 months (range, 1–4 months). The most common indication for Gamma Knife boost was involvement of the cavernous sinus, which was identified in 7 patients. The median margin Gamma Knife dose delivered was 13 Gy (range, 12–20 Gy), with median prescription isodose of 50%. Results All patients tolerated the procedure well, with minimal toxicity. Local control rates were achieved in all patients and no acute grade 3–5 toxicity was observed. One patient experienced late grade 4 toxicity, which was potentially attributable to treatment. Distant failure occurred in 3 patients (1 patient with nasopharyngeal carcinoma and 2 patients with sinonasal malignancies). Conclusions Planned Gamma Knife boost followed intensity-modulated radiation therapy is feasible, safe, and provides excellent local control in patients with sinonasal malignancies and nasopharyngeal carcinoma, particularly in cases with cavernous sinus involvement. Further follow-up will be necessary to determine the long-term effectiveness and complication profile.

Background Meningiomas are the most common primary intracranial tumors. The current diagnosis and treatment of meningioma is dependent on computed tomography and magnetic resonance imaging, with follow-up management relying mainly on magnetic resonance imaging. The limitations of these structural imaging modalities include delineation of the tumor extent, tumor grade, and differentiation from other meningioma mimickers, especially in or around the skull base. Because studies with positron emission tomography (PET) have shown that PET is able to fulfill some of these gaps, the use of PET for meningiomas has been steadily increasing. Fluciclovine, also known as anti-1-amino-3-[18F]-fluorocyclobutane-1-carboxylic acid (Axumin), is a new PET radiotracer approved by the Food and Drug Administration in 2016 for the detection of suspected recurrent prostate cancer with elevated prostate-specific antigen levels. Because the radiotracer is new, very little is known about the utility of this tracer in brain tumors. Case Description We present 3 cases of meningioma with avid uptake of fluciclovine. In each of these cases, the meningioma was incidentally found during surveillance using PET imaging in patients with prostate cancer. Conclusions These cases illustrate that this new radiotracer has the potential to be a complementary tool in the meningioma workup, treatment, and follow-up, especially for skull base lesions.

Cognitive dysfunction is common among patients with intracranial tumors. Most cognitive deficits are subtle, lack specificity, may mimic depression or other neurological disorders and may be recognized in retrospect by the physician. In certain cases, distinguishing between tumor recurrence and cognitive deficits that arise as a consequence of the treatment becomes challenging. Late treatment effects have also become an area of focus as the overall survival and prognosis of patients with brain tumors increases. New data has highlighted the importance of less toxic adjuvant therapies owing to their positive impact on prognosis and quality of life. Various experimental therapies and genetic influences on individual sensitivity towards injury are promising steps towards a better management strategy for cognitive dysfunction. In this literature review, we discuss cognitive dysfunction as a manifestation of intracranial tumors, treatment modalities such as radiotherapy, chemotherapy, surgery and their impact on cognition and patients' quality of life. We also discuss management options for cognitive dysfunction and emerging therapies.

BACKGROUND AND OBJECTIVE Recurrent and anaplastic pleomorphic xanthoastrocytoma (PXA) tumors are challenging to treat due to their rarity and lack of management consensus. About 80% of PXAs harbor BRAF gene mutation. Although the development of BRAF inhibitors has dramatically improved the outcomes for patients with BRAF V600E mutant tumors, resistance develops in the majority of cases. We hypothesize that dual BRAF/MEK inhibitors therapy can improve tumor control and patient survival without added toxicity. METHODS Medical records from 2010 to 2021 in Memorial Hermann Texas Medical Center were reviewed. Patients diagnosed with PXA who received BRAF and/or MEK inhibitors therapies were identified. The data evaluated included age, sex, treatment received, side effects, and outcomes, as well as results from blood tests, pathology, next generation sequencing and MRI. Side effects were evaluated according to the CTCAE Version 5.0. RESULTS Five patients with recurrent or anaplastic PXA were identified. The median age at diagnosis was 22 years old (range 14-66 years old), with 60% male, and 60% grade III. All patients received BRAF/MEK dual inhibitors therapy at various stages of PXA treatment. The median follow-up was 72 months (range 17-108 months). One patient (66 years old) experienced short-term disease stability for 5 months and who died from tumor related brain hemorrhage while off therapy for 9 months. Four patients experienced long-term disease control (17, 22, 94, 108 months, respectively) while three of them remain on dual therapy and one patient died from systemic PXA progression. Dual BRAF/MEK inhibitors were well tolerated with only grade 1-2 adverse effects (AE) including skin rash, fatigue, mild abdominal discomfort, diarrhea. No grade III-V AE were detected. CONCLUSION BRAF/MEK dual inhibitor can provide potential clinical benefit to PXA patients with BRAF mutations. Our study supports the concurrent use of BRAF/MEK inhibitors for best tumor control without unexpected AE.

Background The lymphatic vasculature provides a route for cancer metastases, and its dysfunction after cancer treatment can result in lymphedema. However, changes in the lymphatics before, during, and after surgery and radiation remain unclear. Methods Near-infrared fluorescence lymphatic imaging was performed before and after lymph node dissection and fractionated radiotherapy to assess changes in external lymphatic function. Results Patients who underwent both lymph node dissection and radiotherapy developed lymphatic dermal backflow on treated sides ranging from days after the start of radiotherapy to weeks after its completion, whereas contralateral regions that were not associated with lymph node dissection but also treated with radiotherapy experienced no such changes in external lymphatic anatomies. Conclusion The external lymphatics undergo transient changes during and weeks after lymph node dissection and radiotherapy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1177-1188, 2017.

OBJECTIVEThe object of this study was to investigate the impact of facility type (academic center [AC] vs non-AC) and facility volume (high-volume facility [HVF] vs low-volume facility [LVF]) on low-grade glioma (LGG) outcomes.METHODSThis retrospective cohort study included 5539 LGG patients (2004–2014) from the National Cancer Database. Patients were categorized by facility type and volume (non-AC vs AC, HVF vs LVF). An HVF was defined as the top 1% of facilities according to the number of annual cases. Outcomes included overall survival, treatment receipt, and postoperative outcomes. Kaplan-Meier and Cox proportional-hazards models were applied. The Heller explained relative risk was computed to assess the relative importance of each survival predictor.RESULTSSignificant survival advantages were observed at HVFs (HR 0.67, 95% CI 0.55–0.82, p < 0.001) and ACs (HR 0.84, 95% CI 0.73–0.97, p = 0.015), both prior to and after adjusting for all covariates. Tumor resection was 41% and 26% more likely to be performed at HVFs vs LVFs and ACs vs non-ACs, respectively. Chemotherapy was 40% and 88% more frequently to be utilized at HVFs vs LVFs and ACs vs non-ACs, respectively. Prolonged length of stay (LOS) was decreased by 42% and 24% at HVFs and ACs, respectively. After tumor histology, tumor pattern, and codeletion of 1p19q, facility type and surgical procedure were the most important contributors to survival variance. The main findings remained consistent using propensity score matching and multiple imputation.CONCLUSIONSThis study provides evidence of survival benefits among LGG patients treated at HVFs and ACs. An increased likelihood of undergoing resections, receiving adjuvant therapies, having shorter LOSs, and the multidisciplinary environment typically found at ACs and HVFs are important contributors to the authors’ finding.

Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration.

Over the past century, definitive management of unresectable cervical cancer has evolved and currently employs high-dose radiation treatment with teletherapy and intracavitary brachytherapy (ICBT) components, combined with concurrent chemotherapy. Reflecting high disease prevalence among developing nations, the International Federation of Gynecology and Obstetrics (FIGO) staging of cervical cancer relies on clinical assessment, with limited radiographic studies. However, multiple clinicopathologic analyses describe suboptimal correlation between clinical examination findings and pathologic stage. Over the past two decades, systematic evaluation of volumetric and functional imaging modalities including CT, MRI, and PET-CT has refined our ability to define disease extent and provide posttreatment surveillance. Similarly, traditional ICBT techniques relied on two-dimensional (2D) data for evaluation of target dose coverage and offered limited assessment of exposure to critical structures including the bladder, rectum, and sigmoid colon. During the last several years, investigators at leading European centers have enhanced the capabilities of existing ICBT techniques through dose optimization [high-dose rate (HDR) and pulsed dose rate (PDR)] and by incorporating volumetric imaging methods. Early results are encouraging, from both toxicity and tumor control perspectives. These techniques are currently being adopted in multiple centers. Pertinent aspects are summarized in the body of this report.

Stereotactic body radiation therapy (SBRT) developed as a result of technological advances in image-guided radiotherapy (IGRT), treatment planning, body stereotaxis, and motion management allows precise delivery of biologically potent dose to the tumor targets. Preclinical and clinical studies of SBRT have now demonstrated very promising results without significant toxicity in the treatment of primary and metastatic renal cell carcinoma (RCC) lesions. The additional benefit of SBRT may be the abscopal (distant bystander) effect, mediated by an immunological response. In addition, high single-dose radiation such as SBRT may overcome radioresistance of RCC caused by the von Hippel-Lindau (VHL) tumor-suppressor gene mutation and hypoxia-inducible factor-1 (HIF-1). As radiotherapy is not considered as a definitive treatment of RCC, a combination of radiotherapy and various systemic therapies has not been examined. However, SBRT could change the role of radiotherapy for RCC, and the development of combination therapy needs to be explored in the future trials. This review focused on the role of SBRT in the treatment of primary and metastatic RCC.

Objectives To evaluate biochemical non-evidence of disease and adverse events of salvage intensity-modulated radiotherapy using an endorectal balloon for prostate cancer patients after radical prostatectomy. Methods Data of 107 patients (median age 65 years) with persistent (>0.1 ng/mL) or rising prostate-specific antigen after radical prostatectomy were retrospectively analyzed. The mean dose to clinical target volume was 70 Gy in 32 fractions (the equivalent dose in 2 Gy fraction is 73.2 Gy based on α:β = 2). Biochemical non-evidence of disease and predictive factors were assessed. Genitourinary toxicity and gastrointestinal toxicity were also evaluated using the Radiation Therapy Oncology Group toxicity criteria. Results The median follow up was 37 months (range 6–126 months). A total of 48 patients developed biochemical recurrence. The 3- and 5-year biochemical non-evidence of disease rates of all patients were 52.6% and 48.8%, respectively. The Gleason score (≥4 + 3, ≤3 + 4) and pre-intensity-modulated radiotherapy prostate-specific antigen level (≥0.5 ng/mL

The lymphatic vasculature provides a route for cancer metastases, and its dysfunction after cancer treatment can result in lymphedema. However, changes in the lymphatics before, during, and after surgery and radiation remain unclear.Near-infrared fluorescence lymphatic imaging was performed before and after lymph node dissection and fractionated radiotherapy to assess changes in external lymphatic function.Patients who underwent both lymph node dissection and radiotherapy developed lymphatic dermal backflow on treated sides ranging from days after the start of radiotherapy to weeks after its completion, whereas contralateral regions that were not associated with lymph node dissection but also treated with radiotherapy experienced no such changes in external lymphatic anatomies.The external lymphatics undergo transient changes during and weeks after lymph node dissection and radiotherapy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1177-1188, 2017.

Renal cell carcinoma (RCC) metastases have been reported in almost every organ. The most common involved organs are the lungs, liver, kidneys, bones, and brain.1,2 Autopsy series have reported RCC adrenal metastases rates ranging from 7% to 19%.2-4 Contralateral adrenal involvement is rare. In one study the incidence was 2.5%.5 In addition contralateral adrenal metastases from RCC can present late, even after 23 years from primary tumor resection.4,6 Such unusual delay in presentation, infrequent occurrence, and confusing clinical presentation can lead to misdiagnosis, delayed diagnosis, or failure to treat promptly.3 Herein a case of RCC involving the contralateral adrenal gland that was successfully treated with SBRT is reported. The patient had right nephrectomy and right adrenalectomy 12 years earlier. His resulting adrenal

Owing to the liver’s integral role in biosynthesis and homeostasis, management of primary and secondary malignancies arising in this organ is of paramount oncologic significance. Over the past several decades, substantial progress has been achieved in the imaging and treatment of early and advanced hepatic malignancies. Radiation therapy (RT) has recently emerged as one of many local therapeutic options for both primary and metastatic liver cancer. Recent phase I and II studies describe promising efficacy and side effect profile; however, phase III studies are needed to establish RT among standard of care therapeutic modalities. In this review, we will describe (a) the scope, epidemiology, and standard treatment options for liver cancer; (b) relevant diagnostic imaging techniques; and (c) provide an in-depth review of RT treatment techniques, dose–volume limits of normal tissues, and results of both conventional and hypofractionated RT liver trials pertaining to primary and secondary liver cancers with emphasis on three-dimensional conformal radiation therapy (3DCRT) and stereotactic body radiotherapy (SBRT) studies.

To investigate the utility of stereotactic body radiotherapy (SBRT) in the treatment of painful renal cell carcinoma (RCC) bone metastases, and for a possible dose effect on time to symptom relief.Eighteen patients with 24 painful osseous lesions from metastatic RCC were treated with SBRT. The most common treatment regimens were 24 Gy in 3 fractions and 40 Gy in 5 fractions. The times from treatment to first reported pain relief and time to symptom recurrence were evaluated. Median follow-up was 38 weeks (1-156 weeks).Seventy-eight percent of all patients had pain relief. Patients treated with a BED85 Gy achieved faster and more durable pain relief compared to those treated with a BED85 Gy. There was decrease in time to pain relief after a change in treatment regimen to 8 Gy × 5 fractions (BED = 86). There was only one patient with grade 1 skin toxicity. No neurological or other toxicity was observed.SBRT can safely and effectively treat painful RCC bony metastases. There appears to be a relationship between radiation dose and time to stable pain relief.

Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control.

Stereotactic body radiation therapy (SBRT) is a promising treatment option for prostate cancer. Hypofractionation regimens, such as SBRT, may be more advantageous compared with conventional regimens because low α:β ratio of prostate cancer has high sensitivity to dose per fraction. In addition, a smaller and tighter margin with SBRT is expected to provide a low toxicity rate without reducing tumor control. The purpose of this article is to examine radiobiological, technical and clinical aspects of SBRT for prostate cancer.

Intensity-modulated radiation therapy (IMRT), an advent of three-dimensional conformal radiotherapy (3D CRT), has excited the profession of radiation oncology more than any other new invention since the introduction of the linear accelerator. Approximately 1000 articles have been published on this topic to date, more than 200 of which focus on head and neck cancer. IMRT is based on computer-optimized treatment planning and a computer-controlled treatment delivery system. The computer-driven technology generates dose distributions that sharply conform to the tumor target while minimizing the dose delivered to the surrounding normal tissues. The high dose volume that tailors to the 3D configuration of the tumor along with the ability to spare the nearby normal tissues allows the option of tumor dose escalation. The head and neck region is an ideal target for this new technology for several reasons. First, IMRT offers the potential for improved tumor control through delivery of high doses to the target volume. Second, because of sharp dose gradients, IMRT results in the relative sparing of normal structures, such as the parotid glands, in the head and neck region. Third, organ motion is virtually absent in the head and neck region so, with proper immobilization, treatment can be accurately delivered. Although this is a relatively new technology, single-institution retrospective studies show better dosimetric profiles compared with conventional radiation techniques, as well as excellent clinical results. Salivary gland sparing using IMRT has also resulted in reduced incidence and severity of xerostomia, and this has been tested in a randomized trial against conventional radiotherapy for early-stage nasopharyngeal cancer. The results do confirm that IMRT does decrease xerostomia compared with conventional radiotherapy.

Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome that has classically been associated with familial sarcomas, but now includes brain tumors, premenopausal breast cancer, and adrenocortical carcinomas in its recognized core tumor pathologies. Germline mutations in the TP53 gene are the only known cause of LFS. Affected individuals are typically diagnosed at younger ages than individuals with sporadic tumors and are at risk for multiple malignancies over their lifetime. Characterization of the evolving phenotype of LFS is ongoing, including the use of clinical criteria to identify index patients. Few studies, however, have described the phenotype of primary gliomas in LFS. In this case series, we describe the presentation of four individuals, two male and two female, with primary gliomas and molecularly confirmed LFS at our institution. All individuals presented with high-grade gliomas: two with anaplastic astrocytoma, one with anaplastic oligodendroglioma, and one with glioblastoma multiforme. The age of diagnosis ranged from 25 to 50 years. Glioma was the first presentation of disease in three individuals. The fourth individual had a previous diagnosis of osteosarcoma. Family history was remarkable, positive with regards to Chompret criteria, in two individuals and negative or unknown in two individuals. Molecular tumor testing was available for three individuals: one individual had two somatic TP53 mutations and two individuals had one TP53 mutation with loss of heterozygosity at the opposite allele. These cases demonstrate that individuals with LFS may first present in a neuro-oncology clinic for initial diagnosis. Screening for LFS should be prompted in individuals with a personal and/or family history that includes LFS core tumor pathologies. Further characterization of these individuals is necessary to improve the early identification of LFS, specifically in individuals who present first with glioma, and provide appropriate management recommendations for patients and their families.

We investigated the factors that affect salivary function after head-and-neck radiotherapy (RT), including parotid gland dose-volume effects, potential compensation by less-irradiated gland tissue, and functional recovery over time.Sixty-five patients with head-and-neck tumors were enrolled in a prospective salivary function study. RT was delivered using intensity-modulated RT (n = 45), forward-planning three-dimensional conformal RT (n = 14), or three-dimensional conformal RT with an intensity-modulated RT boost (n = 6). Whole salivary flow was measured before therapy and at 6 months (n = 61) and 12 months (n = 31) after RT. A wide variety of dose-volume models to predict post-RT salivary function were tested. Xerostomia was defined according to the subjective, objective, management, analytic (SOMA) criteria as occurring when posttreatment salivary function was25% of the pretreatment function. Multivariate logistic regression analysis was used to assess the combined effect of dose-volume, patient-, and treatment-related factors.A significant correlation was observed between the relative quality-of-life scores and relative stimulated saliva values at 6 months after RT (Spearman's correlation coefficient [R(s)] = 0.46, p0.001). The dose-volume factors were by far the strongest correlates with stimulated saliva flow, although other factors showed modest significance in multimetric models (chemotherapy, gender, and Karnofsky performance status). Several fitted dose-volume models provided a good mathematical description of the data. Significant noise in the salivary measurements (repeated measurement coefficient of variation was 27% in normal subjects) precluded selection of any one of the models presented solely on the basis of the objective fit criteria. Nevertheless, the mean dose-exponential model, in which each parotid gland's relative salivary gland function equaled exp(-A x mean gland dose), with A equal to 0.054/Gy (68% confidence interval 0.052-0.059), provided a good representation of the data and was incorporated into our multimetric analysis. Using that model, we estimated that a mean parotid dose of 25.8 Gy, on average, was likely to reduce a single parotid gland's flow to 25% of its pretreatment value, regardless of the treatment delivery method. Significant correlations were observed between a logistic multivariate model (incorporating the mean dose-exponential equation, gender, and Karnofsky performance status) and stimulated saliva flow at 6 months (R(s) = 0.73), stimulated saliva flow at 12 months (R(s) = 0.54), and quality-of-life score at 6 months (R(s) = 0.35) after RT.Stimulated parotid salivary gland dose-volume models strongly correlated with both stimulated salivary function and quality-of-life scores at 6 months after RT. The mean stimulated saliva flow rates improved from 6 to 12 months after RT. Salivary function, in each gland, appeared to be lost exponentially at a rate of approximately 5%/1 Gy of mean dose. Additional research is necessary to distinguish among the models for use in treatment planning. The incidence of xerostomia was significantly decreased when the mean dose of at least one parotid gland was kept to25.8 Gy with conventional fractionation. However, even lower mean doses imply increased late salivary function.

Purpose To assess the clinical features, prognostic factors, results, and complications of treatment of carcinomas of the paranasal sinus. Methods and materials The records of 106 patients (72 men and 34 women) with paranasal sinus carcinoma treated with curative intent at Washington University between January 1960 and August 1998 were analyzed. Patient age ranged from 29 to 91 years (median, 64 years). Most tumors originated in the maxillary (76%) or ethmoid (18%) sinus. Most tumors were locally advanced at presentation. All patients underwent radiotherapy (RT), combined with surgery in 65%; 2% received chemotherapy. Results Follow-up ranged from 1.7 months to 24 years (median 5 years). The 5-year local tumor control, locoregional tumor control, disease-free survival (DFS), and overall survival rate was 58%, 39%, 33%, and 27%, respectively. A statistically significant improvement in DFS was noted with the addition of surgical resection to RT (35% vs. 29%, p = 0.05). Nodal status at presentation emerged as a statistically significant predictor for locoregional tumor control and DFS in multivariate analysis. Distant metastases occurred in 29% of patients. Conclusion This review of a large, single-institution experience of paranasal sinus carcinoma patients who underwent RT showed that locoregional tumor progression and recurrence remain predominant patterns of failure despite aggressive local treatment with combined surgery and RT. DFS improved slightly with combined modality treatment. The overall survival rates remained suboptimal, suggesting a need for more accurate determination of tumor extent, as well as more effective locoregional and systemic therapies.

Purpose We propose a model that integrates the spatial location of each voxel within a clinical target volume (CTV) to differentiate the merit of intensity-modulated radiation therapy (IMRT) plans with similar dose–volume histogram (DVH). This conceptual model is based on the hypothesis that various subregions within a given CTV that may carry different degree of risk in containing microscopic disease. Methods and materials We hypothesize that a correlation between the probability of microscopic tumor extension and the risk of lymph node metastasis of a particular voxel point within CTV can be inferred based on its distance from the surface of radiographically evident gross disease. A preliminary observation was gathered from existing clinicopathologic data, and, based on these observations, a conceptual model for exponential-decay microscopic-extension probability function around primary tumor and linear function parameters relating the likelihood of lymph node metastasis to the distance from primary tumor was proposed. This model was generated to provide scoring functions to examine the merit of IMRT plans. To test the feasibility of this model, we generated two IMRT plans with similar and clinically acceptable DVH-based CTV coverage. Planning data were transferred to a data analysis software package (Matlab, The Mathworks Inc.). A 3D scoring function was calculated for each voxel inside the CTV. The adequacy of target coverage was evaluated by several novel approaches: 2D dose–volume scoring-function histograms (DVSH), the integral probability of relative residual tumor burden (RRTB), and tumor control probabilities (TCP) employing the scoring function as a pseudo-clonogen density distribution. Results Incorporating parameters for the risk of containing microscopic disease in each voxel into the scoring function algorithm, 2D DVSHs, RRTBs, integral RRTBs, and TCPs were computed. On each axial image, an RRTB map could locate the regions at greatest risk. These scoring functions were able to differentiate the merit of CTV coverage of clinically different IMRT plans but having very similar DVHs; one with cold spots centrally located over the gross tumor, and the other with more acceptable cold spots on the periphery of the CTV further away from the gross tumor volume. Conclusions We demonstrated the feasibility and potential utility of an IMRT scoring method derived from this conceptual modeling approach. These methods are capable of ranking treatment plans with similar DVH profiles but different underdosed regions within the target. We will examine the accuracy of model parameters by performing tumor-specific image-pathologic correlation studies. Upon validation of these parameters, incorporating this scoring function model into plan optimization may have the potential to avoid underdosing subvolumes within CTV that harbor a higher likelihood of microscopic disease.

Radiotherapeutic management of advanced prostate cancer is challenging. Several retrospective analyses showed a dose response for local tumor control before the availability of conformal radiation therapy. Attempts to escalate dose without the benefit of modern treatment planning was commonly fraught with high rates of bowel or bladder complications. The advent of image-guided or computed tomography-based treatment planning has allowed safe delivery of high-dose radiation therapy in men with prostate cancer with an acceptable rate of side effects and complications. Several prospective clinical trials have been conducted both at single institutions and in the cooperative group setting. Early evidence suggests that patients with high-risk factors such as advanced clinical stage, high initial prostate-specific antigen, or poorly differentiated tumors may benefit from high-dose 3-dimensional conformal radiation therapy with improved biochemical and local tumor control. A published randomized trial with conformal radiation therapy shows that a modest escalation of radiation dose leads to improved biochemical disease-free survival for a select group of patients. A confirmatory trial within the Radiation Therapy Oncology Group is underway to determine if dose escalation will improve overall survival in men without compromising quality of life.

Radiation therapy (RT) is an important modality in the treatment of head and neck cancers. Significant morbidity can result, however, because of exposure of normal tissues to high doses of RT. Advances in planning and delivery, especially intensity modulated radiation therapy, can reduce the risk of these toxicities by ensuring that the tumor and draining lymph nodes are adequately treated, while the surrounding organs and tissues at risk are avoided. Image guidance during treatment delivery allows for smaller margins around the tumor to account for variations in daily setup and positioning. All these advances help to improve the quality of life of cancer survivors.

BACKGROUND The authors previously reported that central lymphatic irradiation (CLI) can induce molecular remission in patients with Stage I–III follicular lymphoma, as measured by polymerase chain reaction analysis for t(14;18) (q32;q21). Hematologic toxicity has been considered a major consequence of CLI. This study was undertaken to analyze the patterns of hematologic recovery after CLI. METHODS Thirty-three patients with Stage I–III follicular lymphoma were treated with CLI between January 1993 and February 1998. CLI consisted of irradiation to mantle, upper two-thirds of abdomen, and pelvic fields. Each field was treated to 30.0–30.6 grays (Gy) at 1.5–1.8 Gy per fraction, with a boost to 36.0–39.6 Gy at the same rate to the sites of macroscopic disease. A break of approximately 4 weeks was given after treatment of each field. Twenty-four patients who were followed for a minimum of 1 year from the end of CLI form the basis of this analysis. Fourteen patients were male. Three patients had Stage I disease, 6 patients had Stage II disease, and 15 patients had Stage III disease. The International Prognostic Index (IPI) for malignant lymphoma was 0 for 5 patients, 1 for 13 patients, and 2 for 6 patients. The Eastern Cooperative Oncology Group performance status was 0 for 21 patients and 1 for 3 patients. The median values for their pretreatment characteristics were as follows: age, 60 years (range, 34–73 years); height, 173 cm (range, 155–193 cm); weight, 79 kg (range, 57–107 kg); body surface area (BSA), 1.95 m2 (range, 1.61–2.31 m2); bone marrow cellularity, 27%(range, 2–75%), platelet count, 233,000/mm3 (range, 139,000–339,000/mm3), white blood cell (WBC) counts, 6400/mm3 (range, 4200–10,900/mm3); and hemoglobin, 14.5 mg/dL (range, 11.8 –16.6 mg/dL). The median duration of CLI was 159 days (range, 137–345 days). Ten patients had cardiovascular disease. The number of sites receiving a boost dose of ≥ 36.0 Gy was 0 sites in 1 patient, 1 site in 6 patients, 2 sites in 11 patients, 3 sites in 5 patients, and 4 sites in 1 patient. The platelet, hemoglobin, and WBC counts were followed every 3 months after completion of CLI. These counts were normalized to the pretreatment counts for statistical analyses. Univariate and multivariate analyses were performed to investigate the correlations between patient factors and hematologic status at 1 year posttreatment. Pearson correlation analysis was used for the continuous factors (patient age, height, weight, BSA, bone marrow cellularity, and duration of CLI), and the Mann–Whitney test was used for categoric factors (IPI, gender, performance status, stage, number of sites receiving ≥ 36.0 Gy, and presence or absence of cardiovascular disease). RESULTS There was continued recovery, essentially approaching the pretreatment levels, over 3 years for platelet, WBC, and hemoglobin counts. Factors that were associated significantly with normalized platelet counts at 1 year by univariate analyses were age (P = 0.015) and cardiovascular disease (P = 0.041). Age was the only significant factor by multivariate analyses, with older patients having lower platelet counts at 1 year posttreatment. No factors were found that were associated significantly with 1-year normalized WBC or hemoglobin levels by either univariate or multivariate analyses. CONCLUSIONS All three of the hematologic components (platelets, WBC, and hemoglobin) essentially recover after patients undergo CLI over a 3-year period. Older age was the only significant adverse factor that affected the platelet recovery, as detected by multivariate analysis. Cancer 2001;92:1074–9. © 2001 American Cancer Society.

To evaluate biochemical non-evidence of disease and adverse events of salvage intensity-modulated radiotherapy using an endorectal balloon for prostate cancer patients after radical prostatectomy.Data of 107 patients (median age 65 years) with persistent (0.1 ng/mL) or rising prostate-specific antigen after radical prostatectomy were retrospectively analyzed. The mean dose to clinical target volume was 70 Gy in 32 fractions (the equivalent dose in 2 Gy fraction is 73.2 Gy based on α:β = 2). Biochemical non-evidence of disease and predictive factors were assessed. Genitourinary toxicity and gastrointestinal toxicity were also evaluated using the Radiation Therapy Oncology Group toxicity criteria.The median follow up was 37 months (range 6-126 months). A total of 48 patients developed biochemical recurrence. The 3- and 5-year biochemical non-evidence of disease rates of all patients were 52.6% and 48.8%, respectively. The Gleason score (≥4 + 3, ≤3 + 4) and pre-intensity-modulated radiotherapy prostate-specific antigen level (≥0.5 ng/mL,0.5 ng/mL) were significant predictive factors for biochemical non-evidence of disease in univariate analysis. In multivariate analysis, only the Gleason score was detected as a significant variable. The highest late genitourinary toxicities were grade 2 in 13% and grade 3 in 6% of patients. The highest late gastrointestinal toxicities were grade 2 in 6% and grade 3 in 3% of patients.Despite a relatively high radiation dose, intensity-modulated radiotherapy with an endorectal balloon can be delivered with acceptable toxicity and efficacy for patients developing biochemical recurrence after radical prostatectomy.

Department of Radiation Oncology, The Methodist Hospital, Research Institute, ouston, TX Department of Radiation Oncology, The Methodist Hospital, Houston, TX Department of Radiology and Radiation Oncology, Kitasato University School of edicine, Sagamihara, Kanagawa, Japan Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy f Medical Sciences, Peking Union Medical College, Beijing, China Department of Radiology, The Methodist Hospital, Houston, TX Medical Branch, The University of Texas, Houston, TX Division of Oncology, The University of Texas, Health Science Center, Memorial ermann Cancer Center, Houston, TX

Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. There are now emerging data that show the safety and efficacy of this treatment modality in genitourinary (GU) malignancies especially in prostate cancer and renal cell carcinoma. Preclinical data, clinical experience, and challenges are reviewed and discussed.

Toxicity from H&N cancer irradiation is complex and multifactorial. The nature and severity of the side effect profile for a given patient result from the interplay of patient-related, tumor-related, and treatment-factors. Among the side effects studied, skin toxicity and mucositis represent the most common acute effects of irradiation. Supportive care is essential to prevent superimposed infection and other complications that might lead to treatment breaks or, in extreme cases, discontinuation of therapy. Technological advances with conformal radiotherapy techniques have allowed for increasing salivary gland sparing. Further protection may be achieved with existing and future medical therapies. Swallowing dysfunction following chemoradiation for laryngeal cancer is significant and may persist for 1-2 years. Efforts should be made to ensure proper patient education and reassurance in this regard.

To investigate interobserver variability in the delineation of head-and-neck (HN) anatomic structures on CT images, including the effects of image artifacts and observer experience.Nine observers (7 radiation oncologists, 1 surgeon, and 1 physician assistant) with varying levels of HN delineation experience independently contoured HN gross tumor volumes and critical structures on radiation therapy treatment planning CT images alongside reference diagnostic CT images for 4 patients with oropharynx cancer. Image artifacts from dental fillings partially obstructed 3 images. Differences in the structure volumes, center-of-volume positions, and boundary positions (1 SD) were measured. In-house software created three-dimensional overlap distributions, including all observers. The effects of dental artifacts and observer experience on contouring precision were investigated, and the need for contrast media was assessed.In the absence of artifacts, all 9 participants achieved reasonable precision (1 SDor =3 mm all boundaries). The structures obscured by dental image artifacts had larger variations when measured by the 3 metrics (1 SD = 8 mm cranial/caudal boundary). Experience improved the interobserver consistency of contouring for structures obscured by artifacts (1 SD = 2 mm cranial/caudal boundary).Interobserver contouring variability for anatomic HN structures, specifically oropharyngeal gross tumor volumes and parotid glands, was acceptable in the absence of artifacts. Dental artifacts increased the contouring variability, but experienced participants achieved reasonable precision even with artifacts present. With a staging contrast CT image as a reference, delineation on a noncontrast treatment planning CT image can achieve acceptable precision.

Toxicity from HN cancer irradiation is complex and multifactorial. The nature and severity of the side effect profile for a given patient result from the interplay of patient-related, tumor-related, and treatment-factors. Among the side effects studied, skin toxicity and mucositis represent the most common acute effects of irradiation. Supportive care is essential to prevent superimposed infection and other complications that might lead to treatment breaks or, in extreme cases, discontinuation of therapy. Technological advances with conformal radiotherapy techniques have allowed for increasing salivary gland sparing. Further protection may be achieved with existing and future medical therapies. Swallowing dysfunction following chemoradiation for laryngeal cancer is significant and may persist for 1-2 years. Efforts should be made to ensure proper patient education and reassurance in this regard.

Purpose: The probability of a specific radiotherapy outcome is typically a complex, unknown function of dosimetric and clinical factors. Current models are usually oversimplified. We describe alternative methods for building multivariable dose–response models. Methods: Representative data sets of esophagitis and xerostomia are used. We use a logistic regression framework to approximate the treatment–response function. Bootstrap replications are performed to explore variable selection stability. To guard against under/overfitting, we compare several analytical and data-driven methods for model-order estimation. Spearman’s coefficient is used to evaluate performance robustness. Novel graphical displays of variable cross correlations and bootstrap selection are demonstrated. Results: Bootstrap variable selection techniques improve model building by reducing sample size effects and unveiling variable cross correlations. Inference by resampling and Bayesian approaches produced generally consistent guidance for model order estimation. The optimal esophagitis model consisted of 5 dosimetric/clinical variables. Although the xerostomia model could be improved by combining clinical and dose–volume factors, the improvement would be small. Conclusions: Prediction of treatment response can be improved by mixing clinical and dose–volume factors. Graphical tools can mitigate the inherent complexity of multivariable modeling. Bootstrap-based variable selection analysis increases the reliability of reported models. Statistical inference methods combined with Spearman’s coefficient provide an efficient approach to estimating optimal model order.

The four recent noteworthy strategies aimed at improving therapeutic outcomes for the curative treatment of head and neck squamous cancers include the development of altered fractionation regimens, integration of chemotherapy, incorporation of intensity-modulated radiation therapy and introduction of targeted biologic therapy. Clinical investigations during the last 30 years have demonstrated the benefits of biologically sound altered fractionation and concurrent chemoradiation regimens in improving locoregional control and overall survival. These results have contributed to redefining the standard of care, with the caveat that proper patient selection for those who will benefit from potentially toxic combined modality treatment regimens remains controversial. These benefits have come at the expense of increased acute toxicity (i.e., mucositis) and sometimes at the expense of late toxicity (i.e., fibrosis and dysphagia). There are two additional developments that may help to further widen the therapeutic ratio. Intensity-modulated radiation therapy allows for the delivery of a highly conformal 3D radiation dose distribution around intended targets, thereby limiting the volumes of mucosa receiving a high dose per fraction and high total doses. The technical basis for intensity-modulated radiation therapy delivery reopens many fractionation questions that are still being addressed and challenges us to determine which of these is optimal for use with intensity-modulated radiation therapy alone or in combination with concurrent sensitizers. Finally, combined radiation therapy and biologic therapies directed at targets expressed predominately or exclusively by tumor cells have the promise to help increase tumor cell kill, while at least not substantially increasing normal tissue toxicity. These strategies are reviewed in a clinical context.