Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

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.

Genomic alterations predictive of response to radiosurgery in recurrent IDH-WT glioblastoma.

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 cm3 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.

Pleomorphic Xanthoastrocytoma: Multi-Institutional Evaluation of Stereotactic Radiosurgery.

BACKGROUND AND OBJECTIVES: Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade glial tumor primarily affecting young individuals. Surgery is the primary treatment option; however, managing residual/recurrent tumors remains uncertain. This international multi-institutional study retrospectively assessed the use of stereotactic radiosurgery (SRS) for PXA. METHODS: A total of 36 PXA patients (53 tumors) treated at 11 institutions between 1996 and 2023 were analyzed. Data included demographics, clinical variables, SRS parameters, tumor control, and clinical outcomes. Kaplan-Meier estimates summarized the local control (LC), progression-free survival, and overall survival (OS). Secondary end points addressed adverse radiation effects and the risk of malignant transformation. Cox regression analysis was used. RESULTS: A total of 38 tumors were grade 2, and 15 tumors were grade 3. Nine patients underwent initial gross total resection, and 10 received adjuvant therapy. The main reason for SRS was residual tumors (41.5%). The median follow-up was 34 months (range, 2-324 months). LC was achieved in 77.4% of tumors, with 6-month, 1-year, and 2-year LC estimates at 86.7%, 82.3%, and 77.8%, respectively. Younger age at SRS (hazard ratios [HR] 3.164), absence of peritumoral edema (HR 4.685), and higher marginal dose (HR 6.190) were significantly associated with better LC. OS estimates at 1, 2, and 5 years were 86%, 74%, and 49.3%, respectively, with a median OS of 44 months. Four patients died due to disease progression. Radiological adverse radiation effects included edema (n = 8) and hemorrhagic change (n = 1). One grade 3 PXA transformed into glioblastoma 13 months after SRS. CONCLUSION: SRS offers promising outcomes for PXA management, providing effective LC, reasonable progression-free survival, and minimal adverse events.

Salvage intensity modulated radiotherapy using endorectal balloon after radical prostatectomy: clinical outcomes.

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:ß = 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, <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. CONCLUSION: 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.

A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases.

BACKGROUND: 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. MATERIAL AND METHODS: 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). RESULTS: Seventy-eight percent of all patients had pain relief. Patients treated with a BED > 85 Gy achieved faster and more durable pain relief compared to those treated with a BED < 85 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. CONCLUSIONS: 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.

Metastatic Neoplasm Volume Kinetics Following 2-Stage Stereotactic Radiosurgery.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 cm3 (1.5-28.5 cm3), 3.3 cm3 (0.8-26.1 cm3), and 2.2 cm3 (0.2-10.1 cm3), respectively. Of 26 lesions, 24 (92%) demonstrated early local control following the first SRS session, with 17 lesions (71%) demonstrating a decrease of ≥30% in T1 postcontrast MRI volume before the second SRS session and 3 lesions (12%) remaining stable. Eventually, 4 lesions showed disease progression after 2-SSRS. The median time to local progression was not reached; the median time to intracranial progression was 9.1 months. CONCLUSIONS: Our 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.

NUT Carcinoma of the Submandibular Gland: A Case at This Uncommon Site with Review of the Literature.

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.

Role of Ethnicity and Geographic Location on Glioblastoma IDH1/IDH2 Mutations.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, P < 0.001) and had improved OS (hazard ratio: 0.82, P < 0.001). 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; P < 0.001), while OS remained similar. CONCLUSIONS: 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.

Landscape of Genomic Alterations in IDH Wild-Type Glioblastoma Identifies PI3K as a Favorable Prognostic Factor.

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.

Epstein-Barr Virus-Positive Large Cell Neuroendocrine Carcinoma of the Nasopharynx: Report of One Case and Review of the Literature.

Epstein-Barr Virus (EBV)-positive neuroendocrine carcinoma (NEC) of the nasopharynx is exceedingly rare, only two cases have been reported in the literature. While EBV infection is strongly associated with nasopharyngeal carcinoma, which is carcinoma with squamous differentiation, the link between EBV and NEC is not well known, and can be diagnostically challenging. In this study, we report the third case of EBV-positive large cell NEC of nasopharynx with neck lymph node metastasis. The patient was treated with combined radiation and chemotherapy and showed complete clinical and radiological response. Similar treatment response has been reported in another patient with high stage EBV-positive large cell NEC, suggesting that EBV status is an important prognostic factor. Recognition of this rare tumor is important for disease management and patient prognosis. We also review the literature about the clinical and pathologic presentation of neuroendocrine tumors of nasopharynx.

Impact of facility type and volume in low-grade glioma outcomes.

OBJECTIVE: The 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. METHODS: This 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. RESULTS: Significant 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. CONCLUSIONS: This 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.

Planned Gamma Knife Boost After Chemoradiotherapy for Selected Sinonasal and Nasopharyngeal Cancers.

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.

Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation.

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.

Multivariable modeling of radiotherapy outcomes, including dose-volume and clinical factors.

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.

Management of radiation-induced head and neck injury.

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.

Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.

PURPOSE: 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. METHODS AND MATERIALS: 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 was < 25% of the pretreatment function. Multivariate logistic regression analysis was used to assess the combined effect of dose-volume, patient-, and treatment-related factors. RESULTS: 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, p < 0.001). 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. CONCLUSION: 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 to < 25.8 Gy with conventional fractionation. However, even lower mean doses imply increased late salivary function.

Dose escalation in locally advanced carcinoma of the prostate.

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.

A conceptual model integrating spatial information to assess target volume coverage for IMRT treatment planning.

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.

Carcinoma of paranasal sinuses: long-term outcomes with radiotherapy.

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.