The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Patterns of failure after radiosurgery for WHO grade 1 or imaging defined meningiomas: Long-term outcomes and implications for management.

BACKGROUND: We analyzed long-term control and patterns of failure in patients with World Health Organization Grade 1 meningiomas treated with definitive or postoperative stereotactic radiosurgery at the authors' affiliated institution. METHODS: 96 patients were treated between 2004 and 2019 with definitive (n = 57) or postoperative (n = 39) stereotactic radiosurgery. Of the postoperative patients, 17 were treated adjuvantly following subtotal resection and 22 were treated as salvage at time of progression. Patients were treated to the gross tumor alone without margin or coverage of the dural tail to a median dose of 15 Gy. Median follow up was 7.4 years (inter-quartile range 4.8-11.3). Local control, marginal control, regional control, and progression-free survival were analyzed. RESULTS: Local control at 5 and 10 years was 97 % and 95 %. PFS at 5 and 10 years was 94 % and 90 % with no failures reported after 6 years. Definitive and postoperative local control were similar at 5 (95 % [82-99 %] vs. 100 %) and 10 years (92 % [82-99 %] vs. 100 %). Patients treated with postoperative SRS did not have an increased marginal failure rate (p = 0.83) and only 2/39 (5 %) experienced recurrence elsewhere in the cavity. CONCLUSIONS: Stereotactic radiosurgery targeting the gross tumor alone provides excellent local control and progression free survival in patients treated definitively and postoperatively. As in the definitive setting, patients treated postoperatively can be treated to gross tumor alone without need for additional margin or dural tail coverage.

Response to high dose ipilimumab plus temozolomide after progression on standard or low dose ipilimumab in advanced melanoma: a retrospective analysis.

Background: Despite advancements in checkpoint inhibitor-based immunotherapy, patients with advanced melanoma who have progressed on standard dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Several studies support a dose-response activity of Ipi, and one promising combination is Ipi 10mg/kg (Ipi10) + temozolomide (TMZ). Methods: We performed a retrospective cohort analysis of patients with advanced melanoma treated with Ipi10+TMZ in the immunotherapy refractory/resistant setting (n = 6), using similar patients treated with Ipi3+TMZ (n = 6) as comparison. Molecular profiling by whole exome sequencing (WES) and RNA-seq of tumors harvested through one responder's treatment was performed. Results: With a median follow up of 119 days, patients treated with Ipi10+TMZ had statistically significant longer median progression free survival of 144.5 days (range 27-219) vs 44 (26-75) in Ipi3+TMZ, p=0.04, and a trend for longer median overall survival of 154.5 days (27-537) vs 89.5 (26-548). All patients in the Ipi10 cohort had progressed on prior Ipi+Nivo. WES revealed only 12 shared somatic mutations including BRAF V600E. RNA-seq showed enrichment of inflammatory signatures, including interferon responses in metastatic lesions after standard dose Ipi + nivo and Ipi10 + TMZ compared to the primary tumor, and downregulated negative immune regulators including Wnt and TGFb signaling. Conclusion: Ipi10+TMZ demonstrated efficacy including dramatic responses in patients with advanced melanoma refractory to prior Ipi + anti-PD1, even with CNS metastases. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher dose Ipi is required for some patients.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Incidence and extent of disease progression on MRI between surgery and initiation of radiotherapy in glioblastoma patients.

Background: A post-operative MRI (MRIpost-op) performed within 72 h is routinely used for radiation treatment planning in glioblastoma (GBM) patients, with radiotherapy starting about 4-6 weeks after surgery. Some patients undergo an additional pre-radiotherapy MRI (MRIpre-RT) about 2-6 weeks after surgery. We sought to analyze the incidence of rapid early progression (REP) between surgery and initiation of radiotherapy seen on MRIpre-RT and the impact on radiation target volumes. Methods: Patients with GBM diagnosed between 2018 and 2020 who had an MRIpost-op and MRIpre-RT were retrospectively identified. Criteria for REP was based on Modified RANO criteria. Radiation target volumes were created and compared using the MRIpost-op and MRIpre-RT. Results: Fifty patients met inclusion criteria. The median time between MRIpost-op and MRIpre-RT was 26 days. Indications for MRIpre-RT included clinical trial enrollment in 41/50 (82%), new symptoms in 5/50 (10%), and unspecified in 4/50 (8%). REP was identified in 35/50 (70%) of patients; 9/35 (26%) had disease progression outside of the MRIpost-op-based high dose treatment volumes. Treatment planning with MRIpost-op yielded a median undertreatment of 27.1% of enhancing disease and 11.2% of surrounding subclinical disease seen on MRIpre-RT. Patients without REP had a 38% median volume reduction of uninvolved brain if target volumes were planned with MRIpre-RT. Conclusion: Given the incidence of REP and its impact on treatment volumes, we recommend using MRIpre-RT for radiation treatment planning to improve coverage of gross and subclinical disease, allow for early identification of REP, and decrease radiation treatment volumes in patients without REP.

Delineating the Subarachnoid Space in the Adult Lumbosacral Spine Using Computed Tomographic Myelography: An Aid for Clinical Target Volume Delineation in Craniospinal Irradiation.

Purpose: Our aim was to characterize the patterns of cerebrospinal fluid (CSF) extension in the lumbosacral spine using computed tomography (CT) myelograms to provide an evidence base for clinical target volume (CTV) definition in adults receiving craniospinal irradiation. Methods and Materials: This was a retrospective analysis of diagnostic CT lumbar myelograms performed in 30 patients between the ages of 22 and 50. Lateral extension of CSF beyond the thecal sac was measured along each lumbar and sacral nerve root to the nearest millimeter, as was the distance of inferior extension of CSF beyond the caudal end of the thecal sac. Each patient's lateral and inferior CSF extensions were mapped onto a standardized CT data set to create a model target volume in the lumbosacral spine that would contain the aggregate observed CSF distributions from the analyzed CT myelograms. The median extension distances, interquartile ranges, and 90th percentile for distance at each level were calculated. Results: The median lateral extension of CSF along nerve roots beyond the thecal sac-as measured perpendicular to the longitudinal axis-increased from 0 mm (interquartile range [IQR], 0-4 mm) at L1 to 8 mm (IQR, 6-12 mm) at S1 and 0 mm (IQR, 0-0 mm) at S4. The 90th percentile ranged from 5 to 14 mm laterally, with a pattern partially extending into the S1 and S2 sacral foramen. Median CSF extension inferior to the caudal sac was 5 mm (IQR, 2-8 mm), with 90% of patients within 12 mm. An atlas was generated to guide CTV delineation for highly conformal radiation techniques. Conclusion: These results provide information on patterns of CSF extension in the lumbosacral spine of adults and can serve as a model for CTV guidelines that balance comprehensive coverage of the CSF compartment while minimizing the dose to nontarget tissues.

Outcomes using linear accelerator stereotactic radiosurgery for the treatment of trigeminal neuralgia: A single-center, retrospective study.

Background: Linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) treatment of trigeminal neuralgia (TN) may have similar efficacy to Gamma Knife SRS (GK-SRS), but the preponderance of data comes from patients treated with GK-SRS. Our objective was to analyze the outcomes for LINAC-based treatment of TN in patients at our institution. Methods: We retrospectively analyzed data for patients who underwent LINAC-based SRS for TN from 2006 to 2018. Data were collected from the patients' medical records. Nonparametric statistics were used for the analysis. Results: Of the 41 patients treated with LINAC-based SRS (typically 90 Gy dosed using a 4 mm collimator for one fraction) during that time, follow-up data of >3 weeks post-SRS were available for 32 patients. The median pretreatment Barrow Neurological Institute (BNI) pain score was 5 (range 4-5). The follow-up period ranged from 0.9 to 113.2 months (median 5 months). There was significant improvement in postradiation BNI pain score (P < 0.001), with 23 (72%) patients who improved to a BNI pain score of 1-3. One patient had bothersome hypoesthesia postradiation. Approximately 38% of patients who had initial pain control had recurrence of symptoms (BNI > 3). Survival analysis showed a median time to pain recurrence of 30 months. There was no relationship between prior microvascular decompression (MVD) surgery and change in BNI pain score pre- to posttreatment. Conclusion: The results demonstrate that LINAC-based SRS is an effective means to treat TN. Prior MVD surgery did not affect efficacy of SRS in lowering the BNI score from pre- to posttreatment in this patient cohort.

Radiation Therapy in Conjunction With Surgical Stabilization of Impending or Pathologic Fractures Secondary to Metastasis: Is There a Difference Between Single and Multifraction Regimens?

PURPOSE: Patients who undergo surgical stabilization for impending or pathologic fractures secondary to metastasis are often treated with radiation therapy to the involved site. We sought to retrospectively analyze outcomes from single versus multifraction regimens of radiation therapy in this setting. METHODS AND MATERIALS: From our institutional radiation database, we identified 87 patients between 2004 and 2016 who had an impending or pathologic fracture from metastatic disease and who underwent surgical fixation in conjunction with either neoadjuvant (within 5 weeks before surgery) or adjuvant (within 10 weeks after surgery) radiation therapy, representing 99 total treatment sites. Patients were included on the basis of intention to treat with bimodality therapy. Baseline patient characteristics were compared using 2-sided t tests and Fisher's exact tests. Cumulative incidence of local failure, reirradiation, and reoperation were calculated using the Fine-Gray method for competing risks. Freedom from complication was calculated using the Kaplan-Meier method. RESULTS: Baseline characteristics between the single (n = 52) and multifraction (n = 47) cohorts were similar with the exception of higher rates of synchronous bony metastasis (83% vs 60%, P = .01) and female patients (71% vs 43%, P = .004) in the single fraction cohort. There was no significant difference in overall survival between treatment groups. After a median follow-up of 13 months, there was no significant difference in the single and multifraction cohorts, respectively, in the 1-year cumulative incidence rates of local failure (4% vs 7%, P = .58), reirradiation (5% vs 4%, P = .95), reoperation (4% vs 0%, P = .30), or 1-year freedom from complication (90% vs 95%, P = .40). CONCLUSIONS: This is the first study comparing outcomes between single and multifraction radiation therapy in conjunction with surgical stabilization of an impending or pathologic fracture. We found no difference in outcomes between single and multifraction regimens in this setting. Given these findings, single fraction perioperative radiation therapy may be a viable treatment option in appropriately selected patients pending prospective validation of these findings.

The Effect of Maximum Tumor Diameter by MRI on Disease Control in Intermediate and High-risk Prostate Cancer Patients Treated With Brachytherapy Boost.

BACKGROUND: Larger maximum tumor diameter (MTD) has been associated with worse prostate cancer (PCa) outcomes. However, the impact of MTD in PCa treated with external beam radiotherapy and brachytherapy boost (EBRT+BB) remains unknown. MATERIALS AND METHODS: Patients with PCa treated with EBRT+BB were identified from an institutional database. Clinical data including MTD, age, androgen deprivation therapy (ADT) use, prostate specific antigen (PSA), International Society of Urologic Pathology (ISUP) group, clinical T-stage, and presence of adverse pathology on imaging were retrospectively collected. Multivariable and univariable cox proportional hazards models for biochemical failure (BF) and distant metastasis (DM) were produced with MTD grouped by receiver operating characteristic (ROC) cut-point. Cumulative hazard functions for BF and DM were compared with log-rank test and stratified by ISUP group. RESULTS: Of 191 patients treated with EBRT+BB, 113 had MTD measurements available. Larger MTD was associated with increased ADT use and seminal vesicle involvement. ROC optimization identified MTD of 24 mm as the optimal cut-point for both BF and DM. MTD was independently associated with both BF (HR 8.61, P = .048, 95% CI 1.02-72.97) and DM (HR 8.55, P = .05, 95% CI 1.00-73.19). In patients with ISUP group 4 to 5 disease, MTD > 24 mm was independently associated with increased risk of DM (HR 10.13, P = .04, 95% CI 1.13-91.12). CONCLUSIONS: This is the first study to evaluate MTD in the setting of EBRT+BB. These results demonstrate that MTD is independently associated with BF and metastasis. This suggests a possible role for MTD in risk assessment models and clinical decision-making for men receiving EBRT+BB.

Comparing adjuvant radiation to adjuvant chemoradiation in postsurgical p16+ oropharyngeal carcinoma patients with extranodal extension or positive margins.

BACKGROUND: Adjuvant guidelines in surgically resected p16+ oropharyngeal carcinoma (OPC) with positive surgical margins (PSM) or extranodal extension (ENE) are based on randomized controlled trials predating p16 status. It remains unclear if adjuvant chemotherapy is necessary in p16+ patients with these features. METHODS: The National Cancer Database was used to identify cases of nonmetastatic p16+ OPC diagnosed from 2010 to 2017. Patients treated with surgical resection followed by adjuvant radiation (aRT) or adjuvant chemoradiation (aCRT) were eligible for analysis. RESULTS: A total of 14 071 patients were eligible for analysis. Overall survival (OS) was not statistically different between aRT and aCRT in patients with PSM (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.56-1.28), ENE (HR 0.93, 95% CI 0.69-1.27) or both (HR 0.73, 95% CI 0.41-1.31). CONCLUSIONS: In patients with p16+ OPC with ENE, PSM, or both, adding chemotherapy to aRT was not associated with improved OS.

The use and efficacy of chemotherapy and radiotherapy in children and adults with pilocytic astrocytoma.

PURPOSE: The aim of this study was to understand the use of chemotherapy (CMT) and radiotherapy (RT) in pilocytic astrocytoma (PA) and their impact on overall survival (OS). METHODS: Data from the National Cancer Database (NCDB) for patients with non-metastatic WHO grade I PA from 2004 to 2014 were analyzed. Pearson's chi-squared test and multivariate logistic regression analyses were performed to assess the distribution of demographic, clinical, and treatment factors. Inverse probability of treatment weighting (IPTW) was used to account for differences in baseline characteristics. Kaplan-Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling were used to analyze OS. RESULTS: Of 3865 patients analyzed, 294 received CMT (7.6%), 233 received RT (6.0%), and 42 (1.1%) received both. On multivariate analyses, decreasing extent of surgical resection was associated with receipt of both CMT and RT. Brainstem tumors were associated with RT, optic nerve tumors were associated with CMT. Cerebellar tumors were inversely associated with both CMT and RT. Younger age was associated with receipt of CMT; conversely, older age was associated with receipt of RT. After IPTW, receipt of CMT and/or RT were associated with an OS decrement compared with matched patients treated with surgery alone or observation (HR 3.29, p < 0.01). CONCLUSIONS: This is the largest study to date to examine patterns of care and resultant OS outcomes in PA. We identified patient characteristics associated with receipt of CMT and RT. After propensity score matching, receipt of CMT and/or RT was associated with decreased OS.

Impact of Brachytherapy Boost and Dose-escalated External Beam Radiotherapy in Margin Positive Cervical Cancer Treated With Chemotherapy and Radiation.

OBJECTIVES: We examined the impact of brachytherapy boost (BB) and external beam radiotherapy (EBRT) dose-escalation on overall survival (OS) for women with cervical cancer receiving postoperative chemotherapy and radiation (CRT) for a positive margin following hysterectomy. MATERIALS AND METHODS: The National Cancer Database (NCDB) was queried from 2004 to 2015 for women with nonmetastatic squamous cell carcinoma or adenocarcinoma of the cervix who had a positive margin following hysterectomy and received postoperative CRT. Patient and treatment characteristics were assessed with multivariate logistic regression. Survival analyses were performed with univariate Cox regression and Kaplan-Meier analyses. Propensity-score weighted cohorts were generated with inverse probability of treatment weighting via generalized boosted regression modeling. RESULTS: Of 630 women receiving CRT, 331 (53%) received EBRT alone and 299 (47%) received EBRT+BB. Eighty-two percent had chemotherapy initiation within 2 weeks of radiation, suggesting concurrent delivery. Median EBRT dose was 5040 cGy. Intracavitary high-dose rate was the most common BB (67%). Inclusion of BB was more likely with larger tumor sizes (odds ratio=1.03, P=0.002). Women receiving EBRT+BB had improved OS compared to EBRT alone for both unweighted (hazard ratio [HR], 0.72; P=0.020) and propensity-score weighted cohorts (HR, 0.70; P=0.017), and this finding was consistent across multiple patient subsets. EBRT dose-escalation >5040 cGy was not found to be associated with OS (unweighted HR, 1.38; P=0.065 and weighted HR, 1.16; P=0.450). CONCLUSION: The addition of BB to standard CRT improved OS for women with cervical cancer and a positive margin after hysterectomy. No consistent survival benefit was seen to EBRT dose-escalation beyond 5040 cGy.

Impact of a Contralateral Tumor Nodule on Survival in Non-Small-Cell Lung Cancer.

INTRODUCTION: Contralateral lung tumors in non-small-cell lung cancer (NSCLC) are classified as stage M1a yet may represent hematogenous metastases or synchronous primary tumors. The impact of these tumors on overall survival (OS) is poorly understood. Here, we aim to determine whether NSCLC patients with M1a disease due only to a contralateral tumor nodule exhibit a favorable prognosis relative to other M1a or M1b patients. METHODS: Retrospective evaluation of the impact of contralateral tumor nodules on OS in NSCLC stratified by primary tumor size and N stage attained from Surveillance, Epidemiology, and End Results database. RESULTS: Of 173,640 patients, 5161 M1a-contra patients were identified. Median and 3-year OS for these patients exceeded that of patients with M1b (p < 0.0001) or other M1a disease (p < 0.0001). Primary tumor size and N stage were strongly associated with OS in M1a-contra patients. Three-year OS demonstrated a delayed convergence between M1a-contra and other M1a patients with primary tumors greater than or equal to 3 cm or mediastinal lymph node involvement. Proportional hazard modeling indicated that T1-2N0-1M1a-contra patients exhibit OS not significantly different (p = 0.258) from that predicted with comparable T and N stage disease plus a second early-stage primary. CONCLUSIONS: Contralateral tumors in NSCLC carry a more favorable prognosis than other M1a or M1b disease. Primary tumor size and N stage may help distinguish M1a-contra patients with hematogenous metastasis from those with a synchronous, second primary.

Choroid plexus tumor epidemiology and outcomes: implications for surgical and radiotherapeutic management.

Choroid plexus tumors (CPTs) are rare neoplasms of the central nervous system whose optimal management is not well defined. The Surveillance Epidemiology and End Results (SEER) Database from 1978 to 2009 was queried to define population-based outcomes for all patients with CPTs. Patient demographic data, histological classification (choroid plexus papilloma [CPP], atypical CPP [aCPP], and choroid plexus carcinoma [CPC]), extent of surgery, and use of radiation therapy (RT) as part of an initial course of therapy were analyzed for impact on overall survival (OS) and cause-specific survival (CSS). Chemotherapy data were not available within the SEER database. A total of 349 patients with CPTs were identified (120 CPCs, 26 aCPPs, and 203 CPPs). Patients with CPC presented at a younger age (median 3, mean 14.8 years) relative to CPP (median 25, mean 28.4 years; p < 0.0001). Histology was a significant predictor of OS, with 5-year OS rates of 90, 77, and 58 % for CPP, aCPP, and CPC, respectively. Older age and male sex were prognostic for worse OS and CSS for CPP. Only extent of surgery had a significant impact on survival for CPC. The use of adjuvant RT in patients with CPC undergoing surgery was not associated with a significantly improved OS (p = 0.17). For patients undergoing GTR without RT as part of an initial course of therapy, estimated 5- and 10-year OS were 70 % (±7 %) and 67 % (±8 %), respectively. Prospective data are required to define the optimal combination of surgery with adjuvant therapies, including chemotherapy.

Image-guided radiation therapy for liver tumors: gastrointestinal histology matters.

OBJECTIVES: To describe the safety and efficacy of single-fraction and hypofractionated image-guided radiotherapy techniques for the treatment of large liver tumors. METHODS: Forty-six patients, with 50 tumors (10 primary liver tumors, 40 liver metastases) from March 2004 to March 2011 were reviewed. The maximal tumor diameter ranged from 1.2 to 11.3 cm (median, 4.2 cm). Eighty-seven percent of patients received prior systemic chemotherapy. Fifty-nine percent had prior invasive local therapy including surgery, ablation, or embolization. Twenty-five lesions were treated with hypofractionated therapy (24 to 30 Gy in 3 to 5 fractions), whereas 19 received a single fraction (18 or 24 Gy). Local control (LC) was calculated using competing risk analysis. Overall survival was calculated by the Kaplan-Meier method. RESULTS: Median follow-up for all patients was 29.8 months (range, 3 to 46 mo). The median survival was 15.4 months. The 1- and 2-year LC rates were 78% and 75%, respectively. Dose and tumor size had no significant effect on tumor progression. The local progression at 1 and 2 years was 29% and 32% for gastrointestinal (GI) histologies versus 0% for non-GI histologies (P=0.02). Tumor volumes larger than 112 cm correlated with decreased survival (P=0.05). Three patients developed late grade 3 GI stricture or ulceration. CONCLUSIONS: Image-guided radiotherapy for liver tumors achieves good rates of LC with minimal toxicity at 1 and 2 years even in patients with large or recurrent disease that has been heavily pretreated. GI histology demonstrated decreased LC rates. Further management strategies should be considered in these patients.

Increased local failure risk with prolonged radiation treatment time in head and neck cancer treated with concurrent chemotherapy.

BACKGROUND: Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation therapy (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear. METHODS: We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001 to 2009. The effects of RTT and other variables on local control and survival were analyzed. RESULTS: Patients with RTT >7 weeks had a significantly increased risk of local failure (hazard ratio [HR], 2.6; p = .018) and death (HR, 1.9 p = .035). These results retained significance even after adjustment for tumor stage (age was not significant). CONCLUSION: For patients treated with concurrent chemoradiotherapy (chemoRT), prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of patients with HNSCC undergoing definitive chemoRT should be managed aggressively to limit treatment interruptions.

Multi-institutional quantitative evaluation and clinical validation of Smart Probabilistic Image Contouring Engine (SPICE) autosegmentation of target structures and normal tissues on computer tomography images in the head and neck, thorax, liver, and male pelvis areas.

PURPOSE: Clinical validation and quantitative evaluation of computed tomography (CT) image autosegmentation using Smart Probabilistic Image Contouring Engine (SPICE). METHODS AND MATERIALS: CT images of 125 treated patients (32 head and neck [HN], 40 thorax, 23 liver, and 30 prostate) in 7 independent institutions were autosegmented using SPICE and computational times were recorded. The number of structures autocontoured were 25 for the HN, 7 for the thorax, 3 for the liver, and 6 for the male pelvis regions. Using the clinical contours as reference, autocontours of 22 selected structures were quantitatively evaluated using Dice Similarity Coefficient (DSC) and Mean Slice-wise Hausdorff Distance (MSHD). All 40 autocontours were evaluated by a radiation oncologist from the institution that treated the patients. RESULTS: The mean computational times to autosegment all the structures using SPICE were 3.1 to 11.1 minutes per patient. For the HN region, the mean DSC was >0.70 for all evaluated structures, and the MSHD ranged from 3.2 to 10.0 mm. For the thorax region, the mean DSC was 0.95 for the lungs and 0.90 for the heart, and the MSHD ranged from 2.8 to 12.8 mm. For the liver region, the mean DSC was >0.92 for all structures, and the MSHD ranged from 5.2 to 15.9 mm. For the male pelvis region, the mean DSC was >0.76 for all structures, and the MSHD ranged from 4.8 to 10.5 mm. Out of the 40 autocontoured structures reviews by experts, 25 were scored useful as autocontoured or with minor edits for at least 90% of the patients and 33 were scored useful autocontoured or with minor edits for at least 80% of the patients. CONCLUSIONS: Compared with manual contouring, autosegmentation using SPICE for the HN, thorax, liver, and male pelvis regions is efficient and shows significant promise for clinical utility.

Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.

PURPOSE: Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. PATIENTS AND METHODS: Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. RESULTS: No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. CONCLUSION: Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

Risk of cerebrovascular events in elderly patients after radiation therapy versus surgery for early-stage glottic cancer.

PURPOSE: Comprehensive neck radiation therapy (RT) has been shown to increase cerebrovascular disease (CVD) risk in advanced-stage head-and-neck cancer. We assessed whether more limited neck RT used for early-stage (T1-T2 N0) glottic cancer is associated with increased CVD risk, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. METHODS AND MATERIALS: We identified patients ≥66 years of age with early-stage glottic laryngeal cancer from SEER diagnosed from 1992 to 2007. Patients treated with combined surgery and RT were excluded. Medicare CPT codes for carotid interventions, Medicare ICD-9 codes for cerebrovascular events, and SEER data for stroke as the cause of death were collected. Similarly, Medicare CPT and ICD-9 codes for peripheral vascular disease (PVD) were assessed to serve as an internal control between treatment groups. RESULTS: A total of 1413 assessable patients (RT, n=1055; surgery, n=358) were analyzed. The actuarial 10-year risk of CVD was 56.5% (95% confidence interval 51.5%-61.5%) for the RT cohort versus 48.7% (41.1%-56.3%) in the surgery cohort (P=.27). The actuarial 10-year risk of PVD did not differ between the RT (52.7% [48.1%-57.3%]) and surgery cohorts (52.6% [45.2%-60.0%]) (P=.89). Univariate analysis showed an increased association of CVD with more recent diagnosis (P=.001) and increasing age (P=.001). On multivariate Cox analysis, increasing age (P<.001) and recent diagnosis (P=.002) remained significantly associated with a higher CVD risk, whereas the association of RT and CVD remained not statistically significant (HR=1.11 [0.91-1.37,] P=.31). CONCLUSIONS: Elderly patients with early-stage laryngeal cancer have a high burden of cerebrovascular events after surgical management or RT. RT and surgery are associated with comparable risk for subsequent CVD development after treatment in elderly patients.