Benjamin H. Kann

Adjuvant chemotherapy and overall survival in adult medulloblastoma

Background Although chemotherapy is used routinely in pediatric medulloblastoma (MB) patients, its benefit for adult MB is unclear. We evaluated the survival impact of adjuvant chemotherapy in adult MB. Methods Using the National Cancer Data Base, we identified patients aged 18 years and older who were diagnosed with MB in 2004-2012 and underwent surgical resection and adjuvant craniospinal irradiation (CSI). Patients were divided into those who received adjuvant CSI and chemotherapy (CRT) or CSI alone (RT). Predictors of CRT compared with RT were evaluated with univariable and multivariable logistic regression. Survival analysis was limited to patients receiving CSI doses between 23 and 36 Gy. Overall survival (OS) was evaluated using the Kaplan-Meier estimator, log-rank test, multivariable Cox proportional hazards modeling, and propensity score matching. Results Of the 751 patients included, 520 (69.2%) received CRT, and 231 (30.8%) received RT. With median follow-up of 5.0 years, estimated 5-year OS was superior in patients receiving CRT versus RT (86.1% vs 71.6%, P < .0001). On multivariable analysis, after controlling for risk factors, CRT was associated with superior OS compared with RT (HR: 0.53; 95%CI: 0.32-0.88, P = .01). On planned subgroup analyses, the 5 year OS of patients receiving CRT versus RT was improved for M0 patients (P < .0001), for patients receiving 36 Gy CSI (P = .0007), and for M0 patients receiving 36 Gy CSI (P = .0008). Conclusions This national database analysis demonstrates that combined postoperative chemotherapy and radiotherapy are associated with superior survival for adult MB compared with radiotherapy alone, even for M0 patients who receive high-dose CSI.

Brachytherapy Boost Utilization and Survival in Unfavorable-risk Prostate Cancer

BACKGROUND There are limited comparative survival data for prostate cancer (PCa) patients managed with a low-dose rate brachytherapy (LDR-B) boost and dose-escalated external-beam radiotherapy (DE-EBRT) alone. OBJECTIVE To compare overall survival (OS) for men with unfavorable PCa between LDR-B and DE-EBRT groups. DESIGN, SETTING, AND PARTICIPANTS Using the National Cancer Data Base, we identified men with unfavorable PCa treated between 2004 and 2012 with androgen suppression (AS) and either EBRT followed by LDR-B or DE-EBRT (75.6-86.4Gy). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Treatment selection was evaluated using logistic regression and annual percentage proportions. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards, and propensity score matching. RESULTS AND LIMITATION We identified 25038 men between 2004 and 2012, during which LDR-B boost utilization decreased from 29% to 14%. LDR-B was associated with better OS on univariate (7-yr OS: 82% vs 73%; p<0.001) and multivariate analyses (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.64-0.77). Propensity score matching verified an OS benefit associated with LDR-B boost (HR 0.74, 95% CI 0.66-0.89). The OS benefit of LDR-B boost persisted when limited to men aged <60 yr with no comorbidities. On subset analysis, there was no interaction between treatment and age, risk group, or radiation dose. Limitations include the retrospective design, nonrandomized selection bias, and the absence of treatment toxicity, hormone duration, and cancer-specific outcomes. CONCLUSIONS Between 2004 and 2012, LDR-B boost utilization declined and was associated with better OS compared to DE-EBRT alone. LDR-B boost is probably the ideal treatment option for men with unfavorable PCa, pending long-term results of randomized trials. PATIENT SUMMARY We compared radiotherapy utilization and survival for prostate cancer (PCa) patients using a national database. We found that low-dose rate brachytherapy (LDR-B) boost, a method being used less frequently, was associated with better overall survival when compared to dose-escalated external-beam radiotherapy alone for men with unfavorable PCa. Randomized trials are needed to confirm that LDR-B boost is the ideal treatment.

Radiosurgery for Brain Metastases: Changing Practice Patterns and Disparities in the United States

Background: Management of brain metastases typically includes radiotherapy (RT) with conventional fractionation and/or stereotactic radiosurgery (SRS). However, optimal indications and practice patterns for SRS remain unclear. We sought to evaluate national practice patterns for patients with metastatic disease receiving brain RT. Methods: We queried the National Cancer Data Base (NCDB) for patients diagnosed with metastatic non-small cell lung cancer, breast cancer, colorectal cancer, or melanoma from 2004 to 2014 who received upfront brain RT. Patients were divided into SRS and non-SRS cohorts. Patient and facility-level SRS predictors were analyzed with chi-square tests and logistic regression, and uptake trends were approximated with linear regression. Survival by diagnosis year was analyzed with the Kaplan-Meier method. Results: Of 75,953 patients, 12,250 (16.1%) received SRS and 63,703 (83.9%) received non-SRS. From 2004 to 2014, the proportion of patients receiving SRS annually increased (from 9.8% to 25.6%; P<.001), and the proportion of facilities using SRS annually increased (from 31.2% to 50.4%; P<.001). On multivariable analysis, nonwhite race, nonprivate insurance, and residence in lower-income or less-educated regions predicted lower SRS use (P<.05 for each). During the study period, SRS use increased disproportionally among patients with private insurance or who resided in higher-income or higher-educated regions. From 2004 to 2013, 1-year actuarial survival improved from 24.1% to 49.6% for patients selected for SRS and from 21.0% to 26.3% for non-SRS patients (P<.001). Conclusions: This NCDB analysis demonstrates steadily increasing-although modest overall-brain SRS use for patients with metastatic disease in the United States and identifies several progressively widening sociodemographic disparities in the adoption of SRS. Further research is needed to determine the reasons for these worsening disparities and their clinical implications on intracranial control, neurocognitive toxicities, quality of life, and survival for patients with brain metastases.

Annual Facility Treatment Volume and Patient Survival for Mycosis Fungoides and Sézary Syndrome

Background: Management of mycosis fungoides and Sézary syndrome (MF/SS) is complex, and randomized evidence to guide treatment is lacking. The institutional treatment volumes for MF/SS might vary widely nationally and influence patient survival. Patients and Methods: Using the National Cancer Database, we identified patients with a diagnosis of MF/SS from 2004 to 2011 in the United States who had received treatment at a reporting facility. The patients were grouped into quintiles according to their treatment facilitys average annual treatment volume (ATV). The characteristics associated with ATV were identified and compared using χ2 tests. Overall survival (OS) was compared among the ATV quintiles using the Kaplan‐Meier method with log‐rank tests and multivariable Cox regression with hazard ratios (HRs). OS was also analyzed using the annual patient volume as a continuous variable. Results: A total of 2205 patients treated at 374 facilities were included for analysis. The ATV quintile cutoffs were 1, 3, 6, and 9 patients. With a median follow‐up period of 59 months, the 5‐year estimated OS survival increased with ATV from 56.7% in the lowest quintile (≤ 1 patient annually) to 83.8% in the highest quintile (> 9 patients annually; P < .001). On multivariable analysis, greater ATV was associated with improved survival when analyzed as a continuous variable (HR, 0.96 per patient per year; 95% confidence interval, 0.94‐0.98; P < .001) and when comparing the highest quintile to the lowest quintile (HR, 0.46; 95% confidence interval, 0.39‐0.55). Conclusion: The present national database analysis demonstrated that higher facility ATV is associated with improved OS for patients with MF/SS. Further study is needed to determine the underlying reasons for improved survival with higher facility ATV. &NA; Mycosis fungoides and Sézary syndrome (MF/SS) management is complex, with heterogeneous treatments. We analyzed a national registry of > 2200 MF/SS patients divided into cohorts by the annual treatment volume quintile of their treatment facility. A greater facility annual treatment volume was associated with improved survival for patients with MF/SS.

Pretreatment Identification of Head and Neck Cancer Nodal Metastasis and Extranodal Extension Using Deep Learning Neural Networks

Identification of nodal metastasis and tumor extranodal extension (ENE) is crucial for head and neck cancer management, but currently only can be diagnosed via postoperative pathology. Pretreatment, radiographic identification of ENE, in particular, has proven extremely difficult for clinicians, but would be greatly influential in guiding patient management. Here, we show that a deep learning convolutional neural network can be trained to identify nodal metastasis and ENE with excellent performance that surpasses what human clinicians have historically achieved. We trained a 3-dimensional convolutional neural network using a dataset of 2,875 CT-segmented lymph node samples with correlating pathology labels, cross-validated and fine-tuned on 124 samples, and conducted testing on a blinded test set of 131 samples. On the blinded test set, the model predicted ENE and nodal metastasis each with area under the receiver operating characteristic curve (AUC) of 0.91 (95%CI: 0.85–0.97). The model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.

Incidence of Radiographically Occult Nodal Metastases in HPV+ Oropharyngeal Carcinoma: Implications for Reducing Elective Nodal Coverage

PURPOSE Initial deescalation studies for human papilloma virus (HPV)-positive driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiation therapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment deescalation. METHODS AND MATERIALS Records of patients with HPV+ OPSCC with preoperative imaging (computed tomography or fludeoxyglucose positron emission tomography/computed tomography) who underwent neck dissection without neoadjuvant therapy from 2010 to 2017 were retrospectively reviewed. The number and location of clinically positive lymph nodes on preoperative imaging were compared with those documented on pathology. These data were then used to establish the probability of missing nodal disease in 3 modified radiation field designs. RESULTS One hundred patients were included. The median time between imaging and surgery was 22 days. The most common clinical N stage was cN2a (35%), whereas the most common pathologic N stage was pN2b (45%). The median number of radiographically and pathologically involved nodes was 1 (range, 0-6) and 2 (range, 0-11), respectively. Forty-three percent of patients had more pathologically involved nodes than predicted on imaging, whereas 21% had pathologic involvement at an additional nodal level not predicted on imaging. Of the 21 patients with additional pathologically involved nodal levels, 14 had involvement of a directly adjacent station, 4 were patients with a cN0 hemineck with pathologically positive level II disease, and 3 had pathologic involvement of level 2 echelons removed from that predicted on imaging. CONCLUSION Our study suggests that radiation fields encompassing only clinically involved nodes or levels has an unacceptably high likelihood of missing subclinical disease. Alternatively, treating the first uninvolved echelon nodes in addition would cover pathologic sites of disease in 97% of patients. This approach merits further study in prospective trials.

Impact of obesity on outcomes for patients with head and neck cancer

OBJECTIVES The prognostic role of obesity in head and neck squamous cell carcinoma (HNSCC) is not well defined. This study aims to determine its effect on disease-specific outcomes such as recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) in addition to overall survival (OS). METHODS For patients with newly diagnosed HNSCC undergoing radiation therapy (RT) at a single institution, body mass index (BMI) at diagnosis was categorized as normal (18.5 to 24.9 kg/m2), overweight (25 to 29.9 kg/m2) and obese (≥30 kg/m2). Outcomes were compared by BMI group using Cox regression. RESULTS 341 patients of median age 59 (range, 20-93) who underwent curative RT from 2010 to 2017 were included. 58% had oropharynx cancer, 17% larynx and 15% oral cavity. 72% had stage IVA/B disease and 28% stage I-III. At diagnosis, 33% had normal BMI, 40% overweight, and 28% obese. 59% had definitive RT and 41% had postoperative RT. Alcoholic/smoking status, advanced tumor stage, hypopharynx/larynx tumors, and feeding tube placement were more common in patients with lower BMI (P < .05 for each). Median follow-up was 30 months (range, 3-91). Higher BMI was associated with improved OS (P < .05) and obesity was associated with longer RFS (P < .05) and DMFS (P < .05), but not LRRFS (P = .07) after adjusting for confounding variables. CONCLUSION Being overweight/obese at the time of HNSCC diagnosis is an independent prognostic factor conferring better survival, while obesity is independently associated with longer time to recurrence, primarily by improving distant control.

Underutilization of proton therapy in the treatment of pediatric central nervous system tumors: an analysis of the National Cancer Database

Radiotherapy (RT) is a mainstay in the treatment of pediatric brain and spinal cord tumors. Indications for RT include the histological type, the extent of the tumor at diagnosis and/or post-operatively, the availability and utilization of chemotherapy regimens, and the age of the child. The sequelae of RT on the developing CNS have been welldescribed, and it is typically avoided in children under the age of 3. RT is most commonly delivered by fractionated external beam radiotherapy, which includes the modalities of 2D radiotherapy (2DRT), 3D conformal radiotherapy (3DCRT), intensity modulated radiotherapy (IMRT) and proton therapy. Each of these techniques can be considered an improvement on the prior in terms of how precisely the radiotherapy is delivered to the target volume. More conformal radiotherapy techniques result in lower doses to the sensitive surrounding normal tissues, and lower late effects of RT. In the Childhood Cancer Survivor Study, over 80% of 5-year survivors had at least one chronic morbidity, and had higher rates of endocrine disorders, hearing deficits and neurological issues compared with siblings [1]. Moreover, cranial RT was associated with higher risks of cognitive impairment and secondary malignancy. Children who received cranial RT doses over 50Gy had a 7% risk of in-field second malignancy. Cognitive impairment was proportion to the doses used for specific tumor types, and dose of RT to the frontal and temporal lobes was associated with lower rates of employment and marriage. Proton therapy can reduce the dose to normal tissues because these heavy particles have unique physical properties resulting in a very different dose profile in tissue. Protons can penetrate the body to a specific depth, based on their initial energy, and then deposit dose in a sharp, discrete peak with no additional dose in the exit path. These unique beams can dramatically change how radiation dose falls off into normal tissues. There are already a few reports that have demonstrated the superiority of protons relative to photons in vulnerable pediatric populations [2–5]. In general, the radiation oncology community, as well as stakeholders among payors and policy makers, agree that pediatric solid tumors, and specifically pediatric CNS tumors, are ideal indications for the use of protons [4,5]. While proton therapy centers are still uncommon, the accessibility of proton therapy has been expanding geographically. In this report, we used the National Cancer Database (NCDB) to study the patterns of utilization of different radiotherapy techniques for the treatment of pediatric CNS malignancies. Our hypothesis was that utilization of proton therapy has increased significantly over the past 10 years. As secondary endpoints, we examined the relationship between clinical and sociodemographic parameters, with use of advanced RT modality, and overall survival. We also examined the trends of IMRT utilization from 1998 to 2011.