Tyler P. Robin

Predictors of overall survival in human papillomavirus-associated oropharyngeal cancer using the National Cancer Data Base

OBJECTIVES This study identifies clinical characteristics associated with HPV-positive oropharynx squamous cell carcinoma (OPSCC) and evaluates predictors of overall survival (OS) in HPV-positive patients undergoing definitive treatment within the National Cancer Data Base (NCDB). MATERIAL AND METHODS The NCDB was queried for patients ⩾18years old with OPSCC and known HPV status who underwent definitive treatment: surgery, radiation (RT), chemotherapy-RT (CRT), surgery+RT, surgery+CRT (S-CRT). Cox proportional hazards model was used for multivariate analysis (MVA) to evaluate predictors of OS by HPV status. RESULTS 3952 patients were included: 2454 (62%) were HPV-positive. Median follow up was 23.7months (range, 1.0-54.5). Unadjusted 2-year OS rates for HPV-positive vs. negative were 93.1% vs. 77.8% (p<0.001) with an adjusted hazard ratio of 0.44 (95% CI, 0.36-0.53; p<0.001). MVA identified multimodality treatment including CRT (HR, 0.42; p=0.024) and S-RT (HR, 0.30; p=0.024), but not S-CRT (HR, 0.51; p=0.086), as predictors for improved OS in HPV-positive stage III-IVB disease. Multimodality treatment including S-CRT was associated with longer OS in HPV-negative OPSCC. Nodal stage was poorly associated with OS in HPV-positive cancers. The presence of positive margins and/or extracapsular extension was associated with worse OS in HPV-negative (HR, 2.11; p=0.008) but not HPV positive OPSCC (HR, 1.61; p=0.154). CONCLUSION The established demographic and clinical features of HPV-positive OPSCC were corroborated in the NCDB. Population analysis suggests that AJCC staging is poorly associated with OS in HPV-positive cancer, and traditional high-risk features may be less impactful. Bimodality therapy appears beneficial in HPV-positive HNSCC.

Allosteric Inhibitors of the Eya2 Phosphatase Are Selective and Inhibit Eya2-mediated Cell Migration

Background: The phosphatase activity of Eya is important for transformation, invasion, migration, and metastasis of breast cancer cells. Results: A class of N-arylidenebenzohydrazide compounds specifically inhibits the phosphatase activity of Eya2 but not Eya3. Conclusion: This class of compounds likely acts through an allosteric mechanism. Significance: These inhibitors may be developed into chemical probes or anti-cancer drugs. Eya proteins are essential co-activators of the Six family of transcription factors and contain a unique tyrosine phosphatase domain belonging to the haloacid dehalogenase family of phosphatases. The phosphatase activity of Eya is important for the transcription of a subset of Six1-target genes, and also directs cells to the repair rather than apoptosis pathway upon DNA damage. Furthermore, Eya phosphatase activity has been shown to mediate transformation, invasion, migration, and metastasis of breast cancer cells, making it a potential new drug target for breast cancer. We have previously identified a class of N-arylidenebenzohydrazide compounds that specifically inhibit the Eya2 phosphatase. Herein, we demonstrate that these compounds are reversible inhibitors that selectively inhibit the phosphatase activity of Eya2, but not Eya3. Our mutagenesis results suggest that this class of compounds does not bind to the active site and the binding does not require the coordination with Mg2+. Moreover, these compounds likely bind within a site on the opposite face of the active site, and function as allosteric inhibitors. We also demonstrate that this class of compounds inhibits Eya2 phosphatase-mediated cell migration, setting the foundation for these molecules to be developed into chemical probes for understanding the specific function of the Eya2 phosphatase and to serve as a prototype for the development of Eya2 phosphatase specific anti-cancer drugs.

Disparities in standard of care treatment and associated survival decrement in patients with locally advanced cervical cancer

PURPOSE Standard of care (SOC) treatment for locally advanced cervical cancer includes pelvic external beam radiation (EBRT) with chemotherapy and interdigitated brachytherapy. We evaluated national utilization trends and factors associated with receiving SOC therapy. MATERIALS AND METHODS We utilized the National Cancer Database (NCDB) to identify women with locally advanced cervical cancer treated with definitive radiation or chemoradiation therapy and stratified these patients by treatment received. RESULTS We identified 15,194 patients. Only 44.3% of patients received SOC treatment and this group had significantly improved OS. High volume centers, academic centers, comprehensive community cancer centers, private insurance, and higher income, were all associated with an increased likelihood of receiving SOC, whereas Black patients were less likely to receive SOC. We found 26.8% of patients received no radiation boost, 23.8% received an EBRT boost only, and 49.5% of patients received EBRT with brachytherapy. Although an EBRT boost was advantageous over no boost at all (HR 0.720, p<0.001), OS was superior in patients who received brachytherapy (HR 0.554, p<0.001). Patients were more likely to receive no radiotherapy boost if they had lower incomes, Medicaid, were treated at low volume centers, or were treated at non-comprehensive community cancer centers. CONCLUSIONS SOC for locally advanced cervical cancer offers superior outcomes, yet less than half of patients receive SOC and there are disparities in which patients receive SOC treatment. No additional treatment, including sophisticated EBRT techniques including IMRT or SBRT, can make up for the survival decrement from lack of brachytherapy as a component of definitive care.

A comprehensive comparative analysis of treatment modalities for sinonasal malignancies

Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality.

Safety of contralateral submandibular gland sparing in locally advanced oropharyngeal cancers: A multicenter review

Previous groups have shown contralateral submandibular gland sparing to improve xerostomia with safe outcomes, but primarily in early‐stage disease. In this study, we present a large cohort of patients with locally advanced head and neck cancer that underwent contralateral submandibular gland‐sparing radiotherapy, to demonstrate feasibility and safety specifically in patients with locally advanced disease.

Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non–Small Cell Lung Cancer

Introduction: Patients with brain metastases (BMs) arising from EGFR‐mutated and anaplastic lymphoma kinase gene (ALK)‐rearranged NSCLC have a favorable prognosis compared with patients with non–oncogene‐addicted NSCLC, emphasizing the importance of minimizing toxicities such as the cognitive sequelae of whole brain radiation therapy (WBRT). Although radiosurgery without WBRT is the preferred strategy for one to three BMs, this paradigm remains controversial for patients with multiple BMs. Methods: We reviewed the cases of patients with EGFR‐mutated and ALK‐rearranged NSCLC presenting to our cancer center between 2008 and 2017 and included only patients receiving treatment to four or more BMs in a single radiosurgery session. Results: We identified 35 patients with a median follow‐up of 4.1 years. The maximum number of BMs treated in a single radiosurgery session ranged from four to 26 (median number of BM treated per radiosurgery course: 6), and in total over all courses the number ranged from four to 47 (median: 10). The median survival was 3.0 years (4.2 for ALK‐rearranged NSCLC; 2.4 for EGFR‐mutated NSCLC) from the diagnosis of BM, and survival was comparable regardless of number of radiosurgery courses, number of BMs treated in total, or number of BMs treated in a single radiosurgery session. The mean hippocampal and whole‐brain doses were exceedingly low even for patients receiving treatment to more than 10 BMs (1.2 and 0.8 Gy, respectively). Radiosurgery was well tolerated overall and the 5‐year rate of freedom from neurologic death was 84%. The 5‐year rate of freedom from WBRT was 97%. Conclusions: Radiosurgery for multiple BMs is controversial, yet patients with EGFR‐mutated and ALK‐rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene‐addicted NSCLC with four or more BMs.

The Impact of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma

Introduction The optimal role for postoperative radiotherapy (PORT) for thymoma and thymic carcinoma remains controversial. We used the National Cancer Data Base to investigate the impact of PORT on overall survival (OS). Methods Patients who underwent an operation for thymoma or thymic carcinoma were categorized into Masaoka‐Koga stage groups I to IIA, IIB, III, and IV. Patients who did not undergo an operation or those who received preoperative radiation were excluded. Kaplan‐Meier estimates of OS and univariate and multivariate Cox proportional hazards regression analyses were performed. Propensity score–matched analyses were performed to further control for baseline confounders. Results From 2004 to 2012, 4056 patients were eligible for inclusion, 2001 of whom (49%) received PORT. On multivariate analysis of OS in the thymoma cohort adjusted for age, WHO histologic subtype, Masaoka‐Koga stage group, surgical margins, and chemotherapy administration, PORT was associated with superior OS (hazard ratio [HR] = 0.72, p = 0.001). Propensity score–matched analyses confirmed the survival advantage associated with PORT. Subset analysis indicated longer OS in association with PORT for patients with stage IIB thymoma (HR = 0.61, p = 0.035), stage III (HR = 0.69, p = 0.020), and positive margins (HR = 0.53, p < 0.001). The impact of PORT for stage I to IIA disease did not reach significance (HR = 0.76, p = 0.156). Conclusions In this large database analysis of PORT for thymic tumors, PORT was associated with longer OS, with the greatest relative benefits observed for stage IIB to III disease and positive margins. In the absence of randomized studies assessing the value of PORT, these data may inform clinical practice.

Radiosurgery alone is associated with favorable outcomes for brain metastases from small-cell lung cancer

INTRODUCTION Whole-brain radiation therapy (WBRT) is the standard approach for brain metastases (BM) arising in patients with small-cell lung cancer (SCLC), but the neurocognitive toxicities of WBRT are well documented. For this reason, stereotactic radiosurgery (SRS) alone is the preferred modality for limited BM in most histologies, but in SCLC there are few data exploring this approach. METHODS We queried the National Cancer Database (NCDB) for patients with SCLC with BM at diagnosis and stratified by upfront SRS compared with upfront WBRT ± SRS. We utilized multivariate Cox regression and propensity score matching (PSM) to determine the impact on overall survival (OS) of each approach. RESULTS 5952 eligible patients (WBRT: 5752; SRS: 200) were identified from 2010 to 2014 with a median follow-up of 40.0 months. Upfront SRS was associated with superior OS (median 10.8 vs 7.1 months, HR 0.65, 95% CI 0.55-0.75, p < 0.001), which persisted on multivariate analysis controlling for comorbidities, extracranial metastases, age, race/ethnicity, and gender (HR 0.70, 95% CI 0.60-0.81, p < 0.001). These results were confirmed in PSM analysis. A subset analysis comparing outcomes after SRS vs SRS + WBRT showed no differences in OS (p = .601). CONCLUSIONS To our knowledge, this is the largest dataset of patients treated with SRS alone for SCLC. The observation of favorable OS with SRS alone in this contemporary dataset suggests that SRS alone may be appropriate for some patients with SCLC. Prospective investigations of SRS in SCLC are warranted.

Utilization of a Web-Based Conferencing Platform to Improve Global Radiation Oncology Education and Quality—Proof of Principle Through Implementation in India

PURPOSE Chartrounds (www.chartrounds.com) was established in the United States in 2010 as a web-based platform for radiation oncologists to review cases with leading disease-site experts. However, the need for access to experts for peer review and education is not unique to the United States, and the Chartrounds platform was therefore adapted for improved global reach. Chartrounds was first expanded to India, and herein we report our initial experience with this initiative. METHODS AND MATERIALS The US Chartrounds platform was adapted to create Chartrounds India (ind.chartrounds.com). Through collaboration with the Association of Radiation Oncologists of India, India-based specialists were recruited, and the associations membership list was used to announce sessions to potential participants. RESULTS Between June 2017 and January 2018, 27 Chartrounds India sessions were completed, led by 21 different specialists (representing 10 centers in India) and covering 11 different disease sites/topics. A total of 240 members from 126 centers (private: 56%; teaching: 36%; public: 8%) across 24 states/territories participated in ≥1 session. Of the 240 members who participated in ≥1 session, 159 (66%) participated in ≥2 sessions and 60 (25%) participated in ≥5 sessions. The average number of participants per session was 34 (range, 13-72). On average, 80% of respondents rated the sessions as high or very high quality; 87% and 95% agreed or strongly agreed that the time was used effectively and that the sessions were relevant to daily practice, respectively. Seventy-six percent agreed or strongly agreed that the sessions will result in a change in their practice. The average feedback survey response rate was 32% (range, 17%-49%). CONCLUSIONS Chartrounds has proven to be an effective resource for US-based radiation oncologists, and our initial experience with Chartrounds India suggests that an online platform for radiation oncology case review and education can be successfully implemented globally with use of local disease site experts.

Strategies to Preserve Cognition in Patients With Brain Metastases: A Review

Brain metastases are common to the natural history of many advanced malignancies. Historically, whole brain radiation therapy (WBRT) has played a key role in the management of brain metastases, especially for patients with multiple lesions. However, prospective trials have demonstrated consistent neurocognitive toxicities after WBRT, and various pharmacologic and anatomic strategies designed to mitigate these toxicities have been studied in recent years. Memantine, an NMDA receptor antagonist, taken during and after WBRT improved cognitive preservation in a randomized trial over placebo. Deliberate reductions in radiation dose to the hippocampus, via hippocampal-avoidance (HA)-WBRT, resulted in improved cognition over historic controls in a phase II trial, and follow-up randomized trials are now ongoing to evaluate cognitive outcomes with HA vs. conventional brain radiation techniques. Nevertheless, some of the most promising strategies currently available to reduce the cognitive effects of brain radiation may be found in efforts to avoid or delay WBRT administration altogether. Stereotactic radiosurgery (SRS), involving focused, high-dose radiation to central nervous system (CNS) lesions with maximal sparing of normal brain parenchyma, has become the standard for limited brain metastases (classically 1–3 or 4 lesions) in the wake of multiple randomized trials demonstrating equivalent survival and improved cognition with SRS alone compared to SRS plus WBRT. Today, there is growing evidence to support SRS alone for multiple (≥4) brain metastases, with comparable survival to SRS alone in patients with fewer lesions. In patients with small-cell lung cancer, the routine use of prophylactic cranial irradiation (PCI) for extensive-stage disease has been also been challenged following the results of a randomized trial supporting an alternative strategy of MRI brain surveillance and early salvage radiation for the development of brain metastases. Moreover, new systemic agents are demonstrating increasing CNS penetration and activity, with the potential to offer greater control of widespread and microscopic brain disease that was previously only achievable with WBRT. In this review, we endeavor to put these clinical data on cognition and brain metastases into historical context and to survey the evolving landscape of strategies to improve future outcomes.