Institution-level Patterns of Care for Early-stage Oropharynx Cancers in the United States.

OBJECTIVES: The adoption of transoral robotic surgery and shifting epidemiology in oropharyngeal squamous cell cancer have stimulated debate over upfront and adjuvant treatment. Institutional variation in practice patterns can be obscured in patient-level analyses. We aimed to characterize institutional patterns of care as well as identify potential associations between patterns of care and survival. METHODS: This was a retrospective cohort study of patients identified from 2004-2015 in the National Cancer Database. We analyzed 42,803 cases of oropharyngeal squamous cell cancer Stage cT1-2N0-2bM0 (AJCC 7th edition) treated with curative intent surgery and/or radiotherapy. We defined facility-4-year periods to account for changing institutional practice patterns. The 42,803 patients were treated within 2578 facility-4-year periods. We assessed institutional practice patterns, including the ratio of upfront surgery to definitive radiotherapy, case volumes, use of adjuvant therapies (radiotherapy or chemoradiotherapy), and margin positivity rates. Survival associations with institutional practice patterns were estimated with Cox regression. RESULTS: The ratio of upfront surgery to definitive radiotherapy ranged from 80-to-1 to 1-to-23. The institution-level median rate of adjuvant radiotherapy was 69% (IQR 50%-100%), adjuvant chemoradiotherapy was 44% (IQR 0%-67%), and margin-positive resection was 33% (IQR 0%-50%). On patient-level MVA, worse overall survival was not significantly associated with institutional case volume, adjuvant radiotherapy, or adjuvant chemoradiotherapy utilization. CONCLUSIONS: High rates of multimodal therapy and positive margins underscore the importance of multidisciplinary care and highlight variable patterns of care across institutions. Further work is warranted to explore indicators of high-quality care and to optimize adjuvant therapy in the HPV era.

Patterns of Treatment Failure in Primary Central Nervous System Lymphoma.

OBJECTIVES: Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. METHODS: This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. RESULTS: Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P =0.02), KPS (HR: 0.10, P =0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P <0.01), and use of intrathecal chemotherapy (HR: 0.03, P <0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P =0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT ( P =0.37), Rituximab ( P =0.12), or attempted gross total resection ( P =0.72). CONCLUSIONS: Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.

Integration of Radiation Oncology Into the Preclinical Curriculum Through Problem-Based Learning.

PURPOSE: Early exposure to oncology care during the preclinical years of medical school may translate to increased student interest in oncology-related fields and improved understanding of oncologic treatment modalities, including radiation oncology. Many schools incorporate problem-based learning (PBL) into the medical school curriculum; this is an opportunity to immerse students in oncologic case management. We describe the effective incorporation of one course into the medical school curriculum that may be replicated at other institutions. METHODS AND MATERIALS: A PBL case regarding pancreatic cancer was created by a radiation oncology resident and faculty member in collaboration with the gastrointestinal course director for first-year medical students at a single institution. Pancreatic cancer was chosen based on curricular needs. Learning objectives were discussed to guide the creation of the case. RESULTS: All 140 first-year medical students participated in the 1-hour small group case focused on oncologic work up, multidisciplinary care, and radiation therapy concepts. Students were provided with a case prompt and resources to review prior to the PBL session. Volunteer radiation oncology facilitators attended a 30-minute educational meeting and were provided a detailed case guide 1 week before the PBL session. During the PBL case, facilitators guided students to achieve desired learning objectives. Among the 76 (54%) medical students who completed an optional post-PBL survey, the majority reported that the case motivated them to learn more about oncology (89%) and radiation oncology (82%). There was an increase in the number of subscribers to the Oncology Interest Group (43% increase from previous year) and preclinical students shadowing in the radiation oncology department. The PBL case was continued in future years for all first-year students and extended to 2 hours to promote additional discussion in response to student and facilitator feedback. CONCLUSIONS: A cancer-specific PBL case facilitated by radiation oncology educators is an effective avenue to integrate radiation oncology into the preclinical curriculum and stimulate interest in oncology among first-year medical students.

Ninety-day mortality following transoral robotic surgery or radiation at Commission on Cancer-accredited facilities.

BACKGROUND: Postoperative mortality for oropharynx squamous cell carcinoma (OPSCC) with transoral robotic surgery (TORS) varies from 0.2% to 6.5% on trials; the real-world rate is unknown. METHODS: NCDB study from 2010 to 2017 for patients with cT1-2N0-2M0 OPSCC with Charleson-Deyo score 0-1. Ninety-day mortality assessed from start and end of treatment at Commission on Cancer-accredited facilities. RESULTS: 3639 patients were treated with TORS and 1937 with radiotherapy. TORS cohort had more women and higher income, was younger, more often treated at academic centers, and more likely to have private insurance (all p < 0.05). Ninety-day mortality was 1.3% with TORS and 0.7% or 1.4% from start or end of radiotherapy, respectively. From end of therapy, there was no significant difference on MVA between treatment modality. CONCLUSIONS: There is minimal difference between 90-day mortality in patients treated with TORS or radiotherapy for early-stage OPSCC. While overall rates are low, for patients with expectation of cure, work is needed to identify optimal treatment.

The impact of operability status on outcomes in patients with T4 larynx cancer undergoing larynx preservation.

BACKGROUND: Large analyses of T4 larynx cancer (LC) have raised concerns that larynx preservation (LP) contributes to reduced survival compared with laryngectomy (LGX). The role of operability has not been previously considered as a confounder. METHODS: We queried the National Cancer Database for T4M0 LC diagnosed 2004-2015. Patients were categorized as undergoing LGX, chemoradiotherapy but operable (LP-operable), and chemoradiotherapy inoperable (LP-inoperable). Overall survival (OS) was estimated by Kaplan-Meier. Cox multivariate analysis (MVA) identified variables associated with OS. RESULTS: We identified 1405 LGX, 164 LP-operable and 1969 LP-inoperable patients. Compared with LGX, MVA demonstrated worse OS among LP-inoperable (HR 1.28 95%CI 1.17-1.40, p < 0.01) but not LP-operable patients (HR 1.12 95%CI 0.91-1.39, p = 0.28). CONCLUSIONS: LP-operable patients did not have significantly worse OS than those undergoing LGX.

Osteoradionecrosis of the craniotomy flap: a rare complication of stereotactic radiosurgery.

Osteoradionecrosis (ORN), ischemic necrosis of irradiated bone without evidence of persisting or recurrent tumor, is a known complication of radiation therapy. ORN of the skull has not been reported following stereotactic radiosurgery (SRS). We report two cases of ORN of the skull following SRS for recurrent meningiomas post-resection. Both patients developed ORN in their craniotomy flaps in areas that received high doses of radiation due to their proximity to the recurrent tumors. In each case, the ORN was asymptomatic and was detected on surveillance magnetic resonance imaging. Both patients were followed closely with imaging that ultimately revealed either stability or improvement in the ORN, confirming the diagnosis without the need for biopsy. The cases reveal a role for close imaging surveillance instead of immediate biopsy in patients with new enhancement involving bone in high-dose radiation treatment regions.

Regional Nodal Irradiation for Clinically Node-Positive Breast Cancer Patients With Pathologic Negative Nodes After Neoadjuvant Chemotherapy.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is increasingly used for operable breast cancer (BC). Appropriate radiation therapy (RT) fields (ie, whole breast [WB] ± regional nodal irradiation [RNI]) in patients who were clinically node positive (cN1) but convert to pathologically node negative (ypN0) after NAC are unknown and the subject of the accruing NSABP B-51 trial. We sought to compare outcomes between WB RT with or without RNI following breast conservation and sentinel lymph node biopsy (SLNB) alone in cN1, ypN0 women following NAC. PATIENTS AND METHODS: We identified all BC patients with cN1, ypN0 who underwent NAC followed by lumpectomy and SLNB between 2006 and 2015 in the National Cancer Database. RNI utilization was evaluated using Cochran-Armitage test. Overall survival between WB RT alone versus WB + RNI was compared using Kaplan-Meier with and without propensity score-based weighted adjustment and multivariable (MVA) Cox proportional hazards. RESULTS: From 2006 to 2015, RNI use increased from 48.13% to 62.13% (Pfor trend <.001). The 10-year survival for WB alone versus WB + RNI was 83.6% and 79.5%, respectively (P= .14). On MVA analysis, the addition of RNI compared to WB alone was not associated with a survival benefit (WB vs. WB + RNI: hazard ratio 0.80, 95% confidence interval, 0.58-1.11, P= .19). Results were unchanged after propensity score-based adjustment. CONCLUSION: For women with cN1 BC who convert to ypN0 following NAC and breast conserving surgery with SLNB alone, more extensive RNI may not provide a long-term survival benefit. Prospective validation via the NSABP B-51 trial will be essential.

Virtual Away Rotations Increase Access to Radiation Oncology.

The COVID-19 pandemic altered the workplace for medical education. As restrictions ease, the opportunities provided by virtual rotations remain. Radiation oncology rotations based on virtual participation with patients (consultations, follow-ups, and brachytherapy), contouring and reviewing external beam plans, didactics, and unstructured office hours have been well received at multiple institutions. Virtual rotations decrease barriers to access including lack of a radiation oncology department at one's home institute and the high cost of travel and housing. Furthermore, rotations can be adapted to preclinical students and those with prior radiation oncology rotation experience. However, the virtual format creates and exacerbates several challenges including technical difficulties with electronic medical record or treatment planning software, lack of the spontaneous interactions common to in-person rotations, and unexpected delays in the clinic. We recommend early scheduled time with information technology services to troubleshoot any potential issues, scheduled office hours with faculty and videoconferencing with nonphysician team members to mitigate omission of in-person introductions, and provision of complete contact information for all staff scheduled to meet with students to facilitate communication when unexpected clinic issues arise. Although we are all excited for quarantine restrictions to safely be lifted, we support the continued development of virtual away rotations as a flexible, more affordable option to increase exposure to the field.

CDK9 Expression Shows Role as a Potential Prognostic Biomarker in Breast Cancer Patients Who Fail to Achieve Pathologic Complete Response after Neoadjuvant Chemotherapy.

Failure to achieve pathologic complete response is associated with poor prognosis in breast cancer patients following neoadjuvant chemotherapy (NACT). However, prognostic biomarkers for clinical outcome are unclear in this patient population. Cyclin-dependent kinase 9 (CDK9) is often dysregulated in breast cancer, and its deficiency results in genomic instability. We reviewed the records of 84 breast cancer patients from Emory University's Winship Cancer Institute who had undergone surgical resection after NACT and had tissue available for tissue microarray analysis (TMA). Data recorded included disease presentation, treatment, pathologic response, overall survival (OS), locoregional recurrence free survival (LRRFS), distant-failure free survival (DFFS), recurrence-free survival (RFS), and event-free survival (EFS). Immunohistochemistry was performed on patient samples to determine CDK9 expression levels after NACT. Protein expression was linked with clinical data to determine significance. In a Cox proportional hazards model, using a time-dependent covariate to evaluate the risk of death between groups beyond 3 years, high CDK9 expression was significantly associated with an increase in OS (HR: 0.26, 95% CI: 0.07-0.98, p=0.046). However, Kaplan-Meier curves for OS, LRRFS, DFFS, RFS, and EFS did not reach statistical significance. The results of this study indicate that CDK9 may have a potential role as a prognostic biomarker in patients with breast cancer following NACT. However, further validation studies with increased sample sizes are needed to help elucidate the prognostic role for CDK9 in the management of these patients.

SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination.

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.