Evaluating the impact of the degree of extranodal extension on outcomes in locally advanced oral cavity cancer.

BACKGROUND: Evaluate whether extranodal extension (ENE) extent impacts outcomes in patients with oral cavity squamous cell carcinoma (OCSCC). METHODS: From an institutional database, patients with OCSCC and pathologic ENE who received adjuvant treatment were included. Surgical slides were reviewed to confirm ENE extent. Multivariable Cox regression was used to relate patient/treatment characteristics with disease-free survival (DFS) and overall survival (OS). ENE was analyzed as both a dichotomous and continuous variable. RESULTS: A total of 113 patients were identified. Between major (>2 mm) versus minor ENE (≤2 mm), there was no significant difference in DFS (HR 1.18, 95%CI 0.72-1.92, p = 0.51) or OS (HR 1.17, 95%CI 0.70-1.96, p = 0.55). There was no significant association between ENE as a continuous variable and DFS (HR 0.97 per mm, 95%CI 0.87-1.4, p = 0.96) or OS (HR 0.96 per mm, 95%CI 0.83-1.11, p = 0.58). CONCLUSION: No significant relationship was seen between ENE extent and DFS or OS in individuals with OCSCC.

Primary fit tracheoesophageal puncture in primary versus salvage laryngectomy: Short-term and long-term complications and functional outcomes.

BACKGROUND: Primary fit tracheoesophageal puncture (TEP) is widely preferred for individuals who have not undergone prior radiation. However, there is no consensus on the relative utility of primary-fit TEP in the setting of salvage laryngectomy. METHODS: A retrospective, single-center review was conducted of individuals undergoing laryngectomy with primary fit TEP between 2012 and 2018. Multivariable analysis was conducted to compare short-term and long-term complications, as well as speech and swallowing outcomes, of those who underwent primary versus salvage laryngectomy. RESULTS: In this study, 134 patients underwent total laryngectomy with primary fit TEP. Aside from a higher rate of peristomal dehiscence (13.1% vs. 1.4%) found in the salvage group, there was no difference in incidence of all other complications, including pharyngocutaneous fistula formation. The groups had comparable speech and swallow outcomes. CONCLUSION: Primary fit TEP is a safe and effective surgical choice for individuals undergoing salvage laryngectomy who desire a voice prosthesis.

Risk of Thromboembolism in Patients Receiving Immunotherapy-Based Combinations as Front-Line Therapy for Metastatic Renal Cell Carcinoma.

BACKGROUND: Most patients with treatment-naïve metastatic renal cell carcinoma (mRCC) receive combination-based immunotherapy with either 2 immune-oncology checkpoint inhibitors (IO/IO) or an IO agent in combination with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (IO/TKI). The rates of thromboembolism (TE) in these cohorts are not clearly described and can potentially impact decision-making between IO/IO and IO/TKI. METHODS: We conducted a retrospective investigation of patients with treatment-naïve mRCC treated with IO-based combinations between January 2015 and April 2021 at the Cleveland Clinic. TE events, including venous and arterial, were identified in each group. Competing risk regression was done to identify factors associated with the development of TE following therapy, with all-cause mortality treated as a competing event. RESULTS: Of 180 patients identified, 77 (43%) received IO/TKI and 103 (57%) received IO/IO. Median age was 65 years, 75% were male, and 80% had clear cell histology. Baseline characteristics were similar between the 2 groups. At a median follow-up of 22.0 months, 10.0% of all patients had a TE. The one-year incidence of TE was 8.1% (95% CI: 3.3%-15.8%) with IO/TKI and 9.8% (95% CI: 5.0%-16.5%) with IO/IO and was not significantly different between the 2 groups (HR 0.89, 95% CI: 0.35%-2.28%). Occurrence of TE was associated with decreased overall survival regardless of IO/IO or IO/TKI therapy (HR 2.80, 95% CI: 1.57-5.02). There was no difference in incidence of TE based on patient age, gender, prior history of TE, International Metastatic Renal Cell Carcinoma (IMDC) risk group, or Khorana score. CONCLUSIONS: Incidence of TE is similar between IO/IO and IO/TKI regimens in treatment-naïve mRCC and is also associated with decreased overall survival. While risk of TE may not guide decision-making in choice of front-line mRCC therapy, careful attention should be given to the high risk of TE in this population.

Intratumoral androgen biosynthesis associated with 3ß-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer.

Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3ßHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3ßHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3ßHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.

Neutrophil to lymphocyte ratio (NTLR) predicts local control and overall survival after stereotactic body radiotherapy (SBRT) in metastatic sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients with local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improve lymphocyte recovery should be investigated.

Margin Assessment Methods in Oral Cavity Squamous Cell Carcinoma and Recurrence: Tumor Bed vs Resection Specimen Sampling.

Importance: Positive margins and margin clearance are risk factors for recurrence in oral cavity squamous cell carcinoma (OCSCC), and these features are used to guide decisions regarding adjuvant radiation treatment. However, the prognostic value of intraoperative tumor bed vs resection specimen sampling is not well defined. Objective: To determine the prognostic implications of intraoperative margin assessment methods (tumor bed vs resection specimen sampling) with recurrence among patients who undergo surgical resection for OCSCC. Design, Setting, and Participants: This was a retrospective study of patients who had undergone surgical resection of OCSCC between January 1, 2000, and December 31, 2021, at a tertiary-level academic institution. Patients were grouped by margin assessment method (tumor bed [defect] or resection specimen sampling). Of 223 patients with OCSCC, 109 patients had localized tumors (pT1-T2, cN0), 154 had advanced tumors, and 40 were included in both cohorts. Disease recurrence after surgery was estimated by the cumulative incidence method and compared between cohorts using hazard ratios (HRs). Data analyses were performed from January 5, 2023, to April 30, 2023. Main Outcome and Measures: Recurrence-free survival (RFS). Results: The study population comprised 223 patients (mean [SD] age, 62.7 [12.0] years; 88 (39.5%) female and 200 [90.0%] White individuals) of whom 158 (70.9%) had defect-driven and 65 (29.1%) had specimen-driven margin sampling. Among the 109 patients with localized cancer, intraoperative positive margins were found in 5 of 67 (7.5%) vs 8 of 42 (19.0%) for defect- vs specimen-driven sampling, respectively. Final positive margins were 3.0% for defect- (2 of 67) and 2.4% for specimen-driven (1 of 42) margin assessment. Among the 154 patients with advanced cancer, intraoperative positive margins were found in 29 of 114 (25.4%) vs 13 of 40 (32.5%) for defect- and specimen-driven margins, respectively. Final positive margins were higher in the defect-driven group (9 of 114 [7.9%] vs 1 of 40 [2.5%]). When stratified by margin assessment method, the 3-year rates of local recurrence (9.7% vs 5.1%; HR, 1.37; 95% CI, 0.51-3.66), regional recurrence (11.0% vs 10.4%; HR, 0.85; 95% CI, 0.37-1.94), and distant recurrence (6.4% vs 5.0%; HR, 1.10; 95% CI, 0.36-3.35) were not different for defect- vs specimen-driven sampling cohorts, respectively. The 3-year rate of any recurrence was 18.9% in the defect- and 15.2% in the specimen-driven cohort (HR, 0.93; 95% CI, 0.48-1.81). There were no differences in cumulative incidence of disease recurrence when comparing defect- vs specimen-driven cases. Conclusions and Relevance: The findings of this retrospective cohort study indicate that margin assessment methods using either defect- or specimen-driven sampling did not demonstrate a clear association with the risk of recurrence after OCSCC resection. Specimen-driven sampling may be associated with reduced surgical margin positivity rates, which often necessitate concurrent chemotherapy with adjuvant radiation therapy.

ERBB2 Amplification and HER2 Expression in Salivary Duct Carcinoma: Evaluation of Scoring Guidelines and Potential for Expanded Anti-HER2 Therapy.

Salivary duct carcinoma (SDC) is aggressive with limited therapeutic options. A subset of SDC display human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry, and some show ERBB2 gene amplification. Guidelines for HER2 scoring are not firmly established. Recent advances in breast carcinoma have established a role for anti-HER2 therapies in lesions with low HER2 expression lacking ERBB2 amplification. Delineating HER2 staining patterns in SDC is critical for evaluating anti-HER2 treatments. In total, 53 cases of SDC resected at our institution between 2004 and 2020 were identified. Androgen receptor (AR) and HER2 immunohistochemistry and ERBB2 fluorescence in situ hybridization were performed in all cases. AR expression was scored for percentage positive cells and categorized as positive (>10% of cells), low positive (1%-10%), or negative (<1%). HER2 staining levels and patterns were recorded, scored using 2018 ASCO/CAP guidelines, and categorized into HER2-positive (3+ or 2+ with ERBB2 amplification), HER2-low (1+ or 2+ without ERBB2 amplification), HER2-very low (faint staining in <10% of cells), or HER2-absent types. Clinical parameters and vital status were recorded. Median age was 70 years, with a male predominance. ERBB2-amplified tumors (11/53; 20.8%) presented at lower pT stages (pTis/pT1/pT2; P = .005, Fisher exact test) and more frequently had perineural invasion (P = .007, Fisher exact test) compared with ERBB2 nonamplified tumors; no other pathologic features differed significantly by gene amplification status. In addition, 2+ HER2 staining by 2018 ASCO/CAP criteria was most common (26/53; 49%); only 4 cases (8%) were HER2-absent status; 3+ HER2 staining was found in 9 tumors, and all were ERBB2 amplified. Six patients with HER2-expressing tumors received trastuzumab therapy, including 2 with ERBB2-amplified tumors. Overall survival and recurrence-free survival did not differ significantly based on ERBB2 status. This work suggests that 2018 ASCO/CAP guidelines for HER2 evaluation in breast carcinoma could be applied to SDC. Our findings also show broad overexpression of HER2 in SDC raising the possibility that more patients may benefit from anti-HER2-directed therapies.

Neutrophil to Lymphocyte Ratio (NTLR) Predicts Local Control Failure and Overall Survival after Stereotactic Body Radiotherapy (SBRT) In Metastatic Sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improved lymphocyte recovery should be investigated.

Reduced Risk of Corporal Tumors in Patients With Head and Neck Paragangliomas With p.Pro81Leu Mutations.

OBJECTIVE: Patients with head and neck paragangliomas who are positive for the SDHD p.Pro81Leu (P81L) mutation are thought to have a distinct phenotype from other SDHx mutations, but few studies have focused on this mutation. The objective of this study was to determine the hazard of developing a second primary, metastatic, or recurrent paraganglioma in SDHx patients with or without P81L. STUDY DESIGN: Retrospective chart review of 60 patients with head and neck paragangliomas and genetic testing, followed for a median of 9 years. SETTING: Single academic medical center. METHODS: Univariable Cox proportional hazards regression evaluated second primary and recurrent paragangliomas in patients with SDHD P81L, SDHx non-P81L, and nonhereditary paraganglioma. RESULTS: This series comprised 31 patients without SDHx, 14 with SDHD P81L, and 15 with other SDHx mutations. At a median 9 years of follow-up, corporal (not head and neck) second primary paragangliomas occurred in 31% of patients with SDHx non-P81L mutations, compared with 0% and 4% of patients with SDHD P81L and without SDHx mutations, respectively. Second corporal paragangliomas were more likely in patients with SDHx non-P81L mutations than in those without a mutation (hazard ratio = 5.461, 95% confidence interval: 0.596-50.030, p = .13). CONCLUSION: This is the first study to report a lower likelihood of corporal tumors for patients with head and neck paragangliomas with SDH mutations positive for P81L. Larger studies are needed to determine if head and neck paraganglioma patients with P81L qualify for less intensive imaging surveillance to screen for second primary paragangliomas outside the head and neck.

Association of Treatment Strategies and Tumor Characteristics With Overall Survival Among Patients With Anaplastic Thyroid Cancer: A Single-Institution 21-Year Experience.

Importance: Survival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans. Objective: To evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC. Design, Setting, and Participants: This retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022. Main Outcomes and Measures: Overall survival (OS). Results: The study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS. Conclusions and Relevance: This retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

Rates of osteoradionecrosis in resected oral cavity cancer reconstructed with free tissue transfer in the intensity-modulated radiotherapy era.

BACKGROUND: Resected oral cavity carcinoma defects are often reconstructed with osteocutaneous or soft-tissue free flaps, but risk of osteoradionecrosis (ORN) is unknown. METHODS: This retrospective study included oral cavity carcinoma treated with free-tissue reconstruction and postoperative IMRT between 2000 and 2019. Risk-regression assessed risk factors for grade ≥2 ORN. RESULTS: One hundred fifty-five patients (51% male, 28% current smokers, mean age 62 ± 11 years) were included. Median follow-up was 32.6 months (range, 1.0-190.6). Thirty-eight (25%) patients had fibular free flap for mandibular reconstruction, whereas 117 (76%) had soft-tissue reconstruction. Grade ≥2 ORN occurred in 14 (9.0%) patients, at a median 9.8 months (range, 2.4-61.5) after IMRT. Post-radiation teeth extraction was significantly associated with ORN. One-year and 10-year ORN rates were 5.2% and 10%, respectively. CONCLUSIONS: ORN risk was comparable between osteocutaneous and soft-tissue reconstruction for resected oral cavity carcinoma. Osteocutaneous flaps can be safely performed with no excess concern for mandibular ORN.

Thromboembolism in Patients with Metastatic Urothelial Cancer Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown. OBJECTIVE: We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. METHODS: Patients with urothelial cancer treated with immune checkpoint inhibitors at the Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. The Kaplan-Meier method estimated overall survival and Cox proportional hazards regression evaluated the impact of TE on overall survival. RESULTS: Of 279 patients, 72% were men with pure urothelial cancer (62%) who started atezolizumab (40%), nivolumab (3%), or pembrolizumab (57%). At a median follow-up of 5.6 months (range 0.3-51.6), 42 patients developed a TE (VTE n = 37, 13%, ATE n = 5, 2%). The cumulative incidence of TE after immune checkpoint inhibitor therapy was 9.1% (95% confidence interval 6.0-13.0) at 6 months and 13.6% (95% confidence interval 9.6-18.4) at 12 months. Most TE (VTE 62%, ATE 100%) occurred within 6 months of immune checkpoint inhibitor initiation (median doses 5, range 1-59), and the majority (VTE 81%, ATE 100%) resulted in hospitalization (median: 5 days, 4 days, respectively). Thromboembolism (hazard ratio 2.296, p = 0.0004), Bajorin score 1 or 2 (hazard ratio 1.490, p = 0.0315), and Bajorin score 2 (hazard ratio 3.50, p < 0.0001) were associated with worse overall survival. CONCLUSIONS: Immune checkpoint inhibitors are associated with a high TE risk. Thromboembolism is associated with worsened survival, among other poor outcomes. Further investigation into the mechanism behind immune checkpoint inhibitor-associated TE is needed.

A Reappraisal of Definitive Chemoradiotherapy for Older Adults With Advanced Head and Neck Cancer.

BACKGROUND/AIM: Definitive treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is often compromised in older adults due to concerns about potential treatment toxicity intolerance. We reviewed our institutional experience with definitive management of older adults with LAHNSCC. PATIENTS AND METHODS: From our Institutional Review Board-approved registry, we identified patients aged >60 years with stage III-IV, M0 LAHNSCC (seventh/earlier editions of the American Joint Committee on Cancer classification) treated with definitive radiotherapy from 1993-2019. Indications for concurrent chemotherapy included T3-4 or N2-3 disease. Multivariable analysis using Fine and Gray regression was performed to identify risk factors associated with recurrence. The cumulative incidence method was used to calculate recurrence rates. RESULTS: Overall, 350 patients were identified: 223 aged 60-69, 82 aged 70-74, and 45 aged ≥75 years. Median follow-up was 36.3 months. Two-year recurrence rates were 13.7%, 20.2% and 34.8%, respectively; human papillomavirus-positive disease was present in 190 (85%), 44 (54%), and 25 (56%), respectively; and systemic therapy was given to 194 (87%), 64 (88%), and 23 (56%) patients, respectively. Factors significantly associated with increased risk of recurrence included age ≥75 years, Karnofsky performance status 70-80, clinical N2c-N3, and Charlson score 2-3. CONCLUSION: Patients aged ≥75 years received less aggressive therapy and experienced increased recurrence compared to younger patients. Outcomes for those aged 70-74 years were similar to younger patients treated with aggressive therapy, despite their inferior performance status/comorbidity, and such patients should not routinely be excluded from standard-of-care therapy. Further study is needed to optimize therapy for a redefined older adult (age ≥75 years) population.

Local Control With Single-Fraction Lung Stereotactic Body Radiotherapy is not influenced by Non-Small Cell Lung Cancer Histologic Subtype.

INTRODUCTION/BACKGROUND: For early stage medically inoperable lung cancer treated with fractionated stereotactic body radiotherapy (SBRT), higher local failure is associated with squamous carcinoma (SqC) compared to adenocarcinoma (AC). This study explored whether histology influences single-fraction SBRT local control. MATERIALS AND METHODS: We surveyed our prospective data registry from 12/2009 to 12/2019 for SF-SBRT cases with biopsy-proven AC or SqC only. Outcomes of interest included local (LF), nodal (NF), distant (DF) failure rates and overall survival (OS), as well as treatment-related toxicity. RESULTS: For the 10-year interval surveyed, 113 patients met study criteria. There was no association between histology and dose received (34 Gy or 30 Gy). Median follow up was 22.9 months. Patient characteristics were balanced between histologic cohorts. Median tumor size was 1.9 cm. Comparing total AC vs. SqC cohorts, 2-year LF rates (%) were 7.3 vs. 9.6, respectively (P = .9805). In %, 2-year LF, NF, DF and OS rates for AC for 30 Gy and 34 Gy, respectively, were 10.8 vs. 6.4; 10.5 vs. 16.2; 15.8 vs. 13.0; 77.9 vs.71.2 (all P = non-significant). In %, 2-year LF, NF, DF, and OS rates for SqC for 30 Gy and 34 Gy, respectively, were 11.8 vs. 8.1; 5.9 vs. 18.0; 23.5 vs. 9.7; 70.6 vs. 77.1 (all P = non-significant). When considering toxicities, there were no grade 4/5 toxicities and no significant differences in any other toxicity rate by histology or dose. CONCLUSION: SF-SBRT local control was not associated with histology, unlike fractionated schedules. This novel finding adds to the evolving understanding of this treatment schedule.

Variability in Depth of Invasion Measurements in Carcinomas of the Oral Cavity and the Effect on Pathologic Tumor Staging.

Depth of invasion (DOI) was added to the staging criteria for carcinoma of the lip and oral cavity in the 8th edition of the American Joint Committee on Cancer Staging Manual (AJCC8). However, there are multiple practical challenges to obtaining an accurate DOI measurement with limited data regarding interobserver variability in DOI measurement. The aim of this study was to investigate interobserver variability in DOI measurement and its effect on tumor stage. We performed an electronic medical record search for excisions of squamous cell carcinoma of the oral cavity between January 1, 2010 and December 25, 2017. All slides containing significant tumor were selected for independent blinded DOI measurement by four head and neck pathologists per AJCC8 guidelines. Pathologic stage was assigned in conjunction with reported tumor greatest dimension. Observers recorded the slide used for measurement and potential issues limiting assessment of DOI. Results were compared for reproducibility in DOI and tumor stage using intraclass correlation coefficient (ICC) analysis. A total of 167 cases of oral squamous cell carcinoma with available slides were included. The ICC score for DOI between observers was 0.91339 (> 0.9 considered excellent). Only 7.2% of cases had uniform DOI amongst observers. Increasing overall tumor size and average DOI correlated with increasing range in DOI amongst observers. Differences in DOI resulted in differences in pathologic tumor staging (pT) for 15% of tumors. Use of different slides for DOI measurements was significantly associated with different pT staging. In contrast, ulceration and exophytic growth did not correlate with higher DOI or pT variability. Despite the excellent ICC score, differences in DOI measurement resulted in variable pT staging for a considerable number of cases. We therefore recommend consensus for DOI in at least some cases in which potential differences in DOI could alter pT stage assignment.

Limited Toxicity of Hypofractionated Intensity Modulated Radiation Therapy for Head and Neck Cancer.

BACKGROUND/AIM: Hypofractionated radiation therapy is not commonly used in head and neck cancers (HNC) due to increased toxicity observed in historical cohorts. This study reviews our institutional experience using hypofractionated intensity modulated radiation therapy (H-IMRT) for HNC. PATIENTS AND METHODS: A retrospective cohort study of 56 patients with HNC treated with H-IMRT with ≥50 Gy in 20 fractions was conducted. The primary outcomes were acute and late toxicity. RESULTS: Two-year locoregional control was 87% and median overall survival was 46 months. There were no acute or late grade 4 or 5 toxicities. Acute grade 2 and 3 toxicity was seen in 79% (N=44) and 25% (N=14), respectively. Late grade 2 toxicity was seen in 9% (N=5). No patients required the placement of a feeding tube or tracheostomy. CONCLUSION: H-IMRT for the definitive or post-operative treatment of HNC using ≥50 Gy in 20 fractions appears safe and well tolerated with modest toxicity.

Nasopharyngeal cancer: Incidence and prognosis of human papillomavirus and Epstein-Barr virus association at a single North American institution.

BACKGROUND: The prognostication of Epstein-Barr virus (EBV) and human papillomavirus (HPV) status in nasopharyngeal cancer (NPC) is unclear. METHODS: This retrospective study analyzed NPC from 2000 to 2019. RESULTS: Seventy-eight patients were included: 43 EBV+ , 12 HPV+ , 23 EBV- /HPV- , and 0 EBV+ /HPV+ . All p16+ tumors were also positive for HPV-CISH. Baseline characteristics were not different between groups except age, N-classification, and Karnofsky Performance Scale (KPS) (p < 0.05). For EBV+ , HPV+ , and EBV- /HPV- respectively, 3-year overall survival (OS) was 89.9%, 69.8%, and 52.5% (p = 0.006). EBV- /HPV- status was significantly associated with worse OS but not freedom from progression (FFP) on univariate analysis, and did not remain a significant predictor of OS after adjusting for KPS, age, and group stage. CONCLUSIONS: EBV+ NPC tumors were seen in younger, healthier patients than HPV+ and EBV- tumors, and there were no cases of coinfection. The association of viral status with OS was insignificant after adjusting for KPS and age.

Association between biologically effective dose and local control after stereotactic body radiotherapy for metastatic sarcoma.

Introduction: Stereotactic body radiation therapy (SBRT) is increasingly utilized for patients with recurrent and metastatic sarcoma. SBRT affords the potential to overcome the relative radioresistance of sarcomas through delivery of a focused high biological effective dose (BED) as an alternative to invasive surgery. We report local control outcomes after metastatic sarcoma SBRT based on radiation dose and histology. Methods: From our IRB-approved single-institution registry, all patients treated with SBRT for metastatic sarcoma between 2014 and 2020 were identified. Kaplan-Meier analysis was used to estimate local control and overall survival at 1 and 2 years. A receiver operating characteristic (ROC) curve was generated to determine optimal BED using an α/ß ratio of 3. Local control was compared by SBRT dose using the BED cut point and evaluated by histology. Results: Forty-two patients with a total of 138 lesions met inclusion criteria. Median imaging follow up was 7.73 months (range 0.5-35.0). Patients were heavily pre-treated with systemic therapy. Median SBRT prescription was 116.70 Gy BED (range 66.70-419.30). Desmoplastic small round cell tumor, Ewing sarcoma, rhabdomyosarcoma, and small round blue cell sarcomas were classified as radiosensitive (n = 63), and all other histologies were classified as radioresistant (n = 75). Local control for all lesions was 66.7% (95% CI, 56.6-78.5) at 1 year and 50.2% (95% CI, 38.2-66.1) at 2 years. Stratifying by histology, 1- and 2-year local control rates were 65.3% and 55.0%, respectively, for radiosensitive, and 68.6% and 44.5%, respectively, for radioresistant histologies (p = 0.49). The ROC cut point for BED was 95 Gy. Local control rates at 1- and 2-years were 75% and 61.6%, respectively, for lesions receiving >95 Gy BED, and 46.2% and 0%, respectively, for lesions receiving <95 Gy BED (p = 0.01). On subgroup analysis, local control by BED > 95 Gy was significant for radiosensitive histologies (p = 0.013), and trended toward significance for radioresistant histologies (p = 0.25). Conclusion: There is a significant local control benefit for sarcoma SBRT when a BED > 95 Gy is used. Further investigation into the dose-response relationship is warranted to maximize the therapeutic index.

125I Interstitial brachytherapy with or without androgen deprivation therapy among unfavorable-intermediate and high-risk prostate cancer.

PURPOSE/OBJECTIVE(S): To determine if patients with unfavorable intermediate-risk (UIR), high-risk (HR), or very high-risk (VHR) prostate cancer (PCa) treated with 125I interstitial brachytherapy benefit from androgen deprivation therapy (ADT). MATERIALS/METHODS: We reviewed our institutional database of patients with UIR, HR, or VHR PCa, per 2018 NCCN risk classification, treated with definitive 125I interstitial brachytherapy with or without ADT from 1998-2017. Outcomes including biochemical failure (bF), distant metastases (DM), and overall survival (OS) were analyzed with the Kaplan-Meier method and Cox proportional hazards regression. PCa-specific mortality (PCSM) was analyzed with Fine-Gray competing-risk regression. RESULTS: Of 1033 patients, 262 (25%) received ADT and 771 (75%) did not. Median ADT duration was 6 months. By risk group, 764 (74%) patients were UIR, 219 (21%) HR, and 50 (5%) VHR. ADT was more frequently given to HR (50%) and VHR (56%) patients compared to UIR (16%; p<0.001), to older patients (p<0.001), corresponding with increasing PSA (p<0.001) and Grade Group (p<0.001). Median follow-up was 4.9 years (0.3-17.6 years). On multivariable analysis accounting for risk group, age, and year of treatment, ADT was not associated with bF, DM, PCSM, or OS (p≥0.05 each). CONCLUSION: Among patients with UIR, HR, and VHR PCa, the addition of ADT to 125I interstitial brachytherapy was not associated with improved outcomes, and no subgroup demonstrated benefit. Our findings do not support the use of ADT in combination with 125I interstitial brachytherapy. Prospective studies are required to elucidate the role of ADT for patients with UIR, HR, and VHR PCa treated with prostate brachytherapy.