Publications by authors named "Zachary S Zumsteg"

83 Publications

Nodal staging convergence for HPV- and HPV+ oropharyngeal carcinoma.

Cancer 2021 Feb 17. Epub 2021 Feb 17.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct pathologic nodal systems. Given that quantitative lymph node (LN) burden is the dominant prognostic factor in most head and neck cancers, we investigated whether HPV- and HPV+ OPC warrant divergent pathologic nodal classification.

Methods: Multivariable Cox regression models of OPC surgical patients identified via U.S. cancer registry data were constructed to determine associations between survival and nodal characteristics. Nonlinear associations between metastatic LN number and survival were modeled with restricted cubic splines. Recursive partitioning analysis (RPA) was used to derive unbiased nodal schema.

Results: Mortality risk escalated continuously with each successive positive LN in both OPC subtypes, with analogous slope. Survival hazard increased by 18.5% (hazard ratio [HR], 1.19 [95% CI, 1.16-1.21]; P < .001) and 19.1% (HR, 1.19 [95% CI, 1.17-1.21]; P < .001), with each added positive LN for HPV- and HPV+ OPC, respectively, up to identical change points of 5 positive LNs. Extranodal extension (ENE) was an independent predictor of HPV- OPC (HR, 1.55 [95% CI, 1.20-1.99]; P < .001) and HPV+ OPC (HR 1.73 [95% CI, 1.36-2.20]; P < .001) mortality. In RPA for both diseases, metastatic LN was the principal nodal covariate driving survival, with ENE as a secondary determinant. Given the similarities across analyses, we propose a concise, unifying HPV-/HPV+ OPC pathologic nodal classification schema: N1, 1-5 LN+/ENE-; N2, 1-5 LN+/ENE+; N3, >5 LN+.

Conclusion: HPV- and HPV+ OPC exhibit parallel relationships between nodal characteristics and relative mortality. In both diseases, metastatic LN number represents the principal nodal covariate governing survival, with ENE being an influential secondary element. A consolidated OPC pathologic nodal staging system that is based on these covariates may best convey prognosis.

Lay Summary: The current nodal staging system for oropharyngeal carcinoma (OPC) has divided human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) OPC into distinct systems that rely upon criteria that establish them as separate entities, a complexity that may undermine the core objective of staging schema to clearly communicate prognosis. Our large-scale analysis revealed that HPV- and HPV+ pathologic nodal staging systems in fact mirror each other. Multiple analyses produced conspicuously similar nodal staging systems, with metastatic lymph node number and extranodal extension delineating the highest risk groups that shape prognosis. We propose unifying HPV- and HPV+ nodal systems to best streamline prognostication and maximize staging accuracy.
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http://dx.doi.org/10.1002/cncr.33414DOI Listing
February 2021

Incidental parathyroidectomy in thyroidectomy and central neck dissection.

Surgery 2021 Jan 11. Epub 2021 Jan 11.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address:

Background: Although higher thyroidectomy volume has been linked with lower complication rates, its association with incidental parathyroidectomy remains less studied. The volume relationship is even less clear for central neck dissection, where individual parathyroid glands are at greater risk.

Methods: Patients undergoing thyroidectomy with or without central neck dissection were evaluated for incidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Univariate and multivariable analyses were performed using binary logistic regression.

Results: Overall, 1,114 thyroidectomies and 396 concurrent central neck dissections were performed across 7 surgeons. Incidental parathyroidectomy occurred in 22.4% of surgeries (range, 16.9%-43.6%), affecting 7.1% of parathyroids at risk (range, 5.8%-14.5%). When stratified by surgeon, lower incidental parathyroidectomy rates were associated with higher thyroidectomy volumes (R = 0.77, P = .008) and higher central neck dissection volumes (R = 0.93, P < .001). On multivariable analysis, low-volume surgeon (odds ratio 2.94, 95% confidence interval 2.06-4.19, P < .001), extrathyroidal extension (odds ratio 3.13, 95% confidence interval 1.24-7.87, P = .016), prophylactic central neck dissection (odds ratio 2.68, 95% confidence interval 1.65-4.35, P <.001), and therapeutic central neck dissection (odds ratio 4.44, 95% confidence interval 1.98-9.96, P < .001) were the most significant factors associated with incidental parathyroidectomy. In addition, incidental parathyroidectomy was associated with a higher likelihood of temporary hypoparathyroidism (odds ratio 2.79, 95% confidence interval 1.45-5.38, P = .002) and permanent hypoparathyroidism (odds ratio 4.62, 95% confidence interval 1.41-5.96, P = .025), but not permanent hypocalcemia (odds ratio 1.27, 95% confidence interval 0.48-3.35, P = .63). Higher lymph node yield in central neck dissection was not associated with higher incidental parathyroidectomy rates (odds ratio 1.13, 95% confidence interval 0.85-8.81, P = .82).

Conclusion: Higher surgical volume conferred a lower rate of incidental parathyroidectomy. Nonetheless, greater lymph node yield in central neck dissections did not result in greater parathyroid-related morbidity. Such findings support the value of leveraging surgical volume to both optimize oncologic resection and minimize complication rates.
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http://dx.doi.org/10.1016/j.surg.2020.11.023DOI Listing
January 2021

Variations in the association of grade with survival across the head and neck cancer landscape.

Head Neck 2020 Dec 10. Epub 2020 Dec 10.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background: Although pathologic tumor grade is a well-established prognostic risk factor that impacts staging and treatment decisions across multiple cancer types, its role in head and neck squamous cell carcinoma (HNSCC) is less certain.

Methods: HNSCC patients diagnosed from 2010 to 2015 and undergoing primary surgery in the National Cancer Data Base were identified. Propensity score matching and multivariable Cox regression were performed.

Results: Among 27 041 HNSCC patients, 13 941 had oral cavity cancers (OCC). Intermediate-grade (hazard ratio [HR] 1.16, 95% CI 1.07-1.26, P < .001) and high-grade (HR 1.38, 95% CI 1.26-1.52, P < .001) tumors had worse survival than low-grade tumors. This magnitude was comparable to other well-established prognostic factors, including margin positivity, extranodal extension, and lymphovascular invasion. By contrast, there was no association between grade and survival in larynx/hypopharynx or HPV(-) oropharynx cancer.

Conclusions: The prognostic impact of pathologic grade is highly variable across head and neck subsites and is the strongest among OCC patients.
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http://dx.doi.org/10.1002/hed.26566DOI Listing
December 2020

Complete and Sustained Remission of Metastatic Cutaneous Squamous Cell Carcinoma in a Liver Transplant Patient Treated With Talimogene Laherparepvec.

Dermatol Surg 2020 Sep 2. Epub 2020 Sep 2.

Department of Dermatology, Cedars-Sinai Medical Center, Los Angeles, California.

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http://dx.doi.org/10.1097/DSS.0000000000002739DOI Listing
September 2020

ASO Author Reflections: Revisiting the Prognostic Significance of Grade in Papillary Thyroid Carcinoma.

Ann Surg Oncol 2020 Dec 30;27(Suppl 3):852-853. Epub 2020 Aug 30.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1245/s10434-020-09055-8DOI Listing
December 2020

Comparison of Survival After Transoral Robotic Surgery vs Nonrobotic Surgery in Patients With Early-Stage Oropharyngeal Squamous Cell Carcinoma.

JAMA Oncol 2020 10;6(10):1555-1562

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California.

Importance: Transoral robotic surgery has been widely adopted since approval by the US Food and Drug Administration in December 2009, despite limited comparative data.

Objective: To compare the long-term outcomes of transoral robotic surgery with those of nonrobotic surgery for patients with early-stage oropharyngeal cancer.

Design, Setting, And Participants: A retrospective cohort comparative effectiveness analysis was performed of patients in the National Cancer Database with clinical T1 and T2 oropharyngeal squamous cell carcinoma diagnosed between January 1, 2010, and December 31, 2015, who underwent definitive robotic and nonrobotic surgery. Multivariable Cox proportional hazards regression analysis and propensity score matching were performed in patients with known human papillomavirus status to adjust for patient- and disease-related covariates. Survival after robotic and nonrobotic surgery was also compared in 3 unrelated cancers: prostate, endometrial, and cervical cancer. Statistical analysis was performed from April 10, 2019, to May 21, 2020.

Main Outcomes And Measures: Overall survival.

Results: Of 9745 patients (7652 men [78.5%]; mean [SD] age, 58.8 [9.6] years) who met inclusion criteria, 2694 (27.6%) underwent transoral robotic surgery. There was a significant increase in the use of robotic surgery from 18.3% (240 of 1309) to 35.5% (654 of 1841) of all surgical procedures for T1 and T2 oropharyngeal cancers from 2010 to 2015 (P = .003). Robotic surgery was associated with lower rates of positive surgical margins (12.5% [218 of 1746] vs 20.3% [471 of 2325]; P < .001) and lower use of adjuvant chemoradiotherapy (28.6% [500 of 1746] vs 35.7% [831 of 2325]; P < .001). Among 4071 patients with known human papillomavirus status, robotic surgery was associated with improved overall survival compared with nonrobotic surgery in multivariable Cox proportional hazards regression (hazard ratio [HR], 0.74; 95 CI, 0.61-0.90; P = .002). Similar results were seen when analyzing only the subset of facilities offering both robotic and nonrobotic surgery. The 5-year overall survival was 84.8% vs 80.3% among patients undergoing robotic vs nonrobotic surgery in propensity score-matched cohorts (P = .001). By contrast, there was no evidence that robotic surgery was associated with improved survival in other cancers, such as prostate cancer (HR, 0.92; 95% CI, 0.79-1.07; P = .26), endometrial cancer (HR, 0.97; 95% CI, 0.90-1.04; P = .36), and cervical cancer (HR, 1.27; 95% CI, 0.96-1.69; P = .10).

Conclusions And Relevance: This study suggests that transoral robotic surgery was associated with improved surgical outcomes and survival compared with nonrobotic surgery in patients with early-stage oropharyngeal cancer. Evaluation in comparative randomized trials is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2020.3172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441465PMC
October 2020

Prognostic Impact of Histologic Grade for Papillary Thyroid Carcinoma.

Ann Surg Oncol 2021 Mar 17;28(3):1731-1739. Epub 2020 Aug 17.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: While numerous factors affect prognosis in papillary thyroid carcinoma (PTC), the comparative impact of histologic grade has not been well described. Moreover, indications for external beam radiation therapy (EBRT) remain imprecise. We evaluate clinicopathologic characteristics and outcomes for PTC stratified by grade.

Methods: We profiled histologic grade for PTC (well differentiated, moderately differentiated, poorly differentiated) via hospital (National Cancer Database) and population-based (Surveillance, Epidemiology, and End Results) registries. Cox regression was used to adjust for clinicopathologic covariates. Statistical interactions between subtypes and the effect of EBRT on survival were assessed.

Results: Collectively, worsening clinicopathologic factors (age, tumor size, extrathyroidal extension, nodal spread, M1 disease) and outcomes (disease-free survival, overall survival) correlated with less differentiated state, across all histologic grades (p < 0.001). Multivariable analysis showed escalating hazard with loss of differentiation relative to well-differentiated PTC (moderately differentiated hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.41, p = 0.02; poorly differentiated HR 2.62, 95% CI 2.23-3.08, p < 0.001). Correspondingly, greater survival benefit was associated with EBRT for poorly differentiated cases (HR 0.36, 95% CI 0.18-0.72, p = 0.004). This finding was upheld after landmark analysis to address potential immortal time bias (HR 0.37, 95% CI 0.17-0.80, p = 0.01).

Conclusions: Worsening histologic grade in PTC is independently associated with parallel escalation in mortality risk, on a scale approximating or surpassing established thyroid cancer risk factors. On preliminary analysis, EBRT was associated with improved survival in the most aggressive or least differentiated subvariants. Further investigation is warranted to examine the efficacy of EBRT for select poorly differentiated thyroid carcinomas.
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http://dx.doi.org/10.1245/s10434-020-09023-2DOI Listing
March 2021

The role of concomitant chemoradiotherapy in AJCC 7 edition T1-2N1 oropharyngeal carcinoma in the human papillomavirus era.

Oral Oncol 2020 11 7;110:104882. Epub 2020 Jul 7.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States. Electronic address:

Background: Radiotherapy (RT) without chemotherapy is considered a standard of care for the management of American Joint Committee on Cancer (AJCC) 7th edition (7E) T1-2N1 oropharyngeal squamous cell carcinoma (OPSCC). Recent data suggests concurrent chemoradiation (CCRT) may benefit these patients but did not include human papillomavirus (HPV) status. Given the radiosensitivity differences between HPV-positive versus HPV-negative OPSCC, the effect of chemotherapy may differ in these patients.

Methods: We analyzed patients in the National Cancer Database diagnosed between 2010 and 2015 with AJCC 7E stage cT1-2N1M0 OPSCC and known HPV status undergoing definitive RT or CCRT.

Results: Overall, 1964 patients were included, including 1297 (66%) HPV-positive and 667 (34%) HPV-negative patients. 66% received CCRT and 34% received RT alone. In multivariate analysis, CCRT was associated with improved survival compared with RT alone (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.57-0.87; P = 0.001). In propensity score-matched cohorts, 4-year overall survival was 87.4% vs 78.4% in HPV-positive patients receiving CCRT and RT alone, respectively (P = 0.002), and 65.5% vs 58.9% in HPV-negative patients, respectively (P = 0.2). There was no evidence that HPV-positivity diminished the association between CCRT and longer survival (HR, 0.57; 95% CI, 0.42-0.81) versus what was observed in HPV-negative patients (HR, 0.86; 95% CI, 0.64-1.16) (interaction P = 0.06).

Conclusions: CCRT is associated with improved survival in AJCC 7E T1-2N1 OPSCC. Despite the radiosensitivity of HPV-positive OPSCC, the association of CCRT with improved survival for T1-2N1 HPV-positive OPSCC was at least as strong, if not stronger, than what was observed in HPV-negative patients.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104882DOI Listing
November 2020

Improved survival in women versus men with merkel cell carcinoma.

J Am Acad Dermatol 2021 Feb 15;84(2):321-329. Epub 2020 May 15.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Studies have observed that women have better outcomes than men in melanoma, but less is known about the influence of sex differences on outcomes for other aggressive cutaneous malignancies.

Objective: To investigate whether women and men have disparate outcomes in Merkel cell carcinoma (MCC).

Methods: Patients with nonmetastatic MCC undergoing surgery and lymph node evaluation were identified from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and Cox proportional hazards regression models were used for overall survival, and competing-risks analysis and Fine-Gray models were used for cause-specific and other-cause mortality.

Results: The NCDB cohort (n = 4178) included 1516 (36%) women. Women had a consistent survival advantage compared with men in propensity score-matched analysis (66.0% vs 56.8% at 5 years, P < .001) and multivariable Cox regression (hazard ratio, 0.68; 95% confidence interval, 0.61-0.75; P < .001). Similarly, women had a survival advantage in the SEER validation cohort (n = 1202) with 457 (38.0%) women, which was entirely due to differences in MCC-specific mortality (5-year cumulative incidence: 16.4% vs 26.7%, P = .002), with no difference in other-cause mortality (16.8% vs 17.8%, P = .43) observed in propensity score-matched patients.

Limitations: Potential selection bias from a retrospective data set.

Conclusion: In MCC, women have improved survival compared with men, driven by MCC-related mortality.
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http://dx.doi.org/10.1016/j.jaad.2020.02.034DOI Listing
February 2021

Addition of Androgen-Deprivation Therapy or Brachytherapy Boost to External Beam Radiotherapy for Localized Prostate Cancer: A Network Meta-Analysis of Randomized Trials.

J Clin Oncol 2020 09 12;38(26):3024-3031. Epub 2020 May 12.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.

Purpose: In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT.

Materials And Methods: A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve.

Results: Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio [HR], 0.71 [95% CI, 0.62 to 0.81]), whereas the addition of BT did not significantly improve OS (HR, 1.03 [95% CI, 0.78 to 1.36]). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 [95% CI, 0.52 to 0.89]). Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.

Conclusion: Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.
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http://dx.doi.org/10.1200/JCO.19.03217DOI Listing
September 2020

The association between facility volume and overall survival in patients with Merkel cell carcinoma.

J Surg Oncol 2020 Aug 15;122(2):254-262. Epub 2020 Apr 15.

Department of Radiation Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Merkel cell carcinoma is an uncommon malignancy often requiring multidisciplinary management. The purpose of this study was to determine whether high-volume facilities have improved outcomes in patients with Merkel cell carcinoma relative to lower-volume facilities.

Methods: A total of 5304 patients from the National Cancer Database with stage I-III Merkel cell carcinoma undergoing surgery were analyzed. High-volume facilities were the top 1% by case volume. Multivariable Cox regression and propensity score-matching were performed to account for imbalances between groups.

Results: Treatment at high-volume facilities (hazard ratio: 0.74; 95% confidence interval: 0.65-0.84, P < .001) was independently associated with improved overall survival (OS) in multivariable analyses. In propensity score-matched cohorts, 5-year OS was 62.3% at high-volume facilities vs 56.8% at lower-volume facilities (P < .001). Median OS was 111 months at high-volume facilities vs 79 months at lower-volume facilities.

Conclusion: Treatment at high-volume facilities is associated with improved OS in Merkel cell carcinoma. Given the impracticality of referring all elderly patients with Merkel cell carcinoma to a small number of facilities, methods to mitigate this disparity should be explored.
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http://dx.doi.org/10.1002/jso.25931DOI Listing
August 2020

Balancing Risks and Benefits: Treat Bilateral Necks, But Omit the Tongue.

Int J Radiat Oncol Biol Phys 2020 04;106(5):902

Department of Radiation Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

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http://dx.doi.org/10.1016/j.ijrobp.2019.02.019DOI Listing
April 2020

Incidence and Mortality Risk Spectrum Across Aggressive Variants of Papillary Thyroid Carcinoma.

JAMA Oncol 2020 05;6(5):706-713

Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California.

Importance: While well-differentiated papillary thyroid carcinoma (WDPTC) outcomes have been well characterized, the prognostic implications of more aggressive variants are far less defined. The rarity of these subtypes has led to their consolidation as intermediate risk for what are in fact likely heterogeneous diseases.

Objective: To analyze incidence, clinicopathologic characteristics, and outcomes for aggressive variants of papillary thyroid carcinoma (PTC).

Design, Setting, And Participants: This cohort study used data from 2000 to 2016 from hospital-based and population-based US cancer registries to analyze aggressive PTC variants, including diffuse sclerosing (DSV), tall-cell (TCV), insular, and poorly differentiated (PDTC) subtypes. These variants were compared against WDPTC and anaplastic cases. Data analysis was conducted from January 2019 to October 2019.

Main Outcomes And Measures: Age-adjusted incidence was calculated via annual percentage change (APC) using the weighted least-squares method. Overall survival and disease-specific survival were analyzed via Cox regression. Propensity-score matching was used to adjust survival analyses for clinical and demographic covariates.

Results: Collectively, 5447 aggressive PTC variants were identified (including 415 DSV, 3339 TCV, 362 insular, and 1331 PDTC cases), as well as 35 812 WDPTC and 2249 anaplastic cases. Over the study period, a substantial increase in aggressive variant incidence was observed (APC, 9.1 [95% CI, 7.33-10.89]; P < .001), surpassing the relative increases observed in WDPTC (APC, 5.1 [95% CI, 3.98-6.12]; P < .001) and anaplastic cases (APC, 1.9 [95% CI, 0.75-3.05]; P = .003; parallelism P < .007). Survival varied markedly based on histologic subtype, with a wide spectrum of mortality risk noted; 10-year overall survival was 85.4% (95% CI, 84.6%-86.3%) in WDPTC, 79.2% (95% CI, 73.6%-85.3%) in DSV, 71.9% (95% CI, 68.4%-75.6%) in TCV, 45.1% (95% CI, 40.2%-50.6%) in PDTC, 27.9% (95% CI, 20.0%-38.9%) in the insular variant, and 8.9% (95% CI, 7.5%-10.6%) in anaplastic cases (P < .001). These differences largely persisted even after adjusting for inherent differences in baseline characteristics by multivariable Cox regression and propensity-score matching.

Conclusions And Relevance: An upsurge in aggressive PTC incidence was observed at a rate beyond that seen in WDPTC or anaplastic thyroid carcinoma. Moreover, long-term survival outcomes for aggressive PTC subgroups exhibit heterogeneous clinical behavior and a wide range of mortality risk, suggesting that treatment should be tailored to specific histologic subtypes. Given increasing prevalence and disparate outcomes, further investigation to identify optimal therapeutic strategies is needed in these diverse, understudied populations.
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http://dx.doi.org/10.1001/jamaoncol.2019.6851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059113PMC
May 2020

Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma.

J Am Acad Dermatol 2021 Feb 16;84(2):312-320. Epub 2020 Jan 16.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Current lymph node (LN) staging for Merkel cell carcinoma (MCC) does not account for the number of metastatic LNs, which is a primary driver of survival in multiple cancers.

Objective: To determine the impact of the number of metastatic LNs on survival in MCC.

Methods: Patients with MCC undergoing surgery were identified from the National Cancer Database (NCDB). The association between metastatic LN number and survival was modeled with restricted cubic splines. A novel nodal classification system was derived by using recursive partitioning analysis. MCC patients undergoing surgery in the Surveillance, Epidemiology, and End Results (SEER) Program were used as validation cohort.

Results: Among 3670 patients in the NCDB, increasing metastatic LN number was associated with decreased survival (P < .001). Mortality risk increased continuously with each additional positive LN when using multivariable, nonlinear modeling. According to a novel staging system derived via recursive partitioning analysis, the hazard ratio for death in multivariable regression compared with patients without LN involvement was 1.24 (P = .049), 2.08 (P < .001), 3.24 (P < .001), and 6.13 (P < .001) for the proposed N1a (1-3 metastatic LNs with microscopic detection), N1b (1-3 metastatic LNs with macroscopic detection), N2 (4-8 metastatic LNs), and N3 (≥9 metastatic LNs), respectively. This system was validated in the SEER cohort and showed improved concordance compared with the American Joint Committee on Cancer, Eighth Edition.

Limitations: Retrospective design.

Conclusions: Number of metastatic LNs is the dominant nodal factor driving survival in patients with MCC.
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http://dx.doi.org/10.1016/j.jaad.2019.12.072DOI Listing
February 2021

Survival outcomes with concomitant chemoradiotherapy in older adults with oropharyngeal carcinoma in an era of increasing human papillomavirus (HPV) prevalence.

Oral Oncol 2019 12 5;99:104472. Epub 2019 Nov 5.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States. Electronic address:

Background: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has dramatically increased in incidence and prevalence among patients aged 70 and older. There are virtually no data regarding outcomes in this population, and thus optimal therapy, including the role of chemotherapy for those undergoing radiotherapy (RT), remains unclear.

Methods: The National Cancer Database was queried for older adults (defined as age 70 years and older) with locally advanced OPSCC (cT1-2N1-3, cT3-4N0-3) diagnosed from 2010 to 2014 with known HPV-status undergoing definitive RT alone or chemoradiation (CRT).

Results: Overall, 1,965 older adults with locally advanced OPSCC met inclusion criteria, including 1,141 HPV-positive (58%) and 824 HPV-negative (42%) patients. 1,211 patients (62%) received CRT. In multivariable analysis, CRT was associated with improved survival in older patients when compared to RT alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.64-0.86, P < 0.001). CRT was associated with improved survival in both HPV-positive (HR = 0.80, 95% CI: 0.64-1.00, P = 0.05) and HPV-negative (HR = 0.69, 95% CI: 0.56-0.85, P < 0.001) subgroups. There was no significant interaction between HPV status and the impact of CRT on survival (P interaction = 0.57).

Conclusions: Despite the radiosensitivity of HPV-positive OPSCC and the challenges in delivering CRT to older adults, CRT was associated with improved survival in older patients with HPV-positive OPSCC, similar in magnitude to the benefit in HPV-negative patients. As the incidence of HPV-positive OPSCC in older patients continues to increase, further studies are needed to investigate optimal therapeutic strategies in this population.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104472DOI Listing
December 2019

Impact of insurance on survival in patients < 65 with head & neck cancer treated with radiotherapy.

Clin Otolaryngol 2020 01 13;45(1):63-72. Epub 2019 Nov 13.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Objectives: The United States has a heterogenous health insurance landscape for patients <65 years. We sought to characterise the impact of primary payer on overall survival (OS) in insured patients younger than 65 with head and neck squamous cell carcinoma (HNSCC) treated with definitive radiotherapy.

Design/study/participants: The National Cancer Database was queried for patients <65 years old diagnosed from 2004 to 2014 undergoing definitive radiotherapy ± chemotherapy for cancers of the nasopharynx, oropharynx, hypopharynx and larynx. Uninsured patients and oropharyngeal cancers without known HPV status were excluded.

Main Outcome: Overall survival.

Results: Overall, 27 292 insured patients were identified, including 17 060 (62.5%) with private insurance. Median follow-up was 52.1 months. In multivariable models, patients receiving Medicaid (HR = 1.66, 95% CI 1.57-1.75, P < .001), Medicare (HR = 1.64, 95% CI 1.55-1.73, P < .001) and other government insurance (HR = 1.44, 95% CI 1.29-1., P < .001) had independently increased mortality in comparison to those with private insurance. In propensity score-matched cohorts, 5-year OS was 65.5% vs 50.6% for privately vs government-insured patients, respectively (P < .001). In multivariable subgroup analysis, private insurance was associated with improved survival in all subgroups. However, the magnitude of this effect was most pronounced in patients with HPV-positive oropharyngeal cancer vs non-HPV-related cancer (interaction P < .001), younger patients (interaction P = .001), and those without comorbidity (interaction P < .001).

Conclusions: Patients <65 with HNSCC undergoing definitive radiation with private health insurance have markedly longer survival relative to patients with government-sponsored insurance. This illustrates that increasing access to care may be necessary, but is not sufficient, to mitigate the significant disparities in the US healthcare system.
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http://dx.doi.org/10.1111/coa.13467DOI Listing
January 2020

Stage I HPV-positive oropharyngeal cancer: Should all patients receive similar treatments?

Cancer 2020 01 19;126(1):58-66. Epub 2019 Sep 19.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy.

Methods: The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7 days of the initiation of radiotherapy.

Results: The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3 months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P = .012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P < .001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P = .05]). Similar results were noted among propensity score-matched cohorts.

Conclusions: Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCC undergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients.
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http://dx.doi.org/10.1002/cncr.32501DOI Listing
January 2020

Development and Validation of an Improved Pathological Nodal Staging System for Urothelial Carcinoma of the Bladder.

Eur Urol Oncol 2019 Nov 31;2(6):656-663. Epub 2019 Jan 31.

Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Background: Current pathological nodal staging for bladder cancer is based on lymph node (LN) location but not on the number of positive LNs.

Objective: We sought to improve prognostic classification by creating a novel staging system incorporating positive LN burden.

Design, Setting, And Participants: We sampled 12515 patients with muscle-invasive bladder cancer (MIBC) from the National Cancer Database (NCDB) and 5928 MIBC patients from the Surveillance, Epidemiology, and End Results (SEER) database for our development and validation cohorts, respectively.

Outcome Measurements And Statistical Analysis: Multivariable Cox proportional hazards analysis with restricted cubic splines was used to assess the association between the number of metastatic LNs and overall mortality (OM). A novel staging system was derived by recursive partitioning analysis (RPA) in NCDB and was validated in SEER by assessing discrimination (Harrel's c-index) and calibration (mean absolute prediction error).

Results And Limitations: Mortality risk increased continuously with more metastatic LNs; the effect was most pronounced up to four LNs (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.12-1.22) and attenuated beyond four nodes (HR 1.03, 95% CI 1.02-1.05). RPA generated a novel staging system predicting mortality by metastatic nodal number with cutpoints at zero (reference), one (HR 1.57, 95% CI 1.46-1.69), two to three (HR 2.03, 95% CI 1.88-2.19), four to seven (HR 2.46, 95% CI 2.25-2.70), and more than seven (HR 3.83, 95% CI 3.38-4.33) positive LNs. Location of LN involvement was not a significant predictor of OM. In external validation, the novel staging system showed good risk discrimination (optimism corrected c-index 0.677, 95% CI 0.672-0.682) and calibration (mean absolute prediction error 0.011 for 5-yr OM). Results are limited by development and validation using secondary data.

Conclusions: The number of metastatic LNs predicts mortality better than LN location and may improve pathological nodal staging in MIBC.

Patient Summary: This retrospective study found that the number of metastatic lymph nodes more accurately predicts survival than the location of metastatic lymph nodes in patients with muscle-invasive bladder cancer. This finding argues for change to the current bladder cancer staging system.
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http://dx.doi.org/10.1016/j.euo.2018.12.012DOI Listing
November 2019

Mortality Risk of Nonoperative Papillary Thyroid Carcinoma: A Corollary for Active Surveillance.

Thyroid 2019 10 24;29(10):1409-1417. Epub 2019 Sep 24.

Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California.

Active surveillance is established as an alternative to surgery for papillary thyroid microcarcinomas, but inclusion criteria and mortality risk for pursuing a nonsurgical approach have not been clearly defined. To gauge the feasibility of expanding active surveillance thresholds, we investigated the effects of increasing size and age on disease-specific survival (DSS) in a large nonoperative thyroid cancer cohort, compared against a matched group of surgical patients. Papillary thyroid carcinoma patients staged T1-4N0M0 were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2015, stratified by nonsurgical and surgical management. Propensity score matching was performed to adjust for imbalances in covariates. Multivariable models were constructed using restricted cubic splines to model nonlinear relationships of age and tumor size with DSS. Overall, 1453 nonoperative patients and 54,718 surgical patients met the inclusion criteria. Collectively, increasing age and size after certain thresholds independently led to greater differences in DSS between nonsurgical and surgical patients. For younger ages (14-55 years), surgical approach compared with nonsurgical approach was not associated with any difference in the 10-year DSS among 0-4 cm cancers (99.8% vs. 100%,  = 0.470), 4.1-6 cm cancers (98.8% vs. 100%,  = 0.599), or >6 cm cancers (97.3% vs. 100%,  = 0.718). Older patients with larger tumors (>75 years, >6 cm) demonstrated the greatest difference in DSS (48.1% vs. 91.3%,  < 0.001). Similar results were found when applying propensity score matching. For age, restricted cubic spline plots showed minimal relative survival hazard in nonoperative cases beginning after age 60 years, with a change point illustrating acceleration in relative hazard beyond age 72 years. For size, relative survival hazard was observed after 2.0 cm and increased slowly with nodule growth up to an inflection point of 4.5 cm. Beyond this, mortality risk escalated with each additional year without plateau. Increasing age and size lead to progressively greater mortality risk without surgery, but only beyond certain thresholds. We define escalating gradients at which a nonsurgical approach may be deemed appropriate, and beyond which survival benefits from surgery become apparent. Such findings reconcile controversial observations regarding age and size in active surveillance and further reshape evolving treatment paradigms in thyroid cancer.
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http://dx.doi.org/10.1089/thy.2019.0060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476400PMC
October 2019

Association of Black Race With Prostate Cancer-Specific and Other-Cause Mortality.

JAMA Oncol 2019 07;5(7):975-983

Department of Radiation Oncology, University of Michigan, Ann Arbor.

Importance: Black men are more likely to die of prostate cancer than white men. In men with similar stages of disease, the contribution of biological vs nonbiological differences to this observed disparity is unclear.

Objective: To quantify the association of black race with long-term survival outcomes after controlling for known prognostic variables and access to care among men with prostate cancer.

Design, Setting, And Participants: This multiple-cohort study included updated individual patient-level data of men with clinical T1-4N0-1M0 prostate cancer from the following 3 cohorts: Surveillance, Epidemiology, and End Results (SEER [n = 296 273]); 5 equal-access regional medical centers within the Veterans Affairs health system (VA [n = 3972]); and 4 pooled National Cancer Institute-sponsored Radiation Therapy Oncology Group phase 3 randomized clinical trials (RCTs [n = 5854]). Data were collected in the 3 cohorts from January 1, 1992, through December 31, 2013, and analyzed from April 27, 2017, through April 13, 2019.

Exposures: In the VA and RCT cohorts, all patients received surgery and radiotherapy, respectively, with curative intent. In SEER, radical treatment, hormone therapy, or conservative management were received.

Main Outcomes And Measures: Prostate cancer-specific mortality (PCSM). Secondary measures included other-cause mortality (OCM). To adjust for demographic-, cancer-, and treatment-related baseline differences, inverse probability weighting (IPW) was performed.

Results: Among the 306 100 participants included in the analysis (mean [SD] age, 64.9 [8.9] years), black men constituted 52 840 patients (17.8%) in the SEER cohort, 1513 (38.1%) in the VA cohort, and 1129 (19.3%) in the RCT cohort. Black race was associated with an increased age-adjusted PCSM hazard (subdistribution hazard ratio [sHR], 1.30; 95% CI, 1.23-1.37; P < .001) within the SEER cohort. After IPW adjustment, black race was associated with a 0.5% (95% CI, 0.2%-0.9%) increase in PCSM at 10 years after diagnosis (sHR, 1.09; 95% CI, 1.04-1.15; P < .001), with no significant difference for high-risk men (sHR, 1.04; 95% CI, 0.97-1.12; P = .29). No significant differences in PCSM were found in the VA IPW cohort (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and black men had a significantly lower hazard in the RCT IPW cohort (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). Black men had a significantly increased hazard of OCM in the SEER (sHR, 1.30; 95% CI, 1.27-1.34; P < .001) and RCT (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) IPW cohorts.

Conclusions And Relevance: In this study, after adjustment for nonbiological differences, notably access to care and standardized treatment, black race did not appear to be associated with inferior stage-for-stage PCSM. A large disparity remained in OCM for black men with nonmetastatic prostate cancer.
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http://dx.doi.org/10.1001/jamaoncol.2019.0826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547116PMC
July 2019

Impact of Biochemical Failure After Salvage Radiation Therapy on Prostate Cancer-specific Mortality: Competition Between Age and Time to Biochemical Failure.

Eur Urol Oncol 2018 09 28;1(4):276-282. Epub 2018 Sep 28.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: Disease progression following salvage radiotherapy (SRT) for prostate cancer (PC) is common, and the time to biochemical recurrence (BCR) is heterogeneous.

Objective: To describe the temporal distribution and clinical impact of BCR following SRT and model outcomes using patient age and time to BCR from SRT.

Design, Setting, And Participants: A retrospective multi-institutional study included 547 consecutive men with lymph node-negative PC receiving SRT from 1985 to 2013. The median follow-up after SRT was 8.4 yr. Intervention All men received SRT with three-dimensional or intensity-modulated RT.

Outcome Measurements And Statistical Analysis: BCR was defined as a rise in prostate-specific antigen (PSA) ≥0.2ng/ml above the PSA nadir followed by a sequentially equal or higher value. Additional outcomes included distant metastasis (DM), PC-specific mortality (PCSM), and overall mortality (OM). Cox proportional hazards models, a landmark analysis, and comparison of c-indices were used. Cumulative incidence curves were estimated from a Fine and Gray regression model.

Results And Limitations: The estimated 10-yr cumulative incidence of BCR was 60%. Of the 274 men experiencing BCR, 149 (54%) had BCR within 18 mo of SRT. BCR ≤18 mo after SRT was associated with a higher risk of DM (hazard ratio [HR] 7.44, 95% confidence interval [CI] 4.91-11.3; p<0.001), PCSM (HR 12.3, 95% CI 5.95-25.2; p<0.001), and OM (HR 2.85, 95% CI 1.94-4.17; p<0.001). We provide a model to estimate the cumulative incidence of DM and PCSM using age and time to BCR. The retrospective nature of our analysis limits our findings.

Conclusions: A strikingly large proportion of men experience early BCR following SRT and are at higher risk of DM and PCSM. Novel predictive biomarkers are needed to identify men harboring micrometastatic disease to avoid potentially futile local therapies or allow for intensification of systemic therapies.

Patient Summary: Many men will develop biochemical recurrence of prostate cancer after salvage radiotherapy. Men with biochemical recurrence within 18 mo of salvage radiotherapy constitute a cohort at higher risk of distant metastasis and prostate cancer-specific mortality.
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http://dx.doi.org/10.1016/j.euo.2018.04.014DOI Listing
September 2018

Evolution of the Oropharynx Cancer Epidemic in the United States: Moderation of Increasing Incidence in Younger Individuals and Shift in the Burden to Older Individuals.

J Clin Oncol 2019 06 26;37(18):1538-1546. Epub 2019 Apr 26.

1 US National Cancer Institute, Rockville, MD.

Purpose: Human papillomavirus-positive oropharynx cancer incidence has increased rapidly in cohorts of US white men born during the 1930s to 1950s. It is unknown how the trajectory of the oropharynx cancer epidemic may be changing in the United States.

Methods: Using US cancer registry information, we investigated whether increases in oropharynx cancer have continued into recent birth cohorts and forecasted the future burden across age, sex, and race/ethnicity subgroups. Log-linear Joinpoint regression and age-period-cohort models were used to evaluate incidence trends during 1992 to 2015 and projections through 2029.

Results: Among white men, oropharynx cancer incidence increased rapidly in individuals born during 1939 to 1955 (5.3% per 2-year birth cohort; 95% CI, 4.8% to 5.7%), but this rate of increase significantly moderated in individuals born during 1955 to 1969 (1.7% per 2-year birth cohort; 95% CI, 1.0% to 2.4%). Should these birth-cohort trends continue, from 2016 to 2029 we forecast that incidence will increase dramatically in older white men 65 to 74 years of age (from 40.7 to 71.2 per 100,000) and 75 to 84 years of age (from 25.7 to 50.1 per 100,000), moderately in white men 55 to 64 years of age (from 40.3 to 52.0 per 100,000), and remain stable in white men 45 to 54 years of age (approximately 18 per 100,000). Accounting for population growth, we project an increase in annual number of cases in the United States from 20,124 (95% CI, 19,779 to 20,469) in 2016 to 30,629 (95% CI, 29,413 to 31,845) in 2029, primarily driven by older individuals (age ≥ 65 years; from 7,976 [95% CI, 7,782 to 8,172] to 18,072 [95% CI, 17,271 to 18,895]) and white men (from 14,453 [95% CI, 14,142 to 14,764] to 22,241 [95% CI, 21,119 to 23,364]).

Conclusion: The exponential increase in oropharynx cancer incidence in young white US men has ebbed, and modest increases are occurring/anticipated in cohorts born after 1955. Continued strong increases in incidence in cohorts born before 1955, and an approximate 50% increase in size of the US population age 65 years or older through 2029, portend a substantial shift in burden to elderly white men.
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http://dx.doi.org/10.1200/JCO.19.00370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599405PMC
June 2019

Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies.

Int J Radiat Oncol Biol Phys 2019 07 6;104(4):778-789. Epub 2019 Apr 6.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Utilization of stereotactic body radiation therapy (SBRT) for treatment of localized prostate cancer is increasing. Guidelines and payers variably support the use of prostate SBRT. We therefore sought to systematically analyze biochemical recurrence-free survival (bRFS), physician-reported toxicity, and patient-reported outcomes after prostate SBRT.

Methods And Materials: A systematic search leveraging Medline via PubMed and EMBASE for original articles published between January 1990 and January 2018 was performed. This was supplemented by abstracts with sufficient extractable data from January 2013 to March 2018. All prospective series assessing curative-intent prostate SBRT for localized prostate cancer reporting bRFS, physician-reported toxicity, and patient-reported quality of life with a minimum of 1-year follow-up were included. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were performed with random-effect modeling. Extent of heterogeneity between studies was determined by the I and Cochran's Q tests. Meta-regression was performed using Hartung-Knapp methods.

Results: Thirty-eight unique prospective series were identified comprising 6116 patients. Median follow-up was 39 months across all patients (range, 12-115 months). Ninety-two percent, 78%, and 38% of studies included low, intermediate, and high-risk patients. Overall, 5- and 7-year bRFS rates were 95.3% (95% confidence interval [CI], 91.3%-97.5%) and 93.7% (95% CI, 91.4%-95.5%), respectively. Estimated late grade ≥3 genitourinary and gastrointestinal toxicity rates were 2.0% (95% CI, 1.4%-2.8%) and 1.1% (95% CI, 0.6%-2.0%), respectively. By 2 years post-SBRT, Expanded Prostate Cancer Index Composite urinary and bowel domain scores returned to baseline. Increasing dose of SBRT was associated with improved biochemical control (P = .018) but worse late grade ≥3 GU toxicity (P = .014).

Conclusions: Prostate SBRT has substantial prospective evidence supporting its use, with favorable tumor control, patient-reported quality of life, and levels of toxicity demonstrated. SBRT has sufficient evidence to be supported as a standard treatment option for localized prostate cancer while ongoing trials assess its potential superiority.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770993PMC
July 2019

Survival Impact of Adjuvant Therapy in Salivary Gland Cancers following Resection and Neck Dissection.

Otolaryngol Head Neck Surg 2019 06 5;160(6):1048-1057. Epub 2019 Feb 5.

2 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Objective: To evaluate the impact of postoperative radiotherapy (PORT) and chemotherapy on survival in salivary gland cancer (SGC) treated with curative-intent local resection and neck dissection.

Study Design: Retrospective population-based cohort study.

Setting: National Cancer Database.

Subjects And Methods: Patients with SGC who were undergoing surgery were identified from the National Cancer Database between 2004 and 2013. Neck dissection removing a minimum of 10 lymph nodes was required. Because PORT violated the proportional hazards assumption, this variable was treated as a time-dependent covariate.

Results: Overall, 4145 cases met inclusion criteria (median follow-up, 54 months). PORT was associated with improved overall survival in multivariable analysis, both ≤9 months from diagnosis (hazard ratio [HR], 0.26; 95% CI, 0.20-0.34; P < .001) and >9 months (HR, 0.75; 95% CI, 0.66-0.86; P < .001). In propensity score-matched cohorts, 5-year overall survival was 67.1% and 60.6% with PORT and observation, respectively ( P < .001). Similar results were observed in landmark analysis of patients surviving at least 6 months following diagnosis. Adjuvant chemotherapy was not associated with improved survival (HR, 1.15; 95% CI, 0.99-1.34; P = .06).

Conclusion: PORT, but not chemotherapy, is associated with improved survival among patients with SGC for whom neck dissection was deemed necessary. These results are not applicable to low-risk SGCs not requiring neck dissection.
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http://dx.doi.org/10.1177/0194599819827851DOI Listing
June 2019

Precision Medicine for Localized Prostate Cancer: Time to Move Beyond NCCN Risk Stratification?

Int J Radiat Oncol Biol Phys 2019 01 12;103(1):92-94. Epub 2018 Dec 12.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2018.09.040DOI Listing
January 2019

Parallels Between Low-Risk Prostate Cancer and Thyroid Cancer: A Review.

JAMA Oncol 2019 Apr;5(4):556-564

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Importance: Across many countries, a rapid escalation of the incidence of thyroid cancer has been observed, a surge that nonetheless underestimates the true extent of the disease. Most thyroid cancers now diagnosed comprise small, low-risk cancers that are incidentally found and are unlikely to cause harm. In many ways, prostate cancer similarly harbors a well-behaved subclinical reservoir, a long natural history, and superlative outcomes that have made active surveillance the de facto guideline recommendation for low-risk disease. This review highlights the parallels and differences between prostate cancer and thyroid cancer regarding screening, diagnosis, risk stratification, and considerations for active surveillance.

Observations: Prostate cancer and thyroid cancer have undergone recalibrated, de-escalatory shifts to counter changing epidemiologic landscapes. The US Preventive Services Task Force has issued cautionary recommendations on screening via prostate-specific antigen testing or neck ultrasonography, while the thresholds to performing biopsy have increased. Comparable changes to cancer terminology and staging have also helped alleviate patient anxiety and minimize pressure for overtreatment. Long-term, randomized prospective clinical trials for prostate cancer have established active surveillance as a first-line treatment approach for properly stratified low-risk patients, while observational trials for thyroid cancer have also made strides in defining risk and eligibility for surgery. Caveats requiring deeper investigation include aggressive disease in older patients, underestimation of the extent of the disease, and patient-physician bias in shared decision making. For prostate cancer, survival may not improve and function will likely worsen after intervention; for thyroid cancer, patients are younger, surgery is safer, and the bar for surveillance will likely be higher.

Conclusions And Relevance: Despite similarities in biological indolence between low-risk prostate and thyroid malignant neoplasms, key distinctions in life expectancy and treatment sequelae may ultimately confer somewhat disparate management paradigms for the 2 diseases. Nevertheless, the experience forged by prostate cancer trials serves as a model for thyroid cancer management, potentially reshaping the perception of active surveillance into a credible, valuable treatment modality.
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http://dx.doi.org/10.1001/jamaoncol.2018.5321DOI Listing
April 2019

Human papillomavirus-associated oropharyngeal cancer among patients aged 70 and older: Dramatically increased prevalence and clinical implications.

Eur J Cancer 2018 11 27;103:195-204. Epub 2018 Sep 27.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence among older adults. However, the role of human papillomavirus (HPV) in driving this trend and its prognostic significance in this population have not been established.

Methods: The National Cancer Database was queried for patients with OPSCC diagnosed from 2010 to 2015 undergoing either surgery or radiotherapy (RT) with known HPV status. Older adults were defined as those aged 70 years or older.

Results: Among 43,427 OPSCC patients, the proportion of HPV-positive OPSCC increased from 45.1% to 63.3% in older adults (P < 0.001). In 19,358 patients meeting the inclusion criteria for survival analyses, HPV positivity was associated with improved survival for older adults undergoing either definitive RT (hazard ratio [HR] = 0.63, 95% confidence interval [CI] 0.55-0.72, P < 0.001) or surgery (HR = 0.37, 95% CI 0.25-0.53, P < 0.001) in multivariable analysis. In propensity score-matched cohorts, 3-year overall survival was 69.1% versus 55.5% (P < 0.001) in older adults with HPV-positive and HPV-negative OPSCC undergoing definitive RT, respectively, and 88.5% versus 69.1% (P = 0.001) for older adults undergoing surgery. Although HPV positivity was associated with improved survival among all age groups receiving RT, the magnitude of the effect diminished with increasing age (interaction P < 0.001). No interaction between age and the impact of HPV status on survival was seen for surgical patients (interaction P = 0.72).

Conclusions: The epidemiologic landscape of HPV-positive OPSCC is evolving, with a dramatic increase in the proportion of HPV-associated OPSCC among patients 70 years or older. HPV remains a powerful predictor of improved survival in elderly patients, but with less pronounced effect on older adults undergoing definitive RT.
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http://dx.doi.org/10.1016/j.ejca.2018.08.015DOI Listing
November 2018

International Multicenter Validation of an Intermediate Risk Subclassification of Prostate Cancer Managed with Radical Treatment without Hormone Therapy.

J Urol 2019 02;201(2):284-291

Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Purpose: The NCCN Guidelines® recently endorsed a subclassification of intermediate risk prostate cancer into favorable and unfavorable subgroups. However, this subclassification was developed in a treatment heterogeneous cohort. Thus, to our knowledge the natural history of androgen deprivation treatment naïve favorable and unfavorable intermediate risk prostate cancer cases remains unknown.

Materials And Methods: Groups at 3 academic centers pooled data on patients with intermediate risk prostate cancer treated with radical monotherapy (dose escalated external beam radiotherapy, brachytherapy or radical prostatectomy) without combined androgen deprivation treatment. We used the cumulative incidence with competing risk analysis to estimate biochemical recurrence, distant metastasis and prostate cancer specific mortality.

Results: A total of 2,550 men at intermediate risk were included in study, of whom 1,063 and 1,487 were at favorable and unfavorable risk, respectively. Of the men 1,149 underwent radical prostatectomy, 1,143 underwent dose escalated external beam radiotherapy and 258 underwent brachytherapy. Median followup after the different treatments ranged from 60.4 to 107.4 months. The 10-year cumulative incidence of distant metastasis in the favorable vs unfavorable risk groups was 0.2% (95% CI 0.2-0.2) vs 11.6% (95% CI 7.7-15.5) for radical prostatectomy (p <0.001), 2.8% (95% CI 0.8-4.8) vs 13.5% (95% CI 9.6-17.4) for dose escalated external beam radiotherapy (p <0.001) and 3.5% (95% CI 0-7.4) vs 10.2% (95% CI 4.3-16.1) for brachytherapy (p = 0.063). The 10-year rate of prostate cancer specific mortality in the favorable vs unfavorable risk groups was 0% (95% CI 0-0) vs 3.7% (95% CI 1.7-5.7) for radical prostatectomy (p = 0.016), 0.5% (95% CI 0.5-0.5) vs 5.6% (95% CI 3.6-7.6) for dose escalated external beam radiotherapy (p = 0.015) and 0% (95% CI 0-0) vs 2.5% (95% CI 0.5-4.5) for brachytherapy (p = 0.028).

Conclusions: This multicenter international effort independently validates the prognostic value of the intermediate risk prostate cancer subclassification in androgen deprivation treatment naïve cases across all radical treatment modalities. It is unlikely that treatment intensification would meaningfully improve oncologic outcomes in men at favorable intermediate risk.
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http://dx.doi.org/10.1016/j.juro.2018.08.044DOI Listing
February 2019

Quantitative survival impact of composite treatment delays in head and neck cancer.

Cancer 2018 08 9;124(15):3154-3162. Epub 2018 May 9.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Multidisciplinary management of head and neck cancer (HNC) must reconcile increasingly sophisticated subspecialty care with timeliness of care. Prior studies examined the individual effects of delays in diagnosis-to-treatment interval, postoperative interval, and radiation interval but did not consider them collectively. The objective of the current study was to investigate the combined impact of these interwoven intervals on patients with HNC.

Methods: Patients with HNC who underwent curative-intent surgery with radiation were identified in the National Cancer Database between 2004 and 2013. Multivariable models were constructed using restricted cubic splines to determine nonlinear relations with overall survival.

Results: Overall, 15,064 patients were evaluated. After adjustment for covariates, only prolonged postoperative interval (P < .001) and radiation interval (P < .001) independently predicted for worse outcomes, whereas the association of diagnosis-to-treatment interval with survival disappeared. By using multivariable restricted cubic spline functions, increasing postoperative interval did not affect mortality until 40 days after surgery, and each day of delay beyond this increased the risk of mortality until 70 days after surgery (hazard ratio, 1.14; 95% confidence interval, 1.01-1.28; P = .029). For radiation interval, mortality escalated continuously with each additional day of delay, plateauing at 55 days (hazard ratio, 1.25; 95% confidence interval, 1.11-1.41; P < .001). Delays beyond these change points were not associated with further survival decrements.

Conclusions: Increasing delays in postoperative and radiation intervals are associated independently with an escalating risk of mortality that plateaus beyond certain thresholds. Delays in initiating therapy, conversely, are eclipsed in importance when appraised in conjunction with the entire treatment course. Such findings may redirect focus to streamlining those intervals that are most sensitive to delays when considering survival burden. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097917PMC
August 2018