Publications by authors named "Wade L Thorstad"

75 Publications

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma: A multi-site validation study.

Authors:
Can F Koyuncu Cheng Lu Kaustav Bera Zelin Zhang Jun Xu Paula Andrea Toro Castaño Germán Corredor Deborah Chute Pingfu Fu Wade L Thorstad Farhoud Faraji Justin A Bishop Mitra Mehrad Patricia D Castro Andrew G Sikora Lester D R Thompson R D Chernock Krystle A Lang Kuhs Jingqin Luo Vlad C Sandulache David J Adelstein Shlomo Koyfman James S Lewis Anant Madabhushi

J Clin Invest 2021 Mar 2. Epub 2021 Mar 2.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, United States of America.

Background: p16 positive oropharyngeal squamous cell carcinoma (OPSCC) patients are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure in p16 positive OPSCC. Pathologist-based visual assessment of tumor cell multinucleation has been shown to be independently prognostic of disease-free survival in p16 positive OPSCC. However, its quantification is time-intensive, subjective, and at risk of interobserver variability.

Methods: We present a deep learning-based metric, the multi-nucleation index (MuNI), for prognostication in p16 positive OPSCC. This approach quantifies tumor multi-nucleation from digitally scanned hematoxylin eosin (H&E)-stained slides. Representative H&E whole slide images from 1,094 previously untreated p16 positive OPSCC patients were acquired from six institutions for optimizing and validating MuNI.

Results: MuNI was prognostic for disease-free (DFS), overall (OS), or distant metastasis-free (DMFS) survival in p16 positive OPSCC with HRs of 1.78(95%CI:1.37-2.30), 1.94(1.44-2.60), and 1.88(1.43-2.47), respectively, independent of age, smoking status, treatment type, and T/N-categories in multivariable analyses. It was also prognostic for DFS, OS, and DMFS in OPSCC patients at stages I and III.

Conclusion: MuNI holds promise as a low-cost, tissue non-destructive, H&E stain based digital biomarker test for counseling, treatment, and surveillance of p16 positive OPSCC patients. These data support further confirmation of MuNI in prospective trials.

Funding: This work was supported by the National Cancer Institute of the National Institutes of Health (under award numbers 1U24CA199374-01, R01CA202752-01A, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, 1U01CA239055-01), the National Institute for Biomedical Imaging and Bioengineering (1R43EB028736-01), the National Center for Research Resources (1C06RR12463-01), the VA Merit Review Award (IBX004121A) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DoD Breast Cancer Research Program Breakthrough Level 1 Award (W81XWH-19-1-0668), the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering, and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University, the Michael E. DeBakey VA Medical Center, an institutional pilot grant (1IK2CX001953) and Dan L Duncan Comprehensive Cancer Center Support Grant (NCI-CA125123). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government.
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http://dx.doi.org/10.1172/JCI145488DOI Listing
March 2021

Risk groups of laryngeal cancer treated with chemoradiation according to nomogram scores - A pooled analysis of RTOG 0129 and 0522.

Authors:
Musaddiq J Awan Haley Gittleman Jill Barnholtz-Sloan Mitchell Machtay Phuc Felix Nguyen-Tan David I Rosenthal Christopher Schultz Bradley J Huth Wade L Thorstad Steven J Frank Harold Kim Robert L Foote Miriam N Lango George Shenouda Mohan Suntharalingam Jonathan Harris Qiang Zhang Quynh-Thu Le Min Yao

Oral Oncol 2021 Feb 25;116:105241. Epub 2021 Feb 25.

Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, United States.

Objectives: To develop nomograms predicting overall survival (OS), freedom from locoregional recurrence (FFLR), and freedom from distant metastasis (FFDM) for patients receiving chemoradiation for laryngeal squamous cell carcinoma (LSCC).

Material And Methods: Clinical and treatment data for patients with LSCC enrolled on NRG Oncology/RTOG 0129 and 0522 were extracted from the RTOG database. The dataset was partitioned into 70% training and 30% independent validation datasets. Significant predictors of OS, FFLR, and FFDM were obtained using univariate analysis on the training dataset. Nomograms were built using multivariate analysis with four a priori variables (age, gender, T-stage, and N-stage) and significant predictors from the univariate analyses. These nomograms were internally and externally validated using c-statistics (c) on the training and validation datasets, respectively.

Results: The OS nomogram included age, gender, T stage, N stage, and number of cisplatin cycles. The FFLR nomogram included age, gender, T-stage, N-stage, and time-equivalent biologically effective dose. The FFDM nomogram included age, gender, N-stage, and number of cisplatin cycles. Internal validation of the OS nomogram, FFLR nomogram, and FFDM nomogram yielded c = 0.66, c = 0.66 and c = 0.73, respectively. External validation of these nomograms yielded c = 0.59, c = 0.70, and c = 0.73, respectively. Using nomogram score cutoffs, three risk groups were separated for each outcome.

Conclusions: We have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105241DOI Listing
February 2021

Low-risk human papilloma virus positive oropharyngeal cancer with one positive lymph node: Equivalent outcomes in patients treated with surgery and radiation therapy versus surgery alone.

Authors:
Reilly A Sample Carey Burton Wood Angela L Mazul Thomas F Barrett Randal C Paniello Jason T Rich Stephen Y Kang Jose Zevallos Mackenzie D Daly Wade L Thorstad Stephanie Y Chen Patrik Pipkorn Ryan S Jackson Sidharth V Puram

Head Neck 2021 Feb 15. Epub 2021 Feb 15.

Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA.

Background: For human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), management recommendations for patients with a single metastatic lymph node <6 cm in diameter remain nebulous, leading to treatment heterogeneity in this common subgroup of patients.

Methods: We utilized the National Cancer Database to perform survival and multivariable analyses of patients with HPV+ OPSCC with one positive lymph node <6 cm and negative surgical margins.

Results: We found that 5-year survival is comparable between patients who receive surgery and adjuvant radiation versus surgery alone. In multivariable analyses, we found no significant difference in the hazard ratio of overall survival after adjusting for various potential confounders.

Conclusions: These data suggest that patients with margin-negative HPV+ OPSCC with a single positive lymph node <6 cm have comparable survival with or without adjuvant radiation. Future studies exploring outcomes for this specific group in randomized-controlled trials will be critical for further evaluating these initial observations.
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http://dx.doi.org/10.1002/hed.26642DOI Listing
February 2021

Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002).

Authors:
Sue S Yom Pedro Torres-Saavedra Jimmy J Caudell John N Waldron Maura L Gillison Ping Xia Minh T Truong Christina Kong Richard Jordan Rathan M Subramaniam Min Yao Christine H Chung Jessica L Geiger Jason W Chan Brian O'Sullivan Dukagjin M Blakaj Loren K Mell Wade L Thorstad Christopher U Jones Robyn N Banerjee Christopher Lominska Quynh-Thu Le

J Clin Oncol 2021 Jan 28:JCO2003128. Epub 2021 Jan 28.

Stanford University, Stanford, CA.

Purpose: Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.

Patients And Methods: In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).

Results: Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( = .04). For IMRT, 2-year PFS was 87.6% ( = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% 52.4%; < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( = .56).

Conclusion: The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.
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http://dx.doi.org/10.1200/JCO.20.03128DOI Listing
January 2021

Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival.

Authors:
Neal Andruska Lily Mahapatra Randall J Brenneman Yi Huang Randal C Paniello Sidharth V Puram Mena Mansour Jason T Rich Brian C Baumann Wade L Thorstad Mackenzie D Daly

Radiother Oncol 2020 Nov 16;155:246-253. Epub 2020 Nov 16.

Department of Radiation Oncology, Washington University School of Medicine, St Louis, United States. Electronic address:

Background: One-third of patients with Merkel cell carcinoma (MCC) present with locally advanced disease involving the regional lymph nodes, but indications for regional lymph node radiation therapy (rLN-RT) are not well established.

Materials And Methods: 72 patients with locally advanced MCC were retrospectively reviewed. Regional lymph nodes were addressed with observation, lymph node dissection (LND) alone, definitive nodal radiotherapy (DnRT), or LND plus adjuvant nodal radiotherapy (AnRT). Cox regression was used to compare treatment modalities in terms of regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS) and disease-specific survival (DSS).

Results: rLN-RT, including both DnRT and AnRT, improved RRFS (Hazard ratio (HR): 0.07, 95% confidence interval (CI): 0.01-0.40, p = 0.003), DRFS (HR: 0.28, CI: 0.11-0.76, p = 0.01), DFS (HR: 0.23, CI: 0.09-0.58, p = 0.002), and DSS (HR: 0.23, CI: 0.06-0.90, p = 0.03). AnRT improved DFS and DSS in high-risk subgroups (e.g., extranodal extension (ENE), ≥ 2 positive lymph nodes, or bulkier lymph nodes). The benefit of AnRT increased with higher disease burden. After controlling for these adverse factors, AnRT significantly improved RRFS (HR: 0.04, CI: 0.01-0.37, p = 0.004), DRFS (HR: 0.14, CI: 0.04-0.50, p = 0.003), DFS (HR: 0.09, CI: 0.02-0.33, p < 0.001), and DSS (HR: 0.21, CI: 0.05-0.89, p = 0.03).

Conclusion: rLN-RT, including both DnRT and AnRT, reduces relapse and death from MCC in patients with node-positive disease. AnRT is particularly beneficial for patients with ENE, multiple involved lymph nodes, or larger nodal foci of disease. These results argue for more liberal use of nodal RT for MCC patients who present with node-positive disease.
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http://dx.doi.org/10.1016/j.radonc.2020.11.003DOI Listing
November 2020

Outcomes of Patients With Single-Node Metastasis of Human Papillomavirus-Related Oropharyngeal Cancer Treated With Transoral Surgery.

Authors:
Stephanie Y Chen Parul Sinha Aisling Last Abhinav Ettyreddy Dorina Kallogjeri Patrik Pipkorn Jason T Rich Jose P Zevallos Randal Paniello Sidharth V Puram Katheryn Van Abel Eric J Moore Peter Oppelt Kevin Palka Douglas Adkins Mackenzie Daly Hiram Gay Wade L Thorstad Ryan S Jackson

JAMA Otolaryngol Head Neck Surg 2021 Jan;147(1):16-22

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri.

Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known.

Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery.

Design, Setting, And Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020.

Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73).

Main Outcomes And Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival.

Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival.

Conclusions And Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment.
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http://dx.doi.org/10.1001/jamaoto.2020.3870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645757PMC
January 2021

Reduced Wide Local Excision Margins are Associated with Increased Risk of Relapse and Death from Merkel Cell Carcinoma.

Authors:
Neal Andruska Lily Mahapatra Randall J Brenneman Jason T Rich Brian C Baumann Leigh Compton Wade L Thorstad Mackenzie D Daly

Ann Surg Oncol 2020 Oct 18. Epub 2020 Oct 18.

Department of Radiation Oncology, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, USA.

Introduction: Current recommendations regarding the size of wide local excision (WLE) margins for Merkel cell carcinoma (MCC) are not well established.

Methods: WLE and pathologic margins were respectively reviewed from 79 patients with stage I or II MCC, who underwent WLE at Washington University in St Louis from 2005 to 2019. Outcomes included local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), and disease-specific survival (DSS).

Results: Thirty-two percent of patients received adjuvant radiotherapy (aRT). At 1 year, DFS was 51.3%, 71.4%, and 87.8% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). At 3 years, the DSS was 57.7%, 82.6%, and 100% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). Multivariable Cox analysis demonstrated that every 1-cm increase in WLE margins was associated with improved RRFS [hazard ratio (HR) = 0.28, 95% confidence interval (CI): 0.11-0.75], DRFS (HR 0.30, CI 0.08-0.99), DFS (HR 0.42, CI 0.21-0.86), and DSS (HR 0.16, CI 0.04-0.61). WLE and pathologic margin size were moderately-to-strongly correlated (r = 0.66). Close or positive pathologic margins (< 3 mm) were associated with reduced DRFS (HR 6.83, CI 1.80-25.9), DFS (HR 2.98, CI 1.31-6.75), and DSS (HR 3.52, CI 1.14-10.9).

Conclusion: Reduced WLE and pathologic margins were associated with higher risk of relapse and death from MCC. Larger WLE margins are important in populations with lower rates of adjuvant radiation.
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http://dx.doi.org/10.1245/s10434-020-09145-7DOI Listing
October 2020

A MicroRNA Expression Signature as Prognostic Marker for Oropharyngeal Squamous Cell Carcinoma.

Authors:
Xinyi Liu Ping Liu Rebecca D Chernock Zhenming Yang Krystle A Lang Kuhs James S Lewis Jingqin Luo Hua Li Hiram A Gay Wade L Thorstad Xiaowei Wang

J Natl Cancer Inst 2020 Oct 15. Epub 2020 Oct 15.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO USA.

Background: Robust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) may facilitate individualized patient management. This study was conducted to develop and validate a clinically feasible prognostic classifier based on microRNA sequencing (miRNA-seq) analysis.

Methods: Tumor tissues were collected for miRNA-seq analysis from 324 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 79) from the TCGA were also included for independent validation. Univariate and multivariate Cox regression analyses were performed to identify miRNAs associated with disease outcomes.

Results: A 26-miRNA signature was identified by miRNA-seq profiling analysis. Based on computed risk scores of the signature, we classified the patients into low- and high-risk groups. In the training cohort, the high-risk group had much shorter overall survival (OS) compared to the low-risk group [hazard ratio (HR) = 3.80, 95% CI = 2.37-6.10, P < .001]. Subgroup analysis further revealed that the signature was prognostic for HPV-positive OPSCCs (HR = 3.07, 95% CI = 1.65-5.71, P < .001). Multivariate analysis indicated that the signature was independent of common clinicopathologic factors for OPSCCs. Importantly, the miRNA signature was a statistically significant predictor of OS in independent validation cohorts (TCGA cohort: HR = 6.05, 95% CI = 2.10-17.37, P < .001; Vanderbilt cohort: HR = 7.98, 95% CI = 3.99-15.97, P < .001; Vanderbilt HPV-positive cohort: HR = 8.71, 95% CI = 2.70-28.14, P < .001).

Conclusion: The miRNA signature is a robust and independent prognostic tool for risk stratification of OPSCCs including HPV-positive OPSCCs.
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http://dx.doi.org/10.1093/jnci/djaa161DOI Listing
October 2020

A prognostic gene expression signature for oropharyngeal squamous cell carcinoma.

Authors:
Xinyi Liu Ping Liu Rebecca D Chernock Krystle A Lang Kuhs James S Lewis Jingqin Luo Hiram A Gay Wade L Thorstad Xiaowei Wang

EBioMedicine 2020 Nov 7;61:102805. Epub 2020 Oct 7.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background: Robust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is important for developing individualized treatment plans. This study was conducted to develop and validate a clinically feasible prognostic classifier based on transcriptome-wide gene expression profiles.

Methods: Tumor tissues were collected from 208 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 70) from the TCGA cohort were also included for independent validation. Based on RNA-seq profiling data, Cox proportional hazards regression analysis was performed to identify genes associated with disease outcomes. Then, Lasso-penalized multivariate survival models were constructed to identify biomarker genes for developing a prognostic gene signature.

Findings: A 60-gene signature was identified by RNA-seq profiling analysis. Computed risk score of the gene signature was significantly predictive of 5-year overall survival of the training cohort (Hazard ratio (HR) 28·32, P = 4·3E-41). Subgroup analysis stratified by HPV status revealed that the signature was prognostic in HPV-positive OPSCC patients (HR 30·55, P = 7·0E-37) and was independent of clinical features. Importantly, the gene signature was validated in two independent patient cohorts, including the TCGA cohort (HR 3·94, P = 0·0018) and the Vanderbilt cohort (HR 8·50, P = 5·7E-09) for overall survival.

Interpretation: The prognostic gene signature is a robust tool for risk stratification of OPSCC patients. The signature remains prognostic among HPV-positive OPSCC patients.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2020.102805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648117PMC
November 2020

Duration of radiation therapy is associated with worse survival in head and neck cancer.

Authors:
Angela L Mazul Katelyn O Stepan Thomas F Barrett Wade L Thorstad Sean Massa Douglas R Adkins Mackenzie D Daly Jason T Rich Randal C Paniello Patrik Pipkorn Jose P Zevallos Ryan S Jackson Stephen Y Kang Sidharth V Puram

Oral Oncol 2020 09 30;108:104819. Epub 2020 May 30.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, MO, United States; Department of Genetics, Washington University School of Medicine, St Louis, MO, United States. Electronic address:

Introduction: Delays in radiation are multifactorial, frequent, and associated with poor outcomes. This study investigates the effect of both primary and adjuvant radiation therapy duration and their interaction with other measures of treatment delay on survival in head and neck squamous cell carcinoma (HNSCC).

Methods: We built a retrospective cohort using the National Cancer Database, consisting of primary oral cavity, hypopharynx, larynx and oropharynx squamous cell carcinoma without distant metastasis and with at least six weeks of radiation. The primary exposure was the duration of radiation therapy (DRT), and the primary outcome was death. We estimated the association between DRT and 5-year overall survival (OS) using Kaplan-Meier curves and hazard ratios (HRs) with Cox proportional hazard regression.

Results: In both primary (definitive) and adjuvant (post-surgical) radiation settings, increased DRT results in decreased survival. In the primary radiation cohort, 5-year OS was 59.7% [59.1%-60.3%] among those with 47-53 days DRT, which decreased significantly with each subsequent week to completion (81+ days: 38.4% [36.2%-40.7%]). In the surgical cohort, survival decreased 16.5% when DRT extended beyond 75 days (40-46 days: 68.2% [67.3%-69.1%] vs. 75+ days: 53.3% [50.1%-56.7%]). Multivariate analyses showed increased hazard of death with increased DRT (primary radiation: 81+ days HR: 1.69 [1.58-1.81]); surgical: 75+ days HR: 1.61 [1.37-1.88]), with effects intensifying when restricting to those receiving full-dose radiation.

Conclusion: A prolonged DRT was associated with worse OS in head and neck cancer. Radiation treatment delays of even a week lead to a significant survival disadvantage. DRT had a stronger association with survival than time to initiation of postoperative adjuvant radiotherapy.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104819DOI Listing
September 2020

Management of primary skin cancer during a pandemic: Multidisciplinary recommendations.

Authors:
Brian C Baumann Kelly M MacArthur Jerry D Brewer William M Mendenhall Christopher A Barker Jeremy R Etzkorn Nathaniel J Jellinek Jeffrey F Scott Hiram A Gay John C Baumann Farrin A Manian Phillip M Devlin Jeff M Michalski Nancy Y Lee Wade L Thorstad Lynn D Wilson Carlos A Perez Christopher J Miller

Cancer 2020 09 1;126(17):3900-3906. Epub 2020 Jun 1.

Division of Dermatologic Surgery, Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making regarding the pros and cons of early versus delayed interventions for localized skin cancer. Patients at highest risk of COVID-19 complications are older; are immunosuppressed; and have diabetes, cancer, or cardiopulmonary disease, with multiple comorbidities associated with worse outcomes. Physicians must weigh the patient's risk of COVID-19 complications in the event of exposure against the risk of worse oncologic outcomes from delaying cancer therapy. Herein, the authors have summarized current data regarding the risk of COVID-19 complications and mortality based on age and comorbidities and have reviewed the literature assessing how treatment delays affect oncologic outcomes. They also have provided multidisciplinary recommendations regarding the timing of local therapy for early-stage skin cancers during this pandemic with input from experts at 11 different institutions. For patients with Merkel cell carcinoma, the authors recommend prioritizing treatment, but a short delay can be considered for patients with favorable T1 disease who are at higher risk of COVID-19 complications. For patients with melanoma, the authors recommend delaying the treatment of patients with T0 to T1 disease for 3 months if there is no macroscopic residual disease at the time of biopsy. Treatment of tumors ≥T2 can be delayed for 3 months if the biopsy margins are negative. For patients with cutaneous squamous cell carcinoma, those with Brigham and Women's Hospital T1 to T2a disease can have their treatment delayed for 2 to 3 months unless there is rapid growth, symptomatic lesions, or the patient is immunocompromised. The treatment of tumors ≥T2b should be prioritized, but a 1-month to 2-month delay is unlikely to worsen disease-specific mortality. For patients with squamous cell carcinoma in situ and basal cell carcinoma, treatment can be deferred for 3 months unless the individual is highly symptomatic.
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http://dx.doi.org/10.1002/cncr.32969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301000PMC
September 2020

Childhood tonsillectomy alters the primary distribution of HPV-related oropharyngeal squamous cell carcinoma.

Authors:
Brannon Altenhofen Todd A DeWees Ji W Ahn Nai C Yeat Shreya Goddu Ishita Chen James S Lewis Wade L Thorstad Richard A Chole Hiram A Gay

Laryngoscope Investig Otolaryngol 2020 Apr 11;5(2):210-216. Epub 2020 Feb 11.

Department of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis Missouri.

Objectives: We investigated how tonsillectomy during childhood may influence the distribution of human papillomavirus (HPV) positive cancer of the tonsils in adult life using p16 as a surrogate marker for HPV infection.

Study Design: Retrospective observational study.

Methods: A total of 280 patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) and known p16 status were eligible for this study. Each participant was called to obtain the childhood tonsillectomy history. Respondents were subgrouped by p16 status and the primary tumor location. Patient demographic and clinical information was analyzed for association with Fisher's exact and Wilcoxon rank sum tests. Location of tumor was modeled using univariate (UVA) and multivariate (MVA) logistic regression with associated odds ratios (OR) and 95% confidence intervals.

Results: Of the 280 patients, 115 (41%) were respondents: 104 (90.4%) were p16 positive and 11 (9.6%) were p16 negative. For p16 positive patients, we observed a majority (93%) of intact tonsils in those with tonsil cancer, compared to 45% of intact tonsils in patients with p16 positive cancer elsewhere in the oropharynx ( < .001). MVA logistic regression showed that female gender (OR = 4.16, = .0675), prior smoking history (OR = 2.6, = .0367), and intact tonsils (OR = 15.2,  < .0001) were associated with tonsillar OPSCC.

Conclusion: We found that patients with p16 positive OPSCC at a non-tonsil site were much more likely to have had prior tonsillectomy vs those with p16 positive OPSCC arising within the tonsil. Nevertheless, we do not advocate tonsillectomies as a public health policy to reduce HPV-related OPSCC.

Level Of Evidence: 6.
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http://dx.doi.org/10.1002/lio2.342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178443PMC
April 2020

Prognostic Significance of Smoking in Human Papillomavirus-Positive Oropharyngeal Cancer Under American Joint Committee on Cancer Eighth Edition Stage.

Authors:
Smrithi Chidambaram Erik R Nakken William Kennedy Wade L Thorstad Stephanie Y Chen Patrik Pipkorn Jose P Zevallos Angela L Mazul

Laryngoscope 2020 08 15;130(8):1961-1966. Epub 2020 Apr 15.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Objective: To determine the prognostic significance of smoking in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) when considering American Joint Committee on Cancer eighth edition (AJCC-8) stage.

Study Design: Retrospective cohort study.

Methods: Three hundred seventeen HPV-positive OPSCC patients with known AJCC-8 stage and smoking status (<10 or ≥10 pack-years) seen at a tertiary center from 1997 to 2017 were studied. We used the Kaplan-Meier method to compare 5-year overall survival (OS) by smoking status and by clinical AJCC-8 stage and smoking status combined. Hazard ratios (HRs) were estimated with Cox proportional hazard regression for the independent effects of smoking and AJCC-8 stage. We also studied pathologic stage and estimated the combined effects of smoking and clinical stage.

Results: The ≥10 pack-years smokers had worse 5-year OS than <10 pack-years smokers (93.6%; 95% confidence interval (CI): 89.7-97.8 vs. 82.3%; 95% CI: 76.0%-89.1%). When stratified by AJCC-8 clinical stage, only stage I <10 pack-years smokers (98.7%; 95% CI: 96.3%-100.0%) had significantly better 5-year OS than their ≥10 pack-years (84.8%; 95% CI: 76.4%-94.1%) counterparts. In a multivariable analysis, ≥10 pack-years smoking was associated with increased hazard of death when adjusting for AJCC-8 clinical (HR: 2.52; 95% CI: 1.16-5.46) and pathologic (HR: 5.21; 95% CI: 1.47-18.5) stage. In both analyses, stage III patients demonstrated worse survival than stage I, and smoking had greater impact at lower stages.

Conclusions: Smoking is a negative prognosticator in HPV-positive OPSCC and interacts with AJCC-8 clinical stage. It is important to understand the impact of smoking in HPV-positive disease when considering treatment plans and deintensification trials.

Level Of Evidence: 2b Laryngoscope, 130: 1961-1966, 2020.
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http://dx.doi.org/10.1002/lary.28659DOI Listing
August 2020

Nomogram to Predict the Benefit of Intensive Treatment for Locoregionally Advanced Head and Neck Cancer.

Authors:
Loren K Mell Hanjie Shen Phuc Felix Nguyen-Tân David I Rosenthal Kaveh Zakeri Lucas K Vitzthum Steven J Frank Peter B Schiff Andy M Trotti James A Bonner Christopher U Jones Sue S Yom Wade L Thorstad Stuart J Wong George Shenouda John A Ridge Qiang E Zhang Quynh-Thu Le

Clin Cancer Res 2019 12 16;25(23):7078-7088. Epub 2019 Aug 16.

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.

Purpose: Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy.

Experimental Design: We analyzed 2,688 patients with stage III-IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat.

Results: Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57-0.94; = 0.016] than those with ω score <0.80 (5-year OS, 46.7% vs. 45.3%; HR of 1.02, 95% CI: 0.92-1.14; = 0.69; = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression.

Conclusions: Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028339PMC
December 2019

Radiation therapy dose de-escalation compared to standard dose radiation therapy in definitive treatment of HPV-positive oropharyngeal squamous cell carcinoma.

Authors:
Prashant Gabani Alexander J Lin Justin Barnes Peter Oppelt Douglas R Adkins Jason T Rich Jose P Zevallos Mackenzie D Daly Hiram A Gay Wade L Thorstad

Radiother Oncol 2019 05 4;134:81-88. Epub 2019 Feb 4.

Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. Electronic address:

Background: Despite existing evidence that human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has a favorable prognosis compared to HPV-negative OPSCC, randomized studies have yet to report the effect of de-escalating radiation therapy (RT) dose for definitive treatment. The aim of this study was to assess the effectiveness of dose de-escalated RT (DDRT) vs. standard dose RT (SDRT) in patients with HPV-positive OPSCC.

Methods: This was an observational study using the National Cancer Database (Year 2010-2014) to identify patients who had HPV-positive OPSCC and were treated with definitive RT or chemo-RT. Patients undergoing surgery were excluded. Patients receiving ≥50 Gy, but <66 Gy were categorized as receiving DDRT. Patients receiving ≥66 Gy were categorized as receiving SDRT. Inverse probability of treatment weighting (IPTW) using propensity scores was used to balance the two groups. Kaplan-Meier analysis was used to estimate overall survival (OS). Subset analyses in patients receiving RT alone and concurrent chemo-RT were also performed. Multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS.

Results: 759 patients with HPV-positive OPSCC were identified: 104 received DDRT and 655 received SDRT. The median follow-up was 30.5 (2.4-81.4) months. After IPTW-adjusted analysis, there was no difference in the 3-yr OS between the two groups (82.2% vs. 79.3%; P = 0.85). In the subset of patients receiving concurrent chemoradiotherapy, IPTW-adjusted analysis also did not show a difference in the 3-yr OS between the two groups (83.1% vs. 79.6%; P = 0.83). On multivariable analysis, DDRT was not associated with an inferior OS (HR 0.88; 95% CI, 0.53-1.47; P = 0.63).

Conclusions: In this study, DDRT was not associated with an inferior OS compared to SDRT in patients with HPV-positive OPSCC. Randomized clinical trials to address DDRT in this patient population are currently ongoing.
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http://dx.doi.org/10.1016/j.radonc.2019.01.016DOI Listing
May 2019

Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials.

Authors:
Carole Fakhry Qiang Zhang Maura L Gillison Phuc Felix Nguyen-Tân David I Rosenthal Randal S Weber Louise Lambert Andy M Trotti William L Barrett Wade L Thorstad Sue S Yom Stuart J Wong John A Ridge Shyam S D Rao Sharon Spencer Andre Fortin David Raben Jonathan Harris Quynh-Thu Le

Cancer 2019 06 26;125(12):2027-2038. Epub 2019 Mar 26.

Stanford University, Stanford, California.

Background: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups.

Methods: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible.

Results: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group.

Conclusions: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.
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http://dx.doi.org/10.1002/cncr.32025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594017PMC
June 2019

In Regard to Bossi et al.

Authors:
Carole Fakhry Phuc Felix Nguyen-Tân Louise Lambert David I Rosenthal Randal S Weber Maura L Gillison Andy M Trotti William L Barrett Wade L Thorstad Christopher U Jones Sue S Yom Stuart J Wong John A Ridge Shyam S D Rao James A Bonner Eric Vigneault David Raben Mahesh R Kudrimoti Jonathan Harris Quynh-Thu Le

Int J Radiat Oncol Biol Phys 2018 11;102(3):669-670

Stanford University, Stanford, California.

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http://dx.doi.org/10.1016/j.ijrobp.2018.06.020DOI Listing
November 2018

Predictors of acute throat or esophageal patient reported pain during radiation therapy for head and neck cancer.

Authors:
Hiram A Gay Jung Hun Oh Aditya P Apte Mackenzie D Daly Douglas R Adkins Jason Rich Peter J Oppelt Pawel T Dyk Daniel F Mullen Laura Eschen Re-I Chin Brian Nussenbaum Bruce H Haughey Wade L Thorstad Joseph O Deasy

Clin Transl Radiat Oncol 2018 Nov 4;13:1-6. Epub 2018 Sep 4.

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Background And Purpose: Acute pain during weekly radiotherapy (RT) to the head and neck is not well characterized. We studied dose-volume metrics and clinical variables that are plausibly associated with throat or esophageal pain as measured with a weekly questionnaire during RT.

Materials And Methods: We prospectively collected weekly patient-reported outcomes from 122 head and neck cancer patients during RT. The pain score for each question consisted of a four-level scale: none (0), mild (1), moderate (2), and severe (3). Univariate and multivariate ordinal logistic regression analyses were performed to investigate associations between both esophageal and throat pain and clinical as well as dosimetric variables.

Results: In multivariate analysis, age was significantly associated with both types of pain, leading to odds ratio (OR) = 0.95 (p = 0.008) and OR = 0.95 (p = 0.007) for esophageal and throat pain, respectively. For throat pain, sex (OR = 4.12; p = 0.010), with females at higher risk, and fractional organ at risk (OAR) mean dose (OR = 3.30; p = 0.014) were significantly associated with throat pain.

Conclusions: A fractional OAR mean dose of 1.1 Gy seems a reasonable cutoff for separating no or mild pain from moderate to severe esophageal and throat pain. Younger patients who received RT experienced more esophageal and throat pain. Females experienced more throat pain, but not esophageal pain.
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http://dx.doi.org/10.1016/j.ctro.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134163PMC
November 2018

Pretreatment metabolic tumor volume as a prognostic factor in HPV-associated oropharyngeal cancer in the context of AJCC 8th edition staging.

Authors:
John M Floberg Todd A DeWees Re-I Chin Adam A Garsa Farrokh Dehdashti Brian Nussenbaum Peter J Oppelt Douglas R Adkins Hiram A Gay Wade L Thorstad

Head Neck 2018 10 26;40(10):2280-2287. Epub 2018 Jul 26.

Washington University School of Medicine, Department of Radiation Oncology, St Louis, MO.

Background: This study evaluates the prognostic significance of F-fluorodeoxyglucose-positron emission tomography ([F-18]FDG-PET)-derived metabolic tumor volume (MTV) in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) in the context of AJCC 8th edition staging.

Methods: We performed a retrospective study of HPV-associated OPSCCs treated with postoperative or definitive radiation. The prognostic significance of pretreatment MTV for freedom from recurrence (FFR), freedom from distant metastasis (FFDM), and overall survival (OS) was determined using Kaplan-Meier analysis. Multivariate analysis (MVA) was performed using Cox regression.

Results: In this 153-patient cohort, stratifying by the optimum MTV (24 cm ) was prognostic for FFR (P = .0002), FFDM (P = .001), and OS (P < .0001). Metabolic tumor volume (MTV) was prognostic of FFR in AJCC 8th edition stage I/II (P = .03), and stage III patients (P = .04). On multivariate analysis only MTV was a significant factor for OS.

Conclusion: Metabolic tumor volume (MTV) is a significant prognostic factor in HPV-associated OPSCCs, independent of AJCC 8th edition stage.
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http://dx.doi.org/10.1002/hed.25337DOI Listing
October 2018

Induction chemotherapy in the treatment of nasopharyngeal carcinoma: Clinical outcomes and patterns of care.

Authors:
Prashant Gabani Justin Barnes Alexander J Lin Soumon Rudra Peter Oppelt Douglas Adkins Jason T Rich Jose P Zevallos Mackenzie D Daly Hiram A Gay Wade L Thorstad

Cancer Med 2018 08 14;7(8):3592-3603. Epub 2018 Jul 14.

Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, USA.

The role of induction chemotherapy in nasopharyngeal carcinoma (NPC) remains controversial. The primary aim of this study was to use the National Cancer Database to evaluate the patterns of care of induction chemotherapy in NPC and its impact on overall survival (OS). Patients with NPC from 2004 to 2014 were obtained from the NCDB. Patients were considered to have received induction chemotherapy if it was started ≥43 days before the start of RT and concurrent CRT if chemotherapy started within 21 days after the start of RT. Propensity score matching was used to control for selection bias. Cox proportional hazards model was used to determine significant predictors of OS. Logistic regression model was used to determine predictors of the use of induction chemotherapy. Significance was defined as a P value <.05. A total of 4857 patients were identified: 4041 patients (87.2%) received concurrent CRT and 816 patients (16.8%) received induction chemotherapy. The use of induction therapy remained stable between 2004 and 2014. Younger patients and those with higher T- and N-stage had a higher likelihood of being treated with induction chemotherapy. The 5-year OS in patients treated with induction chemotherapy and CRT was 66.3% vs 69.1%, respectively (P = .25). There was no difference in OS when these two groups were analyzed after propensity score matching. No differences in OS existed between these treatment groups in patients with T3-T4N1 or TanyN2-3 disease (P = .76). Propensity score matching also did not reveal any difference in OS in patients with T3-T4N1 or TanyN2-3 disease. The use of induction chemotherapy has remained stable in the last decade. In this study of patients with NPC, induction chemotherapy was not associated with improved OS compared to CRT alone.
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http://dx.doi.org/10.1002/cam4.1626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089177PMC
August 2018

Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil.

Authors:
Re-I Chin Yuan James Rao Michael Y Hwang Christopher R Spencer Michael Pierro Todd DeWees Pranav Patel Parul Sinha Hiram A Gay Mackenzie Daly Bruce H Haughey Brian Nussenbaum Douglas R Adkins James S Lewis Wade L Thorstad

Cancer 2017 Dec 7;123(23):4594-4607. Epub 2017 Sep 7.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Background: The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes.

Methods: A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3).

Results: The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT.

Conclusions: Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30931DOI Listing
December 2017

Trials in head and neck oncology: Evolution of perioperative adjuvant therapy.

Authors:
Joseph Zenga Patrik Pipkorn Douglas R Adkins Wade L Thorstad Brian Nussenbaum

Oral Oncol 2017 09 15;72:80-89. Epub 2017 Jul 15.

Washington University, Department of Otolaryngology-Head and Neck Surgery, United States.

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http://dx.doi.org/10.1016/j.oraloncology.2017.07.012DOI Listing
September 2017

Development and Validation of Nomograms Predictive of Overall and Progression-Free Survival in Patients With Oropharyngeal Cancer.

Authors:
Carole Fakhry Qiang Zhang Phuc Felix Nguyen-Tân David I Rosenthal Randal S Weber Louise Lambert Andy M Trotti William L Barrett Wade L Thorstad Christopher U Jones Sue S Yom Stuart J Wong John A Ridge Shyam S D Rao James A Bonner Eric Vigneault David Raben Mahesh R Kudrimoti Jonathan Harris Quynh-Thu Le Maura L Gillison

J Clin Oncol 2017 Dec 4;35(36):4057-4065. Epub 2017 Aug 4.

Carole Fakhry, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, NRG Oncology Statistics and Data Management Center, American College of Radiology; John A. Ridge, Fox Chase Cancer Center, Philadelphia, PA; Phuc Felix Nguyen-Tân and Louise Lambert, Centre Hospitalier de l'Université de Montréal, Montreal; Eric Vigneault, L'Hotel-Dieu de Quebec, Ville de Québec, Quebec, Canada; David I. Rosenthal, Randal S. Weber, and Maura L. Gillison, MD Anderson Cancer Center, Houston, TX; Andy M. Trotti III, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; William L. Barrett, University of Cincinnati Cancer Institute, Cincinnati, OH; Wade L. Thorstad, Washington University, St Louis, MO; Christopher U. Jones, Sutter General Hospital, Sacramento; Sue S. Yom, University of California San Francisco, San Francisco; Shyam S.D. Rao, University of California Davis, Davis; Quynh-Thu Le, Stanford University, Stanford, CA; Stuart J. Wong, Medical College of Wisconsin, Milwaukee, WI; James A. Bonner, University of Alabama at Birmingham Medical Center, Birmingham, AL; David Raben, University of Colorado, Aurora, CO; and Mahesh R. Kudrimoti, University of Kentucky, Lexington, KY.

Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.
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http://dx.doi.org/10.1200/JCO.2016.72.0748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736236PMC
December 2017

Predictive modeling of outcomes following definitive chemoradiotherapy for oropharyngeal cancer based on FDG-PET image characteristics.

Authors:
Michael R Folkert Jeremy Setton Aditya P Apte Milan Grkovski Robert J Young Heiko Schöder Wade L Thorstad Nancy Y Lee Joseph O Deasy Jung Hun Oh

Phys Med Biol 2017 Jul 12;62(13):5327-5343. Epub 2017 Jun 12.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States of America.

In this study, we investigate the use of imaging feature-based outcomes research ('radiomics') combined with machine learning techniques to develop robust predictive models for the risk of all-cause mortality (ACM), local failure (LF), and distant metastasis (DM) following definitive chemoradiation therapy (CRT). One hundred seventy four patients with stage III-IV oropharyngeal cancer (OC) treated at our institution with CRT with retrievable pre- and post-treatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans were identified. From pre-treatment PET scans, 24 representative imaging features of FDG-avid disease regions were extracted. Using machine learning-based feature selection methods, multiparameter logistic regression models were built incorporating clinical factors and imaging features. All model building methods were tested by cross validation to avoid overfitting, and final outcome models were validated on an independent dataset from a collaborating institution. Multiparameter models were statistically significant on 5 fold cross validation with the area under the receiver operating characteristic curve (AUC)  =  0.65 (p  =  0.004), 0.73 (p  =  0.026), and 0.66 (p  =  0.015) for ACM, LF, and DM, respectively. The model for LF retained significance on the independent validation cohort with AUC  =  0.68 (p  =  0.029) whereas the models for ACM and DM did not reach statistical significance, but resulted in comparable predictive power to the 5 fold cross validation with AUC  =  0.60 (p  =  0.092) and 0.65 (p  =  0.062), respectively. In the largest study of its kind to date, predictive features including increasing metabolic tumor volume, increasing image heterogeneity, and increasing tumor surface irregularity significantly correlated to mortality, LF, and DM on 5 fold cross validation in a relatively uniform single-institution cohort. The LF model also retained significance in an independent population.
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http://dx.doi.org/10.1088/1361-6560/aa73ccDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729737PMC
July 2017

Outcomes of surgically treated human papillomavirus-related oropharyngeal squamous cell carcinoma with N3 disease.

Authors:
Joseph Zenga Bruce H Haughey Ryan S Jackson Douglas R Adkins John Aranake-Chrisinger Neel Bhatt Hiram A Gay Dorina Kallogjeri Eliot J Martin Eric J Moore Randal C Paniello Jason T Rich Wade L Thorstad Brian Nussenbaum

Laryngoscope 2017 09 23;127(9):2033-2037. Epub 2016 Dec 23.

Department of Otolaryngology-Head and Neck Surgery, Washington University, St. Louis, Missouri, U.S.A.

Objectives/hypothesis: To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival.

Study Design: Retrospective case series with chart review.

Methods: This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates.

Results: Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2-147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%-99%), 87% (95% CI: 75%-99%), and 84% (95% CI: 72%-96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS.

Conclusions: Patients with HPV-related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence.

Level Of Evidence: 4. Laryngoscope, 127:2033-2037, 2017.
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http://dx.doi.org/10.1002/lary.26455DOI Listing
September 2017

Reevaluation of postoperative radiation dose in the management of human papillomavirus-positive oropharyngeal cancer.

Authors:
Re-I Chin Christopher R Spencer Todd DeWees Michael Y Hwang Pranav Patel Parul Sinha Hiram A Gay Bruce H Haughey Brian Nussenbaum Douglas R Adkins James S Lewis Wade L Thorstad

Head Neck 2016 11 6;38(11):1643-1649. Epub 2016 May 6.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Background: The purpose of this study was to compare outcomes of patients with p16-positive oropharyngeal squamous cell carcinoma (SCC) treated with postoperative intensity-modulated radiotherapy (IMRT) before and after an institutional dose reduction policy effective on February 2009.

Methods: Between 1998 and 2013, 175 consecutive patients with p16-positive oropharyngeal SCC with extracapsular extension (ECE) and/or close or positive margins were treated postoperatively to 66 Gy (n = 109) or 60 Gy (n = 66) in 2 Gy/fx.

Results: Between the 66 and 60 Gy groups, there was no difference in tumor classification (pT4 vs pT1-T3; p = .181) and nodal classification (pN2c-N3 vs pN0-N2b; p = .704), and American Joint Committee on Cancer (AJCC) group stage (IV vs I-III; p = .473). Median follow-up was 5.9 years overall (66 Gy: 7.4 years; 60 Gy: 4.0 years). There was no difference in locoregional recurrence-free survival (2-year: 98.1% vs 98.5%; p = .421).

Conclusion: This study suggests that treating p16-positive oropharyngeal SCC with ECE and/or close or positive margins with postoperative IMRT to 60 Gy may not compromise locoregional recurrence-free survival compared to 66 Gy. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.
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http://dx.doi.org/10.1002/hed.24486DOI Listing
November 2016

Does elimination of planned postoperative radiation to the primary bed in p16-positive, transorally-resected oropharyngeal carcinoma associate with poorer outcomes?

Authors:
Parul Sinha Patrik Pipkorn Wade L Thorstad Hiram A Gay Bruce H Haughey

Oral Oncol 2016 10 10;61:127-34. Epub 2016 Sep 10.

Head and Neck Surgery, Florida Hospital Celebration Health, Celebration, FL, United States; Department of Surgery, University of Auckland Faculty of Medicine and Health Sciences, Auckland, New Zealand. Electronic address:

Objective: The purpose of our study is to compare oncologic and functional outcomes of p16-positive oropharyngeal squamous cell carcinoma (OPSCC) patients, in the presence and absence of planned radiation to the primary bed following transoral surgery (TOS), stratified by T-classification.

Methods: Retrospective cohort study of 261, T1-T4, consecutively TOS-treated OPSCC patients.

Results: At a median follow-up of 61months, local recurrence (LR) occurred in 6 (2.3%)patients (3 each in T1-T2 and T3-T4 groups), of which 5 had tumors in the tongue base and one in the tonsil. Of patients not receiving planned primary bed radiation, LR occurred in 3% of T1-T2s versus 17% of T3-T4s. In patients with T1-T2 tumors, Absolute Risk Reduction of LR with primary bed radiation was 3.26% (95% CI: -0.37%, 7%); Number Needed to Treat to prevent one LR was 31 (95% CI: 14.5, 271). Absolute Risk Increase for gastrostomy-tube with primary bed radiation was 34.4% (95% CI: 24%, 45%); Number Needed to Harm was 3 (95% CI: 2.2, 4.2), i.e., for every three patients with T1-T2 tumors receiving primary bed radiation, one had a gastrostomy-tube.

Conclusions: Elimination of primary bed radiation in margin-negative resected, T1-T2 p16-positive OPSCC was not associated with significant compromise of local control, and correlated with superior swallowing preservation, assessed using gastrostomy rate as a surrogate. Lack of primary bed radiation in T3-T4 tumors associated with significantly increased LR rates.
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http://dx.doi.org/10.1016/j.oraloncology.2016.08.013DOI Listing
October 2016

Oncologic outcomes of selective neck dissection in HPV-related oropharyngeal squamous cell carcinoma.

Authors:
Joseph Zenga Ryan S Jackson Evan M Graboyes Parul Sinha Miranda Lindberg Eliot J Martin Daniel Ma Wade L Thorstad Jason T Rich Eric J Moore Bruce H Haughey

Laryngoscope 2017 03 16;127(3):623-630. Epub 2016 Sep 16.

Head and Neck Surgery Center of Florida, Celebration Hospital, Celebration, Florida, U.S.A.

Objectives: To examine outcomes of selective neck dissection (SND) in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) who present with clinical neck disease.

Study Design: Multi-institutional retrospective review.

Methods: Two institutional databases of patients with HPV-related OPSCC were reviewed to identify patients with clinical (c) N1-N3 neck disease who underwent SND ± adjuvant therapy.

Results: Three hundred and twenty-four patients were identified with a median follow-up of 49 months (range 3-199 months). All patients underwent transoral resection of the primary tumor and SND, including levels II-IV and ± levels I or V, with resection of additional nonlymphatic tissue (extended SND) as indicated by extent of disease, including the spinal accessory nerve (7%), the internal jugular vein (13%), and the sternocleidomastoid muscle (8%). Two hundred and seventy (83%) patients underwent adjuvant radiation. There were 13 (4%) regional recurrences and 19 (6%) distant recurrences. Regional control following salvage was 98%. On univariable analysis, absence of radiation was associated with regional recurrence (odds ratio [OR] 9.2, 95% confidence interval [CI] 2.9-29.4). On multivariable analysis, adjuvant radiation was associated with improved disease-free survival (DFS) (OR 0.27, 95% CI 0.14-0.53) but lost significance for overall (OS) and disease-specific survival (DSS) (P > 0.05). Five-year Kaplan-Meier estimates for OS, DSS, and DFS were 88% (95% CI 84%-92%), 93% (95% CI 89%-96%), and 83% (95% CI 78%-87%), respectively.

Conclusion: In HPV-related OPSCC presenting with clinical neck disease, a SND ± additional tissue resection and adjuvant therapy, when indicated, provides excellent long-term regional control. Omission of radiotherapy increases the risk of regional recurrence, although it may not significantly impact OS or DSS. It appears unnecessary to routinely perform a comprehensive neck dissection.

Level Of Evidence: 4. Laryngoscope, 127:623-630, 2017.
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http://dx.doi.org/10.1002/lary.26272DOI Listing
March 2017

A comparative study based on image quality and clinical task performance for CT reconstruction algorithms in radiotherapy.

Authors:
Hua Li Steven Dolly Hsin-Chen Chen Mark A Anastasio Daniel A Low Harold H Li Jeff M Michalski Wade L Thorstad Hiram Gay Sasa Mutic

J Appl Clin Med Phys 2016 07 8;17(4):377-390. Epub 2016 Jul 8.

Department of Radiation Oncology, Washington University School of Medicine 4921 Parkview Place Saint Louis, MO 63110.

CT image reconstruction is typically evaluated based on the ability to reduce the radiation dose to as-low-as-reasonably-achievable (ALARA) while maintaining acceptable image quality. However, the determination of common image quality metrics, such as noise, contrast, and contrast-to-noise ratio, is often insufficient for describing clinical radiotherapy task performance. In this study we designed and implemented a new comparative analysis method associating image quality, radiation dose, and patient size with radiotherapy task performance, with the purpose of guiding the clinical radiotherapy usage of CT reconstruction algorithms. The iDose4 iterative reconstruction algorithm was selected as the target for comparison, wherein filtered back-projection (FBP) reconstruction was regarded as the baseline. Both phantom and patient images were analyzed. A layer-adjustable anthropomorphic pelvis phantom capable of mimicking 38-58 cm lateral diameter-sized patients was imaged and reconstructed by the FBP and iDose4 algorithms with varying noise-reduction-levels, respectively. The resulting image sets were quantitatively assessed by two image quality indices, noise and contrast-to-noise ratio, and two clinical task-based indices, target CT Hounsfield number (for electron density determination) and structure contouring accuracy (for dose-volume calculations). Additionally, CT images of 34 patients reconstructed with iDose4 with six noise reduction levels were qualitatively evaluated by two radiation oncologists using a five-point scoring mechanism. For the phantom experiments, iDose4 achieved noise reduction up to 66.1% and CNR improvement up to 53.2%, compared to FBP without considering the changes of spatial resolution among images and the clinical acceptance of reconstructed images. Such improvements consistently appeared across different iDose4 noise reduction levels, exhibiting limited interlevel noise (< 5 HU) and target CT number variations (< 1 HU). The radiation dose required to achieve similar contouring accuracy decreased when using iDose4 in place of FBP, up to 32%. Contouring accuracy improvement for iDose4 images, when compared to FBP, was greater in larger patients than smaller-sized patients. Overall, the iDose4 algorithm provided superior radiation dose control while maintaining or improving task performance, when compared to FBP. The reader study on image quality improvement of patient cases shows that physicians preferred iDose4-reconstructed images on all cases compared to those from FBP algorithm with overall quality score: 1.21 vs. 3.15, p = 0.0022. However, qualitative evaluation strongly indicated that the radiation oncologists chose iDose4 noise reduction levels of 3-4 with additional consideration of task performance, instead of image quality metrics alone. Although higher iDose4 noise reduction levels improved the CNR through the further reduction of noise, there was pixelization of anatomical/tumor structures. Very-low-dose scans yielded severe photon starvation artifacts, which decreased target visualization on both FBP and iDose4 reconstructions, especially for the 58 cm phantom size. The iDose4 algorithm with a moderate noise reduction level is hence suggested for CT simulation and treatment planning. Quantitative task-based image quality metrics should be further investigated to accommodate additional clinical applications.
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http://dx.doi.org/10.1120/jacmp.v17i4.5763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690061PMC
July 2016

Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234).

Authors:
Vasu Divi Jonathan Harris Paul M Harari Jay S Cooper Jonathan McHugh Diana Bell Erich M Sturgis Anthony J Cmelak Mohan Suntharalingam David Raben Harold Kim Sharon A Spencer George E Laramore Andy Trotti Robert L Foote Christopher Schultz Wade L Thorstad Qiang Ed Zhang Quynh Thu Le F Christopher Holsinger

Cancer 2016 Nov 15;122(22):3464-3471. Epub 2016 Jul 15.

Stanford University, Stanford, California.

Background: Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival.

Methods: The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group.

Results: Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status.

Conclusions: The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464-71. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237619PMC
November 2016