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Objective: Small carcinomas of the palatine tonsil are often diagnosed via simple tonsillectomy, a maneuver with non-therapeutic intent. Herein, practice patterns for this unique situation are evaluated., Patients and Methods: A retrospective review was performed across 10 facilities to identify patients with cT1-2 squamous carcinomas of the tonsil diagnosed by simple tonsillectomy between 2010 and 2018. Patients who received curative-intent intensity modulated radiotherapy (IMRT) without additional surgery were included. Target volumes were reviewed, and cumulative incidences of local failure and severe late dysphagia were calculated., Results: From 638 oropharyngeal patients, 91 were diagnosed via simple tonsillectomy. Definitive IMRT with no additional surgery to the primary site was utilized in 57, and three with gross residual disease were excluded, leaving 54 for analysis. Margins were negative in 13%, close (<5 mm) in 13%, microscopically positive in 61%, and not reported in 13%. Doses typically delivered to gross disease (68-70.2 Gy in 33-35 fx or 66 Gy/30 fx) were prescribed to the tonsil bed in 37 (69%). Sixteen patients (29%) received doses from 60 to 66 Gy (≤2 Gy/fx) and one received 50 Gy (2 Gy/fx). No local failures were observed. One late oropharyngeal soft tissue ulcer occurred, treated conservatively (grade 2). At five years, the cumulative incidence of severe late dysphagia was 17.4% (95% CI 6.1-28.8%)., Conclusion: Small tonsil carcinomas diagnosed by simple tonsillectomy represent a niche subset with favorable oncologic outcomes. Regardless, radiation oncologists tend to deliver full-dose to the tonsil bed. The necessity of this routine could be questioned in the modern era., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To investigate the association between tumor volume and locoregional failure (LRF) after concurrent chemoradiation (CCRT) for locally advanced larynx cancer (LC)., Methods: This is a retrospective cohort study from 2009 to 2014 identified from an institutional review board-approved registry. Fifty-nine of 68 patients with locally advanced larynx cancer treated with definitive CCRT who had available imaging for review were identified. The main endpoint to be assessed was the association between gross tumor volumes (GTV; T = total, P = primary, N = nodal) and LRF. Receiver operative characteristic (ROC) curves were used to investigate diagnostic accuracy., Results: Twenty LRFs were observed, resulting in a 2-year LRF rate of 39% (95% CI, 23-52%). On UVA, the GTV-T (P = .01), GTV-P (P = .05), and GTV-N (P = .04) were statistically significant predictors of LRF. Furthermore, age, smoking status, N-stage, larynx subsite, and tracheostomy/feeding tube dependence were potentially associated with LRF (P < .3), whereas T-stage (T3-4 vs. T2) was not (HR 1.05, 95% CI, 0.38-2.91, P = .92). In the multivariable model, GTV-P (HR 1.022, 95% CI, 0.999-1.046, P = .07) and GTV-N (HR 1.053, 95% CI, 1.0004-1.108, P = .05) were the two most impactful covariates on the model's R 2 . ROC analysis suggested an optimal cut point of 12 cc in the GTV-T. The 2-year LRF for GTV-T > 12 cc was 64.2% and ≤ 12 cc was 16.4%, P = .006., Conclusion: GTV is associated with LRF after definitive CCRT for LC. Patients with bulky primary and/or nodal tumors may be better served with upfront surgical resection regardless of T-stage. Further investigation into the safety of larynx preservation for low-volume T4 tumors can be considered., Level of Evidence: 4 Laryngoscope, 130:2372-2377, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: We investigated the impact of level I lymph node involvement (LNI) on survival for patients with oropharyngeal squamous cell carcinoma (OPSCC)., Methods: We performed a cohort study of patients with OPSCC who underwent resection with known human papillomavirus (HPV) status in the National Cancer Database (2010-2014)., Results: Among 5591 patients with OPSCC, 599 (10.7%) had level I LNI. Predictors of level I LNI included pT classification (pT3 vs pT1; odds ratio [OR], 1.95; P < 0.001), pN classification (pN3 vs pN1; OR, 1.63; P = 0.05), and level III LNI (OR, 6.05; P < 0.001). Among included patients, 4035 had known survival status. Level I LNI predicted inferior overall survival (OS) while adjusting for covariates (HR, 1.64; P < 0.001). Subset analyses revealed association between level I LNI and inferior OS among patients with base of tongue cancer, pT/pN classification greater than 1, and HPV-negative cancer., Conclusions: Level I LNI predicts inferior OS, particular among patients with at least pT2 or pN2 OPSCC., (© 2019 Wiley Periodicals, Inc.)

Background: To evaluate plan quality using volumetric-modulated arc therapy (VMAT) and step-and-shoot intensity-modulated radiation therapy (SS-IMRT) techniques and for patients treated for oropharyngeal squamous cell carcinoma (OPSCC)., Methods: Treatment plans for patients treated definitively for stages I-IVb, OPSCC between December 2009 and August 2015 were retrospectively reviewed. Dosimetric endpoints of involved organs-at-risk (OARs) were retrieved from clinical plans. Common Terminology Criteria for Adverse Events scores of acute toxicities were compared., Results: Two-hundred twenty-two patients were identified with 134 and 88 receiving SS-IMRT and VMAT with median follow-up time of 23.0 and 7.9 months, respectively. The dosimetric endpoints of the OARs were significantly improved in VMAT cohort, which translated into significantly lower rates of grade 2 or higher acute dysphagia and xerostomia., Conclusion: Improvements in stages I-IVb, oropharyngeal cancer plan quality are associated with reduced grade ≥ 2 acute dysphagia and xerostomia., (© 2019 Wiley Periodicals, Inc.)

Objectives/hypothesis: Patients with human papillomavirus (HPV)-induced cancer of unknown primary (CUP) are generally excluded from clinical trials, despite surgical series reporting detection rates of occult oropharynx primaries of >80%. We performed a matched-pair analysis to compare outcomes between T0N1-3M0 HPV+ CUP and T1-2N1-3M0 HPV+ oropharynx known primary (OPX)., Study Design: Retrospective cohort study at a single institution., Methods: Patients with early T stage, node positive HPV+ OPX or CUP treated with curative intent between 1998 and 2016 were identified. For a subgroup of CUP patients with an unknown HPV status, we imputed HPV status and included patients with a >80% probability of being HPV+. Cohorts were matched based on patient demographics using a nearest neighbor propensity technique. After matching, patients were grouped according to either a favorable or unfavorable risk stratification designations per current NRG Oncology clinical trial enrollment criteria. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier analysis., Results: Of 298 patients with T1-2N1-3 OPX, 48 were matched to 48 HPV+ CUP patients (32 with confirmed and 16 imputed HPV status). Median follow-up for CUP (34.1 months) and OPX (27.8 months) patients were similar (P = .23).There were no significant differences between the CUP and OPX groups for 3-year DFS (89% vs. 85%, P = .44), and 3-year OS (91% vs. 91%, P = .11), respectively., Conclusions: Patients with T0N+M0 HPV-induced CUP have similar survival outcomes to matched patients with T1-2N+M0 HPV+ OPX. These patients can reasonably be included in clinical trials investigating the role of treatment deintensification and risk stratified similar to patients with early-stage known primary OPX cancer., Level of Evidence: 4. Laryngoscope, 128:1379-1385, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC)., Methods: Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively., Results: Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P < .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality (P < .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P = .023)., Conclusions: Tumor progression, measured by clinical-to-pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018;124:1400-14. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Purpose: Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity., Methods and Materials: Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints., Results: From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates., Conclusions: Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups., Patients and Methods: Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40 Gy) who underwent reirradiation with IMRT (≥40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS., Results: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P<.001): class I included patients >2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation., Conclusions: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Two modern methods of reirradiation, intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), are established for patients with recurrent or second primary squamous cell carcinoma of the head and neck (rSCCHN). We performed a retrospective multi-institutional analysis to compare methods., Methods and Materials: Data from patients with unresectable rSCCHN previously irradiated to ≥40 Gy who underwent reirradiation with IMRT or SBRT were collected from 8 institutions. First, the prognostic value of our IMRT-based recursive partitioning analysis (RPA) separating those patients with unresectable tumors with an intertreatment interval >2 years or those with ≤2 years and without feeding tube or tracheostomy dependence (class II) from other patients with unresected tumors (class III) was investigated among SBRT patients. Overall survival (OS) and locoregional failure were then compared between IMRT and SBRT by use of 2 methods to control for baseline differences: Cox regression weighted by the inverse probability of treatment and subset analysis by RPA classification., Results: The study included 414 patients with unresectable rSCCHN: 217 with IMRT and 197 with SBRT. The unadjusted 2-year OS rate was 35.4% for IMRT and 16.3% for SBRT (P<.01). Among SBRT patients, RPA classification retained an independent association with OS. On Cox regression weighted by the inverse probability of treatment, no significant differences in OS or locoregional failure between IMRT and SBRT were demonstrated. Analysis by RPA class showed similar OS between IMRT and SBRT for class III patients. In all class II patients, IMRT was associated with improved OS (P<.001). Further subset analysis demonstrated comparable OS when ≥35 Gy was delivered with SBRT to small tumor volumes. Acute grade ≥4 toxicity was greater in the IMRT group than in the SBRT group (5.1% vs 0.5%, P<.01), with no significant difference in late toxicity., Conclusions: Reirradiation both with SBRT and with IMRT appear relatively safe with favorable toxicity compared with historical studies. Outcomes vary by RPA class, which informs clinical trial design. Survival is poor in class III patients, and alternative strategies are needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To determine the patterns of adjuvant chemoradiotherapy use in elderly patients treated with definitive surgical resection for squamous cell carcinoma of the head and neck with extracapsular extension (ECE) or positive margins and determine whether an association with overall survival (OS) exists with adjuvant concurrent chemoradiotherapy (CRT)., Methods and Materials: The National Cancer Database was queried to identify patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who were treated with primary definitive surgery and adjuvant radiation therapy between 2004 and 2012. For elderly patients (aged >70 years) with pathology revealing ECE or positive margin, the benefit of concurrent chemotherapy was explored using multivariable Cox proportional hazards modeling., Results: A total of 7349 patients were identified meeting study criteria, of whom 1187 were elderly (aged >70 years) with a median follow-up of 30.6 months. Of these elderly patients, 445 had ECE or positive margin and represent the study population, of whom 187 (42%) received CRT. Delivery of CRT in this cohort increased over the study period, and intensity modulated radiation therapy was associated with increased use of CRT (odds ratio 2.07; P=.004). Increasing age was associated with reduced use of CRT (odds ratio 0.88; P<.001). Chemoradiotherapy was associated with a significant improvement in OS on multivariable analysis (hazard ratio 0.74; P=.04) and a trend toward significance on inverse propensity score analysis (hazard ratio 0.78; P=.051). Three-year OS was 53.8% in the CRT group, compared with 44.6% in the adjuvant radiation therapy-alone patients., Conclusions: The use of adjuvant CRT is increasing among elderly patients with resected squamous cell carcinoma of the head and neck exhibiting ECE or positive margins. Chemoradiotherapy was associated with an improvement in OS on multivariable analysis but not propensity-weighted analysis. Among fit elderly patients with ECE or positive margins after definitive surgical resection, concurrent chemotherapy can be carefully considered., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Long term swallowing dysfunction in patients with oropharynx squamous cell carcinoma (OPSCC) treated with concurrent chemoradiation (CRT) is declining. While the use of intensity modulated radiotherapy (IMRT) is commonly believed to be a potential cause, we hypothesize that the increasing incidence of human papillomavirus (HPV) related disease may also favorably impact this outcome., Materials and Methods: We reviewed 130 HPV+ and 17 HPV- patients with stage III-IV OPSCC treated exclusively with conventional 3-field radiotherapy with chemotherapy between 2002 and 2010. The rates of normal diet, limited diet (significant restrictions in the types of foods eaten, and/or requiring nutritional supplementation for weight maintenance) and feeding tube dependence (FTD) were compared between HPV+ and HPV- patients. Cox proportional hazards modeling were used to perform univariate analysis (UVA) to examine predictors of a combined endpoint of dietary limitation, which included limited diet and/or FTD. These outcomes were also compared to our previously reported cohort of OPSCC patients treated between 1989 and 2002 to assess changes in toxicity over time given the changing disease epidemiology, in the setting of identical treatment regimens., Results: With a median follow-up of 55 months, HPV+ patients more frequently had resumed a normal diet (87% vs. 65%) at last follow up and had lower rates of limited diet (9% vs. 18%) and FTD (4% vs. 18%) compared to HPV- patients (p=0.02). HPV status was the only significant predictor of reduced swallowing dysfunction on UVA (HR 0.19; p=0.008). When compared to our 1989-2002 cohort, patients treated between 2002 and 2010 had less FTD (7.5% vs. 34%, p<0.001) and dietary limitations (26% vs.46%, p<0.001) at 6 months post treatment., Conclusions: HPV+ patients with OPSCC have reduced late swallowing dysfunction after chemoradiation compared to HPV- patients. The changing epidemiology of OPSCC may play a role in toxicity reduction in these patients, independent of the increasing use of IMRT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Importance: Important differences exist in the pattern and timing of distant metastases between human papillomavirus-initiated (HPV+) and HPV- oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited., Objective: To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy., Design, Setting, and Participants: In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records., Interventions: All patients were treated with definitive concomitant chemoradiotherapy., Main Outcomes and Measures: The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases., Results: Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV- disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV- disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV- disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV- disease (HPV+ group, 23 of 28 patients [82%]; HPV- group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001)., Conclusions and Relevance: This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV- disease. Human papillomavirus-initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.