Retreatment of Recurrent or Second Primary Head and Neck Cancer After Prior Radiation: Executive Summary of the American Radium Society Appropriate Use Criteria.

Retreatment of recurrent or second primary head and neck cancers occurring in a previously irradiated field is complex. Few guidelines exist to support practice. We performed an updated literature search of peer-reviewed journals in a systematic fashion. Search terms, key questions, and associated clinical case variants were formed by panel consensus. The literature search informed the committee during a blinded vote on the appropriateness of treatment options via the modified Delphi method. The final number of citations retained for review was 274. These informed 5 key questions, which focused on patient selection, adjuvant reirradiation, definitive reirradiation, stereotactic body radiation, and reirradiation to treat nonsquamous cancer. Results of the consensus voting are presented along with discussion of the most current evidence. This provides updated evidence-based recommendations and guidelines for the retreatment of recurrent or second primary cancer of the head and neck.

Nodal Metastasis Count and Oncologic Outcomes in Head and Neck Cancer: A Secondary Analysis of NRG/RTOG 9501, NRG/RTOG 0234, and EORTC 22931.

PURPOSE: A better understanding of the relationship between the spread of head and neck squamous cell carcinoma (HNSCC) to regional lymph nodes (LNs) and the frequency and manner of treatment failure should help design better treatment intensification strategies. In this study, we evaluated the relationship between recurrence patterns, mortality, and number of pathologically positive (+) LNs in HNSCC in 3 prospective randomized controlled trials. METHODS AND MATERIALS: We performed a secondary analysis of 947 patients with HNSCC enrolled in RTOG 9501 (n = 410), RTOG 0234 (n = 203), and EORTC 22931 (n = 334) undergoing surgery and postoperative radiation ± systemic therapy. Multivariable models were constructed for overall survival (OS), disease-free survival (DFS), locoregional relapse (LRR), and distant metastases (DM). Restricted cubic splines were used to model the nonlinear relationship between +LN number and outcomes. RESULTS: In multivariable analysis, OS and DFS decreased with each +LN without plateau, most pronounced up to 5 +LNs (OS: hazard ratio [HR], 1.21 per +LN; 95% confidence interval [CI], 1.10-1.34; P < .001; DFS: HR per +LN, 1.19; 95% CI, 1.08-1.30; P < .001) and more gradually beyond this (OS: HR per +LN, 1.02; 95% CI, 1.01-1.06; P < .001; DFS: HR per +LN, 1.04; 95% CI, 1.02-1.06; P < .001). In contrast to LRR risk, which increased sharply up to 5 +LNs (HR per +LN, 1.28; 95% CI, 1.10-1.50; P < .001) but plateaued beyond this (HR per +LN, 1.00; 95% CI, 0.96-1.04; P = .98), DM risk increased continuously with increasing +LNs (≤5 +LNs: HR per +LN, 1.10; 95% CI, 1.01-1.20; P = .04; >5 +LNs: HR per +LN, 1.05; 95% CI, 1.02-1.08; P = .003). CONCLUSIONS: In high-risk resected HNSCC, increased mortality was associated with increased +LN count. LRR and DM risk both increased in parallel up to 5 +LNs, but only DM continued to increase for further +LN increases. These differing recurrence patterns can help inform design of future treatments.

Systematic review of postoperative therapy for resected squamous cell carcinoma of the head and neck: Executive summary of the American Radium Society appropriate use criteria.

BACKGROUND: The aims of this systematic review are to (a) evaluate the current literature on the impact of postoperative therapy for resected squamous cell carcinoma of the head and neck (SCCHN) on oncologic and non-oncologic outcomes and (b) identify the optimal evidence-based postoperative therapy recommendations for commonly encountered clinical scenarios. METHODS: An analysis of the medical literature from peer-reviewed journals was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Prospective studies and methodology-based systematic reviews and meta-analyses of postoperative therapy for SCCHN were identified by searching Medline (OVID) and EMBASE (Elsevier) using controlled vocabulary terms (ie, National Library of Medicine Medical Subject Headings [MeSH], EMTREE). Study screening and selection was performed with Covidence software and full-text review. The RAND/UCLA appropriateness method was used by the expert panel to rate the appropriate use of postoperative therapy, and the modified Delphi method was used to come to consensus. RESULTS: A total of 5660 studies were identified and screened using the title and abstract, leading to 201 studies assessed for relevance using full-text review. After limitation to the eligibility criteria, 101 studies from 1977 to 2020 were identified, including 77 with oncologic endpoints and 24 with function and quality of life endpoints. All studies reported staging prior to the implementation of American Joint Committee on Cancer (AJCC-8). CONCLUSIONS: Prospective clinical studies and systematic reviews identified through the PRISMA systematic review provided good evidence for consensus statements regarding the appropriate use of postoperative therapy for resected SCCHN. Further research is needed in domains where consensus by the expert panel could not be achieved for the appropriateness of specific postoperative therapeutic interventions.

ACR appropriateness criteria® nasal cavity and paranasal sinus cancers.

The American College of Radiology (ACR) Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Here, we present the Appropriateness Criteria for cancers arising in the nasal cavity and paranasal sinuses (maxillary, sphenoid, and ethmoid sinuses). This includes clinical presentation, prognostic factors, principles of management, and treatment outcomes. Controversies regarding management of cervical lymph nodes are discussed. Rare and unusual nasal cavity cancers, such as esthesioneuroblastoma and sinonasal undifferentiated carcinomas, are included. © 2016 American College of Radiology. Head Neck, 2016 © 2016 Wiley Periodicals, Inc. Head Neck 39: 407-418, 2017.

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

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.

ACR Appropriateness Criteria(®) Locoregional therapy for resectable oropharyngeal squamous cell carcinomas.

BACKGROUND: There are no level I studies to guide treatment for resectable oropharyngeal squamous cell carcinoma (SCC). Treatment toxicities influence management recommendations. Ongoing investigations are examining deintensified treatments for human papillomavirus (HPV)-associated oropharyngeal SCC. METHODS: The Appropriateness Criteria panel, using modified Delphi methodology, produced a literature summary, an assessment of treatment recommendations, and cases to illustrate their use. RESULTS: A multidisciplinary team produces optimum results. Based on HPV status, smoking history, and staging, patients are divided into groups at low, intermediate, and high-risk of death. In the future, treatment recommendations may be influenced by HPV status, which has changed the epidemiology of oropharyngeal SCC. CONCLUSION: T1 to T2N0M0 resectable oropharyngeal SCC can be treated with surgery or radiation without chemotherapy. Patients with T1-2N1-2aM0 disease can receive radiation, chemoradiation, or transoral surgery with neck dissection and appropriate adjuvant therapy. Patients with T1-2N2b-3M0 disease should receive chemoradiation or transoral surgery with neck dissection and appropriate adjuvant therapy. Concurrent chemoradiation is preferred for T3 to T4 disease. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1299-1309, 2016.

ACR Appropriateness criteria® for nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) presents mostly with locally advanced disease and is treated with multimodal therapy; however, consensus is lacking for different clinical scenarios. METHODS: The American College of Radiology (ACR) Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: The ACR Expert Panel on Radiation Oncology - Head and Neck Cancer developed consensus recommendations for guiding management of nasopharyngeal carcinoma. CONCLUSION: Multidisciplinary evaluation is essential to guiding the optimal use of surgery, radiation, and systemic therapy in this disease. © 2015 Wiley Periodicals, Inc. Head Neck 38: 979-986, 2016.

ACR Appropriateness Criteria(®) Aggressive Nonmelanomatous Skin Cancer of the Head and Neck.

BACKGROUND: Aggressive nonmelanomatous skin cancer (NMSC) of the head and neck presents an increasingly common therapeutic challenge for which prospective clinical trials are lacking. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: The American College of Radiology Expert Panel on Radiation Oncology - Head and Neck Cancer developed consensus recommendations for guiding management of aggressive NMSC. CONCLUSION: Multidisciplinary assessment is vital to guiding the ideal use of surgery, radiation, and systemic therapy in this disease.

A Unique Case of Classic Kaposi's sarcoma restricted to the toes.

BACKGROUND: Kaposi's sarcoma associated-herpesvirus causes all forms of Kaposi's sarcoma, and six major subtypes have been described based on the amino acid sequences of the open reading frame K1. MAIN OBSERVATION: A 71-year-old man from China, HIV negative, presented with nodules on the dorsal aspect of his toes. Biopsy confirmed the diagnosis of Kaposi's sarcoma and virology studies of his blood and saliva confirmed the presence of Kaposi's sarcoma associated-herpesvirus infection. Viral genotyping was consistent with subtype C3. Intervention has been deferred as our patient has remained clinically asymptomatic and without evident growth of his lesions over a 2-year follow up. CONCLUSIONS: We herein report the first known case of Kaposi's sarcoma restricted to the toes caused by the viral subtype C3 in an HIV-negative patient from Harbin, China.

Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer.

PURPOSE: To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation. PATIENTS AND METHODS: Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point. RESULTS: Five hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone). CONCLUSION: These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.

Hypopharyngeal dose is associated with severe late toxicity in locally advanced head-and-neck cancer: an RTOG analysis.

PURPOSE: Concurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity. METHODS AND MATERIALS: This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube≥2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors. RESULTS: A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P=.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P=.016). The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome. CONCLUSIONS: Severe late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.

Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck.

PURPOSE: Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months, the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head-and-neck carcinomas. With a minimum of 10 years of follow-up potentially now available for all patients, these results are updated here to examine long-term outcomes. METHODS AND MATERIALS: A total of 410 analyzable patients who had high-risk resected head-and-neck cancers were prospectively randomized to receive either radiation therapy (RT: 60 Gy in 6 weeks) or identical RT plus cisplatin, 100 mg/m(2)i.v. on days 1, 22, and 43 (RT + CT). RESULTS: At 10 years, the local-regional failure rates were 28.8% vs 22.3% (P=.10), disease-free survival was 19.1% vs 20.1% (P=.25), and overall survival was 27.0% vs 29.1% (P=.31) for patients treated by RT vs RT + CT, respectively. In the unplanned subset analysis limited to patients who had microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% vs 21.0% (P=.02), disease-free survival was 12.3% vs 18.4% (P=.05), and overall survival was 19.6% vs 27.1% (P=.07), respectively. CONCLUSION: At a median follow-up of 9.4 years for surviving patients, no significant differences in outcome were observed in the analysis of all randomized eligible patients. However, analysis of the subgroup of patients who had either microscopically involved resection margins and/or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy. The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT.

Immunogenicity of an inactivated monovalent 2009 influenza A (H1N1) vaccine in patients who have cancer.

BACKGROUND: The immune response of patients who have cancer, who may be receiving immunosuppressive therapy, is generally considered to be decreased. This study aimed to evaluate the immune response of cancer patients to the 2009 influenza A (H1N1) vaccine. PATIENTS AND METHODS: We conducted a prospective single site study comparing the immune response after H1N1 vaccination of healthy controls (group A), patients who had solid tumors and were taking myelosuppressive chemotherapy (group B), patients who had solid tumors and were taking nonmyelosuppressive or no treatment (group C), and patients who had hematologic malignancies (group D). RESULTS: At 2-6 weeks after vaccination, seroconversion was observed in 80.0% of group A (95% confidence interval [CI], 65.0%-89.7%), 72.2% of group B (95% CI, 55.9%-84.3%), 87.0% of group C (95% CI, 72.2%-94.7%), and 75.0% of group D (95% CI, 52.8%-89.2%) (p = NS). The geometric mean titer ratio, that is, geometric mean factor increase in antibody titer after vaccination, was 12.6 (95% CI, 7.9-19.9), 12.7 (95% CI, 7.3-22.1), 23.0 (95% CI, 13.9-38.2), and 12.1 (95% CI, 5.3-27.9) (p = NS), and the seroprotection rates were 95.5% (95% CI, 84.0%-99.6%), 79.0% (95% CI, 63.4%-89.2%), 90.5% (95% CI, 77.4%-96.8%), and 90.0% (95% CI, 71%-98.7%) in the corresponding groups (p = NS). Immune responses were robust regardless of malignancy, or time intervals between the use of myelosuppressive or immunosuppressive medications and vaccination. No participants developed clinical H1N1 infection. CONCLUSION: Cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls.

Glioma-associated oncogene family zinc finger 1 expression and metastasis in patients with head and neck squamous cell carcinoma treated with radiation therapy (RTOG 9003).

PURPOSE: Glioma-associated oncogene family zinc finger 1 (GLI1) expression was assessed to determine a potential role of hedgehog (Hh) signaling in head and neck squamous cell carcinoma (HNSCC). Additional proteins known to be modulated by Hh signaling, including beta-catenin (CTNNB1) and epidermal growth factor receptor (EGFR), were also assessed to determine the correlation among these distinct signaling pathways. PATIENTS AND METHODS: Nuclear GLI1 and CTNNB1 expression levels were determined in tumors from patients enrolled on Radiation Therapy Oncology Group (RTOG) 9003, a radiation fractionation trial. The results were also correlated with previously determined EGFR expression. The expression levels were evaluated in relation to three end points: time to metastasis (TTM), time to disease progression (TDP), and overall survival (OS). RESULTS: Among 1,068 eligible patients, data on GLI1, CTNNB1, and EGFR were available in 339, 164, and 300 patients, respectively. Although CTNNB1 expression did not differentiate prognosis, GLI1 was associated with poorer outcomes, adjusted for age, TNM stages, and Karnofsky performance score, and the significant influence persisted in a multivariable analysis (quartile 4 [Q4] v Q1 to Q3: TTM hazard ratio [HR], 2.7; 95% CI, 1.5 to 4.9; TDP HR, 1.6; 95% CI, 1.1 to 2.5; OS HR, 1.9; 95% CI, 1.4 to 2.7). The significance of GLI1 persisted in a multivariable analysis that included EGFR expression levels. CONCLUSION: These data suggest that Hh signaling may play an important role in metastasis and that GLI1 could serve as a marker in HNSCC, but the regulatory mechanisms and oncogenic significance need further investigation. Risk classification based on this analysis needs a validation in independent cohorts.

National Cancer Database report on cancer of the head and neck: 10-year update.

BACKGROUND: We sought to examine the current state of cancer care for head and neck tumors in the United States. We therefore performed a retrospective, longitudinal study of the approximately 822,000 head and neck cancer cases included in the National Cancer Data Base (NCDB) for 1990 through 2004, representing approximately 75% of the estimated incident diagnoses in the United States. METHODS: All cases of head and neck cancer diagnosed and reported to the NCDB during this interval were reviewed, and descriptive statistics, grouped by disease and host factors, were analyzed over time and compared with a prior similar analysis done 10 years ago. RESULTS: Although many similarities persist, several major changes in head and neck cancer have occurred, most notably (1) a decrease in the number of the older-aged patients who have mucosally derived squamous cell carcinomas coupled with an increase in the number of younger-aged patients who have thyroid-origin adenocarcinomas and (2) a decrease in the use of radiation therapy alone for treatment in favor of chemotherapy enhanced radiation therapy. CONCLUSION: Head and neck cancers include a heterogeneous group of tumors whose precise composition changes over time and whose therapy evolves as well. The NCDB is well suited to capture this information and provide both an analysis of the current state of cancer care for head and neck tumors and a longitudinal view over time.

Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis.

PURPOSE: Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT. METHODS: Patients were analyzed from a subset of three previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3 to 4 pharyngeal/laryngeal toxicity (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity scoring system) and/or requirement for a feeding tube >or= 2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pretreatment and treatment potential factors. RESULTS: A total of 230 patients were assessable for this analysis: 99 patients with severe late toxicities and 131 controls; thus, 43% of assessable patients had a severe late toxicity. On multivariable analysis, significant variables correlated with the development of severe late toxicity were older age (odds ratio 1.05 per year; P = .001); advanced T stage (odds ratio, 3.07; P = .0036); larynx/hypopharynx primary site (odds ratio, 4.17; P = .0041); and neck dissection after CRT (odds ratio, 2.39; P = .018). CONCLUSION: Severe late toxicity after CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was associated with an increased risk of these complications.