Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Benefits versus drawbacks of delaying surgery due to additional consultations in older patients with breast cancer.

BACKGROUND: Additional evaluations, including second opinions, before breast cancer surgery may improve care, but may cause detrimental treatment delays that could allow disease progression. AIMS: We investigate the timing of surgical delays that are associated with survival benefits conferred by preoperative encounters versus the timing that are associated with potential harm. METHODS AND RESULTS: We investigated survival outcomes of SEER Medicare patients with stage 1-3 breast cancer using propensity score-based weighting. We examined interactions between the number of preoperative evaluation components and time from biopsy to definitive surgery. Components include new patient visits, unique surgeons, medical oncologists, or radiation oncologists consulted, established patient encounters, biopsies, and imaging studies. We identified 116 050 cases of whom 99% were female and had an average age of 75.0 (SD = 6.2). We found that new patient visits have a protective association with respect to breast cancer mortality if they occur quickly after diagnosis with breast cancer mortality subdistribution Hazard Ratios [sHRs] = 0.87 (95% Confidence Interval [CI] 0.76-1.00) for 2, 0.71 (CI 0.55-0.92) for 3, and 0.63 (CI 0.37-1.07) for 4+ visits at minimal delay. New patient visits predict worsened mortality compared with no visits if the surgical delay is greater than 33 days (CI 14-53) for 2, 33 days (CI 17-49) for 3, and 44 days (CI 12-75) for 4+. Medical oncologist visits predict worse outcomes if the surgical delay is greater than 29 days (CI 20-39) for 1 and 38 days (CI 12-65) for 2+ visits. Similarly, surgeon encounters switch from a positive to a negative association if the surgical delay exceeds 29 days (CI 17-41) for 1 visit, but the positive estimate persists over time for 3+ surgeon visits. CONCLUSION: Preoperative visits that cause substantial delays may be associated with increased mortality in older patients with breast cancer.

Imaging and Biomarker Surveillance for Head and Neck Squamous Cell Carcinoma: A Systematic Review and AUC Document.

Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers.

Osteoradionecrosis rate in oropharynx cancer treated with dose volume histogram based constraints.

OBJECTIVES: Mandibular dose constraints are designed to limit high dose to small volumes to avoid osteoradionecrosis (ORN). Based upon a published experience, intermediate-dose constraints were introduced but have not been independently validated. We hypothesize that these constraints lower ORN rate without compromising other organs at risk (OAR). METHODS: Oropharyngeal cancer patients treated with standard fractionation adjuvant/definitive VMAT from 01/2014-08/2020 were included. In 09/2017, mandibular dose constraint was changed from historical constraint (HC) of D 0.1 cc < 70 Gy to modified constraints (MC) of V 44 Gy < 42%, V 58 Gy < 25%, D 0.5 cc < 70 Gy. OAR dosimetric changes and ORN development were evaluated. Regression modelling predicted long-term ORN cases in MC group. RESULTS: There were 174 patients, 71 in MC group. Seven cases of ORN in HC group at a median follow up (FU) of 39 months and 1 case of ORN in MC group at a median FU of 11 months were observed. More patients in the MC group met V 44 Gy (87% vs 62%, p < 0.01) and V 58 Gy constraints (92% vs 73%, p < 0.01). Mean doses to OARs did not rise. Mandible V 44 Gy and V 58 Gy were significantly associated with ORN (p < 0.01 and p = 0.03, respectively) across all patients. In the HC group, V 44 Gy was independently associated with ORN (p = 0.01). To account for shorter FU in MC group, logistic regression of ORN based on V 44 Gy in HC patients was performed. This predicts 3.2 ORN cases in the MC group (95% CI: 0.00-6.4). CONCLUSION: Achieving V 44 Gy and V 58 Gy was successful in 87% of cases without sacrificing target coverage or OARs and resulted in non-significant ORN decrease.

Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.

Assessing plasma circulating tumor human papillomavirus (HPV) DNA in determining treatment response in HPV-associated oropharyngeal cancer.

BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma is a subset of head and neck cancer with a unique mechanism of carcinogenesis. Local disease is treated definitively with a multimodal approach. Navigating recurrences can be challenging, as they are sometimes indiscernible from de novo primary malignancies. Identification of dynamic biomarkers that are specific to HPV-mediated disease may assist in disease monitoring. We present a 78-year-old man who developed a squamous cell carcinoma in the lung 7 years after completing definitive chemoradiation for his p16+ head and neck squamous cell carcinoma. METHODS: A novel assay for plasma circulating tumor HPV DNA was employed and provided a tool for longitudinal disease monitoring during therapy. CONCLUSION: We bring attention to a novel assay and highlight its potential for use in the treatment paradigm of HPV-mediated oropharyngeal carcinoma.

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.

NCCN Guidelines® Insights: Head and Neck Cancers, Version 1.2022.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis.

OPINION STATEMENT: Oral mucositis (OM) causes significant detriment to patient quality of life. Despite advances in RT, chemotherapy, and surgery for HNC which have led to improved local control and survival, management of certain toxicities such as OM have not kept pace. Numerous strategies have emerged with demonstrable benefit in preventing severe OM. However, ones which are not only effective, but practical and affordable to implement are rare. For example, infusion of growth factors or free radical scavengers, and daily treatment of intra-oral sites with lasers are supported by high-quality evidence but have not become widely adopted. It falls to familiarity of the physician with the available preventative measures and ultimately, patient preference in accepting which strategies for OM amelioration are used. In this review, we present a pathophysiological-based review of prevention techniques available for reducing the incidence and duration of severe OM.

The impact of positive margin on survival in oral cavity squamous cell carcinoma.

BACKGROUND: Positive margins are known to impact survival in oral cavity squamous cell carcinoma (OCSCC). We aimed to determine the impact of positive margins on survival and whether radiation improves survival following positive margins. METHODS: Data was obtained from the National Cancer Database and included patients with cT1T2N0 OCSCC. Survival outcomes were assessed via log-rank test. Cox-regression analysis was performed to determine if positive margins or radiation, when applicable, correlated with survival after accounting for covariates. RESULTS: Positive margin patients had worse overall survival compared to negative margin control (HR = 1.76, p < 0.001) and reduced survival by 13%. On multivariate analysis, positive margins correlated with survival (HR = 1.60, p < 0.001). Radiation did not improve survival in positive margin patients (HR = 0.99, p = 0.55). CONCLUSIONS: Patients with positive margins have an 11-15% worse overall survival. Radiation does not appear to impact survival in patients with a positive margin.

Radiation Treatment Deintensification for HPV-Associated Oropharyngeal Cancer.

Human papillomavirus-associated oropharyngeal cancer (HPV-OPC) is a distinct clinical entity with a favorable prognosis compared with non-HPV-OPC. Surgery and radiotherapy (RT) result in adverse effects, and negative quality of life or functional outcomes, which impact a significant proportion of HPV-OPC survivors. Ongoing studies aim to reduce these negative treatment effects while maintaining high cure rates through deintensified therapy typically use either a primary surgical or RT approach. A single-day curative surgery will remain relevant for many patients with early-stage disease. However, the average patient with HPV-OPC will have indications for adjuvant therapy. A primary RT approach to deintensified therapy has more available data from patients on prospective multi-institutional trials, provides broader patient selection, and may be more cost-effective. Anticipated results from an active phase II/III NCTN trial will help guide the standard of care using primary RT. Next generation trials will help further refine patient selection and/or radical deintensification (30-50 Gy).

Prognostic significance of human papillomavirus status and treatment modality in hypopharyngeal cancer.

BACKGROUND: Management of hypopharynx cancer is often extrapolated from larynx cancer. This report analyses treatment patterns and survival limited to hypopharynx cancer using the National Cancer Database (NCDB). METHODS: There are 9314 patients diagnosed with hypopharynx cancer between 2004 and 2016. The association between treatment modality and survival was analyzed using Kaplan-Meier survival curves and multivariable Cox regression. RESULTS: Five-year overall survival ranged from 45% for stage I to 21% for stage IVB. Treatment modality did not influence survival in stage I/II. For stage III/IV, chemoradiation and surgery + adjuvant therapy were equivalent. Surgery yielded improved survival for T4 disease. Human papillomavirus (HPV)-positive tumors were present in 21% and were associated with improved hazard ratio of death (0.60, p = <0.0001). CONCLUSIONS: Survival is superior for T4 hypopharynx cancer managed with surgery, while treatment modality does not impact outcomes for other T-stages. HPV-positive tumors are associated with improved survival regardless of treatment.

A Pilot Study of a Collaborative Palliative and Oncology Care Intervention for Patients with Head and Neck Cancer.

Background: Palliative care improves symptoms and coping in patients with advanced cancers, but has not been evaluated for patients with curable solid malignancies. Because of the tremendous symptom burden and high rates of psychological distress in head and neck cancer (HNC), we evaluated feasibility and acceptability of a palliative care intervention in patients with HNC receiving curative-intent chemoradiation therapy (CRT). Methods: This was a prospective single-arm study in HNC patients receiving CRT at a single center in the United States. The intervention entailed weekly palliative care visits integrated with oncology care with a focus on symptoms and coping. The primary outcome was feasibility, defined as a >50% enrollment rate with >70% of patients attending at least half of the visits. To assess acceptability, we collected satisfaction ratings post-intervention. We also explored symptom burden, mood, and quality of life (QOL). Results: We enrolled 91% (20/22) of eligible patients. Patients attended 133 of 138 palliative care visits (96%); all 20 attended >85% of visits. Eighteen of 19 (95%) found the intervention "very helpful" and would "definitely recommend" it. QOL and symptom burden worsened from baseline to week 5, but subsequently improved at one-month post-CRT. Overall, patients valued the one-on-one format of the intervention and receipt of additional care. Conclusions: Our palliative care intervention during highly morbid CRT was feasible and acceptable with high enrollment, excellent intervention compliance, and high patient satisfaction. Future randomized studies will further explore the impact on patient-reported outcomes and health care utilization.

The hidden curve behind COVID-19 outbreak: the impact of delay in treatment initiation in cancer patients and how to mitigate the additional risk of dying-the head and neck cancer model.

PURPOSE: The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time-to-treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model. METHODS: An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data. RESULTS: The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time-to-treatment initiation. CONCLUSIONS: This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model.

Identification and management of late dysfunction in survivors of head and neck cancer: Implementation and outcomes of an interdisciplinary quality of life (IQOL) clinic.

BACKGROUND: Identifying and treating late dysfunction in survivors of head and neck cancer (HNC) is important; however, an effective way to do so is not established. METHODS: A quality improvement initiative altering our HNC survivorship clinic to include surveillance by rehabilitation providers was undertaken. The nature of dysfunction identified, along with the number and type of referrals to ancillary/support services were collected and compared to baseline. RESULTS: The baseline, single-provider, clinic evaluated 61 patients and referred 2 (3%) to ancillary/support services. Fifty-seven patients were evaluated in the interdisciplinary clinic, with 36 (63%) referred to at least one ancillary/support service for new/progressive dysfunction. Of 59 referrals made, 22 (37%) were for dysphagia, 17(29%) were for neck/shoulder dysfunction, and 28 (47%) were attended by the patient. CONCLUSION: Many HNC survivors exhibit late dysfunction appropriate for referral to ancillary/support services. A survivorship clinic including surveillance by rehabilitation specialists may optimize identification of dysfunction.

Ipsilateral radiation for squamous cell carcinoma of the tonsil: American Radium Society appropriate use criteria executive summary.

BACKGROUND: We conducted the current systemic review to provide up-to-date literature summary and optimal evidence-based recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil. METHODS: We performed literature search of peer-reviewed journals through PubMed. The search strategy and subject-specific keywords were developed based on the expert panel's consensus. Articles published from January 2000 to May 2020 with full text available on PubMed and restricted to the English language and human subjects were included. Several prespecified search terms were used to identify relevant publications and additional evidence published since the initial American College of Radiology Appropriateness Criteria Ipsilateral Tonsil Radiation recommendation was finalized in 2012. The full bibliographies of identified articles were reviewed and irrelevant studies were removed. RESULTS: The initial search and review returned 46 citations. The authors added three citations from bibliographies, websites, or books not found in the literature search. Of the 49 citations, 30 citations were retained for further detailed review, and 14 of them were added to the evidence table. Articles were removed from the bibliography if they were not relevant or generalizable to the topic, or focused on unknown primary disease. Several commonly encountered clinical case variants were created and panelists anonymously rated each treatment recommendation. The results were reviewed and disagreements discussed. CONCLUSIONS: The panel provided updated evidence and recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil in the setting of primary radiation-based therapy and postoperative adjuvant radiotherapy. This committee did not reach agreements for some case variants due to a lack of strong evidence supporting specific treatment decisions, indicating a further need for research in these topics.