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.

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.

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.

Rapid recurrence in head and neck cancer: Underappreciated problem with poor outcome.

BACKGROUND: Rapid recurrence, defined as gross tumor recurrence after primary operation but prior to initiating postoperative radiation therapy (PORT), is underappreciated in head and neck cancer (HNC). METHODS: CT simulation images in patients with HNC managed surgically with adjuvant therapy at a single center between 2010 and 2017 were retrospectively reviewed. RESULTS: A total of 194 patients with HNC were included. Rapid recurrence occurred in 39 patients (20%) with a median time from operation to CT simulation of 37 days. On multivariable analysis (MVA), extranodal extension (ENE) was the only predictor of rapid recurrence (P = .03). While rapid recurrence, ENE, and perineural invasion were all associated with poor overall survival (OS) on MVA, rapid recurrence was the strongest predictor (hazard ratio [HR] 5.47). CONCLUSION: Rapid recurrence occurs at an underappreciated rate and is associated with poor survival outcomes. Patients with ENE are at highest risk and may benefit from diagnostic imaging evaluations immediately prior to PORT.

Effect of Sentinel Lymph Node Biopsy and LVI on Merkel Cell Carcinoma Prognosis and Treatment.

OBJECTIVE: Prognostic factors and optimal treatment approaches for Merkel cell carcinoma (MCC) remain uncertain. This study evaluated the influences of sentinel lymph node (SLN) biopsy and lymphovascular invasion (LVI) on treatment planning and prognosis. STUDY DESIGN: Retrospective cohort study. METHODS: Stage 1 to 3 MCC patients treated 2005 to 2018. Predictors of nodal radiation were tested using logistic regression. Predictors of recurrence-free, disease-specific, and overall survival were tested in Cox proportional hazard models. RESULTS: Of 122 patients, 99 were without clinically apparent nodal metastases. Of these, 76 (77%) underwent excision and SLN biopsy; 29% had metastasis in SLNs, including 20% of MCCs 1 cm or less. Primary tumor diameter, site, patient age, gender, and immunosuppressed status were not significantly associated with an involved SLN. Among patients who underwent SLN biopsy, 13 of 21 (62%) MCCs with LVI had cancer in SLNs compared with 14 of 44 (25.5%) without LVI (P = .003). Although local radiation was common, nodal radiation was infrequently employed in SLN negative (pathologic N0) patients (21.8% vs. 76.2% for patients with SLN metastases, P = .0001). Survival of patients with positive SLNs was unfavorable, regardless of completion lymphadenectomy and/or adjuvant radiation. After accounting for tumor (T) and node (N) classification, age, immunosuppression, and primary site, a positive SLN and LVI were independently associated with worse survival (LVI/recurrence-free survival [RFS]: hazard ratio [HR] 2.3 (1.04-5, P = .04; LVI/disease-specific survival [DSS]: HR 5.2 (1.8-15, P = .007); N1a vs. pN0/RFS HR 3.6 (1.42-9.3, P = .007); DSS HR5.0 (1.3-19, P = .17). CONCLUSION: SLN biopsy assists in risk stratification and radiation treatment planning in MCC. LVI and disease in SLNs, independently associated with worse survival, constitute markers of high-risk disease warranting consideration for investigational studies. LEVEL OF EVIDENCE: III Laryngoscope, 131:E828-E835, 2021.

Patterns of Multidisciplinary Care of Head and Neck Squamous Cell Carcinoma in Medicare Patients.

Importance: Multidisciplinary care (MDC) yields proven benefits for patients with cancer, although it may be underused in the complex management of head and neck squamous cell carcinoma (HNSCC). Objective: To characterize the patterns of MDC in the treatment of HNSCC among elderly patients in the US. Design, Setting, and Participants: This nationwide, population-based, retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from January 1, 1991, to December 31, 2011, to identify patients 66 years or older diagnosed with head and neck cancer and determine the dates of diagnosis, oncology consultations, treatment initiation, and speech therapy evaluation in addition to MDC completion. Multidisciplinary care was defined in a stage-dependent manner: localized disease necessitated consultations with radiation and surgical oncologists, and advanced-stage disease also included a medical oncology consultation, all before definitive treatment. Data were analyzed between December 2016 and September 2020. Main Outcomes and Measures: Rates of MDC across all subsites of head and neck cancer as measured by the presence of an evaluation for each oncologist on the MDC team and its effect on treatment initiation. Results: This cohort study assessed 28 293 patients with HNSCC (mean [SD] age, 75.1 [6.6] years; 67% male; 87% White) from the SEER-Medicare linked database. The HNSCC subsites included larynx (40%), oral cavity (30%), oropharynx (21%), hypopharynx (7%), and nasopharynx (2%). Overall, the practice of MDC significantly increased over time, from 24% in 1991 to 52% in 2011 (P < .001). For patients with localized (stage 0-II) tumors, 60% received care in the multidisciplinary setting, whereas 28% of those with advanced-stage disease did. A total of 18 181 patients (64%) were treated with initial definitive nonsurgical therapy across all stages. Regardless of stage and subsite, few patients (2%) underwent evaluation by a speech-language pathologist before definitive therapy. Multidisciplinary care prolonged the time to initiation of definitive treatment by 11 days for localized disease and 10 days for advanced disease. Conclusions and Relevance: This cohort study found that most elderly patients with localized HNSCC received MDC, whereas few patients with advanced-stage disease received such care, although a significant proportion received adjuvant therapy. Multidisciplinary care may prolong time to initiation of definitive treatment with an uncertain impact. Consultation with a speech-language pathologist before definitive therapy was rare.