Air pollution is associated with increased incidence-rate of head and neck cancers: A nationally representative ecological study.

INTRODUCTION: Early studies show conflicting findings regarding particulate matter ≤ 2.5 µm in diameter (PM2.5) exposure and development of head and neck cancers (HNC). We analyzed the relationship between PM2.5 exposure and various types of HNC in a nationally representative ecological sample. METHODS: We determined HNC incidence in 608 US counties from 2011 to 2019 using the Surveillance, Epidemiology and End Results (SEER) Program from the National Cancer Institute. We also collected information on sociodemographic factors from SEER and data on smoking and alcohol intake from CDC data frames (county level). PM2.5 exposure levels were estimated using satellite and meteorological data via previously validated general additive models. Flexible semi-nonparametric regression models were used to test the relationship between PM2.5 exposure levels and HNC incidence, adjusting for demographics, socioeconomic factors, and comorbidity. RESULTS: Increased PM2.5 exposure levels were associated with higher incidence-rates of oral cavity and pharyngeal cancers controlling for confounders in our primary analyses (IRR = 1.04, 95 % CI 1.01, 1.07, p = 0.02 per 1 µg/m3 increase in PM2.5). This relationship was maintained after adjusting for multiple testing (Holm s method, p = 0.04) and in ordinary least squares (OLS) regression (ß = 0.17, 95 % CI 0.01, 0.57, p = 0.01). Increased exposure was also associated with other HNC: esophagus (IRR = 1.06, 95 % CI 1.01, 1.11, p = 0.02), lip (IRR = 1.16, 95 % CI 1.03, 1.31, p = 0.01), tonsil (IRR = 1.10, 95 % CI 1.03, 1.16, p < 0.01). However, these relationships were not maintained in secondary analyses. CONCLUSIONS: This nationally representative ecological study shows that increased levels of air pollution are associated with increased incidence of overall oral cavity and pharyngeal cancers in the US.

The First Cold Atmospheric Plasma Phase I Clinical Trial for the Treatment of Advanced Solid Tumors: A Novel Treatment Arm for Cancer.

Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors despite advancements in cancer therapies. Canady Helios Cold Plasma (CHCP) is a novel Cold Atmospheric Plasma device that generates an Electromagnetic Field and Reactive Oxygen and Nitrogen Species to induce cancer cell death. In the first FDA-approved Phase I trial (March 2020-April 2021), 20 patients with stage IV or recurrent solid tumors underwent surgical resection combined with intra-operative CHCP treatment. Safety was the primary endpoint; secondary endpoints were non-LRR, survival, cancer cell death, and the preservation of surrounding healthy tissue. CHCP did not impact intraoperative physiological data (p > 0.05) or cause any related adverse events. Overall response rates at 26 months for R0 and R0 with microscopic positive margin (R0-MPM) patients were 69% (95% CI, 19-40%) and 100% (95% CI, 100-100.0%), respectively. Survival rates for R0 (n = 7), R0-MPM (n = 5), R1 (n = 6), and R2 (n = 2) patients at 28 months were 86%, 40%, 67%, and 0%, respectively. The cumulative overall survival rate was 24% at 31 months (n = 20, 95% CI, 5.3-100.0). CHCP treatment combined with surgery is safe, selective towards cancer, and demonstrates exceptional LRR control in R0 and R0-MPM patients. (Clinical Trials identifier: NCT04267575).

Prior chemoradiotherapy adversely impacts outcomes of recurrent and second primary head and neck cancer treated with concurrent chemotherapy and reirradiation.

BACKGROUND: It has been shown that concomitant chemotherapy (C) with reirradiation (ReRT) is feasible and effective for select patients with recurrent or second primary head and neck cancer (HNC). To examine potential prognostic factors associated with survival, the authors of this report retrospectively reviewed the outcomes of patients who received CReRT. METHODS: The study cohort comprised previously irradiated patients with nonmetastatic disease from 9 consecutive phase 1 and 2 protocols for poor-prognosis HNC. For all patients, reirradiation (ReRT) was delivered with concurrent chemotherapy. Chemotherapy generally was 5-fluorouracil, hydroxyurea, and a third agent. RESULTS: One hundred sixty-six patients were identified, including 81 patients who underwent surgical resection or debulking before enrollment. The median ReRT dose was 66 gray. After a median follow-up of 53 months among surviving patients, the median overall survival (OS) was 10.3 months. The 2-year rates for OS, disease-free survival, locoregional control, and freedom from distant metastasis were 24.8%, 19.9%, 50.7%, and 61.4%, respectively. Thirty-three patients (19.9%) died of treatment-related toxicity. In subgroup analysis, survival was significantly reduced in patients who received previous concurrent chemoradiotherapy (CRT) compared with patients who were naive to CRT (2-year OS rate, 10.8% vs 28.4%; P = .0043). In multivariable analysis, prior CRT was associated independently with OS along with surgery before protocol treatment, full-dose ReRT, and radiotherapy interval. CONCLUSIONS: CReRT achieved a long-term cure for a small group of patients with recurrent or second primary HNC. Previous treatment with CRT was among the important prognostic factors for survival. Because of the associated risk of severe toxicity, CReRT should be limited only to carefully selected patients.

Clinical Practice Guideline: Opioid Prescribing for Analgesia After Common Otolaryngology Operations.

OBJECTIVE: Opioid use disorder (OUD), which includes the morbidity of dependence and mortality of overdose, has reached epidemic proportions in the United States. Overprescription of opioids can lead to chronic use and misuse, and unused narcotics after surgery can lead to their diversion. Research supports that most patients do not take all the prescribed opioids after surgery and that surgeons are the second largest prescribers of opioids in the United States. The introduction of opioids in those with OUD often begins with prescription opioids. Reducing the number of extra opioids available after surgery through smaller prescriptions, safe storage, and disposal should reduce the risk of opioid use disorder in otolaryngology patients and their families. PURPOSE: The purpose of this specialty-specific guideline is to identify quality improvement opportunities in postoperative pain management of common otolaryngologic surgical procedures. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. Employing these action statements should reduce the variation in care across the specialty and improve postoperative pain control while reducing risk of OUD. The target patients for the guideline are any patients treated for anticipated or reported pain within the first 30 days after undergoing common otolaryngologic procedures. The target audience of the guideline is otolaryngologists who perform surgery and clinicians who manage pain after surgical procedures. Outcomes to be considered include whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.The guideline addresses assessment of the patient for OUD risk factors, counseling on pain expectations, and identifying factors that can affect pain duration and/or severity. It also discusses the use of multimodal analgesia as first-line treatment and the responsible use of opioids. Last, safe disposal of unused opioids is discussed.This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not a comprehensive guide on pain management in otolaryngologic procedures. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experiences and assessments of individual patients. ACTION STATEMENTS: The guideline development group made strong recommendations for the following key action statements: (3A) prior to surgery, clinicians should identify risk factors for opioid use disorder when analgesia using opioids is anticipated; (6) clinicians should advocate for nonopioid medications as first-line management of pain after otolaryngologic surgery; (9) clinicians should recommend that patients (or their caregivers) store prescribed opioids securely and dispose of unused opioids through take-back programs or another accepted method.The guideline development group made recommendations for the following key action statements: (1) prior to surgery, clinicians should advise patients and others involved in the postoperative care about the expected duration and severity of pain; (2) prior to surgery, clinicians should gather information specific to the patient that modifies severity and/or duration of pain; (3B) in patients at risk for OUD, clinicians should evaluate the need to modify the analgesia plan; (4) clinicians should promote shared decision making by informing patients of the benefits and risks of postoperative pain treatments that include nonopioid analgesics, opioid analgesics, and nonpharmacologic interventions; (5) clinicians should develop a multimodal treatment plan for managing postoperative pain; (7) when treating postoperative pain with opioids, clinicians should limit therapy to the lowest effective dose and the shortest duration; (8A) clinicians should instruct patients and caregivers how to communicate if pain is not controlled or if medication side effects occur; (8B) clinicians should educate patients to stop opioids when pain is controlled with nonopioids and stop all analgesics when pain has resolved; (10) clinicians should inquire, within 30 days of surgery, whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.

Clinical Practice Guideline: Opioid Prescribing for Analgesia After Common Otolaryngology Operations Executive Summary.

OBJECTIVE: Opioid use disorder (OUD), which includes the morbidity of dependence and mortality of overdose, has reached epidemic proportions in the United States. Overprescription of opioids can lead to chronic use and misuse, and unused narcotics after surgery can lead to their diversion. Research supports that most patients do not take all the prescribed opioids after surgery and that surgeons are the second largest prescribers of opioids in the United States. The introduction of opioids in those with OUD often begins with prescription opioids. Reducing the number of extra opioids available after surgery through smaller prescriptions, safe storage, and disposal should reduce the risk of opioid use disorder in otolaryngology patients and their families. PURPOSE: The purpose of this specialty-specific guideline is to identify quality improvement opportunities in postoperative pain management of common otolaryngologic surgical procedures. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. Employing these action statements should reduce the variation in care across the specialty and improve postoperative pain control while reducing risk of OUD. The target patients for the guideline are any patients treated for anticipated or reported pain within the first 30 days after undergoing common otolaryngologic procedures. The target audience of the guideline is otolaryngologists who perform surgery and clinicians who manage pain after surgical procedures. Outcomes to be considered include whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.The guideline addresses assessment of the patient for OUD risk factors, counseling on pain expectations, and identifying factors that can affect pain duration and/or severity. It also discusses the use of multimodal analgesia as first-line treatment and the responsible use of opioids. Last, safe disposal of unused opioids is discussed.This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not a comprehensive guide on pain management in otolaryngologic procedures. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experiences and assessments of individual patients. ACTION STATEMENTS: The guideline development group made strong recommendations for the following key action statements: (3A) prior to surgery, clinicians should identify risk factors for opioid use disorder when analgesia using opioids is anticipated; (6) clinicians should advocate for nonopioid medications as first-line management of pain after otolaryngologic surgery; (9) clinicians should recommend that patients (or their caregivers) store prescribed opioids securely and dispose of unused opioids through take-back programs or another accepted method.The guideline development group made recommendations for the following key action statements: (1) prior to surgery, clinicians should advise patients and others involved in the postoperative care about the expected duration and severity of pain; (2) prior to surgery, clinicians should gather information specific to the patient that modifies severity and/or duration of pain; (3B) in patients at risk for OUD, clinicians should evaluate the need to modify the analgesia plan; (4) clinicians should promote shared decision making by informing patients of the benefits and risks of postoperative pain treatments that include nonopioid analgesics, opioid analgesics, and nonpharmacologic interventions; (5) clinicians should develop a multimodal treatment plan for managing postoperative pain; (7) when treating postoperative pain with opioids, clinicians should limit therapy to the lowest effective dose and the shortest duration; (8A) clinicians should instruct patients and caregivers how to communicate if pain is not controlled or if medication side effects occur; (8B) clinicians should educate patients to stop opioids when pain is controlled with nonopioids and stop all analgesics when pain has resolved; (10) clinicians should inquire, within 30 days of surgery, whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.

Management of the Clinical and Academic Mission in an Urban Otolaryngology Department During the COVID-19 Global Crisis.

OBJECTIVE: The objective of this study was to assess the strategic changes implemented in the departmental mission to continue safe delivery of otolaryngology care and to support the broader institutional mission during the COVID-19 pandemic response. STUDY DESIGN: Retrospective assessment was performed to the response and management strategy developed to transform the clinical and academic enterprise. SETTING: Large urban tertiary care referral center. RESULTS: The departmental structure was reorganized along new clinical teams to effectively meet the system directives for provision of otolaryngology care and support for inpatient cases of COVID-19. A surge deployment schedule was developed to assist frontline colleagues with clinical support as needed. Outpatient otolaryngology was consolidated across the system with conversion of the majority of visits to telehealth. Operative procedures were prioritized to ensure throughput for emergent and time-critical urgent procedures. A tracheostomy protocol was developed to guide management of emergent and elective airways. Educational and research efforts were redirected to focus on otolaryngology care in the clinical context of the COVID-19 crisis. CONCLUSION: Emergence of the COVID-19 global health crisis has challenged delivery of otolaryngology care in an unparalleled manner. The concerns for preserving health of the workforce while ethically addressing patient career needs in a timely manner has created significant dilemmas. A proactive, thoughtful approach that reorganizes the overall departmental effort through provider and staff engagement can facilitate the ability to meet the needs of otolaryngology patients and to support the greater institutional mission to combat the pandemic.

Enhanced recovery after surgery in head and neck surgery: Reduced opioid use and length of stay.

OBJECTIVES: Enhanced recovery after surgery (ERAS) protocols were first developed in colorectal surgery and sought to standardize patient care. There have been several studies in the head and neck surgical literature looking at outcomes after ERAS protocol, but no studies focusing on narcotic use and length of stay. This study aimed to evaluate narcotic usage and length of stay, in addition to several other outcomes, following the implementation of an ERAS protocol. METHODS: A head and neck-specific ERAS protocol was implemented at this tertiary care center beginning July 2017. A retrospective cohort study was performed comparing this cohort to that of a retrospective control group. Outcomes included mean morphine equivalent dose, mean pain score, and percentage of patients prescribed narcotics on discharge. Secondary outcomes included ICU and total length of stay. RESULTS: The mean morphine equivalent dose (MED) administered within 72 hours postoperatively was significantly lower in the ERAS group (17.5 ± 46.0 mg vs. 82.7 ± 116.1 mg, P < .001). Average postoperative pain scores in the first 72 hours were lower in the ERAS group (2.6 ± 1.8 vs. 3.6 ± 1.9; P < .001). The average length of stay was shorter for ERAS patients (7.8 ± 4.8 vs. 9.7 ± 4.7 days, P = .008); however, there was no significant difference in ICU length of stay. CONCLUSION: Following implementation of an ERAS protocol, patients undergoing head and neck surgery had decreased narcotic use in the immediate postoperative period and at discharge, while also demonstrating improved postoperative analgesia. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 130:1227-1232, 2020.

Association of Perioperative Opioid-Sparing Multimodal Analgesia With Narcotic Use and Pain Control After Head and Neck Free Flap Reconstruction.

IMPORTANCE: An increase in narcotic prescription patterns has contributed to the current opioid epidemic in the United States. Opioid-sparing perioperative analgesia represents a means of mitigating the risk of opioid dependence while providing superior perioperative analgesia. OBJECTIVE: To assess whether multimodal analgesia (MMA) is associated with reduced narcotic use and improved pain control compared with traditional narcotic-based analgesics at discharge and in the immediate postoperative period after free flap reconstructive surgery. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study assessed a consecutive sample of 65 patients (28 MMA, 37 controls) undergoing free flap reconstruction of a through-and-through mucosal defect within the head and neck region at a tertiary academic referral center from June 1, 2017, to November 30, 2018. Patients and physicians were not blinded to the patients' analgesic regimen. Patients' clinical courses were followed up for 30 days postoperatively. INTERVENTIONS: Patients were administered a preoperative, intraoperative, and postoperative analgesia regimen consisting of scheduled and as-needed neuromodulating and anti-inflammatory medications, with narcotic medications reserved for refractory cases. Control patients were administered traditional narcotic-based analgesics as needed. MAIN OUTCOMES AND MEASURES: Narcotic doses administered during the perioperative period and at discharge were converted to morphine-equivalent doses (MEDs) for comparison. Postoperative Defense and Veterans Pain Rating Scale pain scores (ranging from 0 [no pain] to 10 [worst pain imaginable]) were collected for the first 72 hours postoperatively as a patient-reported means of analyzing effectiveness of analgesia. RESULTS: A total of 28 patients (mean [SD] age, 64.1 [12.3] years; 17 [61%] male) were included in the MMA group and 37 (mean [SD] age, 65.0 [11.0] years; 22 [59%] male) in the control group. The number of MEDs administered postoperatively was 10.0 (interquartile range [IQR], 2.7-23.1) in the MMA cohort and 89.6 (IQR, 60.0-104.5) in the control cohort (P < .001). Mean (SD) Defense and Veterans Pain Rating Scale pain scores postoperatively were 2.05 (1.41) in the MMA cohort and 3.66 (1.99) in the control cohort (P = .001). Median number of MEDs prescribed at discharge were 0 (IQR, 0-18.8) in the MMA cohort and 300.0 (IQR, 262.5-412.5) in the control cohort (P < .001). CONCLUSIONS AND RELEVANCE: The findings suggest that after free flap reconstruction, MMA is associated with reduced narcotic use at discharge and in the immediate postoperative period and with superior analgesia as measured by patient-reported pain scores. Patients receiving MMA achieved improved pain control, and the number of narcotic prescriptions in circulation were reduced. LEVEL OF EVIDENCE: 3.

Definitive chemoradiation for locally-advanced oral cavity cancer: A 20-year experience.

OBJECTIVES: Definitive chemoradiation (CRT) for oral cavity squamous cell carcinoma (OC-SCC) is often criticized for poor efficacy or toxicity. We describe a favorable 20-year experience of primary CRT for locally-advanced OC-SCC. MATERIALS AND METHODS: Patients with locally-advanced, stage III/IV OC-SCC receiving primary concomitant CRT on protocols from 1994 to 2014 were analyzed. Chemotherapy included fluorouracil and hydroxyurea with other third agents. Radiotherapy (RT) was delivered once or twice daily to a maximum dose of 70-75 Gy. Intensity-modulated RT (IMRT) was exclusively used after 2004. Progression-free survival (PFS), overall survival (OS), locoregional control (LRC), and distant control (DC) were calculated by the Kaplan-Meier method and compared across treatment decades using the log-rank test. Rates of osteoradionecrosis (ORN) requiring surgery were compared across treatment decades using the Chi-square test. RESULTS: 140 patients with locally-advanced OC-SCC were treated with definitive CRT. Of these, 75.7% had T3/T4 disease, 68.6% had ≥N2 nodal disease, and 91.4% had stage IV disease. Most common primary sites were oral tongue (47.9%) and floor of mouth (24.3%). Median follow-up was 5.7 years. Five-year OS, PFS, LRC, and DC were 63.2%, 58.7%, 78.6%, and 87.2%, respectively. Rates of ORN and long-term feeding tube dependence were 20.7% and 10.0%, respectively. Differences in LRC (P = 0.90), DC (P = 0.24), PFS (P = 0.38), OS (P = 0.10), or ORN (P = 0.38) were not significant across treatment decades. CONCLUSION: Definitive CRT is a viable and feasible strategy for organ preservation for patients with locally-advanced OC-SCC.

Aspiration in chemoradiated patients with head and neck cancer.

OBJECTIVE: To review the incidence of aspiration after chemoradiation therapy in patients with head and neck cancer (HNC). DESIGN: Retrospective review. SETTING: Academic institution. PATIENTS: One hundred thirty patients with advanced HNC underwent chemoradiation therapy at our institution between 1998 and 2002 as part of a larger, multi-institutional, prospective study of induction chemotherapy followed by chemoradiation therapy; the 118 patients (91%) for whom oropharyngeal motility (OPM) study data were available are discussed in this article. MAIN OUTCOME MEASURES: Incidence of trace ( 5%) aspiration (deep laryngeal or tracheal penetration) as determined by pretreatment and posttreatment OPM studies and correlation of the findings with the patients' reported symptoms. RESULTS: Eighty-one patients (69%) underwent at least 1 OPM study demonstrating aspiration within the first year after chemoradiation therapy, with 30 (25%) demonstrating frank aspiration. Of the patients who aspirated, 61 (75%) reported no symptoms of coughing or choking (80% of trace and 67% of frank aspirators). The patients with cancer of the larynx and hypopharynx were more likely to be aspirators (P = .007 and P = .004, respectively). Of the 62 patients with available pretreatment OPM data, 33 (53%) demonstrated aspiration at baseline. CONCLUSIONS: Aspiration is highly prevalent among patients with advanced HNC at baseline and is worse in the posttreatment period after chemoradiation therapy. The majority of these patients report no symptoms. All patients with advanced HNC should undergo instrumental swallow assessment, even in the absence of symptoms, to detect subclinical aspiration and to institute therapeutic maneuvers and swallow precautions as well as to determine the safety of oral feeding.

Intensity-modulated radiation therapy in advanced head and neck patients treated with intensive chemoradiotherapy: preliminary experience and future directions.

We review our recent experience with intensity-modulated radiation therapy (IMRT) and conventional three-dimensional radiation therapy (C3DRT) in advanced head and neck cancer. Sixty-nine patients with Stage IV head and neck cancer (and stage III base of tongue and hypopharynx) enrolled in a Phase II study of definitive chemoradiation; 20 received all or part of their radiation with IMRT. Image-guided set-up, using video subtraction techniques, was used in all patients. Six weekly doses of induction carboplatin (AUC=2) and paclitaxel (135 mg/m2) were followed by alternating weekly chemoradiation to 75 Gy with 1.5 Gy BID fractions, concurrent with paclitaxel (100 mg/m2/week), 5-fluorouracil (600 mg/m2/d) and hydroxyurea (500 mg PO BID). Two consecutive cohorts enrolled, differing in radiation scheme: 75 Gy to gross disease in both, 60 or 54 Gy to first echelon lymphatics and 45 or 39 Gy to second echelon lymphatics. With a median follow-up of 47 months, 3-year overall survival is 68.5% and 3-year locoregional control is 94.0%, with no significant differences between those treated with C3DRT versus IMRT, nor between the two radiation dosing schemes. Actuarial overall survival without tracheostomy or laryngectomy, or without a gastrostomy tube was also similar. Acute mucositis, dermatitis and pain were similar with C3DRT and IMRT. Preliminary data suggests IMRT is well tolerated, and does not compromise locoregional control, indicating that IMRT adequately covers the clinical volume at risk. Building on the present clinical experience, future directions include more directed efforts at reducing toxicity, with better planning software and planning techniques.

Planned post-chemoradiation neck dissection: significance of radiation dose.

OBJECTIVE: The increasing prominence of multimodality therapy for patients with advanced head and neck cancer reflects its high survival and functional preservation rates. We report the pathologic data on patients undergoing neck dissection (ND) after induction chemotherapy followed by concomitant chemoradiotherapy (IC-CRT) in three similar protocols utilizing decreasing doses of radiation therapy. MATERIALS AND METHODS: The databases of 221 patients who underwent IC-CRT between 1999 and 2002 were reviewed. Based on posttreatment residual or pretreatment N2a or greater neck disease, 73 patients without pretreatment neck surgery were eligible for analysis (1 N1, 3 N2a, 26 N2b, 20 N2c, 23 N3). Three additional subgroups were also analyzed with respect to outcome: Undissected patients with less than N2 disease, patients who had neck surgery prior to IC-CRT, and patients with N2a or greater neck disease who did not have post-IC-CRT ND. STUDY DESIGN: Retrospective analysis. RESULTS: Sixty-seven patients underwent unilateral or bilateral selective neck dissection. Six patients had modified or radical ND. There were no wound healing complications. Pathologic analysis revealed viable cancer in 15 of 73 patients (20.5%): 1 had N1, 3 had N2b, 4 had N2c, and 7 had N3 neck disease. The incidence of viable cancer in the neck dissection specimen increased as radiation dose decreased. Complete response induction chemotherapy predicted negative pathology (P = .003). In the subgroup analysis, patients who had pretreatment surgery had a lower risk of dying from the primary cancer CONCLUSIONS: 1) The incidence of positive pathology after IC-CRT increases as radiation dose decreases. 2) Selective neck dissection after CRT has been demonstrated to be feasible and safe; the complication rate of ND after IC-CRT is acceptably low. 3) There is viable posttreatment cancer in 20.5% of patients, indicating necessity of ND in these patients.

Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation for Locoregionally Advanced Head and Neck Cancer.

PURPOSE: The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation. METHODS AND MATERIALS: Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%. RESULTS: 110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients. CONCLUSIONS: The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation.

Twice-daily reirradiation for recurrent and second primary head-and-neck cancer with gemcitabine, paclitaxel, and 5-fluorouracil chemotherapy.

PURPOSE: We previously demonstrated the efficacy of concurrent gemcitabine, paclitaxel, and 5-fluorouracil in conjunction with twice-daily (1.5-Gy) radiotherapy delivered on alternating weeks (TFGX(2)) in locally advanced head-and-neck cancer. Here, we report the clinical outcome and late toxicity of TFGX(2) in a subset of patients previously irradiated to the head and neck. METHODS AND MATERIALS: Twenty-nine previously irradiated patients, presenting with recurrent or second primary head-and-neck cancer, underwent TFGX(2). Twelve patients underwent attempted surgical resection before chemoradiotherapy, 10 of whom were left with no measurable disease. Patients with measurable disease received a median radiation dose of 72 Gy; those with no measurable disease received a median dose of 61 Gy. The cumulative dose ranged from 74.4 to 156.4 Gy (mean, 125.7 Gy; median, 131.0 Gy). RESULTS: The median follow-up was 19.1 months (50.9 months for living patients). The 5-year overall survival rate was 34.5%, and the locoregional control rate was 54.5%. In patients with measurable disease at treatment, the 5-year overall survival and locoregional control rate was 26.3% and 45.1%, respectively, compared with 50.0% (p = 0.14) and 70% (p = 0.31), respectively, for those with no measurable disease. Measurable disease and radiation dose were highly statistically significant for overall survival and locoregional control on multivariate analysis. Of 14 patients assessable for late toxicity, 3 developed Grade 4-5, 8 Grade 2-3, and 3 Grade 0-1 toxicity. CONCLUSION: Aggressive reirradiation with chemotherapy in locally advanced head-and-neck cancer provides a chance for long-term cure at the expense of toxicity. Attempted surgical resection before chemoradiotherapy improved disease control and survival.

Competing causes of death and second primary tumors in patients with locoregionally advanced head and neck cancer treated with chemoradiotherapy.

PURPOSE: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy. EXPERIMENTAL DESIGN: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis. RESULTS: Median follow-up of surviving patients was 5.2 years (2-10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2) CONCLUSIONS: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.

Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, gemcitabine, and twice-daily radiation in patients with poor-prognosis cancer of the head and neck.

PURPOSE: We previously demonstrated high locoregional control, in patients with poor-prognosis head and neck cancer (HNC), using paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant hyperfractionated radiotherapy. In the present phase I trial, gemcitabine, a novel antimetabolite with strong radiation-enhancing activity, replaces hydroxyurea. We sought to determine the recommended phase II dose and clinical efficacy in poor-prognosis HNC patients. EXPERIMENTAL DESIGN: Seventy-two patients enrolled. Eligibility criteria included recurrent or second primary HNC, metastases or expected 2-year survival <20%. Chemoradiotherapy consisted of 5-fluorouracil, 600 mg/m(2)/d, for 5 days; paclitaxel, 100 mg/m(2) on Day 1; and concurrent 1.5 Gy twice-daily radiation for 5 days. Gemcitabine was dose escalated, 50-300 mg/m(2) on day 1. Cycles repeated every 14 days until the completion of chemoradiation. Dose-limiting toxicities (DLTs) included: neutropenic fever; grade > or =4 neutropenia or thrombocytopenia for >4 days; grade > or =4 mucositis or dermatitis for >7 days; or grade 3 toxicity necessitating chemotherapy dose reductions. Non-DLT dose reductions in 5-fluorouracil and/or paclitaxel were allowed. RESULTS: Seventy-nine percent of assessable patients experienced a clinical response. Five-year actuarial survival is 33.0%, and locoregional control is 61.4%. The recommended phase II dose of gemcitabine in this regimen is 100 mg/m(2) during cycles 1-5 (1 of 7 patients with DLT) or 200 mg/m(2) delivered only during cycles 3-5 (3 of 19 with DLT). Grades 3 and 4 mucositis (56 and 21%, respectively) and dermatitis (25 and 21%, respectively) were common. CONCLUSIONS: Gemcitabine, 5-fluorouracil, paclitaxel, and twice-daily radiation, delivered on alternating weeks, is active in patients with poor-prognosis HNC, although severe mucositis limits the clinical applicability of this regimen. Refinements in radiotherapy, including intensity-modulated radiation therapy, may improve the tolerance for this regimen.

Airway management before chemoradiation for advanced head and neck cancer.

BACKGROUND: Patients with upper aerodigestive tract tumors can have development of airway compromise both before and during chemoradiotherapy (CRT). Tracheotomy is the classic method for securing a safe airway, but tumor debulking may also be used. METHODS: This was a retrospective review of locoregionally advanced tumors of the base of tongue, larynx, or hypopharynx undergoing CRT between 1995 and 2007. RESULTS: Forty-two of the 109 patients presented with signs or symptoms of airway obstruction. Of these, 28 underwent tracheotomy before CRT, and 11 had tumor debulking. Two of the 11 patients who underwent debulking required tracheotomy within 1 year after CRT for persistent edema and fibrosis. Larynx tumors were more likely to require tracheotomy or debulking than other tumors (p = .01). CONCLUSIONS: Debulking is a safe and effective alternative to tracheotomy in select patients with tumor-related airway obstruction before CRT. Patients who undergo debulking should be monitored closely for recurrence of airway compromise during and after CRT.

Chemoradiation for patients with large-volume laryngeal cancers.

BACKGROUND: Patients with T4 laryngeal cancers, including those with large-volume (cartilage or tongue-base invasion) lesions, are often excluded from organ-preservation trials due to expectations of inferior outcome in terms of survival and function. We hypothesize that such patients indeed have acceptable survival and function when treated with organ-preservation strategies. METHODS: Retrospective analysis of prospectively collected data of a cohort of patients with T4 laryngeal cancer was carried out. Follow-up ranged from 0.18 to 15.6 years. All T4 laryngeal cancer patients who were enrolled in the University of Chicago concomitant chemoradiotherapy protocols from 1994 to the present were reviewed. This study was composed of 80 newly diagnosed T4 laryngeal cancer patients. Efficacy of treatment was determined through evaluations of survival and function. Survival was evaluated via Kaplan-Meier methods. Swallowing function was evaluated by an oropharyngeal motility (OPM) study and swallowing scores were assigned. Higher scores reflected increasing swallowing dysfunction. RESULTS: Fifty-five of 80 patients (~69%) had documented large-volume tumor. Two- and 5-year overall survivals were 60.0% and 48.7%, respectively. Disease-specific 2- and 5-year survivals for the group were 80.1% and 71.3%, and 79.4 and 74.3%, respectively, for the 55 patients with large volume status. Progression-free survival rates were 52.6% and 47.6%. Forty-four of 65 patients (~68%) with OPM data had a Swallowing Performance Status Scale (SPSS) score of ≤5, indicating various degrees of swallowing abnormalities not requiring a gastrostomy tube. This is a functional-preservation rate of 67.7%. CONCLUSIONS: Chemoradiation for patients with T4 laryngeal cancer appears to be an effective and reasonable option, particularly in light of the satisfactory survival and function-preservation rates.

Performance and quality of life outcomes for T4 laryngeal cancer patients treated with induction chemotherapy followed by chemoradiotherapy.

Organ-sparing approaches with chemoradiotherapy are often used in the treatment of patients with laryngeal cancer, and the oncologic outcomes of these patients are similar to patients who undergo laryngectomy. However, chemoradiotherapy for laryngeal cancer patients with large or locally-invasive (T4) tumors has been more slowly incorporated due to concern for poor post-treatment function of the preserved larynx. Here, we characterize acute and long-term performance and quality-of-life (QOL) outcomes of T4 laryngeal cancer patients treated with induction chemotherapy followed by combined chemoradiotherapy. Using several validated metrics, we find patients experience a decline in most measures of performance and QOL during and immediately following treatment. However, the majority of patients improve to baseline over varying lengths of time following completion of treatment, and many go on to exceed pre-treatment levels of function. Gender, race, alcohol, and tobacco usage were found to be associated with differences in performance and QOL scores across time points. This study suggests that patients with advanced laryngeal tumors who historically had been considered poor candidates for organ-sparing treatment are able to return to, and in many cases exceed pre-treatment performance and QOL following induction chemotherapy and combined chemoradiotherapy.