Treatment of the neck in residual/recurrent disease after chemoradiotherapy for advanced primary laryngeal cancer.

Concomitant chemoradiotherapy (CRT) is extensively used as primary organ preservation treatment for selected advanced laryngeal squamous cell carcinomas (LSCC). The oncologic outcomes of such regimens are comparable to those of total laryngectomy followed by adjuvant radiotherapy. However, the management of loco-regional recurrences after CRT remains a challenge, with salvage total laryngectomy being the only curative option. Furthermore, the decision whether to perform an elective neck dissection (END) in patients with rN0 necks, and the extent of the neck dissection in patients with rN + necks is still, a matter of debate. For rN0 patients, meta-analyses have reported occult metastasis rates ranging from 0 to 31 %, but no survival advantage for END. In addition, meta-analyses also showed a higher incidence of complications in patients who received an END. Therefore, END is not routinely recommended in addition to salvage laryngectomy. Although some evidence suggests a potential role of END for supraglottic and locally advanced cases, the decision to perform END should weigh benefits against potential complications. In rN + patients, several studies suggested that selective neck dissection (SND) is oncologically safe for patients with specific conditions: when lymph node metastases are not fixed and are absent at level IV or V. Super-selective neck dissection (SSND) may be an option when nodes are confined to one level. In conclusion, current evidence suggests that in rN0 necks routine END is not necessary and that in rN + necks with limited nodal recurrences SND or a SSND could be sufficient.

A new prognostic model in chemotherapy-treated patients with recurrent or metastatic head and neck cancer: An analysis of ECOG-ACRIN E1305.

INTRODUCTION: For patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) periodic reassessment of prognostic factors provides valuable information that can aid in patient stratification. PATIENTS AND METHODS: This post hoc analysis included all patients with R/M HNSCC enrolled in the ECOG-ACRIN E1305 phase III clinical trial who received first-line treatment with platinum-containing chemotherapy doublet with or without bevacizumab. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors for OS were identified using univariate and multivariable analyses. A new prognostic model for OS was built retaining the prognostic factors which were significant in the final multivariable analysis (P < 0.05). RESULTS: All 403 study participants were included in the analysis. The median OS in the whole study cohort was 11.8 months (90% confidence intervals [CI], 10.6-13.2). The new prognostic model for OS comprised four risk factors (ECOG performance status [1 versus 0], primary tumor location [other versus oropharynx], presence of bone or liver metastasis, and prior radiation to the head and neck); patients with ≤ 2 (n = 249) and > 2 risk factors (n = 154) had a median OS of 15.2 and 7.6 months, respectively (Hazard ratio, 2.14; 95% CI, 1.73-2.66; P < 0.0001). CONCLUSIONS: The new proposed model includes 4 clinical prognostic factors that can be readily assessed at baseline. Similar models have the potential to improve trial design and optimize stratification of patients with R/M HNSCC.

Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

BACKGROUND: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. PATIENTS AND METHODS: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy. RESULTS: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

TP53 mutations in head and neck cancer.

Head and neck squamous cell carcinomas (HNSCCs) arising in the mucosal linings of the upper aerodigestive tract are highly heterogeneous, aggressive, and multifactorial tumors affecting more than half a million patients worldwide each year. Classical etiological factors for HNSCC include alcohol, tobacco, and human papillomavirus (HPV) infection. Current treatment options for HNSCCs encompass surgery, radiotherapy, chemotherapy, or combinatorial remedies. Comprehensive integrative genomic analysis of HNSCC has identified mutations in TP53 gene as the most frequent of all somatic genomic alterations. TP53 mutations are associated with either loss of wild-type p53 function or gain of functions that promote invasion, metastasis, genomic instability, and cancer cell proliferation. Interestingly, disruptive TP53 mutations in tumor DNA are associated with aggressiveness and reduced survival after surgical treatment of HNSCC. This review summarizes the current evidence and impact of TP53 mutations in HNSCC.

De-escalation studies in HPV-positive oropharyngeal cancer: How should we proceed?

Human papilloma virus (HPV) is a well-established causative factor in a subset of squamous cell carcinomas of the head and neck (HNSCC). Although HPV can be detected in various anatomical subsites, HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is the most common HPV-related malignancy of the head and neck, and its worldwide incidence is constantly rising. Patients with OPSCC are generally younger, have less co-morbidities and generally have better prognosis due to different biological mechanisms of carcinogenesis. These facts have generated hypotheses on potential treatment modifications, aiming to minimize treatment-related toxicities without compromising therapy efficacy. Numerous randomized clinical trials have been designed to verify this strategy and increasingly real-world evidence data from retrospective, observational studies is becoming available. Until now, the data do not support any modification in contemporary treatment protocols. In this narrative review, we outline recent data provided by both randomized controlled trials and real-world evidence of HPV-positive OPSCC in terms of clinical value. We critically analyze the potential value and drawbacks of the available data and highlight future research directions. This article was written by members and invitees of the International Head and Neck Scientific Group.(www.IHNSG.com).

A systematic review and recommendations on the use of plasma EBV DNA for nasopharyngeal carcinoma.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southeast Asia, particularly Southern China. The classical non-keratinising cell type is almost unanimously associated with latent Epstein-Barr virus (EBV) infection. Circulating plasma EBV DNA can be a useful biomarker in various clinical aspects, but comprehensive recommendations and international guidelines are still lacking. We conducted a systematic review of all original articles on the clinical application of plasma EBV DNA for NPC; we further evaluated its strengths and limitations for consideration as standard recommendations. METHODS: The search terms 'nasopharyngeal OR nasopharynx', and 'plasma EBV DNA OR cell-free EBV OR cfEBV' were used to identify full-length articles published up to December 2020 in the English literature. Three authors independently reviewed the article titles, removed duplicates and reviewed the remaining articles for eligibility. RESULTS: A total of 81 articles met the eligibility criteria. Based on the levels of evidence and grades of recommendation assessed, it is worth considering the inclusion of plasma EBV DNA in screening, pre-treatment work-up for enhancing prognostication and tailoring of treatment strategy, monitoring during radical treatment, post-treatment surveillance for early detection of relapse, and monitoring during salvage treatment for recurrent or metastatic NPC. One major limitation is the methodology of measurement requiring harmonisation for consistent comparability. CONCLUSIONS: The current comprehensive review supports the inclusion of plasma EBV DNA in international guidelines in the clinical aspects listed, but methodological issues must be resolved before global application.

Validation of brief symptom indexes among patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A trial of the ECOG-ACRIN Cancer Research Group (E1302).

BACKGROUND: Patients with advanced head and neck cancer have identified pain, fatigue, and difficulties swallowing, breathing, and communicating as high-priority disease-related symptoms. The Functional Assessment of Cancer Therapy-Head and Neck Symptom Index-10 (FHNSI-10) assesses these symptoms. We sought to validate the FHNSI-10, another brief symptom index (FHNSI-7), and individual symptom endpoints representing these high-rated priority disease symptoms among patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients (N = 239) were enrolled in a phase III randomized clinical trial (E1302) and completed the FHNSI-10 at multiple time points. We assessed the internal consistencies and test-retest reliabilities of the FHNSI-10 and FHNSI-7 scores, and the known-groups validity, predictive criterion validity, and responsiveness-to-change of the symptom indexes and individual symptom endpoint scores. RESULTS: The FHNSI-10 and FHNSI-7 indexes showed satisfactory internal consistencies (Cronbach's alpha coefficient range 0.60-0.75) and acceptable test-retest reliabilities (intraclass correlation coefficients = 0.75 and 0.74, respectively). The FHNSI-10, FHNSI-7, and the pain, fatigue, swallowing, and breathing symptom scores showed evidence of known-groups validity by performance status at baseline. The FHNSI-10, FHNSI-7, and the pain, fatigue, and breathing symptom scores at baseline showed evidence of predictive criterion validity for overall survival, but not time-to-progression (TTP). Changes in the symptom indexes and individual symptom scores were not associated with changes in performance status over 4 weeks, though most patients had stable performance status. CONCLUSIONS: There is initial evidence of validity for the FHNSI-10 and FHNSI-7 indexes and selected individual symptom endpoints as brief disease-related symptom assessments for patients with recurrent or metastatic SCCHN.

GEAMP, a novel gastroesophageal junction carcinoma cell line derived from a malignant pleural effusion.

Gastroesophageal junction (GEJ) cancer remains a clinically significant disease in Western countries due to its increasing incidence, which mirrors that of esophageal cancer, and poor prognosis. To develop novel and effective approaches for prevention, early detection, and treatment of patients with GEJ cancer, a better understanding of the mechanisms driving pathogenesis and malignant progression of this disease is required. These efforts have been limited by the small number of available cell lines and appropriate preclinical animal models for in vitro and in vivo studies. We have established and characterized a novel GEJ cancer cell line, GEAMP, derived from the malignant pleural effusion of a previously treated GEJ cancer patient. Comprehensive genetic analyses confirmed a clonal relationship between GEAMP cells and the primary tumor. Targeted next-generation sequencing identified 56 nonsynonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer. In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B. Histological examination of subcutaneous flank xenografts in nude and NOD-SCID mice showed a carcinoma with mixed squamous and glandular differentiation, suggesting GEAMP cells contain a subpopulation with multipotent potential. Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro. Thus, GEAMP represents a valuable addition to the limited number of bona fide GEJ cancer cell lines.

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.

Prognostic and predictive factors in recurrent and/or metastatic head and neck squamous cell carcinoma: A review of the literature.

The pattern of clinical behaviour and response to treatment of recurrent and/or metastatic head and neck squamous cell carcinoma is heterogeneous. Treatment strategies that can be employed vary from potentially curative salvage surgery and re-irradiation to palliative systemic therapies and best supportive care. The advent of new therapeutic options, in terms of more sophisticated surgical approaches and techniques, highly conformal and precise radiation techniques and immunotherapy may offer improved control of disease and longer survival. Moreover, the epidemiological changes during the last decades, including the increase of human papilloma virus-related oropharyngeal primary tumors, are also reflected in the recurrent and metastatic setting. In this complex context the identification of predictive and prognostic factors is urgently needed to tailor treatment, to increase its efficacy, and to avoid unnecessary toxicities. A better knowledge of prognosis may also help the patients and caregivers in decision making on the optimal choice of care. The purpose of our review is to highlight the current evidence and shortcomings in this field.

Pattern of planned systemic therapy usage in newly diagnosed, nonmetastatic squamous cell carcinoma of the head and neck in a commercially insured population in the United States.

BACKGROUND: We analyzed systemic therapy plans submitted for commercially insured patients with untreated, newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) to investigate patterns of practice. METHODS: Consecutive chemotherapy treatment plans were submitted using Eviti Connect (https://www.marylandphysicianscare.com/content/dam/centene/maryland/pdfs/evitiConnectFactSheet.pdf) portal for preauthorization between June 1, 2011, and June 30, 2015, were analyzed. RESULTS: A total of 387 treatment plans were submitted for 340 patients; 68 and 272 patients were from academic centers and community practices, respectively. Single agent cisplatin (57%), cetuximab (18%), and carboplatin (9%) were the most commonly proposed regimens concurrent with definitive radiotherapy (RT). The frequency of cetuximab use was not significantly different between academic centers and community practices. A clinical trial was proposed in only 15% of patients. CONCLUSION: Among commercially insured patients with newly diagnosed, nonmetastatic SCCHN, the choice of systemic therapy in initial treatment plans was not significantly different between academic centers and community practices. Clinical trials are underutilized and should be encouraged.

Phase II Study of Irinotecan Plus Panitumumab as Second-Line Therapy for Patients with Advanced Esophageal Adenocarcinoma.

LESSON LEARNED: Panitumumab plus irinotecan is not active for the treatment of esophageal adenocarcinoma. BACKGROUND: Esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence. Panitumumab (Pa) is a fully humanized IgG2 monoclonal antibody against human EGFR. Cetuximab (Cx) combined with irinotecan (Ir) is active for second-line treatment of colorectal cancer. This phase II study was designed to evaluate Pa plus Ir as second-line therapy for advanced EAC. METHODS: The primary endpoint was response rate (RR). Patients with one prior treatment were given Pa 9 mg/m2 on day 1 and Ir 125 mg/m2 on days 1 and 8 of each 21-day cycle. Inclusion criteria were confirmed EAC, measurable disease, no prior Ir or Pa, performance status <2, and normal organ function. RESULTS: Twenty-four patients were enrolled; 18 were eligible and evaluable. These patients were all white, with a median age of 62.5 years (range, 33-79 years), and included 15 men and 3 women. The median number of cycles was 3.5. The most common grade 1-2 adverse events were fatigue, diarrhea, anemia, leukopenia, and hypoalbuminemia. Grade 3-4 adverse events included hematologic, gastrointestinal, electrolyte, rash, fatigue, and weight loss. The median follow-up was 7.2 months (range, 2.3-14 months). There were no complete remissions. The partial response rate was 6% (1/18; 95% confidence interval [CI], 0.01-0.26). The clinical benefit (partial response [PR] plus stable disease [SD]) rate was 50%. The median overall survival was 7.2 months (95% CI, 4.1-8.9) with an 11.1% 1-year survival rate. The median progression-free survival was 2.9 months (95% CI, 1.6-5.3). CONCLUSION: Irinotecan and panitumumab as second-line treatment for advanced EAC are not active.

Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.

Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

Response assessment after induction chemotherapy for head and neck squamous cell carcinoma: From physical examination to modern imaging techniques and beyond.

Significant correlations between the response to induction chemotherapy and success of subsequent radiotherapy have been reported and suggest that the response to induction chemotherapy is able to predict a response to radiotherapy. Therefore, induction chemotherapy may be used to tailor the treatment plan to the individual patient with head and neck cancer: following the planned subsequent (chemo)radiation schedule, planning a radiation dose boost, or reassessing the modality of treatment (eg, upfront surgery). Findings from reported trials suggest room for improvement in clinical response assessment after induction chemotherapy, but an optimal method has yet to be identified. Historically, indices of treatment efficacy in solid tumors have been based solely on systematic assessment of tumor size. However, functional imaging (eg, fluorodeoxyglucose-positron emission tomography (FDG-PET) potentially provides an earlier indication of response to treatment than conventional imaging techniques. More advanced imaging techniques are still in an exploratory phase and are not ready for use in clinical practice.

Organ preservation with chemoradiation in advanced laryngeal cancer: The problem of generalizing results from randomized controlled trials.

BACKGROUND: The primary goal of treatment in advanced laryngeal cancer is to achieve optimal oncologic outcomes while preserving function and quality of life. Combination of chemotherapy and radiation has been popularized as an alternative to surgery for patients facing total laryngectomy. However, survival analyses from large, population-based databases have not duplicated results reported from randomized trials. METHODS: A comprehensive literature review was undertaken to try to better understand the reasons why results differ among randomized trials and population cohort studies. RESULTS: A variety of reasons are discussed, including differences in patient staging, selection bias, complexity bias, inconsistent terminology, patient compliance and treatment expertise. CONCLUSIONS: Personalized treatment considering all factors is critical for optimal outcomes. In general, evidence supports total laryngectomy for patients with T4 cancers. Definitive chemoradiotherapy strategies are acceptable alternatives for T3 cancers, provided that all resources for the administration of the treatment, follow-up and surgical salvage are available.

Eastern Cooperative Oncology Group and American College of Radiology Imaging Network Randomized Phase 2 Trial of Neoadjuvant Preoperative Paclitaxel/Cisplatin/Radiation Therapy (RT) or Irinotecan/Cisplatin/RT in Esophageal Adenocarcinoma: Long-Term Outcome and Implications for Trial Design.

PURPOSE: Toxicity, pathologic complete response, and long-term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma, staged as II-IVa by endoscopy/ultrasonography (EUS). METHODS AND MATERIALS: A total of 86 eligible patients began treatment. For arm A, preoperative chemotherapy was cisplatin, 30 mg/m(2), and irinotecan, 50 mg/m(2), on day 1, 8, 22, 29 during 45 Gy radiation therapy (RT), 1.8 Gy per day over 5 weeks. Adjuvant therapy was cisplatin, 30 mg/m(2), and irinotecan, 65 mg/m(2) day 1, 8 every 21 days for 3 cycles. Arm B therapy was cisplatin, 30 mg/m(2), and paclitaxel, 50 mg/m(2), day 1, 8, 15, 22, 29 with RT, followed by adjuvant cisplatin, 75 mg/m(2), and paclitaxel, 175 mg/m(2), day 1 every 21 days for 3 cycles. Stratification included EUS stage and performance status. RESULTS: In arm A, median overall survival was 35 months, and 5-, 6-, and 7-year survival rates were 46%, 39%, and 35%, respectively, whereas for arm B, they were 21 months and 27%, 27%, and 23%, respectively. Median progression- or recurrence-free survival (PFS) was 39.8 months with a 3-year PFS of 50% for arm A and 12.4 months (P=.046) with 3-year PFS of 28% for arm B. Eighty percent of the observed incidents of progression occurred within 19 months. Survival did not differ significantly by EUS and performance status strata. CONCLUSIONS: Long-term survival was similar for both arms and did not appear superior to results achieved with other standard regimens.

Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment.

Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials.

Organ Preservation for Advanced Larynx Cancer: Issues and Outcomes.

PURPOSE: To provide a review of the clinical data, controversies, and limitations that underpin current recommendations for approaches to larynx preservation for locally advanced larynx cancer requiring total laryngectomy. METHODS: The key findings from pivotal randomized controlled trials are discussed, including quality of life, late effects, and function assessments. Trials investigating taxane inclusion in induction chemotherapy and trials of epidermal growth factor receptor inhibition for radiosensitization are put into perspective for larynx cancer. Controversies in the management of T4 primaries and the opportunities for conservation laryngeal surgery are reviewed. RESULTS: There are data from clinical trials to support induction chemotherapy, followed by radiotherapy (preferred approach in Europe) and concomitant cisplatin plus radiotherapy (preferred in North America) for nonsurgical preservation of the larynx. Treatment intensification by a sequential approach of induction, followed by concomitant treatment, is investigational. Transoral laryngeal microsurgery and transoral robotic partial laryngectomy have application in selected patients. CONCLUSION: The management of locally advanced larynx cancer is challenging and requires an experienced multidisciplinary team for initial evaluation, response assessment, and support during and after treatment to achieve optimal function, quality of life, and overall survival. Patient expectations, in addition to tumor extent, pretreatment laryngeal function, and coexisting chronic disease, are critical factors in selecting surgical or nonsurgical primary treatment.